Journal of IiMER June 2024 What’s Next? Journal of IiMER Volume 14 Issue 1 June 2024 Invest in ME Research Invest in ME Research www.investinme.org Page 1 of 32

Journal of IiMER June 2024 CHAIRMAN’S MESSAGE We last published a journal in 2019 for the conference week in London – the last before the pandemic hit. The Journal, and conference week events, were always a good time to reflect on what progress had been made and discover what was happening in research. A great deal has happened since the pandemic began and some things have changed, although Myalgic Encephalomyelitis (ME) still faces the same issues as we have recorded over the last eighteen years since the charity was formed. This is plainly apparent from the findings of the European ME Alliance Pan-European ME Patient Survey, which was published, appropriately, on World Health Day 2024. We have the overview of findings from the report included in the Journal. Since 2005, the charity has maintained an unwavering commitment to driving significant strides in the field of ME research. How else could it be as the charity is run by volunteers - patients or parents of children with ME - no salaries, no government funding, not controlled by outside influences - but with wonderful supporters? As an independent UK charity facilitating and funding a strategy of high-quality biomedical research and promoting better education about ME, our journey has been marked by relentless dedication to using innovation to progress biomedical research. In this period, we have organised and hosted sixteen influential annual conferences, thirteen annual and progressive international biomedical research colloquiums, (a sequence broken only by the pandemic), and facilitated four early career researcher workshops. Notably, we have established the first Fellowship for ME, completed five PhDs, and are on the brink of initiating our second Fellowship. The charity is also funding the only clinical trial for ME in the UK, and is looking to fund more research that is on the way, embodying the urgency that defines our approach in translating research into tangible outcomes, where all of our income is used to fund and facilitate biomedical research into ME. Beyond borders, we have been involved in the recent NIH Roadmap Research programme and fostered and galvanised collaboration through the creation of European groups for patients, researchers, clinicians, and young Invest in ME Research DISCLAIMER The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME Research. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Page 2 of 32 INVEST IN ME RESEARCH PO Box 561 Eastleigh SO50 0GQ Hampshire, UK Email: info@investinme.org Web site: www.investinme.org UK charity Nr. 1153730 IN THIS ISSUE PAN-EUROPE SURVEY HIGHLIGHTS Journal of IiMER June 2024 researchers, driving international initiatives that support and strengthen our shared mission. Our work has facilitated the foundations of the Centre of Excellence for ME firmly in place in Norwich Research Park,a source of hope for advancing research and developing treatments. The one missing element – adequate funding – would expedite and complete our efforts for the benefit of all patients. In the last parliamentary debate on ME, we laid out a bold vision for research, proposing a substantial allocation to kick-start biomedical research and support the foundations that we have laid. We recently made a document to update all MPs on the opportunities that have been created. Likewise, we have made the case for investment in the centre in Norwich Research Park in the UK DHSC/UKCRC though, unfortunately, our ideas have neither been fully distributed nor discussed, resulting in no tangible progress being achieved in two years of meetings. Our involvement in the recent far more productive NIH Roadmap Research Programme has guided our Colloquium planning, shaping this year's theme - "Acknowledging the acceptance by both clinicians and researchers of 'THE INFECTIOUS AETIOLOGY’ of ME/CFS" focuses on uncovering the complexities of ME, exploring acute infection, chronic infection, and co-infection. And asking What's Next?' The conference and colloquium are ideal timing as they directly follow from the NIH Roadmap report to be published just before our International Conference Week - so much to discuss and plan. The colloquium, especially, has proven to be important in bringing together researchers. Last year was the first time that the charity had organised in person events in conference week since the pandemic began. Invest in ME Research In the 2017 Colloquium, a new approach had been established for structuring the presentations in sessions to focus more effort in determining the information that was relevant to making progress. Session chairs were tasked with asking presenters to consider - • What we know (proven) • What we think we know (unproven) • What we need to know • How (who?) should the gaps be filled? • How does this relate to other strategies/research? We were pleased to see that the recent NIH Roadmap of webinars during 2023-24 had adopted this same approach to use for structuring their webinars. Our colloquiums and conferences provide an international platform for education and collaboration - uniting professionals, patients, researchers, early-career researchers, doctors, nurses, the media, and ME - and bridging the clinical and research divide to focus on benefits for patients - a testament to our commitment to fostering collaboration and knowledge exchange over almost two decades. The name of our charity truly becomes the main calling for all interested in resolving this disease. Whatever the disappointing experiences from the last two years of the DHSC/UKCRC project we still believe there are the building blocks already in place in the UK and Europe which just require a little ambition and courage and one important factor – funding. What better slogan to use at this point in time than the one that this small charity has uniquely been promoting for so long? Time to #InvestinMEresearch. Welcome to our conference week. Kathleen McCall Page 3 of 32

Journal of IiMER June 2024 Philanthropy ….. is about 'giving' - not just in terms of funding. We are eternally grateful to those supporting the charity and to partners The Hendrie Foundation for their consistent and generous support for the RESTORE_ME clinical trial and other research at the centre; and to LunaNova for their funding of the LunaNova fellowship that begins this year. Also appreciated are non-monetary aspects, such as time, ideas, raising awareness of what the charity is trying to do, or being a volunteer. Our supporters have achieved and they deserve recognition for all their incredible support and efforts to bring change to the landscape of ME research and awareness. From WE - A Community and ME https://www.investinme.org/2019booklet.shtml The Irish ME Trust – Sponsor of #IIMEC16 A word of thanks to the Irish ME Trust who, yet again, will be sponsoring one of the speakers to the conference. IMET have been a constant friend and supporter of IiMER, and of ME patients. They have been a leading member in the European ME Alliance. The Irish ME Trust has sponsored every single Invest in ME Research International ME Conference Week and we would like to thank them for their continued support. We received very sad news as we planned the conference this year. Our good friend and valued and respected advocate for people with ME - 𝗠𝗶𝗰𝗵𝗮𝗲𝗹 𝗢’𝗥𝗲𝗶𝗹𝗹𝘆 - had passed away. Michael was in the Irish ME Trust and, with IMET’s Declan Carroll, were one of the founder members of the European ME Alliance (EMEA). Michael regularly came to the Invest in ME Research international Conferences in London. Michael was a wonderful person and a great storyteller. IMET issued this statementIt is with deep sadness that we announce the passing of our founding member and chairman Michael O’Reilly. As well as being a great family man, Michael devoted a great part of his life in helping those with ME in whatever way he could. Due to his foresight and desire to help, our ME Therapy Week was founded in 2003 and took place each year at An Grianán in County Louth until 2016. Following that event, our ME Therapy Retreat still runs to this day, currently in Adare, Co Limerick. Michael was due to attend this year’s event which takes place next month. He will be greatly missed. Ar dheis Dé go raibh a anJournal of IiMER June 2024 What we have been doing Our research strategy is oriented to achieving the best and most rapid outcome with the resources we have – which is only possible via a coordinated, collaborative structure of biomedical research, using the capacity of Europe. Since the charity was formed it has concentrated on prioritising biomedical research as the quickest way to improve and effect better education and to galvanise advocacy. We concentrated, as best as we could, on setting up some of the key building blocks that would create sustainable and permanent change in how ME is researched and treated, by creating solid foundations for a research programme on ME  research based on solving scientific questions to find treatments based on research evidence  raising standards on all levels of patient care  facilitating European and international collaboration  changing attitudes toward ME from within institutes and organisations via funded researchers and medical students The Only Clinical Trial for ME in UK The charity is fully funding the only clinical trial for ME in the UK. This is being carried out at the centre in Norwich Research Park at the Quadram Institute. The Aim of the RESTORE-ME study is to undertake a clinical feasibility study of FMT in ME/CFS and determine if a full clinical trial is justified. This will be achieved by providing evidence for efficacy in this patient group, a mechanistic understanding of FMT in ME/CFS, the acceptability of the treatment for patients, the measurement properties of outcome measures, and to provide bounds for efficacy. A significant proportion of ME/CFS patients date the onset of their symptoms to a GI illness. FMT may be helpful in these patients. A study undertaken in a single centre in Australia reported significant clinical improvement in 70% of ME/CFS patients administered an FMT (Borody et al., 2012). Since gut dysbiosis might be a contributing factor in ME/CFS, particularly in those with IBS, replacing the gut microbiota could be an effective treatment. This is the hypothesis behind the RESTORE-ME clinical trial – a phase 2b, double blind and placebo controlled – which focuses on establishing safety and efficacy. A pilot study, called Light ME Up, is being supported by Invest in ME Research to assess the acceptability, safety and potential benefit of red light exposure in ME patients. It is a remote feasibility study that patients can undertake from their home. People with ME are reported to have reduced function of mitochondria, the powerhouses in our bodies’ cells that generate energy. Mitochondria can absorb red light and use this to boost energy production, so there is interest in using red light therapy to treat ME. This has been used to manage the symptoms of acne, muscle and joint pain, arthritis, blood circulation issues and hair loss; this will be the first study to assess the use of red light therapy on ME. Symptoms will be monitored for a couple of weeks before and after this period, to see whether the red light therapy provides any benefits. The Light ME Up study will trial objective Invest in ME Research Page 5 of 32

Journal of IiMER June 2024 assessments of cognitive function and physical activity levels and an online clinical trial management platform. A Centre of Excellence for ME Already functioning with world class research, facilities, projects and international collaboration, university and university hospital, collaborations with other groups and local clinic for people with ME. The place to invest. Invest in ME Research asked MPs to consider the following document for last year's' APPG for ME November meeting (which Invest in ME Research are not allowed to attend). We felt that MPs should be made aware of developments and status at the centre in Norwich Research Park rather than the sanitised input they receive. We also updated the Executive Summary for MPs regarding our Centre of Excellence for ME. All available on our web site at investinme.org/centre PhD students introduced to research The charity has funded five PhDs to perform research into ME - including the first crowd-funded PhD for ME - another first. The latest PhD project is with Rik Haagmans, whose research project focuses on the relationship between gut viruses and ME. During the project Rik will be working on the RESTORE-ME clinical trial and look at virology and gut viruses, a field that has gained a lot of public attention in the past years with the outbreak of SARS-CoV-2. While one normally is able to recover from most viral infections, recovery from an infection does not always mean a rapid and full return to health. For example, many COVID-19 patients suffer for a long time after the initial infection from what is sometimes called “Long COVID”. This is something that many ME patients are familiar with. Leading up to the development of ME, many patients experience a viral infection. Various viruses are associated with ME and some of these viruses are also associated with gastrointestinal diseases and dysbiosis. Invest in ME Research This suggests that, at least in a subgroup of ME patients, gut viruses could play an important role. To investigate this, Rik has aimed to:  Identify viruses in faecal samples DNA through sequencing technologies  Define the collection of viruses in the gut of ME patients  Determine if ME patients have unique viruses in their gut  Determine whether FMT leads to a change in gut viruses and how this relates to improvement of symptoms  This has involved preparing experiments that allow us to optimise this process and ensure we can obtain high quality data. Underlying this is the aim to gain valuable information about the mechanism underlying ME and the role of gut viruses in human health. Page 6 of 32 Journal of IiMER June 2024 Invest in ME Research Fellowships The first Fellowship for ME was launched in collaboration with Quadram Institute followed soon after by the second fellowship. The charity decided to name the first fellowship as The Ian Gibson Fellowship for ME – in agreement with Dr Ian Gibson’s wife. Dr Gibson passed away in 2021 and was a great supporter of people with ME and of the charity. This first fellowship for ME recognises Dr Gibson's great influence in supporting people with ME and in helping the charity move ahead with facilitating the research programme and centre for research into ME. Dr Gibson was a unique MP in that he understood the science and politics and was always interested in all kinds of views, and was consistently engaged in debates spanning diverse issues. He was a steadfast advocate for the underdog, lending his voice to those often ignored. This profound commitment to fairness and justice manifested not only in his advocacy but also in his resolute support for organisations that echoed his ethos. It is why he aligned himself with a volunteerdriven charity such as Invest in ME Research. In recognising the intrinsic value of every effort, regardless of size or financial backing, he embodied the transformative power of standing alongside those tirelessly Invest in ME Research working for change, emphasising that true impact arises from the heart, not just the spotlight - something that perfectly describes our supporters. The Ian Gibson Fellowship is being performed by Dr Katharine Seton and continues her career in research into ME at Quadram Institute. Recently, Dr Seton completed her PhD that was funded by Invest in ME Research and the University of East Anglia [2]. This is an important step in supporting the continuity of the research strategy for ME that has been well established and is being performed and planned at Quadram Institute and University of East Anglia. Details of some of Dr Seton’s planned research will include determining the contribution of the intestinal microbiome to oxidative stress in ME patients and whether this can cause alterations in immune function, accelerating premature immune ageing in patients. She also plans to determine the impact of microbiota replacement therapy (MRT) on intestinal and systemic oxidative stress in ME patients. This will be the first study to directly assess intestinal microbiome contribution to oxidative stress in ME patients. Identifying the source of oxidative stress and its impact on immune cell function will enable the development of treatment options to break this cycle. Page 7 of 32

Journal of IiMER June 2024 The Invest in ME Research ‘LunaNova’ Fellowship for ME Invest in ME Research also unveiled the launch of the 'The Invest in ME Research ‘LunaNova’ Fellowship for ME, a new research initiative that will be undertaken at the Quadram Institute, with UK and European collaboration. This fellowship, made possible through the remarkable generosity of LunaNova, the brand of a small UK technology company, underscores the commitment to advancing the Centre of Excellence for ME approach and the benefits it provides. This marks the second fellowship championed by Invest in ME Research, focusing on elevating ME research efforts. The 'LunaNova' Fellowship seeks to deepen our understanding of ME and accelerate progress toward effective treatments. The two-year 'LunaNova' Fellowship exemplifies a pivotal investment in ME research, reinforcing commitment to driving progress in the field. The fellowship leverages Quadram Institute's world-class facilities, incorporating collaboration with European ME Research Group (EMERG) member, Professor Elisa Oltra from the Catholic University of Valencia, Spain, and immune ageing specialists at the University of Birmingham. This collaboration extends our dedication to international partnerships in advancing ME research. Invest in ME Research Page 8 of 32 Mike Buckingham, CEO of LunaNova’s parent company, said: “We have seen first-hand the devastating impact ME has on patients’ lives. Even at its mildest, it is a condition that can completely stunt a person’s potential and at its severest is nothing short of a living death that persists for decades.” “Biomedical research is the only path that can credibly solve this, yet it has been spectacularly neglected over the last few decades in favour of now debunked psychological approaches. During this time the global economic impact of this condition has run into trillions of US dollars.” “Whilst we wait for Governments and policymakers to wake up to the gravity of the situation and begin to fund biomedical research at a scale and pace truly commensurate with the condition’s impact, it is largely charities that have been driving progress. Invest In ME Research (IIMER) are one such charity. They have worked tirelessly in the UK to raise awareness and promote funding of biomedical research.” Journal of IiMER June 2024 European Infrastructure for ME The charity has instigated several initiatives to begin to build this presence in the absence of any official European strategy - a European ME Alliance of ME Patient Groups, a European ME Research Group, a European ME Clinicians Group and a European Young ME Researchers Network. Researchers, clinicians and carers – coming together. Young EMERG The European ME Research Group early career researcher network, formed last year, brings together the new wave of researchers to form a European support base that can facilitate collaboration with early career investigators in other continents. This group published a well-received paper last year – Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives - https://www.mdpi.com/2077-0383/13/2/325 Advocacy The charity has not forgotten the need for advocacy and has regularly commented and acted on issues affecting ME - in parliament, CMO, UKRI, NHS, DHSC. NICE, and abroad. In the 2018/2019 UK parliamentary debates on ME, Invest in ME Research produced a document that summarised the status of ME. It also laid out a bold vision for research - proposing that £20 million be allocated every year for five years to kick-start biomedical research and support the foundations that this small charity has laid. More recently, the charity was involved in the DHSC/UKCRC Delivery Plan for ME that was set up by an ex-health minister – some time after he left that position, where he actually could have made a difference. Sadly, our final report from that two-year project is not optimistic for any breakthrough. The charity had submitted proposals at the first meeting that we attended – proposals meant to take rapid action and address existing issues - but these proposals were not even discussed as the working group exhibited limited vision or ambition and a continual lack of urgency. A two-year project seemed far too long to determine already known issues and provide resolutions – until one realises that two years ago it was well known that a general election would be coming in exactly two years, allowing this particular can to be well and truly kicked down the road on its continuing odyssey to nowhere. Our comments on this initiative are under our Campaigning web page. During the hiatus caused by the pandemic we updated our 5-year plan – leaving major funding now the one missing element. Invest in ME Research Page 9 of 32

Journal of IiMER June 2024 Findings from the European ME Alliance PAN-European ME PATIENT Survey On World Health day 2024, the long-awaited findings of the European ME Alliance (EMEA) Pan-European ME Patient Survey were unveiled, painting a distressing picture of neglect and suffering endured by millions across Europe. The report - EMEA survey of ME/CFS patients in Europe: Same disease, different approaches and experiences - was the result of excellent work by the authors, Arild Angelsen and Trude Schei. Some of the items from the report, authored by Arild and Trude, are shown below. The report is available in full from this link - https://europeanmealliance.org/documents/emeaeusurvey/EMEAMEsurveyreport2024.pdf EMEA Pan-European ME Patient Survey Key Messages 'ME/CFS is a serious and debilitating disease ' '... profound disability levels and unmet needs among European ME/CFS patients' ' underscore the urgent priority for healthcare systems to recognise ME/CFS as a serious physical illness and provide better medical care, financial support, and social services' 'Keeping the activity level within the energy envelope (pacing) is the most helpful strategy ' 'Activity-based therapies do more harm than good' ' Almost half of survey respondents report a deteriorating course of illness ' ' Early diagnosis, activity management (pacing) and avoidance of over-exertion are key to preventing progression to severe disease ' ' Biopsychosocial (BPS) model - a failed and harmful approach to ME/CFS ' ' Therapies involving fixed increases in activity tend to worsen symptoms and risk a deteriorating course of the illness, rather than leading to improvement ' 'Access to medical care and social support varies across Europe, with different approaches taken by national health authorities impacting the course of illness and disease outcomes ' 'The health care system fails ME/CFS patients – and that has serious consequences ' Invest in ME Research Page 11 of 32

Journal of IiMER June 2024 Foreword from the ‘EMEA survey of ME/CFS patients in Europe: Same disease, different approaches and experiences‘ Report In the world of Myalgic Encephalomyelitis (ME or ME/CFS), where decades of misinformation, ignorance, bias and stigma have been allowed to develop and grow without challenge, and eventually influence and then swamp healthcare systems, government policies and media prejudice, people affected by this disease have been left without moral, economic and healthcare support. The advent of social media has levelled the field somewhat, allowing patient groups to challenge the orthodox view of ME/CFS. However, the continued lack of any adequate funding for research into the disease, and no serious attempt to find the cause of the disease by national research agencies or policymakers, has led to the lack of the one essential element that is needed to change policies in government. That element is evidence. The European ME Alliance (EMEA) survey of ME/CFS patients in Europe is a first attempt by patient organisations to bring forward information that can be applied by governments in Europe, and by EU institutions, in order for them to take responsibility for addressing this high burden, under prioritised disease and provide the needed research funding, medical education of physicians, and social support for patients. The objective behind the survey was to find out whether the situation for ME/CFS patients was similar across European countries. The survey originated from the excellent work already performed by the authors of this report – Arild Angelsen and Trude Schei – and their impressive work with Norges ME-forening (Norwegian ME Association), an EMEA member, where they have previously surveyed and reported on the situation with ME/CFS in Norway and Denmark and identified similarities between the onset of ME/CFS and other factors impacting people with this disease. Building upon their work, EMEA members came together to assist in conducting this ‘first ever’ European patient survey. The results show that patients everywhere in Europe face similar stigma regarding recognition and knowledge of the disease, with huge delays in diagnosis that may take up to 12 years in some cases. With patients in Europe often being forced into taking deleterious and flawed biopsychosocial-based therapies that are still recommended by some national healthcare authorities, it may be no surprise that the report shows only 7% of patients reporting improvement over the years, with many having to face health deterioration that can last a lifetime. The survey also indicated that patients who received early diagnosis had better outcomes and were able to manage their energy use earlier by using pacing techniques to avoid over exertion and repeated ‘crashes’. The lack of educated medical professionals leads to a failure of healthcare and welfare systems to provide adequate support – the report highlights the poor level of support for this disease being experienced everywhere. Invest in ME Research Page 12 of 32 Journal of IiMER June 2024 The results compiled here by Arild Angelsen and Trude Schei demonstrate that it is important that information about this disease is also to be collected from patients – to document their ‘lived experience’ as is the currently popular buzzword. The survey provides evidence. The survey results should be a call for action. Investing in ME research will greatly benefit not only the patients, but also the healthcare and social systems as, currently, it takes patients years of medical visits to receive a diagnosis or receive any symptom relief, and their inability to workplaces heavy strains on national insurance and welfare systems. It is important to note that the research community has the interest and the potential to tackle this disease. EMEA member organisations have established a network of experts – researchers and clinicians, namely the European ME Clinicians Council (EMECC), the European ME Research Group (EMERG), as well as an Early Career Researcher Network (Young EMERG). These are well connected internationally with world-renowned research institutes and already have the capability to coordinate the necessary research that can lead to a correct diagnosis and appropriate treatments for ME/CFS patients. In addition, EMEA supports the annual Invest in ME Research International ME Conference (IIMEC) which brings together world renowned researchers and also includes a 'patient day' which is open to the public where the latest advances related to ME/CFS are presented in a language patients can understand. Patient organisations play a key role in providing information, guidance and support to ME/CFS patients. EMEA is committed to continue surveying patients in order to provide ongoing data to support urgent and decisive action from policymakers in Europe in order to improve the situation for p eople with ME and their families in Europe. The EMEA survey of ME/CFS patients in Europe is a valuable part of the resources required as EMEA works to support the implementation of the UN Universal Declaration of Human Rights, the UN Convention on the Rights of Persons with Disabilities, and the UN Political Declaration on Universal Health Coverage, to respect patients’ rights and ensure that European government policies do not leave ME/CFS patients behind. Executive Committee, European ME Alliance Invest in ME Research Page 13 of 32

Journal of IiMER June 2024 Executive summary from ‘EMEA survey of ME/CFS patients in Europe: Same disease, different approaches and experiences‘ Report by Arild Angelsen and Trude Schei This survey of ME/CFS patients in Europe has been conducted by the European ME Alliance (EMEA), which gives a voice for people with ME/CFS in Europe and is the European partner for facilitating high-quality biomedical research. This report presents the findings from the survey of more than 11 000 ME/CFS patients. The aim was to compare patients’ experiences across countries regarding disease characteristics, course of illness, and access to healthcare and support. The survey The data are based on an online survey, conducted in May - August 2021. The questionnaire was translated into 15 languages, and the survey was promoted via patient organisations in European countries. The respondents spanned 44 countries, including responses from a few non-European countries. A total of 11 297 responses were analysed. The questionnaire covered illness characteristics, factors affecting disease course, therapies tried, and support received from healthcare and personal contacts. Potential biases due to non-random sampling are acknowledged. Severely ill and undiagnosed patients are likely to be underrepresented. However, the large sample size is viewed as providing useful insights into patients’ experiences across European countries. ME/CFS is a serious and debilitating disease ME/CFS is typically categorised into four degrees of severity: mild, moderate, severe, very severe It can be argued that the use of the term “mild ME/CFS” is an oxymoron, as even “mild” ME/CFS is a severe disease, with a major loss of function compared to before disease onset. Most patients cannot work and rely heavily on support. In the survey, 24.0% answered that they had mild ME/CFS, 53.8% had moderate ME/CFS (mostly housebound), 16.0% had severe ME/CFS (mostly bedbound), while 2.4% had very severe ME/CFS (bedbound and in need of continuous care). 3.7% described their severity as “better than mild”, while only 0.2% said they had recovered. Strong similarities were found among countries for several factors such as the distribution of degrees of severity, the positive correlation between early onset and disease severity, and the factors associated with a better course of illness, such as coping and support from family and friends. Almost half report a deteriorating course of illness Persistent myths exist about ME/CFS being an illness that gradually “burns out”. Some patients do indeed get much better or even recover, but most do not. As high-quality prospective studies on typical courses of illness are lacking, large patient surveys such as the present one may provide the best information available. Whether ME/CFS is seen as a temporary or chronic condition has major implications for welfare benefits and other services provided. In the survey, 46% described mainly deterioration (26% had initial fluctuations and then deterioration, and 20% have experience mainly deterioration), while 24% answered that they had experienced major fluctuation throughout their course of illness. In total, 70% of respondents described either deterioration or large fluctuations. Only 7% reported improvement. Many patients have a severe or very severe degree of ME early on. 33% among the very severely ill had an onset before turning 20 years old, compared with 14% among those with a mild degree. Invest in ME Research Page 14 of 32 Journal of IiMER June 2024 The health care system fails the ME/CFS patients – and that has serious consequences 3 out of 4 patients (74%) felt they received little or no health care support, while only 1 out of 8 (12%) had experience good or very good support. The dissatisfaction is high across most countries, and even in the best scoring countries (Norway, Iceland and Sweden), about 65% state that they received poor health care support. Yet some differences are notable, indicating that the public approach matters. This is illustrated by the difference found in an otherwise rather homogenous Nordic region. The portion of respondents reporting that they received no help varies from 15-21% in Iceland, Norway and Sweden, to 35% in Finland and more than half (53%) in Denmark. The latter is known for a strong biopsychosocial approach, where ME/CFS is considered a functional illness by the Danish health authority. On the positive side, patients with a more recent onset or diagnosis are less dissatisfied with the health care provided, which may suggest a modest improvement over time. While no objective diagnostic tests, verified biomarkers, curative medications or treatments for ME/CFS exist, health care support matters for the management of the symptoms and the improvement of functional capacity, and thus the course of illness. Respondents experiencing good support from the health care system in their country were more likely to report improvement and less likely to report deterioration. Early diagnostics and disease management critical to improve the course of illness Long delays in the diagnosis were common, with the diagnostic period (from onset to diagnosis) averaging 6.8 years across Europe and large variations across countries. Men are, on average, diagnosed one year earlier than women. Longer delays were associated with a worse course of illness. The risk of experiencing a course of illness characterised by deterioration is more than 50% higher among those with a late diagnosis (10 years or more) compared with those who received an early diagnosis (within 3 years). The survey confirms what several studies (with smaller samples) have found: delayed diagnosis is a risk factor for severe disease. Early and sound advice on the management of the disease, including pacing to avoid Post-Exertional Malaise (PEM), improves the prospects. Patients much more satisfied with support from family, friends and fellow patients 3 out of 5 (60%) stated that they received good or very good support from family members, while 1 out of 4 (25%) had received little or no support. There is a clear relationship between good family support and a lower probability of a deteriorating course of illness (similar to what is observed for health case support); good support in providing daily care and moral support helps staying within the “energy envelope” and avoiding PEM. A similar relationship is observed for support from friends and fellow patients. Keeping the activity level within the energy envelope (pacing) is the most helpful strategy Pacing to avoid post-exertional malaise (PEM) was viewed as the most helpful strategy. 3 out of 4 respondents (75%) considered pacing to have a positive or very positive impact on their course of illness. Successful pacing also requires that the patient knows what pacing is, and – critically – have sufficient help and support from the environment to make pacing possible. While pacing is critical to stabilise the illness, many struggle to find the right balance and adequate support, and experience regular “crashes” and deterioration of their symptoms (PEM). Caring for their family, their financial situation, and stress and worries are factors contributing to the worsening of their symptoms and the overall situation. Invest in ME Research Page 15 of 32

Journal of IiMER June 2024 Activity-based therapies do more harm than good With PEM being a characteristic symptom of ME/CFS, meaning that symptoms worsen upon even the slightest physical or mental exertion, therapies focused on increasing activity levels (Graded Exercise Therapy - GET) or changing illness beliefs (Cognitive Behavioural Therapy - CBT) were pe rceived as harmful by most patients. CBT is a highly controversial as a treatment for ME/CFS. In the survey we distinguished between CBT as a cure and CBT as coping. 3 out of 4 patients experienced a (very) negative effect of CBT as a cure, while 1 in 4 had a negative experience of CBT for coping. Only 5% reported that CBT as a cure to have had a positive effect, compared to 38% in the case of CBT for coping. The more severe the illness, the more negative experiences with CBT, both as cure and as coping. In short, CBT and GET are not only unsuccessful in improving the condition of ME/CFS patients but have a very negative impact on the course of illness. Both the CDC in the US and NICE in the UK have removed advice on CBT and GET from their guidelines for ME/CFS. The Biopsychosocial Model (BPS) – a failed and harmful approach to ME/CFS The dire situation for most ME/CFS patients across Europe is, in part, the result of both ignorance and lack of knowledge among health professionals, social workers, and policy makers. Moreover, the biopsychosocial (BPS) model claims ME/CFS to be psychological and linked to dysfunctional illness beliefs, a pathological focus on symptoms, fear of activity and resulting deconditioning. According to this model, the cure is teaching the patient to ignore, or not to focus on symptoms, and “push through” and follow an exercise program with set increments. This approach has not only failed to get support from interventional studies, or from research that finds critical biological anomalies in people with ME/CFS. It also lacks support from patients and has done harm in its promotion of CBT and GET. The model places the responsibility for both having ME/CFS and for recovery squarely on the patient. This may result in a lack of empathy and sympathy from others, both in healthcare and welfare institutions and within the patient’s family. Conclusions  The survey highlights profound disability levels and unmet needs among European ME/CFS patients. Findings underscore the urgent priority to recognise ME/CFS as a serious illness and provide better medical care, financial support, and social services.  Access to medical care and social support varies across Europe, resulting in both a general but dangerous neglect of the illness, with different approaches taken by national health authorities, impacting courses of illness and disease outcomes.  Therapies involving fixed increases in activity tend to worsen symptoms and risk a deteriorating course of the illness, rather than leading to improvement.  Early diagnosis, activity management (pacing) and avoidance of over-exertion (PEM) are key to preventing progression to severe disease. The full report is available in full from this link - europeanmealliance.org/documents/emeaeusurvey/EMEAMEsurveyreport2024.pdf The European ME Alliance has received ‘official Non-State Actor accreditation’ status from WHO’s Regional Office for Europe. This allows EMEA to participate in WHO Europe Regional Meetings and to make official statements on agenda topics of interest – allowing EMEA to increase awareness, recognition, and action on ME by WHO Europe’s 53 member countries. Invest in ME Research Page 16 of 32 Journal of IiMER June 2024 EMEA Commentary on Pan-European ME Patient Survey The long-awaited findings of the European ME Alliance Pan-European ME Patient Survey, initiated in 2021, have finally been unveiled, painting a distressing picture of neglect and suffering endured by millions across Europe. Drawing upon input from over 11,000 individuals, the report [' EMEA survey of ME/CFS patients in Europe: Same disease, different approaches and experiences'] lays bare the systemic failures and institutional neglect that have perpetuated the suffering for far too long and serves to sound the alarm to all stakeholders - including governments, healthcare providers, research agencies, policy makers, and global organisations - of the urgent need for concerted action to address the humanitarian crisis facing people with ME and their families. The report is an indictment of the status quo. Yet, by shining a spotlight on these issues, the report also seeks to catalyse meaningful dialogue and concrete steps towards redressing the injustices faced by ME patients. The stark revelations underscore the urgent need for concerted action. Key messages extracted from the report highlight the severity of the disease, with profound disability levels and unmet needs prevalent among European ME/CFS patients. Despite mounting evidence, healthcare systems continue to overlook ME/CFS as a serious physical illness, failing to provide adequate medical care, financial support, and social services. Incomprehensibly, it is not even recognised in some European countries despite it being listed under the World Health Organization’s ICD Codes, ICD-10 G93.3 and (later) ICD-11 8E49 as a neurological condition since 1969. This is a clear failing of EU healthcare provision and has resulted in the continued violation of patients’ human rights, especially to the best attainable health, a topic that EMEA is raising with the EU and WHO Europe. In response to these findings, the European ME Alliance has proposed a series of crucial actions to be undertaken. Invest in ME Research Page 17 of 32

Journal of IiMER June 2024 Action 1 EMEA urges all European countries to take immediate action in addressing Myalgic Encephalomyelitis and recognise ME/CFS as a somatic illness, as defined by the World Health Organization (WHO). ME/CFS requires standardised diagnosis and treatment protocols. It is imperative that all European governments swiftly adopt and implement WHO International Classification of Diseases (ICD) codes specific to ME/CFS within their healthcare systems. Action 2 EMEA urges a pan-European strategy of coordinated, collaborative biomedical research to be initiated across Europe, by all governments, using established or developing Centres of Excellence for ME. These centres would be adequately funded and perform translational biomedical research that will look at developing a full understanding of the disease and development of effective treatments to mitigate or cure the disease. Action 3 EMEA urges all European countries to take decisive action in establishing a specialist discipline for ME/CFS by creating academic consultant roles dedicated to ME/CFS and establishing at least one specialist clinical centre aligned with centres of excellence. Recognising the dangerously insufficient awareness and knowledge of ME/CFS, leading to misdiagnosis, missed diagnosis, or very late diagnosis (with an average delay of 6.8 years across Europe), concerted efforts are needed to include the latest scientific evidence on ME/CFS in medical curricula. Academic consultant roles specialising in ME/CFS would play a pivotal role in this effort, providing expertise and guidance to ensure the integration of ME/CFS education and research into medical curricula while utilising standardised diagnostic and treatment protocols for ME/CFS. Action 4 EMEA urges the EU to initiate a pan-European effort to implement accurate and correct recording of cases of ME/CFS, utilising the most up-to-date diagnostic criteria. This is crucial for understanding the full economic burden of the disease. As demonstrated in previous EMEA 'ME/CFS in Europe' webinars, EMEA has highlighted the feasibility for all European countries to implement SNOMED CT to record properly occurrences of ME/CFS, facilitating accurate prevalence figures. EMEA welcomes the opportunity to collaborate with EU institutions, European governments, and other stakeholders, leveraging the achievements of the EMEA pan-European survey, to ensure a thorough evaluation of ME/CFS prevalence and its economic ramifications. By taking these proactive steps, European governments can demonstrate their commitment to addressing the urgent needs of ME patients and improving their quality of life. While we recognise that it will take time to deliver and implement these recommendations their overarching aim is clear: to drive tangible change and improve the lives of ME patients across Europe. The urgency of this call to action cannot be overstated and demands immediate attention and intervention. Failure to act not only perpetuates the suffering of ME/CFS patients and their families but also undermines the integrity of our European healthcare systems. Invest in ME Research Page 18 of 32 Journal of IiMER June 2024 As part of its ongoing efforts to raise awareness and advocate for change, EMEA will also be hosting a webinar to delve deeper into the report's findings and explore potential pathways forward. This EMEA webinar will, again, bring stakeholders together, exchange ideas, and propose a course towards a more compassionate and inclusive healthcare system for all. The release of the report from the EMEA Pan-European ME Patient Survey marks a significant moment in the fight for recognition and support for ME patients in Europe and should be used by policy makers to enact change. It is incumbent upon all stakeholders to heed its findings, heed the call to action, and work collaboratively towards a future where the needs of ME patients are prioritised and their voices are heard. Background to the survey The idea for a pan-European survey among ME-patients originated when a patient survey carried out by Norges ME Forening - later supplemented with a similar survey in Denmark - identified strong similarities in the time of onset of the illness among ME-patients. This then led to a discussion and posed other questions on the similarities and differences across European countries. EMEA performed the pan-European survey in 2021 and, due to resource limitations with analyses, is now publishing the finalised report. We sincerely thank the authors, Arild Angelsen and Trude Schei, and Norges ME Forening for their support of the survey, analysis of the results, and production of the survey report. This survey was the first of its kind comparing the situation and experiences of ME-patients across European countries. As such, it permits cross-country comparison of a number of aspects, The results from the survey confirm much of what has been known by patients and, indeed, healthcare systems for many years but has been ignored. European ME Alliance Invest in ME Research Page 19 of 32

Journal of IiMER June 2024 Response to the 2023 Article in Scandinavian Journal of Public Health In September 2023, a group calling itself the 'Oslo Chronic Fatigue Consortium' issued a statement [OR1] entitled - Chronic fatigue syndromes: real illnesses that people can recover from - and supposedly concerning ME. This consortium ventured the notion that - "...the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation. Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities." One wonders from where this group of 'dedicated' researchers seemed to have arrived at the idea that people with ME are in favour of 'prolonged rest, social isolation and sensory deprivation'. As though patients had some choice in the matter. The article conveniently perpetuates the age-old gaslighting of patients by decrying an imagined 'dominant narrative' that - 'the prediction that patients cannot recover and that activity is harmful. This narrative is most commonly expressed by campaigners concerned with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME), but more recently by those writing about postcovid-19 condition ' Of course, this fits the same actual narrative that has been trotted out year after year for decades - and received the lion's share of funding from government agencies (oblivious to the needs and experiences of Invest in ME Research patients) - that try to prove the efficacy of the biopsychosocial ideology for ME. If it is not the patients who are causing themselves to be ill by their false beliefs then it is those patient organisations who have tried to do something to support the parlous status of treatment of people with ME in Europe! People with ME and their carers, along with most ME charities, will already be aware of the work of some of the people associated with this Oslo Chronic Fatigue Consortium. A handy reference to educate oneself on what has transpired over the years is available in the work of Margaret Williams over many years [OR3]- describing some of what patients have had to endure with these false ideologies. Nowadays the denigration of vulnerable patients is extended to include long covid - grudgingly acknowledged as an 'often referred' to condition. It would be expected that the European ME Alliance, as one of the oldest of patient organisations, would challenge this 'Oslo Declaration'. Therefore, instead of contending this latest misinterpretation of reality it was decided to support a counter-statement organised by researchers who were performing research into this disease or who were experienced in the real world of dealing with this disease. Last year Dr Jesper Mehlsen - co-chair of the European ME Research and Clinicians Groups (EMERG) - organised a reply to the Scandinavian Journal and EMEA helped coordinate signatories in support of this reply – ‘The Stockholm Declaration’ – recognising the genesis of the article Page 20 of 32 Journal of IiMER June 2024 coming from EMEA Sweden member RME, at their conference in that city last year. The response was submitted to the Journal last year - but no reply was received. Another response was sent and this will be published shortly - albeit forced into an abbreviated form before being accepted for publication. References: OR1 OR2 The original response, which was authored and co-signed by a long list of researchers, is shown below for all to see. This letter will be published on the EMEA web site when the abbreviated version has been published in the Scandinavian Journal of Primary Health Care. Scandinavian Journal of Primary Health Care Article https://www.tandfonline.com/doi/full/10.1080/02813432.2023.2235609 Scientific American 2024: People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Have an “Exhausted” Immune System https://www.scientificamerican.com/article/people-with-myalgicencephalomyelitis-chronic-fatigue-syndrome-may-have-an-exhausted-immunesystem OR3 Margaret Williams Articles on ME https://www.margaretwilliams.co.uk The authors initially claim that the current public narrative on severe, persistent fatigue conditions are “most commonly expressed by campaigners concerned with chronic fatigue syndrome (CFS/myalgic encephalomyelitis (ME/CFS)), but more recently by those writing about post-covid-19 condition”. These “campaigners” include the Institute of Medicine and their 400-page review of ME/CFS [1] and the recent guidelines by the National Institute for Health and Care Excellence [2]. The prognosis of ME is not a question of “narratives” but of good, transparent, and reproducible empiric evaluation. The results of research are consistent, suggesting low rates of full recovery of between 5-10 % for adults [3-6]. In claiming a lack of specificity in the newer criteria including post exertional malaise (PEM) as a mandatory symptoms [2, 7], the authors are unaware of recent research, finding lower thresholds for lactate production8 and lower oxygen extraction9 during exercise in ME/CFS-patients as contributors to ME/CFS exertional intolerance-and thus to PEM. Other publications have identified mitochondrial dysfunction to be a likely explanation for PEM10 and have shown a correlation between severity and mitochondrial damage [10, 11]. The authors propose an alternative explanation based on questionable scientific evidence that purports to offer realistic hope of improvement and recovery. This scientific evidence comprises a study in 19 female CFS patients and 21 normal healthy controls showing significant changes in a single measure of heart rate variability after cognitive therapy [12], and a study of long-term follow-up in children and young adults13 that may have a much Invest in ME Research Page 21 of 32

Journal of IiMER June 2024 better prognosis. However, the latter study relies on limited data and is contradicted by a more recent and larger study [14]. Cognitive treatment plays a limited role in ME/CFS as pointed out in the NICE-guidelines [2]. In lumping patients with a diagnosis of ME/CFS in to one non-specific group of patients with fatigue clearly demonstrates the authors’ limited clinical and scientific experience in ME/CFS and the fact that several of the manifestations of this disease may be alleviated by targeted treatment [15-17]. The authors state that the approach often recommended by the public narrative of inactivity, isolation, and sensory deprivation, risks worsening symptoms and associated disability. Firstly, such a statement discloses the authors’ lack of clinical experience with the range of severity and phenotypes in ME/CFS requiring modifications in the therapeutic approach. Secondly, it is an unsubstantiated claim (no references) and for the potential risks, the authors refer to a meta-analysis on bed rest as a primary treatment in conditions such as acute low back pain, preeclampsia, and myocardial infarction [15] and to an unpublished study on long-term sensory deprivation related to space flights [16]. Sensory deprivation is not a choice but a necessity in ME/CFS-patients due to the general increased sensitivity of the nervous system to afferent input secondary to neuroinflammation. Symptoms of neuroinflammation are essential in the diagnosis of ME/CFS and different imaging techniques have shown neuroinflammation to be present in several studies [17,18] and that neuroinflammation is a common denominator in ME/CFS and longCOVID19. In the “Oslo Declaration’s” justification for a new perspective, the authors refer to chronic pain, fibromyalgia, and post COVID syndrome for support, but recent advances do not support their narrative. The “Oslo Declaration” is flawed, and the dismissal of biological evidence as non-specific associations is bewildering, with the authors seeking to replace it with a biopsychosocial model entirely based on associations. A recent study in fibromyalgia has demonstrated that patient autoantibodies mediate the sensory, motor, and anatomical symptoms and signs that patients present with [20]. Similarly, studies have revealed pathophysiological mechanisms including immune cell dysregulation and altered cortisol levels in post COVID patients [21]. The authors claim “After 40 years of research into CFS/ME … neither a specific biological defect or pathology, nor a specific biomarker, has been identified”. It is estimated that at least 10,000 scientific papers have been published on ME/CFS and several distinct biological changes have been discovered resulting in targeted interventions and thorough descriptions of the pathobiology of ME/CFS [22, 23]. In opposition to the vast amount of biopathological evidence, the authors refer to a publication where the initial part of the summary reads: “The basic assumption underlying the model presented here is that the brain makes sense of the internal state of the body by being sensitive to statistical regularities in its own neural activity” [24]. The publication title seems to state the validity of this concept by “Taking the inferential leap” perhaps not knowing that inferring denotes either a conclusion based on known facts or the act of passing from statistical sample data to generalization. The authors fail to provide any of these. Invest in ME Research Page 22 of 32 Journal of IiMER June 2024 Conclusion: The “Oslo Declaration” epitomises the dangers of extrapolating findings from a small underpowered, narrowly focused study with data from unrelated studies (disorders) to explain a complex multi-factorial disease comprising different clinical subtypes that ME/CFS represents. To quote the American literary critic HL Mencken: “For every complex problem there is an answer that is clear, simple, and wrong.” References: 1. 2. 3. 6. 7. 8. 9. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, D.C: National Academies Press; 2015. National Institute for Health and Care Excellence. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. 2021 Cairns R, Hotopf M. Occup Med (Lond). 2005 Jan;55(1):20-31. 4. Wilson A, et al. BMJ. 1994 Mar 19;308(6931):756-9. 5. Andersen MM, et al. J Psychosom Res. 2004 Feb 1;56(2):217–29. Ghali A, et al. Diagnostics 2022, 12, 2540. Carruthers BM, et al 2011 Oct;270(4):327-38. Lien K, et al. Physiol Rep. 2019 Jun;7(11): e14138. Joseph P, et al. Chest. 2021 Aug;160(2):642-651. 10. Booth NE, et al. Int J Clin Exp Med. 2012;5(3):208-20. 11. Tomas C, et al (2020) PLoS ONE 15(4): e0231136. 12. Hansen AL, et al. J Psychophysiol. 2013;27(2): 67–75 13. Rowe KS. Front Pediatr. 2019; 7: e00021. 14. Josev EK, et al. J Clin Med. 2021 Aug 16;10(16):3603. 15. Allen C, et al. Lancet. 1999;354(9186):1229–1233. 16. Arias D, Otto C. 2011 http://www.medirelax.com/v2/wp-content/uploads/2013/11/F.Scope-of-Sensory-Deprivation-for-Long-Duration-Space-Missions.pdf 17. Nakatomi Y et al.J Nucl Med 2014; 55:945–950 DOI: 10.2967/jnumed.113.131045 18. Mueller C, et al. Brain Imaging and Behavior 14, 562–572 (2020). 19. Tate W, et al. Front Neurol. 2022;13: 877772. 20. Goebel A, et al.: J Clin Invest. 2021;131(13):e144201. 21. Klein J, et al. Nature (2023). https://doi.org/10.1038/s41586-023-06651-y 22. Sotzny F, et al. Autoimmunity Reviews Volume 17, Issue 6, June 2018, Pages 601609 23. Stanculescu D, Bergquist J. Front Med (Lausanne). 2022 Mar 8;9:818728. 24. Fedorowski, A., Sutton, R. Nat Rev Cardiol 20, 281–282 (2023). 25. Franke, C., Berlit, P. & Prüss, H. Neurol. Res. Pract. 4, 28 (2022). 26. Möller M, et al.. J Intern Med. 2023 Sep 27. Invest in ME Research Page 23 of 32

16th International ME Conference - Presenters Professor Simon Carding Research Leader, Quadram Institute Bioscience, Norwich Research Park, UK Professor Simon Carding Professor of Mucosal Immunology at University of East Anglia and Institute of Food Research. Following his PhD at London he held postdoctoral positions at New York University School of Medicine, New York and at Yale University School of Medicine, New Haven, USA. He then moved to the University of Pennsylvania, Philadelphia, USA as Assistant and later Associate Professor. He joined University of Leeds as Professor of Molecular Immunology in the Institute of Molecular and Cellular Biology in 1999. His scientific interests are in understanding how the immune response in the gut functions and in particular, is able to distinguish between the commensal microbes that reside in the gut and environmental microbes that cause disease, and in the mechanisms by which the body's immune system no longer ignores or tolerates commensal gut bacteria and how this leads to immune system activation and inflammatory bowel disease. Dr Vicky Whittemore Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States Dr. Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster. Her interest is in understanding the underlying mechanisms of the epilepsies including the study of genetic and animal models of the epilepsies. Dr. Whittemore received a Ph.D. in anatomy from the University of Minnesota, followed by post-doctoral work at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm, Sweden. She was on the faculty of the University of Miami School of Medicine in The Miami Project to Cure Paralysis prior to working with several non-profit organizations including the Tuberous Sclerosis Alliance, Genetic Alliance, Citizens United for Research in Epilepsy (CURE), and the National Coalition for Health Professional Education in Genetics (NCHPEG). She also completed a four-year term on the National Advisory Neurological Disorders and Stroke Council. Recently Dr Whittemore completed the NIH Roadmap for ME/CFS project having taken a leading role in developing the programme and project management. Invest in ME Research Page 24 of 32 Journal of IiMER June 2024 Dr Avindra Nath, NIH, USA NIH National Institute of Neurological Disorders, Bethesda, Maryland, USA Dr. Nath received his MD degree from Christian Medical College in India in 1981 and completed a residency in Neurology from University of Texas Health Science Center in Houston, followed by a fellowship in Multiple Sclerosis and Neurovirology at the same institution and then a fellowship in Neuro-AIDS at NINDS. He held faculty positions at the University of Manitoba (199097) and the University of Kentucky (1997-02). In 2002, he joined Johns Hopkins University as Professor of Neurology and Director of the Division of Neuroimmunology and Neurological Infections. He joined NIH in 2011 as the Clinical Director of NINDS, the Director of the Translational Neuroscience Center and Chief of the Section of Infections of the Nervous System. His research focuses on understanding the pathophysiology of retroviral infections of the nervous system and the development of new diagnostic and therapeutic approaches for these diseases. Professor Lutz Schomburg Charité University Hospital, Germany Prof. Dr. Lutz Schomburg received his training in biochemistry at the University of Hanover, Germany. He completed internships at the Max Planck Institute for Biochemistry in Munich, the Waite Agricultural Research Institute, Adelaide, Australia, and King's College London, UK. He worked at the Max Planck Institute for Experimental Endocrinology in Hannover, Germany, and received his PhD in 1994. As a postdoctoral fellow, he worked at Brigham and Women's Hospital, Harvard Medical School, Boston, USA, with Prof. William W. Chin and at Julius Maximilians University, Würzburg, Germany, with Prof. Josef Köhrle. He is currently President of the International Society for Selenium Research and Deputy Director of the Institute for Experimental Endocrinology at Charité Universitätsmedizin Berlin. Professor Nancy Klimas Director, Institute for Neuro Immune Medicine, Professor of Medicine, Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University Professor Emerita, University of Miami Nancy Klimas, MD, has more than 30 years of professional experience and has achieved international recognition for her research and clinical efforts in multi-symptom disorders, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI), Fibromyalgia, and other Neuro Immune Disorders. She is immediate past president of the International Association for CFS and ME (IACFS/ME), a professional organization of clinicians and investigators, and is also a member of the VA Research Advisory Committee for GWI, the NIH P2P CFS Committee, and the Institute of Medicine ME/CFS Review Panel. Dr. Klimas has advised three Secretaries of Health and Invest in ME Research Page 25 of 32

Journal of IiMER June 2024 Human Services, including Kathleen Sabelius, during her repeated service on the Health and Human Services CFS Advisory Committee. Professor Klimas has been featured on Good Morning America, in USA Today and the New York Times. Dr Rob Wüst Vrije University Amsterdam, Netherlands Rob Wüst is currently assistant professor at the Department of Human Movement Sciences at the VU University Amsterdam. He received a PhD in Physiology from the Manchester Metropolitan University and VU University Amsterdam, and completed postdoctoral training at the University of Leeds and Amsterdam University Medical Center. His research interest is in cardiac and skeletal muscle metabolism and mitochondrial physiology, in health and disease. Rob uses research methods, ranging from MR imaging and spectroscopy, fluorescence microscopy and cellular and molecular techniques. Professor Maureen Hanson Cornell University, USA Maureen Hanson is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, NY. Previously she was on the faculty of the Department of Biology at the University of Virginia in Charlottesville and an NIH NRSA postdoctoral fellow at Harvard, where she also completed her Ph.D. degree. While most of her prior research has concerned cell and molecular biology in plant cells, she began a research program on ME/CFS after noting at a 2007 IACFS meeting the paucity of molecular biologists studying the illness. Her lab was part of the 2012 multicenter study organized by Ian Lipkin's group at Columbia University to assess the actual role of XMRV in ME/CFS. Dr. Hanson has a current project to examine the microbiome of ME/CFS patients and controls, in collaboration with Dr. Ruth Ley (Cornell Microbiology) and Susan Levine, M.D. (Manhattan, NY). Dr Levine is also collaborating with Dr. Hanson on an immune cell gene expression project that involves Dr. Fabien Campagne and Dr. Rita Shaknovich at Weill Cornell Medical School in New York City. Dr. Hanson's third project concerns analysis of blood samples from individuals performing a two-day cardiopulmonary exercise test at Ithaca College under the supervision of Dr. Betsy Keller. Dr Irina R Rozenfeld / Dr Violetta Renesca Institute for Neuro-Immune Medicine, Depart. of Clinical Immunology, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, USA Irina Rozenfeld is a Board Certified Nurse Practitioner committed to the health of her patients. Irina emphasizes patient-practitioner relationships, critical thinking and patient education to develop an optimal treatment plan and achieve sustainable results. She obtained her Bachelor's of Science degree from Nova Southeastern University and a Master's of Invest in ME Research Page 26 of 32 Journal of IiMER June 2024 Science in Nursing Studies from Florida International University. Additionally, she has obtained a Master's degree in Integrative Medicine from George Washington University School of Medicine and a Doctoral degree at the University of North Florida. Before joining the INIM, Irina worked for more than twenty years as a physician assistant in Russia. After relocating to Florida, she worked as a Clinical Research Nurse at Nova Southeastern University. Irina obtained an international certification as a Clinical Research Professional and has been involved in research in many roles. Irina teaches at Nova Southeastern University College of Nursing as an adjunct faculty. Irina's focus at the INIM includes myalgic encephalomyelitis/chronic fatigue syndrome, chronic infections, vector-borne illnesses, metabolic syndrome, chronic pain, environmental issues, detoxification and auto-immune diseases and her research interests include neuroinflammation, biotoxin exposure, detoxification, immune dysfunction, the stress response, neuroendocrinology and implementation of integrative medicine modalities. Violetta Renesca is a Board Certified Adult Nurse Practitioner focusing on functional and integrative approaches to treat patients with complex neuro-inflammatory conditions. She obtained a Bachelor of Science degree in Nursing from Nova Southeastern University and worked as a staff nurse and charge nurse on the Progressive Care Unit at Broward Health. After receiving her Master’s Degree from Florida International University as an Adult Nurse Practitioner, she joined a large multispecialty geriatric center in Fort Lauderdale. Violetta obtained a Doctorate in Nursing Practice from the University of North Florida. Violetta’s focus at the INIM includes myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War illness, chronic infections, metabolic syndrome, chronic pain, environmental illness, detoxification, and autoimmune diseases. As a certified practitioner for the Institute for Functional Medicine, she works with patients to create personalized treatment plans that addresses root causes of chronic illness. She is also the Director of the Veterans Clinic where she sees patients with Gulf War illness. Additionally, she is a member of the American Association of Nurse Practitioners as well as the Institute for Functional Medicine. Dr Jesper Mehlsen Copenhagen University Hospital, Denmark / EMERG Dr Jesper Mehlsen graduated as a medical doctor in 1979 and finished his specialist training in 1990. He has published more than 140 scientific papers in peer reviewed journals, mainly on the autonomic nervous system and more recently on complex diseases possibly resulting form HPV-vaccination. For more than 35 years, he has worked clinically and in research with dysfunction of the autonomic nervous system. Such dysfunction may lead to symptoms from a number of different organs often dominated by diminished control of blood pressure and heart rate. Over the past 5 years, he has worked clinically and in research with patients who suspect side effects due to HPV vaccination to be the cause of a number of symptoms, common to those seen in chronic ME. Dr Mehlsen is co-chair of the European ME Research Group (EMERG). Invest in ME Research Page 27 of 32

Journal of IiMER June 2024 Dr Dezső Modos, Imperial College London, UK Dr Dezső Modos is an Imperial College Research Fellow in the Systems Medicine division of the Department of Metabolism, Digestion and Reproduction. He completed his medical degree at Semmelweis University and a minor in bionics at the Pázmány Péter Catholic University. Later he obtained his PhD at the Semmelweis University on network biology. His primary focus was the intracellular signalling network in cancer and understanding the role of paralogues in signalling. After his PhD he moved to Cambridge and learned cheminformatics. He used network biology to understand and predict compound synergy in cancer. Here he also learned about various cheminformatic techniques, which he is adapting for his fellowship. The current inflammatory bowel disease (IBD) therapies maintain remission only in around 30% of cases forming therapeutic celling. His fellowship aims to find the right drug to the right patient in IBD. Similarly, we can use the targets of IBD drugs as a source node and build a drug specific network footprint. The comparison of patient-specific disease and drug networks, much like connectivity mapping, can aid in identifying the correct drug for each patient. Single nucleotide polymorphisms (SNPs) in inflammatory bowel disease are often in the non-coding region of the genome. He and his colleagues developed a tool called iSNP (https://github.com/korcsmarosgroup/iSNP) which can map these single nucleotide polymorphisms to regulatory regions and through that SNP affected genes. From the SNP affected genes, patient specific signalling networks, individual pathogenetic pathways and patient specific network footprints can be constructed. Already, he has used this method to understand ulcerative colitis pathogenesis. Precision Life, UK PrecisionLife is a precision medicine company focused on finding better, more personalised treatment options for complex chronic diseases such as Alzheimer’s, diabetes, and endometriosis. It analyses large amounts of data from sources such as clinical trials, patient charities, biobanks, and research organisations to stratify, or segment, patients into clinically relevant subgroups. It can then identify potential drug targets based on the cause of each subgroups’ condition and help healthcare providers diagnose these conditions more accurately and effectively. PrecisionLife received an Advancing Precision Medicine grant from Innovate UK to investigate the causes of ME and long Covid. One of the first project objectives will be for PrecisionLife to use its precision medicine approach to identify the biological mechanisms driving disease in different groups of patients. The results will be used to create the first predictive diagnostic tools and risk models that can rapidly triage patients presenting to a doctor with potential ME/CFS or long Covid symptoms. Invest in ME Research Page 28 of 32 Journal of IiMER June 2024 Dr Gunnar Gottschalk, Simmaron Research Inc., USA Carl Gunnar Gottschalk completed his BS in biology at Sierra Nevada College and MS in Biotechnology at Rush University Medical Center. He received his Ph.D. in Neuroscience from Rush University Medical Center. Prior to attending graduate school, Dr. Gottschalk was the lead research coordinator for Sierra Internal Medicine and was responsible for the execution of several large multi-centered investigations in ME/CFS. Dr. Gottschalk has been with Simmaron Research since its formation. In 2020, he was named the Foundation’s Executive Director. Since then, Dr. Gottschalk has served a dual role in the organisation as the Executive Director and Principal Investigator. At present, Dr. Gottschalk is the PI for Simmaron’s multi-centered clinical trial of Rapamycin in ME/CFS. His laboratory is located at the Indiana Center for Biomedical Innovation (ICBI) on the campus of the Indiana University Methodist Hospital in Indianapolis, IN. Dr David Systrom, Assistant Professor of Medicine, Brigham and Women's Hospital, Harvard Medical School, USA Dr. David M. Systrom is a physician at Brigham and Women's Hospital. He is also an assistant professor of medicine at Harvard Medical School where he directs the Dyspnea Clinic and the Advanced Cardiopulmonary Exercise Testing Program. He received his medical degree from Dartmouth Medical School (now known as Geisel School of Medicine). He has been on the Harvard faculty for over 35 years. He has used invasive cardiopulmonary exercise testing to investigate mechanisms underlying fatigue and orthostatic intolerance in ME/CFS and PASC. His recent work suggest commonality between the two, in particular neurovascular dysregulation and related hyperventilation underlying symptoms during exercise. He is the Principal Investigator of an ongoing $8 million study of limb skeletal muscle mitochondrial dysfunction and just completed the first ever randomised clinical trial of pyridostigmine, both in ME/CFS. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA Ronald W. Davis, Ph.D., is a Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California. He is a world leader in the development of biotechnology, especially the development of recombinant DNA and genomic methodologies and their application to biological systems. At Stanford University, where he is Director of the Stanford Genome Technology Center, Dr. Davis focuses on the interface of nano-fabricated solid state devices and biological systems. He and his research team also develop novel technologies for the genetic, genomic, and molecular analysis of a wide range of model organisms as well as humans. The team's focus on practical application of these technologies is setting the standard for clinical genomics. Invest in ME Research Page 29 of 32

Journal of IiMER June 2024 #BRMEC13 PROGRAMME – Day 1 26th June 2024 Arrival Refreshments 08:55 Welcome to BRMEC13 09:35 How infectious diseases (IDs) together with environmental and genetic factors trigger the onset of noncommunicable diseases (NCDs) Underlying Mechanisms of Long Covid Chair: Simon Carding, Quadram Institute Chronic Infection Aetiology Starter (viral / non viral): Chair Fridbjorn Sigurdsson 09:10 10:00 ME/CFS and Long Covid: NIH study 10:25 10:45 Chaired Discussion 11:05 BREAK Physiology: Chair Jonas Bergquist 11:40 12:05 12:30 12:55 13:15 Acute and chronic infections in patients with post–infectious syndromes Diagnostic and potential relevance of autoantibodies for fatigue symptoms Dysautonomia and Results from ICOSS Chaired Discussion Chair: Opening Thomas Vogl, Medical University of Vienna, Austria David Price, Cardiff University Avindra Nath, NIIH A Systems Biology Approach to ME / AI and Phenotypes Tamas Korcsmaros, Imperial College London Discussion Branislav Milovanović, Institute for cardiovascular diseases-Dedinje Department of Cardiology, Serbia Insights from Invasive Cardiopulmonary Exercise David Systrom, Harvard Medical School Lutz Schomburg, Charite Berlin Markku Partinen, University of Helsinki Discussion 13:30 LUNCH Nervous System and Neuroinflammation: Chair Jon Brooks 14:30 14:35 15:00 15:25 15:50 fMRI Observations from NIH Intramural Study Innate immune activation in the whole body and CNS of ME patients using PET/MRI Using fMRI and PET imaging to study neuroinflammation in ME Chaired Discussion 16:10 BREAK Metabolism Body and Cell Chair: Rikke Olsen 16:35 Ancestral allele of DNA polymerase gamma modifies antiviral tolerance 17:00 Mitochondrial dysfunction in ME/CFS 17:25 17:50 18:00 Genetic predisposition to metabolic disturbances in individuals severely affected by long-COVID Chaired Discussion Adjourn Jon Brooks, UEA, UK Avi Nath, NIH Michelle James, Stanford University School of Medicine, USA Michael van Elzakker, Harvard Medical School & Massachusetts General Hospital/Tufts University Discussion Yilin Kang, Suomalainen-Wartiovaara Group, University of Helsinki Rob Wust, Virje University, Amsterdam, Kristoffer Hansen, Aarhus University Discussion Invest in ME Research Page 30 of 32 Journal of IiMER June 2024 #BRMEC13 PROGRAMME – Day 2 27th June 2024 Arrival Refreshments 08:55 Welcome to BRMEC12 Day 2 09:10 Regulatory T cells in the brain 09:35 tbc 10:00 Plasma Proteomics in Response to Exercise 10:25 Autoantiboidies in ME and Long Covid 10:50 tbc 11:05 BREAK 11:35 Discussion Immune System Primary and Secondary Chair: Eva Untersmayr-Elsenhuber , Medical University of Vienna 09:05 Chair: Opening Chair: Simon Carding, Quadram Institute Eva U, Medical University of Vienna Adrian Liston, University of Cambridge Simon Carding, Quadram Institute Maureen Hanson, Cornell University Nancy Klimas, Nova Southeastern University Johanna Rohrhofer, Medical University of Vienna Discussion Epigenomes and Transcriptomes: Chair Elisa Oltra, Univ. of Valencia 12:00 Single cell transcriptomics to reveal the role of thymus in autoimmune diseases, and potential implications for ME/CFS 12:25 Single-cell transcriptomics of the immune system in ME/CFS 12:50 Human endogenous retrovirus expression in the immune system of ME/CFS 13:10 Chaired Discussion 13:30 LUNCH 14:35 NIH / CDC /EMERG Phenotypes 14:55 Longitudinal Study of ME Patients 15:10 Identifying potential candidates for clinical trials using AI network medicine Benedicte Lie, University of Oslo, Norway Andrew Grimson, Department of Molecular Biology and Genetics, Cornell University, USA Karen Gimenez-Orenga, Department of Pathology, Universidad Católica de Valencia San Vicente Mártir, Spain Discussion Beth Unger, CDC Leonard Jason, Chicago De Paul University, USA Wenzhong Xiao, Harvard Medical School, USA Clinical Trials: Chair Jesper Mehlsen, Copenhagen University Hospital, Denmark / EMERG 15:30 Clinical Trials Design and Standards for ME 16:00 BREAK 16:30 Clinical trials Ad-hoc Presentations: 17:00 Involvement of BH4, NO and Oxidative Stress in ME/CFS 17:25 Clinical Trial of Rapamycin 17:50 Flash Talks Various Speakers building standards for clinical trials NIH / CDC / EMERG Continued + action plan + document Ron Davis, Stanford School of Medicine in Stanford, USA Gunnar Gottschalk, Simmaron Research Inc., USA Various speakers 18:00 Summary Day 2 – Chaired Discussion 1815 Adjourn - Discussions continue at the informal Researchers’ Evening Invest in ME Research Page 31 of 32

Journal of IiMER June 2024 #IIMEC16 PROGRAMME – 28th June 2024 Time Arrival Refreshments 09:00 Updates on research into ME 09:15 NIH Roadmap - Future Directions 09:40 Insight into mechanisms of ME/CFS 10:05 Autoantiboidies in ME 10:30 BREAK 11:00 Explaining skeletal muscle-related symptoms in patients with ME/CFS: from skeletal muscle to exercise immunology 11:25 Immune Exhaustion in ME 11:50 Comparing Long Covid and ME Phenotypes 12:15 Discussion 12:25 LUNCH 13:35 Treating ME in USA - A Clinician's Approach 14:00 Treating ME in Europe - A Clinician's Approach 14:25 Diagnostic Criteria and Challenges How to manage severe ME in hospital/care environment 14:45 BREAK 15:15 Precision medicine in complex diseases and AI 15:40 Identifying Genetic Risk Factors for ME/CFS and Long COVID: First Genetic Associations, Novel Targets, Actively Protective Biology, Diagnostics and Repurposing Opportunities 16:05 Update on Clinical Trial of Rapamycin in ME 16:20 Clinical Trial of LDN and Mestinon 16:45 Involvement of BH4, NO and Oxidative Stress in ME/CFS 17:15 Plenary 17:30 Adjourn Chair: Professor Simon Carding, Quadram Institute, UK Dr Vicky Whittemore, NIH, USA Dr Avi Nath, NIH, USA Professor Lutz Schomburg Charité University Hospital, Germany / EMERG Dr Rob Wüst, Vrije University Amsterdam, Netherlands Professor Maureen Hanson, Cornell University, USA Professor Nancy Klimas, Nova Southeastern University, USA Panel discussion Dr Irina R Rozenfeld / Dr Violetta Renesca Nova Southeastern University, USA Dr Jesper Mehlsen Copenhagen University Hospital, Denmark / EMERG Panel discussion Dr Dezső Modos, Imperial College London Precision Life, UK Dr Gunnar Gottschalk, Simmaron Research Inc., USA Dr David Systrom Harvard Medical School, USA Professor Ron Davis Stanford School of Medicine in Stanford, USA Panel Discussion Invest in ME Research Page 32 of 32

Journal of IiMER Volume 13 Issue 1 Invest in ME Research In this Issue In this Issue ............................................................... 3 FOURTEEN YEARS ..................................................... 4 Jonas Blomberg......................................................... 6 Fifty Years - and ME? ................................................ 7 A Centre of Excellence for ME .................................. 9 European ME Clinicians Council ............................. 11 Statement from EMECC .......................................... 12 Encouraging Young Researchers............................. 13 Denmark - Ærlighed varer længst ........................... 14 (HONESTY LASTS LONGEST) .................................... 14 UK - Parliamentary Debate ..................................... 15 Sweden ................................................................... 16 Perceptions of Care in a Hospital’s Emergency Department 20 Chronic fatigue syndrome in the emergency department .............................................................20 Medical Education ..................................................21 Education about ME has been one of the major objectives for Invest in ME Research ......................21 Doctors and Patients ..............................................23 Listen to the patients ..............................................24 Long term illness with ME ......................................27 Caring for someone with ME ..................................30 Disability and Human Rights ...................................33 ME and the EU ........................................................35 Children with ME ....................................................38 Removing isolation .................................................39 No Isolation & Invest in ME Research .....................39 Anne Ortegren - A Year On .....................................41 Conference Abstracts .............................................42

Journal of IiMER Volume 13 Issue 1 Invest in ME Research FOURTEEN YEARS Invest in ME Research is an independent UK charity facilitating and funding a strategy of highquality biomedical research into Myalgic Encephalomyelitis (ME or ME/CFS) and promoting better education about ME. The charity is run by volunteers - patients or parents of children with ME - no salaries, no government funding, but wonderful supporters. This is the fourteenth annual international ME conference that this small UK charity has organised - a fact which surprises us on many levels. It is a surprise that we have managed to continue to arrange these conferences, and even increased their scope - despite comparatively few resources. A surprise that there really has not been the progress in research that we believed would and should have come after all these years. A surprise that it has taken so long before any major national agency has taken this disease seriously. A surprise that many other national research councils, especially in UK, are lagging so far behind and have ignored this disease for so long. Yet where would we be now had it not been for the dedication and efforts of our supporters throughout these years who have made it possible for us to redirect research toward biomedical and influence and force a new direction for ME? These are not just mere words for us - not a fresh update to leaflets, not a soundbite to pacify ME patients in order to retain support, not a new tactic to attempt to maintain the status quo, not another strategy to do deals behind closed doors and maintain establishment influence on progress. During all these years the charity has consistently and unambiguously campaigned for dedicated biomedical research into ME and the necessary funding to achieve it. We believed progress would be more rapid and it is sad that the opportunities that we presented and the offers that we made to engage were not taken up by establishment organisations as so much more Invest in ME Research (Charity Nr. 1153730) might have been achieved in tackling this disease at that early stage, rather than waste lives by doing so little. Yet without the efforts of our supporters throughout these years the scene could have been quite different and far worse. We named the Colloquiums the “Biomedical Research into ME Colloquiums” as we wanted to make the point that we would not compromise. Biomedical research was the way forward to make progress. The conferences were designed for professionals in order to increase the education of healthcare staff and influence the future treatment of people with ME. However, we have always ensured that the conferences were also open to patients and carers, believing that having patients, carers, researchers, doctors, nurses and even the media interacting with each other was a good thing. The charity has facilitated the foundation for a sustainable strategy of biomedical research into this disease. Our plans for a Centre of Excellence for ME have captured the imagination and is clearly seen as the way ahead - and good progress on this has been made, although with more resources the charity could expedite this for the benefit of all patients. The Centre of Excellence for ME project began in 2010 and the charity was able to fund the first PhD studentship some years later. This approach to research offers the best way forward for ensuring biomedical research into ME can be maintained and treatments developed. Collaboration has been at the heart of the charity's innovation following a review after the 2007 conference and our strategy of bringing the best researchers from around the world together was formed. The acceptance of this vision and collaborative strategy has matured to the point where now the NIH is taking a lead in forming centres and collaborative strategies. Collaboration and working together have been themes for our Colloquiums - with real international cooperation forming which can only lead to a better future for patients than would otherwise be the case. To support this strategy the charity has investinme.org Page 4 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research continued to arrange the international ME conferences that have provided a platform for education about ME - with DVDs produced of all the conference presentations which have formed a historical record as well as providing knowledge of the latest research. The Colloquiums and Conferences have always had an international atmosphere – emphasising that international collaboration in research and treatment are necessary. Our original conferences have now developed into a unique conference week in the heart of London with delegates and colleagues and friends coming from over twenty countries around the world. ME Conference Week 2019 now includes a conference for young/early career researchers; a dinner where young researchers can meet more experienced scientists; a two day closed research Colloquium where researchers can share ideas and discuss and plan and collaborate; a researchers' dinner where more discussions can be had; a pre-conference dinner which allows a special gathering of researchers, clinicians, media folk, politicians, ME patient group representatives,carers and patients to interact; a public international conference; a post-conference dinner which allows researchers and patient groups to discuss further after the main events have finished and plan the next steps; and an annual general meeting for the European collaborative patient alliance. A small charity with wonderful supporters has achieved this. When people view charities as being "the largest" or "the main" organisations it is as well first to determine how those adjectives are measured. Is it by income, by number of staff, by the amount of media presence? Or by the amount of income spent on research, or on the least spent on admin and salaries, or on the achievements and ideas that actually are realised? It is achievements that count - always - and hopefully the ideas that actually are realised, where possible. The supporters of the charity may not get the publicity they deserve but actions speak far louder than words, or awards. In the recent parliamentary debate on ME, Invest in ME Research produced a document which Invest in ME Research (Charity Nr. 1153730) investinme.org Page 5 of 52 summarised the status of ME. It also laid out a bold vision for research – including proposing that £20 million be allocated every year for five years to kickstart biomedical research and support the foundations that have been laid. It is this vision that a small charity and dedicated supporters brings to the world of ME. We were happy to contribute to the parliamentary debate that originated from the early work performed by a supporter of Invest in ME Research who is a constituent of the SNP MP Carol Monaghan, who set up the debate. Being an independent charity allows a genuine approach to tackling the problems with ME that benefits patients and their families. As Dr Ian Gibson - our conference chair for all these years - has said "We can change things" As we host our largest ever “invite-only” closed research Colloquium (with more than 130 invitations being sent out) then the name of our charity truly becomes the main calling for all interested in resolving this disease. For our fourteenth conference, and our ninth international researchers' Colloquium, what better slogan to use at this point in time than the one that this small charity has uniquely been promoting for so long. Time to #InvestinMEresearch Kathleen McCall CHAIRMAN INVEST IN ME RESEARCH We would like to thank our friends from the Irish ME Trust, Norges ME Forening and the Open Medicine Foundation for donating to help fund the administration costs of the conference.

“He was a giant and his support for our endeavours was immeasurable. What a tragedy" - Dr Ian Gibson Jonas Blomberg Over the years, whilst the charity has been making huge efforts to encourage and facilitate international collaboration in research into ME, we have come into contact with hundreds of researchers in different research fields, in different institutes and in different countries. There are many researchers whom we have known who have become trusted friends. One of those researchers whom we have called a friend of the charity and a friend of people with ME was Jonas Blomberg. One liked Jonas instinctively from the beginning. He was the type of person who would always give an unbiased and objective view on science - with no pretensions or separate agenda. Jonas was the epitome of a researcher with integrity, honesty, approachability and scientific skills. Jonas came to one of our early international conferences after being encouraged by a member of RME Sverige. Invest in ME Research (Charity Nr. 1153730) Following that meeting we invited Jonas to every conference as our guest. He was also invited to our first Colloquium and attended every one of these events since that time. His was one of the first names that we entered when planning these events ten months before. Such was the level of trust and friendship that we asked Jonas to be a chair for many Colloquium sessions and sum up conclusions from the Colloquiums. Integrity – always. Jonas was scheduled to chair, once again, the Thinking the Future – Young/ECR Conference in London in May – having successfully chaired last year’s inaugural event. Jonas would also have been attending and chairing this year's 'Conference and Colloquium and Thinking the Future events. The news of his sudden death comes as a major shock to all at the charity. This affects all of us and is a great loss to ME. Our memories of Jonas are of the best - and he will be greatly missed by all. investinme.org Page 6 of 52 Fifty Years - and ME? In medicine, healthcare, technology and science the last fifty years have seen some dramatic developments that are nowadays taken for granted. Antibiotics dramatically reduced death rates due to infection and today even new classes of antibiotics are being produced – even synthesised versions – to tackle superbugs Organ transplants have become commonplace - with thousands of transplants being performed every year. Artificial organs have been developed. Anti-viral therapy for HIV has transformed the prospects of patients from a fatal to a managed condition. Vaccinations developed against many infectious diseases have changed society. Imaging technology such as CT, MRI, and PET has revolutionised the detection of disease. Anti-TB therapy practically eradicated tuberculosis, until recently. Major advances in knowledge of the genetic code has laid foundations for the -omics branches of science. Kidney dialysis, endoscopy and laparoscopic surgery, inhaled therapy, cataract treatment, statins, beta-blockers...etc. Invest in ME Research (Charity Nr. 1153730) Revolutionary developments now in everyday use, improving lives of patients. Technologies too have changed the world Computing power and development has turned the future into the present with technologies such as artificial intelligence. With the rapid pace of development in science and technology then this overflows into medicine. Unbelievable changes are being developed and tested - such as 3D printed body parts, new complex and even remote surgical procedures , gene therapy , gut bacteria treatments, cancer immunotherapy, synthetic cells, reprogrammed cells , mitochondrial replacement therapy ................it goes on and on. If one can dream one can think the future. It all seems possible. And myalgic encephalomyelitis? Well, all of the above have had great effects on society and even people with ME will have benefited from some of these developments. However, what of ME itself? investinme.org Page 7 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Fifty years ago, we celebrated the anniversary of the first moon landing. The amazing photograph showed earth as seen from the moon for the first time. How amazing, even today, to see this image and imagine that this could be achieved with computing power less than is now available in a mobile phone, and with technology that seems ancient by today’s norms. Yet who would have thought that fifty years would go by and people with ME would still have no specialist services, no treatments, no funding for fundamental biomedical research? For ME we are still discussing the criteria, the name, the politics. We are still frustrated that there is no adequate research funding. We still suffer – at least since the beginning of this decade – of the evil that is the biopsychosocial (BPS) doctrine. We should have made far more progress than has been the case in fifty years. Yet ME has failed to achieve the progress that other areas of medicine and science have enjoyed. ME has been forced into a retarded development due to the malign forces that have kept a few in positions of influence and power in order to support policies that have long been known to be damaging. Patients have been played. And who benefits from this continued stalling of progress? Progress with ME may well depend on some of the above mentioned developments in science, technology and medicine. The view regarding ME fifty years had seemed to be, until recent years, as bleak as the moon must have appeared to the crew of Apollo 8. Yet we can hope that even the most entrenched of establishment policies will finally be swept away. Fifty years ago we were amazed to see our world from another celestial body in all its splendour. Another fifty years cannot pass without seeing solutions to ME being realised. Status of ME 2018 - www.investinme.org/IIMER-Newslet-180601.shtml Invest in ME Research o an independent UK charity finding, funding and facilitating a strategy of high quality biomedical research into Myalgic Encephalomyelitis o focuses on biomedical research into ME and the education of healthcare staff, the media, government departments, patient groups and patients o run by volunteers with no paid staff - no funding from government or government organisations o overheads are kept to a minimum to enable all funds raised to go to promoting education of, and funding for biomedical research into, ME o a small charity with growing number of supporters with big hearts and determination to find the cause of myalgic encephalomyelitis and develop treatments o we have links nationwide and also internationally and facilitate international collaboration o founder member of the European ME Alliance (EMEA) o organises annual research Colloquium and public Conference attracting delegates from 20 countries o to bring best education and research to bear on ME and find/facilitate the best strategy of research o focused on setting up UK/European Centre of Excellence for ME to provide proper examinations and diagnosis for ME patients and coordinated strategy of biomedical research in order to find treatment(s) and cure(s) - http://www.cofeforme.org/centre o the charity welcomes support for our work – www.investinme.org/donate Invest in ME Research (Charity Nr. 1153730) investinme.org Page 8 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research A Centre of Excellence for ME The charity's proposal for a Centre of Excellence for ME was first made in 2010, after having sat in meetings with the NHS for several years - wasting time and effort where there seemed little progress in attempts to improve things for people with ME. The concept is designed to create a hub of high-quality translational biomedical research into ME using standard and up-to-date guidelines and protocols that allow accurate diagnosis based on relevant tests. These would consist of full examinations, clinical diagnosis, translational biomedical research, clinical trials, bioinformatics, biobank(s) to allow for more research opportunities and support) and improved education and training of healthcare staff. By using the facilities in the Norwich Research Park, the opportunity has been created for clinical trials to be carried out and a central point for medical education on ME to be established. With the help of the Let's Do It For ME campaign our foundation research project was funded and established and began in 2013 at University of East Anglia (UEA)/Quadram Institute (QI) in Norwich Research Park. This was the first crowdfunded PhD for ME. Further projects are now u Norwich Research Park. Concentrating on a Centre of Excellenc hub does not mean that all research must be performed at the one location. IiMER has also been funding research and a PhD studentship at UCL. Thanks to amazing support from The Hendrie Foundation B-cell research was initiated which allowed a preliminary study to be established and performed prior to the UK rituximab clinical trial. The charity had been keen to replicate the Norwegian Rituximab trial find and, in 2012, the charity announced its intention to facilitate and fund a clin trial of rituximab. Invest in ME Research (Charity Nr. 1153730) Dr Oystein Fluge and his team from Haukeland University Hospital in Bergen, Norway, visited Norwich in January 2017 to collaborate with the researchers from UEA/QI. Ultimately, the Norwegian Phase III rituximab trial proved negative but much was gained by establishing necessary collaborations that are needed in such a trial and the work was not wasted. Research, at least in UK, depends on rules, regulations, ethics etc. that all have to be fulfilled. Not often realised is that one of the biggest problems we have managed to overcome was the reluctance of established researchers to enter this field. Now that has been achieved then we have to and expand upon it. rituximab trial in Norway turned o be more positive then we could now have been seeing the elements e Centre coming into play to show what could be done. ertheless, new discussions are erway to achieve this. The new building for the Quadram Institute provides new facilities and new possibilities and publicity for research into ME, and a coordinated environment where the Medical School, Clinical Trials Unit and research lab will be located together. Park is described by Quadram r Ian Charles as follows - investinme.org Page 9 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research “The development of this new centre, together with the other expertise and facilities located at the Norwich Research Park, puts it in a very good position to lead a UK and European Centre of Excellence for biomedical research for M.E. to provide possible prevention and solutions.” - Journal of IiME Conference Abstract 2015 between UK, European and US researchers and institutes. All of this has been achieved without any government support. A sustainable Centre of Excellence for ME that can build on these foundations is now an entirely attainable objective - harnessing the benefits of As can be seen from the Quadram Institute web site ME is already firmly embedded as one of their “research targets” - facilitated by the groundwork performed already by the charity and its supporters. The head of Quadram has spoken twice at the Invest in ME Research International ME Conference and there is a major group performing research with international collaboration taking place - encouraged and facilitated by the charity. The collaboration with other UK and European researchers and institutes will create greater publicity and funding opportunities. In the last year the charity has not been idle. A number of proposals and requests are being looked at and several new ideas are being developed. We hope to be able to support an initial clinical fellowship in the research park soon. International collaboration between researchers is underway thanks to the initiatives facilitated by the charity and researchers. The funds raised by the charity have allowed a research group to be firmly established in the Quadram Institute that will allow clinical trials to be carried out in a state-of-the-art setting. Invest in ME Research has, since establishing this proposal, raised in excess of £900,000 for biomedical research into ME – mainly over the last 5 years. This has enabled new researchers to enter the field and firm collaborative links to be established Invest in ME Research (Charity Nr. 1153730) collaborative international biomedical research in modern facilities with world-class researchers. We aim to continue to support development of this world-class ME research centre based in Norwich Research Park that can form a hub of European research and treatment for this disease and produce a pathway to produce huge benefits for the nation and across the world. This will continue to influence other researchers and institutes in their perception of ME and provide a pathway for career development in researching this disease. This, itself, will allow new ideas to be formed in researching and treating the disease. The foundations are therefore already in place to advance science and provide the promise of better treatment and possible restoration of function and lives back to a section of the community who have received very little help in the past. We welcome all support to enable us to complete this project. investinme.org Page 10 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research European ME Clinicians Council One of the many failings in the way ME has been handled over the last decades has been the lack of education and specialisation in ME. Few clinicians have been able to accumulate enough experience and the disease is treated in healthcare with little regard, partly due to this failure and the lack of funding for fundamental research. Those clinicians who have gained experience in treating ME patients and collaborated with biomedical researchers need to be encouraged and supported. Our international conferences and research Colloquiums have brought together researchers from around the world and been instrumental in forging new and promising collaborations. Our European ME Research Group (EMERG) concept brought European researchers together. In a similar way, we feel it is important for experienced clinicians to share their knowledge on diagnostic and treatment methods and produce documentary aids for the research community focused on clinician guided treatment trials, identification of possible illness subsets, and observations of illness presentation. The charity has therefore facilitated the formation of a new European clinicians group. An inaugural CPD-accredited meeting took place in February 2019 in London. The charity sought out the leading clinicians in Europe who are treating ME patients and whom we felt will be supportive and constructive in going forward for the benefit of people with ME and their families. This meeting followed an American initiative that was started by Dr Lucinda Bateman and Mary Dimmock. We have used the name given to the American group that met in USA early 2018 under the chair of Dr Bateman and named this group the European ME Clinicians Council (EMECC). We have also borrowed from the Invest in ME Research (Charity Nr. 1153730) investinme.org USA experiences and documentation and liaised with Mary over the establishment of this group. We used the American meeting as a model and used similar objectives. We wanted to build a network of clinicians in Europe who could support each other, work together, and come together immediately. As Dr Bateman stated, aggregating the knowledge of experienced clinicians on clinical sub topics related to ME/CFS and providing patients, caregivers, advocates, clinicians and the researchers the most up to date information is a critical outcome. The aims of the inaugural meeting were therefore to bring together clinicians in the field of ME, to review the current state of knowledge, to present and discuss the latest initiatives, and to foster collaboration. Since the meeting the clinicians have been working together and this has become a formal group that will work with the American initiative and be supported by the European ME Alliance (now representing fifteen countries). This group will improve the knowledge of clinicians in Europe and act as a focal point for healthcare agencies, doctors and media outlets who wish to learn more from experienced clinicians about ME. The next meeting has already been planned in order develop the network and it has already increased in numbers since the first meeting. The first EMECC meeting took place over three days and a very positive and progressive atmosphere was created with a range of topics being discussed covering diagnosis, treatments, follow-ups, education, research and how the group continues and expands. One of the first items from EMECC is the following statement - Page 11 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Statement from EMECC LONDON, May 2019 International clinical and research experts participated in the first CPD-accredited European ME Clinicians Council (EMECC) workshop that took place over three days in London in February. EMECC has been formed to bring together clinicians from across Europe and from various disciplines to develop a European foundation of high-quality clinical expertise on myalgic encephalomyelitis (ME, also known as ME/CFS). Myalgic Encephalomyelitis (ME or ME/CFS) is classified as a neurological disease that affects patients’ lives profoundly. The USA Institutes of Medicine (IOM) stated in its 2015 report that “it is clear from the evidence compiled by the committee that ME/CFS is a serious, chronic, complex, multisystem disease that frequently and dramatically limits the activities of affected patients”. In view of this, we are concerned to note the longstanding and continued promotion in many countries of the psychosocial view of this condition, whereby it is regarded as a "non-disease" caused simply by a combination of falsely held patient belief systems combined with deconditioning. In our view, this belief system has done immense harm to both the patient community and the prospects for research on this condition. There is much misinformation for this debilitating disease where the current lack of any effective treatment aggravates patient suffering caused by mismanagement due to inadequate, and sometimes absent, policies of healthcare agencies regarding this disease. IOM state that physicians should diagnose ME/CFS if diagnostic criteria are met following an appropriate history, physical examination, and medical work-up. EMECC aims to harvest effective strategies for patient management and treatment from the pooled clinical knowledge of physicians working extensively with ME/CFS patients. A further important aim is to provide or refine ideas for research in all aspects of the disease based on the extensive clinical, handson clinical experience of the EMECC members. The meeting created a very positive and progressive atmosphere with a range of discussions around diagnosis, management and treatments, follow-up investigations, health personnel education and research and how the group will continue and expand. Arranged by UK charity Invest in ME Research and endorsed by the European ME Alliance this workshop involved leading clinicians from Europe who are treating ME/CFS patients and who will be instrumental in creating a sea change in clinical care for the benefit of people with ME and their families. The group will fill a vacuum in clinical expertise that has allowed false beliefs about the real nature of the disease to be propagated. This group will continue to meet in locations across Europe for follow-on meetings and be able to play an important role in clinical care, biomedical research and guidelines development. The workshop was CPD-accredited and we look forward to this group of clinicians/researchers making huge progress in developing sound clinical care for ME/CFS patients - and with the collaboration with our colleagues in the European ME Alliance. European ME Clinicians Council For more information, please contact info@euro-me.org or info@investinme.org Invest in ME Research (Charity Nr. 1153730) investinme.org Page 12 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Encouraging Young Researchers In highlighting some of the issues with ME a major problem is the lack of biomedical research into ME and the funding required for it. Another issue with ME that the charity has been attempting to resolve is the need for new research talent to enter the field. Medical students receive extremely poor education on ME in their curriculum - sometimes even nothing. Not only might this be negligent, as young doctors are subsequently unqualified to deal with ME, but it also means that potential recruits to ME research and treatment positions are discouraged due to ignorance of the condition. Medical students are unaware of the career opportunities. One way to get around this problem was to make students aware of the research that was being undertaken. With the help of the University of East Anglia Medical School the charity was able to fund and facilitate the participation of a number of medical students in the research being performed at Norwich Research Park. The idea was to fund the inclusion of medical students in research via a process of intercalation during their fourth year of medical studies. This led to collaboration with research at Oxford University with Professor Angela Vincent and with Dr Lesley Hoyles at Imperial College London. This has proven to be very successful. Apart from influencing opinions of their peers the medical students have been very active and well received in the research teams. Navena Navaneetharaja was one medical student funded by IiMER and Navena spent time with Professor Maureen Hanson at Cornell University in Ithaca, New York - developing another of IiMER's strategies in forging international collaboration in research. Thinking the Future network To ensure that a foundation of biomedical research into ME Invest in ME Research (Charity Nr. 1153730) investinme.org can be sustained and to encourage new ideas from new areas then we cannot rely just on this family of researchers that has been built up from all parts of the world at Colloquiums. We need to draw in knowledge and expertise from other areas – as we have been doing for many years with our research Colloquiums and international Conferences. Importantly, we also need to encourage early career researchers – and young researchers. In 2018 the charity initiated the young/early career researcher conference - Thinking the Future - an initiative to build a network of new and young research capacity for the future. The Thinking the Future network has the opportunity for developing this group of international, early career researchers which will, in turn, facilitate further international collaboration in research into ME and new ideas being formulated. In fact we have already had several meetings with NIH to collaborate on developing this network. Recently the Thinking the Future workshop was held by NIH in Washington and 40 young/ecr researchers attended. Dr Daniel Vipond from Quadram Institute represented the charity and spoke at the Washington TtF event. We are happy that eleven young/ecr investigators will be attending the TtF3 in London in ME Conference Week - funded by travel awards from NIH. We wish to facilitate and maximise the easy networking of attendees in order to build the network in USA and join it with the established group of European young/ecr researchers so IiMER will cover all registration costs for these delegates – to the TtF workshop and to the 2-day Colloquium and the public IIMEC14 conference. We hope this initiative will provide a focal point for all young/ecr researchers who wish to become involved in research into ME and help describe the exciting career path that this could become. Page 13 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Denmark - Ærlighed varer længst (HONESTY LASTS LONGEST) DANISH PARLIAMENT SEPARATES ME G93.3 FROM FUNCTIONAL DISORDERS Following excellent work by European ME AllianceDenmark member Dansk ME Foreningen, and work and input by those such as European ME Clinicians Council member Dr Jesper Mehlsen, there is now unified support in the Danish parliament for separating ME G93.3 from Functional Disorders and acknowledgment that the existing treatment of ME patients is inadequate and stigmatising. Specialist services are needed and the Department of Health needs to update its guidance regarding ME. Voting on the adoption of this proposal took place on Thursday 14th March. The Danish parliament voted unanimously for the separation of ME WHO ICD-10 G93.3 from Functional Disorders and called for the Department of Health documentation to be amended to reflect this. This discussion in the Danish parliament on classifying ME as a somatic and not as a functional disease is good progress. It was based on the case of a 29-year-old woman who has been lying in bed in a dark room since 2015, being taken care of by her parents without any help from the Danish healthcare system. Both the Danish ME organisation and Dr Mehlsen had been in contact with a number of politicians on both sides of the aisle and the results are positive. The Danish parliament voted unanimously in favour of ME as a somatic disease to be removed from the centres of functional diseases. That will be a great relief for the family concerned, for physicians, and for the Danish ME community. The result should help Finland too, as a team at Duodecim (Finland's largest scientific association) has been formed to look at Finnish guidelines and there was a proposal to adopt the previous Danish position. That cannot happen now and the Finnish authorities must change course accordingly. Invest in ME Research (Charity Nr. 1153730) investinme.org Page 14 of 52 In fact, the Finnish be improved for patien Duodecim will ne recent Swedish r says there is not to formulate adeq guidelines/propo One of the statem Swedish working guidelines was the f " Considering the situation as regard it is crucial that the interventions off patient diagnosed w ME/CFS or similar must be individu for the patient in q and evaluated. This patient grou need of care measures alleviate sympto improve quality o For the individual p different evidenc interventions can offered on the basis the symptoms presented in the patient in questio example, measur pain or sleep disturbances. The care provider mu be perceptive and take all aspects o the patient’s medical problem and healthcare needs into account." Journal of IiMER Volume 13 Issue 1 Invest in ME Research UK - Parliamentary Debate In UK a parliamentary debate in the main chamber held on 24th January 2019. The person responsible for getting all of this started, a supporter of IiMER, was a constituent of SNP MP Carol Monaghan who put forward the debate. This followed on from a previous parliamentary debate held in June 2018 on the PACE Trial. The debate was entitled - “That this House calls on the Government to provide increased funding for biomedical research into the diagnosis and treatment of ME, supports the suspension of Graded Exercise Therapy and Cognitive Behaviour Therapy as means of treatment, supports updated training of GPs and medical professionals to ensure they are equipped with clear guidance on diagnosis of ME and appropriate management advice to reflect international consensus on best practice, and is concerned about the current trends of subjecting ME families to unjustified child protection procedures.” IiMER made a document - The Debate is Over – Give ME Patients a Future - covering some of the issues relating to the parliamentary debate on 24th January 2019. This is available on our web site. In this summary the charity called for the following A Public Inquiry into ME  Implementation of revised CMO Report Recommendations  Removal of Existing NICE Guidelines for ME immediately  An annual Report to Parliament of the Status of ME  Transparency of Meetings Concerning ME by MRC  Removal of Those Previously Responsible for ME from positions of Influence  Research Funding - A five-year, ring-fenced budget of £20 million per year for biomedical research into ME should be allocated  Guidelines for diagnosis must be as accurate as possible and must be up to date  The CMOs of UK Must Report Annually on Prevalence of ME in UK  Patients Diagnosed with ME Need a Regular Follow-up Pathway Invest in ME Research (Charity Nr. 1153730) In 2018, IiMER carried out an extensive correspondence with the then director of NICE guidelines Professor Mark Baker. We made the case for removing both Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET) as recommendations from the existing NICE guidelines immediately - whilst a new review was underway. This obvious necessity to remove recommendations which harm patients, something IiMER has called for consistently and which most now agree with, was met with disingenuous arguments from NICE as to why they would not be removed. The NICE review of guidelines for ME has now produced a guidelines working group. This has already been criticised by many for creating a “balance” between those who have a disposition to a Biopsychosocial view of ME, and those who believe ME to be a biomedical condition. The shambles of development group selection process reached farcical proportions during the setting up the group, with piecemeal announcements being made as to who had been selected for the development group and who had not, and background lobbying being conducted to get special places for certain individuals in this working group. The lack of transparency in the selection process was typified by the situation whereby some people who had applied to the working group and had been rejected could nevertheless conveniently be found a position connected to the working group. It demonstrates that the whole selection process is flawed. NICE has politicised this whole process where there was no need and really cannot be trusted. There are obvious conflicts of interest still left in place in this investinme.org Page 15 of 52  NICE Must Follow Department of Health View of ME  A specialism consultant needs to be established for ME  Medical curricula need to be revised education needs to extend to social care  Schools need to be educated about ME There are some clear signals for what needs to be done – as always we look for actions to replace words.

Journal of IiMER Volume 13 Issue 1 Invest in ME Research group where positions seem to be able to be negotiated. A “balance” was created where no “balance” was necessary. The Centre for Guidelines (CfG) develops guidance based on - • the promotion of good health • the prevention of ill health • the appropriate treatment and care for people with specific diseases and conditions • social care and service delivery We contend that retaining the existing guidelines – especially the recommendations for CBT and GET that are known to harm patients – is not promotion of good health. We also contend that retaining these recommendations is not preventing ill health. We provided a letter to Professor Baker from an ME patient who was a civil servant and who clearly described the harm done by CBT and GET. Professor Baker’s response was that the existing guidelines had “nuances” (nuances only perceived by Professor Baker it would seem) that apparently meant that patients did not have to accept CBT or GET. The fact is that insurance companies force people to go through these shambolic treatments precisely because they are recommendations by NICE. NICE seem to think that it would be possible for patients suffering from ME to have the capacity (either physically or financially) to fight the might of insurance companies. The level of puerile thinking on the part of NICE is unconscionable. The opportunity to withdraw these irresponsible recommendations from the existing guidelines has been lost and we are left with a shambolic working group selection process that augurs badly for the future. NICE could have removed the politics from this topic if it had approached the whole review with transparency. Now we are left with a compromised working group full of self-interest and conflicts of interest and we can only foresee another wasted opportunity and a fudges being formed for publication in 2020 that will serve nobody. At least NICE must accept all responsibility for any harm caused to patients who are forced into trying CBT and/or GET due to NICE retaining the existing recommendations for CBT and GET. Hopefully, other developments that may come to fruition over the next year will leave these farcical NICE tactics as a redundant relic from the past. One wonders what NICE can really imagine will be available for their review. The IOM carried out an extensive literature review in their 2015 report. Recently the Swedish authorities have examined ME. Their report follows – and it is doubtful that in one year NICE will deliver anything original – unless they remove CBT and GET completely, as many other countries have done or are doing. What NICE could have done is review the recent analysis by Sweden and their National Board of Health and Welfare. Sweden From Article number 2018-12-48 1(2) A review of the current knowledge status for Myalgic encephalomyelitis/chronic fatigue syndrome, ME/CFS Summary Socialstyrelsen (National Board of Health and Welfare) has been tasked by the Government to review the knowledge status and examine the prerequisites for providing support to healthcare professionals through guidelines and insurance medicine decision support (FMB) with regard to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Patients with ME/CFS have autonomous, cognitive and immunological symptoms. Typical symptoms are tiredness or fatigue, influenza-like symptoms with a feeling of fever, general pain in joints and Invest in ME Research (Charity Nr. 1153730) investinme.org Page 16 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research muscles, and disturbed sleep. The symptoms can be exacerbated by physical or mental exertion and the worsened state continues for more than 24 hours afterwards (post-exertional malaise, PEM). Descriptions of this disorder have existed since the 1950s. There are many hypotheses about what causes ME/CFS but up to now it has not been possible to prove any of them. Research is being done but currently there are no biomarkers for diagnostics, nor any medical treatment. The prevalence of ME/CFS depends on what criteria have been used and how data have been gathered. The figure varies from 0.1 percent to 6.4 percent of the population. When it comes to opinions regarding the cause of ME/CFS and its treatment, there are different standpoints: those who support a bio-medicinal view and those who support a biopsychosocial view. The question is whether the disorder should be explained purely through pathological biochemical and physiological findings, or whether mental and social factors must also be included in order to be able to explain certain medical problems. ME/CFS is an exclusion diagnosis. There are no biomarkers. Instead, the diagnosis is made with the help of diagnosis criteria that are only used when other physical or mental causes of the symptoms have been excluded. There are several different diagnosis criteria that overlap one another in part and there is no international consensus about them. There are also different standpoints regarding what illnesses/disorders are to be excluded before the diagnosis is made, and what comorbidity may exist. Patient representatives have pointed out the need for equal healthcare, guidelines and specialist care for this group. Patients’ experiences of healthcare vary both at individual level and according to geographical location in Sweden. Patients have also pointed out the need for more understanding treatment by healthcare professionals and for coordinated interventions. An overview of qualitative studies from SBU (Swedish Agency for Health Technology Assessment and Assessment of Social Services) regarding how adult patients diagnosed with ME/CFS perceive the care they are given shows that diagnosis, advice and support are essential. The patients have described the journey to a diagnosis as being cumbersome and that they have had to fight in order to get help. They feel that people are not interested in their problems and that healthcare professionals at primary care level do not believe the illness exists. Socialstyrelsen’s dialogue with the healthcare professional groups in question has shown that Invest in ME Research (Charity Nr. 1153730) there is a certain demand for national guidelines and insurance medicine decision support. However, specialists in general medicine seldom meet patients with ME/CFS, and no specific specialist field feels they have special responsibility for this patient group. This shows that these patients do not have any proper “home” in the healthcare system. The systematic overview conducted by SBU indicates that the scientific sup-porting documentation for the interventions offered in the relevant studies is insufficient. In addition, Socialstyrelsen’s survey shows that it is not possible to draw conclusions about the benefit of those interventions on the basis of proven experience since the prerequisites for consensus among clinical experts in this field are lacking. Therefore, Socialstyrelsen’s assessment is that it is currently not possible to draw up national guidelines with general advice in this area, as requested by the healthcare sector. Moreover, the basic preconditions for further work on insurance medicine decision support (FMB) for the diagnosis of ME/CFS do not exist. Socialstyrelsen emphasises that being on sick leave can be a correct intervention but no general recommendations can be given. Considering the current situation as regards evidence, it is crucial that the interventions offered to each patient diagnosed with ME/CFS or similar symptoms must be individually adapted for the patient in question and evaluated. This patient group is in need of care measures to alleviate symptoms and improve quality of life. For the individual patient, different evidence-based interventions can be offered on the basis of the symptoms presented in the patient in question, for example, measures for pain or sleep disturbances. The care provider must be perceptive and take all aspects of the patient’s medical problems and healthcare needs into account. The systematic overview and the qualitative report from SBU and this review by Socialstyrelsen can provide the healthcare sector with an up-to-date picture of the knowledge status, and indicate the need for more interventions and research for this patient group. Socialstyrelsen’s intention is to facilitate a dialogue between representatives for different professions in order to increase consensus in the long term. Here is the English version of the summary https://www.socialstyrelsen.se/Lists/Artik elkatalog/Attachments/21182/2018-12-48summary.pdf investinme.org Page 17 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Myalgic encephalomyelitis and Chronic Fatigue Syndrome (ME/CFS) - A systematic review sbu policy support december 2018 | www.sbu.se/295e Summary Aim The aim of this report was to investigate the available body of evidence for the treatment and prognosis of ME/CFS as well as a review of the health care experiences of patients. Background Myalgic encephalomyelitis, also called Chronic Fatigue syndrome (ME/CFS), was first described 70 years ago. The disorder often is preceded by an infection but the pathology and mechanisms behind ME/CFS are still unknown. People with ME/CFS can suffer from a broad spectrum of symptoms, e.g. prolonged fatigue, pain and post-exertional malaise (PEM). Individuals with ME/CFS have decreased activity levels and can have difficulty handling their everyday day duties, work, or studies and maintaining social relationships. For some, the symptoms can be so severe that they are home-or bedbound. There are no biomarkers for ME/CFS that can be used for diagnosis. The criteria for diagnosis have therefore developed over the years and are consensus-based sets of core symptoms. All the criteria include newly-onset severe and persistent fatigue and stipulate that core symptoms must have persisted for at least 6 months. The newer Canadian Consensus Criteria differs from previous criteria in that PEM lasting at least 24 hours after physical or mental exertion is required for a diagnosis. By applying the Canadian Consensus Criteria, the prevalence of ME/CFS is estimated to be about 0,1% of the population. Differentiating between ME/CFS and other diseases with long lasting fatigue, e.g. stress related exhaustion disorder, can be difficult. Studies show that half of patients referred to specialist clinics for suspicion of ME/ CFS were shown to have other diseases after closer examination, mostly sleep or psychiatric disorders. There is no curative treatment for ME/CFS. Health care therefore aims at relieving symptoms and supporting the patients in the management of their everyday lives. Content of the report This report is made up of four systematic reviews, conducted according to international guidelines. The first systematic review focuses on treatments and their effects on fatigue and PEM for persons with ME/CFS diagnosed with the Canadian Consensus Criteria. Treatments that aimed at relieving other symptoms, e.g. sleep problems or pain, or psychological therapies aimed at helping patients manage their disease were not included. Included studies were controlled clinical trials, with or without randomisation. The second systematic review assesses prognosis for recovery and return to work, while the third investigates whether there are any prognostic factors for improvement and return to work. In the fourth systematic review, we explore how patients experience their health care by reviewing studies that used qualitative methods, such as interviews, to address this question. The report only includes studies on adults. Main results A major finding was that the effects of treatments for patients diagnosed with the Canadian Consensus Criteria on fatigue or PEM cannot be estimated. Most studies used older criteria, mainly the Fukuda criteria, meaning there is a risk that the participants in the studies had other conditions, such as stress related exhaustion disorder or depression. Whether these results are valid for persons diagnosed according to the Canadian Consensus Criteria is therefore unclear. A small number of studies, most investigating pharmaceutical treatments, used the Canadian Consensus Criteria. None of these studies reported that the drug reduced fatigue. The prognostic studies identified applied older criteria. Two studies conducted in Scandinavian countries reported that a substantial proportion of the participants had not recovered at follow-up, around 10 years after symptom onset. One English and one Norwegian study found that many patients who had been diagnosed in specialist clinics after several years of disease and unemployment, had not yet returned to work or study at follow-ups conducted many years later. Prognostic factors for recovery or return to work could not be evaluated Invest in ME Research (Charity Nr. 1153730) investinme.org Page 18 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research as there were few studies, which were small and had substantial methodological limitations. The qualitative studies mostly described patient experiences in primary care. Many perceived that getting a diagnosis was a milestone and that individually tailored support was crucial for them to move on with their lives. They experienced the process of obtaining a diagnosis as burdensome and frustrating and felt that they were met with ignorance and lack of understanding. Discussion This report shows that there are many scientific evidence gaps regarding ME/CFS. Many gaps, such as methods for diagnosis and efficacy of curative or disease modifying treatments, are related to the lack of understanding of the aetiology behind ME/CFS. This report also indicates that a thorough diagnostic work-up is crucial. Multidisciplinary specialist competences are necessary to reliably exclude other disorders. Finally, the absence of evidence for effect of ME/CFS treatments does not mean that the treatments lack effect, but rather indicates that Project group Experts Per Julin, MD, PhD, Karolinska Institutet, Stockholm, and the ME/CFS-clinic, Stora Sköndal Per Lytsy, MD, Assistant Professor, SBU Marie Åsberg, Professor, Karolinska Institutet and Danderyd Hospital, Stockholm (advisory role in assessing differential diagnoses) SBU Agneta Pettersson (Project Manager) Susanne Gustafsson (Information Specialist) Caroline Jungner (Project Administrator) Lina Leander (Assistant Project Manager) Hanna Olofsson (Information Specialist) Scientific reviewers Kristina Bengtsson Boström, Skaraborg Kristina Glise, Göteborg Björn Mårtensson, Stockholm Anne Söderlund, Västerås SBU Assessments no 295e, 2019 www.sbu.se/en • registrator@sbu.se English Proofreading: Rebecca Silverstein, SBU Graphic Design: Åsa Isaksson, SBU Invest in ME Research (Charity Nr. 1153730) investinme.org Page 19 of 52 research is needed to clarify the effects of current treatments for people diagnosed with ME/CFS according to the Canadian Consensus Criteria. Meanwhile, it is important to support people with ME/CFS so they can attain the best quality of life, levels of function and participation in society as is possible. Since ME/CFS is relatively uncommon compared to other similar disorders, e.g. stress related exhaustion disorder or chronic pain, specialist clinics for ME/CFS would probably be advantageous, as they would be most likely to be able to closely follow the research and quickly implement new developments into clinical practice. Small charity BIG Cause With no major investment into correct research into myalgic encephalomyelitis during the last decades Invest in ME Research has, with a determined band of supporters, taken action for change in the absence of any coherent or scientific establishment policies. Funding has to be given to biomedical research and new knowledge from other disciplines such as virology, immunology, endocrinology etc. has to be brought in to help research into ME. Invest in ME Research has initiated and funded high-quality biomedical research at UEA and Quadram Institute Biosciences and at UCL - and facilitated development of international collaboration with other research institutes. Vision with action can change the world

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Perceptions of Care in a Hospital’s Emergency Department Division of Rheumatology, Immunology and Allergy, Georgetown University, Washington, DC, USA *Both authors contributed equally to this work A very useful recent paper published by Timbol and Baraniuk discusses Emergency Department visits by ME/CFS patients. "CFS patients present to the ED with a complex list of chronic symptoms, but the acute reasons for presentation are related to orthostatic intolerance, fatigue, PEM, and diarrhea." Professor James Baraniuk - Professor of Medicine at Georgetown University Medical Centre, Washington, USA - is a regular at IiMER colloquiums and conferences and always has very interesting and useful contributions. "This is of importance because it provides a starting point for diagnosis and treatment by ED physicians," Baraniuk said. "This condition is something that can be readily addressed by ED caregivers," he said. "There is a real need for physician education that will improve their efficiency in identifying and treating CFS, and in distinguishing CFS symptoms from other diseases in the exam room." "These patients should feel they are respected and that they can receive thorough care when they feel sick enough to go to an ED," Baraniuk said in a Georgetown news release." Here is the abstract. Chronic fatigue syndrome in the emergency department Available from DovePress https://www.dovepress.com/chronic-fatiguesyndrome-in-the-emergency-department-peerreviewed-fulltext-article-OAEM Christian R Timbol,* James N Baraniuk* Invest in ME Research (Charity Nr. 1153730) Purpose: Chronic fatigue syndrome (CFS) is a debilitating disease characterized by fatigue, postexertional malaise, cognitive dysfunction, sleep disturbances, and widespread pain. A pilot, online survey was used to determine the common presentations of CFS patients in the emergency department (ED) and attitudes about their encounters. Methods: The anonymous survey was created to score the severity of core CFS symptoms, reasons for going to the ED, and Likert scales to grade attitudes and impressions of care. Open text fields were qualitatively categorized to determine common themes about encounters. Results: Fifty-nine percent of respondents with physician-diagnosed CFS (total n=282) had gone to an ED. One-third of ED presentations were consistent with orthostatic intolerance; 42% of participants were dismissed as having psychosomatic complaints. ED staff were not knowledgeable about CFS. Encounters were unfavorable (3.6 on 10-point scale). The remaining 41% of subjects did not go to ED, stating nothing could be done or they would not be taken seriously. CFS subjects can be identified by a CFS questionnaire and the prolonged presence (>6 months) of unremitting fatigue, cognitive, sleep, and postexertional malaise problems. Conclusion: This is the first investigation of the presentation of CFS in the ED and indicates the importance of orthostatic intolerance as the most frequent acute cause for a visit. The self-report CFS questionnaire may be useful as a screening instrument in the ED. Education of ED staff about modern concepts of CFS is necessary to improve patient and staff satisfaction. Guidance is provided for the diagnosis and treatment of CFS in these challenging encounters. investinme.org Page 20 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Medical Education Education about ME has been one of the major objectives for Invest in ME Research. Dr Nina Muirhead and students at Cardiff University have been working on medical education. Invest in ME Research invited them to present poster presentations at the IIMEC14 conference in London. The studies demonstrate the following – 1) What is the Impact on Quality of Life of Family members with ME/CFS using the internationally validated QHOQUOL-BREF and FROM-16? Needless to say results show the negative impact of ME/CFS on family members is greater than any other medical condition. 2) What should medical students be taught about ME/CFS? This explores current teaching in 22 medical schools UK wide and uses qualitative information from patient surveys to make recommendations for not only what should be taught but how and when this could be delivered in the undergraduate medical school syllabus. 3) What is the role of the GP in care of ME/CFS patients in the community? This study draws together patient opinions in the form of 690 patient survey responses plus detailed ideas from qualitative analysis of telephone interviews of patients with a range of illness severity and duration. The patient voice is increasingly used in guideline development. We include here the abstracts for these presentations. The Impact of ME/CFS on the Family: Measuring Quality of Life (QoL) using the WHOQOL-BREF and FROM-16 Questionnaires Brittain EL, Muirhead NL, Finlay AY and Vyas J. ABSTRACT Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic condition Invest in ME Research (Charity Nr. 1153730) investinme.org Page 21 of 52 characterised by a multitude of symptoms, ranging from post-exertional malaise to cognitive difficulties. ME/CFS has been shown to significantly reduce patients’ quality of life (QoL) when compared to both healthy controls and patients with other chronic illnesses. To our knowledge, our study is the first to explore the impact of ME/CFS on QoL of both adult sufferers and their family members using the validated questionnaires: World Health Organisation Quality of Life - Abbreviated Version (WHOQOLBREF) and Family Reported Outcome Measure (FROM-16). The study information was posted on the website and social media pages of the charity WAMES (Welsh Association of ME & CFS Support). A total of 39 volunteers expressed an interest in participating in the study and were posted a questionnaire pack containing one WHOQOL-BREF and four FROM-16 questionnaires. People with ME/CFS completed the WHOQOL-BREF and up to four of their family members completed the FROM16 questionnaire. 29 participants returned the questionnaire packs (74% response rate), of which 5 were excluded due to incomplete data or not meeting the inclusion criteria. There was a negative effect on quality of life for both people with ME/CFS and their family members. People with ME/CFS, on average, scored substantially lower in the ‘Physical Health’ domain of the WHOQOL-BREF and scored highest in the ‘Environment’ domain. Conversely, the higher the FROM-16 score, the greater the adverse QoL impact on family members. FROM-16 total scores showed that the impact on QoL was very high (mean=19.86 SD=7.17 n=42) compared to previous studies of family members of patients with other diseases (mean=12.28, SD=7.47, n=120) and cancer (mean=11.75 SD=5.85 n=248). For people with ME/CFS: there was a strong correlation between health satisfaction and their perception of their QoL (rs=0.50, p=0.013) and none were ‘satisfied’ with their health nor rated their QoL as ‘good’. A significant correlation was found between the QoL of people with ME/CFS and their family members’ mean FROM-16 total score (rs=-0.41, p=0.047, n=24). This study has for the first time used FROM-16 to measure the impact of ME/CFS on the QoL of adults and their family members and highlights the need for additional larger-scale research into this area. The results of this study emphasise the importance of ensuring support is widely available to the family.

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Understanding the Role of the General Practitioner in Caring for Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the Community Allwright EG, Muirhead NL Background Patients with ME/CFS are reliant on their GP for a diagnosis and early management but also holistic support, particularly where secondary services are limited. There has been increasing recognition of the importance of the patient voice. This study aimed to gain a better understanding of the patient perspective of GP care of ME/CFS with a view to identifying ways of improving the patient experience. Methods Information was gathered from: 1) an online question answered by 690 members of the ME Association 2) 47 written responses to this question 3) ten semi-structured interviews with patients with a diagnosis of ME/CFS. Qualitative, thematic analysis of both the written feedback and interview transcripts was used to identify themes. Results The online question demonstrated that patients prioritised the importance of GPs having an understanding of the symptoms of ME/CFS in order to make a diagnosis. Five themes were identified from the online free text responses and nine themes from the interviews. These covered the role of a GP in diagnosing and managing ME/CFS; the patients’ perception of their GP’s knowledge of ME/CFS; the broader role of the GP with links to social care and support to claim Disability Allowances; and patients’ reports of the relationship between patient and GP. The data also supported the concept of having a designated healthcare practitioner, be it a GP, therapist or practice nurse, who could offer consistent care and support. Conclusion Participants believed that their GPs did not have sufficient resources or knowledge to best manage ME/CFS however this was deemed less important to patients than a willingness to listen and sympathise with the patient, to understand their individual experience and work in collaboration with them towards recovery. Overall, participants emphasised the perception that a supportive GP, who is honest and open with patients, can make a significant Invest in ME Research (Charity Nr. 1153730) impact, regardless of their ability to cure the patient; “you hope you have a supportive GP because he will help you, even if he can’t treat you, he will help you”. What Should be Taught to Medical Students about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Lavery GE and Muirhead NL Introduction: The lack of understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) amongst health care professionals has been shown to cause delayed diagnosis, misdiagnosis and harm to people with ME/CFS (PWME). There is a paucity of data surrounding teaching on ME/CFS in UK medical schools. A small study undertaken in 2012 demonstrated that UK medical students 'were unconfident and uncertain around their understanding of CFS/ME, held varying models of aetiology of the illness and had limited knowledge of the symptoms and suitable management strategies’. A larger study conducted in the USA showed that only 28 percent of medical schools met the curricula criterion for ME/CFS teaching. Methods: 1) A quantitative analysis examining current teaching on ME/CFS at UK medical schools was performed. All 34 undergraduate medical schools in the UK were invited to complete an online survey through the website 'SurveyMonkey’, 22 medical schools (65%) completed the survey by the deadline. 2) A qualitative analysis exploring PWME’s perceptions of important topics to teach medical students was subsequently performed. PWME were invited to respond to a post on the Welsh Association of ME & CFS patient charity website (WAMES), entitled “What should medical students learn about ME?”. Thematic analysis applied both manually and using NVIVO 11 software identified key themes. Results: 1) Medical schools were able to skip questions if the answer was unknown. Data from the survey showed that 11 of 19 medical schools include formal teaching on ME/CFS in their curricula, the majority of whom deliver this teaching in lecture format. Only 3 of 12 medical schools spend more than two hours teaching on the topic and 2 of 10 include clinical contact with PWME. Only 5 of 19 include question(s) on ME/CFS in formal exams. Most investinme.org Page 22 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research medical schools expressed an interest in receiving videos, e-learning and lecture materials on ME/CFS. 2) Thematic analysis of 38 written responses from PWME identified three key themes that PWME believe medical students should be taught about: i) the definition and diagnosis of ME/CFS; ii) treatment options; and iii) the ways in which ME/CFS affects quality of life (QoL). Conclusion: The creation of e-learning or a short video to introduce ME/CFS followed by lectures or a teambased learning approach are suggested to improve teaching of medical students on the topic of ME/CFS. It was also concluded that a comprehensive basis for medical student ME/CFS teaching relies on a curriculum that encompasses accurate up to date information on the epidemiology, terminology, aetiology, treatment and effect on QoL of ME/CFS. presented with evidence of the damage caused, is negligent. There are also doctors who clearly remain ideologically challenged by this disease and continue to harbour false views about ME, fed by a Biopsychosocial (BPS) influenced healthcare system. Above all doctors seem to have lost any ability to say, "I don't know what is wrong" - as though this may be a shortcoming. So much easier to assign a diagnosis of the spurious Functional Neurological Disorder (FND). If only doctors would say, "I don't know what is wrong but will work with you to find answers". If only patients were believed. Much of this can be traced back to negligent policies from governments, health departments, research councils and clinical care organisations, and research funding bias that discourages biomedical research into ME. Doctors and Patients Many ME patients, at least those who are still being treated by a doctor, often comment on how doctors do not understand the disease. This itself compromises the future prospects for a patient to receive anything approaching adequate care. The reasons for this may be that doctors receive no training on ME - either during medical school due to flawed and sparse contingency in the medical curriculum for ME - or later during their career where there is little on offer. Invest in ME Research has, since 2006, been arranging CPD-accredited conferences for professionals in London and the participation of doctors has been gradually increasing. Yet there remains a great deal to do. Medical education about the realities of ME is essentially missing - with what is on offer being either inadequate or incompatible with the true requirement to understand this disease and be aware of what can make patients worse. Doctors also may be constrained by NICE guidelines in what they feel they are able to offer. NICE guidelines are currently being reviewed yet the farcical set up of the guidelines development group augurs badly for any positive outcome. NICE’s refusal to remove CBT and GET immediately from the existing guidelines, despite being Invest in ME Research (Charity Nr. 1153730) Despite this, there have been signs of light coming through as more education and more research, funded by organisations like Invest in ME Research, changes the barren landscape that has existed in the UK healthcare system. And there are doctors who think for themselves and listen to their patients. And there are pioneers in treating people with ME. Two such doctors were Dr John Richardson and Dr Irving Spurr. Dr John Richardson had a distinguished career as a physician and published numerous papers. He was a founder member of the Newcastle Research Group in which he was very active and the primary organiser of their annual international conferences. He was also a member of the Melvin Ramsey society and the Environmental Medicine Association as well as other medical research organisations. Following his retirement from the NHS, he continued to see patients privately on a voluntary basis regularly seeing in excess of thirty per day. Many travelled considerable distances from the UK investinme.org Page 23 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research and abroad for his specialist advice and treatment and frequently were referred by hospitals and their own doctors. Dr Irving Spurr was a GP in the rural Weardale Practice in County Durham for 28 years until his retirement in 1997. Listen to the patients Stories of ME Over the years Invest in ME Research has received many stories of people enduring ME, and who have experienced the lack of knowledge about the disease, the ignorance. Some long stories, some short. He was committed to doing his very best for his patients and this led him to become a pioneering researcher into ME. During the early Eighties, a boy of 14 came to see him with all the symptoms. Irving wanted to get to the bottom of what was causing it, but ME was, at the time, belittled in NHS circles as not a ‘real’ condition (some would say little has changed). He became heavily involved in the fledgling John Richardson Research Group, a medical charity in the north-east of England, ultimately leading its work to promote greater understanding and awareness, as well as more effective treatment. His commitment included running ME clinics, with his nurse wife Eileen at his side, but it was extended to delivering lectures all around the country and building links with colleagues in Norway, Canada and Israel. He continued with the clinics until the onset of the ill-health that preceded his peaceful death. In recent years his view on ME — once a lonely one — increasingly become more accepted and mainstream, to the benefit of many sufferers from this disease. Yet he never let his crusade for ME cause him to short-change his other patients. The John Richardson Research Group made a wonderful donation to Invest in ME Research to continue to establish a national and international centre for ME and translational medicine in this area. All underlying the incomprehensibility of retaining the status quo in terms of research, treatments and services – that has suited some organisations, and individuals and benefited those taking salaries or maintaining careers based on this state of affairs. So it is always surprising that the old adage “listen to the patients” is something often ignored. We pointed this out in Listen to the Patients http://www.investinme.org/IiMER-Newslet-180901.shtml where it seems to go wrong, even in a country which has everything required for providing an example of how to perform research into ME, how to develop services for people with ME and how to treat ME as the organic illness that it is. It is sobering to read some of the stories from patients, and carers – even just clips. We alluded to some in them in the Advent Calendar Day 14 article Humour and ME article But definitely not with any humour is the story of the family of Rose - "The consultant said that the some of the symptoms Rose had were not due to ME (i.e. memory loss and paralysis) and that her ME could be a cloak for PRS (Pervasive Refusal Syndrome)." from ‘An ME Carer’s View’ http://www.investinme.org/mestory1019.shtml Invest in ME Research (Charity Nr. 1153730) investinme.org Page 24 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Here we have some, just a few of the many stories written or told or emailed over the years – Some examples – Dr D. "I saw 2 GP's in the summer holidays. They were cold to the point of hostile when I had the temerity to suggest that I had ME/CFS." Sandra "I was interviewed by this supervisor every Monday and every Friday from then on. I felt like I was a criminal. She took me into a small office and every time asked how I was doing and how long would it be before I worked full time again because I was straining the section as they had to cover for my absence" Jim "And because of my test results, they no longer tell me my illness is in my head, they just won't accept ME as the cause.” C "I hope it demonstrates how utterly distressing it is for sufferers to not only cope with their ever deteriorating health, but to cope with supposedly professional people who use every opportunity to psychologically batter them into submission. " R ""you have ME, I am not going to waste time doing tests on you" " Julie " I felt humiliated and ridiculed by someone who was clearly a psychiatrist of some description " Cindy “Being in the medical profession I am angered and embarrassed by the way I'm treated with this illness." Shelley " I went to a Manchester hospital. That’s when my nightmare began. I felt really ill at that time and a sister said it was all in my mind. " There are longer stories too - see Further Reading below. The stories above reflect decades of suffering and are a call for doctors and healthcare staff to believe in patients. Healthcare staff need to remember -nobody really wants to live like this. Rose "So Rose had to do a 6 week diagnostic test for PRS with two 6-second sessions of physio, adding on 10% each week and starting with 10 minutes high activities. This included education, art therapy and visitors. Even if Rose was unconscious from blacking out then someone had to read to her and the curtains had to remain open - 10% each week." Invest in ME Research (Charity Nr. 1153730) investinme.org Page 25 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research One Stupid D ٜt Stacy Hart aka @MamaChill hip hop/rap artist, diagnosed with M.E. in 1991. Stacy still has M.E., 24 years after being diagnosed. Invest in ME Research (Charity Nr. 1153730) investinme.org Page 26 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Long term illness with ME Having ME for decades brings with it many different issues. Apart from obvious direct effects of the illness on one's life, with the impact on family, on career, on financial situation - there are the more insidious and rarely mentioned issues - loneliness, isolation from society, further health issues with new symptoms and possible co-morbidities developing, invisible to healthcare systems due to the label of ME. Care and compassion may also be casualties of health systems that are influenced by commercial or career interests and have no funding and no time for patients suffering from long term ME. People who currently have had an ME diagnosis for several decades will know of all of these issues. If a patient is "lucky" enough to receive attention then they are quite likely to be at the end of a long queue. Healthcare systems that cannot understand the disease, let alone treat it, will have no capacity for managing the longer term consequences. For those recently diagnosed with ME the thought of the situation getting worse, or being long-term, is something that does not initially come to mind. Long term illness from ME is something that is not discussed much - although one can often hear of stories of those who have to endure this disease for decades. Even with their disease these long-term sufferers will have hoped for recovery, for research that brought forth treatments. Many might also have become advocates and contributed what energy they had to changing things for the better, to raise hope that things would be different. It is testimony to the courage and resilience of those long-term ill that they continue to hope, to campaign, to trust for a better life. It is a sad and continuing indictment on successive governments and health departments and, especially, on research councils and their appointed guardians of research into ME that they have failed these people. We invited Dr David Bell (Lyndonville NY, USA) to speak about his longitudinal study at our IIMEC6 conference in 2011. Dr Bell presented his work on the 25-year follow-up of the young people from the initial illness that triggered his research. He described this initial outbreak in 1985 in a small rural community just south of Toronto. 210 people remained ill following a flu-like illness. Many more had the illness, but had recovered by 6 months. Those remaining ill were finally diagnosed as suffering from ME/CFS. 60 were children and adolescents. The 13 year follow-up was written up in the Journal of Paediatrics. 80% described themselves as doing well. Half of these still had symptoms but leading a reasonably normal life, the other half seemed OK. 20% had ongoing illness and were "disabled". The book Lost Voices from a Hidden illness eloquently brought out some issues regarding longterm illness. Those patients who have had ME for several decades were young at the beginning, had dreams and ambitions, aspired to do more. Invest in ME Research (Charity Nr. 1153730) He then asked, "How should recovery be defined?" - "Is it absence of symptoms or adaptation?" If the answer is adaptation, this leads to confusion and a false perception of health. Factors included here would be: patient looks OK, tests are normal, specialists come up with no diagnosis and there is a lack of evolution into an illness such as MS. This confusion is damaging for adolescents. The current study included a follow up of 28 people, and a wide range of assessment tools was used. 3 had developed malignancies (thyroid cancer, cervical cancer and leukaemia) and were excluded. investinme.org Page 27 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research The remainder (25) were represented by 3 groups. 2/25 (8%) were well. 18/25 (72%) had remitting illness - they considered themselves all right, but scores indicated they were not well. The third group - 5/25 (20%) had persistent ME/CFS. They considered themselves disabled with severe symptoms and reduced activity. These people were on disability pensions, but ME/CFS was not used as the diagnosis to be eligible, and the illness was often called other names to ensure the benefit. Dr Bell pointed out how people do learn to adapt to this illness. Many seem to recover but then slide down again. The worst symptoms seem to be associated with sleep and pain. He described his disability scale from 0-100 with 100 being entirely well. Many of these patients scored around 30. He felt one of the most important questions for the clinician to ask was the number of hours of upright activity attainable each day. In his current study, controls scored 15 hours, the persisting severe group 1-5 hours and the remitting group 13 hours. In summary, Dr Bell concluded that at follow up 72% had mild to moderate illness, although considered themselves OK. There was health identity confusion, by remembering self being much worse, and now considering self "well". Time will tell the long-term outcome. He felt strongly that he was looking at the natural history and course of the illness rather than any medication or vitamins promoting recovery. The long-term ME patients constitute an area which is almost totally neglected - something that should be of major concern to healthcare providers, along with the severely ill and children with ME. The long-term ill from ME are not only those in old age either. Younger people are included in this group if they were diagnosed with ME in their early teens. Yet it is ignored, buried in the soundbites of the media who remain oblivious to the reality of ME; callously removed from the policies of research councils and government health departments due to apathy; unable to be researched properly due to the lack of funding from those agencies responsible for funding; and often let down by support organisations who take subscriptions but do little to Invest in ME Research (Charity Nr. 1153730) investinme.org Page 28 of 52 convince anyone of this neglected section of society. We can only hope that we can soon get to a situation where all people with ME will get adequate treatment based on results from wellfunded biomedical research. This subject needs to be included in debates about ME in any parliament setting. It needs to be recognised and addressed in healthcare systems. The long term ME patient needs to be represented. In the meantime, we recognise the courage of those who have had to endure ME through many years with little or no support and yet who continue to remain hopeful and try as best they can to help to change things.

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Caring for someone with ME "She was gradually deteriorating. Every tiniest activity (physical, cognitive and sensory) from washing her hair to rubbish collection day, had devastating results. Sometimes she could recover in a few days, other times it would take months, but often the cumulative effects of the noisy, smelly, bright, sunny, loud, vibrational, fast, chemical based world we live in were all too much and disease progression with permanent damage resulted. Doctors always amaze me when they are puzzled by her severity and wonder why it's taking so long to 'pick up her bed and walk". - Lili It is difficult to convey fully the overwhelming effects of severe ME – on the patient or on carers. We can only allude to the horrendous course that ME can take, point out at how little has been done to address this particular issue of ME, and state what we, as a charity, are trying to do to change things. The odds are stacked against carers if the person(s) they are caring for suffer from ME. Carers have to stop their normal life to try to come to grips with the effects of this disease on themselves as well as the patient. Lack of understanding about the disease by the public – a great deal of which has been caused by misinformation from media centres and compromised media editors - can even affect relationships. If a carer/partner does not understand the illness or has been misinformed due to the media propaganda then subsequent strains on relationships can take its toll – thus further aggravating the situation for the patient. Apart from having to research oneself what this disease is, and what treatments there may be, a carer/parent may suddenly be met, not with compassion or understanding, but with the full force of social services intervening and suddenly becoming victim to the ignorance that pervades society. The other insidious effects of ME that the patient experiences – such as isolation – may also come into play for carers. Kjersti Krisner gave a moving testimony of issues with severe ME in her pre-conference dinner Invest in ME Research (Charity Nr. 1153730) presentation prior to the 11th International ME Conference in London in 2016. If one wished to see all that has been wrong with research policies toward ME by establishment organisations over the years then one would only need to see Kjersti's presentation Kjersti's family of three severely affected children was highlighted in Norwegian TV with the NRK channel Pulse program in 2009. Meridian TV aired a series of programmes in 20052006 covering the effects of ME on severely affected patients. A reporter from Meridian interviewed a number of ME sufferers in Hampshire as well as at the regional ME centre. This set of interviews conveyed the suffering and lack of action regarding ME. One of the most shocking and heart-breaking cases involved Sophia Mirza. The full force of establishment ignorance about ME came crushing down on one poor girl and her family. Had this story occurred today, with all of the effects of social media, then the story would have been a national scandal with resulting action being taken. Instead, Sophia's mother, Criona, had to continue to campaign for years to try to get justice. Invest in ME Research organised a conference call in 2013 with Dr Martin McShane, Director of Domain Two, NHS Commissioning Board, after a supporter contacted her constituency MP (which happened to be the Prime Minister at that time). In that meeting the parents of the very severely ill young person gave a presentation of their experiences since their child became severely ill at the age of 8 in 2000. The presentation was very powerful and was conveyed in a very professional manner despite the obvious anguish and distress that it caused the parents. - There was a cluster of 5 people who became ill at the same time in the small village in which they lived - Not one GP took it upon themselves to investigate - Life was a living hell as their child could not talk, could not swallow and was sensitive to light and noise - Severe ME causes panic in healthcare professionals who want quick fixes, and look around investinme.org Page 30 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research for some other causes in parents or patients (Munchausen’s by Proxy, Pervasive Refusal Syndrome and so on ) despite the CMO report recognising ME as an organic illness - Good doctors who kept children safe from the threat of child protection orders have now retired or passed away so the parents have nowhere to turn to for support - OTs were helpful but in their experience GPs had been terrible - Advice/information given by unhelpful GPs and consultants, paediatricians over the years included removal of parental support, physiotherapy, stating that ME is not a real disease, that it was an illness caused by exam nerves etc. - GP visits were unannounced, and the family was reported to social services for neglect and the family were then asked to leave the GP service - In 2012, after a fairly stable period, tooth surgery caused a severe relapse and the GP decided to resurrect the earlier accusations - The family had kept quiet for 12 years but felt now that enough was enough. They had sent complaints to PALS. The doctors had refused to comment. This representation was enough to convey what many in the UK had felt for a generation and for which little has, or is being done. Dr McShane commented that to change the quality of life with long-term conditions we have to accept what we do not know. IiMER felt this was not good enough. We explained how we had sat in countless meetings, with words said, promises made and nothing ever changes. It was unacceptable. Empathy was fine, and we were grateful for Dr McShane’s acknowledgement of the poor service given to ME patients and their families. However, we needed to progress – and we had ways, proposals which could be used to progress this. Invest in ME Research (Charity Nr. 1153730) IiMER pointed out the difficulties in getting anything done and we did not want to go away from yet another meeting with nothing, and no action plan. The local commissioner at the meeting had promised education of GPs. However, we all felt that there is a major problem in the lack of accountability. Nobody seems to want to take responsibility - and this extends from the local level right the way up the chain to the CMO and the Minister for Health. (IiMER mentioned that CMOs had been invited to every single one of the eight (at that point in time) IiMER annual conferences - without any sign of leading or an agenda for ME) IiMER suggested using this area (ME) as an example of a difficult area of medicine and use it as a model for nationwide services. Dr McShane promised to promote Dr Terry Mitchell’s approach (kind, caring, patient centred). Whilst we felt Dr McShane was genuinely empathetic to the plight of ME patients and their families we saw no appetite from any direction in the NHS to invoke change, to rectify the inadequacies in the NHS or to initiate any visionary approach to progressing ME. And so it proved to be. At the meeting our overriding feeling was that we would have to continue to make the changes necessary ourselves. And so it proved to be. “The carer of an M.E. loved one is like no other carer. Not only is it imperative to learn about myalgic encephalomyelitis in order to give the specialist care required for M.E. (to avoid causing them further harm), it is also necessary to become their protector” Dr Amolak Bansal spoke at the #IIMEC8 conference in 2103. After the conference Dr Bansal added the following especially for Invest in ME for a forthcoming news article (which subsequently was not used), explaining severe ME in the following way - “While it is presently very difficult for modern medicine to fully explain all severe ME symptoms, disordered neural function within the brain and spinal cord would come close. How this occurs is unknown but there are counterparts in certain newly described autoimmune conditions and viral infections of the nervous system. In addition to a direct stimulation of neurones in different parts of the brain and spinal cord there is investinme.org Page 31 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research also an impaired filtering function of the brain stem and a reduced threshold for neurones to fire off. This allows external stimuli such as movement, light, sounds, touch and sometimes even worrying thoughts to produce widespread neuronal activation with ultimate excitotoxic damage to these cells. The consequence is impaired activity of the brain generally but particularly the hypothalamus and prefrontal cortex leading to fatigue, disordered sleep, impaired memory, attention, faintness, palpitations, disordered respiration, temperature dysregulation etc. Outwardly, many patients appear well and routine blood and other investigations are normal. Internally there are severe symptoms that, if unchecked, escalate leading ultimately to immobility and increasing pain and spasms in a proportion of patients. Clearly a greater understanding of this highly disabling condition is required with a greater focus on disrupted immune and neural pathways and not just psychosocial factors as has previously been the case.” Sidsel Elisabeth Kreyberg carried out a small survey on Caring for seriously ill ME-patients that showed how important experience was in the work with ME. Severe ME patients have not often been included in research into the disease. This may be necessary on occasions, depending on the type of research or the logistics of accessing the patients in their delicate state. But IiMER has always stated that severely affected patients should not be excluded from research. Invest in ME Research are currently funding research into ME with severely affected patients being included. Diane - the carer/mother of severely affected daughter Lili, eloquently described her caring for her daughter and how her whole life was lived from her bed. Diane describes her GP "as an aggressive rude man who insulted Lili to such a degree that I wanted to throw him out". Invest in ME Research (Charity Nr. 1153730) Attempts to change things resulted in a different GP being arranged - one who visited Lili but had seemingly already prejudged both carer and patient and who was very keen for Lili to do Graded Exercise Therapy (GET). This already horrendous situation for Lili and Diane turned ever darker when social services intervened amid doctors' allegations of abuse. In Dianes's story of Lili Diane writes – "The carer of an M.E. loved one is like no other carer. Not only is it imperative to learn about myalgic encephalomyelitis in order to give the specialist care required for M.E. (to avoid causing them further harm), it is also necessary to become their protector. This serious illness is very misunderstood, even by doctors. Society as a whole has a very misguided view of M.E. and so the carer has to do all they can to keep this harmful ignorant tribal thinking from entering the world of the M.E. sufferer. They need to protect their healing space from influences, opinions and 'treatment' that will cause disease progression and maybe even death. But who protects the carer? In some ways the carer is as vulnerable as their loved one." ".....the carer is as vulnerable as their loved one....." That says it all about ME And Lili? "Lili collapsed after her last hospital visit. She passed out with a seizure, her body violently shook, and paralysis spread throughout her body. It was an extreme reaction to the overload of physical, cognitive and sensory attack on her body during that year, but this last journey to the hospital was the straw upon the last straw that broke her body down. She never recovered." investinme.org Page 32 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Disability and Human Rights ME is not alone in being an easy target for the DWP to unleash its draconian and ideologically driven policy assault on disabled people. Yet no other disease has had funding from the DWP given to a research team to prove that simplistic therapies could be used to make patients better – or at least avoid them using funds from the public purse. The PACE Trial had DWP funding included in the £5 million that was wasted to prove that Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET) were beneficial for “treating” ME. The tale is rich in irony as it was due, predominantly, to the work of patients that the PACE trial was found to be flawed and totally unusable. The DWP were actually found to have a target of 80% to refuse mandatory reconsideration requests as a Key Performance indicator. Both government contractors have previously been found to have bungled disability tests. Invest in ME Research were long ago told by an ex-member of the DWP fraud team that the actual fraudulent element from benefits was less than 3% and the official government figures for fraud now are far less. The Press Association revealed in 2017 that Atos and Capita were set to be paid more than £700 million for their five-year contracts One is left to wonder if these external profit centres are really required, especially when so many appeals against denial of benefits are eventually won. What of the effect on society? The whole benefits system for disabled people – including ME patients – is in disarray and produces an anxiety-ridden exercise which may further exacerbate a patient's condition. Universal Credit rollout has turned into an exercise in incompetence. And some charities cannot complain as they take money from the government and are under contract not to criticise. ME patients know well what it feels like to be at the sharp end of DWP coercion. The current benefits system means that ME patients are likely to be judged by a third-party subcontractor who is totally clueless when it comes to knowing anything about the disease or its effects. Of course, the DWP keep making the point that they judge on disability not on condition. Yet how can a patient be judged fairly when the person judging them has no idea of the illness and how it affects the person attending the benefits review, either then or days after the interview? The corporate parasites that DWP subcontracts to do the deeds presumably do not have to care about the effects on patients – they just carry out their instructions. Perhaps the DWP (which is effectively the government of the day) and the ministers who decide DWP policies feel cleaner, less soiled this way - yet continually forget that they are servants of the public. In a recent article, “Britain’s most senior tribunal judge says most of the benefits cases that reach court are based on bad decisions where the Department for Work and Pensions has no case at all. Sir Ernest Ryder, senior president of tribunals, also said the quality of evidence provided by the DWP is so poor it would be “wholly inadmissible” in any other court.” And the effects were expertly captured by this tweet from a doctor - Invest in ME Research (Charity Nr. 1153730) investinme.org Page 33 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Professor Tom Shakespeare at University of East Anglia has researched and published work on the biophysical explanation for disabilities and how benefit awards have arisen from the WaddellAylward model. In his preface to book Science, Politics,.......and ME, by Dr Ian Gibson and Elaine Sherriffs, Professor Shakespeare wrote the following – “Rather than judging whether a person has a practical chance of being able to find a job they can do in the actual labour market, the Work Capability Assessment investigates whether the person has the ability, in theory, to do any form of work at all, thus tightening the eligibility criteria substantially and making it more difficult to qualify for Employment Support Allowance.” Another change has been introduced, as he says: “A second change is that instead of using a person’s regular GP, who knows them and their difficulties, an ‘independent assessor’ is used, who does not necessarily understand how illness or impairment impacts their life.” This can result again in the denial of benefits..." The UK welfare system's' treatment of poor people (and that includes disabled people) in recent years has drawn attention from unlikely sources. Philip Alston, "the UN’s rapporteur on extreme poverty and human rights, warned that poverty in the UK is a “political choice” and that compassion and concern had been “outsourced” in favour of tax cuts for the rich.". Of course all of these things overlap when we discuss ME – all interplay – and one can imagine it is all part of the grand establishment strategy. The benefits scandal that denies disabled people what they deserve by using non-medical subcontractors to assess people; where targets are set to deny benefits and make patients undergo unnecessary duress to overcome a pre-conceived outcome for their disability assessment; where the DWP fund research aimed solely at proving ME can be “fixed” by simplistic approaches that fund careers and assist insurance companies; where the official flawed guidelines are rigidly decided by an institute that claims to be responsible for clinical excellence yet seems to ignore patients' experiences and aligns more with the BPS lobby; where insurance companies deny benefits to patients if they choose not to try the recommendations in the flawed official guidelines Invest in ME Research (Charity Nr. 1153730) World Human Rights Day, like many grand ideas, has a noble purpose. Yet despite their profound messages and campaigns the basic rights to health of ME patients are continually infringed and discarded. Lip service only is paid to the world quangos such as WHO and UN by governments and establishment organisations. For ME there is never any follow up on the implementation. Where was the UN when poor ME patient Karina Hansen was incarcerated in Denmark? Who covered the human rights of Sophia Mirza when she was forcibly sectioned? Where have the Governments, DoH, CMO, NICE been in protecting human rights? Who are they serving? Can one think of another case where it is so detrimental to patients when one doctrine is forcibly imposed on vulnerable people by establishment forces against common sense and when there is no evidence base that stands up to proper scientific scrutiny? From the charity's' response to the 2007 NICE Draft guidelines we have reused the comments on human rights provided by R. Mitchell and V.Mitchell. Private Health Insurers cannot force an M.E. client to undergo unwanted treatment before making a payment, unless those treatments are specified in the contract. Unless the contract of a company states clearly that M.E. clients must undergo CBT and/or graded exercise before a payment is made, the company could well be in breach of contract. Also, every individual has freedom to express views as stated by investinme.org Page 34 of 52 that propose harmful therapies such as CBT and GET as treatments; and the possible payment of government funds to charities to avoid criticism by buying their silence. Played out using ME patients as the pawns. Quod erat demonstrandum Journal of IiMER Volume 13 Issue 1 Invest in ME Research The Human Rights Act 1998. If an insurance company ignores a client’s reasons for refusing CBT and/or graded exercise, a client could claim their ‘freedom of expression’ has been violated.2 The Human Rights Act 1998, European Convention for the Protection of Human Rights and Fundamental Freedoms, Section 1, Article 10, no.1 The guidelines should have had a significant increase in evidence-based assessment and treatments beyond the psychosocial model and CBT/GET treatments before it can be accepted as an independent, expert guideline for the treatment of ME/CFS. In 2007 the recommendation from NICE to use psychological therapies for treating ME contravened the human rights of patients. It was stated that by ignoring the serious issues with regard to CBT and GET the NICE guidelines would violate the right of clinicians and patients to the highest, safest standards of medical practice and care, amounting to a violation of their Human Rights, apart from major concerns about the efficacy of use of CBT or about the danger in the use of GET. There was no regulatory framework governing the development and use of CBT and GET thus leaving ME patients vulnerable to exploitation and abuse at the hands of the vagaries of power, politics and prejudice (which has been proven correct). In respect of informed consent for using these therapies the issue did not arise as there simply cannot be informed consent since there are important ethical, safety and regulatory questions arising from these treatments, to be addressed. It was hard to envisage any Independent authority clearing a drug for Human testing or use without ethical and safety issues, like those surrounding Psychological Therapy, being resolved. By ignoring these serious issues with regard to psychological therapy the NICE guidelines violated the right of clinicians and patients to the highest, safest standards of Medical practice and care, amounting to a violation of their Human Rights. This was a Human Rights issue. And what of today when one sees NICE retaining these harmful therapies as recommendations for treatment for ME despite being told they are harmful? Invest in ME Research (Charity Nr. 1153730) ME and the EU What has been causing billions of pounds of damage to the economies of Europe, and affects the lives of hundreds of thousands of people? Yes, ME - of course. However, rivalling it in recent years has been Brexit. Brexit may mean Brexit for some – but leaving the EU does nothing to help patients with ME. Research itself suffers due to the lack of EU funding available and UK researchers will be excluded from leading EU projects. We have already seen examples of how this is affecting research plans. We were hoping that one advantage of Brexit, at least for the remaining EU countries, was that other European healthcare systems would no longer pay any attention to UK’s NICE and its flawed guidelines for ME. Instead new policies could be formed. We may be being led headlong into the Brexit abyss but IiMER does not intend to break links with Europe. IiMER is part of the European ME Alliance (EMEA), now fifteen countries working together on ME and including groups and advocates with the same objectives. EMEA is a member of the European Federation of Neurological Associations (EFNA), with a member on the board representing ME, and works together to improve recognition of ME within Europe. What is clear is that the same problems that exist with ME in the UK also exist, to a greater or lesser extent, in all other European countries. One of IiMER's great supporters – Mike Harley – is running 28 EU marathons to support the charity in raising awareness and developing a Centre of investinme.org Page 35 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Excellence for ME that can perform translational biomedical research in a European hub, able to develop treatments for ME. Apart from raising funds and enormous awareness of ME Mike has also been able to look at issues in each European country. His blog not only details his marathon events. He has also made an effort to report on the situation with ME around Europe by discussing with ME patients in the country in which he is running. And it is very illuminating. Different countries, but all sharing the same problems. Politics, the influence of Biopsychosocial (BPS) doctrine, the lack of funding for proper research, recommendations from official bodies for deleterious Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET), the lack of belief of doctors in the disease, the stigma and mistreatment around ME, patients having to research themselves, the problem not being dealt with and not going away.......... Let us look at some of the comments that Mike brought back from patients in the countries in which he ran. DENMARK “Very few doctors in Denmark know that ME is a biological illness, so most patients do not get an ME diagnosis.” "Instead, when a patient presents with ME symptoms, they are told that they are stressed, just need to pull themselves together and get some exercise. “ “The main reason for this overwhelmingly negative attitude about ME, is a long campaign by a group of psychiatrists who are working to have ME seen as a form of somatoform disorder" AUSTRIA "A doctor in Vienna, recommended to me by a ME / CFS group, made a diagnosis of CFS, amongst other things. I cannot obtain a second opinion, because according to ME / CFS Help Austria, this doctor is the only one in Vienna!" Invest in ME Research (Charity Nr. 1153730) investinme.org “…hardly anyone takes you seriously, you are usually left totally alone, especially by doctors, you are ridiculed, accused of just being lazy, not wanting to get better, and told that you should just make more of an effort. !” MALTA "There is no study or any estimates to show or at least a demarcation if there ever was any study to establish a percentage of how many ME sufferers there are there. Some doctors say it is approx. 0.02 % same as in Europe. Due to unwillingness to diagnose and lack of knowledge on ME, it's difficult for doctors to give an accurate figure." SLOVENIA "They don't support us too much around this disease, like we're nothing. We are not noticed even though we are very tired and we are hurting. We are invisibly ill, like a house that has a nice facade, but you can’t see that inside it has a fallen staircase and a broken sink." NETHERLANDS “I was denied help for cleaning as it was considered anti rehabilitive and a house because a psychologist told me that he didn't see anything wrong with me or my situation. Financial support went well but for many it's very difficult, more often than not people even need to fight it out in court. Very sad”. FINLAND "CFS/ME is classified as a psychiatric disorder by most of the doctors and they tend to treat it with antidepressants and graded exercise therapy (GET) which are potentially very harmful to patients and may permanently worsen their condition. Fortunately for the patients even these harmful therapies seem unavailable as there are no experts even to carry out GET-therapy. Patients are totally left without any care." IRELAND "Our own Department of Health tends to follow the advice given by the UK Department of Health. Page 36 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Following the 2002 CMO report in the UK, our then Chief Medical Officer told an IMET delegation that they wouldn’t intend to reinvent the wheel, but would follow the course laid down by the UK." GREECE "As far as the Government is concerned, it doesn’t have a clue about ME/CFS Greece does not have a specialist clinic for the diagnosis and treatment of ME/CFS" SWEDEN "..the psychosocial view is common, and there is a disturbing tendency to clump ME/CFS together with medically unexplained symptoms (MUS). However, there are a minority of doctors who recognise ME/CFS as a biomedical illness." POLAND "In Poland, the illness is largely perceived as being in the mind and not a biomedical condition. there is one center in Bydgoszcz where ME is diagnosed, but they then tell people to exercise" BELGIUM "ME is being perceived as a psychological disorder treated with CBT and GET despite the fact that the KCE (Federal Knowledge Centre for Health) issued a report in 2008 stating that this therapy given in the reference centres, wasn’t effective Getting diagnosed in Belgium usually takes a lot of time. With the available care facilities being ineffective and insufficient, patients with CFS have to wait sometimes years to receive a diagnosis." FRANCE "Support for ME/CFS patients in France is still very uncertain and often very difficult to obtain. Despite suffering very severely patients often find that their doctors willing to be updated at the international level with the fingers of a hand I've seen/read many other experts in the country say things that are completely out of tune with the international conception of the illness. lot of doctors have laughed at me when I told them I had CFS, others have told me I just needed to get a boyfriend... " LITHUANIA "Some doctors want to get rid of you as quick as possible, because your results are good. They think you are pretending or something. .......... I don’t think the government care, because this illness is invisible and there is not enough proof that it’s real." CZECH REPUBLIC "No diagnostic and therapeutic standards for ME / CFS have been introduced into clinical practice in the Czech Republic. Patient care depends on their luck whether they can find a doctor who does not solve whether or not he is diagnosed (and does not send everyone to psychiatry immediately), but he is treating real problems." We know that the evil of BPS has been allowed to spread its insidious network throughout Europe – like a cancer through each health system, corrupting doctors and research councils everywhere. At a time where the mess of Brexit seems like a microcosm of the unpredictability and the unravelling of the world today then one thing is certain – IiMER will still stay close to Europe via EMEA and other initiatives such as the European ME Clinicans Council (EMECC) concept. Leaving the EU will make no difference to the actual

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Children with ME Losing school, losing contact to friends, losing any social life - isolation. Could it get any worse? In the UK yes! A child may be branded with the scandalously contrived soundbite of Pervasive Refusal Syndrome or some other such nonsensical catchphrase? “There is clear evidence of the impact of ME/CFS on the education and social development of these young people. The stigma and social effects of pediatric ME/CFS include the loss of normal childhood activities and in some extreme instances, inappropriate forcible separation of children from their parents” - Institute of Medicine (IOM) Report - “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness” February 2015 For any parent the event of their child being diagnosed with a disease is one of the worst of experiences that they will ever have. To then discover that there is no treatment, let alone a prospect for any cure, will likely make them search for the reason(s) why - expecting to find answers, but instead finding more questions. To realise that this disease is ignored by governments, restricted from any level approaching adequate funding by research councils, treated inappropriately by institutes supposedly responsible for excellence in care, and used as a means to build careers and support egos for others – all this makes it even more incomprehensible. To learn that a powerful and influential lobby has been largely responsible for maintaining the above and even influencing the establishment policies and the media portrayal of this disease as a condition that can be changed just by trying harder or thinking differently – then the nightmare turns into a continuous horror. For children, of course, the future is often upended - with possible additional consequences caused by the disease, apart from the direct symptoms from the condition itself. Invest in ME Research (Charity Nr. 1153730) Yet, despite this surreal and sometimes ugly scenario, we see many examples of the resilience and courage of children with ME - young people who deal with the effects of ME on their health and their lives and yet continue to hope and believe in a better future. The great majority remain positive and maintain an unbelievable lack of any resentment for their situation - blaming nobody, stoically handling this disease . Quite remarkable. We have many examples also of young people supporting the charity and using what possibilities they have to raise awareness and funds. Some take action themselves. Last summer we received this image from Professor Kristian Sommerfelt in Norway - a drawing by young Emma who so clearly explained in her image here what ME is like for a young person. In the UK an estimated 25,000 children have ME - but nobody knows for sure as data is not currently collected! There are so few paediatricians that understand ME - another failure of establishment policies. Even those who are qualified, knowledgeable and appreciated by parents of children with ME are given a hard time – see http://www.investinme.org/IIME-Newslet-1604NS999.shtml investinme.org Page 38 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research As for paediatric research - well, the less said about that the better. We have commented before on the appalling SMILE trial and on pyramid businesses that are unregulated, unaccountable and unscientific. Junk research that attracts funding thanks to a rigid system that defies any logic or concern for children. It also recreated the social relationships. We feel that it also educated other children – and their families, and teachers and possibly SENCOs. No Isolation & Invest in ME Research Removing isolation Most of the effort from Invest in ME Research in recent years has been aimed at trying to get research into ME started that looked at the long term. However, we have also looked at other issues – the consequences of ME. One insidious consequence is isolation – affecting young and old patients. Little had been done to tackle this. This year we wanted to change how young people may be affected by this. A disease such as ME presents many challenges to a patient and to a family. It can provide challenges also to schools when a child or young person is unable to continue full time education. In such situations families can find themselves on the receiving end of the ignorance about ME that pervades our society where social services and education authorities may use a one-size-fits-all attitude to treating families where the child must remain at home. Children and youths with long-term illness such as ME do not need to be excluded from their friends’ activities and progress and schools have a responsibility not to ignore them – something which can otherwise lead to long term discrimination. We started a trial of remote participation by working with Norwegian company No Isolation to conduct a trial for young people with ME and the results were very good. This trial not only facilitated the re-connection of young ME patients to their schools. Invest in ME Research (Charity Nr. 1153730) No Isolation is a Norwegian-born start up founded with the aim of reducing loneliness and involuntary social isolation through the creation and implementation of warm technology. Its first product is a physical avatar named AV1, which allows children and young adults, who are forced by illness to take extended time away from school, to maintain a presence in the classroom and communicate with friends. In 2017, to expand the number of children it could help, No Isolation launched in the UK, and today, over 900 children use AV1 across Europe. While in the Nordics, AV1 was largely used by children suffering from leukaemia; however, since its arrival in the UK, AV1 has fast become an invaluable lifeline for children with Myalgic Encephalomyelitis (ME) thanks to Invest in ME Research. One of the UK’s most avid users is 15-year-old Makayla Nunn, who was first diagnosed with ME aged eight. Makayla was introduced to the technology through the trial arranged by Invest in ME Research. Her family and school saw how essential AV1 had become to help Makayla maintain the increased attendance in class, and subsequent increase in grades and social confidence. Makayla has been using her AV1, who is lovingly named Robbie, for well over a year now. There is no better way to explore the AV1’s success in transforming the life of someone with ME, than to speak with a real-life user. Ahead of this year’s Invest in ME Research conference, we caught up with Makayla and her mother about their experiences with the technology. Hi Makayla, can you tell us a little bit about your journey with ME? I was diagnosed with ME at eight years old, and since then I have been unable to attend school full time due to tiredness, flu-like symptoms, and brain fog. I also suffer from hyper-mobility syndrome, meaning that it often hurts to move my joints, and POTs (postural orthostatic tachycardia), which causes a spike in my heart rate, leading to dizziness and fainting. As well as missing out on school, I had to give up sports and hobbies, including dancing and investinme.org Page 39 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research swimming. I can’t horse ride as much as want to, either. When did you first encounter AV1? I saw on the news that Jade Gadd had used a robot called Bee (her AV1) to assist her with a different condition, then Invest in ME Research asked me if I would like to try an AV1 out for three months. As I was behind at school, my mum and I thought that the robot could help me attend extra hours of school from home, taking the pressure off my education. I got my AV1 in January 2018, and now, Robbie is part of the family! How did your class react to having AV1 in the classroom? It was quite strange at first. Robbie used to get a lot of attention from my class when we were attending the lesson. My class really like him being there, it was the school that named him, and one of the staff members even made Robbie a cape to keep him warm when he's going between buildings! How has AV1 helped you better cope with your condition? If I am having a day where I am feeling very tired or ill, I often don’t feel up to going into school. With Robbie, I can now work from home on these days, rather than having to miss out entirely. This helps me hugely, because to do this, I don’t have to physically push myself too much, which can make me feel worse. Using Robbie is just like being in class, because when I need to get my teacher’s attention I can light up Robbie’s head, just like putting a hand up. I can also put the ‘sleep mode’ on if I want to be in the lesson but don’t feel up to saying too much. Do you think that your AV1 will give you more opportunities for the future? I'm not as behind in school any more, my grades have improved and I feel more confident. This is good because exam work has started for my GCSE’s, so Robbie is helping me to catch up on the stuff that I have missed previously, having been on reduced hours of school for the last 7 years. We were also lucky enough to catch up with Makayla’s mother, Michelle, too. Hi Michelle, how has AV1 changed family life? AV1 has made me more confident about Makayla’s education. When she is struggling at school she gets Invest in ME Research (Charity Nr. 1153730) frustrated and upset; falling behind the rest of the class. By giving her the ability to attend more lessons through Robbie, it gives her more control, which is a massive boost for Makayla. How has AV1 changed Makayla’s education? Robbie has helped Makayla beyond my expectations! When she’s having a bad day she knows she’s not under pressure to go in anymore, because we can send Robbie in. This has taken a lot of pressure off her and having Robbie as a safety net has made the world of difference. She’s not forcing herself to go to school on days when she needs to rest, which in turn makes her worse in the long run. In a way, Robbie is helping her overall health. How has AV1 changed Makayla’s daily life? As a parent, I am always being told ‘you should limit this’ or ‘Makayla can’t do that’. Robbie has really helped to take the ‘you can’t’ away. Robbie has given hope to other children and parents too, as most with ME have had to drop out of education. Aside from education, Robbie helps Makayla see her grandmother. When illness has prevented Makayla visiting her grandmother (for the worry of contagion), a remote visit through AV1 can help Makayla and her grandmother spend more time together. What do you hope for the future? We are hoping technologies like the AV1 will change people’s attitudes towards ME. Clarifying that the illness is not about people not wanting to do things, but it is about them not wanting to be sick. They have had to give up so much. This is a real illness that affects so much more than just their health - it affects life. I’ve been so surprised at how well Robbie has supported Makayla. Allowing her to carry on with her education has made Makayla far more confident. It has also given Makayla had one less thing to worry about: the isolation that she felt and the awkwardness of feeling left behind. investinme.org Page 40 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Anne Ortegren - A Year On It is a year since news came of the passing of Anne Örtegren. The lives of those who have passed away are placed in the memory of the living. A year passes and the shock of the news of Anne's death may have ebbed away somewhat - yet the void remains, covered by the memory of one woman whose courage, dignity and influence were evident always - and continue to inspire. Reading Anne’s Last Post - an articulate, reasoned and eloquent article that gives insight into the loss of this amazing person - it may seem that she was recounting the situation that she found herself in and reasons for her course of action. That, itself, would have been an enormous effort. Yet, with Anne, this article was also likely to have been written to help so many others in the future - so typical of Anne’s selfless actions. In her last post Anne wrote – “If you are a decision maker, here is what you urgently need to do: - You need to bring funding for biomedical ME/CFS research up so it’s on par with comparable diseases (as an example, in the US that would mean $188 million per year). - You need to make sure there are dedicated hospital care units for ME/CFS inpatients in every city around the world. - You need to establish specialist biomedical care available to all ME/CFS patients; it should be as natural as RA patients having access to a rheumatologist or cancer patients to an oncologist. You need to give ME/CFS patients a future.” Invest in ME Research (Charity Nr. 1153730) A year on. We would have liked to have written that things have changed, that a new path is opened, that Anne's experiences will never have to be repeated. We cannot state this. Our status report from summer of 2018, prior to the UK parliamentary debate on ME, highlighted a picture of wasted lives and wasted opportunities over these many years where little has changed, thanks to establishment apathy. Yet we remain hopeful of change coming - albeit far too slowly. Therefore, the charity is developing a new initiative that will build on Anne's influence and may, in some way, honour her memory. We will continue to arrange for the Anne Örtegren Memorial Lecture to be given at our annual international ME conference in. In memory of Anne we released the tribute to her from last year’s IIMEC13 conference DVD that occurred prior to the inaugural Anne Ortegren Memorial Lecture. Here, quite appropriately, a distinguished Swedish scientist – Professor Jonas Blomberg – spoke of Anne. Little did we know then that a year later we would be mourning the sad loss of Professor Blomberg himself. As we wrote last year - when we lose a friend we lose a part of ourselves. Anne's influence on the lives of others lives on. http://investinme.org/AnneOrtegren.shtml investinme.org Page 41 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Conference Abstracts Dr Ian Gibson Former Dean of Biological Sciences, UEA Dr Ian Gibson, former Labour MP for Norwich North, worked at University of East Anglia for 32 years, became Dean of the school of biological sciences in 1991 and was head of a cancer research team and set up the Francesca Gunn Leukaemia Laboratory at UEA. In 2011 Dr Gibson received an honorary doctorate of civil law from UEA. Professor Markku Partinen University of Helsinki, Finland Prof Markku Partinen is a neurologist and an internationally well-known opinion leader and expert in sleep research and sleep medicine. Professor Partinen is currently Director of the Helsinki Sleep Clinic, Vitalmed Research Centre, Invest in ME Research (Charity Nr. 1153730) and Principal Investigator of Sleep Research at Institute of Clinical Medicine, Clinicum, University of Helsinki, Finland. He has been the coordinator of the NARPANord Narcolepsy Consortium. He has published more than 330 original articles in peer reviewed Journals in addition to writing many book Chapters and editing several books. He has been President of the ESRS congress in 1992 (Helsinki), the World Congress of Sleep Apnea in 2003 (Helsinki), and the WASM congress in 2007 (Bangkok). Currently he is a Member of the Board in the ESRS EU-Narcolepsy Network (EU-NN) and Chair of Scientific Board of the EU-NN, President of the Finnish Parkinson Association and President of the Finnish Sleep Research Society. Professor James Baraniuk Professor of Medicine at Georgetown University Medical Centre, Washington, USA James N. Baraniuk was born in Alberta, Canada. He earned his honours degree in chemistry and microbiology, medical degree, and unique bachelor's degree in medicine (cardiology) at the University of Manitoba, Winnipeg, investinme.org Page 42 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Canada. Thereafter, he moved to Akron, OH, USA, for his internship and internal medicine residency at St Thomas Hospital. After another year of internal medicine residency at Duke University Medical Center, Durham, NC, he trained with Dr C.E. Buckley, III, in allergy and clinical immunology. He moved to the laboratory of Dr Michael Kaliner at the National Institute of Allergy and Infectious Diseases, Bethesda, MD, and there began his longstanding collaboration with Dr Kimihiro Ohkubo. After 2 years studying neuropeptides, he joined Dr Peter Barnes' laboratory at the National Heart and Lung Institute, Brompton Hospital, London, UK. Dr Baraniuk returned to Washington, DC, and Georgetown University, where he is currently Associate Professor with Tenure in the Department of Medicine. Dr Elizabeth R. Unger Chief of Chronic Viral Diseases Branch, National Center for Emerging and Zoonotic Infectious Diseases, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention Elizabeth (Beth) Unger, PhD, MD received an undergraduate degree in Chemistry at Lebanon Valley College, Annville, PA. She then earned her PhD and MD in the Division of Biologic Sciences at the University of Chicago where she also began residency in pathology. Her residency and fellowship was completed at Pennsylvania State University Medical Center. During this time, Dr. Unger developed a practical method of colorimetic in situ hybridization. This work led to interest in tissue localization of HPV and ultimately to her initial appointment to CDC in 1997 to pursue molecular pathology of HPV and CFS. Dr. Unger has served as the Acting Chief of CVDB since January 2010 and has 13 years of experience in CVDB, where she has participated in the design and implementation of CFS research and HPV laboratory diagnostics. During this time, she was coauthor on 25 peer-reviewed manuscripts related to CFS, including the often-cited descriptions of the Wichita and Georgia population-based studies. In addition, Dr. Unger has been instrumental in efforts by WHO to establish an HPV LabNet and serves as Invest in ME Research (Charity Nr. 1153730) lead of a WHO HPV Global Reference Laboratory. She is co-author of 142 peer-reviewed publications and 24 book chapters and serves on the editorial board of six scientific journals. In 2008, for her HPV research accomplishments, she received the Health and Human Services (HHS) Career Achievement Award. Dr Unger has been selected to serve as the Chief of the Chronic Viral Diseases Branch (CVDB) in the Division of High-Consequence Pathogens and Pathology (DHCPP), National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Centers for Disease Control and Prevention (CDC). Dr Vicky Whittemore Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States. Dr. Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster. Her interest is in understanding the underlying mechanisms of the epilepsies including the study of genetic and animal models of the epilepsies. The major goal is to identify effective treatments for the epilepsies and to develop preventions. Dr. Whittemore received a Ph.D. in anatomy from the University of Minnesota, followed by postdoctoral work at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm, Sweden. She was on the faculty of the University of Miami School of Medicine in The Miami Project to Cure Paralysis prior to working with several non-profit organizations including the Tuberous Sclerosis Alliance, Genetic Alliance, Citizens United for Research in Epilepsy (CURE), and the National Coalition for Health Professional Education in Genetics (NCHPEG). She also just completed a four-year term on the National Advisory Neurological Disorders and Stroke Council. investinme.org Page 43 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Professor Maureen Hanson Director, Center for Enervating Neuroimmune Disease. Liberty Hyde Bailey Professor, Department of Molecular Biology and Genetics, Cornell University, USA Maureen Hanson is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, NY. Previously she was on the faculty of the Department of Biology at the University of Virginia in Charlottesville and an NIH NRSA postdoctoral fellow at Harvard, where she also completed her Ph.D. degree. While most of her prior research has concerned cell and molecular biology in plant cells, she began a research program on ME/CFS after noting at a 2007 IACFS meeting the paucity of molecular biologists studying the illness. Her lab was part of the 2012 multicenter study organized by Ian Lipkin's group at Columbia University to assess the actual role of XMRV in ME/CFS. Associate Professor Mady Hornig Associate Professor, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health New York, USA Mady Hornig, MA, MD is a physician-scientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health where she serves as Director of Translational Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, and toxic stimuli in the development of neuropsychiatric conditions, including autism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with Invest in ME Research (Charity Nr. 1153730) environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Professor Don Staines The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University, Australia Professor Staines has been a public health physician at Gold Coast Population Health Unit. He has worked in health services management and public health practice in Australia and overseas. His interests include collaborative health initiatives with other countries as well as crossdisciplinary initiatives within health. Communicable diseases as well as post infectious fatigue syndromes are his main research interests. A keen supporter of the Griffith University Medical School, he enjoys teaching and other opportunities to promote awareness of public health in the medical curriculum. He is now Co-Director at The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University in Australia investinme.org Page 44 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research Abstract: Role of transient receptor potential ion channels in the etiology and pathomechanism of ME/CFS Staines D1,2 Cabanas H1,2,, Muraki K2,3 , Balinas C1,2, Eaton-Fitch N,1,2, , Marshall-Gradisnik S1, 2. 1.The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, Southport, QLD, 4222, Australia. h.cabanas@griffith.edu.au. 2. Consortium Health International for Myalgic Encephalomyelitis, National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, QLD, Australia. h.cabanas@griffith.edu.au. 3. Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Chikusa, Nagoya, Japan. NCNED has confirmed the pathology of transient receptor potential (TRP) ion channels in ME/CFS. TRP Melastatin 3 (TRPM3) impairment has been identified in three separate cohorts of patients. TRPM ion channels are non-selective calcium ion channels increasingly associated with systemic, particularly central nervous system (CNS), pathology. TRPM3 is highly concentrated in the CNS, (autonomic) ANS and (peripheral) PNS. The observed changes in gene structures and TRP receptor ion channel proteins are reflected in perturbations of intracellular calcium signalling. These findings have been demonstrated through electrophysiology patch-clamp technology, the gold standard for research into ion channel function. Drugs are now being analysed in this research context regarding suitability for pharmacotherapeutics and hence treatments. The demonstrated pathology of TRPM correlates with symptom presentation in ME/CFS. Patch clamp identification of impaired TRP ion channels, the findings of drugs in a therapeutic context and the known roles of TRPM ion channels in systemic diseases establishes TRP pathology as the underlying cause of ME/CFS. Additional data demonstrating changes in other TRP sub-family members is currently under publication. Whether these additional changes reflect compensatory mechanisms is being investigated. Invest in ME Research (Charity Nr. 1153730) Dr Jesper Mehlsen Bispebjerg Hospital, Copenhagen, Denmark Jesper Mehlsen graduated as a doctor in 1979 from the University of Copenhagen and became a specialist in 1990. For 35 years he has been working clinically and in research with patients with disorders of blood pressure control, with dizziness, fainting (syncope) and near-fainting in upright position. He is author / co-author of more than 140 articles in international journals and has been the leader of a number of research projects in these fields and with projects related to HPV vaccination. Over the past 5 years, he has performed clinical research with patients who suspect vaccine damage as the cause of the development of a number of symptoms that are often common to those seen in chronic fatigue syndrome / ME. His expertise is in Autonomic nervous system, Heart rate and blood pressure control, Cardiovascular physiology and pathophysiology, HPV vaccines and -complications His Main research areas relate to methods for the study of autonomic cardiovascular control; Mathematical modelling of cardiovascular control; Autoimmune response to vaccination; Mathematical modeling of the neuroinflammatory reflex. His current research involves mathematical analysis of hemodynamic adaptations to the upright posture; mathematical analysis of hemodynamic response to Valsalva manoeuvre; dynamic T-wave alterations and the autonomic nervous system; mathematical analysis of cytokine response to LPS in humans; autoimmunity in patients with possible side effects to HPV vaccination. He places great emphasis on taking time to listen, investigate, explain and find treatment options based on a holistic assessment and in close interaction with the patient investinme.org Page 45 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Dr Øystein Fluge Haukeland University Hospital, Bergen, Norway Oystein Fluge received medical degree in 1988 at the University of Bergen, and is specialist in oncology since 2004. He has worked as a Research Fellow with support from the Norwegian Cancer Society and is now chief physician at the Cancer Department, Haukeland University Hospital. Doctoral work emanates from the Surgical Institute and Department of Molecular Biology, University of Bergen. For example, TRPV1 is activated by noxious high temperature (>42°C), TRPM8 by cool temperatures (<~28°C) and TRPV3 by warm temperatures (>32°C). TRPA1 can also be activated by noxious cold temperatures. TRPV1 and TRPA1 are expressed by sensory nerves that respond to noxious stimuli and these two channels are also sensitive to pungent chemicals such as capsaicin found in chilli peppers (TRPV1) and allyl isothiocyanate found in mustard and wasabi (TRPA1). His interest is to determine the roles of TRP channels and other ion channels and receptors in normal physiology and in disease states. The activities of channels and receptors are studied using electrophysiological measurements from native cells (such as sensory neurons) and cells heterologously expressing molecules of interest. Professor Simon Carding Research Leader, Quadram Institute Bioscience Professor Stuart Bevan Professor of Pharmacology at the Wolfson Centre for Age Related Diseases, Kings College London, UK Professor Stuart Bevan is Professor of Pharmacology at the Wolfson Centre for Age Related Diseases. From 1997 to 2005, he was Head of the Chronic Pain Unit for Novartis based in the Novartis Institute for Biomedical Research laboratories on the UCL campus. Our studies are focused on sensory transduction in neuronal and non-neuronal cells, the transduction and transmission of noxious and innocuous stimuli in peripheral sensory nerves and mechanisms of pain and analgesia. These investigations are carried out using a combination of in vitro and in vivo approaches. Transient receptor potential (TRP) channels Much of our current research involves studies on TRP Channels. TRP channels have diverse roles in sensory transduction and cellular regulation. We have a specific interest in TRP channels expressed by peripheral sensory neurons and interacting cells such as keratinocytes as well as non-neuronal cells in the gastro-intestinal tract. Several of these channels are important sensors of thermal stimuli. Invest in ME Research (Charity Nr. 1153730) Upon completing postgraduate work at the Medical Research Council’s Clinical Research Centre in Harrow, Simon Carding took up a postdoctoral position at New York University School of Medicine, USA,and then at Yale University as a Howard Hughes Fellow in the Immunobiology Group at Yale University with Profs Kim Bottomly and Charlie Janeway Jr. While at Yale an interest in gamma-delta (γδ) T cells was acquired working closely with Adrian Hayday on molecular genetics and then with Prof. Peter Doherty to establish their role in (viral) infectious disease. He left Yale after five years to take up a faculty position at the University of Pennsylvania in Philadelphia where he developed a research interest in mucosal and GI-tract immunology, performing studies in germfree mice with Prof John Cebra that helped establish the role of gut microbes in the aetiology of inflammatory bowel disease (IBD). After 15 years in the USA, he returned to the UK to take up the Chair in Molecular Immunology at the University of Leeds where he established a new research programme on commensal gut bacteria and Bacteroides genetics leading to the development of a Bacteroides drug delivery platform that is being used for developing new interventions for IBD and for mucosal vaccination. investinme.org Page 46 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research In 2008 he was recruited by UEA and IFR to develop a gut research programme, taking up the Chair of Mucosal Immunology at UEA-MED and the position of head of the Gut Biology Research Programme at IFR, which later became part of the Gut Health and Food Safety (GHFS) Programme. GHFS research covers a broad area of gut biology including epithelial cell physiology, mucus and glycobiology, mucosal immunology, commensal microbiology, foodborne bacterial pathogens, and mathematical modelling and bioinformatics. The success of this programme has led to the establishment of the Gut Microbes and Health research programme that is integral to the research agenda of The Quadram Institute. Within these programmes, much of the work undertaken in his research group builds upon that carried out in the USA and latterly in the UK with a major focus on understanding the mechanisms of intestinal microbial (bacterial and viral) tolerance. In particular, identifying the pathways and mediators of microbe-host cross talk and the role they play in establishing and maintaining gut health and in diseases that not only affect the gut but other organ systems. This has led to the development of new research projects relating to the gut-microbiomebrain axis and understanding how the intestinal microbiome impacts on mental health and the development of neurodegenerative diseases, and the intestinal virome and the role that prokaryotic and eukaryotic viruses play in microbial homeostasis and dysbiosis. Professor Karl Johan Tronstad Professor Institute for Biomedicine , Tronstad Lab, Bergen, Norway Prof. Tronstad completed his graduate studies in biochemistry at the University of Bergen (UiB) in 2002. As postdoc at the Haukeland University Hospital, he studied bioactive compounds with the potential to modulate mitochondrial functions in cancer cells. In 2005 he was recruited to the Department of Biomedicine, UiB, where he started his research group to investigate metabolism and mitochondrial physiology. His laboratory seeks to better our understanding of how defective mitochondrial homeostasis may disturb cell physiology, and how this may be involved in mechanisms of cancer and Myalgic Invest in ME Research (Charity Nr. 1153730) Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Karl was involved with the recent paper to come from Bergen - Journal of Clinical Investigation Insight. The Tronstad Lab investigates cell metabolism and mitochondrial biology and we are very fortunate that he can spare time to participate in the Colloquium. Professor Nancy Klimas, Director, Institute for Neuro Immune Medicine, Nova Southeastern University USA Nancy Klimas, MD, has more than 30 years of professional experience and has achieved international recognition for her research and clinical efforts in multi-symptom disorders, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI), Fibromyalgia, and other Neuro Immune Disorders. She is immediate past president of the International Association for CFS and ME (IACFS/ME), a professional organization of clinicians and investigators, and is also a member of the VA Research Advisory Committee for GWI, the NIH P2P CFS Committee, and the Institute of Medicine ME/CFS Review Panel. Dr. Klimas has advised three Secretaries of Health and Human Services, including Kathleen Sabelius, during her repeated service on the Health and Human Services CFS Advisory Committee. Dr. Klimas has been featured on Good Morning America, in USA Today and the New York Times. Dr Ron Tompkins Director of the Center for Surgery, Science and Bioengineering, Massachusetts General Hospital, USA Ronald G. Tompkins, MD, ScD, is the Sumner M. Redstone Professor of Surgery at Harvard Medical School, Founding Director of the Center for Surgery, Science & Bioengineering at Massachusetts General Hospital, and Chief of Staff Emeritus at Shriners Hospitals for Children―Boston. investinme.org Page 47 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research The Center, a division of Surgery at Mass General, is a newly established center for research and innovation based upon the Mass General Burns Division’s collaborative track record and expertise in securing more than $200 million in federal, foundation, and industrial support for basic research and clinical programs. It is a clinically-driven enterprise that engages in the basic sciences and engineering to solve everyday challenges in clinical medicine. The center promotes the development of new approaches to healthcare delivery and personalized medicine, minimally invasive therapies, as well as a myriad of new technologies such as re-engineered organs, smart nano-pharmaceuticals and nano-diagnostics, and living cell-based microfabricated devices for diagnostics, therapeutics, high-throughput drug screening, and basic and applied biomedical investigation. He is a board-certified general surgeon with a doctorate in chemical engineering, which provides him with expertise not only in the clinical evaluation of critical care patients, but also in inflammation biology, genomics, proteomics, and computational biology. Elected as a Director of the American Board of Surgery in 1994, he has received multiple honors including a fellowship from the American Institute for Medical and Biological Engineering and an honorary M.A. from Harvard University. He has served as an officer including as President and Board Member of more than a dozen national and international academic societies. Dr. Tompkins has published more than 450 research papers in medicine and engineering journals and has contributed to the advancement of science and engineering through service on institutional advisory panels, moderating mini-symposia and workshops on biotechnology, and studying the genomics and proteomics of immunology and metabolism resulting from injury. Together with his Division colleagues, nearly 300 fellows have been mentored in the Division’s training programs with many excellent success stories. Professor Michael VanElzakker Massachusetts General Hospital/Tufts University, USA Dr. VanElzakker received a master's degree in behavioral neuroscience at the University of Colorado, Invest in ME Research (Charity Nr. 1153730) working in Dr. Robert Spencer's neuroendocrinology laboratory, and a PhD in experimental clinical psychology at Tufts University, working in Dr. Lisa Shin's psychopathology neuroimaging laboratory. His postdoctoral fellowship is at Massachusetts General Hospital/ Harvard Medical School, at the Martinos Center for Biomedical Imaging, in the Division of Neurotherapeutics. Dr. VanElzakker is interested in uncovering the mechanisms of post-traumatic stress disorder (PTSD), and of myalgic encephalomyelitis - also known as chronic fatigue syndrome (ME/CFS). His PTSD research uses functional and structural brain imaging, behavioral attention tasks, blood, and genetic data to investigate what makes some individuals vulnerable to PTSD following trauma. He is interested in using non-invasive electroceutical medical devices to enhance safety learning, which may eventually serve as an adjunct to enhance exposure-based therapy for PTSD. His ME/CFS research uses functional and structural brain imaging to look for abnormal patterns in brain metabolism and inflammation in this patient population. This research focuses on dysfunction at the intersection of the nervous and immune systems and posits that ME/CFS may be what happens when the nervous system detects an exaggerated and ongoing innate immune response. He is interested in using non-invasive electroceutical medical devices to enhance the antiinflammatory vagus nerve reflex. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA Ronald W. Davis, Ph.D., is a Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California. He is a world leader in the development of biotechnology, especially the development of recombinant DNA and genomic methodologies and their application to biological systems. At Stanford University, where he is Director of the Stanford Genome Technology Center, Dr. Davis investinme.org Page 48 of 52 Journal of IiMER Volume 13 Issue 1 Invest in ME Research focuses on the interface of nano-fabricated state devices and biological systems. He and his research team also develop no technologies for the genetic, genomic, and molecular analysis of a wide range of mo organisms as well as humans. The team's focus on practical application technologies is setting the standard for clin genomics. The genomic revolution has been spurred technological advances that made nucleo sequencing inexpensive, high-throughpu accessible. The next phase in this revolut the way for personalized health entails si breakthroughs in biosensor technologies personal molecular monitoring. Just as w sequencing, the key features to optimize accuracy, sensitivity, cost, and accessibili close collaboration between engineers, biochemists, geneticists, and clinicians, o has developed several such technologies devices. The technologies target the bioph properties of the cells and molecules, and do not rely on introducing labels or other c sample preparation techniques. We have successfully applied these technologies t drug resistance, resolving cells and molecules in bodily fluids and tissues, and engineering multiparametric, wearable biosensors. W begun applying these methods to unders chronic fatigue syndrome, one of the last diseases about which almost nothing is k anticipate that these technological break coupled with data integration of personal profiles will play an instrumental role in t realization of personalized health regimens and disease prevention strategies. Invest in ME Research (Charity Nr. 1153730) investinme.org Page 49 of 52

Journal of IiMER Volume 13 Issue 1 Invest in ME Research Start Presentation Presenter 07.45 Registration 08.45 IiMER 09:00 #InvestinMEResearch 09:10 CDC update 09:25 NIH Update 09:45 Immune Dysregulation in ME/CFS 10.10 Fingerprinting the Phenotypes of ME/CFS Along the Gut-Immune-Brain Axis 10:35 Refreshments Break 11:05 Transient receptor potential ion channels in the aetiology and pathomechanism of CFS/ME 11:30 Pathophysiological Basis of Fibromyalgia 11:55 Characteristics and pathophysiologic changes in a large cohort of Danish ME-patients. 12.20 Lunch 13.20 Anne Örtegren Memorial Lecture: Pain and ME/CFS 13:45 Developments at Quadram Institute 14:05 Rituximab in ME/CFS: a randomised, doubleblind and placebo-controlled trial 14.30 Metabolic profiling and associations to clinical data in ME 14:55 Refreshments Break 15:25 Integrative Medicine Approach to Treatment of ME 15:50 Harvard Plans for Clinical Research 16:10 Physiological and fMRI measures before and after symptom provocation by invasive cardiopulmonary exercise testing 16:35 Stanford Metabolomics & Genetics Study Update 17:10 Plenary Session 17.30 Adjourn Invest in ME Research (Charity Nr. 1153730) investinme.org Professor Nancy Klimas Dr Ron Tompkins Dr Michael VanElzakker Professor Ron Davis Panel discussion Page 50 of 52 Professor Stuart Bevan Professor Simon Carding Dr Oystein Fluge Professor Karl Johan Tronstad Professor Don Staines Dr David Andersson Dr Jesper Mehlsen Opening Dr Ian Gibson Dr Elizabeth Unger Dr Vicky Whittemore Professor Maureen Hanson Assoc. Professor Mady Hornig Journal of IiMER Volume 13 Issue 1 Invest in ME Research Invest in ME Research (Charity Nr. 1153730) investinme.org Page 51 of 52

nal of IiMER Journal of IiMER Volume 12 Issue 1 May 2018 Research into ME Published by UK Charity Invest in ME Research www.investinme.org

“This organization has been working in the trenches of ME, and it has been a notable and significant contribution to the field. Invest in ME has been able to increase awareness and disseminate knowledge to scientists, clinicians, and patients within the ME community. With limited resources, but unlimited creativity and imagination, these patients and their supporters have showed the world what can be done.” - Dr. Leonard A. Jason Invest in ME Research o an independent UK charity finding, funding and facilitating a strategy of high quality biomedical research into Myalgic Encephalomyelitis, as defined by WHO-ICD-10-G93.3 o focuses on biomedical research into ME and the education of healthcare staff, the media, government departments, patient groups and patients o run by volunteers with no paid staff - no funding from government or government organisations o overheads are kept to a minimum to enable all funds raised to go to promoting education of, and funding for biomedical research into, ME o a small charity but we do far more than most with growing number of supporters with big hearts and determination to find the cause of myalgic encephalomyelitis and develop treatments o funding more biomedical research than many other organisations o we have links nationwide and also internationally and facilitate international collaboration o founder member of the European ME Alliance (EMEA) o organises annual research Colloquium and public Conference attracting delegates from 20 countries o to bring best education and research to bear on ME and find/facilitate the best strategy of research o focused on setting up UK/European Centre of Excellence for ME to provide proper examinations and diagnosis for ME patients and coordinated strategy of biomedical research in order to find treatment(s) and cure(s) - http://www.cofeforme.eu o the charity welcomes support for our work – www.investinme.org/donate www.investinme.org Page 2 of 56 Invest in ME Research (Charity Nr. 1153730) www.investinme.org Page 2 of 56 Invest in ME research (Charity Nr. 1153730) 3 Chairman of IiMER 6 Progress in ME 12 NICE Review Comments 18 Centre Research Blog 20 Thinking the Future 21 Quadram Institute Bioscience News 22 UK Biobank: An Open Access Resource 29 Farewell to a Friend – Anne Örtegren 36 A Harsh Debate about ME in Norway 41 Letter from America 43 IiMER’s Own Film Star 45 Conference Abstracts All content in the Journal of IiMER is copyright to Invest in ME Research and/or the authors. Permission is required and requested from Invest in ME Research before republishing from this Journal. DISCLAIMER The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME Research. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME research (Charity Nr. 1153730) Welcome to IIMEC13 A Foundation of International Collaboration in Biomedical Research From the Chairman of Invest in ME Research Invest in ME Research is an independent UK charity facilitating and funding a strategy of biomedical research into Myalgic Encephalomyelitis (ME or ME/CFS) and promoting better education about ME. The charity was built on the firm belief that biomedical research into ME was crucial in order to make progress in treating this disease. The education of healthcare staff, the media, government departments, patient groups and patients was also to be a priority - but something that would develop from the research being undertaken. Although forcing research into ME into the mainstream of academic and clinical consideration has taken too long we do sometimes wonder where we would be if we had not started our conferences and, later, our research Colloquiums. The international conferences were organised from the beginning to provide a platform for research and a means of facilitating education about ME. The research Colloquiums now attract researchers from around the world to a meeting where they are free to discuss, share and collaborate. Collaboration and working together have been themes for our Colloquiums - with real international cooperation forming that can only lead to a better future for patients than would otherwise be the case. www.investinme.org Page 3 of 56

This year we again have representatives from both the USA National Institute of Health (NIH) and Centres for Disease Control (CDC) attending our Colloquium and Conference - endorsing our view of international collaboration as a critical means to an end. We can also see some of the spin-offs that have occurred due to our Colloquium taking place - either research projects, collaboration in planning projects or in other events taking place. Both the Colloquium and Conference are high quality, forward-looking events that serve to improve knowledge of this disease and generate and improve international collaboration into ME. As always the charity takes on the task of producing a high-quality DVD of the conference with all of the presentations included. This serves as a historical record and is an educational tool for doctors and clinicians - demonstrating the seriousness of this disease. For 2017, our conference DVD reached even more countries and allowed us to inform a wider audience. Yet how do we speed up research and move the direction away from the flawed approach to ME research that has been the strategy of establishment organisations that have not responded to the needs of patients? The strategy that Invest in ME Research has created is to develop a Centre of Excellence for ME based on highquality biomedical research and international collaboration. There are now four PhD students performing biomedical research into ME at the Norwich Research Park, where the hub for the UK Centre of Excellence for ME is proposed. The charity continues to fund research at UCL also by supporting the remainder of another PhD studentship there. The charity is doing more than most to provide a sound foundation for research into ME and spends more, proportionately, of its income on biomedical research and associated activities than any other UK charity. The Invest in ME Research strategy of bringing in researchers from other fields to help and improve biomedical research into ME is working. Our conferences bring together patients, researchers, clinicians and healthcare staff and allow knowledge and Page 4 of 56 www.investinme.org experiences to be shared – and IIMEC13 and BRMEC8 will see us entering our thirteenth year in doing this. Our BRMEC8 is again a two-day event with biomedical researchers invited from around the world. This year will be the biggest yet with almost 100 top biomedical researchers participating from over a dozen countries. The IIMEC13 Conference allows researchers, clinicians and patient/ groups/patients and carers to mix with each other, discuss together and network with unique opportunities – all enabling a greater understanding of this disease. In order to bring the best education and research to London each year we welcome all support for these events as there are significant costs involved in achieving this. We are therefore extremely grateful to our friends and supporters who have helped us via online donations. We also wish to thank our sponsors for IIMEC13. The Irish ME Trust A word of thanks to the Irish ME Trust who, yet again, will be sponsoring one of the speakers to the conference. IMET have been a constant friend and supporter of IiMER, and of ME patients. They have been a leading member in the European ME Alliance. The Irish ME Trust has sponsored a speaker at all of our conferences and we would like to thank them for their continued support. Norges ME Forening Norway's ME Association (Norges ME Forening) is sponsoring the IIMEC13 conference. Norges ME Forening has been a long-standing supporter of IiMER we are very grateful for this kind donation. Thank you NMEF. Invest in ME research (Charity Nr. 1153730) Solve ME/CFS Initiative Solve ME/CFS Initiative (SMCI) has sponsored an IiMER conference for the first time but has already granted awards to two of the research groups which currently have research underway that is being funded by IiMER. Thank you SMCI. The Only Form of Graded Exercise Therapy Acceptable for People with ME Thanks to Paul Kayes Welcome to those attending Thinking the Future 2018, BRMEC8 Colloquium, IIMEC13 international ME Conference and European ME Alliance AGM. Welcome to London, Kathleen McCall In This Issue This issue of the journal contains views on the current state of research and advocacy in ME, looking at past mistakes and false views that still pervade the landscape today and have affected the perception and treatment of ME, and especially the research. Has research moved on? We have an opinion piece from Professor Ola Didrik Saugstad on the situation in Norway. If anyone were in doubt of the danger from lack of progress then the story of our friend, Anne Örtegren, is sobering. It is easy for patients to continue to believe in those who have failed them but we feel there are better choices. News from the Quadram Institute Bioscience ahead of their move to a state-of-the-art research, researchers such as Leonard Jason who still provides input to ME research. We have the UK Biobank presenting at our Colloquium – an article of the work of this national/international resource is in the Journal – answering the question what can the UK Biobank do for ME. IiMER continue to use our efforts to develop the UK/European Centre of Excellence for ME in Norwich Research Park. Exercise can be really beneficial for people with ME, but it needs to be the right kind of exercise. This is a list of activities for us to work through as part of a Graded Exercise programme. Don't take it on all at once, aim to undertake one exercise daily - IT WILL make you feel better, promise. ....................……................................. Exercises: Beat around the bush. Jump to conclusions. Climb up the walls. Wade through the morning paper. Drag my heels. Push my luck. Make mountains out of mole hills. Hit the nail on the head. Bend over backwards. Jump on the band wagon. Run around in circles. Toot my own horn. Pull out all the stops. Add fuel to the fire. Open a can of worms. Put my foot in my mouth. Start the ball rolling. Go over the edge. Pick up the pieces. What a Workout! Rest At Last. Face Book Time. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 5 of 56

Although, to be fair, it is maybe not the MRC with whom we take issue as it does some excellent work in many other fields. It is, instead, those whom the MRC have charged with responsibility for ME. They have failed miserably - or succeeded completely - depending on whether the objective was to make progress in research or to be gatekeepers for stalling any progress. If anyone doubts the lack of progress made let us look back to a time long before the disastrous PACE Trial, way before the worthless “expert panels”, before the Gibson Inquiry, even before the CMO report of 2002. In 1988 in Parliament MP Jimmy Hood tabled a motion – “to require an annual report to Parliament on progress made in investigating the causes, effects and treatment of myalgic encephalomyelitis” 30 years ago! It is worthwhile reading again. https://api.parliament.uk/historichansard/commons/1988/feb/23/myalgicencephalomyelitis#S6CV0128P0_19880223_HOC_296 Myalgic Encephalomyelitis HC Deb 23 February 1988 vol 128 cc167-81674.36 pm §Mr. Jimmy Hood (Clydesdale) I beg to move, That leave be given to bring in a Bill to require an annual report to Parliament on progress made in investigating the causes, effects and treatment of myalgic encephalomyelitis. First, I should like to pay tribute to the many sufferers who have written to me in the past few days telling me of their personal suffering from the illness myalgic encephalomyelitis—an illness that is also known as post-virile fatigue syndrome. ---------------------------------------------------------------The ME illness was first observed in Britain 33 years ago in 1955, but it was observed in other countries as early as 1939. Research into the disease is being carried out in Britain at St. Mary's hospital in Paddington, Glasgow university and establishments elsewhere. Research is also being carried out abroad, notably in Australia and the United States of America. Research shows that ME appears to be caused by virile infection, combined with a disfunction of the immune system. There is no doubt that ME is an organic disease. The nature of the disease is such that it primarily strikes the central nervous system, the brain and body muscles. Its most common symptom is a profound weakness of the body, which results in even the most active of people being confined to their bed for long periods, sometimes years. Another symptom that is more distressing than that is the illness's effect on the brain. Some normally bright, alert people find themselves unable to function. Their concentration goes; they have difficulty speaking; and even conversation leaves them completely exhausted. Sufferers lose their jobs and their lives come to a halt. Children affected lose out on their Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 7 of 56

education, sometimes for years. For many children the disease totally devastates their lives. The greatest suffering of all is the anguish caused by misdiagnosis. On top of the physical and mental stress caused by the disease, sufferers' agonies are compounded by being told that they are well, that there is nothing wrong with them, that they are malingering, or that they are neurotic. It is widely acknowledged that many incidences of suicide result from the refusal of doctors to accept that sufferers are ill from myalgic encephalomyelitis. The Bill is a simple measure which merely requires the Secretary of State to make an annual report to Parliament describing the progress that has been made in investigating the causes, effects, incidence and treatment of ME. Such 168a report would be of enormous value in drawing the attention of the medical profession, sufferers themselves and others to whom sufferers may turn for help to what is known about the illness. I cannot emphasise enough how vital it is to give proper recognition to the condition, as the failure to recognise the reality of the illness causes sufferers such great and wholly unnecessary distress. The following are authentic examples of suffering caused by ME. A mother wrote to me saying: My son aged 18 died from this miserable illness last March. He was away at university and had been ill on and off for two years. It all started with an attack of glandular fever. Now we look back over this time and so many things fit into a pattern. He was an active, bright young man with a zest for living and life. This illness got in his way. She concluded by telling me that her son committed suicide. Then there was Jill from Sussex, who said: I have been to hell and back with this devastating illness. I am still not recognised or getting proper benefits. I have received hundreds of letters about similar experiences from all over Britain, as well as Northern Ireland and the Isle of Man. Many well-known persons are afflicted with the disease. Sufferers include the Dean of Westminster; David Provan, a Scottish international footballer who had to retire from a promising career; a famous ballet dancer who is now confined to a wheelchair; and Clare Francis, a well-known adventurer and authoress. I inform the House that one of its Members, my hon. Friend the Member for Pontypridd (Mr. John), who is a sponsor of the Bill, is a sufferer. I submit that the case for justice for ME sufferers is proved beyond all doubt. I have tried today to resist the temptation to speak in strong terms about the failure of the medical profession to recognise myalgic encephalomyelitis and the failure of the Department of Health and Social Security to recognise the plight of ME sufferers. The sufferers are denied proper recognition, misdiagnosed, vilified, ridiculed and driven to great depths of despair. They look to this House for justice. For them all I commend the Bill to the House. Question put and agreed to. Bill ordered to be brought in by Mr. Jimmy Hood, Mr. Alfred Morris, Mr. Jack Ashley, Mr. Brynmor John, Mr. Don Dixon, Mr. Alan Meale, Dr. Lewis Moonie, Mr. Sam Galbraith, Ms. Harriet Harman, Mr. Jimmy Wray, Mr. Tom Clarke and Mr. Jerry Hayes. Look again at the first two paragraphs of the above motion - and this is from 1988! The sad fact is that the above motion could have been brought before parliament today. Page 8 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) In fact, this motion from thirty years is far more advanced than some recent motions that have been brought before parliament. And what was the request from this bill from 30 years ago? “The Bill is a simple measure which merely requires the Secretary of State to make an annual report to Parliament describing the progress that has been made in investigating the causes, effects, incidence and treatment of ME.” An annual report into progress! Logical, simple, coordinated. Something that any health department of chief medical officer might well see as common sense for a disease that affects so many and costs so much. Yet thirty years on we have nothing of the sort. We can wonder how things may have been if this request had been enacted. Thirty years have passed since the above motion was made, and very little has changed, and the scale of the failure of those chosen to deal with ME is apparent. So many false starts and disingenuous actions by those in influential positions! Since the CMO report on ME from 2002 people in positions of influence have had adequate opportunity to support biomedical research into ME. Instead, we witness dead-end “expert” panels and collaboratives formed – coming and going every few years, ending in failure, before another dead end initiative is set up. This pattern of stalling tactics is there to be seen and should fool no one. It is tempting for some to believe those who perform a 180o change of direction to embrace “biomedical research” into ME, or issue statements that CBT and GET should not be offered as treatments – despite having promoted these views for decades. We do not believe in these epiphanies. After years of collaborating or supporting those proponents of the biopsychosocial theories of ME, the motives for changing of views has more to do with selfinterest and less than the good of mankind at heart. Continually offering second chances to organisations that repeatedly failed people with ME is a perverse form of Stockholm syndrome. As we stated in our letters to NICE we would advise people not to believe these statements and only give trust when one sees concrete action and permanent change. Invest in ME research (Charity Nr. 1153730) Are we any closer today to joining the pieces together and creating the bigger picture than we were twelve years ago when the Gibson Inquiry of 2006 suggested that “£11 million should be made available for research to redress the balance in an illness where too much emphasis had been put on psychological ‘coping strategies’ ”? Yes and no. IiMER were probably one of the first to begin discussing the idea of international collaboration in research into ME many years ago as the way forward. We embedded this concept in all we do following the 2007 conference. Now this term is being used more and more. Yet, if we are honest, it is still not how we wished things to be. If we discount the doubtful areas of research that have received large funding in the past – what IiMER refers to as the “Wrong Stuff” – then rather than real coordinated collaboration what we see at the moment is still largely sets of disparate research threads and “territories” which continue to be, to a great extent, competing rather than joining together. Perhaps it is just the phase we are going through where everyone is finding their place in the new world www.investinme.org Page 9 of 56 Research into ME But what of research into ME? This brings us on to our cover image – which sums up the state of current research into ME.

following the decimation of the flawed PACE Trial and glimpses of realisation by the establishment that things must change. IiMER were arguably the first to develop the idea of a Centre of Excellence for ME in UK – started almost a decade ago – a while after the Gibson inquiry and after that charity had sat in interminable meetings with the NHS for years and which had achiev by the time we walked out in disgust. senseless meetings are still going on wi sign of any progress. The Gibson Inquiry recommended an investigation of those vested interests in ME that have so manipulated the research and treatment services. Dr Gibson suggested a standards committee because too often patients had to live with the double burden of fighting for both their health and their benefits. This has not occurred. Instead, it has been left to an independent journalist from outside the UK to expose the flawed PACE Trial and all of its underlying intrigue. Yet, compared to even five years ago there are changes which have occurred. Thanks to leading organisations, such as Invest in ME Research, a great deal of international collaboration has been initiated, some more funding has been found (though still mostly from philanthropic and charitable sources). The recent NIH award is encouraging but far less than Invest in ME Research suggested in our response to IOM and P2P Reports ($250 million dollars for the next five years). However, our cover image shows the reality of the state of research into ME today – lots of pieces to a puzzle, without anyone really knowing what the bigger picture will look like, even though there are hints. The landscape for ME still seems like a jigsaw puzzle with an historical lack of funding meaning that relatively few players have been able to start to create the big picture. In research it is common for false starts to occur when attempting to find the cause(s) and treatment(s) for a disease. The fact that ME has had far fewer false starts, let alone breakthroughs, than other areas of research is also an indication of the pitiful attention that has been given to it by successive governments and health departments and by disingenuous establishment representatives. Biomedical research into ME has not been well served in UK or elsewhere for a generation. Patients are (literally) sick of the biopsychosocial approach to ME and fatigued by the constant false belief that exercise will make them better. r lack of funding have been political n part, and more to do with reasons ated from researching this disease. s has had consequences in scaring off new research interest, in avoiding ME being brought into mainstream biomedical research and lacking any sort of strategy. gress from seed funding research ccasional philanthropic means has ed. is has done is to create more puzzle pieces and nothing has been joined together. So many disparate pieces of research – uncoordinated, using precious funds raised mainly by patients and poor use of the comparatively small research capacity available. Until very recently nobody has been looking at the whole puzzle, with genomics technologies now assisting. This is why Invest in ME Research has been developing a strategy since 2010 to develop the UK/European Centre of Excellence for ME – where a hub of research, based in Norwich Research Park, can be created to build up the bigger picture and then add research onto to it as knowledge develops. To create hypotheses to establish how things may link up. Already, in recent discussions on research, we can see that our Centre approach is functioning and addressing other missing aspects of the big picture that have been allowed to be ignored – such as overall standards and outcome measures which can be used by all. The basics are still lacking and there is an urgent need to raise the standards. This is why Invest in ME Research has spent so much effort in facilitating international collaboration between trustworthy biomedical researchers who wish to work together – such as the European ME Research Group (EMERG) concept. This is why common data elements is required and why the recent NIH work on that may be crucial to move forward. Page 10 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) This is why we need a specialism in ME – a clinical consultancy attached to the research. And this is why we need up to date information that is not serving the biopsychosocial ideology or some careers. These are all elements that Invest in ME Research have been developing for years, with few resources and with little support other than from the great supporters that we have. It is why we need to complete the establishment of the foundation for the Centre of Excellence that we have started - to join research and create the future rather than rely on the status quo that benefits some organisations and individuals – but not patients. An organisation can achieve a lot in five years – or it can achieve nothing. appreciate. We need momentum and international collaboration in research – and this is what Invest in ME Research provides with its cpd-accredited Colloquiums that are designed to bring together researchers, clinicians, patient groups and patients/carers in order to make progress in research into ME. This year’s Colloquium has almost one hundred biomedical researchers from around the world, from all of the main centres of research into ME and the CDC and NIH, binding these research elements together and creating new ones. The Colloquiums are created by a small charity with great supporters without support from large establishment organisations or paid employees doing the work. But then the Colloquiums are the real thing – not carrying any baggage from the wrong stuff or weighed down by affinities to the BPS lobby. Moreover, they are successful – often even helping those who choose not to support the charity. It is five years since we began funding the first biomedical research project at Norwich Research Park. An organisation can achieve a lot in five years – or it can achieve nothing. The difference is often down to individuals – those who have the passion and dedication to make change - or those who fail to do anything and are comfortable with seeing no change, merely making disingenuous platitudes aimed to assuage patient opinion. We have been reminded in recent times of how fragile life is and how healthcare is so important for a just society. Even “established” diseases that have comparatively large research funding and correct The NIH initiative is along the lines we foresaw when we initiated our proposal for a Centre of Excellence. The IiMER concept and development is based on a sound foundation and trusted biomedical researchers who are not serving their own agendas and has no baggage associated with it that can cause harm to people with ME. The key to making ME a disease that receives the highest priority is an objective that we need to attain by establishing basic building blocks and a foundation on which to progress – funding for proper, high-quality biomedical research; education about the disease; and correct perception of the disease. These aforementioned building blocks happen to be the basic objectives of the charity. We do believe that a corner has been turned and more good news is coming – some from IiMER. However, time will tell if we are heading for a new dawn – or watching the stars circle. perception amongst health departments are not without issues. We have seen examples of this close up. The negative early results from the Norwegian Phase III trial has created a vacuum in research into ME. It directly affected the charity’s plans for research and forced a major reassessment of our strategy and that of our supporters. We were recently grateful to learn that the pledge that was provided for the rituximab trial from the Hendrie Foundation has now been granted for use by the charity in other, future biomedical research. The Hendrie Foundation has been an incredible supporter showing not only advice and support but also huge integrity – a particular attribute that we Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 11 of 56

National Institute for Health and Care Excellence Guidelines for ME Correspondence with Professor Mark Baker Centre for Guidelines Director Whilst preparing for the planned NICE Stakeholders' Workshop in January to review the NICE guidelines for ME it was, in our opinion, necessary to make one request to NICE which we felt could not be delayed. We requested that NICE remove the recommendations for Cognitive Behaviour Therapy (CBT) and Graded Exercise Treatment (GET) immediately from the existing guidelines due to the possible deleterious effects on people with ME. All of the correspondence can be seen on our website here - http://www.investinme.org/IIMER-Newslet-180101.shtml. We felt that it must have now surely been realised by all that CBT and GET are inappropriate for treating ME and in many cases have proven to be deleterious to the health of patients. The PACE Trial, which was supposed to prove the efficacy of CBT and GET for ME, has been sown to be flawed and a complete waste of taxpayers’ money. Reanalysis of PACE Trial results by Matthees et al (once the data was forced to be released from the authors following a legal challenge) stated - "This re-analysis demonstrates that the previously reported recovery rates were inflated by an average of four-fold." The PACE Trial is now being used as an example of how not to perform research – and it is widely seen as flawed and is ridiculed. Several articles by David Tuller academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley, have exposed these flaws and demonstrated that the PACE Trial cannot be considered valid. We believe that a full review of the NICE guidelines, that may take two years or more, will leave patients exposed to these harmful treatments (CBT and GET) and it is not acceptable. By removing the recommendations for CBT and GET from the existing guidelines now, with an addendum or correction of some sort, it could go a long way to establishing some trust in NICE from patients that was forfeited when the previous guidelines were published and the views of patients were ignored. Thus began an exchange of letters between Professor Mark Baker of NICE and Invest in ME Research. The final letter from Professor Baker and our summary are illustrative of a system that has failed people with ME in the past and risks continuing to fail them in the future By retaining CBT as a recommendation then this only helps those organisations and individuals who continue to promote biopsychosocial theories about ME for their own vested interests and will continue the threat to the welfare of ME patients. CBT in the existing NICE guidelines is tightly connected to GET as it asserts that fear of exercise and false illness beliefs perpetuate the condition. If the treatments mentioned (CBT and GET) are already accepted to be “inappropriate”, “unacceptable” or “unsuitable” as recommended by the existing guidelines then your (and NICE’s) duty and obligation to sick and vulnerable patients is to remove them immediately. There is no other logical course to take. Summary from Invest in ME Research 9th February 2018 Following the exchange of letters with Professor Baker we have summarised our views on the statements we have received. The replies we have received force us to be very concerned about influences still affecting NICE guideline development for ME.  Professor Baker believes withdrawal of the guidelines would result in the entire support structure being removed. He has said that the services that are now provided to patients will be withdrawn if the existing guidelines are withdrawn immediately. Page 12 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730)  We have said we disagree with that. The reality is that the services offered currently are sparse at best and detrimental to patients’ health at worst and rarely meet the needs of patients. It now must surely be recognised that, in fact, there is a distinct lack of services for ME patients, then we do really think it again illogical to worry about services disappearing. To what majority view is Professor Baker referring? Is the majority view that of doctors? We doubt it! Is the “majority view” that of the lobby of psychiatrists who have so dominated the debate regarding what guidelines are imposed on people with ME, and what research is to be funded? This seems a very odd conclusion in the circumstances.  As all doctors will be told that a new set of guidelines will appear then new services will result from that. CCGs still have a responsibility to patients. In addition, we have suggested that NICE has a choice of action – if NICE does not wish to remove the existing guidelines then just adding the addendum that CBT and GET are no longer valid recommendations would be appropriate. The extremely poor or inappropriate services currently offered should not be a reason to retain flawed guidelines that harm patients.  Professor Baker stated that “the actions of some service agencies (health care commissioners, children’s services, schools and benefits agency amongst others) ”....is not something which NICE has direct influence over”.  Professor Baker claims that NICE guidelines are responsible for services being provided because they will disappear without them – whilst at the same time claiming that NICE has no direct influence over those services using them. It is hard to follow this reasoning.  The actions of some service agencies (health care commissioners, children’s services, schools and benefits agency amongst others) are the direct result of the NICE guidelines and the recommendations therein and NICE must be held accountable and take responsibility.  Despite admitting the unpopularity of the guidelines with patients, which Professor Baker and NICE state they "clearly now empathise with", Professor Baker states that the majority view has been that they have done some good.  The guidelines must surely be created to benefit patients. Professor Baker admits that they are unpopular with patients. Yet patients are only offered empathy - not action. Mere words being thrown around without any substantiation or detail is not just careless - in this situation it is disingenuous and maybe even dishonest. If Professor Baker and NICE state that a majority view supports the retention of the existing guidelines then they must provide details of whom that majority consists of. For it is not amongst patients.  Professor Baker believes that the guidelines legitimise the diagnosis.  Yet how could that be when few services have been offered, when the services that are offered are inappropriate and when Professor Baker acknowledges the horror stories confronting him where patients are not treated seriously? How can it be when the diagnosis of ME is so unreliable and unclear?  In short, we contend that the NICE guidelines have done nothing to legitimise the disease.  In fact, they have maintained an ignorance of the disease and allowed patients to be harmed - and continue to allow patients to be harmed.  Legitimation is not what patients feel.  We also contend that doctors have been ill served by these existing guidelines and cannot help their patients. After two or three decades of seeing this disease mishandled and starved of funding for proper research then we can attest to the fact that it has been anything but legitimised. Even the main protagonists of the BPS ideology, an ideology that has so completely raped this illness with its misinformation and vested interests, have stated that they do not see ME as being a disease – but instead a behavioural illness that can be cured by quack treatments. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 13 of 56

 The existing NICE guidelines have done nothing to legitimise or help ME patients and the services that are on offer are mostly inappropriate or sparse – influenced totally by the existing NICE guidelines.  Professor Baker has stated that the existing guidance is carefully worded with the implication that doctors are somehow not only aware of the “nuances” mentioned by Professor Baker, but are also understanding them.  We have to disagree. If NICE recommend CBT and GET and if these therapies harm patients then no amount of crafted wordsmanship in the world will avoid the situation where patients are harmed.  We have stated that the “nuances” and “craftsmanship” of the wording in the existing NICE guidelines to which Professor Baker refers are lost on doctors, and on almost everyone, except NICE.  Professor Baker states that the (existing) guidance is very carefully worded to protect patients and is "deeply concerned" at the actions of some service agencies (health care commissioners, children’s services, schools and benefits agency amongst others) which clearly do not represent the wording and intentions of the guidance. Professor Baker then states that this is not something which NICE has direct influence over and can only suggest that we direct our ire on those responsible for irrational decisions and the misquoting of our guidance.  This is an astonishing statement to make - and far from true.  Of course NICE directly influences what doctors prescribe.  It is NICE who are responsible for the recommendations which doctors are compelled to take into account.  This statement demonstrates that NICE still really has no idea at how much damage these existing guidelines have done, and no idea of what damage they continue to do.  Professor Baker suggested that we direct our ire on those responsible for irrational decisions and the misquoting of our guidance.  Our "ire" is actually directed at those responsible for irrational decisions or decisions that make ME patients worse. Page 14 of 56 www.investinme.org Professor Baker admitted that the guidelines would be replaced entirely. Professor Baker has agreed that CBT and GET are perceived and experienced by patients as harmful. We believe that Professor Baker accepts the claims that patients have been harmed by CBT and GET It therefore defies logic to retain harmful recommendations for two more years or morewhen it is clearly understood that patients are being harmed by these recommendations.  Professor Baker stated that the PACE Trial has had no effect on the recommendations of NICE (despite last summer the surveillance review quoting the PACE Trial).  In our letter to Professor Baker we did not refer to PACE as being the base of evidence for NICE guidelines. We only intended to refer to PACE in case Professor Baker came back to us to deflect our argument that CBT and GET need to be dropped by referring to PACE.  Yet NICE did use it to base its decisions in the surveillance review of 2017  We have stated it is illogical, and harmful to patients, that NICE retain the existing guidelines when it is admitted they are not fit for purpose, are not what patients want and potentially harm patients, and will be discarded in any case.  NICE must follow the USA and remove recommendations for using CBT and GET as treatments for ME with an addendum to the existing guidelines.  We have requested that this addendum is communicated to other healthcare agencies around the world who have misguidedly used the existing NICE guidelines as any basis for their own treatment of ME patients.  We began this series of letters to Professor Baker due to the comments attributed to him and NICE. These comments have made us wonder how these would be translated into action.  Professor Baker’s reply to us – a few hours before the stakeholder meeting – clearly seemed to be contradictory to the comments that Professor Baker made to the participants in the stakeholder meeting and raised major concerns for us as to the actual way NICE were intending to proceed. Invest in ME research (Charity Nr. 1153730)  This, and further replies to our initial request to remove CBT and GET from existing guidelines, baffled us.  The fact that Professor Baker has stated that the existing NICE guidelines will be torn up indicates this realisation that NICE and the existing guidelines have failed.  What patients have said has proven to be true. Yet NICE did not listen.  We detect even now that these messages still have not been taken on board.  Comments such as “we will tear up” the existing guidelines need to be translated into immediate action.  We have words from NICE - but no action.  NICE must separate the decision on the continuation of the existing guidelines from the review of them. These are two separate matters – linked by the fact that NICE has already decided to tear up the existing guidelines and that Professor Baker accepts that CBT and GET are harmful to ME patients.  The existing guidelines must be withdrawn or NICE must add an addendum that CBT and GET are no longer recommendations.  The refusal to add an addendum to existing guidelines to remove BOTH CBT and GET is illogical in the context of the remarks made by Professor Baker/NICE. To avoid further harm to patients they would remove the drug immediately.  This is the same situation that NICE now face with CBT and GET for ME.  Professor Baker has written to IiMER that he “will discuss at the highest level at NICE what remedial action to help patients we can take in the meantime.” We hope that this will result in issuing the addendum to the existing guidelines that removes CBT and GET as recommendations for ME – or otherwise the withdrawal of the existing NICE guidelines for ME immediately.  We do not share the euphoric tributes to NICE for arranging a workshop where the audience is told everything that they want to hear. Our recommendation to ME patients and their families is not to trust comments by NICE and not to trust NICE at all – until the day arrives that NICE actually deliver and The refusal to withdraw the existing guidelines whilst they are torn up and new guidelines are developed carries a level of illogical reasoning. Professor Baker has admitted the existing guidelines are unfit, he has accepted the horror stories of patients being coerced into trying CBT and GET and being harmed by them, he has heard of insurance companies denying benefits when people refuse to agree to try these flawed theories recommended by NICE. operationalise guidelines for ME that really do reflect the reality and needs of ME patients and their families.  Years of experience of establishment tactics involving wasting several years on initiatives that are already designed to deliver nothing of consequence have made us wary of the corrupt systems in place.  Based on their track record NICE do not yet deserve any such trust.  ME patients have had very little bargaining power over the last decades thanks to the insidious and immoral network of BPS protagonists who have influenced all policies on ME in the UK and taken over decision making in weak and apathetic research councils and government departments. In all of this how can it be logical, or moral, or safe, to retain these existing guidelines, and especially the disastrous and damaging recommendations for CBT and GET? If a drug is recommended by NICE for a disease and some time later the drug is found to be harming patients then surely NICE would take steps to remove that drug. They would not retain it as a recommendation, to be in use for two years whilst they developed a new guideline for the disease. Invest in ME research (Charity Nr. 1153730)  What patients have been able to retain is the ability to give or withhold their trust in new initiatives that promise change to improve their lives. In the world of social media, where the playing field has been levelled in recent times and allowed patients to challenge biased research, this provision of trust by the patient community can be a useful commodity.  We therefore do not give NICE our trust. Our recommendation to ME patients and their families is not to trust comments by NICE and not to trust NICE at all – until the day arrives that NICE actually deliver and operationalise guidelines for ME that really do www.investinme.org Page 15 of 56

reflect the reality and needs of ME patients and their families. Currently that date would be somewhere in two years time. NICE can bring forward that date by acceding to our request to add an addendum immediately to the existing guidelines to remove recommendations for BOTH CBT and GET - or by withdrawing the existing guidelines for ME immediately, and issuing a press release to doctors in UK and abroad that NICE has found the existing guidelines to be unsatisfactory, that they are going to be torn up and completely revised. If NICE do this then trust will surely be given by ME patients. Sir Andrew Dillon might even find it within himself, on behalf of NICE, to issue an apology to ME patients for the wasted years and the distress and the harm which the existing guideline recommendations have caused. If NICE do not take this eminently logical and fair decision immediately then there is no reason to give that trust. We really do hope that NICE now act in a logical and fair way with the patients in mind - uninfluenced by the evil of the BPS network that has been allowed to flourish over the last decades. Add the addendum to remove CBT and GET – or Tear It Up! Now! Finally, look at a communication below, from a patient, that has come to Invest in ME Research in the last month - a letter which neatly describes the appalling consequences of recommending CBT and GET - something for which Professor Baker and NICE cannot pass on responsibility to others. This is the result of NICE's recommendations in their existing guidelines - and this just underlines everything we have been trying to make Professor Baker, and NICE, understand. This letter alone is a testament to the failure of NICE to help people with ME and their families - and a decade on from the creation of the existing guidelines there is enough of an indication that no lessons have been learnt - or any real intent is underway to correct the failings. Throughout our correspondence it seems clear that Professor Baker is oblivious to the elephant in the NICE room - no matter how much damage it is doing to patients. NICE must serve the needs of patients. Page 16 of 56 www.investinme.org Unfortunately, we fear that NICE will not do as we suggest and will not act for the interests of patients. We can only surmise that more influential forces are still present, continuing to force more CBT and GET on to patients. If that were so it would be shameful. NICE, and those deciding on the future for people with ME, must be held accountable if more people are harmed by retaining the existing damaging recommendations for using CBT and GET for another two or more years. Further Reading 1/ 2/ NICE Campaigning Notes on BPS Model From a Patient: To Invest in ME Research I have been closely following your continuing correspondence in relation to the call for revision of the NICE guidelines. In particular the removal of CBT/GET. I have had M.E. for almost four years and am quite severely affected. I am housebound most of the time and often bedbound. I was previously a 'high flyer' (my neurologists' words) and a civil servant with a social work background. Due to my illness I am no longer able to work, and have just been through the very painful process of applying for ill health retirement. My pension provider (through the (name provided) pension scheme) has a two tier system for pension awards in the circumstance of ill health retirement. I have undergone five medical assessments during the process and have been assessed as permanently incapacitated in terms of employment. However, as I have not completed the treatment, as recommended in the NICE guidelines, I cannot obtain the higher rate pension. The treatment namely being CBT and GET. I have engaged with the specialist M.E. service in (location provided) but was unable to continue as attending sessions made me more unwell. I tried CBT through my local mental health service, attending three out of six sessions, this made me more unwell and put me back into bed for weeks. I am in receipt of the highest rate of both ESA and PIPS. These were both awarded following the first medical assessment, which I understand is not the position for far too many M.E. sufferers. Invest in ME research (Charity Nr. 1153730) I have taken my ill health retirement case to appeal within my pension service. The position of the original decision not to award me the higher rate pension has been upheld on the grounds that I have not completed CBT and GET. which takes around three hours to get me ready for, with lots and lots of assistance from my wife, who is also my carer and carer to our 18 year old disabled son. My pension provider will now escalate my appeal to stage two of the process. However, the decision makes it clear that, in order to succeed, I need to prove that I have completed CBT and GET. I am faced with a position that is unfair and takes away any right I have not to undergo treatment that exacerbates my illness. I have had support from my union (name provided), however they aren't familiar with the fight that M.E. suffers like myself face. Please please continue the fight for those of us struggling to do it for ourselves I often find it difficult to construct challenges around my illness as i simply can't find the words due to my diminished cognitive functioning. This is one of the hardest symptoms to deal with. The loss of intellect. It's in there somewhere, I'm in there somewhere, but I just can't get the words to make sense. It is imperative that someone listens to our voices and I am so thankful for your determination in challenging the medical profession around our treatment options. It will probably be too late to make any difference to my case. I have previously had a life where i travelled up and down the country for my career, helping to make a difference in the lives of vulnerable children. I had authority and was very much a professional. I have always worked within the public sector, both local and central government. I had a lively social life, always on the go with my partner and family. Now my life revolves around my bedroom. I rely on pillows, blackout curtains and strong medication to try and control my pain. If I journey out, it is to visit my G.P. I hope that in the future no one will be penalised for not undergoing treatment that is harmful to their health as a result of your campaigning; that CBT and GET will be removed from the guidelines with immediate effect, rather than waiting for years while the guidelines are revised. Please please continue the fight for those of us struggling to do it for ourselves Little more needs to be said. IiMER Conference DVDs The Invest in ME Research conference DVDs are professionally filmed and authored DVD sets consisting of four discs in Dolby stereo and available in PAL (European) or NTSC (N. America) format. They contain all of the presentations from IiMER International ME/CFS Conferences (2006 – 2013). Also included in the DVD sets are interviews with ME presenters, news stories and round-table discussions. The Invest in ME Research conference DVDs have been distributed to more than 20 countries and are available as an educational tool – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at http://www.investinme.eu/IIMEC13pastconferences.shtml or via emailing Invest in ME Research at info@investinme.org Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 17 of 56

Research News from Katharine Seton “Defining autoimmune aspects of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)” I would like to introduce myself to you all. I am Katharine Seton, a 22-year-old PhD student and I have just began the second year of my PhD. I originally came from Cumbria and studied Biomedical Sciences at Newcastle University before starting my PhD funded by Invest in ME Research. I have always had a strong interest in the immune system and ME research. I have a personal investment and interest in ME research, because in January 2009 I was diagnosed with ME, when I was just 13 years old. It was both physically and emotionally challenging to make the transition from a very active and musical child, regularly competing in basketball, swimming, orienteering, hockey, netball and athletic events, to a child too ill to attend school more then 9 hours a week. Up until my ME diagnosis, I had always dreamt of being a stunt woman and having a very active career. When I developed ME, I had to cut out sport, music and socialising, which meant I became focussed on my education. I realised after I managed to achieve 11 GCSE’s grades A* to A whilst attending school on a part time basis that I am academically able, something I did not realise prior to my ME diagnosis because I was always so focussed on sport. It was only once I was at University, studying my undergraduate degree, that I came to the realisation that I could contribute to the ME research field. In the summer of my second year, I had a Wellcome Trust funded Vacation Studentship, researching the heritability of ME with Professor Julia Newton at Newcastle University. I loved every minute of this placement, although it was computer based, and after this valuable work experience I realised that I would love to contribute to laboratory research into the cause of ME. I aspire to help find a cure for ME … so watch this space! The research that I am focussing on in my PhD is the immune system and its interaction with gut microbes, specifically, whether there is an inappropriate immune response triggered by bacteria that has leaked across the gut wall. There is current evidence of an inappropriate immune response and gastrointestinal involvement in ME Page 18 of 56 www.investinme.org patients and I endeavour to find out whether there is a link between the two, and if this link is blocked, would it lead to symptom improvement. As ME patients experience a wide range of symptoms, and have different onset patterns, it is a scientifically challenging area of research to study, often yielding different results between different research groups. The first year of my PhD was focussed on creating a plan for recruitment, sample collection and sample analysis. This study has received ethical approval from the Health Research Authority, and participant recruitment is underway. It has been agreed that this study will focus on the recruitment of severe ME patients and their household controls, recruited through East Coast Community Healthcare Centre and through Dr Bansal at Epsom and St Helier CFS Clinic. As this is a longitudinal study, blood and stool samples will be collected on up to six occasions. Now that we have received ethical approval for this study, the second year of my PhD will be focussed on participant recruitment, sample collection and processing, and sample analysis, hopefully leading to the generation of some interesting, valuable, results. Katharine Seton - Quadram Institute, Norwich A Study Update Posted by: Katharine Seton Post Date: 8 February 2018 With regards to the human study being undertaken at the Quadram Institute, “Defining autoimmune aspects of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” progress has been made, despite hold ups. 50% of the target number of patients have volunteered to participate in the study. The main study obstacle was identifying a trained person for blood sample collection. Invest in ME research (Charity Nr. 1153730) A trained person has been identified at the Quadram Institute to take blood. An amendment application and approval from the Health Research Authority has been obtained, and a contract delegating study responsibilities between the University of East Anglia and the Quadram Institute is underway. Once this is in place, home visits and sample collection can commence. Despite not being able to collect samples yet, major progress in method development and optimisation has been made. This was done using banked samples from Daniel Vipond’s PhD. Between (fellow PhD students) Fiona Newberry, ShenYuan Hsieh and myself we have optimised the following: isolation of virus particles from stool samples, viral identification based on unique sequences, and a method to screen for antibody responses to gut microbes. I have recently had a review with my PhD supervisors, the purpose of which is to identify how much progress has been made. I received positive comments that have given me some added motivation: “The quality of the work undertaken to date is also very good with considerable careful and detailed effort being put into evaluating multiple experimental variables to optimise the assay”. Looking forward, the next couple of months entail home visits, sample collection and sample processing, all of which take a considerable amount of time. While this is occurring, method development will be continued and progressed. In addition, we have also been very kindly invited to give a presentation at the Shropshire ME Group Conference in May. This is a great opportunity to communicate our research to the public, and to engage with the public to hear their thoughts. The move in date to the new Quadram Institute building is now August 2018. This provides us with plenty of time to do the first round of sample collection. On a finishing note, I would really appreciate those who received a study invitation, and are interested in participating in the study to please contact myself soon to register your interest. Bye for now – Katharine Katharine Seton - Quadram Institute, Norwich A New Paper from Fiona Newberry et al IiMER-funded PhD student Fiona Newberry has recently had a paper published - “Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome?” – with an interesting observation “..as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. " https://ueaeprints.uea.ac.uk/66615/ Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 19 of 56

Thinking the Future - Young/Early Career Researchers for ME Research into Myalgic Encephalomyelitis Prior to the conference Invest in ME Research organised the inaugural meeting of a new international network to encourage young and early career researchers to this field. Despite the seriousness of this disease still very little biomedical research is funded or performed on ME. An international family of researchers working together has been facilitated by the Invest in ME Research Biomedical Research into ME Colloquiums. However, the charity felt that we needed to do more to attract and encourage new, younger researchers or those at the early stages of their careers. To ensure that a foundation of biomedical research into ME can be sustained and to encourage new ideas from new areas then we cannot rely just on the family of researchers that has been built up from all parts of the world. We need to draw in knowledge and expertise from other areas – as we have been doing for many years with our Colloquiums and international conferences. Importantly, we also need to encourage new researchers – and young researchers. Now in its eighth year we wish to introduce another level to the Biomedical Research into ME Colloquium to address these points. As part of the European ME Research Group (EMERG) concept - which is building a network of close European biomedical research collaboration to make rapid advances in research and funding for ME - we introduced a new idea. Thinking the Future. An Early Careers Researcher is defined an individual who is within a few years of the award of their PhD or equivalent professional training, or their first academic appointment. IiMER has created this additional event to encapsulate the need to bring in new faces and new ideas to the field of ME research - and initiate a network for new research talent. The charity made this event free for young/ecr researchers in order to facilitate the establishment of these links and it is open to postgraduate students and postdocs involved in biomedical research, and also medical students with an interest in biomedical research into ME. Page 20 of 56 www.investinme.org We will establish this international forum where research into ME can be discussed, ideas can be generated and a network built to allow opportunities for those young or early career researchers who are already involved in research into ME, or involved in another research area which may be of relevance to understanding ME. Importantly, it will provide more awareness of the exciting possibilities of researching this disease – for the betterment of patients and carers. To make this an international group with events being held elsewhere, and in other countries, we have contacted research groups and our friends in other likeminded charities and organisations who have the same objectives as us. We welcome all support for this and hope that more early career researchers and research departments will begin to appreciate the interesting and challenging opportunities that exist for biomedical research in this field. Help us Think the Future - for ME Invest in ME research (Charity Nr. 1153730) Quadram Institute Bioscience News Opening fully in mid-2018, the Quadram Institute will be at the forefront of a new era of food and health research, working at the interface between food science, gut biology and health. It will develop solutions to worldwide challenges in food-related disease and human health, with a lifelong focus from establishing optimum health at birth through to ensuring we age healthily. The Quadram Institute is assembling interdisciplinary teams and working with appropriate international organisations to address these major issues. Scientists and clinicians working together under one roof will deliver innovative new healthcare solutions. Based on the Norwich Research Park, it is a partnership between Quadram Institute Bioscience, the University of East Anglia (UEA) and the Norfolk and Norwich University Hospitals NHS Foundation Trust. This brings together excellent research, teaching and patient care, synergising collaborations between the 3,000 scientists and clinicians working in six world class organisations clustered on the Norwich Research Park. This concentration of interdisciplinary expertise is needed if we are to solve complex health problems facing society. The Quadram Institute, supported by the charity Invest in ME Research, has established a programme of biomedical research addressing the complex causes of Myalgic Encephalomyelitis (ME). Our ME studies are led by Professor Simon Carding, who leads QI’s Gut Microbes and Health research programme, and is also Professor of Mucosal Immunology at the Norwich Medical School at the University of East Anglia. The research builds on recent evidence that ME/CFS has a basis in the immune system. Our focus is on the interactions between the immune system and the microbiota in the gut. Many ME Invest in ME research (Charity Nr. 1153730) sufferers also have gut-related conditions and several studies have recorded altered microbiota communities. The gut is a major focal point of the body’s immune system. It must deal with a constant barrage of potentially harmful microbes taken into the body with our food, whilst also supporting a large community of microbes that benefit health – the microbiota. Part of the Quadram Institute’s mission is to understand how this balance is maintained, and how changes in this balance lead to diseased states. One aspect of this includes the study of what happens when the lining of the gut, the intestinal epithelium, fails to act as a barrier and members of the microbiota are able to cross. This is known as leaky gut syndrome and may be important in a number of conditions, including ME/CFS, as it abnormally presents microbes to the immune system and potentially triggering an autoimmune response. With partners at University College London, we are looking at the nature of autoimmune reaction in patients with ME. An important aspect of our research into links between the microbiota and ME/CFS is to understand better the role played by viruses in the microbiota. Much research has focused on the bacterial populations, but the microbiota contains many other organisms, including fungi and viruses, as well as bacteriophages (viruses that infect bacteria). Viruses in particular are of interest in the study of ME/CFS as there has been evidence suggesting a viral role in triggering ME/CFS without being able to identify specific causes. Working with colleagues at UEA, we are looking to fully study the viral component of the microbiome, the virome, and its relevance to ME/CFS. Much of our work to date has been supported by the charity, Invest in ME Research, who, as well as raising funds for biomedical research are working to raise awareness of the condition and supporting collaborative efforts across the EU to tackle ME. One target is to establish a Centre for ME Research, building on excellent biomedical research, to act as a hub for European research and treatment of ME. www.investinme.org Page 21 of 56

UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age Cathie Sudlow1,2, John Gallacher3, Naomi Allen2,4, Valerie Beral4, Paul Burton5, John Danesh6, Paul Downey7, Paul Elliott7, Jane Green4, Martin Landray4, Bette Liu8, Paul Matthews7, Giok Ong9, Jill Pell10, Alan Silman11, Alan Young4, Tim Sprosen4, Tim Peakman2, Rory Collins2,4* 1 University of Edinburgh, Edinburgh, United Kingdom, 2 UK Biobank, Stockport, United Kingdom, 3 University of Cardiff, Cardiff, United Kingdom, 4 University of Oxford, Oxford, United Kingdom, 5 University of Bristol, Bristol, United Kingdom, 6 University of Cambridge, Cambridge, United Kingdom, 7 Imperial College, London, United Kingdom, 8 University of New South Wales, Sydney, Australia, 9 University of Warwick, Warwick, United Kingdom, 10 University of Glasgow, Glasgow, United Kingdom, 11 University of Manchester, Manchester, United Kingdom * enquiries@ukbiobank.ac.uk Copyright: © 2015 Sudlow et al. The challenge of understanding the determinants of common life-threatening and disabling conditions is substantial. These conditions are typically caused by a combination of lifestyle, environmental, and genomic factors, with individually modest effects and complex interactions, the detection and quantification of which require studies with large numbers of disease cases. While retrospective case-control studies of particular diseases [1] or existing prospective studies of particular risk factors can help to address this challenge [2,3], a complementary approach is to establish large prospective cohorts designed to study a much wider range of known and novel risk factors for a wide range of diseases [4]. Prospective studies can assess exposures before the onset and treatment of disease, diseases that are not readily investigated by retrospective studies, and both the adverse and beneficial effects of a specific exposure on the lifetime risks of different diseases. UK (United Kingdom) Biobank is a very large, population-based prospective study, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases of middle and old age [5,6]. It aims to combine extensive and precise assessment of exposures with comprehensive follow-up and characterisation of many different health-related outcomes, as well as to promote innovative science by maximising access to the resource. Recruitment of Page 22 of 56 www.investinme.org Summary Points • UK Biobank is a very large and detailed prospective study with over 500,000 participants aged 40–69 years when recruited in 2006–2010. • The study has collected and continues to collect extensive phenotypic and genotypic detail about its participants, including data from questionnaires, physical measures, sample assays, accelerometry, multimodal imaging, genome-wide genotyping and longitudinal follow-up for a wide range of health-related outcomes. • Wide consultation; input from scientific, management, legal, and ethical partners; and industrial-scale, centralised processes have been essential to the development of this resource. • UK Biobank is available for open access, without the need for collaboration, to any bona fide researcher who wishes to use it to conduct healthrelated research for the benefit of the public. 500,000 participants and the collection of an unprecedented wealth of baseline data and samples were completed in 2010. Activity is now focused on further phenotyping of participants and their health outcomes and on providing access to researchers from around the world. Cohort Size The large size of the cohort was based on statistical power calculations for nested case-control studies [7], showing that 5,000–10,000 cases of any particular condition would be required for the reliable detection of odds ratios (ORs) for the main effects of different exposures of 1.3–1.5 (the upper end of the range reported from genomewide association studies of various conditions [8]), and around 20,000 cases for detection of interactions with ORs of at least 2.0. To observe such large numbers of cases of particular diseases within a reasonable follow-up period, prospective cohorts need very large numbers of participants. Projected numbers of cases of a range of common conditions expected to occur among 500,000 UK Biobank participants during 20 years of follow-up (Table 1) suggest that reliable assessment of the main determinants of most of these conditions (and others that are similarly common) should be possible during the current decade [6,9]. The age range for inclusion of 40–69 years represented a pragmatic compromise between participants being old enough for there to be sufficient incident health outcomes during the early Invest in ME research (Charity Nr. 1153730) years of follow-up and young enough for the initial assessment to occur before incipient disease had a material impact on exposures. Data Availability Data from the Baseline Assessment The 500,000 participants were assessed between 2006 and 2010 in 22 assessment centres throughout the UK, covering a variety of different settings to provide socioeconomic and ethnic heterogeneity and urban– rural mix. This ensured a broad distribution across all exposures to allow the reliable detection of generalisable associations between baseline characteristics and health outcomes. The assessment visit comprised electronic signed consent; a selfcompleted touch-screen questionnaire; brief computerassisted interview; physical and functional measures; and collection of blood, urine, and saliva (Table 2).Multiple aliquots of different sample fractions are stored in UK Biobank’s automated laboratory, allowing for a wide range of future assays [10]. Data from Additional Assessments to Enhance Phenotyping UK Biobank is conducting a range of additional phenotyping assessments in all (or large subsets) of the participants. Data are already available both from a detailed dietary web questionnaire [11], completed up to four times by over 200,000 participants, and from the first repeat of the entire baseline assessment in around 20,000 participants [12]. Over the comingmonths and years, further data will become available from: a range of biochemical assays and Invest in ME research (Charity Nr. 1153730) genome-wide genotyping of baseline samples from all participants;Web-based questionnaires to assess specific characteristics in more detail (e.g., cognitive function, occupational history); and, in subsets of 100,000 participants, collection of data from physical activity monitors and multi-modal imaging (Table 3). Data from Longitudinal Follow-Up for Health-Related Outcomes Follow-up is conducted chiefly through linkages to routinely available national datasets. Data are already available on over 8,500 deaths, over 75,000 prevalent and incident cancers, and over 600,000 hospital admissions, while linkages are planned to a range of other datasets, including primary care, cancer screening data, and disease-specific registers. In addition, to reduce misclassification and increase biological specificity of health outcomes, UK Biobank is developing methods for accurate identification and detailed phenotyping of outcomes in a range of disease areas. Initial ascertainment of outcomes with electronic and semi-automated sources will be supplemented by more intensive methods (e.g., retrieval of case records, imaging data, or banked tissue samples) for validation and subclassification (Table 3). Online Open Access to Researchers Many cohort studies have mechanisms for sharing data with external researchers on a collaborative basis, but relatively few have arrangements for open access to the data without any need for collaboration, and even fewer have been established from the outset with the intention of making the entire resource available to the www.investinme.org Page 23 of 56

global research community. The development of open access arrangements for data from cohort studies is an important step in maximising their impact with respect to scientific publications, policy making, and understanding of health and disease. Examples of resources whose impact has been enhanced in this way include the UK 1958 birth cohort study [13] and the Australian 45 and Up cohort study [14]. UK Biobank aims to encourage and provide as wide access as possible to its data and samples for healthrelated research in the public interest by all bona fide researchers from the academic, charity, public, and commercial sectors, both in the UK and internationally, without preferential or exclusive access for any user. UK Biobank’s publicly available Data Showcase (http://www.ukbiobank.ac.uk/) presents the univariate distributions and methods used for collection of all the contact are subject to a more rigorous process of scrutiny and scientific review. Following initial assessment by the executive team, all applications are assessed and either approved or rejected (with right of appeal) by an independent Access Subcommittee. Advice is sought on any applications raising potential ethical issues from both the University of Oxford’s Ethox Centre and the Ethics and Governance Council. Only de-identified data are provided to researchers, who must sign a material transfer agreement, undertaking not to attempt to identify any participant, to keep the data secure, and to use it only for the purposes of the approved research. Researchers must also undertake to publish their results and to return details of their methods, derived data, and/or sample assay results for incorporation into the UK Biobank dataset so that they can be made available to other approved researchers (see variables available for health-related research, enabling potential research users to explore what data are available and plan research applications. An online access process, launched in April 2012, aims to be fair, transparent, and streamlined. Applications for data only are approved so long as the proposed research is in the public interest and the data required are, or will become, available. Applications involving the use of depletable samples or requiring participant rePage 24 of 56 www.investinme.org www.ukbiobank.ac.uk/scientists/ for details). UK Biobank encourages, but does not mandate, publication of results of research based on the resource in open access journals. Ensuring that the resource and its access arrangements are widely communicated is Invest in ME research (Charity Nr. 1153730) an important task, requiring a dedicated communications team to manage UK Biobank’s website, scientific meetings, and other methods for communication with the scientific community, including emails, newsletters, and other social media. In the first two years after the launch of open access to UK Biobank, over 1,000 researchers successfully registered, and over 200 applications were submitted (see www.ukbiobank.ac.uk/approved-research/ for a summary of research that is currently underway). Over 80% of registered researchers were from the UK and over 95% from academic rather than commercial institutions. Approximately 85% of applications Invest in ME research (Charity Nr. 1153730) were for data only, with few as yet requesting use of samples or participant recontact. UK Biobank has now started to receive notifications of submitted abstracts and manuscripts based on the first few completed research projects. UK Biobank reviews its access procedures regularly, revising them in the light of experience and user feedback to make the process as streamlined as possible while remaining consistent with participant consent. Running UK Biobank Success so far in developing and enhancing the resource has relied on public willingness to participate www.investinme.org Page 25 of 56

in prospective research studies; close engagement with funders, government health departments, and the UK National Health Service; extensive consultation with the public, scientists, and a wide range of regulatory, legal, and ethics bodies; and the development of costeffective and efficient methodological approaches. The most significant challenges to be overcome are the implementation of scientifically rigorous processes on a very large scale, sustaining the funding required to ensure the benefits of the resource are fully realised, obtaining approvals from multiple regulatory bodies in a frequently changing political and healthcare environment, and ensuring as wide as possible communication of the non-preferential, open access nature of the resource. Interactions with Participants Participant recruitment, retention, and engagement with enhancement projects has benefited from the willingness of very large numbers of British people to take part in observational research without the prospect of direct personal gain [15]. Participants spent an average of about two and a half hours at the recruitment visit. All gave broad consent to use of their anonymised data and samples for any health-related research, to be re-contacted for further substudies, and for UK Biobank to access their health-related records. Large subsets have subsequently completed Web-based questionnaires, agreed to wear a physical activity monitor, and repeated the entire baseline assessment. Of those who attended the first repeat assessment visit and provided feedback, 92% reported that they would be willing to travel for up to two hours for an imaging assessment visit lasting half a day. UK Biobank keeps its participants involved through providing progress updates via its website, with annual newsletters, and through its dedicated Participant Resource Centre (PRC), enabling them to continue to support the project and participate in research over the years ahead. Interactions with Funding Bodies Having established UK Biobank as a charitable company over a decade ago, the UK Medical Research Council and Wellcome Trust have provided the vast majority of its funding so far. These major funders have had the long-term vision to continue to invest substantially in its ongoing development as a global research resource, coordinating both the scientific review of major proposals for developments to the resource and contributions from other funding bodies, including the Department of Health, Scottish and Welsh Governments, North West Development Agency, British Heart Foundation, and Diabetes UK. Long-term funding is not guaranteed, but depends on UK Biobank working Page 26 of 56 www.investinme.org in close partnership with its funders towards the common goal of facilitating high-quality, cost-effective research that will improve the public’s health. Crucial to this partnership is provision and joint discussion of regular updates on progress against challenging milestones, new strategic goals, scientific opportunities, financial plans, and use of the resource to generate new scientific knowledge. Interactions with the UK’s Publicly Funded National Health Service Participant recruitment relied on invitations being mailed to 9 million people whose contact details were obtained from National Health Service (NHS) central registers. Large-scale epidemiological studies in the UK benefit from the fact that 98% of the population is registered with the NHS, which keeps detailed records on all of them from birth to death. Linkages to NHS datasets provide the principal means of follow-up for health-related outcomes. Industrial Scale, Centralised Processes A key step i n achieving the cost-effective recruitment, characterisation, and follow-up of 500,000 participants was the creation of an executive and advisory team with complementary scientific and management skills and a coordinating centre dedicated to the generation of a resource for the scientific community. This facilitated the development of a centralised infrastructure, bespoke information technology (IT) systems, and industrial approaches to collection and processing of data and samples. For example, inviting potential participants via individual general-practice groupings (an approach used by smaller UK populationbased studies) would have been impractical for a study of UK Biobank’s scale, so appropriate approvals were obtained to allow direct mailing of invitations using contact details held centrally by the NHS. The recruitment process itself was coordinated centrally, with up to six assessment centres being active at any one time during the recruitment phase. Staffing and equipment needs were carefully configured to ensure the smooth flow of around 100 participants per day through each assessment centre for six days per week. Biological samples were also processed and handled centrally, requiring the development of bespoke laboratory information management and automated robotic systems to facilitate rapid, error-free sample storage in, and extraction from, the freezers (at rates of up to 1,500 samples per day) according to particular sample and participant characteristics [16]. Each step of the recruitment, assessment, and sample handling process was first piloted, modified as necessary and monitored centrally, using statistical methods to identify potential performance issues. Similar industrialInvest in ME research (Charity Nr. 1153730) scale, centralised processes have been or are being developed for the repeat assessment and imaging visits. Governance Structure UK Biobank’s Board of Directors has overall responsibility for its direction and management. An Executive Management Team, with epidemiology, clinical, management, laboratory, legal, and communications expertise, oversees the development and day-to-day management of the resource and is responsible for the staff working on the study, most of them based at its coordinating centre near Manchester, with others at the Universities of Oxford, Edinburgh, Cardiff, and London. The executive team receives guidance from a Steering Committee of leading UK scientists, supported by specialist working groups advising on baseline data collection, enhanced phenotyping, follow-up and outcomes adjudication, and an international perspective is provided by an International Scientific Advisory Board (see S1 Consent Form and www.ukbiobank.ac.uk/governance/). This governance structure has facilitated effective working between scientific and management disciplines, allowing UK Biobank to respond to advice from a wide network of scientists on the most scientifically valuable design and development of the PLOS Medicine | DOI:10.1371/journal.pmed.1001779 March 31, 2015 7 / 10 resource, with project management and implementation being the responsibility of UK Biobank’s Executive Management Team and dedicated staff. Robust Ethics and Governance Framework UK Biobank has consulted widely not only with the scientific community but also with the public, its participants, and other interested parties [17,18]. This has informed the development of its Ethics and Governance Framework, which lays out its principles and policies [19], as well as its access procedures [20]. UK Biobank’s research ethics committee and Human Tissue Authority research tissue bank approvals mean that researchers wishing to use the resource do not need separate ethics approval (unless re-contact with participants is required). An independent Ethics and Governance Council oversees adherence to the Ethics and Governance Framework and provides advice on the interests of research participants and the general public in relation to UK Biobank. In keeping with the informed consent given by its participants, UK Biobank does not generally provide feedback to individual participants about information derived from analyses of data or samples made following their assessment visits. Participants receive limited individual feedback in two areas. First, they Invest in ME research (Charity Nr. 1153730) receive a summary of standard measures (e.g., blood pressure, body mass index) at the end of each assessment visit and are encouraged to seek medical advice for results outside the normal range. Second, potentially serious incidental findings (i.e., those likely to threaten life span or have a major impact on quality of life) observed by study staff during these assessments (e.g., possible melanoma on exposed areas of skin) are brought to the attention of participants with encouragement to contact a relevant health professional. Similar feedback is occurring in the imaging substudy, with participants and their general practitioners informed of potentially serious incidental findings noticed by radiographers and confirmed by formal radiologist review. In addition, the overall findings and implications of results that derive from research using the UK Biobank resource are made available to researchers, participants, and the wider community so that they can influence public health strategies. Interactions with Regulatory Bodies The wide consultation, rigorous Ethics and Governance Framework, and Ethics and Governance Council oversight role have been essential in paving the way for UK Biobank to accomplish obtaining the multiple ethical and regulatory approvals required for participant recruitment, sample and data storage, linkages to routine health care data, enhancement studies, and the provision of access to data and samples for approved researchers. Substantial amounts of time, resources, patience, tenacity, and evidence of feasibility and/or acceptability from smaller scale pilot studies have also been required to provide regulatory bodies with the reassurance that they need of UK Biobank’s rigorous approach and commitment to protecting the interests of its participants within an acceptable legal and ethical framework. Conclusions The key lessons learned from establishing UK Biobank are that such large-scale studies require not only a clear scientific focus but also streamlined governance; effective working between academic and management disciplines; centralised infrastructure with industrial approaches to collection and processing of data and samples; close partnership with major funders; a wide network of scientific advisors; high-quality, pragmatic legal and ethical advice; and widespread public support [21]. The resource is now facilitating research by scientists from around the world who wish to investigate how different diseases are caused by the combination of lifestyle, environment, and genes, leading to improvements in prevention, diagnosis, and www.investinme.org Page 27 of 56

treatment. Perhaps unsurprisingly, early use has been mainly, but not exclusively, by UK-based scientists. A major aim for the immediate future is to encourage applications from outside the UK. To facilitate this, UK Biobank is further developing its communications strategy to increase awareness of the resource and its access procedures worldwide. Supporting Information S1 Consent Form. (PDF) S1 Text. UK Biobank Committees and Working Groups. (PDF) Author Contributions Wrote the first draft of the manuscript: CS JG NA GO RC. Contributed to the writing of the manuscript: CS JG NA VB PB JD PD PE JG ML BL PM GO JP AS AY TS TP RC. ICMJE criteria for authorship read and met: CS JG NA VB PB JD PD PE JG ML BL PM GO JP AS AY TS TP RC. Agree with manuscript results and conclusions: CS JG NA VB PB JD PD PE JG ML BL PM GO JP AS AY TS TP RC. References 1. Clayton D, McKeigue PM (2001). Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet 358: 1356–1360. PMID: 11684236 2. Willett WC, Blot WJ, Colditz GA, Folsom AR, Henderson BE, Stampfer MJ (2007). Merging and emerging cohorts: not worth the wait. Nature 445: 257– 258. PMID: 17230171 3. Collins FS, Manolio TA (2007). Merging and emerging cohorts: necessary but not sufficient. Nature 445: 259. PMID: 17230172 4. Doll R, Peto R (1981). The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. Journal of the National Cancer Institute 66: 1191–1308. PMID: 7017215 5. Ollier W, Sprosen T, Peakman T (2005). UK Biobank: from concept to reality. Pharmacogenomics 6: 639–646. PMID: 16143003 6. UK Biobank (2006). Protocol for a large-scale prospective epidemiological resource. www.ukbiobank. ac.uk/resources/. 7. Burton PR, Hansell AL, Fortier I, Manolio TA, Khoury MJ, et al (2009). Size matters: just how big is BIG?: Quantifying realistic sample size requirements for human genome epidemiology. Int J Epidemiol 38: 263–273. doi: 10.1093/ije/dyn147 PMID: 18676414 8. Hattersley AT, McCarthy MI (2005). What makes a good genetic association study? Lancet 366: Page 28 of 56 www.investinme.org 1315–1323. PMID: 16214603 9. Collins R (2012). What makes UK Biobank special? Lancet 379:1173–1174. doi: 10.1016/S0140-6736 (12)60404-8 PMID: 22463865 10. Elliott P, Peakman TC (2008). The UK Biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine. Int J Epidemiol 37: 234–244. doi: 10.1093/ije/dym276 PMID: 18381398 11. Liu B, Young H, Crowe FL, Benson VS, Spencer EA, et al (2011). Development and evaluation of the Oxford WebQ: a low cost web-based method for assessment of previous 24 hour dietary intake in large prospective studies. Public Health Nutrition June: 1–8. 12. Clarke R, Shipley M, Lewington S, Youngman L, Collins R, et al (1999). Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol 150: 341–353. PMID: 10453810 13. University of Leicester. About the 1958 Birth Cohort Study. http://www2.le.ac.uk/projects/birthcohort/ 1958bc/about. Accessed 12 October 2014 14. Sax Institute. 45 and up study. https://www.saxinstitute.org.au/our-work/45-upstudy/. Accessed 12 October 2014 PLOS Medicine | DOI:10.1371/journal.pmed.1001779 March 31, 2015 9 / 10 15. Pell J, Valentine J, Inskip H (2014). One in 30 people in the UK take part in cohort studies. Lancet 383: 1015–1016. doi: 10.1016/S0140-6736(14)60412-8 PMID: 24656186 16. Downey P, Peakman TC (2008). Design and implementation of a high-throughput biological sample processing facility using modern manufacturing principles. Int J Epidemiol 37 (Suppl 1): i46–i50. doi: 10.1093/ije/dyn031 PMID: 18381393 17. Manolio TA (2008). Biorepositories—at the bleeding edge. Int J Epidemiol 37: 231–233. doi: 10.1093/ije/dym282 PMID: 18381397 18. Barbour V (2003). UK Biobank: a project in search of a protocol? Lancet 361: 1734–1738. 19. UK Biobank (2007). Ethics and Governance Framework. www.ukbiobank.ac.uk/resources/. Accessed 12 October 2014. 20. UK Biobank (2011). Access Procedures: Application and review procedures for access to the UK Biobank Resource. www.ukbiobank.ac.uk/resources/. Accessed 12 October 2014. 21. Manolio TA, Collins R (2010). Enhancing the feasibility of large cohort studies. JAMA 304: 2290– 2291. doi: 10.1001/jama.2010.1686 PMID: 21098774 PLOS Medicine | DOI:10.1371/journal.pmed.1001779 March 31, 2015 10 / 10 Invest in ME research (Charity Nr. 1153730) In February we received the very sad news that Anne Örtegren from Sweden had passed away. We considered Anne a dear friend - although we had never met Anne in person, one of the sad things we carry with us. Yet we instinctively trusted and liked Anne from the very first time we communicated and counted her as a true friend. When we look at the correspondence with Anne we can see it had started in 2007 - a year after we were formed as a charity. In all the correspondence that we had with Anne one always admired the resilience, the articulate nature of her commenting, her strength of character, her dedication and her determination to continue to battle this disease, and her kindness in helping others and being there to make progress. She was a rock – somebody whose opinion we valued and whose help and support we greatly appreciated - and she was generous with her support. Anne’s determination to help us and to encourage Swedish researchers to participate was a shining light for us. Her help behind the scenes led to real collaborations between researchers who met at our Colloquiums. All of this despite the huge suffering that she endured for years. Yet she rarely referred to this. Anne was never one to promote herself or seek the limelight for the sake of it – a refreshing example in this age. She was irreplaceable. Her spirit was just an inspiration. Though we knew Anne was suffering, and had been for such a long time, we were still communicating with her until very recently and had no knowledge of what was to transpire. It is very difficult to read Anne’s last post (below). Not just because of the suffering and pain and hopelessness that she describes – but because Anne was so articulate in describing her situation – never with self-pity, always displaying the same courage that she showed in her life. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 29 of 56

Her story and her life should be seen as an inspiration and she shames those who pretend to be interested in getting change for ME but who do nothing of consequence. One loses a friend, one loses a part of oneself. Yet there are those who leave footprints in one's memory whom one will always remember. Anne Örtegren is such a person. Anne's facebook page is here https://www.facebook.com/anne.ortegren Extract from “Farewell – A Last Post from Anne Örtegren” Nobody can say that I didn’t put up enough of a fight. For 16 years I have battled increasingly severe ME/CFS. My condition has steadily deteriorated and new additional medical problems have regularly appeared, making it ever more difficult to endure and make it through the day (and night). Throughout this time, I have invested almost every bit of my tiny energy in the fight for treatment for us ME/CFS patients. Severely ill, I have advocated from my bedroom for research and establishment of biomedical ME/CFS clinics to get us proper health care. All the while, I have worked hard to find something which would improve my own health. I have researched all possible treatment options, got in contact with international experts and methodically tried out every medication, supplement and regimen suggested. Sadly, for all the work done, we still don’t have adequately sized specialized biomedical care for ME/CFS patients here in Stockholm, Sweden – or hardly anywhere on the planet. We still don’t have in-patient hospital units adapted to the needs of the severely ill ME/CFS patients. Funding levels for biomedical ME/CFS research remain ridiculously low in all countries and the erroneous psychosocial model which has caused me and others so much harm is still making headway. And sadly, for me personally things have gone from bad to worse to unbearable. I am now mostly bedbound and constantly tortured by ME/CFS symptoms. I also suffer greatly from a number of additional medical problems, the most severe being a systematic hyper-reactivity in the form of burning skin combined with an immunological/allergic reaction. This is triggered by so many things that it has become Page 30 of 56 www.investinme.org impossible to create an adapted environment. Some of you have followed my struggle to find clothes and bed linen I can tolerate. Lately, I am simply running out. I no longer have clothes I can wear without my skin “burning up” and my body going into an allergic state. This means I no longer see a way out from this solitary ME/CFS prison and its constant torture. I can no longer even do damage control, and my body is at the end of its rope. Therefore, I have gone through a long and thorough process involving several medical assessments to be able to choose a peaceful way out: I have received a preliminary green light for accompanied suicide through a clinic in Switzerland. When you read this I am at rest, free from suffering at last. I have written this post to explain why I had to take this drastic step. Many ME/CFS patients have found it necessary to make the same decision, and I want to speak up for us, as I think my reasons may be similar to those of many others with the same sad destiny. These reasons can be summed up in three headers: unbearable suffering; no realistic way out of the suffering; and the lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs. Important note Before I write more about these reasons, I want to stress something important. As for most other ME/CFS patients who have chosen suicide, depression is not the cause of my choice. Though I have been suffering massively for many years, I am not depressed. I still have all my will and my motivation. I still laugh and see the funny side of things, I still enjoy doing whatever small activities I can manage. I am still hugely interested in the world around me – my loved ones and all that goes on in their lives, the society, the world (what is happening in human rights issues? how can we solve the climate change crisis?) During these 16 years, I have never felt anylack of motivation. On the contrary, I have consistently fought for solutions with the goal to get myself better and help all ME/CFS patients get better. There are so many things I want to do, I have a lot to live for. If I could only regain some functioning, quieten down the torture a bit and be able to tolerate clothes and a normal environment, I have such a long list of things I would love to do with my life! Three main reasons So depression is not the reason for my decision to terminate my life. The reasons are the following: 1. Unbearable suffering Many of us severely ill ME/CFS patients are hovering at the border of unbearable suffering. We are constantly Invest in ME research (Charity Nr. 1153730) plagued by intense symptoms, we endure high-impact every-minute physical suffering 24 hours a day, year after year. I see it as a prison sentence with torture. I am homebound and mostly bedbound – there is the prison. I constantly suffer from excruciating symptoms: The worst flu you ever had. Sore throat, bronchi hurting with every breath. Complete exhaustion, almost zero energy, a body that weighs a tonne and sometimes won’t even move. Muscle weakness, dizziness, great difficulties standing up. Sensory overload causing severe suffering from the brain and nervous system. Massive pain in muscles, painful inflammations in muscle attachments. Intensely burning skin. A feeling of having been run over by a bus, twice, with every cell screaming. This has got to be called torture. It would be easier to handle if there were breaks, breathing spaces. But with severe ME/CFS there is no minute during the day when one is comfortable. My body is a war zone with constant firing attacks. There is no rest, no respite. Every move of every day is a mountain-climb. Every night is a challenge, since there is no easy sleep to rescue me from the torture. I always just have to try to get through the night. And then get through the next day. It would also be easier if there were distractions. Like many patients with severe ME/CFS I am unable to listen to music, radio, podcasts or audio books, or to watch TV. I can only read for short bouts of time, and use the computer for even shorter moments. I am too ill to manage more than rare visits or phone calls from my family and friends, and sadly unable to live with someone. This solitary confinement aspect of ME/CFS is devastating and it is understandable that ME/CFS has been described as the “living death disease”. For me personally, the situation has turned into an emergency not least due to my horrific symptom of burning skin linked to immunological/allergic reactions. This appeared six years into my ME/CFS, when I was struck by what seemed like a complete collapse of the bodily systems controlling immune system, allergic pathways, temperature control, skin and peripheral nerves. I had long had trouble with urticaria, Invest in ME research (Charity Nr. 1153730) hyperreactive skin and allergies, but at this point a violent reaction occurred and my skin completely lost tolerance. I started having massively burning skin, severe urticaria and constant cold sweats and shivers (these reactions reminded me of the first stages of the anaphylactic shock I once had, then due to heat allergy). Since then, for ten long years, my skin has been burning. It is an intense pain. I have been unable to tolerate almost all kinds of clothes and bed linen as well as heat, sun, chemicals and other everyday things. These all trigger the burning skin and the freezing/shivering reaction into a state of extreme pain and suffering. Imagine being badly sunburnt and then being forced to live under a constant scalding sun – no relief in sight. At first I managed to find a certain textile fabric which I could tolerate, but then this went out of production, and in spite of years of negotiations with the textile industry it has, strangely, proven impossible to recreate that specific weave. This has meant that as my clothes have been wearing out, I have been approaching the point where I will no longer have clothes and bed linen that are tolerable to my skin. It has also become increasingly difficult to adapt the rest of my living environment so as to not trigger the reaction and worsen the symptoms. Now that I am running out of clothes and sheets, ahead of me has lain a situation with constant burning skin and an allergic state of shivering/cold sweats and massive suffering. This would have been absolutely unbearable. For 16 years I have had to manage an ever-increasing load of suffering and problems. They now add up to a situation which is simply no longer sustainable. 2. No realistic way out of the suffering A very important factor is the lack of realistic hope for relief in the future. It is possible for a person to bear a lot of suffering, as long as it is time-limited. But the combination of massive suffering and a lack of rational hope for remission or recovery is devastating. Think about the temporary agony of a violent case of gastric flu. Picture how you are feeling those horrible days when you are lying on the bathroom floor between attacks of diarrhoea and vomiting. This is something we www.investinme.org Page 31 of 56

all have to live hrough at mes, but know it be over in days. If one told hat point: have to his for the r life”, I am would agree n’t feel o cope with the body in that insufferable state every day, year after year. The level of unbearableness in severe ME/CFS is the same. If we knew there were relief on the horizon, it would be possible to endure severe ME/CFS and all the additional medical problems, even for a long time, I think. The point is that there has to be a limit, the suffering must not feel endless. One vital aspect here is of course that patients need to feel that the ME/CFS field is being taken forward. Sadly, we haven’t been granted this feeling – see my previous blogs relating to this here and here. Another imperative issue is the drug intolerance that I and many others with ME/CFS suffer from. I have tried every possible treatment, but most of them have just given me side-effects, many of which have been irreversible. My stomach has become increasingly dysfunctional, so for the past few years any new drugs have caused immediate diarrhoea. One supplement triggered massive inflammation in my entire urinary tract, which has since persisted. The list of such occurrences of major deterioration caused by different drugs/treatments is long, and with time my reactions have become increasingly violent. I now have to conclude that my sensitivity to medication is so severe that realistically it is very hard for me to tolerate drugs or supplements. This has two crucial meanings for many of us severely ill ME/CFS patients: There is no way of relieving our symptoms. And even if treatments appear in the future, with our sensitivity of medication any drug will carry a great risk of irreversible side-effects producing even more suffering. This means that even in the case of a real effort finally being made to bring biomedical research into ME/CFS up to levels on par with that of other diseases, and possible treatments being made accessible, for some of us it is unlikely that we would be able to benefit. Considering our extreme sensitivity to medication, one could say it’s hard to have realistic hope of recovery or relief for us. In the past couple of years I, being desperate, have challenged the massive side-effect risk and tried one of the treatments being researched in regards to ME/CFS. But I received it late in the disease process, and it was a gamble. I needed it to have an almost miraculous effect: a quick positive response which eliminated many symptoms – most of all I needed it to stop my skin from burning and reacting, so I could tolerate the clothes and bed linen produced today. I have been quickly running out of clothes and sheets, so I was gambling with high odds for a quick and extensive response. Sadly, I wasn’t a responder. I have also tried medication for Mast Cell Activation Disorder and a low-histamine diet, but my burning skin hasn’t abated. Since I am now running out of clothes and sheets, all that was before me was constant burning hell. 3. The lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs The third factor is the insight that the risk for further deterioration and increased suffering is high. Many of us severely ill ME/CFS patients are already in a situation which is unbearable. On top of this, it is very likely that in the future things will get even worse. If we look at some of our symptoms in isolation, examples in my case could be my back and neck pain, we would need to strengthen muscles to prevent them from getting worse. But for all ME/CFS patients, the characteristic symptom of Post-Exertional Malaise (PEM) with flare-ups of our disease when we attempt even small activities, is hugely problematic. Whenever we try to ignore the PEM issue and push through, we immediately crash and become much sicker. We might go from being able to at least get up and eat, to being completely bedbound, until the PEM has subsided. Sometimes, it doesn’t subside, and we find ourselves irreversibly deteriorated, at a new, even lower baseline level, with no way of improving. PEM is not something that you can work around. For me, new medical complications also continue to arise, and I have no way of amending them. I already need surgery for one existing problem, and it is likely that it will be needed for other issues in the future, but surgery or hospital care is not feasible for several reasons: One is that my body seems to lack repairing mechanisms. Previous biopsies have not healed properly, so my doctor is doubtful about my ability to recover after surgery. Another, more general and hugely critical, is that with severe ME/CFS it is impossible to tolerate normal hospital care. For ME/CFS patients the sensory overload Page 32 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) problem and the extremely low energy levels mean that a normal hospital environment causes major deterioration. The sensory input that comes with shared rooms, people coming and going, bright lights, noise, tc, escalates our disease. We are already in such fragile states that a push in the wrong direction is catastrophic. For me, with my burning skin issue, there is also the issue of not tolerati ng the mattresses, pillows, textile fabrics, etc used in a hospital. Just imagine the effects of a hospital stay for me: It would trigger my already severe ME/CFS into new depths – likely I would become completely bedbound and unable to tolerate any light or noise. The skin hyperreactivity would, within a few hours, trigger my body into an insufferable state of burning skin and agonizing immuneallergic reactions, which would then be impossible to reverse. My family, my doctor and I agree: I must never be admitted to a hospital, since there is no end to how much worse that would make me. Many ME/CFS patients have experienced irreversible deterioration due to hospitalization. We also know that the understanding of ME/CFS is extremely low or nonexistent in most hospitals, and we hear about ME/CFS patients being forced into environments or activities which make them much worse. I am aware of only two places in the world with specially adjusted hospital units for severe ME/CFS, Oslo, Norway, and Gold Coast, Australia. We would need such units in every city around the globe. It is extreme to be this severely ill, have so many medical complications arise continually and know this: There is no feasible access to hospital care for me. There are no tolerable medications to use when things get worse or other medical problems set in. As a severely ill ME/CFS patient I have no safety net at all. There is simply no end to how bad things can get with severe ME/CFS. Coping skills – important but not enough I realize that when people hear about my decision to terminate my life, they will wonder about my coping skills. I have written about this before and I want to mention the issue here too: While it was extremely hard at the beginning to accept chronic illness, I have over the years developed a large degree of acceptance and pretty good coping skills. I have learnt to accept tight limits and appreciate small qualities of life. I have learnt to cope with massive amounts of pain and suffering and still find bright spots. With the level of acceptance I have come to now, I would have been content even with relatively small improvements and a very limited life. If, hypothetically, Invest in ME research (Charity Nr. 1153730) the physical suffering could be taken out of the equation, I would have been able to live contentedly even though my life continued to be restricted to my small apartment and include very little activity. Unlike most people I could find such a tiny life bearable and even happy. But I am not able to cope with these high levels of constant physical suffering. In short, to sum up my level of acceptance as well as my limit: I can take the prison and the extreme limitations – but I can no longer take the torture. And I cannot live with clothes that constantly trigger my burning skin. Not alone – and not a rash decision In spite of being unable to see friends or family for more than rare and brief visits, and in spite of having limited capacity for phone conversations, I still have a circle of loved ones. My friends and family all understand my current situation and they accept and support my choice. While they do not want me to leave, they also do not want me to suffer anymore. This is not a rash decision. It has been processed for many years, in my head, in conversations with family and friends, in discussion with one of my doctors, and a few years ago in the long procedure of requesting accompanied suicide. The clinic in Switzerland requires an extensive process to ensure that the patient is chronically ill, lives with unendurable pain or suffering, and has no realistic hope of relief. They require a number of medical records as well as consultations with specialized doctors. For me, and I believe for many other ME/CFS patients, this end is obviously not what we wanted, but it was the best solution to an extremely difficult situation and preferable to even more suffering. It was not hasty choice, but one that matured over a long period of time. A plea to decision makers – Give ME/CFS patients a future! As you understand, this blog post has taken me many months to put together. It is a long text to read too, I know. But I felt it was important to write it and have it published to explain why I personally had to take this step, and hopefully illuminate why so many ME/CFS patients consider or commit suicide. And most importantly: to elucidate that this circumstance can be changed! But that will take devoted, resolute, real action from all of those responsible for the state of ME/CFS care, ME/CFS research and dissemination of information about the disease. Sadly, this responsibility has been mishandled for decades. To allow ME/CFS patients some hope on the horizon, key people in all countries must step up and act. www.investinme.org Page 33 of 56

If you are a decision maker, here is what you urgently need to do: You need to bring funding for biomedical ME/CFS research up so it’s on par with comparable diseases (as an example, in the US that would mean $188 million per year). You need to make sure there are dedicated hospital care units for ME/CFS inpatients in every city around the world. You need to establish specialist biomedical care available to all ME/CFS patients; it should be as natural as RA patients having access to a rheumatologist or cancer patients to an oncologist. You need to give ME/CFS patients a future. Anne ended her letter with – Take care of each other. Love, Anne Anne’s Swedish ME/CFS newsletters, distributed via email to 2700 physicians, researchers, CMOs, politicians and medical journalists https://mecfsnyheter.se/ To Prime Minister Erna Solberg and any other relevant recipients An Apeal for help to a seriously ill child My name is Nicoline and I will soon be 14 years old. The last half year I have been too ill to go to school. For 2 years before this I was often sick with many infections. I really like school and I am what one would probably call a concientious pupil. For me it has been awful not to be able to go to school. This is my first year in secondary school and I had really looked forward to beginning to get marks. My plan is to study law in the future. Luckily I have had extremely good help from PPT (Norwegian educational psychology service) and the school. I have received a robot that makes it possible for me to take part in lessons at school when I am able to. I also have home tuition up to two hours a week. This has meant that I have managed to keep up with the most important subjects and this means a lot to me. The reason I am writing is that, unfortunately, I have met with a part of the system designed to help which does not function at all. I suffer from exhaustion and many other awful symptoms which mean that I am bed bound and isolated at home. I am mostly too ill to meet Page 34 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) any friends and rarely manage to talk on the phone. My mother and many close family members have ME and we are afraid that I have inherited the disease. A little over a week ago I met my doctor at the paediatric clinic. It was an ugly experience for me. The doctor we met would not allow me or my parents to explain my situation and my symptoms. They only talked about psychiatry and how I should be «forced back to life». It was clear that they did not believe in me being physically ill. They did not want to hear about my symptoms because they did not want to «encourage me to be sick». They were totally against the school robot and home tuition because there are local children sick with cancer who do not receive such help. I think that is very wrong because I think it is equally bad for me to be too sick to go to school as it is for other sick children independent of the diagnosis. I am very confident in that I do not have a psychological problem. The PPT have also tested me quite thouroughly since last October and they confirm that there is nothing pointing to school refusal or my having something psychologically wrong. Despite this the doctor had decided even before seeing me that I was mentally sick. So I think that it is very hurtful and bad when a doctor «makes it sound like» I am missing shool for the rest of my life because I myself want to, and things will sort themselves out if only I push myself a bit. If the doctors had listened to me they would have known that I had pushed myself for two years until I collapsed. Just a month ago I was so sick that I just slept for many weeks. My mother had to wake me up regularly to get me to eat and drink. Luckily my mother has a lot of knowledge about exhaustion and I am a little bit better now even though I am still bed bound. I am fearful of going back to see this doctor. My next appointment is in a month’s time. My mother has explored possibilities of getting a referral elsewhere but it looks like children with exhaustion are treated in the same manner in most hospitals in the country. I think this is dreadful. When one gets sick as I did then it should be obvious to be met in a positive manner whilst in hospital. At least it should clearly be so that one is not disbelieved the moment one meets the doctor. I choose to give the doctor the benefit of the doubt and I think they would have treated me in a different manner had they had more knowledge. There is after all no doubt any longer that ME is a physical illness. Nevertheless, children with exhaustion, when there is a reason to suspect ME, are being treated as mentally ill. It is like rubbing salt in the wounds of children and their families who have it bad enough as it is. In my case the doctor has already, after the first appointment, gone as far as phoning my case officer at PPT and asked them to force me back to school. That will most probably make me even sicker. To become sicker does not only mean that I will be more exhausted. It also makes all of the other symptoms worse, such as extreme pain all over the body, nose bleeds, nausea, head ache, flu like feeling, sore throat, dizziness and much more. If it turns out that the symptoms were due to ME, as we suspect, then the chances of getting better will be reduced. It means that if I get pushed into using too much energy now then it may lead to my chances of never getting better or healthy - this is frightening when one is only 13 years old and has numerous plans for one’s life. I therefore think it is strange that the doctor will do this, long before I have a diagnosis – as the doctor is taking a huge risk on my behalf. I have been frightened ever since I came home from the hospital. I am worried that I shall miss all lessons at school now as I am not allowed to receive home tuition or use the school robot. I am also terribly scared of getting sicker than I am already, especially now that I have finally had some improvement. I know that you have previously engaged with ME patients. I think that is wonderful. Unfortunately, the situation for us children being investigated for ME and children who already have the diagnosis is critical – there is no expertise and no help available. It is urgent to improve our situation. I therefore ask you to address this so that we can get help soon. I am happy to contribute if there are any questions. With kind regards, Nicoline Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 35 of 56

Ola Didrik Saugstad A harsh debate about ME in Norway – A personal view from one of the participants orwegian debate on S has for many years been ed between those who E is a psychosomatic claiming Cognitive al therapy (CBT) and Process (LP) are therapies on this condition. ice supporting this view ller, a paediatrican who concluding ME is a stress herefore performed a E patients clonidine, a soenergic agonist which is a to treat high blood g theoretically could esponse and Wyller was e would cure ME patients. did not show any positive s. g his hypothesis might be o preach ME could be ol and he was a firm udy. Welfare workers believed in oung ME patients were d other activities, and the ases requested court orders ad to appear as a witness on several occasions. sease caused by stress and ress control, has therefore orwegian community, in E organisations and a few rt was published in 2015 nd and its defenders have argue against results esearch. Page 36 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) In September 2017 a new public ME debate was kicked off in Norway’s largest newspaper, Aftenposten. During the years there have been many discussions and articles about ME in Norwegian media. However, this time it was different. The debate became intense, lasted for several weeks and was flavoured with the most hatred personal attacks on those who referred to recent biomedical research and were advocating the view that ME is a somatic disease. It all started when a new group of 71 persons called “Recovery Norway” wrote an article with the message: “we know how to be cured of ME. Listen to our message”. The network consisted of previous patients or relatives, and some health personnel who recommend CBT and LP to cure ME. By mind control ME patients are able to control their disease the Norwegian public was told by this group. Not only ME could be cured by such mental exercise, a number of other diffuse conditions as fatigue, pain and tinnitus should be treated with these alternative methods. Why doesn’t anyone listen to us and why do so many doubt we previously have had ME and are now cured? the group asked rhetorically. Four days later September 22nd I wrote as a response with the title: Listen to the ME patients: “In Aftenposten September 18th there is an interesting article by a group of former ME patients who are now recovered. Why not take advantage of their experience using untraditional and alternative therapies such as LP and CBT? It is unfortunate that the group feel they are disbelieved both regarding their previous ME diagnosis and that they today are cured. We are grateful for every patient who have been healed and obliged to try to learn from their experience and what made their improvement.” I continued: “When we discuss ME it is, however, important to know that ME follows phases. Persons who previously were very active and healthy may quickly deteriorate. I have myself the last 10 years or so visited many of the sickest ME patients in Norway in their homes and probably seen more than most. Many have a condition compatible with encephalitis, and this is exactly what modern research seems to reveal. ME is an inflammatory condition affecting several organs, also the brain. The immune system is activated. Some patients improve spontaneously while others are bedridden through years with great pain. This is where those who claim to have improved from ME may contribute with valuable information. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 37 of 56 H s n cu si wi b I P

techniques to master challenging life conditions and diseases without curing these. The authors (Recovery Norway) are wrong and not up to date when they write: ”The debate regarding these problems is often about whether the disease is physical or psychosomatic. Lack of knowledge dominates this field.” After the report about ME from Institute of Medicine (IOM) in USA was published in 2015, there has been a paradigmatic change in the view regarding ME. It was concluded that ME is a serious physical, chronic and complex multisystem disease which is strongly debilitating and the misconception that the disease is psychogenic or a form of somatization must stop.” I then referred to a recent study (2016) from the USA with Maureen Hanson as senior author: “In one study from the Cornell University in the USA the researchers were able to identify biochemical and biological deviations in ME patients, which resulted in the following statement: “Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin." (quote by Maureen Hanson in Medical News Today, Tuesday 28 June 2016). I continued: “It is the supporters of the concept that ME is psychogenic who maintain to underline the lack of knowledge regarding ME. I agree with the Norwegian Research Council which supports biomedical ME research in line with the US effort to find treatment for the disease. Psychosomatic research has not brought us closer to understanding of ME and may have contributed to a prevention of development through years.” I did not, however want to disregard the Recovery Norway group and therefore added: “I belong to those who welcome the initiative of the group. It is useful to obtain information on why some were cured and others not. At the same time the group’s credibility is weakened by lumping together several poorly explained conditions such as fatigue, pain and tinnitus. One problem for ME patients has been that the health care system has not listened to the sickest, nor even cared to examine them. We must listen to the advice both from those who have improved and from those who still have not”. This article from me resulted in an outcry from those who supported the concept of ME as a psychogenic disease. Two neurologists from the University Hospital Page 38 of 56 www.investinme.org in Bergen, one even a professor, wrote that I was misusing my professor title.” Saugstad is exploiting his medical authority to oppress patients who have been cured and want to share their experience.” These two neurologists told us they had treated ME patients for years and never or at least only very rarely, seen any trace of inflammation in the central nervous system. I replied by referring to Mady Hornig and co-worker’s recent article (2017) showing ME patients have an immune signature in Cerebrospinal fluid reflecting the central nervous system and the study of Nakatomi Y et al (2014) indicating ME patients have activated immunecells in the brain. I also quoted Harvard Professor Komaroff who commented that if these findings were reproduced it indicates that ME patients have a low graded inflammation in the brain. A Norwegian professor of immunology confirmed that my comments were relevant. The two neurologists never replied. Wyller wrote a commentary: “Saugstad’s claims are misleading. That the immune-system is activated in ME does not mean ME is an inflammatory process. The immune-system is also activated in depressions, social stress and loneliness. Does Saugstad mean these are inflammatory conditions as well?”. Wyller is a firm supporter of the PACE study and wrote: “The PACE study showed that CBT has positive effect on ME. The study has been criticized but the main conclusion has not been disproven. Another recent study shows equivalent good effect of LP. That mental conditions may contribute to ME is documented well for instance by MRI pictures of the brain. This does not mean that the disease is psychogenic, but that the mechanisms are complex and both mental and somatic factors may play a role.” And Wyller continued: “Professor Saugstad introduces himself as an ME expert but has never carried out ME research himself. He is stuck in an old fashioned distinction between “body and mind” and is followed by a small but vocal group of ME patients who are fighting frantically against the concept that “the mind” has anything to do with this matter.” Wyller concluded his article: “I beg new patients, relatives, health workers – don’t listen to this pessimistic outdated message! Instead listen to the majority of patients - many have been completely cured – who make use of modern and documented therapies.” At this stage of the debate a number of doctors, ME patients and relatives had contributed to the debate with their own opinions and experiences. Wyller did not receive much support. In my reply I underlined I have never pretended to be an ME expert. But I wondered why some people became so emotional because I mentioned recent publications in Invest in ME research (Charity Nr. 1153730) the field. Nobody dared to attack the IOM report, instead they attacked me, a “messenger” informing the public about this ground breaking report. I was worried of the fact that those who went against me seemed to be frightened of new data and not willing to discuss recent international research results. I argued that the PACE study had not shown significant improvement for CBT and the recent Smile study concerning LP had profound weaknesses, only 30% of the eligible patients were enrolled in the study and the sickest ME patients had not been included. I also wrote I was surprised that Wyller characterized ME patients as a small and vocal group. After all, the Norwegian ME association has 4000 members and few of these support Wyller. “Fortunately it is rare for such disrespect from a doctor for the patients he is supposed to care for is uttered so clearly”, I wrote. Further, I wondered how Wyller could characterize international research in the field as old-fashioned and outdated. “Perhaps these new findings are threatening to his psychosomatic position Wyller is basing his academic career, a paradigm which is quickly losing ground? However, for the ME patients this development gives hope for the future” was my conclusion. Wyller’s next move came a few days later: “False information about ME may scare patients from documented treatment”. His article illustrated his views. I therefore refer extensively to parts of it: “Saugstad is a highly recognized researcher in neonatal medicine. It is therefore surprising that he, in the ME debate, breaks several rules for scientific reasoning and dissemination. That inflammation detected in the central nervous system of ME patients does not prove that inflammation is the cause of fatigue. To illustrate this point from another area: That patients with lung cancer often have yellow fingers does not implicate that yellow fingers are causing cancer (both yellow fingers and cancer may be caused by smoking). Saugstad has not published his research findings. Saugstad writes that he has in the last years built up a strong research group on ME. Why have the findings not yet been published? Wyller then continued to inform that he had published 25 research articles in the field with a holistic approach to the complex disease that ME is. He then indicated I am biased due to having a close relative with ME. Two Norwegian professors of medicine gave me their support against his emotional attack. In his next reply he continued to attack these two. As mentioned Wyller is a firm defender of the PACE study and when the results from the SMILE study came he embraced these results – he had for years supported LP and CBT for ME. Why not try them - they do not have any adverse effects, he suggested. I replied this is wrong. “Several ME patients report adverse effects of these two regimes. The major distinction in the understanding of ME is perhaps between those who understand this and those who do not”. Recovery Norway also attacked me claiming that I told ME patients they have an inflammation in the brain. This is definitely wrong I replied, I never diagnose ME patients I only refer to the scientific literature when I am asked. In my final statement I informed that unfortunately Recovery Norway had “forgotten” to disclose that several of their members were heavily involved financially in LP as LP instructors. This debate probably represents a watershed in the Norwegian ME debate and understanding. The psychosomatic ME wing had previously given the impression that they often are harassed by aggressive patients and relatives. They have also spread the information that those who support biomedical findings are afraid of new results. The debate demonstrated that the opposite is the case. The psychosomatic lobby’s reaction to new biomedical information was by resorting to personal and emotional attacks on us who had a different view. Their disrespect for the patients they are supposed to serve shocked many of the neutral bystanders. The debate was probably initiated due to the psychosomatic wing rapidly losing ground after the publication of the IOM report, the new emphasis on biomedical ME research by NIH and also the Norwegian Research Council, the CDC’s change in attitude to CBT, and the reanalysis of the PACE study showing minimal if any effect of CBT. Several of the psychosomatic supporters had invested their prestige and based their whole career on findings that supported their view. I understand it must be painful to see how the basis of their theory quickly eroded. This also explains their uncritical embrace of the Smile study. During the debate which lasted many weeks I received overwhelming support from more than 1000 persons in the newspaper and on social media. Ola Didrik Saugstad, MD, PhD, FRCPE Proferssor (em) of Pediatrics University of Oslo Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 39 of 56

Trial By Error: A Q-and-A with Leonard Jason, on Case Definition http://www.virology.ws/2018/05/02/trial-by-error-a-qand-a-with-leonard-jason-on-case-definition/ MAY 2018 By David Tuller, DrPH A Brief Update: Berkeley’s crowdfunding period closed on April 30th–Monday night. I ended the campaign with $87,580. After Berkeley’s 7.5% in fees, the funds will cover my salary/benefit from July 1, 2018 to June 30, 2019, and some travel costs. I really, really appreciate the fantastic support. Thanks to everyone! I’ve taken a few days to regroup from my Australia trip and catch up on my time zones. ********** Leonard Jason is a professor of psychology at DePaul University in Chicago. He has served as vice president of the International American Association of CFS/ME and as chairperson of the Research Subcommittee of the U.S. Chronic Fatigue Syndrome Advisory Committee. Professor Jason began investigating chronic fatigue syndrome almost 30 years ago. Much of his work has focused on the epidemiology and prevalence of the illness and on the impact of using various case definitions. He has long been concerned that the lack of a uniform set of criteria for identifying study participants has hindered progress in the science. Dr. Jason recently shared his thoughts about these issues. (This Q-and-A has been edited for clarity and length.) How common is fatigue? If you were to ask people right now if they are “fatigued,” which means feeling weak, tired, or lacking energy, about 25% of the population would say yes, so this symptom is very common. In contrast, “chronic fatigue” means that a person has had fatigue for 6 or more months. Only about 4-5% of the population has chronic fatigue. There are multiple reasons for people to be fatigued–for example depression, anxiety, over-exertion, people working three jobs, medications, sleep deprivation, weight problems, poor diet, inactivity, and deconditioning. These are just a few of the many causes of fatigue and chronic fatigue. Physicians see lots of people coming into their practices, where the patients are seeking help for their fatigue, and in fact it is one of the most common reasons for seeing a doctor. But it’s very hard for many physicians to differentiate complaints of general or chronic fatigue versus the illness known as ME [myalgic encephalomyelitis]. Yet it is of critical importance to make a differential diagnosis between those with purely chronic fatigue versus those who have ME. In fact, it is this failure to differentiate these two conditions that has caused so many problems, and the culprit is a flawed and imprecise case definitions as well as failures to gain an international consensus for one research case definition. So what is a case definition, and why are there different research and clinical definitions? A case definition is a set of rules that helps a researcher or a clinician make a decision about whether someone has a particular illness or does not have the illness. It’s that simple. A good case definition is critical for the assessment process, to identify those people who actually have an illness or disease. It is the cornerstone of medicine. A research case definition tries to identify a homogeneous group of people who have the illness and can be recruited for research purposes. In contrast, a clinical case definition is used to identify or diagnose a broader group of patients for treatment purposes, and many of these wouldn’t qualify for research studies. For Page 40 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) example, if someone is very obese, a research case definition might exclude that person because the weight issue could be causing the person’s problems. In other words, for research purposes, we want to select only patients who do not have other psychological or medical conditions that could be causing the illness we are studying. For science to progress, the research case definition is critical, as it can standardize the selection of patient samples so that research groups around the world are all studying the patients with the same disease. So gaining consensus among international scientists for a research case definition is a most critical task, and one that unfortunately has still not been accomplished for our field. One of the parameters that’s important for a research case definition for this illness, in your view, is that psychiatric co-morbidities should be excluded. Can you explain the reason for that? Yes, and let me give an example that illustrates this issue. A patient with a major depressive disorder with melancholic features would probably have fatigue, aches and pains, as well as sleep and cognitive problems. Yet these are also symptoms of ME, so some clinicians and researchers could easily confuse these two conditions. But they are very different illnesses, as people with a major depressive disorder feel selfreproach, whereas those with ME do not. If you ask people with a major depressive disorder what they would do tomorrow if they were well, they would not be sure. In contrast, if you asked people with ME what they would do if they were well, they’d give you a long list of all the things they have wanted to do but been unable due to their illness. If you are studying ME, you need to exclude people who have a primary psychiatric disorder from your study. If researchers misclassify people with a major depressive disorder as having ME, this will have serious negative consequences for identifying biomarkers, estimating prevalence rates, and determining outcomes of treatment trials. The issue of selecting patients who really have ME is the most important issue facing our field. In a sense, the lack of a consensus on a ME research case definition is like building a pyramid of playing cards with a very shaky bottom, and then everything built on top of this foundation is vulnerable to collapsing. Let’s start with what is the broadest case definition that has been used, the so-called Oxford criteria for Invest in ME research (Charity Nr. 1153730) CFS. Can you describe that and explain why it presents a problem? If you have six or more months of fatigue, then you meet this case definition, so it’s a very broad category. Clearly, as I mentioned earlier, a lot of people who meet this criteria have medical or lifestyle reasons causing their fatigue. One of my students, Madison Sunnquist, just published her master’s thesis that indicated how the CBT theoretical model only works if you identify people with a very wide case definition, but when you have a better and more restricted case definition that requires core symptoms of ME, then the CBT model no longer works. In contrast to the CBT approach, my research group for the past 20 years has been doing research on what we call the energy envelope. But this pacing approach is not a cure, just a strategy to help better cope with ME. Our approach involves helping patients to better monitor their energy levels, learn how to stay within their energy envelope, and sustain lifestyle changes that involve reprioritizing activities. So how did the CDC come up with the Holmes and then the Fukuda case definitions? The Holmes case definition came out in 1988. The CDC investigators had gone to Incline Village and ultimately named this illness CFS. Their first case definition included too many symptoms. In fact, to meet their case definition, a patient would have needed to have eight or more symptoms out of a list of 11. But here is the problem that soon emerged–if you develop a case definition that requires so many unexplained somatic symptoms, you have a very high probability of unwittingly selecting people who have a somatoform disorder. And you don’t want to select people who have a purely psychiatric condition. So in 1994, the Fukuda case definition was developed to replace the Holmes definition. For the 1994 case definition, the authors selected eight of the symptoms that had been listed in the Holmes criteria, and a patient needed to have any four of those eight symptoms to meet the new Fukuda case definition. But here is the problem with the Fukuda CFS case definition–patients are not required to have postexertional malaise, cognitive problems and unrefreshing sleep, and as we know, these are core symptoms of ME. So, a person could have four of the eight Fukuda symptoms and be diagnosed with CFS, and not have any of the three critical symptoms. In that case, you would be including in your sample a person who does not have the core elements of the illness. www.investinme.org Page 41 of 56

From 1994 and on, I have been doing research that shows some of the diagnostic problems with the Fukuda case definition. And remember, the Fukuda case definition is the research case definition that has been used throughout the world for the past 25 years. But this Fukuda case definition identifies a heterogenous group of patients, because core symptoms are not required of all patients. So, as a consequence, samples of patients with CFS based on Fukuda case definition vary widely in different research groups and labs. What is the impact of the case definitions on prevalence rates? In the late 1980s and early 1990s, the CDC conducted a prevalence study where they started by asking physicians in four cities to identify patients they thought had CFS. At that time, a lot of physicians didn’t believe CFS existed, so putting physicians as gatekeepers in the selection of patients for this study resulted in a prevalence rate that was very low. Also, many people in the US do not have the financial resources to have a physician, so relying on primary care doctors to identify patients was another reason for low prevalence rates. The study suggested that CFS was a rare disease that affected fewer than 20,000 people in the US. At that point, a group of researchers in Chicago began working on a study that involved finding patients from a random community sample, rather than a sample referred from physicians. In 1995, with NIH funding, our Chicago research team conducted a community-based prevalence study, which found that about a million people in the US had CFS. We also found that CFS affected all ethnic and socioeconomic groups, and thus we helped shatter the myth that CFS was a “Yuppie Flu” disease. What did William Reeves [then-head of the CDC division in charge of the illness] do with the so-called “empiric” criteria? And why did this increase the CDC’s estimate of disease prevalence by a factor of 10? In the early 2000s, Bill Reeves felt there was a need to operationalize the Fukuda case definition. For example, he tried to standardize the way we measure a patient’s disability or a substantial reduction in functioning. He used one instrument that has been referred to as the SF-36. According to Reeves, if a patient met criteria for one of several sub-scales within the SF-36, the patient would meet the disability criteria for having CFS. But one of these domains was “role emotional” functioning. It turns out that every person with a major depressive disorder meets the criteria for “role Page 42 of 56 www.investinme.org emotional” functioning. So you can’t just specify instruments such as the SF-36; you have to specify which sub-scales of the instruments you are going to use, and what are the cut-off points. And if any of these choices are wrong, you will identify people who have another illness. My team gathered data on this point, and we conducted a study that assessed people with major depressive disorder, and found that over onethird of them could be inappropriately classified as having CFS under the so-called Reeves empiric criteria. So, I think in the attempt to operationalize the Fukuda criteria, Reeves made mistakes, and I believe that is one of the reasons the estimated CDC prevalence estimates increased ten-fold, from .24% in a 2003 sample to 2.54% in 2007. They operationalized the Fukuda criteria in a way that classified many people as having CFS when they really had other illnesses. At that time, many thought this increase in prevalence figures that Reeves proposed was constructive as it suggested that far more people had the illness, and thus these findings could be used to argue for more attention and funding due to this illness being so widespread. But if you use a very broad criteria, and bring into the illness case definition people who don’t have the disease, then the entire research effort is seriously compromised. Fortunately, over the past decade, few researchers have used the Reeves way of operationalizing CFS. What about the CCC and ICC criteria? The CCC case definition for ME/CFS in 2003 was better because it specified key symptoms such as PEM. It was developed as a clinical case definition, and now it’s being used by several teams as a research case definition. With the 2011 ME-ICC, I have noticed problems, and in part this is due to them once again requiring too many symptoms that could, as with the Holmes criteria of 1988, bring into the ME category some individuals who have a primary psychiatric disorder. In addition, the ME-ICC criteria is complicated to use, and many clinicians and scientists will have a difficult time reliably using it with patients. What is the problem you see with the IOM case definition, apart from the name? Well, it is true that Systemic Exertion Intolerance Disease (SEID) is a name most patients dislike. However, the IOM report was correct in requiring several core symptoms, such as PEM. But I believe these authors made a mistake in indicating that a patient could have either cognitive impairment or orthostatic intolerance— Invest in ME research (Charity Nr. 1153730) one or the other. Cognitive impairment should have been required for all patients to have. But a more serious problem is that they inadvertently expanded the case definition by having just about no exclusionary illnesses, such as primary psychiatric disorders. My team recently conducted a study where about half the people with a variety of medical and psychiatric illnesses met the IOM criteria. Now the IOM criteria was developed as a clinical case definition, but there was no federal effort to develop a research criteria that selects a more homogenous group of patients. The failure to develop an international consensus on a research case definition means that many researchers will continue to use the problematic Fukuda case definition, or they might use the IOM clinical criteria to select patients for research purposes, and this process has already begun. To summarize, for research purposes, if a person has the core symptoms of the IOM definition, it would be important to exclude those with a primary medical or psychiatric condition, but this is not what the IOM authors recommended. So, the clinical IOM case definition once again over-identifies people as having the illness. That means what occurred with the Reeves criteria of a decade ago has once again occurred with the IOM, as these criteria broaden the types of patients identified as having the illness. What is at stake in this debate? The stakes are high, for if you have an inappropriately wide case definition for research purposes, you will bring into your studies many fatigued people with a variety of conditions. In other words, if you identify the wrong patients, then your study will make conclusions about people who do not have ME, and you will have significant barriers to engaging in critical scientific activities such as estimating accurate prevalence rates or identifying biological markers. Also, if you bring in lots of people who don’t have this illness but lifestyle issues and/or a solely depressive disorder, a good percentage of them will respond favorably to psychogenically oriented treatments. As I have been writing about for many years, this will ultimately lead to some researchers making conclusions about CBT and GET that are not true for patients with ME. My case is simple. You need to have one research case definition that is used by scientists throughout the world. The clinical case definition can be broader, but the research case definition has to be tightly focused on those with the illness so that results can be replicated in different laboratories. This scientific achievement has been accomplished with every illness or disease except for ME. We can do better. After working in this area for almost three decades, I am confident that we have the tools and methods to use psychometrically sound procedures to develop a consensus on one research case definition. I am optimistic that one day this will occur, and for me, there is literally nothing as important for our scientific field. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 43 of 56

Some may not have noticed but Invest in ME Research has its very own film star supporting the cause. Jon Campling is an actor, known to many Harry Potter fans as the 'Trainstopping Deatheater'. He wrote the introduction to the book about ME - Science, Politics …….and ME - written by Dr Ian Gibson and Elaine Sherriffs. Jon is married to Ali, also an actor – an actor-singer-dancer. Ali was diagnosed with ME after 2 years of increasingly debilitating symptoms. Like many, Ali was prescribed 18 months of CBT and advised to use PACING techniques – but realised that there was little real understanding of this illness and no ongoing care. So Jon and Ali have found themselves dealing with the same problems as all people with ME have to deal w ith. Jon has been a staunch support of Invest in ME Research and constantly uses his fame to raise awareness and valuable funds for research. Jon could have just hidden this away and not raised the issue. He didn’t. He uses immense time for fundraising for ME earning the admiration and thanks from so many families where ME has struck. Jon’s fundraising page is here - Page 44 of 56 Invest in ME Research (Charity Nr. https://www.justgiving.com/fundraising/walktall4me Invest in ME research (Charity Nr. 1153730) www.investinme.org Conference Abstracts Conference Chair Dr Ian Gibson Former Dean of Biological Sciences, UEA Dr Ian Gibson, former Labour MP for Norwich North, worked at University of East Anglia for 32 years, ecame Dean of the hool of biological ences in 1991 and was d of a cancer research team and set up the Francesca Gunn Leukaemia Laboratory at UEA. In 2011 Dr Gibson received an honorary doctorate of civil law from UEA Dr Elizabeth R. Unger Chief of Chronic Viral Diseases Branch, National Center for Emerging and Zoonotic Infectious Diseases, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention Elizabeth (Beth) Unger, PhD, MD, received an undergraduate degree in Chemistry at Lebanon Valley College, Annville, PA. She hen earned her PhD and MD in the Division of Biologic iences at the University of icago where she also began a dency in pathology. Her residency and fellowship was completed at Pennsylvania State University Medical Center. During this time, Dr. Unger developed a practical method of colorimetic in situ hybridization. This work led to interest in tissue localization of HPV and ultimately to her initial appointment to CDC in 1997 to pursue molecular pathology of HPV and CFS. Dr. Unger has served as the Acting Chief of CVDB since January 2010 and has 13 years of experience in CVDB, where she has participated in the design and implementation of CFS research and HPV laboratory diagnostics. During this time, she was co-author on 25 peer-reviewed manuscripts related to CFS, including the often-cited descriptions of the Wichita and Georgia population-based studies. In addition, Dr. Unger has been instrumental in efforts by WHO to establish an HPV LabNet and serves as lead of a WHO HPV Global Invest in ME research (Charity Nr. 1153730) Reference Laboratory. She is co-author of 142 peerreviewed publications and 24 book chapters and serves on the editorial board of six scientific journals. In 2008, for her HPV research accomplishments, she received the Health and Human Services (HHS) Career Achievement Award. Dr Unger has been selected to serve as the Chief of the Chronic Viral Diseases Branch (CVDB) in the Division of High-Consequence Pathogens and Pathology (DHCPP), National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Centers for Disease Control and Prevention (CDC). Abstract: Abstract not available at time of printing. Dr Vicky Whittemore Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States. Dr. Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster. Her interest is in understanding the underlying mechanisms of the epilepsies including the study of genetic and animal models of the epilepsies. The major goal is to identify effective treatments for the epilepsies and to develop preventions. Dr. Whittemore received a Ph.D. in anatomy from the University of Minnesota, followed by post-doctoral work at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm, Sweden. www.investinme.org Page 45 of 56

She was on the faculty of the University of Miami School of Medicine in The Miami Project to Cure Paralysis prior to working with several non-profit organizations including the Tuberous Sclerosis Alliance, Genetic Alliance, Citizens United for Research in Epilepsy (CURE), and the National Coalition for Health Professional Education in Genetics (NCHPEG). She also just completed a four-year term on the National Advisory Neurological Disorders and Stroke Council. Abstract: Abstract not available at time of printing. Dr Avindra Nath NIH National Institute of Neurological Disorders, Bethesda, Maryland, USA Dr. Nath received his MD degree from Christian Medical College in India in 1981 and completed a residency in Neurology from University of Texas Health Science Center in Houston, followed by a fellowship in Multiple Sclerosis and Neurovirology at the same institution and then a fellowship in Neuro-AIDS at NINDS. He held faculty positions at the University of Manitoba (1990-97) and the University of Kentucky (1997-02). In 2002, he joined Johns Hopkins University as Professor of Neurology and Director of the Division of Neuroimmunology and Neurological Infections. He joined NIH in 2011 as the Clinical Director of NINDS, the Director of the Translational Neuroscience Center and Chief of the Section of Infections of the Nervous System. His research focuses on understanding the pathophysiology of retroviral infections of the nervous system and the development of new diagnostic and therapeutic approaches for these diseases. Abstract: Abstract not available at time of printing. Professor Simon Carding Research Leader, Quadram Institute Bioscience Upon completing postgraduate work at the Medical Research Council’s Clinical Research Centre in Harrow, Page 46 of 56 www.investinme.org Simon Carding took up a postdoctoral position at New York University School of Medicine, USA,and then at Yale University as a Howard Hughes Fellow in the Immunobiology Group at Yale University with Profs Kim Bottomly and Charlie Janeway Jr. While at Yale an interest in gamma-delta (γδ) T cells was acquired working closely with Adrian Hayday on molecular genetics and then with Prof. Peter Doherty to establish their role in (viral) infectious disease. He left Yale after five years to take up a faculty position at the University of Pennsylvania in Philadelphia where he developed a research interest in mucosal and GI-tract immunology, performing studies in germfree mice with Prof John Cebra that helped establish the role of gut microbes in the aetiology of inflammatory bowel disease (IBD). After 15 years in the USA, he returned to the UK to take up the Chair in Molecular Immunology at the University of Leeds where he established a new research programme on commensal gut bacteria and Bacteroides genetics leading to the development of a Bacteroides drug delivery platform that is being used for developing new interventions for IBD and for mucosal vaccination. In 2008 he was recruited by UEA and IFR to develop a gut research programme, taking up the Chair of Mucosal Immunology at UEA-MED and the position of head of the Gut Biology Research Programme at IFR, which later became part of the Gut Health and Food Safety (GHFS) Programme. GHFS research covers a broad area of gut biology including epithelial cell physiology, mucus and glycobiology, mucosal immunology, commensal microbiology, foodborne bacterial pathogens, and mathematical modelling and bioinformatics. The success of this programme has led to the establishment of the Gut Microbes and Health research programme that is integral to the research agenda of The Quadram Institute. Within these programmes, much of the work undertaken in his research group builds upon that carried out in the USA and latterly in the UK with a major focus on understanding the mechanisms of intestinal microbial (bacterial and viral) tolerance. In particular, identifying the pathways and mediators of microbe-host cross talk and the role they play in establishing and maintaining gut health and in diseases that not only affect the gut but other organ systems. Invest in ME research (Charity Nr. 1153730) This has led to the development of new research projects relating to the gut-microbiome-brain axis and understanding how the intestinal microbiome impacts on mental health and the development of neurodegenerative diseases, and the intestinal virome and the role that prokaryotic and eukaryotic viruses play in microbial homeostasis and dysbiosis. Abstract: Abstract not available at time of printing. Dr Peter Johnsen University Hospital of North Norway, Harstad, Norway - Internal Medicine Dr Johnsen works in the medical department at the University of Northern Norway in Harstad. He is currently involved in the clinical trial of FMT which is being funded by the Norwegian Health Council. Five million Norwegian kroner has been awarded for the trial. Together, it will include 80 participants who either receive treatment with FMT from a healthy donor or placebo. The study is double blinded, which means that neither participants nor scientists will know who received the treatment from donor or placebo before the study ends. Startup with the inclusion of participants begins during Summer 2018. Abstract: The Comeback study – a double blinded randomized placebo-controlled trial testing the efficacy of faecal microbiota transplantation (FMT) in CFS/ME Earlier published data suggests that a dysbiotic gut flora may be an important factor in the pathophysiology of CFS/ME. Differences in host metabolism and immune activation pointing to a leaky gut are found in the context of at gut flora that is less diverse with an altered composition when CFS/ME is compared to healthy controls. In addition, an open label study has shown persistent relief in CFS/ME after transplantation of enteric bacteria. To test the gut dysbiosis hypothesis in CFS/ME we will launch a double blind randomized, placebo-controlled, parallel-group, single-centre trial to test FMT as treatment for CFS/ME. Eighty CFS/ME participants will receive either donor transplant or placebo FMT, with 12 months follow up period. Primary endpoint is the efficacy of FMT at three months. We will use a patient reported outcome by the Chalder Fatigue Scale to determine efficacy. Recently we performed a trial with the same study design testing the effect of FMT in irritable bowel syndrome (IBS). In the primary endpoint three months after treatment there was significant improvement on gastrointestinal complaints. Preliminary results also show a significant effect on fatigue, which is a common complaint in irritable bowel syndrome. Conversely, gastrointestinal complaints are common in CFS/ME. Because of our previous experience with FMT for functional disease, the symptom overlap between IBS and CFS/ME, and the evidence for an involvement of the gut microbiome in both, we are eager to lunch our trial in August 2018. We expect to have the final results ready by August 2020. UK charity Invest in ME Research has provided us with a network of great collaborators that may help us to establish a true cause and effect relationship by performing analysis of immunological markers and the gut metagenome. Biobanking of feces, blood and urine is an important asset to this study and will allow for tandem characterization of the immune response, metabolome and metagenome in CFS/ME. In outlining the study protocol we found the lack of consensus on symptom severity assessment challenging. We are hoping for input on how we can optimize the use of our biobank for insights in CFS/ME pathophysiology and discussions on what are the most relevant endpoints in efficacy studies for CFS/ME. We are thankful for the possibility the Invest in ME Research Foundation has given us to meet and network with the world leading expertise on CFS/ME. There is great interest in and a commercialisation of FMT treatment, including FMT for CFS/ME. However, this enthusiasm needs to be balanced with a need for caution with the use of FMT. The screening regime for FMT donors is just as extensive as the regime for donors of blood, cells and live tissue. Our main aim is to provide physicians and other caregivers to CFS/ME patients’ evidence-based advice regarding the efficacy of FMT. Thereby, this study will fulfil its intention regardless of the conclusion. However, there is a greater potential in this trial. Participants may serve as their own control pinpointing which mechanisms change if they transcend from sick to healthy or improved. In conjunction with the intervention any hypothesis can be tested in silico against the clinical outcomes to identify new therapeutic targets and biomarkers for improving diagnosis or personalizing FMT treatment. Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 47 of 56

Professor Karl Johan Tronstad Professor Institute for Biomedicine , Tronstad Lab, Bergen, Norway Prof. Tronstad completed his graduate studies in biochemistry at the University of Bergen (UiB) in 2002. As postdoc at the Haukeland University Hospital, he studied bioactive compounds with the potential to modulate mitochondrial functions in cancer cells. In 2005 he was recruited to the Department of Biomedicine, UiB, where he started his research group to investigate metabolism and mitochondrial physiology. His laboratory seeks to better our understanding of how defective mitochondrial homeostasis may disturb cell physiology, and how this may be involved in mechanisms of cancer and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Karl was involved with the recent paper to come from Bergen - Journal of Clinical Investigation Insight. The Tronstad Lab investigates cell metabolism and mitochondrial biology and we are very fortunate that he can spare time to participate in the Colloquium. Abstract: Cellular energetics in ME/CFS Irregularities in cellular energy metabolism have been linked to many human diseases, including metabolic disorders, mitochondrial diseases, cancer, neurodegeneration and ME/CFS. The possible consequences of cellular energy failure caused by a metabolic defect are context-dependent, and may range from mild cellular stress to cell death. An energydepleted cellular state may theoretically be counteracted by metabolic rewiring, but if this is not sufficient to re-establish the energy level, additional (patho)physiological responses are activated. The consequences may include elements of cellular fatigue, but the mechanisms involved under such conditions are often poorly understood. Recently we found changes in amino acid levels and gene regulation consistent with altered regulation of the central enzyme pyruvate dehydrogenase (PDH) in patients with ME/CFS compared with healthy individuals. Further, the presence of serum from ME/CFS patients changed energy metabolism in healthy human muscle cells in culture. These findings combined with the anticipated role of dysimmunity in ME/CFS, suggest the presence of an immuno-metabolic Page 48 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) pathomechanism. We are now investigating potential mechanisms involved, and characterizing contextual consequences of cellular energy failure, with particular focus on the mitochondrial oxidation machinery. Defects in this machinery are likely to cause energy deficiency and excessive lactate production, which are hallmarks of fatigue and post-exertional malaise (PEM). By using a translational research approach, we investigate whether impaired energy metabolism may be linked to ME/CFS symptoms, which could provide support for the development of new biomarkers and treatments. Our research strategy is to build on existing knowledge that has recently emerged concerning metabolic changes in ME/CFS, and to adopt new methods and strategies for studying the mechanisms at the cellular level. This presentation will discuss our current approaches and recent data. Professor Don Staines The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University, Australia Professor Staines has been a public health physician at Gold Coast Population Health Unit. He has worked in health services management and public health practice in Australia and overseas. His interests include collaborative health initiatives with other countries as well as cross-disciplinary initiatives within health. Communicable diseases as well as post infectious fatigue syndromes are his main research interests. A keen supporter of the Griffith University Medical School, he enjoys teaching and other opportunities to promote awareness of public health in the medical curriculum. He is now Co-Director at The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University in Australia Abstract not available at time of printing. Professor Theoharis Theoharides Professor of Pharmacology and Internal Medicine, Tufts University, Boston, USA Theoharis Theoharides is Professor of Pharmacology and Internal Medicine, as well as Director of Molecular Immunopharmacology and Drug Discovery, in the Department of Immunology at Tufts University School of Medicine, Boston, MA. He was born in Thessaloniki, Greece, and graduated with Honors from Anatolia College. He received all his degrees with Honors from Yale University, and was awarded the Dean’s Research Award and the Winternitz Prize in Pathology. He trained in internal medicine at New England Medical Center, which awarded him the Oliver Smith Award “recognizing excellence, compassion and service.” He also received a Certificate in Global Leadership from the Tufts Fletcher School of Law and Diplomacy and a Fellowship at the Harvard Kennedy School of Government. He has been serving as the Clinical Pharmacologist of the Massachusetts Drug Formulary Commission continuously since 1986. In Greece, he has served on the Supreme Advisory Health Councils of the Ministries of Health and of Social Welfare, as well as on the Board of Directors of the Institute of Pharmaceutical Research and Technology, and he is a member of the International Advisory Committee for the University of Cyprus School of Medicine. He first showed that mast cells, known for causing allergic reactions, are critical for inflammation, especially in the brain, and are involved in a number of inflammatory conditions that worsen by stress such as allergies, asthma, chronic fatigue syndrome, eczema, fibromyalgia, migraines, mastocytosis, multiple sclerosis, psoriasis, and most recently autism spectrum disorder. He has also shown that corticotropin-releasing hormone (CRH), neurotensin and substance P, peptides secreted under stress, act together, and with the cytokine IL-33, to trigger mast cells and microglia to secrete inflammatory molecules. These processes are inhibited Invest in ME research (Charity Nr. 1153730) by the novel flavonoids, luteolin and tetramethoxyluteolin that he has helped formulate in unique dietary supplements and a skin lotion. He has published over 400 scientific papers (JBC, JACI, JPET, NEJM, Nature, PNAS, Science) and 3 textbooks with 29,887 citations (h-factor 84) and he is in the top 5% of authors most cited in pharmacological and immunological journals. He has received 37 patents and trademarks, including three patents covering the use of luteolin in brain inflammation and autism: US 8,268,365 (09/18/12); US 9,050,275 (06/09/15); US 9,176,146 (11/03/15). Acting as Advisor, he was instrumental in the development of ibuprofen (Upjohn), Cetirizine (UCB) and Niaspan (Kos). He is also the Scientific Director of Algonot, LLC, as well as President of Theta Biomedical Consulting and Development Co., Inc., of BiomedAdvice, LLC, and of the nonprofit Brain-Gain.org. He is a member of 15 academies and scientific societies. He was inducted into the Alpha Omega Alpha National Medical Honor Society and the Rare Diseases Hall of Fame. At Tufts, he served on the Curriculum, Students Promotion, Grievance, Faculty Promotion and Tenure, as well as Strategic Planning Committees. He received the Tufts Excellence in Teaching ten times, the Tufts Distinguished Faculty Recognition Award twice, the Tufts Alumni Award for Faculty Excellence, Boston Mayor’s Community Award, and the Dr. George Papanicolau Award, as well as Honorary Doctor of Medicine from Athens University and Honorary Doctor of Sciences from Hellenic-American University. He is “Archon” of the Ecumenical Patriarchate of Constantinople. Abstract: Brain mast cell involvement in Myalgic Encephalopathy/Chronic Fatigue Syndrome Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) affects about 1-2% of the US population and is characterized by debilitating fatigue of six months in the absence of systemic diseases. Many ME/CFS patients also have fibromyalgia and skin hypersensitivity, which worsen with stress. We hypothesize that stimulation of mast cells (MC) in the hypotahalamus activate microglia leading to secretion of pro-inflammaotry mediators that disrupt normal homeostasis and advesrsely affect mitochondrial function. Corticotropin-releasing www.investinme.org Page 49 of 56

hormone (CRH), neurotensin (NT) and substance P (SP) are secreted under stress and can stimulate MC, necessary for allergic reactions, to release inflammatory mediators that could contribute to ME/ CFS symptoms directly or via activation of microglia. We showed that CRH and NT act synergistically to stimulate MC to secrete VEGF, which increases permeability of the blood-brainbarrier (BBB) and would allow entry of toxins in the brtain. We also showed that NT can activate microglia to secrete IL-1beta. Moreover, we showed that the combined action of SP and the alarmin IL-33 lead to impressive amounts of TNF secretion from human MC. We further investigated the effect of combining ip injection of polyinosinic:polycytidylic acid [poly(I:C)], to mimic a viral infection, with 15 min forced cold swim stress, to mimic exercise and stress, on female C57BL/6 mice locomotor activity, as well as brain gene expression and serum levels of inflammatory mediators. Treated mice showed decreased locomotor activity over 72 hrs, while serum levels of TNF, IL-6 and KC (IL-8/CXCL8 murine homologue), as well as their gene expression in the brain, were increased increased. When other mice were provided with chow high in isoflavones for 2 weeks prior to treatment, this intervention reversed the reduced locomotor activity and minimized the increased serum levels and gene expression of the proinflammatory mediators. Moreover, the unique natural flavonoid, tetramethoxyluteolin potently inhibited both human cultured MC and microglia activation. We are presently seeking funding to measure these neuropeptides and cytokines in the blood of ME/CFS patients before and after exercise, as well as develop an intranasal tetramethoxyluteolin formulation for direct delivery to the hypotalamus through the cribriform plexus (Funded by an Anonymus grant). References from this article will be in the online version of the journal. Associate Professor Mady Hornig Associate Professor, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health New York, USA Mady Hornig, MA, MD is a physician-scientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health where she serves as Director of Translational Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, Page 50 of 56 www.investinme.org and toxic stimuli in the development of neuropsychiatric conditions, including autism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Abstract: Abstract not available at time of printing. Professor Maureen Hanson Director, Center for Enervating Neuroimmune Disease Liberty Hyde Bailey Professor, Department of Molecular Biology and Genetics, Cornell University, USA Maureen Hanson is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, NY. Previously she was on the faculty of the Department of Biology at the University of Virginia in Charlottesville and an NIH NRSA postdoctoral fellow at Harvard, where she also completed her Ph.D. Invest in ME research (Charity Nr. 1153730) degree. While most of her prior research has concerned cell and molecular biology in plant cells, she began a research program on ME/CFS after noting at a 2007 IACFS meeting the paucity of molecular biologists studying the illness. Her lab was part of the 2012 multicenter study organized by Ian Lipkin's group at Columbia University to assess the actual role of XMRV in ME/CFS. Abstract: Research at the Cornell Center for Enervating Neuroimmune Disease The Center for Enervating Neuroimmune Disease (ENID Center) encompasses a number of projects, including research carried out by the Cornell NIH ME/CFS Collaborative Research Center (CRC). The CRC has undertaken 3 projects, all unified by performance of an exertion challenge by subjects, who will perform twoday cardiopulmonary exercise tests (CPETs) using the protocol developed by the Workwell Foundation and Prof. Betsy Keller (Ithaca College). To ensure that all subjects meet the criteria for ME/CFS or for healthy sedentary controls, Drs. Susan Levine, Geoffrey Moore, and John Chia will diagnose and screen volunteers. In a project led by Professor Dikoma Shungu at Weill Cornell Medicine in New York City, subjects will undergo Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) of their brains in order to evaluate oxidative stress and neuroinflammation. The neuroimaging will occur before performing an initial CPET and before performing a second one the next day, in order to determine the effect of exertion. Blood will be collected before and after each CPET at Weill Cornell Medicine, and before and after CPETs supervised by Dr. Keller at Ithaca College and supervised by the Workwell Foundation at Dr. John Chia’s clinic in Los Angeles. Blood will be fractionated and sent to Cornell University in Ithaca. There, my lab group will analyze extracellular vesicle number, size, and content in plasma, and Dr. Andrew Grimson’s lab will isolate individual white blood cells to sequence and identify genes that are expressed. The molecular data, neuroimaging, and subject survey data will be examined by a Data Analysis Core headed by Dr. Fabien Campagne (Weill Cornell Medicine) for correlations to identify relationships specific to diseased or healthy status, or pre- or post-exertion state. By examining patients when at baseline and after postexertional malaise has been induced, we hope to gain insights into the factors that cause this disabling symptom, which also should shed light on the biological basis of the disease. The Center also has an active outreach program, facilitated by Executive Director Susi Varvayanis and our Patient Advocate Committee. More information about Invest in ME research (Charity Nr. 1153730) activities can be found here: http://neuroimmune.cornell.edu/news/ or by following us on twitter: @DrMaureenHanson or @CornellMECFS . The Center also has several other ongoing studies, including comparisons of gene expression, oxidative phosphorylation, and glycolysis in B, T, and NK cells from patients vs. controls. We have begun pilot studies to examine plasma metabolites and extracellular vesicles using an existing set of samples collected from patients at baseline. Information from these studies will be presented. Professor Markku Partinen University of Helsinki, Finland Prof Markku Partinen is a neurologist and an internationally wellknown opinion leader and expert in sleep research and sleep medicine. Professor Partinen is currently Director of the Helsinki Sleep Clinic, Vitalmed Research Centre, and Principal Investigator of Sleep Research at Institute of Clinical Medicine, Clinicum, University of Helsinki, Finland. He has been the coordinator of the NARPANord Narcolepsy Consortium. He became interested in sleep research while studying medicine at the University of Montpellier, France. He obtained his medical degree (DrMed) from Montpellier in 1976 (Supervisor Prof Pierre Passouant). He received his PhD in 1982 (epidemiology of sleep disorders), and degree of a specialist in neurology in 1982, in Helsinki, Finland. He has worked as a postdoc researcher at Stanford University, USA in 1985-86 and in Bologna, Italy in 1987. In addition, he has had several shorter visits as visiting researcher or visiting Professor at different Universities in Europe. His main interests in sleep medicine have been narcolepsy, excessive daytime sleepiness and fatigue (including ME), sleep apnea, and parasomnias. He has published more than 330 original articles in peer reviewed Journals in addition to writing many book Chapters and editing several books. His Hirsch factor (H-factor) is 59 in ISI Web of Sciences and 64 in Scopus. www.investinme.org Page 51 of 56

He has served in the Editorial Boards and as Assistant Editor in Sleep, Journal of Sleep Research and Sleep Medicine. He has had many International positions in different research societies including Member of the Scientific Board and Vice-President of the European Sleep Research Society (ESRS), President of the Scandinavian Sleep Research Society, President Elect and President of the World Association of Sleep Medicine (WASM), Coordinating Secretary of the World Federation of Sleep Research Societies (WFSRS) and President and Member of the Board of the Scandinavian Sleep Research Society. He has been President of the ESRS congress in 1992 (Helsinki), the World Congress of Sleep Apnea in 2003 (Helsinki), and the WASM congress in 2007 (Bangkok). In addition, he has organized several smaller meetings and symposia in the field of narcolepsy, RBD and different sleep disorders. Currently he is a Member of the Board in the ESRS EUNarcolepsy Network (EU-NN) and Chair of Scientific Board of the EU-NN, President of the Finnish Parkinson Association and President of the Finnish Sleep Research Society. Abstract: Abstract not available at time of printing. Professor James Baraniuk Professor of Medicine at Georgetown University Medical Centre, Washington, USA James N. Baraniuk was born in Alberta, Canada, south of Banff. He earned his honours degree in chemistry and microbiology, medical degree, and unique bachelor's degree in medicine (cardiology) at the University of Manitoba, Winnipeg, Canada. Thereafter, he moved to Akron, OH, USA, for his internship and internal medicine residency at St Thomas Hospital. After another year of internal medicine residency at Duke University Medical Center, Durham, NC, he trained with Dr C.E. Buckley, III, in allergy and clinical immunology. He moved to the laboratory of Dr Michael Kaliner at the National Institute of Allergy and Infectious Diseases, Bethesda, MD, and there began his long-standing collaboration with Dr Kimihiro Ohkubo. After 2 years studying neuropeptides, he joined Dr Peter Barnes' laboratory at the National Heart and Lung Institute, Brompton Hospital, London, UK. Dr Baraniuk Page 52 of 56 www.investinme.org returned to Washington, DC, and Georgetown University, where he is currently Associate Professor with Tenure in the Department of Medicine. Abstract: Abstract not available at time of printing. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA Ronald W. Davis, Ph.D., is a Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California. He is a world leader in the development of biotechnology, especially the development of recombinant DNA and genomic methodologies and their application to biological systems. At Stanford University, where he is Director of the Stanford Genome Technology Center, Dr. Davis focuses on the interface of nano-fabricated solid state devices and biological systems. He and his research team also develop novel technologies for the genetic, genomic, and molecular analysis of a wide range of model organisms as well as humans. The team's focus on practical application of these technologies is setting the standard for clinical genomics. The genomic revolution has been spurred by technological advances that made nucleotide sequencing inexpensive, high-throughput, and accessible. The next phase in this revolution to pave the way for personalized health entails similar breakthroughs in biosensor technologies for personal molecular monitoring. Just as with DNA sequencing, the key features to optimize are accuracy, sensitivity, cost, and accessibility. Through close collaboration between engineers, biochemists, geneticists, and clinicians, our team has developed several such technologies and devices. The technologies target the biophysical properties of the cells and molecules, and therefore do not rely on introducing labels or other complex sample preparation techniques. We have successfully applied these technologies to detecting drug resistance, resolving cells and molecules in bodily fluids and Invest in ME research (Charity Nr. 1153730) tissues, and engineering advanced, multiparametric, wearable biosensors. We have begun applying these methods to understand chronic fatigue syndrome, one of the last major diseases about which almost nothing is known. We anticipate that these technological breakthroughs coupled with data integration of personal molecular profiles will play an instrumental role in the realization of personalized health regimens and disease prevention strategies. Abstract: Revolutionizing biomedical research through technology development The genomic revolution has been spurred by technological advances that made nucleotide sequencing inexpensive, high-throughput, and accessible. The next phase in this revolution to pave the way for personalized health entails similar breakthroughs in biosensor technologies for personal molecular monitoring. Just as with DNA sequencing, the key features to optimize are accuracy, sensitivity, cost, and accessibility. Through close collaboration between engineers, biochemists, geneticists, and clinicians, our team has developed several such technologies and devices. The technologies target the biophysical properties of the cells and molecules, and therefore do not rely on introducing labels or other complex sample preparation techniques. We have successfully applied these technologies to detecting drug resistance, resolving cells and molecules in bodily fluids and tissues, and engineering advanced, multiparametric, wearable biosensors. We have begun applying these methods to understand chronic fatigue syndrome, one of the last major diseases about which almost nothing is known. We anticipate that these technological breakthroughs coupled with data integration of personal molecular profiles will play an instrumental role in the realization of personalized health regimens and disease prevention strategies. Patient groups and charities from fourteen European countries working together for ME Campaigning in Europe for people with ME and engaging with health agencies, governments, professionals, the media, patients and public Working closely with researchers and organisations and researchers interested in finding treatments and cures for ME Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 53 of 56

Page 54 of 56 www.investinme.org Invest in ME research (Charity Nr. 1153730) IiMER Advocacy Conferences Colloquiums Educational DVDs Campaigning Young/ECR Researchers Research European ME Research Group www.investinme.org/research Funding www.investinme.org/donate Invest in ME research (Charity Nr. 1153730) www.investinme.org Page 55 of 56

Journal of IiMER I N V E S T in M E R E S E A R C H Journal Of IiMER MAY 2017 VOLUME 11 ISSUE 1 UK Char i ty Invest in ME Research (Char i ty Nr . 1153730)

RESEARCH into ME? Journal of IiMER WE NEEDED A RETHINK Small charity BIG Cause With no major investment into correct research into myalgic encephalomyelitis during the last decades Invest in ME Research has, with a determined band of supporters, taken action for change in the absence of any coherent or scientific establishment policies. Funding has to be given to biomedical research and new knowledge from other disciplines such as virology, immunology, endocrinology etc. has to be brought in to help research into ME. Invest in ME Research has initiated and funded high-quality biomedical research at UCL and UEA and Quadram Institute Biosciences - and brought in collaborations with other researchers in Bergen, Uppsala, Berlin and within the UK in Oxford. Vision with action can change the world Journal of IiMER Journal of IiMER M A Y 2 0 1 7 C O NTE NT 03 Vision of Excellence for Research into ME 08 Biomedical Research Colloquium 10 UK CENTRE of EXCELLENCE for ME 16 Finding, Facilitating, Funding Research into ME DISCLAIMER The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME Research. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. www.investinme.org 18 RESEARCH COLLABORATION 20 Science, Politics, …….and ME 23 PHILANTHROPY and ME 25 The Gut Microbiome in ME 32 No Isolation 34 Letter from America 36 IiMER Visit to CMO 42 The PACE Trial 45 Open Letter to Psychological Medicine 50 Margaret Williams Repository 51 EMEA News 66 Conference Abstracts All content in the Journal of IiMER is copyright to Invest in ME Research and the authors. Permission is required and requested from Invest in ME Research before republishing anything from this Journal. Page 3 of 82

Journal of IiMER I I M E C 1 2: Marking TWELVE Years in Creating a Vision of Excellence for Research into ME Conference welcome from Chairman Kathleen McCall A nother year and a new conference. Invest in ME Research is an independent UK charity whose objectives are to initiate, maintain and augment a strategy of high-quality biomedical research into Myalgic Encephalomyelitis (ME), to provide and promote better education about ME, and to raise awareness of the effects of the disease on patients and families. Finding, facilitating and funding a strategy of biomedical research into ME is, we believe, the only way to make any real and lasting impact on the lives of those affected by this disease. We are a small charity but with a growing number of supporters who have big hearts - and a determination to get the best possible research to be carried out to find the cause of myalgic encephalomyelitis and develop treatments. The charity is run by volunteers - patients or parents of children with ME and supported by patients, family, friends, and others who are determined to change the prospects for people with this disease. We do not receive and have never received funding from government or government organisations and our research Colloquiums and public Conferences are funded by the charity itself. The charity decided early on that biomedical research into ME was crucial in order to make progress in treating this disease. We also decided that education of healthcare staff, the media, www.investinme.org government departments, patient groups and patients was to be a priority. The charity commits itself to a strong stance against deceptive practices, corrupt or flawed policies toward ME and to disingenuous posturing from those seeking to influence governments, the media or even patients. The charity has always spoken out strongly against the flawed and null PACE Trial. However, we have also engaged with the government, Department of Health, Medical Research Council, Chief Medical Officers and, as part of the European ME Alliance (EMEA) have been working closely with European colleagues to make progress in Europe. We have also participated in recent NINDS discussions organised by the NIH. Almost twelve years on from when Kathleen McCall formed the organisation that became Invest in ME Research the charity has an optimism about the future and a continuing determination to force change and create a foundation of biomedical research in Europe that will finally Page 4 of 82 Journal of IiMER provide answers and treatments for this disease. Our efforts are focused on setting up a UK Centre of Excellence for ME that will provide proper examinations and diagnosis for ME patients and a coordinated strategy of translational biomedical research into this disease. Now our twelfth conference is taking place in 2017, as always in Westminster, London, and as the charity has embarked on a new decade of finding, funding and facilitating biomedical research into ME, and research into ME in order to find treatment(s) and cure(s). Our supporters have achieved an incredible feat in making something out of nothing and creating an opportunity for real progress to be attained for ME research. Now, with solid progress made in establishing the UK Centre we can look for more rapid progress in the coming years as CDC and NIH demonstrate more acceptance of this disease and new initiatives continue to realise the charity’s goal of international collaboration in research into ME. These initiatives will eventually drag and force complacent and ineffectual organisations into taking action rather than false posturing. Good collaborations have been built between UK, European, and US organisations that can only strengthen the level and quality of biomedical www.investinme.org increasing knowledge and awareness of the disease. Our conferences and, later, our closed research colloquiums were organised from the beginning in order to provide a platform for research and a means of facilitating education about ME. For Invest in ME Research, education and research are the key to progress, and hence change. The IiMER conferences have formed a crucial part of this education and our research colloquia form a crucial and productive part of the research. The conferences now regularly attract delegates (researchers, clinicians, nurses, patient groups and patients, advocates and, we always hope, a sprinkling of as many politicians, journalists and others whom Invest in ME self-fund to allow people to be exposed to real science) from twenty countries in a unique international event that is friendly and conducive for learning and Page 5 of 82

Journal of IiMER networking. Our choice of venue reflects our commitment to patients, families, carers, researchers and healthcare staff in providing the best venue for conducting this annual event - now #IIMEC12. Our Colloquium banner used the quote attributed to Henry Ford to describe the progress made – "Coming together is a beginning; keeping together is progress; working together is success" Our invited delegates (researchers from 14 countries around the world) embraced this theme. The BRMEC6 Colloquium was a pivotal point in the history of Invest in ME Research as it celebrated its 10th year as a charity. Because, coming from the meeting, one detected a palpable sense of research into ME really having become an international concern – endorsing Invest in ME Research’s strategy of international collaboration in research into ME. For 2017, IIMEC12 brings the best from the world’s Centres of Excellence for ME – now up and running as in the UK at Norwich Research Park or Australia, where the NCNED has been operating for some years, and in Norway and those being developed such as in USA. The charity’s commitment over 12 years to bringing the best research to the public and professionals has given biomedical research into ME a platform that allows researchers to overcome the bias and prejudice built up over the years by false views held by governments, research councils and establishment collaboratives that are more self-serving rather than interested in making progress. The Invest in ME Research conferences bring together this optimism and determination in a happy mixture of wanting, needing to learn, optimism and hope that things will improve. In June 2016, Invest in ME Research held its sixth Biomedical Research into ME Colloquium in London - BRMEC6. The Colloquium had as its theme international collaboration. Collaboration and working together can easily become just buzzwords – meaningless terms given out in press releases and handouts, attempting to make an impression that something is happening. Yet BRMEC6, and the following public IIMEC11 conference, really did validate our long held belief that international collaboration in biomedical research can lead to patients being given back their lives. We are hoping that BRMEC7 this year will produce a similar result. Last year was the first time that the Invest in ME Research conferences had a speaker from a government organisation. It was wonderful to have Dr Vicky Whittemore representing the National Institute of Health, opening both our BRMEC7 Colloquium and IIMEC12 Conference and showing NIH visibility for this disease, and endorsing this international collaboration as a critical means to an end. This year we are honoured also to welcome Dr Elizabeth R. Unger from the USA Centres for Disease Control. Dr Unger will be opening the Biomedical Research into ME 7 Colloquium 7. Also attending will be the Norwegian Health Council – appearing at both Colloquium and www.investinme.org Page 6 of 82 Journal of IiMER Conference – symbolising the huge potential and hope coming from the efforts of dedicated Norwegian biomedical researchers. Both the Colloquium and Conference are high quality, forward-looking events that serve to improve knowledge of this disease, generate, and improve international collaboration into ME. A high quality, professionally produced DVD of the conference proceedings will be produced as always – not a small task for a small charity – but it continues to serve not just as a historical record but also a means to educate doctors and clinicians about the seriousness of this disease. The DVDs have been distributed to twenty countries proving the increasing interest in research into this disease. We were pleased to see that the US NIH listed as its goals for ME research the following -  Advance research on the cause, prevention, diagnosis, pathophysiology and treatment of ME/CFS  Encourage biomedical research investigators and organizations to study ME/CFS  Communicate ME/CFS research information among and between NIH Institutes and Centres, and the NIH Office of the Director The first two goals are similar to those that Invest in ME Research have been promoting and implementing for the past eleven years and have mentioned in our letters to the UK MRC, Department of Health and others in the position of influence. The third has elements that epitomise the IiMER strategy as our proposal for a Centre of Excellence for ME – something we have been aiming for since 2010 – now develops. Progress has inevitably been too slow from the patients’ perspective but as we pass into our twelfth year as a charity, more and more signs and developments are indicating that things are changing. Research into ME has needed a strategy – it was www.investinme.org Page 7 of 82 surely missing when IiMER was formed and has continued to elude the major UK funding organisations. Yet the Invest in ME Research strategy of bringing in researchers from other fields to help and improve biomedical research into ME was a necessity. It has been successful and well worth the effort and cost and we can witness this approach becoming more popular. Our conferences bring together patients, researchers, clinicians and healthcare staff and allow knowledge and experiences to be shared – and IIMEC11 and BRMEC7 will see us entering our twelfth year in doing this. We will see many new faces in London as well as old friends. Back to the theme of collaboration and highquality research with a purpose. Let us remember again these words that illustrate the Invest in ME Research approach to research into ME and the raising of awareness - "Vision without action is merely a dream. Action without vision just passes the time. Vision with action can change the world." Precisely the ethos of the Invest in ME Research Biomedical Research Colloquiums and Conferences! Welcome to London - Welcome to IIMEC12 and BRMEC7 Kathleen McCall CHAIRMAN INVEST IN ME RESEARCH

In 2011, Invest in ME Research initiated a different type of meeting that was appended to our annual public conference. We gave that meeting the term “Corridor Conference” – as most of the productive discussions at seminars often took place in corridors or places away from the presentations. And so the idea of the Biomedical Research into ME Colloquium was born. A meeting that would not compromise our research ethos with false views of ME but would instead concentrate on high-quality biomedical research and international collaboration. Journal of IiMER BIOMEDICAL RESEARCH into ME Building a Future for Research into ME The Corridor Conference organised in London by IiMER was flowed with the impressive and forward-thinking collaboration with the Alison Hunter Memorial Foundation of Australia to form BRMEC2 – the two-day Clinical Autoimmunity Working Group CAWG) research group which met in London the next year and before the IIMEC7 conference. This became our way of making rapid progress in biomedical research into ME. We attract experts from other disciplines to bring their expertise and skills to bear on this disease. By doing this we can bypass the negativity and misinformation that has pervaded the perception of ME for a generation and influenced the establishment research bodies – and instead focus on proper science. The Invest in ME Research Biomedical Research into ME Colloquiums are research meetings organised by the charity to encourage biomedical research into ME and international collaboration amongst researchers. This is one of the main objectives of the charity. Invest in ME Research began arranging biomedical research conferences in our first year and have continued them ever since - mostly funded by the charity but with help from some wonderful supporters and some good friends. The Invest in ME Research International Biomedical Research into ME Colloquiums began as a way of bringing together researchers from around the world in a roundtable discussion of ME research and ideas. They are designed to encourage collaboration and sharing of experience and to bring in new ideas and knowledge from outside the field of ME. A small charity with a BIG cause can www.investinme.org achieve this. Over the years this has broadened into sharing of experiences, data and plans for future research. A culmination of much of this effort was the initiative to bring European researchers together to form The European ME Research Group (EMERG) which had an inaugural meeting in October 2015 in London to set up a strategy of European collaboration in ME research. There is a basis now for creating a strategy of high-quality international biomedical research - something that has been lacking in the past. This will hold great promise of finding funding opportunities and raising awareness of biomedical research into ME. As stated, our aim with the annual CPDaccredited research colloquiums has also been to introduce new researchers into the field of ME research, to gain new insights into the disease and enhance the strategy of research we are building. The Invest in ME Research colloquiums have spawned a number of positive initiatives over the years and are the most successful research meetings for forming new research initiatives for ME with multiple collaborative initiatives being formed across continents. We have proven that high-quality biomedical research can be initiated in an international, collaborative environment and we salute all those researchers who continue to participate and work with us for the benefit of all people with ME and their families. We will continue to work together to facilitate the best hopes to make progress in finding the cause(s) of and treatments for this disease. Page 9 of 82 COLLOQUIUM

Journal of IiMER UK CENTRE of EXCELLENCE for ME To create a base of research into ME has been the ambition of Invest in ME Research since 2007 – with more specific focus from 2010. With the objective of improving and promoting education about ME amongst healthcare staff and raising awareness of the disease, the charity feels that the best way to make progress is to establish a national centre of excellence for ME. To this end we have focused on facilitating research and resources to build the foundations of a UK Centre of Excellence for Biomedical Research into ME. www.investinme.org Page 10 of 82 Journal of IiMER The charity believed that a change needed to be made in the way service provision for ME patients was carried out and proposed a simple but effective structure for providing services and instituting major biomedical research into this disease. This would have profound effects on the way ME is treated in the UK and establish a hub of scientific and clinical excellence for ME within Europe. In the last years real progress has been made in achieving this and the charity has created and facilitated opportunities that can now boast five PhDs involved in research, with another planned to join in 2017 and a post-doc/research assistant being employed to facilitate a UK clinical trial of rituximab. All of this is combined with national and international collaboration that is ongoing. This substantial effort is, even if we say it ourselves, a tremendous achievement by our supporters and a validation of their commitment and support for this new way forward. With our planned research ongoing and developing then we hope this will soon be possible. Diagnostic tests and medical treatments can only be developed from sound scientific biomedical research. This is why the charity has concentrated much effort on establishing the research centre. A clinical lead consultant would assess and plan the development of future services in conjunction with commissioning CCGs It would provide access to specialist assessment, diagnosis and advice on www.investinme.org Page 11 of 82 the clinical management, including symptom control and specific interventions, for both patients and health professionals. The charity has held discussions with the Norfolk and Norwich University Hospital CEO and UEA Medical School to create a position for a consultant who can oversee proper examinations of ME patients which include diagnosis according to correct criteria and possibilities for acceptance into clinical trials being performed at the Centre, or in associated spokes of collaborative research. There are also a number of new ideas being developed. Establishing a Centre of Excellence allows new ideas to be generated and more synergy to be obtained between different research disciplines. The research proposal would build a strategy of research that would involve patients, clinicians and researchers working together. This will take a substantial effort to achieve but we feel it can be done and the rewards for people with ME would be huge. The Centre of Excellence for ME would be welcome news for patients, and their families and doctors, across Europe and would facilitate and initiate new international collaborations, consolidate and improve existing ones, and develop new research ideas. Funding bids would enable cooperation and sharing with joint projects being undertaken.

Journal of IiMER The Centre of Excellence will also provide a highquality partner for those Centres of Excellence being set up or existing in USA and Australia. The Centre of Excellence for ME is not just one building or one lab – it is a model that has fundamental components of collaboration, data sharing and cooperation – sharing facilities, data and ideas. With the help of leading researchers, the charity is proposing a number of initial projects that would help establish a research base and lead to further projects being initiated based on findings. gratitude for the specialised knowledge and input that has been provided. The UCL team are in the regular multi-centre status meetings in Bergen - such is the respect in which they are held, as well as continuing the good collaboration. As we prepare for the UK rituximab trial this is good news indeed. It has now developed into closer collaboration with Dr Fluge and his team visiting Norwich Research Park in January of this year to discuss the UK rituximab trial and collaboration with the UK researchers on developing the best options for the UK rituximab clinical trial. The Norwegian team will visit again in the autumn as the Phase III trial in Norway begins to establish results. The research is the key component for change. Based on a strategy of biomedical research the Centre would create projects that dovetail and would collaborate with other centres where biomedical research into ME was taking place. Apart from those researchers in the Norwich Research Park, the charity has also funded the Bcell research underway at UCL in London where Fane Mensah has been working under supervision of Dr Jo Cambridge. The good relationship that has been established with the researchers at Haukeland University Hospital in Bergen continued and Dr Cambridge and Dr Fluge met in Stockholm at a conference organised by our European ME Alliance colleagues at RME Sweden. This collaboration between high quality biomedical researchers - one of the major themes behind Invest in ME Research's research strategy - has been a great success with the Norwegians expressing to us, and Dr Cambridge, their www.investinme.org Having shown great vision and determination in looking at other areas of research linked to their phase III trial experiences and developing an incremental, evolutionary method of research then we feel the Norwegian Haukeland researchers have exactly the model of how good research should proceed. Establishing such a Centre represents a very progressive step in looking for cause(s) of ME and the possibilities will be further increased as the research team moves into the new Quadram Institute, which will open next year. More information is on our microsite at http://www.cofeforme.eu where there are ways to help us raise funds and awareness of this venture - see http://www.investinm.org/ceSupport-cofeforme.shtml Our hashtags for the Centre are #CofEforME and #LetsCresearch. The Centre of Excellence will also provide a highquality partner for those Centres of Excellence being set up or existing in USA and Australia. The Centre of Excellence harnesses the benefits of Page 12 of 82 Journal of IiMER collaborative biomedical research in modern facilities with world-class researchers. Our aim is to establish a sustainable examination and research centre that would form the hub of European research and treatment for this disease and produce a pathway to produce huge benefits for the nation, and further across the world. We invite all to support us as we move forward with research. Let us make this vision a reality. http://investinme.org/ce-thecentreforme.shtml As a first step to realising the ambition of the Quadram Institute, on April 28 2017, the Institute of Food Research (IFR) transformed into Quadram Institute Bioscience. The lead of the Quadram Institute is Professor Ian Charles – who is again giving the keynote speech at the Invest in ME Research IIMEC12 international Conference. Quadram Institute Bioscience The Institute of Food Research (IFR) and Norwich Medical School will relocate to the new Quadram Institute building that is set for completion in 2018. One can follow the QI progress at this link in Norwich Research Park here - https://quadram.ac.uk/ Professor Charles opened IIMEC10 - the 10th Invest in ME Research International Conference in London in 2015. He has over 30 years’ experience in academic and commercial research and was a founding member of The Wolfson Institute for Biomedical Research at University College London, one the UK’s first institutes of translational medicine. More from Quadram - https://quadram.ac.uk/research_areas/gutmicrobes-health/ Norwich to be Home to the Quadram Institute The Quadram Institute is located on the Norwich Research Park and will integrate under one roof research teams from the current Institute of Food Research (IFR) and University of East Anglia’s (UEA) Faculty of Science and Norwich Medical School with the Norfolk and Norwich University Hospital’s (NNUH) gastrointestinal endoscopy facility.

Journal of IiMER OUR CURRENT FUNDING STREAMS The UK Centre of Excellence for ME Support for the UK Centre of Excellence for ME will provide a solid foundation for high-quality biomedical research into ME. This approach to research will change the landscape for research into ME and make this an area of research that will encourage innovation and novel research. Rituximab Trial/B-Cell Research The B-cell/Rituximab research. The charity is keen to replicate the recent Norwegian findings using Rituximab. We initiated B-cell research at UCL leading to a UK rituximab clinical trial. A specific web site has been set up to document this project – see www.ukrituximabtrial.org. Gut Microbiota Related Projects Beginning with our foundation project at Norwich Research Park. It is not often realised that 60-70% of the immune system is located in the gut as a vast network of lymph tissue referred to as GALT (gut associated lymphatic tissue). The research highlighted in the proposal involves looking at gut microbiota, which is some of the latest thinking in how to go about research. A foundation project at the University of East Anglia began in 2013 - funded by the charity. Medical Students Part of the charity's strategy for improving education has been to involve medical students in research into ME. By participating in the research projects funded by the charity then students are able to learn far more about ME and patients as well as passing on the reality of this disease to their peers. www.investinme.org Page 14 of 82 Journal of IiMER THE Big Give for the BIG Cause Project We welcome investment in developing the UK Centre of Excellence for ME and support from all who wish to see research into ME based on high-quality science and an urgency in all efforts to tackle this disease. Invest in ME Research have a Big Give page describing the basics of establishing a Centre of Excellence for ME and a donate option for supporting this work. The link is here https://secure.thebiggive.org.uk/projects/view/9169 Join our C Selfie Campaign to Raise Awareness To support the UK Centre of Excellence for ME we are asking people to send in photographs - or ask your MP, GP, any celebrities, sportspersons, etc. to support the campaign. To show support please take a photo of the person supporting us by using the right hand and make the C sign for supporting the charity's proposal for a Centre of Excellence for ME. Just send the photos to Invest in ME Research (our e-mail address is cofeforme@investinme.org) and include some short information or story behind the photograph #COFEFORME #LETSCRESEARCH www.investinme.org Page 15 of 82

Journal of IiMER Finding, Facilitating, Funding Research into ME Part of the development of the UK Centre of Excellence for ME consists of involving medical students in the research by intercalating in their fourth year of medical studies, and facilitating and encouraging students to look for a career in researching ME. An example recently demonstrate the benefits in our strategy of having medical students involved in research into ME. Navena Navaneetharaja and Verity Griffiths have been involved in the gut microbiota research in Norwich Research Park. Navena also spent several months with Professor Maureen Hanson at Cornell University in New York, USA. They produced a paper together with Professors Wileman and Carding from the Centre that provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS. This led the authors to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the “infectious “trigger of the disease. Such an approach has the potential to identify disease biomarkers and influence therapeutics. The paper is - A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)? Abstract from the Paper Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous disorder of significant societal impact that is proposed to involve both host and environmentally derived aetiologies that may be autoimmune in nature. Immune-related symptoms of at least moderate severity persisting for prolonged periods of time are common in ME/CFS patients and B cell depletion therapy is of significant therapeutic benefit. The origin of these symptoms and whether it is infectious or inflammatory in nature is not clear, with seeking evidence of acute or chronic virus www.investinme.org infections contributing to the induction of autoimmune processes in ME/CFS being an area of recent interest. This article provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS leading us to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the “infectious” trigger of the disease. Such an approach has the potential to identify disease biomarkers and influence therapeutics, providing muchneeded approaches in preventing and managing a disease desperately in need of confronting. http://www.mdpi.com/2077-0383/5/6/55 Another paper produced from IiMER funded research at UCL was released recently. Fane Mensah produced a paper with Dr Amolak Bansal, Brian Ford and Dr Jo Cambridge Chronic fatigue syndrome and the immune system: Where are we now? Abstract from the Paper Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterised by multiple symptoms including fatigue, headaches and cognitive impairment, which have a significantly adverse effect on the normal functioning and wellbeing of the individual. These symptoms are often triggered or worsened following physical or mental exertion. ME/CFS has long been thought of as having a significant immunological component, but reports describing changes in immune function are often inconsistent between study groups. Although the wide range of physical, neurocognitive and autonomic symptoms reported have seriously hampered attempts to understand pathophysiological pathways, investment in Page 16 of 82 Journal of IiMER biomedical research in ME/CFS is finally increasing with a number of novel and promising investigations being published. The onset of ME/CFS may often be linked to (viral) infections which would be consistent with a variety of alterations in natural killer (NK) cell function as described by a number of different groups. Consistency in cytokine data has been lacking so far, although recently more sophisticated approaches have led to more robust data from large patient cohorts. New hope has also been given to sufferers with the possibility that therapies that deplete B cells can result in clinical improvement. To understand the pathogenic mechanism in this complex condition, it is important to consider repeated analysis in different cohorts. In this review, we will discuss the potential of different components of the immune system to be involved in the pathogenesis of ME/CFS. https://www.ncbi.nlm.nih.gov/pubmed/28410877 “My beautiful daughter is totally bedbound. She has a diversity of symptoms that seem endless. (Most of the very severely affected have between 60+ and 100+ symptoms). The worst thing of all is the relentless, agonising pain. Widespread pain in every muscle, joint, and organ possible. She has not had one day free from pain since the illness began. Her whole life now is lived from her bed. Not her choice for she is a talented artist and photographer and she dreams of being in summer meadows photographing the dancing bees and butterflies and painting the colourful flowers. ….. “Her dreams have been snatched from her by this awful disease that others misunderstand by thinking it's just about feeling tired or attention-seeking”…. “Her days are spent in a darkened room and in as much silence as the outside environment will allow. She is hypersensitive to light, noise, odour, vibration, touch, movement, chemicals, some foodstuffs, and medicinal drugs. …..” “She is unable to sit or stand due to being moribund with pain, orthostatic intolerance, paralysis, blackouts and much more and so her bed is her companion twenty-four hours a day. …... She cannot tolerate touch as her skin is always 'on fire' like it's been grated with a cheese grater. Her description. I have to cut her pyjama tops off (when she can tolerate a change of tops) because any movement causes her indescribable pain. She has difficulty speaking sometimes and so asks me to be her voice…... “ " My amazing daughter has such a positive view of life. I'm stunned that she's not depressed or angry. Although she sometimes has her low days, her courage and inner strength are immeasurable. Not a day passes without seeing one of her magical smiles which sometimes just breaks my heart.” - from Lili http://investinme.org/mestory1010.shtml www.investinme.org Page 17 of 82

Journal of IiMER RESEARCH – COLLABORATION Research News from Fane Mensah Fane Mensah is funded by Invest in ME Research for B-cell research [The potential role of B cells and their products in ME/CFS Patients] Collaboration with Christopher Armstrong As part of our Solve ME/CFS Initiative Ramsay award winning collaboration, Christopher Armstrong from the Bio21 Institute (Melbourne University, Australia) came over to work with us at UCL for one month. A quick flashback to June 2016, at the 6th Invest in ME Research International Biomedical Research into ME Colloquium (#BRMEC6) meeting in London where Chris and I met. We were the two youngest scientists at the meeting to give a presentation about our research. It would not have been the first thing we would have in common! Straight after our presentations we started to talk about each other’s experiments and found out that the two completely different fields we were working in (Immunology and Metabolomics) could be complementary. It is well known that immune issues have often been associated with ME/CFS (B cells, NK cells T cells etc.). More recently, different groups, including Christopher and his colleagues have studied changes in the metabolic profile in ME/CFS patients. Their data is very promising and consistent which supports a possible role in this condition. Following some bonding drinks after the conference, Christopher visited us (myself and Dr. Cambridge) the next week at UCL where we laid the base for our collaboration. After Christopher returned to Australia, and several (late and early) Skype meetings we put together a grant application for the Solve ME/CFS www.investinme.org Initiative Ramsay award which is an award that supports (young) scientists from different fields committed to ME/CFS research. This award gives them the opportunity to lay the basis for more substantial collaborative research projects. The next generation scientists: BSc student internship at UCL With the support of the Invest in ME Research charity, we were very fortunate to have Isabelle de Rooij visiting our laboratory for a 5-month internship. Isabelle is a BSc student from Hoge school Rotterdam in the Netherlands (my old University) undertaking the Bachelor of Science course in biology and medical laboratory sciences. As tipped for the best student in her year, we had big expectations from here and she did not disappoint us! During her internship, she not only learned Page 18 of 82 Journal of IiMER different laboratory skills and techniques but also got an insight into the biomedical research applied to ME/CFS. This was just as important as the technical part of the internship. Isabelle really enjoyed her time her and was very The article by Fane shows the importance of Invest in ME Research's strategy of international collaboration in research into ME. The meeting between Fane and Chris (and Zaher Nahle from Solve ME/CFS) came about because the charity invited all of them to the #BRMEC6 Colloquium. The article also demonstrates the importance of our strategy of funding students in research into ME - a strategy proven to be successful and making a real difference. Subscribe to our Newsletter ME QUOTES passionate about her project. She significantly contributed to the development of new protocols for our future experiments, and assisted me with ongoing projects related to the joint project with Christopher Armstrong. We were very proud of Isabelle when she finished her internship, which was examined based on her technical lab skills and final report, with 9.5/10. A great achievement from a great student! Her university was so impressed and satisfied with her achievements and progress in our group that they have asked us if we would be interested in future collaborations. From Invest in ME Research www.investinme.org "It is of the greatest importance to keep in mind the goal toward which one works in science, but it is also of equal importance to simply explore and define the 'new' while keeping that mind well prepared for finding new treasures. It is only through such efforts that we believe the etiology of CFS will be finally illuminated." Steven Tracy and Nora Chapman, University of Nebraska Medical Center: http://www.investinme.org/ArticleJ31Human Enteroviruses and Chronic Infectious Disease.shtml Page 19 of 82

At the 10th Invest in ME Research International ME Conference in 2015 Dr Ian Gibson announced that he was planning on writing a book about ME - and the politics and prejudice which has affected the way that ME is perceived, treated, researched and funded - as well as the resultant effects on patients and their families. Journal of IiMER Dr Ian Gibson led an inquiry into ME in 2006 [2]. Without official funding, and at a time when unbiased and independent analysis on the way ME was being treated and reported on by the establishment organisations and media was lacking, Dr Gibson provided a checkpoint which attempted to get publicity and force change which would help ME patients. The Inquiry's report made several recommendations [3]. That the then Labour government ignored the report, and its recommendations, will forever cast a shadow on the health minister at the time and on the government itself. Since that time Dr Gibson has been influential in assisting IiMER get high-quality biomedical research established in Europe. He has also chaired the IiMEC* conferences. After 12 years of IIMEC* conferences, and following the tenth anniversary of the Gibson Inquiry, and when change was slowly managing to creep into establishment organisations, Dr continues to be the subject of misrepresentation, inappropriate media reporting, ineffective research funding and a pervading prejudice that needs to be exposed. Dr Gibson is familiar with the political events in the UK, how they affect healthcare and patients and how some organisations and individuals are unduly influencing these policies. It is important to understand the politics of ME and how the ‘establishment’ in most countries reacts. Dr Gibson, and co-author Elaine Sherriffs, started interviews with knowledgeable individuals following the IiMER London conference and established new contacts. Dr Gibson and Elaine visited or interviewed researchers, clinicians, advocates, patients, carers and others to produce this an analysis of ME - the Science and Politics behind the way ME is treated. Gibson felt it was necessary to look at the way that politics and the actions of some have influenced the way ME has been, and www.investinme.org Although heavily constrained by the limited funds that the charity was able to raise interviews were carried out by Elaine and Dr Gibson – and included a visit to Stockholm, Sweden, where they spoke with patients, clinicians, researchers and politicians from Sweden and other countries. The project was aided by a generous donation Page 21 of 82

Journal of IiMER toward the production of the book from the Irish ME Trust. We also had donations from some individuals for which we were extremely grateful. The book was published earlier this year and is available via Amazon. Few diseases can have been so maligned by false information, so manipulated by an insidious establishment-controlled ideology, or so poorly dealt with by those holding the purse strings for research into the disease, than Myalgic Encephalomyelitis (ME). This book examines a scandal in our generation - a scandal still being played out by corrupt, apathetic, inept or ignorant attitudes in governments and Medical Research Councils and health services. We welcome all support for raising awareness of the book – a book able to reach more people in society in a way that should make them want to know more and question why a section of the population are being so abused by crass, self-serving and Please help in raising awareness of this book. Thank you for your support. Buy from Amazon www.investinme.org References: 1 IIMEC10 10th International ME Conference 2 Gibson Inquiry Report 2006 3 Gibson Inquiry Recommendations 4 Gibson Book - JustGiving Donations 5 Gibson Book - The BIG Give Project Page 22 of 82 Journal of IiMER Philanthropy and ME Philanthropy – “the desire to promote the welfare of others, expressed especially by the generous donation of money to good causes” Philanthropists may be thought of as wealthy, individuals or organisations contributing to causes, for reasons either personal or financial or from expediency. But philanthropy comes in all flavours and different guises and not always from obvious quarters, and not always by means of donating money. The philanthropy given and displayed by supporters of Invest in ME Research is of the highest level. Many of the charity’s supporters are very ill and have little means of financially contributing – left with little financial possibilities due to the ravages of the disease on them or their family, exacerbated by punitive and immoral government policies on welfare benefits to disabled people. Yet their efforts made to support the charity and its research has changed the landscape of UK research into this disease – forcing biomedical research into the mainstream when, for years, little was done to make progress by existing establishment organisations. Jo Best and helped on by Jan Laverick and Paul Kayes – all ME patients. Instead of continually reacting to what others were doing or saying they decided to take a proactive approach. A campaign was started to support the Invest in ME Research proposal for the Centre of Excellence for ME. The difference with this campaign? To use the skills and ideas of patients who want more than anything else does to regain their health. By harnessing these ideas and enabling people to feel positive about doing something LDIFME The Let’s Do It for ME (LDIFME) campaign and our core group of supporters are helping to fashion a change in ME research and this determination and enthusiasm will influence researchers – both within the ME research area and those from outside. themselves to effect change then the campaign could be turned into something which was fun. Positive campaigning – with an objective to fund sorely needed translational biomedical research into ME and to harness patient power to influence ME research – something which had been missing from the equation. As the charity initiated a plan to develop a Centre of Excellence for ME an idea was born by www.investinme.org The Let's Do It For ME campaign is a positive and proactive campaign. The aim is to raise funds for Page 23 of 82

Journal of IiMER biomedical research but everyone's input is welcomed - be it just ideas or moral support for other people's fundraising. Whilst raising funds for biomedical research the campaign has also raised much needed awareness and this has allowed more correct information about ME to be disseminated. Let's do it for ME! is a patient-driven campaign to raise awareness and vital funds for the UK Centre of Excellence for ME performing translational biomedical ME research, clinical assessment, diagnosis and treatment for patients, and training and information for healthcare staff based at the Norwich Research Park in the UK but working collaboratively with international biomedical researchers. The Let’s Do It For ME campaign has been running now for 7 years. http://ldifme.org “We constantly receive letters from the Department of Health stating that very little is known about ME and yet without doctors like Dr (Nigel) Speight, who are willing to believe in and listen to children with ME and learn in the process, many patients would have little hope for a better and safe future. Paediatricians and doctors in the UK generally demonstrate an overwhelming degree of ignorance toward ME– either disbelieving it exists, misdiagnosing other diseases in its place, failing to identify the potential consequences of severe ME and failing to spend any time in improving their education about the disease. Sometimes they just continue to hold their pet theories on this disease. The Institutes of Medicine concluded in their report of 2015 [9] that ME is an organic disease. The IOM report looked at the effects on children from this disease [10]. “There is clear evidence of the impact of ME/CFS on the education and social development of these young people. The stigma and social effects of paediatric ME/CFS include the loss of normal childhood activities and in some extreme instances, inappropriate forcible separation of children from their parents” As part of the research review carried out the IOM reported on an Australian study of 189 adolescents by Rowe and Rowe concluded that evidence for somatization disorder among young people with ME/CFS was negligible. “They all note that ME/CFS symptoms often make it more difficult to do schoolwork, so children and adolescents with ME/CFS may be misclassified as having “school phobia.” Invest in ME Research deplore the concocted term school phobia, or pervasive refusal syndrome, and those promoting these terms in relation to ME/CFS, as they have never applied to children with this disease.” Invest in ME Research - Ignoring the Elephant in the Room http://www.investinme.org/IIME-Newslet-1604-NS999.shtml www.investinme.org Page 24 of 82 Journal of IiMER The gut microbiome in Myalgic Encephalomyelitis Maureen R. Hanson and Ludovic Giloteaux (Cornell University, USA) April 2017 © Biochemical Society O ver the last dozen years, increasingly powerful DNA sequencing methods have allowed characterization of the microbes residing on and in humans in much greater detail than ever possible before. Abnormalities present in the gut microbiome—those microbial communities residing in our intestines—have now been observed in a number of diseases. One such illness is Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue Syndrome (CFS). CFS was a name coined by the US Centers for Disease Control (CDC) in 1988, and reviled by patients for the resultant trivializing of this serious illness. Recently, the US National Academy of Medicine (NAM) recommended a new name: Systemic Exertion Intolerance Disease, though this name is not yet widely used. In ME, as in other diseases, the diversity of the bacterial species in the gut microbiome is lower than in healthy individuals. Furthermore, the abundances of different bacterial residents of the gut, which influence health both favourably and negatively, differ between ME patients and healthy controls. Bacteria translocate into the blood in greater amount in ME, leading to inflammation. Dysbiosis in the gut likely contributes to symptoms in this life-limiting disease . Three to four times more women than men have ME. Children and adolescents as well as adults are susceptible to the disease. Prevalence is difficult to determine because of the lack of a simple, objective diagnostic test. While physicians experienced with the disease are readily able to make correct diagnoses, the clinical criteria often vary between studies, making enumeration of patients difficult. An investigation of ME in three regions of England found that about 0.2% fit a widely used 1994 CDC definition. A meta-analysis of 14 studies www.investinme.org found the prevalence by clinical assessment to be 0.76%. These numbers translate into 128,000 to 486,000 ME patients in the UK. Thus, even if the lower figure is used, ME does not fit the definition of a rare disease (see www.raredisease.org.uk). An example of a rare but serious disorder that affects intestinal function is Clostridium difficile infection which is at least 10 times less common than ME. The severity of the disease varies, though most affected individuals are unable to work or attend Page 25 of 82

Journal of IiMER school full time. For example, a small survey of 25 children with ME in the UK found that only one could attend a full day. Indeed, another study found that ME was responsible for 42% of the medically certified, extended school absences in the UK over a five-year period. While the ‘fatigue’ element in the name emphasizes a major symptom of ME, most patients report that the fatigue is not the same as that experienced by healthy individuals after vigorous physical exercise or inadequate sleep. Instead, the fatigue is described as a profound lack of energy, more akin to the sensation of exhaustion that occurs during a severe case of influenza or mononucleosis. Two additional symptoms were identified by the National Academies of Medicine committee in a 2015 report (http://www. nationalacademies.org/hmd/Reports/2015/MEME. aspx) as hallmarks of the disease: postexertional malaise and unrefreshing sleep. The new diagnostic criteria also require either cognitive impairment or orthostatic intolerance. The latter refers to a surge of symptoms when upright that improves when the patient reclines, likely due to a disturbance in the autonomic nervous system. With regard to cognitive impairment, patients often report ‘brain fog,’ like the impaired mental capacity, poor memory and concentration that healthy individuals experience when they have been awake all night. Most people with ME reach a steady-state level of physical and/or mental activity they can sustain without inducing an ensuing increase in symptoms known as post-exertional malaise. Many are homebound – simple acts such as shopping for groceries can result in worsening of their symptoms. For those who are bedbound, any sort of stimulation, even the mental and physical effort to carry on a conversation, can intensify their symptoms. Many ME patients, whether bedbound or not, are unusually sensitive to light and sound. Bedbound patients often require eyeshades and sound-protecting headphones to cope with those stimuli. Among the most severely ill ME patients (Figure 1), some must be supported at the level of those who are comatose. Some are too impaired to speak and cannot eat nor digest food normally and must be tube fed. Possible roles of the gut microbiome in ME Gastrointestinal disturbance is a symptom often reported by ME patients. This fact has encouraged several investigators to compare the gut microbiome in patients versus controls. Our research group undertook a study of the bacterial gut microbiome by comparing 16S rRNA from faecal samples of 48 ME patients and 39 controls. The 16S rRNA sequence is commonly used to identify bacterial species, as the presence of very variable regions in www.investinme.org Page 26 of 82 Journal of IiMER the 16S rRNA gene provides species-specific signature sequences. We obtained an average of 98,000 sequence reads per sample, more than ample to identify almost all of the bacterial diversity. To determine how many reads are needed, the number of species detected per number of sequences can be graphed to produce a ‘rarefaction curve’ (Figure 2). As more sequences are obtained, the number of species detected increases until a plateau is reached, where few additional species will be found despite a large number of additional sequence reads. For our samples, it is evident that 30,000 reads would be more than sufficient. For the example shown of a theoretical sample with low diversity, 5000 reads would have been adequate, while the high-diversity example indicates that even 30,000 reads would not suffice. A conclusion that can be drawn from Figure 2 is that ME cases have reduced bacterial diversity in comparison to healthy controls. Such reduced diversity has been observed in other diseases such www.investinme.org Page 27 of 82

Journal of IiMER as Clostridium difficile infection, inflammatory bowel disease and necrotizing enterocolitis. The sequence data can also be analyzed for differences in the abundance of various species between cases and controls. Some species that we found to be differentially abundant represented a very small fraction of the bacteria present and thus may not have a large effect on gut ecology and function. In Figure 3, we show those genera that a) represent more than 1% of the gut microbiome and 2) varied significantly among faecal samples between ME and healthy controls. The reduced abundances of Bifidobacterium and Faecalibacterium species in patients have also been reported in inflammatory bowel disease and other conditions. Faecalibacterium species produce butyrate, a short-chain fatty acid that has antiinflammatory properties, and thus its reduction would predict lower levels of butyrate. While we did not measure butyrate in our samples, when faecal samples of 34 female cases and 25 controls were examined by Armstrong et al. in another study, surprisingly, butyrate was higher in the ME patient samples. Determining which metabolites are actually present in the gut can be difficult to predict merely from a list of species that reside there, given the complex interactions among different microbial communities and with the cells in the intestine. Several studies in which bacteria were cultured also demonstrated differences between ME patients and controls. However, many gut microbial residents cannot be cultured and are known only by their DNA sequences, so that high-throughput sequencing of 16S ribosomal DNA for identifying bacterial taxonomic groups is beginning to supplant culture methods. Nevertheless, there are also limitations to knowledge from DNA sequences of intestinal contents. For example, while ribosomal DNA sequencing can detect that Escherichia coli is present, it doesn’t reveal whether one of the highly virulent E. coli strains is present in addition to benign or beneficial E. coli strains that reside in www.investinme.org most individuals. To find pathogenic E. coli, bacteria are grown on specific culture media and then tested with an antibody that reacts with proteins present in disease-causing E. coli strains. Thus, a harmful bacterium could be present in ME patients and go undetected by ribosomal DNA sequencing. Leaky gut problems When the intestinal lining is inflamed, bacteria can translocate into the bloodstream through loosened intestinal tight junctions leading to a ‘leaky gut’ (Figure 4). The immune system then detects the presence of bacteria or bacterial components in the blood and mounts an immune response to counter this apparent invasion. There can be collateral damage from the immune system’s attack on perceived threats. ME patients often have symptoms of chronic inflammation such as muscle and joint pain and swollen lymph nodes. In order to find out whether ME patients might have more bacterial products in their blood than healthy people and could be responding to them, we tested whether the levels of certain molecules were different in the blood of the same ME patients and healthy controls whose faecal samples were sequenced. We found that patients had higher levels of lipopolysaccharides (LPS), a large molecule comprised of both lipid and sugar components. LPS are present on the outer membrane of some bacteria and cause a strong immune response. We found that levels of LPS, LPS-binding proteins and a receptor for LPSbinding protein (soluble CD14), which signals the presence of LPS to the immune system, are increased in ME patients. Thus, the abnormal gut microbiome in ME patients likely contributes to their chronic inflammation and ensuing symptoms. While digestion most often comes to mind when considering intestinal bacterial species, there is increasing evidence that the gut microbiome affects the risk of colorectal cancer, obesity and abnormal mental function. Metabolites and proteins from the gut enter the bloodstream in healthy as well as diseased individuals, and some can affect the central Page 28 of 82 Journal of IiMER nervous system and brain. Prospects for treatment Oral prebiotics and probiotics are being investigated for restoration of bacterial diversity and resolution of gastrointestinal diseases. Prebiotics are substances thought to improve growth of beneficial species, while probiotic supplements contain microbes known to be present in healthy guts. In order to be incorporated into a probiotic pill, bacteria must be grown in culture, but culture conditions for growing many of the bacterial species present in the human gut are not known. Thus, only a selection of certain species can be incorporated into commercially available probiotics. How these different species affect people with different types of gut microbiomes, and whether gastrointestinal illnesses can be improved with their aid is an important topic that is currently being explored in the research community being explored in the research community. www.investinme.org Because pure cultures of many gut microbes cannot be obtained, researchers have turned to faecal transplants, i.e. introduction of faecal material from healthy human donors into recipients. This treatment has cured some individuals with severe gastrointestinal dysfunction from Clostridium difficile infection. Whether this process can also help patients with other types of intestinal diseases and ME is less clear. Promising reports have appeared about improvements in ulcerative colitis, Crohn’s disease and autism. With regard to ME, anecdotal reports from patients who have tried faecal transplantation indicate some reduction in symptoms, but not complete recovery nor persistent improvement in their conditions. One study of faecal transplantation indicated that 42/60 ME patients had a favourable response. The results are sufficiently promising to suggest that a clinical trial of faecal transplants in ME would be worthwhile. Page 29 of 82

Journal of IiMER Future directions Multiple studies now show that the gut bacterial composition is abnormal in patients with ME, a lifelimiting disease. These findings are now among many discoveries of biological differences between ME patients and healthy individuals, all of which should dispel any remaining notions that the illness is psychological in nature. Future studies on the eukaryotic microbiome and virome may reveal additional disturbances in the microbial communities of people with the disease. While these gut abnormalities may be a response to some other inciting factor, rather than the basal cause of disease, learning how to ameliorate them could have clinical benefits for patients and help promote recovery, perhaps in conjunction with other treatments. ■ Ludovic Giloteaux Ludovic Giloteaux, PhD, is a Research Associate in Dr Hanson’s lab group. His research addresses the molecular mechanisms of biological processes, ranging from environmental concerns such as the bioremediation of arsenic- and uraniumcontaminated environments to human disease, namely the biological basis of ME. His research uses integrated approaches combining molecular biology and microbiology to study the microbiome in ME, and the effect of the disease on gene expression and proteins from immune cells. Email: lg349@cornell.edu. Further reading 1. Committee on the Diagnostic Criteria for CFS. (2015) Beyond Myalgic Encaphlomyelitis/Chronic Fatigue Syndrome. The National Academies Press, Washington, D.C. ISBN 978-0-309-31689-7. http://www. nationalacademies.org/hmd/Reports/2015/MECFS.aspx 2. Navaneetharaja, N., Griffiths, V., Wileman, T. and Carding, S.R. (2016) A role for the intestinal microbiota and virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (CFS)? J. Clin. Med. 5(6). pii: E55, http://dx.doi.org/0.3390/jcm5060055 www.investinme.org Maureen Hanson Maureen Hanson, PhD, is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, New York. Her research projects concern gene expression and genetic engineering in plants and the molecular basis of ME/CFS, funded at various times by NSF, USDA, DOE, NIH and several non-profit organizations. Her lab has produced over 180 peer-reviewed articles. She is currently Director of the Cornell Center for Enervating Neuroimmune Disease. Email: mrh5@cornell.edu 3. Nacul, L.C., Lacerda, E.M., Pheby, D. et al. (2011) Prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (CFS) in three regions of England: a repeated cross-sectional study in primary care. BMC Med. 9, 91, http://dx.doi.org/10.1186/1741-7015-9-91 4. Johnston, S., Brenu, E.W., Staines, D. and Marshall-Gradisnik, S. (2013) The prevalence of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: a meta-analysis. Clin. Epidemiology 5, 105–110, http://dx.doi.org/10.2147/CLEP.S39876 5. Kennedy, G., Underwood, C. and Belch, J.J. (2010) Page 30 of 82 Journal of IiMER Physical and functional impact of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis in childhood. Pediatrics 125, e1324–1330, http:// dx.doi.org/10.1542/peds.2009-2644 6. Dowsett, E. and Colby, J. (1997) Long-term sickness absence due to CFS in UK schools: an epidemiological study with medical and educational implications. J. Chronic Fatigue Syndrome 3, 29–42, http://dx.doi. org/10.1300/J092v03n02_04 7. Stewart, J.M. (2013) Common syndromes of orthostatic intolerance. Pediatrics 131, 968–980, http://dx.doi.org/10.1542/peds.2012-2610 8. Aaron, L.A., Burke, M.M. and Buchwald, D. (2000) Overlapping conditions among patients with Chronic Fatigue Ayndrome, fibromyalgia, and temporomandibular disorder. Arch. Int. Med. 160, 221–227, PMID: 10647761 9. Giloteaux, L., Goodrich, J.K., Walters, W.A., Levine, S.M., Ley, R.E. and Hanson, M.R. (2016) Reduced diversity and altered composition of the gut microbiome in individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Microbiome 4, 30, http://dx.doi.org/10.1186/ s40168-016-0171-4 10. Armstrong, C.W., McGregor, N.R., Lewis, D.P., Butt, H.I. and Gooley, P.R. (2017) The association of faecal microbita and faecal, blood serum and urine metabolites in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Metabolomics 13, 8, http://dx.doi.org/10.1007/ s11306-016-1145-z 11. Grimm, V. and Riedel, C.U. (2016) Manipulation of the microbiota using probiotics. Adv. Exp. Med. Biol. 902, 109–117, http://dx.doi. org/10.1007/978-3-319-31248-4_8 12. Hudson, L.E., Anderson, S.E., Corbett, A.H. and Lamb, T.J. (2017) Gleaning insights from faecal microbiota transplantation and probiotic studies for the rational design of combination microbial therapies. Clin. Microbiol. Rev. 30, 191–231, http://dx.doi. org/10.1128/CMR.00049-16 13. Borody, T.J., Nowak, A. and Finlayson, S. (2012) The GI microbiome and its role in Chronic Fatigue Syndrome: a summary of bacteriotherapy. J. Australasian College Nutrition Env. Med. 31, 3–8. ISSN: 1328-8040 www.investinme.org Page 31 of 82

No Isolation E arlier this year Invest in ME Research were contacted by a Norwegian company who were interested in use this to publicise awareness of the effects of ME on children. promoting a product which aimed to reduce the isolation experienced by many younger people who were unable to attend school, or were cut-off from social contact due to illness. Obviously, the charity immediately saw the parallels with ME and the possibility of raising awareness of one of the least publicised side effects of this disease on patients, and their families. Our immediate reaction was how we can help We then invited the company – No Isolation – to take a table at the IIMEC12 conference and offered to work further to support this campaign. The charity does not normally advertise products, or businesses, but on this occasion we feel it is a worthwhile cause that could help alleviate some of the unnecessary suffering which careless or ignorant education systems inflict on sick children and their families. In this article from No Isolation researcher, Oda Opdal Zachrisen, the company’s product AV1 is described. The AV1 robot helps children and youths with ME In Norway, a small white robot has become a stand-in in the classroom for children and youths suffering from ME. The robot is now available in the UK. The Norwegian start up No Isolation has developed a robot that helps children and youths with long-term illness www.investinme.org Page 32 of 82 Journal of IiMER participate in the classroom on their own terms. The robot, called AV1, acts as the students’ eyes, ears and voice in the classroom on days where they cannot be physically present. The student is in control The student controls the robot with an app on a tablet. When the student raises their hand, a light flashes on AV1’s head. The robot can be turned 360 degrees, so the student can see the entire classroom and talk to other students. If the student does not feel like actively participating, they communicate it by turning on a blue light on AV1’s head. AV1 is designed to withstand Childs play, and can join classmates in the playground or on after school visits. AV1 is already helping ME-patients Today, more than 170 children and youths are using AV1 in Norway. Children and youths suffering from ME is the largest user group. Research fellow Jorun Børsting and senior lecturer Alma Leora Culén at the Institute for Informatics, University of Oslo, are researching the technology needs of ME-patients. They have studied the use of AV1 among nine children and youths suffering from ME. They see a big advantage in the fact that the robot is designed with ME-patients in mind. – The advantage in participating in class through a tablet is that they have full control over sound levels, light and movement. In a normal classroom they do not have the option to control sensory inputs in this way. Furthermore, they can participate exactly when they feel like it, taking into account that symptoms can fluctuate over the course of the illness, even from hour to hour, Børsting comments. Børsting stresses that the robot cannot fully replace normal attendance at school or home teaching, but act as a supplement. – Of the children I followed several had not attended school in a long time when they first received the robot. Some had been out of school for over six months. After they received AV1, all of them participated regularly, on their own terms. The robot, which has been in use in Norway since autumn 2016, is now available in the rest of Europe. This little helper, which is already underway to children in the UK, can be ordered from No Isolation, at www.noisolation.com www.investinme.org Page 33 of 82

Cuts Threaten Research for Terrible Disease Once Called Chronic Fatigue Syndrome by Llewellyn King Journalist, broadcaster, public speaker Llewellyn King is the creator, executive producer and host of “White House Chronicle,” a weekly news and public affairs program, airing nationwide on PBS and public, educational and government (PEG) access stations, the commercial AMGTV network, and SiriusXM Radio. King writes a weekly column for the InsideSources Syndicate. King was the founder and publisher of The Energy Daily. The newsletter was the flagship of his award-winning King Publishing Group, which he sold in 2006. The group’s other titles included Defense Week and New Technology Week. In 2011 he created a charity for Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome. The charity has a YouTube channel, ME/CFS Alert. When you are sick, very sick, you wait for medicine to work its magic. But if the disease is Myalgic Encephalomyelitis (ME), you have to wait for the medicine to be invented. The bad news is that so little funding is going into solving the ME problem, commonly known as Chronic Fatigue Syndrome, that those sick today may be sick for the rest of their lives. They are living a life that is a nearly intolerable to themselves and a massive burden to their loved ones, spouses, parents and caregivers. What is known is that ME is a disease of the immune system. It is vicious and debilitating, leaving the patient confined to a marginal life, a parallel and unequal existence. Most infections are of healthy people who are struck down often, but not always, after exercise. The first symptoms can be flu-like: The sufferers feel a few days in bed will do the trick. But having ME is a life sentence. There also have been group infections, known as “clusters,” where hundreds www.investinme.org have been stricken. If you have ME, the least exertion can force you to spend days in bed, exhausted, hurting in myriad ways from headaches to what one woman described as “feeling like your bones are exploding.” In severe cases, the patient cannot tolerate light or sound. A young man, newly married, and felled unaccountably, had to live in a closet for an extended period before he could handle light and sound. Symptoms vary but most of the time a victim feels, as one told me, “like you are a car that has run out of gas and your tank cannot be filled up again.” A teenager told me that if she is to go out with friends, she has to weigh that against days of bed rest, in a complete state of collapse. The National Institutes of Health (NIH) ― the principal researcher into ME and dozens of other perplexing diseases ― has historically given ME a pittance. In the last three years funding has been held to $5 million a year, although the Obama Page 34 of 82 Journal of IiMER administration had promised more. To put this in perspective, the trade association of the pharmaceutical industry calculates that it costs $1.2 billion dollars to bring a new drug to market. Sadly that industry has not shown interest in ME, so the research is mostly funded by NIH and private groups and individuals. The news that the Trump administration is thinking of cutting the total NIH budget by $5 billion has caused a palpable anxiety to grip the ME community. The disease is cruel enough, does it need to be compounded by the government? That is why those who could manage it and members of their families were enthusiastic supporters of the March for Science. They were out there with a sense of being at the barricades as the barbarians massed on the other side. The United States has led the world for years in scientific discovery and implementation. It is deeply disturbing to think that the country would draw back from it. But the administration’s ambivalence is clear. The Department of Energy with 17 national laboratories, every one the envy of the world, is headed by Rick Perry. When he ran for president, he did so on a plank that included closing the department. The Environmental Protection Agency, with a history of struggling to get the regulatory science right, is headed by Scott Pruitt. As attorney general of Oklahoma, he sought to hobble the agency with lawsuits. So across science, from the National Aeronautics and Space Administration to the research service of the Department of Agriculture, there is fear among scientists; fear for their jobs, fear for science and fear for America. In the sick rooms of the 1 million or so ME sufferers, despondency has reached new depths. You will not be cured if no one cares enough to look for a cure. Can you double down on despair? www.investinme.org Page 35 of 82

Journal of IiMER Invest in ME Research Visit The CMO of England clinicians in other countries. Therefore, in this discussion we also used the knowledge and collaborative activities from discussions the charity has had with all of our international contacts. Recently Invest in ME Research again invited the Chief Medical Officer of England to our 12th International ME Conference in London [1]. Regrettably, this invitation was declined. However, after the continued orchestrated and misleading headlines relating to the PACE Trial II on children then we felt a new approach was required. In England, the CMO is a member of the board of the National Health Service (NHS), a civil servant in the Department of Health, and head of the medical civil service. So this presents us with an opportunity to cover failings in these areas. We must change the false view of ME constantly being represented by some organisations responsible for funding research and the media. The CMO has a duty to be informed - and support good research and clinical practice. Invest in ME Research therefore arranged a meeting with the CMO in London which will include our advisors and cover areas such as policy around ME since the last CMO report [3], epidemiology of ME, current/future international research, education regarding ME etc. Invest in ME Research is already approaching the issues around ME with an international context. We have already engaged with researchers and www.investinme.org Along with our colleagues in the European ME Alliance (EMEA) we are looking at ME in Europe and EMEA has been working very hard within the European Federation of Neurological Alliances (EFNA). We are also in continuing discussions with NIH on ways to improve diagnosis, research and treatments for ME. Regarding the CMO meeting - this is a UK problem -and therefore requires a UK strategy. Invest in ME Research therefore also invited the CMOs of Scotland, Northern Ireland and Wales to this meeting. But a Summit of CMOs for ME - sounded like something that could be useful. All of the UK's CMOs were invited to our 12th International ME Conference 2017 in London Invest in ME Research had requested a meeting with all four CMOs (England, Wales, Scotland and Northern Ireland) and on Wednesday 11 January 2017 a meeting took place with the Deputy CMO of England Dr Gina Radford at Whitehall Court, London. Invest in ME Research previously wrote about our intention to engage with the Chief Medical Officers of the UK and appraise them of the research into ME that the charity is facilitating and the current issues which continue to exist and which we believe the CMOs have a duty to confront - A Summit of CMOs ATTENDEES:  Dr Gina Radford, Deputy Chief Medical Officer, England  Professor Jonathan Edwards (UCL)  Dr Ian Gibson Page 36 of 82 Journal of IiMER  Countess Mar  Fane Mensah (PhD student, UCL)  Representatives from Invest in ME Research Apologies:  Dr Nigel Speight  CMO Scotland  CMO Northern Ireland  CMO Wales Prior to the meeting the charity had submitted two documents to the CMOs and participants. One concerning children and the deplorable state that exists as well as case studies of children badly affected by the way that the existing mentality toward ME is allowed to distort proper healthcare. In this document evidence was presented to the CMO of the way many families of children with ME are being harassed and subject to child Protection proceedings. Though the establishment organisations have totally failed children with ME the harassment is not, however, confined to vulnerable patients or their families either - as witnessed by this story - (http://investinme.org/IIME-Newslet-1604NS999.shtml). The following document had also been sent prior to the meeting to all attendees - Summary of developments following CMO’s report of 2002 It was agreed that the meeting would take an informal format to allow free discussion and the available agenda would be used as guidance. It was mentioned that Invest in ME Research had sent in information beforehand to allow the CMOs time to familiarise with the issues on the agenda. Dr Radford said she had read the information given and stated that the CMO could not resolve most of the problems mentioned as the CMO’s remit had changed and many of the issues mentioned would be the responsibility of NHS England. She would, however share the notes with other www.investinme.org CMOs in Wales, Scotland and Northern Ireland. The charity pointed out that the CMO’s remit includes influencing policy and that from experience it seems that ME is not on the CMO’s radar. The charity mentioned that the previous and current CMOs had never accepted the charity’s invitations to attend or speak at the international conferences that the charity had organised in the past 11 years. The invitation was always either too early or too late. There never seemed to be a right time and this sent a message to patients, carers, researchers and doctors interested in ME that ME was not on the CMO’s agenda. The charity explained that the meeting was taking place and as far as we were concerned, we were talking directly to the CMOs of the UK. The charity asked directly whether the CMO was happy with the current status of ME research and what was their official opinion on ME? Dr Radford stated that she could not speak for the CMO and she made the point once again that the CMOs of England, Wales, Scotland and Northern Ireland do not run the NHS. It is the NHS England that runs the services and we would need to discuss these matters with them. The CMO’s relationship with the NHS and remit has changed since 2002 when the 2002 CMO report on CFS/ME was published. Parameters have changed and now the CMO’s remit is to give broadly advice to the government. The charity read out the publicly stated remit of the CMO such as protect the public, tackle inequality, review policy (mentioned no policy for ME), influence by statements and discussions. CMO Remit Countess of Mar said Dr Martin McShane makes nice noises but nothing happens. The charity described cases provided in the accompanying document where severely ill children with ME who failed to recover with Page 37 of 82

Journal of IiMER CBT/GET programmes were then re-diagnosed and given labels such as pervasive refusal syndrome and parents/carers accused of Munchausen Syndrome by Proxy. The PACE trial was mentioned and Dr Radford had not read PACE. So Countess of Mar described the well-known shortcomings of the PACE trial including the Information Commissioner’s Office being involved leading to a court case to get raw data released and reviewed according to the original protocol and the damage it has caused to the worldwide patient community. Professor Edwards explained the reasons why the PACE trial and CBT/GET studies were poor science and the system is failing as it allows authors of these papers take on roles as reviewers of the same papers. The Cochrane review was an example of this. Dr Gibson described the annual IiMER Colloquium/Conference and how the science is getting interesting. There seems to be lack of duty for biomedical research into ME, neglect in taking an all- around approach and ME is not getting its fair share. Dualism was a waste of time and research should open up and the government has failed to take it up. Fane Mensah described the situation for a young researcher. He said there needs to be support for young researchers. Students who are thinking about their career choices need to know there is a future in this exciting and complex field. He described how the patients he sees as part of the research funded by Invest in ME Research are so grateful that someone is taking them seriously and listens to them. The charity asked Dr Radford how the CMO made decisions when taking up issues such as antibiotic resistance, Ebola, Zika virus etc.? Dr Radford said it was because they were major worldwide issues. www.investinme.org The charity said that ME is a major worldwide issue - yet no one knows numbers affected (only rough estimates) and the diagnosis is inaccurate and variable. Sally Davies should at least make a brief visit to the conference or send a representative to learn about the latest developments. Dr Clare Gerada as the chair of the Royal College of GPs gave a talk at the IIMEC8 conference in 2013 and admitted GPs knew very little of ME. Professor Edwards said ME was a bigger problem than rheumatoid arthritis. Epidemiology in general was lacking and current service provision was poor. The direction of ME research has not been founded in good science and the Norwegian phase III rituximab trial results will guide the future. The psychiatrists do not understand the problem and that is a BIG problem. The PACE trial is a text book case how not to do a trial. In Practical terms: we need physician led services (very few of which currently exist) which provide help and continued surveillance. ME is an identifiable problem due to the characteristic of post exertional malaise (PEM). Surveillance is needed as other diseases such as lymphoma can be hidden in that cohort. Major change has happened in USA, but not in the UK. Dr Radford asked what we wanted to ask the CMO. The following points were stated -  Genuinely appreciate the size of the ME problem  Maintain consultant led services  Appreciate new research  Appreciate current services have been hijacked by bogus science and patients find that dispiriting and dangerous NICE was briefly discussed and a decision whether the guideline will be reviewed should be made by the summer of 2017. Dr Radford said that it is important there is new Page 38 of 82 Journal of IiMER research that they can look at otherwise the guideline remains in a vacuum. The current recommendation of GET was brought up as harmful and putting children in danger. The severely ill need information and support. Professor Edwards mentioned MS patients get 6 monthly neurology appointments but ME patients get nothing. Problems with FITNET were mentioned and Dr Radford was aware of this and stated that FITNET was being reviewed. Dr Gibson said research is moving toward finding biomarkers. Metabolomics was proving promising as presented at the Invest in ME Research international conference. The approach has been too simplistic in the past. Dr Radford mentioned she is involved in an alliance of rare diseases and that there are hundreds of diseases in the same situation as ME. The charity said these rare diseases are recognised and patients are not dismissed and stigmatised by the establishment the way ME patients are. ME patients’ healthcare complaints, unrelated to ME, are often ignored and dismissed due to the patient’s ME label. The importance of accurate diagnosis with careful history taking was mentioned as endocrine disorders are often misdiagnosed as ME. Actions Dr Radford finished the meeting by summing up action points Highlight emerging research (relevant for NICE guidelines) Mention IiMER colloquium/conference to people of influence Agree that a new meeting arranged by the charity will take place later in the year when the Norwegian rituximab trial results would be known by the team involved. IiMER Summary Did we expect more from the visit with the CMO? Of course! Our aim is not to have just a cosy chat and keep the status quo. Action is required. As we stated before ME is a UK/worldwide problem - we did expect (and request) that all UK CMOs attend. But we have the CMO's attention now, to some extent. We will not leave it alone. We have a follow-up meeting planned and we will ensure that the CMOs of UK do not remain in the dark about the seriousness or severity of the issues with this disease. PostScript: At the CMO’s suggestion the charity contacted Simon Stevens of NHS England and Sir Bruce Keogh. At the current point in time we have to state that the treatment of our request for a meeting by Sir Bruce has been not just disappointing but appallingly apathetic to the plight of people with ME and their families. References ► Articles on PACE Trial ► Articles on ME/CFS by Margaret Williams and Professor Malcolm Hooper www.investinme.org Page 39 of 82

Journal of IiMER Summary of developments following CMO’s report of 2002 The ME community were by and large delighted at the contents of this Chief Medical Officer’s Report in 2002, with its strong implicit acceptance of ME/CFS as a primarily organic/biological illness. The members of the psychiatric viewpoint were sufficiently disheartened by this to refuse to sign up to the report’s conclusions. In 2004 the RCPCH (Royal College of Paediatrics and Child Health) published paediatric guidelines which were very much in line with the CMO’s report. In 2007 NICE guidelines came out, and for all the criticism of these guidelines, regarding their overemphasis of suggested merits of CBT and GET, these also cemented the concept of ME/CFS as an organic illness and made it “official”. What went wrong post 2002? First and foremost, there was an abdication on the part of adult medicine of responsibility for this condition. This must have been partly due to the tendency to specialisation on the part of even DGH physicians. No specialty would accept responsibility. In particular, the neurologists were very reluctant to be involved despite the WHO’s having designated ME as a neurological disease. The main problem was that there was no “ology” for ME, neither was one created. This failure on the part of general medicine had a knock on effect on general practice. GP’s sensed the reluctance of physicians to accept referrals, thus making ME less of an official disease and more of a “controversial” condition. These factors mitigated against the positive recommendations of the above three reports/guidelines. www.investinme.org Secondly, and as a result of this abdication by adult medicine, when specialist ME centres were set up very few medical specialists came forward, and the only people eager to step into the vacuum were the psychiatrists. (Two exceptions to this rule were in Newcastle and Epsom and St Helier, where immunologists took the lead). There has been widespread patient dissatisfaction with most of these centres. Firstly, the patients seldom saw an actual doctor to at least receive an official medical diagnosis. Secondly, the only support on offer consisted of different forms of CBT and GET which patients found either ineffective or harmful depending on the variety of therapy offered. The very existence of these specialist centres, of course, removed the obligation of DGH physicians and paediatricians to actually see, diagnose, help and support ME patients. Thirdly and most importantly, the psychiatric lobby made a concerted counterattack to recover their lost ground. This was all the more effective for being indirect. Their strategy consisted of the following 1) Ensuring that they were well positioned to influence medical education, both undergraduate and postgraduate. Again, they were filling a vacuum left by organic medicine. The two major medical textbooks (The Oxford textbook of Medicine and Kumar and Clark) have chapters on ME/CFS written by psychiatrists and buried in the section on “Functional illness” or “Medically unexplained symptoms”) Of course, the term “ME” is gradually airbrushed out of the narrative and does not occur in the indexes. Likewise, the major paediatric text Forfar and Arneil had a section on CFS placed in the section Page 40 of 82 Journal of IiMER on Child Psychiatry where it is stated baldly “CFS is the commonest psychosomatic illness in adolescence” 2) Use of the term “Biopsychosocial approach” as a further means of muddying the waters. (No one can object to the concept of a “biopsychosocial approach” in theory, as it is just another word for an holistic approach to any patient. However, the psychiatric lobby tend to use it excessively in their approach to ME/CFS, and then seem to forget the “bio” component! 3) Monopolising research and funding for ME/CFS for their own psychiatric agenda. Enormous sums have been involved and large research empires have been created. This all centres round CBT and GET, which have recently been called into question with major criticisms of the PACE trial. Again this has all happened because of the dearth of alternative proposals from those wishing to do research aimed at biological factors. (we should note that this, in turn, has been caused by the total lack of funding given to those biomedical research proposals which have been made – thus influencing attitudes in academia) 4) As already mentioned, the specialist centres are largely run by psychiatrists and psychologists. All this activity is carried on as if the CMO’s Final anecdote A GP phones an ME helpline for advice. He says “ I’m really worried I have developed ME”. Adviser clucks sympathetically. GP “That’s not the main problem – it’s just that I don’t know what to say to my colleagues” Further sympathetic cluck.. “You see, it has always been a policy of our practice to treat patients with ME with unremitting hostility, ridicule and rejection....So I can’t face telling my colleagues. I think I will just tell them I am suffering with depression ....”! report and NICE Guidelines did not exist, and as if there was not a growing body of evidence for biological causation of ME/CFS. Regarding the patient community, the psychiatric group steadfastly avert their gaze from the large number of severely affected patients, none of whom have responded to CBT or GET The current state of affairs -  One still hears GPs saying “we don’t believe in ME in this practice”  Adult patients have difficulty obtaining an official diagnosis of ME/CFS, and this can lead to them being deprived of benefits  ME/CFS has effectively been downgraded from being an official medical condition to one that is unofficial and “controversial”  There are a large number of severely affected adult patients and young people who are being neglected by the profession. Both GPs and consultants frequently refuse to do home visits on patients who are too unwell to attend surgery/outpatients.  Most distressingly, a significant number of families of children with ME/CFS are being subjected to “Abuse by professionals” (see attached paper)  Virtually no doctors are coming forward to establish an “ology” for ME www.investinme.org Page 41 of 82

THE PACE TRIAL THE PACE Trial has been frequently discussed in articles on the Invest in ME Research website and on the charity’s social media since the first paper was published by Lancet in 2011. [1] The PACE Trial has been shown to be flawed and a colossal waste of scarce public funding which should have gone to funding biomedical research which, by now, may well have been leading to a breakthrough in treating this disease. Recently the results from this trial have been thoroughly analysed and destroyed by a series of articles published in Professor Vincent Racaniello’s (Columbia University, USA) Virology blog by US journalist David Tuller. [2] Once these reviews began to create huge interest over the internet then the usual typical orchestrated media reaction appeared. As always happens the establishment media trot out their normal array of buffoons and denialists – spreading more oil on the fire by linking ME patients with militants and those who see stigma in mental health – with no real evidence to support either accusation and demonstrating a profound ignorance of the disease and of ME patients [3]. But then the establishment view is to see any valid criticism against false science as a threat - and their only method of response is to denigrate those who are suffering the most. Despite an orchestrated attempt to maintain the pretence that anything valid was produced by this research it must surely be plain for all to see, including a great many more academics and unbiased opinion, that the PACE Trial is now synonymous with farce, bias and null field research. www.investinme.org On October 27th the Information Commisioner’s Office (ICO) ruled in favour of a complainant that had requested raw data from the PACE trial to be made publicly available by the QMUL. [4]. In attempting to thwart attempts via FOI to get PACE Trial data released QMUL spent, in one month, over twice as much money as patients raised in three years of fundraising for IiMER’s biomedical research foundation project. As our advisor Emeritus Professor Jonathan Edwards from UCL has written - "If scientific interpretation is poor it deserves no protection. If it is good it needs none." The MRC policy is unequivocal on this – as pointed out by James Coyne PhD [Why the scientific community needs the PACE trial data to be released Posted November 11, 2015] [5] The UK Medical Research Council (MRC) 2011 policy on data sharing and preservation has endorsed principles laid out by the Research Councils UK including "Publicly funded research data are a public good, produced in the public interest, which should be made openly available with as few restrictions as possible in a timely and responsible manner. To enable research data to be discoverable and effectively re-used by others, sufficient metadata should be recorded and made openly available to enable other researchers to understand the research and re-use potential of the data. Published results should always include information on how to access the supporting data." -UK Medical Research Council (MRC) 2011 policy on Page 42 of 82 data sharing and preservation ber%202015.pdf So it is even more incongruous that, in all of the recent discussions, the MRC and other funders of this trial were so silent regarding this clear breach of guidance, this utter waste of money, this total waste of years of opportunity for good research into ME? Although it does not surprise us the silence is, nevertheless, indicative of an establishment organisation whose policy toward ME research is being led by those who do not best serve the interests of patients. Retraction of the PACE trial paper and release of the raw data for other scientists to review would no doubt mean that the whole mess around the PACE trial would have consequence elsewhere - as it is not just about one paper but the influence that it has had on health policies across the world. It would, however, send a strong message that misleading research is not tolerated nor should it be used as a means to bolster a universities’ Research Excellence Framework (REF) as has been the case now. The seriousness of the way in which this whole research has been conducted, and the consequences still remaining as referenced research, requires that the PACE Trial paper itself has to be retracted. Retracting the whole paper will send a message that poor quality research, especially when it is designed to influence healthcare policy, cannot be allowed. The Lancet, which fast-tracked the first of the PACE trial papers in 2011, really ought to have favoured patients. The editor of the Lancet failed even to respond to Invest in ME Research’s letters regarding the PACE trial http://www.investinme.org/Documents/Lancet/Lette r%20to%20Editor%20of%20the%20Lancet%20Novem www.investinme.org In this day and age it is unacceptable that research performed with public funding can be allowed to be controlled by anyone who is not transparent and open in their treatment of data related to the research. If raw data from the trial shows that the public has been misled even more than so far identified then there should be a public inquiry The MRC invests in research on behalf of the UK tax payer. The taxpayer has been ill-served by the PACE Trial. The MRC should therefore examine the possibility of having the funds for the PACE Trial returned in part or in full to the public – and from there to be allocated to biomedical research into ME. It must be considered whether the Principal Investigators of the PACE Trial be barred from receiving any further public funding for future research into ME. The MRC need to review the management of this trial and procedures for deciding how funding for research into ME is decided to be allocated. The refereeing system for reviewing research applications for ME needs to be overhauled and made transparent. Those in the MRC who have been responsible for research into ME over the last eleven years must, if still in positions of influence with regard to ME research, be replaced. The MRC policies have been a shambles and valuable years of research possibilities have been wasted - along with a monumental loss of scarce public funding. Conflicts of interest of those in the MRC who have any influence on ME research need to be declared and examined. Page 43 of 82

Journal of IiMER Consideration ought to be made for a government inquiry, or parliamentary committee to scrutinise the conduct of the MRC with regards to its policies, research grant applications and grants for ME made over the last 13 years since the CMO’s report was made. We are sure none of this will happen. The establishment looks after its own. But it seems impossible to see how, after the way the MRC has operated over the last ten years, ME patients or carers or ME patient groups or ME charities could possibly have any faith in an organisation such as this unless it is reformed. We fail to see how any healthcare professional or researcher can have faith in the Lancet until the PACE Trial is recognised for the farce that it has become. Professor Jonathan Edwards wrote the following “The PACE trial of cognitive behavioural therapy and graded exercise therapy for chronic fatigue syndrome/myalgic encephalomyelitis has raised serious questions about research methodology. An editorial article by Geraghty gives a fair account of the problems involved, if anything understating the case. The response by White et al. fails to address the key design flaw, of an unblinded study with subjective outcome measures, apparently demonstrating a lack of understanding of basic trial design requirements. The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed.” http://journals.sagepub.com/doi/full/10.1177/1 359105317700886 References White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, et al. (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 377: 823–836. doi: 10.1016/s01406736(11)60096-2 http://www.virology.ws/2015/10/21/trial-by-error-i/ http://www.virology.ws/2015/10/22/trial-by-error-ii/ http://www.virology.ws/2015/10/23/trial-by-error-iii/ http://www.virology.ws/2015/10/30/pace-trialinvestigators-respond-to-david-tuller/ http://www.virology.ws/2015/10/30/david-tullerresponds-to-the-pace-investigators/ http://www.virology.ws/2015/11/09/trial-by-errorcontinued-why-has-the-pace-studys-sister-trial-beendisappeared-and-forgotten/ http://www.telegraph.co.uk/news/health/11959193/C hronic-Fatigue-Syndrome-sufferers-can-overcomesymptoms-of-ME-with-positive-thinking-andexercise.html https://ico.org.uk/media/action-weve-taken/decisionnotices/2015/1560081/fs_50565190.pdf Professor James Coyne http://blogs.plos.org/mindthebrain/2015/10/29/unint erpretable-fatalflaws-in-pace-chronic-fatiguesyndrome-follow-up-study/http://impact.ref.ac.uk/casestudies2/refservice.svc/ GetCaseStudyPDF/18135 http://impact.ref.ac.uk/casestudies2/refservice.svc/ GetCaseStudyPDF/41185 http://impact.ref.ac.uk/casestudies2/refservice.svc/ GetCaseStudyPDF/17492 http://impact.ref.ac.uk/casestudies2/refservice.svc/ GetCaseStudyPDF/23887 “An open letter to Dr. Richard Horton and The Lancet"http://www.virology.ws/2015/11/13/an-openletter-to-dr-richard-horton-and-the-lancet www.investinme.org Page 44 of 82 Journal of IiMER An open letter to Psychological Medicine about “recovery” and the PACE trial A letter, for which Invest in ME Research helped in obtaining signatures from some of the top scientists, was recently published and sent to Psychological Medicine . The letter included signatures from eminent scientists and researchers from institutions including the following - HHV-6 Foundation University of California DePaul University Cornell University National Cancer Institute USA Georgetown University Bateman Horne Center EVMED Research University of Medicine and Dentistry of New Jersey University of Manchester George Mason University University of Sunderland Columbia University University of Utah University of British Columbia Stanford University Tulane University School of Medicine University of East London Harvard Medical School Ithaca College New York Nova Southeastern University Hunter-Hopkins Center University of Kent Stichting Cardiozorg Northwestern University Pritzker School of Law Linköping University University of Oslo University of Minnesota National Centre for Neuroimmunology and Emerging Diseases George Mason University Solve ME/CFS Initiative Tufts University WorkWell Foundation University of Calgary University of Cumbria Catholic University of Valencia School of Medicine Rutgers Robert Wood Johnson Medical School Soerabaja Research Center London School of Hygiene & Tropical Medicine University of Birmingham Victoria University of Wellington Also signing were organisations from around the world such as Invest in ME Research and our partners in the European ME Alliance, Open Medicine Institute. Also from UK individuals such as - Simon Duffy (Director Centre for Welfare Reform), Jonathan C.W. Edwards, MD (Emeritus Professor of Medicine University College London) and Ian Gibson, PhD (Former Member of Parliament for Norwich North Former Dean, School of Biological Sciences University of East Anglia). The letter (shown on the following page) demonstrates the gathering weight of scientific opinion exposing the PACE Trial. Stanford University School of Medicine Rutgers New Jersey Medical School Duke University School of Medicine Nevada Center for Biomedical Research from “MEDICINE and ME” http://www.investinme.org/IIME-Cartoons-2013-01.shtml www.investinme.org Page 45 of 82

Journal of IiMER 13 MARCH 2017 Sir Robin Murray and Dr. Kenneth Kendler Psychological Medicine Cambridge University Press University Printing House Shaftesbury Road Cambridge CB2 8BS UK Dear Sir Robin Murray and Dr. Kendler: In 2013, Psychological Medicine published an article called “Recovery from chronic fatigue syndrome after treatments given in the PACE trial.” [1] In the paper, White et al. reported that graded exercise therapy (GET) and cognitive behavioural therapy (CBT) each led to recovery in 22% of patients, compared with only 7% in a comparison group. The two treatments, they concluded, offered patients “the best chance of recovery.” PACE was the largest clinical trial ever conducted for chronic fatigue syndrome (also known as myalgic encephalomyelitis, or ME/CFS), with the first results published in The Lancet in 2011. [2] It was an open-label study with subjective primary outcomes, a design that requires strict vigilance to prevent the possibility of bias. Yet PACE suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings. [3] Despite these flaws, White et al.’s claims of recovery in Psychological Medicine have greatly impacted treatment, research, and public attitudes towards ME/CFS. According to the protocol for the PACE trial, participants needed to meet specific benchmarks on four different measures in order to be defined as having achieved “recovery.”[4] But in Psychological Medicine, White et al. significantly relaxed each of the four required outcomes, making “recovery” far easier to achieve. No PACE oversight committees appear to have approved the redefinition of recovery; at least, no such approvals were mentioned. White et al. did not publish the results they would have gotten using the original protocol approach, nor did they include sensitivity analyses, the standard statistical method for assessing the impact of such changes. Patients, advocates and some scientists quickly pointed out these and other problems. In October of 2015, Virology Blog published an investigation of PACE, by David Tuller of the University of California, Berkeley, that confirmed the trial’s methodological lapses.[5] Since then, more than 12,000 patients and supporters have signed a petition calling for Psychological Medicine to retract the questionable recovery claims. Yet the journal has taken no steps to address the issues. Last summer, Queen Mary University of London released anonymized PACE trial data under a tribunal order arising from a patient’s freedom-of-information request. In December, an www.investinme.org Page 46 of 82 Journal of IiMER independent research group used that newly released data to calculate the recovery results per the original methodology outlined in the protocol.[6] This reanalysis documented what was already clear: that the claims of recovery could not be taken at face value. In the reanalysis, which appeared in the journal Fatigue: Biomedicine, Health & Behavior, Wilshire et al. reported that the PACE protocol’s definition of “recovery” yielded recovery rates of 7 % or less for all arms of the trial. Moreover, in contrast to the findings reported in Psychological Medicine, the PACE interventions offered no statistically significant benefits. In conclusion, noted Wilshire et al., “the claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments.” In short, the PACE trial had null results for recovery, according to the protocol definition selected by the authors themselves. Besides the inflated recovery results reported in Psychological Medicine, the study suffered from a host of other problems, including the following: *In a paradox, the revised recovery thresholds for physical function and fatigue–two of the four recovery measures–were so lax that patients could deteriorate during the trial and yet be counted as “recovered” on these outcomes. In fact, 13 % of participants met one or both of these recovery thresholds at baseline. White et al. did not disclose these salient facts in Psychological Medicine. We know of no other studies in the clinical trial literature in which recovery thresholds for an indicator actually represented worse health status than the entry thresholds for serious disability on the same indicator. *During the trial, the authors published a newsletter for participants that included glowing testimonials from earlier participants about their positive outcomes in the trial.[7] An article in the same newsletter reported that a national clinical guidelines committee had already recommended CBT and GET as effective; the newsletter article did not mention adaptive pacing therapy, an intervention developed specifically for the PACE trial. The participant testimonials and the newsletter article could have biased the responses of an unknown number of the two hundred or more people still undergoing assessments—about a third of the total sample. *The PACE protocol included a promise that the investigators would inform prospective participants of “any possible conflicts of interest.” Key PACE investigators have had longstanding relationships with major insurance companies, advising them on how to handle disability claims related to ME/CFS. However, the trial’s consent forms did not mention these self-evident conflicts of interest. It is irrelevant that insurance companies were not directly involved in the trial and insufficient that the investigators disclosed these links in their published research. Given this serious omission, the consent obtained from the 641 trial participants is of questionable legitimacy. Such flaws are unacceptable in published research; they cannot be defended or explained away. The PACE investigators have repeatedly tried to address these concerns. Yet www.investinme.org Page 47 of 82

Journal of IiMER their efforts to date—in journal correspondence, news articles, blog posts, and most recently in their response to Wilshire et al. in Fatigue[8]—have been incomplete and unconvincing. The PACE trial compounded these errors by using a case definition for the illness that required only one symptom–six months of disabling, unexplained fatigue. A 2015 report from the U.S. National Institutes of Health recommended abandoning this single-symptom approach for identifying patients.[9] The NIH report concluded that this broad case definition generated heterogeneous samples of people with a variety of fatiguing illnesses, and that using it to study ME/CFS could “impair progress and cause harm.” PACE included sub-group analyses of two alternate and more specific case definitions, but these case definitions were modified in ways that could have impacted the results. Moreover, an unknown number of prospective participants might have met these alternate criteria but been excluded from the study by the initial screening. To protect patients from ineffective and possibly harmful treatments, White et al.’s recovery claims cannot stand in the literature. Therefore, we are asking Psychological Medicine to retract the paper immediately. Patients and clinicians deserve and expect accurate and unbiased information on which to base their treatment decisions. We urge you to take action without further delay. Sincerely, [1] White PD, Goldsmith K, Johnson AL, et al. 2013. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine 43(10): 2227-2235. [2] White PD, Goldsmith KA, Johnson AL, et al. 2011. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 377: 823–836 [3] Racaniello V. 2016. An open letter to The Lancet, again. Virology Blog, 10 Feb. Available at: http://www.virology.ws/2016/02/10/open-letter-lancet-again/ (accessed on 2/24/17). [4] White PD, Sharpe MC, Chalder T, et al. 2007. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 7: 6. [5] Tuller D. 2015. Trial by error: the troubling case of the PACE chronic fatigue syndrome trial. Virology Blog, 21-23 Oct. Available at: http://www.virology.ws/2015/10/21/trial-by-errori/ (accessed on 2/24/17) [6] Wilshire C, Kindlon T, Matthees A, McGrath S. 2016. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical www.investinme.org Page 48 of 82 Journal of IiMER commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior; published online 14 Dec. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1259724 (accessed on 2/24/17) [7] PACE Participants Newsletter. December 2008. Issue 3. Available at: http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter3.pdf (accessed on 2/24/17). [8] Sharpe M, Chalder T, Johnson AL, et al. 2017. Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior; published online 15 Feb. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1288629 (accessed on 2/24/17). [9] Green CR, Cowan P, Elk R. 2015. National Institutes of Health Pathways to Prevention Workshop: Advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Annals of Internal Medicine 162: 860-865. IiMER Conference DVDs The Invest in ME Research conference DVDs are professionally filmed and authored DVD sets consisting of four discs in Dolby stereo. They contain all of the presentations from Invest in ME Research International ME/CFS Conferences (2006 – 2015). Also included in the DVD sets are interviews with ME presenters, news stories, round-table discussions or pre-conference dinner presentations. The Invest in ME Research conference DVDs have been sold in over 20 countries and are available as an educational tool – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://www.investinme.eu/IIMEC11.shtml#dvd or via emailing Invest in ME Research at mailto:info@investinme.org www.investinme.org Page 49 of 82

Journal of IiMER MARGARET WILLIAMS REPOSITORY www.margaretwilliams.me What we are witnessing now is the gradual destruction of the flawed and negligent perception of ME, which vested interests have created for the last decades in UK and elsewhere and which has so pervasively influenced government departments, academia, medical establishments, the media and, by eventual lemming-like acceptance, the public. The flagship of the those who have promoted (and benefited) from the biopsychosocial view of ME for so long has begun to sink, run aground on the rocks of reason, science and an intractable dedication from some patient organisations and patient advocates. The wreck that is PACE is now dragging down those pillars of the establishment that have supported it. For so many years when establishment organisations and individuals have been following a false path of research and treatments for ME, supported by fickle media editors and buffoon, journalist hacks, there was a constant source of information and analysis about ME - a voice of science, reason, and factual evidence that gave the lie to the biopsychosocialists. This came from Margaret Williams - a severely affected, but articulate patient who saw through the falsehood of the myths perpetrated by vested interests and produced countless articles exposing the corrupt environment maintained by the establishment toward ME. Invest in ME Research has featured many of Margaret Williams' articles during its 11 years as a charity. Now all of her articles have been indexed and made available online at this URL www.margaretwilliams.me Not only is this compendium of articles and information fully indexed but the website also contains a search button enabling one to search on any topic, organisation or individual very easily. This is a resource that will be of historical significance for academics - and a huge testament to one of the great ME advocates. You don’t have to be go crazy to raise funds for Invest in ME Research – simple things such as a North Pole marathon, Everest Base Camp, 28 EU marathons …… Look at current and past fundraising events http://www.investinme.org/fundraising.shtml http://www.investinme.org/prev-fundraising.shtml EUROPEAN ME ALLIANCE NEWS Summary Report Breakfast Colloquium European Parliament – Brussels March 7th 2017 The European ME Alliance recently organised a meeting in the European Parliament to discuss the situation with regard to ME in Europe. This event followed meetings for clinicians on the day before organised by EMEA-Belgium member [ME Association]. The intent with the meeting – labelled Breakfast in Brussels – was to make European MEPs aware of the lack of services for people with ME, the negligible amount of proper research being carried out into the disease across Europe, and the lack of funding given to biomedical research into the disease and the waste which is being given to flawed psychiatric theories which have caused harm to patients across the continent. With the help of MEP, Mrs. Helga Stevens and her staff the Belgian ME Association coordinated the event that consisted of a number of selected speakers addressing a gathering of MEPs. The speakers were Dr. Ian Gibson, Dr. Olli Polo, Dr. Nigel Speight, Dr. Louise Brinth and CRPD Expert Dr. László Lovászy – who shared their knowledge and expertise with the audience. The following are extemporaneous notes compiled by EMEA Belgium during the meeting. www.investinme.org Page 51 of 82

Journal of IiMER Welcome by host MEP Mrs. Helga Stevens MEP Mrs. Helga Stevens thanked everyone for attending, and thanked EMEA for letting her host this event and for organising this important Breakfast Colloquium at the European Parliament. She started by saying that Myalgic Encephalomyelitis (ME) is a very serious, disabling and chronic organic disorder classified by the World Health Organisation as a distinct neurological disorder since 1969 and that ME is often denigrated end denied by doctors, policymakers and the general public. This is why the classification as a neurological disease is an important step towards broader official recognition by the medical and scientific establishment! Personally, she found it very interesting not to look at the disease from a medical point of view but also in terms of it potentially being recognised and understood as a disability and from a social model of disability point of view whereby it is the environment that is disabling rather than victimising the individual him/herself. Mrs. Stevens looked forward to learning more about ME, in particular about children with ME and what good practice examples exist out there. She wished EMEA all the best for the event. Politicians have a predisposition to try and save money and in this area definitions are extremely important in determining whether patients get benefits or not. Putting money into biomedical research, Dr. Gibson said, is much more expensive - even though it might be more productive in the long run and save a lot of money. In the short term, it is about trying to get definitions. Going over to therapy Dr. Gibson touched upon a paper called “The PACE Trial” which is been looked at now by some very serious academics in the United Kingdom and has been discredited. When asking questions in the House of Commons they did not receive any credible answers. On the other hand there was huge support for the MP who asked these very pertinent questions about these decisions, why they were made and about disability and benefits. He became a hero in the ME community. The economic consequences of not being www.investinme.org Page 52 of 82 Dr. Ian Gibson – European Issues Dr. Ian Gibson talked about public disability problems and how those are supported, not just in the Member States but across the European Parliament as well. He referred to Professor Tom Shakespeare (at University of East Anglia) who shows that much of the determination of policy on illness depends on trying to stop people with illnesses getting benefits. Rather than judging whether a person has a practical chance of being able to find a job the new capability assessment investigates whether the person has the ability, in theory, to do any form of work at all. Most likely the eligibility criteria can substantially make it more difficult for people to access benefits. Journal of IiMER diagnosed at an early stage are increasing by the minute, but the research may bring about something in that field. We are not there yet, but we need to support the research that is going on. The Americans have calculated that across the world hundreds of billions of pounds/euro’s in benefits are not being given to people who are not being able to work. Dr Ian Gibson said there are two things for which the UN in developing countries could be supportive. Firstly, the WHO should be able to organise activities to support ME and its patients. Because there is money there and they have worked on diagnosis, treatment and care before e.g. in polio. Secondly, they have defined ME as a neurological problem but nothing is being done about it. So some of us are working very hard to change that. He also mentioned the WHO ICDclassification is still being looked at. The main issue for politicians to consider is the millions of people that have been classified with ME and remember that their lives are being ruined together with that of their families. However, to the question of how many people we are talking about, there is no answer because of lack of any registered data. So we do not really know how many patients have ME but the estimate is about 25 million patients around the world. ME is not recognised or being taken seriously. However, scientific research is finally going ahead and showing progress. It is mostly funded by private money, charities and other organisations and we have to find ways to increase this. The Americans are joining in, and are coming to the Invest in ME Research conference in London, which takes place for the 12th year now in June. At the conference patients and scientist are there together and it is amazing to see them talking to each other because doctors do not like talking to patients because of the difficult questions that are asked. It is also great to show people there is progress. The Norwegians are on the way to making a change for the patients. Conclusion www.investinme.org Many people out there need your support, and benefit from the exchange of different countries and that is something too to bear in mind when one thinks about ME. It is not just the illness itself but also the effect it has on millions of peoples’ lives and the realisation that nothing has changed over the last ten years. Nevertheless, it is starting to change now. Dr. Olli Polo – MD’s View of ME How patients with ME are seen by doctors without any particular knowledge of the disease? Myalgic Encephalomyelitis is a very particular condition and the normal concepts that one can apply to many other diseases cannot be applied here. This is clearly due to the misunderstanding about this disease. Last week one of his patients said: “Going to the doctor, is like going to the court. The doctor is the judge and the patient is guilty.” Dr. Olli Polo wondered if this was true, but there are stories that corroborate this based on the way doctors with a lack of knowledge of ME treat patients. The behaviour of doctors towards ME patients is characterised by loss of contact with reality, altered values and social interaction impairment. Doctors say that their patients are somaticizing their mental symptoms but now we actually know that the doctor is psychiatrizing the patient’s traumatic symptoms. Normally, doctors run the research but, in this case, the patients ask for research and recognition for ME as a real disease. Patients are Page 53 of 82

Journal of IiMER then confronted with the resistance of the medical society to get into this. Investment in medical research is decreasing overall and we are also producing more doctors with differing standard levels of knowledge because they no longer have a scientific background. We have a few written treatment guidelines that should set the minimum level of standard care in primary care and regional hospitals. If patients cannot be treated according to the guidelines then they are referred to the university hospitals. However, the reality today is that, after twenty years, public health care is only provided and available treatment at the university hospitals. In other words, one can only receive evidence based diagnostics and treatments, so if a treatment works but is not in the guidelines one is not entitled to receive this treatment. This makes doctors afraid of regulatory actions (e.g. we had an eleven year old, paralysed girl, who had to be taken to Holland – Rotterdam to get Immunoglobulin-IV treatment.). There is actually written evidence about the use of this therapy in ME but in Finland no one dares to give it or fear of regulatory actions. Doctors who are interested in studying or treating ME/CFS experience the same faith as patients. The doctors lose their credibility, their jobs and jeopardised by the medical establishment. The Finnish health professionals state that the purpose of a health professional is to maintain health, prolong health, heal sick patients and alleviate their suffering. Also in his professional activity he must apply commonly accepted, experience-based, medically acceptable procedures, before giving any medication to a patient which must be continuously updated. Therefore, a research-orientated doctor/scientist may arrive in a contradictory situation, where commonly accepted procedures are more about about promoting health than alleviating suffering of the patient. So what to do? For instance, if an ME patient is misdiagnosed with depression then, unfortunately, they have little expectation other than the increase of exercise, despite the www.investinme.org worsening of symptoms, just in order to get social benefits. Patients who are malnutritioned are proposed Graded Exercise Therapy to improve their fitness. If a doctor fails to alleviate suffering, or fails to use experience-based accepted procedures and medication then the doctor will be subject to regulatory actions. This is also applied by the Ethical Review Board (ERB). Evidence-based medicine has gone somehow too far. There is no evidence-based treatments when treatments are being used for the first time. So they are experimental treatments, and the possibility to carry out these treatments calls for innovations as they are advancing science very much. Nowadays we speak a lot about personal medicine versus quality medicine. In USA some doctors have been sued for their innovative and experimental treatments. This could happen in Europe. A physician and surgeon should not be subject to disciplinary action solely on the basis that the advice or the treatment he/she rendered to the patient is an alternative or complementary medicine, as long as that treatment or advice meets all the following requirements:  There is informed consent  The patient knows he/she is not getting evidence-based standard medical care  they have been fully informed of what the conventional treatments available are  they have been informed of any side effects that may still be allowed but not cause delay in traditional treatments or cause death or bodily injury Conclusion The medical community is getting more and more regulated which is understandable if the educational level of doctors is decreasing. However, at the same time, we should be careful not to throw out the baby with the bathwater for those who are innovative and practise medicine Page 54 of 82 Journal of IiMER with true ethical principles, which they have learned in medical school, in order to help the patients using all their means. If we are intelligent and innovative, why do we not use our qualities just to try to help the patient? was the abuse that families of children with ME suffer as a result of doctors not protecting them properly. Over 30 years he had been involved with 40 families who had been subject to child protection proceedings reaching case conference level, sometimes court proceedings, to remove children. Fortunately, he has been successful in 38 cases but lost one in England and one in Norway. Each case was a tragedy. Dr. Nigel Speight Children with ME Dr. Nigel Speight thanked the Parliamentarians for the opportunity to speak at the European Parliament. A lot has already been said on the basic issue about ME being an organic disease and for him one of the beauties of working with children is they highlight this fact. Dr. Speight once told an adult neurologist that he had an interest in paediatric ME. The neurologist replied: “Oh, I didn’t realise that it occurred in children, maybe I should think again.” In other words the neurologist had the common view that all adults with ME were just depressive losers but if children can get ME, that would make him think again. Dr. Speight says his experience with working with children and seeing happy, healthy, cheerful, sociable children struck down with ME for him is the biggest proof one can have of ME being fundamentally an organic process. He actually accumulated over 600 cases of ME over the last 30 years mainly within the United Kingdom but has also been to Ireland, Norway and Germany. Dr. Nigel Speight briefly shared some of his clinical experience but what he really wanted to talk about www.investinme.org Dr. Speight showed some slides of a follow up study showing progress over time of 49 patients, of which 15 recovered over two to five years. Seven of them who were unlucky and were getting worse, and a large number who were going up and down. ME is a very unpredictable condition, with wide fluctuations in severity. Overall, there is grounds for cautious optimism and the prognoses is probably slightly better in children than in adults. Apart from what we can learn from the fact that children can get ME, he thinks the severe cases of ME teach us something else. These are the severe cases that have not responded to Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT) so those treatments cannot be that effective. Dr. Speight has seen about seven of these, they are bed-ridden, have very severe unpleasant symptoms, have severe sleep problems and five of them are tube fed because they are to tiered to chew and swallow. Dr. Polo mentioned immunoglobulin, he gave this to all the severe cases and they did remarkably well. According to him immunoglobulin as well as Rituximab deserve re-examination for severe cases. Many paediatricians can see ME and when they see their first case, they panic. Dr. Speight talked about a girl who had been handed to him by the court. The girl had been subjected to three months of vigorous physiotherapy and had severely worsened. The court eventually asked to rehabilitate her before going home. She was lying in a darkened room, catheterised and in severe pain. If any doctors are in charge of a severe case, he advises them not to panic. A doctor always has a Page 55 of 82

Journal of IiMER need to treat and investigate and actually trying too hard and over-investigating and treating with things that do not work, is the worst thing you can do for these patients. Immunoglobulins is one possibility, antibiotic therapy just in case there is an atypical infection such as Lyme disease, otherwise they just deserve tender love and care for their palliative symptoms. The last case was a German girl, the worst he had ever seen, treated the same way. She was in hospital, having severe pain, was tube fed and the mother was accused of arguing with the doctors about the treatment being provided. The girl was subjected to an activity regime, where she was put in a wheelchair every day. Dragged out of bed, put in the wheelchair - head strapped to the wheelchair because it kept falling. Shoved around the hospital, she was then exposed to a teacher, then exposed to a psychologist, and then exposed to a physiotherapist. She suffered this treatment month after month after month. Dr. Speight asked the doctor in charge: “Have you got her informed consent for this treatment?” and he said no! Dr Speight asked: “Do you have an assessment of her competence to give consent to this treatment?” Again the answer was no! It was not ethical, but they had a court order and the mother had no rights. Luckily, a nice female judge accepted my evidence and reversed the care order and released the girl from the hospital, restored the mother’s parental rights and allowed her to take her daughter home. Only two months after that ordeal you can see the girl returning, she is a smiling girl with glistening eyes, nothing like the girl from the hospital. She has been given no magical treatment, just the respect of her autonomy and human right and the company of people who believe in her. that usually includes subjective evaluations of both positive and negative aspects of life ”. For me something crucial was missing in this sentence namely that “Quality of life” also depends on the balance between these positive and negative aspects of your life. Starting from this perspective, I looked at how Myalgic Encephalomyelitis or ME affects my life. ME, completely changed my life. I went from an active working mother and wife, with two children - six and nine years old at the time- to a debilitated spouse and mum who could barely make it from her bed to the sofa and back. People around me had no idea what was happening to me and reacted with disbelieve and ignorance. My employer kept asking me to work from home, up to the point when I literally felt my brain sparking. My brother said: “If you were working for me, you would’ve been sacked a long time ago.” and my mother kept repeating I had to do more, she said I was lazy. I ended up losing all my friends, hardly saw any relatives and spend my days between four walls in the company of my husband and children. Nancy Van Hoylandt – Quality of life As an ME patient (and a patient representative) I asked myself what is ‘quality of life’? Looking for a definition I found this on the WHO website: “Quality of life is a broad multidimensional concept www.investinme.org After a few months my GP sent me to a psychiatrist. The seed of depression was planted. The psychiatrist recommended psychotherapy in a day care facility, so I went. This approach did not seem to work and after six months I was told they could not help me, blaming me for the failure of the therapy. By that time I was a complete wreck and needed more therapy to undo the damage from the first round of psychotherapy. My second psychiatrist would eventually apologise for asking too much, too soon, too fast, explaining to me there was more to my condition than meets the eye. I also followed months of hydrotherapy and Page 56 of 82 Journal of IiMER physiotherapy, the result being none other than getting worse. Falling asleep in the car after therapy was no exception; I was exhausted and needed rest. You do not need to worry, I was not the driver! Once I rode my bike and was not able to lift my legs from the pedals approaching a red light. I had fallen down with the bike before, for the same reason. The light turned green at the last minute. I do not want to know what would have happened otherwise. After the red light incident I stopped riding my bike because it became too dangerous. After eight years I was diagnosed. Unfortunately, this did not mean getting access to appropriate care, treatment, necessary benefits, etc. The lack of suitable care and available treatment leaves much room for a lot of question rather than answers. And the commonly used name, chronic fatigue syndrome, maintains the enormous burden of stigma attached Myalgic Encephalomyelitis and the psychiatric opinion of it. Having ME effects every part of my daily life. It starts in the morning when I have to get out of bed, when it feels like I have been run over by a truck, to going to bed when I am not able to fall asleep right away and lie awake for hours. I feel it when I take a shower and I can hardly lift my arms to wash my hair. Or when I am too tired to stand under the shower and need a small stool to sit on or on days when it is really difficult and I ask one of my daughters to help me. On days when I do not have to leave the house I save energy by just walking around in my pyjama, taking no shower and not combing my hair. However, this is something people do not see when they see me. While getting dressed I use a chair, always! Because I cannot stand for a long time. When I stand up straight for a long time I get dizzy, nauseous, weak, everything gets black before my eyes and it feels like I am going to faint. This is why I usually sit, hang or do something in between. During the day the pain varies according to the things I do. When I do too much physical or mental www.investinme.org ‘work’ the pain is worse and I may get a fever. When I go to sleep the following nights, it feels like I have a very sever flu and my whole body aches and shivers. Migraines are my constant companion as a result of stepping over my limits. But that limit can be a scent that is too strong, like my daughter’s perfume or a light that is too bright like the sun. I used to be better but after every severe migraine attack I never returned to my old level of functioning. My digestive problems get worse the more I get tired. The fact that my husband cooks is for two reasons. I cannot manage three pots and pans anymore, and when I do cook I am too tired to eat afterwards. The hardest symptom for me to deal with is the cognitive impairment. This makes me feel like I am losing my intellectual abilities. The work I do takes an enormous amount of time, I have trouble concentrating, organising my files, my orientation is all over the place, etc. Due to my disabilities I am hardly capable of doing housework. The tasks I do take weeks, and some things are just impossible to do. Like I said, my husband usually cooks, does the dishes, the ironing, some of the cleaning and sees to it that I get everywhere I need to be. But, due to financial difficulties, we are not able to afford the necessary help, such as cooking and cleaning, transportation, care, etc. Most of the supportive treatments and food supplements prescribed to me are not reimbursed. We are adjusting our home ourselves without reimbursed benefits. I have been put on retirement due to my illness but I do not have any benefits that come with being retired. ME also has consequences for my family, my husband and children. I cannot do the things I would like to do with my children because they are not physically possible. I once got angry with my husband because the bus stopped too far from the parking lot and I could not Page 57 of 82

Journal of IiMER walk that far anymore. But that was not his fault. I do not qualify for a disabled parking permit because my physical condition is too good. And my family cannot do what they want to do because they have to be quiet or need to do something they do not want to. Intimacy is also a problem in ME. Sometimes I joke about this and say: “I’m getting tired just thinking about it.” What people do not know is that there is truth in what I say, which causes marriages to fail and patients to get isolated. Overall, my ME is an invisible disease, people cannot see I am sick and I am usually not showing it. Even on bad days I keep hearing: “You look fine”. As an ME patient I have learned pretty quick to shut up and say I was fine no matter how I felt. On days when I stay at home, I am completely invisible. Like severe ME patients who are bedridden and housebound. Conclusion From my story you can gather that there are little positive aspects to having ME. However being a volunteer for the Belgian ME Association and the European ME Alliance has brought meaning to my life. Something that had disappeared since my retirement in 2007. I have watched my life go by because of ME. Not being able to participate in my own life and if I did/do, I pay the price. So I am here to raise awareness and advocate for a disease called ME that hinders people, who are disabled in various degrees included long-term physical, cognitive or sensory impairments, to participate fully and effectively in society on an equal basis with others. patients. We use diagnosis to get a shared reality. It is a common language between patients, medical professionals and the healthcare system. Patients with more unexplained symptoms, patients with many symptoms do not always have this luxury of a shared reality and a common language. They may not get a diagnosis, they may get many different diagnoses or they may get misdiagnosed. So patients with many unexplained symptoms, ME patients, they are to some degree very often invisible. They do not pop-up in our studies, when we do witness studies and they do not belong to a dedicated medical specialty. When you get a heart attack you go to a cardiologist, when you have ME or symptoms like ME you do not belong to a medical specialty which is a huge problem. ME has its own WHO ICD-10 diagnose-code G93.3 which puts it in the group of Neurological Disorders. It is a syndrome diagnosis, which means its diagnosis is built on the presence of symptoms and the typical ME symptoms that ME patients will tell you that they have. The symptoms also included in the different diagnostic criteria are, first and foremost, profound fatigue and fatigability, Post Exertional Malaise (PEM) and Post Exertional worsening of all their symptoms. All their symptoms get worse when they exert themselves too much. Dr. Louise Brinth – Challenges and care Dr. Louise Brinth is a medical doctor and said that medical professionals use diagnosis to sort/classify www.investinme.org We have many different names for this disorder and it is very difficult and almost impossible to ascertain to what degree these diagnostic entities overlap. The medical aetiology is very unclear. A lot Page 58 of 82 Journal of IiMER of very exiting research is going on at the moment and we are gathering a piece of the puzzle but we do not have a coherent medical hypothesis so far and we do not have a clear cut diagnostic biomarker for ME. We have very different diagnostic criteria - she thinks there are more than a hundred all together. So, all in all, you can see that this is quite a diagnostic mess. She has seen ME patients when she was asked to co-author the paper on quality of life in ME patients and it was first and foremost the work of Michael Hvidberg who should have all the credit for this and who sends his regards. He used a questionnaire, a standardised nondisease specific questionnaire, which is used to describe and value healthrelated quality of life in patients. It is called the EQ-5D-3L and it has five dimensions. It describes:  mobility  self-care  usual activities  pain and discomfort  anxiety/depression and each of these five dimensions can be valued in three levels of severity: Level 1: Level 3: indicating no problems whatsoever. signifying severe problems So, if you have a very good health, no problems, you will score: 1-1-1-1-1 If you are in the worst possible health condition, you will score: 3-3-3-3-3 We got these raw answers from the completed questionnaires, and then based on these each subject is given a single score. One number which is in a linear scale, from - 0.6 to 1- (1 is perfect health and - 0.6 is absolutely terrible health). And this funny scale anchored around zero which equals www.investinme.org death. So if you have a negative value, you have a health state that’s conceived worse than death. So we compare 103 Danish ME patients to the average population and we found in line with the others, that the typical ME patient is a woman, and found that the ME patients were significantly higher educated than the average population but they were not significantly more depressed than the average population. And this is actually a quite Page 59 of 82

Journal of IiMER important finding because when you hear about the symptoms of ME patients many will at a first glance think, oh maybe they are just depressed, they are a bit tired, a bit withdrawn from everything but these patients are NOT depressed! This is not depression, this is something completely different and the patients are not more depressed than the average population. We also found that ME patients are more disabled and socially marginalised than the average population, they have fewer relationships than the average population, the have a very high degree of unemployment (only 8% were employed), and more than half were disability pensioners, 12% reported being bedridden, more than half of them were unable to perform usual daily activities, in line with what Nancy told you about her own life, and 28% reported being in extreme pain or extreme discomfort. When you hear about the symptoms of ME, you may think these are common symptoms, trivial symptoms. It is a bit like a hangover. I also have these symptoms but this is not just being fatigued. This is not triviality, this is extremely ill, and seriously disabled people. Dr. Brinth told us how they transformed the completed questionnaire into one single score per patient and per subject. So they did that for the ME patients and they got this score of 0.47 and the same has been done for other patient groups in Denmark. From the results one can see that ME is the category of patients with the lowest score. They score lower and report a lower quality of life than any other condition. They have a lower quality of life than lung cancer patients, patients with stroke, diabetes, breast cancer, lung disease, …. What are the consequences?: Most patients never regain their pre-morbid level of health and functioning so often they learn to live with their symptoms but few of them regain premorbid level of functioning. ME is a massive burden, not only for the patients www.investinme.org And this problem is causing a serious controversy Page 60 of 82 but also for the caregivers, and also for all of us for society as such. And it is difficult to ascertain what the burden is for society because they are invisible, undiagnosed, late diagnosed, misdiagnosed. So we cannot count, do the maths or identify how much money this all costs and how much they are suffering. It is a massive problem. She said that patients often live outside society. In the beginning we may meet them, as medical professionals, as frustrated and angry patients because they are tossed around from specialty to specialty and seen by all sorts of different doctors without given any information or treatment. We find they live outside society because they give up on us, and they are even afraid of medical professionals because they are afraid of what will happen. Patients very often report that the feel they are met with scepticism and even hostility of care providers. Conclusion ME is a debilitating and often chronic disease and it is difficult to estimate – affecting maybe 1,000,000 EU citizens. The disease is very poorly understood and, unfortunately, we have several quite contradictory, explanatory models. Some doctors see an ME-like patient and think this is a functional disorder – that is a patient who converses psychological problems into physiological symptoms. Other doctors, other people see these people as patients with physiological severe immunological, mitochondrial, autonomic dysfunction. We do not have any convincing evidence-based treatments so what do we do with the treatment that makes sense in one of these explanatory models? It may seem very harmful for patients from another explanatory model. Graded Exercise Therapy (GET) makes perfectly good sense if you think these patients are young women converting psychological symptoms into physical symptoms, then it is a good thing to push them but if you think they are multi-system ill patients than you will harm them immensely. So it is a matter of should you challenge the patient or should you shield them? Journal of IiMER among medical professionals, and causing grief to patients and everybody else too which also is reported by Dr. Olli Polo. And it is very difficult to understand what this controversy is all about when you are no part of it. It is very bad! In 2015 the American Institute of Medicine (IOM) made a report on ME where they concluded many things based on a very thorough investigation - the main conclusion being that ME is a physiological and NOT a psychological disease. And, they concluded, we should all agree that ME patients need to be recognized, respected and treated. Unfortunately, many of the patients Dr. Brinth has met have not been recognized, or respected and they re not treated. So we need help from the politician, not just for money but we all need to work together to put ME on the agenda and we need to change the culture surrounding these disorders because now it is counterproductive. People are afraid to getting into this business, the patients are afraid of the medical professionals so we have a problem and it is a problem that should affect all of us because it affects many patients! We cannot afford to just let it be! speakers about the disease area and the activities. He touched upon three areas: The Convention itself, Cooperation and coordination in relation to the implementation of the convention, Issues of actively planning and implementation of NGOs The Convention The Convention is the first human rights treaty in the 21st century and became a very popular convention among the Member States Parties. More than 160 countries have joined the Convention. It is very important to know that NGOs themselves played a very important and active role when the Convention was adopted and prepared and that they still do when it comes the standards and the obligations of the Convention being met. In relation to this he highlighted the essential role of the experts when it comes to dialogue and consultations between State Parties and NGOs because the NGOs are the steer provider of very crucial and valuable information for experts and for the cost-active dialogue during the sessions of the Committee. He mentioned that all experts can be approached by NGOs and that they are open for information from them specifically about a given country’s implementations, procedures and feedbacks Dr. László Lovászy – Convention on Rights of Persons with Disabilities (CRPD) Dr. László Lovászy started by introducing himself to the audience. He is a lawyer, a doctor, has a PhD and is the first and only Member of the UN in the Committee on Persons with Disabilities and interested in Biomedical and Technological Development in terms of Disability. He was also interested in learning from the www.investinme.org He mentioned that the International Disability Alliance is also an important player when meeting the NGOs. Governments normally have to learn how to implement the obligations of the Convention via mutual progress, mutual learning and mutual understanding. It is very crucial to realise that there is no perfect country because each and every country has difficulties or challenges in terms of Page 61 of 82

Journal of IiMER implementing the Convention. Cooperation and coordination The definition of disability is an interesting thing From Art.1 – Purpose of CRPD (‘Convention of Rights of Persons with Disabilities’) include: “Persons with disabilities include those who have long-term physical, mental, intellectual or sensory impairments which in interaction with various barriers may hinder their full and effective participation in society on an equal basis with others.” “(e) Recognizing that disability is an evolving concept and that disability results from the interaction between persons with impairments and attitudinal and environmental barriers that hinders their full and effective participation in society on an equal basis with others” h) Recognizing also that discrimination against any person on the basis of disability is a violation of the inherent dignity and worth of the human person, (i) Recognizing further the diversity of persons with disabilities, (j) Recognizing the need to promote and protect the human rights of all persons with disabilities, including those who require more intensive support, Mutual cooperation is important because the Convention strengthens the aspect of international cooperation in Art. 32. The recognition of the importance of independent living and understand reasonable accommodation in an ageing society is not a burden but rather an opportunity. But how because it is a crucial problem we need to fight. Understanding the spirit of the CRPD in terms of research (g) To undertake or promote research and development of, and to promote the availability and use of new technologies, including information and communications technologies, mobility aids, devices and assistive technologies, suitable for persons with disabilities, giving priority to www.investinme.org ME STORY “I have since been sent to another neurologist after my doctor found I was Rhomberg's positive, who made me walk, did a scratch test on my feet, checked the weakness in my legs, and said quite rudely, "you have ME, I am not going to waste time doing tests on you" And that was it. I walked away feeling like I had wasted this man's time. I pray one day a cure will come our way.” - Rowan “Personal Stories of ME Sufferers “ http://www.investinme.org/mestorygall ery1.htm Page 62 of 82 technologies at an affordable cost – Art. 4 – general obligation Recognition of available good practices and possible overlapping interest Art. 4 is quite relevant to the recommendation of good practices we all already heard today because when it comes to more efficient lobby work and the current situation of the EU approach towards rare diseases including the existing cooperation among Member States is very important to understand. Planning and implementation Identifying trends in technology, societal phenomenon and legislative and non-legislative procedures in the EU Parliament in order to visualise and understand how the international bodies and United Nations operate. In relation to this it is important to present and identify the costs and benefits to society and the communities. It is also worthwhile to explain what happens if more people can contribute to society. Journal of IiMER The European ME Alliance The European ME Alliance is a collaboration of ME support charities and organisations in Europe who intend to provide a common view and the scientific facts regarding the neurological illness myalgic encephalomyelitis (ME/CFS). The alliance has been created with a basic set of principles (see EMEA principles and rules regarding membership). The members of the European ME Alliance are currently from Iceland, Norway, Sweden, Finland, Denmark,Germany, Holland, Belgium, Switzerland, Italy, Spain, UK and Ireland. The objectives of the European ME Alliance are to provide a correct and consistent view of myalgic encephalomyelitis (ME/CFS) for healthcare organisations, healthcare professionals, government organisations, the media and patients and the public. Our web site will consist of accurate descriptions of the illness and details of research which has or is taking place. The member groups in the alliance will be working together to promote awareness of ME/CFS and will work closely with organisations and researchers who are interested in finding treatments and cures for ME/CFS. EMEA Principles The members of the European ME Alliance have agreed the following –  That members of the European ME Alliance endorse the principles of the 2003 Canadian Consensus Document for Diagnosis and Treatment for ME/CFS.  That members of the European ME Alliance endorse the principles of the 2006 paediatric definition from Dr www.investinme.org Page 63 of 82 Leonard Jason et al.  Thet members of the European ME Alliance promote the fact that ME (myalgic encephalomyelitis) is a neurological illness in the World Health Organisation’s International Classification of Diseases.  The members of the European ME Alliance understand the necessity to use the composite term ME/CFS at the moment for ease of reference/standardisation.  The members of the European ME Alliance support biomedical research into establishing sub groups of ME/CFS which will lead to treatments and cures for this illness.  That the European ME Alliance has, as an objective, the preparation and promotion of a common set of documentation, in all languages, for Alliance use that is supplemented by local information. http://www.euro-me.org

www.investinme.org Page 64 of 82 https://www.justgiving.com/investinm-e

Journal of IiMER #IIMEC12 PRESENTERS Keynote Speech Professor Ian Charles Leader Quadram Institute, Norwich, UK Professor Ian Charles joined the Institute of Food Research in May 2015 to lead the programme to develop the UK’s new Centre for Food & Health – the Quadram Institute - to be based at the Norwich Research Park. He returned to the UK from Australia where he was Director of the ithree institute, University of Technology, Sydney. Professor Charles has over 30 years’ experience in academic and commercial research. His academic career has included being a founding member of The Wolfson Institute for Biomedical Research at University College London, one the UK’s first institutes of translational medicine. He has also worked in the pharmaceutical industry at Glaxo Wellcome, and has been founder and CSO of biotech companies in the area of infectious disease, including Arrow Therapeutics, sold to AstraZeneca, and Auspherix a venture capital backed company founded in 2013. His current research interests include infectious diseases as well as the microbiome and its impact on health and wellbeing. The new Centre for Food & Health will provide a step change for food and health research, and the translation of science by industry, to benefit society and the UK economy. The Centre will be located at the Norwich Research Park, one of Europe’s largest single-site concentrations of research in Food, Health and Environmental sciences. The multidisciplinary Centre aims to bring together the Institute of Food Research and aspects of the University of East Anglia’s Faculty of Science and the Norwich Medical School with the regional gastrointestinal endoscopy facility at the Norfolk and Norwich University Hospital. With a unique integration of diet, health, nutrition and medicine under one roof, linking closely to world class plant and crop research at the John Innes Centre and bioinformatics at The Genome Analysis Centre (both also located on the Norwich Research Park), it will have the potential to deliver clinically validated strategies to improve human health and wellbeing. Abstract: Not available at time of going to press. Abstract for IIMEC10 Conference in 2015 - http://investinme.org/Documents/Journals/Journal%20of%20IiME%20Vol%209%20Issue%201.pdf www.investinme.org Page 66 of 82 Journal of IiMER Keynote Speech Dr Vicky Whittemore Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States Dr. Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster. Her interest is in understanding the underlying mechanisms of the epilepsies including the study of genetic and animal models of the epilepsies. The major goal is to identify effective treatments for the epilepsies and to develop preventions. Dr. Whittemore received a Ph.D. in anatomy from the University of Minnesota, followed by post-doctoral work at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm, Sweden. She was on the faculty of the University of Miami School of Medicine in The Miami Project to Cure Paralysis prior to working with several non-profit organizations including the Tuberous Sclerosis Alliance, Genetic Alliance, Citizens United for Research in Epilepsy (CURE), and the National Coalition for Health Professional Education in Genetics (NCHPEG). She also just completed a four-year term on the National Advisory Neurological Disorders and Stroke Council. Abstract: NIH Research Into ME Vicky Whittemore, PhD National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA Significant progress is being made on many research fronts impacting individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Dr. Whittemore will highlight recent scientific findings from investigators supported by research grant awards from the National Institutes of Health (NIH) and the need for expansion of collaborative research on ME/CFS. In addition, she will provide an update on NIH research funding plans on ME/CFS, including continued support of investigator-initiated research grants and support for the new ME/CFS Collaborative Research Centers and ME/CFS Data Management Coordinating Center. She will provide updates on other NIH activities, including the ME/CFS Intramural Research Study, ME/CFS stakeholder conference calls, and activities of the Trans-NIH ME/CFS Working Group and the CFS Advisory Committee (CFSAC). www.investinme.org Page 67 of 82

Journal of IiMER Professor Sonya Marshall-Gradisnik The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University, Australia Professor Marshall-Gradisnik is one of Australia's foremost researchers in the area of neuroimmunology and has been instrumental in establishing the Public Health and Neuroimmunology Unit (PHANU) at Bond University. Much of her work relates specifically to autoimmunity in Chronic Fatigue Syndrome sufferers and she is regularly asked to speak to community groups on behalf of Queensland Health and NSW Health. Her research in the area of exercise immunology has also contributed to the body of knowledge relating to the effect of doping in sport and she serves as Sports Medicine Australia's national spokesperson in this area. The vital research conducted by Professor Marshall has attracted more than $1 million in grant funding and she has produced 21 peer-reviewed papers, five book chapters and one provisional patent. In 2008 Dr Marshall was joint leader of the Bond University team responsible for developing the the BioSMART program. The team was awarded a prestigious Australian Teaching and Learning Council Award (formerly known as the Carrick Award) for Outstanding Contribution to Student Learning and for the quality of student learning over a sustained period of time. Professor Marshall-Gradisnik leads The National Centre for Neuroimmunology and Emerging Diseases (NCNED), a research team situated at Griffith University on the Gold Coast. The team focuses on Myalgic Encephalomyelitis. Professor Donald Staines The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University, Australia. Professor Staines has been a public health physician at Gold Coast Population Health Unit. He has worked in health services management and public health practice in Australia and overseas. His interests include collaborative health initiatives with other countries as well as cross-disciplinary initiatives within health. Communicable diseases as well as post infectious fatigue syndromes are his main research interests. A keen supporter of the Griffith University Medical School, he enjoys teaching and other opportunities to promote awareness of public health in the medical curriculum. He is now CoDirector at The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths www.investinme.org Page 68 of 82 Journal of IiMER University in Australia. Abstract: Impaired calcium mobilization and dysregulation of transient receptor potential melastatin 3 ion channels in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis. Staines, D.R1,2., Nguyen, T., 1,2 , Johnston, S1,2., Smith, P 2 and Marshall-Gradisnik, S1,2 1. School of Medical Science, Griffith University, Gold Coast, Australia 2. The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia. Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is disorder with hallmarks of varying changes in immune cells and molecular related mechanisms. Transient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined. Ca2+ flux, TRPM3 and NK cytotoxicity activity was measured under various stimulants, including pregnenolone sulphate (PregS), thapsigargin (TG), 2‐aminoethoxydiphenyl borate (2APB) and ionomycin on CD56dimCD16+NK cells and CD56brightCD16dim/– isolated NK cells. Unstimulated CD56brightCD16dim/– NK cells showed significantly reduced TRPM3 receptors in CFS/ME compared with healthy controls (HC). PregS‐stimulated CD56dimCD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+flux and NK cell lysis. TG‐stimulated CD56dimCD16+ NK cells significantly increased NK cell lysis prior to PregS stimulation in CFS/ME patients compared with HC. Differential expression of TRPM3 and Ca2+ flux between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity in CFS/ME. Professor Nancy Klimas Director, Institute for Neuro Immune Medicine, Nova Southeastern University Director, Clinical Immunology Research, Miami VAMC Professor of Medicine, Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University Chair, Department of Clinical Immunology, College of Osteopathic Medicine, Nova Southeastern University Professor Emerita, University of Miami, School of Medicine Nancy Klimas, MD, has more than 30 years of professional experience and www.investinme.org Page 69 of 82

Journal of IiMER has achieved international recognition for her research and clinical efforts in multi-symptom disorders, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI), Fibromyalgia, and other Neuro Immune Disorders. She is immediate past president of the International Association for CFS and ME (IACFS/ME), a professional organization of clinicians and investigators, and is also a member of the VA Research Advisory Committee for GWI, the NIH P2P CFS Committee, and the Institute of Medicine ME/CFS Review Panel. Dr. Klimas has advised three Secretaries of Health and Human Services, including Kathleen Sabelius, during her repeated service on the Health and Human Services CFS Advisory Committee. Professor Klimas has been featured on Good Morning America, in USA Today and the New York Times. Abstract: The Gene Study – a Patient Science Partnership Goes Viral Nancy Klimas, MD 1,2 , Kelly Gaunt Hilton, OMS-III 1 , Kristina Gemayel, OMS-IV1 ,Melanie Perez3 , Rajeev Jaundoo3, Travis Craddock1, Lubov Nathanson PhD1 1Nova Southeastern University College of Osteopathic Medicine, Ft Lauderdale Florida 2 Miami Veterans Medical Center, Miami FL 3 Nova Southeastern University Hamlos College of Natural Sciences and Oceanography The ME/CFS Gene study is truly unique. Two medical students were challenged to create a study using a social media based platform to ask one of the biggest unanswered questions of our time: what are the genetic underpinnings that put a person at risk for ME/CFS? Why would one person recover from a common infection and the next spin into a chronic disabling illness? Does the genetic signature give us new clues to predict therapies? The challenge was a big one – it takes several thousand volunteers and an expensive genetic assay, then complex analysis to begin to answer questions of genetic risk. The budgets of these studies exceed NIH and foundation caps for funding, and access to that many subjects simply has not happened yet. The study group partnered with advocacy groups across the country and created a novel design: ask patients to donate data not dollars. Use social networking to reach out to the community and ask for access to data from genetic studies that are becoming increasingly common in our society: genomic ancestry platforms. Millions of people have taken advantage of the ancestry platforms at their own expense to have studies of genetic signatures completed. We are asking ME/CFS patients to donate their data to launch the gene study. Using 23 and Me or Ancestry.com data sets owned by the volunteers, we asked that they log on to our study site, review and sign the informed consent, then take the surveys that ask about their illness, its severity, the way it started etc. At the end they upload the raw data sets from their ancestry studies. More student power is then employed to align the data in spread sheets, then check its quality. Students working with Dr. Lubov Nathanson the gene targets are reviewed for function and likelihood that they would indeed impact important pathways that effect cell function. Then we start with analysis – at this point we have enough data to query specific pathways, asking questions about specific genes, but we do not have enough data to ask the larger questions, find the surprises locked in the gene set that could lead to the “eureka” moments. We need the effort to go viral to be truly successful, and we need your help. We have 800 volunteers so www.investinme.org Page 70 of 82 Journal of IiMER far, about half have uploaded the gene data. But we need several thousand to ask the most important questions. So link everyone you know to the website: http://www.nova.edu/nim/research/mecfsgenes.html or email: MECFSGenes@nova.edu. And feel good about this study as it is proof that patient driven, patient sponsored research can lead the way to new treatments. The Blue Ribbon Fellowship, provided by the Blue Ribbon Foundation and the Wisconsin ME/CFS Association, sponsored fellowships for medical students to create the platform and the social media outreach campaign. Patients and advocates helped launch this study and continue to help us promote it. And of course patients and advocates are the participants needed to make this successful. If anyone in the patient community would use their social media skills to get the word out, we could do something truly remarkable: through your efforts partnered with this new generation of physician scientists, answer questions that have been waiting to be answered for far too long. Dr Jakob Theorell Jakob Theorell started his medical training at Karolinska Institutet in 2007. He is currently enrolled in the MD-PhD Program at Karolinska Institutet. He works in the Yenan Bryceson Group in Karolinska Institutet in Stockholm. His work focuses on understanding the mechanisms of disease in patients suffering from chronic immunodeficiency syndromes. The Yenan Bryceson Group is based at the Center for Infectious Medicine and employs a wide range of techniques including multiparameter flow cytometry, confocal microscopy, live-cell imaging, next-generation sequencing, and biochemical techniques. To gain clinical and scientific insights into human diseases, we collaborate closely with clinicians at Karolinska Institutet, across Scandinavia and the rest of the world. Abstract: Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections. Cytotoxic lymphocytes combat intracellular infections. Multiple studies have investigated cytotoxic lymphocyte phenotype and function in ME/CFS, but their specific role in this disorder remains to be established. Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, we aimed to re-assess the role of cytotoxic lymphocytes in ME/CFS, especially for biomarker purposes. To this end, 48 patients fulfilling both Fukuda and Canada criteria for ME/CFS from two independent cohorts were investigated. The phenotype and function of cytotoxic lymphocytes in frozen and thawed PBMC was evaluated by flow cytometry, one cohort at the time. Results were compared to values obtained from simultaneous analysis of cells from age- and sex matched healthy controls. Consistent differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, cytokine production or reprogrammed NK cell expansions. No clear subgroups were identified in unsupervised www.investinme.org Page 71 of 82

Journal of IiMER dimensionality reduction analyses. One patient showed lower levels of perforin, explained by homozygosity for the PRF1 p.A91V variant, previously associated to haematological malignancies. Among the other patients however, this variant was present in heterozygous state at the expected population frequency, and no additional homozygous carriers were identified. In summary, the results of this study does not support the use of NK cell function as a biomarker for ME/CFS. Furthermore, it does not point to a general role for defects in lymphocyte cytotoxicity in the etiology for ME/CFS. Professor Geraldine Cambridge Dr Jo Cambridge is Professorial Research Associate, Div of Medicine Faculty of Medical Sciences, UCL Her group focuses its interests on B cell depletion (an idea which they introduced (with the Professor Jo Edwards) approximately 10 years ago for the treatment of rheumatoid arthritis), exploring more precisely how the technique works and trying to explain the marked variation in response between different patients Fane Mensah Fane Mensah is a research assistant and PhD student studying the immunology of ME in Dr Jo Cambridge’s group at UCL. Fane’s main area of study is B-cell research. Abstract: Not available at time of going to press. www.investinme.org Page 72 of 82 Journal of IiMER Professor Simon Carding Leader, Gut Health and Food Safety Programme Institute of Food Research, Norwich Research Park, UK Professor Simon Carding Professor of Mucosal Immunology at University of East Anglia and Institute of Food Research. Following his PhD at London he held postdoctoral positions at New York University School of Medicine, New York and at Yale University School of Medicine, New Haven, USA. He then moved to the University of Pennsylvania, Philadelphia, USA as Assistant and later Associate Professor. He joined University of Leeds as Professor of Molecular Immunology in the Institute of Molecular and Cellular Biology in 1999. His scientific interests are in understanding how the immune response in the gut functions and in particular, is able to distinguish between the commensal microbes that reside in the gut and environmental microbes that cause disease, and in the mechanisms by which the body's immune system no longer ignores or tolerates commensal gut bacteria and how this leads to immune system activation and inflammatory bowel disease. Abstract: Not present at time of going to press. Associate Professor Mady Hornig Associate Professor, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health New York, USA Mady Hornig, MA, MD is a physician-scientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health where she serves as Director of Translational Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, and toxic stimuli in the development of neuropsychiatric conditions, including autism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth www.investinme.org Page 73 of 82

Journal of IiMER biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Abstract: Not present at time of going to press. Professor Olav Mella Department Director, Oncology, Haukeland University Hospital, University of Bergen, Norway Professor Mella has performed clinical trials to test the benefit of B-cell depletion therapy using Rituximab in ME/CFS patients. Professor Olav Mella of Haukeland University Hospital in Bergen, Norway began his investigation of Rituximab’s effects on CFS after treating several Hodgkin’s Lymphoma patients who had long standing cases of CFS prior to developing cancer. Professor Mella and Dr Fluge have published a paper "Benefit from BLymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study" Abstract: Status of the Norwegian drug intervention studies on ME (RituxME and CycloME) Olav Mella: for the Norwegian cooperative trial group at Haukeland University Hospital (Bergen), Oslo University Hospital, Telemark Central Hospital – Notodden, St. Olav Hospital (Trondheim) and University Hospital of Northern Norway (Tromsø) Haukeland University Hospital has previously performed studies indicating that immune manipulation by B-lymphocyte depletion may result in symptom improvement in a subgroup of patients with ME, pointing at defects in immune function to be important factors in the disease mechanisms. Following www.investinme.org Page 74 of 82 Journal of IiMER previous Phase II studies with the B-cell depleting CD20 monoclonal antibody rituximab, a decision was made to conduct a Norwegian multicenter, Phase III, double blind, placebo controlled intervention study with rituximab, given mainly as outpatient treatment at Day 0 and 14, and at 3, 6, 9 and 12 mths, with follow-up for 24 mths. The number of patients filling Canadian criteria to be recruited at each hospital was predefined, and there was block-randomization to reduce possible practice differences between institutions. The first of the patients started infusion in September 2014, the last patient in September 2015. One primary endpoint is the course in changes of subjectively measured fatigue over 24 mths, with retrospective registration of symptom changes from baseline, every two week periods through follow-up. The other primary endpoint is number of patients achieving clinical response according to predefined criteria. Secondary endpoints are quality of life (SF 36, FSS), changes in physical performance (electronically recorded for 5-7 consecutive days), physical function level at 6, 12, 18 and 24 mths, length of response duration, and patients still in response 24 mths after inclusion. Toxicity is also a secondary endpoint. There is external monitoring of the trial, with full insight into the data. 152 patients were enrolled, but one withdrew before start, leaving 151 evaluable patients. The trial has been performed according to the protocol. There have been hospital admissions, but the safety committee has reported no serious and unexpected toxicity. The randomization and data handling was done through a professional trials company (Viedoc) and the quality of data is judged good by the external monitors. The final follow-up of the last included patient in the trial will be at the end of September 2017. After that the data quality will be checked and locked, thereafter the trial key unlocked and the study analysed. Publication is expected in 2018. Based on a small pilot study, the open-label Phase II (CycloME) cyclophosphamide intervention study with 40 patients at two centers was initiated in March 2015. The trial includes patients previously exposed to rituximab, and patients without previous immune manipulation. The patients were given infusions of the cytotoxic agent cyclophosphamide 600-700 mg/m2 every 4th week, given 6 times. Endpoints were as in the RituxME study, with follow-up for 18 mths. The last patient will have finished follow-up in July 2017 and the data then analyzed. Compliance has been good, with practically no hematologic toxicity. However, acute nausea and vomiting was experienced to a greater extent than seen in cancer patients at the same drug level, and some patients reported initial and transient worsening of ME-symptoms after infusions. Patients reporting improvement from ME-symptoms generally did so after the final infusion. Although the data has not officially been analyzed, a preliminary observation is that also a more unspecific, immune modulating agent than rituximab can improve the clinical course, in a subgroup of ME patients. Trial sponsors: Norwegian Research Council, Norwegian Ministry of Health and Care Services, the Regional Health Trusts, MEandYou fundraising, the Norwegian ME Association, private donations, the Kavli Foundation www.investinme.org Page 75 of 82

Journal of IiMER Dr Øystein Fluge Chief Physician, Department of Oncology, Haukeland University Hospital, University of Bergen, Norway Dr Øystein Fluge received medical degree in 1988 at the University of Bergen, and is a specialist in oncology since 2004. He has worked as a Research Fellow with support from the Norwegian Cancer Society and is now chief physician at the Cancer Department, Haukeland University Hospital. Doctoral work emanates from the Surgical Institute and Department of Molecular Biology, University of Bergen. Abstract: Metabolic profiling indicates impaired pyruvate dehydrogenase function in ME/CFS patients Øystein Fluge, Department of Oncology, Haukeland University Hospital, Bergen, Norway. Metabolic dysfunction has emerged as a plausible contributing factor to ME/CFS. Previous studies have shown reduced levels of selected amino acids in serum or urine from ME/CFS patients. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the tricarboxylic acid (TCA) cycle. The levels of amino acids that may convert to acetyl-CoA independent of pyruvate dehydrogenase (PDH), and also of anaplerotic amino acids that may replenish TCA cycle intermediates thus increasing the cycle capacity, were particularly reduced mainly in female ME/CFS patients. Amino acids that may convert to pyruvate, and are dependent on PDH for oxidation in the TCA cycle, were not reduced in ME/CFS patients. Serum 3methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases (PDKs) 1, 2 and 4, sirtuin 4, and of peroxisome proliferator-activated receptor δ, in peripheral blood mononuclear cells from both genders. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The pattern of amino acid changes could not be explained by symptom severity, disease duration, age, body mass index, or physical activity level among patients. These data support a metabolic “obstruction” in the central energy pathway in ME/CFS, a functional impairment possibly at the PDH level with difficulties in metabolizing glucose to energy in the TCA cycle, and with compensatory use of alternative substrates for acetyl-CoA such as ketogenic amino acids and fatty acids. Presently, we are investigating lipid alterations and B-vitamins in the same serum samples. We hypothesize that the inhibition of energy metabolism is caused by an aberrant immune response, in a subgroup of ME/CFS patients with a central role for B-cells and possibly antibodies. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP www.investinme.org Page 76 of 82 Journal of IiMER generation by oxidative phosphorylation and excessive lactate generation upon exertion. Professor Warren Tate Group Leader, Biochemistry Department, School of Biomedical Sciences, University of Otago, New Zealand Professor Warren Tate from University of Otago in New Zealand - is an internationally respected biochemist, winner of the Royal Society of New Zealand's top science honour - the 2010 Rutherford Medal, and was also named a Companion of the New Zealand Order of Merit. His honour citation noted that Professor Tate was a molecular biologist, whose research had "revolutionised understanding" of how proteins were synthesised in living cells. His research had shown how proteins contributed to memory formation and neurological disease, and had important implications for HIV, Alzheimer's and chronic fatigue syndrome. Professor Tate is a Fellow of the Royal Society of New Zealand and of the New Zealand Institute of Chemistry. He has been a Fellow of the Alexander von Humboldt Foundation of Germany, and an International Research Scholar of the Howard Hughes Medical Institute of the United States. Abstract: Intense molecular study of well characterised patients to understand the acute phase, perpetuation, and relapse/recovery cycles in ME/CFS Warren P. Tate, Department of Biochemistry, School of Biomedical Sciences, Division of Health Sciences, University of Otago, PO Box 56 Dunedin, New Zealand From the moment of my first exposure over 20 years ago to ME/CFS as the illness afflicting a vibrant young teenage daughter, I have puzzled over what physiological ‘control centre’ could mediate such a range of dramatic body-wide responses. As my daughter’s illness progressed into a long-term condition this question evolved into what is preventing recovery and not allowing perpetuation of ME/CFS, and then what physiological changes are occurring during the frequent relapses experienced throughout the chronic phase of the disease. On a brighter note a significant improvement occurred during a pregnancy –why did that happen? Resolution of these unresolved yet important questions would give significant benefit to patients, as well as being of marked scientific interest. As research into ME/CFS has progressed in recent decades there has been a pressing need to collect comprehensive molecular data on well-characterised patients so a framework can be created for evidence-based approaches to the disease. This would have relevance for developing a diagnostic test, and to set directions towards better patient management and therapies. We have studied purified www.investinme.org Page 77 of 82

Journal of IiMER blood fractions from two small patient cohorts, each of 10 patients with age and gender matched controls, one of which was focussed on exercise intolerance and ‘post exertion malaise’. Initially we collected data on the immune cell expressed genes (transcriptome) and proteins (proteome) as well as plasma microRNAs and cytokines with an aim of integrating the data to elucidate linkages between different classes of molecules and give insight into physiological changes. We are currently extending these studies to mitochondrial function and epigenetic changes in the DNA following the recently published research suggesting energy delivery and modulation of expression of specific genes might be significant factors in changes in physiology for perpetuation of the disease. Can a model be developed that might explain most of the diverse symptoms? Evidence of chronic inflammation in the limbic system of the brain and glial cell activation has been shown in neuroimaging studies of Japanese ME/CFS patients, with a degree of inflammation that correlated with severity of disease symptoms. These observations, coupled with the known disturbance of the hypothalamus/pituitary/adrenal axis in ME/CFS, and the hypersensitivity of ME/CFS patients to stress of any kind, has lead us to develop a model whereby the paraventricular nucleus (PVN), the ‘stress centre ‘of the hypothalamus, might be a possible ME/CFS perpetuating centre. The PVN is responsible for absorbing and processing incoming stress signals and chronic fluctuating auto-inflammation in the brain affecting the threshold for managing stress could explain perpetuation of the disease and relapses in the chronic phase of ME/CFS. Detailed molecular and neuroimaging data from patients using cutting edge technologies will allow new models to explain ME/CFS and should provide meaningful benefits for patients for managing and living with their disease. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA Ronald W. Davis, Ph.D., is a Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California. He is a world leader in the development of biotechnology, especially the development of recombinant DNA and genomic methodologies and their application to biological systems. At Stanford University, where he is Director of the Stanford Genome Technology Center, Dr. Davis focuses on the interface of nano-fabricated solid state devices and biological systems. He and his research team also develop novel technologies for the genetic, genomic, and molecular analysis of a wide range of model organisms as well as humans. The team's focus on practical application of these technologies is setting the standard for clinical www.investinme.org Page 78 of 82 Journal of IiMER genomics. Abstract: Establishing new mechanistic and diagnostic paradigms for ME/CFS Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the last major disease we know almost nothing about. To date, very little is understood about the cause of ME/CFS: years of searching for a common triggering pathogen have been fruitless, and no biological assays exist to facilitate diagnosis. Recent evidence strongly supports ME/CFS as a molecular disease, even if many of the symptoms are cognitive and muscular, which indicates that molecular studies will help to understand and diagnose this disease, and that molecular therapies have the potential to treat it. The time is ripe for this change in perspective, because researchers now have highly advanced, sensitive, and comprehensive molecular technologies at their disposal, and the beginnings of a molecular understanding with which to unravel this disease. We are working to unravel the molecular path from health to ME/CFS, and develop cost-effective technology for diagnosis and drug discovery – offering a new level of precision for researchers and physicians to tackle this complex illness. All of this research is being carried out in close collaboration with physician, patient, and advocate communities, including direct involvement of patient partners and dedicated outreach efforts to broaden awareness of the disease. We aim to implement an interdisciplinary, integrative, inclusive precision approach to ME/CFS to fundamentally change how this disease is understood and managed, and most importantly, to give new hope to patients. Invest in ME Research www.investinme.org Page 79 of 82

Journal of IiMER The 12th Start 07.45 08.55 09:00 09:05 09:25 09:45 10:15 10.45 11.15 11:40 12.05 12.30 13.30 14:00 14:30 15.10 15:40 16.10 17.00 17.30 IiMER International ME Conference 2017 #IIMEC12 CONFERENCE PROGRAMME Presenter Registration Invest in ME Research Dr Ian Gibson Professor Ian Charles Dr Vicky Whittemore Professor Don Staines Professor Nancy Klimas Break Dr Jakob Theorell Dr Jo Cambridge / Fane Mensah Professor Simon Carding Lunch Professor Mady Hornig Professor Olav Mella Dr Øystein Fluge Break Professor Warren Tate Professor Ron Davis Dr Ian Gibson Adjourn www.investinme.org Studies of NK cells and cytotoxic T-cells in ME-patients from one Swedish and one Norwegian cohort Update on Immunoregulation in patients with ME – new paper immunological review UEA/Quadram Inst. Gut Virome in ME - Students Gut-metabolome-immune disturbances in ME/CFS subsets Status of the Norwegian drug intervention studies on ME (RituxME and CycloME) Metabolic profiling in ME/CFS Intense molecular study of well characterised patients to understand the acute phase, perpetuation, and relapse/recovery cycles in ME/CFS Big Data Approach: Severely ill ME Patient Cohort Plenary Session Presentation Opening Welcome to IIMEC12 A UK Centre of Excellence for ME Keynote Speech: NIH Research into ME Dysregulation of Transient Receptor Potential (TRP) ion channels and calcium in natural killer cells in CFS/ME patients Genetic Signature Study Page 80 of 82 Mike Harley is running 28 European marathons – raising funds for Invest in ME Research’s Centre of Excellence for ME research and raising awareness of this disease. Please help us in supporting Mike http://www.investinme.org/ce-IIME-Newslet-1504-02.shtml Raising Awareness of Myalgic Encephalomyelitis - The European Way Journal of IiMER #12 Lithuania 10 September 2017 #13 Amsterdam 15 October 2017 #14 Ljubljana 29 October 2017

Journal of IiME Invest in ME International ME/CFS Conference 2007 Special VOLUME 1 ISSUE 1 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 2 Welcome from Invest in ME Welcome to the first Journal of Invest in ME – a combination of research, information, news, stories and other articles relating to myalgic encephalomyelitis (ME). Facts About ME An estimated 250,000 people suffer from ME in the UK This first version is also serving a dual purpose in that it is acting as a component of the delegate’s conference pack for the 2nd Invest in ME International ME/CFS Conference 2007, held in Westminster, London, UK. Invest in ME welcomes delegates, presenters and media from ten ME Story I fell ill with the flu the same time as Antony, my then boyfriend/fiancé. He got over it, I didn't..... It was a struggle to get the illness recognized - Wendy countries around the world to the conference – emphasising that ME recognises no international boundaries. The interest in the conference also demonstrates the need for some of IiME’s main objectives – more education and proper funding for biomedical research into ME. In this document we include articles from renowned ME experts who were not able to be present at the conference this year as well as those who are. We also include other ME experts who are presenting. IiME hope to publish our journal throughout the year. As with the IiME conference it will allow a platform for researchers, scientists, healthcare staff and politicians to be able to share and provide information relevant to those supporting, campaigning for or suffering from ME. IiME are firmly committed to raising ME awareness, facilitating education and lobbying for proper biomedical research into ME. We shall publish articles even though we may share different views – as long as an honest and transparent debate can occur. However, one thing we shall never lose sight of is the tragedy of ME and the way it is treated - and so stories of real life with ME will be featured from people who are living with this illness on a daily basis, showing the tragedy, the courage and also the humour which people with ME and their families endure.. Facts About IiME Invest in ME is made up of volunteers, ME sufferers and parents of children with ME We hope our efforts and those of our regional and international contacts will ultimately avoid the need for all of our combined work and we can look forward to a treatment and cure for ME. Welcome to IiME. Welcome to London. Disclaimer The views expressed in this brochure by contributors do not necessarily represent those of Invest in ME. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 1st and 2nd May 2007 Inside This Issue 3 Introduction – Professor Malcolm Hooper 4 Invest in ME 5 The IiME International ME/CFS Conference 15 IiME Awareness Campaigning 8 Professor Leonard Jason 6 Dr. Ellie Stein 16 ME Clinical Conundrum - Dr. Neil Abbot/Dr. Vance Spence 19 Biomedical research – Dr. Neil Abbot/Dr. Vance Spence 21 The Strategy of the MRC for Research on CFS.ME 25 UK FINE Trials 27 Jane Colby 28 Speaker Profiles 34 News from Abroad 34 ME in Norway 35 ME in Denmark 37 ME in Sweden 36 ME in Germany 35 ME in Spain 37 ME in USA 39 ME/CFS – by a Carer 40 NICE Guidelines 41 Gibson Inquiry 42 Information on ME/CFS - Margaret Williams Introduction – Professor Malcolm Hooper Achievements, Hope, and Future Actions All three are brought together in this conference. We celebrate the successes of the last year in the high quality research studies that have consolidated the understanding of ME-CFS as a multi-system, multiorgan illness with an increasingly understood biological basis that offers a sound basis for challenging the spurious attempts to make ME an illness that is primarily psychogenic in origin - in contradiction to the established international system of nomenclature. A Quotable Quotes booklet available at the Conference illustrates this dishonourable conflict. These achievements include advances in diagnosis and the increasing adoption of what are known as the Canadian Criteria/Guidelines. In truth these are North American Guidelines that involved co-operation between major clinical practitioners in both Canada and the USA. These should now be adopted as the international criteria and guidelines for the diagnosis of ME-CFS. The removal of the term CFS from any description of this illness would be a great advantage and provide clarity about both diagnosis and treatment. Much more is needed to define subgroups within ME-CFS with several useful schemes now available. Scientific and clinical research has continued apace despite the reluctance of the MRC and Government in providing funding for such studies. Immunology has identified low NK, natural killer, cells as a key marker that could be adopted whilst the significance of oxidative stress provides another reliable marker in hsCRP, high sensitivity C-reactive protein. The importance of a diffuse inflammation associated with ME has been found in autopsy examinations of spinal cord and brain tissue and underlines the importance and accuracy of its designation as an inflammatory illness involving the central nervous system and new understandings of neurogenic pain also provides a mechanism for the severe pain experienced by many people with ME. The details of a common underlying mechanism continue to emerge involving PKR, protein kinase R, nitric oxide and intracellular responses to viruses, other micro-organisms, such as borrelia, rickettsia, chlamydia, leading to immune dysregulation. The role of chemicals and heavy metals are accommodated in these overarching and comprehensive mechanisms. A very important new area of research concerns genetics which is beginning to address the complex issue of the interaction between genes and the environment and the questions of patient susceptibility to this and related overlapping syndromes. Hope for others is emerging from all these activities. The scientific and clinical studies are identifying good tests to aid diagnosis and also new (and confirming some old) ways of treating this debilitating illness. Mitochondrial support linked to diagnostic tests is now available in one therapeutic regimen that many find helpful. Cytokines and their inhibitors may also provide effective treatment. (continued on page 4) long and 3 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Professor Malcolm Hooper (continued from page 3) A catalogue of vested interests has been exposed which has given rise to the misleading judgements of the insurance industry and their advisors as well as the lack of the proper provision of appropriate benefits. The implications of the Inquiry for NICE and the MRC, who have become party to the machinations of the psychiatric lobby, are still being worked through. An essential requirement for future progress is the need for all organisations concerned with ME-CFS to provide a coherent and unified approach to the illness and not to be distracted by the large sums of money being put into the current clinics that have been predicated on ME-CFS as a psychiatric illness. Together we shall succeed but divided we shall fail. Finally there is the growing international collaboration that has now become apparent and provides grounds for rapid advancement in understanding ME. Canada, USA, Australia and New Zealand, and Norway have all made big strides forward. We have much to learn from each other and contribute to each others activities. There is much to celebrate, there are real grounds for hope, and future effective actions can be recognised and agreed. Invest in ME Invest in ME (IiME) was formed by parents of children with ME and sufferers in September 2005 and registered as a UK charity in May 2006. The day to day running of the charity takes place in Hampshire and Norfolk. IiME was formed to break with the established way of looking at ME. We are aiming to change positively the situation for people with ME and their families and carers. IiME has no paying members and no salaried staff – all of our work is voluntary. During 2006 we established and strengthened regional and international contacts which we will develop in the future. Our campaigning for more informed education of doctors and for appropriate funding for biomedical research into ME has led to a busy year in which we have spoken with the Deputy Chief Medical Officer, the head of the MRC and numerous politicians. As part of our campaigning we have responded to the proposed NICE guidelines which were, in our opinion, unfit for purpose; attended and given evidence to the Gibson report into M.E. which was published in November 2006; commented on the inadequate and misinformed NHS Plus Guidance leaflet and made representations to the Department of Work and Pensions on their guidance for M.E. and benefits. The media have an important role to play in our efforts to raise awareness and change attitudes. To this end we have continued to build a good working relationship with many journalists, writers and broadcasters. This has been complemented by responding vigorously whenever possible to articles in the press. During the last year we have attended the inquest of Sophia Mirza who died, “… as a result of acute renal failure due to dehydration arising as a result of Chronic Fatigue Syndrome (M.E.)”. Her mother has lodged complaints with the GMC and the Social Services involved in Sophia’s case and we will notify the outcome as soon as we can. We are determined that what happened to Sophia must never be allowed to happen again. Invest In ME will continue to campaign during 2007 and will build on the close working relationships we have with groups and clinicians around the world, as well as continuing to cooperate with ME Research UK in our joint endeavour to improve the lives of people with ME. Invest in ME Charity Nr 1114035 www.investinme.org IiME LOGO What’s in a logo? The IiME Logo is based on a double helix – indicating our firm commitment to treating myalgic encephalomyelitis as the biological illness it is and enforcing our view that only biomedical research will bring about a cure for ME. 4 Journal of IiME Volume 1 Issue 1 5 The IiME International ME/CFS Conference The idea of an international conference began shortly after Professor Malcolm Hooper and Bruce Carruthers gave presentations at a meeting by ME Support Norfolk, in England at the start of 2005. IiME came into being in September 2005 and the need for similar presentations brought about the proposal to host a conference with more ME experts. IiME decided London was the best place to hold the conference as it would allow easier access by politicians and prominent healthcare staff. The first IiME ME conference was held on ME Awareness Day, 12th May, 2006, with Professor Hooper, Dr. Bruce Carruthers, Dr. Byron Hyde, Dr. Jonathan Kerr, Jane Colby, and Professor Basant Puri and with Dr. Ian Gibson giving the key-note speech. The timing was prescient as Dr. Gibson would be soon embarking on his inquiry into ME by a group of parliamentarians – the Group for Scientific Research into ME (see later story). ME Story I remember asking my doctor one day when I would stop feeling so tired!!! ...... She said give it time - Robyn Speakers and delegates from eight countries were present and the presentations from the conference subsequently appeared in the Journal of Clinical Pathology. Invest in ME’s chairman was interviewed by the BBC and ITV and the conference was referred to in the New Scientist and several national newspapers. The DVD of the conference was distributed to over twenty countries and is now sold as an educational DVD for healthcare and education professionals. Those in ME Support Norfolk who initiated the presentations in 2005 and Professor Hooper planted a seed. From this grew the idea of the IiME International ME/CFS Conference. Facts About ME ME Research UK have a document (available also on the IiME website) which has references to a multitude of research publications collected by Dr. J. Gordon Parish concerning possible ME epidemics. The IiME Conference – the Future It is Invest in ME’s intention to continue with the London conference until a treatment and cure is found for ME. This will be our way of raising awareness by providing a platform for researchers, healthcare staff, support, educational professionals, ME support groups and people with ME and the media, to enable the most relevant science, research, information and news to be heard. The conference is now an annual event in May – ME Awareness Month. Invest in ME welcome the support of all ME groups, charities and individuals to make this an even better event next year. We shall be working with our UK regional and international contacts to enable this and, even as we are organising the 2007 conference, we are looking ahead to the conference in May 2008. Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Behavioral Interventions in ME/CFS. What a difference a decade makes! Written for participants of the May 2007 UK ME Awareness Month events By Dr Ellie Stein MD FRCP As research progresses it becomes more clear that ME/CFS is heterogeneous group of biomedical disorders in which disabling fatigue, dysfunction, pain, autonomic dysfunction, cognitive/neurological immune dysfunction and gastrointestinal dysfunction are concurrently and chronically present. There is increasing evidence, much presented during the UK ME Awareness month, that ME/CFS is pathophysiologically distinct from other medical conditions and from psychiatric disorders. In terms of the etiology of ME/CFS, the pendulum has swung from assumptions of infection as a primary linear precipitant in the 1950s to hypotheses of psychological/behavioral causation in the late 1980’s to early 1990’s. Now opinion is swinging back towards biomedical causes. But instead of a linear cause and effect, current research assumes the interaction of a group of facultative vulnerabilities (genetic, biochemical, environmental) with precipitants such as infection, environmental exposure or trauma to cause disease in a complex way which may differ in each individual. Does behavioral medicine have a role to play in ME/CFS? Research suggests that the psyche plays a similar role in ME/CFS as in other biomedical conditions such as arthritis, heart disease and cancer. How one thinks about and reacts to one’s illness does not in most cases change the underlying pathophysiology, but it certainly affects happiness, hopefulness and quality of life. What is the evidence for this statement? A review of all published, controlled behavioral ME/CFS shows that there are subjective benefits in: fatigue, pain and health status. interventions in No other symptom groups have been reported upon. Neither cognitive function nor exercise tolerance seem affected by behavioral intervention. Furthermore, the subjective changes wane after 24 months (Edmonds et al, 2004;Price & Couper, 2000). These results are similar to those found in Fibromyalgia (Koulil et al, 2006). Cognitive and exercise strategies are used in other disorders with similarities to ME/CFS such as Multiple Sclerosis and Rheumatoid Arthritis. is agreed that the role of behavioral symptom self management and In these conditions it intervention is psychological adaptation. Therefore using CBT/GET lacks controversy. Invest in ME Charity Nr 1114035 After more than a decade of debate, I posit that the ME/CFS community has moved beyond the bio-psycho debate. A close read of the methodology of the two most recent behavioral studies in ME/CFS show vastly expanded definitions of CBT and GET (Pardaens et al, 2006;O'Dowd et al, 2006). These studies bear little resemblance to the early studies which angered so many. The field has shifted significantly since the early 1990’s. Does behavioral medicine have a role to play in ME/CFS? Research suggests that the psyche plays a similar role in ME/CFS as in other biomedical conditions such as arthritis, heart disease and cancer. How one thinks about and reacts to one’s illness does not in most cases change the underlying pathophysiology, What is the next step in behavioral research in ME/CFS? Self Management is used in many chronic disorders especially arthritis, metabolic syndrome and pulmonary disease. The most common self management model world wide is the Stanford Model developed by Kate Lorig and others. This is a public health model in which lay patient experts facilitate groups for self referred persons with mixed disorders. The model has proven, positive, long term impact in disorders such as arthritis where evidence based medical care accessible to all participants. However in ME/CFS where many patients cannot find a disease literate physician, the Stanford model may not be as effective. model with more illness specific content are being studied in Australia and we are awaiting publications of that data. Given that neither pharmacological nor behavioral interventions seems sufficient in ME/CFS, it prudent to recommend integrated models is in which biological, psychological and social factors are assessed and addressed. (continued page 7) www.investinme.org 6 Different adaptations of this Journal of IiME Volume 1 Issue 1 (continued from page 6) This requires: • Increased funding for multidisciplinary ME/CFS research • Understanding the pathophysiology of ME/CFS illnesses • Defining distinct subgroups • Educating health care professionals • Ensuring integrated assessment ME Story I attended the graded exercise programme 22 months ago. I was "sold" the programme under an amazing high degree of pressure and selling. I could not do the increase of 30% of my activity, realistically though it was supposed to be 10%. and treatment is available to all persons with ME/CFS independent of financial means References References for this article may be obtained from Dr. Stein Dr. Ellie Stein Dr. Stein is a psychiatrist in private practice in Calgary, Canada [espc@shaw.ca] The physio refused to believe that I could not do it! She told me I must be able to do it after I had tried and failed. My entire immune system seemed to break down and since those few weeks I am now on high doses of anti viral medication from my GP and will be for years. I would never do get/gat again or recommend anyone to do so. Try the pacing, but please refuse to do the Enforced targets. I was an innocent fool. -M (UK person with ME) 7 Facts About ME Due to relatively little funding given to biomedical research in the UK (compared to the extensive funding being given to psychiatric paradigms for therapies and trials) the amount of proper scientific research has been limited. However, there are over 4000 papers of biomedical research which contain indisputable facts related to the organic basis for ME. More ME stories, including all of these contained in this brochure, are available at – http://www.investinme.org/mestorygallery1.htm Stories from parents of people with ME may be found at - http://www.investinme.org/mestorygallery2.htm Order our free newsletter. We aim to publish monthly via email, plain text or PDF. Go to http://www.investinme.org/IIMENewslettersubs.htm Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Professor Leonard Jason Exploratory Subgrouping in CFS: Infectious, Inflammatory, and Other Karina M. Corradi, Leonard A. Jason,∗ Torres-Harding Introduction Professor Leonard Jason Professor of Clin. & Community Psychology, Director, Center for Community Research, DePaul University, Chicago Dr. Leonard Jason, Ph.D., is among the most prolific of all CFIDS researchers. more than a decade, Dr. Jason and his team at DePaul University’s Centre for Community Research have worked to define the scope and impact of CFS/ME worldwide. Professor Jason was intending to speak at our London conference but was forced to cancel due to other engagements. Similar to other disorders such as cancer, it is likely that a number of distinct types of CFS exist, and that grouping all individuals who meet diagnostic criteria together is prohibiting the identification of these distinct biological markers of the individual subgroups Chronic fatigue syndrome (CFS) affects an estimated 836,000 adults in the United States (Jason et al., 1999), and is 3 to 5 times more common in women than men. CFS can impact any number of bodily systems including For neurological, immunological, hormonal, gastrointestinal, and musculoskeletal (Friedberg & Jason, 1998). CFS is a diagnosis of exclusion. There are currently no specific diagnostic tests for its identification. Researchers have reported various biological abnormalities when investigating CFS, including hormonal abnormalities (Cannon et al., 1998; Moorkens, Berwaerts, Wynants & Abs, 2000), immune activation (Miller, Cohen & Ritchey, 2002), neuroendocrine changes, (Farrar, Locke & Kantrowitz, 1995) and neurological abnormalities (Cook, Lange, DeLuca & Natelson, 2001) among others. However, studies involving basic blood work appear to show no typical pattern of abnormality among individuals with CFS (Johnson, DeLuca & Natelson, 1999). It has been suggested that a number of unique subgroups exist within the overall cluster of individuals diagnosed with this disorder (Cukor, Tiersky & Natelson, 2000; Jason et al. 2001; Johnson, DeLuca & Natelson, 1999). In the p aper specifying the current US case definition for CFS diagnosis (Fukuda et al., 1 994), the working group that developed the criteria referred to the importance of subgrouping within cohorts of individuals diagnosed with CFS. This demonstrates that, even as the current definitional criteria were being presented, there was an awareness of the heterogeneity within the identified group. After the publication of these criteria in 1994, many attempts to subgroup have been undertaken, but to date, no one method has proven to be consistently superior in differentiating subgroups. Psychiatric comorbidity has often been considered a differentiating variable in research studies aimed at subgrouping (Borish et al., 1998; Cukor, Tiersky and Natelson, 2000; DeLuca, Johnson, Ellis & Natelson, 1997a; Masuda, Munemoto, Yamanaka, Takei & Tei, 2002). However, when Tiersky, Matheis, DeLuca, Lange, and Natelson (2003) examined individuals with CFS with and without psychiatric co-morbidity, they found that physical functional capacity was not worse in individuals with CFS and a concurrent psychiatric illness. Morriss and associates (1999) also found that depression was not associated with the reporting of pain, FM, with CFS. Similarly, Ciccone, Busichio, Vickroy, and Natelson (2003) did not find that psychiatric illness, alone or in combination with a comorbid personality disorder, was associated with physical impairment. (continued page 9) Susan R. Keywords: chronic fatigue syndrome, subgrouping, physical disability, mental disability, psychiatric comorbidity 8 IBS, or medically unexplained symptoms in individuals Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) In contrast to the findings above, Borish, Schmaling, DiClementi, Streib, Negri, and Jones (1998) found evidence of low level inflammation, similar to that of allergies, in a subgroup of individuals with CFS. Borish et al. suggested that there might be two subgroups of individuals with CFS, those with immune activation (infectious or inflammatory) and those devoid of immune activation with other illness processes, including psychiatric disorders. Lutgendorf, Klimas, Antoni, Brickman, and Fletcher (1995) found that those patients with immune activation had the most severe cognitive deficits, while Natelson, Cohen, Brassloff and Lee (1993) found that those with ongoing inflammatory processes reported greater cognitive and mental disabilities. Buchwald, Wener, Pearlman, and Kith (1997) found individuals with CFS and chronic fatigue to have significant abnormalities in C-reactive protein (an indicator of acute inflammation) and neopterin (an indicator of immune system activation, malignant disease, and viral infections) when compared to controls. Buchwald et al. (1997) stated that groups of individuals with active low-level inflammatory, infectious processes could be identified and that this was evidence of an organic process in these patients with CFS. Cook, Lange, DeLuca, and Natelson (2001) found that individuals with an abnormal MRI and ongoing inflammatory processes had increased physical disability, suggesting an organic basis for some individuals with CFS. Conceivably, individuals without evidence of these infectious or inflammatory processes on basic laboratory screening tests might be more likely to contain individuals who had other neuroendocrine or neurologic illnesses that might not be readily identified using the minimum battery of laboratory of tests recommended by Fukuda and colleagues (1994) in order to diagnose CFS. However, those with infectious or inflammatory processes might be expected to be more physically impaired compared to those without these processes, based on research by Cook, Lange, DeLuca and Natelson (2001) and Lange, et al. (1999). There is also evidence that those individuals with CFS and with inflammatory processes report greater mental difficulties when compared to those individuals without them (Natelson, Cohen, Brassloff & Lee, 1993). Clearly, individuals diagnosed with CFS are heterogeneous with varying illness course and disability patterns (Jason, Corradi, Torres-Harding, & Taylor, 2005). Similar to other disorders such as cancer, it is likely that a number of distinct types of CFS exist, and that grouping all individuals who meet diagnostic criteria together is prohibiting the identification of these distinct biological markers of the individual subgroups. When specific subgroups are identified, even basic blood work may reveal a typical pattern of abnormality on diagnostic tests (DeLuca, Johnson, Ellis & Natelson, 1997b; Hickie et al. 1995; Jason et al., 2001). This exploratory study considered several possible subgroups that fall under the umbrella diagnosis of CFS. It was expected that clinically significant groups would be found on the basis of abnormal blood tests. The laboratory tests that formed the basis for subgrouping were part of the battery of laboratory screening tests recommended by Fukuda et al. (1994). These groups consisted of an ongoing infectious group, an ongoing Inflammatory group, and an “Other” group (having neither infectious or inflammatory processes). Using these subgroups, this study sought to explore the relationships between membership in a subgroup, reported disability (both mental and physical), and psychiatric co-morbidity. It was hypothesized that the individuals with CFS would evidence higher levels of physical and mental disability than those in a control group, and that those in the Infectious and Inflammatory subgroup would exhibit higher levels of physical and mental disability when compared to the Other group. It was also hypothesized that the Inflammatory group would report greater mental difficulties when compared to the Infectious and Other groups. Method Procedure Procedures developed by Kish (1965) were used to select one adult from each household contacted. The person with the most recent birthday was asked to complete the interview. A stratified random sample of several neighborhoods in Chicago was used, and a random sample of adults was screened. In stage one, 28,673 telephone numbers were contacted, with 18,675 adults completing the initial interview (see Jason et al., 1999 for further details). Persons who completed the initial screening stage of the study with indications that they may have had CFS, as well as a group negative for CFS (control group), were invited to participate in the second and third stages of the research study. Stage two involved administration of a structured psychiatric interview, the SCID, conducted by telephone. Stage three involved a (continued page 10) Invest in ME Charity Nr 1114035 www.investinme.org 9

Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) medical exam at Mercy Hospital, including a physical exam, laboratory tests, including a complete blood count (CBC), white blood cell differential, antinuclear antibodies (ANA), sedimentation rate (Sed rate), rheumatoid arthritis (RA factor), chest X-ray, a detailed medical interview, and a structured medical questionnaire. Participants were also asked at this time to release previous medical records to the research study. The authors received IRB approval for conducting the study. Individuals who participated in the medical examination were provided financial compensation. When each participant completed the study, a team of four physicians and a psychiatrist made the final diagnosis of CFS, Idiopathic Chronic Fatigue, Fatigue explained by a medical condition, or no fatigue. These physicians were familiar with the CFS diagnostic criteria and were blind to the experimental status of the participant. Two physicians independently rated each case to determine whether the participant met the CFS case definition (Fukuda et al., 1994). If a disagreement occurred, a third physician rater was used to arrive at a diagnostic consensus. Participants The participants for this project consisted of individuals with CFS and a control group. For the purposes of this study, it was important that the control sample include only individuals who presented themselves as mentally and physically healthy, due to the fact that abnormal medical test results were a primary variable. A total of 19 of 47 individuals in the control group were excluded from this study (e.g., on-going medical, sleep or severe and untreated psychiatric problems). The final sample included 31 in the CFS group (1 CFS participant was excluded due to lack of data on a critical variable), and 28 healthy controls. The CFS group consisted of 23 females and 8 males. The control group had 18 males and 10 females. Further demographic breakdown indicated that the CFS group had 5 African American, 14 Caucasian, 9 Latino, and 3 individuals who identified themselves as “other”. The control group consisted of 4 African American, 20 Caucasian, 2 Latino, and 2 individuals who identified as “other”. Individuals with CFS were then sub-grouped into three groups according to medical evidence of possible inflammatory processes (as evidenced by abnormal eosinophils count, abnormal rheumatoid arthritis factor [RA factor], and abnormal sedimentation rate in the presence of one of Invest in ME Charity Nr 1114035 the prior mentioned inflammatory markers), medical evidence of possible current infection (as evidenced by abnormal results on lymphocytes count or sedimentation rate [Sed rate] without the presence of an inflammatory marker), and a group without evidence of either of these organic processes. Each of these medical markers is discussed in the measures section below. When subgrouped based on these criteria, 8 participants with CFS were categorized into the Other group, 8 in the Infectious group, and 15 in the Inflammatory group. Measures Measures used for this study included laboratory blood tests, a self-report of disability, and a structured clinical interview for the determination of psychiatric diagnosis. 1 [1All measures did not total 59 as all participants did not complete every measure.] Standard laboratory tests were conducted during phase three of the full-scale study. Results used in the current study include: White blood cell (WBC) differential (specifically lymphocytes and eosinophils), rheumatoid arthritis factor (RA factor), antinuclear antibodies (ANA) and sedimentation rate (Sed rate). These laboratory tests were chosen for inclusion into the study based upon the recommendations of Fukuda and colleagues (1994) for diagnosing CFS. These tests are all part of the recommended minimum battery of laboratory screening tests suggested by this group in order to exclude other physiological causes of fatigue or another disease process. All blood-work completed for this study was analyzed through the laboratories at Mercy Hospital in Chicago Illinois, or National Health Laboratories Incorporated-Chicago, in Elmhurst, IL.. Eosinophils and Lymphocytes Eosinophils and lymphocytes are specific leukocytes. To obtain 10 types of the values presented and considered in this study, automated white blood cell differentials were performed. Differential white blood count is part of the complete blood count (CBC) and is composed of five types of leukocytes (WBCs whose chief function is to protect the body against microorganisms causing disease). These five consist of eosinophils, lymphocytes, neutrophils, basophils, and monocytes. The differential WBC is expressed in cubic millimeters and percent of total number of WBCs. antinuclear antibodies [ANA], When elevated, eosinophil counts can indicate the presence of allergic inflammation, some forms of cancer, (continued page11) www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) and parasitic disease. Significantly higher rates of allergy and allergic type reactions have been reported in the CFS population (Borish, et al., 1998). Several studies have also reported significant elevations of the eosinophil counts of individuals with CFS (Conti, Magrini, Priori, Valesini & Bonini, 1996; Baraniuk, Clauw, Yuta, Gaumond, Upadhyayula, Fujita, et al. 1998; Priori, Conti, Luan, Aprino & Valesini, 1994). The normal range endorsed by Mercy Hospital Laboratories for eosinophil count is 100-300 mL. This variable was coded as normal or abnormal depending on the test results from Mercy Hospital Laboratory. When elevated levels of lymphocytes are found, this can be an indication of viral infection, chronic infection, and Hodgkin’s disease, among others. Elevated lymphocytes have been reported in the CFS population (Patarca, 2001), and abnormal lymphocyte responses have also been noted (Krueger et al., 2001). However, elevated levels and abnormal responses have not been found in all studies (Brimacombe, Zhang, Lange & Natelson, 2002). The normal range endorsed by Mercy Hospital Laboratories for lymphocytes is 800-4400mL. This variable was coded as normal or abnormal depending on the test results from Mercy Hospital Laboratory. Rheumatoid Arthritis Factor (RA Factor) RA factor measures antibodies in arthritis, individuals with rheumatoid arthritis. When this test occasionally, the serum of is abnormal, it indicates an inflammatory process such as rheumatoid autoimmune disease and infectious diseases. The presence of rheumatoid arthritis factor has been reported in the CFS population (Kerr et al., 2001). This laboratory test was conducted by National Health Laboratories Incorporated-Chicago, in Elmhurst, the degree of rapidity with which the red cells sink in a mass of drawn blood (Dirckx, 2001). Elevated Sed Rate can indicate bacterial infection, pelvic inflammatory disease, systemic lupus erythematosus, and red blood cell abnormalities (Kee, 2001). Abnormal sedimentation rates have been reported in CFS populations (Richards, Roberts, McGregor, Dunston & Butt, 2000). Results on this test are reported in millimeters per hour, and normal ranges depend on sex and age. The Mercy laboratories normal range for males < 50 is 010.4 mm/hr, and for males > 50, 0-11.4 mm/hr. For females < 50 the normal range is 0-11.0 mm/hr and for females > 50, 0-20.0 mm/hr. This variable was coded as normal or abnormal depending on the test results from Mercy Hospital Laboratories. Antinuclear Antibodies (ANA) ANA tests for the presence of antinuclear antibodies in the blood. A normal result is negative. When positive, it is an indication of systemic lupus or other rheumatoid disorders, which are inflammatory diseases. Occasionally this test can be positive in the presence of specific types of infections. Elevated rates of ANA have been reported in the CFS population (Nesher, Margalit & Ashkenazi, 2001). Several reports of a specific type of ANA found in some individuals with CFS have been published (Itoh et al., 2000; Nishikai, et al., 2001). Psychiatric Diagnosis To measure current and lifetime psychiatric diagnosis, the Structured Clinical Spitzer, Gibbon & Williams, 1995) was used. IL. Serum samples were first run undiluted, and if a positive result was found, the sample was then run diluted at a 1:10 dilution. The reference value for a normal result is < 1:20 titer. Ranges of 1:20-1:80 are positive for rheumatoid and other conditions. Results falling above 1:80 are positive for rheumatoid arthritis. Any positive results on this test were coded as abnormal. As Rheumatoid Arthritis is an exclusionary disorder for CFS diagnosis, all participants were screened for Rheumatoid Arthritis during their medical exam and this disorder was ruled out. Sedimentation Rate (Sed Rate) Sed rate measures the sinking velocity of blood cells, or Interview for the DSM (SCID; First, Previous studies have indicated that the SCID is a reliable measure of psychiatric diagnosis in the CFS population (Taylor & Jason, 1998). The SCID requires administration by master’s level clinicians. To create the categories used in this study, all diagnoses identified as anxiety disorders by the DSM (such as generalized anxiety disorder, phobias etc.) were grouped together into one Anxiety Diagnosis variable, all disorders identified as depressive disorders (such as major depressive disorder, seasonal affective disorder, bipolar disorder etc.) into one Depressive Disorder variable, and all other psychiatric diagnoses (such as substance abuse disorders, somatization etc.) were grouped into an Other Psychiatric Diagnosis variable. Disability To determine disability level, the SF-36 (Stewart, Hays & (continued page 12) 11 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) Ware, 1988) was completed by all participants. The SF-36 is a 36-item questionnaire that in the past assesses individuals’ self- report on physical and emotional health currently, four weeks, and compared to the same time last year. The SF-36 has eight subscales, and one reported health transition score. Two composite scores are available for the SF36, the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Internal consistency coefficients range from .89 -.94 for the PCS, and .84 -.91 for the MCS across age, gender, race, education, medical diagnosis, and disease severity. The current study used these summary scales to determine differences in physical health, and mental health (Ware, Kosinski & Keller, 1994). Results Initial analyses were conducted to determine if any significant differences existed between the control and the entire CFS group on sociodemographic variables. There was only one significant difference, which occurred for gender. Therefore, gender was run as a covariate in all subsequent analyses. Subgroup Differences for Physical and Mental Disability To consider the relationship between subgroup membership and reported physical disability, an ANCOVA was run with subgroup as the independent variable, PCS as the dependent variable, and gender as a covariate. Analyses indicated that significant differences could be found between the subgroups on the PCS (p < .01). Least Significant Difference post hoc analyses indicated that all three CFS subgroups reported significantly higher levels of physical disability than the Control group (M = 56.1). The Other group reported significantly higher levels of physical disability when compared to the Inflammatory group (Ms = 29.2 vs 39.2, respectively), but it was not significantly different from the Infectious (M = 34.7) group. Next, an ANCOVA was conducted with a subgroup as the independent variable, MCS (a measure of mental disability) as the dependent variable, and gender as the covariate. Analyses indicated that significant differences did exist between the subgroups for the MCS variable (p < .01). Following the significant omnibus test, post hoc analyses indicated that the Inflammatory group had significantly greater mental disability compared to the control group (Ms = 36.5 vs 50.8, respectively), but was not significantly different from the Other (M = 43.6) or Infectious (M = 39.7) groups. Invest in ME Charity Nr 1114035 Relationships between Subgroups and Psychiatric Diagnoses To attempt to understand the relationships that might exist between subgroups and psychiatric diagnoses, logistic regressions were conducted considering subgroups as the independent variables (e.g., Other, Infectious, Inflammatory, and Control) and one psychiatric diagnosis per logistic regression (with the following dependent variables in separate analyses: current depression, current anxiety, and current other psychiatric diagnosis). No significant differences were found among the subgroups and the presence of depression, anxiety disorder, or other psychiatric diagnosis. Because prior studies have indicated that the CFS groups have significantly higher rates of current and lifetime psychiatric co morbidity, the analyses above were performed on current and any lifetime psychiatric diagnoses. Two logistic regressions used current psychiatric diagnosis and lifetime psychiatric diagnosis as dependent variables. The odds that an individual in the Infectious group also had a current psychiatric diagnosis were 6.13 times higher when compared to individuals in the control group. The odds that individuals in the inflammatory group had a current psychiatric diagnosis were 12.65 times higher when compared to control group members. The second logistic regression considered lifetime psychiatric diagnosis of any kind between membership in one of the subgroups, and membership in the control group. Analyses indicated that the odds that individuals in the inflammatory group had a psychiatric diagnosis at some time in their lives were 18.66 times higher when compared to individuals in the control group. Ethnic Differences Prior to sub grouping, no significant differences existed between the control and CFS groups on ethnicity. However, when examining the three subgroups separately with the control group, chi square analysis indicated that significant differences did exist between the four groups [χ2 (3, N = 59) = 10.00, p = .019]. The Infectious group (91% minority, 9% Caucasian) were significantly more likely to be of minority status than the Other (32% minority, 67% Caucasian) and control (37% minority, 63% Caucasian) groups, but they were not significantly different from the Inflammatory (56% minority, 44% Caucasian) group. (continued page13) www.investinme.org 12 Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) Discussion While it was hypothesized that the Infectious and Inflammatory groups would be significantly more physically impaired compared to the Other group, we found that the Other group reported significantly greater physical impairment compared to the Inflammatory group. In the present study, the Other group might have reported greater physical impairment because of other on-going physiological processes. For example, supplemental analyses indicated that the Other group was significantly more likely than the Infectious group to present with symptoms of orthostatic intolerance, specifically, having a mental disability when inflammatory dizziness immediately following standing, and dizziness when turning the head. The Other group might have contained individuals with ongoing illness processes that were not identifiable by the laboratory tests available for this study. Orthostatic intolerance is best diagnosed using tilt-table testing, which was beyond the scope of the current study. The Inflammatory group was significantly different only from the control group. This result is consistent with past findings of greater mental disability in the Inflammatory group when compared to the control group, and is consistent with past research indicating individuals with ongoing inflammatory processes are more likely (Natelson, Cohen, Brassloff & Lee, 1993). When measuring participants’ psychological status, the Other group was the only chronic fatigue subgroup that did not have significantly elevated psychiatric diagnoses. No significant relationships emerged between membership in the Infectious, Inflammatory, and Other groups, and current diagnosis of depression, anxiety, and any other psychiatric diagnosis. However, when examining simply the presence or absence of any current or lifetime psychiatric disorder, the Inflammatory group was more likely to have a current or lifetime psychiatric diagnosis when compared to controls. Also, individuals in the Infectious group were found to be more likely to have a current psychiatric diagnosis when compared to controls. It is possible that the presence of a chronic illness may put enough psychological strain individual on an that this strain contributes to or caused psychiatric diagnosis, or that the same processes that increase an individual’s likelihood of processes are present, may increase the likelihood of a psychiatric diagnosis. It is also possible that the psychiatric symptoms are completely unrelated to the CFS diagnosis (Abbey, 1996). The relationship between psychiatric diagnosis and CFS diagnosis is one that is far from being understood and therefore is much in need of further study. Finally, the Infectious group had a greater number of minorities compared to other subgroups and the control group. It is well documented that minority and low SES populations are less likely to have access to health care (Richman, Language barriers, healthcare system, past Flaherty & Rospenda, 1994). experiences with the religious beliefs may all contribute participants being less likely and different medical and to minority to utilize health care, even if they have the access (Borrayo & Jenkins, 2003; Johnson et al., 1995). It is also possible that minorities who are immigrants are more likely to travel to their country of origin and be exposed to different infectious agents in their travels. In addition to this, minority participants may be more likely to be employed in hazardous or environmentally stressful occupations with exposure to infectious agents. to report greater mental difficulties It is possible then that minorities in the present study had poorer health care utilization, and therefore were less likely to have had infectious processes treated. The current exploratory investigation had several limitations. First, the medical tests used as the basis of subgrouping in this study were not exclusive indicators of infection or inflammation. Further, the distinction between infection or inflammation is often one that cannot clearly be made, as these two processes frequently occur together. While inflammation generally accompanies infection, there are distinct instances when inflammation occurs in the absence of known infection, such as allergic inflammation, or sub-clinical level rheumatoid arthritis. Future studies should seek to determine if clear differentiation can be made, with more accurate infection and inflammation. tests, between Second, the limited sample size for African American, Latino, Asian, and other minority groups necessitated the grouping of all minority participants into one larger minority group. It is difficult to be certain if the relationships found (i.e. that of minority participants being more likely to present with on-going infectious processes) are more likely in individuals who (continued page 14) Invest in ME Charity Nr 1114035 www.investinme.org 13

Journal of IiME Volume 1 Issue 1 Dr. Leonard Jason (continued) have minority status in general, or if differences in findings are due to a specific minority group. The current study had small sample sizes, and this could contribute to instability of results, generalizability and lack of statistical power. limited Logistic regressions with small sample sizes can over-fit models and generate high odds ratios. Future research should consider larger sample sizes of each minority group to explore within-group and betweengroup differences. It is notable that these findings emerged when forming subgroups utilizing only a basic battery of laboratory screening tests. These laboratory conducted primarily ME Story tests were for the purpose of screening out other major illnesses that might explain a person’s chronic fatigue, as recommended by Fukuda and colleagues (1994). Many people with CFS exhibit only minimal or subtle abnormalities on these tests, and these abnormalities often are inconclusive or may not be acknowledged by the primary care physician because they do not lead to a diagnosis of another, more recognized disease process. Further, the more commonly reported physiological abnormalities reported in people with CFS, such as the presence of RNase L (Suhadolnik et al., 1997), adrenal insufficiency with subsequent low cortisol levels (Addington, 2000), the presence of orthostatic intolerance (Schondorf, Benoit, Wein, & Phaneuf, 1999), and immunological abnormalities (Patarca-Montero, Mark, Fletcher, & Klimas, 2000), can only be assessed using highly specialized, expensive, or experimental tests to which people with CFS and their physicians typically have little access. This study demonstrates that subgrouping is possible using laboratory tests that are readily available and can easily be ordered by primary care physicians. The identification of clinically significant subgroups is the logical next step in furthering CFS research. There might be multiple pathways leading to the cause and maintenance of the neurobiologic disregulations and other symptoms experienced by individuals with CFS. Depending upon the individual and subtype, these may include unique biological, genetic, neurological, psychological, and socioenvironmental contributions. Previous research examining people with CFS as a homogenous group may have missed real differences that might exist among subgroups of people diagnosed with this illness. Subgrouping might be the key to understanding how CFS begins, how it is maintained, how medical and Invest in ME Charity Nr 1114035 I was assessed for one ME clinic but they said I was too disabled and that there were other issues that needed to be worked on. They also said that because I was confined to a wheelchair they thought that would be too upsetting for the other members of their group - Gary psychological variables influence its course, and in the best case, how it can be prevented, treated, and cured (Jason et al., 2005). Acknowledgements & references Request for these and reprints should be addressed to Leonard Jason, Community Research, DePaul University, 990 W. Fullerton Avenue, Chicago, IL 60614. 14 Center for ME Story 3 yrs ago I came down with what I thought was the flu, but I never recovered. After many doctors I was diagnosed with ME. At this time last year I was able to still care for my own needs but as the summer progressed so did my illness. My ability to get up by myself declined. I had to have help getting to the recliner in the living room and to the bathroom. I started having problems feeding myself, my hands would shake so bad that the food and my drink ending up all over myself. Then it got to the point that walking was impossible. I had a bedside commode that I used and my husband would carry me to the recliner. In Nov it was decided that my mom would move in with us to help care for me. By that time I was totally bedridden unable to care for myself. - Blaze www.investinme.org Journal of IiME Volume 1 Issue 1 INVEST in ME CAMPAIGNING for ME AWARENESS ME AWARENESS MONTH ME Awareness has traditionally consisted of a week in May – with 12th May being recognized as ME Awareness Day. IiME have been suggesting that only a ME Awareness Month is sufficient to mark the seriousness of this illness, with 12th May being recognized as the focal point of the month. We are happy to join with ME Research UK to promote ME Awareness Month – a chance for people around the world to highlight the issues surrounding ME, to recognize the devotion of many carers and the courage of many sufferers of ME. It will also give more opportunity for serious discussion of research and enable ME to be seen more as a mainstream illness. ME AWARENESS MONTH MAY 2007 HAVE a CUPPA for ME ME as a Notifiable Illness Invest in ME are happy to work with other groups and charities for the benefit of people with ME and to make progress regarding the urgent issues which need to be tackled. Our recent campaign to have ME recognised as a notifiable illness in schools was made from an idea by Jane Colby. Jane is a former head teacher who has ME and who formed Tymes Trust. It is now ten years since Jane and Betty Dowsett made the report on ME. These studies along with those of Dr Nigel Speight have clearly shown that ME-CFS is a major illness responsible for most school absenteeism. Although IiME and other ME support groups are campaigning for ring-fenced funding for biomedical research into ME we also recognize that we need to help raise money via a voluntary donation effort. In late 2005 Invest in ME launched the Have a Cuppa for ME event. A simple idea to hold tea or coffee mornings with friends, relatives and neighbours. Around the country groups have organised HACFME events and raised thousands of pounds which has gone towards biomedical research to charities such as ME Research UK. More details can be found on the IiME site – www.haveacuppaforme.org. Invest in ME Charity Nr 1114035 Our campaign called on the Chief Medical officer to make ME a notifiable illness in schools. With no government funding being directed at biomedical research we need as much data as possible in order to apply necessary diagnostics to this illness. By making ME a notifiable illness it would be possible to collate more exact figures for occurrence and geography of the illness. It would have a further advantage in ensuring that children’s lives are not irreversibly disadvantaged due to lack of awareness. were better understood Health and Education Authorities could better target their limited resources for the benefit of these sick children. More on this may be found at – http://tinyurl.com/ypnv2q www.investinme.org If the demographics Energising ME Awareness 15

Journal of IiME Volume 1 Issue 1 Dr Vance Spence & Dr Neil Abbot ME/CFS: a research and clinical conundrum This presentation was given at the ME research UK Colloqium in 2003. My role is to provide an overview of the difficulties surrounding the illness, especially for those of you who are coming fresh to the topic from other scientific areas and specialties. One of our aims is to bring together experts from a variety of disciplines, some with little or no experience of ME/CFS, as we attempt to energise research into this condition with new ideas and novel approaches to solving its inherent problems. The most widely-used definition of “Chronic Fatigue Syndrome” is that developed in 1994 by a consensus conference: the CDC-1994 (Fukuda et al., 1994) definition. This was developed in response to criticisms that previous definitions (including the CDC-1988) were too restrictive. It requires the presence of chronic fatigue of six months duration which is persistent or relapsing, of new or definite onset, not substantially alleviated by rest, not the result of ongoing exertion, resulting in a substantial reduction in activities, and leading to substantial functional impairment. In addition, at least four of the following are required: sore throat, cognitive symptoms, tender lymph nodes, muscle pain, multi-joint pain, headaches, unfreshing Figure 1 Australia (Lloyd et al., 1990) CFS “Oxford Criteria”, UK (Sharpe et al., 1991) CFS World Health Organisation, 1994 (non-clinical) US Centers for Disease Control and Preventation (Fukuda et al., 1994) CFS “Canadian” Expert Consensus Clinical Case Definition for ME/CFS, 2003 Diagnostic criteria (adults) for “CFS-like” illness 1988–2003 London (Dowsett et al., 1990) ME US Centers for Disease Control and Prevention (Holmes et al., 1988) CFS Previous literature Epidemic Neuromyasthenia (Parish, 1978) Myalgic Encephalomyelitis (Acheson, 1959) Epidemic Neuromyasthenia (Henderson & Shelokov, 1959) Invest in ME Charity Nr 1114035 www.investinme.org sleep and post-exertional malaise. Cognitive or neuropsychiatric symptoms may be present, but the definition excludes clinically important medical conditions such as melancholic depression, substance abuse, bipolar disorder, psychosis and eating disorders. Some would argue that I could just mention this definition and sit down again; but in fact it is part of the problem, and it examining why that is so. As you can see, the definition relies on “fatigue” as its major criterion. For that reason many patients who fall under this diagnostic label hate the name — they call it the F-word — since for many of them “fatigue” per se is not the major problem, and does not best represent how they would explain their condition. Thus, this CDC-1994 definition is now widely recognised to have a number of limitations. These include the fact that symptoms are mainly self-reported (e.g. the clinical signs required in the CDC-1988 definition have been removed); the terminological criteria are vague (e.g., “fatigue”, “malaise”, “unrefreshing specificity of sleep”, the definition etc.); the is poor, allowing heterogeneous groups of patients (e.g., those with somatoform disorders, fibromyalgia syndrome, etc.) to coexist under the one umbrella term (Salit, 1996; Jason et al., 1999); and it makes no attempt to differentiate is worth 16 (continued on page 17) Journal of IiME Volume 1 Issue 1 ME/CFS: a research and clinical conundrum (continued) patients on the basis of severity of illness or level of functional disability. Indeed, there is a growing realisation that the current CDC-1994-defined “CFS” term is an impossibly inclusive diagnostic construct, begging Simon Loblay (1995) to ask the ontological question: “Is CFS a recognisable disease entity with a unique pathophysiology, or is it a ragbag of common non-specific symptoms with many causes, mistakenly labelled as a syndrome?” As an example, our work in Dundee has compared three groups of patients each fulfilling the CDC-1994 criteria: Syndrome and patients with a definite history of exposure to rganophosphate pesticides. We showed clear differences between the groups in terms of measured parameters, including muscle pain, and physical and mental status (Kennedy et al., 2004). Importantly, a high proportion of people in each group had measurable signs of muscle weakness in arms or legs, indicating that clinical signs can, in fact, be found in these patients if physicians take care to do a full physical examination. explore such important findings. Future work will There have been other definitions apart from the CDC-1994 Fukuda one (see Figure 1). The most recent attempt to revise the definition (Carruthers et al., 2003) is based on clinical experiences with very large numbers of patients. It will, however, be some time before this new “Canadian” description of ME/CFS replaces the CDC1994 definition in clinical and research practice. When comparing scientific studies, it is important to patients with ME, those with Gulf War bear in mind that different definitions of ME/CFS may have been used, and this complicates interpretation and comparison of data. It can also be seen from the Figure below that there have been several attempts in the past decade to define diagnostic criteria for the illness. Each definition has been problematic, reflecting in part the special interest of the author, and taking little account of the extensive literature prior to 1988 (see Figure) that made the case for myalgic encephalomyelitis as a distinct clinical entity based on reports of epidemic and endemic cases. What was this condition “Myalgic Encephalomyelitis” that existed before 1988, when it was subsumed within the “CFS” construct, and which is still referred to by patients in the lay literature as “ME”? Myalgic encephalomyelitis was first defined by Acheson (1959). It had been found to occur in epidemic and sporadic forms, and was believed to result from a continuing or persisting viral systemic illness, infection. It has been defined as a characterised by marked muscle fatigability (not just weakness); muscle (continued on page 18) Figure 2 Orthostatic Hypotension (Streeten et al., 2000; Stewart, 2003) Brain perfusion (Schwartz et al, 1994; Costa et al, 1995) Endothelial dysregulation (Spence et al., 2000; Khan et al., 2003; Khan et al., 2004) Vascular 2002; Tiev et al., 2003) Anti-viral dysregulation (Suhadolnik et al., 1994; De Meirleir et al., 2000; Shetzline SE et al., et al., 2003; Vecchiet et al., 2003) Oxidative stress (e.g., Richards et al., 2000; Manuel et al., 2001; Pall & Scatterle, 2001; Kennedy Biochemical Physiological and biochemical abnormalities found in “CFS” cohorts Enteroviral sequences in muscle (Lane et al., 2003) Abnormal recovery after exercise (e.g., Paul et al., 1999; McCully & Natelson, 1999) Metabolism (e.g., Fulle et al., 2000; Vecchiet et al., 2003) Muscle Metabolic abnormalities (Tomoda et al., 2000; Puri et al., 2002; Chaudhuri et al., 2003) Brain Invest in ME Charity Nr 1114035 www.investinme.org 17

Journal of IiME Volume 1 Issue 1 ME/CFS: a research and clinical conundrum (continued) pain, tenderness and swelling; variable involvement of the central nervous system (ataxia and cranial nerve involvement); muscle weakness and/or sensory changes due to neuronal damage; impairment of memory; sleep disorders, etc.; vascular tachycardia, pallor); involvement (orthostatic reticulo-endothelial dysfunction; and recurrences of flu-like symptoms with myalgia. From 1934–90 there were at least sixtythree outbreaks of epidemic proportions, all well-documented, distributed geographically in North America (29 outbreaks), the UK (16), the rest of Europe (11), Australasia (4), Africa (2) and Asia (1). One of the most studied, and possibly the most controversial, of these outbreaks occurred at the Royal Free Hospital, London, in 1955, during which 292 people were affected. Indeed, outbreaks may still be occurring, and some of the patients who currently come under the CDC-1994 CFS definition have clinical features similar to the classical description of post-infectious ME patients defined above. The fact that we are still aware of these details is in no small measure due to Dr J. Gordon Parish who is attending this workshop today. Dr Parish has over many years collected reports of these outbreaks of ME (Parish, 1978; Shelokov & Parish, 1989), and has a complete archive of the relevant literature. A complete listing of these references can be found on the MERGE web site (www.meresearch.org.uk). Given the heterogeneous nature of the term CFS, and the different ways of defining it, it is probably no surprise that many of the biomedical studies conducted into the illness — a relatively small number given the scale of the problem — have had inconclusive results. Despite this, however, a range of abnormalities have been found by a number of different research groups, and these are summarised in the Figure 2 (previous page). Today’s workshop will concentrate on the vascular and biochemical aspects of ME/CFS, but MERUK intends to facilitate further workshops concentrating on other aspects of ME/CFS pathophysiology, such as muscle metabolism and function, and neuro-imaging and brain function. References A full list of the references mentioned can be obtained from Dr Neil Abbot, ME Research UK (Charity Number SC036942), The Gateway, North Methven St, Perth PH1 5PP; e-mail meruk@pkavs.org.uk; website www.meresearch.org.uk Invest in ME Charity Nr 1114035 www.investinme.org Facts About ME ME is estimated to cost the UK economy over £6 BILLION per year Dr Vance Spence and Kathleen McCall and Sue Waddle from Invest in ME – at a presentation for Invest in ME entitled Making the Breakthrough [http://tinyurl.com/yreh7a] ME Story At work I have been asked to go to see the company doctor as noone believes I'm unwell yet they see me struggling to walk on occasions! - Clare Dr Vance Spence and Dr Neil Abbot, ME Research UK, The Gateway, Perth, UK. Based on a presentation given at the Royal Society of Edinburgh Research Workshop on ME/CFS 18 Journal of IiME Volume 1 Issue 1 Biomedical Research into ME/CFS Dr Vance A. Spence and Dr Neil C. Abbot Chairman of ME Research UK (charity number SC036942), and Hon Senior Research Fellow, Institute of Cardiovascular Research, University of Dundee, UK Specific research findings from the University of Dundee As a supplement to the talks you are to hear during the IiME Conference 2007, this hand-out presents a brief overview of the recent research findings from the Vascular Diseases Unit in the University Dundee,. One of the cardinal facts about research work generally is that breakthroughs follow funding (since without it there is no possibility of starting the exploration!). This group, with Research UK, has uncovered several blood vessel sensitivity to acetylcholine? c) Increased neutrophil apoptosis of Also, we also have new data indicating that ME/CFS patients have detectable abnormalities in a type of white blood cell (called neutrophil) – specifically a larger proportion of dying (apoptotic) cells than in healthy subjects – consistent with an activated inflammatory funding from ME interesting findings in people with ME/CFS. These findings have been reported in a series of scientific papers published from 2003–2006. a) Increased oxidative stress In our experiments, we have found a pattern of significantly increased oxidative stress – increased oxLDL and isoprostanes with decreased HDL and GSH – in ME/CFS patients (Kennedy et al, 2004). As isoprostanes also act as vasoconstrictors, for ME/CFS patients their presence, accompanied by additional free radicals during exercise may be responsible for some of the symptoms – such as pain - seen after exercise. These findings have now been confirmed by at least four other research groups worldwide who have also shown excessive free radicals in blood, urine and muscle tissues of ME/CFS patients. Isn't it important to discover the source(s) of these molecules, whether from excessive immune activity, chronic infections or abnormalities within muscle tissue? b) Abnormal acetylcholine metabolism Acetylcholine is a substance produced by the layer of endothelial cells lining all blood vessels, causing them to open. Our group has found that vascular responses to acetylcholine are increased compared with matched control subjects (Spence et al 2000; Khan et al, 2004, a and b). This finding is in contrast with research into a wide variety of cardiovascular diseases – such as diabetes, stroke and high cholesterol – where blood flow responses to acetylcholine are normally blunted. Why should ‘CFS’ patients have this thumbprint of increased Invest in ME Charity Nr 1114035 seemingly unique (continued on page 20) www.investinme.org process which is possibly the consequence of a past or present infection (Kennedy et al 2003, 2004a). Accompanying these markers of neutrophil apoptosis, we found that highsensitivity C-reactive protein levels, recognised as a marker of the inflammatory process, were also significantly increased. Might some people with ‘CFS’ disorder, albeit an unusual one? d) Presence of "signs" of physical illness Importantly, a high proportion of the patients investigated in this unit have had measurable signs of muscle weakness in the arms and/or legs, indicating that clinical signs (rather than self-reported symptoms) can, in fact, be detected in these patients if physicians take care to do a full physical examination (Kennedy et al 2004b). Intriguingly, reports in the older literature (1950s and 1960s) on epidemics of ‘classical’ ME included the presence of clinical signs (e.g., muscle weakness/swelling; sensory nerve changes; observable recurrences of flulike illness, etc). Will the presence of clinical signs - believed by many healthcare professionals today to be non-existent in ME patients - come to be recognised as important markers of physical illness? Our purpose here is not to answer these questions, but to show that biomedical investigation can uncover, within a proportion of ME/CFS patients, biological anomalies that might well help to explain many of the clinical features associated with the illness, and might also indicate areas for therapeutic treatment. 19 have a chronic inflammatory

Journal of IiME Volume 1 Issue 1 Biomedical Research into ME/CFS (continued) General research findings from groups worldwide For the first time in many years, there is optimism about the potential for biomedical advances in ME research. A range of groups are beginning to report physiological abnormalities in many patients with ME/CFS, showing what can be achieved if scientific effort and funding are targeted towards biomedical research, leading to therapeutic intervention and treatment. The Table below (from ME Research UK’s report of the Royal Society of Edinburgh/Wellcome Trust workshop on ME - available on our website) lists some recent areas of progress that may prove to be important. The Future? All these results are very exciting, and they may well help us to explain some of the unusual symptoms that these ME/CFS patients experience. It is also important to recognize, however, that these tests are not diagnostic markers. We are currently formulating new hypotheses and designing new experiments in order to unravel the significance of acetylcholine sensitivity, increased oxidative stress, increased early death of neutrophils etc, in the ME/CFS patients. Experience has convinced us, however, that funding will be difficult to maintain, and that the funding strategy for ME must mirror that of cancer research which obtains 85-90% of its revenue from private sources and ground-level fundraising. It is a huge task, but much can be achieved by a determined and collaborative ME community. References A full list of the references mentioned can be obtained from Dr Neil Abbot, ME Research UK (Charity Number SC036942), The Gateway, North Methven St, Perth PH1 5PP; e-mail meruk@pkavs.org.uk; website www.meresearch.org.uk Table: Physiological and biochemical abnormalities found in groups of ME/CFS patients. BIOCHEMICAL Oxidative stress (Richards 2000 et al. ; Manuel 2001 et al.; review by Pall 2001; Kennedy et al. 2003; Vecchiet et al. 2003) Dysregulation of anti-viral pathways - i.e. abnormal activity of the anti-viral immune responses (Suhadolnik RJ et al. 1994; De Meirleir et al. 2000; Tiev et al 2003) VASCULAR – Endothelial dysregulation - i.e. abnormal responses of small blood vessels selectively to acetylcholine (Spence et al. 2000; Khan et al. 2003 and 2004) Altered brain perfusion i.e. areas of reduced blood flow in the brain (Ichise et al 1992; Costa et al. 1995; Tirelli et al. 1998) Orthostatic hypotension i.e. physiological changes to blood pressure/cardiovascular mechanisms on standing (Streeten et al. 2001; Naschitz et al. 2002; Stewart et al. 2003) BRAIN MUSCLE Metabolic abnormalities e.g. alterations of brain choline (important in brain function). (Tomoda et al. 2000; Puri et al. 2002; Chaudhuri et al. 2003) Altered metabolism - e.g. changes in muscle composition or use of fuel. (Fulle et al. 2000, Vecchiet et al. 2003, Fulle et al. 2003) Abnormal response to exercise (Lane et al. 1998; Paul et al. 1999; McCully et al. 2004). Enteroviral sequences in muscle - i.e. evidence of a persisting virus in some CFS patients (Lane et al. 2003; Douche-Aourik F et al. 2003) Invest in ME Charity Nr 1114035 www.investinme.org 20 Journal of IiME Volume 1 Issue 1 The Strategy of the Medical Research Council for Research on CFS/ME By Professor Colin Blakemore Chief Executive, Medical research Council The development of MRC’s CFS/ME Strategy Following the publication of the Report of the Chief Medical Officer’s Independent Working Group in 2002, the MRC convened a CFS/ME Research Advisory Group (the Membership and Terms of Reference of which appear in Annex 1 below). This Group was asked to advise the MRC on a broad strategy for advancing biomedical and health services research on CFS/ME. The Advisory Group met three times between September 2002 and March 2003, and also undertook a consultation exercise, in July and August 2002, using a set of structured questions. The results were independently analysed by the NHS Public Health Resource Unit, Oxford. The lay members of the MRC CFS/ME Research Advisory Group met with ME charities, CFS/ME patients and their carers, in order to improve understanding of their perspectives. A preliminary draft research strategy was made available to key stakeholders, as well as national and international researchers, for external, open consultation. It was also considered by the MRC Research Boards between December 2002 and February 2003. The preliminary draft research strategy was revised by the MRC CFS/ME Research Advisory Group in the light of the results of this consultation, and the final version was presented to the governing body of the MRC, its Council, in March 2003. In May 2003 the MRC published the report of the independent Research Advisory Group. The report can be viewed or downloaded from the MRC website: (http://www.mrc.ac.uk/Utilities/Documentrecord/inde x.htm?d=MRC003412). The Research Advisory Group agreed that the research community should be encouraged to develop high-quality research proposals addressing key issues for CFS/ME research in areas that were considered amenable for study at the present time. In particular, the Group drew attention to the potential for progress in certain areas, for instance in research that addresses: • • the understanding of symptomatology improved case-definition • new approaches to management. Invest in ME Charity Nr 1114035 21 Invest in ME had invited Professor Blakemore to speak at the IiME International ME/CFS conference but unfortunately he was not able to make it. The MRC were invited to send another speaker, and were offered the chance to send representatives to attend as delegates, but these offers were also declined. The MRC CFS/ME Research Advisory Group concluded that there is probably a multiplicity of potential causal factors for CFS/ME and they reviewed the widely disparate results of research so far reported in the scientific literature concerning the biological basis of the condition. They concluded that, as in many other areas of medical progress, valuable treatments might be developed and tested, even if there is not a full understanding of the triggers and causal pathways that lead to CFS/ME. Therefore, the Advisory Group recommended to the MRC that the most likely route to rapid help for patients was through support for research on interventions for CFS/ME, even while there remains incomplete knowledge of its causes and underlying pathogenesis. This recommendation does not debar the consideration of applications exploring the mechanism and aetiology of the condition, if high-quality proposals can be developed. The MRC does not normally set aside specific amounts of money for particular illnesses, not (continued on page 22) www.investinme.org

Journal of IiME Volume 1 Issue 1 MRC Strategy for Research on CFS/ME (continued) even for the most common conditions, although in areas of serious unmet clinical need, we do sometimes issue highlight notices, to alert the research community to our strong interest in funding good research. The MRC issued such a highlight notice for CFS/ME and that highlight notice is still in effect. Thus, the MRC continues to encourage research applications in CFS/ME, and our Research Boards have agreed to prioritise this area. However, applications must not fall below the scientific standards set by our rigorous peer review process, through which applications are judged in open competition with other demands on funding. The main factors in our Research Boards’ funding decisions are: • research excellence; • • the likelihood of major advances in knowledge; and the clinical importance of the topic. This is to ensure that the research supported by the MRC will have the best chance of delivering knowledge that will be useful in tackling medical conditions, and that we therefore use taxpayers’ money to good effect. Needless to say, the MRC has a responsibility to encourage the strong UK research community to contribute as widely and effectively as possible to improving the health of the nation. So, the MRC is very keen to support high-quality studies on CFS/ME that stand a good chance of delivering their stated aims. It would obviously not be acceptable to the public as a whole for the MRC to support research applications that are judged, in open competition, to be of lower quality than other proposals that are more likely to yield results of real value to the sufferers of other conditions. Challenges to understanding the causes and biological bases of CFS/ME There are a number of challenges to advancing the understanding of CFS/ME arising from individual variation in the spectrum of signs and symptoms associated with fatigue conditions, and hence uncertainty about the cardinal signs of CFS/ME. A related problem in the design of research is the variability of response of sufferers to potential interventions, possibly because of differences in underlying aetiology and pathology. Invest in ME Charity Nr 1114035 The intensity as well as the nature of the symptoms vary considerable, not only between patients but also over time for individual patients, and at different stages in the progress of the condition. The lack of consistency of data from experiments on people with CFS/ME presents a huge challenge to the interpretation of the results of research. The fact that some, perhaps many patients have one or more other comorbid conditions, particularly mood and anxiety disorders, makes research even more difficult. The complexity of this condition led the Advisory Group to recommend that researchers should develop high-quality research proposals addressing key issues for CFS/ME research that are amenable for study at the present time. It is hoped that improved definition of the phenotypes of potential subgroups that may come under the CFS/ME spectrum, will help to underpin future research on causes and mechanisms. However, the MRC remains committed to funding scientific research into all aspects of CFS/ME at any time and will consider funding research into the biological basis of the condition, provided it meets the quality thresholds set out above. Another challenge for CFS/ME is the lack of researchers with an adequate understanding of the condition and training in the multidisciplinary approaches that might facilitate ground-breaking discoveries. Unfortunately, the openly expressed frustration of many CFS/ME sufferers has led many researchers to feel under attack from the very community that they are trying to help. The frustration, even hostility, expressed against researchers can only discourage the necessary influx of new researchers to take the field forward. Current MRC funding for CFS/ME The MRC is currently funding six research projects on CFS/ME (see Annex 2) – a total investment of more than £3m. For comparison, this is similar to the level of MRC support for research on autism and on skin cancer. The MRC’s portfolio includes two large clinical trials of new approaches to treating CFS/ME – the PACE trial (£2,076,363) and the FINE trial (£824,129). The PACE trial will be comparing three treatments given to patients in a clinical setting, one of which is Adaptive Pacing Therapy (APT). This (continued on page 23) www.investinme.org 22 Journal of IiME Volume 1 Issue 1 MRC Strategy for Research on CFS/ME (continued) treatment is popular with many patients but has not been scientifically evaluated before. With the help of Action for ME, APT has been adapted to enable the researchers to test it rigorously within the trial. The FINE trial will also test three different treatments. They are delivered to patients at home by specially trained nurses, so are particularly suitable for patients who are too ill to attend a specialist clinic. Conclusions The MRC recognises the scale of suffering caused by the spectrum of disorders characterised by fatigue and wants to use public funds sensibly and productively to help CFS/ME patients. We maintain our highlight notice as an indication of the priority that we attach to this area, and we shall support research on any aspect of CFS/ME that is of high quality and is likely to lead to real advancement of knowledge. Colin Blakemore Chief Executive, Medical Research Council April 2007 Annex 1 MRC CFS/ME Research Advisory Group & Terms of Reference Chair : • Nancy Rothwell, University of Manchester • Jacqueline Apperley, MRC Consumer Liaison Group • Philip Cowen, University of Oxford • • Janet Darbyshire, MRC Clinical Trials Unit Diana Elbourne. London School of Hygiene and Tropical Medicine / Institute of Education • Sue Haslehurst, MRC Consumer Liaison Group • Alan McGregor, Guy’s, King’s and St Thomas's • Jon Nicholl, University of Sheffield • • Jackie Oldham, University of Manchester Chris Verity, Addenbrooke's Hospital • Jonathan Weber , Imperial College School of Medicine • Til Wykes, Institute of Psychiatry Invest in ME Charity Nr 1114035 www.investinme.org Note: All members of the MRC CFS/ME Research Advisory Group acknowledge that inevitably in their professional or personal life they may have indirect connections with individuals who may have undertaken research in this area, or who either themselves or a family member may have or have had CFS/ME. The Group agreed there to be no conflict of interest in such cases. Observers / Secretariat • Susan Lonsdale, Department of Health • 23 Chris Watkins, Medical Research Council • Elizabeth Mitchell, Medical Research Council The Terms of Reference for the MRC CFS/ME Research Advisory Group • To consider the Report of the CMO’s Independent Working Group on CFS/ME, including its recommendations for research, • To consider other recent reviews of current knowledge and understanding of CFS/ME, • To take account of patient and lay perspectives, • To recommend to MRC a research strategy to advance understanding of the aetiology, epidemiology and biology of CFS/ME and, • In the light of current knowledge suggest what areas of further research are needed with regard to possible prevention, management (including diagnosis) and treatment. The MRC CFS/ME Research Advisory Group agreed not to revisit the areas considered by the CMO’s Independent Working Group, but to recommend how research might be undertaken that would improve understanding and treatment of CFS/ME. It was agreed that it was beyond the remit of the Research Advisory Group to decide how the recommendations for a research strategy should be implemented, since this would be the responsibility of funders and sponsors. (continued on page 24)

Journal of IiME Volume 1 Issue 1 MRC Strategy for Research on CFS/ME (continued) Annex 2 - Current MRC support for CFS/ME research 04/05 Expenditure Peter Denton White, G0200434 The PACE trial; A RCT of Cognitive Behavioural Therapy, graded exercise, adaptive pacing and usual medical care for chronic fatigue syndrome, Queen Mary and Westfield College, St Barts Hospital (Trials Grant) Alison Joan Wearden, G0200212 Randomised controlled trial of nurse led self-help treatment for primary care patients with chronic fatigue syndrome, University of Manchester, (Trials Grant) Richard K Morriss, G0100809 Exploratory RCT of training General Practitioners to manage patients with persistent Medically Unexplained Symptoms (MUS), University of Liverpool, (Trials Grant) Kamaldeep Bhui, G0500978 Chronic Fatigue & Ethnicity, Queen Mary and Westfield College, St Barts, London (Research Grant, New Application) Francis Creed, G0500272 The feasibility of a population based study of CFS, IBS and CWP, University of Manchester (Research Grant, New Application) Total expenditure figures Related grant Michael Sharpe, G0300876 A complex intervention for patients with medically unexplained symptoms in neurology clinics: Trial platform Total, including Sharpe ME Story The psychiatrist visited Sophia for 20 minutes one morning. The psychiatrist gave her no physical examination, which I found strange, given that her blood pressure was 80/60 and was unable to understand that Sophia’s “clock” was constantly on the move and that mostly her day-time was in our night-time. The psychiatrist did not seem to understand any of her myriad symptoms and the following day gave a lecture on M.E. to a large number of doctors; never having asked Sophia for her consent. The psychiatrist wanted me to be present, though I had reservations, and gave everyone there a handout about Sophia and our family, (which I only received later as part of the pack of Sophia’s notes). It read like a novel with some horrendous so called “facts” that I did not recognise as a true representation. I was also shocked at the misrepresentation of Sophia’s symptoms to the doctors and started to object, at which point I was ushered out of the room. (from The Story of Sophia and M.E. – http://www.investinme.org/Article-050%20Sophia%20Mirza%2001.htm) Invest in ME Charity Nr 1114035 www.investinme.org £617,354 £870,679 £559,377 £57,977 £751,923 £118,756 Intervention study Intervention study Epidemiology £159,809 £187,488 Intervention study £244,791 05/06 Expenditure £459,208 24 £154,777 £83,925 - - Epidemiology - £21,302 Journal of IiME Volume 1 Issue 1 FINE Trials - Set Up & Objectives ‘..complementary trials into The UK FINE Trials – A view from a Participant Reasons: These trials are funded by the Medical Research Council (MRC) alongside another set of trials called PACE trials. Both are described by the MRC[1] as various treatments options for CFS/ME which aim to improve quality of life for those who are ill.' ‘FINE (Fatigue Intervention by Nurses Evaluation) will test two different treatments that are particularly suited to those who are too ill to attend a specialist clinic.' 'The FINE trial will involve patients in the North West of England and North Wales.' The recruitment of patients for both trials was started in 2004 and, according to the MRC, were expected to take up to five years to complete. The FINE trials are headed by Dr. A. Wearden from Manchester University whose rehabilitative therapy. FINE treatments would be delivered in patients’ own homes (‘so the trial Inclusion Criteria The MRC claims that the trials will use the most inclusive criteria for CFS/ME to determine eligibility to take part (the Oxford criteria) in order for the results to be generalised to the largest number of people possible. FINE TRIAL COSTS The FINE trials cost £1,147,000. background is 1 Data they collected about me was misleading. Only questionnaires were used in the 2 sessions I had with the researchers and the questions were leading and did not reflect my true feelings. Also the researchers spent 2-3 hours with me each time which was so exhausting that I think I didn't really know what my replies were. is particularly suited to those who are too ill to attend specialist clinics.’ – according to the MRC) 2 The trial totally disregards ME/CFS as an illness. It is based on a theory that our symptoms are due to deconditioning and maladapted beliefs about exercise. I was initially suspicious of this but agreed to it because it provided me with a lifeline (was great for me to believe I could get better through exercise) and also because in the initial session the nurse gave me a presentation which lasted over three hours. I was so exhausted. The disregard of the illness was reflected on a practical level. For example, they said that if I recover from exercise in ten minutes then I am working at the right level. I abided by this rule and later crashed due to delayed and accumulated effects (which are widely accepted features of this illness). How this is ethical I do not know! 3 The program was hypocritical. They had strict rules for me to live by regarding pacing (yet gave me very little practical advice on this). Yet they felt it was okay to do 3 hour long sessions with me! It felt unworkable. 4 I crashed after the last session with them, so although my report was not glowing, it is highly misrepresentative of the actual outcome (probably my most important point)!! I am now worse than I have been in the duration of this condition. FINE Trials - EXPERIENCE by Alice I have been phoning the trial office but no answer yet! I want to withdraw (from the FINE trials) for a whole load of reasons. I will try to explain some of them here but may not make much sense due to brain-fogginess so please excuse that. Invest in ME Charity Nr 1114035 5 The therapist who provided the intervention had very selective hearing and she would adapt whatever I said to fit into what she wanted to hear (I have examples of these but won't bore you). 6 The therapist was critical of me and unsupportive. She was defensive when questioned things. I (continued on page 26) www.investinme.org 25

Journal of IiME Volume 1 Issue 1 (continued on page 25) 7. ME Story I believe the consent process was unethical. I was not aware what I was letting myself in for. (they did not explain the details of the intervention until after I had consented). In addition, the deconditioning theory was presented as fact and there was no mention of a balanced viewpoint (I have since read research that goes against this deconditioning theory). 8. Another example of my data not being represented properly: I suspended from University a couple of weeks before the start of the program and had started to improve from the rest. I continued to improve for a little while into the program. I made sure I highlighted that the cause of this improvement could be the effects of the program, or the rest I was getting. They were not interested in this - the fact that there was basically another aspect of my life that could be causing changes in my condition. I was unhappy during the study but wanted to continue because I thought (stupidly) that in some small way I was helping the fight against ME. It is in realising that my data will probably be used in some way to support this program - that I feel made me so much worse - that makes me want to withdraw. Blimey, I have written all this and still don't feel like I've painted the picture. The doctor put me forward for this trial because this was all he knew of to do. I so wish I had done my research first. I will be so much more cautious in the future. It frightens me to think that this research will be used to support clinics offering this in the future. Anyway, I hope that is of help to someone. I can provide more information if anyone is interested. Thanks for your replies and I hope this is a good day for you. Alice x ME Story Despite strenuous efforts on my part ME Story Even if it had been the right treatment, by that time it was too late: so many years of neglect, disbelief, wrong medication, wrong diagnoses; so many times referred to psychiatrists, who to a man sent her away because they couldn’t find anything wrong – with a prescription for an anti-depressant just in case....... - Richard to keep well and fulfil my duties to the best of my capabilities, I suffered a complete collapse in September, 2003 and was almost bed-bound for many months. I have been unable to work full-time since then and even very small, parttime jobs cause the flu-symptoms, severe headaches, blackouts, loss of balance, nausea, weak limbs, IBS, brain-fog and exhaustion to start up again. I'm one of the lucky ones…. - Daphne Invest in ME Charity Nr 1114035 www.investinme.org How do I deal with family that say things like "stop researching that...don't you think your just wallowing in it just the more?" How do you stop looking for answers? When is it time to give up? Why don't people that have known you all their lives...know you and what your suffering is REAL?? Why do doctors still say this doesn't exist and yet look at many of us ...completely destroyed by this disease....... - Cynthia 26 ME Story When I try to get medical care, the strain of trying to convince someone I am ill and the hurtful things they say to me practically make me crack up. Just the physical demands of leaving the house, even in the wheelchair, are enough to make me sicker for weeks. I can't describe how ill it makes me feel - Shannon Journal of IiME Volume 1 Issue 1 Jane Colby Invest in ME are happy to work with other groups and charities for the benefit of people with ME and to make progress regarding the urgent issues which need to be tackled. Our recent campaign to have ME recognised as a notifiable illness in schools was initiated from the work performed by Jane Colby. Jane is a former head teacher who has ME and who formed Tymes Trust. It is now ten years since Jane and Betty Dowsett published their work. Here Jane recalls a historic day for children with ME and describes the day that the term ME Plague was coined. Invest in ME book 2007 - “Schools swept by ME Plague” On 12th May, ME Awareness Day 2006, I was honoured to speak on ‘Children with ME’ at the Invest in ME Conference. I called for ME to be made notifiable due to its encephalitic symptoms and I am delighted that Invest in ME have since been campaigning for this. I was then invited to write a Review for the Journal of Clinical Pathology; called Special Problems of children with ME/CFS and the enteroviral link, it can be read online at www.cfids-cab.org/rc/Colby.pdf and in the printed Journal. On ME Awareness Day 2007 I am in a very different venue - Brentwood Cathedral - for our Remember the Children concert. But 10 years ago it was the 22nd May that caused a storm, when the headline above was splashed across The Guardian front page. I had no idea how big my joint research with Dr Betty Dowsett, a legend in her own lifetime, would become. I’d pre-recorded interviews for the morning television news and was booked for radio news shows, but as the phone rang constantly while I tried to get ready, and I had to use my fax to make outgoing calls, I began to get the message. Dr Dowsett went to ground like Badger in Wind in the Willows! Arriving at the studios at 7.45am I was asked: “Have you seen The Guardian?” I hadn’t. Then I was asked to fit The Today Programme in between the others. Guest Simon Wessely was saying: “I’m sure Jane would agree…” I didn’t, and I’m afraid I ignored his question. There was too much else to discuss. Mainly the fact that ME had just been revealed as the key reason for children and young people missing school long-term due to illness. ME was causing over half of all long-term sickness absence, almost twice that of cancer and leukaemia combined (51% against 23%). Getting the figures had taken five years. We studied a school roll of a third of a million children and over 27,000 staff. Not easy to ignore, although the British Medical Journal discouraged the profession from giving it credence. Six months later, however, published a 450 word letter from Dr Dowsett and myself, choosing the headline: ‘Journal was wrong to criticise study in schoolchildren’. At this distance in time it is easy to forget that it was a school epidemic that sparked off our study. What was the pattern in other schools, we wondered? Almost 40% of cases we uncovered were in clusters of 39 and 21% were in pairs. The clusters involved staff and pupils. We found a prevalence of 70:100,000 in pupils and 500:100,000 in staff. Associated with the clusters were other long term absences caused by viral illness, not yet diagnosed but often described as gastro-intestinal or flu-like. (Enteroviruses, the suspected culprits in many cases of ME, produce both these symptom profiles.) We concluded that the early investigation of infective agents associated with such a serious illness in schools should be instigated, and we recommended this. To our knowledge, nothing has been done. I feel another campaign coming on… You can read all the results of the survey as described by Dr Dowsett at www.tymestrust.org/pdfs/dowsettcolby.pdf 27 it Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 PROFILES of PRESENTERS at the IiME INTERNATIONAL ME/CFS CONFERENCE Norman Lamb MP Member of Parliament for North Norfolk, Liberal Democrat Shadow Health Secretary Norman Lamb entered Parliament at his second attempt in 2001, gaining this seat from the Conservatives. Norman Lamb read law at the University of Leicester. He worked for Norwich City Council as a senior assistant solicitor before joining Norfolk solicitors Steele and Co., where he became a partner and head of the firm's specialist Employment Unit. He worked for a year as a Parliamentary Assistant for Greville Janner, QC, MP. He was a member of Norwich City Council 1987-91, leading the Liberal Democrats for the last two years of his term. He has built a strong reputation in Norfolk as a campaigner for improved health services. He has been a critic of cuts in bed numbers and has highlighted the resulting unacceptable level of cancelled operations. As an MP his work on local issues includes adjournment debates on: orthopaedic waiting times in Norfolk; the lack of school transport services in North Norfolk; police funding in Norfolk; funding for Further Education Colleges; the provision of care for people with dementia; and coastal erosion. Norman has been Lib Dem Deputy Spokesperson for International Development (2001-02), a Treasury spokesman (2002-03), PPS (Parliamentary Private Secretary) to Charles Kennedy (2003-05) and Shadow Trade and Industry Secretary (2005-06). He was a principal author of the party’s policy on Royal Mail. From March to December 2006, Norman was Chief of Staff for party leader Sir Menzies Campbell. In December 2006 he was appointed Liberal Democrat Shadow Health Secretary. He has a particular interest in Africa: he has led Adjournment Debates on the HIV/AIDS crisis facing Africa and Asia, the controversial sale of military air traffic control system in Tanzania and the situation in the Great Lakes region of Africa. Dr. Derek Pheby - Project Coordinator, National ME Observatory, and Senior Fellow, University of Hull Dr Derek Pheby is an epidemiologist, and was Director of the Unit of Applied Epidemiology at the University of the West of England, Bristol. He has a long-term interest in ME, and was a member both of the National Task Force on ME and of the Key Group of the Chief Medical Officer's Working Group on CFS/ME. His unit had an active programme of research into chronic fatigue syndrome and ME. Dr Pheby is a member of the Editorial Board of the International Journal of Chronic Fatigue Syndrome. 28 Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Jonathan Kerr Jonathan Kerr was born in Belfast in 1963, qualified in medicine from Queen’s University of Belfast (1987), and completed training as a medical microbiologist (1995). He has worked as a microbiologist in Belfast, Manchester and London, taking up post as a Consultant Senior Lecturer in Microbiology at Royal Brompton Hospital / Imperial College in June 2001, and then Sir Joseph Hotung Clinical Senior Lecturer in Inflammation at St George’s University of London in 2005. His interest in Chronic Fatigue Syndrome (CFS) began during a study of the consequences of parvovirus B19 infection, when he showed that a percentage of infected cases developed CFS which persisted for several years. He is now the principal investigator in a programme of research in CFS. This involves development of a diagnostic test using mass spectrometry, analysis of human and viral gene expression in the white blood cells, and clinical trials of immunomodulatory drugs. Dr. Jonathan Kerr and colleagues at St. George’s University of London reported in the July 27, 2005 issue of the Journal of Clinical Pathology that a preliminary study of 25 CFS patients and 25 matched healthy controls revealed abnormalities in 35 of 9,522 genes analyzed using microarray technology. Polymerase chain reaction studies showed the same results for 16 of these genes. The study, and its results, raises some important questions. The first of which pertains to the need for funding of microbiological CFS research. He is funded (>£1million) by the CFS Research Foundation (www.cfsrf.com), a charitable organization based in the U.K., and leads a group of 5 scientists at St George's. The Foundation needs private support to continue their research efforts. They also openly post the results of their efforts on their website http://www.cfsrf.com. Dr. Ian Gibson MP for Norwich North Dr. Ian Gibson has been the MP for Norwich North since his election in 1997. He is originally from Scotland and was born in Dumfries on the 26th September 1938. He went to school at Dumfries Academy and acquired a passion for all things scientific- especially biology. He pursued his passion for science by going on to study at Edinburgh University where he gained a BSC and later on a PhD in genetics. He served as the Dean of the School of Biological Sciences at UEA from 1991 to 1997 and headed a research team investigating various forms of cancer, including leukaemia, breast and prostate cancer. In 2003, the university made Fr. Gibson an Honorary Professor. Dr. Gibson first stood for Parliament in 1992. Although losing that election by just 266 votes he tried again in 1997 and won the Norwich North seat by 9470 votes. He has been re-elected twice since 1997- in 2001 and most recently in May 2005. His work in Parliament and in Norwich has primarily consisted of advocacy work and pushing the government to take more notice of the role that science plays (and can play) in the UK. His scientific background has meant that he has been involved in numbers of groups and charities in Parliament. Invest in ME Charity Nr 1114035 www.investinme.org 29

Journal of IiME Volume 1 Issue 1 Professor Hooper Professor Hooper graduated from University of London and had held appointments at Sunderland Technical College, Sunderland Polytechnic and the University of Sunderland, where he was made Emeritus Professor of Medicinal Chemistry in 1993. He has served at many UK universities as well as in India and Tanzania. He has inaugurated links with Indian research institutions and universities and celebrated 25 years of productive and on-going links which have, particularly, 30 involved the design and development of new drugs for tropical diseases and an exploration of natural products associated with Ayurvedic medicine. He has published some 50 papers in peer-reviewed journals in the field of medicinal chemistry together with major reviews on the Chemotherapy of Leprosy, the Chemistry of Isatogens. Edited one book on the Chemotherapy of Tropical Diseases. He acted as a referee for a number of important journals and served on one editorial board. He has served on committees of the Council for National Academic Awards (CNAA), the World Health Organisation (WHO) and the Science and Engineering Research Council (SERC). Professor Hooper is a member of a number of learned bodies, including the Royal Chemical Society, the British Pharmacological Society and the Society for Drug Research (SDR), now renamed the Society for Medicines Research, where he has served on the committee for 12 years and served as Chairman for 2 years. This involved the planning and organising of major national and international conferences. He was appointed Chief Scientific Advisor to the Gulf Veterans Association (GVA) and accepted by the Ministry of Defence (MoD) as their nominee on the Independent Panel established to consider the possible interactions between Vaccines and NAPS tablets. He has also served on the Gulf Support Group convened at the Royal British Legion. His involvement with the GVA brought contact with Chronic Fatigue Syndrome/Myalegic Encephalomyelitis (CFS/M.E.) and related disorders. Gulf War Illness/Syndrome (GWI/S) has much in common with M.E./CFS. He is Patron of the Sunderland and South Shields M.E. Association and a member of the Newcastle Research Group, which includes eminent physicians and scientists performing research in to CFS/M.E., where one recent aspect has been the identification of organochlorine pesticide poisoning being misdiagnosed as M.E./CFS. He has addressed meetings of the Pesticide Exchange Network and consulted to the OrganoPhosphate Information Network (OPIN). He worked with the Autism Research Unit (ARU) at the University of Sunderland for over 20 years, leading to involvement in biochemical studies to offer help, support and treatment for people with autism. This has also lead to research and urine-analysis of Indolyl-Acroyl-Glycine (IAG), which is an unusual metabolite found in excess of 90% of people examined in different groups of GWV, M.E./CFS and Organo-Phosphate (OP) poisoning sufferers. He served on the General Synod of the Church of England from 1970 to 1980 and he is a Christian Lay Leader, Preacher and Teacher. He is currently involved in three environmental campaigns: • Toxic waste dumping, including campaign against sewage in the sea presenting to the Select Committee on Sewage Treatment and Disposal • GWI/S, presenting to the Defence Select Committee • M.E./CFS and OP/Pesticide poisoning Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Abhijit Chaudhuri Dr. Chaudhuri was appointed as a Senior Lecturer and Consultant Neurologist in July 2000. Research on fatigue in common neurological disorders is the main theme of Dr. Chaudhuri's work. He takes special interest in myalgic encephalomyelitis (ME). His other areas of interest are multiple sclerosis, neuroimmunity, neurological infections and adult neurometabolic diseases. Dr. Chaudhuri was responsible for examining spinal tissue from Sophia Mirza prior to the inquest into Sophia's death. Professor Kenny De Meirleir Dr. De Meirleir is a world renowned researcher and is professor of Physiology and Internal Medicine at Free University of Brussels in Belgium. He is co-editor of Chronic Fatigue Syndrome: A Biological Approach, co-editor of the Journal of Chronic Fatigue Syndrome, and reviewer for more than 10 other medical journals. Dr. De Meirleir was one of four international experts on the panel that developed the Canadian Consensus Document for ME/CFS. He assesses/treats 3,000 to 4,000 ME/CFS patients annually. Professor Kenny L. De Meirleir, MD received his medical degree at Vrije Universiteit Brussel, Magna cum laude. His research activities in Chronic Fatigue date back to 1990. His other research activities in exercise physiology, metabolism and endocrinology have led to the Solvay Prize and the NATO research award. He is director of the Human Performance Laboratory and Fatigue Clinic at the Vrije Universiteit Brussel, as well as consultant in the Division of Cardiology and director of the cardiac rehabilitation program at Vrijie Universiteit Brussel. [4/10/01] Dr. Daniel Peterson Dr Peterson is an affiliate of the Sierra Internal Medicine Associates in Incline Village, Nevada; ME/CFS researcher and clinician; a board member of the American Association for Chronic Fatigue Syndrome; and member of the International Chronic Fatigue Syndrome Study Group. Dr. Daniel Peterson was one of the two physicians who identified the original outbreak of CFS in Incline Village, Nevada, in 1984. 31 Dr. Vance Spence Dr. Spence is a graduate of the Universities of London and Dundee. He was a Principal Clinical Scientist responsible for vascular services and research and, in 1997, he rejoined the University of Dundee Medical School as Honorary Senior Research Fellow in the Department of Medicine, with the objective of stimulating research into the causes of ME. Dr. Spence was instrumental in the founding and launching of ME Research UK. Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 Mrs. Annette Whittemore Reno resident Annette Whittemore is President and Co-founder of the foundation. She became active in starting the foundation because she is the parent of a young adult who was severely affected by CFS and HHV-6 for the last 15 years. She and her husband are business owners and philanthropists in Reno and Sparks. She started the foundation with Kristin Loomis from California after a brief meeting in Incline, NV. with Dr. Daniel Peterson, a leading clinical researcher in CFS and HHV-6. "We wanted the ability to stimulate communication and research into the cause and effects of this illness. We've both felt the frustration of seeing too many doctors who could not help," she said. "Unfortunately for the sufferers of this disease, there have been very few doctors who have been able to understand the severe disability that HHV-6 and CFS can cause. By bringing world class researchers together we hope to unravel the path of this disease and develop new therapeutics while searching for a cure." Annette's husband Harvey is a prominent attorney and developer who is currently developing Coyote Springs a 43,000-acre master planned golf community in southern Nevada. Harvey and Annette are both supporters of the University of Nevada's academics and athletics, with a particular interest in the future Knowledge Centre on the Reno campus. The couple is also actively involved philanthropically with several churches and community organizations. 32 Dr. Byron Hyde Dr. Byron Hyde attended the Haileybury School of Mines and worked as a geophysicist. He then did premedicine in the Faculty of Medicine and University College, University of Toronto, obtaining a degree in chemistry and nutrition. He graduated in medicine from the University of Ottawa where he was the Director and Chief of the International Exchange Program for the Canadian Association of Medical Students and Interns (CAMSI). Dr. Hyde founded the International Summer School in Tropical Medicine. He interned at Hotel Dieu in Montreal, was a resident at St. Justine Hospital in Montreal and at the Ottawa Civic Hospital. He also studied in Munich at the University Kinderklinik and in Paris at the Necker Hospital for Children. He was a research chemist at the Roscoe B. Jackson Laboratory at Bar Harbour, Maine, a leading world laboratory in immunological research. Following this, he was Chief Technician in charge of the Electron Microscope Laboratory in Toronto at the Hospital for Sick Children, followed by a similar post at the University of British Columbia. Dr. Hyde has authored a book on Electron Microscopy and two non-medical books. Dr. Hyde has been a physician for 25 years and has performed charitable work as a physician in Laos and the Caribbean. He held the position of Chairman of the Ottawa Community Health Services Association, and is presently Chairman of The Nightingale Research Foundation. In 1984, Dr. Hyde began the full-time study of the disease process then known as Myalgic Encephalomyelitis (renamed in 1986 by Dr. Gary Holmes in the USA to Chronic Fatigue Syndrome). He has worked exclusively with M.E./CFS patients since 1985. In 1988, Dr. Hyde organized an association and founded The Nightingale Research Foundation, dedicated to the study of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. He has also acted as Chairman of the 1990 Cambridge Easter Symposium and of the Workshop on Canadian Research Directions for Myalgic Encephalomyelitis / Chronic fatigue Syndrome in May, 1991, at the University of British Columbia. (The above was extracted from the Nightingale Foundation website) Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 Dr. Sarah Myhill Dr. Myhill is a general practitioner with a particular interest in chronic fatigue syndrome. She qualified from Middlesex Hospital Medical School with honours in 1981 and has worked in the NHS and in private practice. Dr. Myhill is an active figure in the British Society of Allergy, Environmental and Nutritional Medicine, and its Secretary and has been medical advisor to Action for ME. Dr Myhill is interested in diagnosis in the correct sense, finding the cause of illness, not simply in treating the symptoms. She has a special 33 interest in treating chronic fatigue syndrome (CFS) and have consulted over 100 farmers with CFS following organophosphate poisoning and 100 women with CFS following silicone poisoning either from breast implants or injection. Over the past twenty years Dr. Myhill estimates to have seen over 1,500 cases of chronic fatigue syndrome largely caused by viral infection. During the early years she reported these cases individually to the Medical Devices Agency. Ellen Piro President Norwegian ME Association Ellen Piro is the president of the Norwegian M.E. Association. In 1995 she circulated a worldwide petition to get the CFS name changed and she personally brought it to the Dublin CFS conference to urge the scientists to make a change. Recently Ellen has been involved in the investigation into the use of meningitis vaccines in Norw New Zealand and which has ben connected with the cases of over 250 ME patients. She has also contributed to the debate on the Norwegian equivalent of the NICE guidelines. Dr. Nigel Speight Consultant Paediatrician at Durham University Hospital Working as a consultant paediatrician at The University Hospital of North Durham, County Durham, Dr Speight is the best ME children's consultant in the UK. ay and Professor Martin Pall Professor of Biochemistry and Basic Medical Sciences, Washington State University USA Professor Pall has long-term interests in biological regulatory mechanisms. His current research is focussed on a theory he has developed on the cause (etiology) of chronic fatigue syndrome and the overlapping and related conditions of multiple chemical sensitivity, fibromyalgia, and posttraumatic stress disorder. According to this theory, each of these is initiated by stresses that induce increased levels of nitric oxide and its oxidant product peroxynitrite, followed by a biochemical vicious cycle mechanism associated with chronic elevation of these two compounds. Symptoms of these conditions are produced by both nitric oxide and peroxynitrite and treatment should focus on downregulating this vicious cycle mechanism. Vitamin B-12 injections commonly used to treat these conditions are proposed to act through the action of one form of B-12 (hydroxocobalamin) which is a potent nitric oxide scavenger. Dozens of biochemical and physiological observations provide support for this theory. The most puzzling features of these conditions are explained by this novel theory. Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 ME News from Around Europe Invest in ME believe that the seriousness and the scale of myalgic encephalomyelitis requires an international focus and this requires scientists, researchers, healthcare professionals and ME Support groups in all countries to work together. Collaboration may be the key to success and this means taking a consistent approach to research, diagnosis and treatment. The following updates from around Europe and USA were some of those Invest in ME received for the conference from people working in the ME community in other countries and illustrate the current status and problems in these countries. Norway – A Breakthrough? Recent news from Norway gives hope that changes are afoot in the way myalgic encephalomyelitis is being perceived and treated. After much campaigning the results of the Norwegian ME-forening (the Norwegian ME Association - the main support group for people with ME in Norway) is bearing rewards. On Thursday 29th March Stortinget (Norwegian Parliament) completed a 1 hour and 10 min debate about ME and what should be done about the situation. This has led to the Norwegian Minister for Health and Care Services announcing publicly a long list of proposals which she stated will be put into action to ensure that ME-patients get proper care. The minister, Sylvia Brustad, has now engaged herself personally in the case of ME. The health minister is on record as stating that more knowledge, support, research and funding is required to provide an adequate approach to this illness which is estimated to affect 10,000 Norwegians. "This is an illness which is difficult to diagnose and treat, and it is an illness to which health services have, up till now, given too little attention. This the government will change, and we will follow this up in the budget process" said minister Brustad. Severe ME - A story from Norway The story of the Krisner family from Norway was shown on the Invest in ME Conference DVD from 2006 – a story of one family where three siblings severely affected by ME. The mother, Kjersti, is a brave, resourceful and inspirational woman who manages still to see positives from the terrible situation. For those who have not seen the Norwegian TV channel Puls’ film please go to – http://www.investinme.org/Mediatelevision3.htm We called Kjersti to ask her how things were a year on. Her children are still very ill. Katrine, 28 years old in May, has been ill since the age of 20. She is the worst affected. She cannot communicate at all and touching her even gently hurts. She is being tube fed and in nappies. There are moments of hope but they are very tiny and don’t last long – sometimes a smile or being able to hold her mother’s hand. Once her mother was able to give her a hug. Bjornar, 30, is still lying in total darkness but can talk a little bit in the afternoon. He is getting mentally stronger and wants so much to get out of his situation but the body is too weak. The family can’t see him because he cannot tolerate any light and his room has to be kept in total darkness. Frode, 20, can get out in an electric wheelchair and work on a computer a couple of hours a day. He has started an internet company and is stable as he knows his limits. The Krisner family now have help in the form of a community nurse who comes and helps in the daytime. Before, the family had to manage all the care themselves and that has meant that Kjersti hasn’t been able to sleep much for many years as the children are so severely affected and have all different sleep patterns. Kjersti is optimistic and despite everything they laugh a lot in the family and she is constantly helping others in a similar situation. She is collating information on people with M.E. in Norway who are bedbound and who are tube fed. She says it is easier to do that in a small country and it gives vital information for the politicians. Kjersti feels patients themselves, and carers, are the experts in this illness and should be listened to. She wished us well with the conference and would have liked to attend but obviously she can't - but said she believes one day her turn will come. Such a strong and inspiring family despite everything. Invest in ME Charity Nr 1114035 www.investinme.org 34 Journal of IiME Volume 1 Issue 1 Denmark The situation for ME/CFS patients in Denmark deplorable. Although the disease it is is officially accepted as a physical one, the health care community and the media treat like a psychological one. There are no governmentappointed specialists and there are very few doctors who believe the disease is real. Of these very few, we know for sure that two have been told by their hospital supervisors that they may no longer treat “that type of patient.” Given this environment, very few doctors dare to give the G93.3 diagnosis. Some patients have been forced to accept a F48 diagnosis in spite of the fact that no psychological illness was found just to get a much-needed pension. Needless to say, there are no hospitals or clinics that treat or monitor the disease. Only one study has ever been done about ME/CFS in Denmark: "Illness and disability in Danish CFS patients at diagnosis and 5-year follow-up" by Andersen, Permin and Albrecht. The 9-year follow-up paper is soon to be published. It because it shows that is an important study, “recovery and substantial improvement are uncommon” – around 6% - and that “good mental health does not predict improvement.” So although the patient’s mood improved over time as they learned to cope with their illness, their physical symptoms worsened. This should give the pushers of CBT-as-cure something to think about! Overall, ME/CFS patients in Denmark are horribly neglected and many have given up hope of ever being taken seriously by the Danish health care system. The hope of the Danish ME/CFS Association is that we can soon bring about change like that which has recently been seen in Norway - Rebecca Hansen Consultant Association /Danish ME/CFS Spain Dear friends and colleagues far and near, Yesterday, the Catalan Parliament accepted the Popular Legislative Initiative on Chronic Fatigue Popular Legislative Initiative on Chronic Fatigue Syndrome/ME and Fibromialgia (FM), presented by representatives from 80% of the people with CFS/ME or FM who are Catalonia. This acceptance is the first step towards a worldfirst: Invest in ME Charity Nr 1114035 in associations in a law that would ensure proper services for people with CFS/ME and FM and a fair treatment by medical inspectors. No one thought that a group of ill people like us, in a not so user-friendly country would be able to pull this off. So we are all very happy and it is a big boost for the CFS/ME and FM community here. Now that it has been accepted, the signature gathering can begin. We need 50,000 signatures and we have a team of 150 signature- collection coordinators ("fedetarios") ready to roll. Once the signatures are gathered, the law will be discussed in parliament and voted. This will probably take place in the fall. Up to now, it has been a lot of work for us sick folks: writing the law and the document to justify each article of the law (thank you to all of you who sent me the necessary bibliography!), working with all the associations to create unity and the much needed empowerment, meeting with all political groups and sub groups (we have the support of all the political parties, except, of course, the party that runs the Health Ministry), campaigning to recruit signature coordinators, meetings with unions, women's groups others. It has not been easy as we are presenting a proposed law that puts totally into question the government's plan to keep CFS/ME and FM solely in Primary Health Care (where most doctors do not believe these illnesses exist or do not want to work with them and are not allowed to do any relevant tests), while our law, amongst other things, demands CFS-FM units. So we have had (and continue) to deal with pressures, intimidations, etc, from government and government-related organizations. We are also having to deal with the two foundations (one run by the government party, the other run by businessmen) who, up to now, had managed to control and manipulate the CFS and FM associations in Catalonia and create division. Encouraging the associations to be independent and to create unity has been hard but the most rewarding work. The documents (the law, the justification document and other documents) are available in Catalan and some in Spanish. If anyone is receiving them, let us know. -Clara Valverde (Promoting Commission of the CFS/ME-FM Popular Legislative Initiative, Catalonia, Spain) www.investinme.org interested in 35

Journal of IiME Volume 1 Issue 1 ME News from Around Europe (continued) Wasn’t that a headline of “The Economist” some years ago? Referring to the economic situation the magazine certainly didn’t think of the situation of people with ME/CFS in Germany. Though there’s said to be a slight upswing now, “The Economist’s” description still applies to the health care provisions for people with ME/CFS. They are more or less non existent. Germany is – compared to the UK – indeed the sick man of Europe. From our point of view the establishment of 50 CNCCs and LMDTs for England alone is a great success. The public awareness seems to be much more advanced than over here. We admire your determination, resilience and efficiency by which you have achieved this. From our point of view all that is the result of years of tenacious work of hundreds of active people who did not allow themselves to be deterred by all the obstacles they met on their way to a better care for people with ME/CFS. In a way you are our great role model when it comes to the situation of people with ME/CFS – in spite of all shortcomings and tragic cases like that of Sophia Mirza and others who died or are treated badly. Here in Germany the situation is by far not as advanced. There isn’t a single clinic which is specialised in ME/CFS. People are more or less left on their own and depend on their GPs. Only a handful of physicians are interested in the subject and care for people with ME/CFS, among them unfortunately also some quacks and cutthroats. Those who do serious work keep themselves in the hiding because otherwise they would be swamped with desperate and extremely needy people, searching for help and support. However, the patients sometimes have GPs who are sympathetic and willing to support them though their knowledge of ME/CFS mostly is quite limited. The physicians themselves are in a fix because there is no structure like a CFS society for physicians, no advanced training or other provisions where they can get information. Open-minded GPs read the information which is distributed via the national charity Fatigatio or websites like www.cfs-aktuell.de or www.cfs-portal.de . Germany the sick man of Europe? Thus the majority of the 250.000 or 300.000 sufferers in Germany do not even have a diagnosis. Those who suspect having ME/CFS or whose GPs assume this might be the case don’t have a place where to go and confirm or exclude the diagnosis. There is no place where they can get a proper advice in medical, social or legal matters. Most people have difficulties to get incapacity benefits on the basis of having ME/CFS. Yet this is not a “recognised” diagnosis but things are gradually changing. The vast majority of sufferers still end up in a psychiatric ward or in the practice of a psychologist or psychiatrist – getting a psychological or psychiatric “diagnosis”. More often than not incapacity benefits are paid on grounds of such a diagnosis and people often accept it with resistance because they have no choice. The psychosomatic health care provisions in Germany are quite good and they serve as some kind of waste disposal for all diseases which the physicians are not familiar with or cannot diagnose. Small wonder, that almost all ME/CFS patients are given a psychiatric diagnosis, leaving them in an even more desperate situation. They are told they'd have a depression, a psychosomatic or somatoform disorder (meaning it only looks like a somatic disease but in reality is all in the mind), a minor and insignificant functional disease. In Germany ME/CFS is mostly considered to be a functional somatic syndrome, i.e. a more or less psychiatric disease. Only recently (in February 2007) some psychiatrists published an article in “The Lancet” titled “Management of functional somatic syndromes” (by Peter Henningsen, Herzog), Stephan in which completely ignored. There is one national charity for people with Me/CFS founded in 1993 with the name "Fatigatio e.V.". Of course, the few people who run the charity cannot come up with the demand. The charity does not have the necessary resources, neither financially nor personally. There are also some local self-help groups, however, with little influence on the overall situation. Yet, there are more and more physicians who say "Oh yes, I've heard about this," and who take matters seriously. (Continued on page 37) Invest in ME Charity Nr 1114035 www.investinme.org the biomedical Zipfel, Wolfgang research 36 is Journal of IiME Volume 1 Issue 1 ME in Germany – continued from page 36) After all, campaigns like SPARK in the USA and the good work that is done in Great Britain and all over the world has some trickle down effect. Looking to the UK and your achievements provides us hope and confidence that we will one day no longer be forced to living in the sticks. All in all you can see that we in Germany are lagging behind your developments at least 15 or 20 years! By Regina Clos Regina Clos has worked for some years for the national charity Fatigatio and is now running a German spoken website ( www.cfs-aktuell.de ) with up-to-date information on ME/CFS and many translations of articles and booklets published in Great Britain, Australia, the USA and Canada. She is a sufferer herself for more than 20 years and became a translator after she had to give up her job as a teacher for handicapped children. Sweden In Sweden, ME is largely unknown by doctors as well as the general public. To the extent it is discussed, it is under the name of “Kroniskt trötthetssyndrom”, which literally translates as “Chronic tiredness (not fatigue!) syndrome”. There are no ME specialists available for diagnostic evaluation or treatment management. The ME clinic at Huddinge Hospital in Stockholm was closed in 2000. Some patients have been diagnosed at the Gottfries Clinic in Gothenburg which specializes in Fibromyalgia and CFS, but getting a referral can be difficult or impossible depending on where in the country you live. This clinic is also under the threat of losing public funding and being forced to close down. There are a few individual doctors with some knowledge of ME, and some GPs who are willing to learn, but for the most part patients are left to GPs that range from ignorant to downright insulting. The view that all forms of chronic fatigue equal a somatoform syndrome is widespread, and reinforced through articles in the medical union’s member journal, “Läkartidningen”. We believe ME is tremendously under diagnosed in Sweden. The code G93.3 is virtually never used, and patients with this diagnosis code may have it changed by a new doctor without explanation. Most likely, sufferers are instead diagnosed with “burn-out syndrome” (or “exhaustion depression”), as this was a very common problem in Sweden particularly during Invest in ME Charity Nr 1114035 the 1990’s. The obvious problem with this misdiagnosis is that it leads to unreasonable expectations on recovery speed and capacity for physical activity. With time, when the patients don’t improve and claim to be unable to exercise, they are met with increasing disbelief from doctors and others. There is also a strong tendency in Sweden at the moment to question the “overuse” of sickness benefits and reduce the number of claimants by rejecting more claims. As in many other countries, special insurance doctors second-guess the patient’s own doctor, and some claim illnesses such as ME and Fibromyalgia don’t exist. This puts many patients in a desperate financial situation. Some fall between the chairs when they are considered too healthy for sickness benefits, but too sick to register as unemployed and claim unemployment benefits. The research being carried out has mostly focussed on the psychosomatic angle, and included larger groups of chronically tired patients who do not fulfil stricter ME criteria. However, Professor Gottfries and his colleagues in Gothenburg have conducted a very promising trial using a staphylococcus vaccine. 2/3 of patients experienced positive effects, especially on immune symptoms and recurring infections. Many were able to return to work or increase the number of hours worked, and generally increase their quality of life. Unfortunately, this research has now been stopped due to manufacturing problems with the vaccine, and patients doing well on the treatment for several years are being forced back to a life of illness as the supplies run out. The national patients’ organisation, RME, has approximately 370 members, and is working with very limited resources to improve the situation for sufferers and increase awareness. Some regional groups have been making limited progress, but it’s very much a process of one step forward and two steps back. Anna Fenander, RME Stockholm Facts About ME ME is now 5 times more prevalent in the UK than is HIV/AIDS. 37 www.investinme.org

Journal of IiME Volume 1 Issue 1 ME News from USA – Pat Fero – Wisconsin ME Group Investing in ME…from the other side of the pond By Pat Fero, MEPD I live In Wisconsin, which is the other side of the pond, and a few Great Lakes over to the Midwest, USA. It is only though information technology that I know about Myalgic Encephalomyelitis in 2007. When I first saw the words Encephalomyelitis, synthesize medical understanding of CFS issues. Myalgic I did not search with fervor to information into my growing Despite working as Executive Director of the WISCONSIN CFS ASSOCIATION and being on the Board serving in one capacity or another since 1987, it was 2003 or 2004 before I began to look at ME. Why is that? This is the landscape question, the backdrop for what follows, that is, my perceptions about ME and about CFS in the United States. Humans learn best when they have a need to know about a thing. When that happens they are ready to ask questions. Here in US, the need to know about ME exists with a few vocal advocates and people who have quietly investigated ME for the sake of “name change.” Within that group, controversy rages, but that is the only place CFS diagnosed patients give ME an iota of thought. Why is that? First, I believe that in the United States, with about 300 million people and a land area of over 9 million square kilometers, we do not have a CFS community. To foster community development that would create a shared understanding of CFS would mean organized education, awareness and advocacy. If we had a community, the vast numbers of diagnosed CFS patients would be far greater than a mere 20% of an estimated 800,000. By far, the majority of people ill have no diagnosis or are misdiagnosed. That being the case, MD’s and other medical professionals have little need to know about CFS and the few of us presenting in the doctors offices can easily be disregarded. In fact, sweeping CFS into a larger entity of fatigue and pain is the logical outcome. Investing in research centers to study pain mechanisms and fatiguing illnesses, denies the integrity of CFS. Integrity? Historically, ME has integrity as a distinct illness entity with diagnostic criteria until issues Invest in ME Charity Nr 1114035 muddled when the US became international researchers and MDs. involved with is a THIS generalization and an oversimplification. However, we can cite the mid 1950’s work of Melvin Ramsey and John Richardson. in CFS as a distinct illness entity with diagnostic criteria is impossible. I agree with Dr. Byron Hyde that once the Centers for Disease Control became involved in the Lake Tahoe epidemic, outbreak, incident and finally non entity, patients in the US suffering from ME, were left to wander about until the powers that be met in 1988 to label their illness chronic fatigue syndrome. In 1988, where I live, there was integrity in CFS. By this, I mean that my communications were with 100’s of people who had like illness experiences. 5 years and many 100’s of calls later, I knew that the “CFS” experience changed. Much later, I found that my perceptions were correct. The CFS pain and fatigue waste bin was huge as was my familiarity with lists of co morbid psychiatric conditions that heard of until the mid 90’s. In 2000, in WISCONSIN, our CFS organization decided that our mission of education and awareness was too narrow. What was the topic? How could we sort out this waste bin of misdiagnosis, over diagnosis and under diagnosis? What a mess. On a national level with a small group of people compared to the potential whole, we are a huge dysfunctional family. Bitter, personal tiny issues signals the loss of hope to stop the CFS nonentity spiral. I see ways to stop enabling and perpetuating chaos. In the US, community. first, we must work on developing CFS This means a massive information campaign in 52 states. Because our public health institutions are in the middle of the Chaos, the effort has to start grassroots from people like me and the wonderful people in Atlanta and Northern Virginia and Vermont and Chicago and…and. We cannot forget about the people in Wyoming or Montana or anywhere else where the population density is so low that we might think that sick people do not count. Secondly, I believe that existing US national, state organizations and regional groups must be inclusive to promote collaborative efforts that will stop sick people from reinventing the wheel. (continued on page 39) www.investinme.org I had never In contrast, looking for integrity 38 infighting over Journal of IiME Volume 1 Issue 1 (News from USA – continued from page 38) It is a waste time and energy. In addition, we have wonderful independent groups in the US totally devoted to ME. Those involved are sick, they are dedicated and they work. YES! A continuum of thought is as real as the color wheel. Do we say… pink is not a primary color…. OOPS…not allowed? What about sky blue pink? You know exactly what mind image you have of sky blue pink, that hue (s) is not on the color wheel at all. I don’t know how to promote collaborative efforts other than narrow the focus to the basis for all like human endeavors: people in need, people with fractured families, some on the streets need information and help. Many kind people here with CFS work on this every day. We just need a more organized effort and to find ways to help them help others. Thirdly, Chaos creates phantom enemies and it is easy enough for an institution and people to obstruct progress by perpetuating the same old stories. Are there real enemies? I think a combination of factors makes people behave badly and as a result; whole groups suffer with no understanding, let alone help. In addition, people interested in power and establishing an identity through CFS advocacy or CFS research perpetuate chaos because they tend to be exclusive. I mean and whatever My thought would be to ignore anyone who would obstruct by deceit, hostility and engaging in activities to merit a few, not the whole. I would seek out the 100’s of people working for the common good and forget the rest. really sick I am investing in ME by tackling problems in my own back yard. I have to work with what is and we have a long way to go before my ME will be recognized or diagnosed in the United States. I am Investing in ME. The founders, in the right place, at the right time, are bringing order from chaos. What a wonder it has been to watch from afar! HELLO from WISCONSIN and THANK YOU! 39 Story – A Carer of a Person with ME By Greg Crowhurst Caring for someone with severe ME - Five Stark Facts There is no support, there is no cure, there is no treatment, there is no government funded physical research and there is little truth in any of the official policy statements. The scale of the suffering is off the scale. The severely affected will experience not a moment’s relief, and carer are routinely pushed to the limits of human endurance. The severely affected are likely to be experiencing between intolerable symptoms all at once. This pain, paralysis, numbness, sickness, unbearable hypersensitivity and incredible physical disability. Fatigue is not the issue; it is only one symptom among many; Post Exertional Malaise is the major concern. Any exertion is likely to have a shocking after-effect, typically 24 to 48 hours afterwards, which can lead to days, weeks, years of worse symptoms or even death. Invest in ME Charity Nr 1114035 twenty and thirty includes Sufferer’s and carer’s are unwilling pawns in a political game. evidence of powerful There is overwhelming vested financial interests at work, across all levels of government, trying to suppress the physical reality of ME, which is far more prevalent than AIDS or MS. Currently, the main interventions on offer are psychiatric. often for decades on end. Sufferer ME Story My GP thought I had ME but kept saying, work through it, do lots of exercise you'll get over it. They sent me to a sports centre to do a fitness course but I went once and never again. It was about this time I saw the psych and he said there was nothing mentally wrong that feeling well again wouldn't fix - Jas www.investinme.org

Journal of IiME Volume 1 Issue 1 NICE - IiME Response to Draft Guidelines on ME The National Institute for Health and Clinical Excellence (NICE) have recently published their draft document for clinical guidelines. The document is being developed for use in the NHS in England and Wales regarding chronic fatigue syndrome / Myalgic Encephalomyelitis (CFS/ME). Although not an original stakeholder (IiME only became a charity in May 2006) we have nevertheless registered to become a stakeholder in these guidelines and have supplied our response directly to NICE. Our full response is available here – www.investinme.org/Documents/PDFdocuments/Invest%20in%20ME%20Response%20to%20NICE%20Draft%2 0Guidelines.pdf Summary of Response from IiME: The reaction to the NICE guidelines can be summed up as profound disappointment that NICE have chosen to highlight, yet again, Cognitive Behavioural Therapy (CBT) and Graded Exercise (GET) as the most effective forms of management (aka treatment) for ME. Psychiatric paradigms are referred to and recommended as therapies and as treatments for ME despite ME patients and groups stating they are ineffective or harmful. Graded Exercise Treatment (GET), already known to be potentially harmful to people with ME, is put forward as a therapy/treatment GET is put forward, along with Cognitive Behaviour Therapy (CBT), as treatments of first choice The NICE group formulating these guidelines show a disingenuous side by comparing the use of these treatments for ME with the use of these treatments for cancer and diabetes and other illnesses. Yet CBT is not offered as first line treatments for these illnesses which NICE are recommending here for CFS/ME. It is not for sensation that IiME would like to see a lawyer added to the NICE consultation group. The lawyer would be there to represent ME patients as one can foresee that there will be litigation against the people making recommendations for use of GET/CBT when a patient suffers, or dies, from putting into practice such guidelines. IiME believe these Draft Guidelines should state unequivocally that it is unacceptable for patients with ME to be subjected to “sectioning” by psychiatrists, supported by Social Services and the Police, simply because the person has ME. We dispute the frequent statements characterised by this text ‘There is little understanding of the nature of the disease ‘. There are over 4000 biomedical research papers on the illness which the NICE searches should have seen and analysed. The NICE guidelines do not carry a single reference to the relationship between vaccinations or epidemics. The document is inconsistent in a number of areas - especially terminology. The inclusion of as wide a possible base of chronic fatigue states in the draft guidelines is clearly evidenced and does a disservice to pwme Essential biomedical research which distinctly shows the biological nature of ME is ignored The lack of proper discussion of the Canadian guidelines shows not only a bias to outdated and flawed information but invalidates much of the data used to justify the proposals The layout and format of the document is poor. The objectives of the Nice Draft Guidelines are not met. The credibility of NICE is now severely compromised. Yet again ME patients seem to be on the receiving end of another counter-productive and biased analysis. The document shows little new thinking and is clearly lacking in impartial analysis of all areas of research into ME. Both the Chairman and CEO of NICE were invited to speak at the conference but both declined 40 Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 The Gibson Inquiry "This group believes that the MRC should be more open-minded in their evaluation of proposals for biomedical research into CFS/ME and that, in order to overcome the perception of bias in their decisions, they should assign at least an equivalent amount of funding (£11 million) to biomedical research as they have done to psychosocial research. It can no longer be left in a state of flux and these patients or potential patients should expect a resolution of the problems which only an intense research programme can help resolve. It is an illness whose time has certainly come.” Thus concluded the report from Dr Ian Gibson (MP)’s Group on Scientific Research in to Myalgic Encephalomyelitis (ME) – otherwise known as the Gibson Inquiry. Unfortunately, that time is too late for some of the victims who have lost their lives to this devastating illness. Invest in ME welcomed the broad message of this report when it was published in November 2006. The Inquiry called for ME to be given due recognition, alongside heart disease and cancer. It also called for ring-fenced money for bio-medical research as happened with AIDS. ME in fact affects five times as many people as does AIDS in the UK but can have a much more devastating impact on quality of life. The Inquiry recommended that research must be made a priority and suggested that £11 million should be made available for research to redress the balance in an illness where too much emphasis had been put on psychological “coping strategies”. The Inquiry accused the MRC of merely “paying lip-service” to the call for bio-medical research. Invest in ME felt that at last an official acknowledgment was given that ME is a severe, incapacitating, illness and that those who suffer from it, as well as their carers and families, may have their lives completely ruined. Invest in ME have been asking for a long time for very simple, common-sense things such as the adoption of comprehensive diagnostic criteria and epidemiological studies. We were delighted that the report agreed that this was vitally important. This report did not stint in its criticism of the Medical Research Council and NICE. NICE should rethink Indeed, it warns that very carefully one of its recommended treatments, Graded Exercise Therapy (GET), because of evidence that in 80% of M./E. sufferers there was diastolic cardiomyopathy. Invest in ME has warned NICE during our review of the Draft NICE Guidelines for ME that by recommending GET they would put patients lives at risk, and risk Judicial Invest in ME Charity Nr 1114035 Review. We still hope that NICE will take notice. Invest in ME also welcomed the call for an independent scientific committee to be established to oversee all aspects of research, as well as an inquiry into the vested interests of insurance companies whose advisors also act as advisors to the DWP. Dr Gibson’s Group recommended an investigation of these vested interests by a standards committee because, it stated, too often patients have to live with the double burden of fighting for both their health and their benefits. Invest in ME believe that we must use the positive aspects of the inquiry report and move forward and ensure that people are correctly diagnosed with this illness and that doctors and scientists treat patients knowing and accepting that they have a genuine and serious illness. Invest in ME have called on the government and MRC take this opportunity and work with the ME community and biomedical researchers to ensure that this illness can be understood, that proper biomedical research is funded and that archaic and unjust perceptions by government departments, sections of the health service and those responsible for deciding funding strategy are once and for all discarded. Dr. Gibson has created an opportunity to benefit patients and find a cure for this illness. Invest in ME ask the government to ensure that Full 41 this opportunity is not lost and that yet another generation of UK citizens is not abandoned. report available at - http://tinyurl.com/ynqhtc IiME’s reactions to the report are at - http://tinyurl.com/2aqnye ME Story We arrived at the doctors and the female doctor refused to see me, saying I was not her patient, and she wasn't prepared to see me. I was just in a state of shock and my partner was furious. The Doctor in question didn't come out to the waiting room to see me, instead wrote a prescription for three months of anti-depressants - Jan www.investinme.org

Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS by Margaret Williams (updated) April 2007 ME/CFS is a complex, whole body systemic disorder and it is difficult to compile a unified reference list of the documented biomedical abnormalities, immunological, neurological, endocrinological, gastro-intestinal, reference papers themselves overlap considerably. ocular, cardiovascular, respiratory etc). since so many medical disciplines are involved (eg. musculo-skeletal, The The biomedical reference papers now number over 4,000 and some of these reference papers are listed in 92 pages of references online at http://www.meactionuk.org.uk/SUBJECT_INDEX.htm. The few illustrations below provide indisputable evidence of organic disease, thereby demolishing the psychiatric lobby’s assertions that there is no such evidence. The reference papers can be broadly categorised into the following sections and it is necessary to be familiar with all sections. HISTORICAL PAPERS ON ME These date from 1957 -- 1980 and include excellent clinical descriptions, laboratory-determined abnormalities and post-mortem findings. GENERAL PAPERS ON ME/CFS These papers cover more than one aspect of ME/CFS and include for example evidence of impaired oxygen delivery to muscle; evidence of delayed recovery from fatiguing exercise and documented symptoms commonly found in ME/CFS (which number over 60). LABORATORY FINDINGS IN ME/CFS Although there is as yet no single, specific, definitive test for ME/CFS (which is also the case in numerous other medical conditions including multiple sclerosis), nevertheless there is an entirely consistent and reproducible pattern of laboratory-determined abnormalities which have been observed and documented worldwide. Such abnormalities particularly include dysfunction of immunological, cardiovascular, pulmonary and cognitive parameters. QUALITY OF LIFE IN ME/CFS One international ME/CFS expert writes that in his experience, ME/CFS “is one of the most disabling diseases that I care for, far exceeding HIV disease except for the terminal stages”. Australian research describes ME/CFS patients as suffering more dysfunction than multiple sclerosis sufferers; the sickness impact profile (SIP) is more extreme than in end-stage renal disease and heart disease, and only in terminally ill cancer patients has the overall SIP score been found to reach that found in ME/CFS. neurological, neuro-endocrinological, musculo-skeletal, 42 American research found that the quality of life in patients with ME/CFS is significantly, particularly and uniquely disrupted, and that the illness causes marked disruption and devastation. Scandinavian research has shown that patients with “non-visible” disability suffer more stigmatisation than those with visible disability. CHRONICITY AND SEVERITY OF ME/CFS This section provides evidence of the natural history of severe ME/CFS, showing that the prognosis is extremely poor for the severely ill subset, with no symptom improvement (only 4% recovered) and it shows symptom patterns in longduration ME/CFS. PRECIPITATING FACTORS IN ME/CFS The syndrome is known to be related to a dysfunctional stress response, and there is evidence that precipitating factors include physical trauma (specifically a breakdown in the blood-brain barrier) and critical life events. Other factors include infections; anaesthesia; immunisations and exposure to certain chemicals. (continued on page 43) Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) EPIDEMIOLOGY OF ME/CFS Various papers on the epidemiology of ME/CFS reveal that considerable misinformation exists regarding the appropriate evaluation of ME/CFS (including age, gender, occupation, geographical location, length and severity of illness) but that there is increasing understanding of the prevalence, incidence, risk factors, illness patterns and prognosis of this complex multi-system disorder, and emphasis is placed on the importance of subgroups. Although ME/CFS is one of the commonest chronic neurological conditions in the UK today, no official government-sponsored statistical evaluation has yet been made, possibly due to the heterogeneity of the disorder and the lack of a concise case definition. NEUROENDOCRINE ABNORMALITIES IN ME/CFS This section shows evidence for and implications of the endocrine disruption found in ME/CFS, especially that associated with hypothalamic-pituitary-adrenal axis dysfunction. CT scans of the adrenal glands have revealed that both the right and left adrenal glands of some ME/CFS patients are reduced in size by 50% when compared with healthy controls. NEUROLOGICAL ABNORMALITIES IN ME/CFS (including vertigo and seizures) These papers show commonly found dysfunction in both the central nervous system and in the autonomic nervous system; they include papers on dysequilibrium and vertigo which are known components of severe ME/CFS, and there is evidence that seizures may occur in ME/CFS. DEMYELINATION IN ME/CFS Evidence of demyelination and cerebral oedema has been documented in the ME /CFS literature since 1988. OCULAR PROBLEMS IN ME/CFS There is evidence that such problems include intermittent jelly-like nystagmus; difficulty in accommodation / focusing / visual acuities; photosensitivity; photophobia; blurred vision; double vision; crusted eyes; dry eyes; itchiness; narrowed arterioles; retinal defects; fibrillar changes in vitreous; chorioretinal macular abnormalities and optic pallor (the latter is also observed in MS). Objective findings of the anterior segment suggest an organic aetiology. LIVER / SPLEEN INVOLVEMENT IN ME/CFS Published evidence shows that enlargement of the spleen and liver is not unusual. Evidence shows infiltration of the splenic sinuses by atypical lymphoid cells, with reduction in white pulp, suggesting a chronic inflammatory process. HAIR LOSS IN ME/CFS Hair loss in ME/CFS is documented in the literature. One author states “It is a rare woman with CFS who has not had hair loss, usually diffuse and non-scarring”. Elsewhere, it is documented as occurring in 20% of patients. MOUTH ULCERS IN ME/CFS Mouth ulcers have been documented in the ME literature since 1955. VIROLOGY IN ME/CFS Evidence reveals the known tropism of Coxsackie B viruses for muscle, brain, heart and pancreas, all of which are documented as being target organs in ME. There is also evidence of human herpes virus 6 (HHV6) reactivation playing a role in the pathogenesis of both ME/CFS and MS. HHV6 Variant A is more common in AIDS and ME/CFS, whilst Variant B is found in MS. HHV6 used to be called human B-lymphotropic virus (HBLV); it was discovered in 1986. It is possible that reactivation of a composite viral load occurs as an epiphenomenon of an underlying immune system dysfunction, thus giving rise to the protean symptomatology. (continued on page 44) 43 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) OVERLAP OF ME/CFS WITH POST POLIO SYNDROME Prestigious papers, for example, Annals of the New York Academy of Sciences 1995 (containing 50 papers on clinical neurology, neuroscience, electrophysiology, brain imaging, histology, virology, immunology, epidemiology, with contributors from the US, Australia, Canada, France, Sweden and the UK) point out the similarities between post-polio syndrome and ME/CFS, notably that the mechanism of the extreme fatigue (called “visceral exhaustion”) -- is exactly the same in ME/CFS as in PPS. STRESS ENHANCES SUSCEPTIBILITY TO INFECTION There is substantial evidence that concurrent stress at the time of viral exposure leads to more severe disease. Stress is known to increase susceptibility to those diseases that are immune-related, eg. infectious disease, cancer and autoimmune disorders. PSYCHONEUROIMMUNOLOGY There is a vast literature (from 1884 to date) on the pathway of causation whereby stress, especially traumatic stress, affects the immune system and potentiates disease development. CHEMICAL INJURY TO THE BLOOD BRAIN BARRIER There is published evidence to show that one mechanism of causation is likely to be a combination of stress and chemicals, resulting in chemical trauma to the brain via a breaching of the blood brain barrier (BBB): stress can intensify the effects of some chemicals, making them very harmful to the brain, nervous system, and liver (resulting in congested blood vessels, reduction of an important enzyme and abnormal fatty deposits), leading to cellular death, especially when chemicals are combined. The ability of chemicals to leak from one area of the brain to another holds the potential for much greater damage to occur in the entire brain. IMMUNOLOGY IN ME/CFS The most commonly found immune abnormalities are very low natural killer (NK) cells, with decreased cytolytic activity, and an increased CD4 - CD8 ratio; there is an increase in the CD8+ cytotoxic T cells bearing antigenic markers of activation on their cell surface; there are higher frequencies of low levels of various autoantibodies, especially antinuclear and anti-smooth muscle antibodies; there are low levels of circulating immune complexes; there are increased levels of IgE and decreased levels of IgG3. Low levels of IgG3 have been reported since 1986 in patients with aching muscles. Overall, these abnormalities are consistent with evidence demonstrating chronic, low-grade immune activation in ME/CFS. In 1994, an international ME /CFS expert (Dr Paul Levine of the Viral Epidemiology Branch of the National Cancer Institute, Bethesda, Maryland) stated “ the spectrum of illnesses associated with a dysregulated immune system must now include CFS” (ref: Clin Inf Dis 1994:18 (Suppl 1):S57-S60). Importantly, it has been convincingly demonstrated that changes in different immune parameters correlate with particular aspects of disease symptomatology and severity. ALLERGIES and MULTIPLE CHEMICAL SENSITIVITY (MCS) IN ME/CFS The relationship between viral infections and onset of allergic disease is well-documented in the medical literature. With specific relationship to ME/CFS, there is overwhelming published evidence that allergies, food intolerance and multiple chemical sensitivities (MCS) are very common; an increasing sensitivity and adverse reaction to many drugs / therapeutic substances is widely believed to be virtually pathognomonic of ME/CFS. Cells cannot be attacked by the immune system unless they display on their surfaces complex glycoprotein molecules known as Class II MHC antigens; cells can be induced to do this by gamma-interferon, which is an anti-viral chemical produced by the immune system when under viral attack. Allergies in ME/CFS are thought to be the result of this mechanism, which makes the body cells susceptible to on-going attack by the immune system. Because reference to allergies is so widespread throughout the ME/CFS literature, many of these references are to be found throughout the reference papers, mostly in the sections on General ME /CFS, Immunology, and Neuroendocrinology. More and more patients are presenting with “total allergy syndrome”; this is recognised as part of ME/CFS; whilst some psychiatrists are notoriously dismissive about its existence, the literature (from highly reputable internationally acclaimed experts) clearly shows that it does exist, and that such patients do indeed develop abnormal immune parameters whilst under observation. (continued on page 45) Invest in ME Charity Nr 1114035 www.investinme.org 44 Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) A leading professor of clinical immunology in the UK has published papers confirming that these are patients with multiple sensitivities, and that their symptoms are not all in the mind. ANAESTHESIA PROBLEMS IN ME/CFS It is well-established that patients with ME/CFS and others with neuromuscular dysfunction can have problems with anaesthesia: depolarising muscle relaxants have a known risk of causing potassium release from muscle, which can lead to cardiac arrest, and it respiratory failure. VASCULAR PROBLEMS IN ME/CFS References to vascular problems in ME/CFS have been in the medical literature from 1938. Such problems include vasomotor instability; impaired blood flow in the micro-circulation consistent with inflammatory processes; vasculopathy including Raynaud’s disease; cutaneous vasculitis; vasculitis of the liver and cerebral hypoperfusion due to vasculitis. CARDIAC PROBLEMS IN ME/CFS Documented problems include myocarditis; chronic pericarditis; paroxysmal attacks of chest pain, with the intensity of myocardial infarction; palpitations, with sinus tachycardia being particularly troublesome; flattening and inversion of T waves; a lower stroke volume and cardiac output (indicating a defect LUNG / RESPIRATORY PROBLEMS IN ME/CFS There is evidence of shortness of breath in ME/CFS patients (due in part to fatigue of the voluntary muscles of respiration); evidence shows that ME/CFS patients have a significant decrease in vital capacity (VC). The incidence of bronchial hyper-responsiveness is remarkably high. Compared with controls, ME/CFS patients showed a significant reduction in all lung function parameters studied. GUT DYSFUNCTION IN ME/CFS Irritable bowel syndrome (IBS) is a widespread and common problem in ME/CFS; reference to it throughout various sections of the reference papers. BRAIN IMAGING (NUCLEAR MEDICINE) IN ME/CFS The literature contains objective evidence of brain impairment in the majority of patients which is compatible with a chronic viral encephalitis. Patients have a particular pattern of hypoperfusion of the brainstem. Brain perfusion impairment in ME/CFS provides objective evidence of central nervous system dysfunction. COGNITIVE DYSFUNCTION IN ME/CFS Neuropsychological testing reveals a pattern of cognitive impairment which is compatible with an organic brain lesion. Tests on ME/CFS patients revealed a performance which was sevenfold worse than that found in either the controls or in depressed patients. Results indicate that the memory deficit in ME/CFS is more severe than has been assumed by the CDC criteria. A pattern has emerged of brain behaviour which supports neurological compromise in ME /CFS. PSYCHOLOGICAL PROBLEMS IN ME/CFS There is a substantial body of literature which strongly refutes claims that patients are overly suggestible; it is quite specific that patients are not somatising, and it confirms that patients are not exhibiting “abnormal illness behaviour” and that the illness is not explained by inactivity or psychiatric disorder. Any depressive symptoms present are more likely to be a consequence rather than a cause of illness. Serious doubts are raised about the validity of the application of a psychiatric label. A conviction by patients of physical illness is demonstrated to be understandable and legitimate. (continued on page 46) Invest in ME Charity Nr 1114035 www.investinme.org is to be found in the higher cortical modulation of cardiovascular autonomic control). ME/CFS patients have higher heart rates and lower pulse pressure and have baseline differences from normals. is important to avoid histamine releasers. Muscle weakness increases the risk of 45

Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) COGNITIVE BEHAVIOURAL THERAPY IN ME/CFS Evidence shows it is at best ineffective and at worst harmful in authentic ME/CFS. GYNAECOLOGICAL PROBLEMS IN ME/CFS A number of gynaecological conditions have been found to occur more frequently in women with ME/CFS, for example endometriosis is reported to occur in up to 20% of women with the disorder; cystic enlargement of the ovaries may be present and can be seen on ultrasound scan. A history of ovarian cysts, including polycystic ovaries and uterine fibroids was found in one study to be more common in patients than in controls. Prostatitis is common in men with ME/CFS. SPECIAL PROBLEMS IN CHILDREN WITH ME/CFS It is not widely recognised that children and adolescents can suffer from ME/CFS, which has been found in children as young as five. There may be appalling problems with ignorant authorities, with children being forcibly removed from their homes and placed in the “care” of the State and the parents accused of child abuse; one consultant paediatrician who specialises in ME/CFS is on record as confirming that the number of such cases now amounts to an epidemic. The presentation in young people may differ from that in adults. Some children require tube feeding. Education may be a particular problem. There are many horrific stories of inappropriate and damaging psychiatric interventions. The Review Article by Professor Leonard Jason et al is essential reading (Chronic Fatigue Syndrome in Children and Adolescents: A Review. Karen M Jordan, Leonard Jason et al. Journal of Adolescent and Child Health 1998:22:4-18) SIMILARITIES AND DIFFERENCES BETWEEN ME/CFS AND FIBROMYALGIA Although there is some overlap of symptomatology in both conditions, there are significant differences between ME/CFS and FM: the WHO lists them as separate disorders in the ICD and there are important laboratory distinctions (eg. levels of somatomedin C; substance P; CBG levels; secretion of ATP; acetlycholine sensitivity; endlothelin-1 levels etc). Studies suggest that those with co-existent disorders face an additional burden of suffering and a worse outcome. GENETIC ABNORMALITIES IN ME/CFS There is unequivocal evidence of acquired abnormalities in numerous genes involved in energy production and with the neurological and immunological systems. PATTERNS OF MEDICAL MISDIAGNOSIS Misdiagnosis is very common in complex and poorly understood illness and patients are often ignored or dismissed by medical practitioners without justification. This increases their suffering. The literature abounds with evidence that patients have often been given an inappropriate label (usually by psychiatrists), and that such labels abruptly disappear when medical science and knowledge discover an underlying organic aetiology. Examples are legion, and include diabetes, hypothyroidism, pernicious anaemia, peptic ulcer, multiple sclerosis and Parkinson’s disease -- in the 1940s, psychiatrists claimed that the intention tremor was due to the inner conflict of the patient who wished to masturbate but who knew it was wrong, and that the intention tremor was a manifestation of such inner conflict; it was not until the discovery of the neurotransmitters and the role of dopamine that such views were abandoned. Unfortunately, some psychiatrists seem unable learn from past experience. (continued on page 47) 46 Invest in ME Charity Nr 1114035 www.investinme.org Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) 1957 A BRIEF SELECTION OF BIOMEDICAL REFERENCES ON ME/CFS 1983 An investigation into an unusual disease seen in epidemic and sporadic form in a general practice in Cumberland in 1955 and subsequent years. AL Wallis. Doctoral Thesis: University of Edinburgh, 1957. (This is an excellent and accurate description that details the varying clinical picture, the abnormal physical findings and post mortem histopathology). 1969 Disseminated Vasculomyelinopathy. M Poser. Charles Acta Neurol Scand 1969:S37:7-44. (This details postviral infectious states and subsequent development of allergies and is highly relevant in view of recent autopsy findings of severe inflammation in the dorsal horn in the case of Sophia Mirza). 1976 Benign Myalgic Encephalomyelitis or Epidemic Neuromyasthenia. September 1976:539-542. features). 1978 An outbreak of encephalomyelitis in the Royal Free Hospital Group, London, in 1955. Nigel Dean Compston. Journal, November 1978:54:722-724. Postgraduate Medical (This documents the clear evidence of organic involvement of the CNS). 1979 Clinical and biochemical findings in ten patients with Benign Myalgic Encephalomyelitis. AM Ramsay; A Rundle. Postgraduate Medical Journal, December 1979:55:856-857. (This describes the dominant clinical features -- abnormal muscle fatiguability and pain; circulatory impairment and hypothalamic damage; cognitive impairment – and notes impairment of cell membrane permeability). 1981 Was it Benign Myalgic Encephalomyelitis? CS Goodwin. Lancet 1988; January 3rd: 37. (This notes the three major features of the disease and documents abnormal physical findings). Invest in ME Charity Nr 1114035 AM Ramsay. Update: (This sets out the cardinal Sporadic myalgic encephalomyelitis in a rural practice. BD Keighly; 1983:33:339-341. EJ Bell. JRCGP June (This provides a good clinical summary and notes a pattern to the complexity of symptoms). 1985 Electrophysiological studies in the postviral fatigue syndrome. Goran A Jamal; Stig Hansen. JNNP 1985:48:691-694. (This documents abnormalities in muscle, including type II fibre predominance, scattered fibre necrosis; bizarre tubular structures and mitochondrial abnormalities). 1987 Myalgic Encephalomyelitis (ME) Syndrome – an analysis of the findings in 200 patients. J Campbell Murdoch. The New Zealand Family Physician 1987:14:51-54. laboratory findings, including the presence of positive smooth muscle antibodies and antinuclear antibodies). 1987 Phenotypic and functional deficiency of natural killer cells in patients with Chronic Fatigue Syndrome. M Caliguri, AL Komaroff et al. J Immunol 1987:139:3306-3313. abnormally low numbers of NK cells). 1988 Chronic Fatigue chronic viral infections. AL Komaroff. Syndromes: relationship to Journal of Virological Methods 1988:21:3-10. (This documents unusual and abnormal findings, including hepatosplenomegaly). 1988 Allergy and the chronic fatigue syndrome. Stephen E Straus et al. J Allergy Clin Immunol 1988:81:791-795. (This documents the laboratory evidence for an allergy that is described as “substantial”). (continued on page 48) www.investinme.org (This describes 47 (This demonstrates

Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) A BRIEF SELECTION OF BIOMEDICAL REFERENCES ON ME/CFS 1991 Chronic Fatigue Syndrome: clinical condition associated with immune activation. AL Landay et al Lancet 1991:338:707-712. (This documents evidence for three cell surface markers and notes that CD38 and HLA DR markers remain persistently raised). 1992 A chronic illness characterised by fatigue, neurologic and immunologic disorders, and active human herpes Type 6 infection. Gallo, AL Komaroff et al. 1992:116:2:103-113. Ann D Buchwald, R Intern Med (This describes a significantly increased CD4/CD8 ratio; brain scans show punctate subcortical areas of high signal intensity consistent with oedema or demyelination in 78% of patients, suggesting patients may have a chronic, immunologicallymediated inflammatory process of the CNS). 1993 Memory deficits associated with chronic fatigue immune dysfunction syndrome. al. Biol Psych 1993:618-623. (This demonstrates that cognitive impairment is seven-fold worse than in controls and depressives and is worse than assumed by CDC criteria). 1993 Clinical presentations of chronic fatigue syndrome. AL Komaroff. Ciba Foundation Symposium 173:4361. (This describes ME/CFS as a “terribly destructive disease”; it describes the abnormal physical examination and compares the clinical picture with that of lupus). 1996 Chronic Fatigue Syndrome: evaluation of a 30criteria score and correlation with activation. Hilgers A and Frank J. immune JCFS 1996:2:4:35-47. (This paper notes important and consistent symptoms that are not included in the CDC 1994 case definition; these include respiratory problems, Curt Sandman et palpitations; chest pain; dizziness; dyspepsia; parasthesia; nausea and loss of hair. A correlation between the 30-criteria score and immunological parameters occurred in 472 of 505 patients). 1996 Autoantibodies to Nuclear Envelope Antigens in Chronic Fatigue Syndrome. K. Konstaninov et al J Clin Invest 1996:98:8:1888-1896. 1997 Elevation of Bioactive Transforming Growth Factor Beta in Serum from Patients with Chronic Fatigue Syndrome. AL Bennett, AL Komaroff et al. J Clin Immunol 1997:17:2:160-166. (This paper documents the effects of TGF/beta on cells of the immune system and CNS and provides evidence that it may play a role in autoimmune and inflammatory disease). 1997 Elevated apoptotic cell population in patients with Chronic Fatigue Syndrome: the pivotal role of protein kinase RNA. A Vojdani, CW Lapp et al. J Int Med 1997:242:465-478. (This paper indicates abnormal mitotic cell division). 1997 Chronic Fatigue Syndrome: A Disorder of Central Cholinergic Transmission. A Chaudhuri, T Dinan et al. JCFS 1997:3: (1):3 -16. (This paper posits that the pathogenesis of ME/CFS involves upregulation of post-synaptic cholinergic receptors). 1998 Relationship between SPECT scans and buspirone tests in patients with ME/CFS. Richardson J; Costa DC. JCFS 1998:4:3:23-38. (This paper provides evidence that all patients tested had hypoperfusion of the brain: 62% in the brain stem and 51% in the caudate nuclei). Neurally mediated hypotension and chronic fatigue syndrome. PC Rowe H Calkins. Am J Med 1998:105: (3A): 15S –21S. (This paper provides evidence of an autoimmune component in ME/CFS). 48 (This paper documents neuroendocrine changes and shows the link with allergy). Invest in ME Charity Nr 1114035 (continued on page 49) www.investinme.org Journal of IiME Volume 1 Issue 1 INFORMATION ON ME/CFS (continued) 2000 A BRIEF SELECTION OF BIOMEDICAL REFERENCES ON ME/CFS 2005 Comparative analysis of lymphocytes in lymph nodes and peripheral blood of patients with chronic fatigue syndrome. MA Fletcher N Klimas et al. JCFS 2000:7:3:65-75. (This paper demonstrates the link with autoimmunity). 2001 Prevalence in cerebrospinal fluid of the following infectious agents in a cohort of 12 chronic fatigue syndrome patients: HHV6 & 8; chlamydia species; mycoplasma species; EBV; CMV and Coxsackievirus. Susan Levine. JCFS 2001:9: (1-2):4151. (This paper provides hard evidence of a high yield of infectious agents in the cerebrospinal fluid of patients with ME/CFS). 2002 Symptoms occurrence in persons with chronic fatigue syndrome. Psychology 2002:59:1:15-27. evidence of several cardiopulmonary and neurological symptoms that uniquely differentiate ME/CFS patients from controls). 2002 Cytokine response to physical particular reference to IL-6: clinical implications. activity, with sources, actions and Shepherd RJ. Crit Rev Immunol 2002:22:3:165-182. (This paper posits that exercise-induced modulations in cytokine expression may contribute to the allergies seen in ME/CFS). 2003 Abnormal impedance cardiography predicts symptom severity in Chronic Fatigue Syndrome. Peckerman A, Natelson BH et al. Am J Med Sci 2003:326:2:55-60. (This paper provides evidence of reduced cardiac output in patients with severe ME/CFS). 2004 Altered central nervous system signal during motor performance in chronic fatigue syndrome. Aiemionow V, Calabrese L et al. Clin Neurophysiol 2004:115:10:2372-2381. (This paper demonstrates altered CNS signals in controlling voluntary muscle). LA Jason et al. Biological (This paper provides Urinary and plasma organic acids and amino acids in chronic fatigue syndrome. Jones MG et al. Clinica Chimica Acta: International Journal of Clinical Chemistry. Epub June 28, 2005. (This paper provides evidence for underlying inflammatory disease and for a lower threshold for muscle micro-injury). 2005 Chronic fatigue syndrome is associated with diminished intracellular perforin. Maher KJ, Klimas NG, Fletcher MA. Clin Exp Immunol 2005:142:3:505-511. (This paper provides evidence of a Tcell associated cytotoxic deficit. As perforin is important in immune surveillance and the homeostasis of the immune system, its deficiency is likely to be an important factor in the pathogenesis of ME/CFS). 49 ME Petition to PM Blair Please support the E-Petition created by Konstanze Allsopp to enforce the acceptance of ME as a neurological illness. "We the undersigned petition the Prime Minister to get the Health Service and medical profession to accept the WHO classification of ME/CFS as an organic neurological disorder and not as a psychosocial syndrome." http://www.investinme.org/EPetition%202007.htm ME Story My family called the doctor to the house on one occasion after I had become too weak to walk or talk and couldn't make the bathroom without assistance. The GP advised me to go out for a jog in the sunshine. - Cathy Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 International ME/CFS Conference Agenda DAY 1 - 1st May 2007 - ME Awareness & Support Day Start Presenter Presentation 08:30 REGISTRATION & MEDIA INTERVIEWS 10:30 IiME Welcome to the Conference 10:40 Norman Lamb MP Opening Speech/Key Note Speech RESEARCH & FUNDING – A Review of Current Work & Requirements 11:05 Dr. Derek Pheby 11:30 Dr. Jonathan Kerr 12:00 Lunch 13:00 Professor Kenny De Meirleir 13:30 Annette Whittemore 13:55 Dr. Daniel Peterson 14:25 Dr. Vance Spence 14:45 Professor Malcolm Hooper Case Study – Epidemiology of ME/CFS Case Study - Biomedical research (A view of a biomedical research team, how it is funded, what it needs, how it could be improved, what the future research would look like) MODELS for TREATMENT of ME/CFS Treatments for ME/CFS Integrative & Complementary Medicine A Model ME/CFS Clinic - The CFS Clinic – Reno, Nevada, USA Experiences of Research into ME – Past, present and future Biomedical Research into ME/CFS: where does it go from here Future ME/CFS Projects - Research being planned & Common Aims - how to get researchers working together 15:15 Coffee/tea Break CURRENT ISSUES - NICE, GUIDELINES, CAMPAIGNS 15:35 Ellen Piro 16:00 Dr. Byron Hyde 16:30 Open forum NICE Guidelines – Experiences from Norway ME and Insurance companies Plenary Session • International alliances • Guidelines • Diagnostic testing • Tissue Banks • Local Services 17:30 Adjourn Invest in ME Charity Nr 1114035 www.investinme.org 50 Journal of IiME Volume 1 Issue 1 International ME/CFS Conference Agenda DAY 2 - 2nd May - Professionals Day Start Presenter Presentation 07:45 Registration & Media interviews 09:00 IiME 09.30 Welcome to the Conference 09:10 Dr. Ian Gibson MP Key Note Speech Professor Martin Pall 10:00 Dr. Abhijit Chaudhuri 10:30 Coffee/tea Break 10:50 Dr. Vance Spence 11:20 11:50 Dr. Sarah Myhill Professor Kenny de Meirleir 12:30 Lunch 13:30 Dr. Nigel Speight 14:00 Dr. Byron Hyde 14:40 Coffee/tea Break 15:00 Dr Jonathan Kerr Professor Malcolm Hooper Biochemical Underpinnings of ME/CFS Pathology of ME/CFS Vascular aspects of ME/CFS Treatments and Diagnosis – A GP’s Perspective Treatments – A ME Clinical Research Perspective Medical Research and Treatment Updates Paediatrics and ME The epidemiology, definitions and techniques of investigation of the ME and CFS patient and the resulting pathological findings or Case Studies / Thyroid Problems Research: A Year On: Viral and Human Gene Expression, development of diagnostic test, news of clinical trials 15:30 Dr. Daniel Peterson Biomedical Research 16:05 16:35 All Speakers 17:30 Adjourn Summary - Future Strategy for ME Research, Diagnosis and Treatment Open forum / Questions 51 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 1 52 ME Conference 2006 DVD Still available – the IiME ME Conference 2006. Sold in over 20 countries this is now available as an educational tool – useful for healthcare staff (GPs, paediatricians, occupational therapists and others connected with the treatment of ME), researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Comprising 3 DVDs and a data CD the conference has the full lectures from the conference from Dr. Ian Gibson, Professor Malcolm Hooper, Dr. Byron Hyde, Dr. Jonathan Kerr, Jane Colby, Dr. Bruce Carruthers and Professor Basant Puri. Also included are TV programmes from ITV Meridian and Norsk Puls programme about severe ME. Price £13 plus p&p (£2 UK/£3 Europe and USA/Canada/Australia/New Zealand). To order send an email to meconference2006@investinme.org entitled DVD or go to http:///www.investinme.org/tinyurl to order online. Order the 2007 Conference DVD The DVD of the May 2007 conference should be available in early June. To order please email meconference@investinme.org and include your name and contact details plus the number of copies wanted and preferred mode of payment. Available only from Quotable Quotes on ME/CFS IiME. This 42 page booklet has been researched by Maragaret Williams and contains a plethora of quotes from ME experts and from others relating to ME, ME/CFS, CFS/ME and CFS. This is an invaluable document for researchers, healthcare staff, politicians, media, ME support groups and people with ME. Price £3.50 + £1 postage/packing for UK delivery. Apply to info@investinme.org or contact the numbers below. Tel: 02392 252365 or 01603 701980 Invest in ME Charity Nr 1114035 www.investinme.org

V VOO LLUUMMEE 11 II SSSSUUEE 22 Invest in ME Charity Nr 1114035 www.investinme.org

Journal of IiME Volume 1 Issue 2 www.investinme.org Autumn 2007 Facts About ME In the World Health Organisation International Classification of Diseases -to which the UK is a signatory and is therefore bound by it – myalgic encephalomyelitis (ME) has been classified as a neurological disorder since 1969. In the 1992 revision (ICD-10) chronic fatigue syndrome (CFS) is listed as a synonymous term for ME and both terms are listed in the neurological diseases section at G93.3, hence the disorder is referred to as ME/CFS. ME Story This is not the life I want, to be 31 with no job, living with my parents and other people's ignorant attitudes , "everyone gets tired", "you just need to sleep less" makes me mad. The government’s lack of funding into research appalls me and the doctors I have seen know less about M.E than I do - Vikki This issue of the Journal continues with the objectives from the first issue – to provide a platform for serious research, appraisal and awareness of the neurological illness Myalgic Encephalomyelitis (ME). In this issue we have research provided by Dr. Tae H. Park from South Korea. Dr. Park has been involved in treating ME for 10 years and his practice in South Korea has treated thousands of patients. We also welcome Professor Sakudo from Japan who publishes for the first time his paper on the potential of visible and near-infrared (Vis-NIR) spectroscopy for the diagnosis of CFS using serum samples. Possible diagnostic testing has never been far from the demands of the ME patient community and Dr. Estibaliz Olano from Spain also presents news of another possible diagnostic test. Invest in ME recently noticed news of mitochondrial research by Dr. Marisol Corral-Debrinski which asked ‘Can "molecular addressing" correct mitochondrial diseases?’ This seemed of interest, when one considers past research on ME and mitochondrial abnormalities. We asked Dr. Corral-Debrinski to publish articles on her work and she has written a detailed overview of her research. We hope it will provide awareness of wider possibilities relating to ME research. We also have a paper on links between Q-fever and ME by Dr. Dragan Ledina from the University of Croatia. Dr. Nigel Speight gave an excellent presentation at the IiME conference in London in May and in this Journal he presents a personal view of ME and Children over the last twenty years. All of these papers reflect the outcome of the IiME conference in May – that there is an abundance of science available to encourage biomedical research into ME – something IiME and others have been pressing the government to acknowledge and yet something NICE have failed to recognise in their recently published guidelines on CFS/ME. Both biomedical conferences of ME Awareness Month 2007, in which IiME and MER UK worked together to promote biomedical research, also demonstrated what an exciting field ME can be for potential researchers. The need for urgent funding of biomedical research into ME is highlighted even further by Margaret Williams’ article on the PACE trials – controversial trials claimed by the Medical Research Council to be worthwhile - but denounced by the ME community as being worthless and a waste of scarce funding. Finally, with most of the ME community objecting to the prominent role psychiatry plays in the diagnosis and treatment of ME we reference a paper from Dr. Marek Marzanski detailing his research on how psychiatry and the Hippocratic Oath co-exist. The science and the advocacy available for all to see seemingly makes the plight of people with ME, and their families, even more tragic and we continue with stories from patients and carers on their experiences with dealing with this illness – including a harrowing account from one family who have had to deal with their severely ill daughter being apportioned yet another psychiatric diagnostic term – Pervasive Refusal Syndrome. We believe this further endorses the need for Journal of IiME – a blend of research, science, facts, politics and real life experiences. Disclaimer The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME Charity Nr 1114035 Page 2/72 Journal of IiME Volume 1 Issue 2 Inside This Issue 3 From the Chairman 5 Comprehensive Treatments of CFS/ME with IVIG 7 CFS as Major Cause of CKD 8 Introduction and Perspectives for Diagnosis of CFS 19 Identification of Differential Genetic Profiles in Severe Forms of FM and CFS in the UK population 21 Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface 30 Chronic fatigue Syndrome after Q fever 35 The reality and nature of ME/CFS 38 Children and Young people with ME – A Personal Overview of the Last 20 Years 42 ME Story 44 IiME Comment: NICE Guidelines 48 The PACE Trial 68 Attitudes of Mental health Practitioners to the Hippocratoc Oath 69 The IiME International ME/CFS Conference 2008 71 Educational Material from IiME www.investinme.org From the Chairman of Invest in ME Welcome to the second Journal of Invest in ME – a combination of research, information, news, stories and other articles relating to myalgic encephalomyelitis. Our first version of the Journal appeared in the delegates’ conference pack at our International conference in London in May 2007. The conference brought together some of the foremost experts on ME and representatives from ME patient groups from all over the UK and Europe. We believe that everyone left not only with an enhanced knowledge gained from the conference but also with renewed hope for the future treatment and possible cure for myalgic encephalomyelitis. As Professor Malcolm Hooper commented in his introduction to the Issue 1 of the Journal - “achievements, hope, and future actions were brought together in this conference”. The breadth of knowledge, science and experience regarding ME, as discussed and presented at the conference, was not only impressive but also exciting. There are grounds for hope that a treatment and cure are on their way. We are glad to see that the many contacts which were established at the conference have continued. To see renowned experts on ME discussing with each other and forming or re-enforcing collaborative efforts was reward enough for hosting the conference. To turn into reality our efforts to form a world alliance of campaigning ME Support organisations was also justification for the conference. The presentations from our distinguished speakers displayed an amazing amount of knowledge regarding the organic nature of myalgic encephalomyelitis. Invest in ME made the decision to fund the DVD of the conference in order that we had a permanent record of the events of that day and of the impressive science which exists already. The conference DVDs have been sold in twenty countries and testify to the need for education about ME. They are an educational tool for physicians to learn about ME. As with many illnesses to which the government gives insufficient attention, and where some existing organisations seemingly fail to represent patients properly, the patients and carers are those who learn most about the illness, out of necessity. It is they who are forced into lobbying for proper attention. Invest in ME was created through such a state of affairs. Our aim is, where possible, to provide information and educational material either free or at cost price - our recent London conference being an example of that where pwme and their carers could attend for a basic price which covered just food and refreshments. Lobbying can work. The recent case of the GMC attempting to discipline Dr. Sarah Myhill is, perhaps, a case in point. Lobbying by patient groups and patients has perhaps forced the GMC to rethink their strange tactics. Dr. Myhill’s case proves how out of touch an established organisation can be with the needs and welfare of patients and their families. Email: info@investinme.org Similarly NICE has shown itself to be an organisation unwilling to progress the treatment and perception of ME. Invest in ME have written to the current minister responsible for ME at the DoH, Mrs. Ann Keen, requesting a meeting with representatives from ME patient groups. The reply was the standard template from the DoH showing both ignorance and apathy to the plight of ME patients and Invest in ME Charity Nr 1114035 Page 3/72

Journal of IiME Volume 1 Issue 2 www.investinme.org From the Chairman of Invest in ME (continued) families in this country. IiME was also recently asked by the BBC Radio 4 Programme “You and Yours” to supply information for their series of programs on ME. So education is still a huge priority and Invest in ME, and other groups, continue to perform work in this area - much of it unpublished - but with the intention of making ME a mainstream illness and deserving of educated and sufficient debate. We are determined that what happened to Sophia Mirza, who died, “… as a result of acute renal failure due to dehydration arising as a result of Chronic Fatigue Syndrome (M.E.)” must never be allowed to happen again. We shall endeavour to continue the campaign to educate and lobby and improve the lives of people with ME and their carers. Invest in ME has taken over the distribution of the Canadian Guidelines in the UK. Together with both 2007 and 2006 conference DVD sets, and the Quotable Quotes on ME booklet, we have a useful range of educational material for healthcare staff, politicians, media and, of course, ME patient groups and pwme and their carers. Our 52-page response to the NICE guidelines has also been added to our web site. We hope the Journal of IiME will also continue to assist in this area by providing a platform, as does the IiME conference, for biomedical researchers and clinicians to provide details of their research and work. It will also continue to offer real life experiences from those who have to deal with this illness on a daily basis – a fact to which too many politicians and organisations still remain indifferent. As IiME plan for the May 2008 conference we look forward to working together with those interested in campaigning for funding of biomedical research into ME – the only sure way to provide a cure for this neurological illness. We wish everyone a pleasant autumn and hope and believe that progress will continue in providing a future treatment/cure for ME. Best Wishes Kathleen McCall A Arr tt ii cc ll eess ffoorr tthhee JJoouurrnnaa ll oo ff II iiMMEE Invest in ME welcomes articles for inclusion in the Journal, especially research papers on ME. Our aim is to provide as much information, fact and science regarding myalgic encephalomyelitis in the hope that it will encourage research, funding and discussion of ME and provide more accurate perception on this illness. Articles for consideration should preferably be in MS Word. Please send any articles to jiime@investinme.org and provide a contact number and full address details. Invest in ME Charity Nr 1114035 The NICE Guidelines “By pre-determining the result based on its requirements to view this illness as a broad chronic fatigue illness NICE has failed to grasp the reality, failed to analyse and use proper research, failed to respond to patients’ demands and requirements and produced a document that will continue to allow this illness to be blended into a nebulous fatigue syndrome which only benefits psychiatrists interested in funding of their projects and other organisations who depend for their existence on paying members.” - IiME Comment on the NICE Guidelines for CFS/ME (Page 44) Facts About ME The textbook used to train NHS clinicians (and which is likely to be on the desk of every GP in the UK - Clinical Medicine: Kumar and Clark) categorises CFS/ME in the mental health section under ”Functional or Psychosomatic Disorders” - despite the fact that the World Health Organisation has recognised ME as a neurological illness and that this recognition is also officially supported by the British government. Facts About IiME The IiME website was set up in late 2005. The aim is to provide news, educational material, research information and stories of ME. The IiME website usage has steadily grown with up to 60,000 visits per month from around the world. www.investinme.org Page 4/72 Journal of IiME Volume 1 Issue 2 COMPREHENSIVE TREATMENTS of CFS/ME WITH IVIG By Dr. Tae H. Park CFS/ME Clinic of Seoul, South Korea PURPOSE OF STUDY: To see the effectiveness of low dose gammaglobuline treatment in CFS/ME patients with strict control of diet, activities and sleep. As is commonly known the research into CFS/ME patients is progressing rapidly, but treatments of CFS/ME patients in the clinical frontline is very limited, and most of the treatments are aimed toward the symptomatic relief of CFS/ME. Here (in South Korea), we have 10 years experience of treating CFS/ME with IVIG, strict diet control, ample hydration and activity or exercise control. Overall the response rate is 90% with these regimens. Those who responded had returned to work and resumed normal activities. Contrary to the CDC report that initial symptoms are important for the prognosis of CFS/ME, our study showed that the severity and duration of sx of CFS/ME are not major determinants of prognosis (J.Reeves CDC). There have been several reports about IV gammaglobuline therapy (K.S.Row, Lloyd) but the cost and adverse effect of IVIG treatments prevent CFS/ME patients to have IVIG tx. Further more, the results of IVIG tx are not significant enough to recommend for general use for CFS/ME patients Except Dr.Row’s report that 75-80% of children return to normal school activities and 5-6 yr follow-up also showed the significant improvements. Selection of patients Among our clinic’s 5378 patients, we selected 50 patients who met the 1994 Fukuda criteria in random fashion. Duration of illness: from 2 years to 15 years Ages of patients: Gender: Method of treatments Sleep control: Sleep before midnight and at least 7 hours sleep. If there is DIMS (difficulties in initiating and maintaining sleep), used klonopine and (or) prozac (10-20mg) at night. 18 to 50 male: 28 female:22 Dr Tae Park M.D. Dr.Park runs his own CFS clinic in Seoul, Korea. Dr. Park attended the Invest in ME International ME/CFS Conference in London in May 2007 and has subsequently supplied this and the following articles. Diet control Organic foods: rice and vegetables Avoidance of certain foods: bread, canned food, coffee, chocolate, monosodium glutamate, aspartame and hot peppers, orange juice, carbonated beverages. A high protein diet (but avoidance of pork). Ample hydration 2-3 litres of water with 2 tsp of salt. Strict control of exercise and activities. No heavy lifting (anything using upper extremities – such as house cleaning) is prohibited. Walking is allowed if patient improves. If the patient feels any post-exertional malaise, then reduce the exercise. IV Gammaglobuline One gram per week in 500cc of 0.9% normal saline infused over one hour. Avoid NSAID (non-steroidal anti-inflammatory drugs) medication, and avoid tests using contrast media (like CT-scan, or IVP) How to have rest Rest (like monks meditate), No loud music and no reading books. In acute stages, absolutely no exercise. If anyone does exercise they may develop cardiomyopathy or severe cardiac arrhythmia - even death. Results of treatment 90% of patients who were treated with the above regimens recovered and returned to work, or returned to school. Showed KS score from 40 to 90. The fatigue impact scale improved from 120 to 20-40. Especially, we found improvements in the cognitive functions. We found improvements in concentration and comprehension, but short-term memory is the last to recover. Most of our CFS/ME patients showed impaired renal functions. They showed reduced GFR (glomerular filtration rate) and when compared with normal controls (Park, presented at Japan CFS/ME conference 2007). (continued on page 6) Invest in ME Charity Nr 1114035 Page 5/72 www.investinme.org

Journal of IiME Volume 1 Issue 2 www.investinme.org COMPREHENSIVE TREATMENTS of CFS/ME WITH IVIG (continued) In CFS/ME patients, 88% of patients showed GFR below 80ml/min (compared with non-diabetic general populations: 39%), 46% of CFS/ME patients showed GFR below 60ml/min (compared with 19% of general nondiabetic population). Due to the low GFR nearly all of CFS/ME patients we need to be careful to monitor their renal function on a regular basis (every 3 months to check s-creatinine). Method of follow up of patients 1. Check quality of sleep: dreams, DIMS, snoring with apnea, refreshing sleep. 2. Check BP: each time of visit, manually checking BP and record correctly. patient’s fatigue sx is getting better. If BP is still low with hydration of 2 litres of water with 2 tsp of salts, then add florinef. 3. Nocturia: check how frequently patients experience nocturia. If nocturia reduces, then patient’s sx of CFS/ME improves. 5. DIMS (difficulties in initiating and maintaining sleep). If DIMS diminishes then the patient’s sx improves. 6. Strict control of exercise and activity. No heavy lifting (anything using upper extremities such as house cleaning is prohibited). Walking is allowed if patient improves. If patient feels post-exertional malaise then reduce the amount of exercise. 7. Check GFR in all CFS/ME patients (nearly 50% of CFS/ME patient’s GFR is close to chronic kidney disease range (near GFR of 60 ml/min). 8. Avoid the use of NSAID and contrast media using tests such as CT or IVP. 8. Hunger discomfort (such as sudden weakness, sweating) indicates the patient’s liver is enlarged. That means that the patient’s activity level is too high or the patient’s level of exercise is too great. 10. Check liver and spleen at each consultation. If the liver and (or) spleen became smaller then the patient sx improves. If a patient’s liver and (or) spleen are enlarged that means patient’s activity level is too high or patient’s diet control is poor. If BP is rising from low BP, then ME Patient’s Carer’s Story Some time around May or June I got a letter from social services asking me to contact them. In my innocence I thought it was a follow up to our claim for DLA (Disability Living Allowance), so from the disability team offering support. Not a bit of it, my sister had reported me for suspected Munchausen's by Proxy. The fact that she hadn't seen us for two years hadn't held her back. So to add to the difficulties of dealing with the school, the benefits system, a paediatrician from hell and a sick child, I now had to deal with a social services investigation. - Parents of Emma Facts About ME The UK Medical Research Council has a secret file on Myalgic Encephalomyelitis (ME) that contains records and correspondence since at least 1988; The file is held in the UK Government Archive at Kew and cannot be opened until 2023. ME Petition to the Prime Minister The E-petition to the Prime Minister, created by Konstanze Allsopp, to enforce the acceptance of ME as a neurological illness is still open for new signatures. In fact this petition (at http://www.investinme.org/E-Petition%202007.htm) has a closing date of January 2008. One can lend support for this petition, which states - "We the undersigned petition the Prime Minister to get the Health Service and medical profession to accept the WHO classification of ME/CFS as an organic neurological disorder and not as a psychosocial syndrome." Invest in ME Charity Nr 1114035 Page 6/72 Journal of IiME Volume 1 Issue 2 www.investinme.org CFS/ME MAY BE MAJOR CAUSE of CHRONIC KIDNEY DISEASE IN NON-DIABETIC POPULATIONS By Dr. Tae H. Park OBJECTIVE OF STUDY: To prove that CFS/ME is a major cause of chronic kidney disease (CKD) in the general population. DESIGN: Cross-sectional study PATIENTS: Participants are 20 years of age and older 400 CFS/ME patients There is a sudden increase in occurrence of non-diabetic, chronic kidney disease patients in the last 3-4 years. In one report (Class et al), 39% of the non-diabetic population showed GFR below 80ml/min. Among them 14% showed GFR below 60ml/min. We collected data from our 400 CFS/ME patients who meet the Fukuda criteria of 1994 and calculated the GFR using the Cockcroft-Gauld formula. The results which we found in our study are striking. Among our 400 CFS/ME patients we found 88% of the patients showed GFR below 80ml/in and 46% GFR below 60ml/min. If we subdivided stage 3 CKD patients (GFR below I60ml/min) then 38.4% showed GFR between 55-60, 33.6% showed GFR 50-54, 29% showed GFR 45-49. In stage 2 CKD classification (GFR below 90) our study showed 84.7% of CFS/ME patient met stage 2 criteria. Among stage 2 patients we further subdivided patients. The result is as follows - GFR 60-65 is 43%, 65-70 is 45%. Even in stage 2 classification we found 88% of CFS/ME patients were close to CKD. What this means is that these CFS/ME patients will be CKD patients in the near future without any diabetes or hypertension. A recent report showed 80% of CFS/ME patients are not diagnosed yet, with only 20% being diagnosed. If we bear these facts in mind, and if many of CFS/ME patients are misdiagnosed as having a psychiatric disease or as having HIV, then these non-diagnosed CFS/ME patients would contribute to a major risk factor of CKD in general populations. We suggest that every CFS/ME patient is checked for s-creatinine based GFR and that this is recorded. Furthermore, one should avoid medication like Nonsteroidal anti-inflammatory drugs (NSAIDs) to control pain and most importantly to avoid many tests using contrast media - CT scan, intravenous pyelogram (IVP) especially coronary angiography, even if they have non-specific chest pains. Facts About ME “Psychogenesis of these illnesses is based on the shaky foundation of somatoform disorders and somatisation. It is based on emotion-laden phrases, transparent falsehoods, logical flaws, overstated claims, and unsupported or poorly supported opinion”. “It is based on ignoring the existence of a genetic role in these illnesses. It is based on ignoring the long history of false psychogenic attributions of other illnesses” “It is based on ignoring hundreds of studies documenting real physiological changes in multi-system illnesses”. “It is based on a deliberate ignorance, flaws and quicksand. I do not know how long it will take for the scientific community to realise the demise of the psychogenic view of multi-system illnesses, but it will happen”. “My critique of psychogenesis of multi-system illnesses should not be considered as a critique of psychiatry. It is rather a critique of those who either lack wisdom or who have sold their integrity”. “Whilst the most severe long-term damage created by psychogenic advocates has been to the research prospect for these illnesses, the most severe short-term impact has clearly been to sufferers of these illnesses and their families”. Professor Martin L Pall Professor of Biochemistry and Basic Medical Sciences at Washington State University, (Explaining ‘Unexplained Illnesses’:; Haworth Press, 2007) http://www.investinme.org/Documents/PDFdocuments/Martin%20Pall%20Book.pdf Invest in ME Charity Nr 1114035 Page 7/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of Chronic Fatigue Syndrome By Akikazu Sakudo1* Yukiko Hakariya1, Takanori Kobayashi1, and Kazuyoshi Ikuta1 1 Department of Virology, Center for Infectious Disease Control, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan *To whom correspondence should be addressed: Akikazu Sakudo, Department of Virology, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan Tel.: ++81-6-6879-8307 Fax: ++81-6-6879-8310 E-mail: sakudo@biken.osaka-u.ac.jp Summary Currently, chronic fatigue syndrome (CFS) is diagnosed based on clinical symptoms. Although various information on psychological, endocrinological, and immunological abnormalities in CFS patients has been reported, there is no clear consensus, possibly due to the absence of an objective diagnostic method. One experimental approach is the use of instrumentation for diagnosis. Recently, our research group has shown the potential of visible and near-infrared (VisNIR) spectroscopy for the diagnosis of CFS using serum samples. This review will introduce the method and the future perspectives made possible by it. Keywords: Chronic fatigue syndrome; myalgia encephalomyelitis; visible and near-infrared spectroscopy; diagnosis Introduction Chronic fatigue syndrome (CFS) is a debilitating disorder involving persistent fatigue lasting for more than six months [1]. However, the difference between CFS and CFS-like diseases such as myalgia encephalomyelitis (ME), postviral fatigue syndrome (PVFS), chronic fatigue/immune dysfunction syndrome (CFIDS), and ‘Yuppie flu’ remains unclear. The symptoms of CFS include fatigue, pain, breathing problems, depression leading to digestive disturbances, low grade fever, difficulty in concentrating, and weakness of the immune system and muscles [1]. The symptoms are not resolved by sufficient rest [1]. The incidence of CFS is 0.4% in the United States and other countries [2] and 0.26% in Japan [3]. Economic losses caused by the disease are estimated at as high as 9.1 billion dollars per year in the United States [4] and 408 billion yen per year in Japan [3]. However, research conducted by the Centers for Disease Control and Prevention (CDC) estimates that less than 20% of CFS patients in the United States have been successfully diagnosed [2, 5], indicating that the number of patients will increase if more reliable diagnostic methods are established. The main barriers to identifying CFS patients are an absence of biophysical and biochemical signs that identify the disease and lack of diagnostic laboratory tests [6]. This may be at least in part due to the heterogeneity of the symptoms of CFS patients [6]. At present, CFS diagnosed based on the presentation of symptoms and exclusion of other medical entities. Therefore, it relies on symptometology. Most published studies have diagnosed CFS on the basis of CDC criteria [1]. As psychiatric diseases and other treatable conditions are sometimes difficult to distinguish from CFS, the patient’s Invest in ME Charity Nr 1114035 Fig. 1. Our research group Medical spectroscopy group at Department of Virology, Research Institute for Microbial Diseases, Osaka University was composed of a virologist (Kazuyoshi Ikuta), spectroscopist (Akikazu Sakudo), physician (Yukiko Hakariya), and clinical laboratory technologist (Takanori Kobayashi). Researchers with different backgrounds are studying CFS. (continued on page 9) Page 8/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS symptoms should carefully be examined. Physicians should, through a careful investigation of the patient’s medical history and appropriate testing, rule out other diseases including mononucleosis, Lyme disease, thyroid conditions, diabetes, multiple sclerosis, various cancers, depression and bipolar disorder. We feel that the main problems in CFS studies can be attributed to the objectivity of diagnosis and absence of biomarkers. Our research group, composed of a virologist, spectroscopist, physician, and clinical laboratory technologist, has been studying visible and near-infrared (Vis-NIR) spectroscopy (Fig. 1). We decided to apply Vis-NIR spectroscopy to the study of CFS. In this review, we introduce the method and its possible uses for CFS research. Vis-NIR spectroscopy and multivariate analysis The short wavelength (SW)-NIR region and the red region, the so called “optical window” from 600 to 1,100 nm, are together the most useful region for measuring biological samples [7]. The absorption of hemoglobin and water is extensive in the region below 600 nm and above 1,100 nm, respectively, which limits spectroscopic and microscopic studies [8]. Absorption in the SW-NIR region is due to combinations and overtones of vibration such as the stretching and bending of hydrogen-bearing functional groups including –CH, -OH and –NH [9]. Water, melanin, and bilirubin in animals were absorbed by the radiation of this region [8]. In addition, oxyhemoglobin, deoxyhemoglobin, and oxidized cytochrome c oxidase have characteristic absorption spectra in the SW-NIR region [10]. Recently, biologically important molecules such as albumin [11-13], cholesterol [14, 15], globulin [11-13], glucose [13, 16-24], protein [12, 15, 25-28], urea [12, 13, 27], lipid [15], linoleic acid [15], collagen [15], DNA [15], and α-elastin [15] have also been investigated by Vis-NIR spectroscopy. However, there has been considerable debate as to whether the accuracy and stability of Vis-NIR calibration models for non-invasive transcutaneous monitoring of blood glucose levels in patients with diabetes met criteria for clinical diagnosis [18, 29, 30]. Creatine [27], lactate [22, 31], triacetin [20], triglyceride [13], βlipoprotein [25], Vibrio cholerae [32], Escherichia coli [33, 34], Yeast [35, 36], Ethanol [36, 37], RNA [28], Acetate [34], Ammonia [22, 34], Glycerol [34], and Glutamine [22] have also been quantitatively determined by VisNIR spectroscopy. Representative biomolecules studied by Vis-NIR spectroscopy are listed in Table 1. Vis-NIR spectroscopy has been recognized as having diagnostic potential ever since Jöbsis first used it to demonstrate oxygenation in cats [38]. Vis-NIR spectroscopy has also been applied in the clinical setting to aging [39, 40], Alzheimer’s disease [41], cancer [42-50], chronic fatigue syndrome [51-54], dermatological conditions [43], diabetes [18, 21, 55], epilepsy [56], human immunodeficiency virus (HIV) infection [57], seizure types [58], migraine [59], cervical Invest in ME Charity Nr 1114035 dysplasia [60], atherosclerotic plaques [61], rheumatoid arthritis [62], hemodynamics [63], glioma [64], intraocular pressure [65], hemorrhagic shock [66], skin moisture [67], brain edema [68], optic neuritis [69], and maternal hypotension [70] (Table 2). The number of diseases studied by Vis-NIR spectroscopy has been increasing, although most studies have focused on the monitoring of oxyhemoglobin and deoxyhemoglobin. At present, the diagnostic application of this method in the medical field is rare. The development of laboratory instrumentation for Vis-NIR spectroscopy has been well reviewed [71]. Manufacturers and commercially available instrumentation has also been listed [72], and the number of manufacturers has shown further dramatic increase. The range of wavelengths and modes of measurement available must be paid greater attention to select a suitable instrument for analysis. Cuvettes are sometimes used for measurements. Quartz and polystyrene cuvettes are preferable because much Vis-NIR spectral information on quartz and polystyrene has been reported. The methods of measurement are divided into four types: transmission, reflection, transflection, and interactance in spectroscopy [73]. In transmission spectroscopy, radiation transmitted through sample is measured. In reflection spectroscopy, radiation reflected on the surface is measured. In transflection spectroscopy, which is a combination of the transmission and reflection methods, radiation is transmitted through the sample and scattered back from a reflector on the opposite side. In interactance spectroscopy, radiation transmitted through the sample is collected in contact with the surface of the sample with the end of a fibre optic probe, which has both a radiator and a detector [74]. The availability of fibre optic probes is one advantage of Vis-NIR spectroscopy. Vis-NIR spectroscopy enables the rapid, non-destructive, accurate, and simultaneous determination of multiple components in both liquid and solid samples [75]. However, it also has disadvantages. (continued on page 10) Fig. 2. Characteristics of near-infrared radiation. Ultraviolet (UV), visible (Vis), and infrared (IR) radiation is highly absorbed, whereas near-infrared (NIR) radiation is relatively little absorbed, by water and haemoglobin. Notably, 600-1,100 nm including the red region and short wavelength region of near-infrared (SW-NIR) radiation is called the “optical window”, because this region is suitable for biological analysis. Modified from Fig. 1 in Sakudo et al. [103] with permission from Nippon Rinsho Co. Page 9/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS HIV: human immunodeficiency virus principal component analysis PCA: PLS: Table 1. Representative biomolecules studied by Vis-NIR spectroscopy MLR: multiple linear regression analysis PCRA: principal component regression analysis partial least squares regression analysis Vis-NIR spectroscopy is not very sensitive: the limit is only about 0.15% (w/w) for most constituents, and the signal to noise ratio of the instrument is low [less than 10-4 optical density (OD)] [76], but is dependent on several factors such as the measurement accessory, spectrometer including detectors, and acquisition time. A large amount of sample is needed for Vis-NIR spectroscopy compared to other methods of chemical analysis [76]. The direct interpretation of spectral absorbance is very difficult for complex mixtures because of broad overlapping and interacting absorption bands [76]. Vis-NIR spectroscopy thus relies on a multivariate analysis to quantify properties or constituents of interest. A multivariate analysis is an analysis of data with many variables based on statistics and mathematics. It can simplify complicated data and uncover hidden information. The analysis can be qualitative or quantitative. It is based on chemometrics algorithms. Methods of quantitative analysis include the partial least Invest in ME Charity Nr 1114035 SIMCA: software-independent modeling by class analogy squares regression analysis (PLS) and the principal component regression analysis (PCRA), which are used to develop the regression model for the prediction of the reference value [77, 78]. Methods of qualitative analysis include the principal component analysis (PCA) [79] and the software-independent modeling by class analogy (SIMCA) [80]. PCA is a method for transforming an original variable such as absorbance at various wavelengths into new variables called principal components (PCs). By plotting the data defined by PCs, important relationships in the data (e.g., similarities and differences among objects) can be clearly identified. SIMCA is a recently developed method based on PCA [81]. PCA reduces the amount of data, and SIMCA further extracts discriminant rules among different groups. PCRA is a method for performing PCA on x variables such as wavelength and then regressing y variables on the principal components, whereas PLS (continued on page 11) Page 10/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS Hb: deoxyhemoglobin Table 2. Representative clinical applications of Vis-NIR spectroscopy HbO2: oxyhemoglobin HIV: Human immunodeficiency virus PCA: principal component analysis PLS: partial least squares regression analysis gives extra weight to variables that show a high correlation with y variables. Therefore, PLS is usually more effective for predictions than PCR. Further detailed illustrations and mathematical formulas of algorithms are available in many reports about chemometrics [82, 83]. In a multivariate analysis, the number of PCs is important, because too few or too many PCs distort signals or diminish the signal-to-noise ratio, respectively. To choose the correct number of PCs, a validation step is usually included in the process of modeling [9]. For validation steps, internal validation or external validation is used. Most chemometrics software programs include internal cross validation. In internal cross validation, the sample set is repeatedly divided into two groups. One group is reserved for validation and the other, for calibration. This process is repeated until all groups have been used for validation once. In external validation, sample sets are first separated into calibration samples and test samples, which are subjected to validation and used for assessment of the calibration model. By finding the number of PCs when the model shows a minimum standard error of validation (SECV), the number of PCs can be used to describe the signal in the data. Invest in ME Charity Nr 1114035 These results suggest that combining Vis-NIR spectroscopy with chemometrics is a promising way to objectively diagnose CFS. They also suggest that an unknown factor or factors present in the serum of all CFS patients could provide important clues as to the agent causing this debilitating disease. Recently, commercially available chemometrics software programs such as Pirouette (Infometrics, Woodinville, Washington, USA) and Unscrambler (CAMO Inc., Woodbridge, New Jersey, USA) have been used for Vis-NIR analyse. The number of manufacturers of these software programs is increasing. The programs and their manufacturers are listed in Table 3. The software programs are designed to analyze spectral data, and because preprocessing such as standard normal variate (SNV) [84] and smoothing [85], which minimize differences between spectra caused by baseline shifts and noise, is carried out during the analysis, pre-processing handling, which is time(continued on page 12) Page 11/72 LDA: linear discriminant analysis MELAS: myopathy, encephalopathy, lactic acidosis, MERRF: myoclonic epilepsy with ragged red fibers and stroke-like episodes PCRA: principal component regression analysis

Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) Table 3. Reprentative chemometrics software and statistical analysis used in Vis-NIR spectroscopy studies MLR: Mutilinear regression PCR: Principal component regression PLS: PCA: Partial least squares regression Principal component analysis KNN: K-nearest neighbors SIMCA: Soft independent modeling of class analogy HCA: Hierarchical cluster analysis Class least squares CLS: consuming, is not required. Furthermore, cross validation steps are also included, and these reduce the overall handling and risk of error during analysis. Application of Vis-NIR spectroscopy for CFS research Several biochemical changes are reported in CFS patients, but there is no clear consensus for any of them. Therefore, the diagnosis of CFS is currently based on clinical symptoms. As this approach relies on experience and skill, CFS can be diagnosed only by limited numbers of medical doctors. To overcome these problems, an additional method using instrumentation to achieve an objective diagnosis is needed. We reasoned that Vis-NIR spectroscopy might provide new insights if patients could be compared with individuals without the disorder. Here, we describe the results obtained when sera from CFS patients as well as healthy volunteers were subjected to Vis-NIR spectroscopy [86]. At the Medical Hospital of Osaka City University, serum samples from 77 CFS patients (33.0 ± 8.8 years old; Male/Female: 29/48), diagnosed on the basis of clinical criteria proposed by CDC were examined [1]. Samples from 71healthy volunteers (41.7 ± 10.4 years old; Male/Female: 33/38) were also used. The sera of the 77 CFS patients and 71 healthy volunteers served as test samples to develop calibration models for PCA and SIMCA. Another 99 determinations [54 in the healthy group (35.9 ± 9.1 years old; Male/Female: 11/7) and 45 in CFS patients (34.9 ± 7.0 years old; Male/Female: 8/7)] were masked and used for predictions. All samples were diluted 10-fold with phosphate-buffered saline and adjusted to a constant volume (2 ml) in a polystyrene cuvette before the Vis-NIR spectroscopic measurements. Three consecutive Vis-NIR spectra were measured at a resolution of 2 nm with an NIRGUN (Japan Fantec Research Institute, Shizuoka, Japan) at 37°C. The spectral data were collected as absorbance values [log(1/T)], where T= transmittance in the wavelength range from 600 to 1,100 nm. Pirouette software (ver. 3.11; Invest in ME Charity Nr 1114035 Infometrics) was employed for all data processing. To minimize differences between spectra caused by baseline shifts and noise, prior to calibration, spectral data were mean-centered and transformed by SNV [84] and smoothing based on the Savitsky-Golay algorithm [85]. To identify the predominant absorbance peaks in the spectra, PCA and SIMCA methods were further applied to develop PCA and SIMCA models for CFS diagnosis. A clear difference in the sera of CFS patients from those of healthy donors was seen in PCA scores using the first principal component (PC1) and second principal component (PC2) (Fig. 3A, B). The SIMCA model allowed correct separation of the Vis-NIR spectra of 209 of 213 (98.1%) healthy volunteers and 220 of 231 (95.2%) CFS patients. SIMCA using Coomans plots demonstrated that classes of sera from the volunteers and patients did not share multivariate space, providing validation for the separation (Fig. 4A, C). Furthermore, masked samples were subjected to Vis-NIR spectroscopy, and predictions made with the PCA and SIMCA models. PCA clearly distinguished the masked samples of the healthy volunteers from those of the CFS patients (Fig. 3C). SIMCA correctly predicted 54 of 54 (100%) volunteers and 42 of 45 (93.3%) patients (Fig. 4B, D). These results suggest that combining Vis-NIR spectroscopy with chemometrics is a promising way to objectively diagnose CFS. They also suggest that an unknown factor or factors present in the serum of all CFS patients could provide important clues as to the agent causing this debilitating disease. We concede that statistically, the results are not robust enough for clinical use at this time. The PCA and SIMCA model was developed from Vis-NIR (continued on page 13) Page 12/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) Fig. 3. PCA of Vis-NIR spectra of serum samples for CFS diagnosis (A-B) Vis-NIR spectra of serum samples from healthy donors (Blue) and CFS patients (Red) were subjected to PCA and the results plotted as PC1 versus PC2 to establish a PCA model (A). Loadings show the importance of each wavelength for the PCs indicated by peaks (B). (C) Masked samples, which were not used for development of the model, were subjected to PCA and the results plotted as PC1 versus PC2. Modified from Fig. 1 in Sakudo et al. [86] with permission from Elsevier. spectra of 148 individuals including 77 CFS patients and 71 healthy donors, not a sufficient number for practical use in the clinic. The influences of sex and race, etc. on the results of this diagnostic method remain unclear. To obtain more Vis-NIR spectra, samples for the calibration set should be obtained in a similar way to those that will be analyzed for diagnosis. Furthermore, uniformity of the solvent among samples is very important. For example, in blood samples, identical methods of preparation of serum are necessary. Stable humidity and temperature should be maintained during the scanning event, because humidity and temperature may affect water absorption in the NIR region. In this study, we used serum samples for Vis-NIR spectroscopy. Therefore, the method is invasive but nondestructive. Vis-NIR spectroscopy can also be applied to non-invasive analyse and we are now approaching the Invest in ME Charity Nr 1114035 non- invasive diagnosis of CFS (Fig. 5).Hopefully, after these issues are addressed, this diagnostic method might be adopted in the clinic (Fig 6). The next step in terms of research into the disease, as opposed to diagnosis, is to use this approach together with other evidence to try and identify specific biochemical markers common to CFS. This is the best way to understand the cause of CFS. Our experimental system coupling Vis-NIR spectroscopy with chemometrics may also contribute to this issue. Finally, we would like to emphasize that international collaboration is important in the development of this method, because CFS is heterogeneous and diagnostic criteria differ slightly among countries. Differences and similarities between CFS and CFS-like diseases such as ME, PVFS, CFIDS, and ‘Yuppie flu’ would also be made clear by this method. (continued on page 14) Page 13/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) Fig. 4. SIMCA analysis of Vis-NIR spectra of serum samples for CFS diagnosis (A-B) Vis-NIR spectra of serum samples from healthy donors (Blue) and CFS patients (Red) were subjected to SIMCA. Coomans plots show distances to model of healthy donors versus CFS patients to establish a SIMCA model (A). Discriminating power shows the importance of each wavelength for distinguishing healthy donors from CFS patients (B). (C) Masked samples, which were not used for development of the model, were subjected to SIMCA. Coomans plots show distances to model of healthy donors versus CFS patients. Modified from Fig. 2 in Sakudo et al. [86] with permission from Elsevier. References [1] K. Fukuda, S.E. Straus, I. Hickie, M.C. Sharpe, J.G. Dobbins, and A. 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Whistler, E. Aslakson, M. Rajeevan, and W.C. Reeves, Challenges for molecular profiling of chronic fatigue syndrome. Pharmacogenomics 7 (2006) 211-8. (continued on page 15) Page 14/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) [7] S. Nioka, and B. Chance, NIR spectroscopic detection of breast cancer. Technol Cancer Res Treat 4 (2005) 497512. [8] K. Konig, Multiphoton microscopy in life sciences. J Microsc 200 (2000) 83-104. [9] I. Murray, Forage analysis by near infra-red spectroscopy, in: A. Davies, R.D. Baker, S.A. Grant (Eds.), Sward Management Handbook, British Grassland Society, UK, 1993, pp. 285-312. [10] B.L. Horecker, The absorbance spectra of hemoglobin and its derivatives in the visible and near infra-red regions. J Biol Chem 148 (1973) 173-83. [11] K. Murayama, K. Yamada, R. Tsenkova, Y. Wang, Y. 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Journal of IiME Volume 1 Issue 2 www.investinme.org Visible and near-infrared (Vis-NIR) spectroscopy: Introduction and Perspectives for Diagnosis of CFS (continued) Fig. 6. Comparison of current CFS diagnosis and future Vis-NIR CFS diagnosis Currently, CFS can only be diagnosed by skilled doctors. The diagnosis requires experience and sophisticated techniques. Furthermore, even with a skilled doctor, it takes long time to reach a final clinical diagnosis. Vis-NIR spectroscopy would enable an objective and rapid diagnosis. Moreover, it would not require experience and skill. Modified from Fig. 2 in Sakudo et al. [103] with permission from Nippon Rinsho Co. [30] H.M. Heise, Applications of near-infrared spectroscopy in medical sciences, in: H.W. Siesler, Y. Ozaki, S. Kawata (Eds.), Near-infrared spectroscopy (Principles, instruments, applications), Wiley-VCH, Weinheim, 2002, pp. 289-333. [31] D. Lafrance, L. Lands, D. 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Tamura, Impaired interhemispheric integration in brain oxygenation and hemodynamics in schizophrenia. Eur Arch Psychiatry Clin Neurosci 244 (1994) 17-25. [102] A. Koike, H. Itoh, R. Oohara, M. Hoshimoto, A. Tajima, T. Aizawa, and L.T. Fu, Cerebral oxygenation during exercise in cardiac patients. Chest 125 (2004) 18290. [103] A. Sakudo, H. Kuratsune, Y. Hakariya, T. Kobayashi, and K. Ikuta, Spectroscopic diagnosis of chronic fatigue syndrome by multivariate analysis of visible and nearinfrared spectra. Nippon Rinsho 65 (2007) 1051-6. Page 18/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Identification of Differential Genetic Profiles in Severe Forms of Fibromyalgia and Chronic Fatigue Syndrome in the UK population by Estibaliz Olano Fibromyalgia (FMS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) are two controversial diseases with overlapping symptoms, difficult to distinguish and diagnose properly with clinical criteria. To date there are no biological markers for either condition and are diagnosed using separate but overlapping clinical criteria. All too often the patients concerns are dismissed as imaginary or unimportant and only recently they have started to be recognized and accepted by physicians. Since recent studies have started to point out the genetic background of these diseases, Progenika Biopharma, S.A. has developed a new system of DNA testing for the diagnosis and prognosis in Fibromyalgia and Chronic Fatigue Syndrome. A multidisciplinary group led by Dr. Ferrán García, Head of Rheumatology (Clínica CIMA, Barcelona), Dr. Joaquim Fernández Solá, Unit of Chronic Fatigue Syndrome (Hospital Clínic, Barcelona) and Dr. Jose Ignacio Lao, Unit of Molecular Genetics (Echevarne Laboratorie) started this research five years ago, by looking at different mutations (SNPs) associated with FM and CFS/ME. 99.8% of the genetic information is homogenous among humans, and only 0.2% is variable. These differences in our DNA can be due insertions or deletions (e.g. familial hypercholesterolemia), repeat sequences (e.g. Huntington disease CAG repeats) or Single nucleotide polymorphisms – SNPs. These SNPs are changes (mutations) of only one of the nucleotides (“building blocks”) that forms the DNA, and they account of up to 90% of the variability encountered between humans. Variations in these DNA sequences of humans can affect how we develop diseases, respond to pathogens, chemicals, drugs, etc. Therefore, SNP analysis has the potential for identification of markers for genetic predisposition to disease or even define subtypes within diseases with different prognosis, severity, drug response ..... Some of the results of this ongoing study have been presented in the 8th International IACFS Conference on Chronic Fatigue Syndrome, Fibromyalgia and other Related Illnesses held in Florida and in the ME Research conference held in Edinburgh and are summarised here: Among the individuals register in the “Fibromyalgia and/or Chronic Fatigue Syndrome patients Record” (www.fundacionfatiga.org/registro_pacientes.htm) 1500 subjects diagnosed with FM, CFS/ME or both were randomly selected and invited to participate in the study. From these, 1371 gave written consent to take part and filled in a questionnaire which included details about their diagnosis, familiar diagnosis of FM or CFS/ME and presence of mental disorders. In addition, those patients were also asked to answer the Fibromyalgia Impact Questionnaire (FIQ) for FM (Burckhardt et al., 1991; Bennett, 2005) and the CDC Invest in ME Charity Nr 1114035 Dr. Estibaliz Olano Dr. Olano is a senior scientist at Progenika Biopharma (a biotech company based in Bilbao, Spain). She is responsible for investigating the genetic profiling via SNP analysis by using it as an effective tool to discriminate between the more severe forms of fibromyalgia and chronic fatigue syndrome. Symptom Inventory (CSI) for CFS/ME (Wagner et al., 2005) and to provide a blood sample for DNA extraction. Taking into account that there is a recognized gender bias in FIQ (Bennett, 2005), eventually only women were included in the study. Previous treatment for psychiatric disorders was also considered an exclusion criterion. At the end of the selection process the number of recruited subjects was reduced to 403 patients (186 FM patients aged 45-54 years and 217 CFS patients aged 30-39 years). These cases were clinically diagnosed according to the 1990 American College of Rheumatology (ACR) classification for FM (Wolfe et al., 1990) or the US Centres for Disease Control criteria for CFS developed by Fukuda et al.1994 at the Hospital Clinic and Clinica CIMA (Barcelona, Spain). For each sample one hundred and seven SNPs were genotyped by SNPlexTM. An independent second association study with 282 women (126 FM / 156 CFS) was used to validate the results. We identified 15 SNPs able to discriminate between FM and CFS patients with a 11·5 Likelihood Ratio (LR+, 95% specificity). The analysis of further SNPs allowed differential genetic profiling between the most aggressive FM phenotype and the mild forms (12·4 LR+) and between a severe CFS phenotype and a milder one (12·4 LR+). (continued on page 20 Page 19/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Identification of Differential Genetic Profiles in Severe Forms of Fibromyalgia and Chronic Fatigue Syndrome in the UK population (continued) In this study we prove that genetic profiling via SNP analysis can be a very effective tool to discriminate between the more severe FM and CFS cases. In addition we claim that FM and CFS are two separate diseases with an important genetic component, and we suggest that the severe cases might be different disease subtypes with distinctive genetic profiles. However this methodology is still dependable of a preliminary reliable diagnose that fulfils all the disease inclusion and exclusion criteria. These first results of the research carried out so far has lead to the design of “FIBROchip”, a DNAchip for the identification of the patient’s genetic predisposition to develop the most aggressive forms of Fibromyalgia and Chronic Fatigue Syndrome / Myalgic Encephalomyelitis. On the genetic profile base, FIBROchip is able to differentiate between the patients with Fibromyalgia and Chronic Fatigue Syndrome. Additionally, being based on the information provided by FIBROchip, the doctor will be able to know if his patient can develop a Fibromyalgia and Chronic Fatigue Syndrome very severe. The main target of the DNA chip is to identify those patients who have a greater possibility of developing the most aggressive forms of the diseases and this way to apply the most suitable treatment to each patient. The investigation project is in the last phase of clinical validation, and is predicted that their exit to the market is at the end of this year. ME Story Now at 35 I'm 99% bedridden, I am paralysed down the right hand side and in both legs. I am incontinent and have a supapubic catheter fitted through my stomach into my bladder. Four years ago, I was forced to go into an old people's Nursing home as we didn't have enough room downstairs for me to have a bedroom where I could be hoisted. Therefore my O.T. involved a man from disability grants who agreed to fund the building of an extension in which I have a ceiling track hoist, as I can't transfer myself at all, that takes me from my small bedroom into an en-suite shower room & Closomat toilet. I spent 2 years in the nursing home while this was being completed where I deteriorated further, I have between 35-40 symptoms related to M.E including an immune deficiency. Chemical sensitivity disorder, brain fog etc... I am a member of the 25% M.E group who are the only support group for the one Facts About IiME IiME’s May conferences in London have attracted speakers and delegates from all parts of the world. The conference DVDs have sold in twenty countries worldwide. quarter of all M.E sufferers who have severe M.E Some days I feel so ill that I want to go to sleep and never wake up !!! -Mattie Petition to Retain GPs’ Rights to Issue Sickness Notes This E-petition to the Prime Minister, seeks to prevent the application of the return to work legislation that will be overseen by work advisors in surgeries. It will adversely affect chronically ill people like sick Gulf War veterans, ME-CFS sufferers, pesticide poisoned people and MCS sufferers. Text from the petition creator – The administration is seeking to cut the number of people claiming incapacity benefit but penalising poorly people in need of a sick note is not ethical. Making sick people have to mess around even more is counterproductive. GP's have not complained about issuing sick notes all these years, they are professionally trained, well paid, and should be able to deal with this. I see no reason to change what is a decent scheme. "We the undersigned petition the Prime Minister to carry on allowing all GPs to issue sick notes to patients and not alter legislation concerning GP's issuing sick notes themselves.." http://petitions.pm.gov.uk/SickNotesGPs Invest in ME Charity Nr 1114035 Page 20/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Can "molecular addressing" correct mitochondrial diseases? Mitochondria are the power plants of the cell and perform most of the chemical reactions that transform sugars into usable energy. Mitochondrial diseases are estimated to affect at least 1 in 5000 people and can lead to a variety of serious diseases. Many of the genes responsible for energy production are made up of mitochondrial DNA, rather than DNA in the cell's nucleus - and an obvious solution to mitochondrial errors would be to introduce a normal copy of the defective gene into the mitochondrial DNA. Dr. Marisol Corral-Debrinski and her colleagues at the Pierre and Marie Curie University in Paris, France, picked two mitochondrial gene mutations. The team tagged normal versions of these genes with two separate cellular "address codes" and inserted them into the cytoplasm of cells grown in a lab dish. The first code directs the messenger RNA - the molecule that carries the instructions for making a protein - to the surface of the mitochondria, ensuring that the protein gets made at the mitochondrial membrane. The second address code, known as the mitochondrial targeting sequence, tells the protein to enter the mitochondria. These double-tagged genes were able to reverse the effect of both mitochondrial mutations in cell cultures for up to a year. Corral-Debrinski is now planning to test the gene therapy on laboratory mice. Although not directly affecting ME we felt that Marisol’s work on mitochondria might be of interest. Marisol allowed IiME to publish three of her research papers in the Journal but, unfortunately, we have been unable to get the permission to from the publishers to include them here. So instead Marisol has kindly produced the following article describing her work. Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface By Marisol Corral-Debrinski1 1 Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U592, Université Pierre et Marie Curie (UPMC-Paris6), Hôpital St. Antoine–Bât. Kourilsky, Paris, France. 2 INSERM U676, Hôpital Robert Debré 48, Paris, France. Mitochondrial diseases encompass an extraordinary assemblage of clinical problems, commonly involving tissues that have high energy requirements, such as retina, brain, heart, muscle, and endocrine systems. The clinical presentations range from fatal infantile disease to muscle weakness and most of them are characterized by inexorable progression. Recent epidemiological studies have shown that mitochondrial disorders have a prevalence of at least one in 5000, making them probably the most common form of metabolic disorders. 300 mitochondrial DNA (mtDNA) alterations have been identified as the genetic cause of approximately 30 % of these diseases. Moreover, the spectrum of mitochondrial diseases has been expanded by the recognition that mutations in the genes for nuclear-encoded mitochondrial proteins cause not only a number of neurodegenerative diseases but also haematological and ophthalmological disorders. Hence, finding ways to fight these devastating disorders especially in the case of neuromuscular degeneration is the main objective of many laboratories worldwide. Since almost four years we are using the phenomenon of mRNA localization to the mitochondrial surface aimed at developing a therapeutic strategy for replacing inactive proteins inside the mitochondria. Hence, we have optimized the nuclear expression of ATP6, ND1 and ND4 genes, originally located in the organelle, by the addition of cis-acting elements which ensures the transport of their transcripts to the mitochondrial surface. The optimization of this approach, known as "allotopic expression" have led to the complete and long-lasting rescue of mitochondrial dysfunction in fibroblasts from patients harboring a deleterious mutation in either ATP6, ND1 or ND4 genes. Because of their highly sophisticated function in the visual process retinal cells contain a large number of mitochondria. Therefore, any impairment in mitochondrial function leads to retinal cell degeneration that arises from mutations in genes encoding mitochondrial proteins located in either nuclear or mitochondrial genomes, such as neurogenic muscle weakness Ataxia Retinitis Pigmentosa (NARP), Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA). As for the other mitochondrial disorders, no cure is available. Since, the eye is an excellent target organ for gene therapy, given its small size, its relative anatomical isolation and the ease with which vectors can be delivered to retinal cells we have decided to apply our optimized approach as a first step for treating neuromuscular diseases dues to mitochondrial dysfunction. Ultimately, our most important goal is to provide a gene therapy that will impede blindness of adults brutally affected by LHON or DOA, this therapy will subsequently become available for an array of neuromuscular degenerations caused by mutations in both nuclear and mitochondrial DNA genes encoding mitochondrial proteins. Invest in ME Charity Nr 1114035 (continued on page 22) Page 21/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) A. Introduction Mitochondria play a central role in intermediary metabolism, energy production, ion homeostasis and apoptosis 1. Impairment of mitochondrial function is the key pathogenic factor in a growing number of human diseases. Indeed, primary defects in mitochondrial oxidative phosphorylation (OXPHOS) function are implicated in over 130 diseases 2. Their clinical presentations range from fatal infantile disease to adult muscle weakness and/or nervous system dysfunction. Moreover, mitochondrial impairment can lead to tumor formation and probably play a role in the aging process 3 . Mitochondrial OXPHOS disorders are far more common than was previously anticipated. Recent epidemiological studies have shown that their prevalence is at least one in 5000, making this group of diseases probably the most frequent form of metabolic disorders 4. Approximately 300 mitochondrial DNA (mtDNA) alterations have been identified as the genetic cause of mitochondrial diseases, one-third of which are located in coding genes for OXPHOS proteins 5. Despite, more than 70% of human degenerative diseases involving mitochondrial deficiencies remain unravelled at the molecular level; since they are caused by mutations in nuclear-encoded mitochondrial proteins. Hence, only 56 nuclear genes encoding mitochondrial proteins underly clinical mitochondrial disorders 6. The main obstacle encountered for the identification of disease causing genes is that at least half of the 1500 estimated mitochondrial proteins 7 is not yet discovered; indeed, up until today only 807 are ascribed to the most extensive database of human mitochondrial proteins (http://www.mitop.de:8080/mitop2 ), 8. The understanding of the pathogenesis of mitochondrial diseases has improved considerably in the last decade. Nevertheless, the most disappointing area is the lack of efficient treatment for patients with mitochondrial diseases. Indeed, they are still treated with vitamin and cofactor mixtures, harmless but largely inadequate and inefficient. Ocular involvement is a prevalent feature in mitochondrial diseases, indeed retina cells contain a large number of mitochondria, reflecting their high requirements for OXPHOS 9. Moreover, mitochondrial impairment may contribute to changes in macular function observed in aging and age-related macular dystrophy 10. Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA) are both non-syndromic optic neuropathies with a mitochondrial etiology. LHON is associated with point mutations in the mitochondrial genome. The majority of DOA patients harbor mutations in the nuclear-encoded protein OPA1 which is targeted to mitochondria. In both disorders the retinal ganglion cells (RGCs) are specific cellular targets of the degenerative process 11. Neurogenic muscle weakness, Ataxia, Retinitis Pigmentosa (NARP) syndrome is due to a point mutation in the mitochondrial ATP6 gene. The most common ocular feature associated with the mutation is retinal Invest in ME Charity Nr 1114035 dystrophy, with a substantial variability in rod and cone photoreceptor manifestations 9. As for other visual impairments or mitochondrial disorders, no efficient therapies are available at the present time and current understanding of the cellular and molecular mechanisms underlying retinal cell death due to mitochondrial dysfunction is still quite limited. Remarkably, the eye has a combination of features that make it ideally suited as a target organ for gene therapy. The highly compartmentalized anatomy of the eye facilitates accurate delivery of vectors at target sites within the globe especially at the vicinity of retinal cells, which minimizes systemic dissemination and unwanted systemic effects. The blood retinal barrier and the retinal pigment epithelium (RPE), anatomically protect a wide-spread diffusion of the vectors to the systemic circulation. These barriers also provide a beneficial effect in protecting the retina from the immune response 12. Retinal function can be easily monitored with non-invasive and quantitative tests such as ophthalmoscopy, electroretinogram (ERG), optical coherence tomography (OCT), and visual evoked potentials (VEP). Moreover, appropriate animal models resembling human retinal abnormalities are available for the development of experimental therapies. Notable successes have been achieved by gene replacement strategies in some of these models. For instance, the Swedish Briand dog is a model for a null mutation in the RPE65 gene. This gene encodes an RPE-specific visual cycle isomerase involved in the synthesis of 11-cis retinal. Mutations in the RPE65 gene are responsible of Leber’s Congenital Amaurosis (LCA), representing a group of severe earlyonset retinal dystrophies 13. The fact that there are close similarities between human and Briand dogs, in terms of the clinical characteristics of the disease allowed the evaluation of gene replacement therapy. Thus, three independents groups have now reported the restoration of vision in these dogs by the use of recombinant AAV vector-mediated delivery of the RPE65 gene 14, 15, 16. These recent advances have enabled the development of proposals for clinical trials of gene therapy for ocular diseases. In May 2007, the first patient, out of 12, has been treated with the rAAV2-RPE65 vector (Dr. R. Ali, College University, London) at the ophthalmologic hospital of Moorfields in London. This is the first step of phase I/II doseescalation clinical trial for this severe early-onset retinal degeneration. Dr. F. Rolling (INSERM U 649, Nantes) will conduct a clinical trial in 2009. Our main objective is to develop in the near future a gene therapy that could be both preventive and curative for retinal dystrophies due to mitochondrial dysfunctions. In this purpose we were mostly interested in the LHON disease. LHON was the first maternally inherited disease to be associated with point mutations in mtDNA and is now considered the most (continued on page 23) Page 22/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) common mitochondrial disorder with an estimated prevalence of 1 in 25,000 in north-east England. The pathology is characterized by selective death of RGCs leading to central vision loss and optic nerve atrophy, prevalently in young males. The age of onset of visual loss ranges from 8 to 60, typically occurs between ages of 15 and 35 years. The course of visual loss is generally acute or subacute, both eyes are involved sequentially. The average time interval between affected eyes is approximately two months, the duration of progression of visual loss in each eye averaged approximately four months 17. LHON is a devastating disorder with the majority of patients showing no functional improvement and remaining within the legal requirement for blind registration. The three most common pathogenic mutations found in about 95% of LHON’s patients are located in ND1 (G3460A), ND4 (G11778A) or ND6 (T14484C) genes. They encoded subunits of the respiratory chain complex I and the mutations have the double effect of lowering ATP synthesis and increasing oxidative stress chronically 17. Although, extensive studies were conducted since more than 15 years, the pathogenesis of LHON is poorly understood. One recent hypothesis suggests that the pathophysiology of optic neuropathies does not just involve the disorder of ATP production by mitochondria but that the non-maintenance of the sharp mitochondrial gradient at the optic nerve head constitutes the first step in a vicious event cycle that further compromises neuronal respiration and that would eventually lead to profound energy depletion, the increased production of toxic free radicals and neuronal cell death through apoptosis 18, 19. LHON, as the other mitochondrial diseases, is resistant to treatments with quinone analogs, vitamines or oxygen radical scavengers, which were harmless but very inefficient in most of the cases 20. Therefore, the allotopic expression (expression of mitochondrial genes transferred to the nucleus) of some of mtDNA genes has been tried in cybrid cells as a possible therapeutic option to cure mitochondrial diseases. However, several attempts failed to obtain a complete and long-lasting rescue of the mitochondrial defect in cells harboring mutations of mtDNA genes 21, 22, 23. Probably, the highly hydrophobic nature of proteins encoded by the mitochondrial genome represents a physical impediment to mitochondrial import. Therefore, up until today important limitations are found to the allotopic expression as a therapeutic approach for mtDNA-related diseases 24. In previous studies, we demonstrated that in the yeast Saccharomyces cerevisiae, 47% of mRNAs encoding mitochondrialproteins are transported to the organelle surface 25. This phenomenon represents a key step to ensure the proper import and functionality of the corresponding polypeptides inside the organelle 26 and is conserved in human cells 27. The delivery of mRNAs to the organelle surface depends on two sequences: the region coding for the mitochondrial targeting sequence (MTS) and the 3’ untranslated region (3’UTR) 28. Invest in ME Charity Nr 1114035 Thus, we decided to optimize the allotopic expression for mtDNA genes by ensuring the delivery of corresponding mRNAs to the organelle surface. This optimization will prepare the development of an effective treatment for mitochondrial disorders due to mtDNA mutations. The research project of our team is conducted since 2004 along the following complementary axes: Optimize the allotopic expression of mtDNA genes. Rescue of respiratory chain defects in cells harboring different mutations in mtDNA encoded genes. B. Previous activities of our team: 2004-2007 I. Optimization of the allotopic expression of mtDNA genes (Kaltimbacher et al., RNA : 12, 1408-1417 ; 2006) Recently, we have shown that a protein which is normally encoded by mtDNA was efficiently translocated into the mitochondria of HeLa cells by the use of signals that force its mRNA, transcribed in the nucleus, to localize to the organelle surface. We constructed a nuclear version of the mtDNA-encoded ATP6 gene flanked by cis-acting elements of either COX10 or SOD2 mRNAs, which localizes to the mitochondrial surface in HeLa cells 27, 29. The rationale behind this was that mRNA targeting to the mitochondrial surface will lead to a tight coupling between both translation and translocation processes, which should be required for highly hydrophobic proteins, such as ATP6. Noteworthy, when both the MTS and the 3’UTR of SOD2 or COX10 a highly efficient mitochondrial translocation of the ATP6 was observed (Fig.1). Notably, ATP6 protein was insensitive to proteolysis in the presence of detergent, suggesting that it probably was assembled in the complex V of the respiratory chain 30. (continued on page 24) ME Facts Mitochondrial dysfunction provides a physiological basis for the debilitating and overwhelming fatigue suffered by ME/CFS patients whilst the changes in the NTE (neuropathy target esterase) gene provide an intriguing link with OP poisoning and nerve agent exposure found in GWS. - Group for Scientific Research into ME 2006 (http://www.erythos.com/gibsonenquiry/Repor t.html) Page 23/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) Figure 1: Enrichment at the mitochondrial surface of the nATP6 mRNA led to an efficient mitochondrial import of the corresponding protein A. The amount hybrid nATP6 mRNA was determined by RTPCR in RNA purifications obtained from free polysomes (FP) and mitochondrion-bound polysomes (MP). The distribution of the endogenous mRNAs SOD2 and ATP6 were also examined in both polysome fractions. Four independent experiments were compared, the results obtained are illustrated as bar graphs. The presence of the SOD2 MTS in the nATP6 mRNA allowed its enrichment in the MP fraction. Nevertheless, both the MTS and 3’UTR were required in the hybrid mRNA for allowing its exclusively sorting to the mitochondrial surface. B. The amount of the chimeric ATP6 protein was evaluated in six independent mitochondrial purifications subjected to Proteinase K (PK) digestion. This amount was compared to the quantity of ATPα protein insensitive to PK proteolysis. When the synthesis of ATP6 was directed by the gene in which both the MTS and 3’UTR of SOD2 were present, the amount of fully translocated ATP6 protein was not significantly different to the ATPα protein (bar graphs). (continued on page 25) Invest in ME Charity Nr 1114035 Page 24/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) II. Rescue of respiratory chain defects in fibroblasts harboring mutations in ATP6 and ND4 genes (Bonnet et al., Rejuvenation Research : 10, 128-144 ; 2007) With the aim of determining whether allotopically expressed mtDNA-encoded genes could rescue mitochondrial dysfunction, we examined human cultured skin fibroblasts harboring either the NARP T8993G ATP6 mutation or the LHON G11778A ND4 mutation, allotopically expressing the recoded ATP6 or ND4 wild-type genes. Mitochondrial function was evaluated by the measurement of (i) cell ability to grow in galactose medium, which force them to rely on OXPHOS; (ii) in vitro ATP synthesis using respiratory chain substrates; (iii) enzymatic activity of respiratory chain complexes I and V 31. We were able to demonstrate that the allotopic expression of engineered ATP6 and ND4 genes in human fibroblasts harboring either of these genes mutated leads to a complete and long-lasting restoration of respiratory chain function 32 (Tables 1 and 2). Notably, we examined a second LHON patient harboring the G3460A substitution in the ND1 gene. Our optimized allotopic approach significantly rescued respiratory chain I deficiency in these cells. Therefore, our approach for ND1, ND4 and ATP6 genes ensures the efficient mitochondrial translocation of the corresponding precursors, probably via a co-translational pathway. The rescue of mitochondrial dysfunction indicated that the processed polypeptides were fully functional within their respective respiratory chain complexes and, therefore, able to compensate for the endogenous inactive proteins 32, and C.Bonnet, S. Augustin et al. (manuscript submitted, 2007) . (continued on page 26) Table 1: In vitro ATP synthesis rate µM ATP/min/106 cells Complex I substrats Complex II substratI P value ; n Complex I substrats Complex II substrats Control NARP NARP + nATP6 Control LHON LHON + nND4 2081.9 ± 138.1 805.6 ± 262.4 2045.52 ± 428.7 1962.1 ± 352.1 793.3 ± 493.7 1659.4 ± 245.5 1563.1 ± 214.0 400.7 ± 221.7 1659.6 ± 522.5 1266.3 ± 62.1 658.7 ± 185.2 1929.7 ± 480.2 0.004 ; n = 5 0.0013 ; n = 4 0.0003 ; n = 5 0.0022 ; n = 4 P values shown in the third column were obtained according to the Student’s t test for the pairs NARP/ NARP + nATP6 or LHON/ LHON + nND4 for data collected for either complex I or complex II substrates. "n" indicates the number of independent measurements performed. LHON fibroblasts showed a decreased ATP syhtesis rate when complexe II substrates were uses. This result suggests a general perturbation of the respiratory chain activity. Notably, this activity was fully restored by the allotopic expression of ND4. Invest in ME Charity Nr 1114035 Page 25/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) Table 2 : Complexes I and V activity measurements in NARP and LHON fibroblasts after normalisation with the values obtained in control fibroblasts Complexe I Complexe V NARP 1 NARP + nATP6 1 LHON 0.6 ± 0,12 1.05 ± 0,23 0.47 ± 0.009 1 LHON + nND4 0.97 ± 0.24 1 < 0.0001 ; n = 9 P values shown in the fourth column were obtained according to the Student’s t test for the pairs NARP/ NARP + nATP6 or LHON/ LHON + nND4. "n" indicates the number of independent measurements performed. Complex I activity in NARP cells was identical to that measured in control fibroblasts (1). Complex V activiy in LHON fibrolbasts was not different to the one measured in control cells (1). Complex I and V activities were fully restored in LHON and NARP fibroblasts by the optimized allotopic expression of ND4 and ATP6 genes respectively. C. Research Project We are aware that the optimization of allotopic expression represents a real hope for patients suffering from diseases caused by mutations in mtDNA genes. However, all our efforts will remain unfruitful if the biosafety and the beneficial to mitochondrial function of our vectors are not proved in experimental models for mitochondrial diseases. Since, this proof is the mandatory step required before any attempt to the transfer to clinic, it becomes our highest priority. Unfortunately, only one animal model for mtDNA gene invalidation is available. These mice carry a mutation in the mitochondrial COXI gene leading to a decreased cytochome oxydase (COX) activity in several tissues 33. Even though, they do not have any visual impairment, we will try to rescue their muscle COX deficiency using our strategy. Additionally, we decided to use the optimized allotopic expression approach to create an animal model which will mimic LHON disease. First, we performed in vitro mutagenesis of the wild-type engineered human ND4 gene to obtain a nuclear version harboring the G11778A substitution. This mutation, responsible of 60% of LHON cases, converts a highly conserved arginine to histidine at codon 340 17. Each nuclear version of ND4 was combined with the two mRNA targeting sequences of the COX10 gene, which ensures the efficient delivery of the polypeptides inside the organelle 32 . We developed an in vivo electroporation (ELP) method to introduce either the wild-type or the mutated version of ND4 into retinal ganglion cells (RGCs) Invest in ME Charity Nr 1114035 of adult rats, as recently described 34. If we confirm that the animal model generated share an array of similarities with the clinical manifestations of LHON, we will assess the ability of our vector to protect RGCs. If we can demonstrate the proof-of-principle that our approach results in significant quantifiable improvements of RGC function in the experimental model of LHON that we generated we will open the door to gene therapy for retinal degenerations due to mutations in mtDNA. Expected consequences for knowledge in the field of medicine and public health Retinal dystrophies with mitochondrial etiology are inaccessible to curative or pallialtive therapy. Our knowledge on mRNA sorting to mitochondrial surface and its involvement in the organelle biogenesis makes this phenomenon a promising tool to fight these diseases. The transfer to clinic of our gene therapy protocol will undoubtedly represent a major step for the generation of a treatment aimed at improving life conditions of patients suffering for diseases such as LHON or DOA. We can envisage if these trails are successfull that clinical studies on other visual handicaps leading to blindness such as glaucoma 35 and devastating neurodegenerative disorders such as Charcot-Marie Tooth 36 could begin. (continued on page 27) Page 26/72 < 0.0001 ; n = 8 P value ; n Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) Our position in the international research field Mitochondrial disorders can not be ignored anymore in most medical areas. They include specific and widespread organ involvement, with tissue degeneration or tumor formation. Primary or secondary actors, mitochondrial dysfunctions are also playing a role in the ageing process. Despite the progresses made in the identification of their molecular bases, nearly all remains to be done as regards therapy. Research dealing with mitochondrial physiology and pathology has almost 20 years of history all over the world. We are involved, as many other laboratories, in the challenge to find ways to fight these diseases. However, our main limitation is the absence of animal models required for both the understanding of the molecular mechanisms underlying the diseases and to evaluate therapeutic strategies. This is especially true for diseases due to mtDNA mutations, an American team has recently described a strategy similar to the one we have developed, to induce retinal ganglion cell degeneration in mice 37. Nevertheless, their strategy encounters the limitation of the inefficient mitochondrial import of the protein and will not generate a robust experimental model to evaluate putative treatments. If we succeed in creating a long-term animal model for the mitochondrial ND4 mutation and in confirming that it shares similarities with LHON, it will certainly allow the rapid development of new model systems for studying mtDNA mutations which are to date extremely rare. Most importantly, our protocol of gene replacement therapy for both the rat model and the Harlequin mouse strain will permit the development of clinical trials to treat patients suffering for visual impairment due to mitochondrial dysfunction. These clinical studies will be performed in the Vision Institute, a guarantee of expertise, rigour and thorough. Therefore, we are convinced that we possess a significant advance in comparison to laboratories working in the field worldwide. Bibliography 1. Orrenius S GV, Zhivotovsky. Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol. 2007;47:143-183. 2. McFarland R TR, Turnbull DM. Mitochondrial disease-its impact, etiology, and pathology. Curr Top Dev Biol. 2007;77:113-155. 3. Singh KK. Mitochondria damage checkpoint, aging, and cancer. Ann. N. Y. Acad. Sci. 2006;1067:182-190. 4. Schaefer A.M, Taylor R. W., Turnbull D. M., P.F C. The epidemiology of mitochondrial disorders -past, present and future. Biochem. Biophys. Acta 2004;1659:115-120. 5. Shapira AHV. Mitochondrial disease. Lancet 2006;368:70-82. Invest in ME Charity Nr 1114035 (continued on page 28) Page 27/72 Mitochondrial disorders can not be ignored anymore in most medical areas. They include specific and widespread organ involvement, with tissue degeneration or tumor formation. Primary or secondary actors, mitochondrial dysfunctions are also playing a role in the ageing process. Despite the progresses made in the identification of their molecular bases, nearly all remains to be done as regards therapy. 6. Calvo S JM, Xie X, Sheth SA, Chang B, Goldberger OA, Spinazzola A, Zeviani M, Carr SA, Mootha VK. Systematic identification of human mitochondrial disease genes through integrative genomics. Nat. Genet. 2006;38:576-582 7. Taylor SW, Fahy E, Ghosh SS. Global organellar proteomics. Trends in Biotech. 2003;21(2):82-88. 8. Prokisch H AC, Ahting U, Heiss K, Ruepp A, Scharfe C, Meitinger T. MitoP2: the mitochondrial proteome database--now including mouse data. Nucleic Acids Res. 2006;34 (Database issue):D705-711. 9. Perkins GA EM, Fox DA. The structure-function correlates of mammalian rod and cone photoreceptor mitochondria: observations and unanswered questions. Mitochondrion 2004;4:695-703. 10. Feher J KI, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol. Aging 2006;27:983-993. 11. Votruba M. Molecular genetic basis of primary inherited optic neuropathies. Eye 2004;18:1126-1132. 12. Bainbridge J, Tan M, Ali R. Gene therapy progress and prospects: the eye. Gene Ther. 2006;13:1191-1197. 13. Hanein S, Perrault, J., Gerber, S., Tanguy, G., Rozet, J.M. and Kaplan, J. Leber congenital amaurosis: survey of the genetic heterogeneity, refinement of the clinical definition and phenotype-genotype correlations as a strategy for molecular diagnosis. Clinical and molecular survey in LCA. Adv. Exp. Med. Biol. 2006;572:15-20.

Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) 14. Acland G, Aguirre G, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat. Genet. 2001;28:92-95. 15. Narfstrom K, Vaegan M, Katz M, Bragadottir R, Rakoczy E, Seeliger M. Assessment of structure and function over a 3-year period after gene transfer in RPE65-/- dogs. Doc. Ophthalmol. 2005;111:39-48. 16. LeMeur G KS, AJ Smith, M Weber, JY Deschamps, D Nivard, A Mendes-Madeira, N Provost, Y Pereon, Y Cherel, RR Ali, C Hamel, P Moullier, F Rolling. Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther. 2007;14:292-303. 17. Yen M-Y, Wang A-G, Wei Y-H. Leber's hereditary optici neuropathy: A multifactorial disease. Prog. in Retina Eye Res. 2006;25:381-396. 18. Yu Wai Man CY CP, Griffiths PG. Optic neuropathies-importance of spatial distribution of mitochondria as well as function. Med Hypotheses 2005;65(6):1038-1042. 19. Carelli V LMC, Iommarini L, Carroccia R, Mattiazzi M, Sangiorgi S, Farne' S, Maresca A, Foscarini B, Lanzi L, Amadori M, Bellan M, Valentino ML. Mitochondrial optic neuropathies: how two genomes may kill the same cell type? Biosci. Rep. 2007;27:173-184. * Tel.: +33 1 40 01 13 66 fax: +33 1 49 28 66 63. 20. DiMauro S MM. Mitochondrial diseases: therapeutic approaches. Biosci. Rep. 2007;27:125-137. 21. Manfredi G., Fu J., Ojaimi J., et al. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene to the nucleus. Nature Genet. 2002;30:394-399. 22. Oca-Cossio J., KenyonL., Hao H., T MC. Limitations of allotopic expression of mitochondrial genes in mammalian cells. Genetics 2003;165:707-720. 23. Bokori-Brown M, Holt IJ. Expression of Alga1 nuclear ATP synthase subunit 6 in human cells results in protein targeting to mitochondria but no assembly into ATP synthase. Rejuvenation Res. 2006;9(4):455-469. 24. Smith PM, Ross GF, Taylor RW, Turnbull DM, Lightowlers RN. Strategies for treating disorders of the mitochondrial genome. Biochem. Biophys. Acta 2004;1659:232-239. 25. Sylvestre J., Vialette S., Corral-Debrinski M., C. J. Long mRNAs coding for yeast mitochondrial proteins of prokaryotic origin localize to the vicinity of mitochondria. Genome Biology 2003;4(7):R44.1-R44.9. (continued on page 29) E-mail address: corral@st-antoine.inserm.fr Additional articles from Marisol’s team can be found at the following sites: - ScienceDirect RNA Journal http://www.sciencedirect.com/science/journal/01674889 http://www.rnajournal.org/cgi/content/full/12/7/1408 Rejuvenation research http://www.liebertonline.com/doi/abs/10.1089/rej.2006.0526 Invest in ME Charity Nr 1114035 Page 28/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Gene therapy for mitochondrial dysfunctions using optimized mRNA transport to the mitochondrial surface (continued) 26. Margeot A, Blugeon C, J. Sylvestre, Jacq C, CorralDebrinski M. In Saccharomyces cerevisiae, ATP2 mRNA sorting to the vicinity of mitochondria is essential for respiratory function. EMBO J. 2002;21(24):6893-6904. 27. Sylvestre J, Margeot A, Jacq C, Dujardin G, CorralDebrinski M. The role of the 3'UTR in mRNA sorting to the vicinity of mitochondria is conserved from yeast to human cells. Mol. Biol. Cell 2003;14:3848-3856. 28. Corral-Debrinski M, Blugeon C, Jacq C. In yeast, the 3' Untranslated Region or the presequence of ATM1 is required for the exclusive localization of its mRNA to the vicinity of mitochondria. Mol. Cell Biol. 2000;20(21):78817892. 29. Ginsberg MD, Feliciello A, Jones JK, Avvedimento EV, Gottesman ME. PKA-dependent binding of mRNA to the mitochondrial AKAP121 protein. J. Mol. Biol. 2003;327(4):885-897. 30. Kaltimbacher V, C.Bonnet, Lecoeuvre G, Forster V, Sahel J-A, Corral-Debrinski M. mRNA localization to the mitochondrial surface allows the efficient translocation inside the organelle of a nuclear recoded ATP6 protein. RNA 2006;12(7):1408-1417. 31. Benit P., Goncalves S., Dassa E. P., Briere J.J., Martin G., Rustin. Three spectrophotometric assays for the measurement of the five respiratory chain complexes in minuscule biological samples. Clin Chim Acta. 2006;374(1-2):81-86. 32. Bonnet C, Kaltimbacher V, Ellouze S, et al. Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mtDNA mutations affecting complex I or V subunits. Rejuvenation Res. 2007;10:128-144. 33. Kasahara A IK, Yamaoka M, Ito M, Watanabe N, Akimoto M, Sato A, Nakada K, Endo H, Suda Y, Aizawa S, Hayashi J. Generation of trans-mitochondrial mice carrying homoplasmic mtDNAs with a missense mutation in a structural gene using ES cells. Hum Mol Genet 2006;15(6):871-881. 34. Ishikawa H TM, Matsumoto N, Sawada H, Ide C, Mimura O, Dezawa M. Effect of GDNF gene transfer into axotomized retinal ganglion cells using in vivo electroporation with a contact lens-type electrode. Gene Ther.2005;12(4):289-298. 35. Tezel G. Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog. Retin. Eye Res. 2006;25:490-513. 36. Züchner S MI, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schröder JM, Vance JM. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat. Genet. 2004;36:449-451. 37. Qi X SL, Lewin AS, Hauswirth WW, Guy J. The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse. Invest Ophthalmol Vis Sci 2007;48:1-10. ME Story In a few weeks time it will be the one year anniversary of my gorgeous and funny and talented sister's death. If you knew her before she got ill she was like a force of nature. Talented, funny, generous she had loads of friends and was very much a person who lived her life to the full. She had courage and was original and so much more. M.E. was the cruellest thing to ever happen to Sophia. I will not go on about how much she suffered because it is an unbelievable amount. To top it all her illness was not recognised as a neurological disease and so there was the added burden of trying to get the authorities to understand the true nature of her illness. Unfortunately for us all Sophia suffered even more than was necessary. My amazing sister has paid with her life but she all she wanted was that if only one person was helped by her experience it would all have been worth it for her. From Sophia Mirza's sister - Roisin Mirza (written in 2006) Invest in ME Charity Nr 1114035 Page 29/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Chronic Fatigue Syndrome after Q fever By Dr. Dragan Ledina Department of Infectious Diseases, Split University Hospital Center, Split; Croatia Summary Background: Q fever is a common and acute but rare chronic zoonosis caused by Coxiella burnetii. Its acute form manifests as atypical pneumonia, flu-like syndrome, or hepatitis. Some authors observed symptoms of chronic fatigue in a small number of patients after the acute phase of Q fever; in many cases serological assay confi rmed the activity of Coxiella burnetii infection. The effect of antibiotic therapy on post-Q-fever fatigue syndrome has not been studied in south-east Europe thus far. Case Reports: Three patients are presented with post-Q-fever fatigue syndrome. All fulfilled the CDC criteria for chronic fatigue syndrome. IgA antibodies to phase I of the growth cycle of Coxiella burnetii were positive in two patients and negative in one. Two patients were treated with doxycycline for two weeks in the acute phase of illness and one with a combination of erythromycin and gentamycin. After 4–12 months they developed post-Q-fever fatigue syndrome and were treated with intracellular active antibiotics (fl uoroquinolones and tetracycline) for 3–12 months. Effi cacy of the treatment was observed in two patients, but in one patient the results were not encouraging. Conclusions: These results suggest the possibility of the involvement of Coxiella burnetii infection in the evolution of chronic fatigue syndrome. This is the fi rst report on post-Q-fever fatigue syndrome in Mediterranean countries. Evidence of IgA antibodies to phase I of the growth cycle of Coxiella burnetii is not a prerequisite for establishing a diagnosis of CFS. The recommendation of antibiotic treatment in post-Q-fever fatigue syndrome requires further investigation. keywords: chronic fatigue syndrome • Coxiella burnetii • post-Q fever fatigue syndrome • antibiotic treatment BACKGROUND Q fever is one of the most common anthropozoonoses in southeast Europe. It is caused by Coxiella burnetii, an intracellular pathogen whose classifi cation has been changed from the order of Rickettsiaceae to the order of Legionellales [1]. Human infection develops after inhalation of contaminated aerosol or consumption of unpasteurized milk. It is rarely transmitted by vectors, transfusions of contaminated blood, or transplancentally [2,3]. Recently, a major role in disease spread was attributed to air currents [4]. About 60% of infections caused by Coxiella burnetii are asymptomatic [2]. Acute infection usually presents as a febrile state, pneumonia, or hepatitis, while other organs are less commonly affected. Coxiella burnetii is endemic in rural, coastal, and noncoastal areas of southern Croatia and is associated with stockbreeding. Acute Q fever in Split-Dalmatia County (470,000 inhabitants) is most commonly presented with both pneumonia and hepatitis (60.0%), followed by pneumonia (25.8%), hepatitis (9%), and nonspecific febrile illnesses (5.2%). During the period from 1985 to 2002, 155 acute Q fever cases were hospitalized at the Split University Hospital, with a mean annual incidence of 1.82/100,000/year. All cases were verifi ed by serologic testing with C. burnetii phase II antigen as is routinely done in all patients with clinical syndrome of atypical pneumonia that live in endemic areas [5]. In the northern part of Croatia, Coxiella burnetii causes 6.45% of all interstitial pneumonias that are serologically verified [6]. In its chronic form, Q fever mostly presents as endocarditis, infl ammation of intravascular implants, osteoarthritis, and chronic hepatitis [7]. During a follow-up of convalescent patients after acute Q we noticed that some had symptoms that were consistent with chronic fatigue syndrome (CFS). The diagnostic criteria for CFS include fatigue for six months or more together with at least four of the following symptoms: lack of concentration or/and memory that interferes with normal activities, sore throat, tender cervical or axillary lymph nodes, joint pain without swelling, muscle pain, headache, no refreshing sleep, and malaise lasting longer than 24 hours after exertion [8]. CFS is twice as common in females as in males, and it is most common between 25–45 years of age. The cause of CFS is not fully understood. There are three hypotheses about the cause of this impairment: postinfectious, immunological, and depression [9,10]. Penttila and associates found that in Australia, 20% of patients after acute Q fever develop post-Q-fever fatigue syndrome (QFS). Increased concentrations of IL6 and interferon- as well as lowered concentrations of IL-2 that are found after stimulating peripheral blood mononuclear cells in cultures from these patients are presumed to be implicated in the pathogenesis of QFS [11]. The purpose of this paper is to emphasize the existence of CFS after Q fever in Croatia and its incidence and to show the effects of antimicrobial therapy of patients with QFS. We describe three patients who had QFS. During the period from January 2000 to December 2004, 90 patients with acute Q fever were treated at the Split University Hospital and we observed 3/90 patients with post-Q-fever fatigue syndrome. After the diagnosis of QFS was established, these patients were treated with antibiotics. They were asked to fill out questionnaires assessing their clinical condition before (continued on page 31) Invest in ME Charity Nr 1114035 Page 30/72 Journal of IiME Volume 1 Issue 2 Chronic Fatigue Syndrome after Q fever (continued) and after the treatment. The questionnaire survey included subjective symptoms: fatigue, lack of concentration, no refreshing sleep, sore throat, tender cervical or axillary lymph nodes, joint pain without swelling, muscle pain, headache, and malaise lasting longer than 24 hours after exertion. These symptoms were evaluated according to four grades (0: absent, 1: mild, 2: moderate, 3: severe). If the summed result of the survey was halved after the treatment, the effect of antibiotic therapy was considered favorable (Table 1). CASE REPORTS Case 1 A 34-year-old male shopkeeper with atypical pneumonia caused by Coxiella burnetii was treated at the Department for Pulmonary Diseases in February 2000. He did not have any serious illness before he caught Q fever. He arrived from a rural area where Q fever is endemic. Laboratory results showed an erythrocyte sedimentation rate (ESR) of 72 mm/hour, while the other hematological and biochemical parameters showed no abnormalities. The patient received a combination of erythromycin 4×500 mg/day p.o. and gentamycin 1×240 mg/day i.v for two weeks. The clinical response was good. A control chest x-ray was normal. The etiology was confirmed by the complement-binding reaction (CBR), which showed a titer for Coxiella burnetii of 1:64. A repeat CBR for Coxiella burnetii after six weeks was 1:1024. During follow-up within the year 2000, the patient complained of disrupted sleep, morning fatigue, intense headache, prolonged fatigue lasting more than 24 hours after physical work, muscle pain, and persistent low-grade fever. Transthoracic heart ultrasound was normal. Serology for the phase I and phase II replication cycle of Coxiella burnetii did not confirm chronic infection (Table 2). After a one-year duration of symptoms, nine months of treatment with ciprofloxacin (2×500 mg/day p.o.) and doxycycline (2×100 mg/day p.o.) was instituted. The muscle pain and low-grade fever disappeared after this therapy, but the mild headache persisted. Therefore, in January 2002 a lumbar tap was performed. Cytology and biochemistry of CSF showed no abnormalities. The CSF sample was tested for Coxiella burnetii using an indirect immunofl uorescence assay and the result was negative. The patient still has low intensity headache and he suffers from fatigue after physical activity, but it disappears after half an hour of rest. He has returned to work, but has changed his job from shopkeeper to watchman. He now suffers from hyperlipidemia and does not show criteria for chronic fatigue syndrome (Table 1). Case 2 A 32-year-old housewife with pneumonia caused by Coxiella burnetii was treated at the Department for Infectious Diseases in February 2003. Laboratory results showed an ESR of 92 mm/hour. Other hematological and biochemical results, were within physiological limits. She was treated with doxycycline for two weeks with a good clinical response, and her chest x-ray after two weeks confirmed complete regression of pulmonary infiltrations. An indirect immunofluorescence test (IFT) in the acute stage of the disease showed positive IgM (titer: 1:160) and IgG (titer: 1:640) for Coxiella burnetii. Repeated serology one month later showed IgM 1:320 and IgG 1:1280. After she had felt well for two months, she started experiencing pain in her neck. Six months later, in August 2003, in addition to the neck pain she began to suffer from insomnia, headache, sweating, and fatigue, which did not resolve after sleep. The symptoms persisted for 12 months. She was admitted to the Department for Infectious Diseases again in October 2004. Repeated hematological and biochemical results were within physiological values. Electromyography of the upper and lower extremities showed no abnormalities and transthoracic and transesophageal heart ultrasound showed no signs of endocarditis. Rheumatoid factor, antinuclear antibodies, and antimitochondrial antibodies as well as serology for Epstein-Barr virus, cytomegalovirus, and toxoplasmosis were negative. Anti-HIV and hepatitis B and C markers were also negative, and thyroid hormones were within normal ranges. Paired serum samples in ELISA for Coxiella burnetii showed positive phase I IgA and IgG antibodies (Table 2). The therapy included ciprofloxacin (2×500 mg/day p.o.) for two months followed by doxycycline (2×100 mg/day p.o.) for four months. The result of the six months of treatment was regression of symptoms, with only a minor headache persisting. She is now capable of doing all her housework and does not fulfill the criteria for CFS (Table 1). Case 3 A 30-year-old male professional soldier with interstitial pneumonia was treated at the Department for Pulmonary Diseases of the Clinical Hospital of Split in February 2004. In the acute phase of illness his ESR was 46 mm/hour, while other hematological test results were normal. Blood chemistry values were normal with the exception of AST 62 U/l (normal range: 0–29) and ALT 54 U/l (normal range: 0–30). After two weeks of treatment with doxycycline, pulmonary infiltrates resolved and hematological and other laboratory results were all within the normal ranges. IFA for Coxiella burnetii revealed positive IgM 1:64 and IgG 1:320 in a first and IgM 1:320 IgG 1:640 one month later in a second serum sample. Four months later the patient started complaining of fatigue, disrupted sleep, headaches, and muscle and joint pain. Therapy with corticosteroids was introduced and continued for one month without success. In January 2005 the patient was admitted to the Department for Infectious Diseases, and his routine hematological and biochemical tests were within physiological limits. ELISA for Epstein-Barr virus, cytomegalovirus, HIV, and Toxoplasma gondii were (continued on page 32) Invest in ME Charity Nr 1114035 Page 31/72 www.investinme.org

Journal of IiME Volume 1 Issue 2 Chronic Fatigue Syndrome after Q fever (continued) www.investinme.org negative. Transthoracic and transesophageal heart ultrasound showed no signs of endocarditis. Ultrasound of abdomen was also normal. Rheumatoid factor, antinuclear antibodies, and antimitochondrial antibodies were negative. Biphasic ELISA test for Coxiella burnetii showed positive IgA antibodies in phase I (Table 2). After completing three months of antibiotic treatment with doxycycline, the patient still had fatigue, disrupted sleep, headaches, and muscle and joint pain. He still fulfills the criteria for CSF, cannot go back to work, and awaits realization of his retirement (Table 1). DISCUSSION Three patients with diagnoses of chronic fatigue syndrome after Q fever are described. Positive IgA antibodies for phase I of the Coxiella burnetii growth cycle suggest the possibility of chronic infection and the presence of Coxiella burnetii in macrophages [7]. Two of the patients described in this study had positive IgA antibodies for phase I of the Coxiella burnetii growth cycle and serology which was consistent with chronic Coxiella burnetii infection, while patient No. 1 had negative serology for chronic Coxiella burnetii infection (Table 2). As there are no clinical signs or laboratory tests that could Invest in ME Charity Nr 1114035 be taken as definite proof of CFS, the disease is diagnosed based on the patients’ symptoms and by excluding other diseases with similar symptoms [8]. In the last ten years, Q fever has been included in a group of diseases that are associated with the development of CFS after the acute phase of illness [7]. A recent article by Hickie et al. suggests that postinfective fatigue syndrome can occur after clinical infection by several different viral and non-viral microorganisms. The authors suggest that the CFS phenotype was stereotyped and occurred with similar incidence after Epstein-Barr virus, Q fever, and Ross River virus infection. The occurrence of CFS was predicted in the highest degree by the severity of the acute infection [12]. All our patients had moderately severe acute illness. Helbig and associates suggest a genetic predisposition for CFS[13]. Analyzing patients who had Q fever in England, Ayres and associates established that long persistence of fatigue, increased sweating, blurred vision, and shortening of breath are manifested more commonly in the group of patients that suffered from Q fever than in the control group [14]. Similar results were obtained by (continued on page 33) Page 32/72 Journal of IiME Volume 1 Issue 2 Chronic Fatigue Syndrome after Q fever (continued) Marmion’s et al. [15] while comparing slaughterhouse workers who had Q fever with a serologically negative control group. Fatigue, headache, disrupted sleep, and muscle and joint pain were significantly more frequent in the group of workers with previous Q fever. Ayres [14] associated shortness of breath in patients after Q fever with possible myocardial lesions after Coxiella burnetii infection, that were first referred to by Maisch in 1986 [16]. Lovey et al. [17] established a higher incidence of cardiovascular diseases in patients who had Q fever in comparison with a control group. Later studies by Ayres et al. did not show any significant difference in cardiological measurements that would suggest cardiomyopathy or other heart diseases when comparing a group with CFS after acute Q fever and a group without symptoms of CFS [18]. Thomas et al. did not find any significant differences in the frequencies of fatigue, depression, and lack of concentration between individuals with positive antibodies for Coxiella burnetii and serologically negative individuals. The imperfection of this study was that it included all Q-feverseropositive individuals without differentiation between patients who had asymptomatic and those who had symptomatic acute Q fever, as well as the fact that the study was done on a relatively healthy population with little neuropsychiatric morbidity [19]. Although Marmion et al. suggested that the diagnosis of QFS does not require serological criteria for chronic Q fever, low serological titers against C. burnetti were associated with chronic fatigue syndrome by Penttila et al. [15,11]. It is therefore not clear if patients with symptoms of CFS and positive serology of chronic Q fever, but lacking other clinical manifestations of chronic Q-fever such as endocarditis or osteitis, as described in the cases 2 and 3 of this paper, should be included in this syndrome. We therefore believe that patients with CFS criteria, positive phase I serology, and without other clinical manifestations of chronic Q fever should be diagnosed as QFS. Finally, is there any usefulness of antibiotic therapy of post-Q-fever CFS? The results of antibiotic therapy in patients presented in this paper were conflicting: in two cases the symptoms diminished, while the third patient continued to complain of CFS symptoms. These results are based on their clinical findings, before and after the therapy, as well as a questionnaire investigation. Up to now, there are two studies investigating the outcome of QFS therapy. Arashima et al. conducted treatment with minocycline for a period of three months in twenty patients with QFS. The result was satisfactory, and in all patients fatigue resolved, while seven patients with positive PCR test for Coxiella burnetii turned negative [20]. The limitation of this study is the absence of a placebo control group. One year later, Iwakami et al. Studied the effects of three months of antibiotic therapy in patients with post-Q-fever CFS. Although they became negative for C. burnetii DNA, in contrast to Arashima’s study no improvement of their symptoms was observed [21]. Another anecdotal attempt was the treatment of three-year-old girl with post-Q-fever CFS with interferon-g after unsuccessful antibiotic therapy [22]. Invest in ME Charity Nr 1114035 The idea for such therapy was based on the knowledge that interferon-g induces the killing of monocytes infected with Coxiella burnetii. The result of treatment was satisfying and encouraging for further investigations. Although Vissar et al. [23] accentuated the diversity of the immune response of peripheral mononuclear cells in patients with CFS after stimulation with dexamethasone, our patient treated with corticosteroids did not experience amelioration of his symptoms. CONCLUSIONS Our case series of patients from southern Croatia, where Q fever is endemic, is in concordance with more detailed data presented in the past from other areas of the world. Therefore we can conclude that a substantial number of patients develops CFS after acute Q fever in spite of appropriate antibiotic therapy during acute infection. The results of prolonged antibiotic therapy in such the patients are inconsistent. Efforts to establish diagnostic criteria as well as therapeutic recommendations for post-Q-fever CFS require further investigation. REFERENCES: 1. Brouqui P, Marrie TJ, Raoult D: Coxiella In: Murray PR, Baron EJ, Jorgenson JH, Phaler MA, Yolken RH (eds.) Manual of clinical microbiology. 8th ed. Washington D.C, ASM press; 2003; 1030–36 2. Marrie TJ, Raoult D: Coxiella burnetii (Q fever). In: Mandell GL, Douglas JE, Bennett JE (eds.) Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone, 2005; 2296–302 Med Sci Monit, 2007; 13(7): CS88-92 Ledina D et al – Chronic Fatigue Syndrome and Q fever CS91 3. Punda-Polić V, Radulović S: Sero-survey of Q fever in the north-western part of Bosnia and Herzegovina. Croat Med J, 1997; 38: 345–47 4. Medić A, Dželalija B, Punda Polić V et al: Q fever epidemic among employees in a factory in the suburb of Zadar, Croatia. Croat Med J, 2005; 46(2): 315–19 5. Lukšić B, Punda-Polić V, Ivić I et al: Clinical and epidemiological features of hospitalized acute Q fever cases from Split-Dalmatia County (Croatia), 1985–2002. Med Sci Monit, 2006; 12(3): CR126–31 6. Puljiz I, Kuzman I, Daković-Rode O: Clinical and epidemiological characteristics of Q fever in hospitalised patients. Infektol. Glasn, 2005; 25: 75–80 7. Raoult D, Marrie TJ, Mege JL: Natural history and pathophysiology of Q fever. Lancet Infect Dis, 2005; 5: 219–26 8. Fukuda K, Straus SE, Hickie I et al: The Chronic fatigue syndrome: A Comprehensive Approach to its Defi nition and Study. Ann Intern Med, 1994; 121: 953–59 9. Engelberg NC: Chronic Fatique Syndrome. In: Mandell GL, Douglas JE, Bennett JE (eds.) Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone; 2005; 120–25 10. Korzon M, Bukowska W, Szlogatys-Sidorkiewicz A: Chronic fatigue syndrome. Med Sci Monit, 1998; 4(2): 388–92 (continued on page 34) Page 33/72 www.investinme.org

Journal of IiME Volume 1 Issue 2 Chronic Fatigue Syndrome after Q fever (continued) 11. Penttila IA, Harris RJ, Storm P et al: Cytokine dysregulation in the post-Q-fever fatigue syndrome. Q J Med, 1998; 91: 549–60 12. Hickie I, Davenport T, Wakefield D et al: Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ, 2006; 333(7568): 575–81 13. Helbig KJ, Heatley SL, Harris RJ et al: Variation in immune response genes and chronic Q fever. Concepts: Preliminary test with post-Q fever fatigue syndrome. Genes Immun, 2003; 4: 82–85 14. Ayres JG, Flint N, Smith EG et al: Post-infection fatigue syndrome following Q fever. Q J Med, 1998; 91: 105–23 15. Marmion BP, Shannon M, Maddocks I et al: Protracted debility and fatigue after acute Q fever. Lancet, 1996; 347: 977–78 16. Maisch B: Rickettsial perimyocarditis-a follow up study. Heart Vessels, 1986; 2: 55–59 17. Lovey P-Y, Morabia A, vascular complication of Coxiella burnetii Bleed D et al: Long term infection in Switzerland: cohort study. Br Med J, 1999; 319: 284–86 18. Ayres JG, Wildman M, Groves J et al: Long-term Followup of patients from the 1989 Q fever outbreak: no evidence of excess cardiac disease in those with fatigue. Q J Med, 2002; 95: 539–46 19. Thomas HV, Thomas DR, Salmon RL et al: Toxoplasma and Coxiella infection and psychiatric morbidity: A retrospective cohort analysis. BMC Psychiatry, 2004; 4: 326– 29 20. Arashima Y, Kato K, Komiya T et al: Improvement of Chronic Nonspecific symptoms by long-term minocycline treatment in Japanese patients with Coxiella burnetii infection considered to have post-Q fever fatigue syndrome. Intern Med, 2004; 43: 49–54 21. Iwakami E, Arashima Y, Kato K et al: Treatment of chronic fatigue syndrome with antibiotics: assessing the involvement of Coxiella burnetii Pilot study infection. Intern Med, 2005; 44: 1258–63 22. Yutaka M, Hiroshi W, Tomoki T et al: Intractable Q fever treated with recombinant gamma interferon. Pediatr Infect Dis, 2001; 20: 547–57 23. Visser J, Blauw B, Hinlopen B et al: CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-g production and increased sensitivity to dexamethasone. J Infect Dis, 1998; 177:451–54 ME Comment Palliative care is not good enough, and does not stop the progress of the illness. Increasing numbers of PWME in our population, and the high incidence in families as well as in certain areas of the country, point to a disease that is communicable. In disregarding these signs, those responsible for the health of our whole population are guilty of what in history will be seen as criminal negligence - Deborah Invest in ME Charity Nr 1114035 ME Story The future….. There is no cure and therefore no treatment offered by the NHS. As a result I have joined thousands who have tried every avenue desperately trying to get better, spending over £1000 of my own money and having ongoing expenses for supplements which have been trialled and recommended. All I can see is an ongoing battle with the symptoms - the main one being fatigue - and spending more and more money in the hope of getting better. I know I am not as affected as some but I still find it hard. Although my GP has been very helpful (he diagnosed the illness very quickly, has referred me to a specialist and asked for Cognitive Behaviour Therapy for me) he cannot give me a timescale or a prognosis. There is a desperate need to find the cause of this illness and give sufferers a chance of getting their life back. In the meantime, there needs to be a standard 'help package' as the only information I have is what I have found from the internet or from other sufferers. There seems no end to this at the moment so I join all those who are demonstrating today as one of a large number of highly successful, intelligent and able people who have been struck down and had their lives turned upside down, often overnight. We are willing to work and want to get better, rather than rely on benefits but that is all we are offered. - Judith www.investinme.org Page 34/72 Journal of IiME Volume 1 Issue 2 The Reality and Nature of ME/CFS By Professor Malcolm Hooper Eileen Marshall Margaret Williams At the launch by the US Centres for Disease Control in November 2006 of its “Toolkit” to promote better awareness of the reality of ME/CFS, Anthony Komaroff, Professor of Medicine at Harvard, said there are over 4,000 papers on the biomedical nature of ME/CFS. This extensive medical literature spans over 60 years. No-one who is aware of this wealth of information can credibly doubt the reality, the validity and the devastation of this organic multi-system disease. Although the precise cause(s) is yet to be determined, the symptoms of ME/CFS are not “medically unexplained” and it remains beyond reason that the existence of so many documented abnormalities in people with ME/CFS should simply be disregarded and denied, including the following: Abnormalities of the central nervous system include abnormalities of brain cognition, brain perfusion, brain metabolism and brain chemistry; there is evidence of low blood flow in multiple areas of the brain; neuroimaging has revealed lesions in the brain of approximately 80% of those tested and according to the researchers, these lesions are probably caused by inflammation: there is a correlation between the areas involved and the symptoms experienced; abnormalities on SPECT scans provide objective evidence of central nervous system dysfunction; there is evidence of a chronic inflammatory process of the CNS, with oedema or demyelination in 78% of patients tested; there is evidence of a significant and irreversible reduction in grey matter volume (especially in Brodmann’s area 9) which is related to physical impairment and may indicate major trauma to the brain (which could also explain the low recovery rate); there is evidence of seizures; a positive Romberg is frequently seen in authentic ME/CFS patients Abnormalities of the autonomic and peripheral nervous systems: There is evidence of dysautonomia in ME/CFS patients – see, for example, “Standing up for ME” by Spence and Stewart: Biologist 2004:51(2):65-70; according to Goldstein, ME/CFS represents the final common pathway for a multifactorial disorder causing autonomic dysfunction Cardiovascular dysfunction: There is evidence of haemodynamic instability and aberrations of cardiovascular reactivity (an expression of autonomic function); there is evidence of diastolic cardiomyopathy; there is evidence of endothelial dysfunction; there is evidence of peripheral vascular dysfunction with low oxygenation levels and poor perfusion and pulsatilities; there is evidence of abnormal heart rate variability and evidence of abnormal orthostasis; there is evidence of abnormally inverted Twaves and of a shortened QT interval, with electrophysiological aberrancy; there is evidence of abnormal oscillating T-waves and of abnormal cardiac Invest in ME Charity Nr 1114035 There is evidence of an unusual and inappropriate immune response: there is evidence of very low levels of NK cell cytotoxicty; there is evidence of low levels of autoantibodies (especially antinuclear and smooth muscle); there is evidence of abnormalities of immunoglobulins, especially SIgA and IgG3, (the latter having a known linkage with gastrointestinal tract disorders); there is evidence of circulating immune complexes; there is evidence of a Th1 to Th2 cytokine shift; there is evidence of abnormally diminished levels of intracellular perforin; there is evidence of abnormal levels of interferons and interleukins; there is evidence of increased white blood cell apoptosis, and there is evidence of the indisputable existence of allergies and hypersensitivities and positive mast cells, among many other anomalies, with an adverse reaction to pharmacological pathognomonic substances being virtually Virological abnormalities: There is evidence of persistent enterovirus RNA in ME/CFS patients; there is evidence of abnormalities in the 2-5 synthetase / RNase L antiviral pathway, with novel evidence of a 37 kDa binding protein not reported in healthy subjects or in other diseases; there is evidence of reverse transcriptase, an enzyme produced by retrovirus (continued on Page 36) Page 35/72 wall motion (at rest and on stress); there are indications of dilatation of the left ventricle and of segmental wall motion abnormalities; there is evidence that the left ventricle ejection fraction – at rest and with exercise – is as low as 30%; there is evidence of reduced stroke volume Respiratory system dysfunction: There is evidence of significant reduction in many lung function parameters including a significant decrease in vital capacity; there is evidence of bronchial hyperresponsiveness A disrupted immune system: www.investinme.org

Journal of IiME Volume 1 Issue 2 The Reality and Nature of ME/CFS (continued) retrovirus activity, with retroviruses being the most powerful producers of interferon; there is evidence of the presence of HHV-6, HHV-8, EBV, CMV, Mycoplasma species, Chlamydia species and Coxsackie virus in the spinal fluid of some ME/CFS patients, the authors commenting that it was surprising to find such a high yield of infectious agents on cell free specimens of spinal fluid that had not been centrifuged Evidence of muscle pathology: This includes laboratory evidence of delayed muscle recovery from fatiguing exercise and evidence of damage to muscle tissue; there is evidence of impaired aerobic muscle metabolism; there is evidence of impaired oxygen delivery to muscles, with recovery rates for oxygen saturation being 60% lower than in normal controls; there is evidence of prolonged EMG jitter in 80% of ME/CFS patients tested; there is evidence of greater utilisation of energy stores; there is evidence that total body potassium (TBK) is significantly lower in ME/CFS patients (and abnormal potassium handling by muscle in the context of low overall body potassium may contribute to muscle fatigue in ME/CFS); there is evidence that creatine (a sensitive marker of muscle inflammation) is excreted in significant amounts in the urine of ME/CFS patients, as well as choline and glycine; there is evidence of type II fibre predominance, of scattered muscle fibre necrosis and of mitochondrial abnormalities Neuroendocrine abnormalities: There is evidence of HPA axis dysfunction, with all the concomitant implications; there is evidence of abnormality of adrenal function, with the size of the glands being reduced by 50% in some cases; there is evidence of low pancreatic exocrine function; there is evidence of an abnormal response to buspirone challenge, with a significant increase in prolactin release that is not found in healthy controls or in depressives; there is evidence of abnormal arginine – vasopressin release during standard water-loading test; there is evidence of a profound loss of growth hormone; even when the patient is euthyroid on basic screening, there may be thyroid antibodies and evidence of failure to convert T4 (thyroxine) to T3 (tri-iodothyronine), which in turn is dependant upon the liver enzymes glutathione peroxidase and iodothyronine deiodinase, which are dependant upon adequate selenium in the form of selenocysteine (which may be inactivated by environmental toxins) Defects in gene expression profiling: There is evidence of reproducible alterations in gene regulation, with an expression profile grouped according to immune, neuronal, mitochondrial and other functions, the neuronal component being associated with CNS hypomyelination Invest in ME Charity Nr 1114035 Abnormalities in HLA antigen expression: Teraski from UCLA found evidence that 46% of ME/CFS patients tested were HLA-DR4 positive, suggesting an antigen presentation Disturbances in oxidative stress levels: There is mounting evidence that oxidative stress and lipid peroxidation contribute to the disease process in ME/CFS: circulating in the bloodstream are free radicals which if not neutralised can cause damage to the cells of the body, a process called oxidative stress: in ME/CFS there is evidence of increased oxidative stress and of a novel finding of increased isoprostanes not seen in any other disorder; these raised levels of isoprostanes precisely correlate with patients’ symptoms (isoprostanes being abnormal prostaglandin metabolites that are highly noxious by-products of the abnormal cell membrane metabolism); there is evidence that incremental exercise challenge (as in graded exercise regimes) induces a prolonged and accentuated oxidative stress; there is evidence of low GSH-PX (glutathione peroxidase, an enzyme that is part of the antioxidant pathway: if defective, it causes leakage of magnesium and potassium from cells) (continued on page 37) ME Story He was here 2 and a half hours and told me to get rid of my "energise DVD (from the charity ME Research UK)", that ME was all due to deconditioning and negative behaviour patterns. He said the only one keeping me in that bed is me. The confusion is due to me not using my brain, hearing problems due to not using my ears, light sensitivity due to not going out in the light and so on and so forth. Why should I expect a blue badge when that would only discourage me from walking, he said. I felt humiliated and ridiculed by someone who was clearly a psychiatrist of some description. He said he gave seminars to students on "people like me". He seemed to enjoy the whole thing. -Julie (UK person with ME) www.investinme.org Page 36/72 Journal of IiME Volume 1 Issue 2 The Reality and Nature of ME/CFS (continued) Gastro-intestinal dysfunction: There is evidence of objective changes, with delays in gastric emptying and abnormalities of gut motility; there is evidence of swallowing difficulties and nocturnal diarrhoea; there is evidence going back to 1977 of hepatomegaly, with fatty infiltrates: on administration of the copper response test, there is evidence of post-viral liver impairment -- an increase of at least 200 in the copper level is the expected response, but in some severely affected ME/CFS patients the response is zero; there is evidence of infiltration of splenic sinuses by atypical lymphoid cells, with reduction in white pulp, suggesting a chronic inflammatory process; there is evidence that abdominal pain is due to unilateral segmental neuropathy (Gastrointestinal Manifestations of Chronic Fatigue Syndrome: H Hyman, Thomas Wasser: JCFS 1998:4(1):43-52); Maes et al in Belgium have found significant evidence that people with ME/CFS have increased serum levels of IgA and IgM against the LPS of gram-negative enterobacteria, indicating the presence of an increased gut permeability resulting in the autoimmmunity seen in many ME/CFS patients; this indicates that the symptoms of irritable bowel seen in ME/CFS reflect a disorder of gut permeability rather than psychological stress as most psychiatrists believe (gastrointestinal problems are a serious concern in ME/CFS, and 70% of the body’s immune cells are located in the GI tract) Reproductive system: There is clinical evidence that some female patients have an autoimmune oophoritis; there is evidence of endometriosis; there is evidence of polycystic ovary syndrome; in men with ME/CFS, prostatitis is not uncommon Visual dysfunction: There is evidence of latency in accommodation, of reduced range of accommodation and of decreased range of duction (ME patients being down to 60% of the full range of eye mobility); there is evidence of nystagmus; there is evidence of reduced tracking; there is evidence of problems with peripheral vision; there is evidence that the ocular system is very much affected by, and in turn affects, this systemic condition. The above list is by no means comprehensive but merely gives an overview of documented abnormalities seen in ME/CFS that can be accessed in the literature, as well as in the abstracts and reports of international Clinical and Research Conferences [http://tinyurl.com/3xocuc]. This was an extract from the document “CORPORATE COLLUSION?” which may be found at the ME ACTION UK site at http://tinyurl.com/2wxsb8. Invest in ME Charity Nr 1114035 Page 37/72 www.investinme.org ME Parent’s Story We feel this improvement has emerged because of our developing confidence in being able to reject medical approaches to Suzy's severe ME, and to the departures we chose to make from these conventional treatments. For example: 1. No longer trying to wake Suzy twice a day. This was a very difficult decision, which we knew would be a controversial one. But the fact that after a few months she managed her hour awake without us having to sit silently beside her, and that the hour ceased to be broken, reassured us that we'd done the right thing. 2. Forgetting about the concept of 'graded exercise' We were certain that the graded exercise program Suzy followed in the early stages of her ME was a big mistake. We had no hesitation in no longer sticking to any kind of graded exercise routine (which might be beneficial for those patients with less severe ME). Instead we took the approach of letting Suzy do what she felt she could do----- which for nearly two years was nothing at all. This is a second option we are convinced we made the right choice over. 3. Stopping the involvement of psychologists A third decision we know to have been the right decision, was to stop the involvement of psychologists in an illness we are convinced is not psychological. 4. Choosing to see less (which eventually became nothing) of doctors. We eventually accepted that to us, the only safe path was to manage Suzy ourselves by following our own instincts. We had become more and more sure that Suzy needed as much of a stress free environment as possible; an environment we tried to ensure she got. - Parents of Suzy (UK person with ME)

Journal of IiME Volume 1 Issue 2 www.investinme.org Children and Young people with ME– A Personal Overview of the Last 20 Years By Dr. Nigel Speight Introduction Having just retired after 25 years as a Consultant Paediatrician with a special interest in ME, I have been asked to give this personal take on the last 20 years regarding young people with ME and the way the medical profession has treated them. Overall the profession has not (in my opinion) exactly covered itself in glory in many instances. It is possible I received an over-pessimistic picture in that the cases coming to me from other areas tended to be self-selected hard-luck stories. Nevertheless there were some definite cases which in my view amounted to “Child Abuse by professionals”, and of course these were mainly due to ignorance about or disbelief in the reality of ME on the part of otherwise wellmeaning professionals. Fortunately there is currently a brighter picture and better understanding and acceptance of ME in the profession. However, I was still called in on two cases of Care Proceedings in young people with ME in the South of England in the last 6 months of my career. My personal story regarding ME I was never taught anything about ME during my student training or subsequent training in paediatrics, and became a consultant in a state of almost total ignorance on the subject, like most of my peers. I had a slight advantage in that two of my nephews developed the condition, and as they had both been keen sportsmen and were desperately unhappy at being unable to continue sport I had an instinctive reaction of belief in ME as a genuine organic/physical illness, and a natural scepticism for the widespread view that it was “all in the mind”. About 23 years ago I saw my first case, a 13 year old young lady who announced her diagnosis to me. Her symptoms “rang true” to such an extent that this experience cemented my belief system along the lines of an organic causation. The late Alan Franklin had an almost identical introduction to the condition at about the same time Subsequently I took an increased interest in the condition and cases just seemed to gravitate to me, both locally, regionally and from all over the UK. By the time of my retirement I had seen personally c 200 cases in North Durham, 150 in the Northern Region and another 150 from further afield, including Northern Ireland, the Isle of Man and Scotland. Many of the cases who came from further afield did so because of failure to obtain an official diagnosis of ME which had led the family to feel threatened in a number of different ways, the worst being threats of Care Proceedings, fines for non-school attendance, and threatened withdrawal of benefits (or failure to be granted benefits in the first place). The controversy as to the nature of ME Seeing young people develop ME out of the blue in the absence of any psychological trigger made me question the widely held belief that ME is a “psychosomatic” disease. Invest in ME Charity Nr 1114035 Dr. Nigel Speight Dr. Nigel Speight was, before his retirement, consultant paediatrician at The University Hospital of North Durham, County Durham, Dr Speight is one of the most renowned authorities on ME and children in the UK. I felt as if I was the little boy who remarked that the Emperor’s new clothes were non-existent. Accordingly I sent a questionnaire to all consultant Paediatricians in the Northern Region, sometime in the mid 1980s. I was heartened by the response, in that a clear majority (19 versus 7, with about 10 don’t knows) shared my belief that ME was primarily a physical illness which can affect people who are at least initially psychologically normal. Most of these doctors were general paediatricians. When I repeated the exercise with Child Psychiatrists, they almost universally refused to tick any of the boxes on offer but instead deplored the question and gave me lectures on the mind-body continuum! Basically, this was a reflection on how Psychiatry has been allowed to dominate the field of ME for the 30years since 1970, when McEvedy and Beard first alleged that Royal Free Disease had all probably been a manifestation of mass hysteria in nurses. (They did not actually see any of the cases but just constructed their hypothesis form a review of the notes) The discipline of Adult Medicine seemed only too happy to abdicate the field to psychiatry, possibly because with increasing specialisation there wasn’t an “ology” that would own ME. (eg Neurology, (continued on Page 39) Page 38/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Children and Young people with ME – A Personal Overview of the Last 20 Years (continued) Immunology, Rheumatology, Microbiology etc, although in each of these specialties there were individuals who took an interest) I continued to attempt to fly the organic flag. For instance I demanded the right of reply at the annual paediatric conference in Cambridge after a prominent Child Psychiatrist had been invited the year before. Addressing an audience of c 80 paediatricians I won a majority vote on a show of hands at the end of my lecture. Agreeing to see cases from outside my own area was a further very effective way of highlighting the continuing controversy. My general approach to young people with ME The first person to influence me was Dr Betty Dowsett who was invited by one of our local GPs who believed in MEto give a lecture in our hospital. She gave such a clear exposition of the clinical features that she made the condition both “real” and respectable for me, and I felt empowered to make the diagnosis myself in future. Subsequently I heard both Dr Alan Franklin and Dr David Bell talk on the same occasion in Newcastle and this increased my confidence in understanding the condition. I remember that Dr Franklin said we are training younger doctors to be too dependent on performing tests on patients and losing the clinical skill of history taking as a result. I rapidly realised that ME sufferers want above all for their condition to be accepted by their doctor and their symptoms validated. They are enormously grateful for this and very forgiving of our failure to cure them. They then wish their doctor to remain engaged with them and their condition, and not to be discouraged by the failure of the patient to recover. Too often doctors reject patients with ME on the grounds that there is “nothing they can do for them”. Even this is preferable to the “one way ticket to the psychiatrist approach” which is again understandably perceived as a form of rejection by the patient. This need for validation was brought home to me by my seeing a young teenage girl in a wheelchair sobbing her eyes out at a meeting for young people. I asked her mother what was the matter and who had upset her, only for her to reply “Its all right, those are tears of joy – she has just heard a lecture by Dr David Bell after which she said “thank goodness there is one doctor in the universe who understands what I have been suffering from these last three years” “! Another telling anecdote is that of a highly intelligent 6yr old girl with ME whose paediatrician allegedly told her “There can’t be anything wrong with you because all your tests are normal” (How many times have the ME community heard something to this effect?) The girl replied with perfect logic and even better grammar “Maybe I’ve got a condition for which you have not yet invented the right test”! Invest in ME Charity Nr 1114035 The challenge of the Very Severe Case My first very severe case took me by surprise and I made big mistakes in her management. I had already diagnosed her while she was still in the moderate range of severity only for her to deteriorate suddenly following a further viral infection. In retrospect I realise that I was more concerned for my own position than her welfare, in case I had missed some other more treatable diagnosis. (This is an almost universal fear in doctors confronted with ME) I accordingly referred her to tertiary specialists for second and third opinions, and she was subjected to numerous upsetting tests and examinations over a three day period in hospital. This so traumatised her that she had difficulty forgiving both me and her parents over the next three years, and this may well have delayed her recovery. Subsequently every fresh professional whom I introduced to her care managed to upset her further, giving me grounds for being very sceptical of the orthodox teaching of the virtues of a multidisciplinary approach! Too often doctors reject patients with ME on the grounds that there is “nothing they can do for them”. Even this is preferable to the “one way ticket to the psychiatrist approach” Things were further set back when the GP insisted on calling a meeting where the Health Visitor wondered out loud if perhaps the father was sexually abusing his daughter; minutes were sent to the family in a spirit of openness! (Not surprisingly the family changed their GP practice after this episode) Fortunately she eventually made a good recovery despite having been bedridden and tube-fed for 3 years. My next case was almost exactly similar but I handled her according to my new convictions. I strictly limited her from too much contact with other professionals, simply sharing her care with her GP, our home nursing service and our dietician (to supervise her tube-feeding) This second case did much better emotionally, and made a total recovery within 2 years. I did not involve Child Psychiatry, Physiotherapy, Occupational Therapy or any other disciplines and she did not appear to suffer from their absence, making a total recovery in 2 years after 9 months of tube-feeding. In my experience of cases in the rest of the country, this scenario of the paediatrician being panicked by meeting a very severe case is really quite common and has contributed to some of the cases referred to Social Services. (continued on Page 40) Page 39/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Children and Young people with ME – A Personal Overview of the Last 20 Years (continued) Child Protection Cases Every one of these was a nightmare for the young person and the family and in my view added insult to injury for young people deserving sympathy and support but getting the opposite. I was involved in over 20 of these cases, all of which reached the stage of a Child Protection Case Conference. There was usually a combination of one or several of the following factors operating to lead to a Child Protection approach: Single mother A disbelieving and usually absent father Other frustrating medical problems eg allergies A record of the family having put pressure on doctors/SSD etc in the past eg for second opinions, SSD support etc A lack of an official diagnosis of ME Another family member suffering from ME, often “unofficially” Severity of the ME, deterioration or failure to respond to some form of medical regime A reluctance on the part of the family to be referred to Child Psychiatry, especially if it involved admission to a unit and restriction of parental access A tendency for the case to be driven by doctors who had never actually been clinically responsible for the young person, who had not therefore taken a history and were thereby prone to disbelief (usually Community Paediatricians, often concerned about poor school attendance) A failure of doctors and/or Social Workers to actually talk to the young person A belief on the part of doctors in the efficacy of their “treatments”, leading to the mother or young person being blamed for the failure to respond. A frequent tendency to invoke the spectre of Munchausen Syndrome by Proxy (MSBP, aka Factitious and Induced Illness) whereby the mother is alleged to be inventing/exaggerating her child’s symptoms for some perverse motive of her own. A distressing sense of self-righteousness on the part of the professionals involved and a reluctance to open their minds to the possibility they were perpetrating a grave injustice. The term “group folly” sprang to mind as each professional sheltered in the security of the group decision, scared to break ranks. In this last respect Chris Clark (Former CEO of AfME) said to me after hearing some of these stories “It actually smacks of sadism”. The good news is that in every case bar one I was able to reverse the Child Protection juggernaut by my report for court. In addition to making an official diagnosis of ME, I spoke to the young person on his/her own, was often able to assert that the young person was “Gillick competent” and did not consent to be taken into care. Invest in ME Charity Nr 1114035 I would love to say that we have seen the last of this sort of case but fear we have not. In this last respect Chris Clark (Former CEO of AfME) said to me after hearing some of these stories “It actually smacks of sadism”. The good news is that in every case bar one I was able to reverse the Child Protection juggernaut by my report for court. In addition to making an official diagnosis of ME, In my experience of cases in the rest of the country, this scenario of the paediatrician being panicked by meeting a very severe case is really quite common and has contributed to some of the cases referred to Social Services. I spoke to the young person on his/her own, was often able to assert that the young person was “Gillick competent” and did not consent to be taken into care. I would love to say that we have seen the last of this sort of case but fear we have not. Grounds for Hope I personally think that the Report of the CMO’s Working Party of 2002 was the best thing to happen to the ME Community in terms of asserting the genuine (i.e. organic) nature of the condition. I believe its potential has been under-utilised by the ME lobby in their support. (continued on Page 41) Mother of Children with ME We're so aware of how the years are passing since our son and daughter were diagnosed with ME and how cruel it is for all the children with ME that they have missed out on their childhood as well as suffering enormous pain. We live for the day that someone like Jonathan Kerr will say that there is something that can be done to help, if not cure, all those who suffer from these terrible illnesses. Page 40/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Children and Young people with ME – A Personal Overview of the Last 20 Years (continued) It was significant that the Psychiatrists on the Working Party refused to sign up to it on the grounds that it placed too much emphasis on ME being an organic condition! The Gibson report is also likely to prove very helpful in its call for more biomedical research. The College of Paediatrics Guidelines were useful in making ME more of an official condition and helping paediatricians to accept responsibilities. Like many I have my doubts on the NICE Guidelines and feel they are inferior to the CMO’s report. Similarly I sense some scepticism over the new Treatment centres on the part of many ME sufferers. Time will tell. The Role of Chronic Infections Ironically, in the last 12 months before I retired I became very interested in the Lyme Disease/Tic born chronic infection story and am sorry to be unable to pursue it to a conclusion. I attended a fascinating conference in Leicester organised by Lyme Disease Action and heard a brilliant lecture by a doctor from its reality, and their New England called Dr J Burrascano. Over the last year I have come to regard two of my severe cases as likely cases of Lyme disease and was treating them with prolonged courses of antibiotics with some possible improvement. I would recommend the LDA website for anyone interested: http://www.lymediseaseaction.org.uk/. The exciting thing about this area is the possibility of treatment, and of course the model of chronic infection pointing to an organic causation. One last question. Someone who cycled from Land’s End to John of Groats for AfME was accommodated by ME families the length of Britain on his ride. At the presentation ceremony he asked the following interesting question “Does ME only attack nice people and their families, or can it attack anyone and then turn them into nice people?” Fascinating question which I have often asked myself! Any suggestions/comments? ME Story ME Story The following week the psychiatrist asked to see me at the hospital, in a manner that I interpreted that would not benefit Sophia if I refused. I had no option but to comply. I was told that if Sophia refused to go to the M.E. clinic, or if she did not recover within the following 6 months, that she would be sectioned under the Mental Health Act, then added that if I tried to stop this, then the psychiatrist would go to the courts to have me removed as the nearest relative. Furthermore, if I did not open the door when they would come to take Sophia away, that the police would be called to “smash the door down”. When I asked how much better Sophia would get by these proposed actions, the reply was given that it was “none of your business, that it was for the courts to decide”. The psychiatrist wanted to arrange for me to see a psychologist so that I could understand the good that the psychiatrist was doing to Sophia. I refused. (from The Story of Sophia and M.E. – http://www.investinme.org/Article050%20Sophia%20Mirza%2001.htm ) (It is now almost 2 years since Sophia Mirza died from ME) Invest in ME Charity Nr 1114035 Before I had ME, I happily worked as a full-time lecturer for seven years, did classical ballet, contemporary dance and flamenco classes after work, travelled and lived an entirely full life. I have no history of mental illness, no current symptoms of depression and have never taken any medication for these conditions. Considering the appalling misunderstanding of this illness and terrible social pressures, I am amazed by, and proud of, the bravery of ME sufferers across the country. For my part, I find misunderstanding of this illness as difficult to cope with as the illness itself. Maybe it's time for psychiatrists to address their unhelpful beliefs about this illness and their repressed reasons for continuing to block biomedical research. - Sarah Page 41/72

Journal of IiME Volume 1 Issue 2 www.investinme.org ME Story The following is a true story told by the parent of a child with severe ME. It should be emphasized that this is a recent and ongoing experience of one family – happening in the UK in this year. The name of the child has been changed for this story. ROSE Our daughter Rose got the flu when she was nine, in 1998, and never really recovered from it. She saw different doctors and had scans and blood tests. One consultant said it was idiopathic pain syndrome which our GP said means "I don't know". At this time Rose was unable to climb the stairs – she went up and down stairs on her bottom. They also mentioned school phobia - had Rose been bullied or was she too clever for school? Rose tried to carry on at school for a while. The physio she was seeing advised her to walk to and from school. She would arrive home with her face white and fall asleep even at dinner. Over the next few years Rose got worse. In January 2001 Rose fell to the floor and was not able to walk again. My husband took her to the doctors as she was unable to eat or walk. The doctor said that the best place for her was in school. Then we were sent to see a psychiatrist who felt Rose should be seeing a consultant paediatrician because she had started to drink excessive amounts. He was kind but didn't know much about ME. A registrar told us that Rose had ME/CFS and they would speak to the consultant. We went to many meetings at the hospital. The local team kept giving Rose physio and hydro. Rose got worse. She was given lots of different therapies - even art therapy. We were told that if we went against the professionals we would have a Child Protection Order (CPO) served on us. By 2003 Rose was bed bound and on a NG Tube. She saw a new consultant who was nice and did listen to our concerns when we met him. Over the next 3 years whilst going back and forth to the hospital, for two lots of five week stays Rose was made worse – what with the travelling, noise and people in and out of Rose's room, with nurses that had never seen severe ME before and who could not understand that Rose could only remember what was happening on the current day. Her memory became so bad. She was repeatedly asked questions she could not answer. This upset Rose a lot. She was paralysed over her body, fed by NG Tube and was sensitive to light, noise and touch and in a lot of pain. By April 2006 Rose had a PEG fitted after a four and half month stay in hospital, following emergency admission, during which I stayed with her all of the time. As with Rose’s memory problems, she would not know me and from the experience of previous stays, the hospital staff would not give her medicine on time. We were told that if we went against the professionals we would have a Child Protection Order (CPO) served on us. She was in terrible pain all of the time and not receiving her medication made her worse. I was called an over-protective mother at times. By the time we left they wanted Rose to go to rehab, though my husband and I didn't want this for Rose. We felt we were not being listened to. After one meeting we agreed to visit three places in order to show we were willing to have a look, but we reduced this to one place as Rose's consultant was retiring. We visited this hospital but we felt it was not suitable for Rose. In the summer of 2006 Rose started having blackouts and no feeling in her arms and this progressed slowly up her arms and legs. At the moment she has no feeling above her knees and elbows. The consultant then referred us to another consultant who felt we could go and meet. But this never happened. After this things went along quickly. What was happening in the background seemed to be out of our control. (continued on page 43) Invest in ME Charity Nr 1114035 Page 42/72 Journal of IiME Volume 1 Issue 2 ME Story – ROSE (continued) . The consultant said that the some of the symptoms Rose had were not due to ME (i.e. memory loss and The new consultant came to visit Rose and after this there was another meeting which was organised with Rose’s team. The consultant said that some of the symptoms Rose had were not due to ME (i.e. memory loss and paralysis) and that her ME could be a cloak for PRS (Pervasive Refusal Syndrome). We went home to find out what PRS was and all the people in the meeting did the same. We felt very angry about this diagnosis of PRS. Yet people couldn't understand why we felt this way and didn’t understand why it mattered. It matters to us after reading about it. After all, the psychiatrists Rose has seen over the years had never mentioned this to us. So Rose had to do a 6 week diagnostic test for PRS with two 6-second sessions of physio, adding on 10% each week and starting with 10 minutes high activities. This included education, art therapy and visitors. Even if Rose was unconscious from blacking out then someone had to read to her and the curtains had to remain open - 10% each week. Then there were low activities which would be performed all day. This consisted of someone reading to Rose, listening to the radio, chatting with someone or listening to the TV in the background. If she was watching TV then it had to be turned off after a certain time and then listening to music on Cd player. After the six weeks we were told that Rose did not paralysis) and that her ME could be a cloak for PRS (Pervasive Refusal Syndrome). have PRS as she never got worse during the six weeks. We felt those 6 weeks were a nightmare. We prayed every day for Rose not to get worse during this time. The timetable continued after the 6 weeks and when I asked what would happen if Rose got stuck on 25 minutes the reply was that she must be scared of going to school. Rose has not been to school since she was 11 years old (seven years ago)! We got to 20mins on the timetable and the pain and light sensitivity got worse. She kept getting infections. We eventually stopped the timetable. If we had kept going Rose would have been made far worse. We are now doing our own plan for Rose - most of it taken care for by Rose. Now we are left trying to find an adult consultant for Rose - one who understands severe ME. I wanted to tell Rose's story as the phrase PRS still makes feel sick. One member of Rose’s team mentioned a couple weeks ago that they had forgotten who this was all about!! www.investinme.org More ME stories, including all of these contained in this Journal, are available at – http://www.investinme.org/mestorygallery1.htm Stories from parents of people with ME may be found at - http://www.investinme.org/mestorygallery2.htm ME in Parliament Countess of Mar: "If a group of people refuses graded exercise and cognitive behaviour therapy, on the basis either that they are afraid or that they know it will not help them, will they be penalised?" Lord McKenzie of Luton (Parliamentary Under-Secretary, Department for Work and Pensions; Labour Peer): "there is no requirement for individuals to carry out any specific type of activity or treatment. That cannot be sanctioned". - Hansard Hansard (Lords) on 28th February 2007, column GC198 Invest in ME Charity Nr 1114035 Page 43/72

Journal of IiME Volume 1 Issue 2 www.investinme.org IiME Comment – NICE Guidelines on ME In August the National Institute for Health and Clinical Excellence (NICE) published their official document for clinical guidelines. The document was developed for use in the NHS in England and Wales regarding chronic fatigue syndrome / Myalgic Encephalomyelitis (CFS/ME). After almost universal criticism of the draft guidelines from ME patient groups in the UK the guidelines were intended to be revised. IiME was not original stakeholder (IiME only became a charity in May 2006) but became a stakeholder on October 2006 and have submitted our response to the draft guidelines. We have analysed the official guidelines and the summary below is from our response (which can be seen from this address http://tinyurl.com/25wtjq). Background: Invest in ME (IiME) is a UK charity of people with Myalgic Encephalomyelitis (ME/CFS) or parents of children with ME/CFS. The work we perform is unpaid and voluntary and the charity has no paying subscribers. We therefore are independent and do not have any ties to, or receive any finance from, the NHS or from government departments which could influence our opinions when analysing these guidelines. Invest in ME have examined the Full version of the NICE guidelines for CFS/ME (covering ME/CFS patients). IiME’s review is available at http://tinyurl.com/25wtjq In the Preface Professor Richard Baker states that “The publication of this guideline presents an opportunity to improve care for people with CFS/ME. “ That was a very true statement. It is a sad failing of NICE, however, that these guidelines fail to grasp this opportunity and instead deliver a weak and ineffectual document that seemingly attempts to retain much of the ignorance and prejudice existing within healthcare provision for ME/CFS. IiME believe these guidelines provide little to further the treatment of ME/CFS and this is an opportunity missed. The NICE guidelines lack any vision in moving forward the treatment of people with ME/CFS. NICE have chosen only to use the evidence which satisfied a predetermined view – • • • that CBT and GET are preferred methods of treatment for ME/CFS that there is doubt about the true nature of ME/CFS that CFS incorporates ME/CFS within its catchment The remit for NICE was documented at - (http://guidance.nice.org.uk/download.aspx?o=111640) and this was already limiting in deciding the end product– "To prepare for the NHS in England and Wales, guidance on the assessment, diagnosis, management of adjustment and coping, symptom management, and the use of rehabilitation strategies geared towards optimising functioning and achieving greater independence for adults and children of CFS/ME.” Invest in ME Charity Nr 1114035 Baker states that - “In developing the guideline, we kept in mind the overall goal of improving care for people with CFS/ME, that is, improving diagnosis, enabling patients to receive therapy appropriate for, and acceptable to them, and providing information and support, with the patient’s preferences and views firmly driving decision-making. “ Yet how can diagnosis be improved if NICE refuse to adopt consistent, standard guidelines and deem diagnostic tests to be out of scope? NICE have ignored the overwhelming evidence showing the organic nature of the illness and use a deplorable spin on the facts which does not serve ME/CFS patients, their families or healthcare staff who are genuinely interested in helping. The end-result seems to be an exercise in producing a pre-determined view of ME/CFS from an official organisation, supposedly independent, yet who seemingly have little conscience for the effects their document will have on patients and their families. The views of most ME/CFS support groups show that ME/CFS must be seen as a distinct and separate illness from CFS. The guidelines are quite biased and narrow-looking which mix far too many illnesses and attempt to subjugate ME/CFS into a bag of common illnesses all falling under the term CFS. This, we feel, is part of the problem faced by healthcare staff and others – by broadening the view of what ME/CFS is it will inevitably dilute the requirements for diagnosing and treating ME/CFS patients. NICE have done a major disservice to people with ME/CFS who are needlessly suffering from the perceptions of a systemically-biased health service which maintains outdated views with little good scientific evidence. The NICE guidelines fail to deliver in the areas of epidemiology, diagnosis, terminology, treatments and potentially cause infringement of human rights. (continued on page 45) Page 44/72 Journal of IiME Volume 1 Issue 2 www.investinme.org IiME Comment – NICE Guidelines on ME (continued) By pre-determining a view that CBT and GET are the most useful therapies NICE has shown itself as disingenuous – an organisation that is not interested in really helping people with ME/CFS. Compare the NICE guidelines for ME/CFS with the NICE guidelines for other neurological illnesses such as MS and Parkinson’s etc. • • For MS [CG8 Multiple Sclerosis NICE] there is no recommendation for GET for patients. For Parkinson’s [CG35 Multiple Sclerosis NICE] there is no recommendation for CBT or GET! Also, • • For Dementia [CG42 Dementia NICE] – no recommendation for GET for patients. For Epilepsy [CG20 Epilepsy NICE] – no recommendation for GET for patients. This questions the impartiality of NICE and shows a disturbing bias behind the recommendations made in the NICE guidelines. In reviewing the stated objectives with the guidelines IiME conclude that none have been satisfied. Objective: Increasing the recognition of CFS/ME The guidelines provide nothing new for patients and carers. The few places where the document has requested that healthcare professionals take the illness seriously and that the recognition of this is paramount are good. However, essential research showing the multi-system nature of ME/CFS is not discussed – enteroviruses, orthostatic intolerance, oxidative stress etc. – none of these are allowed to be discussed in detail. Yet without a basic understanding or awareness of the pathology of the illness how are healthcare staff supposed to recognise the true nature of ME/CFS? Result: FAILURE Objective: Increasing the recognition of ME/CFS can only be achieved by increasing the knowledge of the illness itself. The recommendations that propose non-functional and biased psychiatric therapies as a management technique will lead to more harm and probably contribute to fostering even more antagonism between healthcare staff (especially those who are untrained in ME/CFS) and the patient/carer. NICE have deliberately ignored essential biomedical research which would undoubtedly increase knowledge of healthcare staff on the multi-system pathology of this illness. Result: FAILURE Objective: Influencing practice in the ‘real world’ By stating that CBT and GET are the most useful therapies NICE has shown itself unwilling to move the issue of ME/CFS into an area which offers any real hope of progress. These guidelines will not influence Invest in ME Charity Nr 1114035 practice but will lead to already established myths being perpetuated. The absence of emphasis on the lack of funding for biomedical research into ME/CFS will not help to alter the government’s position on this subject and therefore gives little to change the current unsatisfactory position where patients are given possible harmful GET. The guidelines will not inform healthcare staff of the missing link in research into ME/CFS – funding for biomedical research. The guidelines show little awareness of biomedical research being carried out or performed in the past. They fail to mention the links between ME/CFS and vaccines, epidemics or organo-phosphate poisoning. They should include references to new research so that healthcare staff can be aware of the overwhelming evidence of the neurological origins of this illness. The guidelines state that a patient/carer can refuse any therapy without it impacting the relationship with the healthcare practitioner(s). We hope this is so but we are afraid that it will not. In the face of insurance companies forcing ME/CFS patients to undergo potentially harmful GET or useless CBT or DWP procedures to prove they are ill due to the lack of acceptance of the authenticity of the illness then we doubt if these guidelines are forceful enough to influence the ‘real world’ and avoid this from happening. In such instances recourse to litigation may be the only possibility for ME/CFS patients. It might have been useful for these guidelines to detail what avenues are open for legal aid for ME/CFS patients who wish to challenge insurance companies and others who insist on ME/CFS patients undergoing GET or CBT against their will. The guidelines do little to influence ‘real world’ issues when they avoid recommending prescription supplements or complementary therapies which are known to help. The guidelines do little to influence ‘real world’ issues such as the frequent need for parents to battle with schools for the rights of their children with ME/CFS. Result: FAILURE Comments on NICE I am an M.E sufferer who has made a remarkable recovery and it certainly was not brought about by CBT and graded exercise - quite the opposite. If I have made errors along the way, I would say it was being treated with anti-depressants and trying to exercise in the early stages – Judy Page 45/72 (continued on page 46)

Journal of IiME Volume 1 Issue 2 www.investinme.org IiME Comment – NICE Guidelines on ME (continued) Objective: Improving access to appropriate services, and supporting consistent service provision The guidelines provide nothing new for sufferers and carers. Little is given in support of ME/CFS patients in their dealings with DWP staff and no reference is made regarding how ME/CFS patients are meant to deal with the harassment and bias of insurance companies who propose psychiatric treatment for ME/CFS. If the service provision is providing treatments which are unfit for ME/CFS then consistency is meaningless. Result: FAILURE Objective: Emphasising the need for multidisciplinary working These guidelines patently fail to achieve this due to the concentration on psychological therapies at the expense of real research from published biomedical research papers. Although there are a few statements stating that multidisciplinary working is required the bias toward psychological therapies in these guidelines means that there is little credit given to non-psychiatric disciplines in treating and managing ME/CFS. Result: FAILURE Objective: Improving care for patients, particularly for those with severe CFS/ME The guidelines offer little for severely affected. There is no provision for specialist treatment – simply rehashed dogma relating to therapies which are entirely inappropriate for severely (and moderately) affected pwme. There is little here for carers. Result: FAILURE Objective: Providing guidance on ‘best practice’ for children with CFS/ME The guidelines add little new of relevance which doctors would not already know today. The best practice is not psychiatric therapies where the onus is on the patient to attend CBT meetings. It does little to move the debate on for children or their families. No mention of ME being responsible for more school absence than any other illness. Result: FAILURE Objective: Balancing guidance with the flexibility and tailored management, based on the needs of the patients By emphasising GET and CBT as primary treatments it is not possible to state that these guidelines help in basing management on the needs of patients. Its predilection for asserting that activity and exercise help ME/CFS patients already undermines any confidence that the ME/CFS community may have about the impartiality of these guidelines. It fails to recommend prescription supplements which can be tailored to manage symptoms of the illness, based on (continued on page 47) Invest in ME Charity Nr 1114035 Page 46/72 Comments on NICE On 22nd August (2007), the day on which the appalling NICE Guidelines have been published, I just want to congratulate all at Invest in ME for the excellent DVD of the recent Conference. If only the representatives of NICE had bothered to attend and take note, if only the nay sayers who extol the psychosocial paradigm could have the integrity to listen to a much more persuasive argument, then we as sufferers of many years or many decades standing, might be experiencing a much happier and healthier state of affairs now. Let's hope that the call to arms opined by many of the speakers who gave their time and wealth of knowledge at the Conference can now be realised in terms of pressure from those who truly understand this illness to ensure a volte-face by those who pretend they do yet are blinkered by their own egos' and self satisfied aggrandisement. - Rosie Comments on NICE Good things in the NICE guidelines... "Healthcare professionals should be aware that - like all people receiving care in the NHS - people with CFS/ME have the right to refuse or withdraw from any component of their care plan without this affecting other aspects of their care, or future choices about care. ". - Joss Journal of IiME Volume 1 Issue 2 www.investinme.org IiME Comment – NICE Guidelines on ME (continued) the needs of the patient. There is nothing flexible with the continued advocacy of useless or dangerous psychiatric therapies. Result: FAILURE Objective: Facilitating communication between practitioners and patients, and their families or carers. The emphasis on psychological therapies posing as treatments using heavily skewed data will inevitably influence GPs and paediatricians – especially if they have little time available for ME/CFS patients. The subject matter is skewed to allow a multitude of fatigue-related patients to be included in this study. If it purports to be for ME/CFS then the studies need to use patients with ME/CFS – not CFS or other fatigue conditions. Result: FAILURE By pre-determining the result based on its requirements to view this illness as a broad chronic fatigue illness NICE has failed to grasp the reality, failed to analyse and use proper research, failed to respond to patients’ demands and requirements and produced a document that will continue to allow this illness to be blended into a nebulous fatigue syndrome which only benefits psychiatrists interested in funding of their projects and other organisations who depend for their existence on paying members. NICE call for “Avoidance of dogmatic belief in a particular view.” Yet this is itself hypocritical and biased as all of the evidence and recommendations made by NICE are using psychiatric paradigms for treatment. The MRC has failed to fund biomedical research yet has paid millions of pounds for trials of psychiatric therapies. Could one foresee any progress being made, for example, in understanding MS if all research was performed on coping strategies for MS sufferers? NICE have demonstrated no vision, no ideas and, seemingly, no wish to progress the treatment and perception of ME/CFS. The official NICE guidelines for ME/CFS are a mediocre effort by an organisation which again fails the people for whom it purports to provide instructions and information. One can only ask was it sensible to have these guidelines made at all at this stage without better analysis and research? If much of the evidence was of poor quality then perhaps these guidelines are premature. IiME believe, however, that there is much research which NICE, if genuinely interested in progressing the treatment and perception of ME, could have used to improve knowledge and treatment of this illness. These guidelines have taken over two years to prepare and it will be another two years before they are revised. Invest in ME suggest they should be revised immediately.♦ Invest in ME Charity Nr 1114035 Facts About ME “We need more research to understand the various subgroups of CFS and to discover treatments that address the true biologic underpinnings of this illness. We need to educate health care professionals about this illness and keep at it until every doctor (and) nurse can quote the diagnostic criteria”. “We know that (ME)CFS has identifiable biologic underpinnings because we now have research documenting a number of underlying pathophysiologic processes involving the brain, the immune system, the neuroendocrine system and the autonomic nervous system”. - From “The State of (ME)CFS Research” by Professor Nancy Klimas, University of Miami Medical School From “Fast Facts: Top Ten Discoveries about the Biology of (ME)CFS” by Dr Christopher Snell-University of the Pacific 1. (ME)CFS is not a form of depression and many patients with (ME)CFS have no diagnosable psychiatric disorder. 2. There is a state of chronic, low-grade immune activation in (ME)CFS. 3. There is substantial evidence of poorly functioning NK cells. 4. Abnormalities in the white matter of the brain have been found. 5. Abnormalities in brain metabolism have been discovered. 6. (ME)CFS patients have abnormalities in multiple neuroendocrine systems in the brain. 7. Cognitive impairment is common in (ME)CFS patients. 8. Abnormalities of the autonomic nervous system have been found, including a failure of the body to maintain blood pressure, abnormal responses of the heart rate and unusual pooling of the blood in the veins of the legs. Some studies also find low levels of blood volume. 9. (ME)CFS patients have disordered expression of genes that are important in energy metabolism. 10. There is evidence of active infection with various herpes viruses & enteroviruses in (ME)CFS patients. Other infections can also trigger (ME)CFS, including the bacterium that causes Lyme disease. Page 47/72

Journal of IiME Volume 1 Issue 2 The PACE TRIAL By Professor Malcolm Hooper Eileen Marshall Margaret Williams The FINE trials were discussed in the last issue of the Journal of IiME. Using flawed diagnostic criteria, which exclude neurologically ill patients, these trials were criticised in an article by one participant. Another set of trials, also funded by the Medical Research Council (MRC), are the PACE trials. Both are described by the MRC as ‘..complementary trials into various treatments options for CFS/ME which aim to improve quality of life for those who are ill.' As with the FINE trials the PACE trials are equally controversial – taking a substantial amount of funding from an illness which has seen little spent on biomedical research. Professor Colin Blakemore, former head of the MRC, stated in the last issue of the Journal of IiME that the PACE trial is a ‘large clinical trial of new approaches to treating CFS/ME “. The PACE trial, he said, cost (£2,076,363).“and “The PACE trial will be comparing three treatments given to patients in a clinical setting, one of which is Adaptive Pacing Therapy (APT). This treatment is popular with many patients but has not been scientifically evaluated before. With the help of Action for ME, APT has been adapted to enable the researchers to test it rigorously within the trial. “. Later in the article Professor Blakemore states “The PACE trial;” uses “Cognitive Behavioural Therapy, graded exercise, adaptive pacing and usual medical care for chronic fatigue syndrome“. In the following extracts, taken from the document CORPORATE COLLUSION? the background to the PACE trial is examined in more detail. The MRC PACE trial into “CFS/ME” On 15th May 2003 the MRC announced the funding of two trials to evaluate the effectiveness of “rehabilitative treatments” for “CFS/ME”. The first trial, known as the PACE trial (Pacing, Activity and Cognitive behavioural therapy: a randomised Evaluation) was to take place in six clinics over a period of four years. Action for ME declared that it was proud to announce its support for the four-year study which “will evaluate pacing against other exercise and behavioural-led approaches in the care of people with ME”. The PACE trial was to be led by Dr (now Professor) Peter White of Barts, Dr (now Professor) Michael Sharpe of Edinburgh, and Dr (now Professor) Trudie Chalder of Kings College, London. It was to be co-funded by the MRC, the Scottish Chief Scientist’s office, the English Department of Health and the Department for Work and Pensions. The second trial was the FINE trial (Fatigue Intervention by Nurse Evaluation), a form of what the MRC terms “rehabilitation therapy” to be delivered by specialist community nurses in patients’ own homes -- though what “fatigue intervention” has to do with severely affected ME patients who require tube feeding was not specified. It was to be led by Alison Wearden PhD at the University of Manchester and was to be wholly funded by the MRC. The MRC media release proclaimed that with the PACE trial, “people can be helped towards recovery”; in the media release, Peter White said: “I’m particularly pleased that the study has been designed in collaboration with the leading patients’ charity Action for ME”. Invest in ME Charity Nr 1114035 The Authors: Margaret Williams, Eileen Marshall and Professor Malcolm Hooper are well respected authorities on ME as well as being ME patient advocates and form an established team whose aim is to expose and prevent the injustice perpetrated on patients with ME/CFS in the UK by those whose job is to help, not abuse, such patients. Professor Hooper is Emeritus Professor of Medicinal Chemistry University of Sunderland. Both Eileen Marshall and Margaret Williams formerly held senior clinical posts in the NHS. One month later, the ME/CFS community became aware that on 12th-13th June 2003, Peter White delivered a lecture entitled “Central Nervous System and Autonomic Nervous System Responses to Exercise in Patients with CFS” in Bethesda, Maryland, USA, at which Dr White explained that the cognitive behavioural model of CFS posits that the symptoms and disability of CFS are perpetuated predominantly by dysfunctional illness beliefs and avoidant coping. White said that beliefs associated with a poor outcome in CFS include the belief that exercise is damaging, that the cause of CFS is a virus, and that CFS is a physical illness. (continued on page 49) Page 48/72 www.investinme.org Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) The MRC website described the FINE trial as follows: “Pragmatic rehabilitation is delivered by specially trained nurses who give patients a detailed explanation of symptom patterns. This is followed by a treatment programme focusing on graded exercise. CFS/ME does not refer to a specific diagnosis”. In response to an enquiry from a Member of Parliament, on 24th October 2003 Professor Colin Blakemore (who had just succeeded Professor Sir George Radda as CEO of the MRC) wrote: “(Your constituent) has raised three main points. The first is that research should be done into the causes of CFS/ME before looking into treatments. It is appropriate to explore potential interventions in the absence of knowledge of causation. For example, the cause(s) of diabetes is not known, but knowledge of the underlying pathophsyiology has meant that effective treatments have been developed. (Re:) the second point (referring to MRC funding priorities), the key factor in deciding whether a proposal is funded or not is the quality of the science and its potential contribution to human health. Neither the PACE nor the FINE trials will provide a cure for CFS/ME but that is not their purpose. The trials are intended to assess a number of possible treatments (sic) to see if they are beneficial to those suffering from CFS/ME”. The UK ME/CFS community noted with bemusement that it is customary for the trial protocol to have been rigorously scrutinised, modified if necessary, and approved by the relevant Ethics Committee before funding was granted. This appeared to be a case of the psychiatric lobby rushing things through willy-nilly. As Christine Hunter of the Alison Hunter Memorial Foundation in Australia pointed out, knowing the cause and knowing the pathophysiology are two different things: pathophysiological research was a priority for diabetes, so why not for ME/CFS? (Christine Hunter’s daughter Alison tragically died from severe ME aged 19; the cause of death on the death certificate stated: “Severe progressive ME”. The pathologist confirmed that Alison had severe oedema of the heart, liver and brain. Alison also suffered seizures, paralysis and gastrointestinal paresis). On 16th January 2004, Dr Charles Shepherd from the ME Association posted an item on Co-Cure ACT:RES in which he said: “In response to recognition for more research, the MRC went on to conclude that research into the underlying cause should not command any high priority. Instead, the MRC recommended yet more money should be spent on researching lifestyles and psychological aspects of management, the results of Invest in ME Charity Nr 1114035 which may not add any significant information to what patients and their doctors already know. The situation regarding a lack of any encouragement to researchers to pursue the underlying physical cause of ME/CFS remains indefensible”. There was considerable confusion about both the start date for the trials and the entry criteria, with The Times correspondent Peta Bee claiming on 2nd February 2004 that the MRC trial was: “now in its second year” (“Fit to fight fatigue”, The Times, 2nd February 2004). The BMJ concurred: “Exercise is the best way to fight chronic fatigue syndrome. In the MRC study, now in its second”. year, patients are advised to follow a carefully graded plan. Dr Trudie Chalder, from King’s College, London, says: ‘The psychological benefits of following a fitness routine for people with CFS are great’ Since in January 2004 the MRC’s website stated that the start date was 2nd January 2004 and that the Oxford (Wessely School) criteria were being used, it was confusing to be informed just one month later by the BMJ that the trial was in its second year. It was even more confusing to be informed by the Health Minister (Lord Warner) on 26th February 2004 that the entry criteria for the trials: “have not yet been finalised” (Hansard: 26th February 2004: HL1273). Matters became yet more perplexing when the Health Minister confirmed on 10th March 2004 that: “the current estimated start of recruitment of patients into both trials is the summer or autumn of 2004. Unconfirmed criteria for both trials are that participants will meet the Oxford diagnostic criteria for CFS”. In March 2004 an advertisement for “PACE Trial Manager, Research Grade 3, Centre for Psychiatry, Institute of Community Health” to be based at St Bartholomew’s Hospital, London (closing date 6th April 2004), announced: “This is a prestigious MRC funded study of promising new treatments (sic) for a condition of considerable public health importance. Other members of the team include Professor Simon Wessely. The lead statistician is Dr Tony Johnson. The Clinical Trials Unit of the Institute of Psychiatry will be leading on database management and analysis”. Then came the following: “Mind body medicine and liaison psychiatry are relevant research areas for our centre. Recent successes include studies using the General Practice Research Database (GPRD). The GPRD studies have shown that diagnostic labels for CFS used in UK primary care have radically changed in the last 14 years and that these labels both reflect and affect prognosis”. What exactly was this radical change in diagnostic labels, who was responsible for it, and on what evidence did it rely? The ME community has little doubt about the answers to those questions. (continued on page 50) Page 49/72

Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) The PACE Trial Identifier (the Funding Application to the MRC) In about April 2004 the UK ME/CFS community managed to obtain a copy of the PACE Trial Identifier, which unless one is involved in the process, is usually impossible. The Identifier contained misleading statements (“Predictors of a negative outcome with treatment include membership of a self-help group, being in receipt of a disability pension [and] focusing on physical symptoms”); vital information was totally omitted; it referred to “treatment” when it would have been more accurate to describe the proposed interventions as “management strategies”; there was to be no subgrouping, and it relied on the biased Systematic Review from the CRD at York. It stated that the results of the trial: “will allow health planners, clinicians and patients to choose treatment on the basis of both efficacy and cost (and will) define the essential aspects of effective treatment”. It acknowledged that: “There is a discrepancy between patients’ organisation reports of the safety of CBT and GET and the published evidence of minimal risk from RCTs”. It undertook to monitor for any adverse effects: “We will undertake a detailed assessment, at home if necessary, for any subject who drops out of treatment for this reason, following which they will be offered appropriate help”. “Appropriate help” was not defined. It described CBT: “CBT will be based on the illness model of fear avoidance. There are three essential elements: (a) assessment of illness beliefs and coping strategies, (b) structuring of daily activity, with a graduated return to normal activity, (c) challenging unhelpful beliefs about symptoms and activity”. It described GET: “GET will be based on the illness model of both de-conditioning and exercise avoidance. Therapy involves an individually designed aerobic exercise programme with set target heart rate and times” (3.4). The inclusion criteria were to be “the operationalised Oxford criteria for CFS. We chose these broad criteria in order to enhance recruitment. Subjects who also meet the criteria for ‘fibromyalgia’ will be included” (3.6). The Oxford (1991) criteria were formulated by the Wessely School and have been criticised for being too broad -- they specifically include those with psychiatric fatigue and they potentially capture people suffering from “fatigue” that occurs in 33 different disorders -- and for specifically excluding those with neurological disorders such as ME. The Oxford criteria have no predictive validity and have never been adopted for use outside the Wessely School. They were superseded by the US Centres for Disease Control (CDC) Fukuda criteria in 1994. The assumptions of outcome were given: “At one year we assume that 60% will improve with CBT (and) 50% with GET”. Information about the day-to-day management of the trial said: “The trial will be run by the trial co-ordinator, with the PI (Principal Investigator). He/she will liaise regularly with Invest in ME Charity Nr 1114035 staff at the Clinical Trials Unit (CTU) who will be responsible for randomisation and database design and management (overseen by the centre statistician Dr Tony Johnson), directed by Professor Simon Wesssely”. The UK ME/CFS community noted with some surprise the involvement of Dr Tony Johnson, Deputy Director of the MRC’s Statistical Unit at Cambridge, because his published views on CBT were already known. In 1998, Johnson published a major review entitled “Clinical trials in psychiatry: background and statistical perspective” (Statistical Methods in Medical Research: 1998:7:209234) in which he came to some unequivocal conclusions. Johnson noted that psychiatric studies have been beset by poor design, inadequate data and incorrect analysis, and he noted the existence of studies produced by psychiatrists that claim “inordinate enthusiasm” for certain therapies. The Oxford (1991) criteria were formulated by the Wessely School and have been criticised for being too broad -- they specifically include those with psychiatric fatigue and they potentially capture people suffering from “fatigue” that occurs in 33 different disorders -- and for specifically excluding those with neurological disorders such as ME. He stated that a major requirement in any clinical trial is to determine the nature of the disease which will be investigated; he noted: “sophisticated technological examination is important in psychiatry to eliminate organic causes of psychiatric symptomatology”, a view that Wessely School psychiatrists seem not to share. Wessely maintains that there is an attractive cost implication of CBT (“The only treatment strategies of proven efficacy are cognitive behavioural ones. We have developed a more intensive therapy; this form of therapy is acceptable to patients, safe, and more effective than either standard medical care or relaxation therapy. It has also been shown to be cost effective”. “Chronic fatigue syndrome. A practical guide to assessment and management” Sharpe M, Chalder T, Wessely S et al. Gen Hosp Psychiatry 1997:19:3:185-199) but Johnson disagreed, stating that a course of psychotherapy typically lasts for 12 weeks or longer and “a major limitation is its cost”. The involvement of Dr Tony Johnson in the PACE trial Dr Johnson’s involvement in the PACE trials merits (continued on page 51) Page 50/72 Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) closer scrutiny. He is the son-in-law of Dr Elizabeth Dowsett, who was formerly Medical Advisor to and President of the ME Association and who is currently Medical Advisor to the 25% ME Group for the Severely Affected. Correspondence exists between an ME/CFS sufferer and Dr Johnson himself, but which also involves Dr Anthony C Peatfield, Head of MRC Corporate Governance and Policy. The correspondence arose from the MRC’s Biostatistical Unit’s progress report for the years 2001 to 2006 that was placed on the website of the MRC Biostatistics Unit (BSU), taken from the BSU’s Quinquennial Review of 2006. One part of the Quinquennial Review states: “Our influence on policy-makers has largely been indirect, through scientists' work on advisory committees, in leading editorials, in personal correspondence with Ministers, Chairs or Chief Executives (such as of Healthcare Commission or NICE), Chief Medical Officers and Chief Scientific Advisers, or through public dissemination when the media picks up on statistical or public health issues that our publications have highlighted. “The Unit's scientists must remain wary of patient-pressure groups. Tony Johnson's work on chronic fatigue syndrome (CFS), a most controversial area of medical research, has had to counter vitriolic articles and websites maintained by the more extreme charities and supported by some patient groups, journalists, Members of Parliament, and others, who have little time for research investigations”. This contention that “CFS” research is beset with vitriol and “extreme” charities was re-iterated by Johnson himself in his own Report within the Quinquennial Review; under “Chronic Fatigue Syndrome (CFS), with P White, T Chalder (London), M Sharpe (Edinburgh)”, Johnson’s Report stated: “CFS is currently the most controversial area of medical research and characterised by vitriolic articles and websites maintained by the more extreme charities supported by some patient groups, journalists, Members of Parliament, and others, who have little time for research investigations. In response to a DH (Department of Health) Directive, MRC called for grant proposals for investigations into CFS as a result of which two RCTs (PACE and FINE) were funded and have started despite active campaigns to halt them. I am part of the PACE study, a multi-centre study comparing cognitive behaviour therapy, graded exercise training, and pacing in addition to standardised specialist medical care (SSMC), with SSMC alone in 600 patients. I have been fully engaged in providing advice about design of PACE and I am a member of both Trial Management Group and Trial Steering Committee. I am not a PI (Principal Investigator) because of familial involvement with one of the charities, a perspective that has enabled me to play a vital role in ensuring that all involved in the PACE trial maintain absolute neutrality to all trial treatments in presentation, documentation and assessment”. (continued on page 52) Invest in ME Charity Nr 1114035 Page 51/72 ME STORY It seems psychiatrists and insurance companies hold a very firm grip of the Department of Health's approach to ME proving, perhaps, that ME treatment in Britain is dictated more by financial considerations rather than by medical or ethical ones. It is a shame that Britain must lag behind the rest of the international community, leaving young, talented people on incapacity benefit, when they could successfully be treated with antivirals and immune modulators as in other countries. While psychiatrists protect their academic careers rather than their patients, there will be more victims of ME like Sophia Mirza. Just how many psychiatrists want to do a squealy u-turn mid-career, hold up their hands, say 'we were wrong' and thereby relinquish research funding for psychiatry? None. They'd rather stay in denial and hold onto their academic careers by their fingernails at the cost of their patient's health. Just how many insurance companies want to pay out to ME patients when they can suggest the illness can be treated with mind over matter approaches that seem to cost the NHS very little? This is, of course, false economy: if ME patients were medically treated it would in fact save the government in costly CBT programmes, incapacity benefit and DLA. If ME patients were treated properly as in other countries like Canada, the insurance companies wouldn't shirk paying up because there wouldn't be the same volume of applications for medical retirement. This piece of commonsense evades the psychiatrists with a stake in receiving research funding. Well, I suppose it would. - Sarah(UK person with ME)

Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) Johnson’s Report on “CFS” research rang alarm bells within the ME/CFS community, since it openly stated that he, personally, had a “vital” role to play in ensuring what ought to have been taken for granted in any MRC trial, namely the “absolute neutrality” of the PACE trial. Upon seeing this on the MRC BSU website, an ME/CFS sufferer wrote first to the MRC Biostatistics Unit and then to Dr Johnson himself, requesting the names and details of all the charities, patient groups, journalists, Members of Parliament and “others” who have little time for research investigations, together with references for all the vitriolic articles and websites mentioned on the MRC BSU website. There was no acknowledgment from either the MRC BSU or from Dr Johnson; however just after the letters had been sent to the MRC, it was observed that much of Dr Johnson’s Report had been removed from the MRC BSU website, indicating that this was a matter of some importance to the MRC. In statistical terms, the deletions from Dr Johnson’s Report amounted to a substantial 42% of the entire Report. Almost a full month later, a letter dated 10th October 2006 was received from Dr Anthony Peatfield, which said: “You refer to some text that was recently published on the website of the MRC Biostatistics Unit. The comments ME Patient Carer’s Story Birgitte is put into the nursing home in August 2004. The head nurse receives a treatment manual for seriously sick ME patients (written by the Norwegian ME organization) and promises to follow this. At this point in time Birgitte was able to sit in a wheel chair, could use the toilet and could move her arms and legs. However, she is put under conditions of extreme stress in the nursing home. Due to a total lack of knowledge and competence of this illness the nurses and the nursing home doctor still think she has a psychiatric illness. The treatment manual from the Norwegian ME organisation is, therefore, not being used and the patient is getting more and more ill. The leaders of the nursing home say it is the patient's own fault and that she is manipulating the situation. The patient says she cannot tolerate noise and light (something very common for ME sufferers). She has to fight, explain, manage, and several nurses are unfriendly and rough. – Leiv (carer from Norway) Invest in ME Charity Nr 1114035 ME Story I have applied for DLA (probably one of the hardest things I have ever done) and have been rejected, despite being mostly housebound. Do these people think that I want to be like this? That to give up my future is an easier option? Or do they think that behind their backs I am secretly earning money and living it up? Why do they not think that it would be a good idea to ask for a report from a GP when assessing my claim? How do they think a visiting doctor can assess my capabilities by sitting in my lounge with me for an hour? So many questions and so few answers. - Alice to which you refer were drawn from a progress report produced by an individual member of staff. The comments have now been removed from the website. I would like to take this opportunity to apologise, on behalf of the MRC, for any offence these comments may have caused either to yourself or any other individual. While the comments were illjudged, it was not the intention of the individual who wrote them, nor the Unit in publishing them, to cause offence”. Curiously, Dr Peatfield further advised that should anyone else contact the MRC about this same matter: “we shall reply to any further requests such as your own as indicated in the third paragraph, above”, meaning that he would simply offer an ‘apology’ regardless of what information or clarification was being requested. Peatfield’s reply implied that those damaging comments were not made by anyone of significance at the MRC, when in fact they had been written by the Deputy Director of the MRC Biostatistics Unit who was intrinsically involved with the actual design of the PACE trial. Out of ten Reports that constituted the Quinquennial Review, the only individual report from which sections were removed, including the Abstract, is that of Dr Johnson. he Abstract could not, however, be removed from the Review Index, where all ten Abstracts by different individuals are located, with links to their full documents. In the case of Dr Johnson’s “re-edited” document (see below), the link to the Abstract no longer works, but the link works for all the other Abstracts. Was this a ploy by the MRC to conceal Johnson’s Abstract, with its references to his close association with the Institute of Psychiatry (see below)? (continued on page 53) Page 52/72 Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) Amongst large amounts of text removed from Dr Johnson’s Report were details of exactly how influential Dr Johnson has been within the MRC and with the Institute of Psychiatry, particularly in terms of securing MRC funding, along with other details of his close connections to key individuals involved in the PACE trial. The following extracts are taken from the Abstract, which was removed in its entirety from the body of Dr Johnson’s Report: “Abstract “I have initiated, developed, and collaborated in both clinical trials and epidemiological studies in four challenging medical specialties working with a large number of collaborators geographically dispersed throughout UK, Europe, and beyond. These have resulted in major advances in the understanding of the efficacy of cognitive therapy. “Over many years my programme has contributed to the successful completion of the three largest clinical trials, all of major international importance. My programme will be exploited in the future in further collaborations with the pharmaceutical industry. “I have enabled a successful collaboration linking the research programmes of this Unit with the MRC Clinical Trials Unit (MRC CTU) in London, that has resulted in the establishment of a new Clinical Trials Unit dedicated to mental health and neurological sciences at the Institute of Psychiatry in London. The linkage has enabled my expertise in clinical trials to be extended to chronic fatigue syndrome and the setting-up of a major MRC study to evaluate the efficacy of four different interventions. “I have advised many clinical trialists on the setting-up of organisational structures including Steering and Data Monitoring Committees, and Management Groups”. Some of Dr Johnson’s credentials, however, remained on the MRC BSU website: “I present my eighth and final Unit review report since joining MRC Neuropsychiatric Research Unit in 1968; a period exceeding 37 years during which I have been very privileged to engage fully in the research programmes of MRC, be a co-editor for 18 years of the first major journal in medical statistics (Statistics in Medicine), found an international society (Society of Pharmaceutical Medicine), draft the Constitution for another (International Society for Clinical Biostatistics), and contribute to UK Government, European, and International working parties and committees. “In view of my retirement in September 2008 I describe only my research programme over the past five years without reference to the future”. The following text was removed: “but note that none of my projects will terminate in the near future, for they will be continued and expanded by others, many of whom I have trained for that purpose. My role within MRC changed radically in 2001, resulting in my switching from independent band 2 to core scientist. My expertise in clinical trials was needed to expand the activities of the Department Without Portfolio into areas such as mental health (and) chronic Invest in ME Charity Nr 1114035 fatigue, currently the focus of government health policy”. From the above, it can be seen that Dr Johnson is an influential figure in the MRC BSU and, as Deputy Director, his in-house review was a substantial document. Johnson’s Report was an important official communication from one professional to others. Coming from such a senior figure within the MRC, and considering his level of involvement with the PACE trials, Johnson’s adverse comments about CFS would have carried considerable authority and influence. Disturbingly, it seems that in his material which was removed from the MRC website, Johnson revealed that he had used data (which he described as a “perspective” that he had been able to obtain through “familial involvement with one of the charities”) to assist in the design of the PACE trial. If this is so, what is he implying? The PACE trial is about challenging ME/CFS sufferers’ beliefs: is Johnson somehow using the “perspective” he has obtained through “familial involvement with one of the charities” to design a trial whose aim is to promote a management regime that has already caused so much harm to members of that charity? Most disturbingly of all, as mentioned above, Johnson stated that he was playing a “vital” role in maintaining “absolute neutrality” by “all involved in the PACE trial”. This clearly indicates that Johnson believed that without his own “vital” role, “absolute neutrality” would not be achieved. The word “vital” means “essential”, so was Johnson effectively conceding that he knew the PACE trial was fundamentally biased but that he – as an individual -- was dealing with the people involved in the trial who are known to be intent on dismissing “ME” and on promoting their own beliefs about the use of CBT/GET for those with “CFS”? Why is it only his own “vital” role that will ensure the “neutrality” of the PACE trial? Having taken seven months to reply to a letter that had been sent to him personally, on 7th November 2006 Johnson attempted to exonerate himself, stating that the views he had expressed were not intended to represent the views of the MRC and that they had been “the initial version of my progress report”, and writing: “I regret the words that I used”. Having earlier informed colleagues in his Report that: “CFS is currently the most controversial area of medical research and characterised by vitriolic articles and websites maintained by the more extreme charities supported by some patient groups, journalists, Members of Parliament, and others, who have little time for research investigations”, Dr Johnson stated in his letter: “I did not have specific individuals or groups in mind and consequently, I cannot provide you with the names and details of the charities, patient groups, journalists, Members of Parliament, and others, who I believed had little time for research. I do not have, and I have never (continued on page54) Page 53/72

Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) thought about, attempting to compile such a list. Similarly, I do not possess, and have never possessed, a list of vitriolic articles and websites, so I cannot provide these”. Also in his letter of 7th November 2006, Dr Johnson simultaneously did “not know when CFS/ME became controversial or why” but nevertheless proffered his speculation that “controversy sometimes arises when the evidence base is slender as many views and ideas can be put forward without any means of resolving them. The publication of a large number of research papers in the medical literature, some of poor quality or based on small samples only leads to further confusion”. This is an interesting piece of conjecture, given that the post of Statistician Clinical Trials Unit (CTU) Division of Psychological Medicine Ref No: 06/A09 is described as the “Johnson_Wessely_Job” (07/07/2006) at the The Institute of Psychiatry where: “The team works under the direction of Professor Simon Wessely, the Unit Director. The team is supported by the regular input of a Unit Management Group from within the Institute of Psychiatry. The statisticians within the Unit also have regular supervision meetings with Dr Tony Johnson from the MRC Clinical Trials Unit. The post holder will be directly responsible to the CTU Manager (Caroline Murphy), supervised by the CTU Statistician (Rebecca Walwyn) and will be under the overall direction of the Head of Department, Professor Simon Wessely”. Against the evidence that mixing study populations is inadvisable, the PACE trial is mixing at least three different groups of patients. As no satisfactory response had been received to a perfectly valid request for further clarification (i.e. the names of individuals involved with the PACE trial who, Johnson believed, would, without his own “vital” intervention, be unable to maintain the requisite “neutrality” which he was able to ensure through his “familial involvement” with one of the charities), the ME/CFS sufferer wrote again with the same request. Over five months after that request, Dr Johnson sent a further letter dated 2nd April 2007 in which he wrote: “The issues that you raise here are complicated. First it is important to realise that there is a substantial range of opinion among clinicians about the relative merits of some treatments”. Johnson’s reply was a five-page masterpiece of confabulation but still did not answer the question asked. Instead, amongst other diversions, he wrote at length about SSMC (standardised specialist medical care) for those with ME/CFS as part of the PACE trial, causing another ME/CFS sufferer to ask: “What is the accepted definition of standardised specialist medical care (SSMC) for those with ME/CFS? In order to achieve an accurate assessment of the PACE trial outcomes, there must be a definition of standardised Invest in ME Charity Nr 1114035 ‘in designing the trial we had to guess the outcomes and our guesses (were) mostly based on published studies”.. specialist medical care, so what is this definition and where is it accessible? (It is a matter of record that there isn't one). Tony Johnson accepts that an early design for the current PACE trial did not include an SSMC group but he seems to have expediently overlooked the reality that there is no SSMC for those with ME/CFS, as Catherine Rye made plain in 1996 about the Sharpe et al paper of the Oxford trial of CBT/GET: ‘I am a sufferer and participated in the Oxford trial. There are facts about the trial that throw into doubt how successful it is. It is stated that patients in the control group received standard medical care. I was in that group but I received nothing’ ” (Independent, 30th March 1996, page 16). The same ME/CFS sufferer also asked: “What is Tony Johnson’s statistical rationale for deliberately mixing patient cohorts in the PACE trial? Against the evidence that mixing study populations is inadvisable, the PACE trial is mixing at least three different groups of patients. “Fibromyalgia patients are included in the Principal Investigator’s own selection of those with “CFS/ME” for the MRC PACE trial, as well as those with other states of chronic fatigue, including psychiatric states, yet all three categories are taxonomically different and are classified differently by the WHO. Fibromyalgia is classified at ICD-10 M79.0; ME/CFS is classified at ICD-10 G93.3 and other fatigue states are classified at ICD-10 F48.0. “In a reply dated 15th April 2005 to Neil Brown, Simon Burden of the MRC wrote: ‘When researchers put together a proposal they are required to define the population they are studying’. Why does this basic requirement not apply to the PACE trial and how will the outright abandonment of this MRC principle affect Johnson’s statistical analysis of the PACE trial? “How does this accord with what Simon Burden asserted was the MRC’s requirement for ‘the high scientific standard required for funding’? “Johnson acknowledges in his reply (on page 4) that: ‘It is important to realise that there is a substantial range of opinion among clinicians about the relative merits of some treatments’. Indeed, this is so. What, then, is his statistical explanation for the MRC’s undue reliance on the ill-founded beliefs of Wessely School psychiatrists, given the large body of undisputed published evidence that their beliefs about the nature of ME/CFS are simply wrong? Johnson states in his reply: ‘in designing the trial we had to guess the outcomes and our guesses (were) mostly based on published studies”. For what statistical (continued on page 55) Page 54/72 Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) reasons did the MRC rely on Wessely School studies, when there is abundant published criticism of those very studies and their flawed methodology in the literature? “This published criticism is readily accessible to all and sundry. The work of the Wessely School on “CFS/ME” has been stringently criticised in the international literature for flawed methodology; particularly for use of a heterogeneous patient population (studies using mixed populations are not useful unless researchers disaggregate their findings); for selective manipulation of others’ work, claiming it supports their own findings when such is not the case; for their focus on the single symptom of “fatigue” whilst ignoring other significant signs and symptoms associated with the cardiovascular, respiratory, neurological and immunological systems; for generating conclusions before generating the data to support such conclusions; for advising Government bodies that the reported biomedical abnormalities ‘should not deflect the clinician away from the biopsychosocial approach and should not focus attention towards a search for an ‘organic’ cause’, and for their recommendation that no advanced tests should be carried out on “CFS/ME” patients when it is those very tests that reveal the unequivocally organic nature of the disorder. We believe that the money being allocated to the PACE trial is a scandalous way of prioritising the very limited research funding that the MRC have decided to make available for ME/CFS, especially when no money whatsoever has so far been awarded for research into the underlying physical cause of the illness. We therefore believe that work on this trial should be brought to an immediate close and that the money should be held in reserve for research that is likely to be of real benefit to people with ME/CFS. - ME Association “Throughout his reply, Johnson uses the terms: ‘In designing a clinical trial (of CBT/GET) we have to estimate the number of patients’; ‘Estimation essentially requires a guess at what the results will be’; ‘In guessing what the results may be…’; ‘The assumptions we make…’; ‘Broadly, we assumed that around 60% of patients in the CBT group would have a ‘positive outcome’ at one year follow-up….’; ‘We speculated that….’, so there is now written confirmation from the MRC Biostatistics Unit that the whole PACE trial is based on guessing, speculation and assumption. Would Tony Johnson explain how this accords with the MRC’s supposed requirement for high standards?”. Invest in ME Charity Nr 1114035 The ME Association has been adamant that the PACE and FINE trials should be halted and on 22nd May 2004 posted the following on its website (which was printed in its magazine “ME Essential” in July 2004): “The MEA calls for an immediate stop to the PACE and FINE trials “A number of criticisms concerning the overall value of the PACE trial and the way in which it is going to be carried out have been made by the ME/CFS community. The ME Association believes that many of these criticisms are valid. We believe that the money being allocated to the PACE trial is a scandalous way of prioritising the very limited research funding that the MRC have decided to make available for ME/CFS, especially when no money whatsoever has so far been awarded for research into the underlying physical cause of the illness. We therefore believe that work on this trial should be brought to an immediate close and that the money should be held in reserve for research that is likely to be of real benefit to people with ME/CFS. We share the concerns being expressed relating to informed consent, particularly in relation to patients who are selected to take part in graded exercise therapy. The Chief Medical Officer’s Report (section 4.4.2.1) noted that 50% of ME/CFS patients reported that graded exercise therapy had made their condition worse, and we therefore believe that anyone volunteering to undertake graded exercise therapy must be made aware of these findings”. It is notable in this respect that Lord (David) Sainsbury of Turville, who at the time was responsible for the MRC, stated in the House of Lords: “Because the trial participants will have provided informed consent, they will receive no compensation if they become more ill, whether or not as a result of the particular treatment” (Hansard [Lords]: 18th November 2004: 4830). The ME Association notice additionally called for all further work on the FINE trial to be halted, saying the MEA “is not convinced by the evidence so far put forward in support of this approach”. From this whole episode concerning Dr Johnson’s Report, the ME/CFS community was left in no doubt about the bitter contempt for sufferers, some charities, and those MPs who support them that exists at the MRC, or that the seam of Wessely School dismissal and denigration does indeed run deep. (continued on page 56) Page 55/72 It was suggested that Johnson be asked to explain how statistics had suddenly become a matter of guesswork, speculation and assumption. In his Report, Johnson had referred disparagingly to “websites maintained by the more extreme charities” but did not mention that it was two of the UK’s major charities (The ME Association and the 25% ME Group for the Severely Affected) that were calling for the PACE trial to be halted.

Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) Representations to the MRC setting out concerns about the PACE trials It is known that enormous public and professional concern was expressed to the MRC about the PACE and FINE trials. Some of the written representations were sent by Recorded Delivery. Few were acknowledged and all seem to have been disregarded. There can be no credible doubt that the Oxford criteria exclude those with ME as distinct from the Wessely School definition of “CFS” and this was confirmed in 1991 by psychiatrist Anthony David (colleague and co-author with Wessely) who described the Oxford criteria shortly after they were published: “British investigators have put forward an alternative, less strict, operational definition which is essentially chronic fatigue in the absence of neurological signs (but) with psychiatric symptoms as common associated features” Those legitimately expressed concerns include the following: Concern about the huge waste of money at UK taxpayers’ expense Originally the MRC PACE and FINE trials of CBT/GET were said to be costing £2.6 million, but according to Michael Sharpe, one of the Principal Investigators, the current figure is £4 million. From the figures awarded by the MRC for “fatigue” research on the National Research Register, the amount that has gone to biomedical research into ME/CFS is virtually non-existent. In March 2005, the MRC confirmed that since 2002, it had funded two further studies into “CFS/ME” (one for Professor Creed [see below] on psychiatric aspects and one on “Chronic fatigue (sic) and ethnicity”), and that it had received 12 applications for funding related to CFS/ME that were not granted. Of the applications that the MRC rejected, seven were under the heading “Pathophysiology of CFS” and included studies regarding genetics / biomarkers, immunology and neuroimaging; three were regarding epidemiology, as well as studies in primary care and clinical and laboratory characterisation of ME/CFS. As mentioned above, the ME Association pointed out that the results of these psychiatric trials may not add any significant information to what patients and their doctors already know, so on what ethical grounds does the MRC justify spending such a vast amount of money to the exclusion of studies with real potential to benefit ME/CFS sufferers? Invest in ME Charity Nr 1114035 As William Bayliss stated on an internet group on 2nd Nov 2004: “The MRC’s PACE trial has been very cleverly designed to exclude most true ME sufferers and include sufferers of mental illness. As such, the trial is a deceitful national scandal and a gross abuse of taxpayers’ money” Concern about the design of the study This is an area of extreme unrest, because the design of the study may well be relevant to the aims of the study, and these are known to be the nationwide promotion of CBT and GET as the management regimes of choice. It is apparent to many people that by using the allencompassing Oxford criteria, the trial objectives have been set so as to achieve this pre-determined agenda and to meet the requirements of political and commercial paymasters. The Oxford criteria expressly include people with psychiatric disorders in which “fatigue” is a prominent symptom (thereby, as noted above, potentially catching at least 33 other disorders that fit the Oxford criteria), but expressly exclude people with neurological disorders; indeed, the Oxford criteria claim to use people with neuromuscular disorders as controls, so by any logical reasoning, ME/CFS (an internationally classified neurological disorder) would be excluded. There can be no credible doubt that the Oxford criteria exclude those with ME as distinct from the Wessely School definition of “CFS” and this was confirmed in 1991 by psychiatrist Anthony David (colleague and co-author with Wessely) who described the Oxford criteria shortly after they were published: “British investigators have put forward an alternative, less strict, operational definition which is essentially chronic fatigue in the absence of neurological signs (but) with psychiatric symptoms as common associated features” (Postviral syndrome and psychiatry. AS David. British Medical Bulletin 1991:47:4:966-988). Given such clarification, how can it be ethical for the MRC to claim that the PACE trials will include those with Ramsay-defined ME? The MRC, however, insists that people with “CFS/ME” will be included in the trials. It is known that enormous public and professional concern was expressed to the MRC about the PACE and FINE trials. Some of the written representations were sent by Recorded Delivery. Few were acknowledged and all seem to have been disregarded. (continued on page 57) Page 56/72 Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) On 16th June 2005, Dr Sarah Perkins, Programme Manager for the MRC Mental Health Board, wrote: “The main entry criteria for the PACE trial are the Oxford criteria. Their use will ensure that the results of the trials will be applicable to the widest range of people who receive a diagnosis of CFS/ME. The exclusion criterion of ‘proven organic brain disease’ will be used to exclude neurological conditions of established anatomical pathology. It will not be used to exclude patients with a diagnosis of ME”. Concern that the MRC classifies “CFS/ME” as a mental disorder Given that the psychiatric lobby demands 100% proof of an organic pathoaetiology for ME/CFS before they will “allow” it to be accepted as a “real” organic disease as distinct from a mental disorder, why does the MRC not require a similar standard of proof from these psychiatrists that ME/CFS is a mental disorder, as they assert? It cannot be emphasised enough that what Wessely School psychiatrists choose to call “CFS/ME” is not Ramsay-defined ME and should not therefore be included as though it were the same disorder. To do so is both a failure of a duty of care towards patients and a corruption of the scientific process. Without doubt, the false beliefs about ME/CFS demonstrated by the MRC are known to be carefullyconstructed “policy-based evidence”, as can be seen from the 32 page Report from a Working Group of the Medical Research Council’s own Neurosciences and Mental Health Board (NMHB) Strategy and Portfolio Overview Group (SPOG) of January 2005. The aim of that Report was to consider the balance of the current MRC research portfolio, and it confirms what the UK ME/CFS community has long recognised – the MRC has considered “CFS/ME” as a mental disorder and will continue to do so: at paragraph 6.2 the Report is unequivocal: “Mental health research in this instance covers CFS/ME”. Other points of note in the SPOG Report include: • the MRC research agenda should be optimally aligned with the injection of Government funding • mental health represents a vast potential market for pharmaceutical companies • under “Mapping the UK research portfolio in mental health”, the Report states: “The analysis will capture all peer-reviewed grants that are live at a given date, which will be classified in terms of a list of mental health conditions based upon ICD-10 classifications” (could this explain the determination of Wessely School psychiatrists formally to re-classify ME/CFS as a “mental” disorder?). In a BBC Radio Five Live broadcast transmitted on 22nd Invest in ME Charity Nr 1114035 February 2005, the Chief Executive of the MRC, Professor Colin Blakemore, exhibited a serious lack of knowledge about ME/CFS, claiming that it does not matter whether “CFS/ME” is an organic or psychological condition. Does he really see no need to search vigorously for the cause(s) of ME/CFS? If not, why does such an approach relate only to ME/CFS and not to all illnesses whose cause is as yet unknown, including cancer, multiple sclerosis and lupus? That the MRC specifically and deliberately classifies “CFS/ME” under “mental health” research is at diametric variance with the Health Minister’s written confirmation given one year prior to the publication of this MRC SPOG Report, which demonstrates the determined defiance of medical science by the psychiatric lobby. Concern about mixing study cohorts The WHO is resolute that taxonomic principles must be observed, but the at the behest of the psychiatric lobby, the MRC is sanctioning the breaching of these taxonomic principles in the “CFS/ME” trials by deliberately mixing study cohorts from the outset. Is this not contrary to the high standards that the MRC claims it requires for all the studies it agrees to fund? Given that the psychiatric lobby demands 100% proof of an organic pathoaetiology for ME/CFS before they will “allow” it to be accepted as a “real” organic disease as distinct from a mental disorder, why does the MRC not require a similar standard of proof from these psychiatrists that ME/CFS is a mental disorder, as they assert? The PACE and FINE trials are flawed from the outset by this deliberate mixing of study cohorts and by excluding those with true ME yet claiming that the results will refer to those with ME. This is important because “the management of the two conditions is different. Patients with ME/CFS should be advised not to increase their activities gradually until they feel 80% of normal, whereas patients with fibromyalgia may benefit from a regime of increasing activity” (D. HoYen; BMJ 1994:309:1515). By lumping together as many states of “chronic fatigue” as possible into what they insist is one “somatoform” syndrome, the psychiatric lobby ignores the known and established differences between fibromyalgia (FM) and ME/CFS, and many in both the FM and ME/CFS communities believe they have a right to know why patients suffering from two different disorders are to be amalgamated in the MRC trials that claim to be studying “CFS”. (continued on page 58) Page 57/72

Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) In his letter of 15th April 2005 to Neil Brown, Simon Burden of the MRC (referred to above) stated that researchers applying to the MRC for funding are “required to define how they will find participants in the study”. In the case of “CFS/ME” -- which is to include fibromyalgia -- the methods include financial inducements (which in other areas may be described as “bribery”). If clinicians have to be tempted by financial rewards to refer patients to these MRC trials, then something is very wrong, but such financial inducements are indeed being offered to GPs to identify and refer patients to the new “CFS” Centres and into the PACE and FINE trials. This was confirmed in July 2004 by Minister of State Dr Stephen Ladyman MP at the All Party Parliamentary Group on Fibromyalgia (now disbanded). Further, in the case of the MRC FINE trials, whilst in the Patient Information Sheet patients are assured that “Your GP is not being paid for his or her participation in this trial”, there is a different message for the GP because in the GP invitation letter it states: “Practices will be recompensed by the Department of Health for time spent in identifying and recruiting patients (£26.27 per referral)”. Does such a discrepancy accord with the MRC’s own definition of “high standards”? (On the subject of high standards, what can be the explanation for the MRC-funded FINE trial literature using the term “myalgic encephalitis”, which is not the same as “myalgic encephalomyelitis”? Is accuracy no longer considered a component of “high standards”?). ..in the Patient Information Sheet patients are assured that “Your GP is not being paid for his or her participation in this trial”, there is a different message for the GP because in the GP invitation letter it states: “Practices will be recompensed by the Department of Health for time spent in identifying and recruiting patients (£26.27 per referral)”. It is a matter of record that Whiting et al expressly excluded FM studies from the Systematic Review of the literature that was commissioned by the Policy Research Programme of the Department of Health and carried out by the Centre for Reviews and Dissemination at the University of York. The systematic review is unequivocal: “Studies including patients with fibromyalgia were not selected for the review” (JAMA 2001:286:1360-1368). Why, therefore, on whose authority and on what evidence, was it decided to include patients with FM in the MRC trials of CBT in a “CFS/ME” population? Of foremost significance is the fact that fibromyalgia is classified as a distinct entity in ICD-10 at section M79.0 under Soft Tissue Disorders and it is not permitted for the same condition to be classified to more than one rubric, since ICD categories are mutually exclusive. Invest in ME Charity Nr 1114035 The literature itself is quite clear about this distinction, stating that up to 70% of those with ME/CFS have concurrent FM, and those who have both FM and ME/CFS have worse physical functioning than those who have ME/CFS alone. Some illustrations from the literature make these distinctions clear: 1991: in spite of some overlap, FM and ME/CFS do not represent the same syndrome. (Primary fibromyalgia and the chronic fatigue syndrome. AJ Wysenbeek et al Rheumatology Int 1991:10:227-229) 1996: “fibromyalgia appears to represent an additional burden of suffering amongst those with (ME)CFS” (Fibromyalgia and Chronic Fatigue Syndrome – similarities and differences. Dedra Buchwald and Deborah Garrity. Rheum Dis Clin N Am 1996:22:2:219-243) 1997: levels of somatomedin C are lower in FM patients but higher in ME/CFS patients (Somatomedin C (insulinlike growth factor) levels in patients with CFS. AL Bennett, AL Komaroff et al. J psychiat Res 1997:31:1:91-96) 1998: “recent studies suggest that (co-existent FM and (ME)CFS) may bode much more poorly for clinical outcome than CFS alone. In contrast to (significantly) elevated CBG (cortisol binding globulin) levels in patients with CFS, no differences were observed in FM patients. Differences in secretion of AVP may explain the divergence of HPA axis function in FM and (ME)CFS” (Evidence for and Pathophysiologic Implications of HPA Axis Dysregulation in FM and CFS. Mark A Demitrack and Leslie J Crofford. Ann New York Acad Sci 1998:840:684697) 1998: there is no evidence for elevated Substance P in patients with ME/CFS, whereas levels are elevated in patients with FM (CFS differs from FM. No evidence for altered Substance P in cerebrospinal fluid of patients with CFS. Evengaard B et al Pain 1998:78:2:153-155) 2001: patients with FM are NOT acetylcholine sensitive (Investigation of cutaneous microvascular activity and flare response in patients with fibromyalgia. AW Al-Allaf, F Khan, J Moreland, JJF Belch. Rheumatology 2001:40:10971101) 2004: patients with ME/CFS ARE acetylcholine sensitive (Acetlycholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome. VA Spence, F Khan, G Kennedy, NC Abbot, JJF Belch Prostaglandins, Leukotrienes and Essential Fatty Acids 2004:70:403-407) 2003: endothelin-1 is RAISED in fibromyalgia (Increased plasma endothelin-1 in fibromyalgia syndrome. Pache M, Ochs J et al Rheumatology 2003:42:493-494) (continued on page 59) Page 58/72 Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) 2004: endothelin-1 is NORMAL in ME/CFS (Plasma endothelin-1 levels in chronic fatigue syndrome. Kennedy G, Spence V, Khan F, Belch JJF Rheumatology 2004:43:252-253) More recent (2007) evidence from Spain presented at the ME Research UK (MERUK) International Research Conference on 25th May 2007 at Edinburgh demonstrated that FM and ME/CFS are two different diseases with two different genetic profiles and that there are very clear distinctions, with a 95.4% specificity. Many polymorphisms in the genes were different (Genetic Profiles in Severe Forms of Fibromyalgia and Chronic Fatigue Syndrome Dr Estibaliz Olano: this presentation is available on DVD obtainable from MERUK, telephone number 01738451234). Consultant rheumatologists who have sufficient experience with both syndromes have observed clinically that in FM, the muscle pain is helped by gentle stretching and exercise, whereas in ME/CFS, exercise makes muscle pain worse. Importantly, on 3rd June 1998, Baroness Hollis from the then Department of Social Security sent a letter to Lindsay Hoyle MP (reference POS(4) 3817/88) which says: “The Government recognises that fibromyalgia syndrome (FMS) is a condition which can cause a wide variety of disabilities from mild to severe. In some cases it can be a very debilitating and distressing condition. People with FMS who need help with personal care, or with getting around because they have difficulty in walking, can claim Disability Living Allowance to help with meeting related expenditure”. From this letter, it is clear that Government already recognises fibromyalgia as a distinct entity. Further, in the Chief Medical Officer’s UPDATE of August 2003 (a paper communication from the CMO sent to all doctors in England) entitled “Improving Services for Patients” there is an item entitled “Fibromyalgia – A Medical Entity”. This means that the CMO considers fibromyalgia to be a separate, stand-alone medical entity (and the fact that it is designated a “medical” disorder means that it is not considered to be “psychiatric” disorder). Is the MRC still content that the PACE trial proposal states: “Those subjects who also meet the criteria for “fibromyalgia” will be included”, given that FM is classified by the WHO as a quite separate disorder from ME/CFS, with discrete biomedical and genetic profiles that are entirely distinct from those found in ME/CFS? How can the deliberate inclusion of patients with fibromyalgia in trials that purport to be studying “CFS” not result in skewed and meaningless conclusions when the patients being entered in the PACE trials are, from the outset, not clearly defined? Invest in ME Charity Nr 1114035 How can the deliberate inclusion of patients with fibromyalgia in trials that purport to be studying “CFS” not result in skewed and meaningless conclusions when the patients being entered in the PACE trials are, from the outset, not clearly defined? Concern about Ethical Standards in the PACE Trial Mrs Connie Nelson wrote to the MRC asking four pertinent questions about the PACE trial: (a) who will decide if the patient has been harmed? (b) in the event of such harm, what will be the speciality of the clinicians who will visit the patient at home? (c) what will be considered a “serious adverse event” within the PACE study? and (d) what would be considered “appropriate help” if the PACE study exacerbates a patient’s condition? On 26th July 2005, Dr Sarah Perkins replied: “The investigators responsible for this trial have established a robust set of procedures regarding the management of any adverse events”. Included in adverse events was listed “any episode of self-harm”. Dr Perkins explained that: “As part of the peer-review process, a comprehensive assessment of any safety and ethical issues was made before the award of the trial grant” and she said the PACE trial was “proceeding under good clinical practice guidelines, which includes independent supervision. This comprises an independent Data Monitoring and Ethics Committee”. On 25th August 2005, Mrs Nelson again wrote to the MRC asking for the composition of the Data Monitoring and Ethics Committee. She pointed out that as this was a publicly funded trial, she would like to know who was on that Committee; she also asked for a copy of the “comprehensive assessment” of safety and ethical issues undertaken as part of the peer-review before the award of the trial grant, saying that -- given the evidence that exercise makes ME/CFS patients worse -- this may help clarify why the trial was ever funded. Mrs Nelson further asked whether an ME relapse would be recognised and accepted as “clinical change”, given that many people feared that the assessor(s) may not believe in ME or in the reality of a relapse. Her final question asked if the published papers of the PACE trial would include – as is normal practice for contentious treatments – details of all drop-outs and adverse events in each trial group. On 21st September 2005, Dr Perkins provided the names of PACE Trial Steering Committee Members and the membership of the Data Monitoring and Ethics Committee. Names of particular concern to the ME/CFS community included Professor Janet Darbyshire (MRC Clinical Trials Unit); Professor Peter White; Professor Michael Sharpe and Professor Tudie Chalder. The Observers (continued on page 60) Page 59/72

Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) included two names of particular concern: Professor Mansel Aylward and Mr Chris Clark of the charity Action for ME. The three names on the Data Monitoring and Ethics Committee were Professor P Dieppe, Dr C Feinmann and Professor A Fletcher. Dr Perkins then stated: “Although we are committed to being as open as possible, we have decided not to release peer review comments”. Concern about misleading information supplied by the MRC In December 2005 a Member of Parliament informed a constituent that: “It is encouraging to see that epidemiological research is being conducted which may yield improved understanding of (ME/CFS)”, when the reality was that the MRC had granted Professor Francis Creed funding for yet more psychosocial research, Professor Creed being well-known for his Wessely School views about “CFS/ME” (see http://www.meactionuk.org.uk/Proof_Positive.htm). Creed is Professor of Psychological Medicine at the School of Psychiatry and Behavioural Sciences at Manchester; one of his main research areas is somatisation disorders (which the Wessely School insist includes “CFS/ME”). He is Editor of the Journal of Psychosomatic Research and has failed to respond to letters written to him in his editorial capacity asking that the Journal present a more accurate and balanced view of ME/CFS. The Member of Parliament had thus been misled. Many MPs erroneously believe that the Government has done a good job in funding the wellpublicised “CFS Centres” and are unaware that those Centres will deliver only psychotherapy regimes that have already been shown to make some ME/CFS patients worse. It seems that the Trial Investigators will have the option to “select out” patients whom they believe will not respond in the desired way to the programme or who are too unwell to remain in the trials. Concern about post-funding alterations to the study Identifier and Protocol Following the outcry by the ME/CFS community about the use of the Oxford criteria as entry into the PACE trial, the MRC announced that a “secondary analysis” would be performed using the “London criteria”. Was this approved by the Data Monitoring and Ethics Committee, given the legitimate concern about the socalled “London” criteria that was submitted to the MRC? The “London” criteria have never been published and are not available as a reference for identification. They were mentioned in the National Task Force Report in 1994 as Invest in ME Charity Nr 1114035 being one of nine different proposed definitions and descriptions. The “London” criteria have never been used in research (before criteria can be used in research, they need to be submitted for peer review and published in an accessible form). The “London” criteria have not even been consistently defined – there are different versions of them and a definitive version has not been identified. The authors of the “London” criteria remain to be established as there are divergent claims about who the authors might be. The “London” criteria have never been accepted into common usage, nor have they ever been validated or operationalised. On what scientific basis can the MRC approve any “secondary analysis” using non-existent criteria? The “London” criteria have no justifiable or validated legitimacy that would in any way provide acceptable criteria for use by the MRC. Moreover, no amount of “secondary analysis” using any additional criteria can select patients with ME/CFS who were by definition excluded from the MRC trials in the first place by virtue of neurological disorders being expressly excluded from the Oxford entry criteria (which basically catch patients with chronic “fatigue”). It should be noted that the so-called “London” criteria are not the same as the Dowsett and Ramsay clinical criteria for investigation of ME, which are exceedingly useful (Postgrad Med J 1990:66:526-530). Other post-funding amendments to the PACE trial are more worrying. It seems that the Trial Investigators will have the option to “select out” patients whom they believe will not respond in the desired way to the programme or who are too unwell to remain in the trials. The list of what constitutes an “adverse reaction” has been shortened. Regarding outcome measures, the only objective measure of improvement seems to have been dropped, in that it seems the trialists no longer propose to use an actometer (an objective measure of activity) as an outcome measure of improvement. The only symptom actually being measured is subjective “fatigue”, which is not an objective scientific measurement and cannot therefore provide a robust clinical evidence base. “Recovery” has been re-defined. It will now be defined by participants meeting all four of the following: (i) a Chalder Fatigue Questionnaire score of 3 or less; (ii) an SF36 physical function score of 85 or above, rather than the working age norm of 90 (the SF-36 measures social and (continued on page 61) Page 60/72 Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) role functioning); (iii) a Clinical Global Impression (CGI) score of 1 (the self-rated CGI has a score range of 1 – 7 and provides only a subjective interpretation), and (iv) the participant no longer meeting the trial entry criteria. To most people, “recovery” means being able to return to full-time work and being able to be self-supporting. Did the MRC Data Monitoring and Ethical Committee approve such significant changes to the trial protocol after funding had been granted? If so, was this in collusion with one of the MRC trial sponsors (ie. the Department for Work and Pensions)? As it seems there will now be no objective evidence from the MRC PACE trials of no activity improvement, will this particular sponsor of the trials continue to maintain that there is no physical disability in ME/CFS patients who are claiming benefit? Of particular concern was the refusal of the MRC to heed the evidence that aerobic exercise (as in graded exercise that is part of the PACE trial) might be dangerous for some patients with ME/CFS and the fact that the Principal Investigators of the PACE trial were not screening for potentially life-threatening cardiac anomalies in trial participants. Concern about the competing interests of the psychiatric lobby who are running the MRC trials Concerns have been expressed that it is simply wrong for the psychiatrists who are carrying out these MRC trials to be paid for studying the regimes which they themselves formulated (Gen Hosp Psychiatry 1997:19:3:185-199), particularly in view of the proven evidence of their commercial interest in obtaining their desired outcome from these regimes. Concern about the MRC’s refusal to heed the existing evidence that CBT/GET does not work As outlined above in the section on NICE, the proponents of the CBT/GET regime themselves are on record as stating that in relation to ME/CFS, it is not “remotely curative”, that relapses occur, that the very modest benefits do not last, and that “many CFS patients, in specialised treatment centres and the wider world, do not benefit from these interventions”. Further, as noted above, the CRD Systematic Review of CBT/GET studies (the Wessely School “bible”) points out that there is no objective evidence of improvement and that the subjective gains may be illusory (JAMA 2001:286:1360-1368). Invest in ME Charity Nr 1114035 As also mentioned above, the MRC’s Chief Executive Officer, Professor Colin Blakemore, stated on 24th October 2003: “Neither the PACE nor the FINE trials will provide a cure for CFS/ME but that is not their purpose. The trials are intended to assess a number of possible treatments to see if they are beneficial to those suffering from CFS/ME”. Given that this information is already known, the ME/CFS community pleaded with the MRC to halt the PACE and FINE trials and to use the money in a more constructive way. The MRC ignored these requests. Concern about the persistent refusal to heed the evidence that graded exercise may be dangerous for people with ME/CFS Substantial published evidence of the organic basis of Ramsay-defined ME/CFS (ICD-10 G93.3) was submitted to the MRC. There are over 4,000 such papers. It was all dismissed or ignored. Of particular concern was the refusal of the MRC to heed the evidence that aerobic exercise (as in graded exercise that is part of the PACE trial) might be dangerous for some patients with ME/CFS and the fact that the Principal Investigators of the PACE trial were not screening for potentially lifethreatening cardiac anomalies in trial participants. Cardiac problems in ME have been documented in the medical literature for over half a century – the fact that normal loss of blood flow may be persistent in ME was documented by Gilliam in 1938. Other cardiac problems have been consistently documented in the literature since that time, for example, Wallis (1957); Leon-Sotomayer (1965) and Ramsay (1950s-1980s). In his 1988 CIBA Foundation lecture, Professor Peter Behan from Glasgow confirmed that he was regularly able to demonstrate micro-capillary perfusion defects in the cardiac muscle of ME patients. Also in 1988 he noted that: “Evidence of cardiac involvement may be seen: palpitations, severe tachycardia with multiple ectopic beats and occasional dyspnoea may occur and are quite distressing. It is of great interest that some patients have evidence of myocarditis” (see Crit Rev Neurobiol 1988:4:2:157178). In 2001, in her Research Update presentation to the Alison Hunter Memorial Foundation Third International Clinical and Scientific Conference on ME/CFS held in Sydney, Professor Mina Behan from Glasgow (now deceased) stated: “Convincing evidence of cardiovascular impairment can be demonstrated”. [For the early references, see “The Clinical and Scientific Basis of ME/CFS” edited by Byron Hyde, Jay Goldstein and Paul Levine, published in 1992 by The Nightingale Research Foundation, Ottawa. See also BMJ 1989:299:1219; Postviral Fatigue Syndrome ed. Rachel Jenkins and James Mowbray, pub. John Wiley & Sons, 1992; Inf Dis Clin Practice 1997:6:327333; Proc Soc R Coll Physicians Edinb 1998:28:150-163; Hum. Psychopharmacol.Clin.Exp 1999:14:7-17; Clin Physiol 1999:19:2:111-120; JCFS 2001:8:(3-4):107-109]. (continued on page 62) Page 61/72

Journal of IiME Volume 1 Issue 2 www.investinme.org The difficulty with some of the earlier references is that the documented clinical observations may not have been scientifically evaluated and in the current climate which dictates that “evidence-based medicine” is the only acceptable medicine, such observations are dismissed and ignored because there is no “evidence-based data”. In the 21st Century, this is called progress in medicine. The Government, Big Pharma and the medical insurance industry all prefer to accept the Wessely School dogma that “CFS/ME” is “medically unexplained chronic fatigue” and is therefore a primary behavioural disorder. It is the case that the Government-funded “CFS” Centres will employ only the psychiatric interventions recommended by the Wessely School. Because this is such a crucial issue, the cardiac anomalies that have been documented in ME/CFS are summarised here. An update of the paper by Carol Sieverling was posted on Co-Cure on 10th April 2005 (“The Heart of the Matter: CFS and Cardiac Issues” – a 41 page exposition of Dr Paul Cheney’s experience and expertise), from which the following notes are taken and to both of whom grateful acknowledgement is made. Cheney’s focus is based on the paper by Dr Ben Natelson (neurologist and Professor of Neurology) and Dr Arnold Peckerman (cardiopulmonary physiologist) at New Jersey Medical Centre (ref: “Abnormal Impedance Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome”. Peckerman et al: The American Journal of the Medical Sciences: 2003:326:(2):55-60). This important paper says that, without exception, every disabled ME/CFS patient (sometimes referred to as Chronic Fatigue and Immune Dysfunction Syndrome or CFIDS in the US) is in heart failure. The New Jersey team looked at many things in CFIDS patients: what they found was the “Q” problem. “Q” stands for cardiac output in litres per minute. In CFIDS patients, Q values correlated -- with great precision – with the level of disability. Q was measured using impedance cardiography, a clinically validated and Government agency-recognised algorithm that is not experimental. Normal people pump 7 litres of blood per minute through their heart, with very little variance, and when they stand up, that output drops to 5 litres per minute (a full 30% drop, but this is normal). Those two litres are rapidly pooled in the lower extremities and capacitance vessels. Normal people do not sense the 30% drop in cardiac output when they stand up because their blood pressure either stays normal or rises when they stand up -- the body will defend blood pressure beyond anything else in order The PACE TRIALS (continued) This important paper says that, without exception, every disabled ME/CFS patient (sometimes referred to as Chronic Fatigue and Immune Dysfunction Syndrome or CFIDS in the US) is in heart failure. to keep the pulse going. This is critical to understanding what Cheney believes happens in CFIDS patients. What the New Jersey team found in people with CFIDS was astonishing – when disabled CFIDS patients stand up, they are on the edge of organ failure due to extremely low cardiac output as their Q drops to 3.7 litres per minute (a 50% drop from the normal of 7 litres per minute). The disability level was exactly proportional to the severity of their Q defect, without exception and with scientific precision. To quote Cheney: “When you push yourself physically, you get worse”. CFIDS patients have a big Q problem; to quote Cheney again: “All disabled CFIDS patients, all of whom have post-exertional fatigue, have low Q and are in heart failure”. Post-exertional fatigue (long documented as the cardinal feature of ME/ICD-CFS but not of other, non-specific, states of chronic fatigue) is the one symptom that always correlates with Q. Among disabled CFIDS patients, 80% had muscle pain; 75% had joint pain; 72% had memory and concentration problems; 70% had unrefreshing sleep; 68% had fever and chills; 62% had generalised weakness; 60% had headaches, but 100% had post-exertional fatigue. Cheney posits that when faced with a low Q, the body sacrifices tissue perfusion in order to maintain blood pressure: ie. microcirculation to the tissues of the body is sacrificed to maintain blood pressure so that the person does not die in the face of too low a cardiac output. This compensation is what is going on in the CFIDS (ME/CFS) patient. In the Peckerman study, the data on the disabled CFIDS patients reveals that even when they are lying down, their Q is only 5 litres per minute. The lower the Q, the more time the patient will spend lying down because lying down is the only time they come close to having sufficient cardiac output to survive. Cheney states that it is important to note that the body does not sacrifice tissue perfusion equally across all organ systems: instead, it prioritises the order of sacrifice and one can observe the progression of ME/CFS in a patient by noting this prioritisation. Invest in ME Charity Nr 1114035 (continued on page 63) Page 62/72 Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) Two organ systems in particular have a protective mechanism (the Renin Angiotensin System, or RAS) against restricted tissue perfusion: the lung and the kidneys. These organs can sustain the greatest degree of Q problems because of this extra protection. Additionally, the heart and the brain also have this extra protection, even in the face of an extremely low Q. Therefore the lung, the brain, the kidneys and the heart are a bit more protected from a drop in Q than the liver, the gut, the muscles and the skin. Certainly, Cheney’s submission seems to tally with the experience of long-term ME/CFS sufferers about the order in which tissue perfusion is sacrificed. The first to be affected is the skin: if the microcirculation of the skin is compromised, several problems can arise. One is that without adequate microcirculation to the skin, the body cannot thermoregulate anymore: the patient cannot stand heat or cold and if the core temperature rises, the patient will not be able to sleep and the immune system will be activated. In order to regulate that problem, the body will kick in thyroid regulation which will down-regulate in order to keep the body temperature from going too high. The result of this is that the patient develops compensatory hypothyroidism, which means that now the patient will have trouble with feeling cold. Also, the body will not be able to eliminate VOCs (volatile organic compounds), which are shed in the skin’s oil ducts, so VOCs build up in the body’s fat stores and the patient becomes progressively chemically poisoned by whatever is present in the environment -- in other words, the patient develops Multiple Chemical Sensitivity. The second effect: if things get worse, the next microcirculation to be sacrificed is that to the muscles and the patient will have exercise intolerance and cannot go upstairs. If things get still worse, the patient begins to experience fibromyalgic pain in the muscles. Cheney posits that if the microcirculation to the joints becomes compromised, it may precipitate pyrophosphoric acid and uric acid crystals and the patient starts to have arthralgia linked to this circulatory defect. The next system to be compromised is the liver and gut. One of the first things the patient may notice in this stage of disease progression is that there are fewer and fewer foods that can be tolerated, partly because microcirculation is necessary for proper digestion. Also the body will not secrete digestive juices so whatever food is tolerated will not be digested: if food cannot be digested, there will be peptides that are only partially digested and therefore are highly immune-reactive; they will leak out of the gut into the bloodstream, resulting in food allergies and / or sensitivities. The body will be unable to detoxify the gut ecology, so the gut will begin to poison the patient, who will feel a sense of toxic malaise, with diarrhoea, constipation, flatulence and all kinds of gut Invest in ME Charity Nr 1114035 problems. If this gets worse, a malabsorption syndrome will develop, resulting in increasing toxicity in which the patient feels “yucky” and which can manifest as a variety of skin disturbances (for instance, a rash), as well as problems in the brain. The fourth affected system is the brain: Cheney posits that there is a devastating effect in the brain as a result of liver / gut dysfunction, which can quickly toxify the brain, resulting in disturbances of memory and of processing speed. Also, the hypothalamus begins to destabilise the patient from the autonomic nervous system perspective. In all probability, the brain and heart suffer simultaneous compromise, but patients usually notice the brain being affected much earlier than the heart – this is because heart muscle cells have the greatest mitochondrial content of any tissue in the body, so when the mitochondria are impaired, the heart muscle has the greatest reserve. Even if the patient is sedentary with not too much demand on the heart, they can still think and make great demands on the brain, and energy is energy, whether it is being used physically or cognitively. ME Story I haven't seen a doctor in years. It doesn't seem worth it, somehow, as they have no answers and, besides, I can't stay upright long enough to make it to the surgery. I become light headed very quickly now and have to lie down before I fall down: something else that used to happen on exertion and which now happens all the time. - Christine The fifth affected system is the heart: Cheney posits that the effect of compromised microcirculation upon the heart has an “a” part and a “b” part: part “a” is the manifestation of microcirculation impairment and part “b” is “the event horizon”. Part “a”: manifestation of microcirculation impairment: the initial manifestation of microcirculatory impairment of the heart is arrhythmia with exercise intolerance: when the patient goes upstairs, more cardiac output is needed but the patient cannot sustain it. As it gets worse, there will be mitral valve prolapse (MVP) because of inadequate capillary function. Finally, when there are even more severe microcirculatory problems, the patient starts to get chest pain as the myocardial cells die because they cannot get adequate oxygen. (continued on page 64) Page 63/72

Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) Part “b”: the event horizon: (once this line is passed, there is no going back): Cheney’s view is that when the microcirculation defect within the heart itself begins to impact Q, a vicious circle begins – microcirculation impairment reduces the Q, which produces more microcirculation impairment, which produces even more Q problems, so down goes the patient into the next phase of cardiac failure, which involves the lungs. The sixth affected system is the lung and kidney: this leads to congestive heart failure and pulmonary oedema, then the kidney is affected (the kidney is the last to go because it has the RAS back-up system). Combined with liver impairment, this stage is known as hepatorenal failure, which is the cause of death due to compensated idiopathic cardiomyopathy. A patient will know if s/he eventually loses the ability to compensate if, when they lie down, they are short of breath. Cheney’s view is that cardiac muscle has lost power because the mitochondria are dysfunctional (ie. there is an energy-production problem in the cells). As long ago as the 1980s, Dr Les Simpson in New Zealand found that the red blood cells of patients with CFIDS were deformed and when deformed, they cannot get through the capillary bed, causing pain. An indication of such deformity is a drop in the sedimentation rate (SED, or ESR) and Cheney has observed that when measured in a laboratory, CFIDS patients’ sedimentation rate is the lowest he has ever recorded, which confirms to Cheney that CFIDS patients have an induced haemoglobinopathy. He believes that the CFIDS patients with the lowest sedimentation rate may have the greatest degree of pain. The more deformed the red blood cells, the more pain may be experienced. Some CFIDS patients have a problem similar to that of sickle cell anaemia in this regard, and sickle cell patients have unbelievable pain. Cheney emphasises that it is bad enough when Facts About ME The incidence of psychiatric co-morbidity in ME/CFS has been greatly over-emphasised: a study in the Journal of the Royal Society of Medicine (2000:93:310-312) found that of patients in a tertiary referral centre who had received a psychiatric diagnosis, 68% had been misdiagnosed, with no evidence of past or current psychiatric illness. ME Comment Having watched the (IiME) Conference DVD I was amazed at:• The groundbreaking science presented by the researchers/scientists. • The level of knowledge of ME by the doctors/physicians. • The empathy from other speakers who understood ME from all angles. (Health, Financial, Social etc.) • The quiet confidence amongst all the speakers that biomedical science will break the chains of the psycho-social model of ME. • The fact that many of the speakers understood that assessment, management and treatments offered to ME sufferers are, unfairly, weighted in the psychiatrists favour. (A few speakers vocally expressed their opinions and well done to them for doing so. They spoke truthfully.) - Caroline patients do not perfuse their muscles and joints (because of poor microcirculation) but it is even worse when red blood cells are so deformed that they can barely get through the capillaries or are blocked entirely. Cheney notes that in the Laboratory Textbook of Medicine, there are only three diseases that lower the sedimentation rate to that level: one is sickle cell anaemia (a genetic haemoglobinopathy); the second is ME/CFS (an acquired haemoglobinopathy) and the third is idiopathic cardiomyopathy. Cheney observes that in order to improve cardiac output in CFIDS, patients need to lie down, as this increases the cardiac output by 2 litres per minute. He notes that some patients need to lie down all the time to augment their blood volume in order to survive. He has found increasing the intake of potassium to be helpful (potassium induces aldosterone, a hormone that significantly increases blood volume), and that magnesium is beneficial as it is a vasodilator and helps reduce the resistance the blood encounters. Invest in ME Charity Nr 1114035 (continued on page 65) Page 64/72 Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) Since Professor Cheney has shown that in ME/CFS patients, cardiac output struggles to meet metabolic demand, how can forced aerobic exercise which forms a major part of the MRC PACE and FINE “rehabilitation” trials help such patients remain as functional as possible? In the light of the Peckerman et al paper that was published in 2003, are the psychiatrists and their peer reviewers at the MRC who approved the PACE trial protocol still convinced that these trials (and the exercise regimes to be meted out by the new Centres) pose no harm for those with ME/CFS? Perhaps they are content to rely on the certainty that they themselves can never be held accountable for any harm to any patient because all participants must sign a compulsory waiver which means that no participant can ever pursue any claim for medical negligence or damages? Since Professor Cheney has shown that in ME/CFS patients, cardiac output struggles to meet metabolic demand, how can forced aerobic exercise which forms a major part of the MRC PACE and FINE “rehabilitation” trials help such patients remain as functional as possible? Concern that the Principal Investigators of the MRC PACE and FINE trials repeatedly reject published evidence of biomarkers of ME/CFS ME Story Since there is such lack of awareness, no exposure in the media and no public consciousness about ME, I find it very frustrating to have to continually explain myself. Even if some people understand and believe I have a real physical illness, I feel that people have a nagging belief that there may be a psychiatric component to it. Due to fear of being misunderstood, I feel that the less I explain my situation the better off I am. However, since I am either unemployed or a part-time worker, it's embarrassing not to have a "suitable" explanation for being off work. I hate to think that people might consider me a layabout or an idler. You have to have ME to even start to understand and appreciate the constant struggle sufferers face if not each day, most days. -Rebecca (pwme from Malta) The psychiatric lobby repeatedly asserts that there is no single, definitive biomarker for “CFS/ME”, yet they themselves are the very people who are instrumental in preventing the research in the UK that would be likely to demonstrate such a biomarker. Even when potential biomarkers are demonstrated by means of non-MRC funding, for example, the finding by Kennedy et al from Dundee of raised levels of isoprostanes that precisely correlate with ME/CFS patients’ symptoms – a laboratory finding that is unique to ME/CFS (Free Radical Biology & Medicine 2005:39:584-589). Other useful biomarkers already exist, including hsCRP (high sensitivity C-reactive protein, a well-established marker of inflammation) and low NK (natural killer) cells, but the psychiatric lobby will not accept such compelling findings as evidence that their own beliefs about the nature of “CFS/ME” are erroneous. Concern about the uncritical acceptance of the “evidence” for the alleged effectiveness of CBT/GET The Systematic Review from the Centre for Reviews and Dissemination (CRD) has been exposed in the Hooper & Reid Review (mentioned above) and this evidence has been submitted to the MRC. It is beyond belief that the MRC continues to condone the acceptance of such a flawed “evidence-base” for the basis of the PACE and FINE trials, or that the Data Monitoring and Ethics Committee apparently remains unaware of (or uncaring about) this evidence. The Countess of Mar was so concerned at the damaging and destructive influence of the Wessely School that she requested a meeting with Professor Blakemore. This took place at the House of Lords on 20th April 2004 and lasted for two hours. Earl (Freddie) Howe was also present. Invest in ME Charity Nr 1114035 (continued on page 66) Page 65/72

Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) Both the Countess of Mar and Earl Howe were seasoned debaters in the House of Lords and both were profoundly disturbed at what occurred at that meeting, the outcome of which was fruitless. Professor Blakemore was accompanied by Elizabeth Mitchell of the MRC and she did most of the talking. It was apparent that as far as the MRC was concerned, Professor Wessely is greatly revered and what he says about “CFS/ME” will be accepted. It was also apparent that the MRC’s mind had been made up and was firmly closed. There was to be no consideration of the biomedical evidence that proved Wessely et al to be wrong. On 10th May 2004, an article called “Why won’t they believe he’s ill” by Jerome Burne in The Independent quoted the Countess of Mar: “A campaigner who has long opposed the purely psychiatric approach is scathing about the MRC trials. ‘They are a farcical, cynical exercise and a huge waste of money’ the Countess of Mar said”. The article continued: “ ‘Whatever their findings’, says Dr Vance Spence, Senior Research Fellow at the University of Dundee and a leading scientist in the field, ‘they [the PACE trial] won’t tell us anything useful about the best way to treat CFS/ME because they are not properly selecting patients with the disease. There is widespread concern about this’. Concern about patients’ dissatisfaction with the MRC trials The disregard of the illness was reflected on a practical level – they said that if I recover from exercise in ten minutes then I am working at the right level. I abided by this rule and later crashed due to delayed and accumulated effects. How this is ethical I do not know. In January 2005 there were disturbing accounts posted on the internet by participants in the FINE trial, and people made known their wish to withdraw. One person who had been forced to suspend from university gave the reasons {see Invest in ME page - http://www.investinme.org/Article-015A%20FINE%20TrialsAlice.htm} “Data they collected about me was misleading. Only questionnaires were used; the questions were leading and did not reflect my true feelings. Also, the researchers spent 2-3 hours with me each time, which was so exhausting that I didn’t really know what my replies were. The trial totally disregards ME/CFS as an illness. It is based on a theory that symptoms are due to deconditioning and maladapted beliefs about exercise. The disregard of the illness was reflected on a practical level – they said that if I recover from exercise in ten minutes then I am working at the right level. I abided by this rule and later crashed due to delayed and accumulated effects. ‘Whatever their findings’, says Dr Vance Spence, Senior Research Fellow at the University of Dundee and a leading scientist in the field, ‘they won’t tell us anything useful about the best way to treat CFS/ME because they are not properly selecting patients with the disease. There is widespread concern about this’ ”.In a letter dated 11th May 2005, Professor Blakemore confidently claimed that the PACE trials “were peer-reviewed and awarded funding on the basis of the excellence of the science”. How this is ethical I do not know. The therapist had very selective hearing and she would adapt whatever I said to fit into what she wanted to hear (I have examples). The therapist was critical of me and was unsupportive. I believe the consent process was unethical. I was not aware what I was letting myself in for (they did not explain the details of the intervention until after I had consented). In addition, the de-conditioning theory was presented as fact (I have since read research that goes against the deconditioning theory). It frightens me to think that this research will be used to support clinics offering this in the future”. Invest in ME Charity Nr 1114035 (continued on page 67) Page 66/72 Journal of IiME Volume 1 Issue 2 www.investinme.org The PACE TRIALS (continued) In respect of the FINE trial, it is worth noting that the trial information says that for severely affected participants who are isolated, the trial may be carried out by means of the telephone or by computer. The sheer impracticality of these two methods reveals how little understanding the Principal Investigators have of the reality of the daily lives of those with severe ME/CFS. How many home-bound severely affected ME/CFS patients have got – or are able to use – a computer? Who is going to pay for the purchase and installation of a computer for those who do not possess one, and who is going to pay for and arrange lessons in basic computing skills (even supposing participants were well enough to undertake such lessons)? People who are severely affected by ME/CFS are unable to talk on the telephone for more than just a few minutes, so three-hour telephone sessions are unfeasible, but none of these practicalities seems to trouble the MRC Principal Investigators or the Data Monitoring and Ethics Committee. Overall, there has been immense concern registered about the MRC PACE and FINE trials and about the psychiatrists who are leading them. The support of AfME for these MRC PACE and FINE trials is disturbing; even more disturbing is the fact that AfME’s website states: “Some evidence suggests that the inactivity and resulting loss of fitness (de-conditioning) that occurs with ME can make the illness last longer and that graded exercise can help to reverse this”. Perhaps AfME is unaware of the results of a Belgian study on over 3,000 patients with “CFS” who were referred to multi-centre clinics. Out of those who undertook the “rehabilitation” programme consisting of CBT and GET, whereas before “rehabilitation”, 18.3% were in paid employment, following “rehabilitation”, this figure was reduced to 14.9% the trial information says that for severely affected participants who are isolated, the trial may be carried out by means of the telephone or by computer. The sheer impracticality of these two methods reveals how little understanding the Principal Investigators have of the reality of the daily lives of those with severe ME/CFS. The support of AfME for these MRC PACE and FINE trials is disturbing; even more disturbing is the fact that AfME’s website states: “Some evidence suggests that the inactivity and resulting loss of fitness (deconditioning) that occurs with ME can make the illness last longer and that graded exercise can help to reverse this”. (ie. participants were working less hours after “rehabilitation”). Equally, perhaps AfME is unaware of a Dutch study which found that at the one year follow-up following “rehabilitation”, 17% of ME/CFS patients who were previously working were no longer able to do so. It is AfME’s duty to be aware of the medical literature and to use it effectively to support the best interests of its members. Moreover, AfME seems to be extraordinarily inconsistent: in its press release of 22nd August 2007 issued to coincide with the publication of the NICE Guideline on “CFS/ME”, AfME stated: “Many patients have reported little or no benefit from CBT and others have experienced seriously adverse effects from GET”, yet the following week, in an Editorial in the BMJ (1st September 2007:335:411-412), AfME’s CEO, Sir Peter Spencer, agreed with psychiatrist Peter White that these same interventions show “the clearest research evidence of benefit”. AfME might care to consider just why the MRC has a secret file of records and correspondence on ME/PVFS that dates from at least 1988 and is held at the Government Archive at Kew, and why this file is deemed so sensitive and controversial that it has been classified as top secret and cannot be made public until the 1st January 2023. AfME may like to recall that members of the CMO’s Working Group were threatened with the Official Secrets Act. In the best interests of its members, AfME might also wish to ascertain exactly why the MRC so resolutely rejects grant applications for biomedical funding into ME/CFS (see http://www.nationalarchives.gov.uk/search/quick_search.a spx?search_text=myalgic). The full document “CORPORATE COLLUSION?” may be found at the ME ACTION UK site at – http://www.meactionuk.org.uk/Corporate_Collusion_2.htm Invest in ME Charity Nr 1114035 Page 67/72

Journal of IiME Volume 1 Issue 2 www.investinme.org Attitudes of Mental Health Practitioners to the Hippocratic Oath Psychiatry has been one of the major areas of contention from the ME community regarding why and how it is implicated in the treatment of myalgic encephalomyelitis. A research paper on how the Hippocratic Oath and psychiatry are perceived to co-exist was made by Dr. Marek Marzanski and colleagues from the Coventry PCT. We asked Dr. Marzanski for permission to republish this paper and he happily agreed. Our intention was to publish the paper in full here. However, the Royal College of Psychiatrists refused to give permission for publication in our Journal – but were happy for us to describe briefly the article and redirect to their site for the content (see link below). Dr. Marzanki’s research “Attitudes of mental health practitioners to the Hippocratic Oath: tradition and modernity in psychiatry” was carried out in 2004 to determine whether psychiatrists believe that medicine should be practised according to the principles of the Hippocratic Oath. Via an anonymous postal questionnaire a survey was carried out at a mental health unit in Coventry. A modern version of the Hippocratic Oath is shown in summarised form on the right. Those psychiatrists taking part in the survey ranged from junior doctors to consultants with an age from late twenties to over 70. Eighty percent were male. The results showed over 80% of the psychiatrists believed that medicine should be practised according to the Hippocratic Oath. However, the results showed that support for different statements derived from the Oath to be at a considerable variation. The questions ranged from treatment of teachers and other colleagues, the welfare of patients and the psychiatrist’s attitudes toward the patient. As Dr. Marzanski points out “Articulated in a contemporary form, Hippocratic values such as avoiding harm, acting in the best interest of the patient, compassion, integrity, honesty and respect for human life maintain their relevance and prove that goodness in medical practice does remain continuous across the ages.” The survey suggested to the author that the majority of psychiatrists agreed that medicine should be practised in accordance with the principles of the Hippocratic Oath – although the small survey might not be representative of UK psychiatrists in general. It would be an interesting study to assess the answers from Dr. Marzanski’s studies when directed toward psychiatrists who are involved in dealing with ME patients on a regular basis. Dr. Marzanski’s research paper can be found at this address – http://pb.rcpsych.org/cgi/reprint/30/9/327 Invest in ME Charity Nr 1114035 The Hippocratic Oath (A Modern Version) I swear in the presence of the Almighty and before my family, my teachers and my peers that according to my ability and judgment I will keep this Oath and Stipulation. To reckon all who have taught me this art equally dear to me as my parents and in the same spirit and dedication to impart knowledge of the art of medicine to others. I will continue with diligence to keep abreast of advances in medicine. I will treat without exception all who seek my ministrations, so long as the treatment of others is not compromised thereby, and I will seek the counsel of particularly skilled physicians where indicated for the benefit of my patient. I will follow that method of treatment which according to my ability and judgment, I consider for the benefit of my patient and abstain from whatever is harmful or mischievous. I will neither prescribe nor administer a lethal dose of medicine to any patient even if asked nor counsel any such thing nor perform the utmost respect for every human life from fertilization to natural death and reject abortion that deliberately takes a unique human life. With purity, holiness and beneficence I will pass my life and practice my art. Except for the prudent correction of an imminent danger, I will neither treat any patient nor carry out any research on any human being without the valid informed consent of the subject or the appropriate legal protector thereof, understanding that research must have as its purpose the furtherance of the health of that individual. Into whatever patient setting I enter, I will go for the benefit of the sick and will abstain from every voluntary act of mischief or corruption and further from the seduction of any patient. Whatever in connection with my professional practice or not in connection with it I may see or hear in the lives of my patients which ought not be spoken abroad, I will not divulge, reckoning that all such should be kept secret. While I continue to keep this Oath unviolated may it be granted to me to enjoy life and the practice of the art and science of medicine with the blessing of the Almighty and respected by my peers and society, but should I trespass and violate this Oath, may the reverse be my lot. Page 68/72 Journal of IiME Volume 1 Issue 2 www.investinme.org Energising ME Awareness The IiME International ME/CFS Conference London 23rrdd May 2008 It is Invest in ME’s intention to continue with the London conference as an annual event and to provide a platform for researchers, healthcare staff, support, educational professionals, ME support groups and people with ME and the media, to enable the most relevant science, research, information and news on ME to be heard. Our 2008 conference is scheduled for 23rd May 2008 in London. More details will be announced during the coming months so please visit our web site. We shall also be sending out details via our free newsletter to all our subscribers. We hope again to work with our UK regional and international contacts to enable this. More details will be available on our web site in due course. Contact: meconference@investinme.org. Energising ME Awareness Invest in ME Charity Nr 1114035 Page 69/72

Journal of IiME Volume 1 Issue 2 www.investinme.org The IiME International ME/CFS Conference London 23rd May 2008 W Weellccoommee t too LLoonnddoonn We believe it is important to provide a possibility for people within government, health departments, social services, education and the media to be able to be informed of the the status of research, treatment and information related to Myalgic Encephalomyelitis. Invest in ME offers the chance for researchers, medical practitioners, healthcare staff, people connected with, or interested in, the care of people with ME to present at the conference. We again hope to provide platforms for the following - • Epidemiology • Diagnosis • Pathology • Treatments and Protocols for ME • Research • Nutrition • Care The conference will again highlight the need for empirical evidence based on valid, modern and scientific diagnostic and treatment protocols. The conference will provide a chance to hear the latest news on ME from the most prominent speakers within the ME community - in ME Awareness Month 2008. ME Conference Comments "…thanks for organising a conference with such impressive speakers & at such reasonable cost. As a humble parent, most conferences are completely out of my price range, so was really delighted to be able to attend. I picked up lots of info & have realised that I need to do loads more h/w to really be on top of all the stuff that’s been discovered since my daughter first became ill – 10 yrs ago." – Helen “Many thanks for the wonderful conference. It was a great atmosphere and very uplifting to know of the wonderful work and people involved in helping us ME Sufferers. … It was a conference of excellence and it honoured us as well as raising us up!” – Jane “I profited so much, I learned so much, I've met so many people I haven't met before - all this was so impressive.” - Regina “I thought it was fantastic, massively informative, encouraging, inspiring, necessary. It was very powerful hearing so much material from the doctors, researchers and speakers themselves, very, very impressive. I do agree that the speakers all came across as deeply humane. As a patient there was an enormous amount of useful applicable material and info on research hot from the lab so to speak. “ – Nikki The above pictures of London and the conference were taken by Regina Klos (www.cfs-aktuell.de). More pictures from the conference taken by Regina may be found herehttp://www.investinme.org/International%20ME%20Confer ence%202007%20-%20review%20gallery%202.htm Invest in ME Charity Nr 1114035 See other comments at http://www.investinme.org/International%20ME%2 0Conference%202007%20%20review%20feedback.htm Page 70/72 Journal of IiME Volume 1 Issue 2 www.investinme.org EDUCATIONAL MATERIAL from IiME INTERNATIONAL ME/CFS Conference DVDs Invest in ME have available the full presentations from both of the International ME/CFS Conferences in London of 2007 and 2006 These professionally filmed and authored DVD sets each consist of four discs, in Dolby stereo and in PAL (European) or NTSC (USA/Canada) format. Containing 9 ½ hours (2007 DVD set) and 6 hours (2006 DVD set) – with all presentations plus interviews with ME presenters and news stories from TV programmes. These DVDs have been sold in over 20 countries and are now available as an educational tools – useful for healthcare staff (GPs, paediatricians, occupational therapists and others connected with the treatment of ME), researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at http://www.investinme.org/InfoCentre%20Education%20Homepage.htm or via emailing IiME at meconference@investinme.org. Price £15 each (UK), £16 (Europe) and £17 (USA/Canada/Australia/New Zealand) - including p&p. Quotable Quotes on ME/CFS This 42 page booklet has been compiled by Margaret Williams and contains a plethora of quotes from ME experts and from others relating to ME, ME/CFS, CFS/ME and CFS. This is an invaluable document for researchers, healthcare staff, politicians, media, ME support groups and people with ME. The booklet will aid those composing letters, performing research, verifying analysis and for general reference purposes. Price £3.50 + £1 postage/packing for UK delivery (for Available from Invest in ME www.investinme.org Europe and USA/Canada/Australia/New Zealand please email for costs of p&p). El http://www.investinme.org/IIME%20ME%20Quotes%20Order %20form.htm Invest in ME Charity Nr 1114035 Page 71/72

Journal of IiME Volume 1 Issue 2 E EDDUUCCAATTIIOONNAALL MMAATTEERRIIAALL ff rroomm II iiMMEE Canadian Guidelines Invest in ME are the UK distributors for the Canadian Guidelines. Described even by NICE as “the most stringent” guidelines available these are proper, up-to-date clinical guidelines which can also be used as a base for research criteria. Findings from the study by Leonard A. Jason PhD (Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome) indicated that the Canadian criteria captured many of the cardiopulmonary and neurological abnormalities, which were not currently assessed by the Fukuda criteria. The Canadian criteria also selected cases with 'less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms' and individuals selected by these criteria were significantly different from psychiatric controls with CFS. The Canadian Guidelines provide a means for clearly diagnosing ME and were developed specifically for that purpose. They are an internationally accepted set of guidelines for which many in the ME community have been campaigning to be adopted as the standard set of guidelines for diagnosing ME. The Canadian Guidelines are available from IiME and the price is 46p per copy plus postage & packaging. To order please contact Invest in ME via this email address: info@investinme.org www.investinme.org Order our free newsletter. We aim to publish monthly via html, plain text or PDF. S Suupp pp oo rr tt II nn tt ee rr nn aa tt ii oo nn aa ll MM EE AA wwaa rr ee nn ee ss ss MMoo nn tt hh MMaa yy 2 200 00 88 w wwwww.. ii nn vv ee ss tt ii nnmmee .. oo rr gg Invest in ME Charity Nr 1114035 Page 72/72

Journal of IiME Conference Section

Journal of IiME Volume 2 Issue 1 www.investinme.org “The identification of clinically significant subgroups is the logical next step in furthering ME-CFS research. There might be multiple pathways leading to the cause and maintenance of the neurobiologic disregulations and other symptoms experienced by individuals with MECFS. Depending upon the individual and subtype, these may include unique biological, genetic, neurological, and socioenvironmental contributions. Subgrouping is the key to understanding how ME/CFS begins, how it is maintained, how medical and psychological variables influence its course, and in the best case, how it can be prevented, treated, and cured. I have a paper on this that was published, and it goes into much more detail. [See "Exploratory subgrouping in CFS: Infectious, inflammatory, and other": [http://www.investinme.org/Documents/Journals/Journal%20of% 20IiME%20Vol%201%20Issue%201.pdf ] “ - Live Chat Q&A with Chronic Fatigue Syndrome Research and Policy Leader Dr. Leonard A. Jason, PhD http://www.immunesupport.com/library/showarticle.cfm/ID /8232 Invest in ME (Charity Nr 1114035) Page 2 Journal of IiME Volume 2 Issue 1 www.investinme.org From the Chairman of Invest in ME Previous IiME Conference Comments “The conference was so fantastic. I now feel fully armed to battle in ignorance about this disease in Denmark. How can any doctor look at the facts and doubt it is a physical disease”- R “Just wanted to congratulate you on an excellent conference last week. It was great to see so many of the leading researchers into ME all in one room, and all pulling in the same direction.”- C “I enjoyed participating enormously and think the whole conference was a great success” - Dr S “It was great to see so many familiar faces, both amongst the audience and the presenters, and as you rightly say, the information conveyed was amazing and exciting. “ - D A very good venue too, I noticed others remarked on what a pleasant environment, the term 'the organisers did us proud' came to mind – N Thank you very much for all the time and effort that the IiME team generously gives, voluntarily, to the ME community. This great effort has ensured that the 2007 Conference was a great success. It is so encouraging and reassuring to know that IiME is standing firm and campaigning for biomedical research into M — C Invest in ME (Charity Nr 1114035) Welcome to the third Invest in ME International ME/CFS Conference in London in May 2008 – an event that brings together the best of biomedical research from some of the most renowned experts on ME/CFS in the world. This third IiME conference coincides with publication of the third version of the Journal of IiME – a unique publication which combines research, information, news, stories and other articles relating to myalgic encephalomyelitis (ME/CFS). In two and half years IiME has now organised three international biomedical research conferences attracting some of the foremost and relevant experts on ME/CFS from around the world and this year’s conference is no exception. The blend of biomedical research, objective data and established experience presented by our distinguished speakers is testament to the increasing knowledgebase for ME/CFS. At the conference you will find citizens of ten nations in attendance – indicating, we hope, not just the popularity of the IiME conferences but also the yearning for education and knowledge of the science regarding this illness. We welcome Dr Judy Mikovits, Dr Leonard Jason, Dr Martin Lerner and Dr John Chia from USA and are grateful to them for taking the time to provide details of their research and vast experience. Our four guests from America are matched by four guests from UK representing old and new research and exhibiting a stunning mix of experience and analysis. We also welcome the Chief Medical Officer, in the shape of Dr. Paul Cosford, Regional Director of Public Health for the East of England and we welcome the Medical Research Council, represented by Dr Joanna Latimer. However, two people whom you will not see at the conference are Mr Alan Johnson and Mrs Ann Keen, Secretary of State and minister responsible for Health, respectively. The Department of Health (DoH) exists to improve the health and wellbeing of people in England – it states this on its website. Yet both ministers have declined our offer to speak at the conference and failed to respond to subsequent offers to attend (despite both having been originally invited when the initial conference plans were evolving over eight months ago). (continued on Page 4) Page 3

Journal of IiME Volume 2 Issue 1 www.investinme.org From the Chairman of Invest in ME (continued) This continues a chain of refusals by the department to try to understand the major issues facing the families of people with ME/CFS by the lack of a government policy for ME/CFS. Yet it is a pity that the UK government continues in failing in its duty of healthcare to its citizens by ignoring the overwhelming evidence which dictates that substantial funding of biomedical research into ME/CFS will likely give results – something recommended in the Gibson Inquiry by establishing a world-leading research community to provide the necessary science for creating treatments and cure for ME/CFS. The conference would have helped the ministers to see for themselves the need for this. Unfortunately, the Health minister has stated that the Gibson Inquiry has been ignored – replaced by the National Institute of Clinical Excellence (NICE) guidelines which have been heavily criticised by IiME and other support groups as lacking in proper objective analysis and offering nothing for people with ME and their families. Our theme for the conference is Sub Grouping of and Treatments for ME/CFS and we believe now is the time to lobby for a more scientific approach by the governments and healthcare organisations toward treatment of people with ME/CFS. one size fits all methodology based on CBT and GET - is shown not only to be costly or dangerous but also unnecessary and pointless for people with ME/CFS. Any unbiased and objective assessment of biomedical research data which has been shown in our past conferences would surely agree that dedicated funding of biomedical research into ME/CFS, made within a national strategy for ME/CFS, would be the most cost-effective, moral and sensible approach to take in order to allow hundreds of thousands of patients, carers and families to reclaim their lives and reduce what is an enormous cost to the UK economy. The need for sub grouping of ME/CFS is becoming more and more accepted and is supported by the increasing biomedical research. The experience and data of researchers such as Dr. Jason, Dr Lerner, Dr Chia, Dr Mikovits, Dr Newton and Dr Kerr, backed by real life experiences of Dr Spurr and Dr Monro shows that there is hope for treating and eventually curing this illness. It is an illness that has no international barriers. The unrealistic and unjust approach shown by NICE with their recent guidelines for ME/CFS – a Yet there may be signs of change - undoubtedly caused by the many dedicated researchers and campaigners who have been continually providing information and advocacy over the many years. Attitudes to ME/CFS are changing. Good quality science is being published in peerreviewed journals (albeit mostly privately funded research). The argument that funding of biomedical research into ME/CFS is denied because of the lack of good quality research proposals is now proven beyond doubt to be specious. News of recent changes in Scotland has brought hope that the UK government might change its position of indifference. Invest in ME pointed out over a year ago that the best hope for change in policy toward ME/CFS may come from smaller countries. We highlighted the work going on in Norway where the Norwegian minister, prompted by the tremendous work of the Norwegian ME Association, has begun changing course. In Scotland recently new hope comes of the way ahead for the work to develop an ME good practice guide for GPs, known colloquially as the Invest in ME (Charity Nr 1114035) Page 4 Journal of IiME Volume 2 Issue 1 www.investinme.org From the Chairman of Invest in ME (continued) Scottish GP Guideline. It is intended to inform the meeting of the Cross Party Group on ME/CFS. If this progresses and patients’ voices begin to be heard then it will be progress. But if it takes the same course as the NICE guidelines then it will be another wasted opportunity. Recently some questions were tabled by an MP in the UK parliament in response to pressure from one of his constituents - a severely affected person with ME who has been writing to IiME. Ian Pearson answered questions about plans ‘to establish an independent scientific committee to oversee research into ME/CFS. He responded by stating that – “the MRC is planning to set up a panel of experts from different disciplines to look more closely at the area. The panel will come from varied fields including neuroscience, immunology, toxicology and imaging, and will involve interested parties and focus on the subtypes and causes of ME/CFS”. If this proves to be true then valid change may be on the way. However, as we recently stated in our newsletter, Invest in ME take the position that any intention to bring together the biological and psychological ME/CFS factions in order to encourage the MRC to give money is misguided. Whilst a holistic approach need to be taken toward any illness it is difficult to reconcile good science with any examination of relationships between valid and proven biological markers and generic, unproven and sometimes deleterious treatments. This will merely delay the only sure way of finding a cure for ME - biomedical research. The only strategy which makes any sense from a scientific, moral or just viewpoint is to fund biomedical research into ME and treat ME in the same way as cancer, Parkinson's, MS or any other mainstream illness. We need to adopt proper diagnostic criteria, the Canadian consensus criteria, to differentiate idiopathic chronic fatigue, burn out, overtraining syndrome, fibromyalgia, multiple chemical sensitivities etc. from ME/CFS and find the correct treatment for each of these groups. Basically, we need and want an objective scientific approach to ME/CFS and sub grouping will facilitate this process. We hope the conference will demonstrate this fact. And so to the conference. This year we are dedicating the conference to the memory of Dr John Richardson. Dr Richardson devoted his life to the treatment of ME and it is fitting that we remember him at a biomedical research conference carrying the theme of sub grouping and treatments for ME/CFS, especially with regard to research on enteroviruses now being presented and which brings us back to the origins of ME. In this small way we honour his work and that of other distinguished professionals over the years who worked with Dr Richardson and have continued his work, including Dr Spurr who is cofounder and chairman of the John Richardson Research Group. As Dr Spurr notes John Richardson was a modest man and did not get the credit he deserved. A day to celebrate research, science and to be able to network in a friendly atmosphere with an eclectic mix of professionals, charities, support groups and others. We shall have details of our ME Book Project on display with Natalie able to discuss this exciting project. The conference day will be a busy time for the IiME team and we won’t be able to spend as much time discussing with our delegates as we would like. But if you are coming to the conference please come up and say hello. For those who are not coming to the conference but are reading this in our Journal then please stay in touch via email. We wish everyone an enjoyable conference and a pleasant summer and hope and believe that progress will continue in providing a future treatment/cure for ME. Best Wishes Kathleen McCall & the IiME team Invest in ME (Charity Nr 1114035) Page 5

Journal of IiME Volume 2 Issue 1 www.investinme.org The 3rd IiME International ME/CFS Conference Dedicated to Dr John Richardson As IiME launch our third annual conference and include a significant part devoted to enteroviral research so we would like to dedicate the conference to a man who devoted a great deal of his life to treating people with ME. The international reputation that John Richardson acquired in the field of myalgic encephalitis (ME) research sprang from the records that he kept for 40 years of enteroviral infections, mostly coxsackie virus. He realised that enteroviral infections were endemic among his practice population on the south bank of the Tyne, spreading from one family to another and from one generation to the next. The public health authorities seemed to be unaware of it and facilities for identification were rarely available locally. The clinical features of these infections varied from Bornholm disease—a common short illness with chest pain—to audible pericarditis, serious myocarditis, and valvulitis with dysfunction. Other features were muscle pain, jitter and weakness, sleep disturbance, hypersensitivity to sound and light, and mild confusion. Many organs in the body could also be affected. In the long term the effects were sometimes serious. While some members of a family would escape with a brief febrile illness only, coxsackie infection could leave one person struggling for years with ME or dilated cardiomyopathy. Worse still, John found that the infection would readily pass from the mother to her unborn child, which would be delivered with fibroelastosis or maldevelopment of the heart, or structural defects of the brain or other organs. He tried to prevent this in early pregnancy by giving the mother intramuscular injections of human immunoglobulin. Early on John believed that ME was an illness that could follow directly from a coxsackie infection and one that was capable of altering the whole personality and abilities of someone he had known for years. The idea that it was just depression or hysteria, a psychoneurosis or "all in the mind," he found not only ludicrous and cruel, but also Invest in ME (Charity Nr 1114035) “This Dr. John Richardson of Newcastle, and others have documented significant associated cardiac and cardiovascular injury as well as other organ injuries associated with the usual CNS and autonomic changes in this group of patients." "[Richardson] has followed ME patients...for three to four generations. I am aware of no other physician in the world with such a historic view of ME patients. He has repeatedly demonstrated that many ME patients go on to develop structural heart injury. Richardson has identified more than several hundred cardiopathies in his ME practice." -Dr. Byron Hyde(source http://www.nameus.org/ResearchPages/ResCirculatory.htm) dangerous, and his records contain several examples of suicide. When patients told him that they had grown tired after taking vigorous or progressively "graded" exercise and found that they had to pay for it by being much worse for the next day or so, he believed them and sought other methods of treatment. The fame of his records led James Mowbray, professor of immunopathology at St Mary's Hospital, London, to offer him unrestricted facilities for identification of the various strains of the coxsackie group of viruses, as well as other viruses less frequently encountered. Leonard Archard, professor of biochemistry at Imperial College, London, was also helpful in culturing virus in samples of tissue sent to him and both became personal friends. John did not publish these records in the form of his book Enteroviral and Toxin Mediated Myalgic Encephalitis/Chronic Fatigue Syndrome and Other Organ Pathologies (Haworth Medical Press) until 2001. (Continued on page7) Page 6 Journal of IiME Volume 2 Issue 1 www.investinme.org John also became acquainted with Dr Melvin Ramsay, who defined benign myalgic encephalomyelitis in 1956 after studying an outbreak of Bornholm disease at the Royal Free Hospital, London. John became a founder member of the ME Association, renamed the Ramsay Research Fund in 1999 after Melvyn Ramsay's death. John's own international reputation grew rapidly after an international symposium on myalgic encephalitis was held in Cambridge, United Kingdom, in 1989. He chaired the conference and the book that followed in 1992, The Clinical and Scientific Basis of Myalgic Encephalomyelitis, edited by Dr Byron Hyde, not only contains a chapter written by John, but is dedicated to him. John gave up all NHS work in 1992 and his appointment as a senior police surgeon. However, he continued to see patients privately. Most came from the United Kingdom, but some also from France, Republic of Ireland, Belgium, and Norway. He refused fees, but suggested instead a contribution to the research fund that he established. This he used partly to finance scientific papers that he wrote and partly as gifts to individuals and university departments where the effects of long term survival of virus in the human body were being studied. His own papers were into what part of the brain was involved in ME. John also used the patient contributions to finance an annual international conference in his local area. The pursuit of these researches did not prevent him playing a full part in the general practice of which he was a partner, including training medical students sent to him by the university. Outside medicine his main interest was music, especially playing the three manual pipe organ, which with assistance he had built in his own house and for which he composed 28 pieces. John Richardson, former general practitioner Ryton, Tyne and Wear (b 1915; q Durham 1952), died in the Freeman Hospital, Newcastle, on Invest in ME (Charity Nr 1114035) 18 July 2002. The above information was taken from the BMJ obituary for John Richardson by Hewan Dewar. The John Richardson Group The Newcastle Group was founded by Drs John Richardson, Hewan Dewar and Irving Spurr back in 1993. Its purpose was to promote research into the origin and consequences of viral infections (entero viruses in particular). The group was renamed following the death of Dr John Richardson in 2002. The group also organises an annual conference which attracts many eminent participants from around the world. More articles from Dr John Richardson: - • Myalgic Encephalomyelitis: Guidelines for Doctors Journal: J of Chronic Fatigue Syndrome, Vol. 10(1) 2002, pp. 65-80 • Enteroviral and Toxin Mediated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Other Organ Pathologies (Hardcover) ME Story I am …. a fully grown man of 44, I am now into my 6th year, soon planned to get married but my girlfriend is very worried about what to expect - the outlook will be for her having to deal with me as I get worse. I have got to the stage where I can no longer breathe through my nose channel despite 4 operations. They have said there is nothing more they can do so I am now finding myself becoming very fatigued by about 11am sleeping for about 9 hours per day and again during the night, I have lost a lot of weight gone from 12 stone down to 9 stone in one month. I wish the government would put more money into research to find a cure for this bad, painful illness. - I Page 7

Journal of IiME Volume 2 Issue 1 C Coonnffeerreennccee IInnttrroodduuccttiioonn This Conference makes clear the rapidly changing understanding of ME-CFS and related “syndromes of uncertain origin”. It provides confirmation of earlier insights concerning viral infections as a common basis of the illness and adds to these the growing recognition of the impact of infection on nervous system, particularly the, autonomic nervous system, endocrine and cardiovascular systems. The validity of the WHO ICD classification of ME as a neurological condition is justified whilst the interrelated impact on other major body systems is demonstrated. The inadequacies of the widely used CDC 1994 research criteria are now clear and much more careful definitions of ME are needed if the accurate diagnosis necessary for effective treatment and management of the illness are to be provided. The key to accurate diagnosis is the careful clinical separation of different sub-groups within the ME spectrum which will, at the same time, assist deeper understanding of this multi-system and multi-organ disorder. The key to accurate diagnosis is the careful clinical separation of different sub-groups within the ME spectrum which will, at the same time, assist deeper understanding of this multisystem and multi-organ disorder. The speakers bring to the Conference years of extensive research and clinical studies that provide new grounds for hope for those who suffer from ME and their carers. It will encourage and inform clinicians and clinical administrators who are wrestling with the complexities of a growing number of patients with this illness and provided better grounds for treatment and the assessment of benefits, insurance and care needs for patients. Dr Leonard Jason has led the field in pressing the case for sub-groups to better understand and treat the illness. Drs John Chia and Martin Lerner are specialists in virally-induced infectious diseases which affect both the nervous system and the heart, two major Invest in ME (Charity Nr 1114035) www.investinme.org By Professor Malcolm Hooper features of sick ME patients. Dr Irving Spurr has for many years cared for and investigated ME patients in Weardale in collaboration with the late Dr John Richardson and Dr Byron Hyde. As a GP he has a long experience of this complex illness and its treatment within the UK. Dr Jean Monro has a great deal of expert clinical experience and developed extensive diagnostic and treatment protocols for ME and related illnesses and provides a private hospital service in addition to seeing patients in other settings. Dr Julia Newton has documented and studied the extensive dysautonomia commonly found in many ME patients and responsible for the well known variations in blood pressure, body temperature, balance etc. Dr Judy Mikovits, as Director of the newly formed Whittemore-Petersen Institute, will provide an up date on the progress of the Institute which is the first one founded to bring together research, clinical assessment and treatment of ME patients. Can we establish such an Institute in the UK? Dr Jonathan Kerr has pioneered the groundbreaking genetic studies of ME patients and shown the strong links with infection, chemicals, mitochondrial and nerve dysfunction. His latest work includes the identification of clinical phenotypes that provide sound grounds for subgroups within the spectrum of ME and point to more focussed treatment. The poverty and misinformation of the psychiatric lobby that dominates the UK understanding of CFS-ME is exposed by this Conference. The work presented will no longer allow the ill-founded somatisation and (bio)psychosocial theories to remain credible. Enjoy! Malcolm Hooper Page 8 Journal of IiME Volume 2 Issue 1 www.investinme.org ME Story I have lived with severe M.E, and a lot of ignorance and prejudice, for 13 years. On many occasions I have been told that there is nothing wrong with me, I am just trying to get attention, or that I am too lazy to do anything. My response is, that if I was going to "fake" being ill then I wouldn't choose an illness where I was going to be disbelieved, ignored, treated badly by most people, loose all of my friends and have my family reject me! - Sarah The International ME/CFS Conference 2008—Sub Grouping of/Treatments for ME/CFS John Herd is a passionate spokesperson and crusader for patients' rights. He has been called a "veteran advocate" by the CFIDS Association for faithful attendance at major conferences, and is "on a first-name basis with most of the pioneers" in ME/CFS research and patient care I'm delighted to read that the International ME/CFS Conference 2008 has chosen its theme to be Sub Grouping of/Treatments for ME/CFS. In the end of the 90's Lenny Jason and I encouraged the then operational health department's Name Change Workgroup (NCW) to include in its recommendations a call for a system of sub-grouping patients. Although sub-grouping had been very briefly mentioned in a few journal articles, the subject had been given almost no attention. Chief Medical Officer ‘..there is a paucity of good research evidence and very little research investment for a serious clinical problem that in likelihood has a pervasive impact on the individual and the community. Insufficient attention has been paid to differential outcomes and treatment responses in children and young adults, the severely affected, cultural, ethnic and social class groupings.’ – The CMO Working Group on CFS/ME 2002 In the years since the NCW distributed its recommendations there has been somewhat increased talk of the importance of sub-grouping, but there remains no standardized system of sub-grouping patients my biologic test results and/or symptom presentation. In research presentations researchers present stratified subgroups of patients based upon the specific data they are testing for. Because there is no standardized system of sub-grouping patients, it is often difficult to compare the results of studies or to know if studies are comparing similar populations. Development of a standardized sub-grouping system would alleviate the problem of different researchers applying differently the various research diagnostic criteria and even applying single criterion differently. Such a system may also help us get beyond the logjam of differing views about what is M.E. and what is CFS as our science progresses. John Herd Invest in ME (Charity Nr 1114035) Page 9

Journal of IiME Volume 2 Issue 1 www.investinme.org PROFILES of PRESENTERS at the IiME INTERNATIONAL ME/CFS CONFERENCE P Prrooffeessssoorr MMaa llccoollmm HHooooppeerr Professor Hooper graduated from University of London and had held appointments at Sunderland Technical College, Sunderland Polytechnic and the University of Sunderland, where he was made Emeritus Professor of Medicinal Chemistry in 1993. He has served at many UK universities as well as in India and Tanzania. He has inaugurated links with Indian research institutions and universities and celebrated 25 years of productive and on-going links which have, particularly, involved the design and development of new drugs for tropical diseases and an exploration of natural products associated with Ayurvedic medicine. He has published some 50 papers in peer-reviewed journals in the field of medicinal chemistry together with major reviews on the Chemotherapy of Leprosy, the Chemistry of Isatogens. He edited one book on the Chemotherapy of Tropical Diseases. He acted as a referee for a number of important journals and served on one editorial board. He has served on committees of the Council for National Academic Awards (CNAA), the World Health Organisation (WHO) and the Science and Engineering Research Council (SERC). Professor Hooper is a member of a number of learned bodies, including the Royal Chemical Society, the British Pharmacological Society and the Society for Drug Research (SDR), now renamed the Society for Medicines Research, where he has served on the committee for 12 years and served as Chairman for 2 years. This involved the planning and organising of major national and international conferences. He was appointed Chief Scientific Advisor to the Gulf Veterans Association (GVA) and accepted by the Ministry of Defence (MoD) as their nominee on the Independent Panel established to consider the possible interactions between Vaccines and NAPS tablets. He has also served on the Gulf Support Group convened at the Royal British Legion. His involvement with the GVA brought contact with Chronic Fatigue Syndrome/Myalegic Encephalomyelitis (ME/CFS) and related disorders. Gulf War Illness/Syndrome (GWI/S) has much in common with ME/CFS. He is Patron of the Sunderland and South Shields M.E. Association and a member of the John Richardson Research Group, which includes eminent physicians and scientists performing research into ME/CFS, where one recent aspect has been the identification of organochlorine pesticide poisoning being misdiagnosed as M.E./CFS. He has addressed meetings of the Pesticide Exchange Network and consulted to the Organo-Phosphate Information Network (OPIN). He worked with the Autism Research Unit (ARU) at the University of Sunderland for over 20 years, leading to involvement in biochemical studies to offer help, support and treatment for people with autism. This has also lead to research and urine-analysis of Indolyl-Acroyl-Glycine (IAG), which is an unusual metabolite found in excess of 90% of people examined in different groups of GWV, ME/CFS and Organo-Phosphate (OP) poisoning sufferers. He served on the General Synod of the Church of England from 1970 to 1980 and he is a Christian Lay Leader, Preacher and Teacher. He has been involved in three environmental campaigns: • Toxic waste dumping, including campaign against sewage in the sea presenting to the Select Committee on Sewage Treatment and Disposal • GWIS, presenting to the Defence Select Committee • M.E./CFS and OP/Pesticide poisoning Professor Hooper will be chairing the International ME/CFS Conference 2008. For additional articles by Professor Hooper on the IiME web site see http://tinyurl.com/6ylm3r Invest in ME (Charity Nr 1114035) Page 10 Journal of IiME Volume 2 Issue 1 www.investinme.org PROFILES of PRESENTERS at the IiME INTERNATIONAL ME/CFS CONFERENCE D Drr.. LLeeoonnaarrdd JJaassoonn Prof. of Clin. & Community Psychology, Director, Center for Community Research, DePaul University, Chicago Dr. Leonard Jason, Ph.D., is among the most prolific of all ME/CFS researchers. For more than a decade, Dr. Jason and his team at DePaul University’s Centre for Community Research have worked to define the scope and impact of ME/CFS worldwide. Dr Jason is Vice President of the International Association for Chronic Fatigue Syndrome (now the IACFS/ME) and has been a key driver of CFS research since 1991, and is uniquely positioned to support collaboration between CFS researchers, patients, and government decision makers. His studies have shown that the direct and indirect costs of ME/CFS amount to $20 billion in the U.S. each year, and more than 1 million people suffer from ME/CFS as opposed to the estimated 20,000 people originally reported by the CDC (Centers for Disease Control and Prevention). C Coonnffeerreennccee PPrreesseennttaatt iioonn C Caassee DDeeff iinnii tt iioonnss ooffM MEE//CCFFSS –– IInncclluuddiinngg PPaaeeddiiaattrriicc CCaassee DDeeff iinnii tt iioonn It is important to determine which case definition to use in defining the ME/CFS syndrome. The benefit of classifying patients into diagnostic categories is that it facilitates communication among clinicians and researchers, selection of treatment methods, and prediction of response to treatment. Currently, scientists throughout the world use the Fukuda et al. (1994) CFS case definition. Efforts to develop a case definition can be traced back even earlier. In 1955, there was an outbreak of a CFS-like illness at the Royal Free Hospital, and Ramsay, the medical consultant in charge, published a definition of this disease using the term Myalgic Encephalomyelitis (ME). Recently, the Canadians have developed a clinical case definition, the IACFS/ME has developed a pediatric case definition of ME/CFS, and the CDC has developed an empirical case definition. This talk will summarize some of the issues and controversies involving these case definitions. Additional links for Dr Jason: • Jason L, et al., "The Economic impact of ME/CFS: individual and societal level cost," Dynamic Medicine, 2008 7:6 (8 April 2008) [PDF Format] • Jason L, "Exploratory subgrouping in CFS: Infectious, inflammatory, and other": http://www.investinme.org/Documents/Journals/Journal%20of%20IiME%20Vol%201%20Issue%201.pdf Invest in ME (Charity Nr 1114035) Page 11

Journal of IiME Volume 2 Issue 1 www.investinme.org PROFILES of PRESENTERS at the IiME INTERNATIONAL ME/CFS CONFERENCE Dr. Jonathan Kerr Jonathan Kerr qualified in medicine from Queen’s University of Belfast (1987), and completed training as a medical microbiologist (1995). He has worked as a microbiologist in Belfast, Manchester and London, taking up post as a Consultant Senior Lecturer in Microbiology at Royal Brompton Hospital / Imperial College in June 2001, and then Sir Joseph Hotung Clinical Senior Lecturer in Inflammation at St George’s University of London in 2005. His interest in Chronic Fatigue Syndrome (CFS) began during a study of the consequences of parvovirus B19 infection, when he showed that a percentage of infected cases developed CFS which persisted for several years. He is now the principal investigator in a programme of research in CFS. This involves development of a diagnostic test using mass spectrometry, analysis of human and viral gene expression in the white blood cells, and clinical trials of immunomodulatory drugs. Dr. Jonathan Kerr and colleagues at St. George’s University of London reported in the July 27, 2005 issue of the Journal of Clinical Pathology that a preliminary study of 25 CFS patients and 25 matched healthy controls revealed abnormalities in 35 of 9,522 genes analyzed using microarray technology. Polymerase chain reaction studies showed the same results for 16 of these genes. Dr. Kerr has recently defined seven genomic subtypes of CFS based on 88 genes that are expressed differently in CFS patients than they are in normal controls. The study, and its results, raises some important questions. The first of which pertains to the need for funding of microbiological CFS research. He is funded (>£1million) by the CFS Research Foundation (www.cfsrf.com), a charitable organization based in the U.K., and leads a group of 5 scientists at St George's. C Coonnffeerreennccee PPrreesseennttaatt iioonn G Geennee EExxpprreessssiioonn iinn MMEE//CCFFSS:: aa MMeeaannss ooff SSuubbttyyppiinngg Chronic Fatigue Syndrome / myalgic encephalomyelitis (CFS/ME) is a multisystem disease, the pathogenesis of which remains undetermined. We set out to determine the precise abnormalities of gene expression that occur in blood of CFS/ME patients. We analysed gene expression in peripheral blood from 25 CFS/ME patients diagnosed according to the Centers for Disease Control (CDC) diagnostic criteria and 50 normal blood donors using the Affymetrix U133+2 microarray using a cut-off fold-difference of expression &#8805;2.5. Genes showing differential expression were further analysed using quantitative PCR in 55 CFS/ME patients and 75 normal blood donors. Differential expression was confirmed for 88 genes, 85 of which were upregulated and 3 downregulated. Highly represented functions were haematological disease and function, immunological disease and function, cancer, cell death, immune response and infection. Clustering of QPCR data from CFS/ME patients revealed 7 subtypes with distinct differences in SF-36 scores, clinical phenotypes and severity. Additional links for Dr Kerr: • Jonathan Kerr, Seven genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): a detailed analysis of gene networks and clinical phenotypes. J Clin Pathol. 2007 Dec 5. ub ahead of print] PMID: 18057078 [PubMed - as supplied by publisher] Invest in ME (Charity Nr 1114035) Page 12 Journal of IiME Volume 2 Issue 1 www.investinme.org PROFILES of PRESENTERS at the IiME INTERNATIONAL ME/CFS CONFERENCE Dr Martin Lerner Dr Martin Lerner is certified by the American Board of Internal Medicine and is an Infectious Disease Specialist. He held a residency in Internal Medicine, at Harvard Medical Services. Boston City Hospital and Barnes Hospital, St. Louis, MO. Washington University School of Medicine, M.D. Two Years, National Institute of Allergy and Infectious Diseases, Epidemiology Unit. Alumni Awardee, Washington University School of Medicine. Three years research fellow in infectious diseases at the Thorndike Memorial Laboratory, Boston City Hospital and Harvard Medical School under the direction of Dr. Maxwell Finland, (founder of subspecialty infectious diseases). Also awarded a 1-year fellowship in molecular biology under the direction of Dr. James Darnell, Massachusetts Institute of Technology, Cambridge Massachusetts. He was Chief of the Division of Infectious Diseases and Professor of Internal Medicine at Wayne State University School of Medicine, 1963-1982. Chief of the Department of Medicine at Hutzel Hospital, Wayne State University, Detroit, MI 1970–1982. He established a clinical virology laboratory and trained 33 physicians in the subspecialty of infectious diseases at Wayne State University, (1963-1982). He was elected member American Society for Clinical Investigation, American Association of Physicians. He is a member of the committee preparing the National Boards in Medical Examiners, US, and a member of the training grant committee, National Institute of Allergy and Infectious Diseases, NIH. Master of the American College of Physicians. He was Governor for Michigan American College of Physicians, 1991 – 1994. Dr. Lerner has published over 10 papers since 1993 on the role of subclinical myocarditis in a subset of CFS patients. He has also reported success with long courses of antiviral therapy in patients with chronic EBV and CMV infections. Dr. Lerner uses antibody tests for early antigen to CMV and EBV that are not available in most commercial laboratories; he believes that they are better for differentiating active from latent infections. Although these papers received very little attention in the past, there has been interest in the tie between viral myocarditis and CFS recently since a series of three papers from Germany have found HHV-6 and parvovirus B-19 to be the most common viruses found in biopsies of patients with viral myocarditis. Both viruses are also implicated in CFS/ME. Dr Lerner holds Five Patents for Diagnosis and Treatment of CFS. C Coonnffeerreennccee PPrreesseennttaatt iioonn A A TTwweennttyy YYeeaarr JJoouurrnneeyy ttoo UUnnddeerrssttaannddiinngg aanndd TT rreeaattmmeenntt ooff tthhee C Chhrroonniicc FFaatt iigguuee SSyynnddrroommee IInncclluuddiinngg AA LLoonnggii ttuuddiinnaall SSttuuddyy o off G Grroouuppss AA aanndd BB CCFFSS PPaatt iieenntt ss,, 22000000--22000066 The Energy Index point score (EI), (copyright, Lerner AM and Deeter RG, 1999), (0-10) is a simple reliable metric easily evaluating the functional capacity at each CFS patient-physician visit. A hanging sign in the examining room, with physician and patient together, is used. Validation of the EI was done using two methods: a) 20 CFS patients and 22 healthy adults, matched for sex, age, place and time; EI, CFS = 3.6; EI, healthy adults = 9.9, p=<0.0001, and b) 55 CFS patients evaluated at the same time by the EI and Fatigue Severity Score, correlation 0.67, p=0.0066. Improvement to disappearance of CFS symptoms correlate with an increasing EI. (Continued on page 14) Invest in ME (Charity Nr 1114035) Page 13

Journal of IiME Volume 2 Issue 1 www.investinme.org PROFILES of PRESENTERS at the IiME INTERNATIONAL ME/CFS CONFERENCE (Continued from page 13) The validated Energy Index (EI) point score (1-10) was calculated for each CFS patient every 3 months at physician visits. A CFS patient has an EI < 5. A CFS patient with an EI of 0 is bedridden; a CFS diagnosis is no longer present at an EI > 5. The EI effect size is 0.25, a medium effect size is 0.5. A large effect size is > 0.8. Administrations of antiviral drugs were given within a defined pharmacokinetic therapeutic window. Eighteen CFS patients with elevated serum IgG serum antibody titers to cytomegalovirus (HCMV) were treated with intravenous ganciclovir 5mg/Kg q 12 h for 30 days. At evaluations, 24 weeks later, 13 patients (72%) returned to their premorbid healthy states (Infectious Diseases in Clinical Practice, 1997:6;110-117). In a second study, 25 CFS patients with elevated serum antibody titers to Epstein-Barr virus (EBV), Early Antigen (Diffuse) and/or EBV, viral capsid antigen (VCA, IgM) were treated with valacyclovir (14.6 mg/Kg po q 6 h) for 6 months. This valacyclovir dose achieved serum acyclovir Cmax > 7µm and high antiviral activity versus EBV (ID50, 4.4 – 13.3µm), but no antiviral activity versus HCMV. The CFS patients EI functional capacity as well as EBV and HCMV serum antibody titers were again assessed after 1, 3 and 6 months of valacyclovir. We concluded that the 16 CFS patients with EBV persistent infection (EBV single-virus subset) improved after 6 months, but 9 CFS patients with elevated serum antibody titers to “both” EBV and HCMV did not benefit from valacyclovir (Drugs of Today, 2002:38;549-561). With this guidance, a randomized double blinded controlled 6 month study of EBV subset single virus (no HCMV serum antibody) showed an EI rise after 6 months of +1.12 units (122 Kcal/day), in the valacyclovir group while the placebo group improved +0.42 units (65 Kcal/day), Invivo 2007:21;707-714. The current inclusive CFS data (May 1, 2001—December 31, 2007) regardless of duration of CFS illness from this treatment center of 201 CFS patients reveal demographic and epidemiologic data, 156 (77.6%) female; 45 (22.4%) male. The mean age of CFS patients is 45.2 years, BMI 26.4 Kg/m2. These 201 CFS patients are two distinct groups with similar demographics; (A) CFS Herpesvirus Illness (EBV, HHV6, HCMV) with no co-infections, and Group (B) CFS Herpesvirus Illness (EBV, HCMV,HHV6) “with” mimicking, coinfections, both A group and B group meeting international criteria for diagnosis of CFS. (Fukuda, Ann Intern Med. 1994:121;953-9). The major co-infections of Group B are Lyme Disease, Babesiosis and Adult Rheumatic Fever. The subsequent data here are those of CFS Group A who were ill an average of 5.2 years before receiving antiviral therapy. Data for CFS Group B are not included. There are 138 group A CFS patients, 104 females (75.4%) and 34 males (24.6%). The mean age is 46.4 years, BMI 26.7 Kg/m2. Patients were further identified by the presence of elevated serum antibody titers to EBV, HCMV, or HHV6. CFS patients (>95%) had abnormal oscillating flat or inverted T-waves at 24Hr ECG monitor and abnormal cardiac wall motion at rest (11.5%) and stress (24.1%). Cardiac biopsies from CFS patients seen in 1997 showed a noninflammatory cardiomyopathy with myofiber disarray, myofiber drop out, apoptosis, and cardiac replacement fibrosis. Among the 138 Group A herpesvirus CFS patients there were single virus infections, EBV patients (27.5%); HCMV (13.8%); and HHV6 (1.4%). However, more commonly, each CFS patient was infected with several herpesviruses simultaneously: (79 patients with multiple herpesvirus infections (57.2%)). There were EBV/HCMV co-infections (28.3%); EBV/HHV6 co-infections (10.9%); HCMV/HHV6 co-infections (5.1%); and EBV/HCMV/HHV6 co-infections (13.0%). Specific long-term pharmacokinetic therapy was administered to each patient until the EI point score reached 8, at which time, antiviral medicines were tapered, stopped, or continued, as appropriate with no change in the EI point score. The EI point score at 3 month intervals for the 6 years of the study was recorded. There were a mean of 46 EI patients at each 3 month time interval and 25 time intervals over the 6 year longitudinal study. The mean EI for the 138 CFS patients at baseline was 4.5. The mean final EI point score was 6.0, an increase of 1.5 EI units and, therefore, a large EI effect size change (Spearman’s p nonparametric correlation test, Spearman’s p=0.562, p=0.0019). These data indicate that specific long-term anti-herpesvirus pharmacokinetic administration of valacyclovir/valganciclovir provides long-term significant benefit to Group A CFS patients. (Continued on page 15) Invest in ME (Charity Nr 1114035) Page 14 Journal of IiME Volume 2 Issue 1 www.investinme.org PROFILES/PRESENTATIONS at the IiME INTERNATIONAL ME/CFS CONFERENCE (Continued from page 14) There was no toxicity to this long-term antiviral therapy as given. For the non-statistician, the data show that the benefit to the CFS patient has the quality of truth 998 times out of a1,000! For the evidence-based physician requiring placebo controlled double blinded trials for veritude, without recognition of the differences between Group A and Group B CFS patients, as defined here, it is likely that the evidence based trial may have falsely yielded “no benefit” from the antiviral therapy. Additional links for Dr Lerner: • Martin Lerner, Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007 Sep-Oct;21(5):707-13. PMID: 18019402 [PubMed - indexed for MEDLINE] • Martin Lerner, Immunoassay with cytomegalovirus early antigens from gene products p52 and CM2 (UL44 and UL57) detects active infection in patients with chronic fatigue syndrome. J Clin Pathol. 2008 May;61(5):623-6. Epub 2007 Nov 23. PMID: 18037660 [PubMed - in process] D Drr JJuull iiaa NNeewwttoonn Senior Lecturer at the Institute of Cellular Medicine, Newcastle University Dr Newton is Senior Lecturer at the Institute of Cellular Medicine, Newcastle University. She is the academic lead of the internationally renowned Cardiovascular Investigation Unit (Falls and Syncope Unit) which is arguably the largest autonomic nervous system testing laboratory in Europe. Dr Newton has been working on autonomic dysfunction in ME/CFS patients. She has a reputation in the investigation of autonomic function in the pathogenesis of fatigue with a research programme funded by the MRC, ME Research UK and Liver North. She founded and chairs the local multidisciplinary Fatigue Interest Group. C Coonnffeerreennccee PPrreesseennttaatt iioonn A Auuttoonnoommiicc DDyyssffuunnccttiioonn:: IIddeenntt ii ffiiccaatt iioonn ooff AAeett iioollooggiiccaall llyy DDiisstt iinncctt SSuubbjjeecctt ggrroouuppss wwii tthhiinn MMEE//CCFFSS The talk today will focus on the physiological changes that occur when humans stand, and how autonomic nervous system responses to assuming the upright position may be impaired in those with CFS/ME. Additional links for Dr Newton: • Symptoms of autonomic dysfunction in chronic fatigue Syndrome J.L. NEWTON, O. OKONKWO, K. SUTCLIFFE, A. SETH, J. SHIN and D.E.J. JONES From the Fatigue Interest group and Liver Research Group, Institute for Cellular Medicine,University of Newcastle, Newcastle, UK Received 5 March 2007 and in revised form 24 April 2007 Invest in ME (Charity Nr 1114035) Page 15

Journal of IiME Volume 2 Issue 1 www.investinme.org PROFILES of PRESENTERS at the IiME INTERNATIONAL ME/CFS CONFERENCE Dr John Chia Dr Chia is an infectious disease specialist practicing in Torrance, California, USA and has published research recently (Chronic fatigue syndrome associated with chronic enterovirus infection of the stomach) on the role of enteroviruses in the aetiolgy of ME/CFS – an area which has been implicated as one of the causes by a number of studies. There are more than 70 different types of enteroviruses that can affect the central nervous system, heart and muscles, all of which is consistent with the symptoms of ME/CFS. By analyzing samples of stomach tissue from 165 patients with CFS, Dr. Chia's team discovered that 82% of these individuals had high levels of enteroviruses in their digestive systems. Dr Chia's research may result in the development of antiviral drugs to treat the debilitating symptoms of ME/CFS. C Coonnffeerreennccee PPrreesseennttaatt iioonn T Thhee RRoollee ooff EEnntteerroovvii rruusseess IInnffeecctt iioonn iinn CCFFSS//MMEE JOHN K. CHIA, M.D., ANDREW Y. CHIA, B.S. EV Med Research, Lomita, CA. The aetiology of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) remains elusive after almost three decades of investigations. Enteroviruses (EV) are clear causes of acute respiratory and gastrointestinal infections, with tropism for the central nervous system, muscles and heart. Chronic EV infections were implicated as causes of CFS/ME by a few European investigators. Pioneer studies detected EV RNA sequences in the blood of CFS/ME patients, but the results were not replicated by other investigators. Observations from in vitro experiments and from animal models of EV infection, however, clearly established a state of chronic persistence through the formation of double stranded RNA, similar to findings reported in muscle biopsies of CFS/ME patients. Production of non-cytopathic viruses, with partial deletion of the 5’ untranslated region of the viral genome, was recently reported in mice with chronic EV myocarditis. Similar to the European studies, our recent data suggested that EV could be a major trigger/cause among the diverse etiologies for CFS/ME. Our studies confirmed EV RNA sequence in the peripheral blood leukocytes (PBL) taken from CFS/ME patients, and the relative frequency of RNA detection correlated with the severity of symptoms. In addition, administration of α-interferon and ribavirin or the combination of α-and γ-interferon to CFS/ME patients with persistent EV infection resulted in significant improvement of clinical symptoms and suppression of EV RNA. Symptomatic relapses and reappearance of EV RNA in PBL after drug discontinuation lend support to the pathogenic role of EV in these patients. Demonstration of EV capsid protein 1 in 82% of stomach biopsies taken from more than 250 CFS/ME patients, and the finding of EV RNA and the growth of non-cytopathic EV in the same tissues provided compelling evidence for persistent EV infection. Renewed interest is needed to further study the cause-effect relationship between viral persistence and clinical symptoms of CFS/ME. Controlled trials with future antiviral drugs will likely provide the ultimate evidence for the pathogenic role of EV in CFS/ME. Additional links for Dr Chia: • John Chia, Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol. 2008 Jan;61(1):43-8. Epub 2007 Sep 13. PMID: 17872383 [PubMed - indexed for MEDLINE] Invest in ME (Charity Nr 1114035) Page 16 Journal of IiME Volume 2 Issue 1 www.investinme.org PROFILES/PRESENTATIONS at the IiME INTERNATIONAL ME/CFS CONFERENCE Dr Irving Spurr Dr Irving Spurr is a GP with 30 years in practice and has over 20 years of experience of running ME/CFS diagnostic and treatment clinics. Dr Spurr worked with the late Dr John Richardson on enteroviruses and their implication in ME/CFS and has been a Trustee and the chairman of the John Richardson Research Group for 20 years, and is currently the chairman of the group. C Coonnffeerreennccee PPrreesseennttaatt iioonn A GP’s experience of Diagnosis and Treatment of ME/CFS Dr Jean Monro Dr. Jean Monro is the Medical Director of the Breakspear Hospital and is an internationally recognised specialist in environmental medicine. Dr Monro is a Fellow of the American Academy of Environmental Medicine, a Board Certified US examination. Dr Monro has previously been Medical Advisor to Sanity and Medical Advisor to the Coeliac Association. In early 2007, Dr Monro was asked to be a witness for the House of Lords' Select Committee on Science and Technology on allergy treatments. Dr Jean Monro has a background in hospital general medicine and worked at the National Hospital for Nervous Diseases, Queen Square, London, researching migraine and multiple sclerosis. She entered full-time practice in environmental medicine in 1982 and in 1988 established Breakspear Hospital for allergy and environmental medicine She has many publications to her name and regularly speaks at conferences worldwide. C Coonnffeerreennccee PPrreesseennttaatt iioonn C Caassee SSttuuddiieess ooff DDiiaaggnnoossiiss aanndd TT rreeaattmmeenntt ss ooff MMEE//CCFFSS Additional links for Dr Monro: • http://www.breakspearmedical.com/ Invest in ME (Charity Nr 1114035) Page 17

Journal of IiME Volume 2 Issue 1 www.investinme.org PROFILES/PRESENTATIONS at the IiME INTERNATIONAL ME/CFS CONFERENCE Dr Judy Mikovits Dr. Mikovits obtained her Ph.D. in Biochemistry and Molecular Biology from George Washington University. Dr. Mikovits served as a senior scientist at Biosource International, where she led the development of proteomic assays for the Luminex platform that is used extensively for cytokine activity assessment in therapy development. She also served as Chief Scientific Officer and VP Drug Discovery at Epigenx Biosciences, where she lead the development and commercialization of DNA methylation inhibitors for cancer therapy and of cell and array-based methylation assays for drug discovery and diagnostic development. She is Research Director at the Whittemore Peterson Nevada CFS centre for Neuro-Immune disorders and has co-authored over 40 peer reviewed publications that address fundamental issues of viral pathogenesis, hematopoiesis and cytokine biology. C Coonnffeerreennccee PPrreesseennttaatt iioonn H Hooww SSuubb GGrroouuppiinngg WWii ll ll AAff ffeecctt RReesseeaarrcchh SStt rraatteeggiieess:: TToowwaarrddss aa M Moolleeccuullaarr DDeeff iinnii tt iioonn ooff MMEE//CCFFSS J. A. Mikovits, PhD1, V.C. Lombardi, PhD1, D. L. Peterson, MD1 and F.W. Ruscetti, PhD2. 1Whittemore Peterson Institute, Reno, NV, USA 2Cancer Inflammation Program, National Cancer Institute (NCI), Frederick MD. USA Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous disease with unknown etiology. Previous studies have shown that viral specific immune responses and immune abnormalities play critical roles in the pathogenesis of ME/CFS. The central problem in the management of patients with CFS is the lack of biomarkers for patient stratification into subgroups according to distinct immune responses, virus infections and neurological abnormalities. This situation hinders both the diagnostic process and development of specific treatments. The overall goal of our current research program is to define viral and host parameters that correlate with distinct disease phenotypes. We have taken advantage of the latest technologies, which allow for multiplex analysis from a single sample to better define a cohort with molecular signatures of immune response and correlate those signatures with virus infections using a custom pan viral DNA microarray. We used our clinically well defined cohort for serum cytokine and chemokine profiling using a bead based suspension ELISA for 25 cytokines and chemokines on a Luminex platform in 90 patients and 120 healthy controls; pan custom viral expression microarrays in 40 patients done at two different time points; profiling of innate immune defects including RNase L function and cytotoxic subset profiling as well as correlating microbial induced gastrointestinal inflammation chronic immune activation. Data will be also be presented on a subgroup of patients who developed a defect in functional T cell subsets characterized by a clonal rearrangement of the T-cell receptor gamma (TCRg). These patients form a distinct subgroup that is characterized by a significantly increased incidence of the development of Non-Hodgkins Lymphoma (NHL). Additional links for Dr Mikovits: • http://lib.bioinfo.pl/auth:Mikovits,J Invest in ME (Charity Nr 1114035) Page 18 Journal of IiME Volume 2 Issue 1 www.investinme.org EDUCATIONAL MATERIAL from IiME IiME International ME/CFS Conference DVDs Invest in ME have available the full presentations from both of the International ME/CFS Conferences in London of 2007 and 2006. These professionally filmed and authored DVD sets each consist of four discs, in Dolby stereo and in PAL (European) or NTSC (USA/Canada) format. Containing 9 ½ hours (2007 DVD set) and 6 hours (2006 DVD set) – with all presentations plus interviews with ME presenters and news stories from TV programmes. These DVDs have been sold in over 20 countries and are available as educational tools – useful for healthcare staff (GPs, paediatricians, occupational therapists and others connected with the treatment of ME), researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at http://www.investinme.org/InfoCentre%20Education%20Homepage.htm or via emailing IiME at meconference@investinme.org. Price £15 each (UK), £16 (Europe) and £17 (USA/Canada/Australia/New Zealand) - including p&p. IiME International ME/CFS Conference 2008 DVD We hope to have a DVD of the 2008 conference available for sale in June. The price is still to be determined but will not be more than the 2007 or 2006 DVDs. Full details via emailing IiME at this address - meconference@investinme.org. Quotable Quotes on ME/CFS This 42 page booklet has been compiled by Margaret Williams and contains a plethora of quotes from ME experts and from others relating to ME, ME/CFS, CFS/ME and CFS. This is an invaluable document for researchers, healthcare staff, politicians, media, ME support groups and people with ME. The booklet will aid those composing letters, performing research, verifying analysis and for general reference purposes. Price £3.50 + £1 postage/packing for UK delivery (for Europe and USA/Canada/Australia/New Zealand please email for costs of p&p). http://tinyurl.com/5kk8b8 Invest in ME (Charity Nr 1114035) Page 19

Journal of IiME Volume 2 Issue 1 www.investinme.org International ME/CFS Conference Agenda Start Presenter 23rd May 2008 Presentation 08:00 Registration Coffee/tea morning refreshments 09:00 IiME 09:05 Professor Malcolm Hooper Welcome to the Conference Introduction to the IiME International ME/CFS Conference 09.15 Dr. Leonard Jason Case Definitions of ME/CFS 10:15 Dr. Jonathan Kerr 10:45 Coffee/tea Break 11:05 Dr. Martin Lerner A Twenty Year Journey to Understanding and Treatment of the Chronic Fatigue Syndrome Including A Longitudinal Study of Groups A and B CFS Patients, 2000-2006 12:05 Dr. Julia Newton 12:35 Lunch 13:35 Dr. John Chia 14:35 Dr. Irving Spurr 15:10 Coffee/tea Break 15:30 Dr Jean Monro Autonomic Dysfunction: Identification of aetiologically Distinct Subject Groups within ME/CFS The Role of Chronic Enteroviruses in CFS/ME A GP’s experience of Diagnosis and Treatment of ME/CFS Case Studies of Diagnosis and Treatments for ME/CFS 16:00 Dr. Judy Mikovits How Sub Grouping Will Affect Research Strategies for ME/CFS: Towards a Molecular Definition of ME/CFS 16:50 Professor Malcolm Hooper & Speakers 17:30 Adjourn Invest in ME (Charity Nr 1114035) Page 20 Summary - and Plenary Session / Open forum / Questions Gene Expression in ME/CFS: a means of Subtyping

The Journal of IiME Volume 2 Issue 1 From Invest in ME

Journal of IiME Volume 2 Issue 1 www.investinme.org 2 22 3 33 4 44 8 88 Inside This Issue E EEdddiii tttooorrriiiaaalll F FFrrrooommm ttthhheee CCChhhaaaiiirrrmmmaaannn B BBiiiooommmaaarrrkkkeeerrrsss fffooorrr CCCFFFSSS I IImmmppprrrooovvveeeddd RRReeennnaaalll FFFuuunnncccttt iiiooonnn i iinnn CCCFFFSSS///MMMEEE PPPaaattt iiieeennntttsss wwwiii ttthhh I IIVVVIIIGGG 9 99 1 11777 2 22000 2 22444 3 33333 E EExxxpppeeerrriiieeennnccceeesss ooofff CCCaaarrreee iiinnn I IInnnsssttt iii tttuuuttt iiiooonnnsss wwwiii ttthhh SSSeeevvveeerrreeelllyyy--- III lll lll P PPeeeooopppllleee wwwiii ttthhh MMMEEE M MMEEE iiinnn EEEuuurrrooopppeee M MMEEE///CCCFFFSSS aaasss aaa M MMiii tttoooccchhhooonnndddrrriiiaaalll DDDiiissseeeaaassseee T TThhheee rrrooollleee ooofff iiimmmpppaaaiiirrreeeddd c ccaaapppiii lll lllaaarrryyy bbblllooooooddd fff lllooowww iiinnn MMMEEE E EEsssssseeennnttt iiiaaalll IIInnnvvveeesssttt iiigggaaattt iiiooonnnsss fffooorrr P PPeeeooopppllleee wwwiii ttthhh MMMEEE///CCCFFFSSS A AAlllsssooo iiinnncccllluuudddiiinnnggg ttthhheee III iiiMMMEEE I IInnnttteeerrrnnnaaattt iiiooonnnaaalll M MMEEE///CCCFFFSSS CCCooonnnfffeeerrreeennnccceee 2 22000000888 ssseeecccttt iiiooonnn Email: info@investinme.org It is one year since we produced the first Journal of IiME as a means of providing a combination of biomedical research, information, news, views, stories and other articles relating to myalgic encephalomyelitis (ME/CFS) – basically, a broad spectrum of information on ME/CFS. Our aim was to distribute this for free four times a year. Due to the current size and financial limitations of IiME we can only provide a snapshot of the wealth of experience which already exists and continues to increase and we currently are only able to produce two copies a year. But we hope to change that in the future. However, this will be our third Journal and, coinciding as it does with the 3rd IiME International ME/CFS Conference, we can look at the last two years and begin wondering if a sea change is occurring in the perception of ME based on good science, objective data, effective advocacy and a realisation (finally) from government and healthcare organisations (albeit forced by pressure from patient groups and researchers) that obfuscation and systemic bias are no just or effective way to provide healthcare. Diagnosis is at the heart of the problems surrounding ME and diagnostic criteria are critical. One of the IiME’s aims was to campaign for such a diagnostic test and this may well be achievable before long. Last autumn’s Journal of IiME reported on work by Dr Sakudo at Osaka university using Visible and nearinfrared (Vis-NIR) spectroscopy on serum samples. Dr Sakudo stated that as ME can only currently be diagnosed by skilled doctors then the diagnosis requires experience and sophisticated techniques - and even with a skilled doctor, it takes a long time to reach a final clinical diagnosis. Vis-NIR spectroscopy would enable an objective and rapid diagnosis and would not require experience and skill. Dr Sakudo returns this month with an article as commentary on the ppossible application of visible and near-infrared spectral patterns in serum to provide emerging clue to biomarkers for chronic fatigue syndrome. Dr Tae Park runs his own CFS clinic in Seoul, Korea and he attended the Invest in ME International ME/CFS Conference in London in May 2007 and wanted to return this year to briefly speak at the conference (which we will try to fit in the plenary section or as a poster presentation). Dr Park has supplied another short article on improved renal function based on treatment with IVIG. The Journal of IiME Volume 2 Issue 1 From Invest in ME Sidsel Kreyberg is a Norwegian doctor who has specialised in pathology and is head of the ME Registry in Norway. Dr Kreyberg has conducted a small survey of those caring for the severely ill ME patients. Her article provides a good insight into the difficulties in caring for this group of ME patients in institutions. The normal rules of rehabilitation do not apply to ME patients and it is important to take the lead from patients. The patient experiences are very important and should be listened to. Eight institutions which had cared for severely affected ME patients were contacted. The objective was to obtain “hands-on” experience of how one could give adequate services in the future for severely ill ME patients, without (continued on page 3) Disclaimer The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME (Charity Nr. 1114035) Page 2/34 Journal of IiME Volume 2 Issue 1 www.investinme.org consideration of existing constraints in resources. As Dr Kreyberg states quite explicitly “grass roots” experiences especially can be as important as recommendations and therapy suggestions from professionals who do not know what the care situation involves. Dr David Bell has been involved in ME/CFS for many years and in his latest Lyndonville newsletter he explains mitochondrial disease and the type of secondary mitochondrial disease ME/CFS patients experience - the inability to sustain activity. He clearly illustrates why ME/CFS has nothing to do with deconditioning. Dr Les Simpson has also studied ME for many years and his aim has been to enable patients to manage their condition better. Dr Simpson provides a very interesting article based on his research of the shape of red blood cells in ME, an area not mentioned very often. He states that ME is one of many chronic disorders with changed red cells which will impair capillary blood flow and that ME is unique insofar as the factor(s) responsible for changes in red cell shape can switch off and, during remissions, red cell shape populations can return to normal. We also have another article from Margaret Williams which, although published on our web site in January, is still valid and worthy of reading. There is already a great fund of knowledge available for the healthcare departments, organisations and staff to appreciate the multi-system nature of ME/CFS and the need to stay current with biomedical research data. The articles in the JIiME, a small subset of the exciting potential of possibilities to treat and cure this illness, continue to frame the thought – what could be possible if proper funding were available for a national or international biomedical research strategy? And where better to demonstrate this potential than with the IiME International ME/CFS Conference 2008. We have a section at the end of the Journal covering the conference and including abstracts and agenda for the event. The theme of the conference is Sub Grouping and Treatments for ME/CFS and we believe some of the best biomedical research currently available. It promises to be an event full of objective data and established experience which cannot be disputed. The unique blend of biomedical research, objective data presented by our distinguished speakers is testament to the increasing knowledge regarding myalgic encephalomyelitis. Returning to our opening paragraph if a sea change in the perception of ME/CFS is occurring then it will be based on the good science and objective data (represented by our conference speakers), effective advocacy (represented by conference delegates from ten different countries and from ME support organisations across the world) and a new realisation from government and healthcare organisations (represented by the presence at Invest in ME (Charity Nr. 1114035) the conference of the Chief Medical Officer’s Office and the Medical Research Council). Enjoy the Journal. Enjoy the conference. Postscript: IiME organise an annual international conference, produce educational DVDs from the conference, produce a Journal and regular newsletter and a web site containing information for all. We are also involved in lobbying for better education and proper funding for ME. In the spectrum of material we use and are supplied there are variations in terminology regarding myalgic encephalomyelitis. We often refer to this illness as ME and that is where we believe it should remain - the illness has been called Myalgic Encephalomyelitis in the U.K. since 1956. However, other acronyms are used. The WHO ICD-10 G93.3 category lists ME, CFS and PVFS. Many of our distinguished contributors and presenters use CFS and in America CFS is commonly used. The UK government, despite officially accepting the WHO classification of ME as a neurological illness and thus implicitly accepting the term ME/CFS to describe the illness, confuse matters even more by using a combination of CFS and CFS/ME. NICE were criticised by IiME in mixing CFS and CFS/ME in their draft guidelines for CFS/ME. Research (and research funding) is often based on using the term CFS and attracting healthcare professionals to events such as the IiME international conferences has to allow for the fact that many still refer to ME as CFS. This subject is a major issue in itself and there are debates currently ongoing regarding name change. Representing this illness properly requires a correct nomenclature. Sub grouping and treating ME will require correct and consistent terminology. However, as extremely important as this is, IiME nevertheless do not wish to spend all of our time on winning the battle (on the correct name) but losing the war (on getting proper funding for biomedical research and up to date education for healthcare services on the real pathology behind ME). Whilst continuing to use the term ME or ME/CFS in our material we will be referring to the neurological illness myalgic encephalomyelitis and hope that readers will not be too confused by the additional use of CFS or CFS/ME by contributors and presenters. The inconsistency of terminology exists in all countries and by many organisations. We will return to this subject in a later issue of JIiME. Page 3/34

Journal of IiME Volume 2 Issue 1 www.investinme.org Possible application of visible and near-infrared spectral patterns in serum to provide emerging clue to biomarkers for chronic fatigue syndrome By Akikazu Sakudo1* Yukiko Hakariya1, Takanori Kobayashi1, Atsuko Sugimoto1 and Kazuyoshi Ikuta1 1Department of Virology, Center for Infectious Disease Control, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan *Correspondence: Akikazu Sakudo, Department of Virology, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan Tel.: ++81-6-6879-8309 Abstract Currently, chronic fatigue syndrome (CFS) is diagnosed based on clinical symptoms. Although various information on psychological, endocrinological and immunological abnormalities in CFS patients has been reported, there is no clear consensus, possibly due to the absence of an objective diagnostic method. Here, we propose that changes of molecules having hydrogen-containing functional groups are reflected in spectral patterns in sera of CFS patients. This is hypothesized from visible and near-infrared spectroscopy, which detects hydrogen-containing functional groups and shows the presence of common factor(s) in CFS patients’ sera, implying that the common factors bear hydrogen-containing functional groups. In this regard, the above findings would facilitate the search for biomarkers for CFS. Key words: Vis-NIR; chronic fatigue syndrome; biomarker; chemometrics. Chronic fatigue syndrome (CFS) is a debilitating disorder involving persistent fatigue lasting for more than six months with symptoms such as fatigue, pain, breathing problems, depression leading to digestive disturbances, low-grade fever, difficulty in concentrating, and weakness of the immune system and muscles (Fukuda, 1994). The problems of this disease are that the symptoms are not resolved by sufficient rest (Fukuda, 1994). This disease causes individual problems but also economical problems. Although the incidence of CFS is 0.4% in the United States and other countries (Jason, 1999) and 0.26% in Japan (Kuratsune, 2007), economic losses caused by the disease are estimated as high as 9.1 billion dollars per year in the United States (Reynolds, 2004) and 408 billion yen per year in Japan (Kurastune, 2007). CFS patients sometimes suffer from the symptoms but also social problems so the abnormality can not be clearly recognized. Recent research conducted by the Centers for Disease Control and Prevention (CDC) estimates that less than 20% of CFS patients in the United States have been successfully diagnosed (Jason, 1999; Reyes, 2003), indicating that the number of patients will increase if more reliable diagnostic methods are established. The main barriers to identifying CFS patients are an absence of biophysical and biochemical signs that identify the disease and lack of diagnostic laboratory tests (Vernon, 2006). This may be at least in part due to the heterogeneity of the symptoms of CFS patients (Vernon, 2006). At present, CFS is diagnosed based on the presentation of symptoms and exclusion of other medical entities (Fukuda, 1994). Most molecules reported as abnormalities in CFS blood have no clear consensus (Table 1). (continued on page 5) Invest in ME (Charity Nr. 1114035) The paper is submitted for publication in Journal of IiME as “Commentary”. Fax: ++81-6-6879-8310 E-mail: sakudo@biken.osaka-u.ac.jp Our research group Some of the Medical spectroscopy group at Department of Virology, Research Institute for Microbial Diseases, Osaka University—virologist (Kazuyoshi Ikuta), spectroscopist (Akikazu Sakudo), physician (Yukiko Hakariya), and clinical laboratory technologist (Takanori Kobayashi). Page 4/34 Journal of IiME Volume 2 Issue 1 www.investinme.org Possible application of visible and near-infrared spectral patterns in serum to provide emerging clue to biomarkers for chronic fatigue syndrome (continued) The main problems in CFS studies can be attributed to the objectivity of diagnosis and absence of biomarkers. Therefore, recently, we have developed a novel method using visible and near-infrared (Vis-NIR) spectroscopy and chemometrics, and showed that VisNIR spectroscopy provides promising diagnostic tools for CFS (Sakudo, 2006). Furthermore, the results also imply the presence of common factors among CFS patients’ sera (Sakudo, 2006). For essentially all clinically relevant biomolecules except hemoglobin, Vis-NIR radiation of the biomolecules is absorbed due to the combination and overtone of vibrations such as stretching and bending of hydrogenbearing functional groups such as C-H, N-H, O-H (Murray, 1993). This is because peaks in Vis-NIR spectra are due to hydrogen-containing functional groups. Our recent findings indicate that Vis-NIR analysis combined with chemometrics analysis of serum achieves complete separation of CFS patients from healthy controls (Sakudo, 2006). This approach deserves further evaluation as a potential novel strategy for instrumental diagnosis of CFS. More importantly, results of chemometrics analysis, such as principal component analysis (PCA) and soft-independent model of class analogy (SIMCA), suggest that unknown factor(s) in serum are commonly present in all CFS patients (Sakudo, 2006). Important peaks of PCA loadings and SIMCA discriminating power indicate at absorption by common CFS biomolecules possibly bearing hydrogen-containing groups of Vis-NIR radiation occurred in that wavelength. If our hypothesis that CFS common factors have hydrogen-containing functional groups (Fig. 1), detailed band assignment would provide promising CFS biomarkers. The first choice for identification of CFS (continued on page 6) Table. 1 Abnormality in blood of CFS patients Autoantibody levels Cytokine levels Low production of immunoglobulin Elevation of activity of 2'-5' oligo-adenylate synthetase RNase L levels Lymphocyte subset Low NK activity Impaired ACTH and cortisol responses Melatonin levels Levels of DHEA and DHEA-S Opioid system and AVP Changes in growth hormone level Decrease of acylcarnitine Reduced folic acid level Levels of various B vitamins and vitamin C Levels of sodium L-tryptophan levels L-carnitine levels Coenzyme Q10 levels Levels of essential fatty acids Levels of magnesium in RBC Decreased level of zinc in serum NK: natural killer ACTH: adrenocorticotropic hormone Vernon, 2005 Patarca, 2001 Patarca, 2001 Nijs, 2005 Nijs, 2005 Patarca, 2001 Whiteside, 1998 Cleare, 2003 Cleare, 2003 Cleare, 2003 Parker, 2001 Allain, 1997 Kuratsune, 1994 Jacobson, 1993 Werbach, 2000 Werbach, 2000 Werbach, 2000 Werbach, 2000 Werbach, 2000 Werbach, 2000 Werbach, 2000 Maes, 2006 DHEA: dehydroepiandrostenedione DHEA-S: dehydroepiandrostenedione sulphate VP: arginine vasopressin RBC: red blood cell Invest in ME (Charity Nr. 1114035) Page 5/34

Journal of IiME Volume 2 Issue 1 www.investinme.org Possible application of visible and near-infrared spectral patterns in serum to provide emerging clue to biomarkers for chronic fatigue syndrome (continued) biomarkers is to use Vis-NIR spectra of the molecules listed in Table 1 to compare sera from CFS patients and healthy donors. Although it is possible, this strategy may not be the best choice, because the peak signals of VisNIR spectra are broad and weak, so it is difficult to identify differences between two groups. Another barrier preventing identification of CFS biomolecules by Vis- NIR spectroscopy is the limited information about Vis-NIR spectra of biomolecules. Infrared (IR) spectroscopy is also vibrational spectroscopy, similar to Vis-NIR spectroscopy (Stuart, 1997). Moreover, the absorption observed in the IR region is dependent on hydrogen-containing bonds. The mechanism of IR spectroscopy is similar to Vis-NIR spectroscopy but there are differences: the absorption observed in IR is due to fewer overtones than Vis-NIR, resulting in a sharp and high intensity band in IR. Furthermore, there is abundant information on IR spectra. IR spectra databases can be obtained commercially from several companies, such as KnowItAll Informatics System (Bio-Rad Laboratories, Philadelphia, PA, USA), which contains 0.22 million IR spectra, including biomolecules. By combining chemometrics analysis of IR spectra from CFS blood with IR spectra database, we can identify potential candidates for CFS biomarkers. From this knowledge, we propose that IR spectroscopy may provide a better choice for identification of CFS biomarkers related to Vis-NIR spectroscopy. Acknowledgments We thank Dr. Hirohiko Kuratsune (Department of Health Science, Faculty of Health Science for Welfare, Kansai University of Welfare Sciences, Osaka, Japan) for discussions. References Allain, T.J., Bearn, J.A., Coskeran, P., Jones, J., Checkley, A., Butler, J., Wessely, S., Miell, J.P. 1997. Changes in growth hormone, insulin, insulinlike growth factors (IGFs), and IGF-binding protein-1 in chronic fatigue syndrome. Biol Psychiatry, 41:567-573. Cleare, A.J. 2003. The neuroendocrinology of chronic fatigue syndrome. Endocr Rev, 24:236-252. Fukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., Komaroff, A. 1994. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med, 121:953-959. Jacobson, W., Saich, T., Borysiewicz, L.K., Behan, W.M., Behan, P.O., Wreghitt, T.G. 1993. Serum folate and chronic fatigue syndrome. Neurology, 43:2645-2647. Jason, L.A., Richman, J.A., Rademaker, A.W., Jordan, K.M., Plioplys, A.V., Taylor, R.R., McCready, W., Huang, C.F., Plioplys, S. 1999. A community-based study of chronic fatigue syndrome. Arch Intern Med, 159:21292137. Kuratsune, H. 2007. Overview of chronic fatigue syndrome focusing on prevalence and diagnostic criteria. Nippon Rinsho, 65:983-990. Kuratsune, H., Yamaguti, K., Takahashi, M., Misaki, H., Tagawa, S., Kitani, T. 1994. Acylcarnitine deficiency in (continued on page 7) Sakudo et al., Fig. 1. CFS common factors have hydrogen-containing functional groups? Invest in ME (Charity Nr. 1114035) Page 6/34 Journal of IiME Volume 2 Issue 1 www.investinme.org Possible application of visible and near-infrared spectral patterns in serum to provide emerging clue to biomarkers for chronic fatigue syndrome (continued) chronic fatigue syndrome. Clin Infect Dis, 18 Suppl 1:S6267. Maes, M., Mihaylova, I., De Ruyter, M. 2006. Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord, 90:141-147. Murray, I. 1993. Forage analysis by near infra-red spectroscopy. In: Davies, A., Baker, R. D., Grant, S. A. (Ed.) Sward Management Handbook, British Grassland Society, UK, pp. 285-312 Nijs, J., De Meirleir, K. 2005. Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome. In Vivo, 19:1013-1021. Parker, A.J., Wessely, S., Cleare, A.J. 2001. The neuroendocrinology of chronic fatigue syndrome and fibromyalgia. Psychol Med, 31:1331-1345. Patarca, R. 2001. Cytokines and chronic fatigue syndrome. Ann N Y Acad Sci, 933:185-200. Reyes, M., Nisenbaum, R., Hoaglin, D.C., Unger, E.R., Emmons, C., Randall, B., Stewart, J.A., Abbey, S., Jones, J.F., Gantz, N., Minden, S., Reeves, W.C. 2003. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med, 163:1530-1536. Reynolds, K.J., Vernon, S.D., Bouchery, E., Reeves, W.C. 2004. The economic impact of chronic fatigue syndrome. Cost Eff Resour Alloc, 2:4. Sakudo, A., Kuratsune, H., Kobayashi, T., Tajima, S., Watanabe, Y., Ikuta, K. 2006. Spectroscopic diagnosis of chronic fatigue syndrome by visible and near-infrared spectroscopy in serum samples. Biochem Biophys Res Commun, 345:1513-1516. Stuart, B. 1997. Biological Applications of Infrared Spectroscopy John Wiley & Sons Ltd New York. Vernon, S.D., Reeves, W.C. 2005. Evaluation of autoantibodies to common and neuronal cell antigens in Chronic Fatigue Syndrome. J Autoimmune Dis, 2:5. Vernon, S.D., Whistler, T., Aslakson, E., Rajeevan, M., Reeves, W.C. 2006. Challenges for molecular profiling of chronic fatigue syndrome. Pharmacogenomics, 7:211-218. Werbach, M.R. 2000. Nutritional strategies for treating chronic fatigue syndrome. Altern Med Rev, 5:93-108. Whiteside, T.L., Friberg, D. 1998. Natural killer cells and natural killer cell activity in chronic fatigue syndrome. Am J Med, 105:27S-34S. Person With ME I have just read about your book (ME Book Project), what a good idea! I have had M E for nearly 4 years now and I can say that it has devastated my life, everyday just feels like walking against the wind. Where once I could participate, now I can only observe. I have become a very diluted form of who I once was. Well done for trying to highlight this illness. - Melanie ME Story ME patients are unfortunate with their doctors. While most other patient groups have a trusting relationship with the medical profession, far too often ME patients complain of neglect, abuse, misdiagnosis and stigma. Our patients have a visceral dislike of the psychiatric construct of ME, and for good reason. Besides the disadvantages of misdiagnosis, it forces them into a clinical environment where the validity of their opinions is routinely delegitimized, where their right to give informed consent is often not respected, and where in some cases they may be subjected to involuntary detention. These are fears which lurk in the minds of all ME patients. For Sophia Mirza they became a nightmare reality. - Horace Reid (on the story of Sophia Mirza) Invest in ME (Charity Nr. 1114035) Page 7/34

Journal of IiME Volume 2 Issue 1 www.investinme.org Facts on ME Improved Renal Function in CFS/ME Patients with IVIG By Dr Tae Park Dr Tae Park M.D. Dr.Park runs his own CFS clinic in Seoul, Korea. Dr. Park attended the Invest in ME International ME/CFS Conference in London in May 2007 and will be in attendance and briefly speaking at the IiME conference in May 2008 Objecitve of study: To prove the effectiveness of IVIG tx in CFS/ME patients. Method of study: The study was made by checking the GFR of 125 CFS/ME patients by s-creatinine clearance with cockcroft-gauld formula. There are several studies about the effectiveness of IVIG tx in CFS/ME patients. But there have been no reports as to how they improve. It has been known that CFS/ME is really an inflammatory disease of the CNS, mainly from micro-vasculitis. Also the immuneglobuline is the only drug to improve the CNS inflammation at the present time. Here we report that there is real measurable evidence to show that there is improved renal blood flow in CFS/ME patients with IVIG tx. We randomly selected 125 patients who met the 1994 Fukuda criteria . We found there were significant renal blood flow improvements in 60 patients (50%) with IVIG tx, . We also found significant improvement of patients’ sx, especially fatigue, sleep disorders, muscle pain and, most of all, they showed marked improvement in the cognitive functions. Among the improved cognitive functions displayed patients showed remarkable improvements in comprehension and concentrations. The improvement of renal blood flow are between 35% to 60% of previous GFR. These findings of improved renal blood flow may be evidence of improved cerebral blood flow. Furthermore, they may explain the improvement of cognitive functions and other symptoms of CFS/ME patients with IVIG tx. This study will lead to further investigation of CFS/ME tx with IVIG tx. Invest in ME (Charity Nr. 1114035) Order our free newsletter. Distributed monthly via html, plain text or PDF. Go to ttp://www.investinme.org/IIMENewslettersubs.htm There can be no doubt that NICE ignored the international evidence that ME/CFS is a biomedical, not psychiatric, disorder, claiming that studying this evidence fell out with its remit. Such a claim is mystifying, since knowledge of the existing evidencebase ought surely to be mandatory before producing a national Guideline on the management of any disorder, especially given that adherence to such a Guideline is obligatory throughout the NHS (and hence for affiliated agencies such as the Department for Work and Pensions and Social Services). - Margaret Williams ME Story I caught glandular fever and just afterwards in my nurse training found I was always getting tonsillitis. In 1996 I came down with a serious set of symptoms which included palpitations, chest pains and very sore joints. I was so ill that I was admitted to hospital with pericarditis. I was unable to walk for 6 weeks. I took ages to respond to treatment and over the next few months I was given so many blood tests which eventually concluded I had a virus from the enteroviral family related to polio - Sue Page 8/34 Journal of IiME Volume 2 Issue 1 www.investinme.org Experiences of Care in Institutions with Severely-Ill People with ME By Sidsel Elisabeth Kreyberg Institutt for allmenn- og samfunnsmedisin, Universitetet in Oslo E-post: s.e.kreyberg@medisin.uio.no (Invest in ME have helped in translation of this article from Norwegian to English and have been given permission to republish the article, which first appeared in Norsk Tidsskrift for Sykepleieforskning, 2007; 9: 2, 16-26) ABSTRACT Caring for seriously ill ME-patients: A small survey Norwegian medical professionals generally lack the knowledge and experience needed to diagnose and provide advice on how to manage Myalgic Encephalopathy. The subject is also absent from the education of nurses and other health workers. Experience must, for now, be accepted as key to understanding and managing this largely unexplained disorder. Seven nursing homes here outline which extra resources would be necessary to adequately treat and care for seriously ill ME-patients, according to their experience. Apart from suggesting specialised units, the answers comprise technical adjustments to provide maximum protection from sound and light, advanced ventilation systems, flexible kitchen facilities and individually adapted dietary regimens; medical advisors; and a carefully selected and limited number of carers to look after the ME-patient around-the-clock. Stability, predictability and consistency are necessary for the patients to cope, and a small team will enable the carers to cooperate, be alert to signs of adverse reactions, and take adequate measures to prevent deterioration. Routines for debriefing staff working with patients in a permanent crisis-like condition was called for; and extra time and resources to support relatives that assist in planning and caretaking, speak on behalf of the patient, and are crucial in providing know-how - all of which necessitates increased staff in general. Key words English: Myalgic encephalopathy, chronic fatigue syndrome, nursing, rehabilitation, experience Introduction Myalgic Encephalopathy, ME, is discussed more often in the media than in professional healthcare curriculum literature. The condition is often given other names such as “Chronic Fatigue Syndrome”, “fatigue syndrome” or “lack of energy”, which are more or less vague definitions of various longstanding fatigue states (Lindal, Stefansson & Bergmann, 2002; Jason, Helgerson & Torres-Harding, 2003; Kennedy, Abbot & Spence, 2004). In addition to subjective symptoms, which come and go, such as self-reported fatigue, nausea and malaise, ME is characterised by reduced stamina brought on by physical or mental activity, otherwise known as activity intolerance or increased fatigability (objective exhaustion). These patients are thus exercise intolerant (Hyde, Goldstein & Levine, 1992). ). In addition they are different from other “low energy” patients in that they are at times disablingly intolerant of sensory stimuli, have markedly reduced tolerance for alcohol, medicines and various food stuffs, with disturbances in autonomous, hormonal, neurological and immunological functions, disturbed body clock, and pains which are not relieved by treatment. In a fully developed illness there are symptoms from all organs and bodily systems. Symptomology is constantly changing. Lack of explanation for a cause gives rise to psychiatric interpretations. Recent studies, however, show changes in the peripheral circulation which can explain a lot of the (continued on page 10) Invest in ME (Charity Nr. 1114035) Page 9/34

Journal of IiME Volume 2 Issue 1 www.investinme.org Experiences of Care in Institutions with Severely-Ill People with ME (continued) phenomena of changing symptomology over time. ( Streeten & Bell, 1998; Rowe, 2002; Peckerman, Lamanca & Dahl, 2003; Khan, Spence & Kennedy, 2003; Khan, Kennedy & Spence, 2004; Spence & Steward, 2004; Kennedy, Spence & McLaren, 2005). Clinical presentation of ME is a condition with large disturbances in the ability to restore the physiological balance. This means prolonged recovery time with subjective symptoms and objective loss in physical and mental functions after activity and stimulation. It depends on the individual how much can be tolerated, and the capacity varies within the course of the illness. The capacity can also vary considerably within one day. Patients benefit from reducing activities to a level which, from experience, can be tolerated without provoking symptoms, and therefore need to be protected from stimuli that provoke symptoms. Increased recovery time makes it necessary to rest after activities and stimulation so that symptoms ease and physical and mental functioning is slowly improved. Problems with circulation make it furthermore necessary to lie down a lot; completely flat in severe cases. ME patients need help in stabilising their condition despite the severity of the illness. When activity limitations are exceeded, there is an increase in symptom intensity, increasing deterioration and ever increasing recovery time. The illness has from experience an inherent tendency for slow improvement over months and years as long as it is not provoked. The best prognosis is for young people who are allowed to rest from the start of their illness, for grown up married or for co-habiting couples or for the ones who have marked improvement during the first 12-18 months. The World Health Organisation classifies ME together with Post Viral fatigue Syndrome (PVFS) as a neurological illness (G93.3, ICD-10), but have not given criteria. The character of the illness is described in the literature, often in the form of symptom lists or set of criteria (Hyde, Goldstein & Levine, 1992; Kreyberg. 1999). The knowledge of the nature of the illness is spread considerably from person to person via formal or informal networks among people with personal experience, also within doctors. The illness is difficult to understand, and what one sees can be difficult to intermediate because connections between cause and effect often are the opposite compared to what one sees in other illnesses. The limitations of the illness are seen clearer after activity and stimulation than beforehand, and there are no adequate concepts to describe the subjective symptoms. Those who try, will often be interpreted in the psychosomatic model of understanding, either are ill themselves or speak for the ill. One of the reasons why ME is still considered a somatic illness is that it can develop as a direct consequence of Invest in ME (Charity Nr. 1114035) another physical illness or trauma. It can also begin acutely after a latency period of several months or years after exposure, possibly in connection with a new unrelated illness episode. It is easiest to diagnose acute, fulminant cases and cases that occur during epidemics. In a fully developed illness the presentation is the same despite the triggering event or the way in which the illness started. ME can therefore be seen as a type of general reaction. The pattern of increasing loss of physical and mental functioning after activity is especially noticeable with the most severe cases, whose reaction most likely shows up straight away. Upon recovery the reaction can be delayed or overruled. Even if the ill person is careful the reaction can happen after hours or days, or even after a longer period, and one has to take this experience into account. The reaction can be abrupt, dramatic and long lasting. Activity level can therefore be increased only in small steps within periods of improvement. If there is a reaction the activity level has to be down regulated straight away. The ill person will feel beforehand if there generally are energy reserves and will spontaneously increase their activity level, expose themselves to stronger stimulus, try new food and more. So the ill person must not be encouraged or stimulated but benefits from adjustment. Observation over time is necessary if one wishes to avoid exposing these very vulnerable patients for lengthy, painful and potentially harmful investigations which can neither confirm nor rule out the diagnosis with today’s routine examinations. At best one achieves ruling out another illness which is only necessary if there is clinical suspicion (Holmes, Kaplan & Ganz, 1988). However, suspicion of another illness comes up often because of the changing symptom flora, where new symptoms show up constantly. It is therefore important that healthcare professionals and others who take care of such patients have certain knowledge of the everyday presentation of the illness. The following sums up a quick survey which was carried out in the autumn of 2006, motivated by the upcoming nursing home reform in Oslo and knowledge of the case of what is officially on offer for ME patients being taken up by parliament (Dåvøy, 2007). Many seriously ill ME patients are cared for at home by their families, often for years, without essential support, respite care or guidance. It is mainly patients themselves and their families who have the knowledge around this area and it is spread via distinct networks. The illness presents itself more or less the same despite sex, age and over national borders, and is most easily recognised in serious cases, those in need of care. For this reason one could expect experiences in (continued on page 11) Page 10/34 Journal of IiME Volume 2 Issue 1 www.investinme.org Experiences of Care in Institutions with Severely-Ill People with ME (continued) institutionalised care situations to be fairly similar, even with relatively restricted material. A Small Survey In all eight institutions which had been known to have taken in a severely affected ME patient, were contacted by telephone. It varied whether it was the ward nurse or someone else in the team around the patient who answered the phone. They were told about the objective, which was to obtain an enunciation from a person with “hands-on”-experience with a severely ill ME patient in an institution, with the idea of how one could give adequate services in the future for this patient group, without taking into account the existing restrictions in resources. It must be said quite explicitly that especially “grass root” experiences can be as important as recommendations and therapy suggestions from professionals who do not know what the care situation involves. It was left to the departments themselves to decide who would formulate the answers. The following questions were asked: Which resources should you be provided with to be able to offer adequate care for a seriously ill ME patient? State reasons for your answer based on your own experience. Seven of the institutions gave written answers by e-mail, post or via both. The eighth considered that ME was not the reason for the patient’s care need and their experiences were irrelevant for our study. One institution asked for the question to be provided in writing but had reformulated the given problem when they gave their answer. This didn’t affect the outcome and was only taken as a novelty. In three cases single statements were elaborated upon after renewed contact. The study’s starting point was five women and two men who needed care. In one case the patient lived with the parents but was cared for by permanent staff from a nearby institution. In one occasion the ill person lived in a care home connected to a nursing home. In one occasion it was a rehabilitation centre that admitted patients on a short term basis, with a clear target of improvement during the stay. In this case the place was used as a half way house because of lack of space elsewhere. In one case it was a short term department within a nursing home that ran the rehabilitation. The others were ordinary nursing homes. Some of the institutions didn’t have any previous experience of ME, whilst others had experience of several ME patients with unequal grades of severity. The extent of this experience material is not known. The relatives were involved in to different extents in the daily care and acted partly as advisers. In a few places the staff also functioned in a supportive role for relatives. Invest in ME (Charity Nr. 1114035) RESULTS The answers are concentrated especially on economical support for physical efforts, extra staff, individually adjusted eating and extra time. One wished for regular staff with a limited amount of chosen carers and guidance both before and after the stay. A few were also concerned about how one could look after relatives and carers after meetings with patients in a permanent crisis. The special problems that materialised when patients got more energy became more apparent in various degrees and are in the borderline toward rehabilitation. Screening against sound The fewest could look after the need for complete sound proofing. Amongst the suggestions were a private room in an area with least noise pollution, a sound proofed room, a sound proofed door and eventually one’s own screened ward. In one case there was a built in sound proofed room within a supportive housing accommodation. Common dining areas were too noisy. Even if a few could physically get to the dining area themselves, the food had to be brought to the room. Many pointed out that the staff had to perform tasks quietly and be aware of their voice level, use of equipment such as plastic utensils, finish as quickly as possible, not talk unnecessarily, possibly use cards instead of spoken words, make sure that housekeeping tasks were done in such a way that the patient was not burdened. Many noticed that tolerance for sound and talk improved as the condition improved and then it was mostly the ill person themselves who initiated discussion with the staff and exposed themselves to sound from the radio or sang to themselves. Screening against light The patient’s need for complete black out could mean problems in caring. Many wished for lights that could be dimmed gradually. In one ward it was suggested, in order to avoid a gap between the window and screening, to install a roller blind inside the double glazing and additionally double curtains. Comfort for lying down For patients who spend most of the time in bed it was identified by one institution of the special need for a good bed/mattress. Temperature and air quality One place which took in several ME patients pointed out that a normal ventilation system was not good (continued on page 12) Page 11/34

Journal of IiME Volume 2 Issue 1 www.investinme.org Experiences of Care in Institutions with Severely-Ill People with ME (continued) enough. The ill people had to have even temperature and could feel uncomfortable by the heat in the summer. For the consideration of both the patients and carers the need for good air circulation meant installation of an air conditioning system, especially where there was extra sound and light proofing. Kitchen and food Customised food was seen to some extent differently depending on the routines of the institution and reflected somewhat the knowledge of, or acknowledgment of food intolerance problems with ME. It was difficult to register if a patient deteriorated due to certain foods. In one case a special diet was only present if there was a doctor’s note. It was, however, known that many institutions avoided usual foods such as milk, sugar and flour. Even this caused extra work. A few found it natural to work with a dietitian and adjusted the food according to the patient’s wishes. Others called for a nutritionist and for a possibility to order special food. To have enough time for feeding was, as a rule, seen as the biggest problem. It was simpler if the ill person took all food in a liquid form. The need for extra time for feeding was seen throughout as a resource problem which had to be solved by adding extra staff elsewhere. Purely physically some pointed out the need for a private kitchen for more flexible solutions for the ill person and their families to be able to cook for themselves. The relatives could then also more easily function in a supporting role for the ill person and at the same time offload the staff. Staff In addition to special physical efforts, there was a need for extra human resources. There was a wish for a regular, stable staff with the fewest possible people, who could cover the ME patient’s need 24 hours a day. “[…] all care such as tidying up, feeding, washing and so on takes at least three times as long as one is used to.” This demands such large resources that it requires increased staff in the ward as a whole. Among other things it was wished for a limited amount people involved with every ME patient because “it is difficult for the patient to relate to too many of the staff”. Here one wished for a lot of accommodation to reduce the amount of people in the team. A few involved also wished for everyone concerned to be able to see warning signs of deterioration and take precaution- “ for example sleep, chest pain, blurred vision, runny eyes, headache, pressure on the forehead, sweaty palms, cold extremities, tingling of toes and Invest in ME (Charity Nr. 1114035) fingers, sound of voice”. The carers also had to act as the ill person’s spokesperson to the outside. ME patients have to mobilize to be able to talk and cannot always talk when it suits others. Forward planning Prediction and the possibility of being as well prepared as possible for what is happening and when, is vastly important for the ME patient to be able to manage the daily life. Ordinary home nursing care doesn’t therefore work well. To be able to take care of the patient’s “physical, psychological and social needs demands a certain amount of understanding of the diagnosis (complexity of problems)”, as expressed by one of the carers. For example, to understand the consequences if one arrives a few minutes late. “We set alarms and change times for other tasks so that we can be precisely with an ME patient. If we don’t attend we know the consequences for the patient becoming worse and having to, for example, rest a day or two afterwards to recover.” Another one explains how deterioration was triggered by the cleaning staff being five minutes late. The two institutes which followed detailed instructions from relatives, and took patients’ wishes to the point, had experienced that this worked and the ill person improved. A leading caregiver was surprised at how little extra work it took to make carers come at agreed times and do all the tasks exactly in a way the patient advised – even though the ill person could additionally call for help outside the agreed times. Many called for information well in advance before the patient arrived to the ward, while others had had enough information from relatives. Many put weight on the usefulness of important people in the ill person’s network. Many on the other hand called for professional guidance, courses and seminars. The setting up of an ambulant specialist team was suggested, possibly regional ME wards. Cooperation Coaxing and stimulation can have the opposite effect of that which was intended. The ill person wants to, but can’t, and becomes frustrated over coaxing – if it is not always so well meant: “It is important when advising the staff connected to the ME patient that one has to think differently compared to how one thinks with other patients in the ward, for example patients in rehabilitation, long term patients, and others.”. As a consequence of improvement there is often a need for stimulation and a big need for talking. “Let the patient make contact without him being bombarded with impressions…”. One can for example “respond with cards or simple nods”. In other words: Let the ill person take the initiative themselves. (continued on page 13) Page 12/34 Journal of IiME Volume 2 Issue 1 www.investinme.org Experiences of Care in Institutions with Severely-Ill People with ME (continued) The staff often became tired in one way or another. It could be to do with constant arranging, the special considerations one had to take into account all the time, and to be related to the ill person’s problems of accepting the diagnosis, their frustration of not being able to do as much as they wanted, set backs and so on. It was pointed out that a care plan was important to ensure that everyone gave the same treatment. Carers who would be part of the team had to be carefully chosen: “The medical follow up […] is important, but the personality of the carers […] is equally important and has to be appraised accurately. One has to have both nurses and nursing assistants in the team, but it is not necessary to have only professional staff as long as they […] understand the illness and are willing to take on the challenge. The illness and its symptoms can seem challenging and the staff have to be well prepared and in a position to handle this in a confident way both in the presence of the patient and others. It demands confident people who can pacify and who can see the fluctuations the illness brings. It can be difficult to tackle the behavioural pattern when the care is very detailed and it is the patient who steers what shall happen and when. The negotiation of this (with the ill person, added by writer) can have negative consequences for the illness development. It is important that the staff themselves are willing to be in with the resource team because this is demanding ‘one to one’ care. […] The staff also has the need for ‘debriefing’. This is not common in a nursing home and one has to set aside a way and time for this. The role of Relatives ME is a long term, demanding condition which takes the relatives’ time, and where all involved have to live with great uncertainty not only for the future, but for what every single effort can bring on – the daily as well as the extra ordinary ones. The risk for a relapse is always present, and poorly ME patients have very small margins. In this context the relatives were mostly seen as a resource. Often they were in a position to guide both beforehand and during the stay, and they acted in various degrees as relief persons. They were also better than the staff in registering a patient’s deterioration and could act as spokespersons for the ill person. Many take on the role as the extended arm of the ill person. The staff expressed on the other hand also a wish for enough time and resources to be able to look after the relatives better: “As it often involves young people it is important that one has also time for the family […]. The life situation for the whole family becomes very insecure, both because at the moment there is so little knowledge Invest in ME (Charity Nr. 1114035) of the illness itself, individually how the illness runs its course and what timescale we are dealing with.” COMMENT The results confirm the expectation of relatively similar answers even though not everyone brought in the same points. The task opened up for suggestions and reflections, and it was varied how thoroughly reasons were given. Some opinions appeared already during the first contact and are included to complement the picture. Everybody emphasized structure initiatives, especially in connection with screening and dining area, and professional guidance. A few also called for readiness for conflict solving and “debriefing”. Several pointed out the need for specially selected staff, great flexibility and extra time because ME patients put demands on staff resources both physically and psychologically. To be able to prioritise ME patients, it was necessary to have extra staff to solve problems elsewhere in the ward. Alternatively one had to set up personal ME wards. Even though relatives were seen as a resource, a few also saw the need to be able to better look after the relatives, also family members who were not directly involved in the care. Some of the differences in the answers are due to different prerequisites regarding the physical conditions of the institution and existing competence. Some are also due to unequal aims regarding the stay and treatment environment in general. Those who actively rehabilitated differed from the pure care wards, mainly regarding expectations of results. Obviously frustration regarding the illness was expressed more clearly by both those among the ill and carers who aimed for advances via mobility. Even if the expectation is improvement over time with ME, the improvement is mostly very slow, with major or minor relapses when limits are exceeded or with extra strain which is outside the ill person’s control, such as moving, infection or a shock of noise. An approach with preplanned aims is in contrast with the nature of the illness unless the aim is stabilisation, which can be achieved most easily by screening against sense stimulation and limiting activity to a level the ill person can tolerate without bringing on a reaction. At the same time there needs to be an activity plan within the tolerance limit. The thought process is in other words opposite of the usual rehabilitation, where active or passive mobility is guided by tolerance levels being pushed in order to get results. With stabilisation over time the tolerance ability in different areas increases unevenly. There is being created a palpable energy reserve which can be used (continued on page 14) Page 13/34

Journal of IiME Volume 2 Issue 1 www.investinme.org Experiences of Care in Institutions with Severely-Ill People with ME (continued) in small doses with pauses in between in such a way that there is time to register a prospective reaction. The improvement starts with a concept of finding out what the ill person can tolerate out of the different challenges, and then these are tested out carefully with gradual introduction of light and sound, new foods, elevated position and so on, and active movement of muscles and joints, preferably without weight bearing to start with. It is considerably harder to work against gravity than it is with it, a relationship that was described as early as 1934 (Gilliam, 1938). Planning and personalised exercises can be useful so that the ill person doesn’t spontaneously increase physical activities too soon and too long while improving. Passive mobilisation and/or massage is validated if it increases well being. ME patients experience well being with an activity within tolerance limits and do not need encouraging. They rather need to be told to take rest breaks before they reach their performance limit so that they don’t push for a reaction ahead of them, with increased symptoms and lengthened recovery time as a result. The impression was that rehabilitation institutes aimed to find an optimal balance between pushing the limits carefully and thereafter stabilising with rest, but found it difficult to calculate the length of the necessary stabilisation, or what would trigger a reaction. The result was frustration both among patients and carers when there was a relapse. It is possible that some of the pressure of expectation is created by the false impression that micro training is favourable with ME. Such an approach goes against all experience and is based on a concept of fatigue being caused by an underlying lack of motivation, which is postulated in the so called Oxford criteria (or similar psychosomatic interpretations) which form the basis of many of the studies concluding that GET (Graded Exercise Therapy) or CBT (Cognitive Behavioural Therapy) are good for “chronic fatigue syndrome” (Kreyberg, 2004a). CBT and GET are activating therapies which do not take into account the ME patient’s tolerance limits in any other way than that taking part is voluntary. The therapy is offered and therefore caters for the patient’s experience of being ill. Such recognition gives hope after years of rejection and disbelief, which many have met within the health care system and/or family. Studies which show positive outcomes for treatment in no circumstances include the most severely affected patients who are not able to attend treatment. The principles of ME treatment are the same regardless of the severity of the illness, but the ill person’s performance abilities are diverse, and efforts for relief follow thereafter. One has to know the Invest in ME (Charity Nr. 1114035) condition can go within hours or days from being selfsupporting in several areas to needing fulltime care, and even someone with a high grade of autonomy can be totally exhausted during parts of the day, without an ability to have a conversation, call for help or look after oneself. A severely affected patient is extremely vulnerable and unstable so that the smallest effort can trigger a reaction. Small details will influence the everyday life a great deal in good and bad, both for the ill person and carers. This can be both demanding and rewarding. It is a big improvement when the ill person can do something themselves, for example lift a glass up to the mouth or type in a telephone number. This saves the ill person from sensory input, which is being loaded by having a helper in the room. But the glass has to be kept at the right height, not be too heavy and so on. The care has to be creative, and carers have to learn from one another. Rehabilitation and care go thus hand in hand, even for the very severely affected. Whether it deals with care or organising an activity by oneself, one has to be aware of the pattern of the ill person’s limits which are not usual in other illnesses – and this at such a detailed level is difficult to imagine. In addition one has to be practically odour free, sound free and invisible. The carers have to develop increased awareness in order that the patient can be saved from using energy to give instructions. They have to do their work and then leave the room because every attendance drains the mental capacity of the patient. On the other hand it can help if (continued on page 15 ) Facts on ME In ME/CFS there are three main abnormalities in gene expression studies: these involve the immune system, mitochondrial function and Gprotein signaling. There are seven genes upregulated in ME/CFS – those associated woth apoptosis, pesticides, mitochondrial function, demyelination and viral binding sites – J Kerr, St. Georges, London ( as listed in the IiME Quotable quotes Booklet ) Page 14/34 Journal of IiME Volume 2 Issue 1 www.investinme.org Experiences of Care in Institutions with Severely-Ill People with ME (continued) someone is around when there are severe and constant symptoms because it gives security and certain diversion. It can be impossible to hold a tooth brush, fork or pen or hold a telephone conversation, yet still be possible to press an sms message with the hand resting on support. Such apparent inconsistencies in what the ill person can and can’t do, show a totally characteristic pattern, but often becomes a source of conflict amongst the staff. These conflicts have to be acknowledged early and have to be solved by someone who knows the nature of the illness. Improvement requires more stimulation and contact and the staff becomes easily overworked when the ill person’s capacity increases. The capacity to talk by oneself is greater than the capacity to take input from others or enter into discussion, which demands adaptation of concentration from outgoing to incoming. All adjustments are abnormally demanding with ME. Even though this wasn’t directly formulated, this insight was expressed in different ways, also considering the difficulties with transport, change of staff and similar. One area where the answers were somewhat different involved food and food intolerance. Food intolerance increases symptoms, and a severe patient becomes just quieter. It is obvious that one can’t experiment with activities even if the rules allowed one to do so, and that the institution should be able to take this into consideration. Here the rules have to be adjusted to the nature of the illness. It is known from experience that people with ME all over the world spontaneously change to a lighter diet with lots of fruit and vegetables. Thinking of the unstable circulation that is a trademark of ME, it is maybe not unexpected as one knows that several litres of blood is redirected to the intestine after a meal, and that the composition of the diet’s nutritional content can make a big difference. (Waaler, Erikse & Janbu, 1990; Waaler & Eriksen, 1992; Eriksen, Waaler, 1994; Waaler & Toska, 1999). Those who didn’t have previous experience of ME patients, wished to a greater degree for medical justification to support the care being given. A few also expressed a certain ambivalence toward relatives’ strong opinions. Those who knew the patient and/or relatives beforehand, were more open for their expertise even if the illness was not medically understood. Even though performance targets were not asked for here, it was clear that systems which were outlined by patients/relatives were followed because they worked well. There is no overview of how ME is distributed in the population. Hospital statistics can show the relative emphasis of those with the strongest resources. There can be a large hidden number among drug users, Invest in ME (Charity Nr. 1114035) students and the young unemployed, farmers, artists, pensioners, vagrants and misdiagnosed people in locked wards in psychiatric hospitals (Kreyberg, 2004b). This small survey shows how important experience is in the work with ME. It would be preferable to do a wider survey of the competence that exists all around the country, and build on this in order to begin to establish adequate and decentralised services for a very vulnerable and forgotten group of patients as soon as possible. REFERENCES • Dåvøy, L. (2007). Interpellasjon i Stortinget • Eriksen, M. & Waaler, B. A. (1994). Priority of blood flow to splanchnic organs in man during pre- and post-meal exercise. Acta Physiologica Scandinavica, 150; 363-372. • Gilliam, A. G. (1938). Epidemiological study of an epidemic diagnosed as poliomyelitis occurring among the staff of the Los Angeles County General Hospital during the summer of 1934. Public Health Bulletin No 240, April. United States Public Health Service, Washington D. C. Government Printing Office • Holmes, G. P., Kaplan, J. E., Ganz, N. M. et al. (1988). Chronic Fatigue Syndrome: A Working Case Definition. Annals of Internal Medicine, 108; 387-9. • Hyde, B. M., Goldstein, J. & Levine, P. (Ed.) (1992). The Clinical and Scientific Basis of Myalgic Encephalomyelitis /Chronic Fatigue Syndrome. Ottawa: The Nightingale Research Foundation. • Jason, L. A., Helgerson, J., Torres-Harding, S. et al. (2003). Variability in Diagnostic Criteria for Chronic Fatigue Syndrome May Result in Substantial Differences in Patterns of Symptoms and Disability. Evaluation and the Health Professions, 26(1); 3-22. • Kennedy, G., Abbot, N., Spence,V. et al. (2004). The specificity of the CDC-1994 criteria for chronic fatigue syndrome: comparison of health status in three groups of patients who fulfill the criteria. Annals of Epidemiology, Feb; 14(2); 95-100. • Kennedy G., Spence V., McLaren, M. et al. (2005). Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radical Biology and Medicine, Sep 1; 39(5); 584-9. • Khan, E., Kennedy, G., Spence, V. et al. (2004). Peripheral Cholinergic Function in Humans With Chronic Fatigue Syndrome, Gulf War Syndrome, and With Illness Following Organophosphate Exposure. Clinical Science,Feb; 106(2); 183-9 (continued on page 16) Page 15/34

Journal of IiME Volume 2 Issue 1 Experiences of Care in Institutions with Severely-Ill People with ME (continued) • Khan, E., Spence,V., Kennedy, G. et al. (2003). Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clinical Physiology and Functional Imaging, 23(5); 282-5. • Kreyberg, S. (1999). ME/CFS En innføring for foreldre og andre som arbeider med barn ogunge hjemme eller i institusjon. Stensil, Universitetet i Oslo, August 1999: Appendix. http://www.kronisktraethedssyndrom.dk • Kreyberg, S. (2004a). Kronisk/postviralt utmattelsessyndrom. Tidsskriftet for DenNorske Lægeforening, 124; 2382-3. • Kreyberg, S. (2004b). Pasienter ut av av ingenmannsland. Norsk Epidemiologi, 14(1); 79-83. • Lindal, E., Stefansson, J. G. & Bergmann, S. (2002). The prevalence of chronic fatigue syndrome in Iceland - A national comparison by gender drawing on four different criteria. Nordic Journal of Psychiatry, 56(4); 273-7. • Peckerman, A., Lamanca, J. J., Dahl, K. et al. (2003). Abnormal Impedance Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome. The American Journal of The Medical Sciences, 326(2); 55-60. • Rowe, P. C. (2002). Orthostatic intolerance and chronic fatigue syndrome: New light on an old problem. The Journal of Pediatrics, 140(4); 387-9 • Spence,V. & Steward, J. (2004). Standing up for ME. Biologist, 51(2); 65-70 • Streeten, D. H. P. & Bell, D. S. (1998). Circulating Blood Volume in Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome, 4(1). • Waaler, B. A. & Eriksen, M. (1992). Post prandial cardiovascular responses in man after ingestion of carbohydrate, protein or fat. Acta Physiologica Scandinavica, 146; 321-7. • Waaler, B. A. Eriksen, M., & Janbu, T. (1990). The effect of a meal on cardiac output in man at rest and during exercise. Acta Physiologica Scandinavica, 140; 167-173. • Waaler, B. A. & Toska, K. (1999). Fordøyelseskanalens store og vekslende behov for blodtilførsel. Tidsskriftet for Den Norske Lægeforening, 119(5); 664-6. Student Doctor "I am horrified, but not entirely surprised by the behaviour of the GPs and psychiatrists involved in this case ( the Sophia Mirza story). I am currently medical student, and I can promise you that I will never forget this case when I am a doctor. I think that the attitudes towards CFS are changing (no doubt largely thanks to Sophia and her mother), but there are still many women who are treated as mentally ill, simply because doctors cannot readily explain the causes for their disease. I send my wishes for full recovery of all the patients using this site and thank you for sharing your story." - Daphna Invest in ME (Charity Nr. 1114035) Page 16/34 www.investinme.org ME Story Throughout school, I was always exhausted and finally came down with EBV when I was sixteen. Although all my friends had mild cases of this, I was incapacitated to the point that I was hospitalized at times and had to leave school for months while I recovered. By now, I was beginning to wonder about my health. I was the "sickest" person I knew with the lowest pain tolerance, despite eating well and exercising. The GP hardly acknowledged me, and told me that it was normal and that I should stop being a hypochondriac. To appease me, he ran various tests and after finding nothing serious or conclusive, told me that he had been right and I should just rest. Now, nearly eight years later, going from a student at the top of my class with an unlimited future to a dependent, rather helpless person with no real hope for healing is something that only others in this situation can understand. Meeting new people, and having them ask, "what do you do?" makes me cringe. The amount of shame and isolation at times is unbearable, but there is also a glimmer of hope that with greater understanding will come better treatments or at least compassion. - Vickie Journal of IiME Volume 2 Issue 1 ME News from Around Europe from Sweden Legislative Victory in Sweden for People with ME/CFS In Sweden, there is still an abysmal lack of specialist care (or any care for that matter) for ME/CFS-patients. However, there is some good news to report. We gained some attention (and many new members) last year when a well-known MP spoke of her illness in an evening newspaper. ME/CFS, like many other illnesses, is still in practice an illness of criteria, in spite of progress in research done in recent years. This has lead physicians and, even more so, representatives of the Social Security system in Sweden to wrongly assume, that the patients are fit and able to work. Even some of those who are severely afflicted have been refused Social Security benefits, because of lack of objective, measurable signs of their illness. “You can be cured of ME/CFS if you jog in the woods 10 kms, 3 times a week”. In a regional law court, the local association RME Västernorrland recently reached a successful verdict for one of its members. It states that the grade of disability of a person should be the ground on which compensation from Social Security should be based, regardless of objective medical findings. Although this verdict is not of precedent character, RME Sweden still considers it to be a great victory, bringing us hope for the future. More news from Sweden: In 2007, RME, the Association for ME/CFS patients in Sweden, carried out a questionnaire survey amongst their members aiming to assess and elucidate the current situation for ME/CFS patients in Sweden. The survey comprised 142 questions. The aim of the survey is to increase knowledge about ME/CFS and to improve medical care for this group of patients. We are currently presenting the results of our survey to political, social and medical authorities. 210 out of 380 members filled out the questionnaire, i.e. 55 %. 183 of these fulfil the Canadian criteria for ME/CFS. 178 have been given the diagnosis. 136 fell ill after infection. been most difficult with having this illness. Here are three typical answers: “Being so exhausted that I just can’t stand upright or feel any interest in what is going on around me. The inability to think clearly or concentrate on anything”. “The physical “restrictions” because of exhaustion, the social isolation due to lack of energy”. “The attitude of authorities, medical service providers and people around me in general. Suspicion, Invest in ME (Charity Nr. 1114035) making light of the illness, questioning it and the constant struggle to try to be taken seriously and get adequate help”. 33% of the participants in the Survey were told by physicians that the illness does not exist, in spite of the fact that most of our members were diagnosed with the illness by (other) physicians! More than 33% have heard comments such as: “If you have ME/CFS we don’t take any tests”. “That illness is not listed anywhere”. “If one wants to get ones´ health back one does”. “The illness is not considered or regarded as a diagnosis”. “You can be cured of ME/CFS if you jog in the woods 10 kms, 3 times a week”. “It is not an illness but an imagined syndrome”. Etc. We are hoping that this survey will help us change the general attitude toward ME/CFS-patients in Sweden. In Stockholm, the regional health care authority has commissioned a report into the situation for patients with ME/CFS. After several years delay this report is now to be presented at the end of May. Two patients' representatives have been included in the reference group connected to the report, along with a number of health care professionals with varying degrees of understanding of the illness. At this point we don't know the outcome of this report, but we are hoping for the best. After the report comes out, the county parliament will probably address a motion to reinstate a specialist ME/CFS clinic. This is important for all of the country, because where Stockholm leads other regions may follow. On May 28th 2008, RME Stockholm are arranging an event on the theme of providing medical care for patients with ME/CFS. The main speaker will be Dr. Daniel Peterson, and we will also hear from two Swedish physicians (Prof. Birgitta Evengård and Dr. Olof Zachrisson) as well as leading regional healthcare politicians. This will be a well-timed event which will tie together the healthcare report, the RME patient survey, and the desperate need for medical care, and we plan to make a big fuss in the media! (If anyone wants to help out, feel free to contact us at stockholm@rme.nu) Another local association, RME Göteborg, is planning two seminars in the autumn of 2008 – one for physicians and other health care personnel and one for ME/CFS-patients in the region. So far we are happy to note that two physicians, who are both well known in Sweden, have accepted our invitation, namely Dr. Paul Kavli, Norway, and Dr. Daniel Peterson, Nevada, USA. We hope that we will be able to carry this out in a successful way and that it will lead to positive results for us, who have this debilitating syndrome. This article was supplied by RME— the Association for ME/CFS patients in Sweden. Page 17/34 www.investinme.org

Journal of IiME Volume 2 Issue 1 www.investinme.org ME News from Around Europe The Netherlands Calling! The developments in the Netherlands in the last years do not raise any hope for improvement in the future. After all those years it has become clear that solid medical facts alone will not be sufficient to win the “war against ME”. In 2005 the Health Council of the Netherlands, which almost completely consisted of proponents of the psychosocial school, published its “biased” Advisory Report for the Dutch Government: ME doesn’t exist, CFS has no biological origin, but must be considered a stress/personality disorder, biomedical research is useless, most patients can recover by cognitive behavioral therapy. The report trivialized, ignored or dismissed all available biomedical evidence. It can be found at: http://www.gr.nl/pdf.php?ID=1169&p=1. Although all state members are bound by international law (WHO), CFS was “not recognized as a disease” by the Dutch Minister of Health. ME does not even exist… Thanks to the combined effort of many (Dutch and foreign) patients writing politicians, supplying them with facts about ME/CFS, CBT/GET and “evidence-based medicine”, the parliamentarians “decided” that more than half the budget should be spent on medical research. The Funding Allocating Organization decided otherwise! Politicians did nothing to correct the “error” of the executive agency, despite conflicts of interest (e.g. allocating budgets to yourself/colleagues etc). Patients are represented by some organisations with a “good working relationship” with the Wessely-driven “Fatigue Experts” of Nijmegen University or who are unwilling to make clear choices, (e.g. ME/not CFS, Canadian Guidelines/not Fukuda or Reeves). The fact that there are almost no medical specialists dedicating their case to patients, means many ME patients do not feel to be represented. When the occasion arises (for example the publication of the very poor results of the Belgium “expertise centres”, implementing the “CBT/GET-paradigm”, and the publication of the Gibson Enquiry Report) patients write to politicians to plead for a fundamental change of course. The response of the new Dutch Health Minister to a petition, backed up by 20 pages of solid scientific facts, (for a summary see diagram Science and Fiction— below), didn’t address a single issue put forward: CBT/GET is the only answer… The dramatic situation of patients in the Netherlands will only change when scientific breakthroughs in the future can no longer be denied and/or when ME patients are represented by ME patient advocacy organizations making clear choices and organizing a creative, actionbased, international strategy. That's why the Invest in ME, MERUK and IACFS conferences are raising hope. Facts speak for themselves and will prove that patients were right all along. This article was supplied by Frank Twisk and Jan van Roijen Invest in ME (Charity Nr. 1114035) Page 18/34 Journal of IiME Volume 2 Issue 1 ME News from Around Europe from Finland R REESSEEAARRCCHH ff rroomm FFii nn ll aanndd (( TTuutt kkiimmuuss SSuuoommee ss tt aa )) An academic dissertation by Jaana Renko from Tampere University, Finland entitled Bacterial DNA Signatures in Arterial inflammation (2008) found signs of past bacterial infections in arterial plaques. Atherosclerosis develops over time starting often in childhood. Plaques develop in arterial walls resulting in narrowing of blood vessels. The plaques contain chronic inflammation and it has been thought for some time that bacteria are involved in causing the inflammation. The most identified of these bacteria are Chlamydia pneumoniae and oral bacteria. Jaana Renko examined arterial samples from autopsies and surgeries and found high overall diversity of bacterial DNA in the atherosclerotic coronary and abdominal artery samples. Her study supports the theory that past infections increase the risk of developing atherosclerosis. It is not clear whether the bacterial findings are the cause or consequence of the illness. It may be that it is easier for bacterial DNA to stick to the damaged arterial wall. This study showed the role of inflammation and possibly infection in the role of atherosclerosis. see http://acta.uta.fi/pdf/978-951-44-7249-7.pdf Chlamydia pneumoniae is implicated in the development of ME/CFS in some cases and is one of the sub groups for which further research is required. The most common causes of death among people with ME/CFS are heart failure, cancer and suicide (Jason et al. 2006). According Jason et al. people with ME/CFS died 25 years earlier than rest of the population. www.investinme.org Canadian Guidelines Invest in ME are the UK distributors for the Canadian Guidelines. Described even by NICE as “the most stringent” guidelines available these are proper, up-to-date clinical guidelines which can also be used as a base for research criteria. Findings from the study by Leonard A. Jason PhD (Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome) indicated that the Canadian criteria captured many of the cardiopulmonary and neurological abnormalities, which were not currently assessed by the Fukuda criteria. The Canadian criteria also selected cases with 'less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms' and individuals selected by these criteria were significantly different from psychiatric controls with CFS. The Canadian Guidelines provide a means for clearly diagnosing ME and were developed specifically for that purpose. They are an internationally accepted set of guidelines for which many in the ME community have been campaigning to be adopted as the standard set of guidelines for diagnosing ME. The Canadian Guidelines are available from IiME. The price is 46p per copy plus postage & packaging. To order please contact Invest in ME via this email address: info@investinme.org Invest in ME (Charity Nr. 1114035) Page 19/34

Journal of IiME Volume 2 Issue 1 www.investinme.org ME/CFS as a Mitochondrial Disease By Dr David Bell (www.davidsbell.com) (Invest in ME have been given permission by Dr. Bell to republish this article which first appeared in the Lydonville News Vol 5 Nr. 2 April 2008 Introduction David S. Bell, MD I get so angry when I read the nightmare stories many of you have experienced. All you did wrong was to get sick. Then the medical industrial complex made your life miserable. The medical industrial complex includes the drug companies who are not interested unless they make a big profit, the health insurance companies who will use any excuse to deny patients medications or testing, and the disability industry who survive only because they take your money and deny benefits if you get sick. All of this is done under the guise of “modern evidence-based medicine”. But evidence-based medicine only works in illnesses like hypertension where yo! u have enormous funding. I think I have become an old codger. Cynical, disappointed….. Enough of that. In my office I have a sign for ME/CFS patients “Whining will be allowed for ten minutes only”. Clinical Notes In the past week I have seen two patients who had an exercise lactate test which showed an elevation of blood lactate after mild exercise. They were told by their physician that they had “mitochondrial disease”. They were advised to take some vitamins, maybe some CoQ10, and have a nice day. Like nearly everything else, the term mitochondrial disease left these patients feeling bewildered and somewhat lost. While I agree that ME/CFS is a mitochondrial disease, this term needs clarification because ME/CFS is a mitochondrial disease like no other. Until recently, when a child was diagnosed as having a mitochondrial disease, it was a disaster, even a death sentence, for it meant that there were major abnormalities in the mitochondrial or nuclear DNA that regulated energy production. Without energy (ATP) it is impossible to survive. These diseases are called MELAS, Kearns-Sayre, Leber hereditary optic neuropathy and so on. Nearly three hundred mitochondrial illnesses have been identified from genetic mutations. It is a specialized area of pediatrics, where it is possible to measure severe abnormalities in the mitochondria on muscle biopsy testing. This is what most clinicians think of when the words mitochondrial disease are mentioned, but these illnesses do not, in general, apply to ME/CFS. Many Invest in ME (Charity Nr. 1114035) Dr Bell completed post doctoral training in pediatrics in 1976 with subspecialty training in Pediatric Behavior and Developmental Disorders. In 1978 he began work at the University of Rochester but soon began a private practice in the town of Lyndonville, New York. In 1985 nearly 220 persons became ill with an illness subsequently called chronic fatigue syndrome in the communities surrounding Lyndonville, New York. This illness cluster began a study of the illness which continues today. Dr. Bell is the author or co-author of numerous scientific papers on CFS, and, in 2003 was named Chairman of the Advisory Committee for Chronic Fatigue Syndrome of the Department of Health and Human Services. Publications include A Disease of A Thousand Names, (1988) and The Doctor’s Guide to Chronic Fatigue Syndrome, (1990). Dr. Bell currently practices general medicine in Lyndonville, New York with his wife Nancy, a amily nurse practitioner. Roughly half of the patients seen in the practice suffer from chronic fatigue syndrome, fibromyalgia, orthostatic intolerance, and/or myalgic encephalomyelitis. patients with ME/CFS have had muscle biopsies and most of the mitochondrial tests on these biopsies are relatively normal. We will return to why! this is in a bit. What are mitochondria? Think of mitochondria as the power factories of the cell. Nearly every cell in the body has them, usually around 500 or so in every cell. They take in oxygen and glucose and put out carbon dioxide and energy (ATP). There are two hundred different steps in this process and we will quiz you after this article. Actually all you need to know is ATP, the prime energy (Continued on page 21) Page 20/34 Journal of IiME Volume 2 Issue 1 www.investinme.org M MEE//CCFFSS aass aa MMii ttoocchhoonnddrriiaall DDiisseeaassee ((ccoonnttiinnuueedd)) storage chemical (battery) of the body, and oxidative phosphorylation (ox-phos) the complex electron transport chains that do the major work. Because the mechanism of energy production is essential to nearly every cell, a defect will have symptoms in every organ system. Sound familiar? Oxidative metabolism, the ability to utilize oxygen to produce energy, is quite efficient, and it is fascinating to look at the theories of how they came to be part of our cells. However, when the energy demand is excessive, the cells revert to a more primitive, and less efficient, form of energy production, anaerobic metabolism (metabolism without oxygen). For an interesting study on the anaerobic threshold in ME/CFS, see the literature review article that follows. When to suspect mitochondrial disease. In a recent review article (Haas 2007) there is a list of symptoms that suggest looking for mitochondrial disease. Among these symptoms are neurologic symptoms such as ataxia, myoclonus, and encephalopathy, exercise intolerance, sensitivity to general anesthesia, and constipation. A score sheet has been developed to help in when to suspect mitochondrial disease and most ME/CFS patients would fall into the positive range. For lots of information on mitochondria please go to www.mitosoc.org, but remember that they are talking about “conventional” mitochondrial disorders, not ME/CFS. There is another form of mitochondrial disease, or secondary mitochondrial disease. In secondary mitochondrial disease the primary problem is not with the mitochondria, but some other problem messes up mitochondrial function. There are many illnesses where the primary defect ends up causing problems with the generation of energy in mitochondria. For example, thyroid hormone is needed for successful oxidative phosphorylation. With hypothyroidism (low thyroid) energy production is impaired and fatigue, weakness, temperature regulatory problems, and difficulty concentrating result. This is one of the reasons that when you start to describe fatigue to your primary care physician, he or she begins to write out a script to test for thyroid hormone. So what is the problem? Why has ME/CFS not been diagnosed, studied and classified as other mitochondrial diseases? There are several reasons: a) Mitochondrial disease is thought of by clinicians as a fatal disease of infancy, not one that occurs later in life. b) Mitochondrial disease is usually thought of as a fixed, structural disease, and ME/CFS is a relapsing, remitting illness with some persons even becoming entirely well. c) Mitochondrial diseases are hard to diagnose, requiring muscle biopsies and detailed ox-phos testing d) Ox-phos testing is often normal in ME/CFS, and this Invest in ME (Charity Nr. 1114035) Page 21/34 has been the critical piece that has diverted attention from mitochondria. e) Physicians are used to thinking of organ-specific diseases (liver, kidney, etc) and mitochondria are in all cells. f) Few physicians have taken ME/CFS seriously until recently, and research in this area has been scant. Of the above reasons, only reason “d” is important to us here. In 1990 I did a muscle biopsy study on ten ME/CFS patients with Dr. June Aprille. All ten persons had relatively normal ox-phos studies. Although we did not publish this finding, it is consistent with the few published studies that have been done. How can you have mitochondrial disease when the mechanism tests normal? I think that the answer to this paradox is just around the corner. Hypothesis: If you have a patient with emphysema who is sitting in an armchair, he or she is not out of breath. You can measure the damage in tests, but to make symptoms, you have to “stress” the system – make the patient run up and down stairs. If a person with G-6-PD deficiency is sitting quietly, the blood looks normal. But feed this person fava beans and abnormalities quickly become obvious. Persons with ME/CFS keep themselves at a balance point. They rest for two hours, then do a half hour of activity, then rest, then do more and so on. The worse the illness, the less overall activity is possible. If a ME/CFS patient does absolutely nothing for a few days, they usually feel pretty good. But go to the shopping mall for eight hours and the crash occurs. Here is the problem: in the patients studied for mitochondrial disease, they have been resting up (staying above the balance point) and a muscle biopsy done at that moment will probably not show much. But have a ME/CFS patient exercise, and then study mitochondrial function. My hunch is that the ox-phos reactions will be seriously impaired, but this has not been systematically and methodically done. For me, this hypothesis is generated by the VanNess, Snell, and Stevens study described in the next section. There are lots of studies that implicate mitochondrial problems; Dr. Kuratsune and carnitine. Dr. Versnon and genomics; Dr. DeMeileir, Dr. Pall, Dr. Cheney and many others. But this problem cannot be studied in tiny fragments. It is time for a good study to look at the different steps of the body’s ability to generate energy. Lets hope we get to see it within our lifetimes. 1. Haas R, Parikh S, Falk M, Saneto R, Wolf N, Darin N, et al. Mitochondrial Disease: A practical approach for primary care physicians. Pediatrics 2007;120(6):13261333 (Continued on page 22)

Journal of IiME Volume 2 Issue 1 R Reevviieeww ooff tthhee ““TTwwoo--ddaayy EExxeerrcciissee TTeesstt”” U U Literature Review Review of the “Two-day Exercise Test” In the most recent Journal of Chronic Fatigue Syndrome (Vol 14, Number 2, 2007) there are two articles which may be the first to offer an objective proof of disability in ME/CFS. More importantly, if shown to be correct, they may give us an avenue to test and measure the biochemical abnormality which causes the symptom pattern. In this short review I would like to review these two papers and present a case of pediatric CFS which demonstrates the same abnormalities. In the first of these papers, Margaret Ciccolella, a lawyer, teams up with Staci Stevens, Chris Snell, and Mark Van Ness of the University of the Pacific to review the legal issues surrounding exercise testing and disability (1). As everyone familiar with CFS well knows, insurance companies require proof of disability, which a standard exercise test may or may not demonstrate. However, even if disability is present, insurance companies have been quick to say that the patient was not trying hard enough, or that the patient is deconditioned. The second paper of this series by VanNess, Snell and Stevens explain the two-day exercise test and presents results for six patients with ME/CFS (2). As clinicians have observed, the symptom of “postexertional malaise” is one of the most distinguishing features of CFS. This symptom is listed as one of the eight in the criteria of the Centers for Disease Control (3), and is central to the diagnosis in the recent Canadian Case Definition (4) and the proposed pediatric case definition (5). It is beginning to look like the symptom of postexertional malaise is at the root of disability, and may be central to the pathophysiology of this complex illness spectrum. A person with ME/CFS may be at home for several days doing little except basic activities of daily living. When this patient decides to go shopping, he or she will drive to the mall and shop for one or two hours. During this time, observers would say that the person looks entirely well, not appearing disabled. However, following this activity the patient will experience an exacerbation of pain and other symptoms of ME/CFS. This exacerbation may last one, two or three days, and, in my opinion, the more severe the illness, the longer and more severe the exacerbation. This phenomenon is known as postexertional malaise. The symptoms of the illness (malaise) are exacerbated by mental, physical or emotional activities (post-exertional). In an employment environment, the patient may be able to do a job well for one or even several days. However disability lies in the inability to sustain this normal ! level of activity. The two-day exercise test is the first to begin to explain this phenomenon. The exercise test is no different from what has been used Invest in ME (Charity Nr. 1114035) for years. The patient exercises on a stationary bicycle (bicycle ergometry) and breathes through plastic tubing to measure the concentration of oxygen and carbon dioxide as well as the total amount of air. The six female patients and six sedentary matched control subjects of the study were all able to achieve maximal exertion. The ME/CFS patients had a slightly lower V02max (maximal oxygen utilization) than controls (28.4 ml/kg/min vs. 26.2 ml/kg/min) and lower VO2 at anaerobic threshold (15.01 ml/kg/min vs. 17.55 mg/kg/min) on the first day of exercise testing. These values are not dramatic nor are they statistically significant. It is on the second day that interesting results are seen. The same test was repeated the following day for all twelve subjects. As is often the case, sedentary controls improved slightly in their ability to utilize oxygen, going from 28.4 to 28.9 ml/kg/min for VO2max and from 17.55 to 18.00 ml/kg/min for oxygen utilization at anaerobic threshold. The CFS patients however worsened in both categories: VO2max fell 22% from 26.23 to 20.47 ml/kg/min, and oxygen utilization at anaerobic threshold fell 27%, from 15.01 to 11.01 ml/kg/min. To put this into perspective, these values are in the severe disability range on the AMA guidelines, and the decline in function from day one to day two cannot be explained by inactivity. Sedentary or de-conditioned persons do not change their oxygen utilization because of an exercise test. Even patients with heart disease, cystic fibrosis or other diseases do not vary more than 7% from one day to the next. However, the patients with ME/CFS in this study had a significant drop; something occurred because of the test on the first day interfered with their ability to utilize oxygen on the next day. And this is exactly what patients with ME/CFS have been describing with the symptom of post-exertional malaise. As the authors state, “The fall in oxygen consumption among the CFS patients on the second test appears to suggest metabolic dysfunction rather than a sedentary lifestyle as the cause of diminished exercise capacity in CFS.” Conclusions: The results of the two-day exercise testing are objective and not dependent upon subjective symptoms. Moreover hypochondriasis, intentional falsification, and/or poor effort can be detected by the physiologic parameters. Therefore the two-day exercise test, if confirmed in a larger trial, could become a clinical trial end point. More importantly, evaluations could be designed which would demonstrate the specific metabolic abnormality generated by the exercise of day one and demonstrated on the second day exercise test. It would be my hope that these findings be explored without delay. 1. Ciccolella M, Stevens S, Snell C, VanNess J: Legal and Scientific Considerations of the Exercise Stress Test. JCFS 2008, 14(2):61-75. (Continued on page 23) Page 22/34 www.investinme.org Journal of IiME Volume 2 Issue 1 Rev ew o he “ wo day Exe c se estt”( (conttiinued)) Reviiew off t the “TTwo--day Exerrciise T Tes ” con nued 2. VanNess JM, Snell CR, Stevens S: Diminished Cardiopulmonary Capacity During Post-Exertional Malaise. JCFS 2008, 14(2):77-85. 3. Fukuda K, Straus S, Hickie I, Sharpe M, Dobbins J, Komaroff A, Group ICS: The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994, 121:953-959. 4. Carruthers B, Jain A, DeMeirlier K, Peterson D, Klimas N, Lerner A, Bested A, Flor-Henry P, Joshi P, Powles ACP et al: Myalgic encephalomyelitis/chronic fatigue syndrome: Clinical working case definition. diagnostic and treatment protocols. J Chronic Fatigue Syndrome 2003, 11(1):1-12. 5. Jason L, Bell D, Rowe K, Van Hoof E, Jordan K, Lapp C, A G, Miike T, Torres-Harding S, De Meirleir K. A Pediatric Case definition for myalgic encephalomyelitis and chronic fatigue syndrome. J CFS 2006, 13:1-44 www.investinme.org Person With ME Dear IiME, Thoroughly enjoyed reading April’s newsletter. Packed full of information and sensible opinions on all aspects of ME research. I agree with IiME that it is wise to be wary of the plan to “fertilise cross-disciplinary research activity in this field.” I believe that any attempt to co-ordinate research amongst researchers who promote that ME is the same as CF, under the guise of CFS, will not bring about any medical understanding of the cause and progression of the illness. I also believe that it would be ethically wrong to work in tandem with any psychiatrist, or follower, who works to the premise that ME is just another form of CF called CFS and that it should be researched, treated and managed as such. The MRC neither understands nor cares that ME sufferers will never forgive or forget the unnecessary suffering caused by the opinions of a few psychiatrists. If they did understand they would realise that it is quite a repulsive Facts on ME Before medical science discovered the aetiology of multiple sclerosis and Parkinson’s Disease, people afflicted with those disorders were subjected to medical dismissal and to charges of hysteria. Those with ME/CFS are suffering the same fate, because even though so much is now known about the pathology, precise causation remains elusive. Causation will continue to remain elusive as long as Wessely School psychiatrists advise the UK Government that no tests should be performed on those with ME/CFS, especially immunological and neuro-imaging, investigations which, when carried out elsewhere, jave already delivered evidence of the organic nature of the disorder. - as listed in the IiME Quotable quotes Booklet ) notion to promote the idea that our tormentors will now become our saviours. It is simply too late for the bad guys to become the good guys. (Will they admit that they were wrong all along?) When will the MRC, DoH, CMO and the NHS inform psychiatrists that they should not be involved in ME research at all? Until this happens ME research will continue to stagnate in the CF pool. On a lighter and more positive note, “Good luck” on May 23rd when IiME hosts the third ME conference. I look forward to ordering my DVD and learning about biomedical research into ME. - C Invest in ME (Charity Nr. 1114035) Page 23/34

Journal of IiME Volume 2 Issue 1 www.investinme.org WHO GETS ME AND WHY INTRODUCTION The role of impaired capillary blood flow in ME By Les Simpson There is no doubt that one of the major problems facing those who suffer from myalgic encephalomyelitis (ME) is the persisting disagreements about the name of the disorder. To a great extent this was exemplified by a group in Florida who decided to change CFS to ME. For that reason alone it is important to recognise Ramsay’s concept of ME so that those with the problem can be identified and separated from other illnesses such as chronic fatigue syndrome (CFS) and post-viral fatigue syndrome (PVFS). Until this happens, ME people will continue to be disadvantaged. In the preface to the second edition of his book, “Myalgic encephalomyelitis and postviral fatigue states,” published in 1988, Dr.Ramsay wrote, “When on the occasion of a recent ITV programme on the subject of myalgic encephalomyelitis, an immunologist stated that ‘ME and PVFS are regarded as synonyms’ I realised that my objection to the latter term was fully justified and that it was incumbent on me to show that such a statement is blatantly untrue.” He stated also, “The clinical identity of the myalgic encephalomyelitis syndrome rests on three distinct features, namely: 1. a unique form of muscle fatigability whereby, after even a minor degree of physical effort, three, four or five days, or longer elapse before full muscle power is restored; 2. variability and fluctuation of both symptoms and physical findings in the course of a day: 3. an alarming tendency to become chronic.” In the text, Ramsay discussed the multiplicity of symptoms in three groups. 1. Muscle phenomena. He noted, when discussing the time for the restoration of normal muscle power, “…it is important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission.” 2. Circulatory impairment. extremities and facial pallor. This was manifested as cold 3. Cerebral dysfunction was manifested in many ways including memory problems, difficulties with concentration and emotional lability. It seems rather surprising that Ramsay did not link the dysfunction of muscles and brain to the recognised problems of circulatory impairment. He stated however, “The chronic case can take two different forms. remission and relapse. In the first there is a recurring cycle of In three doctors who contracted the infection between 1955 and 1958, the alternation of remission and relapse continues. second form is more tragic and no remission occurs.” The It is clear that remissions play a large part in Ramsay’s concept of ME. The introduction, by the Centers for Disease Control in Invest in ME (Charity Nr. 1114035) the USA, in 1988, of the term chronic fatigue syndrome (CFS), almost immediately made life more complicated for ME sufferers, as the criteria for CFS were much more inclusive. Not only were ME patients gathered under the CFS umbrella, but also the results of Americans studying CFS tended to be adopted as being relevant to ME, and to a large extent Ramsay’s experience was ignored. In most countries, despite the opposition of small groups, ME people were diagnosed as having CFS, even though there were no accepted (Continued on page 25) Page 24/34 Leslie Owen Simpson currently lives in Dunedin, New Zealand, but has lived in 6 countries and from 1991 travelled and lectured extensively. He graduated from the University of Otago, majoring in botany and zoology and later worked in the field of tissue transplantation. He became a WHO lecturer in medical biology at the Central Medical School, Suva, Fiji, with a brief to establish a medical biology department and train technical staff. After a spell in teaching he was appointed research officer in the Pathology Department, Otago Medical School, studying the pathobiology of the first animal model of lupus erythematosus, the NZ Black Mouse. After a postdoctorate in experimental pathology he worked as a senior research officer. Although retired in 1985 he has continued to work full time in unpaid appointments as honorary research fellow, first in the Pathology Department and then in the Department of General Practice. In 1999 he set up Red Blood Cell Research Limited and continued his research on red blood cells and privately funded much of the research. He has had 125 letters or articles published in medical journals as well as numerous other articles in journals and textbooks. Journal of IiME Volume 2 Issue 1 www.investinme.org WHO GETS ME AND WHY - The role of impaired capillary blood flow in ME (continued) pathophysiologies for either diagnosis. To a large extent this is the current situation. For example, a 2001 English publication titled “What is ME? What is CFS?” (1) discussed ME mainly in terms of the findings of American investigators, only a 1981 paper by Ramsay was quoted and no reference was made to either edition of his book. In 2007, The Nightingale Research Foundation published, “The Nightingale myalgic encephalomyelitis definition,” (2) even though in their 1992 book, Dr.Hyde had suggested that “encephalopathy” was a more appropriate term. Primary ME was defined as, “…an acute onset biphasic epidemic or endemic (sporadic) infectious disease process where there is always measurable and persistent diffuse vascular injury of the CNS in both the acute and chronic phases. Primary ME is associated with immune and other pathologies.” The concept of “…persistent diffuse vascular injury,” would rule out any involvement of Ramsay-style remissions. It is clear that the possible role for shapechanged red cells as recorded in my paper in the 1992 book, was rejected. At a meeting of Canadian and American investigators who were interested in ME, a consensus was reached and released as the Canadian Consensus. In 2007, a review was published under the title, “Definitions and aetiology of myalgic encephalomyelitis: how the Canadian consensus clinical definition of myalgic encephalomyelitis works.”(3) It was noted, “To improve clinical observation, the Canadian definition and diagnostic protocol lays out several regions of pathophysiological dysfunction, as necessary components of the syndrome of myalgic encephalomyelitis, but the particular expression of symptoms within each region is contingent between individuals and their particular pattern is left open to be decided by clinical observation of the individual and later diagnostic classification.” of the writing, but the enclosed message is far from clear. It was noted also, that, “The possible aetiology of myalgic encephalomyelitis is under scientific observation. This is done by experiment and by controlled observation. Many observers are following various lines of investigation and observation as to the aetiology of myalgic encephalomyelitis, which we are following with interest.” This statement seems not to recognise that ME has been studied for 50 years. like is being compared with like. The crucial factor is whether or not Given the degrees of difference in the various definitions, there seems to be a grave danger that apples are being compared to oranges. In general, two features of the paper stand out. No mention was made of Ramsay’s work or of remissions and there was no indication that blood flow was a problem. Therefore it seems that because of the conflicting views of experts and a general lack of agreement concerning the aetiology and pathophysiology of ME, a small section of the community will continue to suffer a reduced quality of life while experiencing a variety of symptoms, which, if Invest in ME (Charity Nr. 1114035) they are lucky may disappear for variable periods of time during remissions. WHO IS AT RISK OF DEVELOPING ME? In any group of people who suffer from the same viral infection, most return to full health in less than 14 days, while a small proportion become chronically unwell. This implies that those who continue to be unwell (?ME people) are different from the normal population in some feature. About the time I became involved with ME in 1983, I was developing an interest in the measurement of blood viscosity and blood filterability. Control Initially I studied blood samples from the blood donor panel, but through the good offices of Prof.J.C.Murdoch, who had a clinical interest in ME, I obtained blood samples from 21 female and 11 male patients with ME. samples were obtained from age and gender matched blood donors. Blood viscosity was measured at four shear rates and blood was filtered through polycarbonate filters with 5 micron pores at four levels of negative pressure. The results were published in 1986 (4) and showed that although there were differences in the results from blood viscometry of ME people and controls, they did not reach statistical significance. In contrast, at the lowest filtration pressure, the values for ME females were significantly different from controls, (an indication of stiffened red cells) but the differences in the male values did not reach significance. An examination of the data revealed that some ME values were near normal and would have influenced the results. The implications of the results were that ME This 59 word sentence is typical people could be at risk of blood flow problems in the microcirculation because of the effects of poorly deformable red cells. It should be noted that for the assessment of filterability, EDTA-anticoagulated blood was used and filtration took place within half an hour of the sample being drawn. Subsequent developments from the simple technique included the washing of the red cells in saline, but such treatment greatly changed blood filterability. Our report concluded, “ … advances in our understanding of the aetiology of the disorder will come from investigations in the acute phase, and blood rheology may be of value in identifying those who are acutely affected.” Although non-ME subjects may have poorly filterable blood for 12 to 14 days after an infection, ME blood remains poorly filterable as long as they are symptomatic. So ME people respond to agents which change the internal environment, by stimulating change in red cell shape and making them less deformable, probably because of a persisting, but unidentified factor in the blood. As will be discussed later, that factor has the capacity to switch off, resulting in a remission. Until the factor has been identified, it seems inappropriate to (Continued on page 26) Page 25/34

Journal of IiME Volume 2 Issue 1 www.investinme.org WHO GETS ME AND WHY - The role of impaired capillary blood flow in ME (continued) consider cure, as an endpoint and my objective in treatment is simply to improve the quality of life of sufferers. To a large extent it seems that clinicians take red cells for granted, ignoring the fact that the loss of the nucleus as the cell leaves the bone marrow, renders it incapable of independent existence, and at the mercy of its environment. There are many published reports which record the different ways in which red cells respond to change in their environment, both in vivo and in vitro, with the change in shape associated with reduced deformability. The significance of the reduction in deformability is that the average diameter of capillaries lies between 3.5 and 5 microns, whereas the diameter of a red cell is between 7.5 and 8 microns. Therefore, in order to traverse a capillary bed, red cells must be able to deform and any reduction in red cell deformability will increase the resistance to flow in the microcirculation. A 1970 editorial (5) titled, “The importance of erythrocyte deformability,” concluded that, “ …the remarkable deformability of normal mature erythrocytes appears to depend on at least three factors: (1) maintenance of the biconcave shape which in turn depends on a high ratio of surface area to cell volume; (2) normal internal fluidity of the cell which in turn depends primarily on the properties of normal haemoglobin; and finally (3) intrinsic membrane deformability which is significantly affected by the relationship between intracellular ATP, calcium and magnesium and may be affected by pH and oxygen tension in local regions of the microcirculation.” Therefore it can be expected that any change in the cell environment which alters any of those three factors will lead to a reduction in cell deformability. Although viral infections, which will alter the internal environment, are considered to be key factors in the aetiology of ME, other infections, inoculations, vaccinations, severe emotional upsets, herbicidal sprays and heavy physical activity have been reported as causal factors in ME. All those factors will alter the red cell environment. However, it needs to be emphasised that although everyone exposed to such changes will show shapechanged red cells, only a small proportion will go on to develop the symptoms of ME. So those who are at risk of developing ME have some physiological difference which leads to a reduced ability to restore red cell shapes to normal. of the unknown factor or factors involved may persist for 15 to 20 years or longer. WHO GETS ME? (Continued on page 27) As the problems of poorly deformable red cells in Invest in ME (Charity Nr. 1114035) Page 26/34 The action traversing a capillary bed will be greatest in small capillaries, it is proposed that a key factor in determining who gets ME is the anatomical feature of smaller than usual capillaries. The random distribution of clusters of small capillaries provides a basis for understanding the idiosyncratic nature of the symptoms of ME. This implies that some cases may exhibit only a few regions which become symptomatic, whereas other cases may have symptoms in many regions of the body. While the presence of smaller than usual capillaries may have little functional effects when red cells exhibit normal deformability, their presence will become obvious after exposure to an agent which alters the internal environment and stimulates change in the shape populations of red cells. Furthermore, during remissions, when red cell shape populations return to normal, normal functional status indicates normal rates of capillary blood flow. Because a requirement for normal tissue function is a normal rate of capillary blood flow which delivers sufficient oxygen and nutrient substrates to sustain normal function and to remove metabolic wastes, it is clear that when shape-changed, poorly deformable red cells are in the circulation, capillary blood flow will not be normal. The severity of the consequences of impaired capillary blood flow will be determined by the tissue involved. Muscles, the central nervous system and secreting glands are particularly sensitive to oxygen deprivation which may lead to body wide dysfunction. It is not surprising that in ME most symptoms relate to those tissues. Therefore it is proposed that those people who develop the chronic condition we call ME, share the common anatomical feature of having smaller than usual capillaries, the distribution of which will be marked by the development of symptoms when some agent induces change in red cell shape which makes them poorly deformable. Because many other chronic disorders exhibit changes in the shape populations of red cells, the presence of such cells is not diagnostic for ME. A 1992 paper (6) noted that, “ Subjects with the characteristic (of smaller than usual capillaries) would always be at risk of developing red cell shaperelated impairment of capillary blood flow.” Thus, those who will get ME are the small proportion of the population who by chance have smaller than usual capillaries. The severity of the symptoms which develop in the presence of poorly deformable red cells will reflect the extent to which small capillaries are present in the microcirculation. Limited observations have left me with the impression that black and brownskinned races have a lower incidence of small capillaries. Journal of IiME Volume 2 Issue 1 www.investinme.org WHO GETS ME AND WHY - The role of impaired capillary blood flow in ME (continued) BLOOD FILTERABILITY AND RED CELL SHAPE The findings of reduced blood filterability stimulated the thought that some change in the surface features of red cells might be involved (in the terms of Weed’s concept). To explore this possibility, a technique used for the rapid examination of theatre specimens by electron microscopy was adapted to study red cell morphology. The key factor was that the blood samples (3 to 5 drops of venous blood) were fixed immediately by being added to 5ml of 2.5% glutaraldehyde in 0.1M cacodylate buffer at pH 7.4. After fixation for overnight, at least, the cells were dehydrated in ascending concentrations of ethanol to absolute, then passed through three changes of pure, dry acetone. A drop of the acetone-suspended red cells was placed on a glass cover slip fixed to an aluminium stub with double sided adhesive tape. After air-drying, the cells were gold-coated in a sputter coater, then photographed under standard conditions in a scanning electron microscope. The cells in the resulting micrographs were classified into six different shape classes and the proportions expressed as percentages of the total number of cells counted. The first series of blood samples assessed in this way came from healthy blood donors, and from the first sample it was clear that the current teaching that all red cells were biconcave discocytes was not sustainable. In 1989 I was able to report that the red cells in immediately fixed blood samples from healthy animals and humans could be classified into six different shape classes.(7) Later in the year I reported that blood samples from patients with acute ME showed increased proportions of cup forms (stomatocytes), a form which is known to be poorly deformable. (8) At a meeting in India in 1992, I discussed the red cell shape changes which had been found in six chronic disorders. (9) Studies of the relevant literature, while preparing those reports, revealed that there had been earlier reports concerning changes in the shape populations of red cells. From 1974-78, there had been several reports concerning red cell shape in patients with muscular dystrophy. However, only one study (10) used immediately fixed blood samples, and the results were different from those studies which had manipulated the blood cells prior to fixation. The authors (10) noted that they were unable to prevent unfixed red cells from changing shape, even in their native plasma in a refrigerator. This is the expected response of red cells to a changing environment. In 1977, it was reported that patients with Huntington’s Disease had increased proportions of stomatocytes (cup forms). (11) Because increased proportions of stomatocytes would have an adverse effect on capillary blood flow, it is of interest that a 1985 study reported impairment of cerebral blood flow which Invest in ME (Charity Nr. 1114035) was shown to correlate with cognitive impairment of patients with Huntington’s Disease.(12) Even though it was very likely that stomatocytes were responsible for the impaired cerebral blood flow, no reference was made to the 1977 study. In general there was no clinical interest in changed shape populations of red cells, and such reports provoked little continuing interest. However, Mukherjee et al (13) were stimulated by our 1986 study of poorly filterable blood, to embark on a study of red cell morphology in ME people. They reported the presence of small numbers of grossly abnormal red cells. But the cells examined had been washed and centrifuged prior to fixation, and it is very likely that the abnormal cells were a result of the preparation technique. In the 13,000-odd immediately fixed blood samples relating to a number of chronic conditions in eight countries, which I have assessed, I have never seen a cell with the features of that described by Mukherjee et al. At the Cambridge Symposium on ME in 1990, I reported that blood samples from another 99 patients with acute ME showed similar values for increased cup forms to those of the previously reported 102 cases (14). It was noted also that there were small numbers of cases which presented with increased proportions of flat cells or cells with altered margins. In hindsight, it now seems likely that those changes were the beginning of a trend to chronic ME, as by 1992 only about 5% of cases were presenting with the cup forms of acute ME, and increased flat cells was the most common feature of chronic ME. It should be noted that the title of the paper I submitted made no mention of chronic fatigue syndrome, and this was added to the title by the editors, without discussion. Thus, the information relating to reduced blood filterability is reinforced and possibly explained by the changed red cell morphology seen by scanning electron microscopy, so impaired capillary blood flow can be expected. What is important is that change in the cell shape populations is not a benign event. Remember, for example, that Weed (5) had noted that the deformability of red cells depended upon, “…maintenance of the biconcave shape.” Possibly of greater physiological importance were the findings of Vandergriff and Olson (15) that red cell shape was a determinant of the rate of uptake and release of oxygen. margins) were found to have a 45% reduction in the uptake of oxygen and a 23% reduction in release rate. TIREDNESS, MUSCLE DYSFUNCTION AND CAPILLARY BLOOD FLOW It is particularly unfortunate that the term ‘fatigue’ is used so frequently in the ME literature. Both Funk and (Continued on page 28) Page 27/34 For example, crenated cells (cells with altered

Journal of IiME Volume 2 Issue 1 www.investinme.org WHO GETS ME AND WHY - The role of impaired capillary blood flow in ME (continued) Wagnall and the Oxford Concise dictionary define fatigue as the consequence of long-continued exertion, but ME people do not have to run up stairs to feel tired. The authors of a 1921 study of industrial fatigue noted that they could not measure or define ‘fatigue’ and it was recommended that, “The term fatigue should be absolutely banished from precise scientific discussion.” (16) Sir John Ellis noted in a paper titled “Malaise and fatigue,” (17) that patients seldom used such terms. Instead, “They complain of being tired and not feeling well…they say they are knackered, bushed, beat, washed out, drained or utterly exhausted…. They add that it started gradually some time ago, and then say their tiredness is inexplicable.” Although the use of the term ‘fatigue’ may invite controversy, muscle fatigue is an accepted physiological condition. In accordance with the idea that poorly deformable red cells would impair capillary blood flow sufficiently for muscle function to be interrupted by an inadequate oxygen delivery rate, this concept was tested in ME people and in healthy subjects. A healthy young woman acted as a guinea pig and it was found that the repeated pulling of a trigger until trigger finger fatigue, led to a three-fold increase in cells with altered margins in the 35 seconds taken to induce muscle fatigue. (18) Unexpectedly, in applying for approval for a study involving ME people, the Ethics Committee ruled that ME was an unknown entity, but approval was obtained by substituting “subjects with chronic tiredness,” for ME. The study took place at a weekend residential meeting of members of ME support groups where 69 ME volunteers took part. (19) After a 5-drop blood sample had been taken, the trigger of a model revolver was pulled repeatedly until the onset of trigger finger fatigue. A second blood sample was obtained and the number of trigger pulls and the elapsed time were recorded. Five minutes later the procedure was repeated. Subsequently the procedure was repeated in 72 healthy controls who were police officers, firemen, army personnel, nurses and teachers. In general, the results showed that at baseline, ME people had different red cell shape populations from controls and they had fewer trigger pulls with greater changes in their post-trigger pulling blood samples. It was concluded that, “The association of increased nondiscocytes and impaired muscle function could indicate a cause and effect relationship. This would be in agreement with the physiological concept of fatigue as a consequence of inadequate oxygen delivery.” So it is relevant that in his textbook of human physiology, (20) Griffiths noted that muscle fatigue probably was due to oxygen deficiency and the effects of localised accumulations of metabolites including lactic acid, “…when the metabolites were not removed because of impaired capillary blood flow.” Wiles et al (21) considered that energy generation would fail if there was an enzymatic block in Invest in ME (Charity Nr. 1114035) Fig 1: A scanning electron micrograph which shows the red cell population typical of chronic ME, where flat cells are the dominant type. you can find cells with surface features such as bumps, (cells with surface changes) and cells with irregular margins (cells with altered margins). Cells with the shape of biconcave discocytes can be seen at the margins at 2 o’clock, 5 o’clock and 9 o’clock. According to textbooks all red cells have this shape. ‘abnormal’ as they are part of the cell shape populations of normal blood. the glycogenolytic pathway or if there was a failure of oxidative metabolism. They considered the limiting features of energy generation to be blood flow and oxygen delivery. While much has been written about ‘Tired patients,’ and ‘Tiredness,’ a 1960 paper by Ffrench (22) is of special interest. Ffrench considered that, “Tiredness is a symptom rather than a clinical condition,” and that, “Tiredness is a ‘whole’ symptom. It is felt throughout the patient’s body and is not confined to regions, anatomic structures or specific physiological functions, but rather it emanates from the natural whole of the human body and mind.” His study involved 1170 patients, of whom 105 complained of tiredness. After discussing the possible contributions of a number of a number of factors, Ffrench concluded, “There is no doubt that oxygen lack is the first cause of tissue cell exhaustion, which is manifested early by clinical tiredness.” BRAIN DYSFUNCTION AND CAPILLARY BLOOD FLOW It is postulated that the effects of shape-changed, poorly deformable red cells will impair capillary blood flow on a wide basis, with the most severe effects relating to regions small capillaries in tissues which are sensitive to oxygen deprivation. (Continued on page 29) Page 28/34 If you look carefully Note that none of these cell types are Journal of IiME Volume 2 Issue 1 www.investinme.org WHO GETS ME AND WHY - The role of impaired capillary blood flow in ME (continued) Because tiredness is a major problem for those who suffe from multiple sclerosis, (MS) at the conclusion of our 1986 study on ME, we investigated the filterability and other aspects of blood samples from members of the local Multiple Sclerosis Society. As with ME, the rate of blood filterability was much less than that of healthy controls and there were changes in red cell morphology. A possibly relevant implication of these changes is that in 1983, Swank et al (23) had shown by xenon washout that in MS subjects, “…there occurred a progressive, generalised decrease in cerebral blood flow and in red cell delivery with age, which was significantly greater than observed in normal subjects. The rate of decrease in cerebral blood flow and red cell delivery correlated directly with the rate of progress of the disease. Studies using single photon computed tomography (SPET or SPECT) have shown in other conditions with shape-changed red cells, that there can be significant reductions in regional cerebral blood flow. The relevance of this is that on March 30 1994, Dr.D.C.Costa presented his findings from a SPET study of ME patients at the annual general meeting of the British Nuclear Medicine Society. He reported that ME/CFS patients, “… had a generalised reduction in brain perfusion, “ and that, “… brainstem blood flow was significantly lower than in patients with depression and that both patient groups had significantly lower brainstem blood flow than in healthy subjects.” Even though I had published three reports concerning the effects of nondiscocytic red cells in ME patients prior to 1994, Dr.Costa hypothesised that the reduced demand for oxygen in the brain related to an overactive immune system which resulted in an excessive production of cytokines. Dr.Costa’s comparison of the cerebral blood flow of ME/CFS with depression draws attention to a significant literature concerning SPECT scans and depression. Perhaps the most informative was a study by Bench et al (24) which showed that a region of the brain with impaired blood flow during depression, showed normal blood flow rates when the depressive episode resolved. Evidently the regions associated with reduced blood flow have diagnostic significance as shown in another study by Dr.Costa. Lucey, Costa et al (25) reported that in some psychiatric disorders, there were significant differences in regional cerebral blood flow, as defined by SPET. While whole brain blood flow correlated with anxiety, there were significant regional cerebral blood flow differences between patients with obsessive compulsive disorder and post-traumatic stress disorder and controls. REMISSIONS – THE CORNER STONE OF RAMSAY’S CONCEPT OF ME. Even though Ramsay had described remissions as a feature of ME, and gave examples of the Invest in ME (Charity Nr. 1114035) remission/relapse cycle, remissions are unrecognised by American investigators and are little recognised in other countries. This situation could be a possible consequence of ME being considered as the result of a persistent infection or a persistent immunological abnormality, or the consequence of localised pathology, as such beliefs would be incompatible with the remissions which Ramsay recorded. My first experience with a remission related to a young woman who delivered a blood sample about 9am one morning. She explained that she had been too unwell to have had a blood sample taken earlier. On checking the details on her blood test request form it was noted that she had checked the box ‘well with no symptoms.’ pointed out that if she was well when she had the blood drawn then it was likely that the results would be normal. About 4pm on the same day she returned with another blood sample. She had ‘crashed’ about 3.30pm, for no discernible reason, and gone to the laboratory for another sample. The request form was marked ‘severely unwell.’ When the samples had been assessed it was found that the morning sample was normal and the afternoon sample was grossly abnormal. What factor or factors switch off to restore red cell shape populations to normal with improved wellbeing, and switch on to become symptomatic with changed red cell shape populations, remain unknown. However, the observation is consistent with Ramsay’s comment that during remission muscle function returns to normal. Those observations led to an attempt to gain some insight into the frequency of remissions and concomitant changes in ME people in New Zealand. A panel of 37 females and 11 males who had been diagnosed by a physician as having ME at least 2 years previously, gave informed consent to take part in a 40 week-long study. At commencement and at four-weekly intervals thereafter, the panel met to record their symptoms and level of wellbeing and to provide a 5-drop sample of venous blood for red cell shape analysis. A total of 519 blood samples (401 female, 118 male) were assessed. While the majority of blood samples showed the increased flat cells of chronic ME, normal results occurred sporadically. At one extreme there were five women who were unwell and had abnormal blood tests in 11 of 11 blood samples. Because of the four-week space between samples it is not known if remissions had occurred in the interval or if the women were in the group noted by Ramsay, who did not have remissions. At the other extreme was a woman who was well, with normal blood tests in 6 of 11 samples. The most frequent result, for both sexes, was to have two remissions during the 40 weeks of the study. The findings led to the conclusion that remissions were not uncommon events. (Continued on page 30) Page 29/34

Journal of IiME Volume 2 Issue 1 www.investinme.org WHO GETS ME AND WHY - The role of impaired capillary blood flow in ME (continued) Such findings are in accord with the idea that ME is a dysfunctional state arising from inadequate rates of delivery of oxygen and nutrient substrates, rather than a condition associated with tissue pathology. That viewpoint is consistent also, with the improved wellbeing of patients who respond to agents which improve red cel deformability and thus increase capillary blood flow. TREATMENT OPTIONS The major factors in the development of the dysfunctional state manifested as the symptoms of ME are the presence of randomly distributed clusters of small capillaries and the effects of shape-changed, poorly deformable red cells on the rate of capillary blood flow. As it is not possible to influence capillary size, treatment should be aimed at improving red cell deformability, as remissions show that the red cell changes are reversible. 1. Acute ME. As reported at the Cambridge Symposium, a chance event led to an investigation iiv into the possible benefits of injections of vitamin B12 as hydroxocobalamin. A female patient reported that her general practitioner had given her an injection of hydroxocobalamin (Neo-Cytamen) and within 24 hours she felt much better. A blood sample was taken and revealed that her level of cup forms was reduced greatly. However, another patient failed to benefit from a similar injection and there was no change in her cup form value. The improved status of the responder was maintained with injections at about 10 day intervals. Through the co-operation of general practitioners it was found that 15 of 29 cases of ME responded to injections of hydroxocobalamin with symptom relief and reduced cup forms. However, there is no explanation of the mode of action of the B12 or why it was ineffective in 50% of cases. 2. Chronic ME. Some understanding of how the red cell changes in chronic ME might be relieved is based upon two early studies which investigated the effects of prostaglandins on red blood cells. Kury et al (26) used a spin-labelling technique to assess factors in red cells which influenced cell deformability. They reported that prostaglandin E1 (PGE1) increased red cell deformability, while the pro-inflammatory prostaglandin E2 (PGE2) had the opposite effect. By means of a filtration technique based upon standardised paper filters, Rasmussen et al (27) showed that PGE1 improved the filtration rate, while PGE2 had the opposite effect. Those observations were consistent with the findings of Kury et al, but in addition it was reported that catecholamines also reduced the rate of filtration. to explain why both emotional and physical stress are causal factors in the relapses of ME people. Although cis-linoleic acid is the basic precursor for Invest in ME (Charity Nr. 1114035) PGE1, it has to be elongated to gammalinolenic acid (GLA) in a reaction mediated by the enzyme delta-6desaturase. However it is known that in a number of situations the enzyme becomes dysfunctional, impairing the synthesis of GLA. For that reason it has been found useful to use plant sources of GLA. The most effective source is oil of evening primrose although it is unclear why it is responsible for higher production of PGE1 than other plant oils, even if their GLA content is higher. Manku et al (28) have reported that 2 grams daily of oil of evening primrose had no effect on the blood levels of PGE1, while 4 grams daily of the oil caused a significant increase in the concentration of PGE1 in the blood. So at least 4 grams daily of oil of evening primrose is needed to be effective. It needs to be emphasised that for unexplained reasons, not all individuals respond to that dose of evening primrose oil. The omega-3 fatty acids also have the ability to improve red cell deformability and may offer an alternative. The smallest omega-3 is the plant-derived alphalinolenic acid which requires a functional delta-6desaturase to elongate it in the synthesis of eicosapentaenoic acid. Because of the potential problems of delta-6-desaturase it is preferable to take omega-3 in the form of fish oil which is rich in eicosapentaenoic and docosohexanoic acids. Having demonstrated previously, by the use of a spinlabelling technique, that the lipid bilayer of the membranes of diabetic red cells were very viscous, (29) Kamada et al (30) reported that sardine oil taken orally, increased the fluidity of the lipid bilayer and increased the cell deformability. Although some ME people have responded to fish oil, I have not been able to identify which patients will respond to what oil. A lack of funding has prevented investigations into the performance of the oils by double-blinded randomised studies. However, on the result sheets concerning red cell shape analyses, in addition to the results, and a copy of the micrograph there is a suggestion that the effects of the changed red cells might be reduced by a daily intake of 4 grams of oil of evening primrose or 6 grams of fish oil. It is noted also, that if no benefit is perceived by 6 weeks, then another treatment should be tried. A patient in Denmark failed to respond to evening primrose oil or fish oil, but responded to pentoxifylline. That finding could help About 1988 a medical detailer reported that a general practitioner in a country town (Oamaru) was using pentoxifylline (Trental) to treat his ME patients. But before I could arrange a meeting the doctor was killed in a freak accident at a car rally where he was acting as a marshal As many studies have shown that pentoxifylline improves red cell deformability and reduces blood viscosity, it has the properties to be helpful for ME people but no reports of its use in ME have been located. Despite the lack of placebo-controlled studies, I have had many letters and emails from people who have Continued on page 31) Page 30/34 Journal of IiME Volume 2 Issue 1 www.investinme.org WHO GETS ME AND WHY - The role of impaired capillary blood flow in ME (continued) responded to one of the oils, with a restoration of a nearnormal lifestyle. My responses to such messages emphasise the need to persist with the effective treatment, while at the same time recognising that they are not cured and are still at risk. THE IMPORTANCE OF LIFESTYLE IN ME Even though persistent tiredness is a daily problem, it has to be accepted that long-term bed rest will have an adverse effect on muscle function. For that reason the daily programme should include provision for a period of low-intensity physical activity, such as walking 50 yards up the street and back again. Each week the distance walked should be increased, maybe in concert with an increase in speed. An interesting observation relating to a daughter with fibromyalgia was that when she was immersed up to her chin in a warm physiotherapy pool, the buoyancy provided by the water allowed her to do arm and leg exercises that she could not do on dry land. ME people should not get involved in arguments and they should walk away when they see stressful situations developing. Both arguments and stress may raise the blood levels of altered cells sufficiently to cause a relapse Give careful consideration to the nature of your diet. High levels of fat and cholesterol increase the stiffness of red cells. vegetables and of oily fish. tin of sardines in oil two or three times a week. Because low temperatures have an adverse influence on blood viscosity, it is important to dress warmly and if possible spend your time in a warm room. THE ORIGINS OF THE DATA ON WHICH MY CONCEPTS REST According to the entries in my daily diary, between January 1991 and December 2000, I spoke to 274 meetings in six countries. Although the great majority were ME groups, in the USA and Canada, I met CFS and CFIDS groups also. groups were included. From about 1997, fibromyalgia Either during such visits or later, arrangements were made for an experienced venepuncturist to collect 5 drop blood samples which were mixed immediately with fixative When the samples had been evaluated, reports were prepared and submitted for publication. However, reports submitted to Australian, New Zealand and South African journals were rejected. After giving an illustrated lecture to an ME audience in Victoria, British Columbia, I was approached by Dr.Abram Hoffer who introduced himself as the editor of the Journal of Orthomolecular Medicine. He invited me to submit a written version of the talk he had just heard. So in early 1997, a paper titled, “Myalgic encephalomyelitis (ME): a haemorheological disorder Invest in ME (Charity Nr. 1114035) manifested as impaired capillary blood flow,” was published. (J Orthomol Med 1997; 12: 69-76). Later in that year I was able to publish the red cell shape analysis results of blood samples from 1558 female and 620 male members of ME organisations in four countries. (J Orthomol Med 1997; 12 221-6) The numbers involved in that report are so large that it would be strange if the data were not relevant. In other reports I have summarised the information provided by 632 Americans with chronic disorders, and the red cell shape analysis results. In addition there is a report relating to the blood samples from 623 women with fibromyalgia, who resided in four countries. An intriguing aspect of that report is that the blood samples showed similar high values for flat cells to those of people with chronic ME. However, an analysis of the symptom lists showed that the first recorded symptom by the majority of ME people was tiredness, whereas in the fibromyalgia group the first symptom was pain. CONCLUSIONS What began as a study of various aspects of the blood in ME people finished up as a study of the red cell shape populations in a wide range of chronic disorders. In Try and increase your dietary intake of green If this is too expensive, have a those disorders which have been studied by SPECT scans, the reported reductions in regional cerebral blood flow were consistent with the expected effects of shapechanged, poorly deformable red cells. So ME is only one of many chronic disorders with changed red cells which will impair capillary blood flow. It would seem that ME is unique insofar as the factor or factors responsible for the changes in red cell shape, can switch off. During the resulting remission, red cell shape populations return to normal. Unfortunately, at this time, there is no diagnostic feature which can identify the group identified by Ramsay as having unremitting ME. Even though many different factors may initiate the blood changes which are typical of ME, it needs to be emphasised that the baseline changes may be increased by secondary factors which alter the internal environment, such as emotional stress or physical overactivity or hormonal changes as in the pre-menstrual week. Such changes will precipitate relapses. In addition, the immune response to inoculations, vaccinations or other infections will worsen the severity of symptoms and the level of body dysfunction. While the search for the primary problem continues, in order to improve the quality of life of sufferers, urgent attention is needed to define the actions of agents which can improve the deformability of red blood cells in order to provide an effective treatment. However, because of the official reluctance to investigate the pathophysiology of ME, sufferers may need to explore the potential benefits of those agents which will improve red cell deformability, on their own initiative. (Continued on Page 32) Page 31/34

Journal of IiME Volume 2 Issue 1 www.investinme.org WHO GETS ME AND WHY - The role of impaired capillary blood flow in ME (continued) REFERENCES 1. Marshall EP, Williams M, Hooper M. What is ME? What is CFS? December 2001. 2. Anonymous. The Nightingale myalgic encephalomyelitis (M.E.) definition. The Nightingale Research Foundation, Ottawa, Canada. January 29, 2007. 3. Carruthers BM. Definitions and aetiology of myalgic encephalomyelitis: how the Canadian consensus clinical definition of myalgic encephalomyelitis works J Clin Path 2007;60:117-9. 4. Simpson LO, Shand BI, Olds RJ. Blood rheology and myalgic encephalomyelitis: a pilot study. Pathology 1986;18:190-2. 5. Weed RI. The importance of erythrocyte 6. Simpson LO. deformability. Am J Med 1970;49: 147-50. Chronic tiredness and idiopathic chronic fatigue – a connection ? N J Med 1992;89: 211-6. 7. Simpson LO. Blood from healthy animals and humans contains nondiscocytic erythrocytes. Haematol 1989;73: 561-4. Br J 8. Simpson LO. Nondiscocytic erythrocytes in myalgic encephalomyelitis. NZ Med J 1989;102: 106-7. 9. Simpson LO. Red cell shape in health and disease. In: Swamy NVC, Megha Singh (eds) Physiological Fluid Dynamics III. Narosa Publishing House, New Delhi, 1992, pp 230-5. 10. Miller SE, Roses AD, Appel SH. Scanning electron microscopy studies in muscular dystrophy. Arch Neurol 1976; 33: 172-4. 11. Markesbery WR, Butterfield DA. Scanning electron microscope studies of erythrocytes in Huntington’s Disease. Biochem Biophys Res Commun 1977; 78: 560-4. 12. Tanahashi N, Meyer JS, Ishikawa Y, et al. Cerebral blood flow and cognitive testing correlate in Huntington’s Disease. Arch Neurol 1985; 42: 1169-75. 13. Mukherjee TM, Smith K, Maros K. Abnormal red cell morphology in myalgic encephalomyelitis. (letter) Lancet 1987;ii: 328-9. 14. Simpson LO. The role of nondiscocytic erythrocytes in the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome. In: Hyde BM, Goldstein J, Levine P (eds) The clinical and scientific basis of myalgic encephalomyelitis/chronic fatigue syndrome. The Nightingale Research Foundation, Ottawa, Canada, 1992, pp 597-605. 15. Vandergriff KD, Olson JS. Morphological and physiological factors affecting oxygen uptake and Invest in ME (Charity Nr. 1114035) Information for clinicians and lawyers. release by red blood cells. J Biol Chem 1984; 259:12619-27. 16. Muscio B. Is a fatigue test possible ? A report to the Industrial Fatigue Research Board. Br J Psychol 1921;12: 31-46. 17. Ellis J. Malaise and fatigue. Symptoms that depress a doctor and should not. Br J Hosp Med 1984;32: 312-4. 18. Simpson LO. Red cell shape. (letter) NZ Med J 1993;106: 531. 19. Simpson LO, Murdoch JC, Herbison GP. Red cell shape changes following trigger finger fatigue in subjects with chronic tiredness and healthy controls. NZ Med J 1993;106: 104-7. 20. Griffiths M. An introduction to human physiology. New York, NY, MacMillan Publishing Co., Inc.,1981, pp 73-4. 21. Wiles CM, Jones DA, Edwards RHT. 22. Ffrench G. Fatigue in human metabolic myopathy. Ciba Symposium 1981;82: 26482. The clinical significance of tiredness. Canad MAJ 1960;82: 665-71. 23. Swank RL, Roth JG, Woody DC Jr. Cerebral blood flow and red cell delivery in normal subjects and in multiple sclerosis. Neurol Res 1983;5: 37-59. 24. Bench CJ, Frackowiak RS, Dolan RJ. Changes in regional cerebral blood flow on recovery from depression. Psychol Med 1995;25: 247-61. 25. Lucey JV, Costa DC, Adshead G, et al. Brain blood flow in anxiety disorders. OCD, panic disorder with agoraphobia and post-traumatic stress disorder on 99 TchMPAO single photon emission tomography (SPET). Br J Psychiatry 1997;171: 346-50. 26. Kury PG, Ramwell PW, McConnell HM. The effect of prostaglandin E1 and E2 on the human erythrocyte a monitored by spin labels. Biochim Biophys Res Commun 1974;56: 478-83. 27. Rasmussen H, Lake W, Allen JE. The effect of catecholamines and prostaglandins on rat and human erythrocytes. Biochim Biophys Acta 1975;411 63-73. ME Story I have never known how such an illness can be so debilitating and so destructive yet virtually ignored by so many people. It is awful. I hope one day to be free of the ignorance. - Paul Page 32/34 Journal of IiME Volume 2 Issue 1 www.investinme.org Essential investigations for people with ME/CFS? By Margaret Williams On 14th January 2008 Fred Springfield drew attention on Co-Cure to a Review Article associated with inflammation in medically ill patients (“Identification and treatment of symptoms associated with inflammation in medically ill patients”; Robert on Dantzer inflammation, neurosciences and psychoneuroimmunology, attended by experts from the US, France, the UK and Israel. As noted by Fred Springfield, whilst not relating specifically to ME/CFS, the Review may nevertheless be of interest to the ME/CFS community, whose members may be aware that there is evidence of low-grade (but still important) inflammation in ME/CFS -see, example, “Low grade inflammation and arterial wave reflection in patients with CFS”; VA Spence et al, Clin Sci 2007, Epub ahead of print: doi:10.1042/CS20070274, which contains 54 references and demonstrates that, despite the recent reporting that markers of postinfective fatigue syndromes are not sustained into the chronic phase of the illness and play no role in persisting symptoms, hsCRP indicative inflammation. levels of chronic, low-grade, (Within the last ten years, in (ME)CFS are indeed sub-clinical researchers have developed a high sensitivity immunoassay known as hsCRP, which is a much better assay and a more sensitive marker than CRP, as it can measure levels below 10mg/L. Whilst some clinicians may still regard low levels as unimportant, nevertheless at these levels, measurement of conditions indicative of chronic, lowgrade inflammation are now possible). The Review recommends testing for a standardised set of inflammatory biomarkers, but the NICE Guideline on “CFS/ME” issued in August 2007 specifically proscribes such tests. The following are quotations that might be relevant for people with ME/CFS: “The most harmful and costly health problems in the Western World are originating from a few diseases (and) in addition to the specific symptoms that are characteristic of each of these conditions, most patients experience non-specific symptoms that are similar in all these conditions and include depressed mood, altered cognition, fatigue, and sleep disorders”. “The possibility that immune-to-brain communication pathways represent the main biological mechanism for symptom burden experienced by medically ill patients has now gained credibility in the medical community”. “Making fatigue a somatisation disorder overlooks the fact that fatigue has both mental and physical components, thereby denying a possible organic aetiology to explain such fatigue”. “Furthermore, this emphasis on the lack of an organic basis favours missed diagnoses (e.g. fatigue and thyroid abnormalities, or fatigue and inflammation)”. (continued on page 34) Invest in ME (Charity Nr. 1114035) Page 33/34 for et al; Psychoneuroendocrinology 2008:33:18-29). The Review was the result of a meeting on 28th and 29th May 2007 in Bordeaux, France, psychiatry, “This meeting brought together clinicians and basic scientists with a common interest in understanding inflammation and associated symptoms in medically ill patients (and it) focused on: (a) predominant symptoms associated with inflammation, (b) markers of inflammation at the periphery, (c) possible markers of brain inflammation associated with low-grade peripheral inflammation in humans, (d) animal models of inflammation-associated symptoms, and (e) domains of intervention for controlling inflammation-associated symptoms”. “Among the myriad of questionnaires that are available to categorise or assess fatigue, sleep disorders, altered cognition and pain, none specifically refers to inflammation-associated neurobehavioural alterations”. “The diagnostic tools that are favoured by psychiatrists are clearly not the best ones. As pointed out by Joel Dimsdale (San Diego, CA), the concept of somatisation that is used for characterising symptoms in the absence of any detectable disease is of little operational value, if not misleading”. “For instance, the enduring fatigue experienced by the vast majority of breast cancer survivors could easily be labelled as somatisation disorder according to the 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders”. Margaret Williams is a well respected authority on ME as well as being an ME patient advocate. Margaret Williams formerly held senior clinical posts in the NHS.

Journal of IiME Volume 2 Issue 1 www.investinme.org Essential investigations for people with ME/CFS? (Continued) U “Inflammation is not a stable condition. In a given individual it can fluctuate rapidly according to a number of environmental factors (e.g. stressors) and internal variables (e.g. diurnal variation of cortisol)”. “Basic aspects of diagnosis of behavioural disorders remain controversial and lack solid scientific foundations”. “In order to provide consistency, all studies examining the potential impact of inflammatory pathways should include a standard set of inflammatory biomarkers (which should include) the acute phase proteins, CRP, sialic acid and hatoglobin; the inflammatory mediators, prostaglandins E2 and C3A and the innate immune cytokine IL-6 as measured by the high sensitivity (hs)enzyme-linked immunosorbent assay (ELISA) in plasma. These biomarkers, especially hs-CRP and IL-6, have been found to reproducibly identify the presence of an activated immune response in a number of disorders. Most of these assessments can be run in certified commercial or hospital laboratories”. “There have been significant advances in imaging techniques during the past ten years (and) a variety of imaging techniques have enabled inflammation in the brain to be viewed in real time. However, except in conditions of severe systemic inflammation, signalling of systemic inflammation to the healthy brain does not involve structural damage”. “It is important to highlight the distinction between signalling by molecules typically associated with inflammation and an inflammatory response per se. During systemic inflammation there is induction of IL-1β and other proinflammatory cytokines, but there is no inflammatory response in the brain. It is of interest that microinjection of IL-1β into the brain at concentrations that would typically give rise to inflammation in peripheral tissues does not lead to typical inflammation within the brain parenchyma. This indicates that the biological significance of IL-1β in the brain parenchyma is different from that in other tissues”. “Although we have the necessary tools to image inflammation in the brain, it seems we do not have sufficiently sensitive tools to image signalling in the brain consequent to a systemic inflammatory response”. “Proinflammatory cytokines induce the production of Invest in ME (Charity Nr. 1114035) several downstream inflammatory mediators, such as prostaglandins and nitric oxide. Proinflammatory cytokines and other inflammatory mediators are produced by accessory immune cells, such as macrophages and monocytes in the periphery, and microglia within the central nervous system. Targeting cell trafficking into the central nervous system is unlikely to be a very useful approach since symptoms of sickness are dependent on the activation of brain cytokine signalling independently of any blood cell recruitment”. “Peripheral infections can sensitise or exaggerate existing brain inflammatory processes (and) elevated cytokine levels in blood have the potential to reverberate and activate central nervous inflammatory systems”. The Conclusions of the Review note the intense discussion at the meeting that resulted in a series of recommendations for improving understanding of the relationship between inflammation and subjective health complaints. These recommendations note that because inflammation-associated sickness symptoms are a major impediment to human health, research on the mechanisms and treatment of such symptom burden in physically ill patients should be strongly encouraged; that clinical tools for assessing inflammation-associated symptoms should be standardised; that there should be a minimum set of inflammatory biomarkers; that brain neuroimaging techniques should be used for revealing the brain structures that are influenced by peripheral inflammatory processes and whose ability to process information is impaired by excessive amounts of interoceptive stimuli (caused, it seems, not – as asserted by Wessely School psychiatrists -- by aberrant focusing on normal bodily sensations or by “remembered illness” but by inflammatory processes), and that presence of inflammation-associated symptoms ill patients provides a background against the high in physically which it is possible to test alleviating effects of therapies targeting immune-to-brain communication pathways. The Review notes that despite major advances in the understanding of the immune-to-brain communication pathways that underlie the pathophysiology of symptoms in inflammatory conditions, little has been done to translate this knowledge to the clinics. As NICE is now in the process of contacting selected people asking for their input on the advisability of it producing guidance on the use of Ampligen in “CFS/ME”, might NICE also be persuaded to seek the input of experienced vascular biologists on the advisability of it recommending specific testing for inflammation in ME/CFS? Page 34/34

The Journal of IiME Volume 2 Issue 2 From Invest in ME

Journal of IiME Volume 2 Issue 2 www.investinme.org 2 22 3 33 1 11222 1 11555 1 11777 3 33333 4 44333 4 44888 5 55555 Inside This Issue E EEdddiii tttooorrr iiiaaalll CCCooommmmmmeeennnttt Family Illnesses Among People with ME/CFS L LLeeettt ttteeerrr fff rrrooommm AAAmmmeeerrr iiicccaaa E EEuuurrrooopppeeeaaannn MMMEEE AAAlll lll iiiaaannnccceee T TThhheee IIInnnttteeerrrnnnaaattt iiiooonnnaaalll MMMEEE///CCCFFFSSS C CCooonnnfffeeerrreeennnccceee 222000000999 A AA SSSeeevvveeerrreee MMMEEE---AAAwwwaaarrreee NNNuuurrrsssiiinnnggg M MMooodddeeelll T TTeeerrrmmmiiinnnooolllooogggyyy ooofff MMMEEE &&& CCCFFFSSS W WWhhheeeeeelllccchhhaaaiii rrr UUUssseee aaannnddd A AAttt ttt iii tttuuudddeeesss T TThhheee PPPhhhyyysssiiiooolllooogggyyy ooofff EEExxxeeerrrccciiissseee I IInnntttooollleeerrraaannnccceee iiinnn PPPaaattt iiieeennntttsss wwwiii ttthhh M MMEEE aaannnddd ttthhheee UUUttt iii lll iii tttyyy ooofff GGGrrraaadddeeeddd E EExxxeeerrrccciiissseee TTThhheeerrraaapppyyy 6 66111 T TThhheee NNNIIICCCEEE GGGuuuiiidddeeelll iiinnneeesss fffooorrr M MMEEE///CCCFFFSSS ––– RRReeeaaasssooonnnsss fffooorrr R RReeejjjeeecccttt iiiooonnn 6 66555 6 66777 F FFrrrooommm 222 SSScccooorrreee aaannnddd 555 tttooo 333 S SScccooorrreee aaannnddd 111000 R RReeeaaasssooonnnsss WWWhhhyyy MMMEEE DDDoooeeesss NNNooottt B BBeeelllooonnnggg tttooo ttthhheee MMMUUUSSS CCCaaattteeegggooorrryyy Email: info@investinme.org Since Invest in ME was first formed, and especially since our successful 2007 biomedical research conference, we have felt that international cooperation is the likely key to providing the significant progress required for people with ME. It is by uniting across countries and continents that we can better tackle the problems in healthcare services regarding lack of up-to-date information on ME/CFS which are apparent across Europe. Increased knowledge of the findings from the latest biomedical research needs to filter down to doctors, nurses and other healthcare staff who are at the front end of examining and treating people with ME. Eventually that information will work its way into establishment organisations and into government policy – perennially the last areas which accept the latest evidence. International cooperation is also necessary between researchers and research establishments as this makes better use of scarce resources (funding, research units etc.) to achieve the necessary strategic approach to research into ME/CFS. Since the last Invest in ME international biomedical research conference in London in May Invest in ME has been working with our European colleagues and now the European ME Alliance has been set up. This new collaboration is an effort to campaign for funding for biomedical research into ME but it is also going to provide a one- stop site for correct and up-to-date information on ME for all Europeans. We look forward to increasing the benefits for people with ME and their families via our efforts to cooperate across national boundaries. Invest in ME now announces our fourth International ME/CFS Conference for May 2009. We hope to build on the success of the conferences of the past years including the 2008 conference dealing with Sub Groups of ME/CFS – surely the way forward for biomedical research. The severely affected people with ME are neglected by healthcare organisations and by the establishment authorities responsible for funding research. Many believe it is only by examining severely affected patients that a cure will be found for this illness yet those establishment organisations responsible (continued on page 3) Disclaimer The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME (Charity Nr. 1114035) Page 2/74 Journal of IiME Volume 2 Issue 2 www.investinme.org for medical research into ME/CFS continually allow flawed research which purposely ignores the severely affected in their selection criteria. Our own support work with severely affected people with ME in the last 9 months proves that a section of patients receive no attention from the healthcare system – and this is in London. Our International ME/CFS Conference in May will try to focus more on those severely and moderately affected patients in the hope of attracting attention to the need for research into severe ME. In the Journal Greg Crowhurst has provided a nursing model for severe ME and Sue Pearkes has contributed an article to increase understanding of the issues faced by wheelchair users – a very interesting and different perspective which ought to be read by those who are responsible for providing management strategies for people with ME. The lack of proper attention given to severely affected people with ME is highlighted by our new book project – Lost Voices - a book developed over the last year and using the power of pictures to supplement the moving stories of people with ME who have been left on the medical scrapheap. Lost Voices encapsulates the tragedy of this illness and the way in which people with ME are left to deal with this illness by themselves with no hope of a future. We welcome in this Journal articles from distinguished experts on ME/CFS who have presented at our international ME/CFS conferences. Dr Leonard Jason has kindly submitted a paper examining differences between blood and non-blood relatives in five illnesses, including ME/CFS. The findings show genetic and environmental factors are associated with ME/CFS. Research into diagnosing and treating ME/CFS needs to ensure that proper sub groups are being used. In his Letter from America Dr Martin Lerner addresses concerns among ME/CFS physicians endeavouring to help patients. Invest in ME (Charity Nr. 1114035) Dr Bruce Carruthers has provided a very thought provoking and thorough insight into the way researchers and clinicians should work. And so to NICE. If anyone had any doubts about the inappropriateness of the NICE Guidelines for ME/CFS then we have articles in the Journal which simply show why NICE have again failed the people they are meant to serve and why their guidelines are plainly unfit. We have translated an article from the Norwegian ME Association which clearly shows the failings in the NICE guidelines. It is a sad fact that some European healthcare services are under the impression that adoption of the UK NICE Guidelines for ME/CFS would be a sensible approach and could save money. This impression is false and will lead to neither appropriate nor economical services being supplied. NICE ignored the data which existed regarding ME/CFS in favour of a one-size fits all package of rehashed psychiatric paradigms – the same paradigms which have been promoted by the government, MRC and psychiatrists for years and which have not only done damage to people with ME but also completely failed in their supposed intent. Patients bringing legal actions - familiar territory for NICE - an indication of an organisation which is out of step with patients’ needs. NICE needs to ensure it stays current in its knowledge regarding ME, just as front-line doctors and other healthcare staff need the same currency to perform adequately any work related to people with ME. Hopefully the Journal of IiME will help in some small way to keep this currency in tact. We hope the New Year will begin with the NICE guidelines for ME being consigned to the shredder – a fate, unfortunately, which they thoroughly deserve. Invest in ME look forward to the New Year where we have a new book, a new European organisation campaigning for people with ME and a new international ME/CFS conference. All at IiME wish our readers a Happy Christmas and a cure for the New Year. Page 3/74

Journal of IiME Volume 2 Issue 2 ME/CFS and Family Medical History Family Illnesses Among People with ME/CFS: Blood Versus Non-Blood Relatives By Mary Gloria C. Njoku, Leonard A. Jason, Lindsay DiPasquale, Center for Community Research, DePaul University Acknowledgements: Correspondence should be addressed to Leonard A. Jason, Ph.D., Director, Center for Centers #3100, Dietzgen #3100, LPC, 990 W. Fullerton Avenue, Chicago, IL 60614. The authors appreciate the funding provided by NIAID (grant number AI 49720). ABSTRACT Most research examining the family history of persons with ME/CFS have primarily investigated differences between individuals with ME/CFS and control groups without the illness. Research examining differences between blood and nonblood relatives might contribute to understanding genetic and environmental etiologic factors. The current study investigated the occurrence of five illnesses (i.e., diabetes, Lupus, Multiple Sclerosis, Fibromyalgia and ME/CFS) among blood and nonblood relatives of individuals with ME/CFS. Family history of medical illness was obtained from self report data completed by participants. We determined the number of participants reporting a family history of diabetes, Lupus, Fibromyalgia, Multiple Sclerosis, and ME/CFS between the bloodrelated family members and non-blood-related family members of participants with ME/CFS. There was a greater prevalence of diabetes, Lupus, Fibromyalgia and ME/CFS among blood relatives than non-blood relatives. The findings of this study suggest that both genetic and environmental factors are associated with ME/CFS. Keywords: Family Histories, Autoimmune; endocrine; ME/CFS. www.investinme.org Professor Leonard Jason Professor of Clin. & Community Psychology, Director, Center for Community Research, DePaul University, Chicago Dr. Leonard Jason, Ph.D., is among the most prolific of all CFIDS researchers. For more than a decade, Dr. Jason and his team at DePaul University’s Centre for Community Research have worked to define the scope and impact of CFS/ME worldwide. Professor Jason presented at the IiME International ME/CFS Conference 2008 in London. Research on the etiology of ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) suggests that endocrinological factors may influence the development of this illness (Friedberg & Jason, 1998). Endocrine abnormalities such as thyroid dysfunctions and low functioning of the hypothalamic-pituitary-adrenal axis have been linked to the etiology of ME/CFS (Addington, 2000; Demitrack et al., 1991). Other studies have found associations between ME/CFS and Invest in ME (Charity Nr. 1114035) (continued on page 5) Page 4/74 Journal of IiME Volume 2 Issue 2 www.investinme.org Family Illnesses Among People with ME/CFS: Blood Versus Non-Blood Relatives (continued) immune system low-level activation, abnormalities in T-cells, reduced natural killer cells activities and IgG1/IgG3 deficiencies (Bates et al., 1995; Buchwald et al., 1992; Jason, Torres-Harding et al., 2007; Patarca-Montero et al., 2000). Findings in neurological studies have suggested that impaired autonomic nervous system functioning may impact the development of ME/CFS (Freeman & Komaroff, 1997; Pagani & Lucini, 1999). Unfortunately, there is a lack of consistency in findings from different studies (Torres-Harding et al., 2005). Family studies of persons with ME/CFS have examined endocrinological, immunological, and neurological associations with ME/CFS. Endicott (1999) assessed the family histories of 45 psychiatric patients diagnosed with ME/CFS in comparison to 90 psychiatric patients without the condition and 45 randomly chosen patients. The results indicated a higher prevalence of cancer, autoimmune disorders, and ME/CFS related conditions among parents of those with ME/CFS and no differences in psychiatric disorder history (Endicott, 1999). In another family history study of persons with ME/CFS, Walsh, Zainal, Middleton, and Paykel (2001) compared 25 persons with ME/CFS to a matched control group of 36 participants who had inflammatory bowel disease, Crohn’s disease or ulcerative colitis. The findings indicated that persons with ME/CFS were more likely to have a family history of chronic fatigue and ME/CFS than the control group. Endocrine system dysregulations have also been noted in family history of persons with ME/CFS. Torres-Harding, Jason and Turkoglu (2005) examined family medical histories of people with ME/CFS and found that 50 percent of people with ME/CFS had a relative with an endocrine/metabolic illness compared to only 28 percent of the non-ME/CFS group. The illnesses indicated were diabetes/diabetes mellitus, thyroid-related conditions and grave’s disease (Torres-Harding et al., 2005), with diabetes/diabetes mellitus being the most frequently reported illness. As an endocrine/metabolic disorder, diabetes Invest in ME (Charity Nr. 1114035) interferes with the body’s process of digesting food for both growth and energy. The most recent statistics indicate that 8 percent of the U.S. population have been diagnosed with diabetes (American Diabetes Association, 2008). Examining the family history of individuals with ME/CFS may assist in determining the etiology or risk factors associated with ME/CFS. A combination of genetic and environmental factors may be associated with ME/CFS. A study of 124 monozygotic and dizygotic twins suggested that both genetic and environmental components influence the onset of fatigue (Hickie et al., 1999). A particular genetic component was found to predict fatigue and increased immune responsiveness, whereas an environmental component predicted fatigue and decreased immune responsiveness. Most family history studies reviewed above have compared individuals with ME/CFS to a control group without ME/CFS. The current study investigated the family history among blood and non-blood relatives. The occurrence of diabetes, Lupus, Multiple Sclerosis, Fibromyalgia and ME/CFS among blood and non-blood relatives of persons with ME/CFS was examined. It was hypothesizedthat family history of these illnesses would be higher in blood relatives than non-blood relative. Method Participant Recruitment. Study participants were derived from a larger treatment trial investigating the effectiveness of non-pharmacologic interventions for individuals with ME/CFS (Jason et al., 2007). Participants were recruited from a variety of sources, including physician referrals. Information about the non-pharmacologic treatment trial study was disseminated to medical colleagues through mailings and phone communication. In addition, study announcements for new participants were placed in local newspapers and recruitment offers were made at local (continued on page 6) Page 5/74

Journal of IiME Volume 2 Issue 2 www.investinme.org Family Illnesses Among People with ME/CFS: Blood Versus Non-Blood Relatives (continued) ME/CFS support group meetings. These efforts were continued throughout the study period until the target enrollment numbers were achieved. One hundred and fourteen individuals were recruited. Of the 114 individuals, 46% were referred by physicians, 34% were recruited by media (newspapers, TV, radio, etc.), and 20% stemmed from other sources (e.g., heard about the study from a friend, family member, person in the study, etc.). Twenty-four additional individuals who were screened were excluded due to a variety of reasons (i.e., lifelong fatigue, less than 4 Fukuda symptoms, BMI > 45, melancholic depression or bipolar depression, alcohol or substance abuse disorder, autoimmune thyroiditis, cancer, lupus, rheumatoid arthritis). Initial Screening. All participants were required to be at least 18 years of age, not pregnant, able to read and speak English, and considered to be physically capable of attending the scheduled sessions. Bedridden and wheelchair bound patients were excluded due to the practical difficulties of making appointments. Referrals to local physicians who treat ME/CFS and to support groups were offered to these individuals. After a consent form was filled out, prospective participants were initially screened by the third author, using a structured questionnaire. Because ME/CFS is a diagnosis of exclusion, prospective participants were screened for identifiable psychiatric and medical conditions that may explain ME/CFS-like symptoms. These measures were completed at DePaul University and took approximately two hours. After the initial interview was completed, the patients’ information was reviewed to ensure that they met all eligibility requirements. If found to be eligible for the study, all participants attended a medical appointment with the study physician in order to confirm the diagnosis of ME/CFS. After confirmation that the individual fully met the criteria for ME/CFS according to the Fukuda Invest in ME (Charity Nr. 1114035) et al. (1994) case definition, individuals completed a battery of baseline measures (described below). They were also assigned randomly to one of four treatment conditions, and completed measures at three follow-up testing periods. However, only the data obtained at baseline was considered in the current investigation. Measures The ME/CFS Questionnaire. This screening scale was initially validated by Jason et al. (2007). Hawk, Jason, and TorresHarding (2007) recently revised this ME/CFS Questionnaire, and administered the questionnaire to three groups (those with ME/CFS, Major Depressive Disorder, and healthy controls). The revised instrument, which was used in the present study, evidences good test-retest reliability and has good sensitivity and specificity (Hawk et al., 2007). This scale was used to collect demographic, health status, medication usage, and symptom data, and it used thedefinitional symptoms of ME/CFS (Fukuda et al., 1994). For each Fukuda et al. (1994) case definition symptom, rate the intensity of each symptom they endorsed on a scale of 0 to 100, where 0 = no problem and 100 = the worst problem possible. The mode of illness onset was derived from an item on this measure. Illness onset duration of one month defined the sudden illness onset group while onset duration of longer than one month signified gradual illness onset. Medical Examination: The physician screening evaluation included a general and neurological physical examination. Laboratory tests in the battery were the minimum necessary to rule out other illnesses (Fukuda et al., 1994). Laboratory tests included a chemistry screen (which assesses liver, renal, and thyroid functioning), complete blood count with differential and platelet count, erythrocyte sedimentation rate, arthritic profile (which includes (continued on page 7) Page 6/74 Journal of IiME Volume 2 Issue 2 www.investinme.org Family Illnesses Among People with ME/CFS: Blood Versus Non-Blood Relatives (continued) rheumatoid factor and antinuclear antibody), hepatitis B, Lyme disease screen, HIV screen and urinalysis. A tuberculin skin test was also performed. If the TB skin test was positive, a follow-up chest x-ray was conducted to rule out tuberculosis. The project physician performed a detailed medical examination to detect evidence of diffuse adenopathy, hepatosplenomegaly, synovitis, neuropathy, myopathy, cardiac or pulmonary dysfunction. This medical examination was used to confirm the diagnosis of ME/CFS, according to the Fukuda et al. (1994) criteria and to rule out exclusionary medical conditions. Family history of illness: Family history of medical illness was obtained from self report data completed by participants. Participants were asked: "have any of your relatives been diagnosed with the following medical conditions?” Medical conditions included diabetes, Lupus, Multiple Sclerosis, Fibromyalgia, and ME/CFS. The participants were asked to report on these conditions for both blood (i.e., biological mother, father, grandparents, sibling, children, other) and non-blood relatives (i.e., spouse, stepparent/primary care giver, adopted children and other). Seventeen possible blood relatives include: mother, father, daughter, son, brother, sister, aunt, uncle, grand father, grand mother, great grand father, great grand mother, great aunt, great uncle, nephew, niece, and cousin. Seventeen possible non-blood relatives include: spouse, mother in-law, father in-law, adoptive mother, adoptive father, adopted son, adopted daughter, step-mother, step-father, stepdaughter, step-son, step-brother, step-sister, sister in-law, brother in-law, grand father inlaw, and grand mother in-law. We computed the number of participants reporting a family history of each illness. Statistical Analyses The occurrence of each medical illness (i.e., diabetes, lupus, Fibromyalgia, Multiple Invest in ME (Charity Nr. 1114035) Sclerosis, and CFS) between the bloodrelated family members and non-bloodrelated family members of these participants with ME/CFS was examined with McNemar tests. The effect size was computed using a procedure described by Green and Salkind (2003) for the McNemar Test. The difference in the proportions of participants who fell into the two family relative types was computed for each illness to obtain the effect size index. Cohen’s (1988) guidelines for interpreting effect size; 0.01 = small effect, 0.06 = moderate effect and 0.14 = large effect, was used to estimate the strength of the effect sizes. Results The McNemar analyses indicated significant higher percentages of diabetes, Lupus, Fibromyalgia and ME/CFS among blood than non-blood relatives (see Table 1). Of the total of 114 participants, 42.1% (N = 48) reported that they had blood-related family members who had diabetes, whereas 4.4% (N = 5) reported having non-blood family members with diabetes ( p < .01 with an effect size index of 0.38). A person could have more than one family member of non-family member with diabetes, and for the blood relatives, there were a total of 75 cases of diabetes, whereas there were a total of only 5 cases for non-blood relatives. Among the 48 individuals with ME/CFS who had a blood relative with diabetes, 15 (31.3%) indicated that they had 2 or more blood relatives with diabetes (none of the non-blood relatives had 2 or more relatives). Most cases of diabetes occurred for parents (especially the father), with fewer cases among siblings, and with only one report of a child with diabetes. Among the 114 participants who had diagnosed ME/CFS, one reported having diabetes and two reported having borderline diabetes. The individual with diabetes had a mother with diabetes, but the two participants who reported borderline (continued on page 8) Page 7/74

Journal of IiME Volume 2 Issue 2 www.investinme.org Family Illnesses Among People with ME/CFS: Blood Versus Non-Blood Relatives (continued) Table 1 Family History of Medical Illness among Blood vs. Non-blood relatives of Persons with ME/CFS History Blood Relative N (%) Diabetes Lupus MS Fibromyalgia CFS 48 (42.1%) 8 (7.0%) 5 (4.4%) 17 (14.9%) 6 (5.3%) ** indicates significant at .00 level * indicates significant at .05 level diabetes did not have familial history of diabetes. Examining the occurrence of Lupus, 7.0% (N = 8) of the participants indicated having bloodrelated family members who have Lupus as compared to .9% (N =1) for non-blood family members (p < .05, an effect size index of .06). Regarding Fibromyalgia, 14.9% (N = 17) of the participants indicated that they have blood relatives with this illness whereas 2.6% (N = 3) reported having a non-blood relative with Fibromyalgia. (p < .01, with an effect size index of .12). Approximately, 5.3% (N = 6) of the participants reported having blood relatives with ME/CFS whereas none were indicated for non-blood relatives (p < .05 with an effect size index of .05). For Multiple Sclerosis, no significant differences occurred between those with blood relatives (4.4%, N = 5) and those with non-blood relative (.9%, N = 1). Invest in ME (Charity Nr. 1114035) Discussion A higher percentage of diabetes, Lupus, Fibromyalgia and ME/CFS were reported among blood relatives than non-blood relatives of people with ME/CFS. The largest difference was found for diabetes, suggesting that a familial predisposition to endocrine system impairment may contribute to the development of ME/CFS. Similar findings emerged elsewhere (Torres-Harding et al., 2005), and these studies might represent the influence of both genetic and environmental factors. We did not find a high percentage of the participants with ME/CFS to have diabetes, as only one participant had diabetes and two reported borderline diabetes. Certainly, it is important to follow-up these individuals to determine whether more people with ME/CFS develop diabetes over time. (continued on page 9) Page 8/74 Non-blood Relative N (%) 5 (4.4%) 1 (0.9%) 1 (0.9%) 3 (2.6%) 0 (0.0%) Significance ** * ** * Journal of IiME Volume 2 Issue 2 www.investinme.org Family Illnesses Among People with ME/CFS: Blood Versus Non-Blood Relatives (continued) Endicott (1999) reported a higher rate of autoimmune disorders in parents of persons with ME/CFS whereas Torres-Harding et al. (2005) did not find any differences in familial autoimmune vulnerabilities among persons with ME/CFS and a control group. In the current study, we examined two autoimmune diseases: Lupus and Multiple Sclerosis. Whereas a significant difference was found for Lupus, there were no significant differences in the familial history of Multiple Sclerosis between blood relatives and nonblood relatives. Low power and small sample sizes might have been the reasons for not being able to detect statistical differences for Multiple Sclerosis. Certainly, there is a need for larger samples to determine if these findings are replicated by other investigators. Both Endicott (1999) and Walsh et al. (2001) found that persons with ME/CFS were more likely to report chronic fatigue-like illnesses than control groups. In contrast, TorresHarding et al. (2005) found no significant differences in family background for these illnesses. In the present study, there were more familial reports of ME/CFS for blood relatives than non-blood relatives indicating interesting familial links predisposing individuals toward the development of ME/CFS. Many studies have documented that Fibromyalgia tend to co-occur with ME/CFS (Brown & Jason, 2007; Jason et al., 2000; Jason et al., 2001) but little is known about familial history of Fibromyalgia. The current study found significantly higher rates of familial Fibromyalgia history among blood relatives than non-blood relatives suggesting other predisposing factors in the development of ME/CFS. The current study was limited by several factors, including the assessment of only five familial illness histories. It is possible that there may be other illnesses that were not assessed in this study. In addition, recall bias tends to impact the self report data, and it is certainly possibly that individuals tend to recall illnesses of blood relatives more than non-blood Invest in ME (Charity Nr. 1114035) relatives’ illnesses. In addition, this study did not include reports of the demographic information of the relatives, which could have helped to examine other possible sociodemographic factors. The lack of a matched control group by age and race is another limitation of this study. The results may have been impacted by the lack of equal number of blood and non-blood relatives. It is unclear whether people with ME/CFS have more blood or non-blood relatives, so it is at least possible that the results were influenced by this finding. The most serious potential confound in this study was that it could be argued that there are more blood relatives than non-blood relatives. Yet the findings, particularly for diabetes, would even take this into account. If 8% of the population has diabetes (American Diabetes Association, 2008), than among the 114 people in the sample with ME/CFS, there would be 228 parents, and about 18 expected cases of diabetes among these 228 parents. However, among the fathers and mothers of the sample, there were 34 cases of diabetes (and all of these cases came from blood relatives), suggesting a rate more than double what would have been expected, which would have been 18. In addition, if one were to take all cases of non-blood relatives, there were only 5 cases of diabetes. In contrast, there were 75 cases for those with blood relatives. This difference is large, but one might still question whether there were more biological relatives than nonbiological relatives. This concern could also be addressed if one were to limit the number of biological relatives for each person with ME/CFS. For example, if one were to just focus on one type of blood relative, the father of the person with ME/CFS, and compare the 114 fathers of the people with ME/CFS to all the non-blood relatives of the 114 people with ME/CFS, there certainly would be more people in the non-blood group than the blood group. Even though in this comparison there were more non-blood relatives, we only (continued on page 10) Page 9/74

Journal of IiME Volume 2 Issue 2 www.investinme.org Family Illnesses Among People with ME/CFS: Blood Versus Non-Blood Relatives (continued) found 5 total cases of diabetes for all nonblood relatives, whereas for the fathers of people with ME/CFS, there were 20 cases. These findings suggest that at least for diabetes, the outcomes are not likely due to there being more blood relatives than nonblood relatives. Furthermore, one could argue that a person may have more non-blood relatives than blood relatives. According to the United States Census Bureau (2000), the average family size in the United States is 3.14. Using this statistic, after four generations of two parents having one child, a fourth generation person would have 14 blood relatives. These 14 blood relatives are the person’s: 8 great grandparents, 4 grandparents, mother and father. However, when this individual marries their spouse, assuming their spouse is also a fourth generation person from one child families, this individual will gain 15 non-blood relatives. These 15 non-blood relatives include their spouse, and their spouse’s 8 great grandparents, 4 grandparents, and 2 parents. Therefore, it is at least conceivable that there might be as many non-blood relatives, if not more, than blood relatives. In general, the findings of this study found that family members who are related by blood have several medical illnesses at higher rates than those who are non-blood related. Certainly, the findings are strongest for diabetes, and it is always possible that recall bias influenced the results. However, the robust nature of the outcomes indicates this is an area worthy of future investigations, and having medical work-ups of both blood and non-blood relatives would strengthen research. There are policy implications of this work, for if individuals with ME/CFS do have blood relatives with more medical illnesses, it is possible that both genetic and environmental factors need to be considered when understanding the etiology of this illness and when providing treatment for those with this illness. Invest in ME (Charity Nr. 1114035) References Addington, J.S. (2000), 'Chronic fatigue syndrome: A dysfunction of the hypothalamic-pituitary-adrenal axis. Journal of Chronic Fatigue Syndrome, 7, 2, 63-73. American Diabetes Association. (2008). Diabetes Statistics. Retrieved June 26, 2008, from www.diabetes.org/diabetes-statistics.jsp Bates, D.W., Buchwald, D., Lee, J., Kith, P., Doolittle, T., Rutherford, C., Churchill, W.H., Schur, P.H., Wener, M., Wybenga, D., Winkelman, J. & Komaroff, A.L. (1995), Clinical laboratory test findings in patients with chronic fatigue syndrome. Archives of Internal Medicine, 155, 1, 97-103. Brown, M.M. & Jason, L.A. (2007). Functioning in individuals with chronic fatigue syndrome: Increased impairment with co-occurring multiple chemical sensitivity and fibromyalgia. Dynamic Medicine, 6, 6 doi:10.1186/14765918-6-6. Buchwald, D., Cheney, P.R., Peterson, D.L., Henry, B., Wormsley, S.B., Geiger, A., Ablashi, D.V., Salahuddin, S.Z., Saxinger, C., Biddle, R., Kikinis, R., Jolesz, F.A., Folks, T., Balachandran, N., Peter, J.B., Gallo, R.C. & Komaroff, A.L. (1992). A chronic illness characterized by fatigue, neurologic and immunological disorders, and active Human Herpesvirus Type-6 infection. Annals of Internal Medicine, 116, 2, 103-113. Cohen, J. (1988), Statistical Power Analysis for the Behavioral Sciences, Hillsdale, NJ Erlbaum. Demitrack, M.A., Dale, J.K., Straus, S.E., Laue, L., Listwak, S.J., Kruesi, M.J.P., Chrousos, G.P. & Gold, P.W. (1991). Evidence for impaired activation of the hypothalamic-pituitaryadrenal axis in patients with Chronic Fatigue Syndrome, Journal of Clinical Endocrinology and Metabolism, 73, 6, 1224-1234. Endicott, N. (1999). Chronic fatigue syndrome in private practice psychiatry: Family history of physical and mental health, Journal of Psychosomatic Research, 47, 4, 343-54. (continued on page 11) Page 10/74 Journal of IiME Volume 2 Issue 2 www.investinme.org Family Illnesses Among People with ME/CFS: Blood Versus Non-Blood Relatives (continued) Freeman, R. & Komaroff, A.L. (1997). Does the chronic fatigue syndrome involve the autonomic nervous system? The American Journal of Medicine, 102, 4, 357-64. Friedberg, F. & Jason, L.A. (1998). Understanding chronic fatigue syndrome: An empirical guide to assessment and treatment, Washington, DC, US, American Psychological Association. Fukuda, K., Strauss, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G. & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study, Annals of Internal Medicine, 121, 953-959. Green, S.B. & Salkind, N.J. (2003), Using SPSS for Windows and macintosh: Analyzing and understanding data (3rd Edition), New Jersey, Prentice Hall. Hawk, C., Jason, L. & Torres-Harding, S. (2007). Reliability of a chronic fatigue syndrome questionnaire, Journal of Chronic Fatigue Syndrome, 13, 4, 41-66. National Institute of Health (2005). National Diabetes Statistics. Hickie, I., Bennett, B., Lloyd, A., Heath, A. & Martin, N. (1999). Complex genetic and environmental relationships between psychological distress, fatigue, and immune functioning: A twin study. Psychological Medicine, 29, 269-77. Jason, L.A., Ropacki, M.T., Santoro, N.B., Richman, J.A., Heatherly, W., Taylor, R., Ferrari, J.R., Haney-Davis, T.M., Rademaker, A., Dupuis, J.E., Golding, J., Plioplys, A.V. & Plioplys, S. (1997). A screening instrument for chronic fatigue syndrome: Reliability and validity, Journal of Chronic Fatigue Syndrome, 3, 1, 39-59. Jason, L.A., Taylor, R.R. & Kennedy, B.A. (2000). Chronic fatigue syndrome, Fibromyalgia, and Multiple Chemical Sensitivities in a community-based sample of persons with chronic fatigue syndrome-like symptoms. Psychosomatic Medicine, 62, 655-663. Invest in ME (Charity Nr. 1114035) Jason, L.A., Taylor, R.R., Kennedy, C.L., Song, S., Johnson, D. & Torres, S. (2001). Chronic fatigue syndrome: comorbidity with fibromyalgia and psychiatric illness. Medicine & Psychiatry, 4, 29-34. Jason, L.A., Torres-Harding, S., Friedberg, F., Corradi, K., Njoku, M.G., Donalek, J., Reynolds, N., Brown, M., Weitner, B.B., Rademaker, A. & Papernik, M. (2007). Non-pharmacologic interventions for CFS: A randomized trial, Journal of Clinical Psychology in Medical Settings, 14, 275-296. Jason, L.A., Torres-Harding, S., Maher, K., Reynolds, N., Brown, M., Sorenson, M., Donalek, J., Corradi, K., Fletcher, M.A. & Lu, T. (2007). Baseline cortisol levels predict treatment outcomes in CFS nonpharmacologic clinical trial. Journal of Chronic Fatigue Syndrome. 14, 39-59. Pagani, M. & Lucini, D. (1999). Chronic fatigue syndrome: A hypothesis focusing on the autonomic nervous system. Clinical Science, 96, 1, 117-25. Patarca-Montero, R., Mark, T., Fletcher, M.A. & Klimas, N.G. (2000). Immunology of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 6, 3/4, 69-107. Torres-Harding, S.R., Jason, L.A. & Turkoglu, O.D. (2005). Family medical history of persons with chronic fatigue syndrome, Journal of Chronic Fatigue Syndrome, 12, 25-35. United States Census Bureau. (2000). Census 2000: Table DP-1, Profile of General Demographic Characteristics. Retrieved June 26, 2008 from www.census.gov/prod/cen2000/dp1/2kh00.p df. Walsh, C.M., Zainal, N.Z., Middleton, S.J. & Paykel, E.S. (2001), A family history study of chronic fatigue syndrome. Psychiatric Genetics, 11, 123-8. Page 11/74

Journal of IiME Volume 2 Issue 2 www.investinme.org Letter from America A A LLeett tteerr ttoo MMyy EEnnggll ii sshh FF rr iieennddss :: B Byy DDrr .. AA.. MMaarr tt iinn LLeerrnneerr Thank you for your kindnesses to me during my visit to London to participate in your May 2008 International ME Conference. I had the unique opportunity to meet and speak personally with many of you. Thank you again. I address concerns among CFS physicians endeavoring to help our CFS patients. We all agree with criteria for the internationally accepted CFS definition. Dr Martin Lerner Today, the “gold” standard for evidencebased medicine proof of cause depends upon a trial of treatment with two similar equal number groups of patients, matched for age, time and place. One equal group receives the treatment option-in-question, and the second equal group receives a placebo. (We further know in CFS that the placebo improvement healing rate is 19%!) If the treatment group of the proposed randomized blinded trial improves in a much larger percentage, and, if this trial is repeated by a second independent group of investigator physicians, everyone would accept that the treatment in question was useful. To date “useful” CFS treatments are psychotherapy and graded exercise. (I am omitting my own studies for now.) In Europe I believe that the tentative leading cause of CFS is “CFS is a psychiatric condition, a neurosis.” Neither of these courses, graded exercise or psychotherapy with or without psychotropic medicines, leads to a normal life for the CFS patient. Dr Martin Lerner is Clinical Professor Wayne State University School of Medicine Dr Lerner is certified by the American Board of Internal Medicine and is an Infectious Disease Specialist. Dr. Lerner has published over 10 papers since 1993 on the role of subclinical myocarditis in a subset of CFS patients. He has also reported success with long courses of antiviral therapy in patients with chronic EBV and CMV infections.. Dr Lerner presented at the IiME International ME/CFS Conference in London in 2008. • An evidence-based truth according to the famous polymath, David Hume requires cause, etiology, and this requires • A) to be always followed by, • B) a necessary condition. (continued on page 13) Invest in ME (Charity Nr. 1114035) Page 12/74 Journal of IiME Volume 2 Issue 2 Letter from America A A LLeett tteerr ttoo MMyy EEnnggll ii sshh FF rr iieennddss :: (( ccoonn tt ii nnuueedd )) 1) David Hume’s theorem was met by the sputum culture isolation of the “tuberculosis” bacterium, and then, the transference of this organism to produce tuberculosis in an experimental animal. 2) Likewise, typical bacterial lobar pneumonia was cured by administration of penicillin to the sick patient with pneumonia. The conclusions are: 1) the tubercle bacillus causes tuberculosis. 2) penicillin cures lobar pneumonia. All patients with any illness, including CFS, are saddened because they, the CFS patients, in particular, are not well. This “illness-caused depression” is not unique to CFS disease. Likewise, exercise intolerance is universal in all CFS patients. CFS patients have a genetic homogeneity (Jonathan Kerr’s work, our London conference 2008): an immunologic cacophony: abnormal tilt table tests (neurohumoral reflexes): increased RNase L lymphocyte activity: and many other abnormal biological findings consistent only with a non-psychologic cause. Sadness, depression, does not cause any of these physiologic abnormalities. There is no immunologic disarray, increased RNase L in blood or elsewhere, abnormal tilt table test or uniform genetic propensity in the array of psychiatric disease. However, the sore throat, lymph node enlargement and tenderness, and overwhelming fatigue of CFS fit many of the criteria of the illness “infectious mononucleosis” which is caused by a firstepisode experience with Epstein-Barr virus, usually in young persons. Another similar appearing mononucleosis-like illness is caused Invest in ME (Charity Nr. 1114035) by cytomegalovirus. Each of these viruses cause a similar clinical appearance. In May at your International Conference, I reviewed a published (now distant sentinel study (1997) of CFS patients with elevated serum IgG antibody titers) to cytomegalovirus infection whom I treated with intravenous ganciclovir (valcyte orally was not yet available). similar studies of CFS patients with similar elevated serum antibody to Epstein-Barr virus. I treated the Epstein-Barr virus CFS patients with valtrex and repeated the valtrex study with a blinded randomized placebo controlled trial. In these pilot studies, ganciclovir was strikingly effective in cytomegalovirus CFS patients, and valtrex was similarly effective in Epstein-Barr virus CFS patients. Earlier, I had published the hypothesis (1997) of specific Epstein-Barr, cytomegalovirus or Human Herpesvirus 6 etiology, in single or multiple infections for CFS. Montoya (Stanford University 2006) later also demonstrated that valcyte was beneficial to patients with Human Herpesvirus 6 CFS. In May of 2008, I presented at your ME International CFS symposium 124 CFS patients cared-for at my CFS treatment center, 2001 – 2007. I looked for elevated serum evidence of all three viruses, Epstein-Barr virus; cytomegalovirus and Human Herpesvirus 6 in every patient. All CFS patients met International Criteria for CFS diagnosis. No known cause for their CFS illnesses could be found by all conventionally accepted methods. Some of these CFS patients had Epstein-Barr virus, but no cytomegalovirus or Human Herpesvirus 6, and conversely, for other CFS patients with cytomegalovirus infection or human herpesvirus 6 infection. The majority (approximately) 2/3 had (continued on page14) Page 13/74 www.investinme.org I reviewed with you in London two

Journal of IiME Volume 2 Issue 2 Letter from America A A LLeett tteerr ttoo MMyy EEnnggll ii sshh FF rr iieennddss :: (( ccoonn tt ii nnuueedd )) evidence of several (of the three viruses) simultaneously. I treated my patients specifically by their evidence of the specific virus, and (and this had not been done before), I treated CFS patients, regardless of how long they had been ill, carefully, for at least twelve months. this subject can be the theme of a second “Letter to My English Friends,” thank you again for inviting me to London, May 2008. I carefully followed each patient to avoid possible toxicities of both valcyte and valtrex. There was no harm to any CFS patient with these cautions. Previously, Epstein-Barr alone had been considered to be the possible cause of CFS, and trials of treatment, were limited to ONE MONTH. The result of this “then” state-of-theart evidence based trial was “no benefit, no Epstein-Barr virus cause for CFS.” With our knowledge today, this early trial, published in the New England Journal of Medicine was misconceived. CFS is a 3 herpesvirus disease! Longer treatment than one month is needed. Of my 124 CFS patients, the average duration of specific antiviral treatment was 2.9 years, and as presented to you in London, over seventy percent of my patients enjoyed sustained improvement, so that they no longer met international criteria for diagnosis of CFS. The validated metric for measuring the severity of CFS fatigue was the Energy Index Point Score (EIPS). For each average EIPS, at three month intervals, there were an average of 46 CFS patients for each of the 24 three month intervals of the 6 year study. There is a 2:1000 chance of error in these data, or 998 chances of 1000 that CFS is caused by one or several of the three herpesviruses, Epstein-Barr virus, cytomegalovirus or Human Herpesvirus 6. Sincerely yours, A. Martin Lerner With the invaluable help of the A. Martin Lerner CFS Foundation. www.investinme.org Facts About ME In the UK, patients with autoimmune features and neurological signs and symptoms are usually the most sick and as such they are excluded from studies of "CFS" or chronic fatigue undertaken by psychiatrists, so the results of UK studies from which such patients are excluded are not representative of the true situation. A particularly important piece of research in these patients has demonstrated sensitivity of the vascular endothelium to acetylcholine (a major neurotransmitter and vascular dilator) and this finding may have implications for many other cholinergic pathways (which are extensive throughout the body). (58) - from It now is evident that we have the cause and treatment for CFS. This is evidence-based cause(s) for the complex Chronic Fatigue Syndrome disease. There is also a Group B CFS disease. Perhaps, Invest in ME (Charity Nr. 1114035) WHAT IS ME? WHAT IS CFS? INFORMATION FOR CLINICIANS AND LAWYERS Marshall, Williams and Hooper http://www.investinme.org/Article020%20What%20is%20ME%20What%20is %20CFS.htm Page 14/74 Journal of IiME Volume 2 Issue 2 www.investinme.org The European ME Alliance The European ME Alliance is a collaboration of ME organisations within Europe who have the common aim of promoting biomedical research into Myalgic Encephalomyelitis (known as ME or ME/CFS) and increasing awareness of this debilitating neurological illness. The European ME Alliance (EMEA) has the following objectives – • ME is a very serious illness even in relatively mild cases. Research has found that ME-patients experience loss of function that is devastating and comparable to AIDS and late-stage cancer. To establish correct recognition of myalgic encephalomyelitis as an organic illness requiring biomedical research to treat and cure • • To establish correct diagnosis of patients To establish specialised biomedical centres for education/treatment/cures Myalgic Encephalomyelitis is defined by the World Health Organisation as a neurological illness (code WHO-ICD-10-G93.3). The varying symptoms experienced by many severe ME sufferers may include: - - post-exertional malaise and loss of muscle power with delayed and prolonged recovery - - - - - - - - - - - - general chronic weakness of limbs neurological disturbances cognitive problems such as memory loss & concentration difficulties problems with balance and fine motor control muscle pain malaise hypersensitivity sleep & temperature disturbance cardiovascular symptoms digestive disturbances visual problems vocal/muscular limitations. Invest in ME (Charity Nr. 1114035) ME has a prevalence of 0.4% of the population with many of the sufferers being children. It is the major cause for long term absence from school for children. In the UK ME is five times more prevalent than HIV/AIDS. 25% of people diagnosed with ME may be severely affected, house-bound, often bedbound, left with little help from the medical community, often made to struggle to obtain benefits and left to an uncertain and debilitating future. ME is estimated to cost European economies billions of Euros every year. ME is a multi-system illness and distinct sub groups have been identified and some treatments have been shown to be effective. To establish more comprehensive treatments and cures for these and other sub groups requires investment in biomedical research. Yet no public funding of biomedical research is currently taking place in Europe so biomedical research projects are funded solely by the private grants to individual researchers and from ME support groups and individuals. With little funding of biomedical research into ME within Europe the EMEA are hoping to attract more support for research activities and hope to convince governments to recognize the necessity for a European biomedical research strategy to cure this illness. ME needs more awareness from the public, politicians and healthcare staff. (continued on page 16) Page 15/74

Journal of IiME Volume 2 Issue 2 www.investinme.org The European ME Alliance The European ME Alliance has invited other organisations across Europe to support their objectives to change the perception of this illness and force change in government policies and accept the urgent need for biomedical research into the illness in order to establish treatments and cures for this devastating illness. Member organisations of EMEA have agreed the following principles –  Members of the European ME Alliance endorse the principles of the 2003 Canadian Consensus Document for Diagnosis and Treatment for ME/CFS.  Members of the European ME Alliance endorse the principles of the 2006 paediatric definition from Dr Leonard Jason et al.  Members of the European ME Alliance promote the fact that ME (myalgic encephalomyelitis) is a neurological illness in the World Health Organisation’s International Classification of Diseases.  Members of the European ME Alliance understand the necessity to use the composite term ME/CFS at the moment for ease of reference/standardisation.  Members of the European ME Alliance support biomedical research into establishing sub groups of ME/CFS which will lead to treatments and cures for this illness.  The European ME Alliance has, as an objective, the preparation and promotion of a common set of Invest in ME (Charity Nr. 1114035) documentation, in all languages, for Alliance use that is supplemented by local information. The founding members of the European ME Alliance are - Belgium ME-Patientenvereniging Denmark ME-NetDK Ireland Irish ME Trust Germany Fatigatio e.V. Norway Norges ME-forening Sweden Riksföreningen för MEpatienter UK Invest in ME More details will be available in the coming months on the web site at www.europeanmealliance.org or www.euro-me.org. ME Story I've been dismissed, ridiculed, had so called medical professional try to humiliate me. I've had friends and family turn away from me. I've felt alone, been alone. I've felt depression, frustration, despair and anger at the way I've been treated over many years. And I've seen how the attitude of the medical profession changes completely when one of their hallowed tests comes back with a 'positive' result. All it took for me was the great good fortune of finding one doctor who listened to her instincts, that I was genuinely physically ill, and who persevered in trying to find the cause of that illness regardless of how elusive. - Jim Page 16/74 Journal of IiME Volume 2 Issue 2 www.investinme.org Invest in ME announces the 2009 International ME/CFS Conference and continues our commitment to presenting the best knowledge, experience and research from the leading experts on ME/CFS. The conference provides an opportunity for researchers, healthcare staff, support, educational professionals, ME support groups and people with ME and the media, to hear the most relevant science, research, information and news on ME/CFS to be heard. Our 2009 conference takes place on 29th May 2009 in London. More details will be announced during the coming months so please visit our web site. Invest in ME (Charity Nr. 1114035) Contact: meconference@investinme.org. Invest in ME Energising ME Awareness and Biomedical Research Page 17/74

Journal of IiME Volume 2 Issue 2 www.investinme.org The IiME International ME/CFS Conference London 29tthh May 2009 Supported by the Welcome to London M MEE CCoonn ff ee rr eennccee CCoommmmeenn tt ss We believe it is important to provide a possibility for people within government, health departments, social services, education and the media to be able to be informed of the the status of research, treatment and information related to Myalgic Encephalomyelitis. Invest in ME offers the chance for researchers, medical practitioners, healthcare staff, people connected with, or interested in, the care of people with ME to present at the conference. We again hope to provide platforms for the following -  Epidemiology  Diagnosis  Pathology  Management and Treatment Protocols for ME  Research  Nutrition  Care The conference will again highlight the need for empirical evidence based on valid, modern and scientific diagnostic and treatment protocols. The conference will provide a chance to hear the latest news on ME from the most prominent speakers within the ME community - in ME Awareness Month 2009. Visit the conference web site home page at - http://www.investinme.org/IiME%20Conferen ce%202009/IiME%202009%20International%20 ME%20Conference%20Home.htm Invest in ME (Charity Nr. 1114035) "…thanks for organising a conference with such impressive speakers & at such reasonable cost. As a humble parent, most conferences are completely out of my price range, so was really delighted to be able to attend. I picked up lots of info & have realised that I need to do loads more h/w to really be on top of all the stuff that’s been discovered since my daughter first became ill – 10 yrs ago." – Helen “Many thanks for the wonderful conference. It was a great atmosphere and very uplifting to know of the wonderful work and people involved in helping us ME Sufferers. … It was a conference of excellence and it honoured us as well as raising us up!” – Jane “I profited so much, I learned so much, I've met so many people I haven't met before - all this was so impressive.” - Regina “I thought it was fantastic, massively informative, encouraging, inspiring, necessary. It was very powerful hearing so much material from the doctors, researchers and speakers themselves, very, very impressive. I do agree that the speakers all came across as deeply humane. As a patient there was an enormous amount of useful applicable material and info on research hot from the lab so to speak. “ – Nikki See other comments at http://www.investinme.org/International%20M E%20Conference%202007%20%20review%20feedback.htm Page 18/74 Journal of IiME Volume 2 Issue 2 www.investinme.org P Plluuss ççaa cchhaannggee,, pplluuss cc’’eesstt llaa mmêêmmee cchhoossee “ “TThhee mmoorree tthhiinnggss cchhaannggee,, tthhee mmoorree tthhiinnggss ssttaayy tthhee s saammee”” B Byy DDrr BBrruuccee CCaarr rruutthheerrss Dr Bruce Carruthers Bruce Carruthers held an internship at the Charity Hospital of Lousiana, New Orleans, residencies in the Internal Medicine at the Hospital of the University of Pensylvania, Philadelphia, research fellowships at the American Diabetes Association in Philadelphia, and at the Clinical Investigation Unit of Shaughnessy Hospital, Vancouver. He also had a fellowship of the Royal College of Physicians and Surgeons of Canada - specialising in Internal Medicine - and was a Research Scholar of the Medical Research Council of Canada. He has specialised in diabetes and metabolic disorders and continuing clinical research in cellular information processing, diabetes mellitus and metabolic problems with a special interest in chronic fatigue, chronic pain problems of soft tissue origin and health enhancement. From 1999-2003 he was the principal author for Canadian Consensus article 'Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Case Definition, Diagnostic and Treatment Protocols' which was published in Journal of Chronic Fatigue Syndrome 2003, 11: 7-115. Until the present day Dr. Carruthers has continued to follow research interest in the role of consciousness in the clinical activities of Diagnosis, Prognosis, Treatment and Prevention. He produced in 2005 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome : A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview of the Canadian Consensus Document. Dr Carruthers presented at the IiME ME/CFS Conference in 2006 in London (available on DVD from Invest in ME). Invest in ME (Charity Nr. 1114035) In the way that aphorisms have, the above saying describes a struggle between complementary attitudes towards reality that has been ongoing at least since around 500 B.C. in a disagreement between the Greek philosophers Heraclitus, who said the reality was change, and Parmenides, who said that reality was unchanging. This aphorism emphasizes that while being mutually exclusive by definition, the two approaches are both necessary in practice. The practice of medicine is guided by many aphorisms to reflect the complexity of the many complementary approaches essential to proper clinical decisions, which, while remaining mutually exclusive, are both necessary (1), including this aphorism. The practice of scientific medicine also embodies this complementary struggle- while searching for the invariant laws of nature responsible for the mistakes of nature in the form of disease and dysfunction (contranatural), it changes all the time while remaining complementary to the practice of clinical medicine which, while observing the vagaries of an individual’s anecdotal experience of disease and (continued on page 20) Page 19/74

Journal of IiME Volume 2 Issue 2 www.investinme.org P Plluuss ççaa cchhaannggee,, pplluuss cc’’eess tt llaa mmêêmmee cchhoossee ( (ccoonn tt ii nnuueedd )) dysfunction, has remained continuous throughout the time since Hippocrates, and undoubtedly before, since the essential situation has remained the same- a sick patient being tended to by a healer. At the time of Hippocrates, there were 2 adjacent medical schools in Cos and Cnidos, each of which emphasized different approaches to handling the archetypal situation of a clinical patient (Klinikos (Gk meaning bed), presumably with a physician attending to an individual non-ambulatory patient more seriously ill) (2,3). Both types of physician dealt with symptoms, but one group took the nominalist stance that is all they had to deal with (presumably based on the assumption that symptoms are a natural prelinguistic form of language), this is the stance that symptoms have no intentional reference - that is they were not about anything but themselves- and should be dealt with at that level, by “symptomatic” remedies. The opposite realist position is that symptoms tell you about disturbances in an underlying causal reality which you have to learn to interpret properly. Both schools took the distinction between appearance and reality seriously, but the Cnidians felt that the appearance was the reality (nominalist) the surface symptoms were the level to address. They analyzed symptoms as entities in themselves exhaustively, directing their therapies at what we call “symptomatic” measures rather than at any underlying cause of the symptoms. The Coans emphasized that symptoms were the surface appearances of an underlying unmanifest causal reality, towards which therapy should primarily be directed in the form of remedies and regimen to affect the humours, which names the dynamical causal forces they expected to be involved. The Cnidians emphasized a diagnostic search for static symptom clusters (what we now call syndromes) which were readily apparent to the observer, and could Invest in ME (Charity Nr. 1114035) be studied as entities in themselves as to incidence, arrangements, etc. and could be examined by what they considered to be scientific methods (presumably those of Aristotle, since Aristotle’s father was a prominent Cnidean physician, and somewhat similar to our natural history). The Coans, including Hippocrates, emphasized a method of prognosis, the real time search for evidence for less accessible underlying dynamic causal processes which they took to be causing the symptoms, (a realist position, which is also favoured by modern scientists and over which a recent war of attitudes has been fought, called the science wars (4). The realistic attitude certainly drives most research that is necessary to discover the causal network underlying ME/CFS, but given the current strategy prominent in the UK to emphasize a nominalist, at least on the surface, using a static “research” definition to discourage causally directed research and instead empiric methods to study (and also to promote and later institutionalize) nonspecific acausal therapies based on Cartesian body-mind dualism, one wonders about their motivation (see 5). Unlike the NICE strategy, the prognostic search for evidence of underlying cause in individual patients is essentially dynamical, emphasizing change in the symptom severity and configuration as evidence for change in the underlying causal network that is assumed to be underlying these surface manifestations. In this approach any changes in the surface symptoms are assumed to be due to changes in the underlying causal network, and not in the symptoms themselves. This leads to an ambiguity in the assessment of clinical results, since symptomatic remedies can mask underlying causal change, and therapy directed against the underlying cause can result in symptomatic relief as part of the therapy. Note that the evaluation of both surface symptomatic and deep causal therapies depends on a reliable estimate of (continued on page 21) Page 20/74 Journal of IiME Volume 2 Issue 2 www.investinme.org “TThhee mmoorree tthhiinnggss cchhaannggee,, tthhee mmoorree tthhiinnggss ss ttaayy tthhee ssaammee”” ( (ccoonn tt ii nnuueedd )) symptom severity and its changes over time. This struggle in attitude has also resulted in two distinctly different approaches to the significance of syndromes or clusters of symptoms, a concept first used by Sydenham in the 17th century (6,7). A statistical measurement of symptom clustering will characterize it numerically, but cannot give any immediate clues as to the cause of this clustering. The idea embedded in so-called “research definitions” of CFS/ME is to establish symptom clustering by numerical measure, but to leave the search for causes for later science to decide. But what if that does not happen? We can act on the assumption that a cause will be found or that it will not be found, or that too many will be found each of which contribute uncertain force and relevance to the individual illness depending on its type (linear, circular, immediate, delayed, permissive, helping, enabling, allowing, formal efficient, final, pragmatic, etc) with the causal network assumed to be simple linear or complex and nonlinear, but with the whole situation certainly confused and uncertain. This will leave the diagnosis of syndromes in a limbo state, suspended between those that are expected to be caused somatically, and thereby explained, and those that are expected to be somatically unexplained, thus somato-form (having the form of somatic diseases but not the causal content) or caused mentally, “ín the head” as a default assumption. This indeterminate causal state arises when one follows exclusively a Humean type of perception, the acausal presentational immediacy which defers the question of cause and, in Whitehead’s description, avoids the direct perception of “causal efficacy” (8). Hume’s strategy avoids the immediate causal question of why these immediately perceived symptoms have clustered into a syndrome until later, to be decided by science plus inference, (presumably using the prospective, controlled observations of scientific experiment), with Invest in ME (Charity Nr. 1114035) presumably more authority. However, as Montgomery has stated, working oncologists have estimated that they spend about 5% of their time using science to solve their problems in clinical judgment, and the rest doing “common-sense” (1, p 164). Aristotle already knew that science was not able to handle individual situations alone, and that is what clinical medicine is all about. While being informed by the general knowledge of science, a clinical judgment must be made using “phronesis” or practical wisdom(1,pp 3341, 9 pp57-60), which is about unique situations, more or less comparable, and comes from a different sort of knowledge that allows the first person observations of the individual patient to be extended by the second person observations of the patient/ doctor while also bringing them together to interact with the third person general knowledge of science. This last interaction requires a fourth type of explanation that has been called paradeictic or pattern matching is used to bring first person and second person observations governed by deictic coordinates into interaction with the third person knowledge of apodeixis (10). So what is this common sense? And why is it used so often, when scientific knowledge is so much better? It is because it is how we have all have learned about “how the body and the world works”, i.e. the causal efficacy of its structures, based on the direct perception of the dynamic patterns of activity continuing since our babyhood. The implicit assumption that every felt effect has a cause which can and should be sought for is known as essentialism(11). It has been used by all of us since well before we could articulate anything like a theory of realism and is also expressed in the protolanguage of pain, fatigue, sleep, attraction , avoidance, smiles, cries, sneezes, coughs, nausea, anorexia, etc. The direct (anecdotal, uncontrolled) perception of causal efficacy has been demonstrated experimentally by and indirectly by Talmy as described in 12) who has introduced the (continued on page 22) Page 21/74

Journal of IiME Volume 2 Issue 2 www.investinme.org P Plluuss ççaa cchhaannggee,, pplluuss cc’’eess tt llaa mmêêmmee cchhoossee ( (ccoonn tt ii nnuueedd )) concept of “force dynamics” by describing the many words and phrases found in naïve speech used to describe various types of causal relation which have presumably been observed directly in the “common-sense” world. Perhaps the clinicians have been using common sense methods to directly observe the causality lying beneath to explain their patients’ symptoms, such as the direct perception of causality and force when the foot contacts a rock- did the foot kick the stone or the stone hit the foot? Samuel Johnson did not have to wait for RCTs to make his decision about the reality concerning forces and hard objects which are put into play when one kicks a rock, since he knew about intentional action. This common sense direct perception of cause and effect has the advantage of being applicable to the individual person in action, not indirectly inferred from a general group of Samuel Johnsons. The former anecdotal evidence is nonconfirmable from a scientific point of view, and thus to be scorned in some quarters, but essential to the clinician who deals with individual patients. It provides the essential contextual background from which an individual patient’s symptom dynamical pattern arises to decide on what kind of cause and what is its cause, what are the effects and their severity, and whether and how these in turn become causes. Thus one can indirectly through dialogue, and directly, through examination and past experience, characterize the causal forces that lie beneath any symptom cluster, and thus become realists. Clinical admonition;- Listen to your patient. He/she is telling you the diagnosis ( ?Osler see ref 26) This ancient but ongoing clinical struggle involves 2 complementary strategies- 1/ Observing patients as individuals using dynamical, prognostic strategies to obtain reliable local knowledge directly in the local context of here and now (deictic) Invest in ME (Charity Nr. 1114035) coordinates, which are thus changing all the time, and 2/ Obtaining general and (mostly) unchanging knowledge based on invariant laws of nature, using universal unchanging coordinates (apodeictic) to make a static model with decisions based on the group results. These results are assumed to be applicable to the individual patient ( as long as he/she is not an “outlier”). The verdict of history seems to be that the Hippocratic approach has been more viable despite periodic attempts to re-instate a Cnidian approach to clinical medicine by focusing on surface symptoms and delaying or neglecting the search for underlying causes ( for recent efforts besides those of NICE see DSM strategy towards psychiatric illness, which deals with symptom clusters and not with underlying causes(13). A similar nominalist approach is seen when research definitions are used to block research instead of facilitating it, holding on to cause-deferring research definitions well beyond their time. This subverts the proper function of clinical definitions which is to facilitate the identification of underlying general and particular causes in individual patients. Properly used, the general confirmed knowledge that is obtained from science is immensely helpful, but only when it is used as an aid in making adequate clinical judgments, instead of as a substitute for this local individual anecdotal clinical knowledge. Together general scientific knowledge and local clinical knowledge complement each other if used skillfully to cover each other’s deficiencies. The Canadian definition of ME/CFS (14) considers cognitive fatigue to be a member of the “neurological/cognitive” component, necessary to the case definition. It makes a huge difference whether one regards fatigue as a decontextualized, separated entity (see 17) to be included as one member of the numerical cluster of symptoms constituting an acausal syndrome (any interactive causal (continued on page 23) Page 22/74 Journal of IiME Volume 2 Issue 2 www.investinme.org “ “TThhee mmoorree tthhiinnggss cchhaannggee,, tthhee mmoorree tthhiinnggss ss ttaayy tthhee ssaammee”” ( (ccoonn tt ii nnuueedd )) explanations to be deferred until later when we get our RCTs done a few years from now), and if one regards a syndrome as a dynamical pattern, a group of symptoms which constitute the surface manifestations of an underlying causal network or natural kind, the interactive forces of which can be directly felt implicitly even when not observed explicitly. In order to ‘see/feel’ this causal background one must not only observe just the surface manifestations but also feel the causal forces that underlies the surface. These disturbances are what the symptoms are ‘about’, their intentionality. If one separates fact. Other clinical practices have been disturbed the symptoms from what they are about by enumerating them, one decontextualises them (17), separating them from their usual causal background. Only if one observes the symptoms as they arise out of their dynamical background, can one feel this causal connection directly. Thus one must not only observe the symptoms when completed, but as they arise from the flowof- life context in a prospective temporal dynamics, headed towards the future. If these are symptoms observed only by the patient themselves, in a first person perspective, the outside observer can only learn of their causal background by questioning the patient concerning the circumstances of their emergence, maintenance, aggravation, remittance, etc., but also by empathizing with her/him as an undivided whole and questioning/relying on their description of symptoms and their context within the developing second person perspective of the doctor /patient relationship. This is prognostic and direct observation of the clinical course of illness, a dynamical observation which has been emphasized since time immemorial to be at the core of the clinical situation. It is applicable to individuals on-line as they live their lives and suffer their symptoms along with any concomitant deterioration of activities. This is not the numerical “prognosis” which is applicable to members of groups after the Invest in ME (Charity Nr. 1114035) by nominalist, static approaches to the clinical situation. These include estimation of the severity of illness as observed in real time by its impact on the life-world with its deictic, here and now, individual coordinates and not the timeless general coordinates of science or the time of pure succession required by algorithmic approaches. Without the on-line observationin-context of clinical practice one cannot see the impact of illness on a patient’s life flows, their concrete dis-ability, whatever the results obtained in situations which have been decontextualized for the sake of “objectivity”. Without prognosis it cannot directly and accurately measure the effects of therapy, nor choose preventive actions to improve both surface and deeper manifestations of their illness. Let me emphasize that while I feel that the disease title CFS/ME refers to a complex but discrete causal process which causes chronic severe, disabling dysfunction of an essential but extremely complex self-regulatory system of which we are only studying the HumptyDumpty fragments that have been opened up to become amenable to the study the linear causation within which science can identify causation. This search is well worthwhile since there is always the possibility that we can find a pragmatic cause within the complex bodily function, where a bit of biological matter such as viral nucleic acid or a vitamin-like chemical or a nutrient or a protein (e.g Ribonuclease-L) or a cascade of protein reactions, or a genomic dysfunction is responsible for the bodily dysregulation, despite its ultimate complexity. The difference between an individual event which is causally laden and occurring at a specific place in space and time and the (continued on page 24) Page 23/74

Journal of IiME Volume 2 Issue 2 www.investinme.org P Plluuss ççaa cchhaannggee,, pplluuss cc’’eess tt llaa mmêêmmee cchhoossee ( (ccoonn tt ii nnuueedd )) general term which may name it, which is abstracted and thus stripped of its direct causal attributes to become a member of a class with its own attributes, is a crucial one, a difference that makes a difference. An event has causes, but a class has relationships (25, p74 ). A living person is an event subject to a wide variety of causes over her/his lifetime and is a member of innumerable classes. The process of diagnosis consists of fitting a specific pattern of symptoms and signs exhibited by an individual patient in process, on-line into the general medical model to become a case of----, and thus a member of a class, which is abstract, off-line knowledge, a scientific model of disease. (This process has been called paradeixis (10). While one adds a large number of relationships thereby (those within the relevant disease concept of the current knowledge base), one thereby strips the case of the immediate causal relations available to it as an individual where they are felt as forces incurred in the ongoing living process she/he is immersed in. It is expected that these causal relations can be inferred as a result of controlled observations of a sufficient number of members of its class (cases of------). However the individual cannot be studied in this fashion. As previously mentioned, it has been known since Aristotle’s time that no science of individuals is possible. This is because the observations cannot be controlled by comparing them to other members of the same set under various conditions (as members of a set), but that as an individual she/he is incomparable, living in a unique situation. So, since all of us live our lives at least partly anecdotally, uniquely and incomparably and if anecdotal evidence is inherently unreliable, then how do we survive? By learning “force dynamics” (11,12,15) at a young age, so that we can compare events along the time lines of our lives along in the various kinds of causal relations we encounter enroute. We start out as babies pretty incompetent in the ways of the world (by Invest in ME (Charity Nr. 1114035) adult standards), but learn to regulate the movements of our bodies, our minds and our environments in ways reliable enough to allow most of us to live our “allotted” lifespan. We learn how each of these regions of existence “works”. This process of learning goes on throughout our lives and is refined by “experience” and also specific training and practices, by learning how to cope with many kinds of stressors, including illnesses and much more. This makes our actions more and more accurate and reliable as we gain experience before the inevitable “anecdotage” takes over. I would like to discuss three aspects of current situation regarding ME/CFS which are pertinent to what we have been discussing. 1/ Research vs. Clinical case definition. By the time he/she becomes a case, a patient has already been abstracted into a case. Research definitions of ME/CFS(16), which are there to select clusters of similar patients to facilitate research, often include as optional symptoms cognitive dysfunction and sensory overload, listed as separate entities without regard for any causal relations with other symptoms or from its background. In clinical definitions designed to facilitate the identification of ME/CFS in individual patients (14), the search for the pertinent causal background ( which is always unique) is facilitated by suggesting the connection of symptoms with various possible subsystems (pathophysiological systems that the symptom may be participating in) and by describing the various dynamical features of the symptom including on the force of interactions with other symptoms and the environment. These forces are observed directly at the commonsense level, and do not depend on whether these causal forces have been demonstrated to be explainable scientifically. They are there or they are not there. (continued on page 25) Page 24/74 Journal of IiME Volume 2 Issue 2 www.investinme.org “ “TThhee mmoorree tthhiinnggss cchhaannggee,, tthhee mmoorree tthhiinnggss ss ttaayy tthhee ssaammee”” ( (ccoonn tt ii nnuueedd )) While touring the U.K recently, I was visiting Berkeley Castle. It was full of visitors and a number of subgroups were assigned to a docent to inform us concerning all the sites, times and gory details of its historical events. Each subgroup was assigned a different route. Since Berkeley Castle is not that big, the paths of each group crossed 3-4 times during the tour. Another group had a very unhappy baby as a member who was crying most of the time, and whose noise was sometimes close, sometimes distant. I noted that the docent began to lose her ability to keep her docentic speech train coherent during the times when the crying was loud. While this may have been explainable as a normal level of interference, it became apparent that the docent’s cognitive impairment was so bad that she had to stop talking until the other group left the vicinity with each contact. After a decent interval her narrative resumedsmooth and coherent- until the next meeting with this particular noisy group, when the cognitive disturbance repeated itself. This did not happen during contact with other quieter groups. These interactive effects reappeared consistently until the end of the tour ( about 34 times). While one interruption may be explained by chance and/or other causal variables, not a consistent 4, and there was a palpable interactive causal force observable at the times of these interactions, even by myself as an outside but informed observer. It is a common symptom duplex of ME/CFS that sensory overload will aggravate what I call “cognitive fatigue”- fatigue as a dynamic event and not a constant defect. The interrelation between these 2 events (the baby crying and the cognitive fatigue), when repeated consistently, was enough for me to assign interactive causality, whatever her own knowledge was about it and the direction of causation was certain the noise caused the confusion). This type of event if noticed was felt as dynamical and not subjective (as felt by the adult and her observers) , since there Invest in ME (Charity Nr. 1114035) were no feelings of fatigue associated with the deterioration of cognitive fatigue (as far as I know since I did not ask her). The crying of the baby was steadily vociferous, and showed no apparent fatiguing during our relatively short time of observed interaction. This is one of the problems with cognitive fatigue- it has the dynamics of fatigue, but is often not accompanied by subjective feeling of fatigueunlike the fatigue accompanying musculoskeletal exertion, and may not be directly observed by the perpetrator. But it is a very specific and consistent inter-relation, often noted by the patient when she/he is asked about it, and whose causal nature is confirmed by prognostic observation- over the course of repeated interactions over time. This everyday causal relation between interior and environmental events is not often included in discussions of scientific causation. But it is very real, and does not need an RCT to confirm it. It is also important, since it is affecting her competence as a docent. The causal relationship is confirmed by its felt force and consistency over time. It is the correlation dynamics (18) that confirms the causal relevance/irrelevance of this connection between the 2 variables of a baby crying and a docent’s cognitive dysfunction. It is a causal interaction depending on the loudness of the crying and the vigor of the cognitive system involved. The point of cognitive fatigue is that it is dynamical- her mind does not work well in the presence of the disturbing variable, but is fine under many other circumstances. I would expect it to be regarded as inconsistent if the observer is looking for static entity called “loss of concentration” exclusively, since it is not always there. Perhaps the patient cannot screen out other sensations to concentrate on what she is doing, but it is important for her to identify this specific interaction, since she could prevent it in the future by avoiding the situations where it occurs. Thus it will allow her to apply a specific preventive measure that she can learn. Unfortunately this type of (continued on page 26) Page 25/74

Journal of IiME Volume 2 Issue 2 www.investinme.org P Plluuss ççaa cchhaannggee,, pplluuss cc’’eess tt llaa mmêêmmee cchhoossee ( (ccoonn tt ii nnuueedd )) causation is not usually included in descriptions of the etiology of ME/CFS since it is too “anecdotal”. Cognitive fatigue is often not picked up or is under-estimated during psychological testing because an ethical tester is supposed to throw away data obtained while the client is fatigued. This rule results in interpreting dynamical findings as inconsistencies. So here is the dilemma. A “fatigue”, which by definition is dynamic- it comes and goes- is not accounted for in an objective thought system which requires objects, which by definition are stable and unchanging, and thus ignored. In such a system entities are not objects if they are changing, and thus to be discarded. If observed in a dynamical system which is set up to observe this coming and going, the fatigue would be very real and consistent. But to see this requires a prognostic dynamical approach. In such an approach the relevant causal events are not only in the body, they are in the world, (embedded, embodied dynamics), and they may shift with changing circumstances (causal spread- 17). While such an interaction could of course be studied in the standardized environment of scientific experiments, it can also be identified and confirmed in the on-line, ‘wild’, unique, anecdotal, situation described. 2/ Observations of “kinds” of fatigue to identify sites where causal patterns change. Research into the development of mind in children has revealed that children are born “essentialists”. What does that mean? Gelman (11) has given reasons for why children are essentialists, in their ongoing attempts to understand the underlying causal structuring of the world and of their own bodies. It works by learning to identify “kinds” of thing that do this or that so that they can learn to predict their own and others’ Invest in ME (Charity Nr. 1114035) behavior. 1/ they act as if they are aware from earliest infancy that there is an appearance/reality distinction, such as we have mentioned before. They learn what experts would call “induction from property clusters” or what additional properties to expect from a given cluster, especially homeostatic clusters that work to stabilize the organism and maintain its invariance through environmental change . They learn causal determinism, with its search for hidden, nonobvious, as-yet-unknown “natural” properties that can explain cause through inherent properties or essences. They also learn to track identity over time, thus becoming dynamicists and followers of both Heraclitus and Parmenides. They learn deference to trusted experts (starting with their parents) to fill out what they do not know, (and as a corollary, to avoid the opinions of those they have learned not to trust- my addition). In exploring the feeling they later learn to call “fatigue” they learn how it is causally connected with activity (they feel fatigued after activity and restored, more energetic, after rest), and learn to expect this dynamical relation and how the feeling differs from sleepiness and weakness. They learn that there are other kinds of fatigue- that of a different flavour (malaise) that they feel with a viral infection, or the fatigue they feel if they have not had enough sleep or if they have been on a long airplane ride, again with different characteristics or ‘flavours’ which can give causal clues when felt with discrimination. This implicit knowledge about the causal relations surrounding fatigue is embedded in our experience of the varying contexts of daily life, which is a changing flow, not a static state. It is our concepts which have been abstracted from this dynamical state that are constant. In the resting state the body is felt (consciously or not) by the generalized sensation of proprioception, or self-perception, as the presence of an nonmoving body. When (continued on page 27) Page 26/74 Journal of IiME Volume 2 Issue 2 www.investinme.org “ “TThhee mmoorree tthhiinnggss cchhaannggee,, tthhee mmoorree tthhiinnggss ss ttaayy tthhee ssaammee”” ( (ccoonn tt ii nnuueedd )) active, the body is felt more acutely by the same proprioception as a moving body, moving in a variety of dynamic patterns. Selfobservation of this embodied and embedded movement, both inside and in relation to outside, is continued into the environment by the rods of peripheral vision, which are especially sensitive to movement and patterns of movement, and work faster than the complementary colour sensitive cones. Symptoms arise from this proprioceptive base as signals to modulate bodily activity in coordinatation with patterns in the immediate environment. Thus they form a coordination dynamics (18). Since proprioception is a reflexive sense, its truth conditions are of a different kind from those of the distancing senses. They are directly and reflexively felt (nondual), not as an outside observer separated from its object (dualistic). If bodily you feel fatigued, it is time to rest. If you feel energized with more potential to move, you may choose to become active. We have all learned about this causal flow and how to modulate it in relation to the environment since first becoming mobile in infancy. This learning happens semi-automatically, depending on our choice, training and circumstance. What happens if this regulatory system becomes disrupted? What if fatigue becomes “delayed”, and it becomes harder to causally connect the fatigue with the preceding activity. Fatigue does not follow activity in the expected causal rhythm, and the situation becomes confusing since there has been a change in the dynamics. “The goal posts have shifted”, as I tell my patients. A new “attractor” or pattern of activity has been formed in the language of dynamical coordination theory (18). What do we do? At first we try to ignore the fatigue and get on with the work of our life despite the feelings of fatigue by “will power” or the use of Invest in ME (Charity Nr. 1114035) stimulants. This is the King Canute strategy. What happens then? We “crash” as the fatigue gets worse. The more we try to overcome this fatigue, the worse it gets. It is this dynamical pattern change in the activity regulation system of the whole brain-body-world that we must address. It is addressed by pacingadding your consciousness into this ordinarily semi-automatic regulatory system with added regulation using self-directed, non-dual mindfulness(19) that you can begin to connect the fatigue/ activity relationship which has been dissociated. With temporal dissociation from activity , the cause of fatigue is put into turmoil. It could be caused by numerous intervening variables, as it is not work in its usual rhythms. One cannot rely on these subconscious dynamic pattern any more. One needs to intervene with the conscious mind which can re-assert the connection between activity and fatigue if it is there, or search for other answers to the problem that has been posed by consciousness (using mindfulness). Then the pacing of activity can begin, however delayed the causal connection between activity and fatigue has become. While essential for the repair of your basic activity self-regulator, this conscious symptom guided proprioceptive system must learn to discern other kinds of fatigue with varying causal backgrounds- induced by lack of sleep, by intercurrent infections, cognitive overload, exposure to too much noise, light, odours, cognitive work, circumambient noise or busyness, stress, emotional overwork, toxic exposure, etc. This all gives you clues as to what is causing your present state of fatigue. These are the interactive commonsense causal factors coming in from the environment in which it is embedded with variable temporalities. Causal variables also come from the embodied inside. The symptoms of the syndrome will disturb the basic control system depending on how interactive they are. Better regulation of the whole activity/fatigue control system will not come from learning to ignore (continued on page 28) Page 27/74

Journal of IiME Volume 2 Issue 2 www.investinme.org P Plluuss ççaa cchhaannggee,, pplluuss cc’’eess tt llaa mmêêmmee cchhoossee ( (ccoonn tt ii nnuueedd )) these signals in deference to regulation from the outside, using external rules, whether these be cognitive rules from a separated dualistic “mind” see (17) or from the outside as coercion. In either case this would have become an external control system, not a self-regulated one, and clumsy in its reaction to changing circumstances, thus less of a selfregulating system. But what you do need to do to modulate a self-organizing one is to become more mindful of your proprioceptive sensations, including your symptoms, where the observer is identical to the self-observing, self-organizing system. If internal symptoms are very interactive, they should be regarded as part of the syndrome (e.g. if a patient becomes fatigued after having a bowel movement, this interaction should be regarded as causally relevant to the fatigue if it is severe and consistent enough to contribute to disability. If general pain, gastrointestinal pain, headaches, depression or anxiety become sufficiently causally interactive, they should be included in the syndrome. The point is to try to estimate how causally interactive they are, a measure that can only be done using the dynamical methods of clinical medicine with its deictic individual coordinates of “here and now”. The ultimate cause of the disturbance is the dysregulation of a superordinate selforganizing system in its relation to its subordinate systems with both bottom-up and top down control. The ultimate cure is to reestablish proper bidirectional regulation. The dynamical difference between the delayed fatigue of ME/CFS vs. non-delayed normal fatigue implies a distinct change in causal network which underlies this change, and indicates that a causally relevant shift in the “kind” of fatigue is happening. It is not just a more severe variety of the normal kinds of fatigue. It is a distinctly different kind of fatigue, to be classified under a different taxon (20), thus implying a distinctly different Invest in ME (Charity Nr. 1114035) causal pattern lying beneath its surface manifestations. The features of this dynamical shift, if paid attention to, can thus orient research to find the relevant cause(s) responsible for this shift in dynamic patterns without having to render the whole causal system explicit (which may be impossible, or complex enough to keep researchers busy for many years ahead). If one continues to ignore this search for dynamically different kinds of fatigue by using static decontextualized models of “fatigue” conceived as a static entity, this type of research will continue to be blocked. 3/ ME/CFS “fatigue” as embedded in a system which regulates the basic complements of activity and rest, and its comparison with the regulation of blood glucose level in patients with “brittle” diabetes mellitus. Since “fatigue” by being considered as a nominal entity in isolation from what the fatigue is about- an altered bodily state- it will continue to be regarded as “subjective” feeling and thus not as an integral part of a regulatory system which must function orthogonally to the Cartesian type of subject/object split which is a prerequisite for our current scientific thinking to work. Fatigue is embodied, not floating around the subjective mind in an endless chain of cognitions. I will use the framework for a regulatory system first suggested by Ashby, a founding father of the dynamical systems approach (22). His model of the brain is that of a homeostat, a self-regulator. A self-regulator keeps “essential variables” within tolerable limits (unchanging) by changing itself in response to changes in the environment. The self-regulator is the part of the organism that changes in order to keep the essential variables the same. The essential variables must be kept the same if the whole organism is to survive. The changing part, the regulatory part of the system is designed to change on demand. The major parts of the organism that (continued on page 29) Page 28/74 Journal of IiME Volume 2 Issue 2 www.investinme.org “ “TThhee mmoorree tthhiinnggss cchhaannggee,, tthhee mmoorree tthhiinnggss ss ttaayy tthhee ssaammee”” ( (ccoonn tt ii nnuueedd )) are allowed to vary in this way are the brain, the immune system and the endocrine system. If these systems are changing appropriately, the whole organism is healthy. Disorder or disease happens when their changes are not appropriate. Ample research has shown that the major selfregulatory systems are involved in the causation of ME/CFS (brain plus CNS and ANS, endocrine and immune systems). Additional research has indicated that the fluid and energy transport system, including the circulatory system and mitochondrial transport may also be seriously involved. What we don’t know is how this all fits together and works as a self-regulatory system. It is only in the intact patient that we can observe or infer their various dysfunctions. We do not know if a single glitch can upset a lot of biochemistry (e.g. B12 deficiency, aberrant ribonuclease-L molecules, cytokine production, etc) with cure by replacement. But the whole control system that we must focus on is that regulating physical activity/rest, including the subjective feeling of fatigue as one of its essential parts. Dynamical disturbances of other sorts will be causally coordinated with other kinds of fatigue that may be implicated- cognitive fatigue, stress fatigue, immune fatigue, cardiac muscle fatigue, mitochondrial fatigue, acceleration fatigue, etc. While the overall effect of pathophysiology is inappropriate fatigue in a system designed to self-regulate overall activity in a dynamical and holistic system, any glitches responsible for this fatigue may be quite specific. Unfortunately the currently approved treatments for this condition in the U.K. (CBT and GET), are attempting to adjust symptoms using an external site of control. Thus these approaches ignore the crucial self-organizing aspect of any biological control system. I would like to compare this situation with that of the system regulating blood glucose level, Invest in ME (Charity Nr. 1114035) one implicated in the genesis of diabetes mellitus. Many patients with diabetes do not have a serious control problem. Their blood sugars may be too high, but the level is stable or changes slightly and gently. The diabetics who have a control problem are those that are designated as “brittle” because their blood sugars go up and down violently. Before the discovery of the hormonal protein insulin, the more severe diabetics mostly ran the higher blood glucose levels, and many died of diabetic acidosis. Pre-insulin physicians tried to regulate the glucose level using diet and fluid manipulations. (23) With the advent of insulin therapy, most diabetics did well, but a few remained “brittle” because they were sensitive to the insulin so that their blood sugars fluctuated up and down between tolerably high and low blood glucose levels. Because of the effectiveness of insulin therapy, new disease of hypoglycemia or low blood sugar became prominent. The biochemical system underlying this glucose control became more and more complex as problems of insulin resistance, anti-insulin hormones such as glucagon and cortisol were added to the control system as did allergic hypersensitivity to foreign insulin and contaminants of human insulin. With the new iatrogenic disease of hypoglycemia, a new system of anti-insulin hormones were engaged as the adrenalin release that a sudden drop in blood sugar caused became more important. Experienced diabetics could often consciously discern where their blood sugar was, by how there body felt when sugar was up, down, falling slowly or fast, etc. but this estimate was only rough. These estimates were originally vague but became more precise with experience. These symptoms depended not so much on the level of glucose, but on its rate of fall. Because of all these complexities, it has been a great boon for this type of diabetic to be able to measure glucose levels “on-line” as it has improved their ability to regulate their blood sugars immensely. However they have to fall (continued on page 30) Page 29/74

Journal of IiME Volume 2 Issue 2 www.investinme.org P Plluuss ççaa cchhaannggee,, pplluuss cc’’eess tt llaa mmêêmmee cchhoossee ( (ccoonn tt ii nnuueedd )) back on bodily feelings when blood testing is not always available. It is obviously impossible to regulate these patients from afar (external site of control). These patients whether using blood sugar levels or their own internal feelings have to learn to self-regulate, and on a dynamical basis. Of all the potential variables in this complex control system, only 3 are essential- the diet, the dose and timing of insulin, and the exercise must be timed and varied on a frequent basis. The diet raises the blood sugar, depending on its type and amount and the exercise, (again depending on type and amount) and insulin lower it. Osler’s 1914 textbook in internal medicine does not suggest using exercise as a regulator, since it wasn’t yet a crucial control variable, but prescribes “modest exercise” (23). Timing and balancing these variables is an on-line dynamical process. While many other variables can intervene- e.g. rises in the anti-insulin hormones due to stress, infection and anxiety, inability to control due to cognitive problems secondary to hypoglycemia, etc, they are more like external parameters that affect the whole state of the control system than like variables within the system. Emotional problem are common, often during adolescence, when young diabetics during their rebellious adolescent stage will often try to ignore the illness as well as resist such intrusive and bothersome therapy. But it is obvious to all that these emotional disturbances do not cause diabetes, since this is obviously basically a physical kind of dysregulation. They are parametric (22, p71ff) aggravators, quite distinct for the control system itself, and can of either physical or mental kind. Any psychotherapy initiated to get the patient out of her/his adolescent rebellion could certainly improve the diabetic control, and yet not be regarded as a treatment for diabetes. The situation is clear. I would like you to compare this situation with Invest in ME (Charity Nr. 1114035) that of ME/CFS. There is no problem in assigning causal responsibility in diabetics. Why the problem? One is that a complex multicausal regulatory system involved with ME/CFS has proven to be a difficult “entity” to grasp through research. As one does more science, the whole system will undoubtedly become more complex, and we need to guide research towards regions that are likely to be fruitful. Another impediment is that a prominent strategy in current use to guide attitudes and treatment methods regards ME/CFS as a somatoform disorder, i.e. a symptom cluster showing the form of a somatic organic disorder, but without the content. This is actually more of a default position than a diagnosis, but is similar in that it is serving as the termination of a clinical judgment procedure. This has led to disagreement as to whether CFS/ME is a physical or a mental kind of disorder, and within the system which are its constitutive variables that determine its form and which are the parameters that influence it but don’t determine it- with the different kinds of causality that this entails and the different forms of treatment to follow. The result is a mess. We have discussed above how the research definitions have been used not only to guide future research, but also to ignore current research findings until the story has been completely told and “the cause” of CFS/ME is known. If we have not been able to demonstrate the complete causal network with complete scientific certainty, should we continue on the assumption that there is no underlying cause for these symptoms and that they don’t refer to anything except their nominal essence as a name, thus remaining a “somato-form” “nominalist” kind as a default interim position while we search for the underlying cause that fulfills the symptoms’ intention as a “natural kind” ( 21). It is very tempting to slide from the attitude that a symptom’s causal background is uncertain, to the attitude that it is not there, and hence that the illness is all symptom and no reality. From (continued on page 31) Page 30/74 Journal of IiME Volume 2 Issue 2 www.investinme.org “ “TThhee mmoorree tthhiinnggss cchhaannggee,, tthhee mmoorree tthhiinnggss ss ttaayy tthhee ssaammee”” ( (ccoonn tt ii nnuueedd )) here it is easy to slide into an attitude that since by definition somatoform disorders simulate the form of real diseases, that the patients’ experience is not to be trusted. Their illness has been moved from being regarded as a physical kind to a mental kind without giving them the benefit of the considerable doubt. This in turn entails large shifts in trust and attitude from other people and agencies, stigma of a regulatory disorder that have been assigned to the mental side and of the consequences of this- how patients are treated in general at all levels of supervision, the types of treatment offered and how it is administered (21). It interferes with the assessment of symptoms as they have been removed from a natural realm into a distinctly separate symbolic realm, the fruit of Cartesian dualism between mind and body and thus an ontological shift that many patients can feel proprioceptively as a nondual jolt in their second-person discourse with their physicians with immense practical repercussions. Far more preferable would be to give the benefit of doubt to the patient and assume that there is an underlying natural causal network underlying the disease, of which we know fragments but not the complete story. In the meanwhile we should focus scientifically on the evolutionary development of symptoms, what somatic symptoms refer to and what has been the selective value to justify their retention? The biological function of these symptoms is to refer to their underlying causes in the interest of better selfregulation of a mobile organism living in a group. What is the system that they refer to? We should continue studying clinically the dynamic causal patterns that patients produce in their illnesses to identify sites where a shift in pattern makes scientific search in the region exposed more likely to be fruitful. It is a bit like searching for oil. Since these symptom patterns are discovered arising from the anecdotal experience of individual patients, Invest in ME (Charity Nr. 1114035) the lack of anecdotal trust in patient experience has been aggravated by the current thrust towards “evidence based medicine” with its push towards exclusive reliance on general knowledge vs. particular knowledge without accepting a complementary relation between these different kinds of knowledge which are both necessary. We should return to observing patient experience precisely as the symptoms, embedded in the flux of life, arise to out of their causal background in discrete dynamical patterns. In ME/CFS the dominant symptom of fatigue should be observed on-line by both patient and physician as it functions in the selfregulatory system of activity/rest modulation and look for the essential variables that stabilize the system so that the patient can learn to selfregulate it better on an ongoing basis. The interactions between fatigue and other symptoms should be studied for the causal efficacy that makes a syndrome into a dynamical causal entity. These should be distinguished by their dynamics from the external parameters that affect the state of the as a whole, stabilize it, destabilize it, change its dynamic form, etc. In studying these dynamical details it will also be helpful to search for “homeostatic clusters”(24) which are crucial for steadying the system. These studies can be expanded to as examination of how the individual organism can stay self-regulated in the larger social and cultural environment despite the impingement of external regulatory forces which exert greater forces and work according to a different dynamics and undergo parametric change all the time. But this will need yet another study- the world goes on changing, and we stay the same by changing with it. Bibliography:1/ Kathryn Montgomery, “How Doctors Think”, Oxford U. Press, 2004. (continued on page 32) Page 31/74

Journal of IiME Volume 2 Issue 2 www.investinme.org P Plluuss ççaa cchhaannggee,, pplluuss cc’’eess tt llaa mmêêmmee cchhoossee ( (ccoonn tt ii nnuueedd )) 2/ Hippocrates, “Regimen in Acute Diseases” in Loeb Classical Library Vol II, 1923. 3/ Sir JH Biggart, “Cnidos v. Cos” Ulster Medical Journal 41, Winter 1971. 4/ Ian Hacking, “The Social Construction of What?” pp 62-3 Harvard U. Press, 1999. 5/ NICE Clinical Guideline 53, on Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, Aug 2007. 6/ Benjamin H. Natelson “Your Symptoms are Real”, John Wiley 2008. 7/Thomas Sydenham “Medical Observations Concerning the History and Cure of Acute Diseases”, Preface to the 3rd edition- sections 5-20 “The Works of Thomas Sydenham tr. R.G. Latham. Vol 1, printed in London for the Sydenham Society, 1979. 8/ A.N. Whitehead, “Symbolism” see Chap 2, Capricorn Books, N.Y. 1959 9/Bent Flyvbjerg, “Making Social Science Matter” pp55-65 Cambridge U Press,2001. 10/ Albert Borgmann, “Technology and the Character of Contemporary Life” chaps. 5,12,21-23. 11/ Susan A Gelman, “The Essential Child”, esp. chap 11. Oxford U Pre3ss 2003. 12/work of Michotte and Tanley, described in Stephen Pinker “The Stuff of Thought “ pp208233, Penguin, 2007. 13/ see 6/, p47, and Introduction to DSM-IVTR, American Psychiatric Association, 2000. 14/ B.M. Carruthers, et al “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols”, JCFS, No. 1, 2003, pp 7-115. 15. L. Talmy, “Force Dynamics in Language and Cognition”, in L.Talmy, ed. “Concept Sructuring Systems”, MIT Press, 2000. 16/ The primary research definitions in use Invest in ME (Charity Nr. 1114035) have been the CDC Holmes and the Fukuda plus a revision, the Oxford, and now the NICE definition, the last of which has been claimed to be a clinical definition, but still retains the form of the previous research definitions for the most part. 17/ Michael Wheeler, “Reconstructing the Cognitive World” MIT Press, 2005, see section on Cartesian psychology. 18/J. Scott Kelso and David A. Engstrom, “The Complementary Nature” MIT Press, 2006, movement 2. 19/ Daniel J. Siegel, “The Mindful Brain” WW Norton, 2007- see pp20-21 on the difference between mindfulness- based instruction and ordinary means of cognitive therapy based on cognitive skills training for chronic depression. 20/ John Ruscio, Nick Haslam, and Ayelet Meron Ruscio “ Introduction to the Taxometric Method”, Lawrence Erlbaum Associates, 2006. 21/ Nick Haslam, “Psychiatric Categories as Natural Kinds: Essentialist Thinking about Mental Disorder” Social Research, winter, 2000. 22/ W. Ross Ashby “ Design for a Brain” chapter 6 on parameters, Science Paperbacks, Chapman and Hall, Ltd, 1960. 23 Sir William Osler, “The Principles and Practice of Medicine” Appleton, N.Y and London, 1914. 24/ H. Kornblith, “Inductive Inference and its Natural Ground” MIT Press, 1993. 25/ Walter J. Freeman, “Consciousness, Intentionality, and Causality” quoting D. Davidson on P 74 in “Does Consciousness Cause Behavior” ed. Susan Pockett, William P Banks and Shaun Gallagher, MIT Press, 2006. 26/ attributed to Osler, see ref. 23, but I could not find the source in his voluminous writings. Page 32/74 Journal of IiME Volume 2 Issue 2 www.investinme.org A Severe ME-aware nursing model By Greg Crowhurst RNLD , PgDip Experiential Learning , Cert Counselling Skills, MA This article outlines a self-reflective nursing model , in order to enable practitioners to enter into a sensitive partnership with patients who have severe Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. There is an urgent need to develop an appropriate model of practice for people with Severe Myalgic Encephalomyelitis (ME), if practitioners are to avoid tragedies like that of Sophia Mirza, who died from ME , after suffering appalling treatment at the hands of doctors and nurses following sectioning under the Mental Health Act for two weeks in 2003.(Hooper 2006). Crawford, Aitken and McCagh (2008) recently found that nurses still positively to patients with Multiple Sclerosis and Rheumatoid Arthritis than patients with ME/CFS, which they are more likely to wrongly view as a psychological disorder. Nurses also report low levels of training and confidence in their skills when working with patients who have ME/CFS. A great deal of conflicting advice still surrounds ME/CFS , to the care of people with leaving many patients "dismissed and abandoned without support. (Hooper et al 2005). Central ME/CFS and the cornerstone of any nursing model (Archibald 2000) are the beliefs and values, the experience and knowledge of the nurse. Background There are an estimated 62, 500 people with severe ME /CFS in the UK (DH2002) .The disease, which can occur in both sporadic and epidemic forms (Jenkins 1991) has been described in the medical literature for about 70 years. Over 4,000 papers have been published, documenting the biomedical abnormalities found in ME/CFS (CDC 2006) Invest in ME (Charity Nr. 1114035) Greg Crowhurst cares for his wife, a longterm severe ME sufferer. A comprehensive series of video by the author , showing the impact and the reality of severe ME , are available for free online at: http://www.youtube.com/user/gregcrowhurst Contact : gcrowhurst@gmail.com respond more Since 1969 ME/CFS has been classified as a neurological disorder by the World Health Organisation . ME/CFS was recognised as a specific disease entity by The Royal Society of Medicine in 1978 and as an organic disorder by the Department of Health in 1987 (Hansard 1987). Included in the NHS National Service Framework (DH 2004) as a long-term neurological condition, cycles of severe relapse are common in ME/CFS as are further symptoms developing over time. "Substantial improvement is uncommon and is less than 6%" (Anderson et al. 2004); and, "Full recovery... is rare" (Cairns & Hotopf, 2005). The Experience of Severe ME/CFS It is not 'fatigue' or 'tiredness' that is the one essential characteristic of ME/CFS but central nervous system (CNS) dysfunction (Bassett 2006). Bell (1995) describes the word "fatigue" as: 'A very inappropriate term for what patients experience. It's not really fatigue at all, which (continued on page 34) Page 33/74

Journal of IiME Volume 2 Issue 2 www.investinme.org A Severe ME-aware nursing model (continued) is defined as a normal recovery state from exertion and that is precisely what does NOT happen in this illness"; this is extremely important for the nurse to assimilate, in order to effectively work with people with severe ME. Everyday life for the severe ME sufferer is a perpetual struggle. As Owen (2007) points out the most severely affected may not be able to speak, eat, swallow, open their bowels. They may not be able to sit up or move themselves, they may be too exhausted to dress or wash . The sound of running water may be too much for them to bear, they may not be able to open their mouth to brush their teeth. Crowhurst L. (2007) describes how : "Having severe ME is unimaginable ; the experience is so different , intense and unremitting than anything I have ever experienced before. I am never unaware of the range of symptoms that rage through my body , and are dominated by intense never ending pain in every millimetre of my skin and muscles, over and throughout my whole body; head shoulders, back, front , arms legs, hands , feet, toes , fingers, eye lids , scalp the soles of my feet, the tip of my nose , my eyebrows even. They all burn, throb, tingle, itch, and hurt in ways indescribably unbearable , along with other unusual sensations" There are no known appropriate treatments for ME/CFS available at this time and it has been found that some of the mainstream therapies applied to ME sufferers have been unhelpful or harmful on many occasions , especially treatments such as Cognitive Behavioural Therapy and Graded Exercise Therapy.. (Crowhurst 2005). Knowledge, sensitivity and awareness are paramount. The nurse must be able to respond creatively in order to aid the person. This means learning to understand: Invest in ME (Charity Nr. 1114035) Management : Family members and carers, with the patient’s agreement , can contribute a wealth of essential knowledge and valid information, in the development of an individualised management plan. People with severe ME/CFS are at great risk, generally, of a dramatic increase in their symptoms, which could plunge them into even greater depths of illness ; this is especially so if (continued on page 35) Facts About ME 'It is accepted by the most experienced ME clinicians that some degree of encephalitis has occurred both in patients with ME and in those with post-polio syndrome: the areas chiefly affected include the upper spinal motor and sensory nerve roots and the spinal nerve networks traversing the adjacent brain stem (which is always damaged). In nearly every patient there are signs of disease of the central nervous system.' - Professor Malcolm Hooper Page 34/74 - what is needed, - when it is needed and - how it is needed ; which may not always be obvious or repeatable. Any activity where thought and action work together can easily become out of reach of the person with severe ME/CFS, without any clear understanding or explanation of why. Simply speaking on a telephone for example, could be far too much for the person : Journal of IiME Volume 2 Issue 2 A Severe ME-aware nursing model (continued) The person needs to : • Be able to hold the phone or put on a headset. • Be able to bear the noise. • Have the energy to physically answer the phone. • Have the energy to speak. • Have the ability to focus. • Have the ability to concentrate. • Have the cognitive ability to receive the information. • Have the cognitive ability to process the information. • Have the emotional strength to deal with the other person's emotional state. • Have the ability to cope with the tone of voice, loudness of voice , pace of conversation.. • Have the ability to access information if they are asked a question. • Have the stamina to cope with a conversation of unknown length. • Have to ability to cope with waiting in a queue or waiting for a person, which uses an inordinate amount of energy and they may run-out of ability. • Have the ability to cope with the increased symptoms that will follow having used the phone. • Have the ability to cope with the potential shutdown of various systems that should support the actions they are doing, for example, their muscles running out, noise becoming too loud, their voice going, while on the phone. • Have the ability to cope with the post-exertional impact. (You have to remember that physical and emotional energy are equivalent in ME/CFS .) • Have the ability to coordinate their thoughts, energy and physical ability. the more complex the task, the more impossible daily living becomes and the more isolated the person becomes from the normal world; because the normal world becomes out of reach because of the complexity of the tasks and the impact of the multi-system dysfunction of the body. The difficulties of speaking on the telephone for the severe ME/CFS sufferer. they leave the safety and security of their known environment : In planning any transition a host of environmental issues need to be taken into account well in advance, for example : - Physical comfort - Weight of bedding - Softness of mattress Invest in ME (Charity Nr. 1114035) - Neck and back support - Noise and light exposure - Food /chemical sensitivities/allergies - Timing of meals - The how and when of physical assistance The nurse may not have the answers, but it (continued on page 36) Page 35/74 www.investinme.org

Journal of IiME Volume 2 Issue 2 www.investinme.org A Severe ME-aware nursing model (continued) ME/CFS is characterized by (Mark 2005) : - malaise following even modest physical activity - delayed reaction to physical and/or mental activity (up till 24 hours and more); - abnormal length of convalescence (out of proportion to level of activity) - varying and fluctuating symptoms during the day, but also in the course of days, weeks and months is very important to ask the right questions and not assume anything, as this Observation and Assessment tool shows (see Table 1) - As the chart shows, in severe ME/CFS sleep/awake times and personal care needs are unlikely to fit into standard patterns. An ME-aware Nursing Model In the author’s experience (Crowhurst 2005) , the most appropriate nursing approach is one that incorporates the Nursing Process (Yura and Walsh 1967) within a self-reflective model of practice . Crowhurst (2005) has outlined how the experiential learning cycle (Kolb and Fry 1975) can be used to underpin ME/CFS nursing practice , encouraging nurses to reflect upon their practice experientially and holistically. Some important areas for practitioner reflection are listed below in Table 2 : An ME-aware approach requires the nurse to be : - particularly conscious of how ME/CFS manifests. - the full range of symptoms. (continued on page 38) Symptom Hyperacusis Table 1 - Severe ME/CFS : Observation and Assessment tool Questions/Observations What is the patient’s response to electrical equipment, noise, telephone, doorbell, washing machine, Hoover ? Hyperesthesia Does the patient flinch, become irritated and depressed ? Is the skin hypersensitive to touch ? May be unable to tolerate massage, stroking, accidental contact. Comments Noise sensitivity can be so great that even a whisper sounds like a shout; it may be painful and it may increase a whole range of symptoms. The patient may find any kind of contact or movement over the skin unbearable. May flinch, may react strongly, verbally, be very distressed by even a slight brushing. The nurse has to be very careful and aware. (Table 1 continued on page 37) Invest in ME (Charity Nr. 1114035) Page 36/74 Journal of IiME Volume 2 Issue 2 www.investinme.org Pain Is the patient experiencing sleep difficulties because of pain ? Do they need special aids and equipment ? Are there analgesics that help/ease the pain? Is touch and lifting difficult because of pain ? Multiple chemical sensitivity Does the person feel nauseous, experience headaches, rashes or other symptoms in response to being exposed to certain chemicals, smells, perfumes, toiletries, household cleaning agents ? Have they developed specific food sensitivities/allergies ? Orthostatic intolerance The patient may become greatly distressed moving from lying to sitting, to standing. They may be unable to sit upright. They may experience dizziness, increased feeling of illness, panic even, if made to stand. Unrestorative sleep Does the patient feel more ill and in more pain upon waking ? Do they feel unrefreshed and unrested ?Do they have difficulties going to sleep and staying asleep ? Do they have difficulties waking up ? They may need to sleep during the day ? Sleep may push the person into a worse state of illness and paralysis. Muscle dysfunction Can the patient do something one moment and not the next ? Does the person have difficulty holding implements, difficulties with gripping ? Do they have difficulty holding even a light object ? Do they have difficulty sitting or standing at varying times during the day ? They may require help eating, or vary in degree of help needed. The patient with severe ME might experience muscle pain, nerve pain, skin-crawling sensations, burning, itching, throbbing pain. The person with ME might feel extremely ill al the time, on top of the other symptoms. It may help to identify some of the symptoms in order to aim for relief. The nurse must be aware that perfumes, deodorants, might have a deteriorative effect on the person with ME, which can be extreme and immediate. Household cleaning agents etc require careful consideration. Organic products might be less harmful. The severe ME sufferer may feel utterly ill and/or unable to stand, but may not be able to identify why. It is important for the nurse to know there is a physiological reason for this. The sleep pattern in ME is altered. May be awake during the night and asleep during the day. They may not experience restorative sleep. They may have nightmares. Paralysis is a significant symptom in sleep disorder. The ability to use any muscle may come and go and vary throughout the day and night and is beyond the control of the person with severe ME. They may be physically able to do something one moment and not the next. The patient must never be pushed to do something, just because they can it sometimes. There is a postexertional malaise response to using muscles, that can occur up to hours and days afterwards. Invest in ME (Charity Nr. 1114035) Page 37/74

Journal of IiME Volume 2 Issue 2 www.investinme.org A Severe ME-aware nursing model (continued) - the likely impact of any interaction upon the person. The prepared nurse can greatly lessen the chances of any deterioration in symptoms : ASSESSMENT : IMPLEMENTATION : It is the way the nurse approaches the patient with severe ME/CFS that determines the outcome of assessment. Particularly with ME/CFS, the underlying beliefs, knowledge and understanding the nurse has about the disease itself, could result in two very different assessments, depending upon whether the nurse believes ME/CFS is a physical disease or a mental health issue and whether they adopt an authoritarian "I know best" approach or a more empathic partnership style of relating. Not only are the nurse's views and understanding of the illness important, their awareness in regard to their own power and responsibility are vital. An authoritarian approach, coupled together with an assumption that ME/CFS is not a real disease, that somehow the "patient is just not trying hard enough" , or has in some way caused their illness by wrong beliefs, means that the assessment will be deeply flawed. PLANNING : Again, the nurse's underlying assumptions and knowledge of the disease will play a crucial role in planning any intervention. Unless the nurse is aware that the person with ME/CFS is a long term chronically-ill patient, who is unlikely to get better ( anyone severely affected for more than 5 years has a poor prognosis of recovery (DH2002)) , the planning may be way too hopeful with way too high an expectation of the patient. The nurse’s preparation must be done with awareness before intervention in the patient’s life. Invest in ME (Charity Nr. 1114035) Implementation needs to focus on acute awareness of the severity of illness and the multi-system dysfunction the person is experiencing. This cannot be emphasised enough or over-played ; it is the key to any successful intervention. The nurse must be able to be flexible and understand the potential impact of any movement, speech, action, upon the severe ME/CFS sufferer and must always trust and listen to the patient and their reaction. The response of people with ME/CFS is not always predictable; often the opposite rather than the expected occurs. This must be understood by the nurse . It would be well to consider alternative interventions in advance, so the nurse is prepared when something is not working. Even if an intervention is not possible at one moment, it may still be possible at some other point in time, for there are fluctuations of experience of symptoms within the general chronicity of the illness. EVALUATION : Integrity, wisdom and patience are required. Any improvement or response may be extremely small, almost invisible perhaps to the nurse, yet the person with severe ME/CFS may discover significant benefit from what might seem like a small, even insignificant outcome. Patience is particularly required, both for the nurse and for the patient. (continued on page 39) Page 38/74 Planning should be focused upon the way the nurse interacts and responds to the patient. Without key- planning the dangers of an immediate worsening of illness and a long term relapse through poor understanding are likely outcomes. Journal of IiME Volume 2 Issue 2 A Severe ME-aware nursing model Table 2 MIND : • What am I thinking about when I approach the severe ME/CFS sufferer? • Can I focus solely about what I am doing ? • Have I thought ahead about what potential issues might come up ? • Do I understand that ME/CFS is an organic, physical disease ? SPIRIT : • How do I feel about being with the patient ? • Can I connect with the patient and their need ? • Am I flowing with the right energy to make contact with the person ? BODY : • What is my intended posture ? Open ? • Partnership ? • Is my physical posture in keeping with my intention ? • Am I able to be gentle enough , when I help the patient ? • Am I too tired to help sensitively and carefully ? • Am I in pain anywhere myself ? EMOTION : • What is my emotional state ? • Is it going to have a good impact upon my interaction ? • Am I distracted about other issues ? • Am I distressed by the patient’s issues ? • Do I feel good about myself ? • How do I feel about the patient ? Because of the severity and the long-term nature of the illness and the ease with which any intervention can lead to a worsening rather than a bettering of illness, how the nurse approaches an evaluation is very significant. It must be remembered that the person with ME/CFS may have severe cognitive dysfunction, may not be able to write or read, speak, understand or cope with questions. A very gentle approach is essential in developing a partnership with people who have ME/CFS. An example Case Study (see Table 3) : (continued on page 40) Invest in ME (Charity Nr. 1114035) ME Story Now, nearly eight years later, going from a student at the top of my class with an unlimited future to a dependent, rather helpless person with no real hope for healing is something that only others in this situation can understand. Meeting new people, and having them ask, "what do you do?" makes me cringe. The amount of shame and isolation at times is unbearable, but there is also a glimmer of hope that with greater understanding will come better treatments or at least compassion. - Jessica Page 39/74 www.investinme.org (continued)

Journal of IiME Volume 2 Issue 2 www.investinme.org A Severe ME-aware nursing model (continued) Table 3 Ms H is 50 year old woman with severe ME . Nursing intervention : assisting patient with eating lunch Assessment Ms H’s main symptoms are : Symptom Impact Pain : cannot bear touch Transient paralysis unable to use limbs affected. Numbness Muscle fatigueability Light sensitivity Noise sensitivity Food sensitivity/allergies Gastritis cannot feel properly Muscle weakness cannot grip properly post exertional malaise/pain increase needs dark glasses, low light any noise can hurt and aggravate symptoms can only eat certain foods, no dairy, wheat or oil stomach pain, bloating Hypoglycaemia irritability, distress, worsening symptoms Swallowing difficulties Breathing difficulties Spasms food gets stuck malaise increases, chest muscle pain head, limbs, body shaking violently, Presenting Issues : Variability of symptoms and severity Functional difficulties in eating Potential deterioration to complete incapacity Sitting up/postural issues Planning : Intention : Provide finger food Provide padded seating and back/neck support Low light Quiet, peaceful environment Ensure appropriate diet Provide assistance with drinking (straw). To have a warm open accepting posture with no quick movements, minimal noise, sensitivity to physical pain. To proactively respond to the person’s needs, in partnership. Patient not to be stressed or rushed. Implementation : The nurse followed the intended plan however there was a complication which needed creativity, adaptability, patience and calm especially, on the part of the nurse. Complication requiring immediate response : Patient began to spasm severely immediately she attempted to eat. Food fell everywhere, patient became distressed, tearful, breathing difficulties and swallowing difficulties manifested. Response : maintain valuing posture . Wait for spasms to subside. Maintain silence but thinking what to do to help the patient. Patient tried several times to eat unsuccessfully, reduced ability to bite rice Invest in ME (Charity Nr. 1114035) Page 40/74 Journal of IiME Volume 2 Issue 2 A Severe ME-aware nursing model (continued) cake Patient suggested breaking the food into small pieces and placing directly in mouth. Replaced lost food. Successful intervention. Evaluation : Patient evaluation : Was surprised by the strength of spasms and shocked by the loss of ability to even bite a rice cake. Grateful for the calm and valuing posture and support in being enabled to eat, because she needed the food to avoid hypoglycaemia. Shaken by the intensity of the experience. Nurse’s evaluation : Mind : Pleased they had the knowledge and insight to appreciate the complexity of symptoms . Body : Remained very still and maintained an open, calm and affirming posture. Emotion : Felt concerned and dismayed yet managed to convey warmth and positive unconditional valuing. Spirit : Maintained stillness and centeredness, despite distressing circumstances and maintained partnership stance, open for patient’s communication. Learning : although meal planned well, with awareness of potential symptom issues, the strength of the spasms and the rapid deterioration was unexpected in reality. Even under stress and with patient distress the nurse responded as intended. Replacing the food was an important aspect. Conclusion New ways of enabling nurses to assist patients with ME/CFS urgently need developing . The starting point, as this article has stressed , must be awareness that ME/CFS is a neurological disease , with multi-system dysfunction. Some of the complex environmental hurdles that ME/CFS sufferers have to overcome in order access care have been detailed. Invest in ME (Charity Nr. 1114035) References : • Andersen MM et al. Illness and disability in Danish CFS patients at diagnosis and 5year follow-up. J Psychosomatic Research 2004; 56: 217-229. • Archibald G (2000) A Post -modern nursing model , Nursing Standard, May 10/vol14/no34/2000 40--41 • Bassett J (2006) Testing for Myalgic Encephalomyelitis http://www.ahummingbirdsguide.com/te stingforme.htm • Bell, David S MD 1995, The Doctor's Guide to Chronic Fatigue Syndrome, Perseus Books, Massachusetts • Cairns, R. and Hotopf, M. (2005) Prognosis of chronic fatigue syndrome: a systematic review. Occupational Medicine 2005 55 20-31 • CDC ( 2006) The Chronic Fatigue and Immune Dysfunction Syndrome Association of America and The Centers For Disease Control and Prevention Press Conference at The National Press Club to Launch a Chronic Fatigue Syndrome Awareness Campaign NOVEMBER 3, 2006 www.cdc.gov/od/oc/media/transcripts/t 061103.htm • Colby, Jane 1996, ME: The New Plague, Ipswitch Book Company Ltd, Ipswitch to • Corbin JM, Strauss A (1991) A nursing model for chronic illness management based upon the trajectory frame- work. Scholarly Inquiry Nurs Pract: an International Journal 5: 155–74 (continued on page 42) Page 41/74 A self –reflective, partnership-based model of practice has been outlined, in order to begin to meet the complex needs of these still neglected patients. www.investinme.org

Journal of IiME Volume 2 Issue 2 A Severe ME-aware nursing model (continued) • Crawford J, Aitken S, McCagh J (2008) A comparison of nurses attitudes towards people with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome, Multiple Sclerosis and Rheumatoid Arthritis. Liverpool Hope University.. British Psychological Society Conference I, Dublin 2-4th April 2008. Book of Abstracts ; Poster Presentation 0o7,( page 227) : http://www.bps.org.uk/downloadfile.cfm?fil e_uuid=294D335D-1143-DFD0-7E3E511853853E27&ext=pdf • Crowhurst G (2005) Supporting People with Severe myalgic encephalomyelitis , Nursing Standard, 19, 21, 38-43 • Crowhurst L (2007) The reality of living with severe Myalgic Encephalomyelitis BMJ Rapid Responses to R Baker and E J Shaw Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): summary of NICE guidance BMJ 2007; 335: 446-448 http://www.bmj.com/cgi/eletters/335/7617/ 446#175682 • Department of Health (2002) , A Report of the CFS/ME Working Group. Report to the Chief Medical Officer of an Independent Working Group, London, The Stationary Office. • Department of Health (2004) Chronic Fatigue Syndrome (CFS) and Myalgic Encephalopathy (ME) exemplar. National service framework for children, young people and maternity services http://www.dh.gov.uk/en/Publicationsandst atistics/Publications/PublicationsPolicyAndG uidance/DH_4098119 • Hansard (1987) , House of Commons, Nov 1987 p. 353 • Hooper M, Marshall E, Williams M (2005) llustrations of Clinical Observations and International Research Findings from 1955 to 2005 that demonstrate the organic aetiology of Myalgic Encephalomyelitis / Invest in ME (Charity Nr. 1114035) Chronic Fatigue Syndrome http://www.meactionuk.org.uk/Organic_e vidence_for_Gibson.htm • Hooper R (2006) First official UK death from chronic fatigue syndrome NewScientist.com news service http://www.newscientist.com/article/dn93 42-first-official-death-from-chronic-fatiguesyndrome-.html • JenkinsR & Mowbray J.F. (1992) Post-Viral Fatigue Syndrome, New Ed Edition, John Wiley & Sons Publishers. • Kolb D, Fry R (1975) Towards an applied theory of experiential learning in Cooper C(ed) Theories of Group Process, London, John Wiley • Mark L (2005) Symtoms , Information on Myalgic Encephalomyelitis http://www.mesite.dk/Symptoms.htm • ME Research UK, The NICE guideline Breakthrough, Spring 2008, p.4 • NICE (2007) Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management of CFS/ME in adults and children Introduction, Chronic fatigue syndrome / Myalgic encephalomyelitis: NICE guideline (MS word format) http://www.nice.org.uk/guidance/index.js p?action=download&o=36194 • Owen L (2007) Practical Ideas for Managing Severe ME , The Quarterly, 25% Severe ME Group, Newsletter, Issue 24, Winter 2007, pp 17-18 • The Economist (2008) The Roots of Chronic Fatigue May 8th 2008 Science and Technology http://www.economist.com/science/Print erFriendly.cfm?story_id=11326174 • Yura, H. Walsh, M. (1967) The Nursing Process. Appleton-Century-Crofts, Norwalk. www.investinme.org Page 42/74 Journal of IiME Volume 2 Issue 2 The Terminology of ME & CFS By Professor Malcolm Hooper The term BENIGN MYALGIC ENCEPHALOMYELITIS was first introduced in the UK in 1956 by a former Chief Medical Officer (Sir Donald Acheson) and not by Dr Melvin Ramsay as is sometimes claimed. The word "benign" was used because it was thought at the time that the disorder was not fatal (as poliomyelitis could be, with which it had some similarity), but it was quickly realised by clinicians that ME was not a "benign" condition, as it has such high morbidity (i.e. such a lot of suffering and ill-health), so by 1988 clinicians had stopped using the word "benign" and referred to it as ME, the first to do so being Dr Ramsay. However, the ICD still uses the term "benign" in its classification. MYO relates to muscle MYOSITIS = inflammation of muscle MYALGIA = pain in muscles (pain that is called "myalgic") MYOPATHY = any disease or disorder of muscle MYEL (or MYELO) relates to the spinal cord (the main nerve in the body) MYELITIS = inflammation of the spinal cord (NB. Not to be confused with the other meaning of myelitis, which = inflammation of the bone marrow, as in osteomyelitis) MYELIN SHEATH = a layer of fatty white material that surrounds and insulates nerve fibres DEMYELINATION = the loss of this protective insulation round nerve fibres (as seen in multiple sclerosis and sometimes also in ME) ENCEPHALON = the brain Invest in ME (Charity Nr. 1114035) ENCEPHALO = relating to the brain "ITIS" on the end of a word = inflammation (e.g. hepatitis = inflammation of the liver) So, ENCEPHALOMYELITIS = inflammation of the brain and spinal cord BENIGN MYALGIC ENCEPHALOMYELITIS therefore means a non-fatal disorder (inflammation) of the brain and spinal cord, with pain in the muscles ENCEPHALOPATHY = any non-inflammatory disorder affecting the brain Despite the claims of some psychiatrists, IT IS NOT TRUE THAT THERE IS NO EVIDENCE OF INFLAMMATION OF THE BRAIN AND SPINAL CORD IN ME: there is, but these psychiatrists ignore or deny that evidence. For example: 1988 In conjunction with the University of Pittsburgh, the US NIAID held a large research workshop called "Consideration of the Design Studies of Chronic Fatigue Syndrome". There were participants from the Centres for Disease Control and from the National Institutes of Health. One of the presentations was by Dr Sandra Daugherty, who reported that MRI scans on patients demonstrated abnormalities consistent with demyelination and cerebral oedema in 57% of patients studied. (It was at this conference that it was recommended that the term "CFIDS" be used instead of the term "CFS" on the basis of the immune dysfunction that had been observed in the disorder). 1989 Detection of Viral-Related Sequences in CFS Patients using Polymerase Chain Reaction W.John Martin (Nightingale Research Foundation: 1989: 1-5 (continued on page 44) Page 43/74 www.investinme.org

Journal of IiME Volume 2 Issue 2 The Terminology of ME & CFS By Professor Malcolm Hooper 1990 Chronic Fatigue Syndrome and the Psychiatrist SE Abbey, PE Garfinkel Canadian Journal of Psychiatry 1990:35:7:625-626 1992 A Chronic Illness Characterised by Fatigue, Neurologic and Immunologic Disorders, and Active Human Herpesvirus Type 6 Infection D Buchwald, PR Cheney, R Gallo, AL Komaroff et al Annals of Internal Medicine 992:116:2:103 This paper states "Magnetic resonance scans of the brain showed punctate, subcortical areas of high signal intensity consistent with oedema or demyelination in 78% of patients" 1994 Detection of Intracranial Abnormalities in Patients with Chronic Fatigue Syndrome: Comparison of MR Imaging and SPECT. RB Schawrtz, BM Garada American Journal of Roentgenology 1994:162:935-941 1995 Pathophysiology of a Central Cause of Post-Polio Fatigue Richard Bruno et al Annals of the New York Academy of Sciences 1995:753:257-275 1997 A 56-year old woman with chronic fatigue syndrome Anthony J Komaroff JAMA 1997:278:14:1179-1184 It is true that there is no evidence of inflammation of the brain or spinal cord in states of chronic fatigue or "tiredness." It is also true that neither the 1991 (Oxford) criteria nor the 1994 (CDC) criteria select those with ME, as they both expressly include those with somatisation disorders and they expressly exclude those with any physical signs of disease (as is the case in ME), so by definition, patients with signs of neurological disease have been excluded from study. It is also true that Professor Simon Wessely and Invest in ME (Charity Nr. 1114035) his colleagues use the terms "fatigue", "chronic fatigue", "the chronic fatigue syndrome (CFS)" and "myalgic encephalomyelitis (ME)" as synonymous. Such obfuscation has greatly hindered research, as pointed out in the 1994 Report of the National Task Force on Chronic Fatigue Syndrome (CFS), Post-Viral Fatigue Syndrome (PVFS) and Myalgic Encephalomyelitis (ME), published by Westcare, Bristol and supported by the UK Department of Health, which stated: "Chronic fatigue syndromes remain poorly understood. Progress in understanding them is hampered by:  the use by researchers of heterogeneous study groups  the use of study groups which have been selected using different definitions of CFS  the invalid comparisons of contradictory research findings stemming from the above". The Report names psychiatrists Dr Simon Wessely, Dr Peter White and Dr Michael Sharpe and acknowledged their help, but then makes the point that "people who gave their help are not necessarily in agreement with the opinions expressed" (page 87). It was said to be because those psychiatrists strongly disagreed with the findings of the 1994 Westcare Report that in 1996 they produced their own report (the Report of the Joint Royal Colleges on CFS (CR54), which was internationally recognised as being biased and seriously flawed). Classification The WHO was founded in 1948. The International Classification of Diseases (ICD) comes in two volumes: Volume I is the (continued on page 45) Page 44/74 www.investinme.org Journal of IiME Volume 2 Issue 2 The Terminology of ME & CFS By Professor Malcolm Hooper Tabular List and is a list of codes plus the name of the condition which goes with that code. Volume II is the Code Index, which alphabetically lists all the phrases and names of conditions commonly used for a condition, together with the appropriate code. The Tabular List (Volume I) does not list everything which is in the Code Index (Volume II). Benign myalgic encephalomyelitis (ME) has been classified in the International Classification of Diseases (ICD) as a neurological disorder since 1969, when it was included in ICD-8 at Volume I: code 323: page 158 and in Volume II (the Code Index) on page 173. (ICD-8 was approved in 1965 and published in 1969). Prior to 1969, the term benign myalgic encephalomyelitis (ME) did not appear in the ICD, but non-specific states of chronic fatigue were classified with neurasthenia under Mental and Behavioural Disorders. Benign myalgic encephalomyelitis (ME) was included in ICD-9 (1975) and is listed in Volume II on page 182. The term "Chronic Fatigue Syndrome" was not introduced by Holmes et al until 1988 and therefore did not appear in the ICD until 1992, when it was listed as an alternative term for benign myalgic encephalomyelitis (ME). Another alternative term listed is Post-Viral Fatigue Syndrome. In ICD-10 (1992), benign myalgic encephalomyelitis (ME) continues to be listed under Disorders of the Nervous System at G93.3, with the term Syndrome, Fatigue, Chronic, as one of the descriptive terms for the disorder. By contrast, in ICD-10 (1992), neurasthenia and other non-specific syndromes of on-going or chronic "fatigue" are listed at section F48.0 Invest in ME (Charity Nr. 1114035) International ME/CFS Conference 2009 29th May 2009 London www.investinme.org Page 45/74 (Volume I, page 351). Non-specific states of chronic fatigue are classified as Mental and Behavioural Disorders, subtitled "Other Neurotic Disorders". Note: benign myalgic encephalomyelitis (ME/CFS/PVFS) is expressly excluded by the WHO from this section. Note also that the WHO has confirmed in writing that - "it is not permitted for the same condition to be classified to more than one rubric as this would mean that the individual categories and subcategories were no longer mutually exclusive". Therefore, ME/CFS cannot be known as or included with neurasthenia or with any mental or behavioural disorder. Professor Malcolm Hooper From http://www.investinme.org/Article%20010Encephalopathy.htm www.investinme.org

Journal of IiME Volume 2 Issue 2 www.investinme.org EDUCATIONAL MATERIAL from IiME INTERNATIONAL ME/CFS Conference DVDs Invest in ME have available the full presentations from the International ME/CFS Conferences in London of 2008, 2007 and 2006 These professionally filmed and authored DVD sets each consist of four discs, in Dolby stereo and in PAL (European) or NTSC (USA/Canada) format. Containing over 6 hours (2008 DVD set), 9 ½ hours (2007 DVD set) and 6 hours (2006 DVD set) – with all presentations plus interviews with ME presenters and news stories from TV programmes. These DVDs have been sold in over 20 countries and are now available as an educational tools – useful for healthcare staff (GPs, paediatricians, occupational therapists and others connected with the treatment of ME), researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://www.investinme.org/InfoCentre%20Education%20Homepage.htm or via emailing IiME at meconference@investinme.org. Price £14 each - including postage and packaging. Quotable Quotes on ME/CFS This 42 page booklet has been compiled by Margaret Williams and contains a plethora of quotes from ME experts and from others relating to ME, ME/CFS, CFS/ME and CFS. This is an invaluable document for researchers, healthcare staff, politicians, media, ME support groups and people with ME. The booklet will aid those composing letters, performing research, verifying analysis and for general reference purposes. Price £2.00 including postage/packing for UK delivery (£3.50 for other countries). Available whilst stocks last. El http://www.investinme.org/IIME%20ME%20Quotes%20 Order%20form.htm Invest in ME (Charity Nr. 1114035) Page 46/74 Journal of IiME Volume 2 Issue 2 www.investinme.org EDUCATIONAL MATERIAL from IiME Canadian Guidelines Invest in ME are the UK distributors for the Canadian Guidelines. Described even by NICE as “the most stringent” guidelines available these are proper, up-to-date clinical guidelines which can also be used as a base for research criteria. Findings from the study by Leonard A. Jason PhD (Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome) indicated that the Canadian criteria captured many of the cardiopulmonary and neurological abnormalities, which were not currently assessed by the Fukuda criteria. The Canadian criteria also selected cases with ‘less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms’ and individuals selected by these criteria were significantly different from psychiatric controls with CFS. The Canadian Guidelines provide a means for clearly diagnosing ME and were developed specifically for that purpose. They are an internationally accepted set of guidelines for which many in the ME community has been campaigning to be adopted as the standard set of guidelines for diagnosing ME. The Canadian Guidelines are available from IiME and the price is 46p per copy plus postage & packaging. To order please contact Invest in ME via this email address: info@investinme.org Subscribe to Invest in ME’s free newsletter. Distributed monthly via html, plain text or PDF. Go to http://www.investinme.org/IIMENewslettersubs.htm Invest in ME (Charity Nr. 1114035) Page 47/74

Journal of IiME Volume 2 Issue 2 www.investinme.org Wheelchair Use and Attitudes By Sue Pearkes There is a message which needs to be publicised about wheelchairs, to the three groups of people involved: the medical professions, the disabled community, and the able-bodied population at large. Emotional Overtones For some extraordinary reason (historical, perhaps?) there is an emotional subtext attached to wheelchairs. The able-bodied population tend to avoid or ignore them, possibly motivated by fear that they might “catch” disability; wheelchairs make the ablebodied uncomfortable, and they fear the possibility of ending up “in-a-wheelchair” (all one word). There is also the feeling that if one starts using a wheelchair, one has “given up”—one should fight to the utmost to keep out of the wheelchair, regardless of the pain, discomfort and curtailing of activities that one experiences as a result. The disabled community is also affected by this attitude—those who have been able-bodied will tend to have the same fears as ablebodied people, and those who have always been disabled will be influenced subconsciously by the existing negative attitudes of the able-bodied population. There is also the feeling that if one starts using a wheelchair, one has “given up”—one should fight to the utmost to keep out of the wheelchair, regardless of the pain, discomfort and curtailing of activities that one experiences Invest in ME (Charity Nr. 1114035) Sue Pearkes has had Myalgic Encephalomyelitis since January 2007 and has been using a wheelchair for about a year. as a result. (I consider “giving up” and “acceptance” to be two totally different concepts, incidentally.) I have a friend with cerebral palsy who, with advancing years, started to suffer badly with arthritis, and when he finally “gave in” and started using a wheelchair, found that it transformed his life, and he wished he had started using it years ago. These attitudes are not helped by the medical professionals who, being human beings, will also often be influenced by these negative attitudes, having lived in the ablebodied community all their lives, before, during and after qualifying in their professions (I am including nurses, physiotherapists, occupational therapists etc. in “medical professions”). As professionals, they might be expected to help to improve the situation, but in actual fact they perpetuate and reinforce it. They may be conditioned to see wheelchairs as a symbol of failure to achieve “healing” in their patients, and would therefore be very reluctant to promote something which they subconsciously believe shows them in a negative light. While they may need to warn people of the dangers of over-use of a wheelchair (muscle atrophy etc.), they should credit their patients with enough commonsense to use the wheelchair in a responsible way. They should ensure the right balance between general health and increased mobility; not indulging in a blanket rejection of wheelchairs, but considering the (continued on page 49) Page 48/74 Journal of IiME Volume 2 Issue 2 Wheelchair Use and Attitudes (continued) needs and circumstances of the individual patient, and in particular, listening to the patient’s views and desires. The patient, after all, is the one who best knows his or her body and circumstances, and is living with the disability on a daily basis. Diminishing someone’s ability to get around, or even to leave their house, or to condemn them to a daily grind of pain, by preventing them from using a wheelchair, can have an adverse effect on health; just being able to move around more easily, and to get out and about and socialise, surely has great health benefits. A Mobility Aid My attitude towards wheelchairs is that they are no different from glasses. You wear glasses to see better, and to improve your quality of life. You use a wheelchair to get around more easily, and to improve your quality of life. The Wheelchair User Most people (from all three groups, probably, but especially the able-bodied population) have no concept of the part-time wheelchair user. Most people think you are “in-awheelchair” (all one word) because you “can’t walk,” and if you can walk, you don’t need a wheelchair. I know I cause people a lot of confusion when I get out of my wheelchair and pull it up steps into shops etc. People often think that if you move your legs, or get out, then you ME STORY I was assessed for one ME clinic but they said I was too disabled and that there were other issues that needed to be worked on. They also said that because I was confined to a wheelchair they thought that would be too upsetting for the other members of their group! - Gary Invest in ME (Charity Nr. 1114035) are a fraud and don’t need the wheelchair. I have even been challenged by total strangers over this, as if it’s any of their business. “In-a-wheelchair,” “wheelchair-bound,” “confined-to-a-wheelchair,” are all extremely emotive and negative phrases. Not thinking about this until I was disabled, I thought that the phrase “wheelchair user” was a bit of politically-correct-speak. Now, however, I always refer to myself as a “part-time wheelchair user” and realise how important it is to be accurate in this respect. People do not become super-glued to their wheelchairs, becoming a single, freakish entity in the process. This is reminiscent of when the Conquistadors first arrived in South America, and the resident population had never before seen a man on horseback. They assumed that the two together were one unit; some sort of bizarre new creature they had never seen before. My own experience has been interesting. When I mentioned to my GP last year that I was intending to get a wheelchair (I got it privately so didn’t have to humiliate myself by asking for one from a profession that is so against recommending them!!) she gave the knee-jerk response, “Oh. We don’t like wheelchairs very much. People use them all the time and then their legs don’t work any more.” Professionals who say this should credit us with a little common sense. I took no notice of her, knowing full well that a wheelchair would help me, and this has proved to be the case. I got it in time for our holiday last year, and without it I could not have done any of the things the others did; as it was I participated fully, and even did some things the others did not! Since then, it has enabled me to get out and about and do things without causing me great physical discomfort and pain, or completely exhausting myself for the next few days. The other professions involved in my care (continued on page 50) Page 49/74 www.investinme.org

Journal of IiME Volume 2 Issue 2 Wheelchair Use and Attitudes (continued) were much more positive. When the occupational therapist came to assess me at home, the first thing she saw when she came in was the wheelchair, and she said, “Oh good, you’ve got a wheelchair already.” From this I assumed that had I not got one, she would have recommended one for me. When I saw the physiotherapist at the hospital, she commended my healthy and balanced attitude not only towards my illness, but also towards the mobility equipment I have, saying, “You have got your stick, crutches, trolley and wheelchair, and you pick and choose what you want to use according to your need at any given moment.” Neither of these two professionals expressed any The standard wheelchair, with its steel frame, is heavy, unwieldy, oldfashioned and ugly. The design has remained unchanged for decades. No wonder many people wouldn’t be seen dead using them, particularly young people, who tend to be style-conscious. negative attitude towards the wheelchair, or towards me for using it. When I saw my GP again recently, I expressed how much the wheelchair had improved my quality of life, and how the other professionals had approved it and encouraged me. I hope she was able to take this on board and realise that an out-of-hand rejection of wheelchairs is not useful or helpful, and that there is more to the picture than the danger of muscle atrophy. My own approach to my wheelchair has, I hope, challenged the preconceived attitudes of those who know me, and those I meet when out and about. I have decided that if I am to use one, then I might as well make a statement with it, and have decorated it. I started at Christmas, with baubles, tinsel and lights, and Invest in ME (Charity Nr. 1114035) got so much positive feedback that I was amazed and delighted. Total strangers would approach me, wreathed in smiles, and say how cool it was, and they would engage me in conversation, as a creative individual, and not as “someone-in-a-wheelchair” (all one word). When Christmas was over and I had to take the decorations off, suddenly I was invisible again. I couldn’t believe the difference. I decided to do something about it and put on flowers and lights, and immediately I got the positive reactions again. I also have decorated spokeguards; these are available already decorated, or one can purchase plain ones and decorate them oneself, as I have done. They are a great way to express one’s personality and elevate the wheelchair from an anonymous, functional object to the status of fashion accessory. Wheelchair Characteristics Maybe one reason why many disabled people are reluctant to start using a wheelchair is that the wheelchairs themselves are so uninspiring. I am fortunate enough to be the owner of a modern, ultra-lightweight wheelchair with a low back, cambered wheels, optional push-handles and minimalist appearance. Recently, while it was away having some work done, I had to resort to a borrowed NHS-type wheelchair which convinced me even more about the need for decent wheelchairs to be made available to everyone. The standard wheelchair, with its steel frame, is heavy, unwieldy, old-fashioned and ugly. The design has remained unchanged for decades. No wonder many people wouldn’t be seen dead using them, particularly young people, who tend to be style-conscious. They have fixed axles, a fixed back angle, an uncomfortable seat even with a good cushion, cumbersome armrests and enormous footrests which would put the average ice-breaker to shame. Using this type of wheelchair for a week (even parttime) made my back ache and my arms extremely tired, and I found it hard to maintain a good posture. The position of the wheels, (continued on page 51) Page 50/74 www.investinme.org Journal of IiME Volume 2 Issue 2 Wheelchair Use and Attitudes (continued) centre of gravity etc., combined with the weight, made it impossible to do even the smallest wheelie, leaving me feeling as though I were glued to the floor. The turning circle was much too large and it lacked real manoeuvrability. The back was too high, and combined with the large armrests, this left me with a feeling of being trapped in a steel box, virtually unable to move. Finally, the pushhandles on this type of chair convey the negative message, “I am a helpless baby/cripple, push me!” Their very presence encourages well-meaning able-bodied people to push the user, whether they want it or not. Most disabled people prefer not to be pushed if possible, as they value their independence and autonomy as much as any able-bodied person, and have no desire to be moved around by anyone else, and at a speed not of their choice. Being pushed, especially by someone inexperienced, can be alarming, and make one feel vulnerable and out of control. Modern ultra-lightweight wheelchairs are a totally different proposition. They were originally designed by disabled veterans returning from the Vietnam War, who were dissatisfied with the wheelchairs on offer, and re-engineered the wheelchair from the ground up. Their design features give rise to a radically different appearance. Having a rigid frame made of modern lightweight materials such as aluminium alloy or titanium, and doing away with the added bulk of a folding mechanism, large footplates, unnecessarily high back and handles, reduces the weight dramatically, which obviously benefits people with all kinds of disability, especially those with limited energy or muscle power. The low back, while giving excellent support to the lumbar region, allows for total freedom of movement for the upper body, and encourages good posture; I have often been asked whether I need more adequate support for my back, but I reply that on the Invest in ME (Charity Nr. 1114035) contrary, the support is exactly where I need it. Having the axles mounted further forward (the position is adjustable, as are many other features of these chairs) improves the efficiency of each push on the wheels as the user does not have to reach so far behind in order to obtain an adequate range of rotation. Self-propelling with a standard chair, the high back gets in the way, and one cannot get an adequate push. Of course, having the axles mounted further forward places the centre of gravity further back and compromises the stability somewhat, but this is balanced by increased energy efficiency Most disabled people prefer not to be pushed if possible, as they value their independence and autonomy as much as any able-bodied person, and have no desire to be moved around by anyone else, and at a speed not of their choice. and manoeuvrability and control of the chair. Going up steep ramps certainly increases the risk of tipping over backwards, but I have learned by experience that this difficulty can be overcome by going up backwards. (By doing this, one is also using one’s biceps to pull oneself up, rather than the weaker triceps to push. This is reminiscent of reverse gear in the car being a very low gear and giving extra power.) Anti-tip tubes may help some users. If one does require pushing in a modern lightweight, optional push-handles are available, which can be temporarily inserted into brackets and removed again; alternatively some wheelchairs have discreet handles which fold down out of sight when not in use. Having one’s centre of gravity virtually over the (continued on page 52) Page 51/74 www.investinme.org

Journal of IiME Volume 2 Issue 2 Wheelchair Use and Attitudes (continued) axles enables the user to do wheelies with ease; once trained in this technique, it is liberating. Even quite large obstacles, and uneven ground, and even gravel, can be negotiated by raising the front castors off the ground and moving on the two drive wheels only. When moving slowly on normal surfaces, one tends to use all four wheels, but at speed, or over uneven ground, the front castors need hardly touch the ground; this “cruise control” mode allows for less rolling resistance and greater efficiency on the part of the user, thus saving energy. Because of the design, and the lightness of the wheelchair, this does not require much upper body strength on the part of the user. All these features cause the wheelchair to become an extension of the user, and with practice and experience, movement can become easy and natural, and the environment can have a less disabling effect. The whole design, including the quick-release axles so that the wheels may be easily removed, makes it much easier for the disabled person to put the wheelchair in and out of the car, and to carry out other day to day activities independently. Quite apart from all these design and engineering features which improve the use of the wheelchair, turning it into a hi-tech form of locomotion, the appearance in itself is of great benefit to the user. It is modern-looking, cool and sporty, and does not make the user look like an invalid. The absence of push-handles conveys the message that the user is independent and perfectly capable of managing without interference, which in itself improves one’s sense of autonomy. The Importance of Choice It is not only the practical and functional aspect that is relevant, but the style element is also very important. People are out and about using their wheelchairs, and the appearance can have a profound effect on one’s image; we express ourselves by our outward appearance and choice of clothes and hairstyle, and the appearance of one’s mobility aids is of equal Invest in ME (Charity Nr. 1114035) importance. NHS grey, clunky, heavy and old fashioned equipment, whether it be a wheelchair, stick or crutches, do nothing for a person who is style-conscious. For most wheelchair users, it is not a matter of choice; they need a wheelchair in order to function. The able-bodied population (the “shoebound”) have a choice of design and style of the devices they use to interface with the ground, and would be justifiably outraged if some outside agency dictated from above what sort of shoes they should wear, regardless of their suitability or comfort. Why should wheelchairs, the devices many disabled people use to interface with the ground, be any different? Of course, the “does he take sugar” attitude prevails; the NHS remains largely paternalistic—“We know what is best for you”—because the poor little cripple cannot possibly think for himself, and if he expresses an opinion contrary to that of the professionals, he is deemed a “difficult patient.” The argument the NHS gives against prescribing these wheelchairs is cost. However, I have come across people who, in the days when they used NHS chairs, had to own more than one because they were always breaking, and they needed one in reserve to use while the other was being repaired. When used by full-time users, wheelchairs take a lot of punishment, particularly if the user enjoys an active lifestyle. The modern lightweights, however, are immensely strong, and their users generally have no problems with maintenance once they progress beyond the NHS standard. The NHS contract with wheelchair manufacturers must be enormous; if they were to start prescribing modern lightweights, the cost would come down, which would benefit everybody. It does seem wrong that in a society where the welfare state is supposed to provide wheelchairs for those who need them, people have to pay for wheelchairs that actually work for them. (continued on page 53) Page 52/74 www.investinme.org Journal of IiME Volume 2 Issue 2 Wheelchair Use and Attitudes (continued) The fact that modern lightweight wheelchairs are much more adaptable and adjustable would also be a benefit; the “one-size-fits-all” NHS philosophy actually causes a lot of damage, discomfort and pain to users whose wheelchairs do not fit them. My week using the NHS Iron Maiden was enough to convince me of the truth of this. There is no way that I could maintain the lifestyle and independence I enjoy if my modern lightweight were to be exchanged for a standard NHS-issue chair. The original modern lightweight wheelchairs were designed by wheelchair users. I consider this to be a crucial point. Able-bodied designers of wheelchairs do not have inside knowledge of what is needed in a wheelchair. If the NHS insists on using ablebodied designers and prescribers of wheelchairs, these people should at least be compelled to use them for a month or so, just to see what it is like, and experience for themselves what people really need and want. The Need for Education There seems to be a considerable need for education about wheelchairs and their use, amongst all three population groups. I do not know the best way to get this message across, but the purpose of this article is to reach as wide a forum as possible, where it can be read and acknowledged. In particular I should like it to be read by the professionals involved in the care and treatment of disabled people. It may make them stop and think about their attitude, at least— somehow we’ve got to get this message across. These professionals’ entrenched attitudes are doing us more harm than good, and causing no end of distress, when their role and function in life should be to help us. Pushing people to expend their precious reserves of energy, when they could be helped by the sensible use of such a marvellous device as a wheelchair, is totally wrong. We need encouragement, sensible advice and affirmation, not obstruction and condemnation. Finally, sitting down as opposed to standing up is not necessarily a negative thing. At the recent Beijing Olympics, the Aussies accused the Brits of earning most of their medals sitting down!!! The Use of Aids for People with ME – an Alternative View Let us contrast the previous article Wheelchair Use and Attitudes with the views expressed by NICE in their recent Guidelines for ME/CFS and the submissions from St Bartholomew's Hospital Chronic Fatigue Services to NICE in response to those same guidelines. St Bartholomew's Hospital Chronic Fatigue Services is one of the CNCC clinics set up by the government for treating people with ME. As in the case of almost all of the CNCC clinics it offers a biopsychosocial view of ME and is headed by a psychiatrist. These are the views submitted by St. Bartholomew's Hospital Chronic Fatigue Services for the NICE Draft Guidelines Development Group, in relation to such as wheel chairs for people with ME/CFS (source - Invest in ME (Charity Nr. 1114035) http://listserv.nodak.edu/cgibin/wa.exe?A2=ind0709A&L=COCURE&P=R2063&I=-3&m=17215) =============================== (i) On Disability aids and equipment: The NICE Draft text stated - 6.3.6.8 For adults and children with moderate or severe symptoms, provision of equipment and adaptations (for example, a wheelchair, blue badge or stairlift) to allow individuals to improve their independence and quality of life should be considered, if appropriate and as part of an overall management plan. Comment from St Bartholomew's Hospital Chronic Fatigue Services: (continued on page 54) Page 53/74 www.investinme.org

Journal of IiME Volume 2 Issue 2 www.investinme.org The Use of Aids for People with ME – an Alternative View “We disagree with this recommendation. Why should someone who is only moderately disabled require any such equipment? Where is the warning about dependence being encouraged and expectation of recovery being damaged by the message that is given in this intervention? We are in no doubt that it is a powerful message for a therapist of any sort to provide such aids. Our view is that such aids should only be considered by a multi-disciplinary therapeutic team as a whole, and usually in the context of providing a temporary means for a patient to increase their activity levels. An example would be providing a wheelchair for a bed-bound patient as part of their active rehabilitation programme. In our opinion, such aids should never be seen as a permanent solution to disability in this illness.” ------------------------------------------Another part of the NICE Draft Guidelines: 1.3.1.8 For adults and children with moderate or severe symptoms, provision of equipment and adaptations (for example, a wheelchair, blue badge or stairlift) to allow individuals to improve their independence and quality of life should be considered, if appropriate and as part of an overall management plan. In reply to this St Bartholomew's Hospital Chronic Fatigue Services wrote: “Equipment and aids may hinder recovery as much as help it, and their prescription needs to consider both outcomes. We believe disability aids can help a patient towards recovery if their use encourages a widening and increase in their own activities, on a temporary basis, as a means of supporting a rehabilitation programme. They should rarely if ever be used for patients with only moderate disabilities.” ------------------------------------------From their web site - [http://www.bartsandthelondon.org.uk/formedia Invest in ME (Charity Nr. 1114035) /press/release.asp?id=1216] St Bartholomew's Hospital Chronic Fatigue Services claim that theirs is a centre offering pioneering treatment for CFS/ME. “The centre is a unique partnership between three separate Trusts which allows patients to experience an integrated “mind and body” approach involving physicians, psychiatrists, psychologists, physiotherapists and occupational therapists.” The St Bartholomew's Hospital Chronic Fatigue service contains a recommended reading list on its web site which offers literature from wellknown psychiatrists. The treatments offered at St Bartholomew's Hospital Chronic Fatigue Services are indicative of their approach to ME/CFS – “The treatment options that are available at our service include Cognitive Behavioural Therapy (CBT) provided by Clinical Psychologists, Graded Exercise Therapy (GET) provided by Physiotherapists and a Return to Work Programme and activity management run by Occupational Therapy. “ and “we are one of the study centres involved in the PACE trial. This large-scale trial is the first in the world to test and compare the effectiveness of four of the main treatments currently available for people suffering from CFS/ME. “ despite the PACE trials being condemned by ME patients for their use of the flawed Oxford diagnostic criteria [see http://www.investinme.org/Documents/Journal s/Journal%20of%20IiME%20Vol%201%20Issue%20 2.pdf]. The Oxford (1991) criteria have been criticised for being too broad -- they specifically include those with psychiatric fatigue and they potentially capture people suffering from “fatigue” that occurs in 33 different disorders -and for specifically excluding those with neurological disorders such as ME. Page 54/74 Journal of IiME Volume 2 Issue 2 www.investinme.org The Physiology of Exercise Intolerance in Patients with Myalgic Eencephalomyelitis (ME) and the Utility of Graded Exercise Therapy By S. Pierce* & P.W. Pierce † * Department of Structural and Functional Biology, University of Insubria, Via J.H. Dunant 3, I-21100 Varese, Italy. simon.pierce@uninsubria.it † George Eliot Building, Clifton Campus, Nottingham Trent University, Nottingham, NG11 8NS, United Kingdom. ABSTRACT This review discusses the suitability of graded exercise therapy for the treatment of myalgic encephalomyelitis (ME), based on current knowledge of the underlying physiology of the condition and the physiological effects of exertion on ME patients. A large body of peerreviewed scientific literature supports the hypothesis that with ME an initial over-exertion (a period of metabolic stress) in conjunction with viral infection depletes concentrations of the metabolic regulator glutathione, initiating a cascade of physiological dysfunction. The immune system and muscle metabolism (including the muscles of the cardiovascular system) continually compete for glutathione, inducing a state of constant stress that renders the condition chronic. The impairment of a range of functions means that subtly different suites of symptoms are apparent for different patients. Graded exercise therapy has proven useful for a minority of these, and the exacerbation of symptoms for the majority is not subjective but has a physiological basis. Blanket recommendation of graded exercise therapy is not prudent for such a heterogeneous group of patients, most of which are likely to respond negatively to physical activity. Following exercise, patients with myalgic encephalomyelitis (ME) uniquely exhibit exacerbated symptoms and a suite of measurable physiological changes indicative of stress (sub-optimal metabolic performance; e.g. reduced respiration and heart rate, increased glycolysis and lactic acid production, and concomitant limitation of activity1-5). Although these symptoms may not be universal6, a significant subgroup of ME patients are affected in this manner7. The issue of exercise is critical for the treatment of the condition as one school of thought recommends “graded exercise therapy” as a general remedy for ME whilst another recognises that exercise intolerance may have an underlying physiological cause that may actually be aggravated by physical exertion. This difference of opinion influences policy: graded exercise therapy is one of the principal recommendations of the current Invest in ME (Charity Nr. 1114035) NICE draft guidelines for the treatment of patients “mildly to moderately affected” by ME (p. 21, lines 20 to 23) 8. Although recent general reviews of ME exist911, our aim is to specifically review evidence for the mechanisms by which physical activity affects ME patients, and to investigate how graded exercise therapy may help or hinder recovery. Although no single randomised controlled study has yet attempted to investigate every aspect of ME, the combined weight of empirical evidence to date indicates that the condition is characterised by a complex series of events involving reserves of metabolic regulators such as glutathione, muscle metabolism and the cardiovascular system. A significant body of literature suggests that these imbalances are associated with a (continued on page 56) Page 55/74

Journal of IiME Volume 2 Issue 2 www.investinme.org The Physiology of Exercise Intolerance in Patients with Myalgic Eencephalomyelitis (ME) and the Utility of Graded Exercise Therapy dysfunctional immune system impaired by viral infection. Indeed, a hallmark of ME is a range of symptoms, varying in extent between patients, suggesting that a range of functions are impaired to greater or lesser degrees. ME typically follows a flu-like illness, with elevated concentrations of viral particles subsequently detectable in blood and muscle tissues12. Post-viral fatigue is a well established possible consequence of infection by a range of different viruses13-17, with enteroviruses specifically implicated in the case of ME – elevated concentrations of viral RNA sequences resembling coxsachie virus B are detectable in muscle tissue12. Furthermore, the majority of the limited number of ME patients so far treated with antiviral drugs (interferons) were able to return to work following treatment18, also suggestive of a persistent ‘smoldering infection’19. Crucially, post-viral fatigue is not related to the muscle disuse and deconditioning that can result from the initial period of illness12. Indeed, the mechanism underpinning postviral fatigue is a multifaceted physiological imbalance. Nijs and co-workers20 found that, for ME patients, graded exercise resulted in faulty regulation of the immune system, specifically increased activity of the enzymes “elastase” and “RNase L”. RNase L is a key component in the cell’s virus detection system and is up-regulated in response to viral infection. However, elastase degrades RNase L and is normally involved in removing it from the cell when concentrations are too high. Why should both be highly expressed in ME patients? Elastase is activated and degrades the RNase L in the absence of metabolic regulators such as glutathione. (Glutathione is an amino acid complex that modifies enzyme activity throughout the body, and ME patients exhibit either lower concentrations or an imbalance between its active and inactive forms21-23.) Thus the simultaneous overactivation and mis-regulation of this part of Invest in ME (Charity Nr. 1114035) the immune system can be explained by glutathione depletion. A range of factors contribute to glutathione depletion in the general population, including infection, the oxidative stress induced by strenuous or sustained exercise, and the long-term elevation of the stress hormones cortisol and adrenalin24. Furthermore, glutathione is also involved in sustaining respiration (i.e. the production of chemical energy compounds such as ATP in the mitochondria) thereby providing energy for active tissues such as muscle. Thus muscle tissue effectively competes with the immune system for glutathione25 – sustained physical activity reduces the amount of glutathione available to the immune system, resulting in immune dysfunction. Conversely, an overactive immune system reduces the amount of energy available for muscle tissue, also exacerbating oxidative stress, and can account for both the chronic fatigue and pain (by inducing lactic acid production) that characterise ME. Thus, following an initial period of stress, glutathione concentrations may be too low for the optimal function of both the immune system and muscle tissues, paving the way for both persistent viral infection and fatigue, both of which feedback from each other to render the condition chronic. This situation is compounded by the fact that glutathione not only has a supporting role in the immune response but also directly inhibits the replication of enteroviruses by blocking the formation of one particular protein (glycoprotein B) shared by all – including coxsachie viruses. Indeed, glutathione concentration is a major factor influencing the expression of other persistent viral infections such as HIV26-29. Thus glutathione depletion not only suppresses the immune system, it leaves the body particularly defenceless against enteroviruses. Sustained exercise or stress can deplete glutathione (continued on page 57) Page 56/74 Journal of IiME Volume 2 Issue 2 www.investinme.org The Physiology of Exercise Intolerance in Patients with Myalgic Eencephalomyelitis (ME) and the Utility of Graded Exercise Therapy concentrations to the point where viral RNA is no longer prevented from replicating, aiding either an initial infection or the renewed replication of previously blocked viral RNA present in muscle tissue and blood27, 29. Thus glutathione depletion is a strong candidate for ‘the trigger for reactivation of endogenous latent viruses’ in ME30. A small number of studies demonstrate that foods rich in glutathione or direct glutathione injection help to relieve fatigue in ME patients, and may clear active viral infections31, 32. Although the above studies have concentrated on skeletal muscle, the heart (and the postural leg muscle involved in pumping blood back to the heart) is not exempt from glutathione depletion. Thus the above mechanism can also account for the range of cardiovascular problems associated with ME, including orthostatic (standing) intolerance (reviewed by Spence and Stewart33). Patients with orthostatic intolerance ‘have continuous disability and commonly have exercise intolerance’33. Together, this evidence suggests that chronic fatigue in ME is symptomatic of the following sequence of events: a period of infection or strenuous physical or mental activity results in glutathione depletion; this renders the immune system relatively ineffective, particularly against enterovirus infection; the immune system becomes constantly activated (and inefficiently governed) because it has insufficient resources (glutathione) to completely rid the body of viral particles; the constantly elevated energy demand of the immune system detracts from other metabolic functions (particularly energy-demanding systems such as skeletal muscles and the cardiovascular system); limitation of respiratory and cardiovascular systems further locks the patient into a vicious cycle of inefficient energy production and use; increased reliance on anaerobic metabolism leads to lactic acid production and associated muscle pain. Invest in ME (Charity Nr. 1114035) Clearly, the performance of energydemanding activities such as exercise can only aggravate this situation. Indeed, 82 % of ME patients in a recent study stated that graded exercise therapy worsened their condition, and only 5 % found it useful (compared to 70 – 75 % of patients who found either pain management or ‘pacing’ of daily activities useful)34. Furthermore, the Canadian Clinical Treatment Protocol warns that “externally paced ‘Graded Exercise Programs’ or programs based on the premise that patients are misperceiving their activity limits or illness must be avoided”35. If exercise is so detrimental, why is graded exercise therapy often recommended as a treatment for ME? Firstly, many of the studies cited here are recent, and the information and implications have perhaps not yet filtered up to policy makers. Secondly, the reclassification of ME as an ambiguous ‘chronic fatigue syndrome’ (CFS) by members of the psychiatric profession assumes that the symptoms have no physiological basis and are best treated with the traditional psychiatric method of facing and overcoming a problem, rather than direct removal of the problem at source. However, this approach jumps from hypothesis to treatment without investigating the mechanisms involved, perhaps explaining why “no psychiatrist has ever cured an ME patient using psychiatric treatments”19. Psychiatry, by definition, should not have authority over the treatment of physiological disorders, particularly those that occur chiefly in muscle tissues. Graded exercise therapy is founded on, and perpetuates, the myth that ME patients are simply malingering, while most are frustrated by their incapacity to satisfactorily conduct critical aspects of daily life34. ME is a heterogeneous disorder that affects different patients to varying degrees and with (continued on page 58) Page 57/74

Journal of IiME Volume 2 Issue 2 www.investinme.org The Physiology of Exercise Intolerance in Patients with Myalgic Eencephalomyelitis (ME) and the Utility of Graded Exercise Therapy subtly different suites of symptoms. At best, graded exercise therapy has relieved symptoms for (but not cured) a tiny minority of patients, whilst the weight of empirical evidence indicates that exercise has direct and persistently negative impacts on the physiology and quality of life of a significant subgroup of ME patients. Any universally applied therapy is unlikely to address the heterogeneity of ME, and graded exercise is particularly unsuitable as it may worsen the condition, and should not be generally recommended without a high degree of confidence that it will not be applied to susceptible patients: it is difficult to conceive of a more inappropriate therapy for ME. By increasing the risk of relapse and overall health risks, rather than reducing them, graded exercise therapy also risks increasing the burden of illness on society at large. The present review suggests that an approach based on treatment of the underlying physiological dysfunction will be more fruitful. Abbreviations ATP = Adenosine triphosphate, RNase L = 2’,5’-oligoadenylate (2-5A) synthetase/Ribonuclease L Literature cited 1 De Becker PJ, Roeykens J, Reynders N, McGregor N & De Meirleir K. 2000. Exercise capacity in chronic fatigue syndrome. Archives of International Medicine 160: 32703277. 2 Fulcher KY & White PD. 2000. Strength and physiological response to exercise in patients with chronic fatigue syndrome. Journal of Neurology, Neurosurgery, and Psychiatry 69: 302-307. 3 4 Nus J, De Meirleir K, Wolfs S & Duquet W. 2004. Disability evaluation in chronic fatigue syndrome: associations between exercise capacity and activity limitations/participation restrictions. Clinical Rehabilitation 18: 139-148. 5 Sorensen B. Streib JE, Strand M, et al. 2003. Complement activation in a model of chronic fatique syndrome. Journal of Allergy and Clinical Immunology 112: 397-403. 6 Sargent C, Scroop GC, Nemeth PM, Burnet RB & Buckley JD. 2002. Maximal oxygen uptake and lactate metabolism are normal in chronic fatigue syndrome. Medicine & Science in Sports and Exercise 34: 51-56. 7 chronic fatigue syndrome. Journal of Clinical Pathology 58: 1126-1132. 8 National Institute for Health and Clinical Excellence (NICE). CFS/ME: full guideline DRAFT (September 2006). 9 Afari N & Buchwald D. 2003. Chronic fatigue syndrome: a review. American Journal of Psychiatry 160: 221-236. 10 Patarca-Montero R, Antoni M, Fletcher MA & Klimas NG. 2001. Cytokine and other immunologic markers in Chronic Fatigue Syndrome and their relation to neuropsychological factors. Applied Neuropsychology 8: 51-64. 11 Hooper M. 2006. Myalgic Wong R, Lopaschuk G, Zhu G, et al. 1992. Skeletal muscle metabolism in the chronic fatigue syndrome: in vivo assessment by 31P nuclear magnetic resonance spectroscopy. Chest 102: 1716-1722. Invest in ME (Charity Nr. 1114035) Encephalomyelitis (ME): a review with emphasis on key findings in biomedical research. Journal of Clinical Pathology (in press) published online 25 Aug. 2006 doi: 10.1136/jcp.2006.042408. 12 Lane RJM, Soteriou BA, Zhang H, & Archard LC. 2003. Enterovirus related metabolic myopathy: a postviral fatigue syndrome. Journal of Neurology, (continued on page 59) Page 58/74 Chia JKS. 2005. The role of enterovirus in Journal of IiME Volume 2 Issue 2 www.investinme.org The Physiology of Exercise Intolerance in Patients with Myalgic Eencephalomyelitis (ME) and the Utility of Graded Exercise Therapy Neurosurgery, and Psychiatry 74: 1382-1386. 13 Ayres JG, Flint N, Smith EG, et al. 1998. Post-infection fatigue syndrome following Qfever. Q. J. Med. 91: 105-123. 14 Berelowitz JG, Burgess AP, Thanabalasingham T, et al. 1995. Post-hepatitis syndrome revisited. Journal of Viral Hepatitis 2: 133-138. 15 Kerr JR, Barah F, Matley DL. et al. 2001. Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent paravirus B19 infection and are associated with prolonged and chronic fatigue. Journal of General Virology. 82: 3011-3019. 16 Hotopf M, Noah N, Wesseley S. 1996. Chronic fatigue and psychiatric morbidity following viral meningitis: a controlled study. Journal of Neurology, Neurosurgery, and Psychiatry 60: 495-503. 17 White PD, Thomas JM, Amess J, et al. 1995. The existence of a fatigue syndrome after glandular fever. Psychological Medicine 25: 907-916. 18 Chia JK, Jou NS, Majera L et al. 2001. The presence of enteroviral RNA (EV RNA) in peripheral blood mononuclear cells (PBMC) of patients with the chronic fatigue syndrome (CFS) associated with high levels of neutralizing antibodies to enteroviruses. Clinical Infectious Diseases 33: 1157. 19 Hyde B. 2006. A new and simple definition of myalgic encephalomyelitis and a new simple definition of chronic fatigue syndrome & a brief history of myalgic encephalomyelitis and an irreverent history of chronic fatigue syndrome. Invest in ME, UK. 20 Nijs J, Meeus M, McGregor NR, Meeusen R, De Schutter G, Van Hoof E & De Meirleir K. 2005. Chronic fatigue syndrome: exercise performance related to immune Invest in ME (Charity Nr. 1114035) dysfunction. Medicine & Science in Sports and Exercise 37(10): 1647-1654. 21 Richards RS, Roberts TK, Dunstan RH, McGregor NR & Butt HL. 2000. Free radicals in chronic fatigue syndrome: cause or effect? Redox Report 5(2-3): 146-147. 22 Manuel y Keenoy B, Moorkens G, Vertommen J, Noe M & De Leeuw I. 2000. Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium. Journal of the American College of Nutrition 19(3): 374-382. 23 Kurup RK & Kurup PA. 2003. Hypothalamic digoxin, cerebral chemical dominance and myalgic encephalomyelitis. International Journal of Neuroscience 113: 683-701. 24 Ji LL. 1995. Oxidative stress during exercise: implication of antioxidant nutrients. Free Radical Biology & Medicine 18(6): 10791086. 25 Bounous G & Molson J. 1999. Competition for glutathione precursors between the immune system and the skeletal muscle: pathogenesis of chronic fatigue syndrome. Medical Hypotheses 53(4): 347-349. 26 Roederer M, Raju PA, Staal FJT, Herzenberg LA & Herzenberg LA. 1991. Nacetycysteine inhibits latent HIV expression in chronically infected cells. AIDS Research and Human Retroviruses 7: 563-567. 27 Staal FJT, Roederer M, Israelski DM, Bubp J, Mole LA, McShane D, Deresinski SC, Ross W, Sussman H, Raju PA, Anderson MT, Moore W, Ela SW, Herzenberg LA & Herzenberg LA. 1992. Intracellular glutathione levels in T cell subsets decrease in HIV-infected individuals. AIDS Research and Human Retroviruses 8: 305-311. (continued on page 60) Page 59/74

Journal of IiME Volume 2 Issue 2 www.investinme.org The Physiology of Exercise Intolerance in Patients with Myalgic Eencephalomyelitis (ME) and the Utility of Graded Exercise Therapy 28 Ciriolo MR, Palamara AT, Incerpi S, Lafavia E, Bue MC, De Vito P, Garaci E & Rotilio G. 1997. Loss of GSH, oxidative stress, and decrease of intracellular pH as sequential steps in viral infection. Journal of Biological Chemistry 272(5): 2700-2708. 29 Cai J, Chen Y, Seth S, Furukawa S, Compans RW & Jones DP. 2003. Inhibition of influenza infection by glutathione. Free Radical Biology & Medicine 34(7): 928-936. 30 Van Konynenburg RA. 2004. Is glutathione depletion an important part of the pathogenesis of chronic fatigue syndrome? Presented at the AACFS Seventh International Conference, Oct. 8-10/2004, Madison, Wisconsin. 31 with glutathione injections. CFIDS Chronicle January/February 1998. 32 Cheney PR. 1999. Evidence of glutathione deficiency in chronic fatigue syndrome. American Biologics 11th International Symposium, Vienna, Austria. Tape No. 07-199: available from Professional Audio Recording, P.O. Box 7455, LaVerne, CA 91750. 33 Spence V & Stewart J. 2004. Standing up for ME. Biologist 51(2): 65-70. 34 25% ME Group. 2004. Severely affected ME (myalgic encephalomyelitis) analysis report on a questionnaire issued January 2004. 25% ME Group, Troon, Ayrshire, UK. pp. 8. 35 Jain AK, Carruthers BM & Van de Sande MI. 2004. Fibromyalgia Syndrome: Canadian Clinical Working Case Definition, Diagnostic and Treatment Protocols-A Consensus Document. Journal of Musculoskeletal Pain 11(4): 3-107. From CBT, GET And Human Rights: by R. Mitchell and V. Mitchell from http://www.investinme.org/Documents/PDFd ocuments/CBT%20GET%20and%20Human%20 Rights.doc Contrast the intellectual and scientific rigour applied in the approval process for the licensing of drugs for clinical use, with the lack of scientific and intellectual rigour applied in the NICE draft with regard to the recommendations for the use of Psychological Therapy in CFS/ME. When compared with the extensive clinical trialling over many years and the independent scrutiny a drug therapy is subjected to, the small and heavily criticised evidence base used to justify the recommendation of CBT and GET for CFS/ME in the NICE draft is seen to be totally inadequate. In respect of informed consent, it cannot arise. There simply cannot be informed consent Salvato P. 1998. CFIDS patients improve since there are important ethical, safety and regulatory questions arising from these treatments, to be addressed. Ethical and safety questions such as those raised in the MRC Neuroethics Report 2005 should be paramount. It is hard to envisage any Independent authority clearing a drug for Human testing or use without ethical and safety issues, like those surrounding Psychological Therapy, being resolved. By ignoring these serious issues with regard to Psychological Therapy, we believe that, as drafted, the Guidelines violate the right of clinicians and patients to the highest, safest standards of Medical practice and care, amounting to a violation of their Human Rights. This is a Human Rights issue. Without an answer to whether this type of therapy is ‘acceptable to Society’ and if it is, without an effective Regulatory framework governing its development and use, there is the serious risk that sick and vulnerable people everywhere will be vulnerable to exploitation and abuse at the hands of the vagaries of power, politics and prejudice. Invest in ME (Charity Nr. 1114035) Page 60/74 Journal of IiME Volume 2 Issue 2 www.investinme.org On the 22 August 2007 The National Institute of Health and Clinical Excellence (NICE) published guidelines for doctors, titled: Chronic Fatigue Syndrome / myalgic encephalomyelitis (or encephalopathy) - Diagnosis and management for CFS/ME in adults and children. Eight of the biggest ME organisations and more in the UK are strongly critical of the NICE guidelines and have declared them ’unfit for purpose’. They demand a considerable rewrite of the guidelines. We think, as they do, that the NICE guidelines will make the situation even worse for ME patients than it is at present. Some of the critical points include: Cognitive behavioural therapy (CBT) and graded/graduated exercise therapy (GET) are recommended as first line treatments for mild or moderate CFS/ME, and ‘Activity Management strategy’, which has elements of CBT and GET, for the most severely ill. These therapies have shown to have little effect (CBT) or are potentially harmful (GET). Large scale patient surveys in the UK show opposite results to the NICE guidelines. Apart from the outlined concerns, the key psychiatrists themselves, who actively promote these approaches say that CBT and GET cannot be described as ‘curative’ and/or have only a short term effect. ( Michael Sharp, AACFS, (now IACFS/ME) ) International CFS Conference, Cambridge, Mass., 10.-11. oktober 1998. S. Wessely, Editorial, JAMA 19.9.2001:286:11), Marcus JH Huibers + S. Wessely, Psychological Medicine, 2006:36(7):895-900). CBT and GET are not specific methods for ME/CFS because the cause is unknown. Many have been made worse by these therapies. (Devanur & Kerr 2006): http://www.cfidscab.org/rc/Devanur.pdf The NICE Guidelines did not want to include or Invest in ME (Charity Nr. 1114035) Norway’s ME Association The Norwegian ME Association, Norges Myalgisk Encefalopati Forening, was founded in 1987. It has established self-help groups in many counties, and once a year all the group leaders gather in Oslo for an 'update' seminar, and to share their experiences and get new inspiration. Its office is in Oslo, centrally located behind the university. It provides factual information about ME to lay and health professionals, and helps and supports people with ME and their families and carers. Twice a year, it publishes a newsletter, and a magazine "ME-News" with medical articles and useful information. It works both nationally towards health authorities and government, and internationally to raise awareness of the seriousness of ME. The association is also a member of the Norwegian Federation of Organisations of Disabled People (FFO). www.me-forening.no concentrate on research which actually documents the claims of the users. Results of cognitive behavioural therapy and graded excercise therapy from large scale patient surveys * 3074 patients (Jones, 2003) - CBT made no difference 55 % - CBT made worse 22 % - GET made no difference 16 % (continued on page 62) Page 61/74

Journal of IiME Volume 2 Issue 2 www.investinme.org - GET made worse 48 % - Pacing activity with rest was the most helpful 90 % - Bed rest the most helpful 89 % * 2338 patients (Action for M.E., 2001) - CBT helpful 7 % - CBT not helpful 67 % - CBT made worse 50 % - Activity managment most favourable 89 % - Rest most favourable 91 % * 437 patients (25 % M.E. Group, 2004) - CBT helpful 7 % - CBT not helpful 93 % - GET helpful 5 % - GET not helpful 95 % - Psychotherapy helpful 10 % - Psychotherapy not helpful 90 % - McCully 2005): http://www.dynamicmed.com/content/pdf/1476-5918-4-10.pdf Patients can develop training intolerance, and this is shown by reduced activity level after 4-10 days. The inability to maintain an activity level, caused by worsening of symptoms, suggests that patients have reached an activity threshold. See also a more recent study by Yoshiuchi et. al (2007) which documents increased symptoms following graded excercise http://www.cfidscab.org/rc/Yoshiuchi.pdf It has been shown that patients with ME have increased oxidative stress during excercise, and this increase continues even after the the excercise has been stopped(Kennedy et al. 2005): http://www.cfidscab.org/rc/Kennedy.pdf It is important to note that patients do not protest about treatments which make them better, but they do protest against treatments which either do not work or make them worse. The most helpful was activity managment and symptom control respct. 70 % - 75 % At a conference in Fort Lauderdale, January 2007, Professor Fred Friedberg talked about a two year study in which patients used an actigraph ( pedometer) to register their activity level. The patients reported subjectively increased activity levels, but at the same time the actigraph showed that the number of steps taken sank drastically. The results showed that graded excercise therapy did not lead to improvement in relation to increased total activity level (Friedberg 2002). Physical activity exceeding ”limit/ceiling effect” leads to increased symptoms and deterioration of the condition (Black & Invest in ME (Charity Nr. 1114035) Action for M.E. M.E. in the UK. Severely neglected. Membership survey, 2001. http://www.afme.org.uk/res/img/resources/S everely%20Neglected.pdf Jones DM. Some facts and figures on CBT, GET and other approaches, 2003. http://www.meactionuk.org.uk/SOME_FACTS_ AND_FIGURES_ON_CBT.htm 25 % M.E. Group. Severely Affected ME (Myalgic Encephalomyelitis) Report on Questionnaire, Issued January 2004. (continued on page 63) Page 62/74 Journal of IiME Volume 2 Issue 2 www.investinme.org http://www.25megroup.org/Group%20Leaflets/G roup%20reports/March%202004%20Severe%20ME %20Analysis%20Report.doc VanNess JM, Snell CR. Stevens SR, Bateman L, Keller BA. FACSM. Using Serial Cardiopulmonary Exercise Tests to Support a Diagnosis of Chronic Fatigue Syndrome. Medicine & Science in Sports & Exercise: Volume 38(5) Supplement May 2006 p S85 http://www.acsmmsse.org/pt/re/msse/fulltext.00005768-20060500101259.htm;jsessionid=HV9HJwhtvwtNlGyB7vvTzBp DQt0xbKl87pnqpqrSnCTT9QlWCNXx!65375592!18 1195628!8091!-1?nav=search&fullimage=true VanNess and his coworkers (2006) have written the following: “Reduced functional capacity and postexertional malaise following physical activity are hallmark symptoms of Chronic Fatigue Syndrome (CFS). That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing (GXT) with CFS patients. The reproducibility of VO max in healthy subjects is well documented. This may not be the case with CFS due to delayed recovery symptoms. Conclusion: In the absence of a second exercise test, the lack of any significant differences for the first test would appear to suggest no functional impairment in CFS patients. However, the results from the second test indicate the presence of a CFS related postexertional malaise. It might be concluded then that a single exercise test is insufficient to demonstrate functional impairment in CFS patients. A second test may be necessary to document the atypical recovery response and protracted malaise unique to CFS.” Both the Association of British Neurologists and The British Psychological Society have criticised the NICE guidelines. Much of the research referred to, has been done Invest in ME (Charity Nr. 1114035) on patients with fatigue, but who do not have ME. The project has not been a cooperation where professionals and carers have taken part as it is described in the NICE guidelines. It is written that there was cooperation but the ones who have been involved as user representatives feel it was not real cooperation, but a form of masquerade. Considerable and documented contributions from users and experts who support the physical/organic cause of the illness have been ignored in a great degree. This and lack of real user contribution has also been confirmed in personal communication between organisations and Norway’s ME Association. The documents have been delivered to Competence Network co/Cecilie Daae. The NICE guideline’s definition of the illness is so wide that it includes almost everyone with unexplained fatigue, and not ME, diagnostic code G93.3. There is a clear need to subgroup patients who fall under the umbrella term CF (fatique syndromes). The use of overview articles as research methods, have clear weaknesses when studies of heterogeneous populations are included - the methodology critique doesn’t focus on the fact that the evidence base is very weak and the dropout analysis cannot find out who, and why, the dropout rate in a few studies is very high. See also the critique the Association has produced in relation to the Knowledge centre’s report. A lot of information on the physiological abnormalities was presented, but NICE has ignored this for the benefit of the ”biopsychosocial model” of the illness. This is a clear action which favours political strategies instead of medical and scientific evidence. The urgent need for biomedical research to uncover the underlying cause(s) have not been taken onboard. NICE has failed on several “Key Items” (Key Items 3, 5, 8, 10 and (continued on page 64) Page 63/74

Journal of IiME Volume 2 Issue 2 www.investinme.org 20) in the use of AGREE INSTRUMENT (Appraisal of Guidelines Research and Evaluation, the AGREE Collaboration, Sept. 2001). Costing report The cost of these treatment strategies is based on assumptions, which the costing report says in the introduction. In addition the report comments on excisting uncertainties in the diagnosis and treatment of patients with CFS/ME. The high costs are expected to become even higher than estimated. The British organisations are questioning these costs for interventions which don’t have documented effect, and which the ptients themselves don’t want, at the same time when official bodies don’t prioritise biomedical research. Legal evaluation The critique of the NICE guidelines for ME/CFS was taken to High Court in the Royal Courts of Justice on June 17 2008. Two named persons act as litigants. The judge concluded that there are grounds for a full hearing. It is estimated that the hearing will take at least two days. The date has not determined, but expected soon. (Editor: the date is set for 11 and 12 February 2009) There is diminishing trust in NICE within the British population because its decisions are constantly criticised and challenged. One questions its evaluation process and whether some distinct groups are disadvantaged by the process. There is a separate report where a wide range of patient organisations, among others cancer and multiple sclerosis organisations, Alzheimer’s Society and many other organisations for neurological and autoimmune conditions, have come forward with searing critique of NICE’s conduct and evaluations process. (House of Commons Health Committee: National Institute for Health and Clinical Excellence (NICE). Written evidence. HC 503-II. 17. May 2007). Invest in ME (Charity Nr. 1114035) Facts on ME Thyroid malignancy in ME/CFS patients greatly exceeds the normal incidence of thyroid malignancy in any known subgroup. The thyroid malignancy incidence in the ME/CFS group may exceed 6,000 / 100,000. As part of their investigation, Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) patients should be examined by thyroid ultrasound for evidence of thyroid pathology and malignancy. Thyroid pathology may be missed in this group of patients if investigation relies only upon serum testing for TSH, FT3, FT4, microsomal and thyroglobulin antibodies, which are usually normal. Thyroid uptake scans tend also to be normal and may also miss malignant lesions. A newly recognized syndrome may exist in ME/CFS patients characterized by: (a) thyroid malignancy, (b) persistent abnormal cortical and subcortical SPECT brain scans (NeuroSPECT), (c) failure of thyroidectomy surgery and hormone replacement to correct the fatigue syndrome, and (d) an unusual high incidence of cervical vertebrae osteoarthritic changes. ME/CFS patients with treated non-malignant thyroid disease and abnormal NeuroSPECT scans may also fail to improve despite adequate thyroid hormone replacement. From Thyroid Malignancy Association with Cortical & Subcortical Brain SPECT Changes In Patients Presenting with a Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. AJ38-2 Hyde MD, Byron Leveille MD Jean Vaudrey, Sheila Green, Tracy Page 64/74 Journal of IiME Volume 2 Issue 2 www.investinme.org FROM 2 SCORE AND 5 TO 3 SCORE AND 10 A personal view of ME by Nan Socolow My story is similar to all other PWC's (people with CFIDS = people with ME) stories. First the signs and symptoms - bizarre, strange - unlike any other illness we've had. Then, the disbelief, the almost endless search for understanding physicians to name this disease, the expense of medical tests, treatments, forays into alternative therapies (is it all in my head? The mind/body connection?), the vials of useless medications and antibiotics adding injury and insult to our bodies and psyches. Finally, diagnosis and the shock that something chronic was wrong with us, the acceptance of a disease with a name even if the name was "Yuppy Flu" or "Major Kvetch Illness" or Encephalomyelitis. "ME" - Myalgic In short, CFIDS. And resoundingly, the resulting conviction that we are the canaries in the coal mine, the thin edge of the wedge of pollution of the water we drink, the food we eat, the air we breathe, pollution that is causing illness on Earth. My CFIDS started in 1983 when Epstein Barr and Post Viral Fatigue Syndrome were the buzzwords. I was a vital 45 years old, divorced, active and hardworking mother of 3 teenagers, maybe a type A alpha female in linen jackets, silk blouses, heels and hose and smartly bobbed hair. A flu, followed by some sort of existential, clearly felt defining moment - a "click" in my body - changed everything in my life from major to minor and I endured a draconian fluish feeling for months and months and months. The "hit by a truck" poleaxed feeling, the extreme hangover that never goes away even though alcohol is not tolerated, not even a sip. You are familiar with the symptoms - if you're reading this piece in the Chronicle - I won't list them here. But if you've almost fainted in detergent and soap and scented candles and air "freshener" aisles of your supermarket, Invest in ME (Charity Nr. 1114035) Nan Socolow Nan Socolow is a poet who has lived for 20 years on a small island 90 miles south of Cuba in the British West Indies. She was Director of Development at Ford's Theatre in Washington, DC, Administrator of Rockefeller College at Princeton University, a Language Services Escort Officer of the US State Department and United States Information Agency. She worked in the White House during President Carter's Administration on the first Arab-Israeli Peace Treaty Signing events. She has three children and four grandsons and CFIDS). almost keeled over upon entering a department store with the scent of tung oil on new clothing, almost collapsed upon having your car's gas tank topped off, almost passed out from the sensory input (aural, physical, emotional, etc) in any airport or crowded public place, reeled from a few sips of beer or champagne or a gin and tonic, then you've been there, too. The remissions and flare-ups. The awful days, when one could barely get out of bed, and the better ones when a drive to the market was a possible endeavor. The little wee walnut-sized life when everyone else is out there in the can-do life broad as Montana. The good news is that I have had CFIDS for the past 25 years. The bad news is that I have had CFIDS for the past 25 years. I am now 70 years of age, to my great (continued on page 66) Page 65/74

Journal of IiME Volume 2 Issue 2 FROM 2 SCORE AND 5 TO 3 SCORE AND 10 surprise, and looking forward to 2 plus decades, perhaps. In our case - in the case of we who contend with and accept the constraints and miseries CFIDS imposes, financial, emotional, physical - contrary to what Nietzsche said, whatever doesn't kill us lets us keep on living with CFIDS. Instead of moaning or grieving or thinking of what is lost and past, I am grateful for what remains. For the remains of the day. A small home with no stairs, children and grandchildren in touch though living in faraway countries (Singapore, Russia), friends constantly "there" on the internet and through email and in person. I still enjoy reading, writing, gardening, cooking, intellectual pastimes (i.e. thinking about sex but not doing much about it, raging and ranting about politics and voting by email, helping those less fortunate, playing scrabulous and earning freerice.com online and laughing hard as often as possible) and the very rare social occasion. A lunch with friends. A dinner out. A warm bath in the sea. Renunciation of consumerism. I used to wear glad rags, evening clothes, bikinis and the like. Now I wear Saucony sneakers in different colors and long pants, skirts, tshirts, shorts, and am fully dressed with a smile. Comfy. And make-up - what the heck - mascara, lipstick, blush to put as pleasant a phiz as possible on the face of this illness. And I watch my every footstep and try to avoid major hassles, aggro and agita. After burning out in two very high stress jobs in my 40s, in the 1980s (working for an Ivy League University as Administrator of a College of 500 freshmen and sophomores all brilliantly fraught, and then working for the US State Dept and USIA in Washington DC accompanying guests of the US Gov't on allexpenses-paid 30 day trips around the US (sometimes 9 cities in 30 days with no downtime, on call 24/7 very best job and worst job I ever had), I found (with Canadian friends) a small British island 90 Invest in ME (Charity Nr. 1114035) miles south of Cuba where I could live and work in a manana atmosphere in a hotel or real estate firm. A backwater, an island time forgot; only one hour by jet from Miami. A funny and friendly and laidback place; sign in a local's calabaza plot (calabaza, Caribbean orange pumpkin w. green skin, delicious) - "Don't Molest My Vegetables!". Cows still mosey down the island's one road with white cattle heron perched on their shoulders. The sea turquoise and calm and clear as glass. When asked "how are you" the locals reply "not as good as you", "can't complain", "keeping on keeping on" and "fine as sifted flour!". The weather is wonderful here, hot and sunny and salubrious - always summer - most of the time, except during hurricane season when I lost my home in Ivan 4 years ago. Sea went right through my home like Grant through Richmond. Sherman through Atlanta. Katrina through the 9th Ward. I had insurance and so was lucky enough to rebuild - "all new stuff" - , but no longer have any attachment to "things". So, there it is. A chronicle of decades of illness, but of hope as well. Hope that research and development will find a remedy for this global illness. Hope that the medical establishment will recognize this disease for the scourge it is, and will rename it something more worthy of respect like MS or ALS or AIDS or PD... instead of AST (Always Sick and Tired) or PCK (Pitiful Chronic Kvetch) or CFIDS, which doesn't do justice to the miserably lifechanging aspects of this illness. And to all of us patiently bearing the burden of this disease with as much humor as we can muster, I wish us comfort and happy times, a great measure of joy, surcease from suffering, looking ahead and knowing that life is full of surprises, many of them happy. Page 66/74 www.investinme.org Journal of IiME Volume 2 Issue 2 www.investinme.org Reasons why ME Does Not Belong to the MUS Category…and So Forth B Byy NNoorrwweeggiiaann MMEE AAss ssoocciiaatt iioonn 1. ME does not belong to the description of MUS The classic presentation of ME is as an illness with its own diagnosis and diagnostic code, and as such, ME does not fulfill the criteria of the MUS category as “not fitting any known diagnosis”. Contrast this with an invitation to a seminar in the Health Directorate 26. September 2008. Dr Wyller writes that the diagnosis of Chronic Fatigue Syndrome (CFS) is not in the WHO ICD publication (2008:8). This is incorrect information which has been pointed out earlier. CFS is in the index with a reference to the diagnostic code G93.3. As CFS refers to the same diagnostic code as ME, this means that the condition must be classified under the same code and not under a psychiatric illness (e.g. neurasthenia (chronic fatigue - is not the same as ME/CFS) with code F48.0)(ICD10, printed edition from 1992). Many therefore refer to the description ME/CFS. See also KITH 2006. The illness and the illness presentation are not new, neither internationally or in Norway. According to infectious disease specialist and previously head of department at Ullevål University Hospital, Oddbjørn Brukbakk, the condition is described in classic, old medical literature in infectious diseases. The diagnosis myalgic encephalopathy/encephalomyelitis (ME)/Post-Viral fatigue syndrome does not belong to the umbrella term MUS for various reasons. This will be examined more closely below. 2. The WHO classification of ME/Post-Viral Fatigue Syndrome The World Health Organisation (WHO) was established in 1948. Before 1965 the condition debility and undue fatigue in the international classification system was placed under code Invest in ME (Charity Nr. 1114035) Invest in ME have translated this article which was kindly provided by the Norwegian ME Association www.me-forening.no 790.1. The condition was not referred to as ME before 1965. So the first time the WHO referred to ME was in 1965 ICD-8. This was first officially published in 1969 9ICD-8: Vol I code 323, page 158; Vol II (Code Index) page 173). ICD9 was approved in 1977, and ME was listed in the alphabetical index under code 323.9 in Volume II, page 182. The World Health Organisation (WHO) approved ME/Post-Viral Fatigue Syndrome as an illness in its own right in 1969 (Marshall, Williams and Hooper, 2001), and the illness was given the following code in the It cannot be in anyone’s interest (clinicians, researchers, patients, healthcare officials) for doctors to classify an illness based on their personal understanding as to where an illness belongs. international classification of diseases: ICD-10, 93.3 in the chapter of neurological disorders. According to the taxonomic system of the WHO’s international classification system, it is not allowed to classify an illness in more than one category. The Norwegian healthcare officials have endorsed the classification system, something which legally binds the Norwegian doctors and healthcare officials into following (continued on page 68) Page 67/74

Journal of IiME Volume 2 Issue 2 www.investinme.org R Reeaassoonnss wwhhyy MMEE DDooeess NNoott BBeelloonngg ttoo tthhee MMUUSS CCaatteeggoorryy (continued) this system. The system does not allow individual doctors for their own good to classify the condition as F48.0 under mental disorders as long as the criteria for ME are met. It is clearly mentioned under the diagnostic code ICD-10, F48,0 (neurasthenia/chronic fatigue/psychosomatic conditions) that this diagnosis cannot be given until Postviral Fatigue Syndrome/Benign Myalgic Encephalomyelitis (ME,93.3)(ICD10,1999) has been ruled out. It cannot be in anyone’s interest (clinicians, researchers, patients, healthcare officials) for doctors to classify an illness based on their personal understanding as to where an illness belongs. Such practice can lead to mistakes in investigation, diagnosis and treatment. In addition it will lead to incorrect information in the medical records, skews the prevalence numbers and leads to problems in comparing research studies etc. 3. The illness is approved as its own entity in other countries The following information shows the illness is approved as its own entity in several countries. Denmark Now deceased, Professor Viggo Faber MD, knew the illness very well and states the following in one of his articles: ”… involvement of f.ex. ME/CFS among the somatoform is in contrast with many years of research in the USA and elsewhere in the western world, which has led to ME/CFS being acknowledged by the WHO …, and that one in USA and most of the European countries has noted it as a somatic illness giving entitlement to a pension…(there) are very stringent criteria for diagnosing ME/CFS.” (Faber, 2000:22). Invest in ME (Charity Nr. 1114035) Great Britain In 1959 Dr Donald Acheson (later nominated Chief Medical Officer) published an extensive overview of ME entitled The Clinical Syndrome Variously called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia. In this overview ME is clearly seen as a clinical entity. The British Department of Health acknowledged ME as a clinical, organic entity in November 1989 (Hansard HoC: 27th November 1989: 353). Great Britain endorses the WHO ICD-10 and therefore has to follow this classification system. The diagnosis of ME was acknowledged as a distinct clinical entity by the Royal Society of Medicine in 1978 based on thorough work by Lyle and Chamberlain (1978) who had prepared an overview of epidemic neuromyasthenia (another description of ME) in the period 1934-1977. Here a citation of this by Emeritus Professor Malcolm Hooper (2007): ”In 1978 the Royal Society of Medicine accepted ME as a nosological organic entity. The current version of the International Classification of Diseases – ICD-10, lists myalgic encephalomyelitis under G93.3-neurological conditions. It cannot be emphasised too strongly that this recognition emerged from meticulous observation and examination.” (p. 466) ”Today, many patients with fatigue as a major feature of their illness – for example cancer, chronic obstructive pulmonary disease, depression – are being diagnosed with CFS. This has led to confusion, and has left clinicians, patients and carers without recourse to proper clinical and social support.” (p. 467) (continued on page 69) Page 68/74 Journal of IiME Volume 2 Issue 2 www.investinme.org R Reeaassoonnss wwhhyy MMEE DDooeess NNoott BBeelloonngg ttoo tthhee MMUUSS CCaatteeggoorryy (continued) Australia The diagnosis was approved in Australia at the start of 1990. USA In USA the situation is different because they have compiled their own clinical version of ICD. The American CDC published a summary of Chronic Fatigue Syndrome and its Classification in the ICD 31. March 2001 by Donna Dean. It can be found in the archives of Co-Cure or at the following link: http://www.co-cure.org/ICD_code.pdf In the summary it says that ICD-9 was published in 1975 and that the description Benign Myalgic Encephalomyelitis can be found in the alphabetical index and is referred to as code 323.9. 4. The illness was accepted and treated a long time ago in Norway – before 1990 ME is a syndrome diagnosis, and it has been documented that ME was accepted in Norwegian neurology from before 1990. In an article in Tidsskrift for Den Norske Lægeforening (1991;111(2):232) ( Journal for The Norwegian Medical Association) a neurologist, chief consultant Ragnar Stien MD, employed by the Rikshospitalet in the neurology department, confirms that fatigue/tiredness is not a new condition. Dr Stien thought that the Fatigue Syndrome could partly have an organic cause. He thought that the most correct description to use was Post Viral Fatigue Syndrome, a diagnosis he himself had given to a number of patients. Dr Stien demanded that there was extreme asthenia, the patient had muscle pain during physical activity and evidence pointing to a viral infection before. He had examined 20-30 patients with this illness presentation in the 1980s. His impression was that the patients affected suffered from ”abnormally strong fatigability” (p. 232). They had to rest ”hours after minimal exertion”. Even though at that time there was no Invest in ME (Charity Nr. 1114035) scientific evidence to rely on, Dr Stien felt that the patients were so severely affected that the cause was organic. Professor and specialist in general practice medicine, Dr Even Lærum, employed at the Institute of General Practice Medicine, Oslo, underlined the importance of performing a thorough physical examination. He had no objection in using the diagnosis of Chronic Fatigue Syndrome if the patient had extreme fatigue and one could not find other explanations. The treatment was symptom oriented, lifestyle changes and that patients should not put pressure on themselves (TNLF, 1991;111(2):232).The use of the diagnosis was also implemented at the same time by the Neurology department, Haukeland University Hospital. Dr Aarli and Dr Haukenes published an article on the illness in 1995. Here is an extract from this article: ”All experience so far has shown that this illness cannot be beaten by training, because enforced training seems to make the condition worse. This is similar to Post Polio Syndrome, where it has been shown that physical training often makes the muscular weakness worse. Acknowledgement by others that the symptoms are real can be important so as to avoid adding reactive extra symptoms.” (Haukenes and Aarli, 1995:3021) ”... it is patients who have had normal function and work capacity who after a viral illness present with considerable tiredness where causality seems to be connected to the infection as a triggering event ” (ibid.) ”It is well known that an acute infection can be followed by a fatigue syndrome that goes away. The special with this condition is that the fatigue, or exhaustion, lasts so long.” (p. 3017) “ (continued on page 70) Page 69/74

Journal of IiME Volume 2 Issue 2 www.investinme.org R Reeaassoonnss wwhhyy MMEE DDooeess NNoott BBeelloonngg ttoo tthhee MMUUSS CCaatteeggoorryy (continued) read in its entirety on the Internet, and her review of the condition is not therefore referred to here: ”The clinical presentation...appears in immediate connection with an infection” (ibid.). ”Fatigue or exhaustion is the dominating symptom. Even light use of muscles brings on such a feeling of fatigue by the patient that he/she is unable to perform any type of work, often for several days. It is also characteristic that efforts and physical training worsens the fatigue. The physical fatigue has some similarities with myasthenia gravis and has led to the denomination neuromyasthenia.” (ibid., p. 3018) The same year Dr Harald J. Hamre published an article on ME which then was called Chronic Fatigue Syndrome. Here is reproduced some of what he wrote. ”After a thorough diagnostic clarification the patients need a stable, supportive primary care doctor contact, with intermittent diagnostic re evaluation. Support and adequate rest is crucial, based on experience. Many will be totally or partially unable to work for a long time. (Hamre, 1995:3043) Patients with Chronic Fatigue Syndrome "can have significant and long-term relapses if they are pressed for a too high level of activity, e.g. by declaring recovery prematurely ... They have a number of ... symptoms ... that the doctor should know and take seriously.” (ibid., p. 3044). In 1995, Dr Kreyberg also published an article about Chronic Fatigue Syndrome. It can be Invest in ME (Charity Nr. 1114035) http://www.med.uio.no/iasam/forepi/epidem iologi/me/artikler/Et_naergaaende_mote.pdf 5. Diagnosis and necessary investigations And So Forth It is noted in the directorate’s report (2007) that there are strict criteria for diagnosis. In the general practice medicine it is reported that a high proportion of patients present tiredness/fatigue. Extremely few of these get a confirmed diagnosis of ME (G93.3) after years of investigations. The general practice medicine has moreover their own coding system with various umbrella terms. The diagnostic code which is used most often in the general practice medicine is A04 (A, zero, four): ”The diagnosis is difficult because it cannot be confirmed by specific tests, laboratory tests or physical findings. The doctor has to build on the typical illness history and recognition of the clinical presentation. Fatigue is a non specific symptom in the line with fever and nausea and can be provoked by a number of factors. The aim for an operational definition must be a characterisation of this reaction so that it can be recognised clinically and can be limited against other conditions”. (Socialand Health Directorate, 2007:7) At the Ullevål University Hospital, Medical division, a diagnosis is given based on recognised criteria (Carruthers et al, 2003; Fukuda e al. 1994) and a specific diagnostic guide which was formulated by Dr Brubakk and Dr Baumgarten. Infectious disease specialist, previously head of department at (continued on page 71) Page 70/74 Journal of IiME Volume 2 Issue 2 www.investinme.org R Reeaassoonnss wwhhyy MMEE DDooeess NNoott BBeelloonngg ttoo tthhee MMUUSS CCaatteeggoorryy (continued) the infectious disease department at Ullevål, Dr Brubakk, is very familiar with ME/Post Viral Fatigue Syndrome (PVFS) since as long as the 1980s. The occurrence of ME can be compared to Multiple Sclerosis. This is also a diagnosis which demands special investigation. In Bømlo, Hordaland, there are 10 people registered with MS in the MS register. This is a municipality with 12.000 inhabitants. In the same area there are also 10 documented people with ME. In two of the families there is either ME or MS in first degree relatives. This points to clear genetic and immunological components. At the Haukeland University Hospital, department of neurology, where there has been a ”fatigue clinic” for 15 years, they say that disability has to be documented using validated scales such as Fatigue Severity Scale (Krupp et al, 1989), Fatigue Scale (Chalder et al, 1993) and SF-36 (Ware & Sherbourne, 1992). It is considered very important not only to measure physical fatigue, but also cognitive fatigue, because it is often the cognitive dysfunction that patients themselves find most disabling. SF-36 is a well known tool which includes different functional dimensions. Data from a ten year period show that people with ME have fatigue scores at the highest level, from about 23-30 (extreme values) when compared to fatigue in the population (Loge, Ekeberg, Kaasa, 1998). The ME group differs therefore clearly in having far higher scores for total fatigue than one finds in the Norwegian population. More about this can be found in the summary of the biomedical conference in Oslo in 2007 (Stormorken 2007): ): http://www.meforening.no/index.php?option=com_content &task=view&id=103&Itemid=2 Reeves and colleagues at the Centres for Disease Control and Prevention (CDC, Atlanta, Georgia, USA) have explained in a scientific article a clinical, empirical approach to diagnosing and defining CFS (Reeves et al, Invest in ME (Charity Nr. 1114035) 2005). The study showed that patients who had been classified empirically as having ME/CFS, were significantly more disabled (measured using SF-36), more severely fatigued (measured by Multidimensional Fatigue Inventory) and had more frequent and more serious accompanying symptoms than patients with medically unexplained tiredness (MUS/MUPS). The study shows that the empirical definition (by including different fatigue scales) includes all aspects of ME/CFS This is a municipality with 12.000 inhabitants. In the same area there are also 10 documented people with ME. In two of the families there is either ME or MS in first degree relatives. This points to clear genetic and immunological components. which have been specified in the 1994 case definition, and identifies people with ME/CFS in a precise manner which can easily be reproduced both by researchers and clinicians. The empirical definition makes it possible to separate ME from depression and idiopathic fatigue. That said, Jason and Richman (2007) have criticised the empirical definition. The way Reeves and colleagues present it, it will lead to a clear broadening of the criteria in that the prevalence of ME/CFS will increase drastically, from about 800.000-1 million people to 4 million Americans. The critique against Reeves’ empirical definition can be found at the following web address: http://www.iacfsme.org/IssueswithCDCEmpiric alCaseDefinitionandPrev/tabid/105/Default.as px There is a reference to Reeves et al 2007 at: (continued on page 72) Page 71/74

Journal of IiME Volume 2 Issue 2 www.investinme.org R Reeaassoonnss wwhhyy MMEE DDooeess NNoott BBeelloonngg ttoo tthhee MMUUSS CCaatteeggoorryy (continued) http://www.pophealthmetrics.com/content/5/ 1/5 Kathrine Erdman (2008) has published an article in which she explains the biomedical abnormalities that differentiate ME/CFS from depression: http://jaapa.com/issues/j20080301/pdfs/cfs0308 .pdf Harvard-professor Anthony Komaroff has listed up to 10 central findings of biomedical abnormalities in ME/CFS: http://www.cfids.org/cfidslink/2007/062004.pdf Klimas and Koneru (2007) have written an overview of last year’s advances in research. It provides a quick and easy introduction to different areas which document physiological disorders in ME and is highly recommended. ME is not unexplained, it has proven genetic factors, increased inflammation and many immunological changes. There are numerous findings, and one can no longer pretend that the biomedical research does not exist or look away from the biomedical factors in the illness presentation. Lorusso and colleagues (2008) come now up with an article which focuses on the immunological aspects in ME/CFS. They bring forward a high level of cytokines which can explain symptoms such as fatigue and flu like feeling and which can influence NK cell activity. The authors’ hypothesis is that immunological factors form the basis for ME/CFS. Who is best placed at giving the diagnosis? Medicine is based a lot on clinical experience, such has it always been, but with so few patients per general practitioner, it will not be easy to build up enough experience. Based on feedback from patients the Association feels that at present general practitioners do not treat this group of patients in a good enough way (there are exceptions). If the diagnosis is given by a general practitioner, special training is necessary. At present with a demand for a specialist evaluation in NAV (Norwegian Labour and Welfare Organisation) regulations, extensive differential diagnosis and a lot of Invest in ME (Charity Nr. 1114035) clinical experience, the Association can support a trial period of allowing general practitioners to diagnose because there is such a long waiting list for a specialist evaluation. The Association is worried that too many will be diagnosed because general practitioners lack adequate competence (see Dr Spickett’s statements below). It is also pointed out in NAV’s circular that ”The diagnosis of the condition is difficult and labour intensive, and ruling out normal tiredness and other illnesses can be difficult. It is therefore important to perform a thorough medical examination, especially to find out possible other illnesses that can be cured.” http://rundskriv.nav.no/rtv/lpext.dll/rundskriv/r 12/r12-01/r12-p1206?f=templates&fn=documentframe.htm&2.0 Infectious disease specialist Dr Gavin Spickett (2008), specialist in immunology and lead clinician at the Royal Victoria Infirmary, Newcastle upon Tyne, stated at a ME/CFS conference in Cambridge (UK) 6. May 2008 that even though there were strict criteria for referrals to the CFS clinics, there were many who after further investigations turned out to have another diagnosis. ME is a very serious and rare condition. Because the condition is found only in 1-2 per 1000 people, a general practitioner might not have more than 1-2 people with this illness in their practice. Dr Spickett’s presentation dealt with experiences with the so called CFS centres in Great Britain. His focus was on the key role of a medical examination of patients with suspected ME/CFS. When patients were referred to the centre, they underwent a thorough clinical evaluation to rule out other diagnoses that could explain the fatigue and to make sure that patients eventually could get correct treatment if there were other diagnoses. An overview of their work showed that experienced ME/CFS clinicians find other diagnoses among a large proportion of (continued on page 73) Page 72/74 Journal of IiME Volume 2 Issue 2 www.investinme.org R Reeaassoonnss wwhhyy MMEE DDooeess NNoott BBeelloonngg ttoo tthhee MMUUSS CCaatteeggoorryy (continued) patients with referrals due to fatigue. The centre gets unnecessary large numbers of referrals of patients presenting with fatigue with questions about ME/CFS. This is despite the strict guidelines that were developed for referrals with specifications of the examinations that should be performed beforehand. Dr Spickett and his colleagues’ experience shows that quite clear guidelines have not led to a reduction of patients who get another diagnosis in connection with investigations at the specialist centre. This is a clear indication of how difficult it is to diagnose and specialist competence is actually needed. This is especially important when there is no confirming diagnostic test and one depends on the use of internationally approved diagnostic criteria on every single patient. At present the general practitioners do not have enough knowledge of ME, some don’t even believe in the diagnosis and many have big problems in dealing with this group of patients. The Diagnosis is approved by the Social Security/ NAV – strict criteria The State Social Security informed in a circular to local social services in Norway, 30. May 1995, that the condition must be accepted as an illness. The requirement was that certain criteria had to be fulfilled (Holmes criteria, 1988; Fukuda criteria, 1994). The State Social Security (now NAV) thought that this would involve a small amount of cases and these had to be evaluated in a wholly concrete manner. Dr Haukenes and Dr Aarli (1995) thought that the diagnosis of Post Viral Fatigue Syndrome (PVFS) should be used for this type of patients, but only after a thorough clinical evaluation. Therefore there were strict criteria for diagnosis. In their article Drs Haukenes and Aarli (1995) discussed the biomedical functional abnormalities that were known at that time. The diagnosis was officially approved by the State Social Services in 1995 with the following Invest in ME (Charity Nr. 1114035) description: G93.3. Post-Viral Fatigue Syndrome/ Benign Myalgic Encephalomyelitis (ME): Notification no 3/99. The illness must have brought on a considerable reduction in functional ability, i.e. more than 50 percent, where the revenue ability is reduced by more than half. The duration requirement is set to 34 years without sign of improvement in order to be awarded disability benefits. ME has been in the Norwegian version of ICD-10 given the diagnostic code G93.3. Before the diagnosis of ME can be given, MUPS (e.g. neurasthenia, chronic fatigue –F48.0) (ICD-10, 1991) must be ruled out. It is important to remember that both the NAV rules and regulations and the State Social Welfare law is legally binding for all healthcare personnel. The diagnosis is allowed rights in NAV’s notification that was revised 01/06. NAV suggest that the condition should be diagnosed using criteria formulated by the Centers for Disease Control and Prevention in USA. The CDC writes on its website that there is international concensus on the Fukuda definition, and it is used both for research and clinical use: http://www.cdc.gov/cfs/cme/wb1032/chapt er1/overview.html Internationally the Fukuda criteria have been criticised for being too broad and thereby including people with fatigue, but who do not have ME. The discontent with the Fukuda definition led to a strong need for clinical criteria. An international panel with experienced clinicians and researchers, with a mandate from Health Canada, therefore prepared clinical guidelines for diagnosis (Carruthers et al, 2003: http://www.mefmaction.net/documents/jour nal.pdf . These guidelines reflect the patients’ situation best. President of the International Association of CFS/ME, Professor Dr Klimas PhD, has encouraged researchers and clinicians in using these, together with Fukuda criteria, in order to be able to compare research selection. Page 73/74

Journal of IiME Volume 2 Issue 2 www.investinme.org Lost Voices is a powerful addition to Invest in ME’s library of educational aids. The book has been ongoing since our conference last May and Natalie, whose idea this was and who has devoted most of her waking hours to this project since our last London conference, has performed a quite amazing job. The book is of extremely high quality and is offered by Invest in ME at a reasonable price to allow more people to be able to purchase it. The early-purchase discount rate has been set with ME are left to exist in a twilight zone - left to deal with this illness by themselves and with no hope of a future. The moving stories convey the real picture of ME. And yet Lost Voices will show the resilient character of people with ME and their families. The book also contains facts about ME with contributions from experts such as Dr. John Chia, Dr Leonard Jason, Dr Vance Spence at £8.00 (£9.00 for European delivery and £11.00 for delivery elsewhere) and includes postage and packaging. This applies to all payments received before 1st January 2009. After that date the price will be £10 (£11 for European delivery and £13 for delivery elsewhere). The book is an A4 landscape size with a laminated card cover with pictures, mostly in colour. With around 120 pages of stories, pictures and information this is without doubt the only book around which truly encapsulates the tragedy of this illness and the way in which people Invest in ME (Charity Nr. 1114035) and Annette Whittemore of the WhittemorePeterson Institute. If there is one book on ME that you buy then make it Lost Voices. Please buy this book - for yourself or for friends, relatives or your GP - or suggest it as a gift for others to buy. This book will really make a difference. More details can be found by clicking here [http://www.investinme.org/LostVoicesBook/Ii ME Lost Voices home.htm]. Support ME Awareness – Invest in ME Page 74/74

The Journal of IiME Volume 3 Issue 1 from Invest in ME

Journal of IiME Volume 3 Issue 1 www.investinme.org P Prroovviiddiinngg aa vvooiiccee ffoorr tthhoossee sseevveerreellyy aaffffeecctteedd wwii tthh mmyyaallggii cc e enncceepphhaalloommyyeell ii tt iiss Invest in ME has published a book which we hope will help healthcare professionals, media, ME Support groups and people with ME in their quest to improve education regarding Myalgic Encephalomyelitis (ME). The name ' Lost Voices' refers both to the fact that people who are severely ill with ME are generally not in a position to make themselves heard, and also to the way that the prejudiced denial of ME - as an 'aberrant belief' rather than a devastating physical • It clearly and movingly shows the evidence of the devastating impact this physical disease has on individuals and their carers and families • It will bring to more public notice the plight of ME sufferers • It will help change a widespread lack of comprehension based on general misinformation, vague definitions and manufactured statistics, to the development of empathy and concern for those who are so ill illness - has meant that often others are incapable of actually hearing and seeing what is being said and shown. 'Lost Voices' is primarily written by people affected by severe ME- whether as sufferers, carers or families. The book provides the following - • It allows an opportunity for people who are usually invisible and unheard to speak for themselves, so that their situation can be seen and understood more clearly Invest in ME (Charity Nr. 1114035) • It can educate the medical profession, the public and others such as wider family • It will, hopefully, encourage a sense of community among ME sufferers and those supporting them The book is an A4 landscape size with a laminated card cover. The stories and photographs are provided by carers, families and, as far as possible, people with ME themselves. 'Lost Voices' represents Continued page 3 Page 2/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Inside This Issue different families, showing the impact of the illness on all family members and sufferers and carers. 2 2 5 5 3 3 1 111 1 144 L Loo ss tt VVoo ii ccee ss E Edd ii tt oo rr ii aa ll CCoommmmeenn tt S See vvee rr ee MMEE –– AA P Paa tt ii eenn tt ’’ ss VV ii eeww F Foo rr ggee tt --MM.. EE .. --NNoo tt S Siimmii ll aa rr ii tt ii ee ss oo ff CCFF SS aanndd A ASSDD 2 211 WWPP II RRee ss eeaa rr cchhee rr 2 233 3 322 3 355 CCaa ll l tt oo AAcc tt ii oonn 3 399 4 499 5 511 5 555 H Huummaann EE nn tt ee rr oo vv ii rr uu ss ee ss a anndd CChh rr oonn ii cc ii nn ff eecc tt ii oouu ss D Dii ss eeaa ss ee S See vvee rr ee MMEE -- NNoo rr wwaa yy D Dii ee tt aa rr yy SS uupppp ll eemmeenn tt L Lee tt tt ee rr ff rr oomm AAmmee rr ii ccaa E Epp ii ddeemmii cc ss aanndd MMEE A Ann MMEE SS ee rr vv ii ccee 5 566 CCoonn ff ee rr eennccee 2200 00 99 6 600 CCoonn ff ee rr eennccee AAbb ss tt rr aacc tt ss The moving stories convey the real picture of ME. And yet Lost Voices will show the resilient character of people with ME and their families. The book also contains facts about ME with contributions from experts such as Dr. John Chia, Dr Leonard Jason, Dr Vance Spence and Annette Whittemore of the Whittemore-Peterson Institute. If there is one book on ME that you buy then make it Lost Voices. Please buy this book - for yourself or for friends, relatives or your GP - or suggest it as a gift for others to buy. This book can really make a difference. Invest in ME (UK Charity Nr. 1114035) PO BOX 561 Eastleigh SO50 0GQ Hampshire, UK Invest in ME (Charity Nr. 1114035) To order Lost Voices email to info@investinme.org or go to our web page at – [http://www.investinme.org/LostVoicesBook/IiME Lost Voices home.htm]. Support ME Awareness – Invest in ME Page 3/76 The book is of extremely high quality and is offered by Invest in ME at a reasonable price to allow more people to be able to purchase it. With around 120 pages of stories, pictures and information this is without doubt the only book around which truly encapsulates the tragedy of this illness and the way in which people with ME are left to exist in a twilight zone - left to deal with this illness by themselves.

Journal of IiME Volume 3 Issue 1 Lost Voices A A vviieeww ffrroomm OOll iivveerr ,, wwhhoossee oollddeerr ssiisstteerr hhaass sseevveerree MMEE "Lost Voices” is not just a book about ME/CFS, rather it is a book that has been created and written by the very people who experience the illness first hand; severe sufferers, their carers and their families. The combination of photographs, images and writing found in Lost Voices beautifully express the realities of the illness and its impact not only on the sufferers but on their friends and families as well, giving a voice to so many people who have been left to fight this debilitating illness in isolation. It does not just tell one person's story or even one family's story. Lost Voices brings together and shares the stories of many different individuals, families, carers and friends; each story unique, each story providing an insight into a world that has been invisible to most people for too long. Anyone who has suffered from or is still fighting ME/CFS will find Lost Voices a powerful and uplifting reminder that they are not alone, that there are so many others like them, fighting for recognition, fighting for understanding and fighting for fair and effective treatment. This is a book full of love, courage, hope and determination. This book is not just for those suffering from ME/CFS but is also for their carers, friends and family members. You can share the experiences of others who have been sucked into this hidden and isolated world. It provides an invaluable way of explaining this illness and its impact to those who are fortunate enough not to have experienced it first hand. Lost Voices contains contributions offering insight and expertise from leading figures in the ME/CFS research and support community. The forward has been written by Leonard Jason, former Vice President of IACFS/ME: - '...Lost Voices will help healthcare professionals and others become less Invest in ME (Charity Nr. 1114035) judgmental, and more tolerant and understanding of those with ME, for these are the voices of heroes... there were moments of wonder when I realized that these patients have something uniquely profound to share with a world so saturated with materialism... these patients are asking us to wake up from our stupor... Their courage and life affirming stories challenge us to act. Just as the Civil Rights and Women’s movements focused our attention on serious inequalities and the need for activism, so does Lost Voices force us to recognize the needs of children and adults with ME and to join the fight for a cure.' The introduction to Lost Voices is an invaluable asset for anybody who has ever tried to answer the question 'What is ME/CFS?' It examines some key areas of confusion which have resulted in misconceptions and ignorance about the nature and severity of the illness amongst the general public, the government and the medical profession. Cutting through this misunderstanding, the introduction to Lost Voices argues powerfully for a new biomedical focus on subgroups to drive future ME/CFS research and treatment. Lost Voices is a book to help others understand the hidden reality of life with severe ME; a book that allows one to feel the comfort of shared experience whether it be suffering, courage, love, hope or determination; a book with key information about ME; a book to be moved by; a book to enjoy. Please buy Lost Voices and use it to help fight the ignorance and injustice that results in so many ME sufferers struggling invisibly and unheard. The purpose of this book is to educate in the broadest possible sense and it is not being sold for profit by Invest in ME." Page 4/76 www.investinme.org Journal of IiME Volume 3 Issue 1 www.investinme.org Conference Edition Editorial Comment Welcome to the 2009 conference edition of the Journal of IiME – a blend of science, facts, stories and news regarding Myalgic encephalomyelitis (ME or ME/CFS). May is ME Awareness Month and also the month when Invest in ME hosts its annual biomedical research conference. It is an apt time to look back at what has occurred in the last year as well as to look forward to future developments. In the year which has elapsed since our 2008 conference some events have occurred which will have consequences for people with ME and their families, for researchers and health services when it concerns ME. These events are a mixture of regret, disappointment, anger but also progress and hope. The last year has seen the NICE guidelines for ME being promoted and, some would argue, forced upon the health services and unwilling patients. The dissatisfaction with the NICE guidelines has seen a patient revolt and NICE, yet again, being taken before a Judicial Review to defend its processes and its decisions by the very patients it was meant to protect and to treat. A major criticism of NICE is that it failed to look at the established, published biomedical research and instead produced a document which is neither helpful for patients nor useable by medical professionals. Its scope, based on flawed input, was also far too narrow to make any meaningful difference. One of the most disappointing aspects of the Judicial Review was the spectacle of NICE Disclaimer The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. attempting to paint these guidelines as a “gold standard”. This risible self-assessment by NICE showed a flawed organisation which needs overhauling. Another organisation failing people with ME has been the Medical Research Council. The last eighteen months has witnessed the UK Medical Research Council officially acknowledge that its previous policy toward ME research has been an abject failure by setting up a new panel to look at research into ME. There is doubt of the genuineness of the MRC to seriously change its approach. The criticism which IiME has of this panel is that it includes some who wish to reclassify, or who perceive ME as a behavioural illness and this undermines the reason for this panel’s existence and its continued operation. With its usual tardiness the MRC has spent eighteen months since the panel’s inception and has yet to produce anything of substance. We would suggest to the MRC that the patient community might have far greater involvement in this panel than it currently allows. We also believe that the eventual decision-making process of subsequent research proposals by that panel and any peer reviewers must be completely transparent – something the MRC continues to fail to do and which has seen obvious bias in funding of research into ME in the past. The need to sub group ME patients to allow proper research and treatments was Invest in ME (Charity Nr. 1114035) Page 5/76

Journal of IiME Volume 3 Issue 1 Comment highlighted at our last conference and from there we move on this year to focus on severe ME. The severely affected are a group of patients who do not figure often in research – which may be due to the lack to appropriate funding. The severely affected people with ME are neglected by healthcare organisations and by the establishment authorities responsible for funding research. Many believe it is only by examining severely affected patients that the true nature of this illness is revealed and treatments and cures will be found. Appropriately, to coincide this year with our emphasis at the conference on severe ME Invest in ME has published the Lost Voices book – a unique collection of stories, photographs and facts which highlights the effect of severe ME on patients, on families and on society. Lost Voices has already been distributed to twenty countries and is to be found in medical libraries, community libraries, hospitals, GP surgeries, and a whole raft of various places within the community. The IiME International ME/CFS Conference London 29tthh May 2009 Since the last Invest in ME international biomedical research conference the European ME Alliance (EMEA) has also been created and meets in London after the conference for its first AGM. The Alliance now spans across Europe, the most recent addition being Spain, and it is hoped to supplement with the remaining European countries before long. The Invest in ME conference in London in May will be our fourth biomedical research conference and now welcomes delegates from four continents and fourteen countries. We welcome many new delegates as well as old friends. Invest in ME (Charity Nr. 1114035) Some who will not be seen at the conference (as we go to press) will, again, be the Secretary of State for Health, the Medical Research Council and the Chief Medical Officer. Despite the persistence of IiME in asking, and an amazing response from the ME community in petitioning, these main establishment areas still fail to take ME seriously enough to listen to the foremost speakers displaying research on their doorstep. The sad point about this is that treatments are available for ME. The IiME 2008 conference had presentations from Dr John Chia and Dr Martin Lerner, showing effective treatments for some sub groups of ME – treatments which NICE actually refused to endorse. The fact that treatments by antivirals are currently expensive is seen as one reason why they are not used in the UK for ME. Yet the recent outbreak of swine flu has shown how easy it is to provide antivirals to anyone suspected of having contracted this strain of the flu virus. Invest in ME have written to the Chief Medical Officer and asked why is ME any different? Are lives not worth more than money? Should not the Chief Medical officer be making a statement as to why antivirals (or any other relevant medications) are not used for ME? If only the CMO would accept one invitation to the IiME annual biomedical research conference then he would be able to see first hand how this might affect real people. In the absence of progress from the government, Medical Research Council and within the NHS we need a CMO who will stand up for patients. We need action and leadership and we cannot afford to lose yet another generation to this illness. Perhaps the next year will be different. IiME will continue with our conferences and are already putting plans on paper for a bigger conference in 2010 to celebrate our fifth Page 6/76 www.investinme.org Journal of IiME Volume 3 Issue 1 Comment biomedical conference. So let us take a hypothetical situation which occurs between our 2009 conference and leading up to our 2010 conference. Let us suppose that a diagnostic test was developed and that sub groups were more easily able to be identified in order to guide treatments. Let us suppose that the disease mechanism for ME was found? How would ministers and healthcare officials react to such changes? What changes would be seen in the healthcare system? How would the pharmaceutical industry react when there is a promise of great rewards from development of effective treatments and possibly cures for ME based on successful biomedical research? How would NICE react? What changes in attitude would come forth from insurers and Work and Pensions departments toward the current policies where benefits are often denied to people with ME? Would the CMO change his stance? Would the Medical Research Council be more transparent and begin funding biomedical research based on sound science rather than on vested interests? Would the MRC seriously allow funding of biomedical research to begin? We believe that researchers such as those at our conference are making such enormous progress that we should be looking at the above scenario and begin to be prepared to ask these questions. In the last year we have seen the great potential of biomedical research being realised due to the approach adopted by organisations that have a clear strategy – amongst them the Whittemore-Peterson Invest in ME (Charity Nr. 1114035) We can hope that by our next conference in 2010 the landscape might have changed significantly enough so that we will be reporting on progress on this development and talking of a year of success. For next year’s conference we hope to be welcoming more new delegates – including those who are currently conspicuous by their continuing absence. And so to the Journal. Appropriately, to reflect the emphasis on severe ME at the conference we have several articles revolving around severe ME. Following the death of Alison Hunter from complications arising from ME the Alison Hunter Memorial Foundation (AHMF) of Australia was set up by her mother, Chris. Chris Hunter has given us permission to republish a very moving article by Alison – written many years ago but as relevant today as it was when Alison wrote it at the age of 17 – a story which any parent of a child with ME would Page 7/76 www.investinme.org Institute. We feel the newly-established Enterovirus Foundation will also influence the progress of biomedical research into ME. Invest in ME has, since its inception, been advocating a national strategy of biomedical research into ME as the only logical way forward. However, this is now being superseded by the requirement for an international strategy of biomedical research. The WPI and the researchers at our conference are making great strides in progress and Invest in ME wish to publicise their work at every opportunity and encourage people around the world to support them – both in moral and financial support. After the conference Invest in ME will be working with our European colleagues to further the establishment of centres similar to the WPI. Our Biomedical Research Fund, announced, in January, will be used to help with this and provide a focal point for these plans.

Journal of IiME Volume 3 Issue 1 Comment today immediately recognise and which could have come directly from this year’s Lost Voices book. How does it feel when a local health authority fails to provide a biomedical clinical lead for severe ME patients even though it is possible? We have the views of one severely ill patient on this situation. The story of the Krisner family of Norway was highlighted on our 2006 conference DVD – a story of devastating consequences for a family where three siblings have become ill with severe ME. Yet there is hope. After continuing treatment two of the children are making amazing progress and the other has made some improvement. Kjersti and Harald Krisner provide an article showing this progress – a story of great progress and hope. The new Enterovirus Foundation has been created and we welcome members of the EVF, Professor Steven Tracy and Nora Chapman, who have provided an excellent article on Human Enteroviruses and Chronic Infectious Disease. Dr John Chia, who is speaking at our conference, is part of the EVF. We have two papers from Professor Garth Nicolson et al – one showing the similarities between CFS (ME) and Autism Specturm Disorders and the other discussing weight issues with CFS (ME) and the use of an all natural oral supplement mixture. Epidemics are a less well publicised feature with ME. Professor Harald Nyland will be talking about this at the conference yet epidemics are not new. The Incline village episode in the eighties is responsible for some of the foremost ME researchers continuing their work. We have an old article on epidemics from Dr Gordon Parrish which we felt was worthy of being republished to put the work of today’s researchers into context. We also include conference abstracts. Invest in ME wish to thank those organisations Invest in ME (Charity Nr. 1114035) We would like to thank the Irish ME Trust and the Alison Hunter Memorial Foundation for their donations, support and friendly cooperation. and individuals who have donated or sponsored to enable us to bring about the 4th Invest in ME International ME/CFS Conference 2009. Thank you for your generosity. www.investinme.org . To those who attend the conference we hope you enjoy your day and learn a great deal. For those not able to come to the conference then we hope the Journal will provide something of use. The conference promises to reflect the real progress which is finally beginning to benefit people with ME despite being enacted on a background of terrible suffering and intransigence of those responsible for deciding healthcare policy. Enjoy the Journal, enjoy the conference. ME FACTS The US Centres for Disease Control (CDC) website confirms that: “The name ME was coined in the 1950s to clarify well-documented outbreaks of disease; ME is accompanied by neurological and muscular signs (sic) and has a case definition distinct from that of CFS(ME)”. (http://www.cdc.gov/cfs/cme/wb 1032/chapter1/overview.html ). Page 8/76 Journal of IiME Volume 3 Issue 1 SEVERE ME – A PATIENT’S VIEW Severe ME requires investigation and treatment by biomedical researchers and clinicians understanding the biomedical basis for the illness. Against a background of severely affected people with ME facing reluctance from healthcare authorities to consider their future, then when a health authority has an opportunity to employ world-renowned researchers and physicians who understand the illness, when a patient community is pleading with the same health authority to employ these same physicians, then any logical person must ask why isn’t this happening? Here a long time sufferer of ME has dictated the following article. I want you to imagine what it is like to have severe, neurological ME. I want you to try and think what it must be like to experience constant ongoing physical pain, all over your whole body. Pain that throbs, pain that stings, pain that itches and irritates, burns and moves, pain that invades your muscles, your skin, your scalp, your feet, your eyeballs, your tongue, your intestines, so that there is no part of you experiencing any respite from pain, any second of the day or night, in fact the pain increases in intensity and agony every time you try to rest or sleep. I want you to try and imagine muscle paralysis that invades you, so that when you awake you can no longer speak, move your lips open your mouth, open your eyes, move your fingers, feel your hands or your arms, your feet, your toes, your legs. I want you to imagine what its like to desperately need to go to the toilet but to be unable to move, to be unable to sit or stand, to be unable to walk but worse than this to be unable to bear to be touched. So that even if there is someone to move you, to lift you, to stand you up, to sit you in a wheelchair, to push you to the bathroom, you cannot access this help. Invest in ME (Charity Nr. 1114035) Day upon day, year upon , year for hours on end. I want you to imagine the physical torment of hyperacusis, of being so hypersensitive to noise that a whisper sounds like a shout and that any loud noise feels like a physical assault not just on your ears and your head but on your whole body. I want you to imagine the ordinary things of life becoming completely inaccessible because you have no energy, you cannot breathe easily or fully, you cannot eat so many different foods because of allergy and sensitivity, you cannot be in the same room as people because they drain you of any energy you might have had and their voices hurt you and you become more ill if you try to engage with them. I want you to imagine a life where the TV hurts your eyes, where the computer screen hurts your eyes, the sunlight, even the normal daylight, without bright sun, hurts your eyes and gives you severe eye pain. A head pain that goes on and on for days on end. A life where the telephone hurts you to hold it, to hear it and where your brain is unable to process any incoming information rendering Page 9/76 www.investinme.org

Journal of IiME Volume 3 Issue 1 S SEEVVEERREE MMEE –– AA PPAATT IIEENNTT ’’SS VVIIEEWW conversation impossible. I want you to imagine being unable to read because your brain simply is unable to comprehend the mass of information before you; of being unable to imagine, even, because the fog has descended inside your head that blanks out thought and creativity ability. This is only a portion of the reality of having severe ME. Now I want you to think what it must be like to know that despite this severe disability, this chronic unending illness: - There is no biomedical consultant provided to treat you - There is no apparent awareness of the urgent need to do something to physically help you - There is no NHS service offering appropriate biomedical tests or treatments despite the fact there are very serious physical abnormalities in your body and every time you ask for help you are sidelined - Every time you try to raise awareness it doesn't make any difference. What must it be like then to find that there is an opportunity for world class, concerned and interested medical consultants – consultants who know your illness is a physical reality, one that has been grossly neglected, - who actually want to come and provide a new service, to right the injustice of no appropriate medical provision in your area ? Can you begin to imagine what it feels like when, instead of this offer being accepted, you are fobbed off instead with a biopsychosocial, therapy-led service (pretending to be biomedical) that Invest in ME (Charity Nr. 1114035) does not meet the complex medical needs of this disease? When all the PCT has to do is say - “Yes”, “we will take you seriously” , “We acknowledge responsibility for your biomedical care”, “we can see that you need a local consultant and it is not unreasonable to expect one;” “So yes, we will provide you with a new innovative biomedical service that might just begin to meet your needs..” “And we will lead the way.” Please tell me why this is not happening ? www.investinme.org ME FACTS In 1988, UK researchers Archard and Bowles et al published the results of their research into muscle abnormalities in ME/CFS: “These data show that enterovirus RNA is present in skeletal muscle of some patients with postviral fatigue syndrome up to 20 years after onset of disease and suggest that persistent viral infection has an aetiological role. These results provide further evidence that Coxsackie B virus plays a major role in ME, either directly or by triggering immunological responses which result in abnormal muscle metabolism” (JRSM 1988:81:325-331). Page 10/76 Journal of IiME Volume 3 Issue 1 Forget M.E. Not by Alison Hunter Somewhere in the recesses of my mind there is a memory of being active, of having the energy to be active...when sprinting across the street was a reflex action and a good day was a day in the surf followed then by dinner at a new restaurant followed by a movie. This poignant article is as relevant today as when it was written by Alison in September 1993. It has been reproduced here by kind permission of the Alison’s mother Chris Hunter. The Alison Hunter Memorial Foundation The Alison Hunter Foundation was established in 1998. The Foundation is an enduring memorial to Alison Hunter and all those whose lives have been devastated by ME/CFS. Alison died in 1996, aged 19, from complications arising from ME/CFS which There was a time when my body parts just existed... now, they ache as if to remind me of their presence. "Yeah boys, how you doin', still there, GREAT." An average day now consists of showering (with a seat), getting dressed, and perhaps a few hours of study interspersed with hours on the horizontal. The fatigue is not everyday tiredness, experienced after an energetic day's gardening. It is an exhaustion of body and mind so profound that it becomes a concerted effort to think, walk and sometimes even move, sit, eat or breathe. Arms and legs turn to lead; they sink through the mattress to eternity...there is often pain throughout the body which can be constant and localised (for e.g. continual severe headache) or migratory...calf muscles one day, finger joints the next. Then there is nausea, diarrhoea, ringing in the ears... Aside from the physical problems there are the cognitive symptoms (the memory loss, the lack of concentration) alongside the neurological: the dizziness and sensitivities to extremes of temperature, light and noise. Doctors have at last pinpointed the mechanism by which such signs occur - lack of blood flow to Invest in ME (Charity Nr. 1114035) included seizures, paralysis, gastrointestinal paresis and overwhelming infection resembling Behcets Disease. Such complications are rare and only present in a severe subgroup. Alison courageously fought ME/CFS for ten years and was an unstinting advocate for young people. The Alison Hunter Memorial Foundation is a non-profit institution. The Foundation works independently in a spirit of support and cooperation with all researchers, institutions and ME/CFS societies to advance scientific knowledge and medical care. http://www.ahmf.org/ certain areas of the brain. Little comfort when at the age of 18, one finds oneself unable to remember one's home address, misspelling or mispronouncing basic words or walking into a room with no recollection of why or how. "How are you?" is a question I'm asked all the time; every day almost by friends, family. Most Page 11/76 www.investinme.org

Journal of IiME Volume 3 Issue 1 www.investinme.org Forget M.E. Not (continued) people don't really want to know; it's a form of etiquette, and usually a customary "Okay" or "Not too bad" fits the bill. "Not too good", on the other hand, or (heaven forbid) "Quite unwell" is met with a look that says, "Whaddaya mean?!" I have breached the unwritten code of greeting...awkward silence ensues. Admittedly, many don't even listen to the reply: "How are you?" "Not feeling at all well." "That's great, did you see the movie on Channel Nine last night?" A big problem is that aside from pallor I generally look healthy enough...a problem, because one loses credibility when one doesn't conform to the 'sick stereotype'—supposedly thin, frail and slow moving—and are predisposed to comments like "How can YOU be sick, you don't look at all sick?" thinking negative certainly doesn't help, but remarks such as "Chin up", "Look on the bright side", "There are many people worse off than you" only serve to alienate. Surely for a person to be cheerful all the time given the pain level, lifestyle restrictions etc would be a cause for concern. Should these treatments fail it is invariably because you didn't have the right attitude, because "Mrs Jones tried it and hasn't looked back", a mentality accurately summed up as 'wellness macho'. We present a challenge to doctors...if they know us well they believe we are ill but are at a loss as to how to help...most patients aren't so lucky and are labelled neurotic, school phobic, anorexic, menopausal, hypochondriacal, and are handed a referral to see friendly Mr — to have a little chat about why we need to be sick. This is extremely damaging. However even the most understanding doctor becomes frustrated when tests repeatedly come back 'normal'. They cannot give us a pill to make it (and us) go away, and worsening health drives us back With a disease lacking a diagnostic test everyone's an expert...everybody knows someone's niece or cousin twice removed who went to see Dr So-and-so and now she's climbing mountains. Each new regime might be 'the One' to set things moving in the right direction. They stretch from the sublime to the ridiculous but you must try them all lest "don't you ever want to recover?" These treatments aren't always benign, leaving you worse off than when you started, not to mention emotionally and financially. Seven years down the track there's nothing I haven't tried: Chinese herbs, positive thinking, acupuncture, positive thinking, dietary manipulation, positive thinking, aromatherapy, positive thinking, electromagnetic therapy, all the while thinking positive because, "With a positive attitude you're almost there." Well, Invest in ME (Charity Nr. 1114035) again and again in desperation to ask, "Doctor, can't you do something??" Rarely will they say, "I don't know what is wrong with you", which they see as incompetence, when in fact the patient already realises this, and is far preferable to yet another blame-the-patient technique. For pain, other than strong medication, distraction therapy wards off insanity in desperate moments, be it gentle massage, an engaging comedy, company, laughter...distraction as a form of pain relief has been known from centuries such as this quite probably effective (if outmoded) example found in the Oxford Concise Medical Dictionary: "A seton is a skein of cotton or the like passed below skin and left with ends protruding to maintain an artificial issue as a counter irritant." Page 12/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Forget M.E. Not (continued) Having missed altogether four years of schooling I may not have received a formal education, nevertheless I have learnt many invaluable 'life lessons' I don't believe are to be found between classroom walls, for example tolerance, empathy and open-mindedness. I don't hold much with the enriched sufferer theories however: "Great, I've suffered unrelenting pain for seven years, but I'm gonna be a better citizen." Books, newspapers, radio and some television programs...these have been my umbilical cord to outside life, a world I often don't feel a part of. I have reached the conclusion that should be a number one priority although it is generally taken for granted, even by me; in the rare instances I catch a glimpse of it, feel the energy in my fuel tank, I am like a compulsive spender, spending the last drop plus more until I am back in bed. In my world you pay for your fun. Sometimes it is worth it—often it isn't; we have no problem with motivation; quite the opposite, we are our own worst enemies. My family have been wonderful, after all an illness like this impacts upon every member...Mum's had to give up work temporarily, no more spontaneous family holidays, siblings take a back seat. It's hard being a teenager, trying to assert your individuality while so forcibly dependant on people for practical care. Of prime importance to adolescents is the need to feel accepted, normal, "one of the pack". This is impossible to achieve when you mysteriously disappear every day after recess, receive extensions on assignments and have to decline invitations to most parties, sporting activities etc. I am lucky to have a few "healthy" friends who are supportive and as understanding as they can be, who visit when I am bedbound and no longer ask if I'd like to go on interstate hikes. I also have strong friendships with adolescents Invest in ME (Charity Nr. 1114035) Page 13/76 For years I was going to be "all better next week". Now I know better, I know the statistics and am aware that I have moved into the so-called chronic stage with little chance of spontaneous remission. A cure may be just around the corner but I have to face the fact that I may be sick for a long time yet. It's not AIDS, although it's similar, you can feel equally as ill only it doesn't kill you. Not cancer either. I'm not dying or anything drastic like that. It's M.E. Don't forget M.E. with the same illness—we can provide mutual support & encouragement...most of all we can 'Lounge Lizard' together. When you are chronically ill, you tend to lose your identity to the illness; it defines who you are and what you are capable of...particularly in other people's perceptions. Sometimes I'm tempted to yell, "What about me the person?" I have thoughts and feelings aside from those associated with the illness, if not the opportunity, nor indeed the energy, to express them. All the normal adolescent turmoil is experienced, perhaps magnified and without resolution, for how do we assert our individuality if not through experiencing life and interacting with a wide variety of human beings...certainly not lying in bed, doing the rounds of specialists once again, just in case, just to make sure they didn't miss something "fixable".

Journal of IiME Volume 3 Issue 1 www.investinme.org Similarities of Chronic Fatigue Syndrome (CFS) and Autism Spectrum Disorders (ASD): Comparisons of Co-Infections Garth L. Nicolson1, Nancy L. Nicolson1, Jorg Haier2 1The Institute for Molecular Medicine, Huntington Beach, California, 2Department of Surgery, University Hospital, Munster, Germany The 4th Invest in ME International ME/ Chronic Fatigue Syndrome Conference in London, UK, May 28-29, 2009. ABSTRACT Objective: The majority of neurodegenerative diseases, fatiguing illnesses and neurobehavioral disease patients have chronic infections. Therefore, we examined the presence of certain co-infections in the blood of patients with Autism Spectrum Disorders (ASD) and compared these to CFS patients. Methods: North American CFS and ASD patients were examined for various infections by isolation of leukocyte blood fractions and forensic polymerase chain reaction (PCR) to determine various infections. Results: CFS patients (n=100, age=39.7±8.9) show evidence of multiple, systemic infections (Odds Ratio = 18.0, 95% CL 8.5-37.9, p< 0.001) that may be important in CFS morbidity. CFS patients had a high prevalence (51%) of 1 of 4 Mycoplasma species (OR = 13.8, 95% CL 5.8-32.9, p< 0.001) and often showed evidence of co-infections with different Mycoplasma species, Chlamydia pneumoniae (OR = 8.6, 95% CL 1.0-71.1, p< 0.01) and/or active Human Herpes Virus-6 (HHV6) (OR = 4.5, 95% CL 2.0-10.2, p< 0.001). We found that 8% of the CFS patients showed evidence of C. pn. and 31% of active HHV-6 infections. Recently we examined ASD patients (n=48, age 8.4±2.8) and found a large subset (58.3%) of ASD patients showed evidence of Mycoplasma species infections compared to age-matched control subjects (OR = 13.9, p<0.001). ASD patients also had C. pn. (4/48 or 8.3% positive, OR = 5.6, p<0.01) and HHV-6 (14/48 or 29.2%, OR = 4.5, p<0.01) infections in their blood. ProfessorGarth Nicolson Prof. Garth L. Nicolson, PhD, The Institute for Molecular Medicine, P.O. Box 9355, S. Laguna Beach, California 92652. Tel: 949-715-7958; Email: gnicolson@immed.org Website: www.immed.org Conclusions: The results indicate that similar to CFS patients a large subset of neurobehavioral (ASD) disease patients show evidence of chronic infections. Although there were significant differences in median age and diagnoses between the two groups of patients, they tended to have similar incidence of three types of chronic infections: Mycoplasma, Chlamydia and HHV-6. Invest in ME (Charity Nr. 1114035) Page 14/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Similarities of ME/Chronic Fatigue Syndrome (ME/CFS) and Autism Spectrum Disorders (ASD): Comparisons of Co-Infections (continued) INTRODUCTION Although no single underlying cause has been established for CFS, there is growing awareness that CFS can have an infectious nature that is either causative for the illness, a cofactor for the illness or appears as an opportunistic infection(s) that aggravate patient morbidity (1, 2). There are several reasons for this, including the nonrandom or clustered appearance of CFS, sometimes in immediate family members (2-4), the presence of certain signs and symptoms associated with infection, the often cyclic course of the illness and its response to antimicrobial therapies (2, 5, 6). Previously we found that Gulf War veterans with CFS-like illnesses and a positive test for Mycoplasma fermentans transmitted their infections to their spouses and children (4). The adults in these families were diagnosed with CFS (7) but the children were subsequently diagnosed with Autism Spectrum Disorders (ASD) (8). The criteria for diagnosis of ASD are, in general terms, the presence of a triad of impairments in social interaction, communication and imagination (9). Examination of ASD patients in civilian families for the presence of Mycoplasma species infections revealed that the majority of these patients had one or more infections (10). In ASD cases there are reports of nonspecific signs and symptoms similar to those seen in CFS, such as fatigue, headaches, gastrointestinal and vision problems and occasional intermittent low-grade fevers and other signs and symptoms that are generally excluded in the diagnosis of ASD. These suggested to some authors that a subset of ASD patients may suffer from bacterial or viral infections (11). Here we examined three commonly found systemic infections in CFS patients, Mycoplasma species, Chlamydia pneumoniae and HHV-6 (12-14) and compared the incidence to the same infections found in ASD patients (10). Invest in ME (Charity Nr. 1114035) MATERIALS AND METHODS Patients: All CFS patients (North American, n=100) underwent a medical history, completed a sign/symptom illness survey, had routine laboratory tests and met the Fukuda et al. (15) exclusionary criteria. Control subjects (n=100) had to be free of disease for at least three months prior to data collection, and they had to be free of antibiotic treatment for three months prior to blood collection. All ASD patients (N=48) were randomly recruited from patient support groups in California after diagnosis of ASD according to the International Classification of Diseases (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). All ASD patients were assessed by the Autism Diagnostic Interview-Revised (ADI-R) (16) and Childhood Autism Rating Scale (CARS) (17, 18). Most (45/48) had a diagnosis of autism, while 6/48 were diagnosed with ADD (three of which were also diagnosed with autism) and nine autism patients with Asperger’s Syndrome. PCR Analysis of Blood: Blood was collected in EDTA-containing tubes and immediately brought to ice bath temperature as described previously (1214). Samples were shipped with wet ice by overnight air courier to the Institute for Molecular Medicine for analysis. All blood samples were blinded. Whole blood (50 µl) was used for preparation of DNA using Chelex (Biorad, Hercules, USA). Aliquots from the centrifuged samples were used immediately for Polymerase Chain Reaction (PCR) as described previously (1214). Statistics: Subjects’ demographic characteristics were assessed using descriptive statistics and students’ t-tests (independent samples test, t-test for equality of means, 2-tailed). The 95% confidence interval was chosen for Page 15/76

Journal of IiME Volume 3 Issue 1 www.investinme.org Similarities of ME/Chronic Fatigue Syndrome (ME/CFS) and Autism Spectrum Disorders (ASD): Comparisons of Co-Infections (continued) minimal significance. Odds Ratios were calculated using logistic regression (Logit method) Statistica 5.5 (Statsoft, Tulsa, OK). In some cases, Pearson Chi-Square test was performed to compare prevalence data between patients and control subjects. Bacterial and Viral Infections: Using the blood of CFS patients (n=100) and PCR procedures an overwhelming majority of patients showed evidence of multiple, systemic bacterial and viral infections (Odds Ratio=18.0, p<0.001).17 CFS patients had a high prevalence (51%) of one of four Mycoplasma species (Odds Ratio=13.8, p<0.001) and often showed evidence of co-infections with different Mycoplasma species, C. pneumoniae (8%, Odds Ratio=8.6, p<0.01) and active HHV6 (30%, Odds Ratio=4.5, p<0.001) (Table 3). Evidence for Mycoplasma spp. infections was found in 28/48 or 58.3% of ASD patients and RESULTS Patient Demographic Data: These are shown in Tables 1 and 2. TABLE 1. CFS Patient demographic data. n Mean age (SD) Patients Controls Female patients Male patients 100 100 72 28 39.7 (8.9) 34.6 (9.1) 39.8 (9.8) 39.2 (10.3) Range Males (%) 18-66 21-58 18-66 20-60 28 (28) 31 (31) 0 (0.0) 28 (100.0) TABLE 2. ASD Patient demographic data. n Mean age (SD) Range Males (%) Patients Controls 48 45 Rural patients 18 Urban patients 30 8.4 (2.8) 7.9 (3.3) 8.1 (2.9) 8.6 (3.2) Invest in ME (Charity Nr. 1114035) 3-14 4-11 3-14 4-14 36 (75) 28 (62.2) 14 (77.7) 22 (73.3) Females (%) 72 (72) 69 (69) 72 (100.0) 0 (0.0) Females (%) 12 (25) 17 (37.8) 4 (22.3) 8 (26.7) Page 16/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Similarities of ME/Chronic Fatigue Syndrome (ME/CFS) and Autism Spectrum Disorders (ASD): Comparisons of Co-Infections (continued) TABLE 3. Prevalence and Odds Ratio Analysis of Systemic Infections Between 100 CFS Patients and 100 Healthy Control Subjects. Type of infection Number Infected HHV-6 C. Pneumoniae Mycoplasma spp. M. pneumoniae M. fermentans M. honinis M. penetrans Single mycoplasmal infection Multiple mycoplasmal infections M. fermentans +M. pneumoniae M. fermentans +M. hominis M. pneumoniae +M. hominis M. fermentans +M. hominis + M. pneumoniae Mycoplasma + HHV-6 Mycoplasma + C. pneumoniae C. pneumoniae + HHV-6 CFS Patients n = 100 71 31 8 51 29 22 16 8 29 22 10 7 3 2 16 4 3 Control Subjects n = 100 12 9 1 7 3 2 1 1 7 0 0 0 0 0 0 0 0 Odds Ratio, 95% CL, p or Chi2 18.0, 8.5-37.9, p< 0.001 4.5, 2.0-10.2, p< 0.001 8.6, 1.0-71.1, p< 0.01 13.8, 5.8-32.9, p< 0.001 13.2, 3.8-45.4, p< 0.001 13.8, 3.1-61.1, p< 0.001 18.8, 2.4-147.0, p< 0.001 8.6, 1.0-71.1, p< 0.01 13.8, 5.8-32.9, p< 0.001 Chi2 = 24.7, p< 0.001 Chi2 = 10.5, p< 0.001 Chi2 = 7.3, p< 0.007 Chi2 = 3.1, p< 0.08 Chi2 = 2.0, p= 0.16 Chi2 = 17.4, p< 0.001 Chi2 = 4.1, p< 0.04 Chi2 = 3.1, p< 0.08 2/45 (4.7%) age-matched control subjects (Odds Ratio=13.8, p<0.001) (Table 4). C. pneumoniae infections were found in 4/48 or 8.3% of ASD patients and in 1/45 or 2.1% of control subjects (Odds Ratio=5.6, p< 0.01) (Table 4). We also examined the incidence of HHV-6 infections in ASD patients and found that 14/48 or 29.2% of ASD patients were positive compared to 4/45 (8.8%) positives in age-matched control subjects (Odds Ratio=4.5, p<0.01). We did not find any multiple co-infections in control subjects. The differences between infections in ASD patients and control subjects were highly significant (Odds Ratio=16.5, p< 0.001). Significant differences were not found in the prevalence of infections in urban and rural patients, in male or female patients or between autism and other ASD diagnoses. DISCUSSION In contrast to the ASD children in military families where primarily one species of Invest in ME (Charity Nr. 1114035) Page 17/76

Journal of IiME Volume 3 Issue 1 www.investinme.org Similarities of ME/Chronic Fatigue Syndrome (ME/CFS) and Autism Spectrum Disorders (ASD): Comparisons of Co-Infections (continued) TABLE 4. Prevalence and Odds Ratio Analysis of Systemic Infections in ASD Patients and Matched Healthy Control Subjects. Type of infection ASD Patients n = 48 (%) HHV-6 C. Pneumoniae Mycoplasma spp. M. pneumoniae M. fermentans M. hominis M. penetrans Single mycoplasmal infection Multiple mycoplasmal infections M. fermentans +M. pneumoniae M. fermentans +M. hominis M. pneumoniae +M. hominis M. fermentans +M. hominis + M. pneumoniae Mycoplasma + HHV-6 Mycoplasma + C. pneumoniae C. pneumoniae + HHV-6 7 2 1 2 8 (16.7) 2 (4.2) 1 (2.1) 0 0 0 0 0 (0) 0 (0) 0 (0) Chi2 = 4.7, p< 0.01 Chi2 = 1.9, p< 0.3 Chi2 = 1.4, p< 0.2 Chi2 = 1.9, p<0.2 Chi2 = 4.4, p< 0.01 Chi2 = 2.1, p< 0.19 Chi2 = 1.6, p< 0.3 12 (25.0) 0 (0) Chi2 = 11.7, p< 0.001 14 (29.2) 4 (8.3) 28 (58.3) 16 17 5 1 16 (33.3) Control Subjects n = 45 (%) 4 (8.3) 1 (2.1) 2 (4.7) 2 0 0 0 2 (4.7) Odds Ratio, p or Chi2 4.5, p< 0.01 5.6, p< 0.01 13.8, p< 0.001 9.2, p< 0.001 14.8, p< 0.001 11.8, p< 0.01 6.6, p< 0.01 13.8, p< 0.001 Invest in ME (Charity Nr. 1114035) Page 18/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Similarities of ME/Chronic Fatigue Syndrome (ME/CFS) and Autism Spectrum Disorders (ASD): Comparisons of Co-Infections (continued) Mycoplasma was found (usually M. fermentans), the majority of ASD patients in Central California were found to have single or multiple mycoplasmal infections involving M. pneumoniae, M. fermentans, M. hominis or M. genitalium. We also examined two other commonly found infections in CFS patients (4-7), C. pneumoniae and HHV-6 (13, 14). The results suggested that infections are a common feature in ASD as well as CFS. Consistent with this hypothesis is the finding that autism occurs at greater prevalence during periods of more frequent hospitalizations for bronchitis or pneumonia (19), and maternal viral infections during the second trimester of pregnancy are associated with increased risk of autism in their offspring (20, 21). In a separate study on CFS patients the presence of chronic infections has also been statistically related to the number and severity of signs/symptoms seen in CFS patients (14). Although similar studies in ASD patients have no been done, it has been observed that patients with severe ASD are those with systemic infections of the type seen in this study (unpublished observations). The appearance of infections in children diagnosed with ASD may eventually be linked to the multiple vaccines received during childhood either as a source or from opportunistic infections in immune suppressed recipients of multiple vaccines. Although the etiology of ASD is currently unknown and thought to involve both genetic and environmental factors (22, 23), the infections found in ASD patients should be considered along with other factors in the management of these disorders (24). REFERENCES 1. Nicolson, G.L. Chronic infections in neurodegenerative and Invest in ME (Charity Nr. 1114035) neurobehavioral diseases. Laboratory Medicine 2008; 39(5): 291-299. 2. Nicolson GL, Nasralla MY, Haier J et al. Mycoplasmal infections in chronic illnesses: Fibromyalgia and Chronic Fatigue Syndromes, Gulf War Illness, HIV-AIDS and Rheumatoid Arthritis. Med Sentinel 1999; 5:172-176. 3. Walch CM, Zainal NZ, Middleton SJ, et al. A family history study of chronic fatigue syndrome. Psych Genet 2001; 11:123-128. 4. Nicolson GL, Nasralla MY, Nicolson NL, Haier J. High prevalence of mycoplasmal infections in symptomatic (Chronic Fatigue Syndrome) family members of mycoplasmapositive Gulf War Illness patients. J Chronic Fatigue Syndr 2002; 11(2):21-36. 5. Nicolson GL, Nasralla M, Haier J, et al. Diagnosis and treatment of chronic mycoplasmal infections in Fibromyalgia and Chronic Fatigue Syndromes: relationship to Gulf War Illness. Biomed Ther 1998; 16:266271. 6. Nicolson GL, Nasralla M, Franco AR, et al. Diagnosis and Integrative Treatment of Intracellular Bacterial Infections in Chronic Fatigue and Fibromyalgia Syndromes, Gulf War Illness, Rheumatoid Arthritis and other Chronic Illnesses. Clin Pract Alt Med 2000; 1:92-102. 7. Nicolson GL, Nasralla M, Franco AR, et al. Mycoplasmal infections in fatigue illnesses: Chronic Fatigue and Fibromyalgia Syndromes, Gulf War Illness and Rheumatoid Arthritis. J Chronic Fatigue Syndr 2000; 6(3/4):23-39. 8. Nicolson GL, Berns P, Gan R, et al. Chronic mycoplasmal infections in Gulf War veterans’ children and autism patients. Med Veritas 2005; 2:383-87. 9. Wing L, Leekam SR, Libby SJ, Gould SJ, et al. The diagnostic interview for social and communication disorders: background, inter-rater reliability and clinical use. J Child Psychol Psychiatry 2002; 43:307-325. 10. Nicolson GL, Gan R, Nicolson NL, et al. Evidence for Mycoplasma, Chlamydia pneunomiae and HHV-6 Co-infections in the blood of patients with Autism Spectrum Disorders. J Neuroscience Res 2007; 85:114348. Page 19/76

Journal of IiME Volume 3 Issue 1 www.investinme.org Similarities of ME/Chronic Fatigue Syndrome (ME/CFS) and Autism Spectrum Disorders (ASD): Comparisons of Co-Infections (continued) 11. Takahashi H, Arai S, Tanaka-Taya K, Okabe N. Autism and infection/immunization episodes in Japan. Jpn J Infect Dis 2001; 54:78-79. 12. Nasralla M, Haier J, Nicolson GL. Multiple mycoplasmal infections detected in blood of Chronic Fatigue and Fibromyalgia Syndrome patients. Eur J Clin Microbiol Infect Dis 1999; 18:859–65. 13. Nicolson GL, Nasralla M, Gan R et al. Evidence for bacterial (mycoplasma, Chlamydia) and viral (HHV-6) co-infections in chronic fatigue syndrome patients. J Chronic Fatigue Syndr 2003; 11(2):7-20. 14. Nicolson GL, Gan R, Haier J. Multiple coinfections (Mycoplasma, Chlamydia, human herpesvirus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS 2003; 111:55766. 15. Fukuda K, Strauss SE et al. The Chronic Fatigue Syndrome, a comprehensive approach to its definition and study. Ann Intern Med 1994; 121:953-959. 16. Lord C, Pickles A, McLennan J, Rutter M, Bregman J, Folstein S, Fombonne E, Leboyer M, Minshew N. Diagnosing autism: analyses of data from the Autism Diagnostic Interview. J Autism Dev Disord 1997; 27:501517. 17. Van Bourgondien ME, Marcus LM, Schopler E. Comparison of DSM-III-R and childhood autism rating scale diagnoses of autism. J Autism Dev Disord 1992; 22:493-506. 18. Pilowsky T, Yirmiya N, Shulman C, Dover R. The Autism Diagnostic Interview-Revised and the Childhood Autism Rating Scale: differences between diagnostic systems and comparison between genders. J Autism Dev Disord 1998; 28:143-151. 19. Tanoue Y, Oda S, Asano F, Kawashima K. Epidemiology of infantile autism in southern Ibaraki, Japan differences in prevalence in birth cohorts. J Autism Dev Disord 1988; 18:155-166. 20. Ciaranello AL, Ciaranello RD. The neurobiology of infantile autism. Annu Rev Neurosci 1995; 18:101-128. 21. Wilkerson DS, Volpe AG, Dean RS, Titus JB. Perinatal complications as predictors of infantile autism. Int J Neurosci 2002; Invest in ME (Charity Nr. 1114035) 112:1085-1098. 22. Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol 2005; 11:1-10. 23. Lipkin WI, Hornig M. Microbiology and immunology of autism spectrum disorders. Novartis Found Symp 2003; 251:129-143. 24. Kidd P. Autism, and extreme challenge to integrative medicine. Part II: Medical management. Altern Med Rev 2002; 7:472-499. ME FACTS In many of the published studies, graded exercise therapy has been adopted as a component of the CBT programme (i.e. graded exercise was used as a way to diminish avoidance behaviour towards physical activity). Unfortunately, the studies examining the effectiveness of GET/CBT in ME/CFS did not use musculoskeletal pain as an outcome measure (and) none of the studies applied the current diagnostic criteria for ME/CFS. From a large treatment audit amongst British ME/CFS patients, it was concluded that approximately 50% stated that GET worsened their condition. Finally, graded exercise therapy does not comply with our current understanding of ME/CFS exercise physiology. Evidence is now available showing increased oxidative stress in response to (sub)maximal exercise and subsequent increased fatigue and post-exertional malaise - Belgian researchers Nijs and De Meirleir (Manual Therapy 2006: Aug. 11(3):187189). Page 20/76 Journal of IiME Volume 3 Issue 1 www.investinme.org A A RReesseeaarrcchheerr ’’ss VViieeww ff rroomm tthhee WWhhii tt tteemmoorree--PPeetteerrssoonn IInnsstt ii ttuuttee I was originally exposed to the world of CFS research, while taking a class in Biostatistics, as an undergraduate. My professor was a patient of Dr. Daniel Peterson and she approached him with the idea to conduct a research project using his CFS patient data, to which he agreed. Although the semester ended prior to completing the work I continued with the project on my own and ultimately we determined the value of CD4/CD8 ratios in diagnosing CFS and published and presented these data at the meeting of the American Mathematics Society in Eugene Oregon. It was during this time that I became acquainted with several CFS patients and truly understood their frustration regarding the lack of quality CFS research. I continued to work with Dr. Peterson on an informal level conducting other research but eventually I left the Tahoe area and began my Graduate work at Temple University. After a short time on the East Coast things took me in a different direction and I found myself back in Nevada. Shortly after returning I entered Graduate school at the University of Nevada, Reno and that is where I concluded my Graduate work, receiving a Ph.D. in Biochemistry in 2006. Although my Graduate work was conducted in Neuropeptide chemistry, I never lost contact with the CFS community and my desire to help the patients drew me back into the field; to this day I continue the work that started many years ago in the medical office of Incline Village. Although there are many directions a new investigator can take when he or she decides what area of research to pursue, ultimately, my decision was most greatly influenced by the CFS patients I met in Dr. Peterson’s office. I often imagined what it must be like to have a disease where the cause is unknown, the treatment is dubious and the mainstream medical community questions the validity of your disease. With this thought in mind it was an easy decision to continue down the path of CFS Invest in ME (Charity Nr. 1114035) Dr. Vincent Lombardi Dr. Lombardi was introduced to the field of ME/CFS as an undergraduate research assistant for Dr. Daniel L. Peterson, in Incline Village, NV. While working with Dr. Peterson, he was responsible for routine laboratory work, patient interviews, statistical and epidemiological data analysis. He began his graduate studies in the laboratory of Dr. Robert Suhadolnik at Temple University in 1999 studying the role of RNase L dysfunction in ME/CFS. He finished his graduate work at the University of Nevada, Reno in the field of neuropeptides and protein chemistry, receiving his PhD in Biochemistry in 2006. research, even thought the path is not always so easy. I have never been the kind of person that takes the easy road but the patients appreciate my work and that is enough for me. Invest in ME have a page of ways to help support the ME community, including the WPI in its important work. http://www.investinme.org/helpus.htm# Donate-to-the-WPI Page 21/76

Journal of IiME Volume 3 Issue 1 www.investinme.org EDUCATIONAL MATERIAL from IiME I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCoonnffeerreennccee DDVVDDss Invest in ME have available the full presentations from the International ME/CFS Conferences in London of 2008, 2007 and 2006. These professionally filmed and authored DVD sets each consist of four discs, in Dolby stereo and in PAL (European) or NTSC (USA/Canada) format. Containing over 6 hours (2008 DVD set), 9 ½ hours (2007 DVD set) and 6 hours (2006 DVD set) – with all presentations plus interviews with ME presenters and news stories from TV programmes. These DVDs have been sold in over 20 countries and are now available as an educational tools – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://www.investinme.org/InfoCentre%20Education%20Homepage.htm or via emailing Invest in ME at meconference@investinme.org. Price £14 each - including postage and packaging. Canadian Guidelines Invest in ME are the UK distributors for the Canadian Guidelines. Described even by NICE as “the most stringent” guidelines available these are proper, upto-date clinical guidelines which can also be used as a base for research criteria. Findings from the study by Leonard A. Jason PhD (Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome) indicated that the Canadian criteria captured many of the cardiopulmonary and neurological abnormalities, which were not currently assessed by the Fukuda criteria. The Canadian criteria also selected cases with ‘less psychiatric comorbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms’ and individuals selected by these criteria were significantly different from psychiatric controls with CFS. The Canadian Guidelines provide an internationally accepted means for clearly diagnosing ME The Canadian Guidelines are available from IiME and the price is 80p per copy plus postage & packaging. To order please contact Invest in ME via this email address: info@investinme.org Invest in ME (Charity Nr. 1114035) Page 22/76 Journal of IiME Volume 3 Issue 1 Human Enteroviruses and Chronic Infectious Disease Steven Tracy1 and Nora M.Chapman2 Enterovirus Research Laboratory, Department of Pathology and Microbiology, University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE 68198-6495, USA. 1, stracy@unmc.edu 2, nchapman@unmc.edu ABSTRACT Most of what is known about human enteroviruses (HEV) has been derived from the study of the polioviruses, the HEV responsible for poliomyelitis. The HEV are generally not thought to persist for long periods in the host: an acute, sometimes nasty, infection is rapidly eradicated by the host's serotypespecific adaptive immune response. Our discovery that the commonly encountered HEV, the group B coxsackieviruses (CVB), can naturally delete sequence from the 5' end of the RNA genome and that this deletional mechanism results in long-term viral persistence, in the face of the adaptive immune response, has substantially altered this view. This previously unknown and unsuspected aspect of enterovirus replication provides an explanation for previous reports of enteroviral RNA detected in diseased tissue in the apparent absence of infectious virus particles. Introduction The enteroviruses are an incredibly diverse and large genus in the family Picornaviridae. Within the enteroviruses, human enteroviruses (HEV; those which infect humans as opposed to other species) number at least 100 known serotypes, with more known to exist but which have just not been characterized to date. Serotype defines the virus: it is how the immune system recognizes the complex aggregation of proteins which makes up the virus particle or virion. Thus, infection with one HEV serotype induces immunity that protects against disease which that HEV serotype might inflict upon one were the virus is encountered again, but this protective immunity does not extend to other serotypes. This is why the poliovirus vaccines work to protect from poliomyelitis: any Invest in ME (Charity Nr. 1114035) Page 23/76 Professor Steven Tracy Ph.D. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha NE 68198-6495; stracy@unmc.edu; 402-5597747 • Ph.D., 1979, Department of Biology, University of California, San Diego • Primary research interest: Molecular biology and pathogenesis of the group B coxsackieviruses since the early 1980s www.investinme.org

Journal of IiME Volume 3 Issue 1 www.investinme.org Human enteroviruses and chronic infectious disease (continued) subsequent infection with poliovirus is quickly suppressed by the pre-existing anti-poliovirus immunity and the virus infection eradicated. But of course, anti-poliovirus protective immunity does not protect from being infected with a different HEV. Human enterovirus virions are small at 29nm in diameter; said another way, this means about 345,000 viruses would need to be lined up to equal one centimeter. The virus particle consists of an ordered array of 4 capsid proteins that forms an icosahedral structure of incredible beauty. In Figure 1, the reader can see what the coxsackievirus B3 (CVB3) virion would look like were one able to actually see it. This structure was solved with a technique called X-ray crystallography(23) in which X-rays, which are directed through crystals of virus and bent in specific ways, are then interpreted by computer analysis to provide a virus structure. Numerous other images of related enteroviruses can be found by visiting the website of the Institute for Molecular Virology at the University of Wisconsin in Madison WI, USA. The HEV cause a plethora of different human diseases and syndromes, the most important of which are poliomyelitis [now largely, although not entirely, eradicated in the world through use of the vaccines(16)], meningitis and encephalitis, myocarditis, pancreatitis, myositis, and type 1 (insulin dependent) diabetes (T1D)(31). Recent work has also indicated a possible role for HEV in the poorly understood etiology of chronic fatigue syndrome (CFS)(9, 11). Polio, T1D and CFS are noteworthy, in that these diseases are chronic and in the case of polio and T1D, fatal without treatment. Certainly, fatal cases of the other HEV diseases occur as well(28) but as a rule, HEV diseases are deemed to be acute illnesses of relatively low clinical importance because they are so common. Nonetheless, 5-10 million cases of symptomatic HEV infections occur annually in the US alone(27). Group B coxsackievirus infection of the heart Within only a few years after their discovery in Invest in ME (Charity Nr. 1114035) the late 1940s, the group B coxsackieviruses (CVB) were shown to be involved in inflammatory heart disease or myocarditis(6, 12, 32). Because of the ease with which the CVB replicated in mice, an experimental model to study myocarditis was soon available and has been exploited for numerous studies over the years. Once myocardial biopsy techniques became widespread as a clinical assay for the presence of myocarditis(29), researchers became interested in determining how often HEV was associated with myocarditis. These studies have demonstrated that about 15-20% of adult myocarditis cases can be associated with an HEV infection(2). This was carried out in most cases by isolating RNA from very small biopsy samples of the human heart, then analyzing the RNA for the presence of HEV RNA using a variety of techniques. Interestingly, in those adult cases of myocarditis in which the presence of virus was shown by detecting the viral RNA, rarely can an infectious virus be isolated. This is confusing: how can one detect viral RNA and not detect the virus? And indeed, this was a conundrum for many years. Most HEV cause cells in culture to die; this outcome, termed cytopathic effect or cpe, is the result of the virus infecting the cells in culture and killing them in the process of producing the next virus generation. Failure to observe cpe upon inoculating cell cultures with homogenized heart samples, was taken to be evidence that virus qua virus was not present. This goes back to the foregoing discussion, in which the general view of HEV is as a virus that rapidly causes cell lysis (acute disease). As opposed to adult samples, samples of pediatric myocarditic heart tissue generally shows both the presence of cytopathic virus when placed in culture as well as the presence of viral RNA when molecular assays are carried out. We considered the possibility that HEV infections of adult human hearts might generate a population of viruses that have been characterized and termed defective interfering (DI) viruses(10, 13). Although DI Page 24/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Human enteroviruses and chronic infectious disease (continued) Invest in ME (Charity Nr. 1114035) Page 25/76

Journal of IiME Volume 3 Issue 1 www.investinme.org Human enteroviruses and chronic infectious disease (continued) HEV had never been demonstrated in humans or animals, they had been shown to exist in experimental cell culture and thus, the possibility that they might also exist in nature could not be excluded. Defective interfering HEV are viral RNA genomes that have deleted variable parts of the sequence that encode the capsid (coat) proteins of the virus (see Figure 2). This implies such viruses could never be successful, as they could never produce an intact virion. However, DI HEV exist in a dynamic equilibrium with so-called wild type HEV which do produce normal capsids. Therefore, the DI viruses are parasites upon the wild type population of HEV, using their capsids to package the mutated RNA for movement to the next cell. Using a mouse model of CVB3-induced myocarditis, in which viral RNA was detectable in the heart tissue for many days after cytopathic virus was no longer detectable in cell culture, we searched for evidence of DI forms of CVB3 RNA but were repeatedly unsuccessful. We decided to examine the entire viral RNA genome that was present in these mouse heart samples, asking the basic question: are there deletions anywhere else that might explain this odd phenomenon? When this was done, we discovered that one of the ends of the single strand of RNA that makes up the viral genome, was missing: these viral genomes were then called 'terminally deleted' or TD(8, 18, 19). What makes this discovery fascinating to virologists, is that the sequence which the virus naturally deletes, was hitherto thought to be absolutely essential for virus replication. Our results, however, showed that while this sequence was very important for efficient CVB replication, it could nonetheless be done away with, and yet have the virus survive. The cost of this survival is, however, extremely slow replication. A further cost is that this survival can occur only in cell populations that do not divide anymore or divide very infrequently as in muscle tissue. It is this reason why we were able to find these novel virus populations in heart muscle Invest in ME (Charity Nr. 1114035) of experimentally inoculated mice(19) and later, in human heart(8). There are some cell cultures that do not divide continually but stop dividing when the cells contact each other; only in such cultures can CVB-TD populations occur(18). This is very different than current cell culture models for enterovirus infections in which most aspects of the viral biology are examined in immortal continuously replicating cells. While this is a good model for the short term infection of the gastrointestinal tract in which the virus infects, rapidly produces progreny virus and is excreted to infect another individual before the immune response can curtail infection, much of the pathology associated with enterovirus infections is in other differentiated tissues in which relatively little cell turnover may occur. In these nonreplicating (or only intermittently replicating) cells, the wild type virus is at a disadvantage because these cells lack key cytoplasmic factors essential for rapid replication. However, the low level replication of the TD viruses is favored in these cells and as the intracellular portion of the virus replication cycle is much longer, it is relatively hidden to the immune system. Much of our current research focus is upon the mechanism of selection of the TD populations in such cell cultures or tissues. These results provided an answer to the conundrum of failing to find cytopathic virus in myocarditic heart samples despite the ability to find viral RNA. Indeed, virus (in TD form) does exist in such samples but because the TD populations replicate so slowly and produce so little virus, they are difficult to detect. However, because the defect is not in a part of the viral genome that makes viral proteins, they do make all the viral proteins and even virus particles. But what does the finding of TD genomes mean for HEV disease? Chronic disease associated with HEV infections The previous discussion has demonstrated that HEV can persist for longer periods of time in the immunologically-normal host Page 26/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Human enteroviruses and chronic infectious disease (continued) than ever had been suspected but that this came at a price to the virus: very slow replication and relatively very few infectious particles produced. In cases of chronic inflammatory heart disease (chronic myocarditis) or what is often thought to be a sequela of this condition, called dilated cardiomyopathy (DCM), HEV RNA has been detected in the apparent absence of cytopathic virus(4, 7, 21). We can now say with some certainty that in such cases, HEVTD populations were present. In DCM, the heart is failing due to damage to the Invest in ME (Charity Nr. 1114035) cardiomyocytes (muscle cells of the heart). Others have shown that a HEV enzyme that works on and reduces proteins, called a protease, can damage an important cardiomyocyte protein called dystrophin(3) and that in a mouse model of this disease(33), dystrophin is cleaved despite the inability of the virus to produce infectious particles and this leads to DCM in the mouse, a scenario that is closely similar to the low level production of virus particles by TD virus populations. Therefore, in this chronic HEV-induced Page 27/76

Journal of IiME Volume 3 Issue 1 www.investinme.org Human enteroviruses and chronic infectious disease (continued) disease, the long-term persistence of a slowly replicating HEV can lead to cell damage, due to the virus' own enzymes it uses to replicate, and this damage eventually impacts the function of the organ (the heart) itself. Another chronic disease that is closely linked to HEV infections is type 1 (insulin dependent) diabetes (or T1D)(15, 30). Type 1 diabetes occurs due to an inability to control glucose metabolism which is an outcome from the loss of insulin-producing beta cells in the pancreatic Islets of Langerhans(17). Although some cases are thought to be due only to a specific expression of individual genetic traits, most T1D cases cannot be so easily explained and therefore, environmental factors (like infections) have been sought to explain how T1D is initiated(1, 20). One environmental factor that is high on any list, are the HEV: many clinical observations and experimental studies implicate HEV as agents that can and do trigger T1D onset in humans(15, 30). While CVB have been associated with T1D cases, other non-CVB HEV have also been implicated in T1D onset, further adding to the evidence for a role of HEV in T1D onset. At present, it is unclear whether the HEV involved persists in the host after the initial infection that sets the disease in motion, or whether it is more of a classical HEV acute infection, one that is rapidly cleared by the immune response. What is very clear, however, is that CVB can rapidly trigger T1D onset in a T1D-prone mouse called the NOD mouse if the mouse is already prediabetic from its own autoimmune attack on its pancreatic islets(14). This means that under certain circumstances (when one has autoimmune insulitis present, and one is infected with an HEV against which one has no pre-existing protective immunity, and it is the correct HEV at the right dose), T1D in humans could likely be initiated by an HEV infection. Using the rapid onset model in mice to make inferences for humans, we would predict an HEV infection that rapidly kills enough beta cells will initiate T1D. However, the virus infection might not accomplish this: the virus might instead kill insufficient numbers of beta Invest in ME (Charity Nr. 1114035) cells for T1D to ensue. What then? This is where the autoimmune (in which one's immune system attacks oneself) aspect of T1D sets this disease apart from the previously discussed chronic heart disease. In T1D, enough insulin-producing beta cells must be destroyed in order for T1D to occur: this can happen by autoimmune processes, by virus attack, or both occurring together. We are currently assessing whether longterm persistence of HEV is a factor in both the NOD mouse model of T1D and in human beings. Chronic fatigue syndrome and the link to HEV infection In a paper that received much notice, Chia and Chia showed that HEV RNA and protein were detectable in the great majority of stomach biopsy tissue samples from patients diagnosed with chronic fatigue syndrome (CFS) but only in few biopsy samples from control patients without the disease(9). This report has suggested that a commonly circulating human virus group might be a primary etiologic agent involved in CFS, a disease that is marked by a difficult diagnosis and a near complete lack of understanding about what agent(s)/mechanism(s) trigger the disease. As we have seen from the previous discussion, HEV may be able to initiate a disease process just from an acute infection, which is then resolved, or from a continuing infection as well, involving a persistent virus population. Persistence is, however, a relative term. In an immunologically-normal individual, i.e., one who is able to mount normal vigorous immune responses against infectious agents, an HEV infection may be able to persist via a TD genome mechanism for some weeks, perhaps months, but eventually will be eradicated by the immune response. Thus, such infections are temporary (unlike herpesviruses or HIV). Although HEV are common viruses, the very high positive correlation with the CFS stomach samples was surprising. In other known associations of HEV with human Page 28/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Human enteroviruses and chronic infectious disease (continued) diseases, such high correlations have not been observed. Poliovirus caused paralytic disease during epidemics(22) but only about 1 out of every 100-200 infections involved life-threatening paralysis. The HEV, thought to be primarily CVB, which have been closely linked to causing myocarditis, have been detected in about 15-20% of samples in a variety of studies(21). To explain the high number of positive stomach samples with CFS, one must consider the possibility of a continuing process in CFS patients of new infections with different HEV serotypes and/or a significant number of persistent infections in the stomach. The difficulty these workers had in culturing the viruses from stomach tissue, would be consistent with either HEV strains that do not replicate well in standard tissue culture systems and/or the viruses exist in a form that is difficult to detect. While most HEV do replicate in certain cell cultures, others require the use of suckling mice(27). It is interesting to consider that a HEV-TD population would fit such a description of a 'difficult to culture virus". At present, these findings are highly intriguing but need also to be considered with the proverbial 'grain of salt'. It is of the highest and immediate importance to identify the HEV in these stomach biopsies in order to verify and move forward the theory that HEV are involved in the CFS etiology. Are they a specific serotype of HEV or are they many different types? This can be determined without culturing the viruses, by amplification of specific genome regions and determination of the RNA sequence(5, 24-26). Once established which specific HEV are present, relevant model systems might be developed using cell cultures and possibly mice, to study the CFS disease onset process. Summary Basic research into the biology of the HEV has lead to truly fantastic discoveries which Invest in ME (Charity Nr. 1114035) in turn, have lead to 'bench to bedside' advances. Understanding how to culture animal cells in the laboratory, made possible propagation of the agent that causes polio and subsequent studies in primates, work that in turn lead to the development of the successful poliovirus vaccines from which we have all profited. A search for other viral agents that induce polio-like disease lead to the discovery of the coxsackieviruses and indeed many other HEV. The development of a mouse to study retinal disease produced the NOD mouse, a highly useful mouse strain that is regularly used in studies of T1D. We know that serendipity and planning go hand in hand and often in the laboratory, are hard to tell where one begins and the other leaves off. As scientists who focus on all things enteroviral, we are especially interested in the findings of Chia and Chia that suggest the potential for an HEV link in CFS etiology. Our finding that a deletion in the terminal portion of the CVB genome, was the mechanism by which HEV can persist, could not have been predicted based on what was known. This finding has opened a completely new and quite unsuspected chapter in the very well thumbed volume on enterovirus biology. This was elegantly enunciated by Louis Pasteur in his famous quotation: "Where observation is concerned, chance favors the prepared mind." Without the existence of basic science, most of what we know take for granted in medicine would not exist. It is of the greatest importance to keep in mind the goal toward which one works in science, but it is also of equal importance to simply explore and define the 'new' while keeping that mind well prepared for finding new treasures. It is only through such efforts that we believe the etiology of CFS will be finally illuminated. Page 29/76

Journal of IiME Volume 3 Issue 1 www.investinme.org Human enteroviruses and chronic infectious disease (continued) Acknowledgements. Much of our work has been variously supported by the National Institutes of Health, the American Heart Association, the Juvenile Diabetes Research Foundation, and the American Diabetes Association. We also sincerely thank a group of concerned individuals who have lost family due to enteroviral heart disease, for their generous support. References 1. Akerblom, H. K., O. Vaarala, H. Hyoty, J. Ilonen, and M. Knip. 2002. Environmental factors in the etiology of type 1 diabetes. Am J Med Genet 115:18-29. 2. Baboonian, C., M. J. Davies, J. Booth, and W. McKenna. 1997. Coxsackie B viruses and heart disease. Curr Top Microbiol Immunol 223:31-52. 3. Badorff, C., N. Berkely, S. Mehrotra, J. W. Talhouk, R. E. Rhoads, and K. U. Knowlton. 2000. Enteroviral protease 2A directly cleaves dystrophin and is inhibited by a dystrophin-based substrate analogue. J Biol Chem 275:11191-7. 4. Bowles, N. E., P. J. Richardson, E. G. Olsen, and L. C. Archard. 1986. Detection of Coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet 1:11201123. 5. Brown, B., M. S. Oberste, K. Maher, and M. Pallansch. 2003. Complete genomic sequencing shows that polioviruses and members of human enterovirus species C are closely related in the noncapsid coding region. J Virol 77:8973-8984. 6. Chapman, N., A. Ramsingh, and S. Tracy. 1997. Genetics of coxsackievirus virulence. Curr Top Microbiol Immunol 223:227-258. 7. Chapman, N. M., and K.-S. Kim. 2008. Persistent coxsackievirus infection: enterovirus persistence in chronic myocarditis and dilated cardiomyopathy. Curr Topics Microbiol Immunol 323:275-292. Invest in ME (Charity Nr. 1114035) 8. Chapman, N. M., K. S. Kim, K. M. Drescher, K. Oka, and S. Tracy. 2008. 5' terminal deletions in the genome of a coxsackievirus B2 strain occurred naturally in human heart. Virology. 9. Chia, J. K., and A. Y. Chia. 2008. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol 61:43-8. 10. Cole, C. N., D. Smoler, E. Wimmer, and D. Baltimore. 1971. Defective interfering particles of poliovirus. I. Isolation and physical properties. J Virol 7:478-485. 11. Cunningham, L., N. E. Bowles, R. J. Lane, V. Dubowitz, and L. C. Archard. 1990. Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA. J Gen Virol 71:13991402. 12. Dalldorf, G. 1955. The coxsackie viruses. Annu Rev Microbiol 9:277-296. 13. Dimmock, N. J. 1991. The biological significance of defective interfering viruses. Rev Med Virol 1:165-176. 14. Drescher, K. M., K. Kono, S. Bopegamage, S. D. Carson, and S. Tracy. 2004. Coxsackievirus B3 infection and type 1 diabetes development in NOD mice: Insulitis determines susceptibility of pancreatic islets to virus infection. Virology 329:381-394. 15. Drescher, K. M., and S. Tracy. 2008. The CVB and etiology of type 1 diabetes. Curr Topics Microbiol Immunol 323:259274. 16. Dutta, F. 2008. Epidemiology of poliomyelitis - options and update. Vaccines 26:5767-5773. 17. Haller, M. J., M. A. Atkinson, and D. Schatz. 2005. Type 1 diabetes mellitus: etiology, presentation, and management. Pediatr Clin North Am 52:1553-78. 18. Kim, K. S., N. M. Chapman, and S. Tracy. 2008. Replication of coxsackievirus B3 in primary cell cultures generates novel viral genome deletions. J Virol 82:2033-7. 19. Kim, K. S., S. Tracy, W. Tapprich, J. Bailey, C. K. Lee, K. Kim, W. H. Barry, and N. M. Page 30/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Human enteroviruses and chronic infectious disease (continued) Chapman. 2005. 5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA. J Virol 79:7024-41. 20. Knip, M., and H. K. Akerblom. 1999. Environmental factors in the pathogenesis of type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes 107 Suppl 3:S93-S100. 21. Martino, T. A., P. Liu, M. Petric, and M. J. Sole. 1995. Enteroviral myocarditis and dilated cardiomyopathy: a review of clinical and experimental studies., p. 291352. In R. HA (ed.), Human Enterovirus Infections. ASM Press, Washington DC. 22. Minor, P. D. 2003. Polio vaccines and the cessation of vaccination. Exp Rev Vaccines 2:99-104. 23. Mucklebaur, J. K., and M. G. Rossmann. 1997. The structure of coxsackievirus B3. Curr Top Microbiol Immunol 223:191-208. 24. Oberste, M. S., K. Maher, M. R. Flemister, G. Marchetti, D. R. Kilpatrick, and M. A. Pallansch. 2000. Comparison of classic and molecular approaches for the identification of untypeable enteroviruses. J Clin Microbiol 38:1170-1174. 25. Oberste, M. S., K. Maher, D. Kilpatrick, M. Flimister, B. Brown, and M. A. Pallansch. 1999. Typing of human enteroviruses by partial sequencing of VP1. J Clin Microbiol 37:1288-1293. 26. Oberste, M. S., K. Maher, A. J. Williams, N. Dybdahl-Sissoko, B. A. Brown, M. S. Gookin, S. Penaranda, N. Mishrik, M. Uddin, and M. A. Pallansch. 2006. Species-specific RT-PCR amplification of human enteroviruses: a tool for rapid species identification of uncharacterized enteroviruses. J Gen Virol 87:119-28. 27. Pallansch, M. A., and R. Roos. 2007. Enteroviruses: Polioviruses, coxsackieviruses, echoviruses and newer enteroviruses, p. 839-893. In D. M. Knipe (ed.), Fields Virology, vol. 1. Wolters Kluwer, Philadelphia. 28. Romero, J. T. 2008. Pediatric group B coxsackievirus infections. Curr Topics Microbiol Immunol 323:223-239. 29. Shanes, J., J. Ghali, M. Billingham, V. Ferrans, J. Fenoglio, W. Edwards, C. Tsai, J. Invest in ME (Charity Nr. 1114035) Page 31/76 Saffitz, J. Isner, S. Furner, and e. al. 1987. Interobserver variability in the pathologic interpretation of endomyocardial biopsy results. Circulation 75:401-405. 30. Tracy, S., and K. M. Drescher. 2007. Coxsackievirus infections and NOD mice: Relevant models of protection from, and induction of, type 1 diabetes. Ann N Y Acad Sci. 31. Tracy, S., M. S. Oberste, and K. M. Drescher. 2008. Group B Coxsackieviruses. Curr Topics Microbiol Immunol 323. 32. Van Creveld, S., and H. De Jager. 1956. Myocarditis in newborns, caused by coxsackie virus. Ann Pediat 187:100-112. 33. Wessely, R., K. Klingel, L. F. Santana, N. Dalton, M. Hongo, W. Jonathan Lederer, R. Kandolf, and K. U. Knowlton. 1998. Transgenic expression of replicationrestricted enteroviral genomes in heart muscle induces defective excitationcontraction coupling and dilated cardiomyopathy. J Clin Invest 102:1444-53. The Enterovirus Foundation was founded in November 2008 and is a non-profit organisation created to fund research to discover the persistent effects of enteroviruses, to determine the role they play in both acute and chronic disease, and to develop treatments to cure and prevent these diseases. More details at - www.enterovirusfoundation.org

Journal of IiME Volume 3 Issue 1 www.investinme.org SEVERE ME – A NORWEGIAN EXPERIENCE H Haarraalldd aanndd KKjjeerr ss tt ii KKrr ii ssnneerr The Krisner family from Norway whom we intoduced on the Conference 2006 DVD in a TV programme (available from the Invest in ME web site) and in a follow up article has since experienced considerable changes. Katrrine, who has been ill since 1999, has become miraculously better in the past year. In 2003 she woke up from a coma like condition only to become seriously ill again in 2006. At that time she was left bedbound for 2 more years in total darkness, being tube fed and without any ability to communicate at all. Her condition was plagued with severe symptoms, and we fought to keep her alive. In December 2007 she was prescribed broad spectrum antibiotics due to an infection. After 2 ½ months on this medication, she suddenly responded in February last year. She started to speak slowly. Light and sound sensitivities became a little bit better also. She told afterwards how she had gradually felt getting better, but had no means of communicating it. After further blood tests we carried on with the treatment, but now with three different antibiotics at the same time. After two more months, at times with debilitating side effects, Invest in ME (Charity Nr. 1114035) The Krisner Family and ME in Norway In 2006 we were introduced to the Krisner family from Norway whose three children were severely ill with ME. All three siblings Frode, Katrine and Bjørnar lived normal lives before their sickness. Bjørnar was a journalist and TV presenter. In 2006 they agreed to appear on a Norwegian TV programme to highlight the plight of severely ill ME patients. Doctors could not explain why all three siblings had the illness. They did not know whether it was genetic or if there were other factors which forced three young people to live several years in the darkness and confined to bed. At the time of the program the three siblings were 29, 26 and 20 years old. Frode became sick when he was 7 years old, Katrine when she was 20 and Bjørnar became really sick when he was 26. No one could predict if the siblings would ever get better nor say what can be done to return them to a normal life. Page 32/76 Journal of IiME Volume 3 Issue 1 www.investinme.org SEVERE ME – A NORWEGIAN EXPERIENCE everything moved foward quickly, and on the 10th of May 2008 she was in the sitting room for the first time in two years. A couple of weeks later she could venture out into the garden for the first time in seven years. At this point she was able to be without sunglasses indoors, but outside sunglasses were still needed. The improvement this time is completely different from the one in 2003-2006. It is so in every aspect. The change in May was enourmous, almost miraculous. We saw the illness losing its hold, whilst with the previous period of improvement it was a constant battle against something overpowering. Since June last year Katrine has been a patient of Professor Kenny De Meirleir. One tries to remove causes successively and build up the immune system. The treatment, change of seasons, infections, continuing illness and other things, cause the condition to fluctuate. She has since May 10th last year, been up every day and this is something of an experience for us around her. She is engaging, reflectful, caring with lots to give and convey, hungry for information and knowledge, is realistic in relation to the illness and at the same time plans for the future. She still has to be careful and take it easy. Experience tells us, also this time, that going too fast brings relapses or, at the very least, slower recovery. Her younger brother, Frode, who is 23 years old and has been ill since he was 7, also experienced great improvement last year after several months on a similar treatment protocol as Katrine. He had an experience of living with an ’abundance of energy’ for the first time which was a fantastic experience for him. To be free from looking for a chair to sit down on, to avoid detailed planning and giving up a lot the following days if he was out with friends the evening before, to be able to live more like everybody else on good days, became a Invest in ME (Charity Nr. 1114035) great experience. The previous summer was a summer when he could do more and he and his best friend, who has been fantastically supportive all these years, went to south of France for a holiday . Being such car enthusiasts, they could both experience many things they had dreamt of in the past years. Frode has gradually built up his IT company. He still has to live a restricted life, but he has a far greater capacity than before. Bjørnar, the eldest in the family, now 32 years old, was the one who was the main character in the 2006 film when he was interviewed in the dark. The TV programme gave the severely ill a face and set in motion a lot of emotions and engagement. The fact that he was a TV journalist with an exciting career and ended up as a patient needing care, made an impact on many of his colleagues. The effort of being on TV such as having a hair cut and shave, took a lot of energy out of him and led to further deterioration of which he still has not recovered. At present Bjørnar can communicate with signs and speak a little if needed or when he has more energy. If he speaks more than his energy levels allow, it leads to increasing symptoms which in turn can be the start of long term worsening of his condition. This balancing of trying to avoid worsening of the condition, is important in moving the condition in the right direction. Last year in the spring he was put on a similar treatment as his siblings but there was no big breakthrough. Four months ago it looked like his condition was finally on its way to improving. At that time his test samples that were sent to a specialist laboratory were found to be positive for an African amoeba. After a few days on a strong amoeba treatment protocol, he experienced a radical change in his abdominal pain, hunger and bowel movement function. He is still under treatment for many other things that were found. He feels he is getting gradually better. Page 33/76

Journal of IiME Volume 3 Issue 1 www.investinme.org SEVERE ME – A NORWEGIAN EXPERIENCE All three siblings have since June last year been undergoing treatement under the guidance of Professor Kenny De Meirleir. He came along after the extra blood tests that led to treatment had been done. His findings fit in with those performed earlier. It is fantastic to experience improvement and great to see two of our children come back to life. We hope that we shall experience Bjørnar coming out into daylight in a short while. Life is exciting. To be continued next year. Harald and Kjersti Krisner, parents ( May 2009) ME STORY The following day the psychologist came to give me the results, his words were these: "If you are to be believed, and your answers truthful, then you have the mental age of a senile 71 year old, and I should section you immediately! Now if you would truthfully like to tell me what personal experience led to your M.E. then I might be able to help you! What devastating event led to this mental problem, what made you so depressed?" I was appalled at this approach to my illness!! I told him in no uncertain terms that there had been no devastating event, that I had not been depressed, that actually my life for the previous couple of years had been remarkably uneventful but extremely happy. He continued to insinuate that something must have happened and that I was obviously depressed - so I pointed out to him that the only event had been me becoming ill and that any depression I had was a result of that! He then told me he would recommend that I be placed in another hospital to have further psychological review because I was obviously not trying and was actually deliberately acting ill to gain attention! - Debbie Katrine (above) – a photograph taken on her 30th birthday in May 2009. ME STORY In 2004 I caught a kind of flu with an infection of the gut and I never recovered. I needed 3 years for a diagnosis. It was a infernal trip into the jungle of the German health care system. At the onset there was a kind of outbreak in my workplace. The whole staff had been affected by ME-symptoms. In 2007 Prof. Dr. de Meirleir in Belgium attested me: This patient suffers from ME/CFS (WHO 93.3). - Roland Invest in ME (Charity Nr. 1114035) Page 34/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Call to Action Why I Support Invest in ME Like a lot of people, I had no real knowledge about M.E (Myalgic Encephalomyelitis). I just assumed it was some luxury illness or 'yuppie flu', because that is the way the media, especially newspapers had portrayed this disease. Then my sister Sophia developed severe M.E. and two years into her suffering, it began to dawn on me that perhaps I had grossly underestimated M.E. I support Invest in M.E. because they understand the true nature of M.E and help many sufferers of this disease. It was partly ignorance that killed my sister. Yes you read that right, Sophia died from M.E. She was 32 and her suffering and death were largely preventable. Sophia‘s last wish was to help others not go through what she did. My sister was disbelieved by her doctors about the true physical nature of her illness. She was accused of attention seeking and having 'unresolved issues' and she was treated as if her illness had its roots in her mental health. My mum who was my sister’s main carer was accused of enabling Sophia’s illness for the simple crime of believing that her daughter was physically very ill. One of Sophia's doctors actually wanted to section my mum. I wish I were exaggerating but proof of all this is on SophiandMe.org.uk. Invest in ME is a charity that understands that M.E is a physical disease and that M.E has been categorised as a physical neurological disease by the World Health Organisation since 1969. The way M.E. is treated in this country is contrary to how a physical, neurological disease should be treated. In the UK, psychiatrists took charge of the care of people with M.E., but this disease is not a mental illness. It is like being treated by a dentist for a broken leg. The wrong people are in charge of a disease that they have no expertise in dealing with. Invest in ME (Charity Nr. 1114035) Roisin Mirza is the sister of Sophia Mirza and is a qualified nurse. Sophia died from ME. Disbelieved by those providing healthcare for her condition, she was sectioned by psychiatrists who neither understood her condition nor seemingly cared to analyse her symptoms in a medical way. Sophia was “sectioned as a result of exercising her right not to go into a particular ME Clinic. Despite the fact that she was bedbound, she reported that she did not receive even basic nursing care, where her temperature, pulse and blood pressure, were never taken. Sophia told me that her bed was never made, that she was never washed, her pressure areas were never attended to and her room and bathroom were not cleaned From Tuesday 22nd November, Sophia could not move an inch, neither could she sleep. On Friday 25th she died..” - taken from Sophia’s story on the IiME web site Page 35/76 Sophia Mirza

Journal of IiME Volume 3 Issue 1 www.investinme.org Call to Action - Why I Support Invest in ME (continued) We don’t know how you get/develop/contract M.E, and we don’t know how to cure it and therefore we could all be at risk from M.E. So why are psychiatrists and the mental health sector given free reign over M.E? The simple answer is ‘kerching’ and politics/power play. There is a lot of money at stake for the treatment and research of this disease. It is in certain group’s interests to keep M.E treated as a mental illness. The Government is advised by psychiatrists about the treatment of the disease of M.E and it is in their interest to advocate mental health treatments. It is also in medical insurance companies’ financial interests to keep M.E treated as a mental illness. If M.E funding were to go to the physical health camp, it would have to battle with the big boys such as Cancer and Heart Disease for funding. In the mental health camp there is far less competition. The ring of ‘kerching’ is louder than the cry of truth at the moment. However the truth will out, and the sooner M.E is seen and treated as a physical illness the better for everyone. This is not just better for M.E patients and their carers, it is better for everyone. The false security of M.E getting labelled as something in mental health is a dangerous myth. You cannot catch a mental health disease, but you can catch/develop a physical disease. Multiple Sclerosis and Parkinson’s disease were considered mental illnesses before they were wrestled out of mental health and put in their rightful place in physical health treatment. M.E is not the first and will probably not be the last disease to be wrongly taken by the mental health sector. By supporting Invest in ME you are helping liberate everyone. This (event) happened to Sophia but it could happen to anyone of us. My sister was condemned as mentally ill and referred to a psychiatrist, even though no mental health checks were done and it was Invest in ME (Charity Nr. 1114035) blatantly obvious to anyone that Sophia was severely physically ill. Sophia refused treatment at an ME clinic where they treat ME patients with methods such as GET (Graded Exercise) and CBT (Cognitive Behaviour Therapy),. These treatments have been proven to make M.E patients WORSE. The clinics’ own statistics state that Graded Exercise makes people with severe ME worse. Sophia was given a ‘get well by a certain date or be sectioned’ ultimatum which she failed to get well for. Sophia refused to go to the clinic because she was just too ill to be able to risk treatments which would probably cause her great harm. This was a sane decision by Sophia. As a result of making a sane decision an insane one was taken by her doctors. Sophia was sectioned into a mental health hospital and she never recovered from this experience. Sophia’s could not tolerate light, noise, movement or smells. She lived the last few years of her life in the dark, in bed and couldn’t even read a book or listen to music. She was in constant pain and if this were not bad enough, she had to live under a blanket of fear and was treated as if she were mentally ill, despite overwhelming evidence to the contrary. My sister’s post-mortem revealed the physical evidence of M.E in her spinal column. It is a shocking disgrace that Sophia had to die to be believed. I trained as a nurse through my sister’s illness and I saw how M.E was viewed from the other side. I never confided in anyone during my nurse training and nurse working time about my sister having M.E, because of the stigma attached to this disease. I didn’t risk confiding in people because when I had tried confiding in people before, I was met with plastic psychiatry about ‘perhaps she has unresolved issues’. If you got M.E from having ‘issues’ the whole country would be down with it. There was also the risk that a well meaning but ignorant person would add fuel to the fire and go to the Page 36/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Call to Action - Why I Support Invest in ME (continued) authorities with their ‘concerns’. This practise is encouraged by psychiatrists who use peoples ‘concerns’ to back up their mental health treatment assault. By supporting Invest in ME you are supporting human rights. Sophia was stripped of her human rights because of the mental health label. By supporting and bringing to light the truth about the disease of M.E you are helping to save lives. You are helping prevent another Sophia story happening. By supporting Invest in ME you are saying that M.E is a physical disease that needs to be treated as such. This matters to those countless M.E sufferers and their carers that you understand they are genuinely physically ill. There is no physical diagnostic test for ME at the moment but how can there be a physical marker test for ME if no research money is put there? This must change. I will be going back to my old nursing school and giving a talk about Sophia and her ME on June 8th. Ignorance of ME is producing much unnecessary suffering. We need as much help as possible to turn the image of M.E around. Racism is rightly taken very seriously, but what about ’diseasism’ ? There is a stigma with M.E that is similar to a sixteenth century witch hunt. The accusation of being called mentally ill, is similar to that of calling a woman a witch. Treating someone as if they are mentally ill, does not make that person mentally ill. How can someone prove they are physically ill if the doctors treating them do not believe their own eyes and ears? Even without a diagnostic test for M.E there are still physical abnormalities that would show up in a blood test and other basic health checks. Many doctors are reluctant to physically test for ME because the “experts’ ” advice that it ‘encourages aberrant illness beliefs’. ME is not a belief, it is a fact. Invest in ME (Charity Nr. 1114035) Page 37/76 ME is as much a ’belief’ as I ’believe’ in gravity and those psychiatrists ’believe’ they are medically trained. We need research into the physical nature of M.E. We need people to be as aware of M.E as they are of cancer. You wouldn’t accuse a cancer patient of imagining their illness because they had unresolved issues. Not many things in life are black and white, but this is. There is no ‘confusion /controversy’ about the disease of ME except the confusion the 'expert' psychiatrists have put there. By muddying the waters , these psychiatrists, many of whom are in the pockets of medical insurance companies, are keeping M.E in their domain. Chronic Fatigue Syndrome (CFS) and M.E are being lumped together as the same disease but they are not the same. M.E. is a physical neurological disease, and CFS is am umbrella term for any disease with fatigue in. Chronic Fatigue is classified by W.H.O as a mental health illness, but M.E is classified as a physical, neurological disease. One can see how the lack of clarity starts to happen. A small powerful band of psychiatrists have, for years, clouded and complicated the understanding of the disease of M.E, not just in the consciousness of ordinary people, but in the minds of doctors, psychiatrists and the Government, by talking about ME and fatiguing syndromes in the same breath. People are still suffering unnecessarily from the physical disease of ME and from the unspoken accusation that it is 'all in their mind' because of a small group of doctors’ greed for money and position. People are living under fear of being sectioned because they ’believe’ they are physically ill with M.E. Carers of those with ME have a much higher rate of being accused of Munchhausen’s By Proxy .

Journal of IiME Volume 3 Issue 1 www.investinme.org Call to Action - Why I Support Invest in ME (continued) It is scandalous that the very vulnerable ME patients are not only not helped, but actually discriminated against because they have M.E. Please help us change this. Anyone can get M.E. Sophia was half Pakistani and half Irish. This is not just a white person’s disease. We are all at risk and we need urgent research and treatment into the physical nature of this disease. Behind the closed doors of courts, children are being torn away from their parents. These parents are silenced by these same courts. Tell the mental health sector to 'Get your hands off M.E' and put M.E back in its rightful place, back where it belongs, back to where the W.H.O. put it in 1969, back in the field of physical disease. ME STORY I now live on DLA and have to use a wheelchair. I spent years being told I had depression, I was attention-seeking, difficult, lazy. I tired too hard to do the things other children/ young adults did and failed. I felt hopeless and helpless many times. However I refused to give up fighting. THREE years ago after another round of arguing with doctors and neurologists and being told by a neuro psyche I was not genuinely ill my GP found missing notes from the 1980s - notes that had been missing for over 20 years. There in black and white were handwritten notes than indeed I had attended the doctors who had noted possible encephalitis. - Lynn Invest in ME (Charity Nr. 1114035) I have been diagnosed with CFS they (the NHS) will not have ME in their vocabulary. Everything is a fight, to be heard, to be listened to, just to be BELIEVED. I wish with all my heart that I just was a bit tired like people think, I would chop off my arms to be just tired. My life is a process of trying to get through the day and perhaps I'll have a day where I'm not so bad - Maxine Page 38/76 ME FACTS In 2003, Byron Hyde, medical adviser on ME/CFS to the Canadian Government, pointed out that “ME in adults is associated with measurable changes in the central nervous system and autonomic function and injury to the cardiovascular, endocrine and other organs and systems. The patient with the diagnosis of ME/CFS is chronically and potentially seriously ill. These ME/CFS patients require a total investigation and essentially a total body mapping to understand the pathophysiology of their illness and to discover what other physicians may have missed. A patient with ME is a patient whose primary disease is central nervous system change, and this is measurable. The belief that ME/CFS is a psychological illness is the error of our time”. (The Complexities of Diagnosis. Byron Hyde. In: Handbook of Chronic Fatigue ME STORY Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY Garth L. Nicolson, PhD, Rita Ellithrope, MD and Robert Settineri, MS The Institute for Molecular Medicine, Huntington Beach, CA 92647 The Tustin Longevity Center, Tustin, CA 92780 Sierra Productions, Irvine, CA 92606 ABSTRACT Often Chronic Fatigue Syndrome (CFS) patients have weight issues, and weight reduction regimens can increase fatigue. Therefore, we initiated a weight loss clinical trial using an all natural oral supplement mixture containing an FDA-approved amaylase inhibitor plus NTFactorTM, which is known to safely reduce fatigue in aged subjects,1 chronic fatigue2 and CFS.3 The objective was to see if subjects could safely lose weight without increasing appetite and fatigue and without changing eating or exercise patterns or using drugs, herbs or caffeine. A 2-month open label clinical trial was initiated with 30 patients who used an oral mixture (Healthy CurbTM) of amaylase inhibitor (500 mg white kidney bean extract) plus 500 mg of NTFactorTM 30 min before each meal. Weight and measurements were taken weekly, appetite was assessed4 and fatigue was determined using the Piper Fatigue Scale.5 Sixty-three percent of the participants lost an average of 6 pounds along with 2.5 and 1.5 inch reductions in waist and hip circumference, respectively, and the entire group of participants lost an average of 3 pounds with average reductions of 1.5 and 1 inch waist and hip circumference, respectively. Participants experienced gradual and consistent weight loss along with waist and hip, body mass index (BMI) and basal metabolic rate (BMR) reductions during the entire trial. There was a 44% reduction in overall hunger with reduced cravings for sweets; therefore, notable appetite suppression occurred. Using the Piper Fatigue Scale the entire test group showed an average of 23% decrease in overall fatigue. Blood lipid profiles generally improved, suggesting improved cardiovascular health, and no adverse effects were noted clinically or found in blood chemistries. Conclusions: The vast majority of the subjects in this trial lost weight, showed decreased waist and hip measurements and overall body mass. Their overall fatigue was reduced, and they experienced marked appetite suppression. The product was completely safe and void of any side effects and was extremely Invest in ME (Charity Nr. 1114035) Professor Garth Nicolson The Institute for Molecular Medicine, P.O. Box 9355, S. Laguna Beach, California 92652. Tel: 949-715-7958; Email: gnicolson@immed.org; Website: www.immed.org ME RESEARCH “Many studies have found that the immune system appears to be in a state of chronic activation (and) genes that control the activation of the immune system are abnormally expressed in patients with this illness. A number of studies have shown that there probably are abnormalities of energy metabolism in patients with this illness”. Professor Anthony Komaroff of the Harvard Medical School Page 39/76

Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY (continued) well tolerated. HealthyCurb appears to be a safe and effective means for CFS patients to manage weight without changes in eating or exercise patterns. INTRODUCTION Being overweight or obese can present health issues and may also lead to serious chronic illnesses. Dieting is difficult because dieters are unable to endure the commitment required to achieve their weight loss goals. One of the most common complaints of dieters is the constant feeling of hunger associated with reducing calorie intake. Another complaint dieters experience is the lack of energy due to decreased caloric consumption. Nutritional Therapeutic, Inc. has developed a safe, allnatural food-based supplement (Healthy CurbTM) that has been reported to reduce appetite, increase energy levels, reduce fatigue, block starch uptake and help with weight management. The supplement contains NTFactorTM , which has been shown to reduce fatigue and repair mitochondrial membranes.2,3 This study was designed to explore the degree of appetite suppression, the degree of energy level, fatigue reduction, changes in specific blood markers for metabolic health and the amount of weight loss and reduction in waist and hip measurements in a 60 day trial. PROCEDURES A two-month open label clinical trial was initiated with 30 patients, ages 18 and older, who used an all-natural oral mixture (Healthy CurbTM, http://www.healthycurb.com) of FDAapproved amaylase inhibitor (2 tablets containing 500 mg white kidney bean extract plus 500 mg of NTFactorTM) 30 min before each meal. All subjects filled out a medical intake form at Tustin Longevity Center. The medical staff determined if participants were qualified to enter the study based on medical history. Chronic fatigue was an important entry criteria. Weight, waist and hip measurements were taken weekly, appetite was assessed by the procedures of Arumugam et al.,4 and fatigue Invest in ME (Charity Nr. 1114035) was determined using the Piper Fatigue Scale.5 Blood samples were taken at the beginning of the study and at the end of the study. Weight, body composition and measurements were taken every two weeks until the end of the study. During this two-month study the NIH guidelines for alcohol consumption were followed: “Moderate drinking is one drink a day for women or anyone over 65, and two drinks a day for men under 65.” RESULTS Weight and Girth Reduction: The entire group of participants lost an average of 3 pounds (Fig. 1a) with average reductions of 1.5 and 1 inches in hip and waist circumference, respectively (Figs. 2a, 3a). Sixty-three percent of the participants (responder group) lost an average of 6 pounds (Fig. 1b) along with 2.5 and 1.5 inches reduction in hip and waist circumference, respectively (Figs. 2b, 3b), and participants experienced gradual and consistent weight loss along with waist and hip reductions during the entire trial. ME STORY I had suffered neurological symptoms for a number of years but by 2003 they had reached the point where I couldn't ignore them any longer. I decided to go to the doctor. By great good fortune I took the first appointment available and saw a GP new to the practice. I told her my story, we discussed ME and she said she neither believed nor disbelieved in the illness. She was more interested in the patient than a 'tag', she said. But for the first time since my diagnosis I had found a doctor who actually listened to me. - Jim Page 40/76 Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY (continued) Figure 1a Average Weight Loss (lbs) Entire Group -1 -1.25 -1.42 -1.88 -2 -2.9 -3 Wk 2 Wk 4 Wk 6 Wk 8 Figure 1b Average Weight Loss (lbs) Responder Group -7 -6 -5 -4 -3 -2 -2.88 -3.58 -4.72 -6.11 Wk 2 Wk 4 Wk 6 Wk 8 Invest in ME (Charity Nr. 1114035) Page 41/76

Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY (continued) Figure 2a Average Hip Measure Loss (inches) Entire Group -0.5 -0.67 -0.86 -1 -1.06 -1.13 -1.5 Wk 2 Wk 4 Wk 6 Wk 8 -0.5 Figure 2b Average Hip Measure Loss (inches) Responder Group -1 -1.5 -2 Wk 2 Wk 4 Wk 6 Wk 8 Invest in ME (Charity Nr. 1114035) Page 42/76 -0.74 -1.05 -1.28 -1.51 Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY (continued) Figure 3a Average Waist Measure Loss (inches) Entire Group -1 Figure 3b Average Waist Measure Loss (inches) Responder Group -1.34 -1.8 -2 -2.18 -2.43 -3 Wk 2 Wk 4 Wk 6 Wk 8 Invest in ME (Charity Nr. 1114035) Page 43/76

Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY (continued) Body Mass Index Reduction: Body mass index (BMI) was calculated as the weight (in pounds) times 703 divided by height (inches) squared. There was a reduction in average BMI in the entire group of 0.18 (Fig. 4a) and in the responder group of 0.49 (Fig. 4b). -0.1 Figure 4a -0.17 -0.19 Average Body Mass Index Entire Group -0.2 -0.28 -0.3 -0.37 -0.4 Wk 2 Wk 4 Wk 6 Wk 8 -0.4 -0.46 Figure 4b Average Body Mass Index Responder Group -0.6 -0.78 -0.8 -0.95 -1 Wk 2 Wk 4 Wk 6 Wk 8 -0.52 Invest in ME (Charity Nr. 1114035) Page 44/76 Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY (continued) Basal Metabolic Rate Reduction: Basal Metabolic Rate (BMR) uses the variables of height, weight, age and gender to calculate a rate of resting metabolism. The overall change in BMR and change in the responder group are shown in Figs. 5a, 5b. These were calculated as follows: Women: BMR = 655 + ( 9.6 x weight in kilos ) + ( 1.8 x height in cm ) - ( 4.7 x age) Men: BMR = 66 + ( 13.7 x weight in kilos ) + ( 5 x height in cm ) - ( 6.8 x age in years) 0 Figure 5a -10 Average Basal Metabolic Rate Entire Group -20 -28.4 -30 Wk 2 Wk 4 Wk 6 Wk 8 -10.9 -14.8 -16.27 Figure 5b Average Basal Metabolic Rate Responder Group -50 -45 -40 -35 -30 -25 -31.05 -32.16 -31.68 -47.25 Wk 2 Wk 4 Wk 6 Wk 8 Invest in ME (Charity Nr. 1114035) Page 45/76

Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY (continued) Appetite Suppression: There was a 44% reduction in overall hunger (Fig. 6) with reduced cravings for sweets; therefore, notable appetite suppression occurred. 100 Figure 6 Average Hunger Index Entire Group 10 20 30 40 50 60 70 80 90 0 Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Fatigue Suppression: Using the Piper Fatigue Scale the entire test group showed an average of 23% decrease in overall fatigue during the trial (Fig. 7) Figure 7. Overall Fatigue Scores 40.1 31.6 25.2 24.9 22.3 10 0 1 2 3 4 5 6 7 8 9 4.50 4.52 4.04 3.73 3.47 Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Invest in ME (Charity Nr. 1114035) Page 46/76 Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY (continued) Blood Lipid Profiles: Blood lipid profiles generally improved (Table 1), suggesting improved cardiovascular health, and no adverse effects were noted clinically or found in blood chemistries (data not shown). Table 1. Blood Lipid Chemistry Measurement Glucose Cholestrol Triglycerides HDL LDL (Calc) VLDL (Calc) Cholesterol/HDL Ratio LDL/HDL Ratio DISCUSSION Healthy CurbTM has proven to be a safe, all natural food-based supplement that allows weight control without the use of stimulants or herbs that could cause side effects. During the brief trial no adverse effects were reported, and blood chemistries and lipid analyses indicated that subjects actually had improved lipid profiles at the end of the trial. A common complaint while taking dietary supplements is the loss of energy and stamina. Invest in ME (Charity Nr. 1114035) Day 0 Day 60 104.8 mg/dl 209.6 mg/dl 142.6 mg/dl 56.9 mg/dl 124.2 mg/dl 28.5 mg/dl 3.9 2.4 104.4 mg/dl 200.7 mg/dl 129.2 mg/dl 58.0 mg/dl 116.8 mg/dl 25.8 mg/dl 3.7 2.1 Healthy CurbTM contains NTFactorTM, a supplement known to naturally decrease fatigue and increase energy.1-3 During the trial subjects reported increased energy and decreased fatigue, and this was shown by reduction in Piper Fatigue Scores. Thus a major problem in all natural weight loss products was overcome by including NTFactorTM. They also had reduced hunger and reduced cravings for sweets. Page 47/76

Journal of IiME Volume 3 Issue 1 www.investinme.org DIETARY SUPPLEMENT HEALTHY CURB FOR REDUCING WEIGHT, GIRTH, BODY MASS, APPETITE AND FATIGUE WHILE IMPROVING BLOOD LIPID VALUES WITH NTFactor LIPID REPLACEMENT THERAPY (continued) Participants experienced gradual and consistent weight loss along with waist and hip, body mass index (BMI) and basal metabolic rate (BMR) reductions during the trial. Thus Healthy CurbTM proved to be a safe and effective weight loss supplement. REFERENCES 1. Ellithorpe RR, Settineri R, Nicolson GL. Pilot Study: Reduction of fatigue by use of a dietary supplement containing glycophospholipids. J Am Nutraceut Assoc 2003; 6(1):23-28. 2. Agadjanyan, M, et al. Nutritional supplement (NT Factor) restores mitochondrial function and reduces moderately severe fatigue in aged subjects. J Chronic Fatigue Syndr 2003; 11(3):2336. 3. Nicolson, G.L. and Ellithrope, R. Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses. J Chronic Fatigue Syndr 2006; 13(1):57-68. 4. Arumugam V, et al. A high-glycermic meal pattern elicited increased subjective appetite sensations in overweight and obese women. Appetite 2007; 50:228-233. 5. Piper BF, Dribble SL, Dodd MJ, et al. The revised Piper Fatigue Scale: psychometric evaluation in women with breast cancer. Oncol Nursing Forum 1998; 25:667-684. NICE COMMENT Commenting on the final Guideline, one GP from Bath said: “The NICE Guidelines make it more difficult. instead of separating ME from other illnesses with fatigue, NICE is just broadening the umbrella. Nowfatigue and sore throat is enough to have ME. ME patients, and especially patients who don ’t have ME but will be labelled as ME patients, will suffer as a consequence” (Dr Andrew Ashley, eBMJ, 6th September 2007). ME RESEARCH A recent study found VP1, RNA and noncytopathic viruses in the stomach biopsy specimens of CFS/ME patients with chronic abdominal complaints. A significant subset of CFS/ME patients may have a chronic, disseminated, noncytolytic form of enteroviral infection, which could be diagnosed by stomach biopsy. For more information: Chia, JKS, Chia, AY;(2008), "Chronic fatigue syndrome is associated with chronic enteroviral infection of the Subscribe to Invest in MEs free newsletter. Distributed monthly via html, plain text or PDF. Go to www.investinme.org/IIMENewslettersubs.htm stomach," Journal of Clinical Pathology 2008;61:43-48. From The Enteroviorus Foundation - http://www.enterovirusfoundation.org/a ssociations.shtml Invest in ME (Charity Nr. 1114035) Page 48/76 Journal of IiME Volume 3 Issue 1 www.investinme.org Letter from America By Maary Schwweitzer The Current Situation in the U.S. These are exciting times for patients in the United States. The presidential election represented a significant shift in policy towards medicine, treatment, research, and the plight of the neglected. In December, the Obama-Biden transition team asked for community meetings to discuss health care issues. A small group of us “met” online and produced a report on ME/CFS. One community report from every state was chosen for the White House’s new website for Health Reform – and ours represents my state of Delaware: http://healthreform.gov/communityreports/d elaware/delaware_19711.html. It has already been read by Senators, Congressmen, and members of the executive branch. The research group IACFS/ME met in Reno, Nevada, in March, with most sessions devoted to international biomedical research. The new Whittemore-Peterson Institute in Reno is already bearing fruit using the tools of molecular medicine. Dr. Nancy Klimas noted how exciting to see such diverse research presented in a cooperative, not competitive, fashion. April 27, the U.S. CDC held a hasty stakeholders’ meeting on their new 5-year plan for CFS and “fatiguing illnesses.” The Obama administration was, we believe, unprepared for the vehement response. Person after person testified to the consequences of having been rendered invisible by CDC’s adoption of the name and concept of “chronic fatigue syndrome.” Invest in ME (Charity Nr. 1114035) Mary M. Schweitzer, Ph.D. Mary Schweitzer from Delaware, USA, was a tenured professor of history before being disabled with ME in 1994. Mary has been an active and very passionate advocate for people with ME for several years writing articles and taking part in the CFSAC (Chronic Fatigue Syndrome Advisory Committee) meetings to allow the patient's voice being heard. For four hours patients, advocates, and a few physician/researchers called for the immediate end of the current CDC program on CFS. Consensus is building towards the goal of subgroups identified through objective biomedical testing, funding for treatment, and the establishment of Centers of Excellence as we have for cancer. If CDC cannot help, then we want them to step out of the way. Written comments on the CDC’s 5-year plan can be sent from inside or outside the U.S. through June 30. See the website http://www.cdc.gov/cfs/meetings/2009_04.ht m. On May 27 and 28, the Chronic Fatigue Syndrome Advisory Committee (CFSAC) within Health and Human Services will hold its first meeting under the Obama administration. We are all hopeful that the entire approach to our disease will change, particularly regarding NIH and CDC. Page 49/76

Journal of IiME Volume 3 Issue 1 www.investinme.org Letter from America The Current Situation in the U.S. The agenda includes both the CDC’s 5-year plan and the particular plight of children and adolescents with CFS. Unfortunately, just as parents have had to fight to keep their sick children from being sectioned in the UK, in the U.S. we are seeing too many cases where a child has been forcibly removed from his/her parents and isolated in foster care. Patients both at home and abroad are responding to the current plight of 16-year-old Ryan Baldwin, who has a CFS diagnosis. After being diagnosed with a related heart condition last year, Ryan qualified for social security payments for disabled children. In January Ryan was suddenly taken away to a foster home. His parents were charged with “factitious illness by proxy” and denied access, even by phone. Testimony from noted specialist Paul Cheney proved that the heart condition vacated a diagnosis of “factitious illness.” The authorities then responded by asking the mother to plead to “dependency” [upon her child remaining ill]. She refused, and the court recessed for a month with Ryan still in foster care. We are grateful for a letter sent to the governor of North Carolina by Invest in ME. Anyone interested in helping with the case can find information here: http://cfsknowledgecenter.ning.com/profiles/ blogs/free-ryan-baldwin The situation in the United States remains desperate for many patients, but there is also hope. If emphasis turns from the psychosocial to the biomedical, within five years diagnosable subsets can be identified and begin treatment. We thank Invest in ME for its work in achieving that goal. Invest in ME (Charity Nr. 1114035) The European ME Alliance (EMEA) Its aims are to - • Establish correct recognition of myalgic encephalomyelitis as an organic illness requiring biomedical research to treat and cure • Establish correct diagnosis of patients • Establish specialised biomedical centres for education/treatment/cures NICE COMMENT For (NICE’s Professor Peter) Littlejohns and his superiors to ignore completely how damaging this case (the Judicial Review of NICE guidelines ofr ME) has been to NICE is myopic in the extreme. “The only thing worse than being blind is having sight but no vision.” (Helen Keller) How many more patients will need to challenge decisions by NICE before the government is forced to act and overhaul the management and the objectives of this organisation? An organisation that purports to be “committed to promoting equality, eliminating unlawful discrimination, and actively considering the implications of its guidance for human rights” and yet is taken to court by the same patients for whom it claims to promote good healthcare – this is an organisation that deserves to be overhauled. from – http://www.investinme.org/IIME%20Campaigni ng-NICE-Whats-Next.htm Page 50/76 Journal of IiME Volume 3 Issue 1 www.investinme.org It was fourteen years ago, on 18th February 1993, that Dr Paul Cheney, Professor of Medicine at Capital University USA, Medical Director of the Cheney Clinic in North Carolina, and one of the world’s leading exponents on ME/CFS, testified before the FDA Scientific Advisory Committee in a testimony that has become one of the most quoted in history: “I have evaluated over 2,500 cases (of ME). At best, it is a prolonged post-viral syndrome with slow recovery. At worst, it is a nightmare of increasing disability with both physical and neurocognitive components. The worst cases have both an MS-like and an AIDS-like clinical appearance. We have lost five cases in the last six months. The most difficult thing to treat is the severe pain. Half have abnormal MRI scans. 80% have abnormal SPECT scans. 95% have abnormal cognitive-evoked EEG brain maps. Most have abnormal neurological examination. 40% have impaired cutaneous skin test responses to multiple antigens. Most have evidence of T-cell activation. 80% have evidence of an up-regulated 2-5A antiviral pathway. 80% are unable to work or attend school. We admit regularly to hospital with an inability to care for self”. Invest in ME (Charity Nr. 1114035) Page 51/76

Journal of IiME Volume 3 Issue 1 www.investinme.org Epidemics of ME EPIDEMICS of ME Epidemics are associated with ME. A Review of The Clinical Syndrome Variously Called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia by E D Acheson (American Journal of Medicine, 1959) by Dr J Gordon Parish Many of the findings described in the landmark Acheson 1959 paper are very much relevant to our understanding of ME today. The disease was initially thought to resemble poliomyelitis until distinguishing features occurred; no patient developed the paralysis and muscle wasting seen in poliomyelitis which is a disease of the spinal cord. Naldrett White, a Canadian neurologist, and Robert Burtch, an American family physician, described an epidemic in 1950 in Upper New York State in the USA in an area close to the Canadian border. They thought that muscles were directly involved during the initial infection. Accompanying a mildly elevated temperature to 99–100 ºF (37.2–37.8 ºC) in nearly every patient, there was pain and tenderness in various muscles sometimes with increased skin sensitivity over the affected areas making contact with clothes or bedding very unpleasant. In contrast to hypersensitivity, difficulty in moving limbs and numbness with diminished skin sensation on clinical testing suggested peripheral nerve involvement. Where there was weakness on using a hand and sensory symptoms, examination revealed an ulnar nerve disorder. Nerve roots were sometimes involved in the legs and were tender to pressure. This was associated with dragging of the legs on walking or foot drop. Another feature was lymphadenopathy in some patients. Enlarged tender anterior neck or axillary lymph glands are mentioned. Examination of the blood and cerebrospinal fluid showed only minor abnormalities in two patients. White and Burtch thought that they might be dealing with an infection affecting Invest in ME (Charity Nr. 1114035) From the Incline village episode to the Royal Free. Yet little is discussed about these. In the 4th International ME/CFS Conference Professor Harald Nyland will discuss the recent epidemic associated with Giardia in Norway. Yet this isn’t new. It seems relevant to recall this review by Dr Gordon Parrish of an article by E D Acheson in the American Journal of Medicine muscle. The standard test for muscle damage at that time was 24 hour urinary creatine excretion, and this was found to be raised in the 13 patients who were tested with a tendency for the urinary creatine to fall to normal levels as the patients recovered. The creatine phosphokinase enzyme test for muscle damage was not available at that time. Subsequently, it was found to be normal or only slightly elevated in ME suggesting that the disturbance is different from that found in other muscle diseases. The illness had a striking resemblance to the disease described by Sigurdsson and others in Iceland during the winter of 1948–1949, and hence the name Iceland Disease was suggested for the illness. In a leading article published anonymously in the Lancet in May 1956, Acheson reviewed eight similar outbreaks and suggested a title Benign Myalgic Encephalomyelitis for the new clinical entity based on the presumed underlying pathology. He considered the disease to be "benign" compared with other epidemic infections of the nervous system seen in various types of encephalitis and in poliomyelitis due to the absence of patients dying. However, "benign" was later deleted from the title, leading to the abbreviation to ME, because in some cases the severity and duration of the disability resulting from the disease was far from being benign. He mentioned that hepatitis and Page 52/76 Journal of IiME Volume 3 Issue 1 www.investinme.org E EPPIIDDEEMMIICCSS ooff MMEE ((ccoonnttiinnuueedd)) enlargement of the spleen might occur in addition to lymph gland involvement indicating the reticuloendothelial system participated in the clinical picture in some of the epidemics. Alexis Shelokov and colleagues investigated an outbreak involving 50 student nurses and their tutors participating in residential courses at a psychiatric hospital near Washington DC, USA in 1953. Half the patients had muscle weakness and poliomyelitis was suspected then eliminated. No other cause for the muscle weakness was found. All patients had features of a generalised illness similar to that described in patients with Iceland Disease. After the initial illness there was a subacute phase lasting several months consisting of episodes of feeling unwell and further muscle weakness. Donald Henderson and Alexis Shelokov reviewed 23 similar epidemics in 1959. They found that the affected muscles were tender either diffusely or in focal discrete areas, which felt "oedematous, doughy or rubbery in consistence". They introduced the term Epidemic Neuromyasthenia, linking neurasthenia with myasthenia to describe the clinical picture. The term neurasthenia is unfortunate as it implies a disturbance of behaviour, which can follow an infection or be the result of stress, in the form of irritability and an inability to take exercise without excessive fatigue. Similar disturbances including crying spells without provocation are also seen during the convalescence of patients who have had strokes or head injuries. The association of similar behavioural disturbances with brain cell disorders such as cranial nerve palsies and hemiparesis with extensor plantar response is mentioned by Henderson and Shelokov (1959) as an occasional finding in some epidemics. The association is clearly illustrated by Melvin Ramsay in a serious of sporadic cases admitted to an infectious diseases department of a local hospital from the population of North West London in 1955 and 1956. Rather than labelling the illness neuromyasthenia a slight change to Invest in ME (Charity Nr. 1114035) neuronomyasthenia indicating a disease of nerve cells (or neurones) and muscle cells with muscle weakness might be more appropriate. Neurologists prefer to limit the term myasthenia to myasthenia gravis, a disorder of the neuromuscular junction which may present as a severe type of muscle weakness. In patients with Myalgic Encephalomyelitis/Neuronomyasthenia (ME/NM), "myasthenia mitis" has been used to describe a milder form of myasthenia in which muscle weakness develops during normal daily activities. Clinical tests were subsequently developed, which measure the declining muscle performance with activity and the slow recovery of muscle afterwards. In 1998 this delayed recovery of muscle function after a fatiguing isometric exercise test was confirmed in 1999 by Lorna Paul and colleagues. MERGE has funded research which has revealed abnormalities in the function of blood vessels and blood cells. Abnormalities of blood vessels have been described in these epidemics of ME/NM. Infectious material was transferred from patients to monkeys during an epidemic in Adelaide, Australia in 1949–1950. The monkeys became ill and post-mortem examinations were carried out a month later. The only abnormalities discovered by Pellew and Miles (1955) were minute red spots along the course of the sciatic nerves. Under the microscope the red spots contained localised collections of inflammatory cells, which had also infiltrated the area where the nerve roots come out of the spinal cord. The red colour of the spots was due to leakage of red blood cells. ME/NM is very rarely fatal so that a postmortem study showing similar haemorrhages in humans is unique. However, during the North of England epidemic in 1955 Andrew Wallis described the findings in a patient in her fifties, who developed the characteristic febrile illness leaving her debilitated and emotional. During the next fifteen months she continued to run a low grade fever with continued Page 53/76

Journal of IiME Volume 3 Issue 1 www.investinme.org E EPPIIDDEEMMIICCSS ooff MMEE ((ccoonnttiinnuueedd)) mental deterioration before she died. The post-mortem revealed numerous small haemorrhages around blood vessels in the cerebral cortex extending into the midbrain, which were considered to be the cause of her death. These abnormalities may be found when patients die as the result of severe chronic alcoholism. This was not a factor in her case; she had had a febrile illness. Vasculitis involving the skin was recorded during outbreaks in Cumberland, Durham and North West London in 1955. A maculopapular rash may appear during the return of features of the initial illness such as flu-like symptoms and enlargement of lymph glands and liver. This skin overlying areas of localised muscle weakness may be affected at the time of these attacks. In conclusion, Iceland Disease and ME/NM is a muscle/brain disorder, which occurs as clusters of cases in families, in institutions such as hospitals or schools, in districts as far apart as the northern townships in Iceland and Adelaide in Australia or sporadically. It is an infectious disease with an incubation period of 5 to 8 days. Acheson in 1959 used the expression "in a greater or lesser degree" to describe "the symptoms and signs of damage to the brain and spinal cord" in this disease. This expression can also be applied to the febrile illness and muscle involvement. Many patients recover and return to normal activities in weeks or months, while others have relapses with reactivation of features of the initial illness and further damage to new areas of the brain or muscles. In extreme cases deterioration may lead to death. Muscle weakness has been measured in a few patients. After activity the recovery of muscle power is prolonged to an extent not recorded in any other disease. The association between these findings in muscle and vascular abnormalities in blood vessels and blood components needs exploring. For research purposes ME/NM patients with these physical signs should not be coupled with Invest in ME (Charity Nr. 1114035) patients whose main illness is chronic fatigue on exertion and who do not have these signs. References - Acheson ED. The clinical syndrome variously called Benign Myalgic Enchephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia. Am J Med 1959; 26: 569-595. - Henderson DA, ShelokovA. Epidemic Neuromyasthenia – Clinical Syndrome. N Engl 1959; 260: 757-764, 814-818. - Leading Article A new clinical entity? Lancet 1956; 1: 789-790. Written by ED Acheson, introducing the term Benign Myalgic Encephalomyelitis. - Paul L, Wood L, Behan WMH, Maclaren WM. Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. European J Neurol 1999; 6: 6369. - Pellew RA, Miles JA. Further investigations on a Disease resembling Poliomyelitis seen in Adelaide. Med J Aust 1955; 42: 480-482 - Ramsay AM. Encephalomyelitis in North West London. An endemic infection simulating poliomyelitis and hysteria. Lancet 1957; 2: 1196-1200. Description of 10 cases illustrating the association of behavioural disorders (neurasthenia) with brain disorders (cranial nerve palsies). - Shelokov A, Habel K, Verder E, Welsh W. Epidemic Neuromyasthenia. An outbreak of poliomyelitis-like illness in student nurses. N Engl J Med 1957; 257: 345-355. The Chestnut Lodge Epidemic, Washington, USA in 1953. - Sigurdsson B, Sigurjonsson J, Sigurdsson JHJ, Thorkelsson J, Gudmundsson KR. A disease epidemic in Iceland simulating Poliomyelitis. Am J Hyg 1950; 52: 222-238. - Wallis AL. An investigation into an unusual illness seen in Epidemic and Sporadic Form in a General Practice in Cumberland in 1955 and subsequent years. - White DN, Burtch RB. Iceland Disease – a new infection simulating Acute Anterior Poliomyelitis. Neurology 1954; 4: 506-516. Page 54/76 Journal of IiME Volume 3 Issue 1 www.investinme.org WHAT I WANT FROM an ME SERVICE This article appeared in our Journal and on IiME’s web site in August 2007 and was written by Linda Crowhurst, a severely affected person with ME, As we plan to discuss the ME Clinic at the IiME Conference it was felt appropriate to republish this. I need : • Acknowledgement that ME is a WHO (ICD 10 - G93.3)defined neurological disease. An appropriate biomedical definition. • Appropriate diagnostic criteria that acknowledge the wide number of specific physical symptoms. • A biomedical clinician who can recognise the symptoms of ME and their impact. and make appropriate recommendations, based on current physical research. • Appropriate biomedical tests and scans that prove that I have a physical illness and illuminate what is going wrong in my body. • An appropriate biomedical assessment that will provide a medically-informed report about my illness and disability. • Acknowledgement of severe disability so that support can be given to claim benefits and grants etc, to enable true entitlement. • Careful testing and monitoring before any drugs are prescribed. • Advice based on awareness to ensure safe practice and safe treatments regarding how to deal with other medical conditions and illnesses that might arise. • The neurological symptoms to be explored , prioritised and validated. • Access by phone for specific symptom management / backup. • Home visits from a biomedical clinician. • A service that is actively educating other clinicians and paramedical staff regarding the true physical nature and impact of this disease. • The opportunity to choose to participate in Invest in ME (Charity Nr. 1114035) physical research so that people who have severe ME can be reflected in any research evidence compiled. • A service that is particularly aware of the severity of my symptoms and the high level of post-exertional malaise and post-exertional fatigue I experience and can accommodate them; so that I can be seen and given proper ongoing support. • The name "ME" to be used, as opposed to "CFS". What I do NOT want from an ME Service • A focus upon "fatigue". • A "therapy"-led service • To be included with undefined Chronic Fatigue illnesses and states. • A psychosocial model of care. • To be offered CBT and GET, as these are both dangerous and unsuitable for people with ME. • To be patronised by medical professionals who do not believe that I have a physical disease . • To be downgraded and treated as if my very real and severe neurological symptoms, such as paralysis, spasms, parasthesia and pain are insignificant or psychiatric in origin. • To be offered psychiatric - originated management techniques , charading as treatment for this physical illness. • To be described as "tired". • Pretending to meet the needs of people with ME but actually working to a psychiatric paradigm. • Any service based upon the Fukuda or Oxford criteria. Page 55/76

Journal of IiME Volume 3 Issue 1 www.investinme.org The 4tthh Invest in ME International ME/CFS Conference 2009 Emeritus Professor of Medicinal Chemistry the University of Sunderland Professor Hooper has published some 50 papers in peer-reviewed journals in the field of medicinal chemistry. He has By Professor Malcolm Hooper Conference Introduction Invest in ME conferences have rightly become renowned for their high quality and eminent international speakers who have successively presented the most up to date biomedical information about this perplexing and devastating illness. ME is a complex chronic multi-system illness, CMI. Myalgic encephalomyelitis, muscle pain with inflammation of the brain and spinal cord, is a term that is both clinically meaningful and accurately descriptive of the nature of the illness. It has been known since 1934. The name, first coined in 1956 by Donald Acheson who subsequently became Chief Medical Officer, was included, for the first time, in the World Health Organisation’s International Classification of Disease in 1969 chapter G.93.3, neurological conditions. To this day it is still so classified and the UK Government has stated that it accepts this classification although in every other way is acting and legislating to the contrary. The introduction in 1988 of the alternative description, Chronic Fatigue Syndrome, CFS, describes only a symptom and has led to confusion, deception and obfuscation resulting in Invest in ME (Charity Nr. 1114035) served on committees of the Council for National Academic Awards (CNAA), the World Health Organisation (WHO) and the Science and Engineering Research Council (SERC). He is a member of a number of learned bodies, including the Royal Chemical Society, the British Pharmacological Society and the Society for Medicines Research, where he has served on the committee for 12 years and served as Chairman for 2 years. He was appointed Chief Scientific Advisor to the Gulf Veterans Association (GVA) and accepted by the Ministry of Defence (MoD) as their nominee on the Independent Panel established to consider the possible interactions between Vaccines and NAPS tablets. His involvement with the GVA brought contact with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (ME/CFS) and related disorders. Gulf War Illness/Syndrome (GWI/S) has much in common with ME/CFS. He worked with the Autism Research Unit (ARU) at the University of Sunderland for over 20 years, leading to involvement in biochemical studies to offer help, support and treatment for people with autism. He served on the General Synod of the Church of England from 1970 to 1980 and he is a Christian Lay Leader, Preacher and Teacher. Page 56/76 Journal of IiME Volume 3 Issue 1 www.investinme.org The 4th Invest in ME International ME/CFS Conference 2009 (continued) the sometimes acrimonious and bitter debates about the nature of the illness. The imprecise word fatigue has been used by some psychiatrists to label ME as a behavioural and mental disorder. Such disorders are classified under F.48.0 which includes chronic fatigue and fatigue syndromes that are quite distinct from neurological conditions. Today the diagnosis, treatment and management of ME are bedevilled by these two conflicting understandings of the illness leaving People with ME (PWME) frequently marooned, mistreated and misunderstood both medically and socially. C CPPDD AAcc ccrr eeddii tteedd The most severely disabled patients have suffered the greatest neglect. Exciting new possibilities for treatment that can change the lives of patients offer new hope for their future. M Maannaaggeemmeenntt,, TTrreeaattmmeennttss aanndd tthhee L Laatteesstt AAddvvaanncceess iinn RReesseeaarrcchh iinnttoo M MEE//CCFFSS O Onnee BBii rrddccaaggee WWaa llkk ,, WWeess ttmmii nnss ttee rr ,, LLoonnddoonn It is particularly apt that this 4th Conference is specially concerned with the severely disabled who have born the brunt of the present obdurate, heartless and official views of ME that treat sick patients and their carers so cruelly. It is a joy to welcome the speakers for this conference who come from the USA, Norway, Belgium as well as the UK. The Whittemore-Peterson Institute, WPI, offers both challenge and hope to the world of ME with the “can do” energy and commitment so Invest in ME (Charity Nr. 1114035) The third arm of the Institute involves research studies that address the nature of the illness and lay the foundations for new understanding and treatments of ME. Judy Mikovits, Research Director of the WPI, presents her insights in to the diagnosis of the difficult and most complex ME cases. Diagnosis is the key to clinical treatment and definitions of ME are crucial for managing and effectively treating individual patients. An institute that brings patients, clinicians and research workers together can provide a springboard for major advances in the ME. The WPI provides such a working paradigm and is a challenge to every country where ME is a major health issue. John Chia has done great service by providing clear evidence of the role of enteroviruses in ME. Their role first identified by earlier workers in the field including, John Richardson, Irving Spurr, Byron Hyde and others, has been confirmed and extended by John’s work. His story makes it essential that the microbiological services that have been dismantled in this country must be re-established to support clinical need and research into Page 57/76 typical of the American response to any daunting situation. This Institute provides a working model of how to engage with ME and the growing number of complex CMIs that are emerging in today’s world. Annette Whittemore has provided the resources to bring the Institute into being and has an inspiring story to tell of how love, care and sheer ‘guts’ has realised a model for the rest of the world to follow. Dan Peterson is the Medical Director of the WPI and has long wrestled with ME and provided hope, expert clinical care and understanding for numerous patients and carers for PWME.

Journal of IiME Volume 3 Issue 1 www.investinme.org The 4th Invest in ME International ME/CFS Conference 2009 (continued) effective treatments for enteroviral infections. Pooled human immunoglobulins are still effective in the very early stages of the illness, the first 6 months, but if this window of opportunity is missed then the illness may develop into a more chronic condition with serious consequences for the patient and the need for long drawn out and expensive therapy Garth Nicolson has, at great personal cost, engaged with various CMIs and in the early days recognised the strong similarities between ME/CFS and Gulf War Syndrome. The recent Binn’s report on Gulf War Illness clearly identifies the importance of chemical exposures in this CMI although vaccine exposures may still play an important role. Chemical and biological exposures leading to neurodegenerative and neurobehavioural changes need to be better understood. Garth has provided effective antibiotic treatments for ME that follow some intracellular microbial infection, for example with mycoplasma organisms. Previous Invest in ME conferences have emphasised the inadequacies of the current Fukuda/CDC definition of ME/CFS and the importance of sub-groups. Clarity is greatly needed in this area. Norway, as a result of powerful and persistent campaigns by ME suffers and activists led by Ellen Piro, has changed official attitudes towards ME by showing the effects of vaccines in provoking the illness which may also arise from natural infections. Barbara Baumgarten heads a newly established ME-centre that provides correct diagnosis, treatment and management of ME emphasising once again the need for accurate diagnosis as the sine qua non for effective therapy for PWME. Will this new centre be the beginnings of a European WPI? The seminal book by Hillary Johnson makes clear the need to consider the epidemiology of ME which is important for prompt action with regard to the illness. Although intracellular organisms, including rickettsia, chlamydia, borellia are wellknown to give rise to ME the epidemiology of Invest in ME (Charity Nr. 1114035) Giardiasis, an extracellular parasite can teach us lessons that are valuable in engaging with ME. Harald Nyland will make these interesting links in his presentation. Kenny de Meirleir has championed patient needs and treatment in Europe and also contributed to the Canadian definition of ME/CFS. He has written perceptively about the disruption of essential immunological mechanisms in this illness by micro-organisms, heavy metals and other environmental chemicals. Case studies are the key to building up clinical understanding of the complexity of ME and its various manifestations that so perplex those newly encountering with this illness. We will learn much from his experiences. Jonathan Kerr has carried out ground breaking studies in the genetics of ME especially in the most severely affected patients. This new field provides deeper understanding of the multisystem nature of the illness and shows how it can relate to other CMIs. The use of genetic analysis to identify clinical phenotypes for diagnosis and treatment will enable accurate sub-grouping of patients and targeted treatments to be developed and applied to this needy group of patients. Jonathan’s genetic studies show how a multiplicity of environmental insults can impinge upon a smaller number of key biochemical pathways and give rise to a multiplicity of symptoms – this is great gain and supports the experiences of many sick patients. Basant Puri, also at great cost, has used advanced neuro-imaging techniques to investigate the structural and chemical changes in the brain associated with ME and devised useful treatments that specifically address these changes. The multi-system nature of ME requires a conference Chairman who is familiar with the illness in all its manifestations. Jonathan Brostoff is such a person and has a vast experience in all the complexities of immunology and conducts research into allergy and environmental health issues. Page 58/76 Journal of IiME Volume 3 Issue 1 www.investinme.org The 4th Invest in ME International ME/CFS Conference 2009 (continued) We are in for a splendid conference which provides real hope for all who suffer from ME and all those who care for them. The medical and health community and, not least, medical and research administrators need to hear these stories and be prepared to learn from them, support biomedical research, and thereby serve the needs of sick patients. In the UK we need an institute comparable to the WPI. When will the cry of sick patients and their carers be heeded and action taken to make effective treatment(s) available? When will money be allocated for biomedical research that addresses the real nature of this illness. Much money has been devoted to support a model of ME that belittles patients, labels them with a diagnosis of a behavioural and mental disorder, and offers pacing (largely commonsense to people with any chronic illness), cognitive behavioural therapy, CBT, which even its strongest advocate state is “not remotely curative”, and of doubtful efficacy, graded exercise therapy, GET, which makes many patients more ill (confirmed by biological studies), coupled with antidepressants which may provoke chemical sensitivities and are not necessary since many patients are not depressed. This conference once again provides solid biomedical evidence which cannot continue to be ignored by health services increasingly wedded to an ideological, anti-clinical, and anti-scientific view of an illness that is now better understood and for which effective treatments following careful diagnosis are available. Enjoy it! Spread the message, challenge the bureaucrats, in Government, the NHS, and MRC and reclaim this field of medicine for both present and future patients. Malcolm Hooper May 2009 Invest in ME (Charity Nr. 1114035) Page 59/76 OSLER’S WEB To welcome Hillary Johnson to London we would like to highlight the later version of Osler’s Web. This has been updated by Hillary. From the review by Maryann Spurgin at http://www.cfids-cab.org/MESA/reviews4.html “..the most provocative portion of Johnson's discussion concerns the federal research establishment's attempt to manufacture a mental disorder out of a physical symptomatology. In meticulous detail, Johnson shows how bias in the choice of patients, value-laden selection of CFSrelated data and prejudicial allocation of research funds permitted government researchers to conclude that CFS was a psychiatric condition, or rather, something more akin to a behavioral problem. If Johnson is correct, then the government's conclusion is a classic illustration of the Thomas Szasz thesis: The concept of mental illness is often a political tool with which society dismisses its inconvenient members.” Ms Spurgin states that one of Osler's Web's strong points is its illustration of a propaganda system at work where studies citing negative findings in CFS were readily published, whilst studies reporting positive physiological findings were turned down.

Journal of IiME Volume 3 Issue 1 www.investinme.org PROFILES of PRESENTERS at the INVEST in ME INTERNATIONAL ME/CFS CONFERENCE C Coonnffeerreennccee CChhaaii rr :: P Prrooffeessssoorr JJoonnaatthhaann BBrrooss ttooff ff MMAA DDMM DDSScc((MMeedd)) FFRRCCPP FFRRCCPPaatthh FF IIBBiiooll Jonathan Brostoff is Senior Research Fellow and Professor Emeritus of Allergy and Environmental Health at Kings College, London. He was the Foundation Professor of Allergy and Environmental Health and Director of the Centre for Allergy Research at University College London. Whilst at University College Hospital he was Physician in charge of the Allergy Clinic. He is recognized as a leading international authority on food allergy and intolerance. Professor Brostoff was involved in one of the few, and much-quoted Spect scan studies of ME patients [Brainstem perfusion is impaired in patients with chronic fatigue syndrome. Costa DC, Tannock C and Brostoff J. Quarterly Journal of Medicine 1995:88:767 773]. A Annnneett ttee WWhhii tt tteemmoorree Founder and President of the Whittemore Peterson Institute for Neuroimmune Diseases, Reno, Nevada, USA. Annette Whittemore graduated from the University of Nevada with a BS Ed in Elementary and Special Education. Teaching children who had neuro-cognitive deficits, like those found in autism, ADD, and learning disabilities, provided her with a unique experience to later use in her pursuit of answers to her daughter's serious illness. Annette is the parent of a young adult who was severely affected by CFS and HHV-6. She and her husband are business owners and philanthropists in Reno and Sparks. Annette Whittemore is President and Co-founder of the foundation and became active in starting the HHV-6 foundation. She started the foundation with Kristin Loomis from California after a brief meeting in Incline, NV. with Dr. Daniel Peterson, a leading clinical researcher in CFS and HHV-6. When her daughter became ill with a chronic neuroimmune disease, Annette began to seek appropriate medical care. Annette found that few doctors understood the reasons for her daughter's continuing physical decline. For this reason, Annette has committed her time and resources to bringing attention to the serious nature of neuroimmune diseases and change her community in a positive way. She began this important mission in 1994 by supporting a Think Tank on ME/CFS, led by Dr. Daniel Peterson of Incline Village. In 2004 she and another patient advocate began a medical foundation to support research to find biomarkers of disease and treatments for patients impacted by the HHV-6A virus. In order to provide solutions for patients and bring new doctors into this field of medicine, Annette, legislators, and others supported a bill to build a biomedical research center at the University of Nevada, Reno with an Institute for Neuro-Immune disease and the Nevada Cancer Institute. Annette founded the Whittemore-Peterson Institute for Neuroimmune Diseases which is being built on the medical campus with its mission to serve those with complex neuro-immune diseases such as ME/CFS, viral induced central nervous system dysfunction and fibromyalgia. In addition, Annette and Harvey have contributed over one million dollars and pledged another four million dollars in support of the building and programming to bring this project to fruition. Invest in ME (Charity Nr. 1114035) Page 60/76 Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE As the Founder and President, Annette supports the basic and clinical research programs, recruitment of physicians and support personnel, while also leading fundraising activities. Researchers at the University of Nevada Medical School have also become collaborators on projects that are vital to our understanding of the immune deficits seen in these patients. The Nevada Business Journal recently honored Annette and her husband Harvey as Health Care Heroes for their personal commitment to this Institute and its mission. Other community activities include current positions on the Governing Board of the Davidson Institute and the Community Board of Pack Paws (thanks to the HHV-6 Foundation and the WPI web site for this information). P Prrooffeessssoorr GGaarr tthh NNiiccooll ssoonn PPhhDD The Institute for Molecular Medicine, P.O. Box 9355, S. Laguna Beach, California 92652. Tel: 949-715-7958; Email: gnicolson@immed.org; Website: www.immed.org Professor Garth Nicolson Phd (Biochemistry/Cell Biology), President, Chief Scientific Officer and Research Professor, The Institute for Molecular Medicine; Conjoint Professor, Faculty of Science and Technology, University of Newcastle, Newcastle, Australia; Professor of Integrative Medicine, Capital University of Integrative Medicine, Washington DC. Professor Nicolson has been studying the role of infections in chronic illnesses such as Gulf War Syndrome, Chronic Fatigue Syndrome, Autoimmune and Degenerative Diseases for many years. He is also an extinguished cancer researcher and has many publications to his name, including 3 Current Content Citation Classics. The Institute for Molecular Medicine is a research institute and its mission is to contribute to the understanding of and the prevention and cure of catastrophic human chronic diseases, such as autoimmune diseases, fatigue illnesses, rheumatic diseases, cancer, AIDS, and infectious and genetic diseases. This will be accomplished through innovative basic and translational research programs. P Prreesseenn ttaatt iioonn:: SSiimmii llaarr iinnffeecctt iioonnss ffoouunndd iinn MMEE//CCFFSS aanndd N Neeuurrooddeeggeenneerraatt iivvee aanndd NNeeuurroobbeehhaavviioorraall DDii sseeaasseess .. Garth L. Nicolson1, Nancy L. Nicolson1, Jorg Haier2 1The Institute for Molecular Medicine, Huntington Beach, California, 2Department of Surgery, University Hospital, Munster, Germany Objective: The majority of neurodegenerative diseases, fatiguing illnesses and neurobehavioral disease patients have chronic infections.1,2 Therefore, we examined the presence of certain co-infections in the blood of patients with Autism Spectrum Disorders (ASD) and compared these to ME/CFS patients. Methods: North American ME/CFS and ASD patients were examined for various infections by isolation of leukocyte blood fractions and forensic polymerase chain reaction (PCR) to determine various infections.3,4 Invest in ME (Charity Nr. 1114035) Page 61/76

Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE Results: ME/CFS patients (n=100, age=39.7±8.9) show evidence of multiple, systemic infections (Odds Ratio = 18.0, 95% CL 8.5-37.9, p< 0.001) that may be important in ME/CFS morbidity. ME/CFS patients had a high prevalence (51%) of 1 of 4 Mycoplasma species (OR = 13.8, 95% CL 5.8-32.9, p< 0.001) and often showed evidence of co-infections with different Mycoplasma species, Chlamydia pneumoniae (OR = 8.6, 95% CL 1.0-71.1, p< 0.01) and/or active Human Herpes Virus-6 (HHV-6) (OR = 4.5, 95% CL 2.0-10.2, p< 0.001). We found that 8% of the ME/CFS patients showed evidence of C. pn. and 31% of active HHV-6 infections.3,4 Recently we examined ASD patients (n=48, age 8.4±2.8) and found a large subset (58.3%) of ASD patients showed evidence of Mycoplasma species infections compared to age-matched control subjects (OR = 13.9, p<0.001). ASD patients also had C. pn. (4/48 or 8.3% positive, OR = 5.6, p<0.01) and HHV-6 (14/48 or 29.2%, OR = 4.5, p<0.01) infections in their blood.5,6 Conclusions: The results indicate that similar to ME/CFS patients a large subset of neurobehavioral (ASD) disease patients show evidence of chronic infections. Although there were significant differences in median age and diagnoses between the two groups of patients, they tended to have similar incidence of three types of chronic infections: Mycoplasma, Chlamydia and HHV-6. References: 1. Nicolson, G.L. Chronic infections in neurodegenerative and neurobehavioral diseases. Laboratory Medicine 2008; 39(5): 291-299. 2. Nicolson GL, Nasralla MY, Haier J et al. Mycoplasmal infections in chronic illnesses: Fibromyalgia and Chronic Fatigue Syndromes, Gulf War Illness, HIV-AIDS and Rheumatoid Arthritis. Med Sentinel 1999; 5:172-176. 3. Nicolson GL, Nasralla M, Gan R et al. Evidence for bacterial (mycoplasma, Chlamydia) and viral (HHV-6) co-infections in chronic fatigue syndrome patients. J Chronic Fatigue Syndr 2003; 11(2):7-20. 4. Nicolson GL, Gan R, Haier J. Multiple co-infections (Mycoplasma, Chlamydia, human herpesvirus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS 2003; 111:557-66. 5. Nicolson GL, Berns P, Gan R, et al. Chronic mycoplasmal infections in Gulf War veterans’ children and autism patients. Med Veritas 2005; 2:383-87. 6. Nicolson GL, Gan R, Nicolson NL, et al. Evidence for Mycoplasma, Chlamydia pneunomiae and HHV-6 Co-infections in the blood of patients with Autism Spectrum Disorders. J Neuroscience Res 2007; 85:1143-48. Prof Nicolson has published over 500 peer reviewed papers, among them current content citation classics. Here a couple of examples: Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. Nicolson GL. J Cell Biochem. 2007 Apr 15;100(6):1352-69. Review. PMID: 17243117 [PubMed - indexed for MEDLINE] Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders. Nicolson GL, Gan R, Nicolson NL, Haier J. J Neurosci Res. 2007 Apr;85(5):1143-8. PMID: 17265454 [PubMed - indexed for MEDLINE] Invest in ME (Charity Nr. 1114035) Page 62/76 Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE P Prrooffeessssoorr HHaarraalldd NNyyllaanndd MMDD,, PPhhDD Institute of Clinical Medicine, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway On 20 July 2006 Professor Nyland was knighted by the King of Norway for his services for MS research and treatment of MS patients. Since the 1970s he has built up a large multidisciplinary research team at Haukeland University Hospital which has worked with immunological diseases in the brain and other parts of the nervous system. Professor Nyland has published over 100 scientific papers in international publications, either as the main author or as a senior co author. He has also taught neurology students for more than 20 years. Thanks to Professor Nyland’s considerable input the Neurology Department at Haukeland University Hospital is at present a national centre of excellence for MS in Norway. Dr Nyland graduated in 1968 and took his medical PhD in 1982. He has also been strongly involved with ME patients for more than 10 years and during this time he has examined over 1500 patients with suspected ME. P Prreesseenn ttaatt iioonn:: Epidemics & ME: Lessons from the Giardia epidemic in Norway Background In 2004 a few thousand people contracted a gastrointestinal infection due to consumption of contaminated public drinking water (1). According to Nygard et al. (2), approximately 48,000 people were exposed to the contaminated tap water during the outbreak. People affected had been drinking tap water from the public waterworks supplying the inner city of Bergen, a coastal city of western Norway, during the outbreak. Leaking sewage pipes combined with insufficient water treatment were the likely causes of the epidemic (1). The outbreak probably began in August and peaked in early October (2). A total of 1300 laboratory-confirmed cases of Giardia duodenalis were reported (1). In addition one could expect a number of asymptomatic carriers as well (3). It took about six to eight weeks before the medical community and local health authorities acknowledged the epidemic and identified the parasite, G. lamblia, as the cause of the gastrointestinal infection (4). One reason for the late detection of the cause is probably that G. lamblia is non-endemic in Norway and therefore not normally tested for (2). The people infected were mostly women and younger people (2, 4) who had been drinking larger amounts of tap water, often more than five glasses per day (2). The municipality of Bergen city accepted responsibility for the insufficient quality of the water supply and their insurance carrier is expected to pay compensation. Most cases are still being arbitrated, and some may end up in court. G. lamblia is one of the most common causes of protozoally-induced diarrhoea in humans globally (1, 5), but in Norway before 2005, this infection was mainly associated with people travelling to “exotic” places, as more than 90 % of yearly confirmed cases are imported by foreign travellers (5). This outbreak of giardiasis is the largest waterborne outbreak in recent time (5), and the first reported giardiasis outbreak of epidemic proportion in Norway (6). An outbreak of this size is unusual in the Nordic countries, and even in Europe. Information from the Norwegian Prescription Database revealed that probably more than 2,500 cases were Invest in ME (Charity Nr. 1114035) Page 63/76

Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE treated for giardiasis, likely associated with this epidemic (2). Most of the affected patients responded well to standard treatment with antibiotics, although for some only one cure was not sufficient to clear the parasite from the body (4). After treatment some returned to their general practitioners because they experienced recurring symptoms (5). Following the Bergen giardiasis epidemic a few hundred developed post-infectious irritable bowel syndrome [PI-IBS] (8), and many still experienced abdominal symptoms and prolonged fatigue two years after the initial infection (9). Around 2005 and 2006, severely fatigued patients started to be referred to a neurologist specialising in chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) for further investigation. The majority of the fatigued patients subsequently participated in an educational programme in the fall of 2007, focusing on following aspects: post-infectious prolonged fatigue (disease knowledge); physical activity; psychological aspects accompanying severe illness; nutrition; legal entitlements administered by the Norwegian Labour and Welfare Administration, as well as future plans for a rehabilitation programme aimed to facilitate recovery and return to work or education. After a thorough examination, 58 persons fulfilling the 1994 Fukuda et al. (10) criteria for chronic fatigue syndrome were consecutively enrolled in a prospective multidisciplinary research project (11). Data show that among this subgroup of severely fatigued persons, some had become acutely fatigued (25%), some after a few weeks (14.3%), and some more gradually over several months (60.7%). The multidisciplinary research project’s main objectives are: 1) Present the clinical findings for the group of patients with post-infectious fatigue syndrome and to determine symptomatic and functional status during a 5-year follow-up; 2) Explore and describe the patients’ own experience of living with this condition and being in a rehabilitation process. The research study being presented in this paper is focusing on the human aspects of living with giardiasis. References 1. Eikebrokk B, Gjerstad KO, Hindal S, Johanson G, Rostum J, Rytter E (2006). Giardia utbruddet i Bergen. Sluttrapport fra det eksterne evalueringsutvalget. (Report in Norwegian) http://www.sintef.com/ 2. Nygard K, Schimmer B, Sobstad O, Walde A, Tveit I, Langeland N, Hausken T & Aavitsland P. A large community outbreak of waterborne giardiasis - delayed detection in a non-endemic urban area. BMC Public Health, 2006;6:141 doi:10.1186/1471-2458-6-141 3. Rortveit G & Wensaas K-A. En moderne epidemi. [A modern epidemic] Tidsskr Nor Laegeforen, 2004;124(24):3178. 4. Steen K & Damsgaard E. Giardiaepidemien i 2004 og Bergen Legevakt. [The Giardia epidemic in 2004 and out-of-hours service in Bergen] Tidsskr Nor Laegeforen, 2007;127(2):1879. 5. Wensaas KA, Langeland N, Rortveit G. Prevalence of recurring symptoms after infection with Giardia lamblia in a non-endemic area. Scand J Prim Health Care, Dec 2008;12:1-6. 6. Nygard K. Giardiasis – et undervurdert problem i Norge. [Giardiasis--an underestimated problem in Norway?] Tidsskr Nor Laegeforen, 2007;127(2):155. 7. Wensaas K-A, Langeland N, Rortveit G. Avdekking av giardiasisutbruddet i Bergen 2004. [Uncovering the giardiasis-outbreak in Bergen 2004] Tidsskr Nor Laegeforen, 2007;127(17):2222-5. Invest in ME (Charity Nr. 1114035) Page 64/76 Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE 8. Hanevik K, Hausken T, Morken M, Strand E, Morch K, Coll P, Helgeland L, Langeland N. Persisting symptoms and duodenal inflammation related to Giardia duodenalis infection. J Infect, 2007 Dec;55(6):524-30. 9. Morch K, Hanevik K, Rortveit G, Wensaas KA, Langeland N. High rate of fatigue and abdominal symptoms 2 years after an outbreak of giardiasis. Trans R Soc Trop Med Hyg, 2009 Jan 29. Epub head of print. doi:10.1016/j.trstmh.2009.01.010 10. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Study Group. Ann Intern Med, 1994;121:953-959. 11. Nyland H, Nyland M, Stormorken E, Naess H. Post-infectious fatigue syndrome following Giardia infection. An ongoing multidisciplinary follow-up. Poster presentation. The 9th Biennial International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Conference, Reno, Nevada, March 14, 2009. Addditional examples of papers by Professor Nyland: - Vaccination as teenagers against meningococcal disease and the risk of the chronic fatigue syndrome. Magnus P, Brubakk O, Nyland H, Wold BH, Gjessing HK, Brandt I, Eidem T, Nøkleby H, Stene-Larsen G. Vaccine. 2009 Jan 1;27(1):23-7. Epub 2008 Nov 5. PMID: 18984023 [PubMed - indexed for MEDLINE] Vitamin D-dependent rickets as a possible risk factor for multiplesclerosis. Torkildsen Ø, Knappskog PM, Nyland HI, Myhr KM. Arch Neurol. 2008 Jun;65(6):809-11. PMID: 18541802 [PubMed - indexed for MEDLINE] D Drr .. JJoonnaatthhaann KKeerr rr Jonathan Kerr was born in Belfast in 1963, qualified in medicine from Queen’s University of Belfast (1987), and completed training as a medical microbiologist (1995). He has worked as a microbiologist in Belfast, Manchester and London, taking up post as a Consultant Senior Lecturer in Microbiology at Royal Brompton Hospital / Imperial College in June 2001, and then Sir Joseph Hotung Clinical Senior Lecturer in Inflammation at St George’s University of London in 2005. His interest in Chronic Fatigue Syndrome (CFS) began during a study of the consequences of parvovirus B19 infection, when he showed that a percentage of infected cases developed CFS which persisted for several years. He is now the principal investigator in a programme of research in CFS. This involves development of a diagnostic test using mass spectrometry, analysis of human and viral gene expression in the white blood cells, and clinical trials of immunomodulatory drugs. Dr. Jonathan Kerr and colleagues at St. George’s University of London reported in the July 27, 2005 issue of the Journal of Clinical Pathology that a preliminary study of 25 CFS patients and 25 matched healthy controls revealed abnormalities in 35 of 9,522 genes analyzed using microarray technology. Polymerase chain reaction studies showed the same results for 16 of these genes. Dr. Kerr has recently defined seven genomic subtypes of CFS based on 88 genes that are expressed differently in CFS patients than they are in normal controls. Invest in ME (Charity Nr. 1114035) Page 65/76

Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE The study, and its results, raises some important questions. The first of which pertains to the need for funding of microbiological CFS research. He is funded (>£1million) by the CFS Research Foundation (www.cfsrf.com), a charitable organization based in the U.K., and leads a group of 5 scientists at St George's. The Foundation needs private support to continue their research efforts. They also openly post the results of their efforts on their website http://www.cfsrf.com. C Coonnffeerreennccee PPrreesseennttaatt iioonn :: Microbial infections in eight genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) Lihan Zhang,1 Beverley Burke,1* Robert Petty,1* John Gough,1 David Christmas,2 Derek L Mattey,3 Selwyn CM Richards,4 Janice Main, 5 Derek Enlander,6 David Honeybourne,7 Jon G Ayres,7 David J Nutt,2 Jonathan R Kerr.1 1Department of Cellular & Molecular Medicine, St George’s University of London, London, UK; 2Psychopharmacology Unit, Dept of Community Based Medicine, University of Bristol, Bristol, UK; 3Staffordshire Rheumatology Centre, Stoke on Trent, UK; 4Dorset CFS Service, Poole Hospital, Dorset, UK; 5Dept of Infectious Diseases and General Medicine, Imperial College London, St Mary’s Hospital, London, UK; 6New York ME / CFS Service, 860 Fifth Avenue, New York, USA; 7Dept of Respiratory Medicine, Birminghan Heartlands Hospital, UK Reprints or correspondence: Dr Jonathan R Kerr, Room 2.267, Jenner Wing, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK. Email: jkerr@sgul.ac.uk. Abstract Jonathan Kerr We have previously reported abnormal expression of 88 human genes in the blood of patients with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) and 7 genomic subtypes of CFS/ME (Kerr JR, et al. J Infect Dis 2008;197:1171-84). In this study we attempted to reproduce our previous findings in 59 new CFS patients, to determine expression levels of these genes in patients with endogenous depression, and to test the hypothesis that particular microbial infections are associated with particular genomic CFS subtypes. We determined expression levels of 88 human genes in blood of 53 new patients with idiopathic CFS/ME (according to Fukuda criteria), 6 patients with Q-fever associated CFS/ME (Q-CFS/ME) from the Birmingham Q-fever outbreak (according to Fukuda criteria), 14 patients with endogenous depression (according to DSM-IV criteria) and 18 normal blood donors. In patients with CFS/ME differential expression was confirmed for all 88 genes. Q-CFS/ME patients had similar patterns of gene expression to idiopathic CFS/ME. Gene expression in endogenous depression patients was similar to that in the normal controls, except in the case of four genes (APP, GNAS, PDCD2, PDCD6), where significant upregulation (fold-difference ≥1.5) was noted. Taqman PCR delta Ct values for 88 genes in CFS/ME patients in the present study (n=59) and our previous study (n=55) were combined resulting in a gene database of 117 CFS/ME patients. Clustering revealed 8 genomic subtypes with distinct differences in SF-36 scores, clinical phenotypes, severity and geographical distribution. Antibody testing for Epstein-Barr virus (EBV), enterovirus, Chlamydia pneumoniae, Coxiella burnetii and parvovirus B19 revealed significant subtype-specific relationships for EBV and enterovirus, the two most common infectious triggers of CFS/ME. Invest in ME (Charity Nr. 1114035) Page 66/76 Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE Additional links for Dr Kerr: Jonathan Kerr, Seven genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): a detailed analysis of gene networks and clinical phenotypes. J Clin Pathol. 2007 Dec 5. ub ahead of print] PMID: 18057078 [PubMed - as supplied by publisher] D Drr .. BBaa rr bbaa rr aa BBaauummggaa rr tt eenn MMDD Project leader , ME/CFS-center, Oslo University Hospital, Ullevål Dr Barbara Baumgarten was born in Hamburg, Germany, and moved to Norway in 1980. She studied medicine at the University of Oslo and from 1992-93 she worked at a hospital in internal medicine and surgery. From 1993 she has been working in General Practice, with a two year assignment at a nursing home. Since 1996 she has had her own practice and has been seeing patients with ME since 1997. From April 2006 she has been working one day a week as a GP at the department for infectious diseases, Ullevål University Hospital, Oslo. Her work there was to look at the need of specialized medical services for ME-patients. That has resulted in a new ME-clinic. Since August 2008 her main job at Ullevål University Hospital has been leader for the new MEcentre, which was officially opened on December 11th 2008. The ME Centre in Oslo is unique in that patients have been closely involved in its formation. Dr Baumgarten has given many lectures about ME for GP’s, at hospitals and for the Norwegian ME Association. She is a board member at the Oslo branch of the Norwegian Medical Association. P Prreesseennttaatt iioonn DDrr .. BBaauummggaarr tteenn:: S Seerrvviicceess ffoorr ccoorr rreecctt ddiiaaggnnooss ii ss a anndd MMaannaaggeemmeenntt //TT rreeaattmmeenntt ooff MMEE Thanks to the ME-patient organizations in Norway, Norwegian politicians have become aware of the problems ME patients face, both concerning diagnosis and treatment of their condition. Some years ago there were only a few doctors who knew enough about Post infectious fatigue syndrome, as it was most commonly called then, to set the diagnosis. One of the doctors who would recognize the condition was Dr. Oddbjørn Brubakk who was head of the department for infectious diseases at Ullevål University Hospital in Oslo. Two patients had approached him in 2003 and asked if it was possible to start a coping course for patients with ME since there was little other treatment to offer them. A group including the patient representatives and professionals from the medical division and the Patient education center at Ullevaal started working on a concept for a course that has been running twice a year since 2004. Therefore, when political awareness around ME was growing Ullevaal University Hospital was asked by the Eastern Norway Regional Health Authority to have a closer look at the needs of that patient group. Since 2006 I have been working on a concept for a ME-clinic and last year we got funded by the South-Eastern Norway Regional Health Authority to start the clinic as a project. We have today an out-patient clinic where patients can come to get diagnosed, and where they can get help in coping with ME by a multi professional team that includes an occupational therapist, a physiotherapist, a dietitian and a social worker. Patients get help to learn energy economizing, relaxation techniques, dietary advice and advice with their problems with the social security system. When working on the concept I became aware that the permanently bedbound patients wouldn’t be able Invest in ME (Charity Nr. 1114035) Page 67/76

Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE to come to our clinic. So I introduced the concept of an ambulatory team that could go home to people helping to get the correct diagnosis and offering them the same advice with up to five visits by two from the team each time. The limitation is that we must be able to do the visit in one day including transportation, so we cover only eastern Norway. These services have just started and now the South-Eastern Norway Regional Health Authority have asked Oslo University Hospital, Ullevaal (three University hospitals in Oslo joined by January 1st 2009) to investigate the possibility of starting an in-patient service for severe ME-sufferers, which would cover the whole country. The ward would provide the possibility for careful examination to rule out all other conditions that might explain the condition and give those who can profit from treatment/coaching that possibility. Our biggest concern at this time is that patients with very severe ME will be too ill to be moved to the ward and might become worse by physical examinations. The report is handed over to the authority by April 30th and we hope to have an answer by mid June. P Prrooffeessssoorr KKeennnnyy DDee MMeeii rr lleeii rr MMDD PPhhDD Dr. De Meirleir is a world renowned researcher and is professor of Physiology and Internal Medicine at Free University of Brussels in Belgium. He is co-editor of Chronic Fatigue Syndrome: A Biological Approach, and reviewer for more than 10 other medical journals. Dr. De Meirleir was one of four international experts on the panel that developed the Canadian Consensus Document for ME/CFS. He assesses/treats 3,000 to 4,000 ME/CFS patients annually. Professor Kenny L. De Meirleir, MD received his medical degree at Vrije Universiteit Brussel, Magna cum laude. His research activities in Chronic Fatigue date back to 1990. His other research activities in exercise physiology, metabolism and endocrinology have led to the Solvay Prize and the NATO research award. He is director of the Himmunitas Foundation Brussels and Professor at the Vrije Universiteit Brussel, as well as consultant in the Division of Cardiology and director of the cardiac rehabilitation program at Vrijie Universiteit Brussel. P Prreesseennttaatt iioonn PPrrooffeessssssoorr DDee MMeeii rr lleeii rr :: R Reesseeaarrcchh oonn EEeexxtt rreemmeellyy DDeebbii ll ii ttaatteedd MM..EE .. PPaatt iieenntt ss RReevveeaall ss tthhee TT rruuee N Naattuurree ooff tthhee DDii ssoorrddeerr Kenny De Meirleir(1), Chris Roelant(2), Marc Fremont(2), Kristine Metzger(2), Henry Butt(3) (1) Vrije Universiteit Brussel & HIMMUNITAS foundation, Brussels, Belgium (2) Protea Biopharma, Brussels, Belgium (3) Bioscreen & Bio 21, University of Melbourne, Melbourne, Australia In this study we compared totally bedridden patients (Karnofski score 20-30) with less ill ME patients (Karnofski score 60-70), family controls, contact controls and non-contact controls. EBV, HHV6 and Borna virus titers were not different in the three groups. Plasma LPS distinguished the groups, with the highest values in the bedridden patients. LPS is a strong activator of the immune system and high plasma concentrations suggest a hyperpermeable gut. There are many possible causes for this, but a lack of ‘local’ energy production is one of them. In a separate study (In Vivo, in press) we observed intestinal overgrowth of Gram positive D/L lactate producing Invest in ME (Charity Nr. 1114035) Page 68/76 Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE bacteria which are also known to produce H2S in presence of certain heavy metals as a survival defense mechanism. We therefore hypothesized that the urine of the bedridden ME patients would contain more H2S derived metabolites than the less ill and the controls. Using a proprietary simple colorimetric urine test this hypothesis was confirmed. In the extremely ill, urine added to the yellow color reagent immediately turns dark blue, whereas in the less ill the reaction is slower and in the controls no reaction occurs. Being a potent neurotoxin, H2S induces photophobia, intolerance to noise, mitochondrial dysfunction by inhibition of cytochrome oxidase, depresses the cellular immune system and induces neutropenia and low numbers of CD8+ lymphocytes. Its effects, at least in part explain the clinical condition of the severely disabled ME patients. Furthermore bacterial H2S induces increased ROS production by the liver and retaining of heavy metals, particularly mercury, in the body. Mercury is also neurotoxic, induces apoptosis and interferes with the aerobic metabolism. Chronic increased production of H2S by intestinal bacteria leads to build-up of mercury in the body as proven by a Zn DTPA/DMPS challenge test. In about 20% of the ME patients (the most severely ill) we observed using a special luminescence technique the formation of proteins with aberrant conformation which interfere with the energy metabolism. In conclusion, ME is a disorder which is caused by increased endogenous H2S production. H2S initiates a chain of events in the body, with more and more negative effects on the aerobic metabolism and depression of the immune system leading to higher rates of infections and reactivation of endogenous viruses. In the most severe cases of the disease proteins with aberrant conformation may develop which put the patients in a total energy depleted state. Examples of other papers from Professor De Meirleir include – Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients. Metzger K, Frémont M, Roelant C, De Meirleir K. Biochem Biophys Res Commun. 2008 Nov 7;376(1):231-3. Epub 2008 Sep 5. PMID: 18774769 [PubMed - indexed for MEDLINE] Unravelling intracellular immune dysfunctions in chronic fatigue syndrome: interactions between protein kinase R activity, RNase L cleavage and elastase activity, and their clinical relevance. Meeus M, Nijs J, McGregor N, Meeusen R, De Schutter G, Truijen S, Frémont M, Van Hoof E, De Meirleir K. In Vivo. 2008 Jan-Feb;22(1):115-21. PMID: 18396793 [PubMed - indexed for MEDLINE] Dr. Daniel Peterson MD Daniel Peterson is a graduate Magna cum Laude, Phi Beta Kappa of Carleton College in Northfield, Minnesota. He graduated from the University of Rochester School of Medicine in Rochester, New York, in 1976. Dr. Peterson served his internship and residency at the University of Utah Medical Center from 1976-1979 and became a Diplomat of the American Board of Internal Medicine in 1979. He has been caring for patients with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), for two decades, and his clinical work is complimented by a strong commitment to research as evidenced by his participation in more than 17 research studies, numerous drug trials and his foresight to collect and maintain the world's single largest repository of ME/CFS patient samples. Dr. Peterson was on the founding board of the IACFS. Among the numerous awards that he has received, in 2007 he was awarded the prestigious Nelson Gantz Clinician Award. Invest in ME (Charity Nr. 1114035) Page 69/76

Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE With over 25 years of medical practice, Dr Daniel L. Peterson has become a sought-after internist for diagnosing difficult and complex medical cases. When several patients in Incline Village became ill with symptoms that resembled persistent mononucleosis, Daniel Peterson was one of the first physicians to recognize an outbreak of what is known as ME/Chronic Fatigue Syndrome (ME/CFS). He became a pioneering physician and researcher in understanding the biological characteristics and methods for diagnosing, managing and treating ME/CFS. He has also performed major studies of Ampligen as a treatment for ME/CFS, and studying the possible role of human herpes virus 6 (HHV-6) in CFS patients. Dr Peterson is an affiliate of the Sierra Internal Medicine Associates in Incline Village, Nevada; ME/CFS researcher and clinician; a board member of the American Association for Chronic Fatigue Syndrome; and member of the International Chronic Fatigue Syndrome Study Group. Dr Peterson was one of the two physicians who identified the original outbreak of CFS in Incline Village, Nevada, in 1984. (thanks to the WPI web site for this information). C Coonnffeerreennccee PPrreesseennttaatt iioonn :: T Trreeaattmmeenntt RReeggiimmeess ffoorr tthhee MMooss tt S Seevveerree CCaasseess Chronic Fatigue Syndrome/ME is a worldwide problem with incidence of approximately 700 people per 100,000. A subset of patients diagnosed with CFS/ME are severely affected with marked resultant disability and reduced quality of life. In addition to clinical symptoms, these patients can be assessed through objective markers and further categorized by degree of disability and severity of illness. In addition to functional studies, biological markers exist, they are useful in establishing baseline values and used to follow treatment regimens. It is important to thoroughly evaluate these patients in order to rule out comorbid conditions that are also treatable and to establish subsets allowing targeted interventions and rehabilitation strategies. A diagnostic algorithm has been developed to identify this group of patients and to facilitate aggressive treatment strategy. Biological markers can include genetic studies for predisposition to ME, extensive immunological profiling to document perturbations of B-cell and T-cell function and gene expression arrays. Additionally, platforms exist to look for pathogenetic mechanisms including viral arrays and cytokine analysis. Neuroimaging can further determine objective markers of CNS dysfunction. Functional studies employed include studies of VO2 max and neurocognitive testing. Generally, these severely affected subsets of patients have been ill for prolonged period of time and have a guarded prognosis. However, dramatic results have been reported with aggressive targeted strategies. A team approach is required in order to provide necessary services including in-home services, hospitalization, and aggressive management for orthostatic intolerance, cognitive dysfunction, and immune perturbations. Objective markers are followed throughout this process to gauge effectiveness of therapy and axillary supportive services are instituted concomitantly to address issues of secondary mood disorder, deconditioning, and psychosocial dysfunction related to chronic illness. A center of excellence model is currently being developed to implement this broad approach to the most severely disabled patients that include translational research from the laboratory to the Invest in ME (Charity Nr. 1114035) Page 70/76 Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE bedside and includes not only diagnostics but appropriate drug development or alternative interventions. Daniel L. Peterson, M.D. DLP/ldr/rsu D: 05/18/09 T: 05/19/09 P Prrooffeessssoorr BBaassaanntt PPuurr ii MMDD,, PPhhDD Professor and Consultant, MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College School of Medicine Professor Basant K. Puri is both a medical practitioner, working as a consultant at Hammersmith Hospital in London, and a senior scientist, working at Imperial College London. He is head of the Lipid Neuroscience Group at Imperial College and is the author of over 130 peer-reviewed medical and scientific papers and over 30 books. C Coonn ffeerreennccee PPrreesseennttaatt iioonn:: NNeeuurroo-- IImmaaggiinngg –– RReesseeaarrcchh ooff MMEE p paatt iieenntt ss In this talk, the results of recent proton neurospectroscopy and high-resolution structural magnetic resonance imaging studies of myalgic encephalomyelitis carried out at Hammersmith Hospital, London, will be described. Additional links for Professor Puri – Serial structural MRI analysis and proton and 31PMR spectroscopy in the investigation of cerebral fatty acids in major depressive disorder, Huntington's disease, myalgic encephalomyelitis and in forensic schizophrenic patients. Puri BK, Tsaluchidu S, Treasaden IH. World Rev Nutr Diet. 2009;99:31-45. Epub 2009 Jan 9. Review. No abstract available. PMID: 19136837 [PubMed - indexed for MEDLINE] High-resolution magnetic resonance imaging sinc-interpolation-based subvoxel registration and semi-automated quantitative lateral ventricular morphology employing threshold computation and binary image creation in the study of fatty acid interventions in schizophrenia, depression, chronic fatigue syndrome and Huntington's disease. Puri BK. Int Rev Psychiatry. 2006 Apr;18(2):149-54. Review. Proton and 31-phosphorus neurospectroscopy in the study of membrane phospholipids and fatty acid intervention in schizophrenia, depression, chronic fatigue syndrome (myalgic encephalomyelitis) and dyslexia. Puri BK. Int Rev Psychiatry. 2006 Apr;18(2):145-7. Review. PMID: 16777668 [PubMed - indexed for MEDLINE] Invest in ME (Charity Nr. 1114035) Page 71/76

Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE D Drr JJoohhnn CChhiiaa MMDD Dr Chia is an infectious disease specialist practicing in Torrance, California, USA and has published research recently (Chronic fatigue syndrome associated with chronic enterovirus infection of the stomach) on the role of enteroviruses in the aetiolgy of ME/CFS – an area which has been implicated as one of the causes by a number of studies. There are more than 70 different types of enteroviruses that can affect the central nervous system, heart and muscles, all of which is consistent with the symptoms of ME/CFS. By analyzing samples of stomach tissue from 165 patients with CFS, Dr. Chia's team discovered that 82% of these individuals had high levels of enteroviruses in their digestive systems. Dr Chia's research may result in the development of antiviral drugs to treat the debilitating symptoms of ME/CFS. C Coonnffeerreennccee PPrreesseennttaatt iioonn ff rroomm DDrr CChhiiaa:: D Diiaaggnnooss ii ss aanndd TT rreeaattmmeenntt ooff MMyyaallggiicc EEnncceepphhaalloommyyeell ii tt ii ss//CChhrroonn iicc F Faatt iigguuee SSyynnddrroommee AAssssoocciiaatteedd wwii tthh CChhrroonniicc EEnntteerroovvii rruuss iinnffeecctt iioonn.. J Joohhnn CChhiiaa,, AAnnddrreeww CChhiiaa.. EEVV MMeedd RReesseeaarrcchh ME/CFS is an elusive illness without a clear etiology and treatment. Emerging evidences suggest that enteroviruses can persist in the tissues of ME/CFS patients and may be responsible for the various symptoms. Enteroviruses are common causes of respiratory, gastrointestinal and non-specific flu-like illnesses. Major epidemics of enterovirus infections including but not limited to meningoencephalitis, myocarditis, pleurodynia, myositis and hand-foot-mouth diseases have been well-documented in the past decades. In some cases, acute enterovirus infections can cause CD8+ T lymphocytopenia predisposing to reactivation of endogenous herpes viruses. Initial isolation of enteroviruses from patients with acute infections followed by demonstration of persistent viral infection in tissues years after the patients developed chronic symptoms lends support to the pathogenic role of enteroviruses in ME/CFS. Presumptive clinical diagnosis of chronic enterovirus infection requires a high index of suspicion, familiarity with the protean manifestations of acute infections and understanding of chronic viral persistence. There is not yet a specific diagnostic test for ME/CFS. Significantly elevated neutralizing antibody titer over time suggests persistent immunologic response to specific enterovirus(s) infection in the tissues. Neutralizing antibody test for 11 of the most common non-polio enteroviruses is performed by one U.S. reference laboratory. Invest in ME (Charity Nr. 1114035) Page 72/76 Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE In contrast to other types of viremic infections, EV RNA levels in whole blood of ME/CFS patients are extremely low, which likely explain the discrepancy of results reported from different research laboratories over the past two decades. Immunoperoxidase staining for viral protein in the stomach biopsies is more sensitive than the neutralizing antibody test or EV RNA detection, and furthermore, demonstrates the antigens in tissues where viruses are expected to replicate and persist based on the route of transmission. The finding of enteroviral RNA and growth of non-cytopathic viruses from the same tissues support the validity of protein staining. As enteroviruses have been largely forgotten since the eradication of poliomyelitis through effective vaccination, there is no specific antiviral therapy for acute or chronic infections. Pleconaril, an anti-capsid agent, showed limited benefit in 1/4 patients with ME/CFS associated with chronic enterovirus infections. Intravenous immunoglobulin, given monthly or every few months, can ameliorate inflammatory symptoms in less than 1/3 of adult patients, but may be more effective in pediatric patients. The combination of alpha and gamma interferon can induce short-term remission in about 45% of ME/CFS patients with debilitating myalgia, but is quite expensive and often poorly tolerated. One of the Chinese herbs, oxymatrine, has beneficial effect in 52% of 300 ME/CFS patients, but transient increase in symptoms are expected in most of the patients. Cytokine gene expression study during therapy demonstrates an increase of IL12/Il10 ration in 7/7 responders but in 0/10 non-responders. A decrease of stainable enteroviral protein is demonstrated in the stomach biopsies of three responders on oxymatrine therapy. Previous evidence for enterovirus infection in ME/CFS from over a decade ago has been confirmed and extended in recent studies. Development of antiviral therapy against enteroviruses is paramount; and the importance of enteroviruses in ME/CFS can be realized with a randomized, placebo-controlled antiviral drug trial. Additional links for Dr Chia: John Chia, Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol. 2008 Jan;61(1):43-8. Epub 2007 Sep 13. PMID: 17872383 [PubMed - indexed for MEDLINE] Enterovirus infection as a possible cause of pityriasis rosea: demonstration by immunochemical staining. Chia JK, Shitabata P, Wu J, Chia AY. Arch Dermatol. 2006 ul;142(7):942-3. No abstract available. PMID: 16847226 [PubMed - indexed for MEDLINE] Diverse etiologies for chronic fatigue syndrome. Chia JK, Chia A. Clin Infect Dis. 2003 Mar 1;36(5):671-2; author reply 672-3. No abstract available. PMID: 12594650 [PubMed - indexed for MEDLINE] Invest in ME (Charity Nr. 1114035) Page 73/76

Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE D Drr JJuuddyy MMiikkoovvii tt ss PPhhDD Dr. Mikovits obtained her Ph.D. in Biochemistry and Molecular Biology from George Washington University. Dr. Mikovits served as a senior scientist at Biosource International, where she led the development of proteomic assays for the Luminex platform that is used extensively for cytokine activity assessment in therapy development. Dr. Mikovits spent more than 20 years at the National Cancer Institute in Frederick MD during which time she received her PhD in Biochemistry and Molecular Biology, investigating mechanisms by which retroviruses dysregulate the delicate balance of cytokines in the immune response. This work led to the discovery of the role aberrant DNA methylation plays in the pathogenesis of HIV. Later in her career at the NCI, Dr. Mikovits directed the Lab of Antiviral Drug Mechanisms (LADM) a section of the NCI's Screening Technologies Branch in the Developmental Therapeutics Program. The LADM's mission was to identify, characterize and validate molecular targets and to develop high-throughput cell-based, genomic and epigenomic screens for the development of novel therapeutic agents for AIDS and AIDS-associated malignancies (Kaposi's sarcoma). Formally trained as a cell biologist, molecular biologist and virologist, Dr. Mikovits has studied the immune response to retroviruses and herpes viruses including HIV, SIV, HTLVI, HERV, HHV6 and HHV8 with a special emphasis on virus host cell interactions in cells of the hematopoietic system including hematopoietic stem cells (HSC). Dr. Mikovits' commercial experience includes serving as a senior scientist and group leader at Biosource International, where she led the development of proteomic assays for the Luminex platform that is used extensively for cytokine activity assessment in therapy development. She also served as Chief Scientific Officer and VP of Drug Discovery at Epigenx Biosciences, where she led the development and commercialization of cell and array-based methylation assays for drug discovery and diagnostic development. She is Research Director at the Whittemore Peterson Nevada CFS centre for Neuro-Immune disorders and has co-authored over 40 peer reviewed publications that address fundamental issues of viral pathogenesis, hematopoiesis and cytokine iology. (thanks to the WPI web site for this information). C Coonnffeerreennccee PPrreesseennttaatt iioonn DDrr MMiikkoovvii tt ss :: T Trraannss llaatt iioonnaall RReesseeaarrcchh TToowwaarrddss tthhee DDiiaaggnnooss ii ss ooff DDii ff ff iiccuull tt aanndd C Coommpplleexx MMeeddiiccaall CCaasseess ooff MMEE//CCFFSS The research program of the Whittemore Peterson Institute is unique in that it has taken a systems biology approach to the study of CFS. This approach involves profiling a patient with respect to genetics, immune system phenotype and function and expression of viruses. Both research and clinical data are entered into a central database for correlation with clinical Invest in ME (Charity Nr. 1114035) Page 74/76 Journal of IiME Volume 3 Issue 1 www.investinme.org P PRROOFFIILLEESS ooff PPRREESSEENNTTEERRSS aatt tthhee IINNVVEESSTT iinn MMEE I INNTTEERRNNAATTIIOONNAALL MMEE//CCFFSS CCOONNFFEERREENNCCEE data. These data are then translated into diagnostic and treatment strategies that can be personalized” for each patient. This model can be extended to each physician such that data from individual cohorts or subgroups of patients can be entered into a fully secure/ international national database that can be queried by physicians anywhere in the world giving each physician tools with which to diagnose and treat patients with similar genetic, immune and pathogen profiles. We used this strategy to study more than 100 difficult and complicated CFS patients from a well-defined Nevada ME/CFS cohort resulting from outbreak of ME/CFS that occurred between 1984 and 1987. Immune profiling reveals immune defects including in T, B and NK cell compartments. These abnormalities are suggestive of a persistent infection and predicative of the development of lymphoma. Moreover using antibody microarrays to profile serum biomarkers in this cohort we have developed a five-cytokine/chemokine signature that can identify CFS patients from controls with 94% sensitivity and specificity. Viral microarray studies demonstrate persistent active herpes viruses, enteroviruses, adenoviruses and parvoviruses. Genetic profiling revealed HLA and killer immunoglobulin receptor (KIR) genotypes predictive of susceptible and protective genotypes in this cohort. Taken together these data suggest that this systems biology strategy can be developed diagnostically, for the development of serum biomarkers to stratify subgroups of ME/CFS patients for appropriate anti-inflammatory, antimicrobial and antiviral therapeutics. Additional links for Dr Mikovits: http://lib.bioinfo.pl/auth:Mikovits,J Example of other work: Epigenetic control during lymphoid development and immune responses: aberrant regulation, viruses, and cancer. Muegge K, Young H, Ruscetti F, Mikovits J. Ann N Y Acad Sci. 2003 Mar;983:55-70. Review. PMID: 12724212 [PubMed - indexed for MEDLINE] The Invest in ME International ME/CFS Conferences Invest in ME (Charity Nr. 1114035) Page 75/76

Journal of IiME Volume 3 Issue 1 I Innvveesstt iinn MMEE I Inntteerrnnaattiioonnaall MMEE//CCFFSS 2299tt hh MMaayy 22000099 CCoonnffeerreennccee A Aggeennddaa 07:45 Registration 08:55 IiME Welcome 09:00 Welcome 09:05 Key Note Speech 09:35 Similar infections found in ME/CFS and Neurodegenerative and Neurobehavioral Diseases 10:25 Epidemics & ME: Lessons from the Giardia epidemic in Norway 10:55 Coffee/Tea Break 11:15 Microbial infections in eight genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) 11:45 Services for correct diagnosis and Management/Treatment of ME – including ambulatory services for severe ME 12:15 The ME Clinic - Discussion 12:30 Lunch 13:25 Research on extremely debilitated M.E. patients reveals the true nature of the disorder 14:10 Treatment Regimes for the Most Severe Cases 15:10 Coffee/Tea Break 15:30 Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Associated with Chronic Enterovirus infection 16:15 Research and Diagnosis of difficult and complex medical cases of ME 17:00 Plenary Session 17:00 Adjourn Invest in ME (Charity Nr. 1114035) Page 76/76 Dr John Chia Professor Kenny De Meirleir Dr Dan Peterson 14:55 Neuro-Imaging – Research of ME patients Professor Basant Puri IiME Professor Brostoff Annette Whittemore Professor Garth Nicolson Professor Harald Nyland Dr Jonathan Kerr Dr Baumgarten Professor Brostoff + Presenters www.investinme.org Dr Judy Mikovits Professor Brostoff + Presenters

A New Era in ME/CFS Research The Journal of IiME Volume 4 Issue 1 from UK Charity Invest in ME (www.investinme.org)

Journal of IiME Volume 4 Issue 1 www.investinme.org P Prroovviiddiinngg aa vvooiiccee ffoorr tthhoossee sseevveerreellyy aaffffeecctteedd wwii tthh MMyyaallggiicc E Enncceepphhaalloommyyeell ii tt iiss Lost Voices' is a book to help healthcare professionals, those in the media and people with ME in understanding Myalgic Encephalomyelitis (ME). The name ' Lost Voices' refers both to the fact that people who are severely ill with ME are generally not in a position to make themselves heard, and also to the way that the prejudiced denial of ME - as an 'aberrant belief' rather than a devastating physical illness - has meant that often others are incapable of actually hearing and seeing what is being said and shown. 'Lost Voices' shows the impact of the illness on all family members, sufferers and carers. Yet it can educate the medical profession, the public and others and clearly shows the resilient character of people with ME and their families. The book is an A4 landscape size of extremely high quality with a laminated card cover. With over 120 pages of stories, pictures and information this is book truly encapsulates the tragedy of this illness and the way in which people with ME are left to exist in a twilight zone -left to deal with this illness by themselves. The book also contains facts about ME with The stories and photographs in 'Lost Voices' are provided by carers, families and, as far as possible, people with ME. The book allows an opportunity for people who are usually invisible and unheard to speak for themselves, so that their situation can be seen and understood more clearly. The book clearly and movingly shows the evidence of the devastating impact this physical disease has on individuals and their carers and families. It will help change a widespread lack of comprehension based on misinformation, vague definitions and manufactured statistics and raise awareness of the plight of ME sufferers. Invest in ME (Charity Nr. 1114035) contributions from experts such as Dr. John Chia, Dr Leonard Jason and Annette Whittemore. Please buy this book - for yourself or for friends, relatives or your GP - or suggest it as a gift for others to buy. This book will really make a difference. To order Lost Voices email to - info@investinme.org or go to our web page at – http://www.investinme.org/LostVoicesBook/Ii ME Lost Voices home.htm Price £8 (includes p&p) Page 2/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Conference Edition Editorial Comment Inside This Issue Welcome to the 2010 conference edition of the Journal of IiME – a blend of science, facts, stories and news regarding Myalgic Encephalomyelitis (ME or ME/CFS). May has become the month when Invest in ME organises and hosts its annual biomedical research conference, the month in which we have tried to focus attention as International ME Awareness Month. An illness which is responsible for causing such suffering and yet which has been treated with such ineptness by governments and healthcare organisations during the last generation deserves a full month to raise awareness of the issues. 2 Lost Voices 3 Editorial Comment 8 On the Front Foot – Back to the Future 10 The PACE Trials 11 Research, Research, Research 13 An Effort to Influence Medical Textbook Writers 21 EDUCATION on ME/CFS – The GMC Position 23 Definition of Recovery in CFS 28 LL ee tt tt ee rr ffrroomm AAmmee rr ii cc aa 32 Ampligen® in Severely Debilitated CFS Patients 37 Around Europe – European ME Alliance 45 Presenters & Abstracts at 5th Invest in ME International ME/CFS Conference 2010 Invest in ME (UK Charity Nr. 1114035) PO BOX 561 Eastleigh SO50 0GQ Hampshire, UK Email: info@investinme.org W b i ti Invest in ME (Charity Nr. 1114035) Page 3/56 Our first two conferences were, in a sense, testing the water in order to find a balance for future events. Since after our 2007 conference we decided to carry a theme for each conference where presentations and publicity could be aimed at a particular area regarding ME. In 2008 we decided to publicise sub grouping within ME with research clearly identifying the sub groups which could already be clearly defined. In 2009 we decided to focus on the severely affected people with ME – a cohort of patients who have been disenfranchised and neglected by society. The introduction of the book Lost Voices coincided with the theme of the 2009 conference eloquently showing the effect on patients and their families of a disease which is actually well understood by patients and which needs a strategy of proper science to resolve. The conference this year has the theme of education of healthcare professionals with a mixture of the latest research and clinical experiences from the most renowned ME researchers and clinicians in the world. A phrase often quoted by the UK government, Chief Medical Officer (CMO) and the Medical Research Council (MRC) in the UK is that there is little known about ME. This scientific myopia is unacceptable. Five international ME/CFS conferences held at the heart of power in London have proven there is research and knowledge about this disease. What is missing is an acceptance that previous policies – based on vested interests, Journal of IiME - Disclaimer The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times.

Journal of IiME Volume 4 Issue 1 www.investinme.org poor science, ignorant perceptions and misinformation – have so prejudiced the healthcare system in the UK that people have become blind to the actual research which has been going on and deaf to the countless demands from sick and vulnerable patients asking for change and fairness. Nowhere has this impairment of senses been more apparent than with the MRC and the CMO. Another reincarnation of an MRC expert panel to look at ME has, after two years gestation, still failed to deliver anything but a few meetings. Their latest panel is riddled with remnants of the now defunct and discredited psychosocial viewpoint – where ME patients are still being maligned as suffering from a behavioural illness. The strategy of this panel is to marry the psychosocial and biomedical sides together. This strategy will not work. There is no more need for a so called "balanced approach". It will further waste precious resources and, more importantly, prolong the suffering of patients. The MRC policy toward ME continues to be a failure. An unequivocal change in emphasis must now be made by the MRC toward a policy of biomedical research. The CMO has failed to engage with ME organizations, such as Invest in ME, and will again fail to be present at a fifth international conference held just a few hundred metres from his office. The lack of serious research by the MRC and the lack of leadership by the CMO has led to stagnation in the UK with little funding of research and lack of any urgency in dealing with the problem. And then we have October 2009. A seminal moment in the history of ME. Science magazine published research by the Whittemore-Peterson Institute (WPI), the National Cancer Institute (NCI) and the Cleveland Clinic (CC) showing links between a gamma retrovirus – (XMRV) and ME. Though doubts have been thrown at the WPI/NCI/CC research by the establishment organizations which are suddenly forced into covering the blatant bias of the past this has only shown clearly how professional the XMRV research by WPI/NCI/CC has been. Not only has this discovery energised ME Invest in ME (Charity Nr. 1114035) research and highlighted the need for more funding for biomedical research it has also energised patients. As Invest in ME have pointed out in its newsletters power has now been given to the patients who have become enabled in ways which the government and MRC have failed to predict. In the time that the UK MRC have organized a few meetings of its expert panel to discuss research into ME, producing nothing substantive and even lacking minutes for the last of these meetings, the WPI have achieved a major breakthrough – not just in science but in awareness. Education of healthcare professionals means that the National Health Service (NHS) needs to rid itself of the bias which has been allowed to exist regarding ME. This needs education – correct education and awareness of the disease and the symptoms and side effects. To tackle education we need to get back to basics and ensure that medical students are properly trained and aware of the biomedical research into ME. The General Medical Council, we thought, were crucial as they arranged the curriculum. Their response to our letter is contained in the Journal and shows some confusion regarding who actually decides what is taught about ME. Recent decision by Canada and Australia to ban people with ME from donating blood clearly shows the urgency which responsible governments are showing toward a possible contamination of the blood supply by people with ME who may be carrying this retrovirus. The continuing research which is being carried out, and which is being presented at the IiME conference in London, is showing these decisions to be more prescient as time goes on. We can only wonder when Europe will follow. After continual requests by Invest in ME and our colleagues in the European ME Alliance to persuade European health ministers to consider such a ban there is still no unified action. The Chief Medical Officer of the UK government has admitted that people with ME are exempt from blood donation – but then continues by adding that they may give blood when they are “recovered” or “feeling better”! The lack of any science supporting a definition of “recovery” and the ignorance behind the statement that one can donate blood once one “feels better” is Page 4/56 Journal of IiME Volume 4 Issue 1 www.investinme.org astonishing from any healthcare provider – let alone the nation’s guardian of health. Education is the key to progress and Invest in ME provide the 5th international ME/CFS Conference to show what can be achieved by dedication, proper science and clear strategy. A year ago, in our 2009 conference Journal of IiME (Volume 3 Issue 1), we posed a hypothetical situation which might occur between our 2009 conference and leading up to our 2010 conference. We supposed that a diagnostic test was developed and that sub groups were more easily able to be identified in order to guide treatments, and that a disease mechanism for ME was found? We asked – • how would ministers and healthcare officials react to such changes? • what changes would be seen in the healthcare system? • how would the pharmaceutical industry react with the promise of great rewards from development of effective treatments and possibly cures for ME based on successful biomedical research? • How would NICE react? To some extent our hypothetical situation has come about. The XMRV research was published – but what has been the reaction? An establishment mired in vested interests has been quick to malign the WPI/NCI/CC studies issuing results from rushed trials which have failed to replicate the painstaking research carried out in the USA. NICE have been quiet. Their much maligned guidelines for ME which allows a model of ME to be retained as a behavioural or mental disorder, recommending common-sense (pacing), noncurative and ineffective (cognitive behavioural therapy) and injurious (graded exercise) therapies. With the head of NICE even having failed to read a 400+ page analysis and criticism of the hugely expensive MRC-funded PACE trials by Professor Malcolm Hooper and Margaret Williams before rejecting it, the credibility of NICE is surely at its nadir. Perhaps predictably the Department of Health (DoH) has not acted. A department and a Chief Medical Officer which found it easy to Invest in ME (Charity Nr. 1114035) recommend large purchases of antivirals for pandemic of H1N1 which failed to materialize and which closed schools when a single pupil was found to have contracted this influenza variant, has been inconsistent and tardy in its reaction to the pending threat posed by XMRV and thousands of patients with an infectious disease being let loose on the blood banks of UK. The MRC have done nothing except to continue their failed policies of accommodating vested interests promoting psychosocial therapies to treat a disease for which every IiME conference has provided clear proof of the organic origin. As the Journal goes to press we are still awaiting decisions from the National Blood Supply agency on what is to happen. Meanwhile a potentially grave situation is allowed to continue with no action – with the risk to hundreds of thousands of people. Yet in the absence of progress from the government, Medical Research Council and from within the NHS it is the patients who are now being empowered. Invest in ME has recently used its Biomedical Research Fund (BRF), announced in January 2009, to part fund WPI research in UK studies of XMRV. The WPI have extended the original scale of the UK study agreed with IiME, thanks to the determination of their staff who have devoted their free time and the compassion of their president and research director. The response from UK patients has been overwhelming, with patients who have had no access to medical care and no involvement in research suddenly allowed to bypass the status quo enforced on their situation by a failed system and direct their own involvement in medical trials. This empowerment of the patient is an interesting corollary to the biomedical research taking place - demonstrating the fact that the UK healthcare provision as well as the policies of the MRC have failed the ME community. Perhaps this is the model for the future. IiME wishes to play its part in facilitating advances in biomedical research into ME and will be continuing to attempt to fund this research. To echo the oft-quoted MRC/CMO spin IiME are Page 5/56

Journal of IiME Volume 4 Issue 1 www.investinme.org interested in high-quality proposals for research – something for which there is an abundance of potential. The only strategy which makes any sense from a scientific or moral viewpoint is to fund biomedical research into ME and treat ME in the same way as cancer, Parkinson's, MS or any other mainstream illness. Proper diagnostic criteria, the Canadian consensus criteria, needs to be adopted to differentiate idiopathic chronic fatigue, burn out, overtraining syndrome, fibromyalgia, multiple chemical sensitivities etc. from ME and find the correct treatment for each of these groups. The treatments, which do exist for some sub groups, need to be made aware of and made available. An objective scientific approach to ME and sub grouping is required to facilitate this process. We hope the conference will demonstrate this fact - again. In the UK there is now a new government, a new Chief Medical Officer pending, and a new CEO at the Medical Research Council about to be selected – a unique opportunity to displace the non-science of the last decades with a strategy based on proper science, unaffected by bogus input from those vested interests promoting a psychosocial view of ME. For researchers and medical students there can be no more rewarding area in which to specialize than myalgic encephalomyelitis. For ME patients in the UK and their families there are grounds to hope we are on the crest of change and they can perhaps begin to see the light at the end of one of the darkest and most scandalous tunnels of medical ignorance. As with Multiple Sclerosis, which was denied as a real disease before a diagnostic method was developed, ME is likewise on the brink of that same breakthrough. Once it does arrive then patients can begin to see a future of funding for biomedical research and more effective treatments. A New Era in ME/CFS Research. And those who have for a generation denied this illness with misinformation and malpractice may Invest in ME (Charity Nr. 1114035) well then be brought to account. ---------------------------------------------------Invest in ME publish the Journal of IiME for free, and as often as our funds permit. For the conference version of the Journal (provided to conference delegates and available from IiME for a small fee) we have the following. Professor Hooper describes the IiME conferences and introduces the speakers. Appropriately, for a Journal produced for a conference which carries the theme of education of healthcare professionals, this version contains an illuminating study of ME in the medical literature by Professor Leonard Jason, showing coverage of ME (CFS) was severely lacking in medical textbooks. Dr Ian Gibson is no stranger to ME and the effects on citizens. He set up an inquiry into ME in 2006 which made several recommendations (increased ring-fenced money for bio-medical research, for ME to be given due recognition, alongside heart disease and cancer, an inquiry into the vested interests of insurance companies whose advisors also act as advisors to the DWP) – none of them taken up by the government. When the UK Secretary of State for Health and the UK government’s Chief Medical officer seem to define recovery from ME as “feeling better” we have an article form an expert who has studied ME for several decades. Dr David Bell supplied a definition of recovery from ME (CFS) – something which the government officials would be well advised to read. ME needs pharmaceutical companies to take a moral position on treatment of this neurological illness and begin funding biomedical research. We therefore invited Hemispherx Biopharma Inc. a Philadelphia based company, to contribute an article on their experiences developing drug treatments for ME. HB is developing Ampligen - potential treatment of globally important viral diseases and disorders of the immune system including HPV, HIV, Chronic Fatigue Syndrome (CFS), Hepatitis and influenza. It can only be a matter of time before such forward-thinking companies will provide the treatments for people with ME. The European ME Alliance (EMEA), comprising Page 6/56 Journal of IiME Volume 4 Issue 1 www.investinme.org patient support groups, meets also in London and now spans across nine countries in Europe. EMEA provides a voice for European patients and is beginning to make its voice heard – and will continue to do so in cooperation with international organisations. Some of the member groups have provided news of what is happening in their countries. EMEA members are announcing new conferences for the later in the year, including a European Tour by Dr David Bell. The abstracts of the conference speakers’ presentations are also included in the Journal. The Invest in ME conference in London in May is our fifth biomedical research conference and now welcomes delegates from eighteen countries. We would like to thank two organizations who have donated funds to enable Invest in ME to carry out this conference. ME STORY When I finally did get a diagnosis it was only through travelling to a GP who had 40 years of clinical experience of M.E. I couldn't get a diagnosis locally. I'm sure the lack of an accurate diagnosis is no news to most people listening. I would, however, like to emphasise that, even after 8 years, when you finally receive a diagnosis it's not much use to you. It is a great relief to have an explanation; and confirmation of what you've been dealing with. However, if every health professional you subsequently meet – be that for acute care in an A & E unit or resources from a wheelchair assessment advisor – if every health professional you meet then doesn't believe in M.E. it's of very little practical value when you seek services. Worse than that, it can actually be detrimental to the service user–service provider relationship to mention that you have this condition. Once the M.E. diagnosis comes up, all the negative responses ensue. The Alison Hunter Memorial Foundation (AHMF) of Australia, set up by the mother of Alison Hunter, has again provided support. - a person with ME ME FACTS UK donor selection guidelines state that people Likewise the Irish ME Trust (IMET) has provided support for the fourth year running. These two organizations have track records of supporting biomedical research into ME and share a common ethos to that of IiME. We are profoundly grateful to these organizations for helping us in this way. To those who attend the conference we hope you enjoy your day and learn a great deal. For those not able to come to the conference then we hope the Journal and the resultant DVD of the conference will provide something of use. Enjoy the Journal, enjoy the conference. Best Wishes Invest in ME Invest in ME (Charity Nr. 1114035) who have previously been diagnosed with CFS/ME are able to donate blood once they have recovered and are feeling well. There is no set timescale for this, and no additional diagnostic tests are carried out before they can donate blood. -UK government Chief Medical Officer May 2010 Canadian Blood Services has accepted blood donations from donors who report a history of CFS but are now well. Donors who are not well may not donate blood. However, …., we are changing the way we manage donors such that any donor who has a medical history of CFS will be indefinitely deferred from donating blood. Once we understand more about this issue, we will revisit this decision to determine whether the indefinite deferral is still warranted - Canadian Blood Services April 2010 Page 7/56

Journal of IiME Volume 4 Issue 1 www.investinme.org The 5th Invest in ME International ME/CFS 2010Conference 5th Invest in ME Conference “On the Front Foot – Back to the Future” Emeritus Professor of Medicinal Chemistry the University of Sunderland Professor Malcolm Hooper was appointed Chief Scientific Advisor to the Gulf Veterans Association (GVA) and accepted by the Ministry of Defence (MoD) as their nominee on the Independent Panel established to consider the possible interactions between Vaccines and NAPS tablets. His involvement with the GVA brought contact with Myalgic Encephalomyelitis and related disorders. Gulf War Illness/Syndrome (GWI/S) has much in common with ME/CFS. By Professor Malcolm Hooper The ME community owes a great debt to Invest in ME for arranging a succession of International conferences that present the biomedical evidence for this debilitating complex, chronic multi-system illness which has devastating effects on the sufferer and imposes enormous strains on families and carers. For several years a galaxy of international speakers has comprehensively presented overwhelming evidence of the nature of ME its classification, aetiology, diagnosis, pathology and possible treatments. In the UK and other counties, Governments, the National Health Service, Medical Research Council, Department of Works and Pensions, and the Insurance industry have refused to engage with this evidence, refusing all invitations to attend, learn from, and contribute to these conferences. Instead they have espoused, despite all the evidence, an ideological position that seeks to establish ME/CFS as a mental and behavioural disorder in defiance of the international classification, WHO, ICD-10 G93.3, as a neurological disorder. This attitude compounded by widespread vested interests, particularly in the medical insurance industry, has resulted in limiting support and benefits for very sick people and their carers, repeated misdiagnoses of patients, and ultimately the abandonment and inhumane treatment of Invest in ME (Charity Nr. 1114035) Professor Hooper’s latest article describes the role of “Magical Medicine” in UK MRC strategy. See http://www.investinme.org/Article400%20Magica l%20Medicine.htm Professor Hooper is also assisting Invest in ME in current projects. patients who are very ill and suffer from a complex chronic illness that is dismissed without proper investigation and without regard to the very extensive published peer-reviewed literature. No research funding from official bodies has been made available leaving the ME community and individuals to find funding for vital studies. I believe that this conference marks the beginning of a significant reversal of these positions. We are in, cricketing parlance, “on the front foot” attacking the bowling. Today, our first speaker, Professor Leonard Jason, engages with the issues round case definition which bedevils ME. Confusion, prevarication, and downright deception have through a succession of advisors to Government and other bodies succeeded in stigmatising patients. The use of heterogeneous patient cohorts has led to flawed epidemiology and spurious conclusions. There is a desperate need for clarity in this area so that valid studies can be carried out. It is important that patient sub-groups are recognised for the purpose of research, treatment and care. Persistent viruses have been known for decades to play an important role in ME, particularly those of the coxsacchie family. Page 8/56 Journal of IiME Volume 4 Issue 1 www.investinme.org The 5th Invest in ME International ME/CFS Conference 2010 (continued) A “back to the future” return builds on earlier clinical observations and takes us back to the question of persistent virus infections and nature of such infections associated with increasing disability in the sufferer. Professor Nora Chapman addresses the complexities of such infections at the cellular level revealing the ways I which these viruses are able to avoid destruction by the immune system and initiate disabling illness. Dr John Chia, a previous conference speaker, examines the specific role of enteroviruses in ME and links this to both diagnosis and treatment for patients. Coxsacchie viruses have long been known to be both neurotropic and cardiotropic – they are multi-system pathogens- and many people with ME have compromised heart function. Dr Cheney has made a special study of the cellular energy defects in cardiac function that will help our understanding of ME and ways it can be diagnosed and treated Dr Jonathan Kerr’s studies in gene expression in ME are groundbreaking and have deepened our understanding of the illness and provided a sound clinical basis for diagnosis, sub-groups and possible new treatments. One very important aspect of his work has been the inclusion of the severely affected patients who are usually not included in any research studies. ME are the initials for myalgic encephalomyelitis = muscle pain with inflammation of the brain and spinal cord. The inflammatory nature of ME had long been recognised and has been the subject of much research. Dr Nancy Klimas is world famous for her work in inflammation that offers the possibility of finding biomarkers that will confirm the biomedical basis of ME and provide other physicians with an essential tool for diagnosis and possible treatment of ME. Professor Brigitte Huber has found associations between mononucleosis (Epstein Barr virus, EBV)-related ME and a human endogenous retrovirus, HERV, that offers the possibility of new biomarkers for this illness and introduces us to the world of retroviruses. Annette Whittemore shares much in common with many people at the conference in that she is the mother of a child (now a young woman) who Invest in ME (Charity Nr. 1114035) has suffered with ME for many years. Like many here today she has devoted her life and family resources to fighting this illness and finding better ways of understanding and treating ME. Due to her initiative and generosity the Whittemore–Peterson Institute, WPI, was established to provide the first centre for integrated medical care for people with ME, bringing together patients, clinicians and research staff to combat this illness. The groundbreaking and astonishing discovery of XMRV (Xenotropic Murine-like Retrovirus) emerged as a major collaborative research work from the WPI and is a first in this field. The XMRV ‘bombshell’ took the ME world by storm and offers a possible integrated understanding of earlier diverse and extensive research studies on ME. This is advanced science of very high quality. Dr Judy Mikovits was a key member of the team that first reported the association between XMRV and ME. This sensational discovery, coming out of ‘left field‘, caused astonishment, delight to many but regrettably also acrimony, accusation and spiteful comments. Several attempts to replicate this study were unsuccessful but on close examination all the attempts at replication were found to be seriously flawed since the same methodology was not followed. So we are particularly privileged to have Judy to bring us up to date in the implications of the discovery of XMRV for the world of ME. We have the world expert on this topic making our final presentation. Today’s conference is aflame with hope and new possibilities. No longer can the old, tired, defensive psychiatric view of ME be sustained or remain credible, groundbreaking advanced science and medicine has vindicated the humane caring compassion of those involved with suffering ME patients and given them new hope for effective treatment of this complex, chronic, disabling illness. Just as the recent election in the UK has ushered in a new era of political change so, I believe, this conference has changed the medical and scientific landscape for ME – cause for celebration and renewed commitment to our common goals. This conference will re-energise all seeking truth and a proper justice for ME. Be energised! Malcolm Hooper May 2010 Page 9/56

Journal of IiME Volume 4 Issue 1 www.investinme.org The PACE TRIALS – MAGICAL MEDICINE The Medical Research Council (MRC)’s PACE Trial of behavioural interventions for Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) attracted considerable opposition from the outset and the Principal Investigators had difficulty in recruiting a sufficient number of participants. PACE is the acronym for Pacing, Activity, and Cognitive behavioural therapy, a randomised Evaluation, interventions that, according to one of the Principal Investigators, are without theoretical foundation. The MRC’s PACE Trial seemingly inhabits a unique and unenviable position in the history of medicine. It is believed to be the first and only clinical trial that patients and the charities that support them have tried to stop before a single patient could be recruited and is the only clinical trial that the Department for Work and Pensions (DWP) has ever funded. the unusual personal financial interest of the Chief Investigator; the vested interests of the Principal Investigators; high rates of Severe Adverse Events (SAEs) and in particular, the underlying non‐clinical purpose of the trial, which seems to have the politically generated aim of removing patients from benefits (i.e. the use of motivational behaviour therapy to achieve the intended result of the cessation of benefits for patients with “CFS/ME”). The Manuals used in the Trial seem to show that the authors either ignore medical science or they do not understand medical science. Since 1993, the giant US permanent health insurance company UNUM Provident has been advising the UK DWP about the most effective ways of curtailing sickness benefit payments. The PACE Trial is run by psychiatrists of the Wessely School, most of whom work for the medical and permanent health insurance industry, including UNUM Provident. These psychiatrists insist – in defiance of both the World Health Organisation and the significant biomedical evidence about the nature of it ‐‐ that “CFS/ME” is a behavioural disorder, into which they have subsumed ME, a classified neurological disorder whose separate existence they deny. Their beliefs have been repudiated in writing by the World Health Organisation. In 1992, the Wessely School gave directions that in ME/CFS, the first duty of the doctor is to avoid legitimisation of symptoms; in 1994, ME was described as merely “a belief”; in 1996 recommendations were made that no investigations should be performed to confirm the diagnosis and in 1999 patients wit ME/CFS were referred to as “the undeserving sick”. There are legitimate concerns about the MRC PACE Trial that are centred on apparent coercion, exploitation of patients, contempt in which patients are held, manipulation, pretension, misrepresentation, flawed studies yielding meaningless results and lack of scientific rigour; Invest in ME (Charity Nr. 1114035) There is rightful objection to the denial of appropriate investigations and to the nationwide implementation of behavioural modification as the sole management strategy for the nosological disorder ME/CFS. That strategy is believed to be based on (i) the commercial interests of the medical and permanent health insurance industry for which many members of the Wessely School work and (ii) the dissemination of misinformation about ME/CFS by the Wessely School, whose members also act as advisors to UK Government agencies including the DWP, which it is understood has specifically targeted “CFS/ME” as a disorder for which certain State benefits should not be available. The Wessely School rejects the significant body of biomedical evidence demonstrating that chronic “fatigue” or “tiredness” is not the same as the physiological exhaustion seen in ME/CFS and persists in believing that they have the right to demand a level of “evidence‐based” definitive proof that ME/CFS is not an “aberrant belief” as they assert, when their biopsychosocial model of “CFS/ME” that perpetuates their own aberrant belief about the nature of ME/CFS has been exposed by other psychiatrists as being nothing but a myth. There are some extremely disquieting issues surrounding the MRC PACE Trial and documents obtained under the Freedom of Information Act allow the full story to be told for the first time. from “Magical Medicine: How to Make a Disease Disappear” by Professor Hooper. See http://tinyurl.com/2uv8j95 Page 10/56 Journal of IiME Volume 4 Issue 1 www.investinme.org The 5th Invest in ME International ME/CFS Conference 2010 Research, Research, Research By Dr. Ian Gibson Dr. Ian Gibson Dr. Ian Gibson was MP for Norwich North thirteen years. He acquired a passion for all things scientific- especially biology – and pursued his passion for science by studying at Edinburgh University where he gained a BSC and later on a PhD in genetics. He served as the Dean of the School of Biological Sciences at UEA from 1991 to 1997 and headed a research team investigating various forms of cancer, including leukaemia, breast and prostate cancer. In 2003, the university made Dr. Gibson an Honorary Professor. I spoke to a friend who works as a GP in a major Norwich surgery the other day. We talked about matters medical and political. I raised with him the subject of ME. Whilst being sceptical of many of the claims by different groups he did acknowledge that more needed to be done in resolving causes, treatments and definitions. He was keen on a more comprehensive study for symptoms which of course could be related to causes. His suspicion, as with many others, is that ME is really a series of illnesses some of which may have similar causes or symptoms. He supported research in that area to allow for the focussing of treatments. A local medic responsible for providing the local treatment service has been working tirelessly to find an appropriate physician to run a service. What they both acknowledge is that the subject raises deep hostility, anger, suspicion and frankly libellous claims on the issue of people’s sincerity to tackle the problems. Following two inquiries in the last parliament it is time to move on and develop a research network. A statement from the last inquiry on NHS service provision for ME/CFS said – “To date research in the field of ME/CFS has produced little substantive progress but there are a number of encouraging findings e.g. the XMRV research which need to be pursued. As noted in the Gibson report there has been far too Invest in ME (Charity Nr. 1114035) Dr. Gibson’s work in Parliament and in Norwich has primarily consisted of advocacy work and pushing the government to take more notice of the role that science plays (and can play) in the UK. His scientific background has meant that he has been involved in numbers of groups and charities in Parliament. He was a member of the Select Committee on Innovation Universities Science and Skills and was a member of the science and technology select committee from his election in 1997 and served as its chairman between 2001-5. He was chair of the All Party Parliamentary Group on Cancer. Whilst he was the dean of biology at the University of East Anglia he was the head of a research team investigating cancer, and has been awarded a 'Champion' award by Macmillan Cancer Relief for his work in support of people with cancer. He was a major campaigner against top-up fees for universities. He headed the Inquiry into ME in 2006 – an independent inquiry which made recommendations regarding ME – such as funding for biomedical research. See http://tinyurl.com/2eqw55 Page 11/56

Journal of IiME Volume 4 Issue 1 www.investinme.org Research, Research, Research much emphasis in the past on psychological research and insufficient attention to biomedical research. The Group welcomed the recent Medical Research Council initiative to attract new researchers and new technologies in this area. However the Group is sure that it is vital that further biomedical research is undertaken to help discover a cause and more effective forms of management for this disease” A recent Guardian article on ‘Health &Food’ edited by Sarah Boseley contained a map of England showing the geographical areas and variations in the frequency of illnesses. The major illnesses were heart, cancer etc. but other illnesses featured in the description of health problems. There was no mention of ME/CFS or some other new illnesses anywhere in the article. Presumably this is because of the paucity of data which raises the question of how we obtain that information. If we are to progress on understanding of these new illnesses which involve thousands of patients and individuals of all ages then we will need the support of not just the official government bodies but also that from support groups. In our understanding of ME/CFS it is important, I believe, to set up a research unit where we can investigate the statistics of the illness and the role of biomedical agents/factors. Our conference today, I believe, will throw light on the research areas we need to take up. To further this pursuit we should debate the setting up of a research laboratory, its financing etc. It needs advice from colleagues in other countries like Norway, the USA etc. and we welcome representatives here today. Invest in ME has entered discussions to investigate a laboratory in Norwich in association with the University Hospital. We will need a management structure to run the laboratory and to organise its activities. This is not to replace the activities of organisations who are seeking to improve treatments and services but to complement them. Like many other charities, trusts etc. in the cancer field they develop their own programmes. Research, however, as we have found out with other illnesses can re-instate you in your priorities. Invest in ME (Charity Nr. 1114035) Prevention strategies and treatments can develop in novel innovative ways. Research has a habit of throwing up major surprises. Drugs and treatments for other illnesses can become useful in your particular research. Prions were discovered in B.S.E. and mobile genes first emerged from work on maize. We need to attract researchers who understand the field and its challenges as well as the technologies. Lastly but as a major feature we need to ensure patients, carers and others are involved from the beginning. If clinical trials are to be developed then patients, nurses and others must be part of the process of setting up and interpreting the trials. I believe the will is there to set up such a research and this conference can be the talisman for the exciting new initiative. Further details from Dr. Ian Gibson Dr Gibson is working with Invest in ME on a project to provide services for people with ME. ME & MEDIA “…for many years doctors argued that Chronic Fatigue Syndrome (ME) didn’t exist. They refused even to dignify it with the name Myalgic Encephalomyelitis. ME, they said, was just ‘me’ writ large… Scientists could (now) be on the brink of a breakthrough. We must hope they are. That would – at least – go some way to compensating for the shameful manner in which sufferers were treated for so long by the medical profession”. - The Independent October 2009 Page 12/56 Journal of IiME Volume 4 Issue 1 www.investinme.org An Effort to Influence Medical Textbook Writers Leonard A. Jason, Nicole Porter, Nicolette Walano, Ilana Barach, Morgan Morello, Erin Paavola - DePaul University Abstract A recent study found that coverage of CFS was severely lacking in medical textbooks with a representation rate of less than .01% (Jason, Paavola, Porter, & Morello, 2010). The current study consisted of sending letters to editors that contained the findings from Jason et al.’s original study pertaining to the lack of quality information in medical texts on CFS. Twelve editors replied to our letter, and five (42%) had positive remarks, stating that the information was helpful and would be included in new editions of texts. We determined whether editor responses to the information sent differed as a function of theoretical orientation of their section on CFS. Those who could not be classified because they had too little information or no CFS information responded the most. This study suggested that it is possible to take proactive stances in attempting to inform editors about the issues related to the quantity and quality of information concerning chronic fatigue syndrome in medical textbooks. An Effort to Influence Medical Textbook Writers Chronic fatigue syndrome (CFS) is a complex illness (Fukuda et al., 1994; Jason & Richman, 2007), which can have devastating consequences in functional, employment and relationship areas (Jason, Fennell et al., 2003). Patients suffering from CFS are more functionally impaired than those suffering from type II diabetes mellitus, congestive heart failure, Multiple Sclerosis (MS), and endstage renal disease (Anderson & Ferrans, 1997; Buchwald, Pearlman, Umali, Schmaling, & Katon, 1996). Although all patients do not demonstrate the same medical abnormalities, some evidence points to immune dysfunction (Patarca-Montero, 2002; Lorusso et al., 2008), HPA malfunction (Scott & Dinan, 1999), and reduction in gray matter in the brain (De Lange et al., 2004). In addition, physician minimization of physical symptoms frequently occurs (Green, Romei et al., Invest in ME (Charity Nr. 1114035) Professor Leonard Jason PhD Professor of Clin. & Community Psychology, Director, Center for Community Research, DePaul University, Chicago Dr. Leonard Jason, Ph.D., is among the most prolific of all CFIDS researchers. For more than a decade, Dr. Jason and his team at DePaul University’s Centre for Community Research have worked to define the scope and impact of CFS/ME worldwide. Professor Jason presented at the IiME International ME/CFS Conference 2008 in London. Author Notes Address correspondence to Leonard A. Jason, Ph.D., Professor, DePaul University, Center for Community Research, 990 W. Fullerton Ave., Chicago, Il. Ljason@depaul.edu 1999). Patients with CFS tend to report a very low level of satisfaction with conventional medical healthcare. Twemlow, Bradshaw et al. (1997) found that 66% of patients with CFS reported that treatment with their physicians made their illness worse. According to Anderson and Ferrans (1997), 77% reported negative interactions with their healthcare provider. Dissatisfaction of CFS Page 13/56

Journal of IiME Volume 4 Issue 1 www.investinme.org An Effort to Influence Medical Textbook Writers (continued) patients with physician interactions may be caused by negative attitudes towards CFS patients. These attitudes may be due to lack of education about the illness. Bowen, Pheby and Mcnulty (2005) found that 48% of physicians do not feel confident in making a diagnosis of CFS and 41% do not feel confident in treating CFS patients once they have been diagnosed. Chew-Graham (2008) found that family physicians reported that continuing education and training left them unable to adequately diagnose and treat CFS. Jason et al. (2010) recently examined 119 medical textbooks for CFS material. Of 129,527 total pages only 116.3 pages, less than .1%, mentioned CFS. Multiple Sclerosis was represented on .12% and Lyme disease was on .15%; yet, CFS has a prevalence rate of .42% (Jason et al., 1999), four times the prevalence rate of Multiple Sclerosis and ten times that of Lyme disease. Further, only 21% of the texts reviewed included the criteria for diagnosis of CFS and only 28.6% included treatment options, two vital topics of knowledge for physicians working with CFS patients. These findings suggest not only that the topic of CFS is under reported in published medical textbooks, but also that there are large discrepancies in the information provided. These types of inequities of the material covered in medical textbooks have rarely been the focus of interventions. One exception is the work of Rabow, Hardie et al. (2000), who conducted a content analysis on end-of-life care in multiple medical specialties, and then held a conference with major textbook publishers where they discussed their results; this effort was successful in initiating some change (Rabow, McPhee et al., 1999). In the present study, we attempted to change the amount of CFS coverage in medical textbooks. The authors contacted the editors of the textbook sample from the study by Jason et al. (2010) and encouraged them to increase the representation of CFS. In addition, we classified the chapters that mentioned CFS as psychological, biological, or biopsychosocial and determined if theoretical orientation influenced the editors’ receptiveness to our efforts to influence them. Methods Contacting Editors We used the sample of textbook chapters collected in Jason et al.’s (2010) previous content analysis. We used the Internet to locate the lead editor of each textbook and found their current email address. If the lead editor’s email address was not Invest in ME (Charity Nr. 1114035) available then a secondary editor’s email address was used instead. We then emailed one editor per textbook explaining the importance of improving the material on CFS in textbooks. The letter sent is located in Appendix A. We succeeded in emailing 78 editors. Of those 78 who were emailed, four had written multiple textbooks. The e-mails only addressed one book to eliminate confusion, and each editor was sent only one email. Three of those four editors had edited two texts; the fourth had been lead editor on four texts. Though there was a total of 119 texts there were only 113 editors. Classifying CFS Section The sections on CFS in our sample of textbooks were categorized into four groups: biological, psychological, biopsychosocial, and an exclusion group. The criterion for a biological classification was that the section discussed CFS as a biological illness (e.g., biological tests to rule out other illnesses before diagnosis of CFS, pathophysiology, biological etiology, and biological treatments). The criterion for a psychological classification was that the section focused on the psychological factors of CFS (e.g., the text discussed individuals with personality types thought more prone to suffer from CFS, or the psychological effects of the illness. For biopsychosocial classification, the section needed to combine both biological and psychosocial factors contributing to CFS. The exclusion category indicated that there was inadequate information to make a classification into one of the three categories above (often there was no CFS information in these texts). Two research assistants individually read and classified each section. The two research assistants then discussed every section where they did not agree and carefully came to an agreed-upon consensus. Classifying Replies The replies from editors were categorized by two research assistants and were deemed positive, negative or neutral. Positive responses were categorized as such because the editors had stated in their responses that they would either edit their current sections on CFS to include the information provided to them, or that a new section was going to be added to the next edition containing this information. Neutral was used to classify those editors who had given a positive response; however, they chose for one reason or another not to include CFS in any future editions of their text. Negative responses indicated that the editors had not only chosen not to make a change in their inclusion of CFS but that they still viewed the Page 14/56 Journal of IiME Volume 4 Issue 1 www.investinme.org An Effort to Influence Medical Textbook Writers (continued) illness as highly controversial. Results Descriptive Statistics Of the textbooks, 18.5% were classified as biopsychosocial, 6.7% were biological, and 7.6% were psychological, leaving the remaining 67.2% to fall into the exclusionary category. Editor Replies Only 12 editors replied of the 78 contacted, giving a total response rate of 15%. Of the twelve editors who replied to our letter, three were associated with biopsychosocial, two with psychological, one with a biological section, and six with the exclusion category. Five of the responding editors (42%) had positive remarks, stating that the information was helpful and would be included in new editions of texts. Of these five responses one was associated with a biopsychosocially oriented chapter and the remaining four were part of the exclusion category that did not contain enough material on CFS to categorize. Six editors (50%) were placed in the neutral category, stating that they appreciated the information but could not use it in their texts usually due to the nature of the text (e.g. neuroscience or physically manifested diseases.) Of these editors one had written a biopsychosocial chapter, one a biological chapter, two wrote psychological chapters and two did not contain enough material on CFS to categorize. Only one reply (8%) of the total responses was categorized as negative. The editor stated that CFS would not be included due to its controversial nature and unknown etiology. The negatively responding editor had previously omitted CFS from the text. Discussion While the majority of the responses from the editors were positive, it is of importance to note that only 12 editors replied of the 78 contacted, giving a total response rate of 15%. Of the twelve total editors who replied to the letter, three were associated with biopsychosocial chapters, two with psychological chapters, and one with a biological chapter. The remaining six editors who replied were associated with an exclusion chapter. Five of the responding editors (42%) had positive Invest in ME (Charity Nr. 1114035) remarks. The editor of Neuroscience wrote the following: “Thanks for this good suggestion and information. We will definitely include a section on CFS in the next edition of Neuroscience.” The editor of Harrison’s Textbook of Internal Medicine wrote: “As Harrison's Textbook of Internal Medicine is used by many, if not the majority of, medical schools throughout the U.S. during the students' internal medicine rotation, it would be very important to make sure that we get this textbook's CFS chapter right for its next edition…Harrison's will have a new author for the CFS chapter. I'll share your position paper with the new author as the chapter is prepared.” Further, the editor of Pathophysiology: the Biological Basis for Disease in Adults and Children wrote: “[We] decided to wait until more data was available. We are going to include CFS in the alterations of musculoskeletal chapter… We agree with you that CFS is a very important disease/disorder and thank you for including all of your information.” The editor of General and Systemic Pathology wrote: “Your comments will be helpful when we come to decide what to include in subsequent editions.” Another was concerned about textbook sales, and this editor of Essential Family Medicine: Fundamentals and Cases wrote: “If there is another edition of the textbook (sales of all books are down significantly), I will certainly include a case illustrating CFS. I agree that it needs to be addressed.” Six editors (50%) were positive but did not indicate they would use our material or other CFS sources in a revised text. The editor of Pathophysiology: Concepts of Altered Health States wrote: “I agree that the topic warrants coverage in texts used in the education of physicians. Hopefully, we will soon gain a better understanding of its pathogenesis and insights into more effective treatment methods.” The editor of The Handbook of Stress Medicine Page 15/56

Journal of IiME Volume 4 Issue 1 www.investinme.org An Effort to Influence Medical Textbook Writers (continued) wrote: “I have done research on this topic myself and understand its' importance. Good luck in sending out the message.” An editor of The Atlas of Pediatrics wrote: “The text is not intended to be encyclopaedic like standard textbooks of paediatrics. Hence, many disorders are purposely not included. I appreciate the need for education about CFS”. Further the editor of Clinical Neuroanatomy and Neuroscience wrote: “Mine is not a textbook of clinical neurology. It is addressed to students who are 'just in off the street' and is designed to convince them that a sound understanding of the fundamentals of basic neuroscience will pay off big time later on in the interpretation of clinical disorders.” Only one reply (8%) of the total responses could be categorized as negative. “While I appreciate your position and I am sympathetic to CFS sufferers it is still a highly controversial topic regarding etiology and not one for which there is sufficient evidence as to cause to include it in a clinical virology text meant for professionals.” While the entire sample size of textbooks (N=119) was large, the sample of editors that responded was relatively small. Hopefully, in the future we can follow-up to see if there are actual changes made in the textbooks. There certainly is a need for more efforts to influence medical textbook writers so that they adequately provide more information about CFS to students in the healthcare field. References Anderson, J.S., & Ferrans, C.E. (1997). The quality of life of persons with chronic fatigue syndrome. Journal of Nervous and Mental Disease, 185, 35967. Bowen, J., Pheby, D., Charlett, A., & McNulty, C. (2005). Chronic fatigue syndrome: a survey of GPs’ attitudes and knowledge. Family Practice, 22, 389-93. Buchwald, D., Pearlman, T., Umali, J., Schmaling, K., & Katon, W. (1996). Functional status in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals. The Invest in ME (Charity Nr. 1114035) American Journal of Medicine, 101(4), 364-370. Chew-Graham, C. A., Cahill, G., Dowrick, C., Wearden, A., & Peters, S. (2008). Using multiple sources of knowledge to reach clinical understanding of chronic fatigue syndrome. Annals of Family Medicine, 6(4), 340-348. de Lange, F. P., Kalkman, J. S., Bleijenberg, G., Hagoort, P., van der Werf, S. P., van der Meer, J. W., et al. (2004). Neural correlates of the chronic fatigue syndrome--an fMRI study. Brain : a Journal of Neurology, 127(Pt), 1948-1957. Fukuda, K., Straus, S. E., Hickie, I., & Sharpe, M. C., (1994). The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Annals of Internal Medicine, 121(12), 953-9. Green, J., Romei, J., & Natelson, B. H. (1999). Stigma and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 5(2), 63-76. Jason, L., Fennell, P., & Taylor, R. R., (2003). Handbook of chronic fatigue syndrome. Hoboken, N.J., Wiley. Jason, L., & Richman, J., (2007). How science can stigmatize: the case of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 14(4), 85103. Jason, L. A., Paavola, E., Porter, N., & Morello, M., (2010). Frequency and content analysis of CFS in medical textbooks. Australian Journal of Primary Health Retrieved from http://www.publish.csiro.au/view/journals/dsp_j ournals_pip_abstract.cfm?nid=262&ver=3&pip=PY 09023 Jason, L. A., Jordan, K. M., Richman, J. A., Rademaker, A. W., Huang, C.-F., McCready, W., et al. (1999). A community-based study of prolonged fatigue and chronic fatigue. Journal of Health Psychology, 4(1), 9-26. Lorusso, L., Mikhaylova, S. V., Capelli, E., Ferrari, D., Ngonga, G. K., & Ricevuti, G. (2008). Immunological aspects of chronic fatigue syndrome. Autoimmune Review, 8(4), 287-91. Patarca-Montero, R. (2002). Chronic fatigue syndrome and the body's immune defense system. Page 16/56 Journal of IiME Volume 4 Issue 1 www.investinme.org An Effort to Influence Medical Textbook Writers (continued) New York, Haworth Medical Press. Rabow, M. W., Hardie, G. E., Fair, J. M., & McPhee, S. J. (2000). End-of-life care content in 50 textbooks from multiple specialties. Journal of the American Medical Association, 283(6), 771. Rabow, M. W., McPhee, S. J., Fair, J. M., & Hardie, G. E. (1999). A failing grade for end-of-life content in textbooks: what is to be done? Journal of Palliative Medicine, 2(2), 153-5. Scott, L. V. and T. G. Dinan (1999). The neuroendocrinology of chronic fatigue syndrome: focus on the hypothalamic-pituitary-adrenal axis. Functional Neurology, 14(1), 3-11. Twemlow, S. W., Bradshaw Jr, S. L., Coyne, L., & Lerma, B. H. (1997). Patterns of utilization of medical care and perceptions of the relationship between doctor and patient with chronic illness including chronic fatigue syndrome. Psychological Reports, 80(2), 643-58. Appendix A I would like to thank you for the important service you have provided to the medical community through compiling and editing the textbook "(Name of text was placed here)". Medical textbooks are crucial to the education of medical students and also serve as reference tools for experienced physicians. I would like to inform you of an issue regarding medical education of chronic fatigue syndrome (CFS). The Center for Community Research at DePaul University has done research on the coverage of CFS provided in medical textbooks, and there is reason for concern. We did a content analysis of 119 medical textbooks from a variety of medical sub-specialties. Out of the 119 textbooks examined, only 48 mentioned CFS. CFS was discussed less than diseases such as Lyme disease and Multiple Sclerosis (MS), which have a lower prevalence than CFS. It is crucial that textbooks contain sufficient information on illnesses, as a professor may use a textbook as a course guide. Additionally, textbooks fill in gaps to inform students of disorders and illnesses which professors may not explicitly describe in the classroom. It is essential that physicians receive sufficient training to identify CFS, as the wrong diagnosis, or lack of a diagnosis can be very damaging to people who suffer from this illness. Research shows that many physicians may lack the Invest in ME (Charity Nr. 1114035) knowledge to properly diagnose and mange CFS. Two studies have found that primary care physicians report feeling a lack of confidence and knowledge in CFS diagnosis and management. 95% of individuals with CFS in one study reported feelings of estrangement. Better education of medical students will help combat this widespread stigma and improve the quality of life and treatment for individuals with CFS. The dearth of information on CFS in textbooks is of course not to blame for this problem, as it is only a reflection of the larger lack of understanding of CFS in society today. However, textbooks that contain in-depth and un-biased coverage on CFS could help to raise awareness about the illness, as textbooks are a key component to medical training. As an attachment to this email, we have provided a model section, providing information on CFS; and it has been endorsed by the International Association of ME/CFS, the scientific organization that organizes conferences and publications on CFS. We hope that you will use this model in considering what to include about CFS in future revisions of your publications. As an author and editor, you can help move the medical community in the right direction and improve the education of today's physicians. Chronic Fatigue Syndrome (Statement endorsed by the International Association of ME/CFS) Chronic fatigue syndrome (CFS) is a multi-systemic illness, which is characterized by debilitating fatigue, as well as other symptoms such as unrefreshing sleep, memory and concentration problems, as well as post-exertional malaise. The total direct and indirect yearly costs in the U.S. due to CFS range from $18.7 to $24 billion dollars.1 Patients with CFS are more functionally impaired than those suffering from type II diabetes mellitus, congestive heart failure, Multiple Sclerosis (MS), and end-stage renal disease.2,3 The term chronic fatigue syndrome was created in 1988 by Holmes et al.4, but this illness had previously been referred to as Myalgic Encephalomyelitis after an outbreak in Britain in 1955. 5 Many patients with this illness feel that the term chronic fatigue syndrome trivializes the seriousness of the illness, and some researchers and patients suggest using a combination of the terms: Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS).6 Most scientists use the Fukuda et al. 7 CFS case Page 17/56

Journal of IiME Volume 4 Issue 1 www.investinme.org An Effort to Influence Medical Textbook Writers (continued) definition, although there is a Canadian clinical case definition that is being increasingly used.8 The Fukuda case definition7 includes the following symptoms: persistent or relapsing fatigue for 6 or more months. The fatigue must be severe, impair ability to function, not be relieved by sleep or rest, and not be the result of physically exhausting activity. Also at least four of the following eight symptoms must persist for at least 6 months: tender/sore lymph nodes, sore throat, muscle pain, joint pain without swelling or redness, impaired memory or concentration, unrefreshing sleep, postextertional malaise, and headaches of new type, pattern, or severity. Onset of CFS symptoms are often abrupt, commonly associated with a flu-like illness. CFS can also have a gradual onset, not associated with a particular event or illness. CFS tends to be a chronic illness, with less than 10% of individuals returning to pre-CFS levels of functioning.9 CFS may be expressed differently in children, so there is a different case definition for pediatric CFS, 10 and prognosis for youth is better than for adults. The prevalence of CFS is approximately .4%,11 and this illness is most prevalent among women, individuals who are of middle age, and among individuals of lower socioeconomic status.11 CFS is also found in adolescents, although at a lower rate of about .2%.12 One challenge in diagnosing CFS is that it shares symptoms with several illnesses, such as Lyme Disease, MS, Major Depressive Disorder (MDD), and Fibromyalgia.13 There are several key ways to differentiate MDD from CFS. In MDD fatigue is not as prominent as in CFS. Additionally, the onset of CFS is often sudden, while the onset of MDD tends to be gradual. Other common indications of CFS are postexertional malaise, sore throat, swollen lymph nodes, and night sweats, and these symptoms are not commonly found in individuals with depression. Cortisol levels tend to be higher in MDD and lower in CFS. While some argue that the high prevalence of MDD in people with CFS is an indication that the disease may be psychogenic, depression commonly occurs in individuals who are chronically ill.14 Fibromyalgia and multiple chemical sensitivities commonly co-occur with CFS and share symptoms. A variety of studies have shown that approximately 35% to 75% of people with ME/CFS also have fibromyalgia.13 In a community sample of individuals with CFS, only 40.6% had pure CFS; 40.6% had multiple chemical sensitivities (MCS), 15.6% had fibromyalgia, and 3.1% had fibromyalgia and MCS in Invest in ME (Charity Nr. 1114035) addition to CFS.13 While these illnesses share some symptoms, they are each characterized by unique symptomology and may be differentiated with careful evaluation. De Lange et al. observed significant reductions in grey matter volume in patients with CFS.15 Other abnormal biological findings among some patients have included aberrant ion transport and ion channel activity, low natural killer cell cytotoxicity, a shift from Th1 to Th2 cytokines, cortisol deficiency, sympathetic nervous system hyperactivity, left ventricular dysfunction in the heart, and EEG spike waves.16-23 Higher brain abnormalities appear to occur among patients with CFS who do not have concurrent psychopathology, versus those who have concurrent psychopathology.24 A variety of theories have been proposed to explain these findings, and they have implicated viruses, immune dysregulation, neuroendocrine problems, as well as neurologic abnormalities. Kindling25 and oxidative stress26 theories have also been offered as ways of explaining the psychopathology of this illness. Important genetic data has also been accumulating on this illness.27 Treatment of this illness often focuses on management of symptoms, whether they are for cognitive problems or unrefreshing sleep. Trials of pharmacologic agents have not yielded success to date. One of the more popular treatments for patients with CFS has been cognitive behavior therapy (CBT). Price, Mitchell, Tidy, and Hunot 28 reviewed 15 studies of CBT with a total of 1,043 CFS participants. At treatment end, 40% of people in the CBT group showed clinical improvement in contrast to only 26% in usual care, but changes were not maintained at a 1-7 month follow-up when including people who had dropped out. Patient surveys have suggested that graded exercise, which is a component of CBT, was felt to be the type of treatment that made more people with CFS worse than any other. A possible reason for negative patient reaction to these graded exercise strategies is suggested in a study by Jammes, Steinberg, Mambrini, Bregeon, and Delliaux,29 which found that incremental exercise among individuals with CFS was associated with oxidative stress and marked alterations of muscle membrane excitability. Other approaches to helping patients with CFS have included pacing30 and Envelope Theory, 31 and these approaches do not unilaterally increase activity for Page 18/56 Journal of IiME Volume 4 Issue 1 www.investinme.org An Effort to Influence Medical Textbook Writers (continued) all patients. For example, the Envelope Theory recommends that patients with CFS pace their activity according to their available energy resources. In this approach, the phrase, “staying within the envelope,” is used to designate a comfortable range of energy expenditure, in which an individual avoids both over-exertion and underexertion, maintaining an optimal level of activity over time. Some people with CFS need to be encouraged to increase their activity, as they have the appropriate amount of perceived energy to do so. However, there are also people with CFS that need to be encouraged to do less in order to decrease the discrepancy between perceived and expended energy. This theory emphasizes the need to understand the differential needs of subtypes of patients with CFS. The key is to not over-expend their energy supplies or consistently go outside their “envelope” of available energy. Rather than a cure, this approach focuses on improving the ability of patients to cope with this illness. References 1. Jason, LA, Benton, M, Johnson, A, & Valentine, L. The economic impact of ME/CFS: individual and societal level costs. Dynamic Medicine. 2008;7(1):6 2. Anderson, JS & Ferrans, CE. The quality of life of persons with chronic fatigue syndrome. Journal of Nervous and Mental Disease.1997;185:359-67. 3. Buchwald, D, Pearlman, T, Umali, J, Schmaling, K & Katon, W. Functional status in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals. American Journal of Medicine. 1996;101;364-70. 4. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Annals of Internal Medicine. 1988;108(3):3879. 5. Hyde BG, JA; Levine, P. The clinical and scientific basis of myalgic encephalomyelitis/chronic fatigue syndrome. Ottowa, Ontario: The Nightingale Research Foundation; 1992. 6. Jason L, Richman J. How science can stigmatize: the case of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome. 2007;14(4):85103. 7. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its Invest in ME (Charity Nr. 1114035) definition and study. International Chronic Fatigue Syndrome Study Group. Annals of Internal Medicine. 1994;121(12):953-9. 8. Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. Journal of Chronic Fatigue Syndrome. 2003;11:7-116. 9. Joyce J, Hotopf, M, Wessely, S. The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. Journal of Chronic Fatigue Syndrome. 1998;4(1):80. 10. Jason L, Porter N. Shelleby E, Bell DS, Lapp CW, Rowe K, De Meirleir K. A case definition for children with myalgic encephalomyelitis/chronic fatigue syndrome. Clinical Medicine: Pediatrics. 2008;1(1):1-5. 11. Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. Archives of Internal Medicine. 1999;159(18):2129-37. 12. Jordan KM, Jason LA, Mears CJ, et al. Prevalence of pediatric chronic fatigue syndrome in a community-based sample. Journal of Chronic Fatigue Syndrome. 2006;13(2/3):75-8. 13. Jason LA, Taylor RR, Kennedy CL. Chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities in a community-based sample of persons with chronic fatigue syndrome-like symptoms. Psychosomatic Medicine. 2000;62(5):655-63. 14. Friedberg F, Jason LA. Understanding chronic fatigue syndrome: an empirical guide to assessment and treatment. Washington, DC: American Psychological Association; 1998. 15. De Lange, FP, Kalkman, JS, Bleijenberg, G, Hagoort, P, van der Meer JWM, & Toni, I. Gray matter volume reduction in the chronic fatigue syndrome. NeuroImage, 2005;26:777-781. 17. Patarca-Montero, R, Mark, T, Fletcher, MA, & Klimas, NG. Immunology of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2000;6:69-107. 18. Peckerman, A, Chemitiganti, R, Zhao, C, Dahl, K, Natelson, BH, Zuckler, L, Ghesani, N, Wang, S, Quigley, K, & Ahmed, SS. Left ventricular function in chronic fatigue syndrome (CFS): data from nuclear ventriculography studies of responses to exercise and portural stress. Federation of American Societies for Experimental Biology. 2003;17(F Suppl: Part 2), A853. 19. Scott LV, Dinan TG. The neuroendocrinology of chronic fatigue syndrome: focus on the Page 19/56

Journal of IiME Volume 4 Issue 1 www.investinme.org An Effort to Influence Medical Textbook Writers (continued) hypothalamic-pituitary-adrenal axis. Functional Neurology. 1999;14(1):3-11. 20. Chaudhuri, A, & Behan, PO. Fatigue in neurological disorders. The Lancet. 2004;363,978-988. 21. Kuratsune, H, & Watanabe, Y. Chronic fatigue syndrome. In: Watanabe Y, Evengard B, Natelson BH, Jason LA, & Kuratsune H, eds. Fatigue Science for Human Health. Tokyo: Springer; 2007:67-88. 22. Komaroff, AL. The biology of chronic fatigue syndrome. American Journal of Medicine, 2000;108:169-171. 23. Evengard, B, Schacterle, RS, & Komaroff, AL. Chronic fatigue syndrome: new insights and old ignorance. Journal of Internal Medicine. 1999;246:455-469. 24. Lange, G, DeLuca, J, Maldjian, JA, Lee, H, Tiersky, LA, & Natelson, BH. MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. Journal of Neurological Sciences. 1999;171:3-7. 25. Pall, M. Explaining "unexplained illnesses": disease paradigm for chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia, posttraumatic stress disorder, gulf war syndrome and others. Bighamton, N.Y.: Haworth Press. 2007. 26. Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ. Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radical Biology and Medicine. 2005;39(5):584-9. 27. Kerr, JR, Petty, R, Burke, B, Gough, J, Fear, D, Sinclair, LI, Mattey, DL, Richards, SC, Montgomery, J, Baldwin, DA, Kellam, P, Harrison, TJ, Griffin, GE, Main, J, Enlander, D, Nutt, DJ, & Holgate, ST. Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis. Journal of Infectious Disease. 2008;197:1171-1184. 28. Price, JR, Mitchell, E, Tidy, E, & Hunot, V. Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database of Systematic Reviews. 2008;2(CD001027). 29. Jammes, Y, Steinberg, JG, Mambrini, O, Bregeon, F, & Delliaux, S. Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal of Internal Medicine. 2005;257:299-310. 30. Goudsmit, E. (2001). Measuring the quality of trials of treatments for chronic fatigue syndrome. Journal of the American Medical Association. 2001;286:3078-3079. Invest in ME (Charity Nr. 1114035) 31. Jason, L, Melrose, H, Lerman, A, Burroughs, V, Lewis, K, King, C, & Frankenberry, E. Managing chronic fatigue syndrome: overview and case study. AAOHN Journal. 1999;47:17-21. ME FACT “Postviral fatigue syndrome / myalgic encephalomyelitis… has attracted increasing attention during the last five years…Its distinguishing characteristic is severe muscle fatiguability made worse by exercise…The chief organ affected is skeletal muscle, and the severe fatiguability, with or without myalgia, is the main symptom. The results of biochemical, electrophysiological and pathological studies support the view that muscle metabolism is disturbed, but there is no doubt that other systems, such as nervous, cardiovascular and immune are also affected…Recognition of the large number of patients affected…indicates that a review of this intriguing disorder is merited…. The true syndrome is always associated with an infection… Viral infections in muscle can indeed be associated with a variety of enzyme abnormalities…(Electrophysiological results) are important in showing the organic nature of the illness and suggesting that muscle abnormalities persist after the acute infection…there is good evidence that Coxsackie B virus is present in the affected muscle in some cases” (PO Behan, WMH Behan. CRC Crit Rev Neurobiol 1988:4:2:157-178). From Documented involvement of Viruses in ME/CFS [http://www.investinme.org/Article365%20Documented%20involvement%20of%20vi ruses%20in%20ME%20CFS.htm] ME RESEARCH “A significant elevation in the relative amounts of 4 of 5 pro-inflammatory cytokines in peripheral blood plasma of patients with (ME)CFS was found when compared with the controls. In cases, lymphotoxin (LT) was elevated by 257% and IL-6 by 100% over the controls." - Professors Mary Ann Fletcher and Nancy Klimas, (Journal of Translational Medicine 2009:7:96: doi:10.1186/1479-5876-7-96) Page 20/56 Journal of IiME Volume 4 Issue 1 www.investinme.org EDUCATION on ME/CFS – The General Medical Council Position The 2010 Invest in ME conference has the theme of education of healthcare staff. It is important for healthcare providers to be aware of the symptoms of ME, the means to diagnose, the knowledge of potential treatments and the possibilities around mis- or missed diagnoses. It is only by better education of healthcare staff that people with ME can obtain the correct information, advice and treatment. The GMC play a vital role in all of this. The standard textbook used by medical students in the UK still, erroneously, categorises ME in the mental health section. Invest in ME had understood that the GMC are responsible for the curriculum of medical students. We invited the GMC to send a representative to speak at the conference on the subject of the medical curriculum content relating to ME. The GMC declined to send anyone. They did reply to Invest in ME’s letter where we asked about the medical curriculum. This is their reply. To Invest in ME: Thank you very much for inviting the General Medical Council to speak at your international conference, on 24 May, about the education of medical students on ME/CFS. Please accept my apologies for the delay in responding. I am sorry, but we must decline your invitation on this occasion. Perhaps I could explain the GMC's position in the context of the process which governs the development and inclusion of elements in curricula for medical education and training, and, allied to this, the GMC's relationship with the 32 UK medical schools in respect of their undergraduate curricula and the medical Royal Colleges in respect of the 61 specialty curricula. For undergraduate education, the GMC require medical schools to develop curricula which meet the outcomes and standards set out in Tomorrow's Doctors - http://www.gmcuk.org/education/undergraduate/tomorrows_docto rs_2009.asp. Although the revised version of Tomorrow's Doctors (published in September 2009) was more prescriptive than the previous edition, the GMC does not prescribe the precise content of undergraduate curricula. We do not have the legal power to set a national curriculum for the universities' undergraduate courses and we believe that it is important to preserve the independence of universities, the diversity of their courses and the Invest in ME (Charity Nr. 1114035) innovation that can follow from that diversity – subject to the courses meeting our requirements in order to ensure patient safety and the fitness to practise of new graduates. As you will see, Tomorrow's Doctors does not specify what should be taught to undergraduates about any specific conditions. This is decided by the medical schools when drawing up their own curricula. If you would like input to your conference from a medical school perspective I suggest that you try approaching the Medical Schools Council to see if they can identify an appropriate speaker. The curricula for the 61 specialty training areas in postgraduate medical training are developed by medical Royal Colleges and approved by the General Medical Council. The GMC's Standards for Curricula and Assessment Systems http://www.gmc-uk.org/Standards_for_Curricula Assessment_Systems.pdf_31300458.pdf - set out the high level requirements for specialty curricula design and content. Against this background, I am sure you will appreciate that it is impossible for the GMC to respond to individual requests for prioritisation of highly technical and complex medical conditions. It is important, therefore, that the GMC work closely with the medical Royal Colleges and Faculties which have the relevant expertise and technical understanding of the medical conditions which relate to their specialty areas. Page 21/56

Journal of IiME Volume 4 Issue 1 www.investinme.org Canadian Guidelines E EDDUUCCAATTIIOONN oonn MMEE//CCFFSS –– TThhee G Geenneerraall MMeeddii ccaall CCoouunncc ii ll P Pooss ii tt iioonn You could try approaching the Academy of the Medical Royal Colleges or the Royal College of Physicians (London) in particular if you wish to pursue the postgraduate perspective. We do of course have links with the medical Royal Colleges and specialty associations, with patient networks and with research bodies such as the Picker Institute. In developing our curricular requirements we engage and consult widely, as we did in developing the 2009 edition of Tomorrow's Doctors. Once again, I am sorry that the GMC has no specific role or expertise on what should be included in medical curricula about ME/CFS, or any other individual conditions, in order to contribute productively to your conference. Invest in ME are the UK distributors for the Canadian Consensus Criteria – the Canadian Guidelines. Described even by NICE as “the most stringent” guidelines available these are proper, up-to-date clinical guidelines which can also be used as a base for research criteria. Findings from the study by Leonard A. Jason PhD (Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome) indicated that the Canadian criteria captured many of the cardiopulmonary and neurological abnormalities, which were not currently assessed by the Fukuda criteria. The Canadian Criteria also selected cases with ‘less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms’ and individuals selected by these criteria were significantly different from psychiatric controls with CFS. ME STORY Comments from ME patients about their doctors: • "I was told I was lazy and laughed at" • "(he said) the illness was a load of trollop, he laughed me out of the surgery" • "(he) laughed when I told him I could only visit him if I felt fit enough" • "I was called ‘stupid’ and shouted at on more occasions than I care to mention…one neurologist said he ‘couldn’t care less’ whether I ever got better" • "I was told I was a disgrace" • "My illness started with a sudden, severe collapse. The doctor said that it was due to ‘attention seeking’" • "(I was) told that I was a nutter" • " (I was) told I was selfish and introverted and it was nothing but hysteria" • "(the) doctors said to me ‘if you go on like this you will be struck off the register’ " • "(the doctor) said my symptoms / signs ‘didn’t exist’ " • "It was suggested ‘a good man’ was all I needed". • That same year, a severely affected female patient was informed by her GP that ME "is a condition developed by the patient for what they can get out of it". from Magical Medicine: How to Make a Disease Disappear [http://tinyurl.com/38yuj83] Invest in ME (Charity Nr. 1114035) Page 22/56 The Canadian Guidelines provide an internationally accepted means for clearly diagnosing ME. The Canadian Guidelines are available from Invest in ME- the price is 83p per copy plus postage & packaging. To order please contact Invest in ME via this email address: info@investinme.org Journal of IiME Volume 4 Issue 1 www.investinme.org Definition of Recovery in Chronic Fatigue Syndrome Dr. David S. Bell & David E. Bell Definition of Recovery in Chronic Fatigue Syndrome Authors: David S. Bell MD, FAAP Associate Clinical Professor of Pediatrics, State University of New York at Buffalo David E. Bell, MPH Department of Medical Anthropology, State University of New York at Buffalo Key Words: Myalgic Encephalomyelitis, Chronic Fatigue Syndrome; Prognosis Abstract The definition of clinical recovery has long been debated in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). Clinically, many persons who have had ME/CFS declare themselves "recovered" or "nearly recovered" while continuing to present for medical care because of ongoing somatic symptoms. In this study ten persons who considered themselves "recovered" or "nearly recovered" were given questionnaires to assess health status and compared to healthy adults. Half of the "recovered" subjects would be considered ill with CFS based upon the disability requirements of the CDC empiric definition of CFS, and all "recovered" subjects had significant somatic symptoms. Yet these subjects had all returned to normal in the symptom of orthostatic intolerance so that their daily activity was normal. Thus the perception of recovery in ME/CFS is related to the ability to sustain upright activity and not related to the degree of somatic symptoms, including fatigue. Introduction Contact: D. S. Bell MD dsbellmd@yahoo.com In 1985, a cluster of ME/CFS occurred in Upstate New York involving 210 persons, 60 of whom were children or adolescents. The cluster was located in a 180 square mile rural region located between (but did not include) Rochester and Buffalo, New York. Based Invest in ME (Charity Nr. 1114035) Dr David Bell MD has vast experience of ME/CFS. He graduated from Harvard College in 1967 with an AB degree in English literature followed by Boston University with an MD degree in 1971. Post doctoral training in paediatrics was completed in 1976 with subspecialty training in Paediatric Behaviour and Developmental Disorders. In 1978 he began work at the University of Rochester but soon began a private practice in the town of Lyndonville, New York. In 1985 nearly 220 persons became ill with an illness subsequently called chronic fatigue syndrome in the communities surrounding Lyndonville, New York. This illness cluster began a study of the illness which continues today. Dr. Bell is the author or co-author of numerous scientific papers on CFS, and, in 2003 was named Chairman of the Advisory Committee for Chronic Fatigue Syndrome of the Department of Health and Human Services. Publications include A Disease of A Thousand Names, (1988) and The Doctor’s Guide to Chronic Fatigue Syndrome, (1990). Dr Bell has recently been performing studies on XMRV. Dr. David Bell MD http://www.davidsbell.com Page 23/56

Journal of IiME Volume 4 Issue 1 www.investinme.org Definition of Recovery in Chronic Fatigue Syndrome (continued) on the symptoms of the first 100 patients, diagnostic criteria were published(1), but with the publication of the Holmes criteria(2), it became clear that this cluster was the same as what was being termed chronic fatigue syndrome. The children involved in this outbreak were a subject of particular attention. Of interest, the proportion of ill children to adults was similar to that of other community-wide epidemics described previously(3, 4). Because adolescents have lower Epstein-Barr virus (EBV) seropositivity, it was possible to eliminate EBV as the cause of this outbreak(5), a hypothesis prevalent at the time. Seventy-five percent of the children ill in this outbreak met criteria for fibromyalgia syndrome(6). This cohort of children and adolescents with ME/CFS has now been followed clinically for twentyfive years. Four subjects have developed malignancy, and many have tested positive to the gammaretrovirus XMRV, a subject to be described in detail in subsequent studies. In 1995 a follow-up study was published(7) which demonstrated that 80% of those children and adolescents who became ill in 1985 considered themselves "well". However of those 80%, half were doing well despite ongoing somatic symptoms, while the other half had minimal or no somatic symptoms. Twenty percent of the subjects in that study were very ill and disabled. A full study detailing the current health status will be presented under separate cover. In the course of clinical practice and primary care, many of these persons have stated that they have "recovered" or "nearly recovered". However, they continue to present with symptoms suggestive of ME/CFS. The definition of recovery has been difficult to address because of the non-specificity of the symptoms. Current criteria for the diagnosis of CFS, the CDC empirical case definition(8) has one section that specifies degree of disability based upon the Medical Outcomes Survey Short Form-36(9). It has been noted that patients who report themselves "recovered" or "nearly recovered" may have low scores on this instrument. The present study was undertaken to further examine this aspect of the definition of recovery in CFS. The current study was stimulated by CFS patients who have stated that they are "recovered", yet on clinical evaluation and questionnaire are demonstrated to have persistent symptoms. Methods - Subjects Ten adults followed clinically for many years with CFS had stated that they had either "recovered" or "almost recovered." To assess the degree of Invest in ME (Charity Nr. 1114035) recovery, questionnaires were administered to assess the current severity of somatic symptoms and orthostatic intolerance. Institutional Review Board approval was obtained through the Medina Memorial Hospital Ethics Committee, and all subjects signed informed consent prior to questionnaire administration. No subject in this study had developed malignancy nor alternative causes for fatigue over the twenty-five years since being diagnosed with ME/CFS. Ten healthy adults also completed the same questionnaires. Methods - Instruments: a) Hours of Activity Scale: This scale is a measure of orthostatic intolerance; it asks the subject to estimate the average total number of hours of "upright activity within an average 24 hour day." Healthy subjects consistently describe more than 12 hours of upright activity in a day. Severe CFS patients experience 2 or less hours per day, moderate CFS experience 3 to 7 hours, and mild CFS have 8 to 10 hours of upright activity within a 24 hour period (unpublished observations). b) Visual Analog Scale of 9 Symptoms. This self-rated severity scale from 0 (no symptom) to 10 (very severe symptom) measures fatigue, sore throat, lymph node pain, headache, muscle pain, joint pain, sleep disturbance, memory and cognitive symptoms, and post-exertional malaise, all common symptoms of ME/CFS. c) Fisk Fatigue Impact Scale (FIS) (10). This instrument is scored from 0 (no impact) to 4 (severe impact) for each of sixty questions. It is designed to assess the impact that fatigue has on daily activity. The maximum score is 160. d) Bell Activity Scale (11, 12). This scale combines somatic symptoms with activity restriction. Persons score themselves from 0 (bed bound with very severe symptoms, requiring assistance for daily living) to 100 (full and vigorous activity with no significant symptoms). This is a simple and rapid assessment of ME/CFS severity for use at clinic visits (unpublished observations). A copy of this one page questionnaire is attached as an appendix and may be freely used. e) Short Form-36 (9). Also called the Rand-36, this thirty-six item questionnaire has extensive use in evaluating general health and health perceptions in CFS(13, 14). It is also used to help determine diagnosis in the most recent CDC empiric criteria (8). Page 24/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Definition of Recovery in Chronic Fatigue Syndrome (continued) Results The first question of the MOS-36 is a general rating of health status. All ten subjects in this study rated themselves as either "good" or "very good," confirming the perception that they viewed themselves as either "recovered" or "almost recovered". No subject, other than control subjects, rated themselves as "excellent." Patients who were "recovered" were quite different from healthy controls in three areas: VAS, Ability Scale and FIS. For the Visual Analog Scale, mean recovered CFS score was 19.8 +/- 14.67 while the mean control subject score was 6.1 +/- 4.63. This mean difference is significant at the 0.05 alpha level (p=0.011). For the FIS, mean recovered score was 22.8 +/- 25.83, and the mean control score was 4 +/5.81. This difference is significant with a p-value of 0.038. Mean scores for the Bell Ability scale were 99 +/- 3.16 for recovered and 90 +/-12.47 for controls. This was significant with a p value of 0.040. Scores for the MOS-36 will be presented under separate cover. However, the two groups did not differ in the hours of activity scale. Recovered CFS subjects had a mean of 14 +/- 1.94 hours of upright activity, while control subjects had 15.5 hrs +/-1.67 hours of upright activity. The average difference of the means proved to be not statistically significant (p=0.080). The data is presented in Table 1. Discussion The results of this small study suggest that all of ten persons who, in clinical follow-up had stated they had either "recovered" or "almost recovered" had persistent symptoms on several questionnaires. In fact, if the MOS-36 scores are used as an index of disability as suggested by the CDC empirical case definition(8), five of the ten "recovered" subjects would still meet criteria as having CFS. Comparing the ten "recovered" subjects to the healthy controls, clear differences were seen in visual analog scores, Bell Ability Scale, and the Fatigue Impact Scale scores. Of these three, the least significant scores were seen in the Ability scale, perhaps because this scale attempts to combine orthostatic intolerance with somatic symptoms. However, the Hours of Activity Scale scores, a measure of orthostatic intolerance, were the same in the two groups. This implies is that the perception of recovery is based on the symptom of orthostatic intolerance and is independent of somatic symptoms. That is, when persons with CFS improve and reach a point where they can sustain upright Invest in ME (Charity Nr. 1114035) activity for more than twelve hours in a day, they perceive themselves as "recovered" or "almost recovered", despite the fact that other somatic symptoms remain. This observation has relevance in the definition of recovery in ME/CFS, an illness that has no clearly defined biologic markers at present. If confirmed in larger studies, it may explain the large discrepancy in recovery rates in studies of ME/CFS. Thus, future studies of the natural history of the illness will need to discriminate between somatic symptoms and overall activity. It may be that after a number of years, persons with ME/CFS adjust to ongoing somatic symptoms. And if they return to normal activities with improvement of orthostatic intolerance, they perceive themselves as "recovered", when in fact only one aspect of their illness has improved. Again, if this is confirmed, it implies that full recovery from ME/CFS is exceedingly rare. One specific concern related to the definition of recovery in ME/CFS is that when people consider themselves recovered, they feel able to donate blood. One "recovered" subject in this study had normal activity but significant somatic symptoms and was a regular blood donor. Recently the gammaretrovirus XMRV has been implicated in persons with CFS(15). While the relationship of XMRV and ME/CFS is still under debate, these findings carry important implications. Furthermore, it should be remembered that only 20% of persons with ME/CFS receive a diagnosis of CFS from their health care provider (16). A further possible implication of the uncertain definition of recovery in ME/CFS is the interpretation of XMRV incidence in the healthy control population. It will be important in the future to inquire if subjects have ever had a CFS-like illness in the past. References 1. Bell D, Bell K. Ann Intern Med. 1988;109:[Letter]167. 2. Holmes G, Kaplan J, Gantz N, al e. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108:387-9. 3. Parish J. Epidemic neuromyasthenia: a reapprailsal. Journal of International Research Communications Medical Science. 1974;2:22-6. 4. Bell D. Children with ME/CFIDS: Overview and review of the literature. Ottawa: Nightingale Research Foundation; 1992. 5. Bell D, Bell K. Chronic fatigue syndrome in Page 25/56

Journal of IiME Volume 4 Issue 1 www.investinme.org Definition of Recovery in Chronic Fatigue Syndrome (continued) childhood: relation to Epstein-Barr virus. In: Ablashi D, editor. Epstein-Barr Virus and Human Disease; 1989 1989; Rome, Italy: Humana Press; 1989. p. 412-7. 6. Bell D, Bell K, Cheney P. Primary Juvenile fibromyalgia syndrome and chronic fatigue syndrome in adolescents. Clin Inf Dis. 1994;18(Suppl 1):S21-S3. 7. Bell D, Jordan K, Robinson M. Thirteen-year follow-up of children and adolescents with chronic fatigue syndrome. Pediatrics. 2001;107(5):994-8. 8. Reeves W, Wagner D, Nisenbaum R, Jones F, Gurbaxani L, Solomon L, et al. Chronic fatigue syndrome - A clinically empirical approach to its definition and study. BMC Medicine. 2005;3:http://www.biomedcentral.com/17417015/3/19. 9. Ware N, Sherbourne C. The MOS 36-Item Short Form Health Survey. Medical Care. 1992;30:473-83. 10. Fisk J, Ritvo P, Ross L, Haase D, Marrie T, Schlech W. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994;Suppl 1:S79-S83. 11. Bell D, editor. The Doctor's Guide to Chronic Fatigue Syndrome. Reading, MA: Perseus Books; 1993. 12. Myhill S, Booth N, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial Table 1: Comparing equality of means between "recovered" ME/CFS and control subjects Clinical Assessment Tool Patient Status Std. Fisk FIS Control VAS Total Recovered Control Hours of Activity Bell Ability Scale Recovered Control Recovered Control Recovered Invest in ME (Charity Nr. 1114035) Number Mean 10 10 10 10 10 10 10 10 Deviation 4.00 22.80 6.10 19.80 15.50 14.00 99.00 90.00 5.812 25.828 4.630 14.673 1.667 1.944 3.162 12.472 Independent Samples T-Test: Std. Error Mean 1.838 8.167 1.464 4.640 .527 .615 1.000 3.944 Page 26/56 p = 0.040 2-Tailed Significance (Equal Variances Assumed) p = 0.038 p = 0.011 p = 0.080 dysfunction. Int J Clin Exp Med. 2009;2:1-16. 13. Komaroff A, Fagioli L, Doolittle T, Gandek B, Gleit M, Guerriero T, et al. Health status in patients with the chronic fatigue syndrome and in general population and disease comparison groups. Am J Med. 1996;101:281-90. 14. Buchwald D, Pearlman T, Umali J, Schmaling K, Katon W. Functional status in patients with chronic fatigue syndrome, other fatiguing illnesses, and healthy individuals. Am J Med. 1996;171:364-70. 15. Lombardi V, Ruscetti F, Gupta J, Pfost M, Hagen K, Peterson D, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. . Science. 2009;326(5952):595-89. 16. Jason L, Richman J, Rademaker A, al e. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999;159:212937. 17. Levine P. Epidemic neuromyasthenia and chronic fatigue syndrome: epidemiological importance of a cluster definition. Clin Infect Dis. 1994;18 (Suppl 1):S16-20. Appendix I: Bell Ability Scale (Ref: Bell DS. The Doctor's Guide to Chronic Fatigue Syndrome. Perseus Books, Reading, MA; 1993) Journal of IiME Volume 4 Issue 1 www.investinme.org Definition of Recovery in Chronic Fatigue Syndrome (continued) Appendix I: Bell Ability Scale (Ref: Bell DS. The Doctor's Guide to Chronic Fatigue Syndrome. Perseus Books, Reading, MA; 1993) 100. No symptoms at rest or with exercise; normal overall activity; able to work or do house/home work full time without difficulty. 90. No symptoms at rest; mild symptoms with vigorous activity; normal overall activity level; able to work full time without difficulty. 80. Mild symptoms at rest; symptoms worsened by exertion; minimal activity restriction for activities requiring exertion; able to work full time with difficulty in jobs requiring prolonged standing or exertion. 70. Mild symptoms at rest; some daily activity limitation noted; overall functioning close to 90% of expected except for activities requiring exertion; able to work full time. 60. Mild to moderate symptoms at rest; daily activity limitation clearly noted; overall functioning 70% to 90%; able to work full time in light activity if hours flexible. 50. Moderate symptoms at rest; moderate to severe symptoms with exercise or activity; overall activity level reduced to 70% of expected; unable to perform strenuous activities but able to perform light duties or desk work 4 to 5 hours a day, but requires rest periods. 40. Moderate symptoms at rest; overall activity 50% to 70% of previous normal; able to go out of the house for short excursions; unable to perform strenuous activities; able to work sitting down at home 3 to 4 hours per day, but requires rest periods. 30. Moderate to severe symptoms at rest; severe symptoms with exercise; overall activity reduced to 50% of expected; usually confined to house; able to perform light activity (desk work) 2 to 3 hours per day but requires rest periods. 20. Moderate to severe symptoms at rest; unable to perform strenuous activity; overall activity 30-50% of expected; able to leave house only rarely; confined to bed or couch most of day; unable to concentrate more than 1 hour per day. 10. 0. Severe symptoms at rest; bedridden the majority of the time; rare travel outside the house; marked cognitive symptoms preventing concentration. Severe symptoms on a continuous basis; bedriddren; unable to care for self. ME Fact Clustering of combined gene data in CFS/ME patients for this and our previous study (n=117 CFS/ME patients) revealed genomic subtypes with distinct differences in SF-36 scores, clinical phenotypes, severity and geographical distribution. Antibody testing for Epstein-Barr virus (EBV), enterovirus, Coxiella burnetii and parvovirus B19 revealed subtype-specific relationships for EBV and enterovirus, the two most common infectious triggers of CFS/ME. Kerr et al. J Clin Pathol doi:10.1136/jcp.2009.072561 Invest in ME (Charity Nr. 1114035) Page 27/56

Journal of IiME Volume 4 Issue 1 www.investinme.org Letter from America Annette Whittermore – Testimony to CFSAC The United States governmental entity responsible for alerting and protecting the American public from threats to their health is the Centers for Disease Control, better known as the CDC. The CDC’s mission is to collaborate to create the expertise, information, and tools that people and communities need to protect their health – through health promotion, prevention of disease, injury and disability, and preparedness for new health threats. Yet, one to four million Americans still suffer from a poorly understood, debilitating disease which was first identified in the United States in three separate recorded outbreaks over 25 years ago, including: Incline Village, Nevada Lyndonville, New York and Miami, Florida. The individuals who became ill that year came from various economic classes, different age groups, including children and adults and affected people in a small rural town, a large lakeside community and a huge metropolitan area. The individuals in those outbreaks all exhibited the same complex symptoms, yet none of the patients were examined by the government employees who were sent to investigate. The doctors who alerted the CDC were not told of the other communities in the United States experiencing the same phenomenon. Despite the serious concerns about the severity of the patient’s symptoms and their rapid decent into disability, the CDC refused to investigate further. The CDC concluded that this was a new form of EBV mono. They convened a meeting, in which they decided to call this illness “chronic fatigue syndrome” rather than adopt the name that was being used in the UK: myalgic encephalomyelitis (M.E.). M.E. at that time was already a well characterized infectious neurological disease causing a similar complex illness. Thus began a twenty five year battle between patients and doctors who fully realized the severity of this illness and a government that has yet to commit an appropriate level of financial resources to aid the discovery process necessary to help individuals with this disease. Invest in ME (Charity Nr. 1114035) Annette Whittemore Annette Whittemore is founder and President of the Whittemore-Peterson Institute of Nevada, USA. The CFSAC The Chronic Fatigue Syndrome Advisory Committee was established to provide sciencebased advice and recommendations to the Secretary of Health and Human Services and the Assistant Secretary for Health on a broad range of issues and topics pertaining to chronic fatigue syndrome (CFS). The Committee advises and makes recommendations to the Secretary, through the Assistant Secretary for Health, on a broad range of topics including: (1) the current state of knowledge and research about the epidemiology and risk factors relating to chronic fatigue syndrome, and identifying potential opportunities in these areas; (2) current and proposed diagnosis and treatment methods for chronic fatigue syndrome; and (3) development and implementation of programs to inform the public, health care professionals, and the biomedical, academic and research communities about chronic fatigue syndrome advances. Not only has the lack of adequate resources been a major road block to discovery, but the CFS scientific review committees are currently ill-equipped to review many of the biologically complex scientific grant requests. Attempts to engage in biological research by basic researchers from virology and retro virology have generally been turned down in favor of studies aligned with a psychological theory of illness. Years of misdirected research have resulted in a lack of a medical specialty for this group of patients to rely on for expert care. Doctors have been left without adequate knowledge and the tools to effectively care for their patients. The sick have been turned away by major medical centers, ignored by government, and their claims denied Page 28/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Letter from America Annette Whittermore – Testimony to CFSAC by insurance companies who refuse to pay for diagnostic tests and experimental treatments. How could this happen to such a large group of sick people in this day and age of modern medical technology? Who could possibly benefit by this inhumane treatment of sick human beings? My husband is fond of the quote made popular in the Watergate era: “follow the money”. His take on it is more specific: When something doesn’t seem right, “follow the money”. So if one follows the money in this case, we can perhaps begin to unravel the mystery of this crime against humanity. We know that when this disease was first reported to our governmental authorities, another more deadly illness had recently been identified, HIV-AIDS. Our nation was debating how to approach this new “gay man’s disease”, until it struck a young child and a famous athlete, neither who were gay. Countries around the world were struggling to meet the heavy demands of HIV, when myalgic encephalomyelitis began to take its equally heavy toll on the lives of the innocent. But this disease was a disease that apparently could be ignored. It seemed to impact mainly woman. There was no immediate organ damage that could be detected. It did not kill the afflicted rapidly enough; it only caused a profound disability that could last a life time. However, a life time of disability requires a life time of disability payments and huge medical bills; something no government or private health insurance provider wants to be responsible for. The only way to avoid medical and disability payments for the sick is to claim the illness is due to a psychological disturbance or mass hysteria, blame the patient for their illness and offer cheap psychological treatment and exercise therapy. As long as no one discovers the true cause of the disease, these entities are safe from any expectation of actual medical intervention. A physical disease may remain in the psychiatric domain if it is called a psychosomatic illness; “meaning a disorder in which mental factors play a significant role in the development, expression, or Invest in ME (Charity Nr. 1114035) resolution of a physical illness.” Despite years of private research and thousands of papers describing the physical deficits found in these patients with this illness, our government and medical entities continue to ignore the evidence in favor of those who espouse a simplistic psychological theory of illness. But those who stand to gain by misdirecting research funding can not stop the truth from being revealed. What greater evidence is required to support the request for responsible action than the finding of a new human retrovirus replicating in this population of patients? Knowing the significance of this discovery, why has the US government not asked CFS patients to stop donating blood until the cause of this disease is better understood? Prostate cancer and XMRV research has been made a priority at the National Cancer Institute and major universities as evidenced by the publication of new findings. Yet, there has been no such commitment by those at the National Institute of Allergy and Infectious Disease. Why is this? Are we to blindly and meekly accept that those who suffer from XMRV (who have been inappropriately branded as having a fatiguing illness called “CFS”) are undeserving of the same medical care afforded others infected with a retrovirus? I believe this is not the time to end the CFSAC but rather a time for the CFSAC to exhibit its commitment by sending its strongest recommendations to the Secretary of Health and following those recommendations with actions: • Educate the research and medical communities about the number of individuals impacted and the severity of this disease. Recommend that the CDC define ME by the immunological and neurological abnormalities that exist, the many co-infections that are frequently found and the physical complications of this long term illness. It is time to agree on a proper name for this disease and to reflect the most current scientific knowledge in the definition of this disease. • Seek congressionally mandated research dollars Page 29/56

Journal of IiME Volume 4 Issue 1 www.investinme.org Letter from America Annette Whittermore – Testimony to CFSAC that more closely match the number of individuals impacted by the disease and the severity of the illness. Millions of Americans are ill with ME and yet the NIH allocates a mere $1.00 to $4.00 per year per person. The loss in economic dollars is conservatively estimated to be $9 billion per year. With that kind of economic loss to our society, why isn’t this disease funded at the level of hepatitis C which is currently at $93 million a year? Patients diagnosed with ME also suffer from inflammatory bowel disease, cognitive impairment, fibromyalgia, anaemia, gall bladder disease, chronic Lyme disease, sleep disorders, chronic pain, depression, hormonal dysregulation, frequent viral infections, heart disease, and cancer. Yet these sick Americans are forced to seek unproven medical treatments for symptomatic relief due to the lack of scientific understanding of the underlying immune deficiency that is driving this disease. • Request that research be conducted on XMRV in infectious disease by the NIAID and outside researchers to continue the valuable work begun at the WPI. The human retro virus, XMRV, has been found by WPI researchers in diverse disease populations, including cancer, autism, fibromyalgia, gulf war illness and ME, in men, woman and children. Yet four of WPI’s most recent grants were denied funding on the basis that not enough is known about XMRV to warrant further investigations. • Create and fund Centers of Excellence in neuroimmune diseases to care for patients with complex disorders caused by infectious agents. Scientific medical criteria should be developed that hold these Centers to standards of performance that include timelines and effectively measure demonstrated outcomes. All such Centers should be interconnected to provide medical consistency in care. They should include research, clinical care and medical education components from classroom lectures, to residencies and fellowships in neuroimmune disease. • Request a congressional hearing to determine why this disease has been so poorly managed by the CDC and NIH, in order to assure the American public that the failure to recognize a serious threat to the nation’s health will not be repeated. There is no question that the CFSAC, as defined by its charter, can be an important avenue to a meaningful discourse between those who care Invest in ME (Charity Nr. 1114035) about M.E. and those who are capable of initiating action from within the government. The question is: Has the CFSAC achieved the goals stated in their charter? The charter states its purpose …..as established to provide science-based advice and recommendations to the Secretary of Health and Human Services and the Assistant Secretary for Health on a broad range of issues and topics pertaining to chronic fatigue syndrome (CFS). Is this goal being aggressively pursued? Is scientific evidence being reported to the Secretary of Health? What actions have been taken by the Secretary of Health that would provide evidence that this information is being acted upon? The Function of the committee is stated below: The Committee shall advise and make recommendations to the Secretary, through the Assistant Secretary for Health, on a broad range of topics including: (1) the current state of knowledge and research about the epidemiology and risk factors relating to chronic fatigue syndrome, and identifying potential opportunities in these areas; (2) current and proposed diagnosis and treatment methods for chronic fatigue syndrome; and (3) development and implementation of programs to inform the public, health care professionals, and the biomedical, academic and research communities about chronic fatigue syndrome advances. The WPI took the earlier recommendations of this committee seriously. In fact, we built our Institute on the premise that this disease and others very similar to it, deserves “Centers of Excellence” that can bring answers to patients and doctors, in the same manner as multiple sclerosis and muscular dystrophy have successfully done. We believe that to find answers to this complex disease we must combine the translational efforts of basic and clinical researchers working in collaboration with knowledgeable physicians. This is the dream of the WPI: to bring discovery to a disease which has impacted millions of lives, to develop effective treatments and to one day provide preventative measures that will stop the spread of the disease. This is not something that we can afford to do Page 30/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Letter from America Annette Whittermore – Testimony to CFSAC alone. If this committee will confirm that it is more than a sounding board for frustrated patients and doctors and that it can effectuate the necessary changes in this field, then the WPI fully supports the renewal of its charter. Martin Luther King, Jr. once said, “The ultimate measure of a man is not where he stands in moments of comfort and convenience, but where he stands at times of challenge and controversy”. I believe that courage is the combination of knowing the right thing to do and then doing it. Please show us you have the courage to make this happen. Thank you for your time and attention. It is unknown whether or not the refusal of the MRC to investigate David Sampson’s legitimate complaint has anything to do with the fact that the MRC has a secret file on ME that contains records and correspondence since at least 1988 which, co-incidentally, is about the time that (Professor) Simon Wessely began to deny the existence of ME. The file is held in the UK Government National Archives at Kew (formerly known as the Public Record Office) and was understood to be closed until 2023, but this closed period has been extended until 2071, at the end of which most people currently suffering from ME will be conveniently dead http://www.nationalarchives.gov.uk/catalogue/d isplaycataloguedetails.asp?CATLN=7&CATID=-54 75665. ME STORY The person writing the story (..) values life. Yet she has spent hers in isolation from those she ever loved, without seeing friend or family member. She stresses that she is not being negative in sending this (an appeal to the CMO), only "wanting people to acknowledge the seriousness of this illness and thereafter funding all that is necessary". "I just want to be better. To be less ill on a daily basis. To receive some help with this appalling illness and for it not to be too late for me. I am 53 years of age and have been living with ME for 30 years. But inside I am still 23 years old because I never got to live those 30 years fully or otherwise.” - from The UK Chief Medical Officer 1998 – 2010 A Testament to Failure [http://tinyurl.com/39d7mzx ] Invest in ME (Charity Nr. 1114035) As one puzzled ME sufferer recently noted: "why on earth have a 73 year embargo on these documents on an illness where a load of neurotic people, mostly women, wrongly think they are physically ill?" The MRC’s secret files on ME/ CFS are closed (i.e. unavailable to the public) for an unusually lengthy period of 83 years. The standard closure period is 30 years but, as in the case of these files on ME/CFS, the standard closure period may be extended. The 30- year rule usually applies to documents that are exempt from release under a Freedom of Information Act (FOIA) request and include, for example, documents concerning the formulation of government policy, documents related to defence, to national security, to the economy, and documents that are considered very confidential. It may be recalled that during the life of the Chief Medical Officer’s Working Group on ME/CFS (1998- 2002), lay members were ordered not to discuss the deliberations and were even threatened with the Official Secrets Act, for which no explanation was proffered. (Hooper, Williams,Magical Medicine, February 2010) [http://www.investinme.org/Article400%20Magi cal%20Medicine.htm] Page 31/56 ME FACTS The MRC’s secret files on ME/CFS

Journal of IiME Volume 4 Issue 1 www.investinme.org Ampligen® in Severely Debilitated CFS Patients Introduction Chronic fatigue syndrome (CFS) is a seriously debilitating disorder characterized by disabling fatigue and a combination of flu-like symptoms. The fatigue is not improved by bed rest and may be worsened by physical activity. The Centers for Disease Control (CDC) has identified CFS as an economically and emotionally devastating illness whose functional impairment can be equivalent to multiple sclerosis, heart disease, chronic obstructive pulmonary disease, or end-stage renal disease. The etiologic basis for CFS is unknown and may be multifactoral. With no approved drug therapy available, treatment is aimed at symptom relief and improved ambulatory function. Ampligen® [rintatolimod; poly(I) ·poly(C12,U)] is a double-stranded RNA compound in late-stage clinical development for treating CFS and a New Drug Application (NDA) has been filed with the US Food and Drug Administration (FDA). Exercise tolerance (ET) testing is an objective measurement of treatment efficacy and is accepted as a standard test for drugs ameliorating exertional fatigue. AMP-516, the key Phase 3 multi-center, doubleblind, placebo controlled trial, used ET as its primary endpoint in the evaluation of Ampligen® in the treatment of CFS through its action as a selective Toll-like receptor 3 (TLR3) agonist. TLRs are evolutionary preserved host defense systems which recognize various “microbial mimics”. TLR3 specifically recognizes double-stranded RNA, part of the replicative cycle of many pathogens including viruses. Given the likely multifactorial etiology of CFS, the rationale of the study was to determine whether chronic exposure to a selective TLR3 ligand would result in quantitatively and medically significant ambulatory/exercise improvements. As has been previously communicated, Hemispherx Biopharma received a completed response letter from the FDA regarding the NDA for the use of Ampligen® to treat CFS. In this letter, the FDA has recommended at least one additional clinical study which shows a convincing effect and confirms safety in the target population. Since receiving the letter, Hemispherx has instituted a new clinical study protocol to Invest in ME (Charity Nr. 1114035) Ampligen® in Severely Debilitated CFS Patients 1, 2 Article submitted by Nancy McGrory Richardson, Education and Outreach Director for Hemispherx Biopharma, Inc. Hemispherx Biopharma, based in Philadelphia, is a biopharmaceutical company engaged in the manufacture and clinical development of new drug entities for treatment of viral and immune-based disorders. Hemispherx’s flagship products include Alferon N Injection® and the experimental immunotherapeutics/antivirals Ampligen®. More information One Penn Center 1617 JFK Blvd., 6th Floor Philadelphia, PA 19103 Phone: (215) 988-0080 Fax: (215) 988-1739 E-mail: info@hemispherx.net retrospectively monitor blood from patients enrolled in the key pivotal study, AMP-516. The primary purpose of this study protocol is to identify target subsets of patients who are most likely to benefit from active treatment with Ampligen®. This study specifically is monitoring patients for evidence of xenotropic murine leukemia virusrelated virus (XMRV) which has recently been implicated as having a strong association with CFS. One of the key research organizations, The Whittmore Peterson Institute, is performing the analysis for this on-going study. We anticipate that this data will be available for analysis by late summer. The information gained from this study and the recommendations made by the FDA in the complete response letter along with their review of the new subgroup analysis, when completed, will guide the design of the next clinical study using Ampligen® to treat CFS. This article will review the findings of a number of clinical studies which explore the use Ampligen® in Page 32/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Ampligen® in Severely Debilitated CFS Patients (continued) CFS patients. The studies reviewed in this article examine the following: 1.) QT interval prolongation in CFS and increase in exercise tolerance, and 2.) interferon and cytokine levels in a Phase 3 clinical trial. QT Interval Prolongation in CFS and Increase in Exercise Tolerance Method: Data was analyzed from two well-controlled (double-blind, randomized, multi-center, placebocontrolled) studies, AMP-502 and AMP-516 (totaling >300 subjects), of poly(I) ·poly(C12,U). The purpose of this research was to determine the effect of treatment with rintatolimod on exercise tolerance and the use of concomitant medications, including medications known to prolong the QT interval. Summary of Results: In both studies, poly(I)·poly(C12,U) resulted in a statistically significant (p<0.05) increase in mobility and stamina (exercise tolerance) compared to placebo supported by patient responses to twice weekly dosing. The results from the two key studies are summarized in Table 1. Exercise treadmill testing (ETT) was the primary endpoint in the largest (n=234) placebo-controlled trial (AMP-516) and the proportions of subjects with changes from mean baseline ETT duration at Week 40 of at least 25% and 50% were 1.7-and 1.9 fold greater for the poly(I)·poly(C12,U) cohort than placebo, 39% vs. 23% and 26% vs. 14%, respectively (p<0.036). Of AMP-516 subjects, who took concomitant medications, 72% receiving poly(I)·poly(C12,U) decreased use of concomitant medications used to control the signs and symptoms of CFS versus 56% of subjects receiving placebo (p=0.015). An integrated analysis of efficacy shows that poly(I)·poly(C12,U) increases ETT and decreases the medications needed to suppress and control the symptoms of CFS. Voluntary use of concomitant medications significantly decreased in the poly(I)·poly(C12,U) group compared to the placebo arm in both studies (p<0.05). Many of these drugs used for symptomatic relief are known to prolong the QT interval. Drugs which prolong the QT interval are associated with an increased risk of Torsades de Pointes and sudden death. The list of drugs that prolong the QT Interval and/or induce TdP are shown in Table 2. An analysis of the QT interval in the Phase 3 study showed an increased risk of proarrhythmic potential in the placebo group compared to the poly(I)·poly(C12,U) treated group. Within the placebo group, patients who were prescribed one or more medications known to prolong the QT interval had a significant increase from their baseline QT interval. The use of concomitant medications (known to prolong the QT interval) used to alleviate symptoms of CFS was significantly decreased in the poly(I)·poly(C12,U) cohort. Patients randomized to receive poly(I)·poly(C12,U) were approximately three times more likely to have reduced exposure to medications known to prolong the QT interval, compared to patients randomized to receive placebo in AMP-502. Assessment of Interferon and Cytokine Levels Objective: To perform assessments of stored serum samples from CFS patients who participated in the AMP-516 study for markers of innate immune response (interferon and cytokine induction). The pretreatment interferon and cytokine levels, and the intra-patient changes from baseline, were also compared between the randomized groups to determine if Poly I : Poly C12U had a significant effect on serum levels. Table 1: Summary of ETT Efficacy Findings (Intent-to-Treat) from the WellControlled Trials Trial Time-to-Endpoint (Weeks) AMP-502 24 AMP-516 40 Invest in ME (Charity Nr. 1114035) Mean Change (Seconds) 95 96 p-value 0.010 0.047 Page 33/56

Journal of IiME Volume 4 Issue 1 www.investinme.org Ampligen® in Severely Debilitated CFS Patients (continued) Figure 1: Use of Medications Known to Cause QT Prolongation: Individual Study Results from AMP-516 100 90 70 80 50 60 30 40 10 20 0 DE CREASED USE OF MEDICATIONS NO DECREASE D USE OF MEDICATIONS Poly I:Poly C12U Placebo P=0.048 (Chi-square test) 68 55 45 32 Decrease is defined as a reduction in the total number of days of exposure during the first 4 weeks of the study compared to the total number of days of exposure during the last 4 weeks of the study, only considering medications known to prolong QT. Methods: Elevated cytokine and interferon levels have been reported for a myriad of disorders, including CFS. Although the safety of poly(I)·poly(C12,U) has been demonstrated in over 30,000 patient treatment weeks and a wide dosing range without evidence of significant acute or cumulative toxicity, additional analyses of interferon and cytokine levels in patients’ sera were examined. A random sample of 48 patients (active and placebo) who completed the AMP-516 (Stage I ) study plus subjects who discontinued prematurely were selected for analyses of serum levels of interferons (α, β, and γ) and cytokines (TNF-α, IL-6, IL-10, and IL-12) at Baseline and Week 32 (or last observation for patients who discontinued prematurely). Invest in ME (Charity Nr. 1114035) Results: Elevated levels of interferons α, β, γ or cytokines IL6, IL-10, IL-12, or TNF- α, were seen at the baseline/pre-treatment visit for a subset of active and placebo patients, but no significant modulation of interferons or cytokines was seen. For each of the interferons and cytokines monitored, the data showed that the group changes from baseline levels in the poly(I)·poly(C12,U) treatment group over the treatment period up to Week 32 were indistinguishable and overlapped the observed levels in the placebo group. Two placebo treated subjects had the greatest increases in interferon levels and both completed the study. One poly(I)·poly(C12,U) treated subject had the greatest increases in the four cytokines, tolerated the treatment well, and completed the study. The data Page 34/56 PERCENTAGE OF PATIENTS Journal of IiME Volume 4 Issue 1 www.investinme.org Ampligen® in Severely Debilitated CFS Patients (continued) Table 2: Drugs That Prolong the QT Interval and/or Induce Torsades de Pointes Which Were Taken by Subjects in AMP-516 Study Generic Name (Brand Name) Amitriptyline (Elavil®) Azithromycin (Zithromax®) Ciprofloxacin (Cipro®) Clarithromycin (Biaxin®) Doxepin (Sinequan®) Fluconazole (Diflucan®) Fluoxetine (Prozac®) Fluoxetine (Sarafem®) Levofloxacin (Levaquin®) Salmeterol (Serevent®) Sertraline (Zoloft®) Sumatriptan (Imitrex®) Tizanidine (Zanaflex®) Venlafaxine (Effexor®) Zolmatriptan (Zomig®) Drug Class / Clinical Usage Tricyclic Antidepressant/depression Antibiotic/bacterial infection Antibiotic/bacterial infection Antibiotic/bacterial infection Tricyclic Antidepressant/depression Anti-fungal/fungal infection Anti-depressant/depression Anti-depressant/depression Antibiotic/bacterial infection Sympathomimetic/asthma, COPD Anti-depressant/depression Migraines/cluster headaches Muscle relaxant Anti-depressant/depression Migraines suggested that, relative to placebo treatment, poly(I)·poly(C12,U) treatment is not associated with consistent increases or decreases in interferon or cytokine levels in this population. None of the group changes from Baseline to Week 32 (or last observation available) were considered to be clinically relevant. Results from the 2-factor analysis of treatment assignment and completion status revealed there was no significant difference in interferon or cytokine serum levels, suggesting similar profiles between active and placebo. Conclusion Poly(I)·poly(C12,U) treatment in this debilitated population of CFS patients resulted in a medically and statistically significant increase in exercise treadmill duration, compared to placebo. Poly(I)·poly(C12,U) treatment allowed CFS subjects to reduce their dependence on concomitant medications used to treat debilitating symptoms of CFS, coincidentally reducing exposure to drugs known to prolong the QT interval. This may suggest a new therapeutic strategy to potentially Invest in ME (Charity Nr. 1114035) mitigate the incidence of heart failure/sudden death in this relatively young predominantly female population. Poly(I)·poly(C12,U) therapy improved physical performance of CFS patients without significant modulation of serum levels of interferons α, β, γ or cytokines IL-6, IL-10, IL-12, or TNF-α. In addition, no differences were observed between poly(I)·poly(C12,U) and placebo patients in either the interferon or cytokine profiles between patients who completed the study vs. patients who discontinued early. No safety concerns were raised regarding interferon and cytokine levels and the poly(I)·poly(C12,U) therapy was generally welltolerated. Overall, there have been over 90,000 drug exposures in the combined CFS and non-CFS studies. The most frequently seen adverse event was flu-like symptoms. An integrated analysis of safety (over 1200 subjects in 13 studies) shows that poly(I)·poly(C12,U) is generally well-tolerated in both CFS and Non-CFS populations. At present, only supportive, symptom-based care is available Page 35/56

Journal of IiME Ampligen® in Severely for CFS patients. Over its developmental history, this experimental therapeutic has received various designations, including Orphan Drug Product Designation (FDA), Emergency (compassionate) Cost Recovery Sales Authorization (FDA) and “promising” designation by the Agency on Health Research Quality (AHRQ). Hemispherx Biopharma remains committed to the development of Ampligen® as a treatment option for patients suffering from debilitating CFS. Reference 1. DR Strayer, BC Stouch, JC Horvath, SR Stevens, WA Carter and AMP-516 Investigators. Interferon and Cytokine Levels in a Double-Blind, Randomized, Placebo-Controlled, Phase III Clinical Trial (AMP516) of Ampligen® (Poly I : Poly C12U) in CFS. Presented at the 9th International IACFS/ME Research and Clinical Conference, March 12-15, 2009, Reno, Nevada. ME FACTS Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe systemic, acquired illness that is defined by the WHO in the ICD-10 code G93.3 as a neurological illness. In the UK ME/CFS is estimated to be five times more prevalent than HIV/AIDS. ME/CFS has clear clinical symptoms which manifest predominantly based on neurological, immunological and endocrinological dysfunction. While the pathogenesis is suggested to be multifactorial, the hypothesis of initiation by a viral infection has been prominent. A wide range of viruses and other infectious agents, such as EpsteinBarr Virus, Human Herpesvirus-6 and 7, Enterovirus, Cytomegalovirus, Lentivirus, Chlamydia and Mycoplasma have been investigated. Before acquiring the illness most patients were healthy, leading full and active lifestyles. Recent research has discovered a new retrovirus – XMRV – as being implicated in ME/CFS. ME/CFS most frequently follows an acute prodromal infection, varying from upper respiratory infections, bronchitis or sinusitis, or gastroenteritis, or an acute “flu-like” illness. Biomedical research has provided evidence of distinct subgroups within ME/CFS. Invest in ME (Charity Nr. 1114035) Volume 4 Issue 1 www.investinme.org Objective signs in ME/CFS Debilitated CFS Patients (continued) …. despite the Wessely School’s insistence that there are no objective signs of organic disorder in ME/CFS, there are numerous objective reproducible abnormal signs that are discernable by any reasonably competent physician. They include the following: • labile blood pressure (this is a cardinal sign); low systolic BP ‐‐ <100 in 50% • nystagmus and vestibular disturbance (vestibular dysfunction seen in 90%) • sluggish visual accommodation • fasciculation • hand tremor • neuromuscular incoordination • cogwheel movement of the leg on testing • muscular weakness • marked facial pallor • postural orthostatic tachycardia syndrome (POTS) • positive Romberg • abnormal tandem or augmented tandem stance • abnormal gait • evidence of Raynaud’s syndrome and vasculitis (vascular signs cross dermatomes) • mouth ulcers • hair loss • singular reduction in lung function (shortened breath‐holding capacity seen in 60%) • enlarged liver (not usually looked for by psychiatrists) The problem is that many doctors refuse to examine ME/CFS patients – or even to lay a finger on them – because ME/CFS patients are largely despised by the medical profession. Indeed, in 1994 one of the medical trade magazines published an article entitled “GPs despise the ME generation” (GP: April 1994). The article itself said at the time: “studies have shown that that most ME patients rate contact with medical services as unhelpful” and little has changed in the intervening fifteen years. Abnormal findings on testing include flattened or even inverted T‐waves on 24 hour Holter monitoring; abnormal glucose tolerance curves; elevated lactate levels in the ventricular system (seen in 70% of patients); neuronal destruction and elevated choline peaks (seen in 10% of patients); punctate lesions consistent with small strokes (seen in 78% of patients); very poor oxygen transport on pulse oximetry readings (seen in 90% of patients) and an abnormal venous blood gas picture. None of these can rationally be explained as evidence of a behavioural disorder. from “Magical Medicine: How to Make a Disease Disappear”. See http://tinyurl.com/2uv8j95 Page 36/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Around Europe – European ME Alliance Spain The European ME Alliance (EMEA) Liga SFC, Spain, May 2010 Clara Valverde In Spain Liga SFC have been busy. This is a brief summary of what we have done in the past year, since May 2009. Informing and Educating Doctors and Patients a- Distributing and promoting the Canadian Criteria in its Spanish translation b- Writing, publishing and distributing a manual (150 pages) for health professionals on ME/CFS, fibromyalgia and MCS (Multiple Chemical Sensitivities), the illnesses (including the Canadian Criteria) and how to communicate with the patient (the social and emotional aspects of living with these Central Sensitivity Illnesses). 10,000 copies of the manual ("Nuevos retos en la consulta"..."New challenges in the doctor's office") have been distributed by hand to primary health care doctors throughout Spain and more than 20,000 digital copies have been distributed by our web and other webs. We are having tremendous feedback. c- We made a one-hour long documentary on ME, the first in Spanish. It is the voices of ME patients and also includes Dr Nancy Klimas and another Spanish doctor. We have taken the film on tour and have given copies to ME associations in Spain for their own viewing events. Invest in ME (Charity Nr. 1114035) The European ME Alliance (EMEA) was created in 2008 and is a group of European organisations/charities which works together to improve the situation for people with ME/CFS and their families in Europe. It now comprises nine countries -Ireland, UK, Norway, Denmark, Sweden, Belgium, Spain and Switzerland. EMEA’s aims are to - • Establish correct recognition of myalgic encephalomyelitis as an organic illness requiring biomedical research to treat and cure • Establish correct diagnosis of patients • Establish specialised biomedical centres for education/treatment/cures Contact EMEA: Dorp 73 3221 Nieuwrode Belgium Email:info@euro-me.org Web: www.europeanmealliance.org www.euro-me.org Working on behalf of patients with ME (myalgic encephalomyelitis) Page 37/56

Journal of IiME Volume 4 Issue 1 www.investinme.org Around Europe – European ME Alliance d- We have written and published a book on living with ME from one person's viewpoint. The book was published by Spain's largest publishing house, Planeta. The book has gone on tour with the documentary. The media has covered this book extensively. e- We have written and published an 18 page social science article criticising the use of CBT in ME. The article was published in a major Spanish psychiatry magazine. The article consisted of a bibliographical review of all the research that has been performed proving that CBT is either useless or harmful for ME and of our own qualitative research with Spanish patients on their experiences with CBT. This article was also distributed digitally extensively and it has had much impact. As a result, the main hospital in Spain that treats ME (well, treats would be an overstatement for what they do...they diagnose), Hospital Clinic in Barcelona, is rethinking their CBT treatment. f- Upkeep of our website www.ligasfc.org: no small feat because of the heavy traffic it has and the amount of hackers who are determined to knock it down. Every day we receive about 100 emails mostly of patients who are caught in the medical or legal ME pilgrimage. We give the information, encourage contacts with their local associations, and give support. gInforming of ME information, research, events, news, etc through our web which is linked to hundreds of Spanish webs and blogs 2. RESEARCH INVOLVEMENT a. In November 2009, we met with the top retroviral research team in Spain (Dr Clotet's team at the IrsiCAixa lab) that worked solely on HIV and persuaded them to start an XMRV research project. It has taken a lot of work! But it is now underway. Dr Judy Mikovits is working closely with Clotet's team and in April 2010 she spent a week working with them on the lab. We have worked closely with doctors and patients on this research and on the blood bank issue. b. We organized a lecture by Dr Mikovits in Barcelona c. We are fundraising for the study: campaign, a concert, etc. d. We are educating and giving talks about the XMRV and the research and taking much flack Invest in ME (Charity Nr. 1114035) for it (which takes up energy and time). We are very excited and hopeful about this research. Dr Mikovits said she was very impressed by the high level of competence of the research team which has been one of the leading retrovirus research team in the world since the mid 1980s. 3. POLITICAL WORK a. We continue our political work in the follow up of the Resolution 203/VIII, passed unanimously by the Catalan Parliament on May 21, 2008 to create ME/CFS-FMS treatment units in Catalonia. The Department of Health (Ministry) is, of course, trying all possible tricks in order not to carry out the Resolution, so we work very hard in the Resolution Follow-Up Commission, researching the "progress" of the implantation of the Resolution in each region of Catalonia. We have written massive reports with details provided to us by patients, health workers, etc. This Resolution is the result of two years of major work: writing legislation, meeting with politicians, gathering 150,000 signatures (Catalonia has a population of 7 million), meeting with leading Catalan figures to get their support, etc. b. We have researched and written a report on the type of training that the Catalan government is giving doctors and nurses. This training is outrageous, attempting to say that ME is actually a mild form of fibromyalgia and that it has psychological aetiology. The report was presented with a PowerPoint presentation at the Parliament's Health Commission in the fall of 2009. The report was distributed by our web massively both in Spanish and in Catalan. 4. ALLIANCES a. We work in alliance with the other Central Sensitivity Syndrome patients' associations: fibromyalgia and MCS. We have been involved in major initiatives in Spain concerning the recognition of MCS and education regarding toxics and Environmental Control. b. We give presentations to groups such as health rights coalitions, universities, nursing congresses, etc on ME and the issues around it. 5. MAY 12, 2010 - we are doing, for this May 12, a campaign, in collaboration with No Fun (the MCS-ME must Page 38/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Around Europe – European ME Alliance frequented blog in Spain) and Delirio (a digital artists collective that do social issues), on the topic of the lies of government, doctors and pharmaceutical companies. The idea is to reach out to the people with ME, MCS or FMS who are younger, more radical and feel that the patient’s association are too old fashioned for them (too full of middle-age housewives who only want to complain). This Manifesto that we have released will be in 9 languages. In Spain it is being taken up and published by news services, political magazines and being read at various May 12 events. The early response to the Catalan and Spanish versions of the Manifesto (“We Know They Are Lying”) is massive. Just the first day we had 1200 visitors and a lot of debate. We also have a Vimeo version with rock music. Current status of ME in Denmark The answers have been, that ME/CFS in Denmark has always been defined by CDC (Holmes et al), but since this definition was revised in 1994 (Fukuda et al), ME/CFS is considered identical to Chronic Fatigue Syndrome (CFS). A very interesting conclusion that seems to be shared by health authorities in practically most countries worldwide. Only a handful of doctors in Denmark know what ME is. Those who know claim that ME is identical to CFS. So here we go ... The Danish ME Association is, as one of its goals, committed to spread information and knowledge about ME – the original ME – and we have prepared medical information material from the original scientific papers on ME or medical professionals and have already sent out to some doctors, social workers and jobcentres. We have chosen to let the patients tell their GP, specialist or social worker about ME and our association and about our information material, so that the doctors can relate the material to a patient of theirs in stead of throwing it away without even having looked at it. In Denmark ME has been registered in our NIH's Classification of Diseases as a neurological disease – following the WHO ICD Classification to which DK has submitted. In spite of this very few people has been given the diagnosis ME during the last two decades. In 1992 the diagnosis ME/CFS (defined by CDC Holmes et al) was introduced by the first ME/CFS Association in Denmark, considering it to be identical to ME. This year ME/CFS has officially been declared a psychosomatic, functional illness. The patients will be offered treatment like CBT, ACT and GET, like recommended by the NICE Guidelines. A new diagnostic term has been invented by the Danish psychiatrist Per Fink and his colleagues at the University Hospital in Aarhus, Functional Disease Research Unit, called Bodily Distress Disorder, under which ME/CFS will be placed. Letters of protest have been sent to our Secretary of Health and our National Institute of Health. Invest in ME (Charity Nr. 1114035) They have all accepted that we send this material to their office, and through the feed-back from their patients we know, that they have been reading it, which in most cases is reported to have been of great help for both doctors and their patients. Also the very seriously ill patients report, that they have been treated with greater respect and understanding – something they have never experienced before. Right now we are in the process of contacting one of our local health spokesmen in order to bring this huge problem with ME and ME/CFS to the government's attention. Within the huge bunch of ME/CFS diagnosed patients, people with ME need to be located, separated and treated in the appropriate way by doctors, carers and social workers. There is still long way to go – but taking one step at a time we hope to get there. on behalf of the Danish ME Association Lajla Mark Chair Page 39/56

Journal of IiME Volume 4 Issue 1 www.investinme.org Around Europe – European ME Alliance NEWS FROM GERMANY New ME/CFS Alliance in Germany Several groups advocating for people with ME/CFS, including the national charity Fatigatio e.V. formed a new national alliance, the Bündnis ME/CFS. Its members want to join forces to have more clout when calling for the recognition of ME/CFS by German health care providers, for research and special treatment facilities for people with ME/CFS. Its first activity was a demonstration in front of the venue of the annual general meeting of the main organisation of German doctors, the “Deutsche Ärztetag” in Dresden this year – on May 12. The alliance prepared big banners with photos of people with ME/CFS – with the aim to “Give ME/CFS a face”. We published an open letter, sent it to the federal chancellor, the minister of health and other top politicians, a press release and printed a short booklet to provide basic information for physicians – on the cover “30 of 300.000 faces of ME/CFS”. For photos and results of this demonstration have a look on www.cfsaktuell.de or on www.fatigatio.de New ME/CFS Foundation to be established On the basis of her professional expertise in banking business Nicole Krüger, a young woman, suffering from ME/CFS, is about to establish a foundation for neuro-immune diseases, mainly ME/CFS. We were so impressed by IiME’s book “Lost Voices” we decided to call it “Lost Voices Stiftung” because the foundation’s mission is to give a voice to those unheard and unseen by society, by health care professionals and often even by friends and family. We are still in the process of collecting an amount of money required for the registration of a foundation and to satisfy all the red tape, but we are optimistic to have overcome all these hurdles within the next two years. Invest in ME (Charity Nr. 1114035) Hardly any treatment options for patients Still the situation in Germany is quite bad and progress is coming very slowly: only a few physicians are experts in treating multisystem disorders like ME/CFS, and they are inundated with patients so that some of them take refuge in only treating private patients. The majority of patients have no specialised treatment at all and try to get along with their often badly informed GPs and some kind of “home made” treatment, i.e. they draw some information on treatment approaches from the Internet or from Fatigatio’s publications. There’s just one clinic in the south of Germany (Spezialklinik Neukirchen) who may offer some treatment for people with ME/CFS but the waiting list is very long. Yet this clinic is not prepared to care for severely ill people, they simply don’t have the necessary equipment and provisions. There are no other clinics or centres of excellence for people with ME/CFS, and the majority of the doctors still follow our official treatment guidelines (“AWMFLeitlinien”) which are dominated by the “biopsychosocial” model. These guidelines are more or less identical to the British NICE guidelines. The standard treatment is based on the assumption that ME/CFS is a somatoform disorder which is best treated with CBT and GET. Most patients are sent or even forced to go to a “Psychosomatic Clinic” and are forced to “activate” themselves, rendering them more ill than ever. More often than not people get a psychiatric diagnosis (depression, somatoform disorder, all kinds of unproven “diagnoses”), are declared as physically healthy and sent back to the work market. Because they are simply too ill to come up with the demands of a job, they remain unemployed and, consequently, they have to live on “Hartz 4” or other minor social benefits. So the majority of the German patients is very sick and impoverished, with no appropriate treatment and too poor to pay for supplements and other helpful medication. The compulsory health insurance Page 40/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Around Europe – European ME Alliance fund and most insurance companies don’t pay for supplements and other helpful medication like antioxidants etc. There is, however, a very small group of physicians and researchers, organised in the “European Academy for Environmental Medicine” (EUROPAEM, see http://www.europaem.de) who try to withstand to the mainstream medical system and to spread their expertise on multisystem disorders like ME/CFS and related disorders. Only recently they had their annual conference in Wuerzburg (23 – 25 April) which conveyed not only a wealth of information but also hope for a better future – there are, after all, sensible and intelligent doctors who fight for us. Research ME STORY Apart from the physicians and researchers, organised in the above mentioned EUROPAEM, there’s a famous clinic in Berlin, the Charité Berlin Mitte, which is doing a little research on EBVassociated ME/CFS. The only funding they have is 20.000Euro from Fatigatio, an amount which is nothing more but a drop in the ocean. Prof. Scheibenbogen will present the results of her work on our International ME/CFS Conference in September in Dortmund. They neither have the necessary funding nor the personnel to start studies or offer treatment approaches. Moreover, Prof. Scheibenbogen is cooperating with some researchers at the Robert Koch Institute, the leading state funded medical research institute in Germany which is comparable to the MRC in Great Britain. The results of their search for XMRV in people with ME/CFS was presented at the Centennial Retrovirus Meeting in Prague (29 April – 4 May 2010). Media reports Several articles and TV reports on ME/CFS published within the last 12 months were quite different in quality, yet the number of good reports is increasing. While the renowned (or notorious…) weekly magazine “DER SPIEGEL” repeated only in March this year the old rubbish of CBT/GET and conveyed the message that it were only up to the patients whether they’ become healthy again or stay ill, the reputable weekly “DIE ZEIT” published a very balanced and well informed article. Several TV reports, though short, depicted the desperate situation of the patients appropriately. Conclusion: there’s a lot of work ahead to change Invest in ME (Charity Nr. 1114035) For a significant percentage of us deterioration is a one-way street. The NHS should aim to avoid making people more ill. In the clinics and hospitals in which I have spent time the most respect and consideration was always shown to the person most likely to die or most visibly impaired. M.E. was not seen as life- threatening and not considered to be a `serious' illness. In 1999 Dr. David Bell, a researcher and experienced clinician with a vast caseload of field experience in M.E. gave a lecture at Christie's in London entitled: "M.E. and the Autonomic System". He stated that: "People with M.E. have less activity than people, dying of HIV/AIDS, who are within two months of death." Dr. Bell was explaining that quite moderately affected M.E. patients are less able and active than terminally ill AIDS patients. The NHS needs to be educated about this patient group: A group of people who are living at a lower level of functioning than the terminally ill but who must continue in this way for years, often decades. For the severely affected M.E. sufferer management of one's health and care at a daily level is often an unsuccessfully waged battle. It is impossible to stabilise one's condition and therefore deterioration is ongoing - A person with ME Page 41/56 the situation of ME/CFS patients in Germany for the better, and we desperately need our international network to achieve some progress. European ME Alliance www.euro-me.org

Journal of IiME Volume 4 Issue 1 www.investinme.org International CFS/ME Conference CFS/ME in the 21st century – Search for groundbreaking diagnostics and treatment approaches Organised by Fatigatio e.V. – member of the European ME Alliance 25-26 September 2010 in Dortmund/Germany Venue: Best Western Parkhotel Wittekindshof Westfalendamm 270 · 44141 Dortmund Registration: Contact Fatigatio e.V., Albrechtstr. 15, 10117 Berlin/Germany or send a fax to: 0049-30-310 188 920 or visit www.fatigatio.de or (try to) call 0049-30-310 188 90. The conference is a “ticket only” event. Conference rates for patients: 30 €, for professional health care staff: 60€ Conference Speakers Prof. Dr. Rüdiger von Baehr Dr. Kurt E. Müller Dr. Annedore Höck IMD Berlin Waltenhofen Köln Personal experiences and conclusions resulting from working with CFS patients Impact of the COMT defect Chronic Fatigue Syndrome in Critical Analysis of the theoretical foundations of psychotherapeutic approaches in case of fatiguing diseases Dr. Lorenzo Lorusso / Dr. Enrica Capelli Dr. Judy Mikovits Prof. Dr. Carmen Scheibenbogen Priv. Doz. Dr. Wilfried Bieger Pavia WPI Reno Nevada CFS/ME in Italy: Clinical Approach and Research in Progress XMRV in CFS and Cancer Charité Berlin-Mitte Chronic viral infection as cause of CFS Lab4More, München Viral genesis of CFS, is XMRV involved? Prof. Dr. Wolfgang Huber Heidelberg Therapeutic approaches in CFS and differential diagnostics of fibromyalgia and multiple chemical sensitivity as related diseases Dr. Barbara Baumgarten Oslo The ME/CFS-Centre at Oslo’s university hospital. Approach in diagnostics and treatment and provisions for patients. Invest in ME (Charity Nr. 1114035) Page 42/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Around Europe – Film on ME "Make me well!" "Make me well!" I became interested in ME when a colleague told me he had a family member who had to be sheltered in a dark room. And that family member had done this for several months already. I had met them at work just one year earlier. He was 26 years old then and had all his life ahead of him. I could almost not believe that was true. I had to find out more about this. I began to read a little on the subject and talking more with my colleague about how the situation was in their home. This was a young couple who had just become parents. Also a very difficult situation when one of the parents cannot participate in the development of the child. I fully understand that they did not want to have a camera close in the next few years. But my interest in the topic had developed by then. My colleague meets a lot of people, among them 38 year old Anette Gilje, one Sunday evening at McDonalds. She had rested all day to join her friend for a little outing. My "man" comes into conversation with the ladies. They start talking about ME and he said that I'm interested in doing something on the subject. Anette had by then been ill for 12 years after having caught glandular fever in 1995. In 2000 she was diagnosed with ME. Anette was now so determined to find out how she could get rid of this something that was in her body that she was willing to let a camera follow her. Anette was used to being in the spotlight when she released a book about the controversial father of the Norwegian princess. But even for her, it was unusual that someone would film her while she was poorly. There were only very few who had seen her like that. We began the long and winding road to the target "Make Me Well!" First there was the new miracle cure that had just arrived in Norway, the Lightning Process in which 85% are cured after three days. And those who do not recover do not do the process correctly. Anette had to go through an interview process before she was to be found worthy of a place on the course. And the course would begin on nothing less than the 17th of May, the Norwegian National Day. Happily and optimistically Anette drives the wheelchair down the city centre to the course. I can only film the introduction, not the course itself. Then I wait in the hallway and watch the 17 May procession that Invest in ME (Charity Nr. 1114035) But then she heard that there was a Belgian doctor in Norway, Kenny De Meirleir, working with a group of ME patients. Anette managed to get a place in this group. Blood samples were taken and sent to different places in the world. Anette was excited. She felt that this was to be or not to be believed that something was wrong with her body. Weeks go by and then the appointment with Dr. De Meirleir arrives. He says that Anette has a systemic mycoplasma infection which they need to begin to treat before they get more information from the other blood samples. Anette is delighted that something is wrong with her?! It seems like Page 43/56 moves up to the castle. Back home Anette moves out furniture and objects that remind her of the disease. She has been told that she has imagined herself ill in all these years. But now it is over. Now she has to create a new positive thinking pattern. And then she has to begin to live like others, write, exercise, walk, dance, meet friends, etc. Course days are over and Anette has not been cured. Yet she continues to do the process, hoping that things will loosen up over time. But weeks go by and the more Anette lives like others, the more distant she becomes and the less her body seems to be functioning. In Norway there are several experts who believe that the reason people do not get better from ME is because their brains have not realised that the body is healed. Anette talks to a doctor who has a PhD in this line of thinking - an approach similar to the theories of the Lightning Process. Has Anette really kept herself sick all these years? Anette’s doctor, Barbara Baumgarten (who attended the Invest in ME conference last year), asks her anyway to stop the process if it is not helping her. She thinks it is not helpful to say that you are healthy if the body is not functioning. Anette retrieves her furniture and starts to rest again as before. But she has not lost her courage. She is a positive person. In Norway there is a centre that uses pulse diagnostics among other things to cure ME patients with a focus on massage, meditation, and healthy food and rest. Anette received full boarding for a week. But when the week was over Anette still felt that the main problem had not disappeared. The flu like feeling was still there.

Journal of IiME Volume 4 Issue 1 www.investinme.org Around Europe – European ME Alliance with this disease patients will be happy when someone finds something. Contrast this with cancer patients for example. The months go by, and new appointments. De Meirleir says that Anette has a bowel problem with overgrowth of bacteria and that this is something she was born with. This has kept her sick for all these years. Now she will start on a cocktail of drugs and syringes costing thousands of dollars. This she must cover from her own savings, because she does not have the right diagnosis for them in Norway. Anette is angry at the Norwegian health services, because she had asked the infectious disease department if they could check her bowel problems. But no luck. Now she must pay the bill. It was impressive to observe the commitment and the willingness of Anette putting herself into the clinical picture and witness the medications she had to take. I felt nauseous over everything she would put or stick in her body over the next year. First, she became worse and rested a lot and then there was sudden improvement due, in particular, to the pig liver preparation Nexavir. That did the trick for Anette. But it was an untrained body which had to begin to function again. So she got help at a rehabilitation centre in Norway with simple exercises and physiotherapy. The previously optimistic Anette actually floated now. On a rose tinted cloud. That was how it was to have a body that was not feeling sick. Anette began to engage in the situation of ME patients and went to among other things to this London conference last year. She followed and understood most of the conference, without falling apart. For me, this has been an exciting journey that has opened my eyes to the fact that what we now refer to as ME is something more than a problem in the head. And if one starts with the physical problems first, and takes care of them, I think the positive thinking comes by itself. Without having to pay a lot of money for it. Anette says that she feels 80-90% recovered since the autumn and hopes to be able to consider job opportunities, either as a student or a 50% position in book writing on the side. She is now working on a book about the journey out of darkness, which she hopes will be ready for next year's conference. Good luck with this year's conference! Best Wishes, Pål Winsents, documentary filmmaker Invest in ME (Charity Nr. 1114035) Anette pictured at home with Pål filming Make Me Well was shown first on 12th May 2010 in Oslo. Invest in ME is providing help with English subtitles and it is hoped that the film will be available to a wider audience soon. ME RESEARCH In this review we invalidate the (bio)psychosocial model for ME/CFS and demonstrate that the success claim for CBT/GET to treat ME/CFS is unjust. CBT/ GET is not only hardly more effective than non-interventions or standard medical care, but many patients report that the therapy had affected them adversely, the majority of them even reporting substantial deterioration. Moreover, this review shows that exertion and thus GET most likely have a negative impact on many ME/CFS patients. Exertion induces post-exertional malaise with a decreased physical performance/ aerobic capacity, increased muscoskeletal pain, neurocognitive impairment, “fatigue”, and weakness, and a long lasting “recovery” time. This can be explained by findings that exertion may amplify pre-existing pathophysiological abnormalities underpinning ME/CFS, such as inflammation, immune dysfunction, oxidative and nitrosative stress, channelopathy, defective stress response mechanisms and a hypoactive hypothalamic-pituitary-adrenal axis. We conclude that it is unethical to treat patients with ME/CFS with ineffective, non-evidencebased and potentially harmful “rehabilitation therapies”, such as CBT/GET. - A Review on Cognitive Behavorial Therapy (CBT) and Graded Exercise Therapy (GET) in Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) Frank N.M. Twisk and Michael Maes published by Neuroendocrinology Letters Volume 30 No. 3 2009 (http://www.ijcem.com) Page 44/56 Journal of IiME Volume 4 Issue 1 www.investinme.org SPEAKERS and ABSTRACTS of the 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Our 2007 conference was spread over two days, as a trial of developing the conference into a larger event going forward. The job of conference chair needs to be professionally performed. It became evident then that we should consider inviting a known professional to chair the conferences in order to provide greater depth and some impartiality during the conference day. Our intention was also to enable a wider awareness of the conference and the information provided. Invest in ME approached Professor Malcolm Hooper to chair the major Invest in ME conference of 2008 which dealt with sub grouping of ME. For 2009 we invited Professor Jonathan Brostoff of King’s College to chair. Both chairmen performed excellently and enhanced both conference days. This year we again welcome back Professor Hooper. Conference Chair: Professor Malcolm Hooper Emeritus Professor of Medicinal Chemistry Sunderland University, UK Professor Malcolm Hooper has served at many UK universities as well as in India and Tanzania. He has inaugurated links with Indian research institutions and universities and celebrated 25 years of productive and on-going links which have, particularly, involved the design and development of new drugs for tropical diseases and an exploration of natural products associated with Ayurvedic medicine. He has published some 50 papers in peer-reviewed journals in the field of medicinal chemistry together with major reviews on the Chemotherapy of Leprosy, the Chemistry of Isatogens. He edited one book on the Chemotherapy of Tropical Diseases. He acted as a referee for a number of important journals and served on one editorial board. He has served on committees of the Council for National Academic Awards (CNAA), the World Health Organisation (WHO) and the Science and Engineering Research Council (SERC). Professor Hooper is a member of a number of learned bodies, including the Royal Chemical Society, the British Pharmacological Society and the Society for Medicines Research, where he has Invest in ME (Charity Nr. 1114035) served on the committee for 12 years and served as Chairman for 2 years. This involved the planning and organising of major national and international conferences. He was appointed Chief Scientific Advisor to the Gulf Veterans Association (GVA) and accepted by the Ministry of Defence (MoD) as their nominee on the Independent Panel established to consider the possible interactions between Vaccines and NAPS tablets. He has also served on the Gulf Support Group convened at the Royal British Legion. His involvement with the GVA brought contact with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/M.E.) and related disorders. Gulf War Illness/Syndrome (GWI/S) has much in common with M.E./CFS. He is Patron of the Sunderland and South Shields M.E. Association and a member of the John Richardson Research Group, which includes eminent physicians and scientists performing research into CFS/M.E.. He has addressed meetings of the Pesticide Exchange Network and consulted to the Organo-Phosphate Information Network (OPIN). He worked with the Autism Research Unit (ARU) at the University of Sunderland for over 20 years, leading to involvement in biochemical studies to offer help, support and treatment for people with autism. This has also lead to research and urineanalysis of Indolyl-Acroyl-Glycine (IAG), which is an unusual metabolite found in excess of 90% of people examined in different groups of GWV, M.E./CFS and Organo-Phosphate (OP) poisoning sufferers. He served on the General Synod of the Church of England from 1970 to 1980 and he is a Christian Lay Leader, Preacher and Teacher. He has been involved in three environmental campaigns: • Toxic waste dumping, including campaign against sewage in the sea presenting to the Select Committee on Sewage Treatment and Disposal • GWI/S, presenting to the Defence Select Committee • M.E./CFS and OP/Pesticide poisoning Invest in ME invited Professor Hooper to chair the 3rd Invest in ME International ME/CFS Conference 2008. For additional articles by Professor Hooper on the IiME web site see http://tinyurl.com/2wkbaar Page 45/56

Journal of IiME Volume 4 Issue 1 www.investinme.org SPEAKERS and ABSTRACTS of the 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Professor Leonard Jason PhD Prof. of Clin. & Community Psychology, Director, Center for Community Research, DePaul University, Chicago Professor Leonard Jason, Ph.D., is among the most prolific of all CFIDS researchers. For more than a decade, Professor Jason and his team at DePaul University’s Centre for Community Research have worked to define the scope and impact of CFS/ME worldwide. Professor Jason was Vice President of the International Association for Chronic Fatigue Syndrome (now the IACFS/ME) and has been a key driver of CFS research since 1991, and is uniquely positioned to support collaboration between CFS researchers, patients, and government decision makers. His studies have shown that the direct and indirect costs of ME/CFS amount to $20 billion in the U.S. each year, and more than 1 million people suffer from ME/CFS as opposed to the estimated 20,000 people originally reported by the CDC (Centers for Disease Control and Prevention). Professor Leonard Jason – Abstract: The scientific enterprise depends on reliable and valid ways of classifying patients into diagnostic categories, and this critical research activity can enable investigators to better understand etiology, pathophysiology, and treatment approaches for CFS and other disorders. When diagnostic categories lack reliability and accuracy, the quality of treatment and clinical research can be significantly compromised. A misdiagnosis may lead to improper treatment and in cases of severe illness, the matter of an incorrect diagnosis can have serious consequences. In other words, the validity (i.e., usefulness) of a diagnostic category is inherently limited by its reliability. Therefore, to the extent to which a diagnostic category is unreliable, a limit is placed on its validity for any clinical research. The poor understanding of the pathophysiology of ME/CFS may be due case definitions lacking reliability and validity, and improving the case definition Invest in ME (Charity Nr. 1114035) may prevent complications in identifying biological markers in this illness. In this presentation, issues concerning reliability of clinical diagnosis will be presented, and they are complex and have important research and practical implications Professor Nora Chapman Ph.D. Associate Professor Department of Pathology and Microbiology University of Nebraska Medical Center 986495 Nebraska Medical Center Professor Nora Chapman is a Research Scientist at the University of Nebraska Enterovirus Research Laboratory and Associate Professor at the University of Nebraska Medical Centre. Professor Chapman studies persistent coxsackie infections in murine models of chronic myocarditis and dilated cardiomyopathy. She and her associates have demonstrated that selection of defective enterovirus in heart and other tissues leads to persistent infections despite active antiviral immune responses. Dr. Chapman is presently studying the mode of selection of these viruses and the effects of replication of these viruses upon infected cell function. Dr. Chapman and her associates at the University of Nebraska are further investigating Dr. John Chia’s work in regards to enterovirus in the gut biopsies. Professor Nora Chapman – Abstract: Persistent Enterovirus Infections Enterovirus infections have been found in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Enteroviruses are readily cleared by the immune response in most individuals. However work on inflammatory heart disease has demonstrated the presence of enteroviral RNA in human hearts after enterovirus infection cannot be detected by cytopathic assays. We have demonstrated that this type of Page 46/56 Journal of IiME Volume 4 Issue 1 www.investinme.org SPEAKERS and ABSTRACTS of the 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE persistent infection by a group of enteroviruses, the coxsackievirus B viruses (CVBs), is due to the continued but low level infection by defective CVBs. These defective viruses have a defect which lowers the level of enterovirus RNA but does not preclude the expression of the viral proteins. This mode of persistent infection normally occurs in tissues which do not have a high level of cell division. The defective enteroviruses are selected by the absence of a nuclear protein in the cytoplasm of non dividing cells. This mode of persistent infection leads to a number of conclusions: (1) persisting defective enterovirus can only be detected by assays for viral protein or RNA, not by cytopathic assays, (2) (3) if enterovirus is persisting, the level of viral RNA per cell will be low, leading to a requirement for a high level of sensitivity and the effects of an enterovirus infection can persist for a period of months. As enteroviruses infect a number of tissues, muscular or neurologic effects of this infection may be associated with some of the symptoms of ME/CFS but confirmation of this type of persistence requires sensitive assays. Dr John Chia MD Dr Chia is an infectious disease specialist practicing in Torrance, California, USA and has published research recently (Chronic fatigue syndrome associated with chronic enterovirus infection of the stomach) on the role of enteroviruses in the aetiology of ME/CFS – an area which has been implicated as one of the causes by a number of studies. There are more than 70 different types of enteroviruses that can affect the central nervous system, heart and muscles, all of which is consistent with the symptoms of ME/CFS. By analyzing samples of stomach tissue from 165 patients with CFS, Dr. Chia's team discovered that 82% of these individuals had high levels of enteroviruses in their digestive systems. Dr Chia's research may result in the development of antiviral drugs to treat the debilitating symptoms of ME/CFS. Invest in ME (Charity Nr. 1114035) Dr. John Chia – Abstract: Enterovirus Infection in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Diagnosis and Treatment. John Chia, Andrew Chia. EV Med Research ME/CFS is an elusive illness without a clear etiology and treatment. Emerging evidences suggest that enteroviruses can persist in the tissues of ME/CFS patients and may be responsible for the various symptoms. Enteroviruses are common causes of respiratory, gastrointestinal and non-specific flu-like illnesses. Major epidemics of enterovirus infections including but not limited to meningoencephalitis, myocarditis, pleurodynia, myositis and handfoot-mouth diseases have been well-documented in the past decades. In some cases, acute enterovirus infections can cause CD8+ T lymphocytopenia predisposing to reactivation of endogenous herpes viruses. Initial isolation of enteroviruses from patients with acute infections followed by demonstration of persistent viral infection in tissues years after the patients developed chronic symptoms lends support to the pathogenic role of enteroviruses in ME/CFS. Presumptive clinical diagnosis of chronic enterovirus infection requires a high index of suspicion, familiarity with the protean manifestations of acute infections and understanding of chronic viral persistence. There is not yet a specific diagnostic test for ME/CFS. Significantly elevated neutralizing antibody titer over time suggests persistent immunologic response to specific enterovirus(s) infection in the tissues. Neutralizing antibody test for non-polio enteroviruses is not widely available. In contrast to other types of viremic infections, EV RNA levels in whole blood of ME/CFS patients are extremely low, which likely explain the discrepancy of results reported from different research laboratories over the past two decades. Immunoperoxidase staining for viral protein in the stomach biopsies is more sensitive than the neutralizing antibody test or EV RNA detection, and furthermore, demonstrates the antigens in tissues where viruses are expected to replicate and persist based on the route of Page 47/56

Journal of IiME Volume 4 Issue 1 www.investinme.org SPEAKERS and ABSTRACTS of the 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE transmission. The finding of enteroviral RNA and growth of non-cytopathic viruses from the same tissues support the validity of protein staining. As enteroviruses have been largely forgotten since the eradication of poliomyelitis through effective vaccination, there is no specific antiviral therapy for acute or chronic infections. Pleconaril, an anti-capsid agent, showed limited benefit in 1/4 patients with ME/CFS associated with chronic enterovirus infections. Intravenous immunoglobulin, given monthly or every few months, can ameliorate inflammatory symptoms in less than 1/3 of adult patients, but may be more effective in pediatric patients. The combination of alpha and gamma interferon can induce short-term remission in about 45% of ME/CFS patients with debilitating myalgia, but is quite expensive and often poorly tolerated. Oxymatrine, or Equilibrant, have beneficial effects in 52% of 500 ME/CFS patients, but transient increase in pre-existing symptoms are expected in most of the patients. Cytokine gene expression study during therapy demonstrates an increase of IL12/Il10 ratio in 7/7 responders but in 0/10 non-responders. A decrease of stainable enteroviral protein is demonstrated in the stomach biopsies of few responders on oxymatrine or Equilibrant therapy. Previous evidence for enterovirus infection in ME/CFS from over a decade ago has been confirmed and extended in recent studies. Development of antiviral therapy against enteroviruses is paramount; and the importance of enteroviruses in ME/CFS can be realized with a randomized, placebo-controlled antiviral drug trial. and scientific presentations in a range of fields relevant to the illness. While practicing in Lake Tahoe in 1984-1987, Dr. Cheney, along with Dr. Dan Peterson, helped lead a research effort with the NIH, the CDC and Harvard University School of Medicine studying a localized outbreak of what would eventually be known as ME/CFS. He was a founding Director of the American Association of CFS (now the International Association for CFS/ME). Dr. Cheney holds a PhD in Physics from Duke University in Durham, NC and is a graduate (MD) of Emory University School of Medicine in Atlanta, GA where he also completed his internal medicine residency. He is a board certified internist. Since 1990, Dr. Cheney has headed the Cheney Clinic, presently located in Asheville, NC. The Cheney Clinic specializes in evaluating CFS patients and has expertise in diagnosis, disability support for and treatment of chronic fatigue syndrome. No single clinic has drawn as many CFS patients (currently over 5,000) from as many states (48) and foreign countries (22) as has the Cheney Clinic. Dr. Paul Cheney – Abstract: Oxygen Toxicity as a Control Point in the Management of Chronic Fatigue Syndrome By Paul R. Cheney MD, PhD Dr. Paul Cheney MD, PhD Dr. Paul Cheney, MD, PhD, is Medical Director of the Cheney Clinic in Asheville, North Carolina. For more than 25 years, Dr. Cheney has been a pioneering clinical researcher in the field of ME/CFS and has been an internationally recognized authority on the subject of ME/CFS. He has published numerous articles and lectured around the world on ME/CFS. Dr. Cheney has been interested in many aspects of ME/CFS, and is author or co-author of numerous publications Invest in ME (Charity Nr. 1114035) BACKGROUND The subject of oxygen utilization, and especially the lack of it in CFS, has been the focus of many investigations. The oxygen response deficit with exercise in CFS is very appealing as an avenue of explanation for fatigue. Whether it is cause or effect, however, is unknown. We began our studies on oxygen itself by noting with echocardiography that patients with CFS had a much higher incidence of diastolic dysfunction than control groups. Cardiac diastolic dysfunction has a strong energy dependent component and therefore potentially related to oxygen utilization and to CFS. METHODS: During a ten-month period, 67 consecutive patients plus 24 additional patients presenting for either initial or follow-up evaluation for CFS were evaluated using echocardiography coupled to a series of varied interrogations on the echo Page 48/56 Journal of IiME Volume 4 Issue 1 www.investinme.org SPEAKERS and ABSTRACTS of the 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE table in real time. After routine, though expanded echocardiography, each patient was evaluated for IVRT response before, during and after oxygen administration for 5 minutes each, initially at 4 lpm NC and then typically at progressively higher doses up to 40% FIO2 mask oxygen at 10 lpm flow rate if they were non-toxic to 4 lpm NC. IVRT or isovolumetric relaxation time is an internal timing measurement in milliseconds (msec) on echocardiography, which is inversely related to cellular free energy in myocardial cells. All 67 patients were categorized as either new patients or patients on various treatment algorithms if they were follow-up patients. The various treatment algorithms are complex as well as novel and cannot be fully discussed here but serve to illustrate the power of the proposed oxygen toxicity model to discriminate among various treatments. RESULTS: The 91 total patients were segregated into a) new patients, b) patients treated in this clinic with standard therapies, c) patients treated in this clinic with standard therapies plus one novel, low molecular weight (LMW), cell signaling factor (CSF) peptide in a transdermal gel and d) patients treated in this clinic with standard therapies plus an expanded set of LMW, cell signaling factor gels. Of the 67 consecutive patients, less those who did not meet criteria for CFS and/or were deemed atypical (6 were so categorized), 26 were new patients and 25 of 26 or 96.1% were toxic to oxygen as evidenced by a rise in IVRT on exposure to oxygen and indicating a reduction in myocardial cellular energetics. 26 of 26 new patients or 100% were toxic to 40% mask oxygen. This contrasts to 6 of 17 or 35% of the controls that were toxic to oxygen at 4 lpm and 11 of 17 or 65% of controls that were toxic to 40% mask oxygen. When patients from the group of 67 consecutive cases, excluding the 6 outliers as well as treatment responders, were statistically compared (N = 53) in their IVRT response on oxygen to the controls (N = 17) on oxygen at 4 lpm NC, there was almost no chance they could have been the same group (p < 0.0004). CONCLUSION: These results demonstrate that within certain well defined limits of the case definition for CFS, the relative cardiac cellular energetic response to oxygen in CFS (strongly negative) compared to Invest in ME (Charity Nr. 1114035) controls (strongly positive to weakly negative) is significantly different (p < 0.0004). Furthermore, that the absolute response to oxygen (toxic vs. tolerant) yields 96% sensitivity (CFS being essentially a strongly oxygen toxic state) and 65% specificity compared to controls (35% are weakly toxic) at 4 lpm NC. At 40% mask oxygen, 100% of CFS cases are toxic, but so were 65% of controls. When patients were sub-categorized according to increasingly powerful treatment algorithms, they were increasingly transformed to an oxygen tolerant state, which in the case of the most powerful algorithm, was associated with a significantly (p<0.006) improved clinical status. We conclude that CFS is an oxygen toxic state and that oxygen toxicity status appears to determine outcome in therapeutic trials and is therefore, a control point in the evaluation of chronic fatigue syndrome. DISCUSSION: These findings appear to force a narrowing of potential causes of CFS because whatever pathophysiology one puts forth must explain universal oxygen toxicity in chronic fatigue syndrome. It is also important to view oxygen toxicity as less a cause of CFS but rather a final common pathway whose presence is downstream from the issue of etiology or etiologies, though it appears to determine outcome. Dr. Jonathan Kerr MD, PhD “Sir Joseph Hotung Senior Lecturer in Inflammation” at St.George’s University of London and Consultant in Microbiology in the Dept. of Cellular and Molecular Medicine Jonathan Kerr qualified in medicine from Queen’s University of Belfast (1987), and completed training as a medical microbiologist (1995). He has worked as a microbiologist in Belfast, Manchester and London, taking up post as a Consultant Senior Lecturer in Microbiology at Royal Brompton Hospital / Imperial College in June 2001, and then Sir Joseph Hotung Clinical Senior Lecturer in Inflammation at St George’s University of London in 2005. His interest in Chronic Fatigue Syndrome (CFS) began during a study of the consequences of Page 49/56

Journal of IiME Volume 4 Issue 1 www.investinme.org SPEAKERS and ABSTRACTS of the 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE parvovirus B19 infection, when he showed that a percentage of infected cases developed CFS which persisted for several years. He is now the principal investigator in a programme of research in CFS. This involves development of a diagnostic test using mass spectrometry, analysis of human and viral gene expression in the white blood cells, and clinical trials of immunomodulatory drugs. Dr. Jonathan Kerr and colleagues at St. George’s University of London reported in the July 27, 2005 issue of the Journal of Clinical Pathology that a preliminary study of 25 CFS patients and 25 matched healthy controls revealed abnormalities in 35 of 9,522 genes analyzed using microarray technology. Polymerase chain reaction studies showed the same results for 16 of these genes. The study, and its results, raises some important questions. The first of which pertains to the need for funding of microbiological CFS research. He is funded (>£1million) by the CFS Research Foundation (www.cfsrf.com), a charitable organization based in the U.K., and leads a group of 5 scientists at St George's. His research on gene expression has resulted in several published papers – including evidence of 7 distinct sub types of ME/CFS. Dr. Kerr also runs a ME/CFS research program. He studied the consequences of parvovirus B19 infection in ME/CFS and showed that a percentage of infected cases developed ME/CFS which persisted for several years. He has reported 88 human genes whose dysregulation is associated with CFS, and which can be used to derive genomic CFS subtypes which have marked differences in clinical phenotype and severity. Dr Jonathan Kerr – Abstract: Study of single nucleotide polymorphisms (SNP) in Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) and CFS/ME subtypes Nana Shimosako, Jonathan R Kerr. 1CFS Group, Division of Clinical Sciences, St George’s University of London, London, UK. We have recently reported gene expression Invest in ME (Charity Nr. 1114035) changes in patients with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) and the utility of gene expression data to identify subtypes of CFS/ME with distinct clinical phenotypes (Kerr JR et al. J Infect Dis 2008;197:1171-84). Due to the difficulties in using a comparative gene expression method as an aid to CFS/ME disease and subtype-specific diagnosis, we attempted to achieve such a method based on single nucleotide polymorphisms (SNP) alleles. To identify SNP allele associations with CFS/ME and CFS/ME subtypes, we tested genomic DNA of CFS/ME patients (n=108), endogenous depression patients (n=17), and normal blood donors (n=68) for 454 - 504 human SNP alleles based within 88 CFS-associated human genes using the SNP Genotyping GoldenGate Assay (Illumina, San Diego, CA, USA). 359 Ancestry informative markers (AIM) were also examined. 21 SNPs were significantly associated with CFS/ME, when compared with depression, & normal groups. 148 SNP alleles had a significant association with one or more CFS/ME subtypes. For each subtype, associated SNPs tended to be grouped together within particular genes. AIM SNPs indicated that 4 subjects were of Asian origin while the remainder were Western European. Hierarchical clustering of AIM data confirmed the overall heterogeneity of all subjects. This study provides evidence that human SNPs located within CFS/ME associated genes are associated with particular gene expression subtypes of CFS/ME. Further work is required to develop this into a clinically useful aid to subtypespecific diagnosis. Dr. Nancy Klimas MD Dr Nancy Klimas MD, is a Professor of Medicine, Psychology, Microbiology and Immunology at the University of Miami School of Medicine. She is the University’s director of the Allergy and Immunology Clinic as well as Director of Research for the Clinical AIDS/HIV Research at the Miami Veterans Affairs Medical Centre. She is a member of the federal CFS Advisory Committee (CFSAC) and former President and Page 50/56 Journal of IiME Volume 4 Issue 1 www.investinme.org SPEAKERS and ABSTRACTS of the 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE current Board Member of the International Association of CFS/ME (IACFS/ME) and a founding editor of the Journal of Chronic Fatigue Syndrome. Dr Klimas has been a leader in the field of ME/CFS research for many years and recently opened a model clinic for CFS patients with the aim to treat patients as well as train doctors. Dr Klimas has published over a 130 peer reviewed scientific papers. As the principal investigator of one of the NIH sponsored CFS Research Centers she leads a multidisciplinary research team representing the fields of immunology, autonomic medicine, neuroendocrinology, behavioral psychology, rheumatology, nutrition, and exercise physiology. The University of Miami CFS Research Center is exploring interactions between the immune, autonomic and neuroendocrine. Dr Nancy Klimas – Abstract: Immunologic Biomarkers in ME/CFS Nancy Klimas, M.D* # , Gordon Broderick, PhD**, Mary Ann Fletcher, PhD* University of Miami Miller School of Medicine, Miami VAMC* Medical Director, CFS Clinic www. CFSClinic.com# University of Alberta** In this presentation the current data supporting immune biomarkers will be presented and the sorts of interventions suggested will be explored. The search for biomarkers in ME has become increasingly urgent, both in their potential role in diagnostics and in the design of clinical trials. Biomarkers can be used to define subgroups of patients appropriate for specific interventions such as immunologic abnormalities suitable for immunomodulatory trials. Within the immunologically impacted patient ME/CFS populations there are two primary areas ripe for immune interventions: interventions that would enhance cytolytic function promoting antiviral activity and improve cancer surveillance, and interventions to quiet immune inflammatory pathways or quiet chronic immune activation. Invest in ME (Charity Nr. 1114035) The evidence supporting each of these areas of immune dysfunction will be presented, s well as their clinical implications. Chronic immune activation has been documented by many investigators, including our group. The potential causes of chronic immune activation will be discussed, as well as concerns for health consequences related to living in a state of chronic immune activation. These sorts of therapy are possible, have promising preliminary data and deserve further clinical trials. There is another interesting area of potential intervention coming from ongoing studies of immune-autonomic and immune endocrine linkages. Data will be presented from an ongoing exercise challenge study that has discovered substances made by the immune system that directly turn on sympathetic (adrenaline) responses in the autonomic nervous system. By discovering these biomarkers in our studies, we have also discovered pathways that could be targeted in interventive trials. Finally, by putting the immune dysregulation into the bigger context of systems biology this lecture will conclude with the concept of virtual clinical trials to expedite and focus clinical trials efforts in the most effective and efficient fashion. Professor Brigitte Huber PhD Professor Huber studied immunogenetics at University of London and is currently Professor of Pathology at Tufts University, Boston, USA. Dr. Huber joined the faculty of Tufts Medical School in 1977, and her laboratory has investigated the cellular and molecular mechanisms involved in the immune response since that time. She has studied the presence of retrovirus HERV K-18 as a marker for those who might develop ME/CFS after an acute infection such as mononucleosis. Her research shows that EBV induces the HERV K-18 envelope gene to trigger the expression of a specific superantigen and that Page 51/56

Journal of IiME Volume 4 Issue 1 www.investinme.org SPEAKERS and ABSTRACTS of the there are more HERV K-18 alleles in post-mono ME/CFS patients than in controls. Professor Brigitte Huber – Abstract: Presence of Retrovirus as a Biomarker for ME/CFS The etiology of Chronic Fatigue Syndrome (CFS) is far from understood and is likely due to multiple genetic components. Infection with EBV (EpsteinBarr virus) and treatment with IFN-α have been implicated in the pathogenesis. Our laboratory has shown that EBV-infection, as well as exogenous IFN-α, activate transcription of the env gene of a Human Endogenous Retrovirus, HERV-K18. This provirus is normally silent, but when induced it encodes a superantigen (SAg), which is a class of proteins that is capable of deregulating the immune system. In preliminary studies we had observed that HERV-K18 mRNA levels are significantly higher in B cells from CFS patients compared to the baseline expression seen in healthy controls. Thus, we hypothesized that HERV-K18 is a risk factor for CFS. To address this working model in more detail, we are collecting a cohort of blood samples from patients who developed CFS after suffering from infectious mononucleosis, caused by EBV infection. Each individual is bled 3x over a two-year period, in order to check for fluctuations in HERV-K18 expression, in relation to disease symptoms. This cohort is compared to two other cohorts, consisting of 1) CFS patients who did not have infectious mononucleosis, and 2) healthy controls that have baseline HERV-K18 expression only. The data we have obtained so far from these ongoing studies will be presented. These patients have also been tested for XMRV, a newly discovered g-retrovirus, xenotropic murine leukemia virus-related virus, that has been claimed to be prevalent in CFS patients. Our data on this work will be presented and discussed. 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Annette Whittemore Founder and President of the Whittemore Peterson Institute for Neuroimmune Diseases, Reno, Nevada, USA Annette Whittemore graduated from the University of Nevada with a BS Ed in Elementary and Special Education. Teaching children who had neuro-cognitive deficits, like those found in autism, ADD, and learning disabilities, provided her with a unique experience to later use in her pursuit of answers to her daughter's serious illness. Annette is the parent of a young adult who was severely affected by CFS and HHV-6. She and her husband are business owners and philanthropists in Reno and Sparks. Annette Whittemore was President and Cofounder of the foundation and became active in starting the HHV-6 foundation. She started the foundation with Kristin Loomis from California after a brief meeting in Incline, NV. with Dr. Daniel Peterson, a leading clinical researcher in CFS and HHV-6. When her daughter became ill with a chronic neuroimmune disease, Annette began to seek appropriate medical care. Annette found that few doctors understood the reasons for her daughter's continuing physical decline. For this reason, Annette has committed her time and resources to bringing attention to the serious nature of neuroimmune diseases and change her community in a positive way. She began this important mission in 1994 by supporting a Think Tank on ME/CFS, led by Dr. Daniel Peterson of Incline Village. In 2004 she and another patient advocate began a medical foundation to support research to find biomarkers of disease and treatments for patients impacted by the HHV-6A virus. In order to provide solutions for patients and bring new doctors into this field of medicine, Annette, legislators, and others supported a bill to build a biomedical research center at the University of Nevada, Reno with an Institute for Neuro-Immune disease and the Nevada Cancer Institute. Annette founded the WhittemorePeterson Institute for Neuroimmune Diseases which is being built on the medical campus with its mission to serve those with complex neuroimmune diseases such as ME/CFS, viral induced central nervous system dysfunction and Invest in ME (Charity Nr. 1114035) Page 52/56 Journal of IiME Volume 4 Issue 1 www.investinme.org SPEAKERS and ABSTRACTS of the 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE fibromyalgia. In addition, Annette and Harvey have contributed over one million dollars and pledged another four million dollars in support of the building and programming to bring this project to fruition. As the Founder and President, Annette supports the basic and clinical research programs, recruitment of physicians and support personnel, while also leading fundraising activities. Researchers at the University of Nevada Medical School have also become collaborators on projects that are vital to our understanding of the immune deficits seen in these patients. Dr Judy Mikovits PhD WPI, Reno, Nevada, USA Dr. Mikovits obtained her Ph.D. in Biochemistry and Molecular Biology from George Washington University. She served as a senior scientist at Biosource International, where she led the development of proteomic assays for the Luminex platform that is used extensively for cytokine activity assessment in therapy development. Dr. Mikovits spent more than 20 years at the National Cancer Institute in Frederick MD during which time she received her PhD in Biochemistry and Molecular Biology, investigating mechanisms by which retroviruses dysregulate the delicate balance of cytokines in the immune response. This work led to the discovery of the role aberrant DNA methylation plays in the pathogenesis of HIV. Later at the NCI, Dr. Mikovits directed the Lab of Antiviral Drug Mechanisms (LADM) a section of the NCI's Screening Technologies Branch in the Developmental Therapeutics Program. The LADM's mission was to identify, characterize and validate molecular targets and to develop high-throughput cell-based, genomic and epigenomic screens for the development of novel therapeutic agents for AIDS and AIDS-associated malignancies (Kaposi's sarcoma). Formally trained as a cell biologist, molecular biologist and virologist, Dr. Mikovits has studied the immune response to retroviruses and herpes viruses including HIV, SIV, HTLVI, HERV, HHV6 and HHV8 with a special emphasis on virus host cell interactions in cells of the hematopoietic system including hematopoietic stem cells (HSC). Dr. Mikovits' commercial experience includes serving as a senior scientist and group leader at Biosource International, where she led the Invest in ME (Charity Nr. 1114035) development of proteomic assays for the Luminex platform that is used extensively for cytokine activity assessment in therapy development. She also served as Chief Scientific Officer and VP of Drug Discovery at Epigenx Biosciences, where she led the development and commercialization of cell and array-based methylation assays for drug discovery and diagnostic development. She is Research Director at the Whittemore Peterson Nevada for Neuro-Immune disorders and has co-authored over 40 peer reviewed publications that address fundamental issues of viral pathogenesis, hematopoiesis and cytokine iology. (thanks to the WPI web site for this information) Dr Judy Mikovits – Abstract: Implications of XMRV Research for ME/CFS In 2006, sequences of a novel human retrovirus, XMRV, were identified and reported to be associated with a subset of hereditary prostate cancer. Although the public health implications of this finding were not immediately clear, the seminal study published late in 2009 showed XMRV is clearly a health concern (Lombardi et al, Science 2009;326:585-589). This study describes the detection of XMRV in about two-thirds of patients diagnosed with ME/CFS. Moreover, it was the first demonstration of the replication and production of infectious XMRV in human blood cells. Because of the potential risk of blood transfusion transmission of this emerging virus, national transfusion services in Canada, Australia, and New Zealand took the precautionary step to defer donors with CFS from giving blood. Data will be presented showing in both prostate cancer and ME/CFS as well as other neuroimmune diseases and cancers, the host mounts a humoral response to XMRV and infected patients are viremic for transmissible virus present in the plasma. Despite the fact that XMRV research is in its infancy, considerable attention has been focused on this recently discovered human retrovirus. This discovery opened up a new area of research with many unanswered questions: What is the prevalence of XMRV in the human population? Is XMRV a direct cause of one or both of these diseases or does it contribute their development or progression? How is XMRV transmitted? What are the tissue reservoirs of XMRV? Does XMRV affect innate and/or adaptive immune responses? What is Page 53/56

Journal of IiME Volume 4 Issue 1 www.investinme.org ME STORY SPEAKERS and ABSTRACTS of the 5th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE the key immune cell target? It is present in other immune compromised individuals? Does XMRV play a role in malignancy or other neuroimmune illnesses? XMRV is the first human infectious gamma retrovirus identified. There are now three known human exogenous retroviruses, HIV, HTLV (both complex retroviruses) and XMRV (simple retrovirus). Human retroviruses are all associated with cancer and neurological disease. The existence variants of HIV and HTLV with different pathogenic profiles suggesting there could be variants of XMRV which contribute to the divergent disease profiles seen in ME/CFS and may explain the inability to detect XMRV using PCR primers highly specific to the current infectious molecular clone VP62 constructed from prostate cancer sequences. Like other retroviral infections, XMRV integrates into hostcell DNA and becomes lifelong. Information on murine xenotropic viruses as well as current research on cellular tropism, and cis-acting glucocorticoid response elements, provides intriguing clues for viral persistence, mechanisms of pathogenesis and opportunities for XMRV as a diagnostic biomarker and therapeutic target in ME/CFS. For a significant percentage of us deterioration is a one-way street. The NHS should aim to avoid making people more ill. In the clinics and hospitals in which I have spent time the most respect and consideration was always shown to the person most likely to die or most visibly impaired. M.E. was not seen as life- threatening and not considered to be a `serious' illness. In 1999 Dr. David Bell, a researcher and experienced clinician with a vast caseload of field experience in M.E. gave a lecture at Christie's in London entitled: "M.E. and the Autonomic System". He stated that: "People with M.E. have less activity than people, dying of HIV/AIDS, who are within two months of death." Dr. Bell was explaining that quite moderately affected M.E. patients are less able and active than terminally ill AIDS patients. The NHS needs to be educated about this patient group: A group of people who are living at a lower level of functioning than the terminally ill but who must continue in this way for years, often decades. For the severely affected M.E. sufferer management of one's health and care at a daily level is often an unsuccessfully waged battle. It is impossible to stabilise one's condition and therefore deterioration is ongoing - A person with ME Comments of doctors to ME patients: • “Throw away your crutches – it’s your head that needs them, not your legs” • “Women of your age imagine aches and pains–are you sure you’re not attention-seeking?” • “I’m not prepared to do any tests, they cost money” • “Shut up and sit down” • “You area menace to society–a pest. I wish you’d take yourself away from me” • “You middle class women have nothing else to worry about” • “Its one of those thing you silly young women get” • “Hypochondriac, menopausal, you have the audacity to come here and demand treatment for this self-diagnosed illness which does not exist” • “Stop feeling sorry for yourself – I have patients with real illnesses, patients who are dying from cancer” • “ME is a malingerer’s meal ticket” • “Your inability to walk is in your mind” • “I’m not going to further your career of twenty years of being ill” • “Nothing at all wrong with this woman – Put her on valium” (to GP from Consultant). from “Magical Medicine: How to Make a Disease Disappear”. See http://tinyurl.com/2uv8j95 Invest in ME (Charity Nr. 1114035) Page 54/56 Journal of IiME Volume 4 Issue 1 www.investinme.org Dr. David Bell European Lecture Tour Autumn 2010 European ME Alliance Members Sponsor Dr. David Bell on European Lecture Tour Members of the European ME Alliance are to sponsor a series of lectures in Europe by Dr David Bell. The lectures are to take place in late September and EMEA are hoping that Dr. Bell will be able to visit most of the countries included in the EMEA group - Ireland, UK, Norway and Sweden with Belgium and Spain being possibilities. In the UK Invest in ME will be arranging the schedule with Oxford, Norwich and Sunderland being likely venues for presentations. Dr Bell has recently been performing studies on XMRV and will have results in time for the lectures. For more information on the David Bell Lecture Tour please contact EMEA - http://www.eurome.org/contact.htm For more information on the David Bell Lecture Tour in the UK please contact IiME at info@investinme.org. The Invest in ME International ME/CFS Conference DVDs Invest in ME have available the full presentations from the International ME/CFS Conferences in London of 2009, 2008, 2007 and 2006. We shall also have the 2010 conference available on DVD. These professionally filmed and authored DVD sets each consist of four discs, in Dolby stereo and in PAL (European) or NTSC (USA/Canada) format. Containing between six and nine hours for each DVD set they contain all conference presentations plus interviews with ME presenters and news stories from TV programmes. Because the conferences are CPD accredited these DVDs may also be used for CPD training and count towards healthcare professionals’ training quota. These DVDs have been sold in over 20 countries and are available as an educational tools – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://www.investinme.org/InfoCentre%20Education%20Homepage.htm or via emailing Invest in ME at meconference@investinme.org. UK Price £12 each - including postage and packaging. Invest in ME (Charity Nr. 1114035) Page 55/56

Journal of IiME Volume 4 Issue 1 55tt hh I Innvveesstt iinn MMEE I In ern attiiona ME CFS 24 h 07:45 Registration 08:55 Welcome 09:05 09:50 10:35 11:15 11:35 12:20 12:50 13:40 14:25 15:10 15:30 15:45 16:40 17:30 In How Case Defin Implications for Epidemiology, Aetiology, and Pathophysio itions Can Stigmatize: iology Persistent Enteroviral Infections Enteroviruses in ME/CFS, Diagnosis and Treatment Coffee/Tea Break Diastolic Dysfun nction in ME/CFS: A Cardiac Manifestation of Cellular Energy Defects in ME/CFS. Study of SNPs to determine subtype status in CFS patients Lunch Immunological Biomarkers in ME/CFS Presence of Retrovirus as a Biomarker for ME/CFS Coffee/Tea Break Future Pathway ys of Research into ME Plenary Session Adjourn Ways to help Invest in ME • Wristbands Suppo ort biomedical research into ME – IiME • Donate to the Invest in ME Biomedical research Fund • Donate to IiME Support ME Aware http://www.investinme.org/helpus.htm eness Invest in ME (Charity Nr. 1114035) Invest in ME www.investi inme.org Page 56/56 An Implications of XMRV Research for ME/CFS Dr J nette Whittemore Judy Mikovits PhD Professor Hooper + Presenters Dr Nancy Klimas MD Professor Brigitte Huber PhD Pr Ch Dr J ofessor Nora apman PhD John Chia vest in ME Pro Jaso ofessor Leonard son PhD ntterna onall ME//CFS 24tth May 2010 CCoonnffeerreennccee AAggeennddaa May 2010 www.investinme.org Dr Paul Cheney MD, PhD Dr J PhD Jonathan Kerr MD, D

The Journal of IiME Volume 5 Issue 1 from Invest in ME www.investinme.org

Journal of IiME Volume 5 Issue 1 (May 2011) The name ' Lost Voices' refers both to the fact that people who are severely ill with ME are generally not in a position to make themselves heard, and also to the way that the prejudiced denial of ME - as an 'aberrant belief' rather than a devastating physical illness - has meant that often others are incapable of actually hearing and seeing what is being said and shown. 'Lost Voices' is primarily written by people affected by severe ME and clearly and movingly shows the evidence of the devastating impact this physical disease has on individuals and their carers and families. It illustrates the plight of ME sufferers and can help change a widespread lack of comprehension about the disease based on general misinformation, vague definitions and manufactured statistics, The book also contains facts about ME with contributions from experts such as Dr. John Chia, Professor Leonard Jason and Annette Whittemore. Please buy this book - for yourself or for friends, relatives or for your GP - or suggest it as a gift for others to buy. To order „Lost Voices‘ Email to info@investinme.org or go to our web page athttp://www.investinme.or g/LostVoicesBook/IiME Lost Voices home.htm IiME Conference DVDs These Invest in ME conference DVDs are professionally filmed and authored DVD sets consisting of four discs in Dolby stereo and in PAL (European) or NTSC (USA/Canada) format. They contain all of the presentations from Invest in ME International ME/CFS Conferences (2006 – 2011). Also included in the DVD sets are interviews with ME presenters, news stories and round-table discussions. These Invest in ME conference DVDs have been sold in over 20 countries and are available as an educational tool – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://www.investinme.org/InfoCentre%20Education%20Homepag e.htm or via emailing Invest in ME at info@investinme.org Invest in ME (Charity Nr. 1114035) www.investinme.org Page 2/58 Journal of IiME Volume 5 Issue 1 (May 2011) 3 10 Inside This Issue Editorial Using Cardiopulmonary Exercise Testing to Evaluate Fatigue and Post-Exertional Malaise in ME/CFS 13 18 22 The Media and ME Letter from America International Science Symposium on ME 30 A UK Centre for Biomedical Research into ME 34 The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the DWP 42 55 47 55 PACE is dead, long live PACE? CFS Education in USA Presenters at IiME Conference Conference Agenda Invest in ME (UK Charity Nr. 1114035) PO BOX 561 Eastleigh SO50 0GQ Hampshire, UK Tel: 02380 251719 07759 349743 E-mail: info@investinme.org Web: www.investinme.org Invest in ME (Charity Nr. 1114035) This is our seventh Journal of IiME and forms part of each delegate‟s conference pack at the 6th Invest in ME International ME/CFS Conference 2011. The Journal of IiME was created as a means of providing a broad spectrum of information on ME/CFS, combining biomedical research, information, news, views, stories and other articles relating to myalgic encephalomyelitis (ME/CFS). Our aim has always been to distribute this for free four times a year. However, due to the current size and financial limitations of IiME we can only provide a snapshot of the wealth of experience which already exists and continues to increase and currently we are only able to publish a maximum of two copies a year. We hope to change that in the future. Some years ago we wondered if a sea change was occurring in the perception of ME based on good science, objective data, effective advocacy and a long-overdue realisation from government and healthcare organisations (albeit forced by pressure from patient groups and researchers) that obfuscation and systemic bias in the healthcare services are no just or effective way to provide healthcare. We think this is borne out. When flawed research such as the recent PACE Trial is published then it is no longer the case that such a study is accepted without closer scrutiny. The improvement in information technology and the spread of social networking has allowed a better-informed patient base to question seriously the research, and the motives of researchers. When a study purporting to be researching ME does not achieve a single useful function then it is now the patients themselves who can critique such a study and articulate on the poor research as well as the waste of money. Patients are now empowered and will not accept mediocrity and prejudice in research. It only remains for the media to realise what a scandal has been occurring and for politicians then to force through good science via policy change. The government and the media have a lot of catching up to do. Listen to the patients is still a maxim to which healthcare providers, politicians and the media should pay heed. Continued page 4 Disclaimer The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. www.investinme.org Page 3/58

Journal of IiME Volume 5 Issue 1 (May 2011) Diagnosis continues to be at the heart of the problems surrounding ME and diagnostic criteria are critical. One of the IiME‟s aims has continued to be to campaign for such a diagnostic test. Already there is enough research which has identified biomarkers for ME – more awareness of this needs to be given to healthcare providers so that doctors are more easily able to diagnose ME patients correctly. When Invest in ME started the international biomedical research conferences we were learning of the scientific and political issues that surround ME. We have come a long way since and the publication of a study showing association of XMRV and ME/CFS by Lombardi et al. in the Science magazine in October 2009 has created enormous publicity and interest among scientists who are new to this disease. The science has been discussed at the highest level of the National Institute for Health (NIH) and in conferences and workshops around the world. A USA blood working group was set up and countries around the world have banned patients with the diagnosis of ME/CFS from donating blood. In the UK the blood donation ban is permanent - the official reason given being that ME is a remitting and relapsing neurological illness and patients need to be protected from further deterioration of their health. This reason was something which most patient organisations ridiculed as preposterous as the nature of ME has been known for many years. The real reason for introducing the ban was, of course, concern for the recipients and for potential contamination of blood supplies. Over the past decades UK governments have shown complete disdain for any attempts to properly research and treat ME - a policy decision implemented by the negligence of the National Institute for Clinical Excellence (NICE) and by the corruption and bias in policy-making in the Medical Research Council (MRC) which has allowed a gravy-train of continual research funding to be directed only to a lobby of Invest in ME (Charity Nr. 1114035) psychiatrists – culminating recently in the hapless and flawed PACE Trial which typifies the bogus science which has dominated UK research. In the Republic of Ireland the blood donation ban came into force in August 2010 (although curiously there was no public announcement). The Irish authorities gave the lie to the UK position on blood donations by providing the true reason for a ban “to protect of the recipient of the blood donation of possible infectious agent”. The politics regarding this disease have not gone away – something which may be expected when new discoveries are made – though we doubt if the motives behind some of the denial regarding ME and new research is anything to do with good science. Invest in ME directed attention to this issue this year by arranging a pre-conference evening with Dr Ian Gibson and the US journalist Hillary Johnson presenting on Science, Politics…and ME. This will be available on the conference DVD from IiME. The IiME conference this year will display biomedical research which, in any other context, would be of interest to policy makers and healthcare strategists. Yet the Chief Medical Officer of England continues to uphold what is now becoming a tradition at the Department of Health - namely to ignore proper research and play no role in changing the way ME is treated and perceived. Invest in ME wrote to the Lancet to invite the editor (someone who publicly declared that ME advocates should be willing to debate the way ME is treated) to attend. At the time of going to press the Lancet had again declined this offer. These are attitudes from the establishment organisations which are typical of the continuing hypocrisy and abdication of responsibility at the heart of healthcare provision in the UK. Yet the IiME conferences do allow a platform Continued page 5 www.investinme.org Page 4/58 Journal of IiME Volume 5 Issue 1 (May 2011) for the biomedical research which is occurring and which will continue to undermine the apathy and indifference of officials who are paid to ensure adequate healthcare is available to patients. As patients and carers and advocates we have to do ourselves what others should be doing. Invest in ME was set up with the objectives of making a change in how ME is perceived and treated in the press, by health departments and by healthcare professionals. We aim to do this by identifying the three key areas to concentrate our efforts on in order to raise funding for biomedical research - education, publicising and lobbying. This will provide the focus and funding to allow biomedical research to be carried out. Our aim is to bring together like-minded individuals and groups to campaign for research and funding to establish an understanding of the aetiology, pathogenesis and epidemiology of ME – which will lead to the development of a universal diagnostic test that can confirm the presence of ME and, subsequently, medical treatments to cure or alleviate the effects of the disease. The seriousness of the situation regarding ME makes it necessary for governments to provide "ring-fenced" funding for bio-medical research into ME (as was provided for HIV/AIDS) in order to address the need for development of diagnostic tests and remedial treatments. We believe governments should standardise on usage of the Canadian Consensus Criteria for diagnosis, so that there is an agreed basis (noting that evolutionary improvement would be welcomed). We believe governments need to not only endorse and adopt the World Health Organisation classification of ME as a neurological illness, as defined by ICD-10-G93.3. They also need to officially promote it underlining that it is completely separate from the psychological illnesses classified under ICD10-F48. This will provide the unequivocal distinction for this neurological disease and Invest in ME (Charity Nr. 1114035) avoid the sham science which has been allowed to be perpetuated by psychiatrists who wish to maintain their cash-cow of research funding. We believe that governments should provide a national strategy of biomedical research into ME to produce treatments and cures for this illness. But failing this we must take action ourselves. Since the last Invest in ME conference we have been working to initiate an examination and research institute in Norfolk, UK, which would properly diagnose and then research people with ME. The proposal is described later in the Journal. Thanks to the efforts of the IiME steering group members and to Dr Ian Gibson, who has been working tirelessly to support this proposal, we have come within one decision of initiating this and creating a unique UK scenario which would have the potential to lead the world. But the first step toward creating an improved future is developing the ability to envision it. And so we have to continue to debate, discuss and promote this work to enable others to see the possibilities. We welcome your support. The people working for and with Invest in ME are advocates of better education regarding ME. In a sense the speakers who present at the conferences are also advocates – often lonely voices who have fought against a biased and corrupted establishment that has treated this disease so poorly. It is no accident that the presenters at the IiME conferences are people who have consciences and who work for the benefit of patients. Annette Whittemore, the president and founder of the Whittemore-Peterson Institute is making our key-note speech Translating ME/CFS Research into Treatments to tell us about the future plans of the WPI. Mrs. Whittemore has Continued page 6 www.investinme.org Page 5/58

Journal of IiME Volume 5 Issue 1 (May 2011) worked tirelessly to bring ME/CFS to the attention of decision makers so that this illness receives the consideration it needs and deserves. Millions of patients are suffering around the world and the ratio of money being spent on this disease and the economic losses it causes is at odds with any scientific, economic or moral viewpoint. Dr Judy Mikovits, one of the authors of Science study, was presenting here in May 2009 and had to keep this new information secret. She returns to the IiME conference to tell us how the work has progressed at the WPI and provide data regarding living humans who are infected and being treated with various immune modulators, as well as anti-retrovirals. We have the great pleasure of hearing Professor Geoffrey Burnstock, President of the Autonomic Neuroscience Centre at UCL, London, who is no stranger to being on the wrong side of established views in his long and distinguished career. Professor Burnstock‟s work has resulted in no fewer than three paradigm shifts, something that is desperately needed in the policies regarding ME/CFS research and management of patients. Professor Burnstock‟s work on autonomic nervous system and purinergic signalling is immensely important and may be very relevant to ME/CFS and we hope that his work gives inspiration to other scientists and ideas for clinical trials. The work of Professor James Baraniuk is concerned with looking at proteins in the cerebrospinal fluid of ME/CFS patients. Dr. Baraniuk and his team's current CFS study builds on a previous study where the team discovered some specific proteins in the spinal fluid of CFS and GWI patients. In the current study they will have a larger group of people with and without CFS/GWI and they will look for those and other unique sets of proteins in the spinal fluid and blood using more sensitive equipment. The team's hypothesis is that these specific proteins are seen in the spinal fluid of CFS and Gulf war Illness but not in healthy controls and that those Invest in ME (Charity Nr. 1114035) proteins will help us understand the cause of these conditions. Dr David Bell's name is familiar to anyone involved in ME/CFS. He was the local doctor in Lyndonville, New York when 214 people, many of them children, fell ill with mystery flu. He has carried on treating patients and performing research ever since. Currently he is involved in research on retroviruses and CFS being performed by Professor Maureen Hanson of Cornell University. From Norway promising research by cancer researchers from the University of Bergen using Rituximab is indicative of the value of clinical trials for ME. Professor OIav Mella has 30 years of experience in treating cancer patients. After a patient with a diagnosis of ME/CFS developed non- Hodgkins Lymphoma and was treated for it with Rituximab with unexpected resolution of ME/CFS symptoms as well Professor Mella and Dr Fluge initiated a pilot study with 2 other patients. This has led to further clinical trials with larger number of ME/CFS patients. We welcome Dr Andreas Kogelnik from California, USA, the Medical Director of the Open Medicine Clinic - a community-based research clinic focused on chronic infectious diseases, neuroimmune disease, and immunology. Dr. Kogelnik has published numerous scientific papers and book chapters, is an Editor of Computers in Medicine and Biology, and is a Consulting Assistant Professor at Stanford University. Together with Dr. José Montoya, he was instrumental in the conception, design, and execution of the EVOLVE study - a placebo-controlled, doubleblind study of a subset of chronic fatigue syndrome patients with evidence of viral infection. Dr John Chia has been a regular speaker at Invest in ME conferences. His work on enteroviruses and ME builds on previous research done in the UK by pioneers such as the late Dr John Richardson. Dr Chia works with his Continued page 7 www.investinme.org Page 6/58 Journal of IiME Volume 5 Issue 1 (May 2011) son Andrew Chia and their aim is to develop drugs to treat enterovirally-induced ME/CFS. Professor Kenny De Meirleir has also been a regular speaker at Invest in ME conferences. He is the most prolific and experienced ME/CFS researcher in Europe and treats a great number of patients. His work concentrates on the immune system in the gut. Professors Tom Wileman and Simon Carding are from the University of East Anglia and will be presenting on the possibilities of research into ME using the facilities and expertise in virology and immunology which are present in the Norwich Research Park area and which we hope to utilise in our proposal for a centre for ME. Dr Wilfried Bieger practises private medicine in Munich, Germany concentrating on neurostress illnesses such as burn out, depression, multiple chemical sensitivities (MCS) and CFS. After the Science magazine 2009 research article on XMRV Dr Bieger decided to look for XMRV in German CFS patients and the results of this study will be presented here today. May is ME Awareness Month and IiME have a number of events around the conference which have been organized. Apart from the conference the Science, Politics …and ME preconference presentation will provide more awareness of the reasons why good science is inhibited by policy-makers and vested interests. We have an article in the Journal by Margaret Williams which also describes the effect of the UK Science Media Centre. IiME were recently invited to join the All Party Parliamentary Group (APPG) for ME. We have not always felt this body has been useful for improving the situation with regard to ME but we have decided to accept and hopefully influence future events. As a first step we have asked for the chair of the APPG to accept our invitation to meet with researchers on the day before the IIMEC6 conference in the UK parliament. That will now happen. This is a way Invest in ME (Charity Nr. 1114035) for MPs can hear about real science and research. IiME are also organizing a meeting with researchers – our Corridor Conference – as much of the good work at conferences and symposiums is carried out in the corridors between lectures. The idea with this meeting is to promote collaboration and coordination of research. Our Awareness Month campaign slogan is Burst Our Bubble – a reference to the isolation which people with ME and their families have to endure caused by misinformation, ignorance and bogus science. Our posters have been distributed around UK (one is on the back cover of the Journal) – see here http://www.investinme.org/IiME%20ME%20Awa reness%20Burst%20Our%20Bubble.htm. Invest in ME were chosen as Charity of the Month by London Business Matters – the magazine for the London Chamber of Commerce. The charity took out a full page advert in the magazine to raise awareness of the disease. The ad can be seen in the online version of the magazine here – http://www.londonbusinessmatters.co.uk/archi ve/2011-05/index.html#/38/ At the conference members of the European ME Alliance will also meet to decide on new initiatives across Europe. Invest in ME wish to thank those individuals who have donated to us to bring about the 6th Invest in ME International ME/CFS Conference 2011. Thank you for your generosity. We would like to thank the Irish ME Trust for again sponsoring a speaker and for their continued support and cooperation Continued page 8 www.investinme.org Page 7/58

Journal of IiME Volume 5 Issue 1 (May 2011) For this issue of the Journal we have included some old and some new articles. With the misinformation about the PACE Trial which has been spread by establishment organisations and individuals, motivated by vested interests or ignorance, it is only right that we take articles from our web site which show the fallacy of the bogus science behind PACE. We have articles from Margaret Williams which show the disquiet behind how the PACE trial was instigated and also how the reporting on the poor results is spun into a positive message with the help of the Science Media Centre. Long time advocate Kevin Short, who famously took NICE to a judicial review regarding their ineffectual Clinical Guidelines for ME, has also written on PACE. From the USA patient advocate Chris Cairns has contributed our Letter from America article. Chris writes an illuminating blog which is mandatory reading for ME patients and others interested in what is really happening under the covers with the announcements, research and decisions being made in USA. Chirs Snell discusses the research at University of the Pacific which can use peak respiratory exchange ratio to measure post-exertional malaise and aid in identifying ME patients. There is already a great fund of knowledge available for the healthcare departments, organisations and staff to appreciate the multisystem nature of ME/CFS and the need to stay current with biomedical research data. The articles in JIiME, a small subset of the information which exists regarding ME, allow some of that to be seen. The research at the conference continues to echo the question of previous years – what would be possible if proper funding were available for a national or international strategy of biomedical research? At the conference there will be researchers, clinicians, nurses, patient groups and patients, advocates and, we always hope, a sprinkling of as many politicians, journalists and others whom Invest in ME self-fund to allow people to be Invest in ME (Charity Nr. 1114035) exposed to real science. The IiME conference provides not just a platform for proper, high-quality science – it allows also a platform for the hopes of millions of people around the world. Enjoy the Journal. Enjoy the conference. Clinical Trials Our theme for the conference is Clinical trials for ME – something which is now clearly needed. A clinical trial is a scientific research study in which patients participate to help physicians find new or better ways of treating patients. Normally a clinical trial tests a new drug or new medical intervention and its ultimate value in the prevention, diagnosis or treatment of a disease, disorder or illness. Now is the time to start some well controlled clinical trials into ME/CFS. For far too long patients have been left to manage their symptoms as best they can themselves, often left at the mercy of unregulated businesses promising cures at exorbitant costs and severely ill patients in hospital are often made worse rather than better by unhelpful beliefs about the nature of the disease held by healthcare staff. In a recent survey (Wojcik et al., doi:10.1016/j.jpsychores.2011.02.002) 84% of neurologists did not consider ME/CFS as a neurological illness – a finding which, if true, would categorically show how the misinformation and lack of proper education among the medical profession is costing lives. It also shows how inept and incompetent UK governments and medical organisations have been in regulating medical training, and how organisations such as the General Medical Council, the Royal Colleges of Physicians and Child Health have knowingly or unknowingly contributed to the mess around ME – something which benefits psychiatrists who maintain their status and funding but which does not serve patients. The Invest in ME conferences are aimed at correcting this misinformation. There have been very few controlled clinical Continued page 9 www.investinme.org Page 8/58 Journal of IiME Volume 5 Issue 1 (May 2011) trials into ME/CFS. The most recent trial ,the so called PACE Trial, which tested the efficacy and safety of cognitive behaviour therapy (CBT), graded exercise therapy (GET), adaptive pacing therapy (APT) comparing it to standard medical care (SMC), gained a lot of publicity form the friends of the investigators who control the media misinformation – but it was soundly criticised by most patient groups who have condemned these results as flawed and not fit for purpose for neurological ME/CFS patients. We need clinical trials to help healthcare professionals make decisions on how to best help their patients and even if causation of this disease is not known the results of such trials can give researchers ideas where to look. Without evidence from clinical trials treatment remains elusive for most patients suffering from this disease. ME RESEARCH ME press conference September 1990 in San Francisco, with Dr Paul Cheney. Wishing to make sure that the press corps understood how serious a disease ME/CFS is, Cheney continued: “I think it‟s really important for members of the press to recognise that what we‟re talking about here is not common fatigue….What we‟re talking about here in this systemic illness is that the debilitating fatigue is one of the primary symptoms, as it is in almost all autoimmune diseases and many other systemic diseases….We need to constantly separate out people who have common fatigue from people who have this illness….People who have competent immune systems don‟t get bad diseases like this in any numbers….Retroviruses have the capacity to impair immune systems in a subtle way”. - “Grey” Information about ME/CFS http://tinyurl.com/6xrk9x8 Invest in ME (Charity Nr. 1114035) Canadian Guidelines Invest in ME are the UK distributors for the Canadian Guidelines. Described even by NICE as “the most stringent” guidelines available these are proper, up-to-date clinical guidelines which can also be used as a base for research criteria. Findings from the study by Leonard A. Jason PhD (Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome) indicated that the Canadian criteria captured many of the cardiopulmonary and neurological abnormalities, which were not currently assessed by the Fukuda criteria. The Canadian criteria also selected cases with 'less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms' and individuals selected by these criteria were significantly different from psychiatric controls with CFS. The Canadian Guidelines provide a means for clearly diagnosing ME and were developed specifically for that purpose. They are an internationally accepted set of guidelines for which many in the ME community have been campaigning to be adopted as the standard set of guidelines for diagnosing ME. www.investinme.org Page 9/58

Journal of IiME Volume 5 Issue 1 (May 2011) Using Cardiopulmonary Exercise Testing to Evaluate Fatigue and Post-Exertional Malaise in ME/CFS The absence of reliable diagnostic laboratory tests or biomarkers presents significant problems for persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), treating physicians, and the ME/CFS research community alike. Typically ME/CFS diagnoses rely on self-report measures where patients describe the extent and duration of their fatigue and attendant symptoms either verbally or on a questionnaire. An alternative to the current binary approach (i.e., fatigue or no fatigue) or use of paper and pencil inventories for evaluation of symptoms in ME/CFS is to employ direct, objective multisystem, measures of physical function that may also provide insights to the underlying pathophysiology of fatigue in ME/CFS. One such methodology is cardiopulmonary exercise testing (CPET). With a long history of use by exercise physiologists in research settings, this non-invasive, integrative assessment approach is now increasingly endorsed for the clinical evaluation of undiagnosed exercise intolerance and for the objective determination of functional capacity and impairment.[1] An early definition conceptualizes fatigue as reduced efficiency after doing work.[2] CPET is uniquely able to quantify this reduction in efficiency with measures of both workload and the metabolic cost of that work. Additionally, other available cardiovascular, pulmonary and symptom data further enhance the value of CPET for diagnostic, clinical and research purposes. As a corollary to extreme fatigue, postexertional malaise (PEM) or exacerbation of symptoms following physical exertion, is considered one of the most common and recognizable aspects of ME/CFS. For the objective assessment of PEM, CPET has the advantage of serving as both an indicator of clinical status and a quantifiable model of physical exertion. The principles underlying CPET are simple. Invest in ME (Charity Nr. 1114035) Chris Snell is scientific director of the Pacific Fatigue Laboratory, and chairs the federal Chronic Fatigue Syndrome Advisory Committee (CFSAC). He was one of the presenters at the recent state of knowledge workshop organised by the NIH. Christopher R. Snell, PhD1,2; Staci R. Stevens, MA2; Todd E. Davenport, DPT, OCS2,3; J. Mark Van Ness, PhD1,2 1 Department of Sport Sciences, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, USA 2 Pacific Fatigue Laboratory, 3601 Pacific Avenue, Stockton, CA 95211, USA 3 Department of Physical Therapy, Thomas J. Long School of Pharmacy and Health Sciences, 3601 Pacific Avenue, Stockton, CA 95211, USA Physical exertion requires that the cardiovascular system supply oxygen (O2) to active muscles and the pulmonary system remove carbon dioxide (CO2) from the blood. Taxing these systems has the capacity to reveal abnormalities that may not be apparent at rest and thus elucidate the mechanisms underlying exercise intolerance in ME/CFS. Procedures for CPET are widely available [1] as are results profiles for a variety of disabling conditions. [3] These data can facilitate differential diagnosis to rule out conditions that could otherwise explain patient symptoms. CPET is generally performed using a motorized treadmill or stationary cycle ergometer. For reasons of safety, the cycle is preferable when testing ME/CFS patients. Possible orthostatic intolerance and the extreme exhaustion patients usually experience post-testing can make using a treadmill particularly hazardous. Individualized ramp protocols, which involve Continued page 11 www.investinme.org Page 10/58 Journal of IiME Volume 5 Issue 1 (May 2011) Using Cardiopulmonary Exercise Testing to Evaluate Fatigue and Post-Exertional Malaise in ME/CFS continued only modest increases in work rate per stage should be used and tailored to yield a fatiguelimited exercise duration of 8 to 12 minutes. Longer durations may result in patients terminating exercise because of specific muscle fatigue or orthopedic factors rather than cardiopulmonary end points. An important consideration for ME/CFS is to begin the test at a very low workload. Starting at too high a level will make for a very short test with results that are difficult to interpret. Test durations of less than 6 minutes may not show a linear relationship between oxygen consumption and work-rate. [1] Some of the key measures available from CPET include: maximal aerobic capacity (Peak VO2 or VO2 max ); ventilatory or anaerobic threshold (VT); and peak respiratory exchange ratio (RER). In addition to these gas exchange variables, workload at any given point and, with the integration of electrocardiography, key indicators of cardiovascular dynamics can also be measured. Often synonymous with functional capacity or exercise tolerance, Peak VO2 defines the physiological limits of an individual. However it is important to note that when such terms are used to describe performance on activities like timed-walk tests, or the commercial functional capacity assessments often used to evaluate disability, these are only estimates of aerobic capacity which tend to overpredict VO2 .[1] CPET is required for precise measurement of functional capacity. Most activities of daily living (ADL) are performed at levels below peak. VT is an important index of submaximal exercise capacity. It denotes the point at which energy production transitions from primarily aerobic to increasingly anaerobic glycolosis and is a crucial measure in CPET as it represents the onset of fatigue. Due to a lack of oxygen in the working muscle cells, work intensity cannot be maintained resulting in the reduction or cessation of activity. It may also be central to Invest in ME (Charity Nr. 1114035) understanding the activity limitations in ME/CFS. If VT occurs at very low levels of oxygen consumption and/or at very low workloads, then even normal ADL may exceed the VT threshold. It is possible therefore that in ME/CFS the increased stress of requiring a greater anaerobic energy contribution even for normal ADL precipitates the symptom exacerbation seen in PEM. CPET provides the only way to noninvasively assess this significant transition point in energy metabolism. Assessment of subject effort might be considered essential to interpreting any measure of physiological function. Exclusive to expired gas analysis, RER is defined as the ratio between inspired O2 and expired CO2. As exercise intensity increases the volume of CO2 begins to exceed that of O2. A ratio of CO2 to O2 greater than 1.10 is considered an indicator of excellent effort during an exercise test .[1] As an accurate and reliable indication of subject effort, RER substitutes for age-predicted maximal heart-rate values in this respect. Variability of 10-15 beats per minute can be expected within an age group which complicates interpretation of results where percentage of predicted maximal heart rate is the exercise endpoint.[4] There are also difficulties posed by use of pharmacological agents [1] and the cardiovascular abnormalities seen in ME/CFS.[5] Problems of response bias in self-report indictors of effort are also averted. Because RER permits accurate comparison of subject effort across serial exercise tests, it should be of prime consideration for any clinical intervention trial with functional endpoints.[1] CPET data including RER also allow for the more reliable interpretation of results when an exercise challenge is used to elicit symptoms as part of ME/CFS research studies. As a quantifiable measure of both physiological stress and effort, CPET enables direct comparison between patients and controls on these critical measures. This may be particularly Continued page 12 www.investinme.org Page 11/58

Journal of IiME Volume 5 Issue 1 (May 2011) Using Cardiopulmonary Exercise Testing to Evaluate Fatigue and Post-Exertional Malaise in ME/CFS continued relevant to research looking at immune function where individual fitness levels and exercise intensity can profoundly affect the immune response.[6] The availability of RER also gives CPET the capacity to objectively document PEM in ME/CFS patients. The reproducibility of both metabolic and work intensity measures obtained through CPET is well documented.[1] But research using CPET to examine functional capacity in CFS has found that a single test may be insufficient to identify abnormalities in work performance among CFS patients.[7, 8] By employing a dual test paradigm (i.e., 2 exercise tests, each separated by 24 hours) it is possible to compare data across tests. A significant change in exercise capacity during follow-up testing with similar peak RER values, it could be argued, is clear evidence of PEM. It should also be noted that RER is a critical arbiter when dealing with accusations of malingering or lack of effort! REFERENCES 1. Balady GJ, Arena R, Sietsema K, et al. Clinician's guide to cardiopulmonary exercise testing in adults: A scientific statement from the american heart association. Circulation. 2010;122:191-225. 2. Bitterman ME. Fatigue defined as reduced efficiency. American Journal of Psychology. 1944;57:569–73. 3. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Principles of exercise testing and interpretation: Including pathophysiology and clinical applications, 2nd ed. Philadelphia, PA, USA, Lippincott Williams Wilkins, 2004. 4. Piepoli MF. Exercise tolerance measurements in pulmonary vascular diseases and CHF. Respiration. 2009;77:241–251 5. Maes M, Twisk FN. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular Invest in ME (Charity Nr. 1114035) disorders in ME/CFS. Neuro Endocrinol Lett. 2009;30(6):677-93. 6. and the immune system: Regulation, integration, and adaptation. Physiol Rev. 2000;80:1055-81. 7. VanNess J.M., Snell, C.R., and Stevens, S.R. Diminished Cardiopulmonary Capacity During Post-Exertional Malaise in Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome. 2007;14(2): 77-85. 8. W, Scholte HR. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med. 2010;8:93. ME FACTS From over 2,000 pages of information obtained under the Freedom of Information Act, much is already known about the design and progress of the PACE Trial, including the fact that its entry criteria were intentionally broad (“We chose these broad criteria in order to enhance generalisability and recruitment”; Trial Identifier 3.6). Despite the use of such broad entry criteria, there were serious recruitment difficulties, so the entry criteria were broadened even further when on 14th July 2006 Peter White sought approval from the West Midlands MREC to write to GPs imploring them to send anyone with “chronic fatigue (or synonym)” for entry into the PACE Trial, thereby opening the trial to anyone who was merely chronically tired. from Magical Medicine: How to Make a Disease Disappear - http://tinyurl.com/38yuj83 www.investinme.org Page 12/58 Pedersen BK, Hoffman-Goetz L. Exercise Vermeulen RC, Kurk RM, Visser FC, Sluiter Journal of IiME Volume 5 Issue 1 (May 2011) The Media and ME by Margaret Williams Margaret Williams is a well respected authority on ME as well as being an ME patient advocate. Margaret Williams formerly held senior clinical posts in the NHS. Ever since the foundation of the UK Science Media Centre in 1999 – whose purpose is to ensure that the media deliver only headline science stories that accord with Government policies – the reporting of the biomedical science surrounding ME/CFS has been noticeable by its absence. Instead, there has been a wealth of spin promoting the benefits and success of CBT and GET for every disorder imaginable, including ME/CFS. In plain terms, the Science Media Centre presents only a one-sided view of the available information about ME/CFS, and direct contact with editors and health editors of broadsheet newspapers has revealed their policy of limiting their reporting of ME/CFS to what they receive from the Science Media Centre. The fanfare of unlimited praise for the PACE Trial results at the press conference held at the Science Media Centre on 17th February 2011 is a case in point, with the media failing to use its critical faculties and regurgitating only what it had been spoon-fed. There are a staggering number of flaws in the PACE Trial article published in The Lancet (Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Peter D White et al. The Lancet, 18 February 2011 doi:10.1016/S0140-6736(11)60096-2), not one of which was mentioned in the press conference. Invest in ME (Charity Nr. 1114035) These flaws and errors have been identified in a detailed complaint/statistical analysis sent by Professor Malcolm Hooper to The Lancet on 28th March 2011, upon which The Lancet has asked Professor Peter White to comment (a response with which Professor White has apparently not complied within the time allotted for its receipt by The Lancet). It is understood that under the Elsevier complaints policy, Professor Hooper will be asked to respond to Professor White‟s reply when it is received by The Lancet; it is also understood that the PACE Trial article was to be sent for re-review by different reviewers and statisticians whilst The Lancet was awaiting Professor White‟s comments on Professor Hooper‟s complaint. There are a staggering number of flaws in the PACE Trial article published in The Lancet Professor Hooper‟s analysis will shortly be placed in the public domain; he had agreed with The Lancet to withhold his complaint from publication during the time allotted by The Lancet to Professor White to respond to it, but this agreed time limit has now expired. There is one crucial point that should not be overlooked amidst the multitude of comments, spin, disquiet and anger surrounding the clearly contrived and exaggerated results of the PACE Trial, which is that if the PACE Trial Investigators had claimed to be studying the effect of CBT/GET on people with medically unexplained or idiosyncratic “fatigue”, few people would have objected. What is fuelling the opprobrium is the fact that Continued page 14 www.investinme.org Page 13/58

Journal of IiME Volume 5 Issue 1 (May 2011) The Media and ME continued the PACE Trial Investigators insist that they have been studying those with “CFS/ME”, which is how they refer to the neuroimmune disorder ME/CFS. The pressing question has to be how the Wessely School can be permitted to disregard the everincreasing biomedical evidence-base on ME/CFS and to refuse – on no evidence whatever -- to accept the WHO classification of ME/CFS as a neurological disorder. Some authors have attempted to dismiss this disease as hysterical, but the evidence now makes such a tenet unacceptable….The organic basis is clear What can be done to halt the Wessely School‟s anti-science activities and misinformation about ME/CFS which they propagate and disseminate with consummate skill? Since they will not budge from their beliefs, could they be right and the biomedical scientists be wrong? Not at all: the Wessely School is gravely mistaken about the nature of ME/CFS and about their ascription of its symptomatology to a somatoform disorder. In 1978 (33 years ago), the BMJ published a summary of the symposium on ME held that year at The Royal Society of Medicine: (BMJ 3rd June 1978) “there was clear agreement that myalgic encephalomyelitis is a distinct nosological entity. Other terms used to describe the disease were rejected as unsatisfactory for various reasons: the cardinal, clinical features show that the disorder is an encephalomyelitis….Some authors have attempted to dismiss this disease as hysterical, but the evidence now makes such a tenet unacceptable….The organic basis is clear – from the finding that the putative agent can Invest in ME (Charity Nr. 1114035) be transferred to monkeys, the detection of an increased urinary output of creatine, the persistent findings of abnormal lymphocytes in the peripheral blood of some patients, the presence of lymphocytes and increased protein concentration in the cerebrospinal fluid of occasional patients, and the neurological findings” Apart from their close involvement with the medical and permanent health insurance industry and the unpalatable fact that their professional lives may be shown to have been spent in a null field of research (i.e.. trying to prove that ME/CFS is an aberrant illness belief), it remains a mystery as to why, as bona fide mental health researchers, the Wessely School so persistently refuse to engage with the extensive biomedical evidence-base that exists on ME/CFS. As Dr David Bell said in his book “Faces of CFS – Case Histories of Chronic Fatigue Syndrome” (Lyndonville, New York, 2000): “I have no problem with not understanding the exact mechanism of the symptoms of CFS…I do have a problem with the lack of respect given patients with poorly understood neurological disease”. Bell points out that the chest pains, racing pulse, shortness of breath, flushing, trembling, twitching, difficulty maintaining balance, headache, physiological exhaustion to the point of collapse, inability to walk, and pooling of blood on standing experienced by ME/CFS patients all result, not from what Wessely School psychiatrists deem to be deconditioning or “hypervigilance to normal bodily sensations”, but from the dysautonomia that is so prevalent in ME/CFS (in an effort to supply blood to the brain, the patient‟s blood pressure sky-rockets almost to levels that could cause a stroke but then dives, www.investinme.org Continued page 15 Page 14/58 Journal of IiME Volume 5 Issue 1 (May 2011) The Media and ME continued such lability being the easily confirmed hall-mark of classic ME/CFS that was identified many years ago by Dr Melvin Ramsay ). Bell explains that these symptoms are caused by elevation of adrenaline levels that are released in an attempt to compensate for impaired blood flow to the brain due to blood volume deficits and to problems in the blood vessels themselves, which result in the wellknown (post-adrenaline-surge) exhaustion: “(The blood vessels) must be constricted so tight in the brain that little blood gets through. Perhaps it is one of the hormones that constricts blood vessels. Perhaps an infection of the blood vessels. Perhaps it is an excessive sensitivity of the blood vessels to adrenaline….CFS is a devastating physiologic process that undermines the body‟s energy and the brain‟s cognitive ability….CFS is not…an illness behaviour for lazy people. The consequences of this illness weigh heavily not only on the victim, but also on family, community and society”. ME/CFS is an inflammatory disease (Pasi A et al. Mol Med Report 2011:4(3):535-540). Kennedy et al from the Vascular and Inflammatory Diseases Research Unit at the University of Dundee have reported a whole raft of abnormalities in adults (and subsequently in children) with ME/CFS that are consistent with vascular instability and dysautonomia. These findings include an increase in apoptosis of white blood cells; raised levels of oxidative stress which can damage blood vessels and other organs; increased markers of inflammation, and abnormalities in blood vessel function (Co-Cure RES, MED: 17th May 2010). Another pressing question must be why the media so frequently fail to report such serious pathology in ME/CFS patients and to rely so unquestioningly on the Science Media Centre to do their work for them. Where is their own intellectual judgment and journalistic skill? Invest in ME (Charity Nr. 1114035) Following the NIH State of the Knowledge Workshop in April 2011, Professor Leonard Jason from DePaul University, Chicago, took part in a televised discussion hosted by Llewellyn King transmitted on 8th April 2011 (The Voice of America, episode #3012) in which Jason said that patients with ME/CFS “get thrown to the psychiatrists….These are patients who are victimised by an illness and then the media further victimises them, and then the medical community also does it”. Another contributor, author Deborah Waroff from New York, made the point that “UK patients (with ME/CFS) are probably the most unfortunate in the entire world”. Victimisation by the media is well illustrated in the article on the PACE Trial by Adam Morris in The Edinburgh Evening News published on 15th April 2011: “If implemented, it means patients would be placed on recovery schemes, with thousands benefitting from a new regime of exercise and a „positive mental attitude‟ ”. This statement should be compared with the comment by Professor Paul Cheney from the US on graded exercise (made in the UK at the Invest in ME conference in May 2010, proceedings of which are available on DVD from IiME – (http://www.investinme.org/IiME%20International %20ME%20Conference%202010%20%20DVD%20Order.htm): “The whole idea that you can take a disease like this and exercise your way to health is foolishness. It is insane ”. Continued page 16 www.investinme.org Page 15/58

Journal of IiME Volume 5 Issue 1 (May 2011) The Media and ME continued Media coverage of ME/CFS remains problematic; comments on the PACE Trial by Vivienne Parry written for the charity AYME (The Association of Young People with ME) published on 14th April 2011 are illustrative. Ms Parry sits on the Council of the Medical Research Council and was awarded an OBE for services to the public understanding of science. She is on the Board of the Science Media Centre, whose Science Advisory Panel includes Professor Simon Wessely. The Science Media Centre itself states: “The team at the SMC is advised by a Science Advisory Panel and a Board” which would seem to indicate a close working relationship between Ms Parry and Professor Wessely. Ms Parry is described by AYME as a “highly respected scientific journalist” but her comments on the PACE Trial do not assist patients with ME/CFS because many of them are inaccurate:  it is not known “for sure” that two treatments (GET and CBT) are “safe and moderately effective” for people with ME/CFS because it cannot be certain how many patients with ME/CFS as opposed to “CFS/ME” were included in the PACE Trial (“CFS/ME” being chronic fatigue in the absence of neurological signs)  the PACE Trial was not “as rigorous a study as it is possible to have”; as a respected scientific journalist, Ms Parry will know that if a trial is not a controlled trial, it cannot be so described  it is not quite true to say that it was carried out by “a team of experts”, since 22 of those carrying out one arm of the trial were trainee psychiatrists employed to work at the Kings College PACE Invest in ME (Charity Nr. 1114035) Centre, London   APT is not the same as pacing, and pacing was not studied in the PACE Trial people with ME/CFS do not have “fatigue as their main symptom”; they have post-extertional fatigability accompanied by malaise as their main symptom (their voluntary muscles do not work properly and are exquisitely painful after exercise)  Ms Parry says: “There are two problems here. One is about science. Research is about coming up with a hypothesis and then trying to knock it down”. This is precisely why the PACE Trial cannot be considered “scientific”. Although the Investigators‟ hypothesis that “CFS/ME” is exactly the same as ME/CFS and that it is a behavioural disorder reversible by CBT and GET was indeed knocked down by the results, the Investigators refuse to accept that the trial failed People genuinely cannot understand how individuals who profess to be speaking up for the primacy of science can defend, let alone promote, such a transparently flawed study as the PACE Trial.  Ms Parry then says: “Long held, cherished and utterly plausible ideas are regularly demolished by evidence”. This is true, but Ms Parry fails to understand that the results of both the FINE and PACE Trials demonstrate that the Wessely School‟s psychosocial model of ME/CFS is wrong and has been demolished by evidence  seemingly with no awareness of the paradox in her comments, Ms Parry continues: “This can be incredibly disappointing but you have to move on and ask the next question, not constantly keep asking the same one in the hope www.investinme.org Continued page 17 Page 16/58 Journal of IiME Volume 5 Issue 1 (May 2011) The Media and ME continued that eventually you will get a different answer”. Refusing to relinquish long held and cherished ideas about the nature of ME/CFS is exactly what the Wessely School have done for the last 25 years, and indeed they continue to do so  Ms Parry continues: “Some people also said that the trial was meaningless because it excluded those with a neurological disease, therefore could not have contained anyone who had ME since this is a classified neurological disease. This is a bit silly because why would you design a trial that excluded the very patients you wanted to study?”. The answer, Ms Parry, is simple: the Wessely School refuse to accept that ME/CFS is a neurological disorder. As another, more informed, commentator (JT) has remarked, Ms Parry‟s article “is an embarrassment….The trial was not studying the neurological disease ME/CFS but people with chronic fatigue in the absence of neurological signs, or “CFS/ME”….If the Oxford criteria had been applied correctly there would be no people present with ME….People should now be aware that the results were not clinically significant, and there remains little evidence to support the use of CBT and GET in the management of ME/CFS” Is it not important that highly respected scientific journalists get their facts right and refrain from contributing to the prevailing media bias about which Professor Jason was so outspoken? People genuinely cannot understand how individuals who profess to be speaking up for the primacy of science can defend, let alone promote, such a transparently flawed study as the PACE Trial. The failure of CBT/GET is written in the numbers: even the skewed data presented and published in The Lancet show that CBT/GET are of no clinical value in the cohort studied, and certainly do not confirm that the interventions are safe and effective enough to be generalised to everyone with ME/CFS or even “CFS/ME”. ME FACTS 1993: In his now world-famous Testimony before the US FDA Scientific Advisory Committee on 18th February 1993, Dr Paul Cheney said: “I have evaluated over 2,500 cases….We have seen the worst and the best of the range of scenarios that can befall a patient with this disorder. At best, it is a prolonged postviral syndrome with slow recovery or improvement within one to five years. At worst it is a nightmare of increasing disability with both physical and neurocognitive components. The worst cases have both an MS-like and an AIDS-like clinical appearance….We have lost five patients in the last six months….The most difficult thing to treat is the severe pain….The most alarming is the neurological and neurocognitive elements of this disease. Half have abnormal MRI scans, 80% have abnormal SPECT scans, 95% have abnormal cognitive evoked EEG brain maps. Most have abnormal neurologic examinations….40% have impaired cutaneous skin test responses to multiple antigens. Most have evidence of T-cell activation….From an economic standpoint, this disease is a disaster. 80% of the cases evaluated in my clinic are unable to work or attend school…The yearly case production, if plotted, is exponential….The medico-legal aspects of our practice steadily grow as this disease eats at the fabric of our communities. We admit regularly to the hospital (with)…inability to care for self….CFS is an emerging, poorly understood disorder with a distinctive clinical presentation. I am not at all sure that it is as heterogeneous as some would lead you to believe….This disorder is a socio-economic as well as medical catastrophe that will not end….This disease is too complex to rely on standard medical orthodoxy to explain it….Listen to patients with an open mind. Failing that, then listen to those who have spent countless hours with a thousand patients. Most of us have some wisdom to impart and most of that came from patients”. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 17/58

Journal of IiME Volume 5 Issue 1 (May 2011) Letter from America By Chris Cairns The CFS Patient Advocate A month ago President Obama was asked a question about Chronic Fatigue Syndrome at a news conference. The question came from Courtney Miller, the wife of CFS advocate and patient Robert Miller. For one second, ME/CFS hit the big-time. The job of Patient Advocate came upon me uninvited. I did not apply for this job, nor did I have any qualifications for it. I am a sculptor, not a doctor or a researcher. My daughter became sick with a mysterious fatigue illness and I was the obvious person to fill the job. Learning the job of a PA unfolds over time and there is no instruction manual. Certain ideas and thoughts can be transferred from former jobs and former lives, but much has to be learned from scratch. It is helpful in doing the PA job if you have a lot of time and a lot of money, as the solution to this disease takes a great deal of both. It would also be helpful to have an education in bio-chemistry, of which I have none. The most important qualification that a Patient Advocate needs is persistence and discipline. A PA also needs to remain objective and detached, even under the most extreme conditions. Every Patient Advocate has a patient. My patient is my daughter. The objective of this particular Patient Advocate is to make his daughter better. How to set about it is another matter, and turns out to be a complex and sustained set of illusive problems. While most doctors look at a broad and confusing set of symptoms and try to attach treatments to an entire cohort of partially differentiated patients, the PA‟s problem is slightly different. The Patient Advocate, by job definition, is obliged to help one person - in this case, his daughter - his patient. Thus the PA is looking at one narrow and confusing set of symptoms, which makes his problem slightly easier. Chris Cairns‟ blog is at - http://cfspatientadvocate.blogspot.com Invest in ME (Charity Nr. 1114035) www.investinme.org Obama answered that he had heard of Chronic Fatigue Syndrome but "did not know much about it". He said that "he would look into it". If Obama has heard of CFS, no doubt it was from Senator Harry Reid of Nevada. If Obama sincerely wants to know more about CFS, he only needs to ask his friend Senator Reid. Senator Reid was instrumental in the formation of the Whittemore Peterson Institute in Reno, Nevada. Senator Reid is the best friend of ME/CFS in the US government. In the last year and a half, the patient voices of ME/CFS have become more spirited, consolidated and articulate. This is a very important development. This elevated collective voice can be seen in many blogs, posts, message boards and advocacy groups. Significant among blogs are those of Mindy Kitei (cfscentral.com) and Jamie Deckoff-Jones (treatingxmrv.blogspot.com) and XMRV Global Action Facebook page (http://www.facebook.com/pages/XMRVGlobal-Action/216740433250). There are many worthy blogs and voices. Forums on phoenixrising.me and mecfsforums.com have many strong and clear voices. To be further convinced of the strength of these patient voices one only need to read the current testimonials of ME/CFS patients that will be presented on May 12, 2011 at the CFSAC conference. All this increased vocal and written activity can be directly attributable to the WPI Continued page 19 Page 18/58 Journal of IiME Volume 5 Issue 1 (May 2011) Letter from America The CFS Patient Advocate and their effort to find a cause for ME/CFS. The publication in October 2009 of an association of the retrovirus XMRV with ME/CFS ignited a broad and increased interest in this illness. The publication of this fine study stirred great interest, one that went way beyond the particulars of XMRV. The paper was a real jolt - and with ongoing repercussions. In the past year, Amy Marcus of the Wall Street Journal and David Tuller of the NY Times each have written a series of articles on ME/CFS and on the scientific struggles that surround the association of a retrovirus (or virus) with this illness. In doing this both of them have painted a broader picture of the devastation of this illness. These articles have had nationwide coverage in the United States, and have brought ME/CFS to a higher consciousness for many people. These articles and this coverage of ME/CFS can also be directly attributed to the efforts of the Whittemore Peterson Institute. The October paper has fueled a discussion on the cause or potential cause of CFS/ME that has never been seen before at this level. Lombardi and Mikovits raised the stakes. Meanwhile the battle over XMRV continues. In the larger picture, XMRV is a detail. The battle really is about another issue - and it is a furious fight to the death. The issue centers on whether ME/CFS is either directly virally induced or an immunological problem that is virally induced. For 25 years there have been great efforts to sink any association of ME/CFS with viruses, (or bacteria, for that matter). Very few people have been looking for such a cause, but very many people have made great efforts to squash any viral cause association. One would have to wonder why? What is the real issue here? It is difficult to comprehend. Do these people just have an individual stake or are there larger forces at work? Why is there so much hostility towards this disease and the patients who suffer Invest in ME (Charity Nr. 1114035) from it? Why is there so little research into the illness and into potential treatments, some of which are currently available? The recent NIH State of Knowledge conference did very little to advance anything meaningful. A number of government and academic scientists did meet in the same room and exchange ideas - which is always a good idea. However, the NIH meeting itself came to no conclusions, no attempt was made to put the pieces together, no plan was made for future research to address gaps in our knowledge (as promised in the introduction to the meeting) and most importantly, no funding for research was proposed. All of this has to be seen as "by design" - or incompetence. More can be read about this on my blog, cfspatientadvocate.blogspot.com, with particular attention to the longer report that was actually not written by me. One recent positive sign involving the government was the presentation of Dr. A. Martin Lerner at the October 2010 CFSAC Science Day meeting. Dr. Martin Lerner was invited to make a presentation on his treatment data involving antivirals in selected ME/CFS patients. I believe this was the first time that the government sponsored a talk on a potential treatment for a subset of ME/CFS patients. However, neither the HHS nor the CDC has recommended Dr. Lerner's treatment for any patients, continuing their position that there is no known cause for this illness and no known treatments. While it is clear that the surge in articulating the seriousness of this illness can be attributed to the WPI, Judy Mikovits, Vincent Lombardi, Annette Whittemore and others, this is not to say that important research and treatment are not ongoing in other areas of the United States. Various long-term ME/CFS clinicians have www.investinme.org Continued page 20 Page 19/58

Journal of IiME Volume 5 Issue 1 (May 2011) Letter from America The CFS Patient Advocate continued the struggle to understand this illness and what might work as treatments. Their good work has continued. This includes the practice of Dr. Dan Peterson, who recently made a presentation in Calgary. Dr. Peterson continues to work with some success with the drug Ampligen, as do Dr. Charles Lapp and Dr. Lucinda Bateman. Hemispherx sponsored an important conference on Ampligen in ME/CFS, detailing new studies and attempts to increase efficacy of the drug. Dr. Paul Cheney continues to work on his own treatment protocol, sharing treatment and research ideas with other clinician/researchers, including Dr. Kenny de Meirleir - and also the WPI. Dr. Cheney is doing experimental work with GcMAF and also with Stem Cells. Dr. Joseph Brewer has been working with HIV, ME/CFS and Lyme patients for many years and is interested in new treatment protocols, examining in particular biological associations between CFS and HIV patients, looking for commonalities. Dr. Brewer, too, is interacting with others. Dr. Patricia Salvato has also worked extensively with ME/CFS patients and HIV patients. She, too, is examining a broad treatment protocol based on emerging ideas combined with her vast clinical experience. There certainly are those in the ME/CFS field, including myself, who believe ME/CFS is best characterized or described as "non-HIV AIDS". Dr. Derek Enlander who also has his eyes and ears open to new treatment protocols, is perhaps starting his own Ampligen trial. Dr. Enlander worked closely with Dr. Kerr, until Dr. Kerr was stripped of his academic job and was forced to end his very promising ME/CFS research. Dr. John Chia continues to work with enteroviral involvement in ME/CFS, building his research - with possible new treatments coming in the next couple of years. Several researcher/clinicians have opened their own ME/CFS clinical/research operations. The first is Dr. Jose Montoya at Stanford who runs the Stanford CFS clinic. Dr. Montoya is working on a large study ferreting out the relationship of a host Invest in ME (Charity Nr. 1114035) of pathogens associated with ME/CFS. He is working with Ian Lipkin on this study. Another is Dr. Andreas Kogelnik of Mountain View CA. Dr. Kogelnik will be speaking at the 2011 Invest in ME conference. The third is Nancy Klimas in Miami FL who combines a clinical practice with a research effort that she shares with Mary Ann Fletcher and Broderick Gordon. No systematic framework is in place for these clinician/researchers to work together. No one, except for the WPI, even seems to think about this. For instance the WPI, Dr. Klimas and Dr. Montoya are all working on a cytokine array to identify patients with this illness. No one seems to have an interest in or even an awareness of, what the other is doing. As my daughter characterizes it, ME/CFS is the Wild West of illnesses. Sparked by this Invest in ME conference, more researchers and clinicians are talking to each other - and exchanging research and treatment possibilities. The positive that can be taken away is that there are many very smart and dedicated people working on this illness - additional candidates to get involved emerged at the NIH State of Knowledge conference, particularly Dr. Michael Dean, and Dr. Theoharis C. Theoharides. We do not want to forget the contributions made by Rich van Konynenburg and his ideas about methylation blockage/glutathione depletion, Dr. Kenny de Meirlier's work with GcMAF, Marian Lemle's hypothesis of H2S involvement in ME/CFS, and Jill Belch‟s important research at the University of Dundee and the important work being done with Rituxamab in Norway - to mention a few. I apologize to those whom I might have left out. The biggest problem in ME/CFS is the public and "behind the scenes" working of what I would call the "dark force". These are the many people with "black haloes" who want to submerge these ME/CFS patients for the next 25 years - as they have done for the last 25 years. Who are these Continued page 21 www.investinme.org Page 20/58 Journal of IiME Volume 5 Issue 1 (May 2011) Letter from America The CFS Patient Advocate people? They are many, and it would take up too much space to name them. Some are now even dead, to be replaced by new heartless people. Since October 2009 a fresh and resourceful concerted effort is being made to stop all meaningful research into the cause or treatment of this illness. This is a continuing phenomenon and again one must ask why? What is behind this hostility and indifference to a broad and deeply suffering patient population? There are many people who seem to enjoy the negative positions that they can take relative to ME/CFS - and very few who will stick out their necks, and actually try to do something with this illness. Certainly the US government has made it clear that they are not going to directly grapple with this illness. The aggravated, grinding, meanspirited, indifferent attacks on this illness are ongoing. Does this happen in other diseases? The answer is no, this situation is particular with ME/CFS. Why? The bottom line is the negative forces have been splendidly successful in blunting any momentum forward with this illness. Great confusions have been generated, with many attendant sideshows of power and ego involvements that are difficult to comprehend. What are the stakes of the game that is being played? Meanwhile a few patients taking selected antiretroviral drugs show improvements. In talking to Dr. Dale Guyer about a year ago, I mentioned that some patients were going to start taking antiretroviral drugs. Dr. Guyer suggested that he felt these medications certainly might work for a subset of ME/CFS patients, even though one does not know exactly what the drugs are hitting. Dr. Guyer has no problem realizing how sick these patients are. It has become apparent that the WPI is developing a framework to try a number of Invest in ME (Charity Nr. 1114035) protocols or combo protocols on patients in limited trials. Because of a lack of funding, it is possible that they might just bypass trials and start treating patients and building data. Dr. Judy Mikovits pointed out quite clearly that the WPI was not going to wait another two years to move on to the treatment of these sick patients. They feel that there is a very sick patient population of ME/CFS patients that can clearly be identified. They feel that there are the means by which these patients' immune function can be measured and tracked. They feel that there are treatments to try both on the side of pushing back pathogens and on regulating the immune system. Some of these treatments already exist, some are experimental, and some are coming down the line. From the WIP‟s perspective, everything is in place to start treating these patients. The WPI is also actively looking for clinicians, researchers and drug companies to help in this effort. The question now is will the United States government help or hinder the WPI's efforts? All signs right now indicate that the government will hinder the advance of knowledge about ME/CFS. At the end of the NIH State of Knowledge Workshop there was no indication of further plans to accomplish the stated goals of the Workshop: to identify gaps in knowledge and make a plan to solve identified problems. There is also no indication that agencies responsible for health care delivery in the United States have plans to improve the deplorable situation patients face when they try to find a doctor knowledgeable about ME/CFS. Until the U.S. government shows clearly that they are going to address these issues, patients have few choices. We must continue to support those researchers and institutions that are working independently, especially the WPI, who ignited the field in 2009. It is as yet a small spark, but we must nurture it until the causes and treatment of this disease are found. www.investinme.org Page 21/58

Journal of IiME Volume 5 Issue 1 (May 2011) International Science Symposium on ME Bond University, Queensland, Australia 3-4 December 2010 Bond University, Queensland, Australia. The first paper was by Nancy Klimas (Miami,USA), and she presented a systems biology approach to ME/CFS. She described CFS is a disorder of homeostatic imbalance. She briefly outlined her 25 year history of involvement with this illness, when initially she worked on the theory of a chronic immune activation syndrome, with an immunological focus. It was next recognised as a neuro-inflammatory disorder, and now genomics have become involved. She listed and described some of her current research work. One study involved an exercise challenge to induce relapse, looking at the gene expression and immune changes before, immediately after and 4 hours later. 3 matched groups were studied: Gulf War illness, CFS and controls. The exercise challenge was 8 minutes on an exercycle with measurement of VO2 max. The gene expression showed significant differences in those with GWI and CFS. (By case definition GWI and CFS meet the same criteria). Immunological pathways were similarly affected – these were mainly inflammatory, and the immune cascade led to many symptoms 4 hours later. Symptoms involved the endocrine, immune, autonomic and neurological systems. The genes regulating NK function which included abnormal perforin and granzyme levels were affected. She then went on to describes Broderick‟s 3 basic elements of analysis of immune signals, and related this to the states after the 8 minute challenge: 1. Those that looked different 2. 3. Those that hang out with a different crowd Those that behave differently (altered response dynamics) Invest in ME (Charity Nr. 1114035) The International Symposium on ME/CFS was organized by the Alison Hunter Memorial Foundation of Australia and Bond University in Brisbane and held in Brisbane on 3-4 December 2010. Invest in ME sponsored a researcher to the symposium. This was an important meeting and attracted new researchers to the field of ME and we feel this excellent summary by Rosamund Vallings needs to be published again to show the possibilities with research into ME. Dr Rosamund Vallings from New Zealand is the secretary and newsletter editor of the International Association for Chronic Fatigue Syndrome/ME (IACFSME). Dr Vallings has over three decades of experience in the field of ME/CFS. She has written numerous summaries of medical ME/CFS conferences and meetings from around the world for the benefit of others. In 2008 she was appointed a Member of the New Zealand Order of Merit (MNZM) for services to people with chronic fatigue syndrome (CFS). In this study there was persistent inflammation, a surge in immune interaction and an IL-1 “splash” effect. There was a huge cascade effect in 8 minutes and persisting 4 hours later. Homeostasis is “messed up” and needs to remodel. Continued page 23 www.investinme.org Page 22/58 Journal of IiME Volume 5 Issue 1 (May 2011) International Science Symposium on ME There is a need to focus on autonomic and immune therapies which do interface with each other. This study confirms that graded exercise is not good for those with CFS, and patients must stop exercise well short of the aerobic threshold. Breaks between exercise need to be twice as long as the duration of the exercise. Hugh Perry (Southampton, UK) discussed the adaptive and maladaptive components of what he describes as “sickness behaviour”. He then focused on the language of “sickness” in relation to the way the systems behave during inflammation, for example “feeling ill” with pain and fever. He described sickness behaviour as an organised strategy which is not “bad”. Infection leads to an inflammatory response with release of cytokines, which then communicate with the brain and cause symptoms such as malaise, fever and depression. Systemic inflammation activates selective brain regions, with different challenges activating different regions. This mechanism works through the macrophages in the brain via the blood-brain-barrier. Endothelial cells communicate with the macrophages via the microglia. This is an important part of homeostasis, and is usually transient. He then went on to talk about chronic neurological disease when microglia increase in number and activation and become “primed”. Exaggerated sickness behaviour then occurs in those with chronic brain disease, in response to infection. The microglia release cytokines very readily if already primed. A maladaptive pathway develops. One study involved the follow up of 300 Alzheimer‟s disease (AD) patients 2 monthly for 6 months. Those who had an infection had a more rapid mental decline, while those who had suffered no infection showed no change. Other “behaviours” also changed greatly as a result of infection. He described obesity, smoking, age and grey hair as all contributing to earlier AD as all these have inflammatory Invest in ME (Charity Nr. 1114035) effects. He concluded by saying that systemic infections lead to distortion and maladaption exhibited by sickness behaviour, because of the primed microglia. This in turn leads to accelerated progression of brain disease. He said that a vaccination can be used as a challenge to demonstrate changes. Functional MRI has more use at detecting these changes. Mary Ann Fletcher (Miami, Florida) presented her work on biomarkers for CFS. The goal in CFS research has been to find a biomarker or combination of biomarkers. This will enhance the ability to diagnose and demonstrate severity of the illness, define subsets and help to manage trials. Natural killer (NK) cells were studied initially looking at function and the diminution of perforin and granzyme. 176 CFS patients showed significantly lower function in NK cells compared to controls. She then went on to describe how neuropeptide-Y (NPY) is involved in the stress reaction with increase in norepinephrine and NPY from the sympathetic nerve endings. In a controlled study, NPY was considerably higher in CFS compared to controls. Use of receiver operating curve (ROC) analysis was described, and this showed discrimination between CFS patients and controls. Using ROC, NPY was found to be 80% sensitive in CFS, (which is better than the PSA test we use to help diagnose cancer of the prostate). NPY also correlates with markers of disease severity. Other potential biomarkers using this technique included 10 of 16 cytokines measured, NK cell cell function and dipepdyl peptidase/CD26 which is indicative of immune activation. This is all part of a complex integrated system. In future exercise challenge will be included in testing this paradigm, and computer analysis will be developed to stimulate research in further clinical trials. These abnormalities may have applications in other diseases. Continued page 24 www.investinme.org Page 23/58

Journal of IiME Volume 5 Issue 1 (May 2011) International Science Symposium on ME continued Dominic O’Donovan, (Cambridge,UK) a neuropathologist presented the results of autopsy on 4 patients who had a specialist diagnosis of CFS: 1. A 32 year old male with a 20 year history of CFS, who died of a suicide overdose of medication. Spinal cord and brain at autopsy showed excess corpora amylacea, which was in excess of normal ageing. There were intermediate filaments closely related to glial cells, and maybe within the glia rather than the axons. No evidence of ganglionitis. (EBV negative) 2. A female of 32 with a 5 year history. She had been unable to tolerate food or water, due to the pain and discomfort of ME/CFS. She finally died of renal failure. The pathology showed a focal chronic inflammatory infiltrate (T8 lymphocyes) in the dorsal root ganglia. (EBV negative). 3. A female of 43 – an assisted suicide in Switzerland with a barbiturate overdose. The brain showed global ischaemia, but this was likely due to the drugs used. Dorsal root ganglia showed mild excess of lymphocytic nodules of nageotte but with no obvious inflammation, but this could represent a subtle chronic inflammatory state. 4. A female of 31 whose death may have been due to opiate ingestion. There was some toxic demyelination with spinal subarachnoid haemorrgae, but she was on warfarin. There was some mild possible chronic ganglionitis. Differential diagnosis here was discussed and would have included AIDs, Sjorgren‟s syndrome, varicella zoster and paraneoplastic disease. These results have raised the possibility that some cases of CFS may have sensory or autonomic ganglionitis. A specific brain and tissue bank in the UK is proposed. Invest in ME (Charity Nr. 1114035) Olga Sukocheva (Adelaide, Australia) presented the immunohistochemical and microbiological post mortem findings in a 20 year old patient with fatal idiopathic encephalopathy. This patient had been diagnosed with CFS following a severe encephalitic like illness aged 10. There was evidence of inflammatory damage with suppression of microglial cells. Down regulation of ankyrin B was detected in the white matter of the hippocampus. There was no significant difference in ankyrin G. Tests for Coxiella burnetii and Legionella were instituted. C.burnetii antigens were present in astrocytes, and in the microglial cells in the grey matter of the hippocampus. C.burnetii antigen was also found in spleen and liver macrophages,lymphoid tissue, bone marrow, lung and heart tissues. Legionella antigen was not found. Dan Peterson (Nevada,USA) started his talk with a brief overview of the incidence and effects of CFS in the USA. He then went on to describe research problems, such as the varied definition, heterogeneity of patients, lack of biomarkers, patient self-selection, researcher bias and lack of funding. He described a number of “scientific journeys” undertaken in CFS research. He stressed the importance of the bringing together of the patient, biotechnology, database informantics, genomics and clinical medical guidelines. Diseases can now be defined from a molecular perspective. Networking and collaboration are keys to successful research. There needs to be large-scale clinical data gathering, with international biospecimen collection. He then went on to discuss the importance of looking at viral infections in CFS. Leukotropic herpes viruses particularly HHV6, HCMV and EBV are among a number of major candidates in CFS. He reported on large studies in which active HHV6 was detected in 28%, HCMV in 29% and EBV in 51%. 10% were co-infected. Active EBV infection significantly correlates with Continued page 25 www.investinme.org Page 24/58 Journal of IiME Volume 5 Issue 1 (May 2011) International Science Symposium on ME continued the presence of auto-antibodies, with antibodies directed at thyroid peroxidase and parietal cells. Up to 30% of patients may respond to antiviral medication. Ekua Brenu (Queensland, Australia) had looked at innate and adaptive immunity in CFS. It was postulated that her study could assist in developing biomarkers. The study involved 253 patients and 100 controls. Studies were undertaken at zero and 6 months. Cytotoxic activity of NK cells and CD8+T cells was significantly reduced. Perforin and granzyme activity was reduced. When looking at NK cell phenotypes, CD56 bright cells were significantly diminished. Cytokine secretion from CD4+T cells showed significant elevation of IL-10, IFN-γ and TNF-α. FOXP3 expression was also heightened in the CFS group. Vasoactive intestinal peptide (VIP) receptors were also investigated and found to be significantly elevated. Kenny de Meirlier (Brussels, Belgium): Because chronic activation of the immune system is present in progressive HIV and is a better predictor of disease outcome than viral load, it is important to test the hypothesis that a similar pattern may be observed in XMRV positive CFS patients. 16 XMRV positive patients (using culture assay) had a large number of tests performed. These patients were found to have reduced lymphocyte numbers and CD57+lymphocytes reduced, as observed in HIV. There was evidence of an activated innate immune system (increased elastase activity and C4a). sCD14 was significantly higher than expected, and this correlated with plasma lipopolysaccharide (LPS) a proinflammatory component of the gram-negative bacterial envelope. Low stool IgA indicated dysfunctional mucosa-associated lymphomal tissue in XMRV positive patients. Serum IL-8,IL10,MCP-1 and MIP-1β are increased and might constitute a biological signature for viral infection. This all provides supportive evidence for Invest in ME (Charity Nr. 1114035) microbial translocation being part of the pathology of XMRV +ve patients. He described a Norwegian study of severely disabled CFS patients in which the plasma LPS was elevated in those with a low Karnofsky score. This suggests a leaky gut syndrome. Stool analysis in CFS patients has indicated overgrowth of enterococci, streptococci and fungi with diminished E.Coli count. This can lead to overproduction of hydrogen sulphide which is toxic to mitochondria and affects ATP. Richard Kwiatek (Adelaide, Australia) is a rheumatologist with a particular interest in neuro-imaging. MRI was performed to look for brainstem dysfunction in CFS. Whole-brain optimised voxel-based volumetry and novel quantification of T1-weighted and T-2 weighted signal levels in structural MRI were used. Voxels build a 3-D map of the brain. In the CFS patients seated pulse pressure was reduced, and seated heart rate and asleep heart rate were increased, compared to controls. This was then correlated with brain change, other symptoms and fatigue. Prefrontal white matter volume reduced with increasing sleeping heart rate in CFS with the opposite in controls. Midbrain white matter volume reduced with increasing fatigue. There was a strong correlation between total brainstem grey matter volume and seated pulse pressure in the CFS patients. Brainstem grey matter changes suggest a failure of cerebrovascular auto-regulation, potentially mediated by astrocytes. Astrocyte dysfunction may therefore be central to CFS pathogenesis. There seems to be disrupted autonomic nervous system homeostasis. He does not feel it is reduced blood volume that will be causing this. Barrie Marmion (Adelaide, Australia) has studied Q-fever and its aftermath for many years. There were 11 suffering from post Qfever fatigue syndrome out of 39 who had had the acute illness in one study cited. The Continued page 26 www.investinme.org Page 25/58

Journal of IiME Volume 5 Issue 1 (May 2011) International Science Symposium on ME continued C.burnetii antigen persists, and causes immune modulation with gene expression and symptoms. Usually it is continuous from the initial onset, but episodic relapses may occur due to re-infection or inadvertent Q-fever vaccination. IL-6 is elevated and IL-2 is down. The symptoms fit the criteria for a diagnosis of CFS. 3 Q-fever groups were studied and there were differences in the frequency of carriage of HLA-DR B1*11 and of IFN-γ. 35% were positive in the post-Q-fever syndrome group, and the levels were low in the controls and Q-fever recovered group and the Q-fever endocarditis group.. These differences support the concept of different immune states in chronic Q fever, determined by genetic variations in host immune responses, rather than by the properties of C.burnetii. Anne Boullerne (Illinois, USA) discussed the issue of chronic fatigue in relation to CFS and MS. She described MS as a characteristic autoimmune disorder. She outlined the differences in incidence, symptoms, duration of illness etc. She emphasised that while MS is a neuroimmune disease, CFS is an acquired severe complex system dysfunction. In MS there is oligoclonal IgG in the CSF in 95% of cases, and brain lesions with T and B cells are seen on MRI. She asks the question “Is gliosis present in CFS?” In CFS MRI abnormalities maybe found such as small punctate subcortical white matter intensities in the frontal lobes, small ventricular volume, slow blood flow and some atrophy. She had looked at functional MRI in relation to control imagery and visual imagery. Both were found to be slower in CFS compared to controls. Changes associated with finger tapping and auditory monitoring correlated with subjective fatigue and brain response during challenge involving memory. Using M.R.Spectroscopy, there was an increase in choline in the basal ganglia, no significant difference in glutathione, and ventricular lactate was elevated. There was no alteration in levels of GABA and glutamate. Invest in ME (Charity Nr. 1114035) In a rat model for Gulf War Syndrome, using pyridostigmine, there was no gliosis and no increased permeability of the blood brain barrier. A possible auto-immunity including vasoactive neuropeptides is hypothesised. Warren Tate (Dunedin, NZ) and his team have just initiated a study to develop tools that can accurately detect molecular changes within cells in response to double-stranded RNA (dsRNA) relevent to CFS. He explained how recent XMRV findings had stimulated research and a need for a bank of genetic material. Biomarkers need to be established as well as less specific markers to reflect changes in global homeostasis.There needs to be targetting of a vulnerable point in the biology of XMRV viral RNA that determines the ratio of its structural and enzyme proteins. He went on to describe types of biomarkers: 1. Specific such as in a cell undergoing apoptosis: RNaseL, PKR, phosphorylation of PKR etc 2. Specific biomarkers of disturbed homeostasis 3. General biomarkers – marking global disturbed homeostasis of various organs He explained the RNaseL activation pathway. RNaseL cleavage may be specific to CFS. He is currently studying the ratio of the RNaseL terminal fragment to uncleaved protein. He will also be looking at abnormal PKR activation. This is cleaved by caspase to form the 37D fragment. This undergoes phosphorylation which can be measured – the protein-synthesis factor e1F2α. These 2 phosphorylation events will be detected by specific antibodies against the phosphopeptides of the 2 proteins. Douglas Feinstein (Illinois,Chicago) presented study of noradrenergic treatments for neurodegenerative diseases. Glial cells are activated producing neurotoxins, which Continued page 27 www.investinme.org Page 26/58 Journal of IiME Volume 5 Issue 1 (May 2011) International Science Symposium on ME continued induce neuronal damage and leukocyte infiltration into the CNS. Noradrenaline regulates glial inflammatory responses, exerts neuroprotective effects and helps maintain the integrity of the blood brain barrier (BBB). Dysregulation of noradrenaline signalling could exacerbate disease. The supposed reductions of noradrenaline increase inflammatory responses, the amyloid burden and neurotropic factors. Noradrenaline is mainly produced in the locus coeruleus (LC). This part of the brain is damaged in Alzheimer‟s and Parkinsonism. LC loss correlates with plaque and tangle numbers. The question was asked “does increasing noradrenaline in the CNS improve things?” The drug Droxidopa is a precursor of noradrenaline. This drug is in phase 3 trials for neurogenic orthostatic hyopotension. In mice the drug leads to improvement in plaques and learning. This drug used in MS and experimental autoimmune encephalmyelitis (EAE) showed stabilisation compared to controls. This trial indicates that the LC is significantly damaged in MS and EAE. Noradrenaline directed therapies need to be considered if there is perhaps also LC disturbance in CFS. Doina Ganea (Philadelphia,USA) spoke about Vasoactive Intestinal Peptide (VIP) – an endogenous and exogenous immunomodlator. VIP downregulates the innate immune response by inhibiting the release of pro-inflammatory cytokines, chemokines and nitric oxide by activated macrophages, microglia and dendritic cells. It also affects the adaptive immune response by reducing the co-stimulatory capacity of antigen-presenting cells, and by inducing Th2 type responses. She had looked at several diseases, such as collagen-induced arthritis and autoimmune encephalmyelitis. She had used dendritic cells generated in the presence of VIP/PACAP as immunomodulatory agents, with positive results. Monica Carson (California,USA) had studied the CNS expression of the classic chemokine Invest in ME (Charity Nr. 1114035) CCL21. This is a predisposing factor for autoimmunity due to the proliferation induced preactivation. It thus contributes to chronic inflammatory disease and auto-immunity. Experimental work was done using mice. Resulting data indicated that CCL21 expression within the CNS has the potential to contribute to T-cell mediated CNS pathology. This could occur via homeostatic priming of CD4+T cell lymphocytes outside the CNS, and CD4+T cell migration into parenchymal site after infection with organisms such as toxoplasma. Donald Staines (Gold Coast, Australia) rounded off the formal papers with a presentation looking at novel treatments in CFS. He considered whether auto-immunity affecting vaso-active neuropeptides suggest a pathomechanism. ME/CFS may be associated with auto-immunity affecting the function of vaso-active neuropeptides, such as VIP and PACAP (pituitary adenylate cyclase activating peptide). Upsets in adenylate cyclase (AC) signalling and cAMP functioning possibly involving ATP toxicity may be a feature of VN auto-immunity. Purinergic receptors such as ATP negatively regulate AC. He outlined some basic biochemical principles to clarify things; AC amplifies incoming intracellular signals; PACAP is an acetylcholine co-transmitter; AC is involved in long term potentiation and enhanced maintenance of neuronal activity. VIP/PACAP synergism is involved with potentiation of cardiac firing, anti-apoptosis function, cAMP and insulin control, hypoxia regulation and glutamate metabolism. Purinergic signalling is involved in centrally mediated pain (neuropathic pain). He then went on to describe some likely treatment possibilities based on these principles. These included purigenic signalling modulators, VIP/PACAP mimics/analogues, phosphodiesterase inhibitors: eg Rolipram (toxic), Ibudilast, Roflumilast; B cell depletors (Rituximab); chondroitinase; VIP liposomes and Continued page 28 www.investinme.org Page 27/58

Journal of IiME Volume 5 Issue 1 (May 2011) International Science Symposium on ME continued lentivirus agents. Some of these could be considered for clinical trials. DAY 2 – was involved in general discussion with various panels looking at clinical matters, case definition, guidelines and research collaboration. Possible name change was also discussed. There was plenty of open discussion, and being a small group meant an interactive forum with everyone participating. Some of the salient points: Name change: most people acknowledged that patients do not find the name CFS describes the severity of the illness – tends to trivialise it. It was agreed that the name ME was more appropriate in many ways, although still not entirely accurate for this illness. There was some discussion as to whether gut symptoms and possible auto-immune activity could be incorporated. Case Definition: The Fukuda definition is still useful for research and one must bear in mind that many previous studies have used this defintion so it should not be entirely abandoned, although all agreed that the Canadian consensus defintion is more suitable for clinical diagnosis, and should generally be adopted. It is hoped that this definition will be adopted internationally and renamed accordingly. All agreed that the CDC empirical definition should not be used. The issue brought up earlier at this symposium of “sickness behaviour” as terminology was thought to be a backward step, and would be unpopular with patients, although Hugh Perry explained his reasoning very clearly. Diagnosis: The importance of biomarkers was reiterated. These need to be user friendly and readily available. There should be opportunity to sub-group according to type of onset, symptoms and gene expression. Clinicians new to this illness need to be aware of the range of longterm diagnoses that may emerge in those with CFS, so that regular ongoing surveillance is important. Uniform assessment tools should be Invest in ME (Charity Nr. 1114035) encouraged, although it is acknowledged that not all types of testing will be available everywhere. Management/guidelines: Guidelines need to be unified, and there should be collaboration among those working on guidelines. Nancy Klimas stressed that financial assistance should be available for a face to face meeting among experts to work on this. There was some discussion about the importance of off-label prescribing, as many clinicians feel uncomfortable if they do not stick to evidence based medicine. A recommendation should go out in support of being able to use medication in this illness, where there is some useful research backup, even if not formally trialled, so that practitioners do not need to fear litigation. A longitudinal “n of one” trial of a treatment approach on one patient should be deemed useful, and clinicians should be encouraged to do this and write up their results. Clinical overview: 5 clinicians presented their views on management, and there was much discussion contributed from those on the floor also. Mieke van Driel (Queensland, Australia) presented an overview of drugs used in CFS. Few trials have been done, and those that have showed little benefit. She recommended that we should let patients guide the research agenda by teaching us what works for them. Don Lewis (Melbourne, Australia) discussed the importance of food intolerances, and emphasised that although gut symptoms maybe prominent, they may not always occur. A strong family history of intolerances is relevant. He firmly believes that intestinal dysbiosis occurs in almost all his patients and the hydrogen sulphide test was positive in 85% of patients. antibodies were found to many different foods. He now proposes formal laboratory based clinical trials. Bill Cassimatis (Queensland,Australia) has a number of CFS patients in his general practice and he outlined his general approach. He www.investinme.org Continued page 29 Page 28/58 IgG Journal of IiME Volume 5 Issue 1 (May 2011) International Science Symposium on ME continued mentioned that a number of women with this illness seemed to be worse cyclically, confirming that in some women, hormones are involved. This was discussed further by Rosamund Vallings (Auckland,NZ) who uses oestrgen and progesterone often in women with CFS with cyclical or post menopausal symptoms. Nicole Phillips (Melbourne, Australia) who is a psychiatrist pointed out that some women can become depressed on Depo-Provera. Norman Hohl (Southport, Australia) Is relatively new to dealing with this illness, but as a travel medicine consultant and qualifications in infectious diseases, he has a strong interest in preventative strategies. Research directions: All agreed that this symposium will lead to collaboration internationally. International concurrent trials are needed, and more funding is essential. Larger worldwide studies are likely to increase funding availability. Collection of observational data can be of value. The idea of establishing a CFS registry was considered a valuable approach although this could be often difficult and time consuming for medical practitioners. Using internet self report will not necessarily generate patients fitting diagnostic criteria. Diagnosis needs to be made with face to face encounter by physicians familiar with the illness. More medical education is thus a very important issue to be addressed. Immediate plan: A formal press statement was produced for distribution after the symposium outlining the salient points raised. A list of future directions was also formulated. Some further e-mail discussion and collaboration between the scientists and clinicians is envisaged, and this was a very positive outcome from this symposium. Many of these people were new to CFS and had never met before, and it seems a whole new set of directions for future research will ensue. Those who had presented papers were encouraged to make the full paper available for the website which will be set up and Invest in ME (Charity Nr. 1114035) meanwhile the abstracts will be available. Christine Hunter and her AHMF team were formally thanked, together with the team from Bond University. Without all the dedication and hard work by all of these people, this symposium would never have been possible, and everyone agreed it was an enormous success. The event had been ably chaired by Prof Ken Donald and Prof Mel Miller. I would like to thank the Alison Hunter Memorial Foundation and ANZMES for enabling me to attend. ME QUOTES “…there is a chronic inflammation, neuro-inflammation, and it upsets the whole balance of your systems…the patients become terribly ill…. The immune system is really cranked up; it‟s a tremendous amount of inflammation. I think that if doctors could get this in their heads that it‟s sort of like lupus or one of these really inflammatory disorders…it is that level of inflammation. There‟s a tremendous amount of inflammatory stuff going on, and there‟s a lot of inflammation in the brain itself” (http://www.litemiami.com/spotlite/inde x.aspx) [Also see Invest in ME International ME/CFS Conference 2010 DVD] The evidence of inflammation in people with ME/CFS is important because the incremental aerobic exercise recommended by the Wessely School and encapsulated in NICE‟s Clinical Guideline 53 is contra-indicated in cases of inflamed and damaged tissue and inevitably results in post-exertional relapse with malaise, which is the cardinal symptom of ME/CFS. - Knowledge or Belief http://www.investinme.org/Article413 %20Knowledge%20or%20Belief.htm www.investinme.org Page 29/58

Journal of IiME Volume 5 Issue 1 (May 2011) A UK Centre for Biomedical Research into ME Invest in ME‟s outline proposal At the 5th Invest in ME International ME/CFS Conference in London in May 2010 Invest in ME announced that we had entered into discussions with the University of East Anglia to instigate a research facility for ME. Discussions continued after the conference and we decided to publicise our attempt to set up this facility. Below is a summary of information relating to a proposal which was formulated by an Invest in ME steering group that was formed to oversee the setting up of this facility. BACKGROUND People with ME need early and correct diagnosis, proper treatment and advice. The current status of services for people with ME and their families in the UK is poor with little knowledge of current biomedical research being applied and possible treatments not being made available to patients or healthcare staff. This has resulted in ME patients having no service and there being little progress in attracting new researchers or clinicians to study the disease. The dangers for people with ME of having no proper clinical examination and no access to possible treatments is that the disease can develop into more severe forms with significant loss of functioning. There is also the danger of mis- or missed diagnosis – a common problem with people thought to suffer from ME. THE AIMS and OBJECTIVES After five years of campaigning for awareness and promoting better education about ME/CFS the charity felt that the best way to make progress is to establish a national centre of excellence for ME. The Invest in ME Steering Group (ISG) was formed - consisting of carers of people with ME - to begin work on establishing a facility leading to a UK Centre of Excellence for Biomedical Research into ME. The ISG believe that a change needs to be Invest in ME (Charity Nr. 1114035) made in the way service provision for ME patients is carried out and is suggesting a simple but effective structure for providing services and instituting major biomedical research into this disease which will have profound effects on the way ME/CFS is treated in the UK and establish a hub of scientific and clinical excellence for ME within Europe. THE PROPOSAL The ISG propose for a facility to be instigated with four main elements for diagnosis, treatment and research into ME/CFS – service commissioning, service provision with clinical diagnosis and examinations, translational biomedical research and a research database to allow for more research and improved training of healthcare staff. Figure 1 shows the elements of the model with patient care and treatment at the centre of the model. The proposal would be located around the Norwich Research Park in Norfolk. This area contains world-class facilities with a leading university (the University of East Anglia (UEA)), leading research institutes and a modern university hospital (the Norfolk and Norwich University Hospital) - all of which complement the necessary biomedical research which would take place. Service Commissioning Service commissioning would be performed by the local PCT. The service would require early and correct diagnosis, examination and Continued page 31 www.investinme.org Page 30/58 Journal of IiME Volume 5 Issue 1 (May 2011) A UK Centre for Biomedical Research into ME Training Figure 1 treatment of ME/CFS using a clinical biomedical lead consultant with GPs with special interest being connected to the service. Diagnosis and Clinical Examinations The examinations of people with ME/CFS would be commissioned by the PCT. Referrals to the university hospital would be via existing methods from GPs. An important issue is for early and correct diagnosis to be determined. The service would include a clinical biomedical lead consultant who would perform correct diagnosis (using the international standard Canadian Consensus Guidelines), perform a full examination using a standard clinical protocol and, once patients have been formally diagnosed as having ME, administer possible treatments and participate in biomedical research into the disease. Using a standard diagnostic and clinical protocol the service would allow a model of care and appropriate care packages for people with severe presentations and would establish and co-ordinate a clinical network and disseminate best practice across that Invest in ME (Charity Nr. 1114035) network. Follow-up examinations would be scheduled so that patients are provided with a service and possible treatments and results from any treatments would be fed back into a database which is administered between the university hospital and the university research faculty. GPs in the area with a special interest in ME would be used to assist and be trained in proper diagnosis and treatment of ME. Translat ional Biomedical Research A parallel but complementary element will be for translational biomedical research to be started by the university in association with other complementary research organisations. The university would undertake biomedical research into ME using cohorts of patients from those being examined at the university hospital and provide possible recommendations for treatment. The university research would be used for more rapid provision of possible treatments for Continued page 32 www.investinme.org Page 31/58

Journal of IiME Volume 5 Issue 1 (May 2011) A UK Centre for Biomedical Research into ME patients whilst at the same time building up the research database for ME/CFS and allowing fostering of new areas of cooperation with other biomedical research facilities. The research being proposed at the university would be of the most advanced possible – using virology and immunology as the key for examining patients. An important aspect of the biomedical research is that properly defined and distinct patient cohorts are defined and maintained. The research would be oriented toward translational biomedical research, which allows results from research to be applied toward treatments for ME patients. The initial proposal for research would aim to initiate studies using the TGAC genome sequencing facility at the Norwich Research Park which would allow all viruses present to be identified in a cohort of well defined patients. Allied to this would be biomedical research projects – the first of which would examine the possible link between ME and gut inflammation. A Research Database These initial and ongoing projects would enable a database to be established for use in further research. This research database will assist epidemiological studies, enhance research potential and provide patients with proper records of treatment. A research protocol will be established to outline all the study procedures, including data collection and planned data analysis. THE CURRENT INFRASTRUCTURE This proposal would make use of the existing infrastructure where patients are initially seen by GPs and referred to a consultant. Where it differs is that a specialist biomedical clinical lead would be used to perform diagnosis and provide treatment and would be working with a translational biomedical research facility at the university in order to deliver real improvement in patient care from scientific discovery. Invest in ME (Charity Nr. 1114035) THE BENEFITS Proper examination and treatment benefits patients, their families and the PCT by ensuring that adequate services are provisioned for people suffering from this disease. The hospital and associated staff will be able to be educated in the latest knowledge regarding this disease and would therefore be able to make better decisions. The research proposal would establish this as the most advanced facility in Europe, thus bring more potential for investment and publicity. The above proposal would lead to a facility with the following benefits –  early and correct diagnosis of ME/CFS  the clinical lead consultant would assess and plan the development of future services in conjunction with commissioning PCTs  it would provide access to specialist assessment, diagnosis and advice on the clinical management, including symptom control and specific interventions, for both patients and health professionals  development of a network of local multiagency domiciliary services to support people who are more severely affected and who are unable to access hospital and primary care services  eventual provision of an ambulatory service and/or tele-medical services for those severely ill patients who cannot be moved  allow ME/CFS patients (including those severely affected) to participate in clinical trials, where novel research will be conducted, and where medical students can learn about this disease  facilitate training and education opportunities for healthcare staff to enhance their knowledge and skills in the diagnosis and management of CFS/ME  lead the development of services within primary and secondary care and support GPs and other health professionals in the care of patients with ME. Continued page 33 www.investinme.org Page 32/58 Journal of IiME Volume 5 Issue 1 (May 2011) A UK Centre for Biomedical Research into ME  Allow healthcare staff to feel more comfortable with the diagnosis of ME/CFS being made  undertake comprehensive assessments and provide a care package for each patient to include carer and family support  Savings on existing consultant referrals and staff by concentrating ME/CFS examination in one area. TRAINING of HEALTHCARE STAFF The need for training in ME/CFS is one of the main areas of interest for the ISG. The proposed model would allow the GP network to have access to up to date information about ME/CFS including data on treatments and prognosis. Specialist advice for more complex cases across the country could be provided based on referrals from other PCTs. This in turn would complement the research database thus increasing knowledge and awareness of treatments. Models of care and appropriate care could be developed with packages for people with severe presentations. FUTURE DEVELOPMENTS This model would be developed in the future with an ambulatory service and/or tele-medical services being employed for those who are too ill to attend the hospital examination. Phlebotomy services would be provided for home visits to be made to allow the severely affected to participate in the research and allow treatments for these disenfranchised patients. We would seek to establish additional biomedical research projects to be undertaken by the university which would increase the knowledge about the disease and facilitate development of treatments for patients. In partnership with the charity more training courses would be arranged with visiting experts (researchers and clinicians) being able to share experiences and data and facilitate more education about the disease. Future developments would see the potential of referrals from other areas (and other countries) Invest in ME (Charity Nr. 1114035) to be created thus generating income and helping to establish the translational research and treatment facility as the foremost facility in Europe for treating myalgic encephalomyelitis. CHARITY SUPPORT Invest in ME are supporters of the WhittemorePeterson Institute (WPI) of Nevada, USA, and have funded UK research by WPI. The WPI have expressed their support for the charity‟s efforts in establishing a translational biomedical research base in Norwich and have agreed to cooperate. The charity also has European connections and links to other researchers and institutes in Europe and Australia. Our aim is to facilitate collaboration on biomedical research into ME. The foundations are therefore already in place to advance science and provide the promise of better treatment and possible restoration of function and lives back to a section of the community who have received very little help in the past. HOW TO LEARN MORE Contact Invest in ME at info@investinme.org. SUPPORT US Our objective is to establish a UK Centre of Excellence for Biomedical Research into ME. We will continue to campaign for this facility to be established. We welcome all support. Donations to the Invest in ME Biomedical Research Fund will be used to support the establishment of this facility. Help us by contributing to the Invest in ME Biomedical Research Fund for ME – http://tinyurl.com/ydh6whu ME FACTS In 1969 the World Health Organisation classified ME as a neurological disorder. In 1978 The Royal Society of Medicine accepted ME as a nosological entity. www.investinme.org Page 33/58

Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions by Margaret Williams Following publication of the PACE Trial results and mindful of the fact that the Department for Work and Pensions (DWP) was a co-funder of the trial, it may be salutary to reflect afresh on the involvement of Principal Investigators Professors Peter White and Michael Sharpe and the Director of the Clinical Trials Unit (Professor Simon Wessely) with the DWP. The extracts below are from recent DWP/Atos Healthcare Training Programmes for medical practitioners carrying out assessments on State benefit claimants with ME/CFS. They graphically illustrate the pervasive influence of the Wessely School‟s biased beliefs about ME/CFS at the Department for Work and Pensions and the degree of involvement of Professors White, Sharpe and Wessely (a depth of involvement which may indicate that in setting up the PACE Trial, they were not openminded clinicians seeking to help patients but rather that the PACE Trial was mounted (to quote an influential expert in appraisal of biases in medical research): - “not to answer a question, but in order to demonstrate a pre-required answer” (Why most published research findings are false. J.Ioannidis; PloS Medicine 2005:2:8:e124 – note that this article by Ioannidis is the most down-loaded in the journal‟s history). MEDICAL SERVICES provided on behalf of the Department for Work and Pensions Training and Development: Continuing Medical Education Programme: Chronic Fatigue Syndrome – Guidelines for the Disability Analyst Version 4; April 2009. Updated by Dr Peter Ellis. Version 1 written by Dr Tony Fisher. “The authors and Medical Services gratefully acknowledged the contribution of the authors (Professor S Invest in ME (Charity Nr. 1114035) Wessely, Professor PD White and Professor M Aylward) of the enclosed articles and their kind permission to reproduce them in this module. In addition the author would like to express his gratitude to Dr P Dewis for his helpful comments and suggestions”. For more information on Professor Mansel Aylward and his stance on ME/CFS, see pages 428 ff at http://www.investinme.org/Article400%20Magi cal%20Medicine.htm Together with (then) Dr Aylward, Dr Peter Dewis from the Disability Living Advisory Board authored the Disability Handbook before Dewis became Chief Medical Officer at UNUMProvident in July 2000 after 16 years at the Department of Social Security (now the DWP). In 2002, Dewis wrote about the patients whose claims management posed difficulties for UNUMProvident; in the company‟s Report “Trends in Health and Disability”, he stated: “I have commissioned a number of papers from leaders within the medical profession whose disciplines are particularly relevant to those people…whose claims most frequently pose us difficulties in their management. “A paper from Michael Sharpe has reviewed the developments, not only in chronic fatigue syndrome, but also the range of disorders where the symptoms experienced by individual patients appear to be out of proportion with the physical findings or objective evidence of disease. “Mansel Aylward who is Chief Medical Adviser to the Department of (sic) Work and Pensions has set out the current trends in government strategy relating to both health and social security. Continued page 35 www.investinme.org Page 34/58 Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions continued “My intention would be for this report to be repeated on an annual basis and so become an authoritative and informative document on the current state of medical thinking on those issues which are of greatest importance to us. “Dr Lipsedge (and) Dr Sharpe have identified the importance of cogni-tive behaviour therapy of (sic) influencing the outcome in …chronic fatigue syndrome. This again represents a challenge in ensuring that people are directed towards this approach”. Thus the interest of the DWP and the insurance industry in ME/CFS is clear: it is a disorder that poses “difficulties” for them, so it seems it must be “eradicated”, preferably by those who already work for these agencies. It appears that it is those commercial interests, not the plight of sick people, which are paramount. It also seems that, as part of the triple strategy of the “CFS” clinics and the NICE Clinical Guideline on “CFS/ME”, the PACE Trial was the ideal vehicle to remove the “difficulties”. Extracts from the DWP Medical Services Training and Development on Chronic Fatigue Syndrome Guidelines: “This training has been produced as part of a Continuing Medical Education programme for Health Care Professionals (HCPs) approved by the Department for Work and Pensions Chief Medical Adviser to carry out assessments”. “…it must be remembered that some of the information may not be readily understood without background medical knowledge and an awareness of other training given to Health Care Professionals”. “The series is designed to encourage consistency in our approach to complex conditions, provoke reflection on our own Invest in ME (Charity Nr. 1114035) In the first self-assessment exercise, Medical Services assessors are instructed to read the questions and then tick one of the boxes, one of the questions being: “Most cases of chronic fatigue [sic] are attributable to abnormal illness behaviour”. “Chronic fatigue” is not the same as “CFS/ME”, but even if applied to “chronic fatigue”, this is a Wessely School assertion that is not supported by clinical evidence: when carefully examined and diagnosed, patients with many organic illnesses have chronic fatigue, including patients with cancer, COPD, thyroid disease, multiple sclerosis, Parkinson‟s Disease, liver disease, TB, and many viral illnesses, none of which disorders can be categorised as “abnormal illness behaviour”. The training programme then presents a case study: “Mrs D is a 42-year old woman. You have been asked to assess her and provide a report for a non-medical decision maker. She has completed a claim form herself, amplifying it with several additional pages of hand-written text and a pamphlet describing features of „ME‟ ”. Such loaded wording immediately introduces denigration, disparagement and bias into the Continued page 36 www.investinme.org Page 35/58 perception with regard to them, and foster awareness of current medical thinking” (i.e. the Wessely School‟s thinking). “Chronic fatigue syndrome (CFS) is a disorder, or group of disorders, which continue to cause considerable difficulties for clinician and disability analyst alike (no mention of difficulties caused to patients). Since the terms „myalgic encephalomyelitis‟ and „post-viral fatigue syndrome‟ both carry implications relating to causation, the generic term CFS is preferred”. “The purpose of this module is to encourage Health Care Practitioners working in disability analysis to adopt a common approach to this difficult and complex illness”.

Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions continued training programme for DWP assessors. The Guidelines for DWP assessors state that anhedonia (loss of any pleasure/interest in life) is commonly present in CFS, which is erroneous, as it is not present in ME/CFS. In 1991, John Wiley & Sons published “Post-Viral Fatigue Syndrome” edited by Professors Rachel Jenkins and James Mowbray; in her own contribution, Professor Jenkins, a Principal Medical Officer at the Department of Health and Director of the WHO Collaborating Centre for Mental Health at the Institute of Psychiatry, made it clear on page 242 that there is no anhedonia in ME. The DWP Training Guidelines on CFS continue: “At one end of the scale are the (uncommon) cases where there is a very clear history of the sudden onset of fatigue after a proven viral infection, such as Epstein Barr virus; at the other, cases strongly associated with current or pre-existing psychiatric disorder. In fact, most patients with CFS will also meet the criteria for a current psychiatric disorder” (citing Simon Wessely and Trudie Chalder). “From the point of view of the disability analyst, by the time an individual has reached the stage of requiring a functional assessment the diagnosis is likely to have been in place for some time and behaviour patterns firmly established in the minds of the claimant and his medical attendant”. The claimant‟s medical attendant may be entirely correct in his/her management, but this implied criticism has long been a feature of the Wessely School‟s dismissal of “naive” clinicians who do not subscribe to their own beliefs about ME/CFS: for example: “Suggestible patients with a tendency to somatise will continue to be found among sufferers from diseases with ill-defined symptomatology until doctors learn to deal with them more effectively….It has been shown (by whom?) that some patients have always preferred to receive, and well-meaning Invest in ME (Charity Nr. 1114035) doctors to give, a physical rather than a psychological explanation…such uncritical diagnoses may reinforce maladaptive behaviour” (Old wine in new bottles: neurasthenia and ME. Simon Wessely. Psychological Medicine 1990:20:35-53) and “The prognosis may depend on maladaptive coping strategies and the attitude of the medical profession” (The psychological basis for the treatment of CFS. Wessely S. Pulse of Medicine, 14 December 1991:58). The DWP Guidelines continue: “It will almost always be appropriate to assess the claimant‟s mental state, and in the case of IB PCA (Incapacity Benefit Personal Capability Assessment) and ESA (Employment and Support Allowance), to complete a mental health/function assessment”. “The combination of cognitive behavioural therapy (citing Wessely and Chalder) and graduated exercise (citing Peter White) is at present the mainstay of treatment”, “treatments” which have been shown to be ineffective in numerous international reports and in surveys carried out by ME/CFS charities, as well as in the UK FINE and PACE Trials themselves. The Training Programme then instructs DWP assessors to read only a heavily psychiatrically biased reading list (with no mention of any of the biomedical evidence on ME/CFS), including “Occupational aspects of the management of Chronic Fatigue Syndrome: A National Guideline” (2006) in which Professors White, Sharpe and Chalder were instrumental; the NICE Guideline CG53 (2007) which recommends only CBT/GET as the primary intervention, and the 1996 report on CFS of the DWP Chief Medical Adviser‟s “Expert Group” which included Dr John LoCascio (Medical Director of UNUMProvident insurance company), Professor Anthony Pinching, Dr Peter White, and Dr Charles Shepherd, (Medical Adviser, ME Association). Continued page 37 www.investinme.org Page 36/58 Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions continued This “Expert Group” advised that: “The Chief Medical Adviser (at that time, Dr Mansel Aylward) is very anxious to ensure consistency of medical advice which is based on the prevailing consensus of informed expert opinion on this subject (ie. on the advice of Simon Wessely, Peter White and Michael Sharpe, again with no mention of the substantial biomedical evidence-base). “The following interests and disciplines were represented: academic research into CFS, clinical interest in the field (from psychiatry, neurology, infectious diseases and general practice), occupational medicine, the insurance industry…and the Disability Living Allowance Board”. Key recommendation of this “Expert Group” were: “The sooner appropriate management was started, the better the prognosis” and “Activity should be increased in a managed, step-wise manner”. The “Expert Group” agreed that: “Recovery should not necessarily be equated as getting back to the same condition as before the illness” (which seems to be a portender of the PACE Trial results). “Recovery” is defined in The Penguin English Dictionary as “To regain health after sickness”, which means restoration of full health after sickness; the term “recovery” is not open to idiosyncratic interpretation by the DWP or its “Expert Group”. The “Expert Group” recommended that its report to the DWP‟s Chief Medical Adviser should be widely available to all those with an interest in CFS (ie. throughout the NHS). At the end of the Training Programme, assessors were asked to tick more boxes and informed that “If the objectives have been achieved, you should have no difficulty in responding correctly”: one of the tick-box choices was: “The combination of cognitive behavioural therapy and antidepressants should be the mainstay of treatment”. The signed, completed form (together with the person‟s GMC or NMC registration number) Invest in ME (Charity Nr. 1114035) was to be returned to the “Medical Manager at your Medical Services Centre”. The 2010 version The Foreword to the DWP Medical Services 2010 version (Training and Development: Chronic Fatigue Syndrome [CFS] and Fibromyalgia Learning Set Continuing Medical Education) states: “The training has been produced as part of a Continuing Medical Education programme for Health Care Professionals (HCPs) approved by the Department for Work and Pensions to carry out assessments”. For the DWP Medical Services to conflate “CFS” and fibromyalgia is in breach of the WHO ICD-10 classification which classifies FM as a separate disorder from “CFS/ME” at M79. This version is particularly prescriptive and has become even more didactic: it ensures that only one message about ME/CFS and FM (the Wessely School‟s message) is delivered and received: “A Learning Set is dedicated to the sharing of team knowledge, and must be conducted using internal sources only. External speakers are not acceptable at these events”. (This is knowledge control, which is unacceptable ethically, morally and academically). “This Learning Set is designed to encourage competency based on the subject of CFS and FM and the functional effect of these conditions on the claimant”. “The learning aims are defined and the „manager‟ of the Learning Set is encouraged to ensure that these are kept prominently to the fore-front throughout the event, keeping them in view of all participants”. “The only absolute givens are that the essential Continued page 38 www.investinme.org Page 37/58

Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions continued content is adhered to and the Learning Set aims achieved”. There is a requirement to ensure that “verification of the learning aims have been satisfied”. Although nominally a DWP Training and Development Programme for assessors, the DWP Medical Services Guidelines state: “It is also necessary to demonstrate that the outcomes of the Learning Set satisfy the requirements of the Continuing Professional Development Programme for Atos Healthcare”. This sounds disturbingly like cult indoctrination and it is little wonder that so many people with ME/CFS report that their assessment(s) by DWP and Atos-trained assessors are traumatic experiences. In February 2011, the BMJ published an article by Margaret McCartney about Atos Healthcare (Well enough to work? Increasing numbers of people previously deemed medically unfit to work are being taken off state benefits after assessments by a doctor. BMJ 2011:342:d599). McCartney‟s article was enlightening: Atos Healthcare is a “French information technology firm, which is subcontracted to the Department for Work and Pensions to provide work capability assessments. In November last year (2010) Atos announced a three year extension to its contract with the department, worth £300 million, to „support the UK government‟s welfare reform agenda‟. Atos is the sole contractor….A quick glance at internet discussion forums suggests widespread dissatisfaction from people who have been assessed”. “The adverts for Atos, however, consist of a smiling, badged professional saying, „Getting home on time has become part of my daily routine‟. The lack of on-call duties and the 9-5 office hours were also the major advantage plugged at the evening, where nurses and doctors working for Atos helped to promote joining the company”. From her attendance at an Atos recruitment evening, McCartney reported: Invest in ME (Charity Nr. 1114035) “The message from the recruitment evening was quite clear. We were told: „You are not in a typical caring role….We don‟t call them patients…We call them claimants‟. Training is provided for each type of benefit examination. Its length…depends on experience but is generally up to five days of classroom training, followed by sessions accompanied by a trainer that are audited afterwards”. “Full time doctors can earn £54,000 as basic salary plus various benefits including private healthcare. Sessional doctors work a minimum of four sessions a week….The application forms for sessional doctors state that ‟10 DLA domiciliary visits per week would earn £40,211.60 per annum. Five LCWRA cases (limited capacity for work related activity) per session, for six session per week, would earn £62,883.60 per annum”. “From the recruitment evening, it was clear that the medical examination consisted of a computerised form to be filled in by choosing drop-down statements and justifying them”. “Is the current method of assessment fit for purpose? There is a queue of people who think not. „Citizens Advice Scotland (CAS) is extremely concerned that many clients are being found fit for work…despite often having severe illness and/or disabilities. Our evidence has highlighted the cases of many clients with serious health conditions who have been found fit for work, including those with Parkinson‟s disease, multiple sclerosis, terminal cancer, bipolar disorder, heart failure (and) strokes‟. The report found that clients often „felt hurried in their assessment and that the healthcare professional was ignoring the answers they were providing to the questions in the assessment. There was a general feeling that the assessor made little eye contact with the claimant and spent most of the assessment entering information into their laptop‟. This tallies with the recruitment evening, when it was made clear that efficiency with entering details into the computer system was a stipulation of employment”. www.investinme.org “The Department for Work and Pensions says… Continued page 39 Page 38/58 Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions continued „It‟s unfair to suggest that the system isn‟t working….If a decision is overturned at appeal, it does not necessarily mean that the original decision was inaccurate…‟. However, this doesn‟t really deal with the problem that the healthcare professionals doing the assessment are not…forwarding sufficient evidence to enable reliable decisions”. “At the meeting I asked how it was possible to know the variation in symptoms that a patient may have during a one-off assessment. I was told that this could be „difficult‟ but this was….a „functional assessment‟ ”. “The Citizens Advice Bureau…wants „better accuracy‟ in reports. But how can this be achieved when funding is devolved to Atos with no routine access to detailed specialist or general practice based information and opinion?”. Returning to the DWP‟s Medical Service 2010, its “Learning Aims” are: (i) (ii) (iii) (iv) (v) to define CFS and FM (perhaps more accurately, to “re-define” them as functional disorders) to consider “possible causes and functional effects of these conditions” to “consider current management and treatment guidelines (ie. NICE CG53) to “consider benefit issues in children and adults with CFS or FM” and to “consider effects of these conditions on work/occupation and effect of work on these conditions”. “It is essential that the Learning Set achieves its learning aims and covers the essential content….It is recommended that all attendees are reminded of the purpose of the Learning Set, the responsibilities of all those present and the learning aims reinforced”. During training discussions, participants must explore the following factors: Invest in ME (Charity Nr. 1114035)  “Ways in which relevant functional problems can present in a claim” (neither ME/CFS nor FM is a functional disorder)  “The likely functional effects of CFS and FM”  “Attitudes amongst the team towards the condition”  “The claimant‟s perceptions of their disability and barriers to recovery” (such a “barrier” is cited as belonging to a support group). “The challenge for the facilitator is to ensure that all participants are engaged and prepared to commit to the consensus conclusions” -- in other words, 100% commitment and absolute adherence to the Wessely School model of “CFS/ME” is obligatory on the part of all DWP/Atos Healthcare assessors dealing with patients with ME/CFS. Would such indoctrination be part of a training programme to assess those with other classified neurological conditions such as multiple sclerosis or Parkinson’s Disease? These DWP training programmes for assessors are extremely disturbing because, as Jason et al have pointed out in a compelling article looking at kindling as the underlying mechanism for the symptomatology seen in ME/CFS, these patients have evidence of extremely serious pathology (An Aetiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Neuroscience and Medicine 2011:2:14-27). Jason et al posit that kindling occurs when an organism is repeatedly exposed to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity, and that in ME/CFS patients, chronically repeated lowintensity stimulation due to an infectious illness might cause kindling of the limbichypothalamic-pituitary axis and that, once this system is charged or kindled, it can sustain a high level of arousal with little or no external www.investinme.org Continued page 40 Page 39/58

Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions continued stimulus, which in turn could lead to hypocortisolism seen in ME/CFS patients, and that seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur in ME/CFS patients. Jason et al cite impressive supporting evidence, for example, Broderick, Fletcher and Klimas et al “applied network analysis to cytokines in patients with ME/CFS and healthy controls, and outcomes were consistent with a latent viral infection (ie. attenuated Th1 and Th17 immune responses, an established Th2 inflammatory milieu, and diminished NK cell responsiveness)….Chronic cortisol deficiency can cause over-production of the proinflammatory cytokine interleukin-6 (IL-6), which has been associated with symptoms of ME/CFS. Lower cortisol, as well as an overactive sympathetic nervous system, could be responsible for the ejection fraction decreases (fraction of blood pumped out of the ventricles per heartbeat) and lower cardiac output among patients with ME/CFS….Because of the Th2 shift, the body would not have an effective defence against viral or intracellular infections….”. “Baraniuk et al suggested that patients with ME/CFS had unusual proteins in the cerebrospinal fluid, and the aggregation of these abnormal proteins…could cause small amounts of bleeding in the brain (by) causing small punctures in the blood vessels and then small amounts of blood leak into the brain. Other proteins suggest a proteaseantiprotease imbalance, increased free radical production, vasoconstriction of the blood vessels, inflammation, and altered rates of cell suicide. Baraniuk et al suggest that inflammation, haemorrhagic elements, increased cell death, and free radical production could be by-products of damage (by these) abnormally folded proteins impeding blood flow and ultimately puncturing blood vessels in the brain”. Invest in ME (Charity Nr. 1114035) “Biswal, Kunwar and Natelson found significant cerebral blood flow reductions in nearly every region of the brain assessed….Neary et al tested whether patients with ME/CFS have reduced oxygen delivery to the brain during and after exercise challenge. They found that in addition to significant exercise intolerance, patients in comparison to controls (have) reduced prefrontal oxygenation, suggesting altered cerebral oxygenation and blood volume in the brain….Neurotropic viral infections could be responsible for the appearance of lesions in the brain and the presence of focal epileptiform seizure activity”. Referring to the work of Light et al, Jason notes that “Light et al maintain that exercise could send a continuous signal of muscle sensory fatigue to the central nervous system causing dysregulation of sympathetic nervous system reflexes….About 90% of the ME/CFS patients could be distinguished from control subjects using just 4 of the genes measured…The researchers concluded that ME/CFS patients might have enhanced sensory signal for fatigue that is increased after exercise. These finding all indicate persistent changes in cell membrane function”. Referring to his earlier (2009) work, Jason notes that it: “suggests that being over-extended and going beyond energy reserves can be an impediment to improving functionality and fatigue levels” and it concludes that “specific environmental cues” may trigger ME/CFS. He is clear: “We need studies based on systems biology that explain the illness, in combination with more details about the environmental contributors to the illness”. None of these proven pathologies can be ascribed to deconditioning or to abnormal illness beliefs that are reversible with cognitive restructuring and aerobic exercise. Just as Peter Dewis of UNUMprovident sees a challenge in ensuring that people are directed towards the Wessely School‟s behavioural approach, a far greater challenge faces the Continued page 41 www.investinme.org Page 40/58 Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions continued ME/CFS community in directing agencies of State such as the DWP, NICE, the MRC and the NHS away from the Wessely School‟s inflexible approach to a chronic, inflammatory neuroimmune disorder. For those involved at the highest level in directing the DWP‟s policy towards people with ME/CFS to have been the ones involved with the PACE Trial could be seen to indicate an unacceptable level of bias and commercial collusion against extremely sick and vulnerable people for whose disorder there exists an abundant biomedical evidence-base which continues to be systematically ignored by the PACE Trial Principal Investigators and those they advise. ME QUOTES “if you look at the activation markers, they are raised in both CFIDS and acute viral illness….Some individuals…will not be able to turn off that activated state. The agent remains as a constant thorn, forcing the immune system to be activated until the agent is eliminated. In these individuals, the immune system never returns to a normal resting state. So these people are in a state of chronic immune activation. What is the result of this chronic immune activation? If an activated white cell is doing its duty, it has to be producing a certain number of lymphokines or cytokines that are working to control the agent that is infecting the body. But these cytokines can have side effects….Cytokines affect the brain, the bowel, the muscle, the liver (which) one sees in CFIDS. So, increased cytokine activation can affect many different tissues in the body (and) can also cause reactivation of other viruses….This disorder could be controlled by eliminating the causative agent or quieting down the hyperimmune system….There is much clinical information showing that (CFIDS) has often led to other immune diseases….The sequelae…include autoimmune disease and, on some occasions, MS”. - Dr Jay Levy ME FACTS in patients with ME/CFS, CBT/GET has been shown to be counterproductive in many patients. Based on the evaluation of the Belgian Reference Centres, the Belgian Minister of Health officially declared that CBT/GET should not be regarded as a curative therapy for ME/CFS. This evaluation revealed that the exercise capacity/condition of the patients treated had not improved and that the occupational participation had even decreased after CBT/GET. Two large-scale patient surveys in the UK and Norway, and two smaller surveys in Scotland and The Netherlands indicate that CBT/GET aggravates the condition of many ME/CFS patients. - Chronic fatigue syndrome: Harvey and Wessely's (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways by Michael Maes and Frank NM Twisk - http://www.biomedcentral.com/1741-7015/8/35 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 41/58

Journal of IiME Volume 5 Issue 1 (May 2011) PACE is dead, long live PACE? by Kevin Short In my view, in relation to the PACE trial into 'Chronic Fatigue Syndrome/Myalgic Encephalomyelitis'[1] (published by The Lancet) and some subsequent supportive publications, it is timely for the scientific community and interested observers to consider three questions and revisit some previously published material for possible answers. The first question is, just why do certain UK psychiatrists apparently refuse to adhere to WHO disease taxonomy, as per ICD-10-G93.3 neurological ME/PVFS and ICD-10-F.48.0 psychiatric FATIGUE SYNDROME respectively, by erroneously conflating what the WHO and an increasing body of biomedical evidence rightly separate? (That, according to some such psychiatrists, 'CFS/ME' is allegedly and primarily both physical and psychiatric and that most illnesses are comprised of both such primary components is often cited as justification: an unlikely assertion if, for example, applied to lungcancer or HIV/AIDS. Like cancer and AIDS patients, ME sufferers do not object to secondary/co-morbid psychiatric complications being addressed for what they are. They do however object to primary physical illness being misrepresented and mistreated as psychiatric. Such misrepresentation of primary physical illness in the case of cancer and AIDS would rightly be dismissed as ludicrous by most informed people and ditto should be the case for neurological ME/Postviral Fatigue Syndrome categorised by the WHO in ICD 10, G93.3.). Perhaps in no small part the answer is to be found in earlier published comment. In this case the 2006 UK Parliamentarian Group on the Scientific Research into ME (GSRME) which, in connection with such psychiatrists' role in advising the UK Department of Work and Pensions (the DWP was one of the major funders of the PACE study) on ME/CFS, cautioned: “There have been numerous cases where advisors to the DWP have also had consultancy roles in medical insurance companies. Particularly the Company UNUM Provident. Given the vested interest private medical Invest in ME (Charity Nr. 1114035) Kevin Short Kevin Short is a long-time patient advocate who was instrumental in bringing better education and information to the ME community, including key meetings and research which led to the Gibson Inquiry into ME of 2006 . His work has influenced many activities in raising awareness and led indirectly to the IiME conferences being initiated, Short, along with Douglas Frazer, forced NICE to a Judicial Review regarding the NICE Clinical Guidelines for ME. Kevin Short Anglia ME Action April 2011. insurance companies have in ensuring CFS/ME remain classified as a psychosocial illness there is blatant conflict of interest here. The Group find this to be an area for serious concern and recommends a full investigation of this possibility by the appropriate standards body. It may even be that assessment by a medical „expert‟ in a field of high controversy requires a different methodology of benefit assessment.” - GSRME Report, Page 30. www.erythos.com/gibsoninquiry/index.html The second question is, how on earth does so much psychiatric 'research' that is poorlyconceived, of questionable-quality and undertaken by investigators with demonstrable conflicts of interest receive so much funding and peer-reviewed journal exposure? Again, in no small part, perhaps the explanation is to be found in earlier published comment. In this case taken from the introductory summary of Professor Bruce Charlton's 2008 peerreviewed paper entitled 'Zombie Science – a sinister consequence of evaluating scientific theories purely on the basis of enlightened selfinterest': "Although the classical ideal is that scientific theories are evaluated by a careful teasing-out of their internal logic and external implications, and checking whether these deductions and predictions are in-line-with old and new www.investinme.org Continued page 43 Page 42/58 Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions continued observations; the fact that so many vague, dumb or incoherent scientific theories are apparently believed by so many scientists for so many years is suggestive that this ideal does not necessarily reflect real world practice. In the real world it looks more like most scientists are quite willing to pursue wrong ideas for so long as they are rewarded with a better chance of achieving more grants, publications and status." "The classic account has it that bogus theories should readily be demolished by sceptical (or jealous) competitor scientists. However, in practice even the most conclusive „hatchet jobs‟ may fail to kill, or even weaken, phoney hypotheses when they are backed-up with sufficient economic muscle in the form of lavish and sustained funding. And when a branch of science based on phoney theories serves a useful but non-scientific purpose, it may be kept-going indefinitely by continuous transfusions of cash from those whose interests it serves. If this happens, real science expires and a „zombie science‟ evolves." In seeking examples of such 'zombie science', in my opinion, few contenders can match the recent UK PACE trial study by Professor Peter White et al published in The Lancet this February that was rightly, and eruditely, criticised by Professor Malcolm Hooper. Outside of the usual supporters, The Science Media Centre and what many would regard as misinformed converts, PACE is widely viewed as a disgrace: having conflated illness rightly separated by the WHO, having effectively ignored a large body of biomedical evidence, having used unscientific and disingenuous patient selection criteria, and having almost exclusively employed subjective and highly unreliable measurement techniques. See: http://www.meactionuk.org.uk/COMPLAINT-toInvest in ME (Charity Nr. 1114035) Lancet-re-PACE.htm With PACE etc in mind, Professor Charlton's 'Zombie Science' critique paper is well worth reading in full. The reference & link for the full text of the paper is: Professor Bruce Charlton – Zombie Science – a sinister consequence of evaluating scientific theories purely on the basis of enlightened self-interest, Medical Hypotheses (2008) 71 327-329, DOI: 10.1016/j.mehy.2008.05.018: http://medicalhypotheses.blogspot.com/2008/ 07/zombie-science-dead-but-wont-liedown.html If the psychiatrists involved in the PACE trial were serious about science, and genuinely believed ME was maintained by fear of activity and muscle deconditioning as they assert, they would have exclusively used rigorous and internationally accepted patient selection criteria to ensure their study was beyond reproach. They did not. If they were serious about science they would have applied objective assessment criteria to properly informed patients. They did not. In my view, PACE represents a gross abuse of the scientific process and a gross abuse of ME patients. Ditto for much of the largely rhetorical and uncritical literature supportive of PACE that, unlike the many patient protestations such as this article, find their way into the so-called scientific literature. From its inception, PACE was roundly and eruditely criticised as being seriously flawed, that it was publicly funded amounts to a gross abuse of millions of pounds of UK taxpayers' money. In terms of the real-world clinical setting amongst real-world ME patients, I believe the full scientific evidence-base shows that PACE CBT/GET will ultimately contribute nothing positive[2,3]. It will not improve ME patient function in the medium to long term, if at all, Continued page 44 www.investinme.org Page 43/58

Journal of IiME Volume 5 Issue 1 (May 2011) The Involvement of the PACE Trial Principal Investigators and the Director of the Clinical Trials Unit with the Department for Work and Pensions continued and will eventually be seen by most as having been dead on arrival and a complete waste of money: Zombie therapies based upon Zombie science. Moreover, I believe that most of the PACE Principal Investigators actually know this. If so, my third question is what then could be the real purpose of PACE? Professor Charlton's following observation seems to me to answer that question perfectly: "If zombie science is not scientifically-useable – what is its function? In a nutshell, zombie science is supported because it is useful propaganda to be deployed in arenas such as political rhetoric, public administration, management, public relations, marketing and the mass media generally. It persuades, it constructs taboos, it buttresses some kind of rhetorical attempt to shape mass opinion. Indeed, zombie science often comes across in the mass media as being more plausible than real science; and it is precisely the superficial face-plausibility which is the sole and sufficient purpose of zombie science." In my opinion PACE is an issue for more than just ME patients. It is an affront to British science and to British society. ENDNOTES: [1] Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial; PD White et al; published online, The Lancet, February 18, 2011 DOI:10.1016/S01406736(11)60096-2. [2] For example, a recent large scale randomised controlled trial demonstrated exactly that: Núñez M, Fernández-Solà J, Nunez E, Fernandez-Huerta JM, Godás-Sieso T, GomezInvest in ME (Charity Nr. 1114035) The Enterovirus Foundation was founded in November 2008 and is a non-profit organisation created to fund research to discover the persistent effects of enteroviruses, to determine the role they play in both acute and chronic disease, and to develop treatments to cure and prevent these diseases. More details at - www.enterovirusfoundation.org www.investinme.org Page 44/58 Gil E. (2011) Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clinical Rheumatology. 2011 Jan 15. (E-publication ahead of print). [3] As Professor Komaroff rightly stated back in 2006: “…there are now over 4,000 published studies that show underlying biomedical abnormalities in patients with this illness. It‟s not an illness that people can simply imagine that they have and it‟s not a psychological illness. In my view, that debate, which has waged for 20 years, should now be over.” Professor Anthony Komaroff, Harvard Medical School: Speaking at the USA Government CDC (Centers for Disease Control and Prevention) press conference on 3 November 2006: http://www.cdc.gov/media/transcripts/t06110 3.htm Journal of IiME Volume 5 Issue 1 (May 2011) Chronic Fatigue Syndrome Education in the United States Testimony on CFS Education to the CFS Advisory Committee - 2009 Improved education regarding ME is at the heart of IiME aims. The poor quality if medical education in UK and the apathy of organizations such as the General Medical Council toward correct education regarding ME also has parallels in USA. Dr. Kenneth Friedman PhD is an outspoken advocate for better education and also a critic of the way education about ME/CFS is being performed in the USA. His testimony at the CFS Advisory Committee Meeting Friday, October 2009 was applauded by the ME community but it also cost Dr. Friedman. He subsequently lost his position as Associate Professor of Pharmacology & Physiology at University of Medicine and Dentistry of New Jersey due to his continuing stand on improving education in the medical community about ME/CFS. Testimony for the Chronic Fatigue Syndrome Advisory Committee, Oct 30, 2009 by Kenneth J. Friedman, PhD Good morning! My name is Kenneth Friedman and I am a medical school professor. I have been asked by the IACFS/ME to comment upon the status of Chronic Fatigue Syndrome education in the United States. Comments on the Academic, Medical School Environment The Director of the Office of Ethics and Compliance of my employer has informed me that my off-campus activities related to CFS which include: testifying before this Committee, serving on this Committee, providing continuing medical education courses, establishing medical student scholarships and assisting with healthcare legislation are not part of my responsibilities as a University Professor. Invest in ME (Charity Nr. 1114035) I am told that I will be punished with a penalty as severe as termination of my employment for these activities. I am not a unique target. • Colleague Ben Natelson has left the same school. • A different medical school has refused to permit access to their medical students to discuss CFS or inform them of a medical student scholarship. • A statewide health care provider, with no physician capable of managing CFS patients, refuses to permit a CFS training session for their physicians. The failure of the CDC to convince the medical-academic establishment of the legitimacy of CFS, and the urgent need for its treatment, has created this environment. Comments on Medical Student Education High ranking officials of medical education have testified before this Committee that they are powerless to control the curriculum of medical schools, and cannot mandate the inclusion of Chronic Fatigue Syndrome in the medical school curriculum. • Were the CDC to mandate the reporting of CFS to the Federal Government, as it does for other illnesses, the National Board of Medical Examiners would have no choice but to put CFS questions on the National Boards. • If CFS questions were to appear on National Board licensure examinations, medical schools would have no choice but to include CFS in their curriculum. I have appeared before this body on two separate occasions arguing for the use of existing student programs within both the NIH and the CDC to rotate medical students through NIH and CDC laboratories. I have Continued page 46 www.investinme.org Page 45/58

Journal of IiME Volume 5 Issue 1 (May 2011) Chronic Fatigue Syndrome Education in the United States continued pleaded for dialogue and feedback on any of my proposals. I have heard nothing. The only mechanism for medical student education for CFS is the medical student scholarship programs run by patient advocate organizations. We now have programs running in three states. How many scholarship programs must be mounted by state patient advocate groups before the CDC mounts a single, national medical student program? Comments on Continuing Medical Education for Physicians To my knowledge, the CDC's on-line continuing medical education CFS course is the only involvement of the federal government in healthcare provider education. Does the CDC honestly believe that sitting in front of a computer screen for a few hours will make a physician capable of diagnosing and treating CFS? From the CFS Community's perspective, what is the impact of the on-line course on diagnosis and treatment of CFS? • From Vermont CFIDS Association: There is no increase in the number of physicians who diagnose or treat CFS in this state. • From New Jersey Chronic Fatigue Syndrome Association: The number of requests for physician referrals to our helpline has not diminished. Comments on Chronic Fatigue Syndrome Educational Materials In my opinion, all federal and private sector literature concerning Chronic Fatigue Syndrome is out of date. There is no established mechanism for updating health care provider literature. Of the available literature, the most authoritative and accepted source of information on Chronic Invest in ME (Charity Nr. 1114035) Fatigue Syndrome is a physician's diagnosis and treatment manual not produced by the Centers for Disease Control, not produced by the National Institutes of Health, but produced by the New Jersey Chronic Fatigue Syndrome Association - The Consensus Manual for the Primary Care and Management of Chronic Fatigue Syndrome. I ask that this Committee recommend to the U.S. Secretary of Health: • That a national diagnosis and treatment manual for CFS be created, • That a panel be formed to write this manual, • That the Department of Health and Human Services underwrite the expense of producing and distributing this manual. With regard to the recent Spark! Awareness Campaign and the accompanying Physicians Toolkit, not one patient in the State of Vermont ever saw the patient pamphlet. An incredible waste of money! Conclusions The only on-going educational programs for medical students and physicians that involve human contact come from patient advocate groups. • Patient advocate groups are the current source of educational materials for CFS. • They rely on the assistance of academicians. • If academicians are threatened with termination of employment for participating in Chronic Fatigue Syndrome education, there will be no educational programs. I beg you to consider the magnitude of this problem. I beg you to undertake a course of remedial action. Thank-you! www.investinme.org Page 46/58 Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Annette Whittemore Annette Whittemore is President and Co-founder of the Whittemore-Peterson Institute in Nevada, USA. She graduated from the University of Nevada and taught children who had neuro-cognitive deficits, like those found in autism, ADD, and learning disabilities. Annette is the parent of a young adult who was severely affected by CFS. She found that few doctors understood the reasons for her daughter's continuing physical decline and therefore committed her time and resources to bringing attention to the serious nature of neuroimmune diseases and change her community in a positive way. She began this important mission in 1994 by supporting a Think Tank on ME/CFS, led by Dr. Daniel Peterson of Incline Village. In 2004 she and another patient advocate began a medical foundation to support research to find biomarkers of disease and treatments for patients impacted by the HHV-6A virus. In order to provide solutions for patients and bring new doctors into this field of medicine, Annette and others supported a bill to build a biomedical research center at the University of Nevada with an Institute for Neuro-Immune disease and the Nevada Cancer Institute. Annette founded the Whittemore-Peterson Institute for Neuroimmune Diseases which is built on the medical campus with a mission to serve those with complex neuro-immune diseases such as ME/CFS, viral induced central nervous system dysfunction and fibromyalgia. As the Founder and President, Annette supports the basic and clinical research programs, recruitment of physicians and support personnel, while also leading fundraising activities. Researchers at the University of Nevada Medical School have also become collaborators on projects that are vital to our understanding of the immune deficits seen in these patients. Abstract: WPI‟s discovery of a human retrovirus in patients with ME (CFS) is significant and may be life changing for those who are impacted. Although additional studies are necessary to clarify the role of gamma retroviruses in human disease, WPI remains committed to research that will help define the causes of complex neuro-immune diseases such as ME. Identifying accurate biomarkers of disease and translating this information to better treatments continues to be most important to the WPI. To insure that there are adequate levels of vital biomedical research the WPI continues to encourage and engage in advocacy at all levels on behalf of those who suffer. Despite many areas of progress much more still remains to be done to educate the public to the realities of this disease and to remove the barriers that prevent effective patient treatment. ME FACTS In 1969: the World Health Organisation classified ME as a neurological disorder. 1978: The Royal Society of Medicine accepted ME as a nosological entity. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 47/58

Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Dr. David Bell Dr. David Bell graduated from Harvard College and gained an MD degree at Boston University. Post doctoral training in paediatrics was completed with subspecialty training in Paediatric Behaviour and Developmental Disorders. In 1978 he began work at the University of Rochester and then began a private practice in the town of Lyndonville, New York. In 1985 nearly 220 persons became ill with an illness subsequently called chronic fatigue syndrome in the communities surrounding Lyndonville, New York. This illness cluster began a study of the illness which continues today. Dr. David Bell is the author or co-author of numerous scientific papers on CFS, and, in 2003 was named Chairman of the Advisory Committee for Chronic Fatigue Syndrome of the Department of Health and Human Services. Publications include A Disease of A Thousand Names, (1988) and The Doctor's Guide to Chronic Fatigue Syndrome, (1990). Dr. Bell is currently performing ME/CFS research into the XMRV retrovirus. Abstract: Twenty five Year Follow-up of Adolescent Subjects with ME David S. Bell MD, FAAP; State University of New York at Buffalo David E. Bell MPH; Department of Anthropology, State University of New York at Buffalo Contact Information: dsbellmd@Yahoo.com From 1984 until 1987 an apparent outbreak of Myalgic Encephalomyelitis (ME) occurred in New York State, in a small rural area between Rochester and Buffalo. Two hundred ten persons (sixty one children) were identified during this period, and have been followed for the ensuing twenty-five years. Diagnostic criteria for this outbreak were published in 19881 prior to publication of the CDC criteria2; in retrospect this outbreak would fulfil current criteria for ME or for chronic fatigue syndrome (CFS). Early papers showed no connection with Epstein Barr virus infection3, and similarity with Primary Juvenile Fibromyalgia Syndrome4. An epidemiologic study showed increased incidence within families and association with drinking unpasteurized milk, this latter finding remaining unexplained5. In 1995 a paper documented the health of the adolescent-onset subjects 13 years after onset6. In this study, twenty percent were disabled and remained very ill, with the most predictive factor being the severity of illness at onset. The remaining eighty percent considered themselves either "much better" or "recovered". Half of these considered themselves entirely well and the other half had mild to moderate symptoms but were functioning fairly well. This study, published in 1995 helped foster the incorrect conclusion that children with ME recovered at a very high rate. In the current study emphasis was placed upon disability instruments, thus preventing comparison to the 1995 study. Three subjects had developed malignancy (thyroid cancer, cancer of the cervix, and acute myelocytic leukemia) and were not included in the present study (10.7% of respondents). 25 remaining subjects were the subjects of this study. Instruments used included the SF-36, Pittsburg Sleep Questionnaire, McGill Pain Questionnaire, Bell Ability Scale, Visual Analog Scores for 7 symptoms, Number of Hours of Upright Activity Scale, and the Fisk Fatigue Impact Scale. Two subjects (2/25 or 8%) had scores on these instruments that were close to control scores and Continued page 49 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 48/58 Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE were considered recovered. Eighteen subjects (18/25 or 72%) had "remitting illness", and five subjects had "persisting illness" (5/25 or 20%). The remainder of the study consisted of characterizing illness severity in the "remitting illness" group and the "persisting illness" group. All subjects in the persisting illness group were severely disabled and acknowledged their disability. Of surprise was that many subjects in the "remitting illness" group was also disabled yet perceived themselves as doing well. Most in this group had altered lifestyles so that they were able to work part time, or had elected to stay at home as parents. The variations between perceptions of health and scores on disability questionnaires led to the conclusion that the majority of subjects in this 25 year follow up study had "health identity confusion, and that this "health identity confusion" should be considered an anticipated outcome of ME in adolescence." 1. Bell D, Bell K. Chronic fatigue syndrome: diagnostic criteria [Letter]. Ann Intern Med. 1988;109:167. 2. Holmes G, Kaplan J, Gantz N, al e. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108:387-9. 3. Bell D, Bell K. Chronic fatigue syndrome in childhood: relation to Epstein-Barr virus. In: Ablashi D, editor. Epstein-Barr Virus and Human Disease; 1989 1989; Rome, Italy: Humana Press; 1989. p. 412-7. 4. in adolescents. Clin Inf Dis. 1994;18(Suppl 1):S21-S3. 5. Bell K, Cookfair D, Bell D, Reese P, Cooper L. Risk factors associated with chronic fatigue syndrome in a cluster of pediatric cases. Rev Inf Dis. 1991;13(Suppl 1):S32-8. 6. Bell D, Jordan K, Robinson M. Thirteen-year follow-up of children and adolescents with chronic fatigue syndrome. Pediatrics. 2001;107(5):994-8. Dr. Andreas Kogelnik Dr. Andreas M. Kogelnik, is the Founding Director of the Open Medicine Institute, a collaborative, community-based translational research institute dedicated to personalized medicine with a human touch while using the latest advances in medicine, informatics, genomics, and biotechnology. The Institute works closely with the Open Medicine Clinic and other clinics to conduct research and apply new knowledge back into clinical practice. Dr. Kogelnik received his M.D. from Emory University School of Medicine in Atlanta and his Ph.D. in bioengineering/bioinformatics from the Georgia Institute of Technology. Subsequently, he completed his residency in Internal Medicine and a Fellowship in Infectious Diseases at Stanford University and its affiliated hospitals. Following his clinical training, he remained at Stanford with NIH funding to engage in post-doctoral research in microbiology, immunology and bioinformatics with Dr. Ellen Jo Baron and Dr. Stanley Falkow, where he explored host-response profiles in severely ill patients. Together with Dr. José Montoya, he was instrumental in the conception, design, and execution of the EVOLVE study - a placebo-controlled, double-blind study of a subset of chronic fatigue syndrome patients with evidence of viral infection. Dr. Kogelnik worked with Dr. Atul Butte in translational informatics to determine patterns that indicated a high risk for adverse events in paediatric patients at Lucille Packard Children's Hospital. Invest in ME (Charity Nr. 1114035) www.investinme.org Continued page 50 Page 49/58 Bell D, Bell K, Cheney P. Primary Juvenile fibromyalgia syndrome and chronic fatigue syndrome

Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE He is the Medical Director of the Open Medicine Clinic - a community-based research clinic focussed on chronic infectious diseases, neuroimmune disease, and immunology. Dr. Kogelnik has published numerous scientific papers and book chapters, is an Editor of Computers in Medicine and Biology, and is a Consulting Assistant Professor at Stanford University. With the Open Medicine Institute, he has led the formation of CFS and Lyme Registries and Biobanks as well as creating an infrastructure for providers to collect better data and implement clinical trials across a network of sites. Professor Kenny De Meirleir Professor De Meirleir is a world renowned researcher of ME/CFS. He is full professor of physiology, pathophysiology and medicine at the Virje Universitet Brussel and practices Internal Medicine at Himmunitas Foundation also in Brussels. He has published several hundred peer reviewed articles and is co-author of the book 'Chronic Fatigue Syndrome: a biological approach' and was co-editor of the Journal of Chronic Fatigue Syndrome, and reviewer for more than 10 other medical journals. Professor De Meirleir was one of four international experts on the panel that developed the Canadian Consensus Document for ME/CFS. He assesses/treats thousands of ME/CFS patients annually and is the most experienced researcher in Europe regarding ME/CFS. His research activities in ME/CFS date back to 1990. His other research activities in exercise physiology, metabolism and endocrinology have led to the Solvay Prize and the NATO research award. Abstract: CLINICAL DIAGNOSIS, TREATMENT AND TRIALS OF ME/CFS Part I : Clinical Diagnosis In the first part of the presentation relevant data with regards to abnormal laboratory findings in ME/CFS patients will be presented. The intention is to give an overview of the most striking abnormalities with clinical relevance. Results of routine laboratory and of specialized tests are discussed with explanation as how they fit in the pathophysiology of the disorder. In a majority of patients serum sCD14 is increased and CD57+ lymphocyte numbers are low. Using different methods XMRV/MLV is detected in a majority of ME/CFS patients and this is significant when compared to the prevalence of this retrovirus in healthy blood donors. XMRV positive ME/CFS patients show a distinct inflammatory signature based on their cytokine blood levels (De Meirleir et al. 2010 ; Lombardi et al. 2011). Recently we demonstrated that XMRV is present in the gut. In one ME/CFS patient XMRV was recovered from his appendix after he underwent appendectomy. ME/CFS patients have a Th1  Th2 shift and show increased H2S metabolites in the urine. This can be demonstrated by a simple self testing urine kit. A subgroup of ME/CFS patients carries abnormal cell surface proteins, which has negative consequences for ion channel function. Continued page 51 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 50/58 Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Faecal analysis and faecal microbial analysis are very useful in the diagnostic workup. They reveal specific chemical and microbial abnormalities with therapeutic implications. Part II : Treatment and trials of CFS/ME Apart from the use of anti-inflammatory drugs or compounds, antioxidants and certain nutraceuticals and based on laboratory test abnormalities, following elements of therapy are common to the therapy of all ME/CFS patients : 1. individualized diet 2. treatment of dysbiosis (pre-, pro- and antibiotics) 3. use of immunomodulators In specific ME/CFS subgroups, we use antivirals, antimycotic drugs, antibiotics for zoonoses (ILADS protocols) and other directed at specific opportunistic or other infections. Professor Tom Wileman Professor Wileman is Professor of Molecular Virology and Director at the Biomedical Research Centre at the University of East Anglia in Norwich, UK. His previous positions in the UK have included the Head of the Department of Immunology and Pathology at the BBSRC Institute of Animal Health, Pirbright. He was Assistant Professor at the Department of Medicine at Harvard Medical School in Boston, USA where worked at the Dana Farber Cancer Institute and Beth Israel Hospital. He held investigator awards from the Claudia Adam's Barr Foundation for Cancer Research, the Medical Foundation of the Charles King Trust and was Basil O'Connor Scholar of the March of Dimes Research Foundation. Prior to that he was SERC NATO Fellow and Fellow of the Parker Francis Pulmonary Research Foundation within the Department of Cell Biology, Washington University Medical School, St Louis. Professor Simon Carding Professor Simon Carding Professor of Mucosal Immunology at University of East Anglia and Institute of Food Research. Following his PhD at London he held postdoctoral positions at New York University School of Medicine, New York and at Yale University School of Medicine, New Haven, USA. He then moved to the University of Pennsylvania, Philadelphia, USA as Assistant and later Associate Professor. He joined University of Leeds as Professor of Molecular Immunology in the Institute of Molecular and Cellular Biology in 1999. His scientific interests are in understanding how the immune response in the gut functions and in particular, is able to distinguish between the commensal microbes that reside in the gut and environmental microbes that cause disease, and in the mechanisms by which the body‟s immune system no longer ignores or tolerates commensal gut bacteria and how this leads to immune system activation and inflammatory bowel disease. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 51/58

Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Dr. John Chia Dr John Chia is an infectious disease specialist, Torrance, California, USA. He has published research ("Chronic fatigue syndrome associated with chronic enterovirus infection of the stomach") on the role of enteroviruses in the aetiology of ME/CFS - an area which has been implicated as one of the causes by a number of studies. There are more than 70 different types of enteroviruses that can affect the central nervous system, heart and muscles, all of which is consistent with the symptoms of ME/CFS. By analysing samples of stomach tissue from patients with CFS, Dr. Chia's team discovered that high levels of these individuals had high levels of enteroviruses in their digestive systems. Dr Chia's research may result in the development of antiviral drugs to treat the debilitating symptoms of ME/CFS. Abstract: Clinical & Research Experience of Enteroviral Involvement in ME/CFS. John Chia, Andrew Chia. EV Med Research A number of infectious agents have been implicated in the pathogenesis of ME/CFS. Emerging evidences suggest that enteroviruses can persist in the tissues of ME/CFS patients after acute infections and may be responsible for the various symptoms. Enteroviruses can cause major epidemics of respiratory, gastrointestinal and non-specific flu-like illnesses and disseminated infections including but not limited to meningoencephalitis, myocarditis, pleurodynia, myositis and hand-footmouth diseases. Initial isolation of enteroviruses from patients with acute infections followed by demonstration of persistent viral infection in tissues years after the patients developed chronic symptoms lends support to the pathogenic role of enteroviruses in ME/CFS. Presumptive clinical diagnosis of chronic enterovirus infection requires a high index of suspicion, familiarity with the protean manifestations of acute infections and understanding of chronic viral persistence. A number of tests can support the clinical diagnosis of chronic enterovirus infection. Significantly elevated neutralizing antibody titer over time suggests persistent immunologic response to specific enterovirus(s) infection in the tissues. In contrast to other types of viremic infections, EV RNA levels in whole blood of ME/CFS patients are extremely low, which likely explain the discrepancy of results reported from different research laboratories over the past two decades. Immunoperoxidase staining for viral protein in the stomach biopsies is more sensitive than the neutralizing antibody test or EV RNA detection, and furthermore, demonstrates the antigens in tissues where viruses are expected to replicate and persist based on the route of transmission. The finding of enteroviral RNA and growth of non-cytopathic viruses from the same tissues support the validity of protein staining. The recent finding of double-stranded RNA(dsRNA) in the stomach tissue supports the mechanism of viral persistence in accessible tissue. Although there is renewed interest in drug development for enteroviruses, clinical studies are still many years away. Presently available therapy is directed toward the continuing immune responses against persistent viral infection. Intravenous immunoglobulin, given monthly or every few months, can ameliorate inflammatory symptoms in less than 1/3 of adult patients, but may be more effective in pediatric patients or patients with severe myalgia. The combination of alpha and gamma interferon can induce short-term remission in about 45% of ME/CFS patients with debilitating myalgia, but is quite expensive and often poorly tolerated. Oxymatrine or Equilibrant have beneficial effects in 52% of 700 ME/CFS patients, but transient increase in pre-existing symptoms are expected in most of the patients. Dose titration improves tolerance. Cytokine gene expression study during therapy demonstrates an increase of IL12/Il10 ratio in responders but not in non-responders. A decrease of Continued page 53 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 52/58 Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE stainable enteroviral protein and dsRNA is demonstrated in the stomach biopsies of few responders on oxymatrine/Equilibrant therapy. Previous evidence for enterovirus infection in ME/CFS from over a decade ago has been confirmed and extended in recent studies. Mechanism of viral persistence through the formation of dsRNA is similar to observations in tissue cultures and in animal models. Development of antiviral therapy against enteroviruses needs to be expedited; and the importance of enteroviruses in ME/CFS can be realized with a randomized, placebo-controlled antiviral drug trial. Dr. James Baraniuk James N. Baraniuk was born in Alberta, Canada. He earned his honours degree in chemistry and microbiology, medical degree, and unique bachelor's degree in medicine (cardiology) at the University of Manitoba, Winnipeg, Canada. Thereafter, he moved to Akron, OH, USA, for his internship and internal medicine residency at St Thomas Hospital. After another year of internal medicine residency at Duke University Medical Center, Durham, NC, he trained with Dr C.E. Buckley, III, in allergy and clinical immunology. He moved to the laboratory of Dr Michael Kaliner at the National Institute of Allergy and Infectious Diseases, Bethesda, MD, and there began his long-standing collaboration with Dr Kimihiro Ohkubo. After 2 years studying neuropeptides, he joined Dr Peter Barnes' laboratory at the National Heart and Lung Institute, Brompton Hospital, London, UK. Dr Baraniuk returned to Washington, DC, and Georgetown University, where he is currently Associate Professor with Tenure in the Department of Medicine. (from Georgetown University site http://explore.georgetown.edu/people/baraniuj/) Our research team is examining proteomic (protein) differences between veterans with Gulf War Illness (GWI) and healthy veterans in hopes of learning more about how GWI works. In our first study, we are also looking at differences in genetics, pain sensitivity, muscular, and autonomic nervous system function between GWI vets and healthy vets. Based on current data, we believe that GWI may be related to a certain genotype for an enzyme (carnosine dipeptidase-1) that degrades two of the body's important antioxidants. Our second project is a treatment study using Carnosine, one of these antioxidants. If this genetic difference does contribute to GWI, then replacement of this antioxidant could provide relief of symptoms. Finally, we are conducting a Chronic Fatigue Syndrome research study. The CFS study is similar to our GWI study, except that we are also doing lumbar punctures (sometimes called a spinal tap) for the people who participate in this study. We are doing the lumbar puncture procedure for two reasons: 1) We believe that increased spinal pressure could be associated with some of the symptoms like recurrent headaches, sleep problems, memory problems, chronic fatigue and pain. For this reason, we measure the spinal fluid pressure during the procedure. 2) During a previous study, our research team and our research collaborators discovered some specific proteins in the spinal fluid of CFS and GWI patients. In this study we will have a larger group of people with and without CFS/GWI and will look for those and other unique sets of proteins in the spinal fluid and blood using more sensitive equipment. Our hypothesis is that these specific proteins are seen in the spinal fluid of CFS and Gulf war Illness but not in healthy controls and that those proteins will help us understand the cause of these conditions. http://explore.georgetown.edu/people/baraniuj/?action=viewresearch Invest in ME (Charity Nr. 1114035) www.investinme.org Page 53/58

Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Dr. Øystein Fluge / Professor Olav Mella Institute of Medicine, Section of Oncology, University of Bergen, Norway Dr. Øystein Fluge received medical degree in 1988 at the University of Bergen, and is a specialist in oncology since 2004. He has worked as a Research Fellow with support from the Norwegian Cancer Society and is now chief physician at the Cancer Department, Haukeland University Hospital. Doctoral work emanates from the Surgical Institute and Department of Molecular Biology, University of Bergen. Professor Olav Mella and researcher Dr Oystein Fluge from University of Bergen, Haukeland University Hospital, department of oncology are currently conducting a clinical trial on B-lymphocyte Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Severely Affected Chronic Fatigue Syndrome Patients. This study is based on pilot patient observations, and experience from the prior study KTS-1-2008. The investigators anticipate that severely affected chronic fatigue syndrome patients may benefit from B-cell depletion therapy using Rituximab induction with maintenance treatment. The hypothesis is that at least a subset of chronic fatigue syndrome (CFS) patients have an activated immune system involving B-lymphocytes, and that prolonged B-cell depletion may alleviate symptoms. Professor Geoffrey Burnstock Professor Geoffrey Burnstock studied theology, maths and physics at King‟s College London, before completing a PhD at King‟s and University College London under the supervision of the neurophysiologist, JZ Young. Between 1959 and 1975, Professor Burnstock worked at the University of Melbourne, beginning with a senior lectureship in zoology. Most of his major research has been on the autonomic nervous system, notably autonomic neurotransmission and he is best known for his discovery that ATP is a transmitter in NANC (nonadrenergic, non-cholinergic) nerves and also for the discovery and definition of P2 purinergic receptors, their signaling pathways and functional relevance. Professor Burnstock‟s work in this area has had an impact on the understanding of pain mechanisms, incontinence, embryological development, bone formation and resorption, and on skin, prostate and bladder cancer. Professor Burnstock returned to London in 1975, becoming Head of Department of Anatomy and Developmental Biology at University College London and Convenor of the Centre of Neuroscience. He has served as editor-in-chief of the journals Autonomic Neuroscience and Purinergic Signalling and has been on the editorial boards of many other journals. He has been elected to the Australian Academy of Science, the Royal Society and the Academy of Medical Sciences, and was awarded the Royal Society Gold Medal in2000. He was President of the International Society for Autonomic Neuroscience (ISAN), and was first in the Institute of Scientific Information list of most cited scientists in Pharmacology and Toxicology.. (from The UCL Centre for the History of MEdicine) Continued page 55 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 54/58 Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Abstract Purinergic signalling and CNS disorders The talk will open with some background information about purinergic signalling, including: its discovery in the early 1970‟s; the recognition that ATP is a cotransmitter with established neurotransmitters in most nerves in both the peripheral and central nervous systems; the cloning and characterisation of 3 subclasses of receptors for purines and pyrimidines; the widespread distribution of these receptors on non-neuronal cells as well as nerves; and the physiological release of ATP from cells in response to gentle mechanical stimulation and hypoxia. There will then be a description of the distribution of purinoreceptors in the CNS, the importance of purinergic neuron-glial interactions and their roles in normal behaviour. In the last part, studies of the roles of purinergic signalling in CNS disorders, including stroke, ischaemia, neurodegenerative diseases, epilepsy, cognitive, mood and neuropsychiatric disorders will be described and potential novel therapeutic strategies discussed. Dr. Judy Mikovits Dr Judy Mikovits is Research Director at the Whittemore Peterson Institute for Neuro-Immune Diseases and has co-authored over 40 peer reviewed publications that address fundamental issues of viral pathogenesis, hematopoiesis and cytokine biology. Formally trained as a cell biologist, molecular biologist and virologist, Dr. Mikovits has studied the immune response to retroviruses and herpes viruses including HIV, SIV, HTLVI, HERV, HHV6 and HHV8 with a special emphasis on virus host cell interactions in cells of the hematopoietic system including hematopoietic stem cells (HSC). Dr Mikovits is one of the authors of the ground-breaking study published in Science magazine in October 2009 which detected XMRV in CFS patients (Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome) and is a member of the US Department of Health and Human Services Blood Working Group. Researchers at the University of Nevada Medical School have also become collaborators on projects that are vital to our understanding of the immune deficits seen in these patients. Abstract Clinical implications of XMRV and MLV-Related (MRV) Human Gamma Retrovirus infection. In 2009, using a classical virology approach of viral isolation and transmission, electron microscopy, serology and PCR, Lombardi et. al. demonstrated the first isolation of a Human Gamma retrovirus (HGRV): XMRV from blood from patients with chronic fatigue syndrome (CFS) predominately from the west coast of the United States. In 2010, Lo et al. extended these studies by detecting nucleic acids of MLV-related variants in the peripheral blood mononuclear cells of CFS from the northeastern United States suggesting additional strains capable of infecting humans exist. We have identified several footprints of HGRV infection that can also be used both as therapeutic targets and to monitor clinical trials of therapeutics. These footprints include clonal TCR gamma rearrangements, B cell populations having a mature CD20+, CD23+ phenotype, which have been shown by our lab and others to harbor XMRV proviral DNA and produce infectious HGRVs. Therefore, XMRV infection may accelerate the development of B cell malignancies by either indirect chronic stimulation of the immune system and/or by direct Continued page 56 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 55/58

Journal of IiME Volume 5 Issue 1 (May 2011) PRESENTERS at the 6th INVEST in ME INTERNATIONAL ME/CFS CONFERENCE infection of the B-cell lineage. Since viral load in peripheral blood is low, these data suggest that B cells in tissues such as spleen and lymph nodes could be an in vivo reservoir for XMRV. In addition, we have identified an inflammatory cytokine and chemokine signature that distinguishes XMRV infected CFS patients from healthy controls with 94% sensitivity and specificity; an XMRV patient population with aberrant methylation profiles consistent with a gammaretroviral infection and a XMRV infected patient population with high nagalase activity. This particular population of XMRV infected patients has responded favorably to treatment with the immune modulator GcMAF. Additional populations of XMRV infected CFS patients have responded favorably to antiretroviral therapy and another population has responded favorably ton the immune modulator AmpligenTm . Monitoring XMRV viral load, co-infecting pathogens and immune dysfunction affords the opportunity to begin to understand the clinical implications of XMRV/HGRV infection. Dr. Wilfried Bieger Dr. Wilfried Beiger is a docent of Medicine in private practice at Applied Immunology Clinic in Munich, Germany. Dr Bieger has been performing a study in co- operation with researchers from Heidelberg University to test German ME patients for XMRV. Abstract I will present the results of cooperative efforts undertaken together with Prof. M. Kramer and Prof. R. Wallich from University of Heidelberg in detecting XMRV in German CFS patients. The patients were recruited from all over Germany with a majority in Bavaria. So far, we tested about 80 patients fulfilling all Fukuda criteria for CFS, starting in November 2010 after about 8 months of work to set up a highly sensitive, specific and uncontaminated assay protocol for virus detection in blood. Major advice throughout the experimental period came from J Mikovits who was extremely helpful with methodical advice and testing of parallel samples including sequencing of XMRV specific viral DNA sections. We have also set up a western blot technique for XMRV antibody testing. Blood was taken at my clinic in München and sent directly by mail to the laboratory. We used both heparin and EDTA-blood in the first time but switched over to EDTA alone, which gave better, i.e. more positive results. We could not find viral DNA or RNA in fresh samples except one, but had to cultivate the PBMC for up to 6 weeks under stimulating conditions and partly during coculture with virus permissive LnCap cells. After 2 weeks of culture cells began to turn positive in some patients and continued to display virus for the next weeks. The presence of XMRV was confirmed by sequencing XMRV specific DNA. Recently we started with the antibody tests as well using freshly drawn or deep frozen serum. So far we found retrovirus/XMRV-specific reactions only in a minor proportion of our CFS patients but improvement of the testing procedure is underway. In conclusion we have no doubt that XMRV is present in German CFS patients although the prevalence may not be as high as reported before in the USA. Professor Malcolm Hooper – Conference Chairman Chair of the 6th Invest in ME International ME/CFS Conference 2010 will be Professor Malcolm Hooper, Emeritus Professor of Medicinal Chemistry, University of Sunderland. Professor Hooper is an internationally-renowned expert on ME/CFS and a tireless campaigner for patients' rights. Professor Hooper has previously chaired Invest in ME conferences and participates in The Hooper Interviews - interviews with conference speakers at the Invest in ME Conferences and available on the conference DVDs. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 56/58 Journal of IiME Volume 5 Issue 1 (May 2011) 6th Invest in ME International ME/CFS 20th May 2011 Conference Agenda Start Presenter Registration 07.45 08.55 Invest in ME 09:00 Mrs Annette Whittemore 09:20 Dr. David Bell 10:05 Dr. Andreas Kogelnik Break 11:10 Dr John Chia 10.50 Clinical & Research Experience of Enteroviral Involvement in ME/CFS 11:50 Professor Geoffrey Burnstock Purinergic Signalling and CNS disorders 12:15 Dr James Baraniuk Cerebrospinal Biomarkers for ME/CFS 13.00 Lunch 13:50 Professor Tom Wileman Professor Simon Carding 14:15 Dr Øystein Fluge / Professor Olav Mella 16:05 Coffee/tea Break Dr. Judy Mikovits UK Research: Genome Sequencing, Virology & Immunology for ME/CFS B-cell Depletion Therapy Using Rituximab in ME/CFS 15:00 Professor Kenny de Meirleir Clinical Diagnosis, Treatments and Trials of ME/CFS 15.45 16:50 Dr. Wilfried Bieger 16:55 Plenary Session 17.30 Adjourn Support Biomedical Research into ME. Order our free newsletter. Distributed monthly via html, plain text or PDF. http://www.investinme.org/IIMENewslettersubs.htm Invest in ME (Charity Nr. 1114035) www.investinme.org Invest in ME wristbands http://www.investinme.org/IiME -Wristbands.htm Page 57/58 Clinical Implications of XMRV Research for ME/CFS XMRV Results from Germany with Professor Malcolm Hooper and BMJ Welcome to the Conference Key Note Speech: Translating ME/CFS Research into Treatments 25 Year Follow-up of ME Patients Translational Research in ME/CFS Presentation

Journal of IiME Volume 5 Issue 1 (May 2011) ME AWARENESS MONTH 2011 People who suffer from Myalgic Encephalomyelitis (ME) are forced to live in a bubble – a bubble created from ignorance  ME is a neurological illness  ME patients are banned from giving blood for life  Over 60 outbreaks of ME have been recorded worldwide since 1934  ME is 3 times more prevalent than HIV/AIDS – twice as prevalent as MS  25% of ME patients are severely affected - housebound, bedbound  25,000 patients are children  ME is the largest cause of long term sickness absence from school for pupils and staff  ME patients have no approved drugs for treatment  ME patients have no access to specialist ME consultants  ME does not discriminate, anyone can be affected  There is no centre of excellence in the UK that treats and researches ME as a physical illness. UK Charity Invest in ME wants to change that - Please Help Us BURST OUR BUBBLE Invest in ME (Charity Nr. 1114035) Charity Nr. 1114035 www.investinme.org Email: info@investinme.org 6th Invest in ME International ME/CFS Conference 2011 20th May Westminster, London ge 58/58

The JOURNAL of IiME Volume 6 Issue 1 www.investinme.org

IiME Conference DVDs These Invest in ME conference DVDs are professionally filmed and authored DVD sets consisting of four discs in Dolby stereo and in PAL (European) or NTSC (USA/Canada) format. They contain all of the presentations from Invest in ME International ME/CFS Conferences (2006 – 2012). Also included in the DVD sets are interviews with ME presenters, news stories and round-table discussions. These Invest in ME conference DVDs have been sold in over 20 countries and are available as an educational tool – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://www.investinme.org/InfoCentre%20Education%20Homepage .htm or via emailing Invest in ME at info@investinme.org Journal of IiME Volume 6 Issue 1 (June 2012) Welcome to the Conference Invest in ME welcome you to the 7th International ME/CFS Conference in London. Inside This Issue 3 Welcome to the Conference 6 8 Let’s Do It for ME The New International Consensus Criteria for ME 13 19 20 23 29 99 The Drug and the Possibilities of Changing Everything Current Status of ME in Sweden Treatment of ME and FM with a Staphylococcus Vaccine Transcranial Sonography in the Diagnosis, Follow-up and Treatment of ME The Immunological Basis of ME Presenters at IiME Conference 107 Conference Agenda Invest in ME (UK Charity Nr. 1114035) PO BOX 561 Eastleigh SO50 0GQ Hampshire, UK Tel: 02380 251719 07759 349743 E-mail: info@investinme.org Web: www.investinme.org Disclaimer The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME (Charity Nr. 1114035) Invest in ME is a UK charity established in 2006 by ME patients and parents of children with ME (myalgic encephalomyelitis). The aim of the charity is to raise the profile of ME and awareness of the need for a strategy of biomedical research in order to treat and cure this disease. We hope to achieve this by educating healthcare professionals and the wider public about the true nature of ME. The conferences have formed a crucial part of this education. We recognise that the term CFS is used widely in many countries and the medical and research literature but we use the term ME and by that we refer to the WHO ICD10 classification G93.3. We have come a long way since we started these conferences in 2006. The first few years involved more politics than science. This year we are pleased to be able to show interest from the wider academic scientific disciplines. The trend started with the publication of XMRV and ME/CFS by Lombardi et al. in the Science magazine in 2009. This led to controversies but brought ME into the attention of new researchers not normally involved in ME. At this time we await results from the NIH funded study led by Professor Ian Lipkin from Columbia University in USA to confirm whether a gammaretrovirus is found in blinded blood samples. We are pleased to see that the interest in ME continues following on from the positive results of the Norwegian clinical phase II trials using Rituximab to treat ME/CFS patients. Last year we had the privilege of hearing pre-publication results from the principal investigators Professor Mella and Dr Fluge and we welcome them again this year to update us on their continuing research. The publication of this phase II clinical trial in Plos One in October 2011 led to much publicity in Norway. The Norwegian government apologised for the past treatment of ME patients which promoted ME as a behavioural illness to be treated with CBT (Cognitive Behavioural Therapy) and GET (Graded Exercise Therapy) despite patients having protested that such treatment made them worse. Prior to the 2011 conference IiME organised a researchers meeting – our “Corridor Conference” www.investinme.org Page 3 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) – where we hoped to use the opportunity presented by the conference to network and exchange information to launch new collaborations. When one reads this Journal news will have been publicised regarding a two day closed researcher meeting which preceded this year’s conference and which focussed on exploring autoimmunity and ME based on the results of the Norwegian Rituximab research. The Clinical Autoimmunity Working Group (CAWG) has been formed by the best of the best in the field of immunology/autoimmunity. The CAWG has been convened by The Alison Hunter Memorial Foundation and Invest in ME, in collaboration with Bond University, Australia and the University of East Anglia, UK. Dr Don Staines will be presenting a summary of this meeting at the 7th Invest in ME conference. Invest in ME’s intention is to fund research where we can and to facilitate cooperation and collaboration between researchers across the world. It is, we believe, only by these means that patients will be able to see real and rapid progress being made in treating this disease. Patient power is described in the Journal with the Let’s Do It for ME campaign being the best example of positive campaigning – where patients influence the progress of research. The conference programme is a mixture of experienced ME researchers and clinicians such as Drs Peterson, Baraniuk, Marshall-Gradisnik, Staines, Kogelnik and recent newcomer to ME research, Professor Ljungar as well as experts in related fields such as Dr Delgado, Professor Fitzgerald and Professor Perry whose work is very important in helping us find clues to ME. Professor Perry is also the recently appointed chair of the MRC Neurosciences and Mental Health Board (NMHB) so we welcome his input. Then of course we all want to hear the latest from Dr Fluge’s and Professor Mella’s research. Dr Ian Gibson, is a former cancer researcher and Dean of Biological Sciences at UEA and MP, will be chairing this year’s conference. Dr Gibson has been instrumental in helping Invest in ME initiate negotiations to set up an examination and research facility in Norwich using the excellent resources the Norwich Research Park has on offer. Invest in ME (Charity Nr. 1114035) The conference is focal point for research and networking but there is a great deal of work behind the scenes. The Journal has a Scandinavian slant to it in this issue. This reflects our view and the events of the past year, that change will likely come from that direction. Thanks to years of gallant efforts from the Norwegian ME Association, and now from the Norwegian researchers in Bergen, there is real hope of a breakthrough. The Norwegian minister of health has officially and publicly apologised for the treatment given to ME patients. The Swedes are similarly playing a forceful and proactive role in getting Swedish researchers and clinicians to the conference this year with EMEA Sweden member RME working closely with IiME. We have articles from Norwegian journalist Jørgen Jelstad and Professor Olof Zachrisson from Sweden. Jørgen’s article covers the story of the Norwegian researchers’ work with Rituximab. Jorgen has written an excellent book “De Bortgjemte” – (The Hidden ones). Professor Zachrisson’s article covers experiences with staphylococcus vaccine treatment which was successful in alleviating symptoms but which is no longer available due to the vaccine manufacturers having taking it out of production. While the charity attempts to initiate the first biomedical research into ME in Norwich as a prelude to further examination and research so we look to Scandinavia to lead the way in Europe. Margaret Williams is a prolific and incisive commentator on the state of ME. She has produced another enormous piece of work on immunology – the theme behind this year’s conference – and we are pleased to publish this in the Journal. The Journal of IiME was created as a means of providing a broad spectrum of information on ME, combining biomedical research, information, news, views, stories and other articles relating to myalgic encephalomyelitis . Invest in ME was set up with the objectives of making a change in how ME is perceived and treated in the press, by health departments and by healthcare professionals. We aim to do this by www.investinme.org Page 4 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) identifying the three key areas to concentrate our efforts on in order to raise funding for biomedical research - education, publicising and lobbying. This will provide the focus and funding to allow biomedical research to be carried out. Our aim is to bring together like-minded individuals and groups to campaign for research and funding to establish an understanding of the aetiology, pathogenesis and epidemiology of ME. We hope this will lead to the development of a universal diagnostic test that can confirm the presence of ME and, subsequently, medical treatments to cure or alleviate the effects of the illness We believe that governments should provide a national strategy of biomedical research into ME to produce treatments and cures for this illness. Since our last conference Invest in ME has been working to initiate an examination and research institute in Norfolk, UK, which would properly diagnose and then research people with ME. The proposal is available here and is described later in the Journal. Thanks to the efforts of the IiME steering group, which includes Dr Ian Gibson who has been working tirelessly to support this proposal, we have come within one decision of initiating this proposal and creating a unique UK scenario which would have the potential to lead the world. But vision is meaningless without action and we have to continue to debate, discuss and promote this work to enable others to see the possibilities. The unique blend of biomedical research, objective data presented by our distinguished speakers is testament to the increasing knowledge regarding myalgic encephalomyelitis. To repeat a line from a previous Journal, which is still relevant today - if a sea change in the perception of ME is occurring then it will be based on the good science and objective data (represented by our conference speakers), effective advocacy (represented by conference delegates from twenty different countries and from ME support organisations such as EMEA and AHMF working together across the world). Change will be forced by patients – the alternative in doing nothing is not an option. Invest in ME (Charity Nr. 1114035) Building a Future for Research into ME The Corridor Conference organised in London last year by IiME and the more impressive and forward-thinking CAWG research group which meets in London this year before the conference is our way of making progress in biomedical research into ME. We attract experts from other disciplines to bring their expertise and skills to bear on this disease. By doing this we can bypass the negativity and misinformation which has pervaded the perception of ME for a generation and instead focus on proper science. The Let’s Do It for ME campaign and our core group of supporters are helping to fashion a change in ME research and this is determination and enthusiasm will influence researchers – both within the ME research area and those from outside. The Invest in ME conferences bring together this optimism and determination in a happy mixture of wanting, needing to learn, optimism and hope that things will improve. At the conference there will be researchers, clinicians, nurses, patient groups and patients, advocates and, we always hope, a sprinkling of as many politicians, journalists and others whom Invest in ME selffund to allow people to be exposed to real science. We would like to thank our friends at the Irish ME Trust for once again sponsoring one of the speakers at the conference. The IiME conference is not only a platform for proper, high-quality science – we hope it continues to be a platform for the hopes of millions of people around the world. Enjoy the Journal. Enjoy the conference. Let’s do it for ME. All content in the Journal of IiME is copyright to Invest in ME and the authors. Permission is required and requested from Invest in ME before republishing anything in this Journal. www.investinme.org Page 5 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) something which was fun. Positive campaigning – with an objective to fund sorely needed translational biomedical research into ME and to harness patient power to influence ME research – something which has been missing from the equation. In the summer of 2011 ME patients and their families were exposed to a torrent of inflammatory and biased media mis-information in a seemingly coordinated campaign relating to the illness, to patients and to research into ME. Misinformation and ignorance about ME is not a new response from a simplistic and manipulated press. The distress and concern caused to Invest in ME supporters and their carers forced the charity to submit a formal complaint to the Press Complaints Committee about these series of articles [1] – all seemingly emanating from the same source. The charity’s actions were not due simply to the fact that extremist views of the disease and the alleged actions of patients were being falsely portrayed by the media and by paid buffoons masquerading as journalists – it was due to the effect it had on patients who yet again were seeing their situation, and the disease from which they are suffering daily, being ridiculed and misrepresented by poor journalism and missing editorial rigour. How does a patient community respond to such prejudice and propaganda? How can a change be made in the way that the media view this disease and the sick and vulnerable people that suffer from it? other people's fundraising. At around this time an idea was born by Jo Best and helped on by Jan Laverick and Paul Kayes – all ME patients. Instead of continually reacting to what others were doing or saying they decided to take a proactive approach. A campaign was started to support the Norwich examination and research facility proposal which Invest in ME had made to initiate a UK Centre of Excellence for ME. The difference with this campaign? To use the skills and ideas of patients who want more than anything else to regain their health. By harnessing these ideas and enabling people to feel positive about doing something themselves to effect change then the campaign could be turned into Invest in ME (Charity Nr. 1114035) Whilst raising funds for biomedical research the campaign is also raising much needed awareness and allowing correct information about ME to be disseminated. Carole Carrick and her husband Clive have been doing several supermarket collections and by doing so they have met many members of the public and passed on information about ME by talking to people. Carole also attended an ME event at the Scottish Parliament in Edinburgh as an IiME representative and again raised much needed awareness of IiME's activities and the LDIFME campaign. Kathryn Lloyd was so severely affected for many years that she could not even www.investinme.org Page 6 of 108 There are an estimated 250 000 ME patients in the UK, twice as many as MS patients and MS charities manage to raise millions of pounds for research. ME patients and their families should be able to do the same. The Let's Do It For ME campaign is a positive and proactive campaign. The aim is to raise funds for biomedical research but everyone's input is welcomed - be it just ideas or moral support for Journal of IiME Volume 6 Issue 1 (June 2012) speak so she raised several thousand pounds by doing a sponsored silence. James Wythe pledged to raise £3000 if others raised a matching sum. It was achieved. The fundraising efforts have grown and now we have several people taking part in various events. There are marathon runners – in Brighton, Paris and Edinburgh. Little 10 year old Teigan ran a minimarathon to raise funds for IiME. Teigan’s mother suffers from ME . There are people taking part in events such as 'The Big Sleep', school non uniform and awareness raising days, art exhibitions etc. Jan Laverick and Carmel Hillary have set up online shops to sell t-shirts and other gifts with IiME and LDIFME logos. In order to facilitate fund-raising campaigns a subscription to Just Giving has been set up thanks to a kind donation to cover the first year's subscription fees to Just Giving. In a short article such as this we cannot mention everyone who has taken part, or contributed with money or ideas. But the campaign has been effective and re-energised research, making the goahead for the IiME proposal nearer to reality. Rather than waiting for others to do things – a strategy which has not faired well over a generation – the people involved in the efforts to make the IiME proposal a reality are taking it on themselves to make a difference. Let's do it for ME! is a patient-driven campaign to raise awareness and vital funds for a centre of excellence for translational biomedical ME Invest in ME (Charity Nr. 1114035) www.investinme.org Page 7 of 108 research, clinical assessment, diagnosis and treatment for patients, and training and information for healthcare staff based at the University of East Anglia in the UK and aiming to work collaboratively with international biomedical researchers. Reference: [1] http://www.investinme.org/Article505%20PCC%20Complaint%20Aug%202011.htm (The pictures in the mosaic on this page are some of the volunteers and supporters from the Let’s Do It for ME campaigns). Further details – http://www.investinme.org/IiME%20Awareness% 20Events%20LDIFME.htm or http://blog.ldifme.org/ ME FACTS 1969: the World Health Organisation classified ME as a neurological disorder.

DIAGNOSTIC CRITERIA The New International Consensus Criteria for ME - content and context by Professor Bruce M.Carruthers, MD,CM, FRCP(C) The New International Consensus Criteria for M.E. - content and context By Bruce M.Carruthers, MD,CM, FRCP(C). CONTENTS Sir William Osler said “Look wise, say nothing and grunt. Speech was given to conceal thought.” This is a typically Canadian form of advice. As a compatriot, it is with great trepidation that I deviate from it. In the new ICC the general thrust of the 2003 Canadian Consensus Criteria is retained but developed further. • We recognize the international scope of the problem of ME and its solution by moving to an international consensus panel. • The 6 month waiting period is no longer required, but left to clinical judgment. • The distinct dynamical symptom pattern of Post-Exertional-Neuroimmune-Exhaustion is kept criterial and further articulated as having the dynamical structure of unusual physical and/or cognitive fatiguability after the appropriate kind of exertion, which may be immediate or delayed, and has a prolonged recovery period. • Other symptoms and signs arising from dysfunction within the following subsystems often share a coherent dynamics with PENE, to suggest an interactive underlying causal context- neurological (neuro-cognitive, pain processing, sleep disturbances, neuro-sensory Invest in ME (Charity Nr. 1114035) and motor), immune, gastrointestinal, genitourinary and endocrine subsystems, as well as dysfunction in the energy production and transport systems-cardiovascular, microvascular, respiratory, and maintenance of thermostatic homeostasis and intolerance of temperature extremes). • Interactive dynamical pattern matches between the criterial PENE symptom pattern and the symptom/sign patterns arising from other patho-physiological subsystems are first articulated in individual patients and then as projectable in individuals, if they remain coherent and consistent over time, as well as onto larger groups of similar patients. Thus these observations become mutually confirmable as pointing to real and natural structures/patterns/kinds that exist “out there” as part of the causal structure of the body in its world- and not as creatures of the mind that happens to be trying to observe and re-present it (nominalist, constructed kinds). • Modulations for paediatric cases are added. • Exclusions that are likely to become necessary for the individual case as part of her/his differential diagnosis are listed. • The ICC keeps its focus on selecting relatively homogeneous subsets of patients with interactive symptoms, essential for clinical research if its observations are to be properly controlled, while including a discussion of recent pertinent research results. www.investinme.org Page 8 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) Context “ME” as the name for a chronic fatiguing disease of bio-pathological causation has a long history, primarily in the U.K., even though the specific biohypotheses of causation underlying its name proved difficult to confirm, given the technology available at that time (1954-94). Over vigorous objections, the name then largely shifted to “CFS”, a noncommittal umbrella disease concept that includes all fatigues that are severe, chronic and unexplained, but ignores the “syndromeness” embedded in its etymology by putting symptoms onto lists that ignore their dynamical relations of causal inter-activity. This latter points to a common underlying causal structure, however complex and currently unknown, and is found in the etymology of the word “syndrome” (Gk. running together). However elaborately symptoms are entered into lists, the problems resulting from this neglect of their natural inter-active dynamical causal structure will remain. • In his study of the Reeves criteria for Chronic Fatigue Syndrome, Jason et al found that only 10% of patients identified as having CFS actually had ME, and confirmed the efficacy of the Canadian criteria in separating out this 10% subset.(J Disabil Pol Studies 2009; 20: 91100). • Why was this maneuver of the Canadian criteria so effective in separating out this subgroup? By recognizing that fatigue showing the specific dynamical patterns of ME characterized a large subset of fatigued patients, and thus was different in kind from the patterns underlying the majority of severe, chronic and unexplained fatigues (CFS). It thus pointed to a different underlying causality- a natural kind or real pattern whose underlying causal organization lies in the world, not just our representative models of the world, that could be researched using biological methods- given adequate comparative controls. • With major advances in technology, recent research guided by properly scientific hypotheses has given strong support to “ME”s implication that a different underlying causal Invest in ME (Charity Nr. 1114035) structure- one involving inflammation and dysfunction within the CNS, ANS and immune systems, plus more- underlies this large subset of CFS patients. • While it has always been essential, it has now also become urgent to segregate the subset that we are calling ME more clearly, using the ME International Consensus Criteria, so that researchers can confirm/disconfirm their results using patients who have chronic fatigue of this clearly bio-pathological origin. Otherwise the all-inclusive umbrella of “CFS”, in ambiguating natural and psychosocial kinds of fatigue, will continue to dilute the results of any investigations and maintain the pervasive confusion resulting when biopathological kinds are mixed indiscriminately. Conclusion • The results of Jason et al’s studies have confirmed that the Canadian Definition of ME/CFS had clearly separated cases who have ME (fatigue of bio-pathological or natural origin, arising out of a pathological causal structure present in the world apart from the mind that is observing it) from those who have CFS (which includes the minority of the specific natural kinds we are calling ME plus a majority of fatigue kinds that are secondary to other diseases, plus parts of the normal homeostatic activity-rest cycle designed by evolution, plus fatigue kinds constructed by the re-presentational observing/thinking and thus dualistic model-making mind). • The prevalent use of symptom-based definitions has been adding to the confusion by analyzing complex syndromes using a Cartesian method of analysis that isolates symptoms by putting them onto standardized lists of separated subjective entities, thereby bypassing the dynamical subjective/objective interactive processual causal on-line context that points to an underlying interactive causal www.investinme.org Page 9 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) organization, even if we are as yet unaware of its details. • Contrariwise the new ICC encourages that symptom structure be observed on-line as interacting embodied and embedded causally interactive dynamical process(es) that have multiple subjective/objective manifestations. These are first observed (or ignored) in a clinical dialogue as (subjective) symptoms and (objective) confirmatory signs which are disambiguated on-line, in their natural context, as temporally dense and as having felt/observed causal efficacy. These individuated observations are in turn confirmed by objective biochemical measures, pathophysiological functional testing and imaging. The “same” phenomena can also be studied off-line using epidemiological studies which observe the generalisable constancies found in groups of variously homogenous groups of cases using standardizing techniques of questioning and observation to obtain generalisable results and case definitions. In the standardized and properly randomized environments of scientific experiments, the effects of interventions can be properly controlled, and thus general rules of causality inferred and quantified. • As the ICC panel members add clinical guidelines and symptom scales (ICSS), these three essential kinds of observation will be integrated by using a transductive and mutually confirmative language that matches the dynamical causal patterns to be found in each realm. This pattern “language” must be flexible enough to negotiate the changes in scale and context involved in comparing observations arising from disparate clinical, epidemiological and research methodologies, scales and contexts, all of which necessarily remaining distinct, yet interrelated. We are confident that this will lead to mutually confirmed outcomes that can be generalized and standardized world-wide- meanwhile remaining adequate to the particularities and Invest in ME (Charity Nr. 1114035) demands of each patient’s complex illness/disease structure. • As Osler also said “Listen to your patients. They are giving you the diagnosis”. Now we have the technology to confirm this directly for this complex disease- if we use it. Since this presentation was given in Ottawa Sept 24, 2011, the Journal of Internal Medicine has published 3 articles concerning these issues that are freely accessible on line1/ The ICC for ME was published- J Internal Med Oct 2011, 270: 327-38. 2/ A critique- ´A controversial consensus” published JWM van der Meer and AR Lloyd J Internal Medicine 271: 29-31, Jan 2012. In particular the above authors discussed the “unscientific” way the ICC was laid out, discussing the “pseudoscience of pathophysiology” “notional” pathophysiology, and the “intrinsic heterogeneity in syndromal diagnoses” but neglecting to mention how their recommended approaches to syndrome description had contributed to this situation by treating symptoms as separated subjective things on lists, thereby destroying any consideration of their embodied interactive dynamic context or “syndromalness” (Gk etymology, running together on a track), and rendering research directed towards underlying causality more elusive. 3/ A rebuttal of the critique by G Broderick J Internal Med vol 213-17 Feb 2012. corrects some of these misapprehensions, and points out that the Reeves and Oxford criteria for CFS select patient sets that are approximately 10x larger and more inclusive than those selected by the Fukuda criteria, and that the Canadian consensus criteria selected patients with even more severe physical functional impairment, less psychiatric comorbidity than the Fukuda definition(see Jason et al Am J Biochemistry and Biotechnology 6: 120135, 2010) and obviously brought to salience the distinctive pathophysiological pattern of delayed reactive fatigue, which it made criterial. This symptom is not the simple name of an isolated subjective feeling put on a list, but points to its participation in a higher level fatigue/activity www.investinme.org Page 10 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) control network which we know to be present by its disregulated causal efficacy in the world, even if we do not yet know what its details are, and which we are calling “ME” in honor of the earlier (and current) sufferers and prescient observers of this kind of suffering. Other earlier and revised case definitions based on the disease concepts of Ramsay had made postexertional malaise and impairment of memory and concentration central to the diagnosis of ME (Lloyd AR et al Med J Aus., 153: 522-528, Goutsmit, E et al Health Psycholog. Update 18:27-31), but none before the Canadian Definition of 2003 had made this specific dynamic and projectable pattern of pathological fatigue criterial for the diagnosis of ME/CFS, and the ICC case definition of ME is carrying on and developing this strategy further. The specificity of this illness pattern provides a level of detail that is necessary for patients to adapt to the aberrant pattern of fatigue as experienced in their own illness using pacing. Research can be designed to study the pathogenetic details of this particular pattern and the many others that I expect will be uncovered as the ICC strategy is used more widely, with the assurance that results are not being continually diluted out by the 90% majority of CFSers who don’t have this kind of fatigue pattern. We can finally search for specifically directed remedies. This is the way towards scientific progress after what has been a long delay, indeed a paradigm war- not arguments between results but between opposing assumptions made before beginning observations. All three of these contributions agree on one point- that whatever it is we are talking about, it is a complex disease/illness- but on little if nothing else. There was special confusion on whether we were talking about CFS or ME, regarding them as mutually exclusive dualistic entities and not complementary parts of a single disease concept. And confusion reigns about what we mean by complexity itself in various realms (the topic itself is complex)- and we are dealing with the realm of medicine, where not much serious thought has been put to it as yet, e.g. producing long symptom lists and symptom counts doesn’t help. Simple or Complicated structures have a known stable causal structure, of variable intricacy, that hence are predictable if you can extrapolate from knowledge garnered from one astute observation. Complex structures do not, as their causal Invest in ME (Charity Nr. 1114035) structure is forever recursively changing-as a result of the causal interaction of their constituents-and hence are inherently unpredictable. As a consequence a complex structure must be observed continually, while the complicated one does not have to be, while confirming/disconfirming inferences, tests, and imagings are made. For complex diseases the only observer who is constantly observing the patient is the patient her/himself. We all must learn to utilize this kind of continual common sense selfobservation by patients in dialogue with their physicians, as we together observe the development of complex diseases over real time through a robust and productive doctor/patient relationship. This will entail a large qualitative shift in attitude and appreciation of the value of the direct self-observation of illness structure as it evolves in real time, if done properly- and without diversion into cognitive dualisms. There are also repercussions of post-cognitive theoretical moves in psychology into direct nonrepresentational perception and radical embodied cognitive science ( see “Radical Embedded Cognitive Science) Anthony Chemero MIT Press, 2009 and “The Mind, the Body and the World- Psychology after Cognitivism? Ed. B Wallace, A Ross, J Davies and T Anderson, ImprintAcademic.com, 2007.), which point to the need for a distinct shift in strategy (in our realm of medicine) from its current emphasis on developing generalized cognitive disease models to directly observed, individuated diagnosis of illness and its therapeutics. This is also emphasized by the development of bottom-up systems biology and translational and systems medicine (Nielsen J.J Internal Medicine 271, pp 108-110). Our current treatment of symptoms and syndromes in diagnosis and prognosis, and of pacing and the role of self-organization in therapeutics, will also need great adjustments as we move from an “anthropogenic” to a “biogenic” approach to them. (see “The biogenic approach to cognition” Pamela Lyon, Cognitive Processing 2007: 11-29) . Opportunities are arising with the rapid development of technology to allow direct confirmation of the clinical symptoms and signs observed by individual patient/physicians without a detour through the medical model, but by attending to directly observed individual illness structure, with mutual transductive confirmation www.investinme.org Page 11 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) of the symptom patterns felt directly by a patient in dynamically congruent patterns observed within the under-overlying causal systems at different OMIC scales (genomic, cellular, organ, physiological system, as well as at the emergent organismic, organismic/environmental/ epidemiological, etc. scales. What is in process for our ICC endeavour are the preparation of an ME Physicians’ Primer/Guidelines and the preparation and testing of an International Symptom Scale to improve cross-standardization of symptom questioning when comparing groups of patients where clinical epidemiological and other statistical studies are being planned. guidelines for which many in the ME community have been campaigning to be adopted as the standard set of guidelines for diagnosing ME. ME FACTS 1978: The Royal Society of Medicine accepted ME as a nosological entity. The Canadian Guidelines Invest in ME are the UK distributors for the Canadian Guidelines. Described even by NICE as “the most stringent” guidelines available these are proper, up-to-date clinical guidelines which can also be used as a base for research criteria. Findings from the study by Leonard A. Jason PhD (Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome) indicated that the Canadian criteria captured many of the cardiopulmonary and neurological abnormalities, which were not currently assessed by the Fukuda criteria. The Canadian criteria also selected cases with 'less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms' and individuals selected by these criteria were significantly different from psychiatric controls with CFS. The Canadian Guidelines provide a means for clearly diagnosing ME and were developed specifically for that purpose. They are an internationally accepted set of Invest in ME (Charity Nr. 1114035) ME STORY “I have since been sent to another neurologist after my doctor found I was Rhomberg's positive, who made me walk, did a scratch test on my feet, checked the weakness in my legs, and said quite rudely, "you have ME, I am not going to waste time doing tests on you" and that was it. I walked away feeling like I had wasted this man's time. I pray one day a cure will come our way.” - Rowan - “Personal Stories of ME Sufferers - http://www.investinme.org/mestorygall ery1.htm www.investinme.org Page 12 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) THE DRUG AND THE POSSIBILITY OF CHANGING EVERYTHING Author: Jørgen Jelstad Jørgen Jelstad is a Norwegian journalist and author of the documentary book “The Hidden Ones: and how ME came to be the most controversial disease of our time” (only available in Norwegian – named “De Bortgjemte”). The book received great reviews from Norwegian critics, some of them citing it as a must-read for health care workers. It has also been referenced on several occasions by some of Norway’s most prominent politicians. Jelstad has a blog: www.debortgjemte.com This article will focus on the recent Rituximab findings in ME/CFS, something Jelstad has followed closely since he started working on the book in 2009. “They soon found that new ideas aren’t always welcome in science – even if the old ones aren’t working.” - Switch off, switch on, The National, 2009. 2004: Patient zero Anne Katrine walks into the Cancer Department at Haukeland University Hospital in Bergen in 2004 to get treatment against the lymphoma the doctors discovered one year earlier. After four rounds of chemotherapy the cancer seemed to be beaten, but suddenly it came back and she is in for her second treatment regimen. Anne Katrine also has ME/CFS since she suddenly fell ill with mononucleosis in 1997. For several years she had mostly been housebound with muscle pain, problems with sleep and great cognitive difficulties. An overwhelming fatigue and malaise has made her unable to leave the house for more than short periods of time. Five weeks after starting the new treatment against lymphoma, something unexpected happens. Suddenly she notices a marked improvement in all the ME/CFS symptoms that she Invest in ME (Charity Nr. 1114035) has endured for more than seven years. She has never before experienced anything like this. Her teenage son had one time told her that he was not sure if he could manage to live with someone as sick as his mother. Now, they were able to go to Turkey together for the holidays. But suddenly it all comes back. The headache, the aching muscles, the cognitive decline and the devastating fatigue and malaise. Back to scratch. “When you had cancer, mom, we had the best dinners ever,” Anne Katrines daughter tells her after the relapse. Sitting in his office at Haukeland University Hospital, cancer specialist Øystein Fluge scratches the back of his head, puzzled. What really happened to his patient Anne Katrine? For years to come he cannot forget what he saw during these months in 2004. 2009: Pioneering In October 2009 I sat in a small office at Haukeland University Hospital in Bergen, a city on the west coast of Norway. I remember it well. The two doctors enthusiastic telling of their surprising tale. I was in the very beginning of researching my book about ME/CFS when I came across a small pilot study from the very same people I was meeting for the first time this day. Even then, without the extensive knowledge about ME/CFS that I have now, I remember thinking: If this turns out to be true, it will change everything. www.investinme.org Page 13 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) It was a beautiful sunny day, with snow covering the peaks around Bergen. On my way to the meeting with Professor Olav Mella and Doctor Øystein Fluge, I saw signs pointing the public to the mass vaccinations against the swine flu. In a few weeks Norwegian authorities had spent more money on buying vaccines than everything the American government had spent on ME/CFS research for the last 25 years. I remember seeing that as a telling comparison pointing towards a still grim future for ME/CFS. But now, I was wondering if these two doctors story could be a turning point. After 25 years of controversies, lack of funding, maltreatment, ridicule and dashed hopes. Could this be the game changer? Dr Fluge was talking about Anne Katrines remarkable story of recovery from most of her ME/CFS symptoms, and after those months she had never let Fluge off the hook. She begged him to find out what had happened. And in the end, Fluge and Olav Mella, the head of the Cancer Department at the hospital, decides to give it a try even though they have never before worked with ME/CFS, barely heard of it. “Our starting point was: Could this be an autoimmune disease? And if so, could it be that it was methotrexate in Anne Katrines treatment that was working on her ME/CFS symptoms”, said Fluge. Methotrexate is a medication which dampens the immune response. It is used in large doses in some cancer treatments, but it is also used in smaller doses against different autoimmune diseases, for example rheumatoid arthritis. Anne Katrine had gone through three different courses of cancer treatment, but only with one of them did she experience a near resolution of her ME/CFS symptoms. In that treatment she got methotrexate, something she did not get during the other treatments. “We could not know if this hypothesis was right, but our idea was to try to treat CFS with Rituximab, which is a medication that works directly on the B-cells in the immune system,” said Fluge. Like methotrexate, Rituximab is a medication that dampens the immune response, but through a Invest in ME (Charity Nr. 1114035) different mechanism. It basically wipes the B-cells out for a few months before they slowly grow back. Both of these medications are used in the treatment of cancer and autoimmune diseases. In 2007, Fluge and Mella decided to do a small pilot study on three ME/CFS patients. One of the three patients they contacted was Svein. “Before Olav Mella called me, I remember I discussed with my wife how long I would manage to go on with this disease,” said Svein when I asked his story in a phone interview. He worked at the local hospital, but after a serious viral infection ten years earlier he never recovered. For a long time he tried to stay at work, but in the end had to give it up. “I have been so ill that I was bedridden and had to get help to get to the toilet. But of course, I still hope to get back to work some day,” Svein said. Six weeks after his first infusion with Rituximab something happened. In just a few days Svein experienced major improvement in all ME/CFS symptoms. “My father in law has a cabin, and it is situated just a hundred meters from the road from where we had to walk. Usually my stay at that cabin had been just managing to get there, and then I had to lie on the couch or the bed during the whole stay. Now I went skiing with my kids,” said Svein. In their pilot study, published in BMC Neurology in early 2009, Mella and Fluge writes: He could take one-hour walks and started to do carpentry on his house. Myalgic pain was markedly reduced. Cognitive functions improved remarkably, and he could now read a whole book without interruption. The hypersensitivity to noise decreased. He and his wife confirmed that family life had improved considerably. “After my first treatment I finished two books in a weekend. Before treatment I could not even read two pages,” said Svein. But after ten weeks of major improvement Svein crashed. Back to a life within the four walls of his house. All the symptoms came back as fast as they had gone away. He received a second treatment www.investinme.org Page 14 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) course, and the same thing happened. Major improvement after six weeks, then ten weeks with maintained improvement, and then a crash. In February 2009 he got a new infusion. “Then I had the best effect so far, and it lasted even longer. I started doing carpentry on the house, made a new roof and new walls, put down cables. I throw myself at these kinds of projects when I feel better, because I feel there is so much I have undone. As soon as my body functions again, I’m ready,” said Svein. Before treatment with Rituximab, Svein had only been able to watch pictures of his kid’s activities outside the house. “That feels terrible. When I get this treatment I manage to participate. It is like being brought back to life again,” said Svein. The two other patients in the pilot study, one of them Anne Katrine, and the other a woman in her early twenties, had similar major improvements after Rituximab treatment. Mella and Fluge were themselves surprised when they saw the astounding pilot results, where the patients at times experienced near resolution of all of their symptoms. “Then we felt that we were touching a central mechanism in the disease,” said Fluge back in 2009. They started a double blinded, placebo controlled and randomized study on Rituximab in 30 ME/CFS patients – what is called a RCT. Placebo controlled means that the patients are divided into two groups – 15 got placebo (salt water) and 15 got Rituximab. Double blinded means that neither the patients, nor the researchers, know who gets real drugs and who does not. Randomized means that it is random which group the 30 patients end up in. This is considered the gold standard in medical research on drugs. At my first meeting with the two doctors that day in 2009 none of them knew if their study would turn out positive. They did not yet know which patients got the drug and who got placebo. 2011: Praise “It’s the most encouraging drug result so far in the history of this disease. Although it’s a small trial, it’s produced dramatic results,” said Charles Shepherd, MD and medical advisor to Britain’s biggest patient association for ME/CFS, to New Scientist in October 2011. The Norwegian Rituximab study had just been published in PLoS ONE, and it generated a massive amount of media coverage. “Immune system defect may cause ME” reported BBC. “Cancer drug can help chronic fatigue” was the headline in Europe’s leading news magazine Der Spiegel. Never before had a study on a drug in ME/CFS had such promising results. The study on 30 patients showed that 10 out of 15 patients (67 %) got a significant improvement from the cancer drug Rituximab which wipes out most of the B-cells in the immune system. 9 out of the 10 responders got a “major improvement” according to the paper. In the placebo group only 2 out of 15 (13 %) got a significant improvement. The result was 10-2 between the groups. Or 9-1 if you only look at “major improvers”. It turned out that most of the responders, unlike two out of three pilot patients who were early responders, started their improvement as late as 3-7 months after the infusion with the drug. Another significant finding was that most patients relapsed when the effect of the B-cell depletion wore off, which is consistent with the effect of such treatment in some autoimmune diseases. “Thus, we believe that B-cell depletion targets a central player in the pathogenesis of the CFS disease, directly or indirectly”, the study authors wrote in their paper. The director of Haukeland University hospital, Stener Kvinnsland, who was not directly involved in the study, said to the Norwegian broadcaster TV2 that he ”had a strong feeling that this was a breakthrough”. Dr. Kvinnsland is one of Norway’s most respected cancer researchers with a solid track record, and to a Norwegian newspaper he said that the Rituximab finding was one of the Invest in ME (Charity Nr. 1114035) www.investinme.org Page 15 of 108 I followed Mella and Fluge closely the next two years. Ups and downs. Uncertainty and promise. And now we all know: new hope. Let us take a leap to October 2011.

Journal of IiME Volume 6 Issue 1 (June 2012) most exciting things he had followed in his professional career. Professor Carmen Scheibenbogen, Deputy Director of the Institute of Medical Immunology at the Charité University Hospital in Berlin, described the results of the study as a possible breakthrough. “This is a very important first step. For the first time, a therapeutic study has been conducted with medication that was originally applied to the immune system, and which proved effective for a majority of the patients”, she told bto.no. In Norway, a country where ME/CFS has generated a lot of media attention the last few years, the Rituximab study led to a media blitz. For several days the media reported on the study, the lack of good care for the patients and all the broken promises about better services for ME/CFS patients from the government and the responsible health care providers. It was like Rituximab was a tipping point for not longer being able to give the impression that this disease was not real, or that it was mainly a psychosomatic problem. Because how do you argue against a big gun cancer drug? In a way, Rituximab did not just heal some of the study participants, it also healed the self-respect of thousands of Norwegian ME/CFS patients who finally experienced something else than suspicion and disbelief. In a rare public statement the National Institutes of Health in Norway even apologized to the patients for the lack of services and years of mismanagement. Before the Rituximab study hit the news, I called Sheba Medical Center in Tel Aviv to talk to the Israeli scientist and world renowned expert on autoimmunity, Yehuda Shoenfeld. He is editor in chief of Autoimmunity Reviews and has written several books and published hundreds of scientific articles on autoimmunity. In a review article in 2009 he wrote that recent findings in ME/CFS “points toward an ongoing autoimmune phenomenon in such patients that, although not fully understood, is likely to be enhanced by the presence of certain infectious agents and other adjuvants”. Invest in ME (Charity Nr. 1114035) “I cannot say for sure that this is an autoimmune disease, but CFS has a lot in common with this group of diseases”, a busy Shoenfeld told me over the phone. At this time he had only seen Mella and Fluge's pilot study on three patients, but he said that what they reported there looks much the same as what you see when you use Rituximab in diseases like rheumatoid arthritis and SLE (lupus). Then he said that if they got positive results in a controlled study, it would indicate that a central mechanism in ME/CFS will be found in the immune system. I asked him if that would be surprising to him. “No, not to me, but it depends who you ask. I have the idea that CFS belongs in this group of autoimmune patients”, said Shoenfeld. I have since talked to several international ME/CFS experts, all of them enthusiastic about the Rituximab results. At last year’s Invest in ME conference I sat down with one of the most respected ME/CFS-clinicians, Daniel Peterson, and asked him his thoughts. - I think it is a crucial step forward, he told me. And then he went on to say that he had seen effects of Rituximab himself. Several of his ME/CFS patients had developed lymphoma and therefore got treated with Rituximab, one of them for several years. - And after starting treatment his ME/CFS symptoms disappeared, said Peterson. The future: Persistence Of course, like everything in ME/CFS, no promising study without controversy. So the study in PLoS ONE also met criticism right away. This is science after all. Controversy is the rule, and more so in ME/CFS than anything else. A group of prominent ME/CFS researchers commented the study at the PLoS ONE pages, implying the results were oversold and with methodological flaws, and they challenged the conclusions. Then one of the world leading authorities on Rituximab quickly commented on a lot of flaws in the critics own criticism. Professor Jonathan Edwards from University College London said their criticism “contains several errors”, and went on to say that the “trial’s authors give the account that is by far the most consistent with the data”. www.investinme.org Page 16 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) “In the end I think we have to find the cause behind the disease, or else no one will believe us. If we are right, which I think we are, we will make it. In a few years I think the scientific community will have the answer”, said Fluge responding to some of the doubting critics. It is important to acknowledge, like Fluge and Mella themselves have repeatedly said, that there is need for bigger studies before concluding on Rituximab and ME/CFS. And this study, like every innovative scientific study, also needs to be subject for criticism and disagreements to make headway for what we all want in the end – the truth. So why did I mention Jonathan Edwards? I did because he has been here, right where ME/CFS is now with Rituximab, just with a different disease. And Jonathan Edwards won the dispute. No one ridicules his ideas anymore. In the 1990s Edwards, together with another British scientist, Geraldine Cambridge, came up with a theory about possible B-cell involvement in rheumatoid arthritis (RA). They met a cold shoulder from the rest of the research community. The importance of T-cells was then the only accepted theory in RA, and therefore most in the medical community automatically thought that the theory of Edwards and Cambridge were not worth pursuing. But Edwards and his colleagues pursued their idea despite the resistance, starting off with a small pilot study on Rituximab in five RA patients. "When the patients' B cells disappeared, so did most of their arthritis," Edwards told New Scientist in 2001. Three of the five patients remained well for a longer period, while symptoms of the disease came back in two patients once their B cells returned. After years of unproductive battling trying to get this groundbreaking idea of the importance of Bcells in RA acknowledged in the medical community, Edwards talked to the press, and the story made headlines. Something which of course made some of his critics even more critical, but it worked. Finally they got funding for a big study on Rituximab in RA, and in 2004 the results were published in the prestigious New England Journal of Medicine. The result? Rituximab turned out to be a superior treatment in the study, and suddenly B-cells were on everybody’s lips. An article on the history of RA and Rituximab in The National in 2009 ends by mentioning Mella and Fluge’s pilot study on Rituximab in three Invest in ME (Charity Nr. 1114035) ME/CFS patients, which then had just been published: “With so few patients, it’s hardly definitive proof of a cure. Yet it is just the situation Prof Edwards and Dr Cambridge found themselves in a decade ago. CFS sufferers must be hoping medical researchers are not about to repeat history by rejecting these intriguing findings out of hand – despite not having any better ideas themselves.” Against the odds, Jonathan Edwards and his colleagues turned the whole field of RA around through pure persistence. He definitely knows that paradigm shifts do happen in medicine. No stranger from controversy, maybe Edwards gets that old feeling back reading the PLoS ONE study from Mella and Fluge, tempting him to have his say in public. Maybe he knows that the Norwegian scientists are in for a hell of a ride. And maybe, just maybe, he wants them to win too. After the article was written Jørgen Jelstad also conducted a short Q&A session with Dr Fluge – Q & A with Olav Mella and Øystein Fluge 1. What is your current hypothesis for why Rituximab works? Our working hypothesis has been, and still is, that ME/CFS might be an autoimmune disease. Maybe it should at this stage be called a disease of immune dysregulation, and inflammation probably also is a factor. So right now our hypothesis is that ME/CFS might be an autoimmune/autoinflammatory condition. 2. Why do most of the responding patients relapse after experiencing several months of improvement? We do not yet know. But we see that with maintenance treatment some patients have a continuous major improvement lasting for months, even years. Another interesting observation is that some patients have a worsening of ME-symptoms right after the www.investinme.org Page 17 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) infusion, which we must remember consists of a monoclonal antibody – an immunoglobulin. This worsening may last from a few days to some weeks. This reaction may tell us something important and be a clue to pathogenesis. There are no consistent correlations between B-cell numbers and relapses, but this is also the case with Rituximab treatment in RA. Another important thing to understand is why there is a latency period before response, where some patients get a response as early as six weeks, while others get the response only after 6-8 months. 3. What kind of follow-up studies are already underway? We have one open label maintenance study on 28 patients. We promised the patients in the placebo group in the first RCT to be offered treatment if the study turned out positive, which it did, so this is an ethical responsibility. But most importantly, we want more experience and dose-response data before doing a larger RCT. If we get adequate funding, we plan to initiate a multicenter RCT in more than 100 ME/CFS patients. We also have one pilot study on six severely disabled patients, four of them mostly bedridden. And recently the ethical committee in Norway approved a pilot study trying a TNF-alfa inhibitor (Etanercept) on non-responders to Rituximab. And finally we are doing different studies on pathogenesis with a goal of finding biomarkers. In our biobank we have a lot of samples collected at several time points during our Rituximab studies, and we are attempting to unravel the mechanism behind the disease. From what we see in our studies, we feel confident that at least in a subgroup of patients the pathogenesis at some level will involve B-cells. 4. When do you expect to publish more results? We hope to publish a few articles after this summer. We have done a lot of experiments on immune measurements, autoantibodies, gene expression etc. Some of the data are negative findings, but it is important that the negative data also get published to get the total view of what is happening. 5. Are you encouraged so far by what you see in the follow-up studies? Yes, so far we have not discovered anything that undermines our previous findings. However, the disease probably is even more complex than we originally thought. Invest in ME (Charity Nr. 1114035) Jorgen Jelstad’s book – De Bortgjemte – is currently only available in Norwegian. The charity hopes we can further influence the publishers to have the book translated into English as we feel it is currently the best book available to describe the political situation and the scientific situation surrounding ME. ME STORY I started to feel unwell about the age of 11. I started to feel fatigue, headaches aching muscles, felt like I had the flu all the time and my speech went funny. I went to the doctors and ended up in hospital. They didn’t know what to do with me so I went to another hospital. That’s when my nightmare began. I felt really ill at that time and a sister said it was all in my mind. I was left on a hard plastic chair all day. I was struggling to feed myself and my weight went down to 3 and a half stone because of the neglect that I had at that hospital. I was close to death so my family took me out of that hospital. It saved my life. The disgusting treatment that I had at that hospital I could go on. - Shelley www.investinme.org Page 18 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) Current status of ME in Sweden The Swedish ME/CFS Association, RME, was founded in 1993 and restarted in 2002 in order to support and spread information and knowledge about ME/CFS to patients and their families, to doctors, researchers, the public and authorities. Today RME is a member of EMEA and has 944 members, 4 local associations and 12 supporting groups. The National Board of Health and Welfare in Sweden has registered ME/CFS as a neurological disease – following the WHO ICD Classification. Despite that, very few patients get the diagnosis ME/CFS in our country. In 2011, a book with the title “Fatigue is the wrong word” was written by 19 members, who all wrote their own medical history and described their present life. The book was completed with facts by doctors with ME/CFS experience. The book is today printed in 2100 copies. Of those we have sent more than 200 free copies to researchers, specialists, doctors, medical associations, medical advisers at The Swedish Social Insurance Agency and politicians all over the country. A translation from the book is found at the EMEA website. There have been initiatives taken for establishing biomedical treatment for ME/CFS in some county councils in Sweden. Last year a ME/CFS-clinic in the county council of Stockholm/Danderyd was founded by Dr Per Julin. Per and his colleague Indre Bileviciute Ljungar will present their experiences at a seminar at Region Skane in autumn. In Ostergotland a ME/CFS-clinic, Gotahalsan, has been established by the neurologist Anders Osterberg. In Molndal near Gothenburg, the Gottfries Clinic accepts patients suffering from ME/CFS or fibromyalgia. Several county councils are interested in starting care units. A Swedish network of researchers for biomedical ME/CFS research has been founded by among Invest in ME (Charity Nr. 1114035) others Professor Emeritus Jonas Blomberg, Clinical Virology, Uppsala University, Professor Jonas Bergquist, Analytical Chemistry, Uppsala University, Dr Per Julin, Danderyd Hospital and Post Doc Yenan Bryceson, Center for Infectious Medicine, Karolinska Institutet. Professor Jonas Bergquist published in 2011, with a group of researchers, a study about protein profiles in the cerebrospinal fluid in ME/CFS patients. This study received much attention. Riksföreningen för ME-patienter, Sweden http://www.rme.nu/ The European ME Alliance (EMEA www.eurome.org) is a collaboration of ME support charities and organisations in Europe who intend to provide a common view and the scientific facts regarding the neurological illness myalgic encephalomyelitis (ME/CFS). EMEA are campaigning for funding for biomedical research to provide treatments and cures for ME. The alliance was formed in 2008 by national charities and organisations in Europe. The Alliance now has representatives from Belgium, Denmark, Germany, Holland, Ireland, Italy, Norway, Spain, Sweden, Switzerland and the UK. The alliance has been created with a basic set of principles to provide a correct and consistent view of myalgic encephalomyelitis (ME/CFS) for healthcare organisations, healthcare professionals, government organisations, the media and patients and the public. Our objective is to establish a UK Centre of Excellence for Biomedical Research into ME. We welcome all support. Donations to the Invest in ME Biomedical Research Fund will be used to support the establishment of this facility. Help us by contributing to the Invest in ME Biomedical Research Fund for ME – http://tinyurl.com/ydh6whu www.investinme.org Page 19 of 108

Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM) with a Staphylococcus Vaccine Olof Zachrisson MD, PhD Institute of Neuroscience and Physiology, University of Gothenburg, Sweden Gottfries Clinic, Krokslätts Torg 5 SE 431 37 Mölndal SWEDEN oz@gottfries.se Background The general scientific strategy evolved from a seminal observation made by professor Gottfries in 1958. He then noticed an increasing number of patients in his clinical psychiatric practice presenting a fatigue condition similar to the syndrome that in the 1990ies was named chronic fatigue syndrome or myalgic encephalomyelitis (ME/CFS). The patients continued to have a status indicating ongoing mild infection long after they had recovered from the Asian flu, an influenza which was epidemic in Sweden in 1958. This observation led to attempts of treatment with vaccine compounds in order to modulate/stimulate the immune system and thereby improve the status of the patients. Clinical benefit was noted in some individuals after repeated treatment with a staphylococcus toxoid vaccine (Gottfries, 1999). Based on this uncontrolled experience, the vaccine treatment was reuptake in the 1990ies, when the diagnoses of ME/CFS and also the Fibromyalgia syndrome (FM) were established within medicine. The vaccine used in the clinical research, Staphypan®, contained a mixture of staphylococcal vaccine and toxoid. It was manufactured by the Swiss Serum and Vaccine Institute Berne until 2005 and used for the prophylaxis of staphylococcal infections, especially before surgery. Controlled clinical studies The first controlled double blind study was conducted in 1997 and included 28 patients (Andersson et al. 1998). The study drug, Staphypan or coloured sterile water as placebo, was administered subcutaneously on weekly basis. The start dose of 0.1 ml was increased by 0.1 ml every week up to 1.0 ml. Endpoint ratings were performed at week 12. Observer-based rating scales (CPRS-15) were used for the primary assessment of outcome. Significant beneficial Invest in ME (Charity Nr. 1114035) effect was seen in favour of active treatment and the drop-out rate was low. Encouraged by the positive results a second extended trial was performed. This was a 6-month randomised controlled study, including 100 women fulfilling the criteria of combined ME/CFS and FM (Zachrisson et al. 2002). The study drug (Staphypan/coloured sterile water) was administered subcutaneously in doses of 0.1 to 1.0 ml at weekly intervals for eight weeks and then in booster doses of 1.0 ml every 4th week. End-point ratings were performed at week 26. Main outcome measures were proportion of responders on global ratings and proportion of “good responders”, defined as patients with a symptom reduction of ≥50% from baseline in ratings on an observer-based rating scale (CPRS15). Blind ratings were repeated at week 32 for evaluation of withdrawal effects. The treatment was well tolerated (drop-out rate 8%) and 65% responded to active treatment. The placebo response was 18% (p < 0.001). Patients on active treatment were significantly more often “good responders”. At withdrawal, deterioration was seen in the Staphypan group only, indicating the need of long-term treatment in order to maintain the effect. The majority of participant wanted to restart the treatment after the study. Working mechanism The clinical positive response to vaccine treatment was found related to the response of the patient’s immune system. In corporation with Professor Roland Möllby, the Karolinska Institute, the antibody status during treatment was evaluated (Zachrisson et al. 2004). In 14 patients receiving active vaccine treatment and 14 receiving placebo, the serological antibody status against extracellular toxins/enzymes, cellwall components, and enterotoxins was evaluated at baseline and after six months of treatment. www.investinme.org Page 20 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) Significant changes were recorded in the group on active treatment while no change was seen in the controls. Treatment led to an increase in the capacity of serum to neutralize alpha-toxin (p< 0.001) and led to a significant increase in serum IgG to alpha-toxin (p< 0.01) and lipase (p< 0.01). Furthermore, the increase in the serum parameters paralleled the improvement in clinical out-come. Thus, the greater the serological response, the greater was the clinical effect. This relationship could indicate a working mechanism of the vaccine. Long term treatment In long-term studies the safety of the treatment were found good and the adherence to the treatment were impressive (Gottfries et al. 2006). In one followup study, 160 patients with FM and ME/CFS were continuously observed during another year of treatment. The patients had previously participated in controlled vaccine studies and were continuing on vaccine treatment with 1 ml Staphypan every 3rd to 4th week. At inclusion the mean treatment period with Staphypan was 22±10 months. The mean age of the patients was 53±11 years. The rating scale CPRS-15, handled by medically educated and trained staff, was used to evaluate efficacy. Ratings at inclusion showed improvement compared to start of treatment. Repeated ratings during the one year follow-up period showed further improvement. The total mean rating CPRS15 score was reduced by more than 50 % compared to start of treatment. Five items (Concentration difficulties, Failing memory, Irritability, Sadness and Autonomic disturbances) had mean levels below one (range of scores 0-6) at the time of the last rating, indicating that these symptoms on a group level were within the range of normality. In a somewhat younger subgroup of 97 patients (age 48±10 years) with a mean treatment time of 50.4±17.8 months (variance 30Invest in ME (Charity Nr. 1114035) 120), nine CPRS-15 core items were rated before as well as during treatment with the vaccine. They were analyzed with Principal Components Analysis (PCA) and a model was created using the clinical rating data at patient inclusion together with the assumed healthy profiles (Gottfries et al. 2009). The patient profiles after start of treatment were predicted by the PCA model and overlaid for comparison. The predicted values show loadings (black triangles in Figure), which have changed clearly in direction towards the normal group indicating improvement. The data show that this subgroup of middle-aged women after four to five years’ treatment still has an impressive beneficial effect. FIGURE Scatter plot indicating PCA scores for the model. Red boxes indicate assumed healthy objects. Blue points for untreated patients as rated at inclusion.  Black triangles for treated patients. Each patient was re-assessed with last rating 50.4±17.8 months after study start (n=97) and his or her individual ratings predicted by the PCA model. The distribution after treatment with vaccine (black triangles) showed a shift of patient scores towards symptom relief. Adverse events during long-term treatment Safety was evaluated continuously. Adverse events were few and the adherence to the www.investinme.org Page 21 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) treatment was surprisingly fine. During the observation period of one year on 160 patients, 22 of them (14%) withdrew from treatment. Very few side effects were seen in relation to the treatment and no severe complications were recorded. According to the manufacturer, the vaccine had been used in more than 10 million dosages over the years, and no severe complications have been reported. Our clinical impression is that a majority of patients with FM/CFS are prone to infections. In many cases patients also have an irritable bowel. The clinical impression was that the frequency of infections and symptoms of irritable bowel were reduced during long-term treatment. Our patients found the increased resistance to infections of great value. In 2005 Staphypan was withdrawn from the market. Staphypan was an old product where the manufacturing process had to be developed to cope with modern GMP standards in EU and US. We have tried to find a vaccine that could replace Staphypan but there is no such product at least in the western world. We would assume that a vaccine treatment of the kind presented here eventually due to a super-antigen effect can be of use for patients with ME/CFS, FM and possibly other immune deficiency syndromes. Conclusions ME/CFS is a disorder of unknown aetiology. In controlled investigations it was shown that an immunotherapy, as conveyed by repeated injections of a staphylococcus vaccine preparation, Staphypan, was of clinical benefit for a significant number of patients. The effect was seen at the time when the treatment dose of Staphypan has been increased to 1 ml, the maximum dose used in our studies. The treatment was continued longterm with booster injections of 1 ml vaccine every 3rd to 4th week in order to maintain the effect. The treatment was found safe and the adherence to the treatment was impressive. REFERENCES Andersson M, Bagby JR, Dyrehag LE, Gottfries CG (1998) Effects of staphylococcus toxoid vaccine on pain and fatigue in patients with fibromyalgia/chronic fatigue syndrome. European Journal of Pain 2, 133-142 Barregard L, Rekic D, Horvat M, Elmberg L, Lundh T, Zachrisson O (2010) Toxicokinetics of mercury Invest in ME (Charity Nr. 1114035) after long-term repeated exposure to thimerosalcontaining vaccine. Toxicol Sci. 120, 499-506 Gottfries CG (1999) Treatment of fibromyalgia and chronic fatigue syndrome with staphylococcus toxoid. In: The clinical and scientific basis of chronic fatigue syndrome: “From myth towards management”. Proceedings of the International meeting in Sydney, Australia, 11-12 February, 1998, pages 69-78 Gottfries CG, Häger O, Regland B, Zachrisson O (2006) Long term treatment with a staphylococcus toxoid vaccine in patients with fibromyalgia and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 13, 31-43 Gottfries CG, Häger O, Gottfries J, Zachrisson O (2009) Immunotherapy of fibromyalgia and chronic fatigue syndrome by a staphylococcus toxoid. Vaccine Bulletin of the IACFS/ME. 17(4 ),111 Gottfries CG, Matousek M, Zachrisson O (2009) Immunologic disturbances can explain chronic fatigue syndrome. Biological findings point towards somatogenesis. Lakartidningen. 106(36):2209-2210, 2212-2215. Review. Swedish. No abstract available Zachrisson O, Regland B, Jahreskog M, Jonsson M, Kron M, Gottfries CG (2002) Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome – a randomised controlled trial. European Journal of Pain 6, 455 – 466 Zachrisson O, Regland B, Jahreskog M, Kron M, Gottfries CG (2002) A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J Psychosom Res. 52(6), 501-509 Zachrisson O (2002) Fibromyalgia/Chronic Fatigue Syndrome. Aspects on biology, treatment and symptom evaluation. Doctoral thesis, Göteborg University (ISBN 91-628-5386-4) Zachrisson O, Colque-Navarro P, Gottfries CG, Regland B, Möllby R (2004) Immune modulation with a staphylococcus preparation in fibromyalgia/chronic fatigue syndrome: antibody levels are related to clinical improvement. European Journal of Clinical Microbiology & Infectious Diseases 23, 98-105 www.investinme.org Page 22 of 108 Transcranial sonography in the diagnosis, followup and treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Marco Ruggiero¹, Maria G., Fiore¹*, Stefano Magherini², Silvia Esposito1, Gabriele Morucci², Massimo Gulisano² and Stefania Pacini² ¹Department of Experimental Pathology and Oncology, University of Firenze. Viale Morgagni 50, 50134 Firenze, Italy. 2Department of Anatomy, Histology and Forensic Medicine, University of Firenze. Viale Morgagni 85, 50134 Firenze, Italy. Author for correspondence: Prof. Marco Ruggiero, MD, PhD Department of Experimental Pathology and Oncology Viale Morgagni 50, 50134 Firenze, Italy E-mail: marco.ruggiero@unifi.it Keywords: Transcranial sonography, Chronic Fatigue Syndrome, Myalgic Encephalomyelitis. Acknowledgements: This study was funded by a grant from the Progetto di Ricerca di Interesse Nazionale (PRIN) 2009 to M.R. and S.P. Abstract We used a modified transcranial sonography technique to study the cortex of the temporal lobe, a brain region involved in the processing of functions that are often compromised in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. We studied the meninges, the subarachnoidal space and the cortex. The spatial resolution and the ability to visualize structures of 200-300 µm size, led us to hypothesize that the linear structures parallel to the subarachnoidal space could be referred to the neuronal layers of the cortex. In real-time mode, we could observe pulsation of the meninges and the cortex synchronous with the heart beat and independent of blood flow. This pulsation was more evident at the level of the meninges, but it was also appreciable at the level of the layers of the cortex and it was not accompanied by any type of flow. In addition to these findings, we observed that the subject undergoing the procedure experienced a series of changes that might prove potentially useful in the treatment of ME/CFS. In particular, we observed a decrease of tachycardia accompanied by an increase in systolic blood pressure and by a significant increase in muscle strength measured by the degree of muscle fibre shortening at the level of the biceps brachii. These findings, together with the low cost and simplicity of the procedure, suggest that modified transcranial sonography has a significant potential in the study and treatment of ME/CFS. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 23 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) Introduction Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) designates a clinical condition characterized by a complex simptomatology that includes, but is not limited to, long-lasting disabling fatigue. According to the most recent classification, it is considered a neurological disease in the World Health Organization’s International Classification of Diseases (ICD G93.3) and it is characterized by widespread inflammation and multisystemic neuropathology (1). As of today, the aetiology of ME/CFS is unknown and, just like in any syndrome, it is quite likely that there may be multiple causes leading to a shared clinical picture. Several events may act as triggers, from external environmental or microbiological triggers, such as chemical exposure or infections, to psychological and social factors that may be critical in perpetuating the symptoms (2). It is worth noting that from the point of view of evolution of the human brain, ME/CFS may be defined as a “phylogenic disease” (3-7), according to principle of “integrated phylogeny” of the primate brain (8), because of its possible relation to evolution. For patients as well as for health care professionals, the issue of treatment of ME/CFS is a truly dramatic and controversial one. In fact, proposed treatments are as diverse as cognitive behavioral interventions (9), coiling dragon needling and moving cupping on back (10), treatment with Lactobacillus acidophilus (11), or with antipsychotics (12), just to name a few of the most recent studies. Oddly enough, among the variety of proposed treatments for ME/CFS, the application of transcranial ultrasounds by means of a common ultrasound imaging machine has not been evaluated so far. A search of the literature revealed that transcranial sonography had been used as a diagnostic tool only in one study describing cerebral and systemic hemodynamic changes during upright tilt in CFS (13). However, in that study, the Authors were focussed on observation of the middle cerebral artery using transcranial doppler monitoring, and did not use probes and techniques able to study in detail the cerebral cortex with particular reference to the gray matter of the temporal lobe. Based on our background in clinical radiology and anatomy, we were interested in studying the cerebral cortex of Invest in ME (Charity Nr. 1114035) the temporal lobe because of the well known involvement of the temporal lobe in the processing of functions, such as semantics and memory, that are often compromised in ME/CFS patients (14). To this end, we modified the conventional procedure for transcranial sonography and we used a linear probe that is normally used for muscle-skeletal ultrasound imaging. To our surprise, we observed that not only such a procedure allowed detailed visualization of the cortex of the temporal lobe, a finding potentially important for the diagnosis and follow-up of ME/CFS patients, but also affected brain function in such a way that it could be proposed as a safe and easy treatment for a variety of diseases including ME/CFS. Materials and Methods The ultrasounds used for imaging, also known as sub-thermal ultrasounds, are is considered safe and have been used for foetal imaging in utero, and virtually every part of the body, including brains of newborn babies through fontanelles. For transcranial sonography we used an Esaote MyLabFive ultrasound imaging machine approved for many applications including cephalic (brain) imaging. We used the default settings for adult transcranial imaging, but instead of a transcranial probe, we used a conventional linear probe for muscle-skeletal examination and we selected 7.5 MHz frequency. Acoustic power was set to 1.0. The length of the probe was about 4 cm, i.e. much less than the size of the temporal cortex that we examined that is 7-8 cm. The procedure was performed at the Laboratory for Exercise Sciences Applied to Medicine of the University of Firenze (LSMAM, Director, Prof. M. Gulisano). The volunteer healthy subject, a certified clinical radiologist (M.R.), sat in front of the imaging machine in the position he normally uses to perform an examination, and positioned the probe on his right temporal region in correspondence of the acoustic window of the temporal squama (Fig. 1). An improvised support to his right arm was provided to ensure stability. In this position, the subject was able to look at his own brain while performing the examination. Heart rate was recorded 10 min prior to the transcranial sonography procedure, immediately before, during the procedure at intervals of 30 s, at the end of the procedure that lasted 10 min, and 10 min after the end of the procedure. Systolic and www.investinme.org Page 24 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) diastolic blood pressure were recorded 10 min prior to the procedure, immediately before, at the end of the procedure, and 10 min after the end of the procedure. Thickness of the biceps brachii was measured with the same probe, but this time with the conventional setting for muscle-skeletal examination. Results During 10 min transcranial sonography, no side effect was reported. The parameters adopted for visualization of the temporal cortex allowed to distinguish the meninges, the subarachnoidal space and the cortex (Fig. 2). The meninges appeared as a well organized array of layers of about 5 mm thickness. The thickness of the cortex (3.8 mm) led us to hypothesize that we were observing the temporal areas designated as TG and TE, i.e. those areas involved in the control of eye movements and balance in standing position (area TE), social behaviour, mood and decision making (area TG). It is worth remembering that most of these functions are altered to various degrees in ME/CFS patients’ symptoms (2). The spatial resolution and the ability to visualize structures of 200-300 µm size, led us to hypothesize that the linear structures (alternate gray-white stripes) parallel to the sub-arachnoidal space could be referred to the well known neuronal layers of the cortex (15). Considering the role of neuronal layer architecture alterations in neurodegenerative diseases (16), detailed study of these layers in ME/CFS might prove instrumental in diagnosis, prognosis and follow-up. With this type of setting and using Doppler technique, we could also observe arterial vascularisation of the meninges and pulsating arteries of less that one mm diameter could be easily visualized (Fig. 3). During transcranial sonography, we could also observe a peculiar pulsation of the meninges and of the cortex that was synchronous with the heart beat, but was not accompanied by any type of flow. This pulsation was more evident at the level of the meninges, but was also appreciable at the level of the layers of the cortex. A similar type of pulsation was described in 1987 by Klose et al. who used Magnetic Resonance Imaging to study the oscillation of the cerebrospinal fluid within the cardiac cycle (17). We have no evidence, as yet, that the observed pattern of brain pulsation may be altered in ME/CFS patients nor that this observation may contribute to diagnosis or followup. However, the easy reproducibility of the Invest in ME (Charity Nr. 1114035) procedure as well as the absence of any discomfort, render this type of approach worth of further investigation. In fact, it was proposed that alteration of the so-called cranial rhythmic impulse might have a role in the pathogenesis of ME/CFS (18), and spinal fluid abnormalities are common in ME/CFS patients (19). Although the primary goal of our research was to set up a technique to study brain morphology and function in ME/CFS patients, while performing transcranial sonography with the indicated setting, we noticed that some notable changes happened in the subject who was at the same time the operator of the echo machine and the object of observation. In fact, an ill-defined feeling of strength and well-being that had been reported during the first measures prompted us to further investigate whether the ultrasounds used for imaging could somehow affect brain function. The use of transcranial ultrasounds in both military and civilian settings to stimulate the central nervous system has been recently proposed (http://www.darpa.mil/Opportunities/Universities /Young_Faculty_Award_Recipients.aspx) (20), and a preliminary study performed at the University of Arizona demonstrated that transcranial ultrasound stimulation improved mood and increased heart rate, systolic and diastolic pressure and decreased oxygen saturation (http://www.quantumconsciousness.org/docume nts/ATUS201101634A.pdf ). In the study reported above, however, transcranial ultrasound application was performed by an operator and the subject being investigated did not look at his own brain while performing the procedure. This difference might be significant because of the ensuing bio-feedback, an effect that has proven effective in a variety of conditions from neurological disorders to cancer (21, 22). In our study, we observed that heart rate significantly decreased from 81 beats per minute (bpm) at the beginning of the procedure to 71 bpm at the end of the procedure, to 70 bpm 10 min after the end of the procedure. Systolic blood pressure increased from 115 mm/Hg (10 min before the procedure) to 125 mm/Hg (10 min after the end of the procedure). Unlike the study quoted above, diastolic pressure did not change and remained constant at 75 mm/Hg before and after the procedure. It is well assessed that cardiovascular symptoms and hypotension are www.investinme.org Page 25 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) common in ME/CFS patients (23), and it has been suggested that hypotension associated with orthostatic stress may impair neurocognitive functioning in ME/CFS patients with postural tachycardia syndrome (24). Therefore, our results as well as those presented by Hameroff et al. (http://www.quantumconsciousness.org/docume nts/ATUS201101634A.pdf) may lead to interventional applications of transcranial sonography in the treatment of orthostatic intolerance, one of the major symptoms of ME/CFS. The observed increase in systolic blood pressure in the absence of a concomitant increase in heart rate or diastolic pressure, is of particular significance for ME/CFS, and it can be interpreted as if transcranial sonography was associated with increased cardiac output; in particular, as if it increased the stroke volume, an index that is frequently decreased in ME/CFS patients and is associated with the most common symptoms reported in ME/CFS, i.e. shortness of breath, dyspnea on effort, rapid heartbeat, chest pain, fainting, orthostatic dizziness and coldness of feet (23). The observed decrease in heart rate might also prove useful in those ME/CFS where tachycardia is a symptom associated with neurocognitive defects (25). In order to determine the anatomical correlate of the subjectively perceived increase in muscle strength, we measured by ultrasonography the thickness of the biceps brachii in relaxation and maximal contraction, before and after transcranial sonography (Fig. 4).Ten min before transcranial sonography, the thickness of the biceps increased from 24.9 mm (Fig. 4, panel A) to 38.3 mm during maximal contraction (Fig. 4, panel B). Ten min after the end of the procedure, the thickness of the biceps increased from 24.9 mm (Fig. 4, panel C) to 43.2 mm (Fig. 4, panel B). The increase in thickness was accompanied by a concomitant increase in the angle between the muscle fibres and the muscle aponeurosis. These results demonstrate that the subjectively perceived increase in muscle strength was indeed associated with a measurable increase in the capacity of the muscle to contract with significant increase in muscle fibre shortening. Discussion The results presented in this study raise the possibility of using transcranial sonography as a tool for the diagnosis, follow-up and treatment of ME/CFS patients. In recent years the cost of ultrasound imaging machines is significantly decreased and a good quality apparatus is now sold (in the year 2012) for about 20.000,00 Euros. In the hands of properly trained health care professionals the procedure of transcranial sonography described here can be used for the study of brain pulsations and/or rhythmic impulses and for the study of vascularisation of the meninges. Furthermore, considering that significant neuroanatomical changes occur in ME/CFS, and that these changes are consistent with impaired memory (26), transcranial sonography may prove a simple and inexpensive tool to assess these changes and monitor progression of the disease as well as improvements associated with treatments. The inherent safety of the technique as well as the absence of discomfort make this procedure quite acceptable by patients and this characteristics may prompt extensive studies on a significant number of patients. In addition to its use a tool contributing to diagnosis and follow-up, our results suggest that transcranial sonography may also prove useful in controlling some of the most disturbing symptoms of ME/CFS, i.e. chronic pain and mood alterations as demonstrated by Hameroff et al. ((http://www.quantumconsciousness.org/docume nts/ATUS201101634A.pdf), hypotension, tachycardia and muscle weakness. Figure legends Figure 1. The operator (M.R.) applying the probe to his right temporal region. Sitting in front of the ultrasound imaging machine, the operator is able Invest in ME (Charity Nr. 1114035) www.investinme.org Page 26 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) to observe his own brain in real time. In this way it is possible to observe brain pulsations as well as blood flow through meningeal arteries. We hypothesize that direct observation of the brain triggers a bio-feedback effect. Figure 2. Two dimension image of the temporal region. The skin layers and the temporal muscle are clearly visible. The temporal squama appears as an hyperreflecting (white) irregular line of about 1.4 mm thickness. The meninges appear as a well organized array of layers of about 5 mm thickness. The sub-arachnoidal space (white arrow) is identified by two hyper-reflecting (white) lines sandwiching an hypo-reflecting (black) space containing liquor. The size of the sub-arachnoidal space was about 0.6 mm. The neuronal layers of the temporal cortex (3.8 mm thickness) appear as alternate layers of hyper- and hypo-reflecting structures. The thickness of the cortex corresponds to that of the TE and TG areas. Figure 4. Two dimension image of the left biceps brachii. Also in this case the operator applied the probe to his own biceps. A. Thickness of the relaxed biceps 10 min before the procedure; 24.9 mm. B. Thickness of the contracted biceps 10 min before the procedure; 38.3 mm. C. Thickness of the relaxed biceps 10 min after the procedure; 24.9 mm. Please notice; this image is not the same shown in panel A, as clearly visible looking at the orientation of the fibres. Nevertheless, the measurement is identical, thus demonstrating the reproducibility of the procedure. D. Thickness of the contracted biceps 10 min after the procedure; 43.2 mm. References 1. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. 2011; 270: 327-38. 2. Holgate ST, Komaroff AL, Mangan D et al. Chronic fatigue syndrome: understanding a complex illness. Nature Reviews Neuroscience. 2011;12: 539-44. 3. Hughlings Jackson, J. (1884). In: J. Taylor (Ed.), Selected Writings of John Hughlings Jackson. Evolution and Dissolution of the Nervous System. Vol. 2, pp. 3-118. Basic Books, New York. Figure 3. Pulsating arterial blood vessels in the meninges. 4. Roofe, PG and Matzke, HA. (1968). In: J. Minkler (Ed.), Pathology of the Nervous System. Introduction to the study of evolution: its relationship to neuropathology. Vol. 1, pp.14-22. Blakiston, New York. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 27 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) 5. Sarnat, HB and Netsky, MG (1981). Evolution of the Nervous System, 2 edn. Oxford University Press, Oxford. 6. Rapoport, SI. Brain evolution and Alzheimer's disease. Revue Neurologique. 1988;144:79-90. 7. Rapoport, SI. (1989). Hypothesis: Alzheimer's disease is a phylogenic disease. Medical Hypothesis. 1989; 29:147-150. 8. Rapoport, SI. Integrated phylogeny of the primate brain, with special references to humans and their diseases. Brain Research Reviews. 1990; 15: 267-294. 9. Wiborg JF, Knoop H, Frank LE. Towards an evidence-based treatment model for cognitive behavioral interventions focusing on chronic fatigue syndrome. Journal of Psychosomatic Research. 2012; 72: 399-404. 10. Xu W, Zhou RH, Li L. Observation on therapeutic effect of chronic fatigue syndrome treated with coiling dragon needling and moving cupping on back. Zhongguo Zhen Jiu (Chinese Acupuncture and Moxibustion). 2012; 32: 205-8. 11. Sullivan A, Nord CE, Evengárd B. Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutrition Journal. 2009; 8: 4. 12. Calandre EP, Rico-Villademoros F. The role of antipsychotics in the management of fibromyalgia. CNS Drugs. 2012; 26: 135-53. 13. Razumovsky AY, DeBusk K, Calkins H, et al. Cerebral and systemic hemodynamics changes during upright tilt in chronic fatigue syndrome. Neuroimaging. 2003; 13: 57-67. 14. Bassi N, Amital D, Amital H et al. Chronic fatigue syndrome: characteristics and possible causes for its pathogenesis. The Israel Medical Association Journal. 2008; 10: 79-82. 15. Molnár Z. Evolution of cerebral cortical development. Brain, Behaviour and Evolution. 2011; 78: 94-107. 16. Romito-DiGiacomo RR, Menegay H, Cicero SA et al. Effects of Alzheimer’s disease on different cortical layers: the role of intrinsic differences in Abeta susceptibility. The Journal of Neuroscience. 2007; 27: 8496-504. 17. Klose U, Requardt H, Schroth G, et al. MR tomographic demonstration of liquor pulsation. RöFo : Fortschritte auf dem Gebiete der Röntgenstrahlen und der Nuklearmedizin. 1987; 147: 313-9. Invest in ME (Charity Nr. 1114035) 18. Perrin RN. Lymphatic drainage of the neuraxis in chronic fatigue syndrome: a hypothetical model for the cranial rhythmic impulse. The Journal of the American Osteopathic Association. 2007; 107: 218-24. 19. Natelson BH, Weaver SA, Tseng CL, et al. Spinal fluid abnormalities in patients with chronic fatigue syndrome. Clinical and Diagnostic Laboratory Immunology. 2005; 12: 52-5. 20. Tufail Y, Yoshihiro A, Pati S, et al. Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound. Nature Protocols. 2011; 6: 1453-70. 21. Lantz DL, Sterman MB. Neuropsychological assessment of subjects with uncontrolled epilepsy: effects of EEG feedback training. Epilepsia. 1988; 29: 163-71. 22. Cohen M. A model of group cognitive behavioral intervention combined with biofeedback in oncology settings. Social Work in Health Care. 2010; 49: 149-64. 23. Miwa K, Fujita M. Cardiovascular dysfunction with low cardiac output due to a small heart in patients with chronic fatigue syndrome. Internal Medicine. 2009; 48: 1849-54. 24. Ocon AJ, Messer ZR, Medow MS, et al. Increasing orthostatic stress impairs neuro cognitive functioning in chronic fatigue syndrome with postural tachicardia syndrome. Clinical Science (London). 2012; 122: 227-38. 25. Stewart JM, Medow MS, Messer ZR, et al. Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome. American Journal of Physiology. Heart and Circulatory Physiology. 2012; 302: H1185-94. 26. Puri BK, Jakeman PM, Agour M, et al. Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3-T MRI study. British Journal of Radiology. 2011; Nov 29. [Epub ahead of print] ME COMMENT “Respondents found the least helpful and most harmful interventions were Graded Exercise Therapy and Cognitive Behavioural Therapy” Norfolk and Suffolk ME Patient Survey 2009 http://www.norfolkandsuffolk.me.uk/surveylink. html www.investinme.org Page 28 of 108 THE IMMUNOLOGICAL BASIS OF ME/CFS: what is already known? A compilation of documented immune system abnormalities in ME/CFS from 1983-2011 by Margaret Williams March 2012 Introduction There can be few practising health care professionals in the UK National Health Service who are unaware of the contentious battleground in which the disorder myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains mired even though it has been formally classified as a neurological disorder by the World Health Organisation since 1969, currently at ICD-10 G93.3. Essentially, there are two camps, one consisting of internationally renowned medical scientists and clinicians who acknowledge that ME/CFS is a multi-system neuro-immune disorder with protean symptomatology and who understand the extensive and compelling biomedical evidencebase that underpins the demonstrated organic pathophysiology. Given the extent of this international peerreviewed published evidence, one would have thought that no competent medical scientist, clinician or medical journal could credibly deny or reject the evidence that ME/CFS is a disorder of disrupted immune function, yet this continues to be the case. The second camp, a small group of UK psychiatrists and their adherents known as the “Wessely School” (Hansard: Lords: 9th December 1998:1013) choose to ignore this body of scientific evidence and they continue to subsume ME/CFS within their own construct of “CFS/ME” (which they insist is the same as “ME/CFS” or “ME” or “CFS” alone) and is defined by them as “medically unexplained chronic fatigue”. They assert that it is a functional (behavioural) disorder resulting from wrong attributions so is curable by “cognitive restructuring” (a form of brain washing intended to convince patients that they do not suffer from a physical disease but from “aberrant illness beliefs”), together with graded exercise to reverse their alleged “deconditioning”. The Wessely School believe that the more symptoms of which a patient complains, the greater the confirmation Invest in ME (Charity Nr. 1114035) that s/he is suffering from a psychogenic disorder and that the distressing symptoms are merely “hypervigilance to normal bodily sensations” and to “the perception of visceral phenomena” (The Cognitive Behavioural Management of the Postviral Fatigue Syndrome; S Wessely, et al; In: PostViral Fatigue Syndrome, ed. Rachel Jenkins & James Mowbray, John Wiley & Sons, 1991, page 311; Professor Peter White: Presentation to the British Neuropsychiatry Association, St Anne’s College, Oxford, December 2008). As key members of the Wessely School are advisors to Departments and agencies of State, it is their term and interpretation that is used by those agencies, as the Wessely School’s influence appears to be without limit when it comes to this disorder. The Wessely School’s intention is known to be to “eradicate” ME by dropping the “ME” from “CFS/ME” when expedient (Pfizer/Invicta: 4-5 /LINC UP, 15th April 1992; BMJ 2003:326:595-597) and then to reclassify “CFS” as a “functional” or behavioural disorder in the forthcoming revisions of both the WHO’s International Classification of Diseases (ICD–11) and the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM-5). Most of the Wessely School members also work for the permanent health insurance industry and have demonstrable financial interests in claiming “CFS/ME” as a functional disorder, since functional disorders are excluded from benefit payment. This unacceptable situation has for some years caused grave parliamentary concern (http://erythos.com/gibsonenquiry/Docs/ME_Inqu iry_Report.pdf). Notwithstanding, Professor Wessely has just published a paper in the Journal of Neurology, Neurosurgery and Psychiatry in which he appears www.investinme.org Page 29 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) to favour deliberately deceiving patients: “The term ‘functional’ has increasingly come to mean ‘hysterical’…The DSM-V working group (which includes Professor Michael Sharpe from the UK, a prominent member of the Wessely School) proposes to use ‘functional’ as the official diagnostic term for medically unexplained neurological symptoms (currently known as ‘conversion disorder’)….Interviewing the neurologists in a large UK region and then surveying all neurologists in the UK on their use of the term, (the interviews) revealed four dominant uses – ‘not organic’; a physical disability; a brain disorder and a psychiatric problem – as well as considerable ambiguity….The ambiguity was seen as useful when engaging with patients. The survey (found) a majority adhering to a strict interpretation of ‘functional’ to mean only ‘not organic’…. ‘Functional’ can, for example, be used to mean a disturbance of bodily function or it can be used to denote conversion disorder; and by telling a patient they have a ‘functional disorder’ they may encourage them to contemplate the former meaning, without being aware of the latter … There is a divergence between the terms neurologists use medically and with lay people. One advantage of ‘functional’ (allows) neurologists to use the same term to mean one thing to colleagues and another to patients….Its diversity of meaning allows it to be a common term while meaning different things to different people….and thus conceal some of the conflict in a particularly contentious area” (JNNP 2012 Mar;83(3):248-250). Further muddying the waters is the fact that the Wessely School use their own case definition of “CFS” (the “Oxford” criteria: JRSM 1991:84:118121) and they intentionally include within their terms “CFS” or “CFS/ME” those with chronic “fatigue” or on-going tiredness. Indeed, in the notorious £5 million PACE Trial, the Chief Principal Investigator, Professor Peter White (another prominent Wessely School member), stated at section 3.6 of the Trial Identifier: “Subjects will be required to meet operationalised Oxford criteria for CFS. This means six months or more of medically unexplained, severe, disabling fatigue affecting physical and mental functions. We chose these broad criteria in order to enhance generalisability and recruitment”. Deliberately to broaden entry criteria for a clinical trial purporting to be looking at people with ME whilst including Invest in ME (Charity Nr. 1114035) patients who do not have the disorder in question would seem to contravene elementary rules of scientific procedure. The Wessely School have for decades dismissed the need to sub-group “CFS”: the UK Chief Medical Officer’s Working Group 2002 Report (Annex 4: section 3) with which they were involved asserts that sub-grouping “may be considered a matter of semantics and personal philosophy”, but biomedical experts have long called for subgrouping in order to better understand the pathophysiology and to more effectively direct therapeutic interventions, since it has been shown that ME/CFS patients with a particular immune dysfunction do not respond favourably to exercise. Given the extent of the international peerreviewed published evidence that proves these psychiatrists to be wrong, it is reprehensible that the medical journals for which they serve as peerreviewers and the agencies of State to which they are advisors continue to permit their disproven beliefs about ME/CFS to remain unchallenged, with the result that patients with ME/CFS continue to suffer iatrogenic harm. It was eighteen years ago that Professor Paul Levine from the Division of Cancer Aetiology, National Cancer Institute, Bethesda, Maryland, pointed out that: “In the study of a complex illness such as (ME)CFS, the most important aspect is case definition….The spectrum of illnesses associated with a dysregulated immune system now must include (ME)CFS” (Paul H Levine. Clin Inf Dis 1994:18 (Suppl 1):S57-S60). In October 2009, Nancy Klimas, Professor of Medicine and Immunology, (then at the University of Miami) and one of the world’s foremost AIDS and ME/CFS researchers said: “I hope you are not saying that (ME)CFS patients are not as ill as HIV patients. I split my clinical time between the two illnesses, and I can tell you that if I had to choose between the two illnesses I would rather have HIV” (New York Times, 15th October 2009). In the autumn of 2011, commenting on and supporting the Norwegian study by Drs Fluge and Mella that used the anti-cancer drug Rituximab with good effect in ME/CFS patients (PloS ONE www.investinme.org Page 30 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) October 2011:6:10:e26358), Professor Klimas said: “Many clinicians fail to realise the severity of the illness that has been termed ME/CFS. This is a profoundly ill population” (http://bergento.no/the-mecfs-study-by-mellaand-fluge-is-a-key-study-for-our-field ). The situation in the UK is a travesty of both medical science and human rights; things have become so serious and patients with ME/CFS in the UK are so neglected – indeed, they are treated with undisguised contempt and are abused by those working in the very system that is designed to support them -- that discussions are taking place concerning the European Commission on Human Rights, as the Human Rights Act is intended to protect people from neglect and abuse, whatever the source. In summary, reproducible laboratory immunological abnormalities in ME/CFS include very low numbers of NK cells, with decreased cytolytic activity; circulating immune complexes (two-thirds of ME patients have circulating immune complexes, which are insoluble and can remain trapped in blood vessels and tissues); autoantibodies, especially antinuclear and smooth muscle; increased T4:T8 ratio facilitating allergies and hypersensitivities (which always corresponds with disease severity); abnormal SIgA; positive IgG3 (linked to gastrointestinal tract disorders); positive IgM (in his Medical Address at the AGM of the ME Association on 25th April 1987, James Mowbray, Professor of Immunopathology, St Mary’s Hospital Medical School, London, said: “If someone has IgM antibodies they have either been recently infected or they are still infected”); and a particular HLA antigen expression. Given the extent of the Wessely School’s involvement with (and influence over) State policy for ME/CFS, it is notable that, on his own admission, Professor Wessely does not understand immunology. On 10th August 2004 in his evidence to the Lord Lloyd of Berwick Independent Inquiry into Gulf War Illnesses, when discussing immunology and the shift from Th1 to Th2 (as has been shown to occur in ME/CFS also), Wessely said: “Now, please do not ask me what that means because I do not really know. A man has got to know his limitations and my limitations are Invest in ME (Charity Nr. 1114035) immunology” (www.lloydgwii.com/admin/ManagedFiles/2/GWI1008%2000. doc). It must also be recalled that the 1996 Joint Royal Colleges’ Report on CFS (in which Wessely School members were instrumental) specifically recommended that no investigations should be performed to confirm the diagnosis (page 45) and that immunological abnormalities “should not focus attention…towards a search for an ‘organic’ cause” (page 13), or that Wessely advises that “Unhelpful and inaccurate beliefs about CFS include the following…CFS is due to a persistent virus or…immune disorder” (Update, 20th May 1998:1016-1026). Documented immune system abnormalities in ME/CFS There is an extensive and significant published evidence-base of reproducible immune dysfunction in ME/CFS. All are important, as they show that for the last 30 years immunological problems have been known to underpin ME/CFS. (Note that for reasons of space, extracts are sometimes sequentially condensed). It must be remembered that there are equally undeniable evidence-bases on the documented abnormalities observed in the neurological system (central, autonomic and peripheral, including vestibular dysfunction), as well as in the endocrinological, cardiovascular, musculoskeletal, respiratory, gastro-intestinal and ocular systems, and also on the cognitive impairment that has been shown in ME/CFS; on the proven abnormalities that have been repeatedly demonstrated on nuclear medicine imaging, and in the abnormal gene expression in ME/CFS patients (indeed, one senior research scientist has stated that there are more abnormal genes in ME/CFS than in cancer). Given the extracts below, readers may be shocked to learn that in 2012 in the UK, influenced by the Wessely School, immune system investigation of people with ME/CFS remains proscribed by NICE (the National Institute for Health and Clinical Excellence, to whose nominally “advisory” Guidelines clinicians are required to adhere on pain of losing their registration to practise medicine), and the only www.investinme.org Page 31 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) interventions permitted are cognitive restructuring and graded exercise. 1983 “Our research and that of others working in collaboration with us has shown conclusively that post-viral fatigue state, i.e. myalgic encephalomyelitis, has an undisputed organic basis….We were also able to show by looking at receptors on lymphocytes i.e. markers on white blood cells, that there was an increased association of patients with the disease with one particular type of marker. This type of marker is usually found in patients with immunological abnormalities of a particular type. We furthermore were able to demonstrate that there was impaired regulation of the immune system in patients with the disease, both in the acute and chronic stage….we did this serially on several occasions and the abnormality persisted. The abnormality was..of the sort that is found with persistent virus infection. A number of other subtle but definite immunological abnormalities were found and described that…are of the type found in association with disorganised immunoregulation….This meeting at Cambridge showed that using… advanced immunological tests…that patients with myalgic encephalomyelitis had definite proven abnormalities of a specific type” (Dr – later Professor -- Peter Behan; consultant neurologist. Symposium on ME, Cambridge, September 1983). 1985 “Our detailed studies have uncovered a series of subtle yet objective organic abnormalities in these patients. Importantly, nearly all of the patients studied had increased T cell mediated suppression…which showed increased numbers of OKT4 positive (helper-inducer) cells” (Stephen E Straus, G Tosato et al. Ann Int Med 1985:102:716). 1986 “Eighty percent of patients demonstrate clinically significant IgE mediated allergic disease, including food and drug reactions. The data indicate that patients have a high association with hypersensitivity states. Percent positive responsiveness to allergens is consistent with the high degree of allergy observed in these patients” Invest in ME (Charity Nr. 1114035) (George B Olsen, James F Jones et al. J All Clin Immunol 1986:78:308-314). 1986 “We have now studied about 1000 samples from patients with ME….Virtually all of the samples of patients with a good clinical diagnosis of ME have circulating IgM complexes in their blood…In addition 25% of them have detectable IgM antiCoxsackie virus antibodies in the blood. These antibodies are made shortly after exposure and their presence after many years suggests that the exposure and the immunisation is continuing. In addition…it has been possible to show that about 40% of the patients have Coxsackie group specific antigens bound to the antibody in their blood. The majority of patients have high IgG titres of antibody to Coxsackie viruses as well” (Professor James Mowbray’s Report on Research on ME to the ME Association, June 1986). 1986 In his Foreword to Dr Melvin Ramsay’s publication “Post-Viral Fatigue Syndrome – the Saga of Royal Free Disease”, promoted and sold by the ME Association, Dr Peter Behan said: “The disease follows viral infections, and laboratories on both sides of the Atlantic have now provided convincing evidence that these patients do have histological, electrophysiological and immunological abnormalities”. 1987 Irving Salit, Associate Professor of Medicine and Microbiology at the University of Toronto and Head of the Division of Infectious Diseases at Toronto General Hospital, noted: “Findings include mild immunodeficiency, slightly low complement, anti-DNA antibodies and elevated synthetase, which is an interferon-associated enzyme commonly increased in infections. This illness is of major importance because it is so prevalent and because it has such devastating consequences: afflicted patients are frequently unable to work or carry on with usual social activities….Patients tend to tolerate medications very poorly and many have a history of drug allergies. Most patients do not improve on anti-depressants and are usually exquisitely sensitive to the side effects” (Clin Ecol 1987/8:V:3:103-107). www.investinme.org Page 32 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) 1987 US clinicians and researchers who became world leaders in ME/CFS (including Drs Paul Cheney, Daniel Peterson and Anthony Komaroff) noted: “These studies demonstrated that a majority of patients with (ME)CFS have low numbers of NKH1+T3- lymphocytes, a population that represents the great majority of NK cells in normal individuals. (ME)CFS patients had normal numbers of NKH1+T3+ lymphocytes, a population that represents a relatively small fraction of NK cells in normal individuals. When tested for cytotoxicity against a variety of different target cells, patients with (ME)CFS consistently demonstrated low levels of killing. In humans, studies suggest a correlation between low NK activity and serious viral infections in immunocompromised hosts. We have carried out extensive phenotypic and functional characterisation of NK cells in patients with this syndrome (and have) found that the majority had abnormally low numbers of NKH1+ cells. Further characterisation of such cellular subset abnormalities and the resulting alteration in quantitative and qualitative NK cytotoxic function will hopefully improve our understanding of the immunopathogenesis of this illness” (M Caliguri et al. The Journal of Immunology 1987:139:10: 33063313). 1987 At the CFS Society, USA, conference held on 4th-7th November 1987, Dr Alfred Johnson said that 97% of ME/CFS patients have allergies and that allergic patients have high helper (T4) cells and low suppressor (T8) cells, causing over-reactivity. Dr Paul Cheney confirmed that the T4:T8 ratio is elevated in two-thirds of cases, and that this is considered a more reliable marker of the illness than other markers, saying that there are “impressive abnormalities” in mitogen stimulus status (an immune function test) and that symptoms are caused by a hyper-immune response. 1988 In the “News Focus” section of the Nursing Times, Pamela Holmes reported the view that (ME) PVFS is due “to a variety of aberrant immune system responses involving monokines, lymphokines and Invest in ME (Charity Nr. 1114035) abnormal interferon production and breakdown (and) a poorly functioning immune system” (Nursing Times 1988 January 13:84:2:19). 1988 “This article summarises recent studies of the syndrome and emphasises our assessment of one of its more common manifestations, allergy. Many patients report inhalant, food or drug allergies. Allergies are a common feature of patients with the chronic fatigue syndrome. Among the features of this syndrome is a high prevalence of allergy, an allergy that appears to be substantial, both by history and by skin testing” (Stephen E Straus, Janet Dale et al. J Allergy Clin Immunol 1988:81:791-795). 1988 “A variety of immunological abnormalities were detected, including abnormal T4/T8 lymphocyte subset ratios, dysfunction of natural killer cells, abnormal proliferation of B cells and decreased IgG concentrations” (PO Behan, WMH Behan. Crit Rev Neurobiol 1988: 4:2:157-178). 1988 “We report patients (who) had a specific deficiency of IgG1 subclass. The finding of IgG1 subclass deficiency in these patients is novel, as lone deficiency of this subclass is rare and affected patients appear to have common variable hypogammaglobulinaemia. Further scrutiny of cases (of ME/CFS) may reveal a range of subtle immunological abnormalities” (Robert Read, Gavin Spickett et al. Lancet, January 30 1988:241-242). 1988 The ME Association’s magazine “Perspectives” carried an article on “Viruses and ME” by consultant microbiologist Dr Betty Dowsett, who wrote: “Many viruses (including enteroviruses) can enter and alter the function of the immune cells specially designed to destroy them. It is important to recognise that these immune abnormalities are secondary to the virus infection….The mopping up of free viruses in the bloodstream can be counterproductive if excess antibody is produced. The insoluble ‘immune complexes’ that result can be www.investinme.org Page 33 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) trapped in the blood vessels and tissues and…maintain infection in the body….The chemical composition of a virus may mimic that of a normal body component (such as brain or muscle protein) whereupon the immune attack is misdirected against the host while the virus disappears unnoticed. Cardiac and other complications in ME are an example of such an anomaly”. 1988 The June 1988 issue of The CFIDS Chronicle stated: “Eminent physicians have publicly stated that this is primarily a disease of immune dysfunction and this is substantiated by the very significant immune abnormalities found in CFIDS patients by medical researchers. This is a ‘real’ illness of immune dysfunction”. 1988 1988 “Lymphocyte phenotyping…has revealed several abnormalities. Dr Paul Cheney and others have found that the circulating suppressor T cell number is decreased in many CFIDS patients…In some CFIDS patients, the number of circulating B cells is reduced…Natural killer cell abnormalities in CFIDS patients have been reported….In addition, NK cells from CFIDS patients did not function as well as NK cells from normal individuals….In a controlled study conducted by a group of Australian researchers, T cell function…was decreased in over 80% of patients….Lymphokines are proteins which act as messengers for the immune system. Dr Paul Cheney and other researchers have found elevated levels of alpha interferon…Interleukin-2 levels have also been found to be elevated in many CFIDS patients….In conclusion, the results of several immune system tests are abnormal in CFIDS patients and indicate that there is immune dysfunction involved in this illness” (Susan E Dorman. The CFIDS Chronicle, September 1988). 1988 “On immunological testing, we and others (Dubois 1984; Jones 1985; Straus 1985; Tosato 1985; Olson 1986; Caliguri 1987) have found evidence of subtle and diffuse dysfunction: partial hypogammaglobulinaemia (25-80%); partial hypergammaglobulinaemia (10-20%); low levels Invest in ME (Charity Nr. 1114035) A landmark conference/research workshop on (ME)CFS took place in September 1988 at the University of Pittsburgh; it was co-chaired by Seymour Grufferman, Professor and Chairman of the Department of Clinical Epidemiology and Preventive Medicine at the University of Pittsburgh and Stephen Straus, Head of Medical Virology at the National Institute of Allergy and Infectious Disease (NIAID). Professor Grufferman used the term “chronic fatigue and immune dysfunction disease” (CFIDS) and commended the use of this term on the basis of the immune dysfunction that has been observed in this disorder. Several researchers noted that the pathophysiology of (ME)CFS includes an inappropriate and/or inflammatory response (The CFIDS Chronicle, October 1988). 1988 “The Third International Symposium on EpsteinBarr Virus and Associated Malignant Diseases was held in Rome on 3rd – 7th October 1988. For the first time, scheduled presentations and a round table discussion on post-viral chronic fatigue syndrome (CFIDS, [ME]CFS) were included in the programme. Dedra Buchwald MD from the University of Washington presented an overview of the laboratory abnormalities which have been www.investinme.org Page 34 of 108 of autoantibodies, particularly anti-thyroid antibodies and antinuclear antibodies (15-35%); low levels of circulating immune complexes (3050%); elevated ratios of helper-suppressor T-cells (20-35%)…reduced in vitro synthesis of interleukin-2 and interferon by cultured lymphocytes; increased IgE-positive T and B cells; and deficient functional activity of natural killer cells. Some investigators have found increased levels of circulating interferon, whereas others have not. Straus demonstrated a significant increase in levels of leucocyte 2’5’-oligoadenylate synthetase activity, an enzyme induced during acute viral infections (Straus 1985)” (Anthony L Komaroff: Chronic Fatigue Syndromes: Relationship to Chronic Viral Infections. In: Persistent Herpes Infections: Current Techniques for Diagnosis; Ed: Gerhardt RF Krueger, Dharham Ablashi and Robert C Gallo; Pub: Elsevier Press 1988). Journal of IiME Volume 6 Issue 1 (June 2012) found in (ME)CFS patients….Circulating immune complexes have been observed in an average of 59% of (ME)CFS patients….A decrease in NK cell number or percent has been observed in up to 75% of patients, and NK cell function has also been found to be diminished…The immunologic aberrations…support the hypotheses of an underlying organic pathology”. Drs Nancy Klimas and Mary Ann Fletcher et al noted the increase in numbers of a certain subset of B cells which are associated with autoimmune disease, concluding: “Significant immunological abnormalities have been recognised in this group of (ME)CFS patients. The possibility of an underlying immunodeficiency should be considered as a potential aetiological mechanism in the natural history of this syndrome” (The CFIDS Chronicle, November/December 1988). 1989 Susan Dorman commented on the study by Drs Paul Cheney and David Bell that was published in The Annals of Internal Medicine 1989:110(4), noting that average levels for IL-2 were significantly higher in (ME)CFS patients than for controls. The average serum IL-2 value for Dr Cheney’s patients was 56.2 units per millilitre and for Dr Bell’s patients the average serum IL-2 value was 55.5 U/mL. The average serum IL-2 for the controls was 1.4 U/mL. The normal range for the assay used is less than 5 U/mL. “This objective immune system abnormality may also help to legitimise the disease” (The CFIDS Chronicle, January/February 1989). The same issue noted the NIAID press release of 15th February 1989 which quoted Dr Stephen Straus: “Many physical and immunologic features of (ME)CFS cannot be explained by psychiatric illness”. It also noted that in 1988 congressional hearings, Dr Anthony Fauci, NIAID Director (the NIAID being a division of the NIH) reported that the basis of CFIDS involves immunological aberrations. The issue also carried an article by Dr Susan Levine from Mt Sinai Hospital Department of Immunology, New York, on “Allergy, Immune Invest in ME (Charity Nr. 1114035) Function, and Endocrinological disorders in CFIDS” in which she said: “Allergic manifestations are often seen hand in hand with certain immunodeficiencies, such as the absence of IgA and of specific IgG subclasses”. 1989 The UK ME Association published “Latest Research Findings” in March 1989: “Dr Peter Behan in Glasgow has made some remarkable new findings about ME….Though B cells appear normal, they are lacking a particular antigen (an antigen is a substance that stimulates the production of antibodies). This abnormality appears to be unique to ME. On measuring levels of Interleukin1 (a chemical messenger of the immune system) in ME sufferers and comparing them with normal controls…it was found that the average level in the ‘normal’ control group was 20 titograms per ml (sic -- ? picograms/pg per ml), while in people with rheumatoid arthritis it was up to 51. In many people with ME it was around 20,000 (this is not a typographical error). IL-1 is known to turn on the production of other chemical messengers….act on the liver to displace protein production (and) decrease the white cell count….It appears from these findings that many ME sufferers have abnormalities of the immune system. In the case of IL-1, so abnormal were the levels that the lab which was doing the measurements thought there had been a mistake”. 1989 The San Francisco (ME)CFS Conference was held on 15th April 1989; notably, Dr Jay Levy, a wellknown AIDS researcher at the University of California, informed healthcare professionals that CFIDS may be linked to the eventual development of multiple sclerosis (an autoimmune disease) and said “I think this is a new agent that is clearly attacking the immune system. And what you’re seeing is an immunological disorder that’s allowing a reactivation (of common viruses) very similar to what we saw in AIDS…. I point out that we’re not just examining something that is fatigue – we’re looking at something that gives immunological disorders….The agent is kept so far underground by the immunological reaction, you will never find it”. Several parameters of the www.investinme.org Page 35 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) disease “tell us this is an autoimmune response to something”; autoimmune-like parameters included “enhanced T4 helper cell numbers (and) decrease in T8 cells, which is a model in the MRL mouse for autoimmunity”. At that Conference, Drs Anthony Komaroff and Paul Cheney outlined some of the laboratory findings in people with CFIDS; these include lymphocytosis; low level ANA; monocytosis; antithyroid antibodies; elevated transaminases; circulating immune complexes; elevated B cell numbers; depressed levels of IgA; elevated T4/T8 ratio; NK cells not stimulated by IL-2, and elevated levels of cytokines – including IL-2 levels 50 times higher than normal (The CFIDS Chronicle, Spring 1989). Dr Paul Cheney noted that 70% of ME/CFS patients tested had depressed levels of salivary IgA (SIgA), and that ME/CFS patients with low SIgA levels tended to have high levels of insoluble circulating immune complexes. Microscopic analysis of tissues showed lymphocytic vasculitis (lymphoid infiltrates in the blood vessel wall) in 75% of patients tested. Reporting this medical conference, (Meeting Place issue 32), the Journal of the Australia and New Zealand ME Society (ANZMES) stated in its December 1989 issue: “The consensus of the conference was that CFIDS represents a growing pandemic of immune dysfunction”. 1989 The Summer/Autumn (Fall) 1989 issue of The CFIDS Chronicle was a 180 page journal that reported on numerous conferences on (ME)CFS at which the immunological abnormalities were confirmed; it also addressed other areas of medical research into the disorder. One book in particular was reviewed, this being “The Body at War: The Miracle of the Immune System” by Professor John M Dwyer (New York NAL Books, 1988; 253 pages). The CFIDS Chronicle reviewer (Dr Dennis Jackson) noted that Dwyer, an Australian immunologist, condemned the Invest in ME (Charity Nr. 1114035) “intellectual arrogance” of his fellow physicians who have continued to chase easy theories about the psychiatric origin of the disorder and that Dwyer declared: “Unfortunately, continued widespread ignorance of the condition perpetuates psychological harassment for many….A genetic defect downgrading the efficacy of a response to infection should translate into an immunological defect, and this has now been established as fact. The reproducible demonstration of T-cell abnormalities in patients with (ME)CFS is the reason we are discussing this disease in this book on the immune system….Patients with classical symptoms of (ME)CFS almost always have reduced numbers of immunoregulatory cells in their blood….So consistent are these abnormalities they allow us to make a positive diagnosis”. 1989 “Our investigations suggest that (ME)CFS is characterized by objective laboratory abnormalities. A more appropriate name for this syndrome would be chronic fatigue-immune dysfunction syndrome (CFIDS), since immune dysfunction appears to be the hallmark of the disease process” (Nancy Eby , Seymour Grufferman et al. In: Natural Killer Cells and Host Defense. Ed: Ades EW and Lopez C. 5th International Natural Killer Cell Workshop. Pub: Karger, Basel, 1989:141-145). 1989 “(ME)CFS has been associated with abnormal T cell function. These patients have diminished phytohaemagglutinin-induced lymphocyte transformation and decreased synthesis of interleukin. We studied the display of CD3, CD5, CD2, CD4, CD8 and Leu-M3-defined antigen in peripheral blood mononuclear cells in (ME)CFS who fulfilled the (1988 Holmes et al) criteria. Patients had reduced expression of CD3. These data indicate that in (ME)CFS, some patients have T lymphocytes (CD2- and CD5- positive cells) without immunoreactive CD3” (ML Subira et al. The Journal of Infectious Disease 1989:160:1:165166). www.investinme.org Page 36 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) 1989 “Disordered immunity may be central to the pathogenesis of (ME)CFS. Reduced IgG levels were common (56% of patients), with the levels of serum IgG3 and IgG1 subclasses particularly affected. The finding of significantly increased numbers of peripheral blood mononuclear cells that express Class-II histocompatibility antigens (HLA-DR) in our patients implies immunological activation of these cells. Once activated, these cells may continue to produce cytokines which may mediate the symptoms of (ME)CFS” (AR Lloyd et al. The Medical Journal of Australia 1989:151:122-124). 1989 “On medical history, the only clearly striking finding is a high frequency of atopic or allergic illness (in about 50 – 70%)…. On immunologic testing, we and others have found evidence of subtle and diffuse dysfunction” (AL Komaroff & D Goldenberg. J Rheumatol 1989:16:19:23-27). 1989 In 1989 The CFIDS Association of America published a “Brief Summary” by Anthony Komaroff from Harvard and Director of the Division of General Medicine and Primary Care at Brigham and Womens Hospital, Massachusetts: “Considerable progress is being made in identifying various objective abnormalities, such as unusual immune system and nervous system findings. These advances are important (because) they identify measurable abnormalities that the patients cannot ‘fake’ ”. 1990 On 17th March 1990 Professor Peter Behan from Glasgow made a presentation to the Mid-Anglia branch of the ME Association in Cambridge; he noted that 50% of ME patients cannot produce steroids in response to stimulus. 1990 On 10th- 12th April 1990 the First World Symposium on ME/CFS was held at the University of Cambridge. Speakers presented evidence on Invest in ME (Charity Nr. 1114035) acute, latent, persistent and reactive virus/host interaction; on cytopathological studies; on electron microscopy studies; on immunological abnormalities, genetics and autoimmunity; on interferons and their role in virus infections; on muscle studies of abnormal metabolic function; on cardiac disease in ME/CFS; on lesions in the brain and on paediatric ME/CFS. The predominant view was of a persistent or chronic viral infection which either gave rise to, or was the result of, a continuing abnormal immune response and abnormalities of the muscle and central nervous system. Evidence was presented of an infective vasculitis in ME/CFS. The Symposium brought together leading international researchers to review all aspects of ME/CFS. The proceedings were subsequently published as the 724 page seminal textbook on ME/CFS (The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue Syndrome, edited by Drs Byron Hyde, Jay Goldstein and Jay Levy; The Nightingale Research Foundation, Ottawa, 1992). 1990 The 184-page issue of The Spring/Summer CFIDS Chronicle again covered (ME)CFS conferences and medical research; in addition it carried a section on “Women’s Issues”, noting the immunological findings in women with endometriosis (often present in women with (ME)CFS), these being strikingly consistent with immunological findings in (ME)CFS in general. They also include the presence of anti-endometrial antibodies in peritoneal fluid and serum; deposits of complement C3 and C4 fractions in the endometrium, peritoneal fluid and sera, and increased number of activated macrophages in the peritoneal cavity. 1990 “The subgroup of patients with immunological abnormalities may have a prolonged illness” (DO Ho-Yen. JRCGP 1990:40:37-39). 1990 “In order to characterise in a comprehensive manner the status of laboratory markers associated with cellular immune function in www.investinme.org Page 37 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) patients with this syndrome, patients with clinically defined (ME)CFS were studied. All the subjects were found to have multiple abnormalities in these markers. The pattern of immune marker abnormalities observed was compatible with a chronic viral reactivation syndrome. A substantial difference in the distribution of lymphocyte subsets of patients with (ME)CFS was found when compared with normal controls. Lymphocyte proliferation after PHA and PWM stimulation was significantly decreased in patients (by 47% and 67% respectively) compared with normal controls. Depression of cell-mediated immunity was noted in our study population, with over 80% of patients having values below the normal mean. The present report confirms that a qualitative defect is present in these patients’ NK cells (which) might represent cellular exhaustion as a consequence of persistent viral stimulus. Results from the present study indicate that there is an elevation in activated T cells. A strikingly similar elevation in CD2+ CDw26+ cells has been reported in patients with multiple sclerosis. In summary, the results of the present study suggest that (ME)CFS is a form of acquired immunodeficiency. This deficiency of cellular immune function was present in all the subjects we studied” (Nancy G Klimas et al. Journal of Clinical Microbiology 1990:28:6:1403-1410). 1990 “It is also clear that acquisition of T cell deficiency, particularly of the CD8 subset, can itself impair immune regulation and predispose to atopy not previously experienced by the patient. Three of the criteria are sufficiently frequent to suggest they should become part of the routine screening of such patients, and these are a subnormal level of CD8 lymphoctyes, a raised serum IgE level and a positive VP1 antigen…. In the present ME study, patients show a 40% incidence of both clinical and laboratory evidence of atopy…. It has been shown that T cell deficiency, particularly of the suppressor subset, can predispose to atopy, which can indeed be acquired by patients without a genetic family history. We have undertaken extensive T cell subset measurements in normal subjects subjected to psychological stress and would point out in none of these did we see CD8 levels as low as in some 40% of our ME patients” Invest in ME (Charity Nr. 1114035) (JR Hobbs, JA Mowbray et al. Protides of Biological Fluids 1990:36:391-398). 1990 The CFIDS Association of America held a Research Conference on 17th-18th November 1990 at Charlotte, North Carolina. Amongst the notable presentations were the following:  Dr Irina Rozovsky (speaking on “Levels of Lymphocytes, Soluble Receptors & IL-2 Inhibitors in Sera from CFIDS Patients”) said: “Chronic fatigue syndrome can be described as an immune dysregulative state, characterised by global immune upregulation with discrete immune defects….Normally T-helper cell activation is mediated by two intracellular signals. The first signal is the activation of protein kinase C….The second major signal for Tcell activation is the mobilisation of both cytotoxic and extracellular calcium. This activation finally leads to the secretion of interleukin-2 (IL-2) and the expression of IL2 receptors on the surface of T cells….Soluble IL-2 receptors have been found in…sera from patients with multiple sclerosis, autoimmune diseases, AIDS, different types of lymphomas and leukaemias and in cancer patients who use IL-2 therapy. It is well-known that patients in IL-2 treatment have the same kind of symptomatology as our chronic fatigue syndrome patients….We have measured the levels of these soluble IL-2 receptors and T8 receptors in chronic fatigue syndrome patients….We have found that our patients have an elevated level of IL-2 receptor compared to healthy controls. Their level of soluble T8 receptor will also be significantly higher than for the control group….These two soluble receptors (IL-2 and T8 receptors), which reflect certain T-cell responses, could be very good markers for the disease and may even reflect the degree of severity of the illness”.  Dr Anthony Komaroff said: “Our model for CFIDS is…that fundamentally, the illness involves a compromised immunity….This www.investinme.org Page 38 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) compromised immunity leads to a reactivation of latent viruses including HHV-6 and EBV. In some patients, it may well include the entero, coxsackie, echo, and even polio viruses….In other patients, environmental toxins could possibly compromise immunity….What all of the data indicates to me is something that will come as no surprise to any of you, and that is that CFIDS is not simply a state of mind”.  Professor Nancy Klimas in her presentation entitled “Immunological markers in (ME)CFS” said: “The most compelling finding was that natural killer cell cytotoxicity in chronic fatigue syndrome was as low as we have ever seen in any disease. This is very, very significant data with very, very low levels of lymphocyte response to mitogens….The actual function was very,very low – 9% cytotoxicity; the mean for the controls was 25. In early HIV and even well into ARC (AIDS-related complex) NK cytotoxicity might be around 13 or 14 percent….Chronic fatigue syndrome patients represent the lowest cytotoxicity of all populations we’ve studied”.  Dr Alan Landay said: “We have found changes in three markers which seem to be the most significant. First, the CD 11 B marker, which identifies the suppressor cell, decreases in CFIDS patients….There is also an increase in the CD38 and the HLA DR indicating activation….Flow (cytometry) has been a useful tool for studying a number of diseases, including cancer, AIDS, and autoimmune disease. It can identify individuals with immune disorders by using a large panel of markers….Flow cytometry has revealed evidence of CD8 activation in CFIDS”.  Dr Jay Levy said: “if you look at the activation markers, they are raised in both CFIDS and acute viral illness….Some individuals…will not be able to turn off that activated state. The agent remains as a constant thorn, forcing the immune system to be activated until the agent is eliminated. In these individuals, the Invest in ME (Charity Nr. 1114035) 1991 The Spring 1991 (131-page) issue of The CFIDS Chronicle reported in full on the Charlotte, North Carolina, Conference, noting that Professor Nancy Klimas “unequivocally stated that all of her (ME)CFS patients had predictable laboratory abnormalities and that (ME)CFS is a form of acquired immunodeficiency”. 1991 In a Statement on 16th April 1991 by Dr Elaine DeFreitas and Dr Hilary Koprowski regarding CFIDS/ME to the US House of Representatives Committee on Energy and Commerce Subcommittee on Health and the Environment, Washington DC, Dr DeFreitas spoke out with a very strong voice: “Let us note at the beginning that CFIDS or CFS/ME is not about being tired. Researchers have demonstrated numerous abnormalities of the immune, muscular, cardiovascular and central nervous systems in people with CFS/ME; it is truly a multi-system disease with a strong component of immune dysfunction”. immune system never returns to a normal resting state. So these people are in a state of chronic immune activation. What is the result of this chronic immune activation? If an activated white cell is doing its duty, it has to be producing a certain number of lymphokines or cytokines that are working to control the agent that is infecting the body. But these cytokines can have side effects….Cytokines affect the brain, the bowel, the muscle, the liver (which) one sees in CFIDS. So, increased cytokine activation can affect many different tissues in the body (and) can also cause reactivation of other viruses….This disorder could be controlled by eliminating the causative agent or quieting down the hyperimmune system….There is much clinical information showing that (CFIDS) has often led to other immune diseases….The sequelae…include autoimmune disease and, on some occasions, MS”. www.investinme.org Page 39 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) 1991 “Compared with controls, (ME)CFS patients showed an increase in CD38 and HLA-DR expression. These data point to a high probability (90%) of having active (ME)CFS if an individual has two or more of the CD8 cell subset alterations. Laboratory findings among (ME)CFS patients have shown low level autoantibodies, which may reflect an underlying autoimmune disorder. A persistent hyperimmune response of the remaining CD8 cells might lead to an outpouring of cellular products and cytokines (e.g. interferon, tumour necrosis factor, interleukin-1) that are characteristically associated with myalgia, fatigue, (and) neurological signs and symptoms associated with acute viral infections. Unless the immune system is brought back into balance, this chronic activation affects the individual further and might eventually lead to other clinical illnesses” (Alan L Landay et al. Lancet 1991:338:707-712). 1991 “Despite the broad divergence of opinion in the medical community, there is little doubt that classic allergy and atopy are inexplicably prevalent in (ME)CFS. In a recent study, a high proportion (50%) of patients were found to be reactive to a variety of inhalant or food allergens when inoculated epicutaneously in the classic manner. Certainly patients with (ME)CFS differ immunologically from their healthy counterparts and it is this observation, more than any other today, that is evoked in support of the organic hypothesis of disease causation” (Stephen E Straus. Reviews of Infectious Diseases 1991:13: Suppl 1: S2-S7). 1991 “Various abnormalities revealed by laboratory studies have been reported in adults with (ME)CFS. Those most consistently reported include depressed natural killer cell function and reduced numbers of natural killer cells; low levels of circulating immune complexes; low levels of several autoantibodies, particularly antinuclear and antithyroid antibodies; altered levels of immunoglobulins (and) abnormalities in number and function of lymphocytes” (Dedra Buchwald Invest in ME (Charity Nr. 1114035) and Anthony Komaroff et al; Reviews of Infectious Diseases 1991:13 (Suppl 1): S12- S28). 1991 “Our investigations have…produced evidence of …a decrease in CD8 suppressor cells with resulting elevation of the ratio of CD4 to CD8 cells” (Sandra Daugherty, Daniel Peterson et al. Reviews in Infectious Diseases 1991:13 (Suppl 1):S39-S44). 1991 “Preferably, patients with (ME)CFS who have such abnormalities might be considered a subset of the larger group: i.e. persons with (ME)CFS who have immune dysfunction” (Gary P Holmes. Reviews of Infectious Diseases 1991:13:1:S53S55). 1991 Referring to the seminal work of Dr Elaine DeFreitas, the Autumn (Fall) 1991 issue of The CFIDS Chronicle heralded “Convincing Evidence of Retroviral Infection and Immune Activation Found in CFIDS Patients”; other topics included a review of an article published in The Lancet (1991:338:8769:707-712) by Drs Jay Levy, Alan Landay, Carol Jessop and Evelyne Lennette from the University of California School of Medicine entitled “Immune Activation in CFS”. The review noted: “Drs Levy, Landay, Jessop and Lennette reported the results of their study which further explored findings that (ME)CFS may be due to one or more immune disorders that have resulted from exposure to an infectious agent….Flow cytometry studies, white blood cell counts, differential counts and viral serology studies were performed. Analysis of all clinical data enabled the research team to group the patients according to symptoms number and severity. Group A was comprised of 67 patients whose illness was so severe that they had less than 25% of their normal daily activity and also had multiple symptoms….The immunophenotypic data presented here indicate that many individuals with symptoms of (ME)CFS have CD8 cell immune activation….Most noteworthy is the statistical evidence that an individual with two or more of the CD8 cell subset alterations (increased CD11b-, CD38, and HLA-DR) www.investinme.org Page 40 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) has a high probability (90%) of having active (ME)CFS. These findings are consistent with chronic stimulation of the immune system, perhaps by a virus”. 1992 On 20th December 1991 the Principal Investigator of (ME)CFIDS studies at the US Centres for Disease Control (CDC) , Dr Walter Gunn, had announced to The CFIDS Association: “Our Surveillance Study does not support the notion that (ME)CFS is a psychiatric illness and in fact suggests that it has an organic basis. Recent published reports suggest that the immune system may be involved in this illness” (The CFIDS Chronicle, February 1992). 1992 A major study looking at neurological, immunological and virological aspects in 259 (ME)CFS patients found that neurological symptoms, MRI findings and lymphocyte phenotyping studies suggest that patients “may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system” and that “ We think that this is probably a heterogeneous illness that can be triggered by different environmental factors (including stress, toxins and infectious agents), all of which can lead to immune dysfunction and the consequent reactivation of latent viruses” (Dedra Buchwald, Paul Cheney, Daniel Peterson, Robert C Gallo, Anthony Komaroff et al. Ann Int Med 1992:116:2:103-113). 1992 “It is known that such patients are remarkably likely to have a history of atopy pre-dating the onset of chronic fatigue syndrome (50-83%). Patients may have an immune system that responds over-emphatically to environmental or internal stimuli…aspects of the immune reaction may not be stoppable even after an insult is over” (WK Cho & GH Stollerman. Hospital Practice 1992:221-245). 1992 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 41 of 108 “Patients with chronic fatigue syndrome are reported to have a higher incidence of allergic conditions. Indeed, it has been speculated that heightened allergic responsiveness may be a risk factor for the development of the syndrome. In particular, the diverse clinical and immunological features have been argued to reflect an ongoing state of immune activation” (MA Demitrack, Stephen E Straus et al. Biol Psychiatry 1992:32:1065-1077). 1992 In September 1992 The CFIDS Association produced another issue of “A Physicians’ Forum” (entitled “CFIDS: The Diagnosis of a Distinct Illness”), with contributions from world-class experts including Professors/Drs David Bell, Leonard Calabrese, Paul Cheney, Jay Goldstein, James Jones, Nancy Klimas, Anthony Komaroff, Charles Lapp, Benjamin Natelson, and Daniel Peterson. Dr David Bell said: “Differential diagnosis includes rheumatoid arthritis, lupus erythematosus, Lyme disease, multiple sclerosis, sarcoidosis, hepatitis B, polymyalgia rheumatica, human immunodeficiency virus infection and malignant disease….Numerous immunologic abnormalities have been described in patients with (ME)CFS….Decreased natural killer cell function is perhaps the most reproducible immunologic abnormality”. Dr Leonard Calabrese (Head of the Clinical Immunology Section in the Department of Rheumatic and Immunologic Disease at the Cleveland Clinic Foundation) said: “Growing experimental evidence suggests that a portion of patients with (ME)CFS have both qualitative and quantitative immunologic abnormalities. When the immune system of patients with (ME)CFS is challenged, the response is quantitavely abnormal. Mononuclear cells from patients with (ME)CFS proliferate at half the expected rate following challenge with phytohaemagglutinin and pokeweed mitogen….A deficiency in certain natural killer cells has been proposed to explain many of these abnormalities”.

Journal of IiME Volume 6 Issue 1 (June 2012) Drs Paul Cheney and Charles Lapp said: “Immunologic tests have been frequently applied to patients with (ME)CFS in part because they are frequently abnormal and in part because the signs and symptoms of (ME)CFS can be explained as a consequence of immunologic dysfunction….We propose a set of tests that look for evidence of T-cell activation along with discrete immune defects….Immune tests become more valuable when used as an array or set of tests used to determine a pattern of immune dysfunction” Dr Jay Goldstein noted that “The sed rate (erythrocyte sedimentation rate or ESR) is often very low” (an important observation because many physicians dismiss ME/CFS as an infectious disease unless there is a high ESR, but if inflammatory processes are activated in other ways, the ESR can remain normal or low, which does not exclude an inflammatory illness); “Immune complexes and positive anti-nuclear antibodies are encountered very frequently….Elevated levels of various cytokines and their receptors are often seen”. Professor Nancy Klimas said: “Our group in Miami has been actively working to better understand CFIDS since 1985. This work has focused on the immunologic abnormalities seen in the majority of patients (and) has helped to develop a sense of diagnostic certainty in the evaluation of CFIDS patients, as well as to identify subgroups that are immunologically different from the majority of CFIDS patients evaluated….We have found the immune evaluation to be … important, as it not only helps classify the patients, but also helps to direct the care of the patient….Such an evaluation must touch on three points: (1) level of T cell activation….while there are many markers of T cell activation…the most sensitive in CFIDS is CD3+CD26+ phenotype by flow cytometry, the T cell expressing transferrin receptor. In ‘normals’, about 18 percent of circulating T cells express this activation marker, while CFIDS patients show double to triple these levels of activation. Other phenotypic markers help to fill out the picture. CD8+DR, or activated cytotoxic cells, are elevated in the majority of patients with recent exacerbations but seem to normalise during healthier times. (2) diminished cell Invest in ME (Charity Nr. 1114035) function….CFIDS patients have diminished T and B cell function in response to cell activators (mitogens) in culture. The most sensitive is diminished response to pokeweed mitogen (PWM), which reflects poor T and B cell interaction. Even more remarkable is the very poor ability of NK cells to kill virally infected target cells in culture…People with CFIDS often have very diminished NK cell function….While we routinely look at both mitogen response and NK cytotoxicity, I believe assessing NK cytotoxicity is more important. We also routinely assess B cell function by looking at immunoglobulin production. Basically this is accomplished by looking at total immunoglobulins (IgG, IgA, IgM), at IgG subclasses (IgG. IgG2, IgG3, IgG4)….(3) evidence of viral reactivation. Serology for common reactivation viruses…adds further evidence that the immune dysfunction now quantified is of a serious enough nature to cause secondary viral reactivation….The Miami group’s enthusiasm and excitement are based on …our understanding of the underlying immune defects are finally sharply focused. This clear understanding of the immune disorder is driving new therapeutic approaches”. Professor Anthony Komaroff said: “Our studies indicate that two additional tests are elevated more often in patients with CFIDS: immune complexes and immunoglobulin G (IgG)”. Dr Benjamin Natelson (Professor of Neurosciences at the University of Medicine and Dentistry, New Jersey) said: “The major lab tests I check are those indexing immunological dysfunction. I do a standard immunological profile, including circulating immune complexes, complement levels and IgG subclasses. I have found a rough correlation between disability and the number of these tests that are positive….Being able to report such examples of immune dysfunction is often of practical value in assisting the severely ill CFS patient in obtaining disability (payment)”. 1992 On 2nd – 4th October 1992 the First Biennial International Research conference on (ME)CFS was held at Albany, New York. It was reported in the CFIDS Chronicle, Summer 1993; pages 64 – 72. www.investinme.org Page 42 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) Professor Nancy Klimas et al considered the possibility of a genetic predisposition and by using HLA phenotyping they were able to provide substantial support for it; DQ1 and DR4 appear to be present in a large percentage of the (ME)CFS population and Klimas et al were investigating the possibility that HLA DR4 and DQ1 may be genetic markers for (ME)CFIDS. Whilst HLA DR4 and DQ1 represent less than 5% of the general population, they were present in 93% of the (ME)CFIDS population. Charles Lapp (Associate Professor of Family Medicine, Duke University) commented “This study establishes that two gene markers occur frequently in (ME)CFIDS but not in the general population”. Drs David Bell and Paul Cheney discussed the T4/T8 ratio in (ME)CFIDS, noting that low CD8 counts are more likely to occur in (ME)CFIDS than low CD4 counts, so the ratio is likely to be high in this disorder (i.e. facilitating an allergic or hyperimmune response). Dr Emmanuel Ojo-Amaize reported on the association between decreased NK cell activity and the severity of (ME)CFS; the results confirmed and extended previous reports demonstrating that a pronounced and consistent immunological abnormality detected in (ME)CFS patient is low NK cell cytotoxicity. 1993 A press release of 5th February 1993 from the NIAID stated: “Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) report finding subtle immune abnormalities in people with chronic fatigue syndrome (CFS) that ultimately may explain why they develop painful muscles and joints, and tender lymph nodes and other symptoms associated with the illness….When the researchers compared blood samples from…healthy volunteers with those from…CFS patients, they found several immune differences. These findings confirm and add new information to other immunological studies of CFS. Most notably, the CFS patients had significant differences in the number and character of one Invest in ME (Charity Nr. 1114035) type of immune cell – T cells that carry helper molecules, called CD4, on their surfaces. These cells, known as CD4+T cells, orchestrate the immune response….(Dr Stephen Straus said) ‘More CD4+T cells appear to change location, shifting from the blood into the tissues. These tissue-based cells escape detection by research blood tests’….In the tissues, CD4+T cells release molecules that help regulate the immune response. These molecules can cause mild inflammation and pain. ‘The same process causes pain in the intestines of people with inflammatory bowel disease’ says Dr (Warren) Strober, another member of the team who is an immunologist and expert in inflammatory bowel disease….The NIAID study will continue for several years….the data collected will be analysed to determine if these or other immune differences found vary with time or correlate with symptoms severity or recovery” (The CFIDS Chronicle, Winter 1992-1993). 1993 On 8th February 1993 The CFIDS Association of America issued a press release: “Government Finally Confirms Private Sector Research: Immune Abnormalities Found in Chronic Fatigue Syndrome. Federal scientists at the National Institute of Allergy and Infectious Diseases have published a study in the January 1993 issue of the Journal of Clinical Immunology reporting findings of immune abnormalities in (ME)CFS patients which confirms earlier studies performed by private sector researchers….It is the first acknowledgement by federal scientists that the ‘ID’ in CFIDS is indeed real. Over the past several years private sector researchers have been publishing similar studies, reporting various immune abnormalities in CFIDS patients”. 1993 At the 1993 Los Angeles Conference (7th - 9th May) on (ME)CFS, evidence was presented by Professor Nancy Klimas from the University of Miami that she and her team have been able to accurately predict 88% of (ME)CFS patients with a mathematical model of immunological parameters. This model combines levels of activated T cells and CD4 inducers of cytotoxic T cells with NK cell count and function: “In a normal population, 20% of lymphocytes are active at any www.investinme.org Page 43 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) given time. ‘In (ME)CFS, up to 80% of the cells are working’. These lymphocytes and cytokines are so up-regulated that they cannot be driven any harder. It is as if they have been pushed as far as they can go and the immune system is completely exhausted”. At the same conference, Dr Catherine Rivier from the Salk Institute in La Jolla, California, said: “Upregulation of the immune system has been welldocumented in the CFIDS literature….That this immune activation is responsible for many CFIDS symptoms has been accepted by most researchers and physicians. Stress in any form places undue pressure on the immune system….In a normal immune system, interleukin (IL-1) is produced in response to stress. In CFIDS, IL-1 may be obstructed, resulting in a blockage of corticotropin releasing factor (CRF), an immunosuppressor. If CRF is not released, the immune system will remain activated indefinitely” (CFIDS Chronicle: Summer 1993). 1993 “Using the immunophenotypic data presented, we were able to demonstrate that almost 50% of (ME)CFS patients, especially those with severe symptoms, showed signs of CD8+ cell activation and an abnormal suppressor/cytotoxic CD8+ cell ratio. Our observations strongly suggest that a large population of (ME)CFS patients have immunologic disorders and that their symptoms could be explained by a chronic immune activation state (and) that (ME)CFS represents a type of autoimmune disease in which a chronically activated immune system reacts against the host. The 3:1 female/male ratio would not be unexpected: autoimmune syndromes are more common in women. Because of the autoreactive nature of this condition, it might also lead to other immune disorders, such as wellrecognised autoimmune diseases and multiple sclerosis” (Jay A Levy et al. Contemp Issues Infec Dis 1993:10:127-146). 1993 “On past medical history, the only clearly striking finding in our studies is a high frequency of atopic or allergic illness (in approximately 50 – 80%, in Invest in ME (Charity Nr. 1114035) contrast to a background prevalence of about 10% in the population at large)…..Immunological studies suggest that in CFS, the immune system is in a state of chronic activation” (AL Komaroff. Ciba Foundation Symposium 173: Chronic Fatigue Syndrome. John Wiley, Chichester 1993:43-61). 1993 “A dysfunctional immune system may be related to the failure of other organ systems frequently observed in CFIDS….Some CFIDS patients produce very low levels of DHEA (dehydroepiandrosterone, a naturally-produced hormone and a precursor of oestrogen and testosterone in humans….Many CFIDS patients are very sensitive to medications and do not tolerate normally-recommended dose levels. Many drug agents, including DHEA, are toxic to CFIDS patients’ lymphocytes at routinelyprescribed dose levels” (Dr James McCoy from Louisiana; The CFIDS Chronicle Physicians’ Forum, Autumn (Fall) 1993). Two further important points were made in that issue of Physicians’ Forum; Dr Robert Sinaiko from San Francisco mentioned something that is very common but frequently dismissed by uninformed physicians: “Many CFIDS patients experience lower right abdominal pain, which (Sinaiko) hypothesises is mycotic mesenteric adenitis, an inflammation of the lymph nodes in the abdomen as a result of immune activation”, whilst Vicky Carpman pointed out: “Autoimmunity is commonly seen in CFIDS….Once an autoimmune condition begins, it cannot be reversed”. 1993 “What is ME? ME is a potentially severe and chronic condition affecting the immune and central nervous system” (Perspectives -- the magazine of the UK ME Association, September 1993, page 10). 1993 In September 1993 meetings took place at the CDC to review the CFS case definition. A common theme articulated was the urgent need to change the name: “Dr Nancy Klimas (a noted CFIDS immunologist at the University of Miami) www.investinme.org Page 44 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) supported a formal change to ‘chronic fatigue and immune dysfunction syndrome’ in recognition of the various immune abnormalities documented by private and public-sector researchers….Dr Klimas presented Dr Reeves with a notebook filled with medical articles on the immune abnormalities found in CFIDS in defence of this recommendation”. During those meetings, Dr Phillip Peterson acknowledged the immune system abnormalities and the adequacy of evidence to support immunotherapy, stating that he had found no other disease with such global immune disturbance (The CFIDS Chronicle, November 1993 and Winter [January] 1994). 1994 An International Meeting on (ME) Chronic Fatigue Syndrome was held in Dublin on 18th-20th May 1994 under the auspices of the World Federation of Neurology. Professor Dr Rainer Ihle from Germany said that data on 375 (ME)CFS patients demonstrated various immunological changes and autoantibodies (especially antinuclear antibody and microsomal thyroid antibodies) in an abnormally large proportion of patients, suggesting impaired immunity and facilitating transition to autoimmune disease (“On the basis of these immunological serological and organspecific findings, which affirm previously published results, it would appear that the organic nature of the pathogenesis of (ME)CFS has now been demonstrated”). Dr Jay Levy from San Francisco presented serological and immunological data from (ME)CFS patients, pointing out that, by lymphocyte phenotype analysis, the T8 suppressor subset was decreased, a notable and important finding. He also found that activated T cells were increased, with the most pronounced increases seen in the sickest patients, and that NK cell activity and cytotoxic lymphocyte activity were both depressed in (ME)CFS patients. 1994 Invest in ME (Charity Nr. 1114035) “The up-regulated 2-5A pathway in (ME)CFS is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of (ME)CFS. The object of this study was to measure key parameters of the 2-5A synthetase/RNase-L antiviral pathway in order to evaluate possible viral involvement in (ME)CFS. The data presented suggest that 2-5A synthetase/RNase L pathway is an important biochemical indicator of the anti-viral state in (ME)CFS. Evidence that this pathway is activated in (ME)CFS was identified in this subset of severely disabled individuals as related to virological and immunologic status. This pathway phenotype could result from chronic overstimulation due to chronic viral reactivation” (RJ Suhadolnik et al. Clin Inf Dis 1994:18(Suppl 1):S96S104). 1994 “Controlled studies of T cells in patients with (ME)CFS have (shown that) the three most prominent and apparently reproducible findings for (ME)CFS patients are as follows (1) Impaired lymphocyte proliferation in response to stimulation…has been repeatedly documented and also has been shown to be dissociated from the potential effect of concurrent mood disturbance on this response. (2) …several investigators have reported increased numbers of peripheral blood lymphocytes bearing activation markers (such as HLA-DR and interleukin-2R) in these patients. (3) Impaired cell-mediated immune function in vivo is suggested by reports of an increased number of reduced or absent DTH (delayed-type hypersensitivity) skin testing responses in patients with (ME)CFS” (AR Lloyd. Clin Inf Dis 1994:18: (Suppl 1): S134-5). 1994 “Compared with those of healthy individuals, patients’ CD8+ T cells expressed reduced levels of CD11b and expressed the activation markers CD38 and HLA-DR at elevated levels…These findings indicate expansion of a population of activated CD8+ cytotoxic T lymphocytes. A marked decrease in NK cell activity was found in almost all patients with (ME)CFS, as compared with that in healthy controls…The results of this study suggest that immune cell phenotype changes and NK cell www.investinme.org Page 45 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) dysfunction are common manifestations of (ME)CFS…Because several immune abnormalities have been associated with this syndrome, the disorder has also been termed chronic fatigue immune dysfunction syndrome…A characteristic of (ME)CFS is a disordered immune system characterised by abnormal cell-surface marker expression and cellular immune function. …In patients manifesting incapacitating symptoms, the CD8+11b+ population is considerably reduced, and this reaches statistical significance….in agreement with the findings of other investigators, a decrease in NK cell-mediated lysis appears to be directly related to symptoms observed in (ME)CFS…The loss of these regulatory cells may allow for enhanced activation of other CD8+ lymphocytes such as the cytotoxic cells. Activated cells can over-produce cytokines that cause the symptoms characteristic of (ME)CFS” (Edward Barker, Alan L Landay, Jay A Levy et al. Clin Inf Dis 1994:18: (Suppl 1): S136-41). 1994 “Overall, 60% of patients had elevated levels of one or more of the nine soluble immune mediators tested…In patients with (ME)CFS – but not in controls – serum levels of TNF-alpha, IL-1 alpha, IL-4, and sIL-2R correlated significantly with one another and (in the 10 cases analysed) with relative amounts (as compared to betaglobin or beta-actin) of the only mRNAs detectable by reverse transcriptase-coupled polymerase chain reaction in peripheral blood mononuclear cells….These findings point to polycellular activation…. The immune system is a readily accessible, sensitive indicator of environmental or internal changes, and studies conducted by different groups over the past few years have provided valuable evidence for changes in immune status among individuals with (ME)CFS…. To gain insight into the nosology and aetiology of (ME)CFS, we assessed patterns of soluble immune mediator expression at the protein and mRNA levels in individuals with (ME)CFS….The data presented in this report are consistent with previous evidence of immune dysregulation among patients with (ME)CFS and point to a dysregulation of TNF (tumour necrosis factor) expression as a distinctive feature of this condition….Imbalances in TNF and associated changes in levels of other cytokines may underlie Invest in ME (Charity Nr. 1114035) many of the characteristic features of (ME)CFS…. In addition, TNF- can have deleterious effects on the central nervous system” (Roberto Patarca, Nancy G Klimas et al. Clin Inf Dis 1994:18: (Suppl 1):S147-153). Tumour necrosis factor is a cytokine involved in systemic inflammation. Its primary role is in the regulation of immune cells. Increased TNF causes apoptosis, inflammation and tumorigenesis. 1994 “The chronic fatigue immune dysfunction syndrome (CFIDS) is a major subgroup of the chronic fatigue syndrome (CFS)…. We and other investigators have reported a strong association between immune dysfunction and a serological viral activation pattern among patients in this group. This finding appeared similar to that for a variety of conditions, such as chronic active hepatitis…and systemic lupus erythematosus, in which a definite association between a particular HLA-DR/DQ haplotype and increased disease frequency has been reported. We thus elected to examine a cohort of patients with CFIDS, with use of HLA-DR/DQ typing…. A significant association between CFIDS and the presence of HLA-DQ3 was noted…. The association with HLA-DQ3 could represent an additive effect for patients who also have HLA-DR4 and/or HLA-DR5…. The results presented are intriguing. DQ3… was significantly more prevalent in patients than the …control groups. It is possible that DR4 and DR5 are also associated with an increased risk of developing CFIDS…. These findings strongly suggest that further evaluation of persons with CFIDS, including an investigation of an HLA Class I linkage dysequilibrium…are warranted….The data presented herein suggest that CFIDS, together with a variety of immune-mediated diseases…may share similar sequences of pathogenic mechanisms….It may be speculated that in a subpopulation (of CFIDS), a genetic predisposition may be triggered immunologically by any number of potential stimuli, resulting in a state of chronic immune dysequilibrium. This model could easily explain the recent findings with regard to acute viral infections, chronic active viral infection (and) allergies” (RH Keller, N Klimas, MA Fletcher et al. Clin Inf Dis 1994:18: (Suppl 1): S154-156). www.investinme.org Page 46 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) 1994 “These data suggest a correlation between low levels of NK cell activity and severity of CFIDS…. Compromised or absent natural immunity is associated with…acute and chronic viral infections such as AIDS, CFIDS… and various immunodeficiency syndromes. Our results confirm and extend previous reports that low NK cell cytotoxicity is a pronounced immunologic abnormality found in some patients with (ME)CFS… The fact that NK cell activity decreases with increased severity and duration of certain clinical variables suggests that measurement of NK cell function could be useful for stratification of patients and possibly for monitoring therapy for and/or the progression of CFIDS” (EA OjoAmaize et al. Clin Inf Dis 1994:18: (Suppl 1):S157159). 1994 “In summary, recent data, including findings presented in this supplement, have continued to support the possibility that immunologic factors are important in the development of (ME)CFS. Several potentially important clues to the nature of the immunologic disturbance are available. The time is ripe for more sophisticated immunologioc hypotheses for the pathogenesis of (ME)CFS) to be developed and tested” (Andrew R Lloyd and Nancy Klimas. Clin Inf Dis 1994:18: (Suppl 1):S160-161). 1994 “Abnormalities of immune function, hypothalamic and pituitary function, neurotransmitter regulation and cerebral perfusion have been found in patients with (ME/CFS). Recent research has yielded remarkable data. The symptoms of (ME)CFS have long been viewed as a neurologic pattern, as confirmed by other names such as myalgic encephalomyelitis. A link is being forged between the symptoms pattern of (ME)CFS and objective evidence of central nervous system dysfunction. The view that (ME)CFS is a primary emotional illness has been undermined by recent research” (David S Bell. Postgraduate Medicine 1994:98:6:73-81). Invest in ME (Charity Nr. 1114035) 1994 On 13th September 1994 the Report of the UK National Task Force on CFS/PVFS/ME was published; it was an initiative of the charity Westcare (no longer in existence) and was supported by the Department of Health and the Wellcome Trust. The section on immunology states: “Many groups have suggested that an immunological disturbance could account for the clinical features of the chronic fatigue syndrome (and) many have described abnormalities of immune function….NK cells have been studied particularly intensively in patients with (ME)CFS….Two main patterns of immunological abnormality have emerged from detailed studies of patients…the first is immunodepression and the second is activation of the immune system….Reduced NK cell function has been consistently reported….Strict criteria for diagnosing (ME)CFS have improved the correlation between the results of the immunological investigations and the clinical features of the patients studied….Perhaps the principal practical value of immunological tests, as currently performed, is to give additional evidence for an organic component”. 1994 The Autumn (Fall) 1994 issue of The CFIDS Chronicle published questions and answers in the section “Ask the Doctor”. One such was the reply provided by Professor Anthony Komaroff from Harvard, who is also Chief of the General Medicine Division at Brigham & Women’s Hospital, Boston, as well as leading a research team for one of the three NIH-funded CFS Co-operative Research Centres. In reply to the question “Why do (ME)CFS patients tend to relapse after exercise?”, Komaroff was clear: “this is due to an unusual reaction of the immune system to exercise”. He went on to explain that: “Research groups around the world continue to report that the (ME)CFS patient’s immune system seems to be in a chronically stimulated state, as if it is engaged in a battle against something it perceives as foreign to the body. Even though the immune system is often in a chronically-stimulated state, some parts of the system seem not to be working very well --- perhaps because they have been working too hard”. www.investinme.org Page 47 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) 1994 The Second Biennial International Clinical and Research Conference co-sponsored by the American Association for Chronic Fatigue Syndrome (AACFS) was held in Ft Lauderdale, Florida, on 7th – 10th October 1994; it was also sponsored by the NIH, the CDC and the University of Miami. Dr Seymour Grufferman (Pittsburgh Cancer Institute) described an (ME)CFS outbreak in the North Carolina Symphony Orchestra; the cases demonstrated persistent decreases in NK cell cytotoxicity and CD56 and CD16 cell populations and elevations in the CD4 population. These alterations were not seen in control subjects and could not be attributed to stress or gender. He concluded that (ME)CFS cases have a broad dysregulation of the immune system that persists over time. Dr Richard Lanham (State University of New York) presented a study of autoimmune disease in the families of patients with (ME)CFS and found more autoimmune disorders in their families, including thyroiditis, lupus, rheumatoid arthritis and allergy, causing him to consider that (ME)CFS patients may have an inherited genetic predisposition to immunological diseases such as (ME)CFS. Dr Joseph Cannon (Pennsylvania State University) provided historical and scientific evidence that females are more resistant to infection than males because of upregulation of the immune system. However it is because of this upregulation that women are more susceptible to autoimmune diseases. Dr Alison Mawle (from the CDC) reported that patients with (ME)CFS suffer from higher rates of allergy-related symptoms than normal controls and these were present in 70% of patients investigated. Dr James Jones (National Jewish Centre for Immunology, Denver), in the “Ask The Experts” session, said: “There is literature that suggests that allergic patients, when they get sick, have more symptoms and are sicker longer than other individuals…A number of my patients with allergies have seen increases in their systemic illness when treated with immunotherapy”. Invest in ME (Charity Nr. 1114035) Dr Adrienne Bennett (from Brigham & Women’s Hospital, Boston) measured transforming growth factor beta (TGF) and found that it was elevated in (ME)CFS patients, which might reflect the body’s attempt to down-regulate an over-active immune system. Dr Lawrence Borish (National Jewish Centre for Immunology, Denver) measured TNF-, IL-1, IL-6 and IL-10 (all associated with lethargy and inflammation); they found that TNF- and INF- (interferon alpha) were increased in ME/CFS patients but decreased in major depression. Most remarkably, IL-10 was absent in ME/CFS patients (IL-10 is produced by all T-helper cells and is stimulated by TNF-, the presence of which implies an inflammatory reaction). The absence of IL-10 supports the characterisation of ME/CFS as an immune disorder with a defect in the immune system’s ability to suppress the on-going immune reaction. Dr Irving Salit (Toronto General Hospital) found that the percentage of CD4 (T-helper cells) was increased in ME/CFS patients (a finding that is seen in people with allergies) compared with chronically fatigued controls who did not meet the CDC case definition for ME/CFS. He determined that ME/CFS patients have “a variety of immunologic abnormalities (including deviations in) immunoglobulins, T lymphocyte subsets and cell mediated immunity”. Drs Roberto Patarca, Nancy Klimas and Mary Ann Fletcher et al (Miami) described three groups of ME/CFS patients based on patterns of cytokine dysregulation: (1) dysregulation of TNF-/ expression in association with changes in serum levels of IL-1, IL-4, (soluble) IL-2R and IL-1 receptor agonist; peripheral blood mononuclear cell-associated expression of IL-1, IL-6 and TNF- messenger RNA, and T-cell activation; (2) interrelated and dsyregulated expression of soluble TNF receptor types 1, (s)IL-6R and 2microglobulin, and significantly decreased lympho-proliferative activity; (3) significantly decreased NK cell cytotoxic activity. Dr Kenny De Meirleir (Brussels) studied 149 patients with ME/CFS, categorising patients’ functional abilities using the Karnofsky Performance Scale (KS) which scores from 100 www.investinme.org Page 48 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) (perfectly well) to 0 (dead). 56 ME/CFS patients had a functional ability of less than 65 and 62 scored between 65 and 75. Flow cytometry was used to measure cellular immune status and the majority of immune abnormalities were found in the ME/CFS group with KS scores between 65 and 75. The immune abnormalities included increases in CD3+HLA-DR+ve T cells and an increase in the CD4/CD8 ratio (an increase in this ratio is found in allergies); there was also a decrease in NK cells. 1995 At the ACMA (Australian Complementary Medicine Association) National Consensus Conference held on 18th and 19th February 1995 in Sydney, Dr Paul Cheney presented his protocol for immunological testing: “Low level ANAs that fluctuate positive/negative are very common; various dysgammaglobulinaemias, including high IgG levels, low IgG levels and subclass deficiencies, are fairly common, and C1Q immune complexes can be common; (using) two colour flow cytometry looking at various immune activation markers, the one that we found the most sensitive is the CD3 CD26 marker for immune activation: a very interesting one has been the CD4/CD8 ratio – in the Lake Tahoe patients we see extraordinary elevations with this ratio, well above 10, we see 10 – 12 – 14 as the value of this ratio (due to both CD8 depletion and CD4 expansion). We’ve also seen a subset of patients, about 15%, with low CD4 counts….(With) serum and then cell-associated alpha interferon levels, we’re getting 60% on serum and on cell associated testing, 90% positivity…(The) IL-2 receptor can mark immune activation in the various immune function tests with respect to NK function. I’ve learnt that it’s important to assess the NK killing per NK cell and not just the gross kill….(We also use) various mitogen stimulation tests”. 1995 “One rationale for the immunological approach stems from the experience accumulated with similar syndromes such as autoimmune and environmentally-triggered diseases. (ME)CFS may be associated with certain HLA Class II antigens, as are some forms of environmental disease. These observations underscore the distinction Invest in ME (Charity Nr. 1114035) between (ME)CFS and psychiatric maladies. Viruses are frequently reactivated in association with immune system dysregulation in (ME)CFS and may contribute to symptomatology” (Roberto Patarca. JCFS 1995:vol I:3/4:195-202). 1995 On 23rd September 1995 350 people gathered in Charlotte, North Carolina, to attend a CFIDS Association conference at which esteemed researchers and clinicians from across America presented current information about (ME)CFIDS. It was reported in The CFIDS Chronicle, Autumn (Fall) 1995. Professor Nancy Klimas presented her University of Miami research group’s model of the proposed mechanism of (ME)CFDS, explaining that in this preliminary model, her group found genetic similarities very similar to those found in autoimmune diseases such as lupus erythematosus. She said that the typical CFIDS immune system is “noisy” or over-active, churning out chemicals in a chronic war against a real or perceived invader. In healthy people only 20% of the immune system cells (cytokines, interleukins and interferons) are activated at any one time, but in (ME)CFIDS, 60% of the cells are activated. For chronic immune activation to occur, something must be perpetuating the illness, which may include latent viral infections such as HHV-6, allergies and HPA axis dysregulation. Dr Jay Levy explained that once the immune system is activated, if the cells designed to quieten the immune response were not available, a disease such as (ME)CFIDS might be the result. Based on advanced immunological testing, Levy et al found that the immune system’s NK and suppressor cells are not working in (ME)CFIDS patients and he regularly screens (ME)CFIDS patients for this potential marker. 1995 The First World Congress on Chronic Fatigue Syndrome and Related Disorders, organised by The Department of Human Physiology at the Vrije Universiteit, Brussels, with The Ramsay Society, The World Federation of Neurology and The www.investinme.org Page 49 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) University of Glasgow, was held at The European Conference Centre, Brussels, on 9th – 11th November 1995. Session V was on the Immunology of (ME)CFS and was chaired by Professor Nancy Klimas and by Professor Umberto Tirelli. Professor Nancy Klimas (Miami) spoke on “The Immunopathogenesis of (ME)CFS” -- “(ME)CFS is characterised by a state of chronic immune activation and dysfunction, an observation confirmed by investigators in the US, Australia, Italy, Germany and the UK. The Miami group has longitudinal data suggesting patterns of immune dysfunction that correlate with the relapse/remitting nature of the illness. Specific patterns of soluble mediators suggest a key role for TNF alpha, and TNF receptor. Miami and other groups have shown that the degree of cellular dysfunction correlates with illness severity” (Conference Proceedings, page 28). Professor Umberto Tirelli (Director, Department of Medical Oncology, National Cancer Institute, Aviano, Italy) spoke on “Immunologic abnormalities in (ME)CFS” – “Immunological abnormalities so far associated with (ME)CFS include a decreased number and function of NK cells, the presence of chronically activated circulating T cells, abnormal distribution of T cell subsets, monocyte alterations, changes in B cells subsets, and abnormalities in cytokine serum levels or in vitro response of lymphocytes to mitogenic stimulation….Overall, (ME)CFS appears most likely to be a chronic disorder of the immune system probably caused by an infectious agent…with a chronic immune activation, in particular of cytokines and T lymphocytes” (Conference Proceedings, page 29). Dr Arnold Hilgers (Dusseldorf, Germany) spoke on “CFS: Evaluation of a 30-Criteria Score and Correlation with Immune Activation” – “Correlation between this 30-criteria score and immunological parameters could be evaluated in 472 out of the 505 patients. Significant positive correlation to the 30-criteria score was found in: CD8+ T-lymphocytes, DR+ T-lymphocytes, gamma globulin, IgM, IgG, and the number and types of autoantibodies (mainly ANA, ACA, thyroidal and parital antibodies)….In more and more larger groups of patients with (ME)CFS…we often see Invest in ME (Charity Nr. 1114035) clinical signs (and) specially a high prevalence of…prolonged inflammatory processes. Together with other results published by us and other investigators the data further confirm the hypothesis that a reduced or unstable immune control or delayed immune reaction to persisting viruses or bacterial intracellular pathogens can – triggered by common infections or other environmental factors – lead to a chronic neuroimmune activation state and autoimmune disorders” (Conference Proceedings page 30). In Poster Session I on 10th November 1995, Drs Mary Ann Fletcher, Roberto Patarca and Nancy Klimas posted on “Soluble receptors and chronic fatigue syndrome”, whilst L Habets, H Knechten and P Braun (Aachen, Germany) posted on “Patterns of immune dysfunction in patients with CFS”. In Poster Session II on 11th November 1995, C Demanet, E Joos, P de Becker, B Fischler and Kenny De Meirleir posted on “Evidence for immune activation in a subset of chronic fatigue syndrome patients”, whilst HJ Whelton, TJ Smith and EJ Fitzgibbon posted on “HLA-DR class II antigens and postviral fatigue syndrome”. 1995 On 18th November 1995 Professor Anthony Komaroff, Director and Professor of Medicine at Harvard Medical School, addressed an audience in London. For the benefit of the UK audience, he referred throughout to CFS as ME. With reference to the immune disturbance in ME/CFS, he said: “Now let’s turn to other objective laboratory studies. This is a paper we published three months ago, in which we basically summarised 10 years of laboratory studies, conducted on over 7,000 patients with ME from two different geographic areas in the States, who over 10 years have had 18,000 lab tests. These patients were compared with healthy people of the same age and sex. All blood samples were tested by technicians who did not know if a sample came from a healthy or an ME person. We found very striking increased frequencies of abnormalities: immune complexes were found nearly 27 times more often in ME patients than in healthy people. Elevated levels of immunoglobulin G were found nearly nine times more often in the ME patients. Unusually shaped white blood cells were found www.investinme.org Page 50 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) eleven times more often, also several other abnormalities. So these tests are saying there is, in the true ME patient, an activation of the immune system….There is more evidence in the literature that the immune system in ME is chronically turned on. I think that the body of evidence overwhelmingly says there is a chronic state of immune activation in these patients – as if they are fighting against something” (Perspectives, March 1996). 1996 “Many CFS patients have a history of allergies years before the onset of the syndrome…Sometimes patients report a worsening of allergic symptoms or the onset of new allergies after becoming ill with CFS…..Allergies are common in people with CFS….(there is a) high prevalence of allergies in the CFS population….many patients are extremely sensitive to drugs” Chronic Fatigue Syndrome. Information for Physicians. Issued in September 1996 by The National Institute of Allergy and Infectious Disease; National Institutes of Health (NIH), US Department of Health and Human Services. 1996 An important paper from Konstantinov and Tan et al demonstrated the occurrence of autoantibodies to a conserved intracellular protein (lamin B1), which provides laboratory evidence for an autoimmune component in ME/CFS. The authors found that 52% of patients with ME/CFS develop autoantibodies to components of the nuclear envelope (NE), mainly nuclear lamins, suggesting that in addition to the other documented disturbances of the immune system, humoral autoimmunity against polypeptides of the NE is a prominent immune derangement in ME/CFS. 67% of ME/CFS patients were positive for NE reactivity compared with 10% of normal controls. Autoantibodies to NE proteins are relatively infrequent and most fall into the category of an unusual connective tissue disease characterised by brain or skin vasculitis. The authors concluded that such activation “could be the result of various triggering agents, such as infections or environmental toxins. Future work should be directed at a better understanding of the autoimmune response of (ME)CFS patients to Invest in ME (Charity Nr. 1114035) other NE antigens” (K Konstantinov et al. J Clin Invest 1996:98:8:1888-1896). 1996 As presented at the First World Congress on (ME)CFS held in Brussels in November 1995, Hilgers and Frank developed a score for severity of ME/CFS to correlate with parameters of immune activation. This was effected by a 30-point criteria score, basic laboratory programmes and immunological profiles in 505 patients. In addition, tests of the complement system, immune activation markers, hormones and viral/bacterial intracellular serology were evaluated. Seventeen significant symptoms not currently in the CDC case definition were added, these being respiratory infections, palpitations, dizziness, dyspepsia, dryness of mouth/eyes, allergies, nausea, paraesthesia, loss of hair, skin alterations, dyscoordination (sic), chest pain, personality changes, eczema, general infections, twitches and urogenital infections. A significant correlation between the criteria score and immunological parameters could be evaluated in 472 of the 505 patients. The data confirm that a reduced or unstable immune control or delayed immune reaction to persisting viruses or bacterial intracellular pathogens, possibly triggered by common infections or other environmental factors, can lead to a chronic neuroimmune activation state and autoimmune disorders (JCFS 1996:2: (4):35-47). 1996 The Third Biennial AACFS Clinical and Research Conference was held on 13th – 16th October 1996 in San Francisco (reported in 67 pages of the January 1997 edition of The CFIDS Chronicle, to which grateful acknowledgment is made). Vicki L Carpman reported on the Endocrinology Sessions (“Stess-Associated Immune Modulation”), noting Dr Ronald Glaser’s presentation that stress directly modulates the immune, endocrine and central nervous systems and that research has shown that stress can induce viral reaction in at least three ways. Dr Glaser made a recommendation to (ME)CFS researchers: “The bottom line is that when (ME)CFS researchers have discussions about what immune markers to www.investinme.org Page 51 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) measure and why to measure them…my suggestion is to include the hormones because of their effect on immune function”. The Immunology Sessions included the following: Theresa L Whiteside, Professor of Pathology at the University of Pittsburgh School of Medicine and Director of the Immunologic Monitoring Laboratory at Pitt’s Cancer Institute, had applied her expertise in natural killer cell biology and immunology to the study of (ME)CFS. She recommended stratifying (ME)CFS patients by immune profile, noting that the immune abnormality that has been most commonly found is low NK cell account and cytotoxic activity (NK cells have a number of roles including defending against viruses, bacteria and tumours and interacting with the central nervous system). She said that in most diseases characterised by low NK cells such as cancer and AIDS, researchers understand the cause, but in (ME)CFS researchers do not know why NK cells are low. She concluded by saying she believes that (ME)CFS is actually a group of immune-mediated diseases and that the immune system may contribute to the pathogenesis. Professor Nancy Klimas reported on her work investigating the role of cytokine abnormalities reported in (ME)CFS; significant elevation of tumour necrosis factor receptor-type 1 (TNF R1) was found in the (ME)CFS samples and the data was also skewed for TNF , IL-5 and IL-10. This pattern is similar to that found in autoimmune diseases and allergy. Dr Eng Tan (from the Autoimmune Disease Centre and Department of Cell Biology, the Scripps institute, La Jolla, California) reported that of 60 (ME)CFS patients, 68% had evidence of antinuclear antibodies, an indication of autoimmune disease. Dr Konstantin N Konstantinov (Albuquerque, New Mexico) reported that his work “provides new laboratory evidence for an autoimmune component in (ME)CFS”. Dr Richard Lanham (State University of New York) noted the incidence of autoimmune or other immunological disease in the families of patients with (ME)CFS, which was reported by 64% of Invest in ME (Charity Nr. 1114035) (ME)CFS patients; Dr Lanham speculated that autoimmune conditions in the family history might be a predisposing factor for (ME)CFS. Dr Edward Barker (University of California, San Francisco) had compared CD+ cell function in patients with (ME)CFS and controls; CD69 expression on CD8+ cells was 58% in (ME)CFS patients whilst it was only 33% in controls. Specific lysis of anti-CD3 antibody-stimulated CD+ 8 cells was 62% in (ME)CFS and 32% in controls. The researchers concluded that “(ME)CFS is associated with an increase in CD8+ cell activity following activation” and that “CD+8 cell dysfunctions can be common findings in individuals with (ME)CFS”. Dr Neil Abbot et al (Scotland) carried out allergy and immune marker testing on patients with (ME)CFS and healthy controls, the (ME)CFS patients being stratified into three groups based on severity of symptoms. When immune activation markers were measured, CD38 levels were elevated in the sickest patients compared with the other two patient groups. Dr Arnold Hilgers (Germany) compared immune panels in 285 (ME)CFS patients, 40 MS patients, 44 rheumatoid disease patients and 100 atopic (allergic) disease patients. 41-88% of (ME)FS patients had functional abnormalities. Food protein hypersensitivity (Type IV) was more common than viral infections in all the patients groups studied. The researchers explained that food protein hypersensitivity might cause chronic immune activation. Dr Adrienne Bennett measured the four subclasses of IgG in a case-control study; levels of IgG1, IgG3 or IgG4, and levels of IgG2 were higher in the (ME)CFS cases than controls. The Immunology Workshop. Professor Nancy Klimas and Dr Jay Levy moderated this 2-hour Workshop, the goal being to improve consistency among (ME)CFS research studies. The Workshop’s conclusions were:  CD4, CD8, and NK cells should be included in the minimum immune panel. The activation markers DR, CD11, CD26, CD38 and CD69 and the cytokines IL-2, IL-4, IL-5, www.investinme.org Page 52 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) Il-6, IL-10 and IL-12 are of research interest  NK cell function should be measured as soon as possible following blood draw, within 4 hours  Researchers should consider the effect of the endocrine system on the immune system  A chronic infection may be causing the immune activation seen in (ME)CFS patients. 1997 On 17th January 1997 Dr Darryl See (Head of the CFIDS Clinic at the University of California, Irvine) gave a lecture in Los Angeles entitled “New Concepts in Cause and Treatment of CFIDS”, noting the low levels of IgG3 and IgG1 and the consequent loss of anti-viral activity, and the very, very low levels of IL-10 in people with (ME)CFIDS, pointing out that IL-10 is a down-regulator of the immune system and in normal people calms it down by decreasing the number of inflammatory cytokines. He also warned about taking prednisone: “You only take prednisone if you’re in the T-cell activation group. If you have natural killer cell dysfunction, and you give a lot of prednisone, your NK cell activity will go down (further) and you’ll start reactivating viruses. dangerous”. It’s 1997 Dr Charles Shepherd from the UK ME Association published an article in the British Journal of Social Work (1997:27:755-760) in which he drew attention to the most relevant findings to date, including the immunological dysfunction in ME/CFS: “Almost all reported studies have found laboratory abnormalities”, citing Strober W (1994) “Immunological function in chronic fatigue syndrome”; in: Straus S (ed): Chronic Fatigue Syndrome; New York, Mark Dekker, pp 237-240. 1997 “The level of bioactive transforming growth factor  was measured in serum from patients with (ME)CFS and compared with normal controls, patients with major depression, patients with Invest in ME (Charity Nr. 1114035) systemic lupus erythematosus and patients with multiple sclerosis. Patients with (ME)CFS had significantly higher levels of bioactive TGF than the healthy controls, patients with major depression, patients with systemic lupus erythematosus and patients with multiple sclerosis. Of greatest relevance to (ME)CFS are the effects of TGF  on cells of the immune and central nervous systems. There is accumulating evidence that TGF may play a role in autoimmune and inflammatory diseases” (AL Bennet, AL Komaroff et al. J Clin Virol 1997:17:2:160-166). 1997 “(ME)CFS is associated with dysregulation of both humoral and cellular immunity, including mitogen response, reactivation of viruses, abnormal cytokine production, diminished natural killer (NK) cell function, and changes in intermediary metabolites. The biochemical and immunologic data presented here identified a subgroup of individuals with (ME)CFS with an RNase L enzyme dysfunction that is more profound than previously observed (and) is consistent with the possibility that the absence of the 80-kDa and 40-kDa RNase L and presence of the LMW RNase L correlate with the severity of (ME)CFS clinical presentation” (Robert Suhadolnik, Daniel Peterson, Paul Cheney et al. Journal of Interferon and Cytokine Research 1997:17:377-385). Professor Suhadolnik explained in lay terms the significance of this paper (reported by Patti Schmidt in CFIDS Chronicle, Summer 1997, page 17): “He has found a particular place in the immune system, the 2-5 RNase L antiviral pathway, where something is wrong. ‘The whole antiviral pathway heats up out of control’ explained Suhadolnik. ‘You’re really sick physiologically. Your body just keeps going and going like the Energiser bunny, making ATP and breaking it down. No wonder you’re tired’. He’s found a novel protein in CFIDS patients in that viral pathway. ‘In most cases, the human body is able to resist infection thanks to a cascade of biochemical events triggered by the body’s immune system. If these antiviral defence pathways are functioning correctly, the spread of the virus is prevented’. www.investinme.org Page 53 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) Suhadolnik believes that (ME)CFS patients’ bodies are responding to a central nervous system virus that interferes with their viral pathways’ ability to fight off infection ”. 1997 On 16th August 1997 Professor Anthony Komaroff from Harvard made a presentation at NorthWestern Memorial Hospital, Chicago, where he summarised areas of the most exciting research. He said there were a number of biological and immunological measures that show promise and he was encouraged by the growing recognition of the disease as “one of the brain and not one of the mind”. He stated that there are objective physical abnormalities that occur in (ME)CFS, both neurological and immunological measures, mentioning specifically NK cells and autoimmune findings. 1997 A highly-respected paper by Vojdani and Lapp et al stressed the importance of cell apoptosis (and the pivotal role of protein kinase RNA in this) in ME/CFS: “A prominent feature of (ME)CFS is a disordered immune system. Recent evidence indicates that induction of apoptosis might be mediated in a dysregulated immune system by the up-regulation of growth inhibitory cytokines. The purpose of this study was to evaluate the apoptotic cell population, interferon- and the IFN-induced protein kinase RNA (PKR) gene transcripts in the peripheral blood lymphocytes of (ME)CFS individuals, as compared to healthy controls. One of the distinguishing manifestations of (ME)CFS is abnormal immune function, characterised by a decreased NK cell-mediated cytotoxic activity, reduced mitogenic response to lymphocytes, altered cytokine production, elevated titres of antibodies to a number of viruses, and abnormal production of interferon (IFN). The induction of apoptosis through immune defence mechanisms is an important mechanism for elimination of cancer cells as well as virusinfected cells. In the present study, the upregulation of IFN- and the IFN-induced PRK in (ME)CFS individuals is accompanied by the induction of apoptosis. In addition, dysregulation of cell cycle progression is associated with the induction of apoptosis in (ME)CFS individuals. Invest in ME (Charity Nr. 1114035) Quantitative analysis of apoptotic cell population in (ME)CFS individuals has shown a statistically significant increase compared to healthy controls. The population of apoptotic cells in 76% of (ME)CFS individuals was well above the apoptotic cell population in the control cells. Activation of PKR can result in induction of apoptosis. This activation of the PRK pathway could result from (a) dysregulated immune system or chronic viral infection” (A Vojdani et al. Journal of Internal Medicine 1997:242:465-478). 1997 “Previous studies from this laboratory have demonstrated a statistically significant dysregulation in several key components of the 2’ 5’A synthetase / RNase L and PKR antiviral pathways in (ME)CFS. The 2-5A synthetase / RNase L pathway is part of the antiviral defence mechanism in mammalian cells. An accumulating body of evidence suggests that (ME)CFS is associated with dysregulation of both humoral and cellular immunity, including mitogen response, reactivation of viruses, abnormal cytokine production, diminished natural killer (NK) cell function and changes in intermediary metabolites. Marked and striking differences have been observed in the molecular mass and RNase L enzyme activity of 2-5A binding proteins in extracts of PBMC from individuals with (ME)CFS compared with healthy controls. The biochemical and immunological data presented in this paper have identified a potential subgroup of individuals with (ME)CFS with an RNase L enzyme dysfunction that is more profound than previously observed in (ME)CFS, and which the authors believe is related to the severity of (ME)CFS symptoms” (Daniel L. Peterson, Paul R. Cheney, Kenny de Meirleir et al; Journal of Interferon and Cytokine Research 1997:17:377385). 1997 On 24th –26th October 1997 a CFIDS Association conference was held at St Charles, Illinois, attended by such luminaries as Drs Anthony Komaroff, Leonard Jason and Nancy Klimas. www.investinme.org Page 54 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) Professor Komaroff said that researchers have become more interested in the immunological abnormalities, and among the more consistent findings are depressed activity of NK cells and increased number of certain T-cell. Recent studies have found unusual antibodies attacking the nucleus of cells in (ME)CFIDS patients: “These have not been seen with this frequency in other illnesses”. Professor Klimas said that a temptation for doctors pondering how to approach treatment for (ME)CFIDS patients is to look at the activated immune system and try to calm it down, but “the dilemma in (ME)CFS is that we don’t know why that activity is there. We don’t know if this activation is in response to something in the body that needs the immune system to protect it. You run the risk of suppressing the immune system so I don’t think that’s a fair target now for (ME)CFS treatment” (The CFIDS Chronicle, January/February 1998). 1998 On 11th – 13th February 1998 a conference entitled “The Clinical and Scientific Basis of Chronic Fatigue Syndrome: From Myth towards Management” was held at Manly, Sydney, at which notable speakers included Dr David Bell, Dr Peter Rowe, Dr Martin Lerner, Dr Charles Lapp, Dr Byron Hyde, Dr Hugh Dunstan, Dr Neil McGregor, Dr Richard Burnet, Professor Gary Scroop and Professor Kenny De Meirleir. Speakers noted the detection of abnormalities in immunological measures including the CD4:CD8 ratio, an abnormality in NK cells and positive anti-nuclear antibodies. Colin Little presented a paper on the relationship of TGF and its relationship to fatigue and food intolerance, explaining that if small amounts of an ingested antigen (i.e. food) induce TGF and Th2 cells (which produce IL-4 and IL-10), then active suppression of protective Th1 cells occurs, with the result that patients experience intolerance/allergies to food, accompanied by autonomic symptoms. 1998 On 16th July 1998 Professor Stephen Straus from the USA gave a lecture at the Royal College of Invest in ME (Charity Nr. 1114035) Physicians, London, in which he said: “It is a disease that perhaps arises from immune dysfunction….There are reasons to implicate immune problems in CFS…There are many published reports of a range of immune abnormalities – immunoglobulin deficiencies, increased levels of cytokines, abnormal T cell subsets and NK cells”. 1998 “The increased expression of Class II antigens and the reduced expression of the co-stimulatory receptor CD28 lend further support to the concept of immunoactivation of T-lymphocytes in (ME)CFS and may be consistent with a viral aetiopathogenesis in the illness. We report, for the first time, increased expression of the apoptosis repressor protein bcl-2 (and) we demonstrated changes in different immunological parameters, each of which correlated with particular aspects of disease symptomatology (and) measures of disease severity” (IS Hassan, WRC Weir et al. Clin Immunol & Immunopathol 1998:87:1:60-67). 1998 The fourth Biennial AACFS International Research and Clinical Conference was held on 10th – 12th October 1998 at Cambridge, Massachusetts, with over 60 doctors and researchers attending. Professors Klimas, Fletcher and Patarca et al described (ME)CFS as “an illness which is associated with immune dysfunction, including abnormalities in the function of lymphocytes and expression of pro-inflammatory cytokines” (Conference Proceedings, page 19). Dr Eng Tan et al (from the Autoimmune Disease Centre and Department of Cell Biology, the Scripps institute, La Jolla, California) noted: “In previous studies (J Clin Invest 1996:98:1888-1896; Arthritis Rheum 1997:40:295-305) it was found that patients with (ME)CFS had autoantibodies to a relatively insoluble cellular antigen localised at the nuclear envelope called lamin B1….(Results) suggested that there might be an epitope on lamin B1 that was specific for (ME)CFS…..Conclusion: www.investinme.org Page 55 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) (ME)CFS patients have autoantibody responses which target epitope or epitopes in the Nterminal region of lamin B1” (Conference Proceedings page 26). Drs Aristo Vojdani, Charles Lapp et al noted that “A prominent feature of (ME)CFS is a disordered immune system. Recent evidence indicates that induction of apoptosis might be mediated in a dysregulated immune system by the upregulation of growth inhibitory cytokines….Increased apoptotic cell population was observed in (ME)CFS individual as compared to healthy controls” (Conference Proceedings page 27). S. Wagner, N Klimas et al: “The purpose of this study was to investigate the relationship between immunologic status and physical symptoms in (ME)CFS patients. The findings suggest that the degree of cellular immune activation is associated with the severity of (ME)CFS physical symptoms. Specifically, elevations in the T-helper/inducer cells, activated T-cells, activated cytotoxic/suppressor T-cells, and CD4/CD8 ratio are associated with greater disease severity”. The immune system abnormalities were (i) a low percentage of cytotoxic T cells; (ii) a low number of cytotoxic T cells; (iii) a high percentage of T helper cells; (iv) a high number of T helper cells; (v) a high CD4/CD8 ratio; (vi) a high number of activated T cells; (vii) a high percentage of cytotoxic T cells; (viii) high numbers of activated T cells (Conference Proceedings page 28). Professor Klimas said that the most important thing in this type of research is to carefully define the study population, and that the lack of definitional rigour may be the reason why study results have conflicted so widely. She also talked about four possible causes of persistent immune activation: (i) a persistent virus, bacteria or toxin; (ii) autoimmune disease; (iii) a ‘super-antigen’ which turns on the entire immune system (e.g. silicone), and (iv) allergy. She recommended that because the immune, endocrine and neurological systems are Invest in ME (Charity Nr. 1114035) interdependent, scientists integrate their findings in (ME)CFS. 1999 On 23rd and 24th April 1999, a “Fatigue 2000” International Conference was held in London. There were 25 speakers, including several from the US as well as from Europe. Many aspects of ME/CFS were addressed, including the immunological dysfunction. Professor Jonathan Brostoff (an immunologist and Director of the Centre for Allergy Research, University College, London) described the type of patient he saw at his clinics and discussed allergy in (ME)CFS. He was emphatic that environmental factors played a much more crucial role in (ME)CFS than has been acknowledged. 1999 “It is of great importance to develop biomarker(s) for differentiation between virally induced (ME)CFS (without sensitivity to chemicals) versus chemically-induced (ME)CFS. Since interferon induced proteins 2-5A Synthetase and Protein Kinase RNA (PKR) have been implicated in the viral induction of (ME)CFS, the objective of this study was to utilise 2-5A and PKR activity for differentiation between (ME)CFS induced by either viruses or chemicals. A clear induction of 2-5A and PKR was observed when MDBK cells were exposed to HHV6, MTBE, and benzene. We conclude that 2-5A and PKR are not only biomarkers for viral induction, but biomarkers to other stressors that include (chemicals)” (Vojdani A, Lapp CW. Immunopharmacol Immunotoxicol 1999:21(2):175-202). 1999 An article from researchers at the Institute of Immunology in Moscow discussed immunity impairment as a result of neurohormonal disorders and noted that at the base of (ME)CFS lie disturbances of the central nervous system, the endocrine system and the immune system: “It was found back in 1987/8 that there is an increase in the level of HLA DR and IL-2 receptors and an increase in the ratio CD4/CD8 in patients www.investinme.org Page 56 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) suffering from this syndrome” (Artsimovich NG et al. Russ J Immunol 1999:4(4):343-345). It is notable that Russian researchers were aware of these cardinal biomarkers of (ME)CFS as long ago as 1999, but that eight years later, the NICE Guideline Development Group who produced the Clinical Guideline on “CFS” (who were clearly influenced by the Wessely School but who were acclaimed by NICE as “experts” in the disorder) were apparently unaware of these diagnostic biomarkers. 1999 The Second World Congress on (ME)CFS and Related Disorders took place on 9th-12th September 1999 in Brussels; as was the First World Congress in 1995, it was organised by Professor Kenny DeMeirleir. Medical experts from around the world presented their most recent findings in 48 oral and 26 poster presentations to an estimated 150 conference delegates. Professor Nancy Klimas gave a comprehensive and authoritative overview entitled “Immunological Abnormalities in CFS”. She started by listing various factors affecting the immune system in (ME)CFS: (i) genetic predisposition (51%); (ii) triggering events (infections), and (iii) mediators (endocrinological and psychological factors), observing that the health outcome in any individual depends on how all these interact. She said the role of the immune system in illness is twofold: (1) it plays a direct role in contributing to the symptom complex: immune competence decides effective or defective prevention of reactivation of infections. When turned on, the lymphocyte antigen-driven response may generate a Type I response (CD4+, Th1, IL 2 / IL 12, INF - gamma, with activation of CD8+ cells that kill viruses). Lymphocytes play a vital role: they function through a messenger system -- cells have memories; they are antigen-driven and recognise infections, transplants, toxins, foods etc. Invest in ME (Charity Nr. 1114035) (2) it plays an indirect role, because it interacts with the brain (it has receptors for neurotransmitters) and with the endocrine system. Cortisol reduces inflammation through down-regulation of immune activation -- low cortisol in CFS could play a role in chronic immune activation. Stress has a profound impact on the immune system. Interaction with the hypothalamic/pituitary axis affects neurotransmitters and impacts on sleep. The Type II response (Th2, IL6, IL10, activation of B cells, and antibody production, which prevents/clears infection) comes to dominate as the illness extends. The importance of the 2-5 RNase -L (a product of INF- gamma activation) leads to an up-regulation of RNA synthesis and pro-inflammatory cytokines, TNF -alpha and IL 1, which also disturb circadian rhythms. Specific oligoclonal and not polyclonal antibodies are involved. With regard to oligoclonal versus polyclonal activation, Professor Klimas observed that there is a lack of abnormal serology to most latent viruses, suggesting that immune activation was antigen-specific. The effects of stress and negative life events were similar in CFS patients and in controls, but the long-term outcome depends on the shift from Th1 to Th2. There is evidence of chronic immune activation: enzyme systems are up-regulated (e.g. interferon, 2-5A RNase L activation, mRNA (cytokines). There is evidence of cytokine abnormalities – cytokines change over time and with illness severity: TNF-alpha receptor expression increases with flares of the illness, and there is increased evidence of Type II expression as the illness persists for years. Long-term, stress results in immune dysfunction illness (e.g. reduced numbers of CD8 (suppressor) cells, blunted growth hormone (GH) response and thyroid releasing factor (TRF), www.investinme.org Page 57 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) and increased corticotrophin releasing factor (CRF). Professor Klimas said (ME)CFS was an excellent model of neuroendocrine-immune interaction and re-stated the PNI (psychoneuroimmunological) paradigm as a basis for understanding the complex relationships which underlie the extensive changes occurring in (ME)CFS patients. She concluded by confirming that immune abnormalities play an integral role in the pathogenesis of (ME)CFS and that they contribute to the symptom complex, and that they interact with the autonomic and endocrine systems; the pattern and type of immune activation are equal to “cause and effect”. Following this conference, on 19th October 1999 The Medical Post (volume 35, number 35) published an article pointing out that, according to a US study by Professor Paul Levine from George Washington University that was presented at the Second World Congress on CFS and Related Disorders, patients with (ME)CFS who show signs of recent immunosuppression should be monitored for certain types of cancer: “This study suggests that immune dysfunction is an important aspect of at least one CFS subgroup….according to Dr Levine, the types of cancer reported included B-cell lymphoma, brain tumours, adenoid cystic carcinoma of the breast, transitional carcinomas of the bladder, uterine cancer, basal cell carcinoma… and non-Hodgkin’s lymphoma. Two (patients) reported multiple primaries. ‘These weren’t the type of cancers you’d see in a typical population’ (said Dr Levine)….The mechanism for this effect might involve natural killer cell activity, Dr Levine said. People with (ME)CFS have decreased (NK) activity, which is associated with cancer”. 2000 “The purpose of the present study was to investigate the relationship between immunologic status and physical symptoms in (ME)CFS. (Results) revealed significant associations between a number of immunologic measures and severity of illness. Specifically, elevations of Thelper/inducer cells, activated T cells, activated cytotoxic/suppressor T cells, and CD4/CD8 ratio Invest in ME (Charity Nr. 1114035) were associated with greater severity of several symptoms. Furthermore, reductions in Tsuppressor/cytotoxic cells also appeared related to greater severity of some (ME)CFS-related physical symptoms and illness burden” (SE Cruess, Nancy Klimas et al. JCFS 2000:7(1):39-52). 2000 “Most long-term sufferers (ill an average of 16 years)…showed a higher percentage of infection with viral and immune-related illnesses including allergies” (Friedberg F et al. J Psychosomatic Res 2000:48:59-68). 2000 “Over the past 15 years, scientists have identified numerous biological abnormalities that provide evidence for the reality and seriousness of (ME)CFS….In particular, they have provided evidence that the illness involves both the brain and the immune system….The leading model of (ME)CFS pathogenesis is rooted in scientifically identified abnormalities in the brain (central nervous system) and the immune system….Low levels of circulating cortisol, identified in several (ME)CFS research studies, can increase immune activation, which is also a key feature of (ME)CFS….Several immune system patterns are seen more often in patients with (ME)CFS. The identified abnormalities mimic the immune pattern of a body fighting a virus….(and include) low NK cell function (and) elevated immune complexes. The most intriguing recent immunological finding in (ME)CFS is the discovery of a novel low molecular weight protein in an antiviral pathway called the RNase-L pathway. This novel protein is found much more often in (ME)CFS patients than in healthy controls” (Anthony L Komaroff. The CFS Research Review, Spring 2000:1: 1-3). 2000 In 2000 Professor Anthony Komaroff from Harvard wrote about Professor Kenny De Meirleir’s work on RNase L in an Editorial in the American Journal of Medicine: “What is this research telling us? It is another piece of evidence that the immune system is affected in chronic fatigue syndrome and it reproduces and extends the work of www.investinme.org Page 58 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) another investigator (Professor Suhadolnik from the US), lending credibility to the result” (Am J Med 2000:108:169-171). (Belgian research has focused on the abnormal enzyme pathways and 88% of (ME)CFS patients tested positive for RNase L. The 37kDa is produced by calpain cleavage, and the whole process affects the calcium and potassium ion channel mechanisms. RNase L is a likely marker for (ME)CFS and correlates with severity. It is negative in AIDS -- with acknowledgement to Dr Rosamund Vallings). 2000 “Blood and lymph nodes samples were obtained from patients with (ME)CFS. While a greater proportion of T lymphocytes from both lymph nodes and peripheral blood of (ME)CFS patients are immunologically naïve, the proportions of lymphocytes with a memory phenotype predominate in lymph nodes and peripheral blood of (ME)CFS patients. (ME)CFS has been proposed to be a disease of autoimmune aetiology and in this respect it is interesting to note that decreased proportions of CD45RA+T (naïve) cells are also seen in the peripheral blood of patients with autoimmune diseases” (Mary Ann Fletcher, Nancy Klimas et al. JCFS 2000:7(3):65-75). 2000 A major and detailed Review of the immunology of (ME)CFS was published by internationallyrenowned immunologists Professors Robert Patarca and Nancy Klimas, together with the distinguished long-time ME/CFS research immunologist Professor Mary Ann Fletcher. It contains 212 references. It is clear that people with (ME)CFS have two basic problems with immune function: (1) immune activation and (2) poor cellular function. These findings have a waxing and waning temporal pattern consistent with episodic immune dysfunction. The interplay of these factors can account for the perpetuation of (ME)CFS with remission/exacerbation cycles. The Review considers the evidence of immune cell phenotypic distributions; immune cell function; cytokines and other soluble immune mediators; immunoglobulins; autoantibodies; circulating Invest in ME (Charity Nr. 1114035) immune complexes; Type I to Type II cytokine shift and the relationship between stressors, cytokines and symptoms. The data summarised indicate that (ME)CFS is associated with immune abnormalities that can account for the physiopathological symptomatology, and recommends that future research should further elucidate the cellular basis for immune dysfunction in (ME)CFS and its implications (JCFS 2000:6(3/4):69-107). 2000 The US National Institutes of Health held a State of the Science Conference on (ME)CFS on 23rd-24th October 2000 in Arlington, Virginia, and was attended by more than 200 people. The conference was divided into six topic areas: neuroendocrinology, neurocognition, pain, immunology, fatigue and orthostatic intolerance. Panelists included well-known (ME)CFIDS physicians such as Drs Nancy Klimas, David Bell, Dedra Buchwald and Peter Rowe. The Immunology section was described in the UK ME Association’s magazine “Perspectives” (Spring 2001) as the most interesting. It was noted that (i) previous studies suggested that the immune system and immune modulators (the chemical cascade that stimulates the immune system to act) are involved in the process of the illness; (ii) HLA markers are more common in (ME)CFS patients and these markers could be associated with autoimmune disease; (iii) the chemicals of the immune system may be directly or indirectly linked to symptom expression; (iv) NK function is low; (v) some classes of IgG are low; (vi) a CD3 receptor may have reduced expression in (ME)CFS patients; (vii) there is a shift during the illness from cellmediated immunity to humoral immunity (antibody-based), and this pattern is associated with autoimmune disease and chronic infection. The conference concluded with the expert panel summarising (ME)CFIDS research needs, most notably that researchers must subgroup patients by unique features such as immunology. 2000 “There is now so much literature from so many varying aspects of biology in ME/CFS that it is simply not possible to summarise it all in a paragraph or two. By calling the illness CFS we www.investinme.org Page 59 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) start with a conundrum – the name. This is a small point to many academics and clinicians but to sufferers and researchers alike it is at the hub of the enigma in terms of treatment and management and, also, for the researcher in the classification and definition of cohorts – the hallmark of good science….ME is a neurological illness (WHO ICD 10 G93.3) with evidence of immunological and toxicological signs, clear disturbance to the neuro-endocrine stress axis, impairment of the autonomic nervous system, irregularities in perfusion to the brain and indeed to the peripheral vascular system….A review of the literature on the immunology of (ME)CFS (Patarca-Montero R et al: JCFS 2000:6:69-107) reveals that people who have more strictly defined CFS equating with ME have two basic problems with immune function that have been documented by most research groups: 1. immune activation, as demonstrated by elevation of activated T lymphocytes, including cytotoxic T cells, as well as elevations of circulating cytokines, and 2. poor cellular function, with low NK cell cytotoxicity, poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgG1 and IgG3…..Although the causes of ME/CFS remain to be elucidated, many studies provide evidence for abnormalities in immunological markers among patients….Although a subset of patients with immune activation can be identified, serum markers of inflammation and immune activation are said by advocates of the psychiatric aetiology to be of limited diagnostic usefulness in the evaluation of patients with ME/CFS (even though) ME/CFS patients can be categorised by immunological findings….The same psychiatrists carelessly or expediently ignore the increasing evidence for the physical case for ME/CFS” (Research Report in ME/CFS for the Fife Health Board, Scotland. Dr Vance A Spence. November 2000). 2001 The Fifth Biennial International AACFS Research and Clinical Conference was held in Seattle from 26th – 29th January 2001. From the Immunology sessions, the following are highlighted: Professor Kenny De Meirleir (Brussels) presented evidence that a large number of (ME)CFS patients Invest in ME (Charity Nr. 1114035) have an abnormal immune profile; this altered immune system can result in the production of immunologic mediators such as interferons, interleukins and other cytokines. Recently, an up-regulation of the 2-5A Synthetase/RNase L pathway has been shown in (ME)CFS patients, indicating an activated immune state. According to their immununologic profile, patients were divided into three groups and significant differences were found for IFN gamma between groups 2 and 3 and between the controls and group 3. The presence of an increased amount of LMW (low molecular weight) RNase L correlated with higher levels of IFN gamma, which has antiviral properties (Conference Proceedings # 017). Drs K Sugiura, A Komaroff, Eng Tan et al reviewed autoimmunity in (ME)CFS and reported on a multi-centre study. Low titres of antinuclear antibodies have been found in (ME)CFS. The study looked at the presence of autoantibodies to a cellular protein expressed primarily in neuronal cells, MAP2 (a microtubule-associated protein). Initial studies with immunohistochemistry showed a high percentage of (ME)CFS sera reactive to centrosomes. Evidence shows that other proteins besides MAP2 might also be target antigens in (ME)CFS autoimmunity. Of interest was the high frequency of reactors with lupus erythematosus and rheumatoid arthritis compared with (ME)CFS patients (Conference Proceedings #037). Drs Kevin Maher, Nancy Klimas and Mary Ann Fletcher presented on “Flow Cytometric Measurements of Perforin and Natural Killer Cell Activity”: the intracellular content of the Natural Killer (NK) cell is perforin, a cell lytic protein common in many cells of the immune system which correlates with the cytolytic potential of the cell. In (ME)CFS, this chemical is reduced in NK cells. This finding substantiates claims of an NK associated defect in (ME)CFS and suggest a molecular basis for the reduced cytotoxicity (immune system killer cell function). This defect may not be NK specific but may encompass the cytotoxic T cell subset as well. Mice which were genetically engineered to have low or absent levels of perforin showed the same immune abnormalities as (ME)CFS. Other abnormalities www.investinme.org Page 60 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) found include activated lymphocytes in various subsets, elevated levels of immunoglobulins (IgG in particular) and increased levels of immune molecules called pro-inflammatory cytokines (Conference Proceedings #047). Drs Patrick Englebienne, Kenny De Meirleir et al provided evidence of apoptosis (programmed cell death) in (ME)CFS that has been suggested to contribute to the symptomatology. RNase L has been directly linked to the induction of apoptosis. This study showed that the activation of RNase L in the PBMC (peripheral blood mononuclear cells) of (ME)CFS patients up-regulates apoptotic activity in these cells. This suggests that the perturbed apoptotic process may play a role in the altered immunologic function in (ME)CFS (Conference Proceedings #068). The final session on 28th January 2001 was a name-change open forum (Professors Nancy Klimas, Leonard Jason and Charles Lapp) because a new and more appropriate name than “chronic fatigue syndrome” was deemed necessary: the Committee came to the view that there was enough scientific evidence to base a new name on the fact that this illness has neurological, immunological and endocrine components, hence the suggestion of NIEDS (neuro-immuneendocrine dysfunction syndrome, which describes the underlying pathology) to replace CFS. This conference was reported in The CFIDS Chronicle, Spring 2001:14:2:1-6 and also in The CFS Research Review Spring 2001:2:2:4-8. 2001 In his “Directions in Immunotherapy”, Professor Roberto Patarca-Montero from the University of Miami School of Medicine said: “In a subset of (ME)CFS patients, the immune system is always activated…One hypothesis is that it is caused by a lingering infection or an infection that leaves autoimmune sequelae. Although the immune systems of some (ME)CFS patients are chronically activated, parts function poorly, particularly the T cells and natural killer cells….(ME)CFS patients’ T cells have a decreased capacity to divide and generate new T cells, and their NK cells have Invest in ME (Charity Nr. 1114035) significantly decreased cytotoxic activity. In (ME)CFS, the immune system is based on the type of response T cells mount to infection. Two types of T-helper cells boost the immune attack – Thelper type 1 (Th1) cells and T-helper type 2 (Th2) cells. The Th-1 cells stimulate macrophages and NK cells, which directly attack microbes that replicate in the body’s tissues. This type of response is called cellular immunity. Th2 cells attack foreign matter too large to be killed by macrophages or NK cells by preferentially stimulating B cells to produce antibodies. This type of response is called humoral immunity. In (ME)CFS, as in many autoimmune diseases, the body tends to mount a humoral response. Activated T-helper cells from (ME)CFS patients produce fewer Th-1 cytokines (substances that convey messages to other cells and mediate their function) and produce more interleukin-5, a Th-2-type cytokine. Several therapeutic interventions are being studied to help reverse this unfavourable cytokine expression in (ME)CFS patients” (The CFS Research Review Winter (January) 2001:2:1:1). 2001 “Of significant interest was the fact that, of all the cytokines evaluated, the only one to be in the final model was IL-4 (which) suggests a shift to a Type II cytokine pattern. Such a shift has been hypothesised, but until now convincing evidence was lacking” (Hanson et al; Clin Diagn Lab Immunol 2001:8(3)658-662). 2001 “There is considerable evidence already that the immune system is in a state of chronic activation in many patients with (ME)CFS” (Anthony Komaroff, Assistant Professor of Medicine, Harvard Medical School: American Medical Association Statement, Co-Cure, 17 July 2001). 2001 In late autumn 2001 a Symposium on the immune system in (ME)CFS convened, with a panel of experts co-chaired by Dr Timothy Gerrity (Georgetown University Medical Centre) and Dr Dimitris Papanicolaou, (Emory University, Atlanta) and participants including Professors Nancy Klimas, Anthony Komaroff and Leonard Jason. It www.investinme.org Page 61 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) was sponsored by The CFIDS Association, the US Centres for Disease Control, and the National Institutes of Health Office of Research on Women’s Health and was the third in a series of scientific symposia on (ME)CFS. This series of (ME)CFS assessment symposia series was designed to examine the role of the neurological, endocrine, circulatory and immune systems in (ME)CFS. The Immune System symposium developed a strategy on key issues surrounding the immune system in (ME)CFS, with agreement on the following: (i) The immune system is involved in (ME)CFS: substantial published evidence shows that many (ME)CFS patients have immunological abnormalities; (ii) infections may also play a role: the panel concluded that direct and indirect evidence points to the involvement of active viral or bacterial infections in some case of (ME)CFS; (iii) (ME)CFS is a multi-system disorder: in addition to the immune system, the endocrine and autonomic nervous systems may be implicated and (iv) more research is needed to define the immunological aspects of (ME)CFS. The symposium particularly noted “the inappropriate practice of combining patients with…various comorbid conditions in studies and then attempting to draw conclusions across the subgroups” (The CFIDS Chronicle, Winter (January) 2002; The CFS Research Review, Winter (January) 2002:3:1). 2001 In December 2001 The Alison Hunter Memorial Foundation (AHMF) hosted the third international ME/CFS Research and Clinical Scientific Meeting in Sydney, Australia; the AHMF is an enduring memorial to Alison Hunter and to all those whose lives have been devastated by ME/CFS. Alison died aged 19 in 1996 from severe ME, suffering seizures, paralysis, gastrointestinal paresis, severe recurrent mouth ulcers and overwhelming infection, having courageously fought ME/CFS for ten years. Professor Anthony Komaroff (Harvard) spoke on “The Biology of ME/CFS”, noting that immune abnormalities are seen more often in patients, including low levels of circulating immune complexes, elevated total complement (CH50), elevated IgG, atypical lymphocytosis and low levels of antinuclear antibodies (ANA). Invest in ME (Charity Nr. 1114035) Immunological studies have revealed a variety of immunological abnormalities, especially impaired function of natural killer cells and increased numbers of activated CD+T cells. Whilst neither finding is specific enough to constitute a diagnostic marker, they are nevertheless consistent with a chronically activated immune system in ME/CFS. Two groups have reported what appears to be a more specific immune system abnormality in ME/CFS: an increased activity of the 2-5A enzymatic pathway in lymphocytes. Patients with ME/CFS were very different from those with depression, fibromyalgia and healthy controls. The evidence indicates an organic basis, with abnormal regulation of the immune system. Dr Patrick Englebienne and Professor Kenny De Meirleir (Brussels) spoke on “CFS and MS as Subsets of a Group of Cellular Immune Disorders”. Apoptosis (programmed cell death) is a critical component of adaptive cellular immunity. When challenged by infection, type I interferons elicit apoptotic responses by inducing the expression of 2-5A synthetase (2-5OAS), RNaseL and the p68 dependent kinase (PKR). Results from the authors’ laboratories point to an improper activation of 25OAS in monocytes of both patients with ME/CFS and with chronic (but not in relapsing/remitting) MS, which results in an inappropriate activation of RNaseL. This process ultimately leads to a blockade of the RNaseL-mediated apoptotic programme and it supports the involvement of environmental factors. Such cellular stress is capable of generating small RNA fragments and/or of inducing the transcription of endogenous retrovirus sequences. The ‘abnormal’ RNA sequences are responsible for the inappropriate activation of 2-5OAS and have been implicated in the aetiology of both ME/CFS and MS. Depending on their origin and structure, these RNA fragments are capable of either activating or down-regulating PKR. This results in a differential effect not only on the PKR/RNaseL-mediated apoptotic programmes but also on the activation by PKR of the inducible NO (nitric oxide) synthetase. A release of nitric oxide at either high rates (as in ME/CFS) or low rates (as in chronic MS) by lymphocytes has corollary consequences, triggering the skeletal and cardiac muscle ryanodine receptors (calcium channels), NK cell function, COX2 activation and glutamate release by activated T-cells in the brain. Glutamate www.investinme.org Page 62 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) upregulation leads to oligodendrocyte excitotoxicity in MS, whilst glutamate downregulation in ME/CFS impairs hypothalamic CRH secretion. These results suggest that ME/CFS and MS are extremes of an array of dysfunctions in the 2-5A/RNaseL/PKR pathways into which other autoimmune diseases such as lupus erythematosus might fit. Dr Pascale de Becker (Belgium) presented a poster showing that a number of different stressors and consequent immunological and neuro-endocrinological changes can contribute to the onset of ME/CFS. C.H. Little (Mt Waveney, Victoria, Australia) said that their laboratory has identified a separate class of immune products (T cell antigen binding molecules) which may be the basis for adverse reactions experienced by some patients to foods. Research indicates that an appropriate immune response to ingested food proteins is an absence of both Th1 and Th2 immune responses. This outcome (i.e. no response) may depend on antigen-specific regulatory cells whose function is to maintain tolerance to food proteins. The presence or absence of an immune response depends critically on signals delivered by special antigen-presenting cells (dendritic cells). This process can be potentially disrupted by environmental influences. (With grateful acknowledgement to Dr Rosamund Vallings from New Zealand). 2002 In an article entitled “CFS Research: The Need for Better Standards”, Professor Nancy Klimas was unequivocal: “Research effort is hampered by poorly conceived, constantly changing – even non-existent – standards….Authors of the 1988 case definition set out to identify a group of patients sharing similar symptoms and clinical signs, but problems using the definition quickly became apparent. A revision in 1994 (i.e. the Fukuda CDC definition, with which the Wessely School was involved) …attempted to address some of the difficulties, but the resulting guidelines are rife with ambiguity and vagueness. Symptoms are counted as either present or absent, without regard to severity or frequency….The use by some groups of outdated Invest in ME (Charity Nr. 1114035) case criteria developed in England (the Wessely School’s Oxford criteria) and Australia obscures comparability….A stronger research effort will enhance credibility for the illness….Overcoming the methodological challenges of studying (ME)CFS is essential to making progress in understanding this complex illness and to uncovering more direct means of diagnosis and effective treatments” (The CFS Research Review 2002:3:2:5-7). It is worth recalling that, eight years earlier, the Report of The UK The National Task Force (see above) stated exactly what Professor Klimas needed to repeat in 2002: the Task Force Report was unequivocal in concluding that progress in understanding (ME)CFS is hampered by the use of heterogeneous study groups and definitions of CFS; by the lack of adequate comparison groups; by the lack of standardised laboratory tests, and by the invalid comparison of contradictory research findings stemming from these factors. Research has shown that using the Holmes et al CDC 1988 criteria, 80% may have (ME)CFS; using the Fukuda et al CDC 1994 criteria, 40% may have (ME)CFS, and using the 1991 Oxford (Wessely School) criteria, 10% may have (ME)CFS; the Australian criteria give roughly the same results as the Oxford criteria (Co-Cure RES.MED, 3rd December 2002: New Canadian clinical definition – ME/CFS). It is also worth recalling Professor Wessely’s published view that “It is usual to try to discover the causes of an illness before thinking about treatments. Some illnesses are treated without knowledge of the cause…examples include… chronic fatigue syndrome” (New Research Ideas in Chronic Fatigue. Ed: Richard Frackowiak and Simon Wessely for The Linbury Trust; pub: The Royal Society of Medicine, 2000). This is in direct contradiction to Professor Klimas’ (and other biomedical researchers’) call for progress in understanding such a complex illness in order to find effective treatments. 2002 “The present review examines the cytokine response to acute exercise stress. The magnitude www.investinme.org Page 63 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) of this response bears a relationship to the intensity of effort but many environmental factors also modulate cytokine release. The main source of exercised-induced IL-6 production appears to be the exercising muscle. Cytokine concentrations are increased in (ME)CFS. Exercise-induced modulations in cytokine secretion may contribute to allergies (and) bronchospasm” (Shepherd RJ. Crit Rev Immunol 2002:22(3):165-182). 2002 In 2002 an important book was published by CRC Press: “Chronic Fatigue Syndrome – A Biological Approach” edited by Patrick Englebienne and Kenny De Meirleir. It provides a technical treatise on the scientifically documented basis of (ME)CFS and includes advances not only in the immunology, but also in the virology, bacteriology, protein chemistry and biochemistry, physiology and metabolism, clinical biology, pharmacology and epidemiology of (ME)CFS. 2003 On 31st January – 2nd February 2003, the Sixth Biennial AACFS International Research and Clinical Conference was held at Chantilly, Virginia. The number of oral and poster presentations (44 and 47 respectively) was down from the 2001 conference (72 and 41 respectively) and from the 1999 conference (57 and 46 respectively), but the conference was attended by over 190 physicians and health professionals from more than 14 countries, including Professors Anthony Komaroff, Leonard Jason, Robert Suhadolnik, Benjamin Natelson, Charles Lapp and Dr Daniel Peterson. Dr Kevin Maher (University of Miami Medical School) described his work to determine the molecular mechanisms underlying the decreased NK cell cytotoxicity found in (ME)CFS patients, including activated T cells, elevated cytokines and immunoglobulins and reduced NK cell activity. His studies demonstrated significantly elevated expression of the activation molecule CD26 on Thelper cells and significantly reduced NK cell cytotoxicity relative to controls. His studies concluded that perforin and granzymes A and B (used by T cells for killing infected cells) were significantly reduced in the T cells of (ME)CFS Invest in ME (Charity Nr. 1114035) patients, and that activation of T cells is correlated with increased IL-4 and with decreased IL-6 that are typically seen in (ME)CFS patients. In addition, the data suggest that the cytotoxic defect may not be NK specific but may encompass the cytotoxic T cell subset as well (with grateful acknowledgement to Drs Charles Lapp, Rosamund Vallings and Neil Abbot). Dr Patrick Gaffney (Department of Medicine, University of Minnesota) demonstrated that white blood cells from patients with (ME)CFS exhibit distinct gene expression profiles, with differential regulation of 54 genes between patients with (ME)CFS and normal healthy controls. 2003 In Spring 2003 the Canadian Clinical Case Definition was published (“Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnosis and Treatment Protocols”. JCFS 2003:11(1):7-115). It was developed by an international Expert Consensus Panel of physicians who are world leaders in ME/CFS and who between them had diagnosed and/or treated more than 20,000 ME/CFS patients. It presents a systematic clinical working case definition that encourages a diagnosis based on characteristic patterns of symptom clusters that reflect specific areas of pathogenesis; in particular, it differs from previous definitions in that it includes the hallmark symptom of (ME)CFS (post-exertional fatigability and malaise) and requires the presence of pain, sleep disturbance and cognitive dysfunction, and at least one of the given symptoms from two of the categories of neurological/autonomic, neuro-endocrine and immune manifestations. The expert panel member specialising in immunology was Professor Nancy Klimas. It was widely acclaimed internationally by clinicians, scientists and patients alike, but in the UK the Wessely School actively opposed its use within the NHS and Departments of State, with the result that NICE recommended against its use in its 2007 Clinical Guidelines on “CFS”. (Markedly different from the situation in the UK, a commissioned Report to the New Zealand Ministry of Health, November 2003, found that: “Of all the www.investinme.org Page 64 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) guidelines reviewed, this was the one which the reviewers were most enthusiastic to recommend for adaptation in New Zealand…. Rigorously produced and published in a peer-reviewed journal, the (Canadian) guidelines have a good, comprehensive and up-to-date evidence-based, well-referenced. The reviewers also found the Canadian guideline to be written with compassion and understanding for people with (ME)CFS…and that it adopted a more balanced…model of (ME)CFS”). 2003 On 12th-13th June 2003 a scientific workshop was held on “Neuro-Immune Mechanisms and CFS” at the Bethesda Marriott Hotel; it was hosted by the NIH and was designed to enhance understanding of (ME)CFS by examining the interface between the brain, the immune system, and the symptoms of (ME)CFS. Dr Esther Sternberg (Director of the Integrative Neural Immune Programme and Chief of the Section on Neuroendocrine Immunology & Behaviour at the NIH) spoke on “Health Consequences of a Dysregulated Stress Response”. A summary of her presentation by Rich Van Konynenburg was published on Co-Cure RES on 2nd July 2003. Firdhaus Dhabhar (Associate Professor at Ohio State University) spoke about the effects of stress in people with (ME)CFS and noted that the problems with stress and the immune system occur when the stress situation is long-term. Professor Nancy Klimas spoke on the immune dysfunction observed in (ME)CFS. She said there is a lot of data indicating that there is chronic immune activation in (ME)CFS, that there is a fair amount of data indicating that there is a shift from Th-1 to Th-2 type of immune response (which means that in (ME)CFS, the Th-1 response that kills infected cells is missing), that there is considerable data showing that there are changes in cytokine expression, and there is a lot of data showing lowered NK cell cytotoxicity. In addition, there is evidence for elevated numbers of immune complexes, elevated levels of Invest in ME (Charity Nr. 1114035) antinuclear antibodies (ANA), higher prevalence of allergies, and an activated RNase L pathway. Professor Klimas noted that there is a correlation between immune parameters and symptoms. In particular, when low NK cell activity and elevated T-cell activation are combined together, this correlates well with increased symptoms severity, and those with lower NK cell function had more severe fatigue and worse cognitive function. She also spoke about her group’s finding that NK cells in people with (ME)CFS are low in perforin (the substance normally used by NK cells to punch holes in infected cells in order to inject granzymes into them to kill them). She once again mentioned the problems resulting from the study of heterogeneous populations and from non-standardised methodology (Reported by Rich Van Konynenburg on Co-Cure RES, 3rd July 2003). 2003 A study was carried out by Belgian researchers to determine whether bronchial hyperresponsiveness (BHR) in patients with (ME)CFS is caused by immune system abnormalities. Measurements included pulmonary function testing, histamine bronchoprovocation test, immunophenotyping and ribonuclease (RNase) latent determination. There were 137 (ME)CFS participants. “Seventy three of the 137 patients presented with bronchial hyper-responsiveness. The group of patients in whom BHR was present differed most significantly from the control group, with eight differences in the immunophenotype profile in the cell count analysis, and seven differences in the percentage distribution profile. We observed a significant increase in cytotoxic T-cell count and in the percentage of BHR+ patients. Immunophenotyping of our sample confirmed earlier reports on chronic immune activation in patients with (ME)CFS compared to healthy controls, (with) BHR+ patients having more evidence of immune activation” (Nijs J, De Meirleir K, McGregor N et al. Chest 2003:123(4):998-1007). 2003 Japanese researchers focused on immunological abnormalities against neurotransmitter receptors www.investinme.org Page 65 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) in (ME)CFS using a sensitive radioligand assay. They examined serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1) and other receptors in patients with (ME)CFS and the results were compared with those in patients with autoimmune disease and with healthy controls. The mean antiCHRM1 antibody index was significantly higher in patients with (ME)CFS and with autoimmune disease than in controls. Anti-nuclear antibodies were found in 56.7% of patients with (ME)CFS. The patients with positive autoantibodies to CHRM1 had a significantly higher score of ‘feeling muscle weakness’ than negative patients among (ME)CFS patients. The authors conclude: “Autoantibodies to CHRM1 were detected in a large number of (ME)CFS patients and were related to (ME)CFS symptoms. Our findings suggest that subgroups of (ME)CFS are associated with autoimmune abnormalities of CHRM1” (Tanaka S, Kuratsune H et al. Int J Mol Med 2003:12(2):225-230). 2003 Looking at complement activation in (ME)CFS in the light of the need to identify biological markers in (ME)CFS, US researchers used an exercise challenge to induce symptoms of (ME)CFS and to identify a marker that correlated with those symptoms. “Exercise challenge induced significant increases of the complement split product C4a at six hours after exercise only in the (ME)CFS group” (Sorensen B et al. J All Clin Immunol 2003:112(2):397-403). 2003 “(ME)CFS is an increasing medical phenomenon leading to high levels of chronic morbidity. The aim of this study was to screen for changes in gene expression in the lymphocytes of (ME)CFS patients. In a small but well-characterised population of (ME)CFS patients, differential display has been used to clone and sequence genetic markers that are over-expressed in the mononuclear cells of (ME)CFS patients. Many researchers have recognised that current methods of diagnosis lead to the selection of a heterogeneous sample, and these data support that view. It is encouraging that the wide ‘spread’ of data seen in (ME)CFS patients is not seen in the control Invest in ME (Charity Nr. 1114035) samples. The data presented here add weight to the idea that (ME)CFS is a disease characterised by over-expression of genes, some of which are known to be associated with immune system activation. Identifying the triggering events for the induction of these genes will increase our understanding of this disease. Some interesting possibilities include viral infection, neuroendocrine disturbances, and allergen exposure. A link with allergy may be particularly pertinent since approximately 80% of (ME)CFS patients are atopic. Some of the genes identified in this study may therefore be linked with the increase in allergic effects seen in (ME)CFS” (R Powell, S Holgate et al. Clin Exp Allergy 2003:33:1450-1456). 2003 In an Invited Review, Patrick Englebienne from the Department of Nuclear Medicine, Vrije University, Brussels, explained in simple terms the significance of RNase L: “RNase L (2-5oligoadenylate-dependent ribonuclease L) is central to the innate cellular defence mechanism induced by Type I interferons during intracellular infection. In the absence of infection, the protein remains dormant. Recent evidence indicates, however, that the protein is activated in the absence of infection and may play a role in cell differentiation (and) immune activation. A deregulation of this pathway has been documented in immune cells of (ME)CFS patients. This protein escapes the normal regulation (resulting in) a cascade of unwanted cellular events. Recent data indicate that the RNase L system role is not limited to the cell defence mechanism against intracellular infection but extends to the complete innate and adaptive immune systems, including NK and T-cell proliferation and activation, as well as to cell differentiation and proliferation. The presence of unregulated active RNase L fragments in immune cells may lead to deleterious effects which are inherent to the cellular targets of the protein (because) an unregulated destruction of rRNA and of mitochondrial RNA leads to cell apoptosis. Should the RNase L de-regulation exist in muscle cells, it would necessarily restrain normal muscular development and hence activity (and) muscular weakness is a common feature of (ME)CFS” (JCFS 2003:11(2):97-109). www.investinme.org Page 66 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) 2004 A study of immunological aspects of ME/CFS by Wessely School psychiatrist Professor Peter White et al deserves particular attention: this is because he was Chief Principal Investigator (PI) of the PACE Trial and despite his prior knowledge of the immune abnormalities associated with exercise in ME/CFS patients, the PACE Trial did not use that evidence but instead focused on attempting to prove that correction of patients’ “aberrant illness beliefs” and graded exercise could “cure” ME/CFS. “We designed this pilot study to explore whether the illness was associated with alterations in immunological markers following exercise. Immunological abnormalities are commonly observed in CFS…Concentrations of plasma transforming growth factor-beta (TGF-) (antiinflammatory) and tumour necrosis factor-alpha (TNF-) (pro-inflammatory) have both been shown to be raised….Abnormal regulation of cytokines may both reflect and cause altered function across a broad range of cell types…..Altered cytokine levels, whatever their origin, could modify muscle and or neuronal function. “Concentrations of TGF-1 (anti-inflammatory) were significantly elevated in CFS patients at all times before and after exercise testing. “We found that exercise induced a sustained elevation in the concentration of TNF- (proinflammatory) which was still present three days later, and this only occurred in the CFS patients. “TGF- was grossly elevated when compared to controls before exercise (and) showed an increase in response to the exercise entailed in getting to the study centre. “These data replicate three out of four previous studies finding elevated TGF- in subjects with CFS. “The pro-inflammatory cytokine TNF- is known to be a cause of acute sickness behaviour, characterised by reduced activity related to ‘weakness, malaise, listlessness and inability to concentrate’, symptoms also notable in CFS. Invest in ME (Charity Nr. 1114035) “These preliminary data suggest that ‘ordinary’ activity (i.e. that involved in getting up and travelling some distance) may induce antiinflammatory cytokine release (TGF), whereas more intense exercise may induce proinflammatory cytokine release (TNF-) in patients with CFS” (Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. White PD, KE Nye, AJ Pinching et al. JCFS 2004:12 (2):51-66). 2004 “Many patients with (ME)CFS have symptoms that are consistent with an underlying viral or toxic illness. Because increased neutrophil apoptosis occurs in patients with infection, this study examined whether this phenomenon also occurs in patients with (ME)CFS. Patients with (ME)CFS had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, and increased expression of the death receptor, tumour necrosis factor receptor-1 on their neutrophils than did healthy controls. These findings provide new evidence that patients with (ME)CFS have an underlying detectable abnormality in their immune cells” (Kennedy G et al. J Clin Pathol 2004:57(8):891-893). Commenting on this paper, Dr Neil Abbot, Director of Operations at ME Research UK, noted: “The new paper by Dr Gwen Kennedy (MERGE Research Fellow) and colleagues reports evidence of increased neutrophil apoptosis (programmed cell death) in ME/CFS patients. Neutrophils represent 50-60% of the total circulating white blood cells and are fundamental to the functioning of an intact immune system. The data presented in this report are consistent with the presence of an underlying, detectable abnormality in immune cell behaviour of many ME/CFS patients, consistent with an activated inflammatory process, or a toxic state” (Co-Cure RES MED 30th July 2004). Also commenting on this paper, Dr Charles Shepherd of the UK ME Association said: “The BMJ doesn’t normally show any interest in research which supports a physical cause for ME/CFS. However, today’s edition does refer to some www.investinme.org Page 67 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) interesting new findings relating to neutrophil apoptosis (increased cell death involving a particular type of white blood cell) that was reported in the Journal of Clinical Pathology (2004:57:891-893). The BMJ goes on to conclude: ‘Evidence is emerging that people with chronic fatigue syndrome may have a detectable immunological abnormality’. They may be 15 years behind the rest of us in coming to this conclusion, but better late than never!” (Co-Cure MED, NOTICE, 20th August 2004). 2004 “The exacerbation of symptoms after exercise differentiates (ME)CFS from several other fatigueassociated disorders. Research data point to an abnormal response to exercise in patients with (ME)CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune dysregulation in (ME)CFS patients. The dysregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycaemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in (ME)CFS patients. The activation of the protein kinase R enzyme, a characteristic feature in at least a subset of (ME)CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with (ME)CFS. Elevated NO is known to induce vasodilation, which may cause and enhance post-exercise hypotension” (J Nijs, K De Meirleir, N McGregor, P Englebienne et al. Med Hypotheses 2004:62(5):759-765). 2004 “Immunological aberration (in ME/CFS) may be associated with an expanding group of neuropeptides and inappropriate immunological memory. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are immunogenic and known to be associated with a range of autoimmune conditions. They are widely distributed in the body, particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, Invest in ME (Charity Nr. 1114035) blood cells and other tissues. They have a vital role in maintaining vascular flow in organs and are potent immune regulators with primary antiinflammatory activity. They have a significant role in protection of the nervous system (from) toxic assault. This paper provides a biologically plausible mechanism for the development of (ME)CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection or significant physical exercise. Such an occurrence would have predictably serious consequences resulting from the compromised function of the key roles these substances perform” (Staines DR. Med Hypotheses 2004:62(5):646-652). 2004 The November 2004 issue of NeuroImmunoModulation contained the Report of the Research Symposium on ME/CFS convened by the CFIDS Association and co-sponsored by the CDC and the NIH. The report is entitled “Immunologic Aspects of Chronic Fatigue Syndrome” and is important because it sets out the necessary direction of future research. “(ME)CFS is a serious health concern …. studies have suggested an involvement of the immune system. A Symposium was organised in October 2001 to explore the….association between immune dysfunction and (ME)CFS, with special emphasis on the interactions between immune dysfunction and abnormalities noted in the neuroendocrine and autonomic nervous systems of individuals with (ME)CFS. This paper represents the consensus of the panel of experts who participated in this meeting….Data suggest that persons with (ME)CFS manifest changes in immune responses that fall outside normative ranges…(ME)CFS seems to be a multi-system disorder….There is substantial evidence that a large proportion of patients has some immunologic abnormalities, including decreased natural killer cell activity, an increase in the percentage of T cells expressing activation markers, decreased lymphocyte stimulation by certain mitogens and soluble antigens, and increased production of certain pro-inflammatory cytokines. The humoral immune system has also shown frequent abnormalities, including hypergammaglobulinemia, increased titres of www.investinme.org Page 68 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) various antibodies, and the presence of immune complexes. These changes support the conclusion that dysregulation of cellular and humoral response are associated with CFS…..The pattern of immune abnormalities suggests that immunologic factors may contribute to the pathogenesis….It seems plausible that the overproduction of some cytokines contributes to the fatigue. The recent demonstration of activation of the 2-5A synthetase pathway (associated with interferon- signal transduction) in some (ME)CFS patients provides support for this hypothesis…The search for infectious agents in (ME)CFS patients should be initially guided by…the detection of circulating antibodies and antigens to agents that have been implicated in (ME)CFS….A good experimental model…should…utilise wellcharacterised and homogeneous subject populations…. The panel recommends the implementation of longitudinal studies that include the following key elements: wellcharacterised cases and controls; assays designed to measure immune function: (a) natural killer cell activity; (b) percentage of peripheral blood lymphocytes expressing activation markers; (c) pro-inflammatory cytokines and soluble receptors; (d) Th-1 and Th-2 responses; (e) activity of the 2-5A synthetase pathway, and (f) serum immunoglobulin levels; selected measures of autonomic nervous system and neuroendocrine functioning; functional magnetic resonance imaging studies; studies… to demonstrate the presence or absence of viral/microbial genetic material….The use of interdisciplinary, multi-site (including international) longitudinal studies to explore links between the variations noted in (ME)CFS patients’ immune, neuroendocrine, and cardiovascular systems is critical to developing an understanding of relationships among causal factors, symptom progression, and recovery…. Three primary methodological barriers impair the investigations of (ME)CFS: poor study design, the heterogeneity of the CFS population, and the lack of standardised laboratory procedures. The quality of previous CFS research (is hampered by) multiple differences in methods of subject recruitment and classification (and) clinical definitions applied and outcome measures used. It is our obligation to overcome the methodological barriers outlined above” (Gerrity TR et al. NeuroImmunoModulation 2004:11(6):351-357). Invest in ME (Charity Nr. 1114035) 2004 “Patients (with ME/CFS) are more likely to have objective abnormalities of the immune system than control subjects. We measured the frequency of certain HLA antigens (and) restricted our analysis to Class II molecules, as these appear to be more specific predictors of susceptibility to immunologically-based disorders. The frequency of the HLA-DQ1 antigen was increased in patients compared to controls. This association between (ME)CFS and the HLA-DQ1 antigen translates into a relative risk of 3.2” (RS Schacterle, Anthony L Komaroff et al. JCFS 2004:11(4):33-42). 2004 The Seventh Biennial AACFS International Research and Clinical Conference was held on 8th – 10th October 2004 at Maddison, Wisconsin. It was attended by 120 doctors and 112 patients, and research presenters came from people from about 16 different countries, but Professor Klimas commented that there was no-one from England (in discussion afterwards, she said “But none from England this year, and I don’t know why”). As one attendee put it: “Her statement was one of dismayed puzzlement…it was spoken by a busy researcher who doesn’t have time for politics and is completely baffled why (researchers from the UK) are no longer present at the research symposium…. Probably the most expressive part of Dr Klimas’ comment was her non-verbal expression – she was expressing deep and personal concern” (private communication). As another person observed: “I was assured by the Department of Health that those running the PACE Trial are international specialists, yet not one of them thought it necessary to attend such an important international conference where the ‘immunologic and neurologic malfunctions’ of ME/CFS featured so strongly. Doesn’t that just say it all?” (private communication). Professor Anthony Komaroff (Harvard) began the conference with an over-view of current research, saying that research has shown abnormalities in many systems: “Studies of immune activation indicate that activated lymphocytes can pass through the blood-brain barrier in small www.investinme.org Page 69 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) numbers…and thereby activate lymphocytic dendritic cells that reside in the brain, particularly microglia and perivascular cells, and this state of low-level activation can last decades. Activated microglia, like macrophages, secrete proinflammatory cytokines (e.g. TNF, IL-1) and NO (nitric oxide). There is increased neutrophil apoptosis in (ME)CFS”. Professor Robert Suhadolnik (Temple University, Philadelphia) reviewed the evidence and effect of the up-regulated 2-5A synthetase RNase L antiviral defence pathway. There is a 500-fold excess of bioactive 2-5A in (ME)CFS. The higher the RNase L activity, the lower the patient’s ability to function. These patients also have a low molecular weight 37 kDa RNase L which is not found in healthy controls, patients with depression, or fibromyalgia patients. The patient has lowered signal transduction, lowered cell proliferation, lowered ATP production, lowered cellular metabolism, lowered protein synthesis, impaired NK cell function, abnormal exercise response, loss of potassium from muscle, abnormal sodium retention, hyperventilation, central fatigue, sleep disturbances, and muscle cramps and weakness. Dr Kevin Maher (University of Miami) presented evidence that “key proteins associated with the cytolytic process (granzymes A and B) are present at lower cellular concentrations in NK cells from individuals with (ME)CFS”. Dr Jo Nijs (Belgium) presented evidence for an association between intracellular (elastase activity) immune dysregulation and impairments in cardio-respiratory fitness in (ME)CFS patients. This study indicates subtle underlying lung damage. (A presentation by Dr Anna GarciaQuintana from Spain showed that the average maximal oxygen uptake of (ME)CFS patients was only 15.2, whereas the sedentary controls’ uptake was 25.9, and the physically active controls’ uptake was 66.6). Professors Nancy Klimas and Leonard Jason discussed sub-grouping, concluding that finding distinct sub-populations has clear clinical implications by defining groups for targeted Invest in ME (Charity Nr. 1114035) intervention. Objective measures are needed for this approach and can include issues such as immune disturbance (cytokines, cell function). “Sub-grouping is the key to understanding how (ME)CFS begins, how it is maintained, how medical and psychological variables influence its course and how it can be prevented, treated and cured”. In her summary Professor Klimas noted that all the reports confirmed and augmented the same cycle of immunological and neurological malfunctions but said that there is a risk of (ME)CFS being defined as a behavioural disorder if (biomedical) research is not supported (with grateful acknowledgement to Paula Carnes, Dr Rosamund Vallings and Dr Charles Lapp). 2005 In her Incoming Presidential Address for the AACFS, immunologist Professor Nancy Klimas said: “I am proud to assume the role of president of the AACFS, an organisation with a pressing and compelling mission. The AACFS exists to promote research, education, and advocacy to further our understanding and eventually develop effective treatments for this disabling illness….Our patients are terribly ill, misunderstood, and suffer at the hands of a poorly informed medical establishment and society” (Co-Cure ACT: 21st March 2005). 2005 “There are a group of diseases that the allergistimmunologist may be called up to manage…that appear to be initiated by allergic mechanisms….In patients with (ME)CFS, there appears to be a fundamental dysfunction of the neuroendocrineimmunological system with deficiencies of immunological and neurological function which, together with chronic viral infection, may lead to a sequence of events responsible for the symptoms of this disorder….An understanding of the interactive responses involved in the neuroendocrine-immunological network is essential for a comprehension of the pathophysiology of…(ME)CFS…and the role of allergies appears to be an important triggering www.investinme.org Page 70 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) event…” (Bellanti JA et al. Allergy Asthma Proc 2005:26(1):19-28). 2005 “Arguments exist as to the cause of (ME)CFS. Some think that it is an example of symptom amplification indicative of psychogenic illness, while our group thinks that some (ME)CFS patients may have brain dysfunction. We did spinal taps (lumbar puncture) on (ME)CFS patients. We found that significantly more (ME)CFS patients had elevations either in protein levels or numbers of cells than healthy controls and (some) patients had protein levels and cell numbers that were higher than laboratory norms. In addition, of the 11 cytokines detectable in spinal fluid, (some) were lower in patients than in controls (and some) were higher in patients. The results support two hypotheses: that some (ME)CFS patients have a neurological abnormality and that immune dysregulation within the central nervous system may be involved in this process. A recent study showing elevations of IL-8 and IL-10 levels during chemotherapy-induced symptoms resembling some of those seen in (ME)CFS provides additional evidence for this hypothesis” (Benjamin H Natelson et al. Clin Diagn Lab Immunol 2005:12(1):52-55). 2005 An article in The Scientist pointed out the need to measure cytokines in diverse disorders: “The immune system is often likened to the military. The body’s army has weapons such as antibodies and complement, and soldiers such as macrophages and natural killer cells. The immune system sports an impressive communications infrastructure in the form of intracellular protein messengers called cytokines and the cellular receptors that recognise them. The cytokine family consists of such soluble growth factors as the interleukins, interferons, and tumour necrosis factor, among others. Their measurement has become an integral part of both clinical diagnostics and biomedical research” (JP Roberts. The Scientist 2005:19:3:30). It needs to be noted that in the UK, the NICE Clinical Guideline 53 on “CFS” (2007) proscribes such measurements in people with ME/CFS, as did Invest in ME (Charity Nr. 1114035) the MRC’s “CFS/ME Research Advisory Group Research Strategy” Report of 1st May 2003, as did the CMO’s Report of 2002, and as did the Joint Royal Colleges Report (CR54) of 1996. 2005 “Hyperactivation of an unwanted cellular cascade by the immune-related protein RNase L has been linked to reduced exercise capacity in persons with (ME)CFS. This investigation compares exercise capabilities of (ME)CFS patients with deregulation of the RNase L pathway and CFS patients with normal regulation. The results implicate abnormal immune activity in the pathology of exercise intolerance in (ME)CFS and are consistent with a channelopathy involving oxidative stress and nitric-oxide toxicity” (Snell CR et al. In Vivo 2005:19(2):387-390). 2005 “Diminished NK cell cytotoxicity is a frequently reported finding (in ME/CFS). However, the molecular basis of this defect has not been described. Perforin is a protein found within intracellular granules of NK and cytotoxic T cells. Quantitative fluorescence flow cytometry was used to the intracellular perforin content in (ME)CFS subjects and healthy controls. A significant reduction in the NK cell associated perforin levels in samples from (ME)CFS patients compared to healthy controls was observed. There was also an indication of a reduced perforin level within the cytotoxic T cells of (ME)CFS subjects, providing the first evidence (of) a T cell associated cytotoxic deficit in (ME)CFS. Because perforin is important in immune surveillance and homeostatis of the immune system, its deficiency may prove to be an important factor in the pathogenesis of (ME)CFS and its analysis may prove useful as a biomarker in the study of (ME)CFS” (Maher KJ, Klimas NG, Fletcher MA. Clin Exp Immunol 2005:142(3):505511). 2005 “Previous research has shown that patients with (ME)CFS present with an abnormal exercise response and exacerbations of symptoms after www.investinme.org Page 71 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) physical activity. The highly heterogeneous nature of the CFS population and the lack of uniformity in both diagnostic criteria and exercise testing protocols preclude pooling of data. Still, we conclude that at least a subgroup of CFS patients present with an abnormal response to exercise. Importantly, the exacerbation of symptoms after exercise is seen only in the (ME)CFS population and not in fatigue-associated disorders such as depression. Earlier (studies) revealed that in (ME)CFS patients, irrational fear of movement is not related to exercise performance. The aim of this study was to examine the interactions between several intracellular immune variables and exercise performance in (ME)CFS. These data add to the body of literature showing impairment of intracellular immunity in patients with (ME)CFS. The results provide evidence for an association between intracellular immune dysregulation and exercise performance in patients with (ME)CFS” (J Nijs, N McGregor, K De Meirleir et al. Medicine & Science in Sports & Exercise 2005:Exercise Immunology in CFS:16471654). 2005 “The hypothesis of the present study is that the appearance of cell-specific autoimmune antibodies may define subsets of (ME)CFS. (ME)CFS is clinically similar to several autoimmune disorders that can be diagnosed and characterised by autoantibody profiles. For this reason, we conducted an exhaustive evaluation of 11 ubiquitous nuclear and cellular autoantigens in addition to two neuronal specific antigens. Very few studies have evaluated the presence of autoantibodies in people with (ME)CFS. The findings of this study hint that evaluation of certain autoantibodies may give clues to on-going pathology in subsets of (ME)CFS subjects. Among (ME)CFS subjects, those who had been sick longer had higher rates of autoantibodies” (S Vernon et al. Journal of Autoimmune Diseases May 25th, 2005:2:5). 2006 The CFIDS Association produced a special issue of the Chronicle entitled “The Science and Research of CFS” (2005-2006); it contained a major article by Professor Nancy Klimas entitled “The State of Invest in ME (Charity Nr. 1114035) CFS Research” in which she noted factors that have contributed to the slow progress in unravelling (ME)CFS: these included the troublesome case definition, the need to identify sub-groups and the need to attract good researchers. Professor Anthony Komaroff considered the known abnormalities of the neurological and immune systems, and Dr Susan Levine provided a detailed overview of the immune abnormalities in her article entitled “Immune System Gone Haywire?” in which she focused in the six prominent immune abnormalities consistently shown over the previous 18 years: (i) impaired function of NK cells; (ii) increased number of destructive T cells and increased number of T cells expressing activation markers; (iii) activation of several proinflammatory cytokines; (iv) dysregulation of the 2’5 A RNase L antiviral pathway; (v) predominance of Th-2 cellular immunity and (vi) differential expression of gene markers whose products cause T cell activation. She noted that these findings are important and intriguing, in particular that intracellular perforin, an NK-cell lytic protein, is reduced in (ME)CFS patients. She noted that in (ME)CFS there is often reactivation of latent viruses and she also drew attention to the observation of aberrant cytotoxicity in (ME)CFS subjects who demonstrated a differential gene expression of at least 35 gene sequences compared with matched normal controls that suggest a link with organophosphate exposure. In addition, she noted that stress is known to affect both immune activity and neuroendocrine responses in (ME)CFS. 2006 In an article entitled “Exploring the Gene Scene”, Dr Jonathan Kerr from St George’s University of London said: “In 2001 I became increasingly involved in a collaborative study group concerned about the lack of research attention (ME)CFS has received, particularly in terms of how the disease is actually caused and perpetuated. We also take issue with the trivialisation of (ME)CFS and the labelling of patients as sufferers of a psychiatric or psychological disease. To address the problem, we turned to the study of gene activity……Most genes are expressed in the white blood cells and various groups have shown that the white blood cells of (ME)CFS patients exhibit reproducible www.investinme.org Page 72 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) alterations in gene expression as compared with normal controls….Certain themes of gene activity are emerging, of which ‘immunity and defence’ is the most prominent. This supports previous findings on the role of the immune system in the maintenance of this disease….16 genes were shown to be expressed at very different levels in the (ME)CFS cases compared with the controls. These differentially expressed genes were involved in several processes, including the immune response, the mitochondria (or powerhouse of the cell), conversion of DNA to RNA (termed transcription) and conversion of RNA to protein (termed translation). Although this indicates a complex picture, it’s proof that (ME)CFS patients exhibit significant and reproducible differences in gene expression compared with controls….Knowledge of how a disease is caused can lead directly to design and utilisation of treatments to correct the abnormal processes, which can eventually lead to improvement or cure of the disease” (The CFIDS Chronicle, Spring 2006:8-11). 2006 At the Invest in ME Conference held on 12th May 2006 in London, expert speakers presented their work, including evidence from Dr Jonathan Kerr from St George’s University, London, that most of the abnormally expressed genes seen in (ME)CFS are involved in the immune system. The take-home message was:  Since a prolonged inflammation is at the heart of this condition, all speakers advocated the use of the term Myalgic Encephalomyelitis, not Chronic Fatigue Syndrome, since most if not all illnesses cause ‘fatigue’  Inflammation is at the heart of ME – the immune system response is indicative of inflammation; inflammation is in the muscles and in the blood vessels  The illness is not and never has been ‘all in the mind’  There is a genetic predisposition for ME Invest in ME (Charity Nr. 1114035)  ME is a legitimate physical illness and patients are really ill – their immune, endocrine and neurological systems are compromised and they should not be made to exercise  The truth about ME is already out there, so why does widespread ignorance and misinformation remain? (Co-Cure ACT; 17th May 2006). 2006 “The diagnostic criteria of CFS define a heterogeneous population composed of several subgroups. This study was designed to examine NK cell activity as a potential subgroup biomarker. The results (provide) evidence in support of using NK cell activity as an immunological subgroup marker in (ME)CFS. Improved treatment options will only come with better understanding of the syndrome’s underlying pathophysiology. The present study specifically investigated the existence of an immunological subgroup of CFS patients. Reduced NK cell activity may contribute to enhanced cytokine production. Given the role that NK cells play in targeting virally infected cells, a clinically significant reduction in NK cell activity may lead to activation of latent viruses and new viral infections. (ME)CFS is a misunderstood condition. Research in the last two decades has produced little advancement in the understanding of the pathophysiology of (ME)CFS. Unfortunately, this lack of progress seems to have further contributed to the belief among some members of the medical community that (ME)CFS is not an actual organic condition” (Scott D Siegel, Mary Ann Fletcher, Nancy Klimas et al. J Psychosom Res 2006:60:6:559-566). 2006 “(ME)CFS is a poorly defined medical condition which involves inflammatory and immune activation. The Type I interferon antiviral pathway has been repeatedly shown to be activated in the most afflicted patients. An abnormal truncated form of ribonuclease L (37kDa RNase L) is also found in (ME)CFS patients www.investinme.org Page 73 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) and this protein has been proposed as a biological marker for (ME)CFS. The levels of this abnormal protein have been significantly correlated to the extent of inflammatory symptoms displayed by (ME)CFS patients” (M Fremont, K De Meirleir et al. JCFS 2006:13(4):1728). 2006 In a study of cytokine genomic polymorphisms in (ME)CFS, Italian researchers found “a highly significant increase in TNF-857 and CT genotypes among patients with respect to controls and a significant decrease of IFN gamma low producers among patients with respect to controls…We hypothesise that (ME)CFS patients can have a genetic predisposition to an immunomodulatory response of an inflammatory nature probably secondary to one or more environmental insults” (N Carlo-Stella et al. Clin Exp Rheumatol 2006:24(2):179-182). 2006 On 8th September 2006 Professors Nancy Klimas and Mary Ann Fletcher attended a “Questions and Answers” Patient Session in Wellington, New Zealand at which Professor Klimas said she proves (ME)CFS disability by carrying out laboratory testing with Immune Activation Panels: (DR, CD26 expression, Th2 cytokine shift, proinflammatory cytokine expression TNF, IL-1 and IL-6) and evidence of functional defects (NK cell dysfunction, CD8 abnormalities, decreased perforin, granzymes, macrophage abnormalities and antibody production). When asked if these were available in New Zealand, she replied: “Putting panels together shouldn’t be a problem. These kinds of tests are not routine, but they should be do-able by immunologists”. When then asked: “Given the evidence of an inflammatory response, wasn’t the old name ME better than CFS?”, to which she replied: “Sure, ME is a much better name. The problem is that we’ve fought so hard in the US to get recognition as CFS (because) there is a Social Security ruling under that name, that changing it now would cause a lot of issues. I’m just trying to get slash (/) ME into it”. She was then asked why there was a Th-2 shift and she replied: “By measuring the number of Type 1 Invest in ME (Charity Nr. 1114035) 2006 On 3rd November 2006 the US Centres for Disease Control (CDC) announced its “CFS Toolkit” to inform not just the US but the whole world about the nature and severity of ME/CFS. The following are extracts from the Press Conference: Dr Julie Gerberding, Director of the US CDC: “One of the things that CDC hopes to do is to help patients know that they have an illness that requires medical attention, but also to help clinicians be able to understand, diagnose and help people with the illness. But more importantly, to be able to validate and understand the incredible suffering that many patients and their families experience in this context. We are committed to improving the awareness that this is a real illness and that people need real medical care and they deserve the best possible help that we can provide. The science has progressed (which has) helped us define the magnitude and understand better the clinical manifestations (and this has) led to a sorely needed foundation for the recognition of the underlying biological aspects of the illness. We need to respect and make that science more www.investinme.org Page 74 of 108 lymphocyte cells and comparing them to Type 2 lymphocytes, we find more of Type 2. We also find fewer numbers and poorer functioning NK cells which is an outcome of this shift. We proved that this was implicated in the symptomatology of the illness by the self-autologous infusion experiment where people were re-infused with the corrected ratio and their symptoms improved….Why the immune response is being pushed this way is at the heart of the cause of the illness”. She was then asked: “What are the consequences of this Type 2 shift?” to which she replied: “A lot of pro-inflammatory immune activation is not held in check and this gives rise to a host of symptoms”. Professor Fletcher was asked if people with ME/CFS should give blood, and she replied: “No, I don’t think it’s a good idea for two reasons – (a) most patients are 1 litre low in blood (most of Dr Klimas’ patients have around 3.5 L instead of 4.5 L, so why would you want to take out another litre?); (b) to my mind there are no studies to prove that ME is not infectious, so we can’t say with complete certainty that an infection will not be passed on” (Co-Cure MED 8th December 2006). Journal of IiME Volume 6 Issue 1 (June 2012) visible. I have heard from hundreds and hundreds of people who are telling their stories – their courage, their commitment to try to live the best possible life they can (and) the tremendous impact that this is having on their ability to function”. Dr William Reeves, Chief of Chronic Viral Diseases Branch at CDC: “We’ve documented, as have others, that the level of impairment in people who suffer from (ME)CFS is comparable to multiple sclerosis, AIDS, end-stage renal failure, chronic obstructive pulmonary disease. The disability is equivalent to that of some wellknown, very severe medical conditions. We found that (ME)CFS follows a pattern of remitting and relapsing symptoms, the symptoms can change over time, and that spontaneous recovery is rare. We found that the best predictor for (ME)CFS was intensity of the initial infectious disease. The sicker the patient when s/he first got infected, the more likely they were to have persisting chronic symptoms. There were no other factors, psychological or biological, that held up under thorough analysis”. Professor Anthony Komaroff, Harvard Medical School: “There are now over 4,000 published studies that show underlying biological abnormalities in patients with this illness. It’s not an illness that people can simply imagine that they have and it’s not a psychological illness. In my view, that debate, which was waged for 20 years, should now be over. A whole bunch of studies show that the hormone system is different in patients with (ME)CFS than in healthy people, people with depression and other diseases. Brain imaging studies have shown inflammation, reduced blood flow and impaired cellular function in different locations of the brain. Many studies have found that the immune system appears to be in a state of chronic activation (and) genes that control the activation of the immune system are abnormally expressed in patients with this illness. A number of studies have shown that there probably are abnormalities of energy metabolism in patients with this illness”. Professor Nancy Klimas, Professor of Medicine, University of Miami: “I’ve treated over 2,000 (ME)CFS patients. Today, there is evidence of the biological underpinnings. And there’s evidence Invest in ME (Charity Nr. 1114035) that the patients with this illness experience a level of disability that’s equal to that of patients with late-stage AIDS, patients undergoing chemotherapy, patients with multiple sclerosis. And that has certainly given it a level of credibility that should be easily understood. There are diagnostic criteria that enable clinicians to diagnose (ME)CFS in the primary care setting”. The full Press Conference is available at: http://www.cdc.gov/media/transcripts/t061103.h tm 2006 Commenting on a study in the November 2006 issue of Archives of General Psychiatry (Childhood Trauma Ups the Risk of Chronic Fatigue Syndrome), Professor Nancy Klimas said: “We’re not talking about a bunch of stressed-out people. We’re talking about the biological underpinnings of a real and very debilitating illness. We’re trying to remove the stigma of a psychiatric overlay and put it back in biology, where it belongs…..It’s important to see that CFS has subgroups. It’s really important not to merge all these observations into one solid, big group” (CoCure Res 8th November 2006). 2006 In the press follow-up of the CDC Toolkit launch, on 24th November 2006 Professor Nancy Klimas said that research over the past 20 years was beginning to figure out the biological underpinnings of the syndrome, which she thinks is badly misnamed: “If it were called chronic neuroinflammatory disease, then people would get it. Up until now nobody’s been willing to change the name, but now there’s proof that inflammation occurs in the brain. There’s evidence that the patients with this illness experience a level of disability that’s equal to that of patients with late-stage AIDS, patients undergoing chemotherapy (and) patients with multiple sclerosis”. She and other investigators have shown that different types of cells within the immune system are abnormal either in number or function (Co-Cure ACT 25th November 2006). 2007 www.investinme.org Page 75 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) The 8th International Association of Chronic Fatigue Syndrome (IACFS, formerly the AACFS) Conference was held at Fort Lauderdale, Florida, from 10th-14th January 2007. The following notes are taken from published reports of conference attendees (including Professor Charles Lapp, Dr David Bell, Dr Rosamund Vallings, Dr Lesley Ann Fein, Virginia Teague, Pat Fero, Cort Johnson, John Herd and Pamela Young, whose various reports are on the internet), to whom grateful acknowledgment is made. The conference was attended by over 250 clinicians and researchers from 28 different countries and there was a strong sense that they were all co-operating to build on the science, and that it is the science that has freed the world from any doubt that ME/CFS is a legitimate disease with an aetiology that is not rooted in the psyche. It was described as “this miserable illness”. One of the most striking elements was the convergence of research findings: the three areas that came up again and again were inflammation, mitochondrial abnormalities, and vascular problems. There was a significant confluence of findings on (i) elastase (a protease enzyme which digests and degrades a number of proteins, including elastin, a substance that supports the structural framework of the lungs and other organs); (ii) vascular problems; (iii) apoptosis (programmed cell death); (iv) free radical production (highly damaging to DNA, to cell membranes and to proteins); and (v) the presence of inflammation in ME/CFS. In ME/CFS, testing for elastase, RNase-L, Creactive protein, selected cytokines and NK cell activity are recommended because they are objective markers of pathophysiology and severity. The importance of sub-tying was recognised and emphasised. There are elevated pro-inflammatory cytokines (immunologically-based chemicals that can cause viral symptoms) in patients with ME/CFS. Invest in ME (Charity Nr. 1114035) Dr Brian Gurbaxani and Dr Suzanne Vernon et al (CDC, Atlanta) demonstrated that increased levels of IL-6 correlate well with C-reactive protein (CRP) and are proportionate to symptom severity in ME/CFS. Dr Barry Hurwitz from the University of Miami showed that pro-inflammatory cytokines have a secondary effect in reducing red blood cell (RBC) volume, due to probable suppression of RBC production in the bone marrow. Professor Mary Ann Fletcher, a colleague of Professor Nancy Klimas from the University of Miami, found that perforin (a molecule in cytotoxic lymphocytes) is low in ME/CFS, as are NK cells. Anthony Komaroff (Professor of Medicine, Harvard) summarised the immune abnormalities that have been demonstrated in ME/CFS. These include activated CD8 (T cells); poorly functioning NK cells; novel findings – seen only in ME/CFS -of abnormalities of the 2-5A pathway (RNase-L ratio); cytokine abnormalities (pro-inflammatory dysregulation); increased TGF, and 27 times more circulating immune complexes than in controls. Other areas of abnormality seen in ME/CFS that were addressed at this conference included the cardiovascular system (especially the evidence of microvascular inflammatory problems and arterial stiffening; the evidence that 70% of people with ME/CFS have a low red blood cell volume; the low cardiac index of ME/CFS patients, this being so severe that it falls between the value of patients with myocardial infarction and those in shock, and inverted T waves), brain imaging (especially the evidence of reduced blood flow to the brain including the area responsible for the autonomic nervous system; the evidence of reduced grey matter volume, and the evidence of arteriolar vasculopathy or a blood vessel disease described as a “systemic mico-vascular inflammatory process”, a process that would affect not only the brain but every organ system in the body), proteomics (the “unbelievable” finding of unique markers in the cerebrospinal fluid of ME/CFS patients that are completely absent from the control group, and the finding of one protein – keratin – that is associated with inflammation of membranes covering the brain and spinal cord), www.investinme.org Page 76 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) evidence of persisting viral activity, gastrointestinal dysfunction, sleep disruption, pain, cognitive impairment, neuroendocrine dysfunction, genomics (especially the findings of three main abnormalities in ME/CFS, involving the immune system, mitochondrial function and Gprotein signalling: of seven genes up-regulated in ME/CFS, three in particular are notable, these being gelsolin that is involved in apoptosis, one that is upregulated by organophosphates, and the other being a mitochondrial gene that is involved in the demyelination of nerves), and paediatric issues. This conference highlighted the difference between psychiatry and science (http://www.meactionuk.org.uk/Facts_from_Flori da.htm). 2007 On 25th May 2007 the charity ME Research UK (MERUK) hosted an International Research Conference at the Edinburgh Conference Centre, Heriot Watt University, Edinburgh. There were six keynote lectures and eight presentations, with several Question & Answer sessions. The following notes are taken from the keynote lectures and presentations. Items relating to the immunology of ME/CFS include the following: Presentation by Mark Robinson (Department of Applied Physiology, University of Strathclyde): “Response of plasma cytokine IL-6 and its receptors to exercise in ME/CFS” “The physiological role of IL-6 has classically been studied in the context of the immune response, since it is able to exert both pro- and antiinflammatory activities. More recently, IL-6 has been of keen interest to exercise physiologists, with the observation that, even without skeletal muscle damage, plasma levels of this cytokine increase dramatically. In 2000 (researchers) demonstrated that the source of this increased IL-6 can almost exclusively be attributed to the working of skeletal muscle, where it is both produced and subsequently released”. “Exercise-induced IL-6 in the muscle acts in a hormone-like manner, helping to maintain the fuel Invest in ME (Charity Nr. 1114035) homeostasis during exercise and when skeletal muscle glycogen levels become depleted”. “The main finding of the study was a clear trend towards a lower resting level of the soluble IL-6 receptor in ME/CFS patients”. Keynote Lecture by Professor Nancy Klimas (University of Miami): “The Immunology of ME/CFS”. Nancy Klimas, Professor of Medicine & Immunology at the University of Miami and worldrenowned expert on the immunology of ME/CFS, delivered a compelling keynote lecture. She said there is a real genetic component in ME/CFS (HLA-DR, which predisposes to autoimmune illness). She stressed the findings of an Australian study which found that the severity of the initial infection is the single predictor of perpetuation of ME/CFS and that there is no psychological component in its perpetuation. Professor Klimas explained the imbalance seen in ME/CFS between Type I and Type II cytokines: in ME/CFS they see a lot of Type II cytokine expression, which means there is an inhibition of Type I expression, which in turn triggers the inflammatory cascade of tumour necrosis factor (TNF), IL-6 and IL-1. This is important, because Type I cytokines are needed for the function of cytolytic T cells and NK cells are part of the whole immune mechanism, which is being inhibited in ME/CFS. She pointed out that what has been seen over many years of research by many different groups is (quote) “a lot of evidence of this chronic immune activation, looking at expression of activation markers on the cells, looking at cytokine levels, looking at cytokine expression. The consequence, or may be a part of this, is a lot of functional abnormalities of cytotoxic T cells and NK cells, macrophage abnormalities, antibody production abnormalities and neutrophil abnormalities. NK cell function is very poor—NK cells should kill in a certain unit of time: in normals this is 30-40% in four hours, but in ME/CFS it is half of that”. www.investinme.org Page 77 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) Professor Klimas said the most important thing that has come out of her group recently is the discovery of very low perforin (which she described as “the killing stuff of the cell”). She said that very low perforin levels in the cytotoxic T cell matters, because the anti-viral defence is impaired. In ME/CFS the perforin is half what it should be. She emphasised that in addition to poor cell function, the cells are very activated and very stimulated, and there are consequences of an activated cell – what is seen is not only “this big immune activation, but apoptosis – a lot of cell death”, resulting in a constant drive to make more cells, especially neutrophils and lymphocytes. Thus there is “a constant drive to keep the system in overdrive in trying to keep up with cell loss”. Her group has also seen a CD26 cell receptor in ME/CFS – this is seen in an activated cell, and the number of cells expressing this receptor is elevated, even though there are fewer molecules per cell. This matters, because the number of these activated receptors on the cell determines the function of that cell (which cannot “activate up” the function). Professor Klimas summarised all this as (i) an over-activated system; (ii) a system that is not functional and (iii) what she described as “the stuff of the cell – the thing you need to make the cell function well – being under-produced”. She then spoke about neuropeptide Y, which is a very important neuropeptide of interest to the vascular biologists’ findings in ME/CFS. It has a large number of regulatory functions, including the immune system and the autonomic system. It is a biomarker. They looked at more than 100 patients and found a significant difference between ME/CFS patients and controls. Professor Klimas said this is important. She went on to speak about clinical correlates: they had found that people who had low cognitive difficulties had good T cell function but Invest in ME (Charity Nr. 1114035) people who had very high cognitive difficulties had the poorest T cell function, so there is a definite clinical correlate. This correlate has also been shown with NK cells, and once again she emphasised that this immune connection matters. She discussed the fact that genomics have put some focus on the HPA axis dysregulation and said that IL-6 is associated with the intensity of that dysregulation. She mentioned the role of infection, saying she herself had needed to be convinced about the role of viruses and it was the work of Dr Peterson that had convinced her. Peterson had shown transmissible living virus in spinal fluid cultures of ME/CFS patients (which definitely should not be there): “You should not be able to culture anything out of anybody’s spinal fluid in the way of a virus or bacteria or anything – it’s not OK. That was impressive”. Professor Klimas went on to talk about enteroviruses in ME/CFS: “Enteroviruses keep reappearing – they keep coming back (into the picture). Most recently at our conference in January (the IACFS/ME conference in Florida), Dr Chia from Los Angeles had looked at more than 100 intestinal biopsies (and showed) slide and slide after slide with enteroviruses – it was phenomenal”. She said that people had previously looked at enteroviruses in muscle, but “looking at the intestine was a place no-one had ever looked before, and yet the intestine is, beyond the skin, the second biggest immune system component you have, and a tremendous place to have a lot of antigen exposure and a good reason to have chronic immune activation”. She then pointed out that the genomics work is very exciting as applied to immunology and virology, as it replicates the immune data by a completely different method. Professor Klimas began her lecture by saying: “People are finding things that fit. This all makes sense. It’s a very exciting time because the puzzle www.investinme.org Page 78 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) we’ve talked about all these years is really fleshing out into a real picture”. She concluded by conveying her own enthusiasm, saying that due to new techniques that were not available even five years ago, “there’s been tremendous progress” and that both patients and investigators should be heartened. In the Question & Answer session, in response to a question from the floor, Professor Klimas said “What subgroup do people fit in? What we’re down to now is looking for the biological markers that put people in the proper group to give us targeted treatment approaches that make sense for that individual – certainly that’s the way, thank goodness, the field is finally moving”. (It must be stressed that this is in direct contrast to the Wessely School, who are intent on collating all states of medically unexplained “fatigue” and rolling out “cognitive restructuring” across the board of “fatigue”). 2007 “For decades, (ME)CFS patients were – and still are – dismissed as lazybones or hypochondriacs. Many medical doctors and insurance companies still assert that (ME)CFS is a mental condition. The mainstream treatment for (ME)CFS is CBT, which means that patients with (ME)CFS are being treated as having a mental illness with ‘treatments’ that do not treat any underlying cause. Doctors who treat (ME)CFS patients as suffering from an organic disorder and scientists who examine the biological causes of (ME) are often considered quacks by their colleagues (and) insurance companies, which are sometimes even officially supported by governments in their attempts to eliminate the scientific view that (ME)CFS is an organic disorder. The official acceptance of the latter obviously would mean that the national health care systems are obliged to financially support those patients who are now considered hypochondriacs and, therefore, may easily be suspended from the national health care systems. There is, however, evidence that (ME)CFS is a severe immune disorder with inflammatory reactions and increased oxidative stress. Maes et al show that patients with (ME)CFS show very high levels of nuclear factor Invest in ME (Charity Nr. 1114035) kappa beta in their immune cells. NFk is the major mechanism which regulates inflammation and oxidative stress. Thus, the increased production of NFk in the white blood cells of patients with (ME)CFS is the cause of the inflammation and oxidative stress (seen) in (ME)CFS” (Maes et al. Neuroendocrinology Letters, 2007. http://www.michaelmaes.com/ ). 2007 “Recent research has evaluated genetic signatures, described biologic subgroups, and suggested potential targeted treatments. Acute viral infection studies found that initial infection severity was the single best predictor of persistent fatigue…. Studies of immune dysfunction (have) extended observations of natural killer cytotoxic cell dysfunction of the cytotoxic T cell through quantitative evaluation of intracellular perforin and granzymes. Other research has focused on a subgroup of patients with reactivated viral infection…. Our expanded understanding of the genomics of (ME)CFS has reinforced the evidence that the illness is rooted in a biologic pathogenesis that involves cellular dysfunction and interactions between the physiologic stress response and inflammation…. A large body of evidence links (ME)CFS to a persistent viral infection…. (ME)CFS patients exhibited a distinct immune profile compared with fatigued and non-fatigued individuals. These patients displayed increased anti-inflammatory cytokines (IL-10, decreased IFN-/IL-10 ratio) and reductions in pro-inflammatory cytokines (IL-6, tumour necrosis factor-)…Investigators noted the tropism with brain and muscle and suggested that the neuroinflammation seen in neuroimaging studies of a subgroup of CFS patients may result from enteroviral infection…. The clinical implications are consistent with an immune system that may allow viral reactivation and raises a concern for tumour surveillance as well…. The preponderance of available research confirms that immune dysregulation is a primary characteristic of (ME)CFS. Advances in the field should result in targeted therapies that impact immune function, hypothalamic-pituitary-adrenal axis regulation, and persistent viral reactivation in (ME)CFS patients” (Nancy G Klimas et al. Current Rheumatology Reports 2007:9:6:482-487). www.investinme.org Page 79 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) 2007 “Understanding how non-pharmacologic interventions differentially affect the subgroups of patients with CFS might provide insights into the pathophysiology of this illness….Baseline measures of normal versus abnormal cortisol were compared on a variety of immune markers….Subgroups of individuals with CFS may react differently to exercise than healthy controls….Early researchers describing nonpharmacologic behavioural interventions for CFS reported high levels of success (Deale, Chalder, Marks & Wessely, 1997;…Sharpe et al 1996), but more recent studies have had somewhat more mixed results…. Those individuals with most impaired HPA axis function might be least able to improve with non-pharmacologic interventions….Jeres, Cleare, Wessely, Wood and Taylor (2005) have confirmed that mean cortisol levels are significantly lower for individuals with CFS when compared with controls across the entire 24-hour span….Many studies do show that CFS is characterised by hypocortisolemia…It is possible that some individuals with CFS have a cortisol deficiency and others do not, but when all are combined into one large CFS category, these important differences are ignored….Immunologic abnormalities have frequently been reported in the CFS literature…(a) poor cellular function, with low natural killer cell (NKC) cytotoxicity and frequent immunoglobulin deficiencies (most often IgG1 and IgG3) and (b) elevations of activated T lymphocytes, including cytotoxic T cells, and elevations of circulating cytokines….The results of one study found that immunologic functioning did not improve as a result of CBT (Peakman, Deale, Wessely et al, 1997); however, that study did not subgroup according to baseline cortisol findings….In (our) study, baseline measures of normal versus abnormal cortisol were compared on a variety of immune markers….The results of this study demonstrate that….individuals with normal baseline cortisol levels exhibited the most improvement….This indicates that those who are most impaired on HPA functioning might be least able to improve when provided with nonpharmacologic interventions….There were significant time and interaction effects of the CD45RA-CD62L- subsets. The normal cortisol group experienced decreasing levels of this subset over the intervention, whereas the abnormal group underwent a significant expansion. This Invest in ME (Charity Nr. 1114035) effector subset has been shown in healthy subjects to express high levels of 1 and 2 integrins that are required for homing to inflamed tissues and produce perforin and high levels of IL-4, IL-5 and IFN….The continued expansion of this subset in the abnormal cortisol group suggests that a stimulus, present in these individuals but absent in the normal cortisol group, is responsible for driving the proliferation….The modulation of these effector subsets in distinctly different directions, that are associated with HPA axis abnormalities and efficacy of CBT, likely represents an important component of the immune dysfunction associated with the pathogenetic process of CFS…. In summary, subgroups of individuals with either normal or abnormal cortisol levels exhibited different outcomes in a nonpharmacologic treatment trial….This suggests that cortisol levels may serve as an important marker for individuals with CFS that might benefit from non-pharmacologic interventions such as cognitive behavioural therapies” (Leonard A Jason, Mary Ann Fletcher et al. JCFS 2007:14(4):39-59). 2008 In January 2008 the CFIDS Association of America produced a special publication entitled “Defining Moments – 20 years of making CFS history”, the key message being that “Scientific research…has provided incontrovertible evidence that CFS is one of the most complex and widespread illnesses of our time, and that there is a sound scientific basis for the biological origins of the disease (but) many physicians are still incredibly resistant to treating CFS”. Professor Nancy Klimas wrote: “Over the years, people have often asked me if CFS is an immune disorder, a brain disease or a dysfunction of the endocrine system….As an immunologist, I once would have said CFS is clearly an immune dysfunction state, while an endocrinologist would call attention to the adrenal glands irregularities, and a specialist in the autonomic nervous system would be convinced CFS is all about blood pressure abnormalities. Given what we’ve discovered about the illness, I now tell people CFS is all of these things. We know that (ME) chronic fatigue syndrome has identifiable biologic underpinnings www.investinme.org Page 80 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) because we now have research documenting a number of pathophysiologic processes involving the brain, the immune system, the neuroendocrine system and the autonomic nervous system”. Professor Anthony Komaroff from Harvard wrote: “Today we have powerful new research technologies… Newer molecular biology technologies allow us to study gene activity inside circulating immune system cells and to look for infectious agents with an accuracy that wasn’t possible two decades ago”. 2008 On 6th May 2008 the charity ME Research UK (MERUK) hosted an International Conference on ME/CFS Biomedical Research at the Wellcome Trust Conference Centre, Cambridge (“New Horizons 2008”), at which Professor Nancy Klimas from the University of Miami gave the first Keynote Lecture which was entitled “Clinical Aspects of ME/CFS”. Her emphasis was on the need to assess patients by sub-grouping on the basis of clinical tests and symptom clusters as outlined in the 2003 Canadian Consensus Definition, of which she was a co-author. In her view, the post-exertional nature of the symptoms is key. She described her model for the development of the disease and reviewed the chronic immune dysfunction; she also reviewed the evidence for viral persistence and reactivation before discussing the evidence for endocrine dysfunction such as reduced cortisol output. She noted that gene expression microarray data has become a highly productive tool, mentioning recent studies showing the differential expression of 35 genes for T-cell activation, neuronal and mitochondrial regulatory abnormalities. She particularly noted that pre-and post exercise challenge studies have indicated differences in genes that regulate ion transport and intracellular functions, saying it may be that evaluation of gene expression profiles will allow pathophysiologic sub-grouping of patients that could result in targeted therapies to impact immune function (with acknowledgement to Dr Neil Abbot). 2008 Invest in ME (Charity Nr. 1114035) On 23rd May 2008 the charity Invest in ME held its third International Conference on ME in London; it was attended by about 165 people including health care professionals and patients. Dr Jonathan Kerr (St George’s University, London) spoke on “Gene Expression in ME/CFS: A Means of Subtyping”. His team looked at a microarray of 47,000 genes from ME/CFS patients and controls taken from normal blood donors. Genes showing differential expression were further analysed using real-time PCR. 13 transcription factors were over-represented and differential expression was confirmed in 88 genes, these being associated with haematological and immunological diseases and function, cancer, apoptosis, immune responses and infections. Graphs showed hugely different results in ME/CFS patients compared with controls (with acknowledgement to Doris Jones MSc). 2008 “CFS is an incapacitating illness….The benefit of classifying individuals with CFS into diagnostic categories is that it facilitates selection of treatment methods, predictions of response to treatment and communication among clinicians and researchers….Evidence for multiple immunological abnormalities in CFS have frequently been reported in the literature….People with CFS appear to have two basic problems with immune function: 1) poor cellular function, with low natural killer cell cytotoxicity and frequent immunoglobulin deficiencies (most often IgG1 and IgG3), and b) elevations of activated T lymphocytes, including cytotoxic T cells, and elevations of circulating cytokines. Natelson et al (Spinal fluid abnormalities in patients with chronic fatigue syndrome, 2005) found increases in cytokines (IL8 in some patients and IL-10 in others), and these findings support the hypothesis that in some patients with CFS, symptoms may be due to immune dysfunction within the central nervous system….If there are distinct subgroups, then treatment might need to be tailored to the differential needs of patients….Several studies suggest that subgroups of patients with CFS react differently to exercise than healthy controls….In (our) study we examined baseline measures involving immune function… for those who www.investinme.org Page 81 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) improved and those who did not improve following exposure to non-pharmacologic interventions….Past research has shown that CFS is associated with a shift toward a Type 2 immune response, and in the present study, those with this pattern tended not to improve….In other wards, a dominance of the Type 2 over Type 1 immune response, as indicated by the patterns of lymphocytes subset distributions among those with CFS, did not improve over time….The current study further supports the contention that clinically distinct subsets of patients within the current definition of CFS….Such differences…highlight the need to define clinical subsets in CFS….Subgrouping is the key to understanding how CFS begins (and) how it is maintained” (Leonard A Jason, Mary Ann Fletcher et al. Tropical Medicine and Health 2008: 36:1:2332). 2008 “The main hypotheses include altered central nervous system functioning resulting from an abnormal immune response against a common antigen….This review discusses the immunological aspects of (ME)CFS and offers an immunological hypothesis for the disease process….Present data from various sources support the model that (ME)CFS has a propensity to over-produce proinflammatory cytokines, coupled with a misregulation of anti-inflammatory cytokines….These immunological findings show that patients with (ME)CFS may have an infection and that the immune system is chronically activated in response. Several of the differentially expressed genes are related to immunological functions and implicate immune dysfunction in the pathophysiology of the disease” (Lorenzo Lorusso et al. Autoimmunity Reviews 2008: doi:10.1016/j.autrev2008.08.003). 2008 “(ME)CFS is a neuro-immune disorder linked to chronic immune activation and dysregulation of the HPA axis….Upsets in immune demographics are reflected in cell-cell signalling and elevated levels of pro-inflammatory cytokines such as INF and TNF- in (ME)CFS. The HPA axis is central in modulating this inflammatory response through the synthesis of cortisol via a cascade involving Invest in ME (Charity Nr. 1114035) adrenocorticotrophic hormone (ACTH) and corticotropin-releasing hormone (CRH)….Accordingly HPA axis dynamics are tightly coupled with those of the immune system….(ME)CFS patients inhabit a stable hypocortisolic state highly conducive to the emergence of chronic inflammatory immune signalling….The reported changes in connectivity of immune functional nodes align well with observations of altered immune activity in (ME)CFS….We have successfully constructed association networks demonstrating the key role of immune function in (ME)CFS” (Jim Fuite, Suzanne D Vernon, Gordon Broderick. Genomics 2008:92:6:393-399). 2008 “(ME)CFS is characterised by immune dysfunctions including chronic immune activation, inflammation, and altered cytokine profiles. T helper 17 (Th17) cells belong to a recently identified subset of T helper cells, with crucial regulatory function in inflammatory and autoimmune processes. Th17 cells are implicated in allergic inflammation, intestinal diseases, central nervous system inflammation, disorders that may all contribute to the pathophysiology of (ME)CFS…To investigate the role of Th17 cells, and more specifically of the cytokine IL-17F, in the pathogenesis of (ME)CFS, we studied the association between (ME)CFS and the frequency of the IL17F His161Arg variant…We found a significantly lower prevalence of the His161Arg variant in the (ME)CFS population compared to the control population… The His161Arg variant antagonises the pro-inflammatory effects of…IL17F, and thereby exerts a protective effect against asthma. Similarly, we can make the hypothesis that the development and/or maintenance of (ME)CFS involves an increase in the production of IL-17F, and that the expression of the inactive variant confers protection against the disease (an expression that is significantly lower in patients with (ME)CFS)….(Our) results suggest a role of TH17 in the pathogenesis of (ME)CFS…The proinflammatory effects of Th-17-secreted cytokines are also consistent with other specific dysfunctions observed in (ME)CFS patients: IL-17 and IL-22 can disrupt the blood-brain barrier; Th17 lymphocytes transmigrate across the blood-brain barrier endothelial cells and promote inflammation of the www.investinme.org Page 82 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) central nervous system (and) blood-brain barrier permeability and CNS inflammation is thought to be a key aspect in the pathogenesis of (ME)CFS” (Metzger K et al. Biochem Biophys Res Commun 2008:376(1):231-233). 2008 “Myalgic encephalomyelitis/chronic fatigue syndrome is a heterogeneous disease….The central problem in the management of patients with ME/CFS is the lack of biomarkers for patient stratification into subgroups according to distinct immune responses, virus infections and neurological abnormalities….Our data shows for the first time in ME/CFS a cytokine and chemokine profile, which suggests a Th17 shift in subgroups of our cohort. We conclude that cytokine and chemokine patterns in subgroups of ME/CFS can be used diagnostically, as serum biomarkers to stratify patients for appropriate anti-inflammatory, anti-microbial and anti-viral therapeutics” (Serum cytokine and chemokine profiles of individuals with myalgic encephalomyelitis (ME) reveal distinct pathogen associated signatures. Vincent C Lombardi, Kenny DeMeirleir, Judy A Mikovits et al. Cytokine 43 (2008):243-262: doi:10.1016/j.cyto2008.07.077). 2008 At the 6th International Conference on HHV-6 & 7 held in June 2008 at Baltimore, Maryland, Day 4 (23rd June 2008) included a presentation by Professor Nancy Klimas, then at the University of Miami, whose presentation was entitled “Immune markers in viral reactivation”. She is reported as having said: “Remember the immune, the autonomic and the neuroendocrine (systems) are over-lapping….the pathognomonic thing in (ME)CFS is this over-activated immune system…the immune system is antigen-driven. Look for the antigen when you have an activated system….There are only so many things that can activate and drive a system: a pathogen, or more than one pathogen; an allergen; sympathetic nervous system activation of the immune system…and autoimmunity, so – how many different ways might you turn on the button and leave it pushed on – well, maybe five different ways….And that’s what the clues are we have here….anything that overdrives a system can turn Invest in ME (Charity Nr. 1114035) on the pro-inflammatory cytokine cascade..(that) is turned on in the sickest group of (ME)CFS patients. Apoptosis is when a cell has been on so long it’s been driven into cell death. If you push the button on (for) so long and don’t release it, the cell will apoptose, and that’s been shown in many different cell lines, including T cells and neutrophils. Functional defects that we (and others) have shown (include) natural killer cell dysfunction; cytotoxic T-cell abnormalities; (abnormally low cell content of) perforin and granzyme, and macrophage antibody production abnormalities (very important in sustaining longterm inflammatory responses). We’ve shown NK cell function to be different in (ME)CFS, and significantly different – we think this is a useful biomarker. It’s certainly one that circles an important group in (ME)CFS….If you split the chronic fatigue patients into fairly normal NK-cell function versus abnormal NK-cell function, you find that the SF-36 (fatigue scale) is significantly different between these two groups, so again immune dysfunction is correlating with the severity of illness in this patient population. A different objective marker of severity is the PASAT (cognitive assessment tool) – how well your higher levels of thinking are working, and again (there is) a low NK and a normal NK split, and the more severely impaired NK-cell function people have more impaired cognitive function”. Looking at lymphocyte activation and at the percentage of CD2+CD26+ lymphocytes, Professor Klimas said: “This is probably the only study I know of in (ME)CFS that looked for surrogate cytotoxic T-cell function and..it’s not there….we see a significant difference across the board on the amount of CD26 expression on these cells. Now this is an important thing to see. There are more cells expressing this, there’s more activation, but on a per cell basis, the ability of these cells to actually put that marker where it is on the receptor – which is a very important functional marker – is quite a bit lower than the controls. So there’s more activation, but the functional ability of the cell to express that marker…is diminished, and it’s a very significant thing…we think this is a very good biomarker for circling the group that is (ME)CFS…..Neuropeptide Y is a very active substance that has many functions across brain and immune system, so we looked at this, thinking maybe this might be a biomarker (and) sure enough we find neuropeptide Y is elevated as compared to controls in a very significant www.investinme.org Page 83 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) way….the higher it is, the worse the function of the patient….(In summary) (1) The immunologic changes seen in (ME)CFS and GWI are consistent with that seen in chronic viral illnesses (2) Immune dysregulation has been extensively studied, and patterns that would reasonably leave the subject vulnerable to viral reactivation have been shown (3) In considering clinical trials, consideration of immune modulators should be considered, together with antiviral therapies. To sum up, the immune changes that we see in (ME)CFS are absolutely what you should see in a chronic viral state; the cells that clear viruses that are latent that are trying to reactivate – the very cells that prevent reactivation of latent viruses – are the ones that are most dysfunctional. It’s an important point to be made….NKCC and intracellular perforin are biomarkers for (ME)CFS. CD2+26+ lymphocytes, rmolCD26 on lymphocytes and sCD26 in plasma are likely to be biomarkers for (ME)CFS. NPT is elevated in (ME)CFS; this may be an important biomarker and has high correlation with cognitive symptoms…. The NK cell is a good surrogate marker for the severity of the illness (and) so is the perforin content, so is the granzyme content (and) it’s also important to recognise that the cytotoxic T-cell is equally affected. Finally, these biomarkers coming from immunology-land might be very very useful in clinical trials”. 2009 On 20th February 2009 Professor Nancy Klimas gave an interview and an international press release in which she said: “A biomarker for ME/CFS may be less than two years away….We are closing in on being able to identify the root causes of a disease which affects millions of people around the world – one that is poorly understood and treated by the medical community….No longer will those afflicted be dismissed by the medical community and, all too often, by their own family and friends as having that ‘yuppie thing’….There are at least three, perhaps even seven, sub-groups of what we call ME/CFS…they may be thought of as three to seven different conditions with closely related symptoms…ME/CFS is a world wide problem that afflicts at least 28 million people, perhaps many more than that….The disease is so widespread that…a clearly focused international approach will Invest in ME (Charity Nr. 1114035)  the metabolic, adrenergic and immune ion channel receptors were up-regulated for days after exercise in people with ME/CFS, with virtually no up-regulation in healthy controls -- metabolic, adrenergic and immune ion channel receptor mRNA markedly increases in people with ME/CFS but not in healthy controls  Professor Mary Ann Fletcher (University of Miami) provided evidence that neuropeptide Y (NPY), a neurotransmitter that is concentrated in sympathetic nerve endings, is elevated in people with ME/CFS in relation to stress much more than in normal controls clearly and dramatically speed up…the benefits for those afflicted”. The interviewer commented that this was simply a deeply concerned and compassionate physician and research scientist speaking about that to which she has devoted her life (Co-Cure NOT; RES 24th February 2009). 2009 The world’s most knowledgeable ME/CFS scientists and clinicians met at the 9th International Association for ME/CFS Research and Clinical Conference (formerly the American Association for CFS – AACFS – but now the IACFS/ME) held on 12th – 16th March 2009 in Reno, Nevada. Of special note is that Professor Leonard Jason, a world-renowned ME/CFS investigator from De Paul University, USA, reported in his presentation “Activity Management” that one group of ME/CFS patients did not benefit from cognitive behavioural interventions: this was the subset of patients whose laboratory investigations showed them to be the most severely affected and who had increased immune dysfunction and low cortisol levels. In his Summary of the Reno Conference, Professor Charles Lapp noted that: www.investinme.org Page 84 of 108 Journal of IiME Volume 6 Issue 1 (June 2012)  from presentations by Dr Vincent Lombardi and Professor Nancy Klimas, it was indisputable that numerous cytokines were significantly different in subjects and controls  IL-8 and IL-15 were decreased in patients with ME/CFS, while the pro-inflammatory cytokines (TNF, IL-1, IL-1 and IL-6) and Type 2 cytokines (IL-4, IL-5) were increased in ME/CFS, and the antiinflammatory cytokine IL-13 was reduced: this is consistent with the Th2 or upregulated immune pattern usually seen in ME/CFS  Dr Marc Fremont from Belgium showed that bowel dysfunction (dysbiosis, leaky gut, viral infections of the gastric mucosa) is frequently seen in ME/CFS and there is also a Th1/Th2 immune imbalance. Th1 (normal immunity) is antagonistic to the Th17 immune axis. Th17 cells are crucial regulators of inflammation and autoimmunity, and alterations of the Th17 pathway are frequently associated with intestinal disorders such as irritable bowel syndrome. Th17 cells produce IL17F protein and a variant known as His161Arg, which confers protection against inflammation. His161Arg was found in only 6% of people with ME/CFS. This suggests that the Th17 axis and intestinal dysfunction are involved in causing inflammation and possibly in the pathogenesis of ME/CFS  The conference confirmed that multiple bodily systems are involved in ME/CFS (this is important, as Wessely School psychiatrists insist that the higher the number of bodily symptoms, the greater the certainty of a somatoform disorder)  Possible biomarkers include: salivary HHV6; ATP profiling of ion channel receptors; mitochdondrial energy score; cytokine and chemokine analysis; nearinfrared; EEG profiles; low molecular weight RNase L, and HLA haplotype 4.3.53, MSH, VIP, C4a. Invest in ME (Charity Nr. 1114035) 2009 In “Contemporary Challenges in Autoimmunity”, the Annals of the New York Academy of Sciences published several articles looking at autoimmunity in (ME)CFS. One such paper states: “In association with (ME)CFS physiopathology, immune imbalance, abnormal cytokine profile or cytokine genes, and decreased serum concentrations of complement components have been reported…Many studies have shown the presence of several autoantibodies in (ME)CFS patients. Antibodies to diverse cell nuclear components, phospholipids, neuronal components, neurotransmitters, as well as antibodies against some neurotransmitter receptors of the central nervous system have been described”. The authors consider the different types of antibodies that have been reported in (ME)CFS patients and consider in particular antibodies to nuclear components (52% of (ME)CFS patients are reported as having autoantibodies to components of the nuclear envelope, particularly to lamin B1 molecule); to neurotransmitters and receptors (especially to neurotransmitters such as serotonin (5H-T), adrenals, ACTH and to receptors such as muscarinic cholinergic receptor I and -opioid receptor 1), and to diverse micro-organisms, noting that serum levels of IgA were significantly correlated to the severity of illness. The authors state that the results showed that enterobacteria might be involved in the aetiology of (ME)CFS and that an increased gut-intestinal permeability could cause dysregulation of the immune response to the LPS of gram-negative enterobacteria. The authors note that for many years, enterovirus infection has been associated with (ME)CFS and they note: “However, several negative studies, combined with the rise of the psychiatric ‘biopsychosocial model’ of (ME)CFS have led to a diminished interest in this area” (OD Ortego-Hernandez et al; Ann N Y Acad Sci 2009:1173:600-6009). (For the avoidance of doubt, in the above paper the authors cite only two “negative studies” associated with enteroviral infection in (ME)CFS: the first by Lindh G et al [Scand J Infect Dis www.investinme.org Page 85 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) 1996:28:305-307] used the 1994 CDC criteria which do not exclude those with psychiatric disorder, and the second by McArdle A et al [Clin Sci 1996 90:295-300] was co-authored by Professor Richard Edwards, known for his belief that “many of the symptoms of these patients could be a consequence of their reduced habitual activities” [Ergonomics 1988:31:11:1519-1527] and for his objection to the publishing by the ME Association of “substantial amounts of information on the ‘disease’ “). 2009 “Examination of anticardiolipin antibodies (ACAs) in the sera of patients clinically diagnosed with (ME)CFS using an enzyme-linked immunoassay procedure demonstrated the presence of immunoglobulin M isotypes in 95% of (ME)CFS serum samples tested. The presence of immunoglobulin G and immunoglobulin A isotypes were also detected in a subset of the samples….Testing for antibodies to cardiolipin is routinely performed as one of a panel of tests for autoimmune disorders. In our studies, the presence of ACA at relatively high titres in patients with (ME)CFS suggests the possibility of alterations to the inner membrane of liver mitochondria, thereby exposing cardiolipin in a manner so as to elicit an antibody response….A survey of the literature reports ACAs as common serological markers in many different types of diseases, including viral diseases such as illnesses resulting from chemical…exposure…HIV and EBV, haematological cancers including CLL (chronic lymphocytic leukaemia)…and autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, autoimmune hepatitis and more. This study demonstrates that a large percentage of patients clinically diagnosed with (ME)CFS have elevated levels of the IgM isotype to cardiolipin (955), suggesting that (ME)CFS may be an autoimmune condition (and) classification of (ME)CFS as an autoimmune disorder may serve to increase the availability of treatment options for patients suffering from this disease. Experiments are under way to elucidate why ACAs are produced in individuals afflicted with (ME)CFS. Such studies include investigating the effects of specific chemical agents…on mitochondrial metabolic pathways that are indicative of reduced or blocked energy production that may lead to the fatigued Invest in ME (Charity Nr. 1114035) state in (ME)CFS” (Yoshitsugi Hokama et al. J Clin Lab Anal 2009:23:210-212). 2009 “Recent research has implicated vitamin D deficiency (serum levels of 25-hydroxyvitamin D <50 nmol/L) with a number of chronic conditions, including autoimmune conditions such as multiple sclerosis, lupus and psoriasis, and chronic conditions such as osteoporosis, osteoarthritis, metabolic syndrome, fibromyalgia and (ME)chronic fatigue syndrome….These findings support the use of 1,25-D as a clinical marker in autoimmune conditions” (Blaney GP et al. Ann N Y Acad Sci 2009:1173:384-390). 2009 “This study aimed to determine the influence of autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen (HLA) class II genes on age at (ME)CFS onset and symptoms…Our results reveal that in (ME)CFS, like other autoimmune diseases, different genetic features are related to age at (ME)CFS onset and symptoms” (OD Ortega-Hernandez et al. Ann N Y Acad Sci 2009:1173:589-599). 2009 “Cancer and (ME)CFS are both characterised by fatigue and severe disability. Besides fatigue, certain aspects of immune dysfunction appear to be present in both illnesses. In this regard, a literature review of overlapping immune dysfunction in (ME)CFS and cancer is provided. Special emphasis is given to the relationship between immune dysfunctions and fatigue….It may be clear that fatigue is a major complaint in both diseases….The immunological problems in particular are clearly apparent and quite similar in both diseases” (Mira Meeus, Jo Nijs et al. Anticancer Research 2009:29:4717-4726). 2009 “(ME)CFS studies from our laboratory and others have described cytokine abnormalities….This study screened plasma factors to identify circulating biomarkers associated with (ME)CFS….The following cytokines were elevated in (ME)CFS www.investinme.org Page 86 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) compared to controls: LT, IL-1, IL-1, IL-4, IL-5, IL-6, and IL-12. The following cytokines were decreased in (ME)CFS: IL-8, IL-13 and IL-15. Cytokine abnormalities are common in (ME)CFS. In this study, 10 of 16 cytokines examined showed good to fair promise as biomarkers. However, the cytokine changes observed are likely to be more indicative of immune activation and inflammation, rather than specific for (ME)CFS….Many of the symptoms are inflammatory in nature….A significant elevation in the relative amounts of 4 of 5 proinflammatory cytokines in peripheral blood plasma of patients with (ME)CFS was found when compared with the controls….In cases, lymphotoxin (LT) was elevated by 257% and IL-6 by 100% over the controls. (The antiinflammatory cytokine) IL-13 was significantly lower (15%) in (ME)CFS patients….IL-12 was significantly elevated (120%) and IL-15 decreased 15% in cases compared to controls. (The chemokine) IL-8 (CXCL8) was 42% lower in the (ME)CFS patients….In the (ME)CFS cases we found an unusual pattern of the cytokines that define the CD4 T cell….Allergy is common in (ME)CFS cases….The decreased NK cell cytotoxic and lymphoproliferative activities and increased allergic and autoimmune manifestations in (ME)CFS would be compatible with the hypothesis that the immune system of affected individuals is biased towards a T-helper (Th) 2 type, or humoral immunity-orientated cytokine pattern. The elevations in LT, IL-1, IL-1 and IL-6 indicate inflammation, likely to be accompanied by autoantibody production, inappropriate fatigue, myalgia and arthralgia, as well as changes in mood and sleep patterns….Cytokine abnormalities appear to be common in (ME)CFS. Several showed promise as potential biomarkers. The changes from the normal condition indicate immune activation and inflammation….The data from this study support a Th2 shift, pro-inflammatory cytokine upregulation and down-regulation of important mediators of cytotoxic cell function” (Mary Ann Fletcher, Nancy Klimas et al. Journal of Translational Medicine 2009: 12th November:7:96). 2010 Invest in ME (Charity Nr. 1114035) The fifth Invest in ME International Conference was held on 24th May 2010 in London. The immunological aspects of ME/CFS were discussed by Professor Nancy Klimas (Miami), who informed attendees that there is already a biomarker for ME/CFS – NK cell function. This should be considered to be a consistent finding in ME/CFS patients, and it is a good indicator of severity; it is also useful in defining sub-groups. As an NK cell abnormality is not unique to ME/CFS, it cannot be used as a diagnostic biomarker, but NK cell cytotoxicity does appear to be a marker of disease activity in subgroups. The main theme of her presentation was the need to find biomarkers involved with the immune dysfunction seen in ME/CFS patients. She summarised important markers of immune activation:  An elevated proportion of CD26 lymphocytes (a specific type of white blood cell) expressing the activation marker dipeptidase IV (DPPIV)  Polarisation of the Th-2 (helper type 2) immune response  Elevation of pro-inflammatory cytokines such as TNF, interleukin 1 (IL-1) and IL-6 (a cytokine of marked inflammation)  Important defects in immune system function (especially NK cytotoxicity), CD8 and macrophage abnormalities and antibody production. Professor Klimas also referred to new research showing that CD26 lymphocyte activation can lead to the production of neuropeptide Y (NPY), which acts on adrenaline responses in the sympathetic nervous system, i.e. on the autonomic control of heart, bladder and bowel function (with acknowledgement to Dr Charles Shepherd). 2010 “(ME)CFS is a multifactorial disorder that affects various physiological systems including immune and neurological systems….The objective of this present study was to determine deficiencies in lymphocyte function and erythrocyte rheology in (ME)CFS….Immune dysfunction may therefore be an important contributory factor to the mechanism of (ME)CFS, as indicated by decreases in neutrophil respiratory burst, NK cell activity and NK phenotypes. Thus, immune cell function www.investinme.org Page 87 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) and phenotypes are possible diagnostic biomarkers for (ME)CFS” (Ekua Brenu et al. Journal of Translational Medicine 2010:8:1). 2010 “(ME)CFS is a complex illness….Instead of searching for a deficiency in any single marker, we propose that (ME)CFS is associated with a profound imbalance in the regulation of immune function. To identify these imbalances we apply network analysis to the co-expression of 16 cytokines in (ME)CFS subjects and healthy controls….These showed highly attenuated Th1 and Th17 immune responses in (ME)CFS. High Th2 marker expression…pointed to an established Th2 inflammatory milieu” (Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. Brain Behav Immun 2010; 3rd May: Epub ahead of print). 2010 (ME)CFS studies from our laboratory and others described decreased natural killer cell cytotoxicity (NKCC) and elevated proportion of lymphocytes expressing the activation marker DPPIV also known as CD26. However, neither of these assays…are widely accepted for the diagnosis or prognosis of (ME)CFS. This study sought to determine if NKCC or DPPIV/CD26 have diagnostic accuracy for (ME)CFS….Cytotoxic function of NK cells for 176 (ME)CFS subjects was significantly lower than in the 230 controls….By ROC (receiver operating curve) analysis, NKCC and three methods of measuring DPPIC/CD26 examined in this study had potential as biomarkers for (ME)CFS….Abnormalities in DPPIV/CD26 and in NK cell function have particular relevance to the possible role of infection in the initiation and/or the persistence of (ME)CFS….The predominance of evidence indicating that people with (ME)CFS have decreased function of NK cells and abnormal activation of T and NK cells was supported by this study….The findings of this study give support to the concept that cause and/or the pathophysiology of (ME)CFS are related to infection…The spectre of infectious disease further emphasises the significance of this research to public health” (MA Fletcher, Gordon Broderick, Nancy G Klimas et al. PloS ONE 5(5): e10817. doi:10.1371/journal.pone.0010817). Invest in ME (Charity Nr. 1114035) 2010 On 16th June 2010 Professor Nancy Klimas was quoted in an interview: “The low NK cell function group are sicker, have more inflammation, more evidence of viral reactivation….NK cells are important, but they also reflect cytotoxic cell function – and that may be even more important. Having said that, most (ME)CFS patients have poor NK cell function; there is poor and poorer still”. When asked by the interviewer: “Is natural killer cell dysfunction in ME/CFS the T-helper cell dysfunction of AIDS and if so, why doesn’t it get more attention?”, Professor Klimas replied: “Well, you have to agree that having so many people die of AIDS was impossible to ignore….my (ME)CFS patients are much more ill day to day, and yes, some of them die from (ME)CFS related conditions. But the misery quotient in (ME)CFS is terribly high day in and day out” (http://phoenixrising.me/archives/1606). 2010 “Participants with (ME)CFS were grouped into viral and non-viral onset fatigue categories and were assessed for differential immunological marker expression….The viral in comparison to the nonviral group demonstrated significant elevations in several Th1 type subsets….The viral group demonstrated a pattern of activation that differed from that of the group with a non-viral aetiology….These findings imply that the homeostatic mechanism responsible for the regulation of the Th 1 (cell-mediated) and Th2 (humoral) immune responses is disturbed in (ME)CFS….In this sample, the viral group demonstrated elevations in this and the CD4+ and CD2+CD26+ subsets, which suggests an on-going process of systemic inflammation. The present findings support the premise that reductions in the efficacy with which natural killer cells are able to eliminate target cells, concomitant with elevations in activated T-cell subsets, may contribute to the maintenance of inflammation and immune activation” (Nicole Porter, Leonard A Jason, Mary Ann Fletcher et al. Journal of Behavioural and Neuroscience Research 2010:8:(2):1-8). 2010 www.investinme.org Page 88 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) At the CFSAC Science Day meeting on 12th October 2010, Professor Nancy Klimas is reported to have said that chronic immune activation is a key component of the systems imbalance seen in (ME)CFS; that IgG1 and IgG3 are also skewed; that the more symptomatic patients are, the worse their lymphocytes are functioning; that patients with poor NK cell function have less perforin function in their NK cells; that NK cell function is a very good indicator of the severity of the illness; that neuropeptide Y goes up in (ME)CFS patients and it is an important link to the autonomic nervous system – the higher the neuropeptide Y, the more significantly ill patients are, and that neuropeptide Y has links to the cardio-respiratory system and the immune system as well as to other systems; that proinflammatory cytokines are ALL elevated, some more than others, with IL-1  being the most dramatic; that Type 2 cytokines are elevated and are skewed to allergy and autoimmunity; that IL6 is a great biomarker in the (ME)CFS population; that there is a blunted adrenal axis and abnormal serotonin function; that cortisol levels are abnormal and the physiological response to stress in (ME)CFS is very poor (“the connectedness of the endocrine stress response and the immune response is very blunted”); that in (ME)CFS, 25 genes are expressed differently than in healthy controls, but when exercising, one sees many more genes being differently expressed and that exercising is a very, very impressive tool to understand things, as it is an autonomic trigger and that exercise (autonomic stimulus) is enough to inflame pathways; that other diseases with these markers activated include lymphoproliferative disorders and chronic viruses; that (ME)CFS patients are vitamin D deficient and B12 deficient; that(ME)CFS patients have mitochondrial dysfunction; that “we have biomarkers”; that “you can subgroup by symptom and severity”; that “I think I get a pretty good handle on pointing out inflammation with cytokine assays”; that enteroviruses are very important and that “herpes, coxsackie, endogenous viruses – all could reactivate”; that the immune system is a very important player in this disease; that abnormalities seen in the immune system are consistent: immune activation, inflammation, cytokine dysregulation, cellular abnormalities, which are typically seen in infection or autoimmunity (because cytotoxic Tcells are affected, this leans more to infection Invest in ME (Charity Nr. 1114035) than to autoimmunity, but autoimmunity is still an important issue) (http://www.facebook.com/pages/XMRV-GlobalAction/216740433250#!/notes/xmrv-globalaction/here-is-our-close-transcript-of-the-firstpart-of-the-cfsac-science-day/451191706796). 2010 In November 2010 Professor Klimas visited New Zealand on a lecture tour addressing doctors in Auckland, Dunedin and Wellington; the following are from notes taken by a NZ patient with ME, JillNZ, on www.mecfsforums.com. Professor Klimas likes the Canadian Consensus Criteria in preference to the Fukuda criteria because the CCC emphasise post-exertional malaise, which is unique to (ME)CFS; in the last 20 years her team found chronic immune activation (Th2 shift, DR CD26 expression, TNF, IL-1, IL-6) and defects (NK cells, CD8 -- cells do not have enough perforin or granzymes) and macrophages are abnormal: “If you had a chronic virus the immune system would look EXACTLY like this; it doesn’t prove it yet, though, because the pattern is also consistent with an autoimmune problem”; the immune pattern correlates with severity: those with more problems have higher numbers and scores of immune abnormalities; various viruses have been found to be (re)activated – EBV, CMV, HHV6, enteroviruses – all baggage viruses which should remain latent but which have interestingly been found to be activated in (ME)CFS, and something needs to be driving this; we have to remember that blood is not the only reservoir and we need to look at tissue as Chia has shown; a virus does not have to be whole to cause problems; exercise will normally increase cortisol, which acts to control inflammation, but in (ME)CFS, when patients exercise, cortisol goes down and inflammation goes unchecked and gets worse, with pain and delayed autonomic symptoms; the autonomic problems can cause gut motility issues and cerebral perfusion slows down, giving rise to cognitive impairment; her new Dynamic Modelling study looked at 105 patients who used an exercycle for 8 minutes, with blood being drawn at VO2 Max, then again 4 hours later to see all the genes that were turned on and turned off: in (ME)CFS, at VO2 max, it was all the inflammatory cytokines that were turned on (and increased TNF has 80 downstream effects on www.investinme.org Page 89 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) the body); four hours later, it was the autonomic genes that showed up. The study that she was presenting in Australia reveals 7 or 8 biomarkers for the illness. (ME)CFS patients should not donate organs; a Holter monitor should be used to look at the heart over a few days -- and a good cardiologist is needed because not all will know about cardiac problems in (ME)CFS. 2010 Following her visit to New Zealand, as one of the world’s leading immunology researchers, in December 2010 Professor Klimas presented her team’s findings at Bond University’s Faculty of Health Sciences and Medicine International Science Symposium on ME/CFS held on 3rd-4th December 2010, Gold Coast, Queensland, Australia, as reported by Dr Rosamund Vallings from New Zealand, extracts from whose summary are reproduced with grateful acknowledgement. Professor Klimas presented a systems biology approach to (ME)CFS. She described (ME)CFS as a disorder of homeostatic imbalance and briefly outlined her 25 year involvement with the disorder, saying she initially worked on the theory that it was a chronic immune activation syndrome, but it was next recognised as a neuroinflammatory disorder, and now genomics have become involved. Repeating some of her presentation in New Zealand (see above), she described an exercise challenge of 8 minutes with measurement of VO2 max, and the evidence that the immunological pathways affected were mainly inflammatory, with the immune cascade leading to many symptoms 4 hours later. Those symptoms involved the endocrine, immune, autonomic and neurological systems. The genes regulating NK cell function which included abnormal perforin and granzyme levels were specifically affected. In this study there was persistent inflammation. There was a huge cascade effect after 8 minutes which persisted 4 hours later. This study confirms that graded exercise is not good for those with (ME)CFS, and patients must stop exercise well short of the aerobic threshold. Other presentations made included that by Hugh Perry, Professor of Experimental Neuropathology, University of Southampton, who discussed how systems behave during inflammation, for example, Invest in ME (Charity Nr. 1114035) “feeling ill”, and how infection leads to an inflammatory response with release of cytokines which then communicate with the brain, leading to malaise; he noted that systemic inflammation activates selective brain regions, a mechanism that works through macrophages in the brain via the blood-brain barrier. Professor Mary Ann Fletcher (University of Miami) presented her work on biomarkers for (ME)CFS, initially looking at NK cell function and the diminution of perforin and granzyme, then at neuropeptide Y , which is involved in the stress reaction and she showed how, in a controlled study, NPY was considerably higher in (ME)CFS compared with controls and how ROC analysis showed discrimination between (ME)CFS patients and controls, where NPY was found to be 80% sensitive in (ME)CFS. NYP also correlates with disease severity in (ME)CFS. Ekua Brenu (PhD candidate, Bond University, Queensland, Australia, under the direction of Professor Sonya Marshall-Gradisnik, one of Australia’s foremost researchers in neuroimmunology) had looked at innate and adaptive immunity in (ME)CFS seeking biomarkers in a study of 253 patients and 100 controls at baseline and at 6 months. Cytotoxic activity of NK cells and CD8+T cells was significantly reduced, and perforin and granzyme activity was reduced. When looking at NK cell phenotypes, CD56 bright cells were significantly diminished. Cytokine secretion from CD+4 T cells showed significant elevation of IL-10, IFN and TNF; FOXP3 expression was also heightened in the (ME)CFS group. Vaso-active intestinal peptide (VIP, an endoegenous and exogenous immunomodulator) receptors were also investigated and found to be significantly elevated. Donald Staines (Bond University, Gold Coast, Australia; Associate Professor and Public Health Physician at PHANU – Australia’s Public Health and Neuroimmunology Unit), considered whether autoimmunity affecting vaso-active neuropeptides suggest a pathomechanism for (ME)CFS, as (ME)CFS may be associated with autoimmunity affecting the function of vaso-active neuropeptides such as VIP and PACAP (pituitary adenylate cyclase activating peptide); VIP/PACAP synergism is involved with potentiation of cardiac www.investinme.org Page 90 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) firing, anti-apoptosis function, 91amp and insulin control, hypoxia regulation and glutamate metabolism. 2010 “(ME)CFS is a complex, multi-symptom illness with a multi-system pathogenesis involving alterations in the nervous, endocrine and immune systems….Plasma levels of NPY are reported to be elevated in other complex multi-symptom illnesses associated with immunologic dysfunction, including…systemic lupus erythematosus (SLE)…. Given these reports, it seemed likely that plasma NPY would be elevated in (ME)CFS….We tested and confirmed that elevation of peripheral NPY occurs in (ME)CFS and that elevation of NPY is associated with severity of stress, negative mood and clinical symptoms….Immune activation and inflammation are postulated to be principle components in the pathophysiology of (ME)CFS….Normally cortisol induces a downregulation of inflammation. However, this mechanism is disrupted in the typically hypocortisolic (ME)CFS patient….Dysautonomic conditions…have been reported in (ME)CFS patients….A recent study from our group demonstrated reduced stroke volume and cardiac output in more severely afflicted (ME)CFS patients….Of interest is the finding…that NPY inhibits the production of cortisol in human adrenal H295R cells via the Y1 receptor….This study is the first in the (ME)CFS literature to report that plasma NPY is significantly elevated over healthy controls….Duration of this illness typically exceeds 10 years. Persistence is likely to involve complex interaction of immune, autonomic and neuroendocrine regulation” (Neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome. Mary Ann Fletcher, Gordon Broderick, Nancy Klimas et al. Behavioural and Brain Functions 2010: 6:76 doi:10.1186/17449081-6-76). 2011 “Heterologous immunity is a common phenomenon present in all infections. Most of the time it is beneficial…but in some individuals that have the wrong crossreactive response it leads to a cascade of events that result in severe immunopathology. Infections have been Invest in ME (Charity Nr. 1114035) associated with autoimmune diseases such as diabetes, multiple sclerosis and lupus erythematosus, but also with unusual autoimmune-like pathologies where the immune system appears dsyregulated, such as sarcoidosis, colitis…and (ME)CFS” (Selin LK et al. Autoimmunity 2010: Jan 20. Epub ahead of print). 2011 On 29th April 2011 Dr Daniel Peterson gave a presentation at Calgary, Alberta, to medical practitioners. He said that cytokines, low NK cell function, increased activation markers, oxidative stress and mitochondrial dysfunction are a few of the possible markers found in ME/CFS patients, and that while there is no diagnostic test, there are definitive biomarkers for ME. He said that an association has been found between several critical human molecules such as the thyroid peroxidase protein and leucotropic human herpes viruses, which suggests a mechanism for the commonly reported finding of increased prevalence of autoantibodies in people with ME. Dr Peterson said he is involved with a large study being conducted at Bond University, Gold Coast, Australia, that is looking at NK cell phenotype and function; he recommends measuring NK cell function for a diagnosis of ME, as it is the most reliable marker for ME (reported by Anne-Marie Woynillowicz Kemp: Co-Cure NOT: 12th May 2011). 2011 “Derangement of the interaction between the immune and neuroendocrine systems represents one of the major mechanisms in the development of (ME)CFS. Induction of (ME)CFS by i.p. administration of the synthetic double-stranded RNA poly I:C provides a suitable experimental model for studying these mechanisms…The results lead to the conclusion that impairments between the immune and neuroendocrine systems during the development of (ME)CFS, including changes in the hypothalamo-hypophyseal-adrenocortical system (HHACS) activity, are mediated both at the level of changes in immunocompetent cells and directly on brain cell membranes” (Rybakina EG et al; Research Institute of Experimental Medicine, Russian Academy of Medical Sciences. Neurosci Behav Physiol 2011: 41(2):198-205). www.investinme.org Page 91 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) 2011 “Compared to healthy controls (ME)CFS patients displayed significant increases in IL-10, IFNgamma, TNF alpha, CD4+CD25+ T cells, FOXP3 and vasoactive intestinal peptide receptor 2 expression. Cytotoxic activity of NK and CD8+ T cells and NK phenotypes, in particular the CD56 bright NK cells were significantly decreased in (ME)CFS patients. Additionally granzyme A and granzyme K expression were reduced….These data suggest significant dysregulation of the immune system in (ME)CFS patients” (Ekua Brenu, Don R Staines, Nancy G Klimas et al. Journal of Translational Medicine 2011: 9:81doi:10.1186/1479-5876-9-81). 2011 “(ME)CFS is characterised by unexplained fatigue…with a constellation of other symptoms….Recently, the AISA (autoimmune/inflammatory syndrome induced by adjuvants) syndrome was recognised, indicating the possible contribution of adjuvants and vaccines to the development of autoimmunity” (Hemda Rosenblum et al. Infectious Diseases Clinics of North America. Elsevier Inc. doi:10.1016/j.idc.2011.07.012). 2011 The tenth IACFS International Research and Clinical Conference was held on 22nd-25th September 2011 in Ottawa, Canada. It was entitled “Translating Evidence into Practice”. The immunology section (“The Latest Research in Immunology”), chaired by Professor Nancy Klimas, included the following: Ekua Brenu (PhD candidate, Bond University, Queensland, Australia, et al): Cell specific immune investigations have demonstrated a possible link between (ME)CFS and failure to maintain immunological homeostasis. The most common immune cells with known dysfunction in (ME)CFS are cytotoxic cells, NK cells and CD8+T cells. This study examined cytotoxic function and markers in (ME)CFS patients at 6 month intervals to determine the stability of these observations over time. Preliminary results indicated that Invest in ME (Charity Nr. 1114035) compared with healthy controls, (ME)CFS patients demonstrate significant decreases in cytotoxic activity at baseline, at 6 months and at 12 months. Additionally, NK CD56 bright cells remained decreased in (ME)CFS patients. The study demonstrated and confirmed reduced immune function in patients with (ME)CFS and substantiates the use of NK cell cytotoxicity as a biomarker for (ME)CFS. Ekua Brenu presented a further study which suggested that the cytokine profile in (ME)CFS changes during disease progression and that this may be associated with disease severity, hence the need to match laboratory findings with the clinical state of the patient with (ME)CFS. Mangalathu S Rajeevan, Elizabeth Unger et al (CDC, Atlanta) said there is evidence that immune and inflammatory alterations are important in (ME)CFS, so they set out to determine if genetic variants in inflammation and immune pathways could be linked to (ME)CFS. Compared with nonfatigued controls, (ME)CFS was associated with 34 functionally relevant SNPs (single nucleotide polymorphisms). Twelve of these SNPs are genes playing a role in pathways related to complement cascade, chemokines, cytokine/cytokine signalling and Toll-like receptor signalling. The authors concluded that this study identified a number of novel and functionally relevant genetic variants in complement cascade, chemokine and cytokine signalling pathways associated with (ME)CFS. Of note is the rider stating: “The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency” (i.e. the CDC). Jeanna M Harvey (MD candidate, University of Miami), together with Professors Mary Ann Fletcher and Nancy Klimas, looked at twelve biomarkers that had significant changes as a result of exercise in three groups (Gulf War Syndrome, ME/CFS and healthy controls). Upon exercise, the number of CD26+ lymphocytes was higher for GWS and the healthy controls but lower in patients with (ME)CFS. The authors concluded that biomarker measurement during the course of an aerobic exercise challenge indicates major differences among GWS, (ME)CFS and healthy controls which may help the understanding of these complex disorders. www.investinme.org Page 92 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) Maria A Vera (University of Miami), together with Professors Mary Ann Fletcher and Nancy Klimas, noted that Metabolic Syndrome (MetSd) is a known risk factor for cardiovascular and cerebrovascular disease, and that previous studies have shown that patients with (ME)CFS were twice as likely to have metabolic syndrome as controls. They set out to compare cytokine levels in patients with (ME)CFS with and without metabolic syndrome. They concluded that the prevalence of metabolic syndrome in an (ME)CFS population was 26%, and that similarly to their previously reported findings in (ME)CFS, patients with both (ME)CFS and metabolic syndrome had abnormalities in pro-inflammatory, Th2, Th1 and IL-8 compared with healthy controls and were biased towards a Th2 cytokine pattern, accompanied by autoantibody production. The investigators recommend that large longitudinal studies should be performed to determine the contributing factors to this increased risk. Professors Mary Ann Fletcher and Nancy Klimas (Miami) looked for biomarkers in (ME)CFS. Prospective biomarkers included NK cell cytotoxicity (NKCC), T lymphocyte proliferation in vitro in response to mitogen (LPA), lymphocyte activation markers (CD26, CD38), 16 plasma cytokines and neuropeptide Y. The results provided credible biomarker status for NKCC, LPA, and markers of lymphocyte activation in (ME)CFS. A significant elevation in the relative amounts of four of five pro-inflammatory cytokines in peripheral blood plasma of patients with (ME)CFS was found when compared with the controls. Both IL-4 and IL-5 were elevated in (ME)CFS. The anti-inflammatory cytokine IL-3 was significantly lower (15% lower) in (ME)CFS patients. IL-12 was significantly elevated (120% higher) and IL-15 decreased 15% in cases compared with controls. IL-8 was 42% lower in the (ME)CFS patients. The stress hormone NPY was elevated in plasma of (ME)CFS patients and positively correlated with perceived stress. The authors concluded that fifteen useful biomarkers were identified in their studies, and that the differences in these markers compared with controls give important information regarding the pathophysiology of (ME)CFS. The association of low LPA response, elevated proportion of activated CD4 and CD8 T cells, defective NKCC, elevated Th2 cytokines in (ME)CFS cases suggests Invest in ME (Charity Nr. 1114035) that T cells are metabolically limited in performing their helper function. All but one of the inflammatory cytokines were elevated, as was the stress hormone NPY, supporting the hypotheses that inflammation and abnormal stress responses are important components in the pathophysiology of (ME)CFS. Ekua Brenu et al (Bond University, Queensland) studied the effects of vaccination on immune function in (ME)CFS. Noting patients’ inability to tolerate certain toxins and their hypersensitivity, they set out to examine the effects of routine vaccination on immune function in patients with (ME)CFS. They concluded that their findings suggest a potential role of vaccines in the pathophysiology of (ME)CFS. It is notable that Dr Daniel Peterson is on record in relation to the above study at Bond University saying on 14th October 2011 that the investigators assessed immune functioning before and after people with (ME)CFS were vaccinated and they found evidence that vaccinations may be significantly affecting immune functioning (http://forums.phoenixrising.me/content.php?490 -Dr-Peterson-Talks-On-Diagnosing-Treatin-XMRVCFS-MECFS-chronic-fatigue-syndrome ). This may tie in with the AISA syndrome (autoimmune/inflammatory syndrome induced by adjuvants in vaccines) noted by Rosenblum et al in Infectious Diseases of North America mentioned above. It is further notable that on 23rd March 2012 neurosurgeon Dr Russell Blaylock was reported as saying in an interview that vaccines switch the immune system to Th2 and that they suppress immunity rather than boosting it by confusing the immune system and altering the way it responds to viruses and bacteria: “We found that, in fact, (vaccination) causes the immune system to switch to what we call Th2-type cytokine production which inhibits immunity. And your major protection against viruses…is your cellular immunity. Well, vaccines don’t stimulate cellular immunity at all, in fact they suppress it” (http://tv.naturalnews.com/v.asp?v=DFBE7C32CB DBF43B7342333B7D827EB0). 2011 “There is evidence that inflammatory pathways and cell-mediated immunity (CMI) play an www.investinme.org Page 93 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) important role in the pathophysiology of ME/CFS. In this study we therefore measured plasma IL-1, TNF, and PMN-elastase, and serum neopterin and lysozyme in 107 patients with ME/CFS, 37 patients with chronic fatigue (CF) and 20 normal controls. Serum IL-1, TNF, neopterin and lysozyme are significantly higher in patients with ME/CFS than in controls and CF patients. Plasma PMN-elastase is significantly higher in patients with ME/CFS than in controls and CF patients and higher in the latter than in controls….The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flulike malaise, may be caused by inflammatory mediators” (Maes M, Twisk FN, Kubera M, Ringel K. J Affect Disord 2011: Oct 3 Epub ahead of print). 2011 In a presentation given on 22nd October 2011 in Seville, Spain, Kenny DeMeirleir (Professor of Physiology, Pathophysiology and Medicine, Vrije Universiteit, Brussels) provided a list of laboratory tests that support the clinical diagnosis of ME/CFS; those involving the immune system included the following: Immunophenotype:  Total number of lymphocytes  CD4/CD8 ratio  CD4+ lymphocytes  CD8+ lymphocytes  Ratio of NK cells  B cells  Soluble CD14 (increased in 90% of ME/CFS patients and correlates with severity)  CD57 lymphocytes (low in most ME/CFS patients)  Leucocyte elastase activity (increased in a sub-group of patients)  C4a (increased in 80% of patients)  Expression of perforin mRNA  IgM and IgG Cytokines: (cytokine serum levels)  IL-8, MCP1, MIP-1  IL-6, IL-10  IL-12  TGF 1  TNF Invest in ME (Charity Nr. 1114035) Food intolerance panel of IgG:  Casein  Gluten  Lactose  Tissue transglutaminase and gliadin antibodies (IgA / IgG)  Defective lactase gene. It will be recalled that, due to the influence of the Wessely School, none of these tests is permitted in the UK National Health Service for people thought to have ME/CFS. 2011 In October 2011 the International Consensus Criteria for Myalgic Encephalomyelitis were published in the Journal of Internal Medicine 2011:270:4:327-338 (http://onlinelibrary.wiley.com/doi/10.1111/j.136 5-2796.2011.02428.x/abstract). The following is an extract on “Immune Impairment”, together with the references cited: ”Publications describe decreased natural killer cell signalling and function, abnormal growth factor profiles, decreased neutrophil respiratory bursts and Th1, with a shift towards a Th2 profile [4–8, 92, 93]. Chronic immune activation [27], increases in inflammatory cytokines, pro-inflammatory alleles [4–8, 94–96], chemokines and T lymphocytes and dysregulation of the antiviral ribonuclease L (RNaseL) pathway [62, 97–100] may play a role in causing flu-like symptoms, which aberrantly flare in response to exertion [5,92]. 4. Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun 2010; 24: 1209–17. 5. Lorusso L, Mikhaylova SW, Capelli E, Ferrari D, Ngonga GK, Ricevuti G. Immunological aspects of chronic fatigue syndrome. Autoimmun Rev 2009; 8: 287–91. 6. Fletcher MA, Zeng XR, Maher K et al. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and www.investinme.org Page 94 of 108 dipeptidyl peptidase IV. PLoS ONE 2010; 5: e10817. Journal of IiME Volume 6 Issue 1 (June 2012) 377–85. 7. Mihaylova I, DeRuyter M, Rummens JL, Basmans E, Maes M. Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells. Neuro Endocrinol Lett 2007; 28: 477–83. 8. Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990; 28: 1403–10. 62. Snell CF, VanNess JM, Stayer DF, Stevens SR. Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS). In Vivo 2005; 19: 387–90. 92. Brenu EW, Staines DR, Baskurt OK et al. Immune and haemorheological changes in chronic fatigue syndrome. J Transl Med 2010; 8: 1. 93. Klimas NG, Koneru AO. Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions. Curr Rheumatol Rep 2007; 9: 483–7. 94. Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in women with chronic fatigue syndrome. J Transl Med 2009; 7: 96. 95. Cameron B, Hirschberg DL, Rosenberg-Hassan Y, Ablashi D, Lloyd AR. Serum cytokine levels in postinfective fatigue syndrome. Clin Infect Dis 2010; 50: 278–9. 96. Carlo-Stella N, Badulli C, De Sivestri A et al. The first study of cytokine genomic polymorphisms in CFS: positive association of TNF857 and IFNgamma 874 rare alleles. Clin Exp Rheumatol 2006; 24: 179–82. 97. De Meirleir K, Bisbal C, Campine I et al. A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome. Am J Med 2000; 108: 99–105. 98. Sudolnik RJ, Peterson DL, O’Brien K et al. Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome. J Interferon Cytokine Res 1997;17: Invest in ME (Charity Nr. 1114035) 99. Nijs J, Fremont M. Intracellular immune dysfunction in myalgic encephalomyelitis ⁄chronic fatigue syndrome: state of the art and therapeutic implications. Expert Opin Ther Targets 2008; 12: 281–9. 100. Nijs J, De Meirleir K, Meeus M, McGregor Nr, Englebienne P. Chronic fatigue syndrome: intracellular immune deregulations as a possible aetiology for abnormal exercise response. Med Hypotheses 2004; 62: 759–65. 2011 “(ME)CFS is a disease of unknown aetiology. Major (ME)CFS symptom relief during cancer chemotherapy in a patient with synchronous (ME)CFS and lymphoma spurred a pilot study of Blymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response. The…response…suggests that (ME)CFS is an autoimmune disease….The results support the assumption that (ME)CFS is not primarily a mental health disease….The B cells have multiple immune functions, the main ones being antibody production, antigen presentation and regulation of the function and activity of other immune cells, i.e. T-regulatory cells, NK cells and macrophages….We believe the results are best compatible with an autoimmune disease mechanism and that the presented findings may have a major impact on the direction of biomedical research in (ME)CFS” (Oystein Fluge, Olav Mella et al. PloS one: October 2011:6:10:e26358: doi:10.1371/journal.pone.0026358). Replying on 31st October 2011 to criticisms levelled by van der Meer et al, Dr Fluge pointed out that “an autoimmune component is probable in many patients (with ME/CFS)…(and that) (ME)CFS according to Fukuda or Canadian criteria is in many patients a very serious and debilitating disease”. Commenting on the Norwegian study, Dr Gordon Broderick (Associate Professor, University of Alberta) said: “As mentioned by the authors, Rituximab is a B-cell suppressor used in the www.investinme.org Page 95 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) treatment of non-Hodgkin’s lymphoma. Abnormal B-cell activity has long been suspected as playing a key role in (ME)CFS. As early as 2006 Maes and colleagues…presented evidence of increased IgM antibodies directed specifically at cellular products of oxidative and nitrosative stress. That same year, our work with Dr Suzanne Vernon and her colleagues also produced evidence of sustained oxidative stress in circulating immune cells based on their gene expression….Evidence of altered status in the B-lymphocytes of (ME)CFS patients was found in a study of gene expression conducted by our group…Further work…conducted with Drs Nancy Klimas and Mary Ann Fletcher of the University of Miami documented immune signalling patterns suggestive of an over-active Th2 or B-cell mediated immune response….In a nutshell, these positive clinical trial results are not only welcome but they represent a logical continuation of a line of investigation that has been ongoing” (http://www.research1st.com/2011/10/21/broder ick). Also commenting on the Norwegian study, Professor Nancy Klimas said: “The recent study of Drs Oystein Fluge and Olav Mella demonstrating significant improvement in ME/CFS patients treated with the B-cell depleting agent Rituximab is a key study for our field. By showing that depleting B cells can cause dramatic improvement, the investigators point the field in the direction of autoimmunity, and autoimmunity caused by an autoantibody. However, there is one other plausible explanation: that the B cells were acting as a reservoir of infection and by depleting the B cell line the viral load can be brought down to the point of suppression by the immune system….I believe that both of these theories deserve vigorous scientific pursuit….Many clinicians fail to realise the severity of the illness that has been termed ME/CFS. This is a profoundly ill population” (http://bergento.no/the-mecfs-study-by-mellaand-fluge-is-a-key-study-for-our-field/ ). Conclusion There can be no possible doubt that ME/CFS is essentially a disorder of the immune system. Given the extent of the evidence-base (of which the above illustrations may barely scratch the surface), it is incomprehensible how the Wessely School psychiatrists continue to wield such powerful influence over the ME/CFS arena. Many people deem this situation to be a scandal of epic proportions. As Dr Vance Spence, a respected medical scientist specialising in vascular medicine in ME/CFS, said in an article on 25th May 2004 in the Derry Journal (“The ME Scandal”): “I can think of no other illness where such a powerful schism exists between those who suffer from it and those whose responsibility is to care for them. How can it be that an illness that affects between 100,000 and 200,000 persons of all ages in the UK and maybe as many as one million in the United States of America is no longer referred to in medical textbooks, is not cited in medical research indexing systems and rarely features in the syllabus of undergraduate medical education in medical schools? Why have the experiences of these patients been largely ignored, their testimonies…undervalued, even ridiculed, and their requests for assistance met often with prejudice and disbelief? (Co-Cure RES, ACT 8th June 2004). Could the answer lie in just three words: The Wessely School? On 1st August 2004 John Herd re-published an article he had written seven years earlier (in 1997), saying how profoundly rhetoric has permeated the (ME)CFS arena, and that the tragedy of lasting misperceptions means that it is not enough for doctors to conduct their research and see patients in their clinics – they must speak up about their evidence that ME/CFS is not a psychiatric disorder: “Throwing forth theories of psychiatric causations of ME/CFS…is not science. Science, hard science, is objective….The proof that transforms theory into science is concrete evidence found in cells…Psychiatric research is…highly interpretive… (it) lacks the concrete evidence of biologic research (and thus) can be driven by its original theories instead of…concrete evidence… “Science” seems to mean different things to different people. Speculation, especially if it comes from a well-known name, in some people’s eye becomes fact as soon as it appears in a peer Invest in ME (Charity Nr. 1114035) www.investinme.org Page 96 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) reviewed medical journal….Why is anyone listening to self-proclaimed experts who have direct connections with corporate entities that only wish to protect their financial assets?” (CoCure ACT, 1st August 2004). Herd followed this up by saying: “More and more doctors have become entrenched in an ‘all in the head’ bias about ME/CFS that is not founded upon evidentiary science. Instead of welcoming advancements of science, their minds have become ever more closed to objective laboratory findings that conflict with their belief systems….Doctors who are uninformed about the illness and those firmly entrenched in flawed ideologic bias may not even bother to read new research articles (so) many patients see no improvement in accessibility to adequate clinical care…Proponents of the idea that ME/CFS is a psychosocial phenomenon have been getting more and more of their articles in the medical journals. They hold a powerful and influential position in the World Health Organisation and in many influential governmental/medical committees….We must find ways to remove ideology and speculation from the equation (and) develop new means of having science speak for itself to break the logjam of flawed ideologic bias” (Co-Cure ACT: 19th October 2004). It is high time for the Wessely School and all to whom they act as advisors to engage with the immunological basis of ME/CFS. As one sufferer pointed out in 2005, attributions do not maintain this illness, any more than they maintain cancer, diabetes, multiple sclerosis, or any other physical illness (Co-Cure ACT: 27th July 2005). In fact, the objective and reproducible evidence plainly shows that ME/CFS is maintained by a dangerously dysregulated immune system. There is such a gross mismatch between the severity and complexity of ME/CFS and the medical/public perception of the disorder as promulgated by the Wessely School that, until these psychiatrists are held to account (and health care professionals and public alike are informed and educated about the nature of ME/CFS), patients will continue to suffer iatrogenic harm. Wessely has often claimed that he does not want to get into the fruitless “organic” versus “functional” debate, but many people believe Invest in ME (Charity Nr. 1114035) (justifiably, when one reads what he has actually published about people with ME/CFS over the last 25 years) that he has done more than anyone else to fan this particular flame by distorting the perception of the disease; they also believe that he has done much to prevent ME/CFS attaining disease legitimacy and thus to halt not only the progress of medical science but also the provision of care for very sick patients. The body of biomedical evidence about ME/CFS from across the disciplines is now so extensive that the question repeatedly asked is: at what point will that body of scientific knowledge be so great that it will be considered serious professional misconduct to ignore it and to continue to deceive physicians and patients alike by pretending that it does not exist? There is a body of informed opinion (including clinicians, medical scientists, lawyers, research analysts, university lecturers and members of other professions) that the General Medical Council ought to be required to assess the Wessely School’s fitness to practice medicine: many people are of the view that the Wessely School are a risk to ME/CFS sufferers by their erroneous assertion that ME/CFS patients’ multiple symptoms “have no anatomical or physiological basis” (Brit J Hosp Med 1994:51:8:421-427), a categoric Wessely School view that has not changed over the intervening 18 years and which seems to be reflected in NICE’s proscription of appropriate laboratory tests (in particular, no immunological tests may be carried out); by their ignoring of the biomedical evidence, and by their insistence that ME/CFS is a functional/behavioural disorder and a “pseudo-disease” that must not be investigated as this would reinforce sufferers’ alleged misperceptions that they are physically sick. However, even though the national implementation of the Wessely School’s personal philosophy is not based on medical science, nothing might come of a complaint to the GMC because, as Dame Janet Smith (The Rt Hon Lady Justice Smith, a High Court Judge and former President of the Council of The Inns of Court) aptly said on 3rd October 2011, the GMC is “a deeply dysfunctional institution” (Channel 4; Dispatches). www.investinme.org Page 97 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) On 26th March 2012 the Prime Minister, David Cameron, said on television that the dementia situation in the UK is “a national crisis”. He needs to be aware that there is also a national crisis with the ME/CFS situation in the UK, where sick people are denied the scientific reality of their disease and instead are coerced into inappropriate psychological interventions that have been shown to make 82% of ME/CFS sufferers worse (http://www.investinme.org/Article400%20Magic al%20Medicine.htm). ME FACTS Over 20 renowned international experts on ME have provided written statements of concern effectively stating that cognitive behavioural therapy and graded exercise therapy used to support the alleged existence of the “biopsychosocial model” do not work for people with ME (Magical Medicine pp 88-92). Furthermore, numerous trials have shown that not only is the “biopsychosocial model” unsuccessful in the management of ME/CFS but that the model itself is not evidence-based and it may be actively harmful: -the evidence that behavioural modification techniques have no role in the management of ME/CFS is already significant and has been confirmed by a study in Spain, which found that in ME/CFS patients, the two interventions used to justify the biopsychosocial model (CBT and GET) did not improve HRQL (health-related quality of life) scores at 12 months postintervention and in fact resulted in worse physical function and bodily pain scores in the intervention group (Nunez M et al; Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year follow-up. Clin Rheumatol 2011, Jan 15: Epub ahead of print) More Concerns About the Current UK Welfare Reform http://www.investinme.org/Article441%20UK%20Welfare%20Reforms.htm Invest in ME (Charity Nr. 1114035) ME STORY I live in constant fear of a crisis driving me into hospital; our hospitals have shown such lack of consideration for the special needs of patients like me that time spent in hospital is torture (eased only by the incredible kindness shown by some nurses and doctors) and invariably causes further deterioration. Many days I feel utter despair. But, unlike some sufferers, over the long years in which I’ve had severe ME (the illness began mildly and has taken a progressive course) I have at least had periods of respite from the absolute worst of it. During those periods I was still very ill, but it was possible to enjoy something of life. So in these dark days I know there is a real chance of better times ahead and that keeps me going. My entire future, and the greatly improved health I so long for, however, currently hinges on luck alone. This is wrong. As I lie here, wishing and hoping and simply trying to survive, I (and the thousands like me – severe ME is not rare) should at least have the comfort of knowing that there are many, many well-funded scientists and doctors who are pulling out all the stops in the quest to find a treatment which may restore my health and that the NHS is doing all possible to care for me as I need to be cared for – but I don’t. This wretched, ugly disease is made all the more so through the scandalous lack of research into its most severe form and the lack of necessary, appropriate support for those suffering from it. This is something that must change. - Emily Collingridge Emily Collingridge passed away in March - losing her fight against this awful disease myalgic encephalomyelitis. These words were written over many weeks – while Emily still had the strength in her body to do so. http://www.investinme.org/EmilyCollingridge.htm www.investinme.org Page 98 of 108 PRESENTERS at the 7tthh Dr Ian Gibson INVEST in ME INTERNATIONAL ME/CFS CONFERENCE Dr Ian Gibson, former Labour MP for Norwich North, worked at UEA for 32 years, became dean of the school of biological sciences in 1991 and was head of a cancer research team and set up the Francesca Gunn Leukaemia Laboratory at UEA. In 2011 Dr Gibson received an honorary doctorate of civil law from UEA. Dr Gibson will chair the conference this year. Professor Don R Staines New Directions for ME/CFS Research Don Staines is a public health physician at Gold Coast Population Health Unit. He has worked in health services management and public health practice in Australia and overseas. His interests include collaborative health initiatives with other countries as well as cross-disciplinary initiatives within health. Communicable diseases as well as post infectious fatigue syndromes are his main research interests. A keen supporter of the Griffith University Medical School, he enjoys teaching and other opportunities to promote awareness of public health in the medical curriculum. Abstract Autoimmunity as a plausible hypothesis in the aetiology of ME/CFS has been explored by our research group in Australia since 2004. Recent clinical data from Norway support an autoimmunity hypothesis with benefit from antiCD20 monoclonal antibody demonstrated in a Invest in ME (Charity Nr. 1114035) clinical trial. Autoimmunity remains a challenging area for research with complex interactions between innate and acquired immune system responses. Identification of a putative target for autoimmune attack in ME/CFS remains elusive. Hence a Clinical Autoimmunity Working Group (CAWG) was established to bring autoimmunity and neuroscience specialists together to consider recent clinical data and consider future directions in this research area. Topics discussed included autoimmunity pathomechanisms and presentations, identification of autoimmune targets, laboratory models including experimental autoimmune encephalomyelitis (EAE), vascular changes in the central nervous system, advances in vasoactive neuropeptide (VN) research and novel biomarkers assisting the diagnosis of ME/CFS. Recent developments in purinergic signalling and neurological models of autoimmunity including reactive gliosis, and pathomechanisms involving VNs may contribute to the understanding of CFS/ME. ATP, NO and VIP are now recognised as co-transmitters and may be involved in these pathomechanisms. Moreover gliosis is invariably associated with brain insult and may be a feature of ‘virtual’ oxygen glucose deprivation likely to occur from VN failure. The neurovascular unit (NVU) has a vital role in cerebral vasculature and immune competency and these functions might be lost in VN compromise. Effects would be expected to be more severe in the CNS where blood brain barrier (BBB) and blood spinal barrier (BSB) function could be compromised by the activation of purinergic receptors and initiation of inflammatory mechanisms. Other organs systems including heart, gut and lung may also be compromised through these pathomechanisms which may in part explain the prolonged and difficult course of CFS/ME. New techniques for investigating BBB and BSB function are being developed and may have applications in this condition. Therapeutic opportunities may arise through renewed understanding of immunological and neuroinflammatory mechanisms involved in ME/CFS. www.investinme.org Page 99 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) Dr Sonya Marshall-Gradisnik Title: Immunological dysfunction as possible biomarkers for Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) Dr. Sonya MarshallGradisnik is an Associate Professor in Immunology. Since obtaining her PhD (2004) she has received over $4 million dollars in competitive external grant funding. In 2010, Dr Marshall-Gradisnik was awarded the prestigious Queensland Women in Technology Research Award-Rising Star Award for her research into immunological biomarkers for ME/CFS. Dr Marshall-Gradisnik has edited two books, published 52 publications in high impact journals, eight book chapters, and published sixtyfour conference abstracts in immunology. She is a reviewer for the Australian Research Council (ARC) and was in 2011 one of the authors of the ME: International Consensus Criteria. Dr MarshallGradisnik has recently received the following awards/grants: Queensland Government ($533,000); Queensland Government CoInvestment Fund ($830,000); Mason Foundation ($831, 000) and the Alison Hunter Memorial Foundation Research Grants. Dr MarshallGradisnik leads a large research team that is not only developing early diagnosis of immunological biomarkers for ME/CFS but also focusing on gene expression studies in severe and moderate ME/CFS patients. She has received the National Award as Best Young Science Investigator at the Australian Conference for Science and Medicine for her studies into natural killer cell function and genotyping. Abstract Sonya Marshall-Gradisnik 2,3, 4 Donald R Staines,1, 2 Kevin J Ashton 3 Daniel Peterson 6, Sharni Hardcastle1,2, Mieke van Driel 2, 3,5 and Ekua, Weba Brenu 2, 3 1. Gold Coast Population Health, Queensland Health, Robina, Australia, 4229 2. Population Health and Neuroimmunology Research Unt, Faculty of Health Science and Medicine, Bond Unversity, Robina, Australia, 4229 3. Faulty of Health Science and Medicine, Bond University, Robina, Australia, 4229 4. School of Medical Sciences, Griffith Health, Invest in ME (Charity Nr. 1114035) Griffith University, Gold Coast Campus, Gold Coast, Australia, 4560 5. Scool of Medicine, University of Queensland, St Lucia, Brisbane, QLD 6. Siera Internal Medicine at Incline Village Chronic Fatigue Syndrome (CFS) is a multi-factorial disease that may involve disparities in neuroendocorine immune function. Presently, a number of neuropeptides have been associated with CFS. This may be attributed to their role in regulating immune function. Our research has investigated patients diagnosed with CFS to identify immunological/neuroimmunological and genetic differences in patients compared with nonfatigued controls where our investigations have shown dysfunction in Natural Killer cell lysis, Natural Killer Cell Phenotype, Cytotoxic T cell Cytotoxic Lysis, GZMA lytic protein decreases for NK and T Cytotoxic cell function, Neuropeptide receptor dysfunction (VPAC1R and VPAC2R), Foxp3 expression, Cytokine dysregulation (T-Helper 1 and T-Helper 2 Dysregulation) and microRNA immune regulation in CFS patients compared to nonfatigued controls. These collective studies suggest their application as potential biomarkers for early identification of ME/CFS patients for clinicians. Professor Hugh Perry Neuroinflammation in chronic disease Professor Perry and his team study Inflammation in the CNS and its contribution to Neurological Disease. The results of this research may help in the development of therapies to treat acute and chronic neurodegenerative conditions, which at present are largely untreated. Inflammation biology in the brain is a complex subject and requires expertise in many different areas. The CNS Inflammation Group has collaborations with academic laboratories across the University of Southampton, the UK, as well as with laboratories across Europe. Abstract The resident immune cells of the brain, the microglia, are observed to be morphologically activated, express a greater diversity of immunefunction related molecules and increase in number during the progression of many chronic www.investinme.org Page 100 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) neurodegenerative diseases. Observational studies in human post-mortem material and studies in animal models seek to define the contribution that this innate immune response makes to the pathogenesis and rate of progression of these diseases. It is well recognized that age is a significant risk factor for diseases such as Alzheimer’s disease and Parkinson’s diseases and that elderly people commonly have systemic comorbidities that give rise to systemic inflammation. There is a growing body of evidence to show that systemic infection and inflammation impact on the progression of chronic neurodegeneration in animal models: this involves the switching of the microglia phenotype from a relatively benign phenotype to an aggressive tissue damaging phenotype by the systemic inflammation. Clinical studies in patients with Alzheimer’s disease show that chronic systemic inflammation and acute infections are associated with accelerated cognitive decline and exacerbation of the symptoms of sickness. These observations show that immune to brain communication normally part of our mechanisms for fighting infection may become maladaptive in those with degenerative diseases of the brain. These findings offer new routes to therapeutic interventions to improve the quality of life of those suffering from chronic neurodegenerative disease. Professor Maria Fitzgerald An Overview of Chonic Pain Mechanisms Professor of Developmental Neurobiology Dept Anatomy & Developmental Biology, University College London. Maria Fitzgerald graduated in Physiological Sciences at Oxford University and studied for a PhD in Physiology at UCL. She was awarded a postdoctoral MRC training fellowship to work with Professor Patrick Wall in the Cerebral Functions Group at UCL and remained in that group as a postdoctoral fellow until starting her own research group in the Anatomy & Developmental Biology Dept at UCL. She became a Professor of Developmental Neurobiology in 1995 and was elected as a Fellow of the Academy of Medical Sciences in 2000. Maria is Scientific Director of the Paediatric Pain Invest in ME (Charity Nr. 1114035) Research Centre at UCL www.pprg.ucl.ac.uk, and is a member of a number of research boards including the Medical Research Council Neurosciences and Mental Health Board, the Scientific Board of the Migraine Trust and the French National Research Agency (ANR). She is an Editorial Board member of ‘Pain’ and of ‘Pain Research and Clinical Management. Maria has published over 130 research papers and reviews in the area of pain neurobiology (taken from UCL site http://www.ucl.ac.uk/npp/research/mfi). Abstract: Chronic pain arises from plastic changes in the peripheral and central nervous system. These changes are triggered and may be maintained by an insult to tissues, organs or to the nervous system itself. Damage to the nervous system itself can result in neuropathic pain, a particularly unpleasant chronic pain which is especially difficult to treat. Because neural connections within the sensory and nociceptive systems have been altered, pain can take on a ‘life of its own’ and no longer require the presence of tissue damage. As a result, the pain will often persist beyond the resolution of the original injury. Thus chronic pain has a clear biological origin, but that origin lies within the nervous system itself and if we are to prevent or treat it effectively we need to understand these neural changes. Poor pain recovery following the resolution of a physical insult can lead to the conclusion that patients are catastrophizing or have aberrant health beliefs, while in fact defined neurobiological changes in neural pain pathways are the source of the problem. This lecture will provide an overview of our current understanding of chronic pain mechanisms. Dr Mario Delgado Neuropeptides and their role in chronic disease Mario Delgado Institute of Parasitology and Biomedicine, CSIC, Granada, Spain As a neuroimmunologist, his main research focus has been to understand the bidirectional communication that exists between immune www.investinme.org Page 101 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) and neuroendocrine systems. A primary objective of the Delgado laboratory is to identify endogenous anti-inflammatory factors, mainly neuropeptides and hormones, that are produced under inflammatory and autoimmune conditions, with the aim of identifying therapeutic agents for immune disorders where tolerance is compromised. Abstract: Vasoactive intestinal peptide (VIP), a 28 aminoacid neuropeptide, is widely distributed in both the central and peripheral nervous system. VIP is released by both neurons and immune cells. Various cell types, including immune cells, express VIP receptors, which act via stimulation of cAMP/protein kinase A pathway. VIP has potent effects as a neurotransmitter, vasodilator and secretagogue, but in the last two decades, numerous works indicate that VIP is a pleiotropic immunomodulatory factor with potential for its therapeutic use in inflammatory, autoimmune and neurodegenerative disorders. Based in our knowledge on VIP, my group have recently characterized other neuroprotective and immunomodulatory neuropeptides, which have been proven to be effective in the treatment of chronic neuroinflammatory and autoimmune diseases. In this meeting, I will highlight the most recent data relevant in the field and we will offer our opinion on how therapy with VIP and other neuropeptides might impact clinical immune diseases, including myalgic encephalomyelitis/chronic fatigue syndrome, and the challenges in this field that must be overcome before achieving medical progress. Finally, we will discuss how a physiologically functional neuropeptide system contributes to general health and how neuropeptides educate our immune system to be tolerant. Professor James Baraniuk Systems Biology of Interoceptive Disorders James N. Baraniuk was born in Alberta, Canada. He earned his honours degree in chemistry and microbiology, medical degree, and unique bachelor's degree in Invest in ME (Charity Nr. 1114035) medicine (cardiology) at the University of Manitoba, Winnipeg, Canada. Thereafter, he moved to Akron, OH, USA, for his internship and internal medicine residency at St Thomas Hospital. After another year of internal medicine residency at Duke University Medical Center, Durham, NC, he trained with Dr C.E. Buckley, III, in allergy and clinical immunology. He moved to the laboratory of Dr Michael Kaliner at the National Institute of Allergy and Infectious Diseases, Bethesda, MD, and there began his long-standing collaboration with Dr Kimihiro Ohkubo. After 2 years studying neuropeptides, he joined Dr Peter Barnes' laboratory at the National Heart and Lung Institute, Brompton Hospital, London, UK. Dr Baraniuk returned to Washington, DC, and Georgetown University, where he is currently Associate Professor with Tenure in the Department of Medicine. Abstract: We apply the term interoceptive disorders to encompass symptom complexes with excessive, prolonged perceptions of discomfort stemming from expansion and contraction of the walls of hollow organs [Adam]. Nasal, pharyngeal, bronchial, esophageal, stomach, large and small bowel, bladder, urethra and vagina have extensive networks of sensory neurons in their walls. Mechanical receptors detect the degree of stretching of these nerves and the organ. The molecular mechanisms and proteins of these sensors are still being determined. These will be targets for new classes of drugs to treat nonallergic rhinitis, dyspnea, "nutcracker esophagus", dyspepsia, irritable bowel syndrome, irritable bladder syndrome and vulvodynia. These interoceptive disorders are fundamental to the pathology of ME/CFS and allied disorders as can be demonstrated by analysis of syndrome subtypes using the 1994 Fukuda criteria and questionnairebased definitions of "fatigue". These criteria suggest that central sensitization of nociceptive sensory input to the spinal cord and brain leads to the pain, tenderness, hyperalgesia and allodynia. Critical mechanisms include (i) increased activation and up regulation of sensor protein systems on peripheral nociceptive nerve endings (peripheral sensitization); (ii) increased glutamate release from peripheral nerves in the dorsal spinal cord; (iii) changes in glutamate and AMPA receptor expression on the secondary, www.investinme.org Page 102 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) nociceptive, somatosensory interneurons that convey the pain messages to the thalamus and higher centers; (iv) microglial cell activation that potentiates these effects; (v) modification of inhibitory dorsal horn regulatory interneuron signals with the loss of protective, antinociceptive effects; (vi) development of new synaptic connections by light touch, proprioceptive, and other myelinated neurons onto the nociceptive secondary interneurons so that normally innocent sensations now stimulate pain (allodynia). We propose that similar mechanisms account for increased perception of interoceptive messages to the brain. Dr. Øystein Fluge and Professor Olav Mella Institute of Medicine, Section of Oncology, University of Bergen, Norway Dr. Øystein Fluge received medical degree in 1988 at the University of Bergen, and is a specialist in oncology since 2004. He has worked as a Research Fellow with support from the Norwegian Cancer Society and is now chief physician at the Cancer Department, Haukeland University Hospital. Doctoral work emanates from the Surgical Institute and Department of Molecular Biology, University of Bergen. Professor Olav Mella and researcher Dr Oystein Fluge from University of Bergen, Haukeland University Hospital, department of oncology are currently conducting a clinical trial on Blymphocyte Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Severely Affected Chronic Fatigue Syndrome Patients. This study is based on pilot patient observations, and experience from the prior study KTS-1-2008. The investigators anticipate that severely affected chronic fatigue syndrome patients may benefit Invest in ME (Charity Nr. 1114035) from B-cell depletion therapy using Rituximab induction with maintenance treatment. The hypothesis is that at least a subset of chronic fatigue syndrome (CFS) patients have an activated immune system involving B-lymphocytes, and that prolonged B-cell depletion may alleviate symptoms. Professor Indre Bileviciute Ljungar One year experience of a standardised team-based assessment of suspected ME/CFS in a New ME/CFS-project Dr. Indre Bileviciute-Ljungar is an associate professor in rehabilitation medicine at Karolinska Institutet and working as a specialist in rehabilitation medicine at ME/CFS-project at Dept. of Rehabilitation Medicine, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden. The aim of the team-based ME/CFS-project is to improve the diagnosis of ME/CFS patients, to transfer clinical knowledge to the primary care structures, to establish rehabilitation methods for ME/CFS-patients, and to conduct multidisciplinary research in collaboration with Karolinska Institutet, Stockholm. Dr. Indre Bileviciute-Ljungar is particularly interested in complicated clinical pain problems such as patients with chronic fatigue. Her past research concerns mechanisms of pain physiology and neuro-immune communications in experimental pain models. Nowadays she conducts research on neuro-immune communication in patients with fibromyalgia in collaboration with immunologists at Stockholm University, Sweden. Together with multidisciplinary team lead by Dr. Per Julin she is also conducting research on ME/CFS-patients. Abstract: ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) is a complex disease characterised by chronic fatigue, post-exertional malaise, sleep disturbances, cognitive failure, pain symptoms, autonomic, endocrine and immune manifestations. The clinical picture of ME/CFS patient is quite complicated and requires a detailed examination as well as exclusion of other diseases or syndromes. Since one year ago a www.investinme.org Page 103 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) multidisciplinary team-based clinical project has been started at Dept. of Rehabilitation Medicine, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden. The aim of the ME/CFSproject is to improve the diagnosis of ME/CFS patients, to transfer clinical knowledge to the primary care structures, and to establish rehabilitation methods for ME/CFS-patients. The research on ME/CFS from a broad perspective, including assessment, biomarkers, rehabilitation and treatment is also included The multidisciplinary team consists of clinician (1.5 position), medical nurse, physiotherapist, psychologist (1.5 position), social worker and occupational therapist. Three weeks team-based evaluation includes: one visit to the doctor, nurse and social worker; 2 visits to psychologist and occupational therapist and 3 visits to physiotherapist. The ME/CFS diagnosis is based on patient history, subjective and objective findings according to CDC (Fukuda 1994) and Canadian (Carruthers et al 2003) criteria. To exclude other somatic disorders, extended blood and urine analysis as well as polysomnography and 3T brain MRI (including assessment of cerebral blood flow for research purpose) are performed. Moreover, important previous investigations, previous treatment and rehabilitation experiences are also considered. Since April 2011, the ME/CFS-project had 101 new visits to physician. In 55% of cases (55 patients: 11 male and 44 female) there was a clear indication for further team evaluation because of suspected ME/CFS. After team evaluation 33 patients fulfilled the criteria for ME/CFS: 28 according to Canadian and CDC and 5 only according to CDC-criteria. In cases which did not fulfil the criteria for ME/CFS, other diagnoses were found: 10 cases of chronic psychiatric or neuropsychiatric disorders, and 7 of them together with chronic pain syndrome/fibromyalgia. In 2 cases idiopathic fatigue was explained by chronic sleep disturbances. In 17 cases the previous ME/CFS diagnosis concluded by other clinicians was confirmed by the team, whereas in 11 patients it was given for the first time. It is of interest to note that in 14 cases the existing ME/CFS diagnosis was explained by other disorders either during the first visit to the doctor or after team evaluation. Altogether, the results of one year multidisciplinary team evaluation show that it is a Invest in ME (Charity Nr. 1114035) great advantage to use a multidisciplinary approach in ME/CFS in combination with a thorough medical investigation since the symptoms are very complex and overlap with other disorders that sometimes are very difficult to exclude only by a physician interview/examination and standard laboratory tests. From the clinical point of view a correct diagnosis is of course vital as specific medical treatments or effective rehabilitation techniques exists for many of the other disorders that seemed to mimic ME/CFS, e.g. sleep apnoea, chronic stress-related psychiatric disorders with accompanying pain syndrome, neuropsychiatric disorders, etc. We also believe that a thorough multidisciplinary assessment is beneficial for research purposes, e.g. as a clinical basis for studies of the immunological and CNS patophysiology of ME/CFS, both for diagnostic biomarker- and treatment-studies. Dr Daniel Peterson Clinical Research Update 2012 Daniel L. Peterson, M.D., is an internist in Incline Village, Nevada and recognized medical expert on CFS/ME. Dr. Peterson is founder of Simmaron Research, and serves on its Scientific Advisory Board. Dr. Peterson has devoted 25 years of his clinical career to diagnosing and caring for patients with CFS/ME and related neuroimmune disorders, and collaborating with researchers to better understand the illness. Dr. Peterson’s repository of more than 1,000 patient biological samples and records is a rich resource for research studies. His experience as both a clinician and a research collaborator provides a unique perspective on CFS/ME for developing translational science. In 2011, Dr. Peterson was appointed Adjunct Professor on the faculty of Health Sciences and Medicine at Bond University in Queensland, Australia. ABSTRACT: In spite of many years of intensive research in both the basic sciences and clinical realms, CFS/ME continues to present challenges to scientists and www.investinme.org Page 104 of 108 Journal of IiME Volume 6 Issue 1 (June 2012) clinicians with respect to pathogenesis, aetiology, diagnostic criteria and treatment strategies. Perhaps the greatest challenge to making strides in CFS/ME research is the very nature of this disorder, which is multisystem in scope (both symptoms and pathogenesis); heterogeneous in onset, duration, aetiology; and lacking in specific simple objective and reproducible biomarkers. Over the past decade, there has been worldwide emphasis on translational medicine to increase the effectiveness of basic research in order to bring appropriate diagnostics and therapies to patient groups in a more cost-effective, orderly, and timely fashion. This philosophical change is reflected in many of the recent studies employed for the study of CFS/ME. Additionally, there has been increased emphasis on integrating informational technology to the study of CFS/ME in order to establish geographically diverse databases and biobanks from which basic researchers as well as clinicians can search, contribute to, and utilize in their respective disciplines. The CFIDS Association of America has been at the forefront of sponsoring and funding for small pilot projects, particularly seeking innovative approaches to research into CFS/ME with specific timelines and objectives. In 2012, six such studies were selected from a large number of qualified projects and are now underway. These studies will be discussed with respect to study design, objectives, and progress. The NIH recently sponsored a multi-centered study under the direction of Ian Lipkin at Columbia University to validate the findings of XMRV previously reported by other researchers. The study has now been completed. The multicentered study design will be presented. Results are expected to be published in the near future. The Chronic Fatigue Initiative, has designed and supported a multi-centered study, "A Clinical and Biosample Database to Enable Discovery of Pathogens and Pathogenic Mechanisms in Chronic Fatigue Syndrome" to look at an extensive array of clinical aspects of patients with CFS/ME with particular emphasis on patients with acute viral type of onset (duration less than 3 years) versus patients with longstanding illness and classical patients as described both clinically and in the Invest in ME (Charity Nr. 1114035) laboratory. A large database is currently being collected with respect to family history, onset, natural history, and associated laboratory findings including serologies, immunological studies, neuroimaging, and functional studies (such as sleep studies, and exercise tolerance tests). Phase 1 of this initiative will evaluate patients and controls for the presence of known human pathogens as well as potential novel agents using the technology available at the Center for Infection and Immunity at the Mailman School of Public Health at Columbia University. This study already has significant enrolment at multiple centers and preliminary results may be available shortly. Phase 2 of the Chronic Fatigue Initiative effort will provide support for investigator initiated projects and access to databases and biobank repositories. Details of the study design, inclusion/exclusion criteria, and timelines will be presented. There has been increased interest in the study of cerebrospinal fluid due to the multiple neurological symptoms and objective findings by neuroimaging that CFS/ME patients demonstrate. A study looking at cerebrospinal fluid in patients with CFS/ME versus multiple sclerosis patients and normal controls has recently been launched. This project is named “Collaborative Research Using Cerebrospinal Fluid Novel Pathogen Discovery” and will use the technology available at the Center for Infection and Immunity. In collaboration with Population Health and Neuroimmunology Unit (PHANU) at Bond University in Australia, a pilot project was initiated to evaluate cytokines and microRNA in the spinal fluid. Correlating these findings with peripheral blood with special attention to Natural Killer Cell function and phenotypes may produce clinically relevant biomarkers. Lastly, a collaborative effort with the acronym CASA (Collection, Aggregation, Storage and Analysis) has recently joined resources of the NIH, CDC, clinicians, and researchers with diverse backgrounds to evaluate by consensus domains of a critical nature to the study of CFS/ME. One of the goals of this collaboration is to establish standards for research in the area of CFS/ME with particular emphasis on determining appropriate tools. These include questionnaires, laboratory studies, histories, and physical examinations which have been validated and recommended for www.investinme.org Page 105 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) researchers and clinicians to utilize in research and treatment. The structure of this working group, their goals and objectives and progress to date will be presented. Dr Andreas Kogelnik New Paradigms and Collaboration in the Diagnosis and Treatment of ME Dr Andreas Kogelnik is the Founding Director of the Open Medicine Institute, a collaborative, community-based translational research institute dedicated to personalized medicine with a human touch while using the latest advances in medicine, informatics, genomics, and biotechnology. The Institute works closely with the Open Medicine Clinic and other clinics to conduct research and apply new knowledge back into clinical practice. Dr. Kogelnik received his M.D. from Emory University School of Medicine in Atlanta and his Ph.D. in bioengineering/bioinformatics from the Georgia Institute of Technology. Subsequently, he completed is residency in Internal Medicine and a Fellowship in Infectious Diseases at Stanford University and its affiliated hospitals. Following his clinical training, he remained at Stanford with NIH funding to engage in postdoctoral research in microbiology, immunology and bioinformatics with Dr. Ellen Jo Baron and Dr. Stanley Falkow, where he explored host-response profiles in severely ill patients. Together with Dr. José Montoya, he was instrumental in the conception, design, and execution of the EVOLVE study - a placebocontrolled, double-blind study of a subset of chronic fatigue syndrome patients with evidence of viral infection. Dr. Kogelnik worked with Dr. Atul Butte in translational informatics to determine patterns that indicated a high risk for adverse events in Invest in ME (Charity Nr. 1114035) paediatric patients at Lucille Packard Children's Hospital. He is the Medical Director of the Open Medicine Clinic - a community-based research clinic focussed on chronic infectious diseases, neuroimmune disease, and immunology. Dr. Kogelnik has published numerous scientific papers and book chapters, is an Editor of Computers in Medicine and Biology, and is a Consulting Assistant Professor at Stanford University. With the Open Medicine Institute, he has led the formation of CFS and Lyme Registries and Biobanks as well as creating an infrastructure for providers to collect better data and implement clinical trials across a network of sites. Abstract not available. Simmaron Research Mission to play a key role in bringing science to the clinicians to better diagnose and treat patients with CFS/ME. to help fund and conduct pilot studies that have the potential of leading to the identification of diagnostic markers and potential treatments for CFS/ME and related neuroimmune disorders. to openly share our findings with the scientific and medical communities to help advance translational science that leads to the clinician’s office and ultimately improves the quality of life for people suffering from CFS/ME and related neuroimmune diseases. http://www.simmaronresearch.org Norwegian ME Association 25 Years Anniversary 2012 http://www.me-foreningen.no/ www.investinme.org Page 106 of 108 7th Invest in ME International ME/CFS 1st June 2012 Conference Agenda Start from 07.45 Presenter Registration Futures and Biomarkers 08.55 09:05 09:45 10:25 10.35 Dr Ian Gibson Dr Donald Staines Dr Sonya Marshall-Gradisnik Plenary Refreshment Break Biological Factors Involved in Chronic Disease and Their Impact on ME Research and Treatments 10:55 Professor Hugh Perry 11:30 12:05 12:40 12.50 Professor Maria Fitzgerald Dr Mario Delgado Plenary Lunch Clinical Diagnosis and Knowledge sharing 13:40 14:20 15:05 15.15 Plenary Refreshment Break Clinical Trials 15:35 15:50 16:30 17:10 17.30 Professor Indre Ljungar Dr Daniel Peterson Dr Andreas Kogelnik Plenary Adjourn One Year Experience of a Standardised Teambased Assessment of Suspected ME/CFS Patients Clinical Research Update 2012 New Paradigms and Collaboration in the Diagnosis and Treatment of ME Dr Ian Gibson - Questions Professor James Baraniuk Dr Øystein Fluge / Professor Olav Mella An Overview of Neuro-inflammation in Chronic Disease Neuropeptides and their role in chronic disease Neuropeptides and their role in chronic disease Questions Welcome to the Conference Key Note Speech: New directions for ME/CFS Research Current Knowledge of Immunological Biomarkers Questions Presentation Systems Biology of Interoceptive Disorders B-cell Depletion Therapy Using Rituximab in ME/CFS Questions Support Biomedical Research into ME. Order our free newsletter. Distributed monthly via html, plain text or PDF. http://www.investinme.org/IIMENewslettersubs.h Invest in ME (Charity Nr. 1114035) www.investinme.org Invest in ME wristbands http://www.investinme.org /IiME-Wristbands.htm Page 107 of 108

Journal of IiME Volume 6 Issue 1 (June 2012) SUPPORT ME AWARENESS The BIG CAUSE Building a future for research into ME  ME is a neurological disease  Over 60 outbreaks of ME have been recorded worldwide since 1934  ME is 3 times more prevalent than HIV/AIDS – it is twice as prevalent as MS  25% of ME patients are severely affected - housebound, bedbound  25,000 patients are young children  ME is the largest cause of long term sickness absences from school  ME does not discriminate, anyone can be affected  There is no centre of excellence in the UK that treats and researches ME as a physical illness  UK Charity Invest in ME wants to change this with a strategy of biomedical research Please support our proposal for an examination & research facility for ME in the UK - http://tinyurl.com/2f6gk66 Let the Science Do the Talking Invest in ME Invest in ME (Charity Nr. 1114035) Charity Nr. 1114035 www.investinme.org Email: info@investinme.org 7th Invest in ME International ME/CFS Conference 2012 1st June 2012 , London Page 108 of 108 www.investinme.org

The Journal of IiME Volume 7 Issue 1 May 2013 Mainstreaming ME Research IIMEC8 Conference 2013 Published by UK Charity Invest in ME www.investinme.org

Journal of IiME Volume 7 Issue 1 (May 2013) IiME Conference DVDs The Invest in ME conference DVDs are professionally filmed and authored DVD sets consisting of four discs in Dolby stereo and available in PAL (European) or NTSC (N. America) format. They contain all of the presentations from Invest in ME International ME/CFS Conferences (2006 – 2013). Also included in the DVD sets are interviews with ME presenters, news stories and round-table discussions. The Invest in ME conference DVDs have been distributed to more than 20 countries and are available as an educational tool – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://bit.ly/10YB6n3 or via emailing Invest in ME at info@investinme.org Invest in ME (Charity Nr. 1114035) www.investinme.org Page 2 of 36 Journal of IiME Volume 7 Issue 1 (May 2013) Inside This Issue 3 Welcome to the Conference 7 9 14 18 21 22 24 Biomedical Research into ME Collaborative Meeting IiME Proposal for Examination and Research Facility Let’s Do It For ME Lili – Diane’s Story Guidelines Sarah’s Story - JustGiving Presenters at IiME Conference 32 OMI-MERIT Initiative 34 Conference Agenda Invest in ME (UK Charity Nr. 1114035) PO BOX 561 Eastleigh SO50 0GQ Hampshire, UK Tel: 07759 349743 E-mail: info@investinme.org Disclaimer The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME (Charity Nr. 1114035) Welcome to IIMEC8 This is our ninth Journal of IiME and is made available online for free on the charity’s web site. A hard copy also forms part of each delegate’s conference pack at the 8th Invest in ME International ME Conference 2013. Invest in ME have now organised eight biomedical research conferences for ME – myalgic encephalomyelitis - and the conference has become a good checkpoint to determine how things are progressing with research into ME. We have been reminded in recent times of how fragile life is and how healthcare is so important for a just society. Yet for ME services to magically attain the levels for existing diseases, whilst absolutely justified and to be expected, is realistically not something which will appear overnight. Even “established” diseases which have comparatively large research funding and correct perception amongst health departments are not without issues. We have seen examples of this close up. The key to making ME a disease which receives the highest priority is an objective which we need to attain by establishing basic building blocks and a foundation on which to progress – funding for proper, quality research; education about the disease; and correct perception of the disease. Invest in ME was set up with the objectives of making a change in how ME is perceived and treated in the media, by health departments and by healthcare professionals. These aforementioned building blocks happen to be the basic objectives of Invest in ME. The people who run and support the charity are all volunteers. There are no salaried staff and all work is performed in spare time, for free. The charity does not exist just to exist – we exist to make progress. For us biomedical research into ME has not been well served in UK or elsewhere for a generation. Patients are literally sick of the behavioural approach to ME and fatigued by the constant false belief that exercise will make one better. The PACE Trial provided evidence that CBT and GET do not produce any objective positive results. Yet although heavily criticised and eventually dismissed by ME patients, with hindsight, perhaps the PACE Trial actually did the cause of biomedical research into ME a huge favour. As knowledgeable patients have been able to point out the flaws in its design, execution and implementation, and debunked implausible attempts to spin the results into a justifiable end point, so the PACE Trial has clearly shown why the psychosocial view of ME is now www.investinme.org Page 3 of 36

Journal of IiME Volume 7 Issue 1 seen by mostly all objective observers to be a waste of funding and of lives. On a more positive and deliberate note the Let's Do It For ME campaign has forced biomedical research into ME - by amazingly positive efforts by people who are not interested in complaining all the time without offering anything - but instead put their thoughts and energy into imaginative ways of crowd funding biomedical research - often pushing themselves beyond their limits. IiME supporters have been showing the real side of ME patients - people wanting to get better and willing to be proactive in achieving this. And thus, by their example, things change. The promise of treatments developed from the exciting research at Haukeland University Hospital in Bergen has generated campaigns by three European ME Alliance members - Norway’s ME Association, Sweden's RMEand Switzerland's Verein ME/CFS to fund this research. The MEandYOU campaign in Norway has an ambitious target to raise 7 million Norwegian Kroner in 90 days and has achieved a commendable result already. Education is another key to progress. This applies to education of medical professionals as well as politicians, the media, patients and the public. The IiME conferences have formed a crucial part of this education and served to provide a platform for the latest and the best biomedical research into ME – demonstrating how false is the belief that little is known about the disease. The charity has recently completed the distribution of 25 GP packs to GPs and GP clinics in Scotland. The packs contain information about ME, diagnostic guidelines, charity Journal and DVD and other items of specific information about ME which will help the healthcare professional better understand the disease and what progress is being made. Our conference DVDs allow a historical record of the conference events while at the same time making it available to those around the world who wish to hear of the biomedical research. The charity has heard many times of the usefulness of the DVDs and in many cases where they have helped patients and healthcare staff. Recently the charity began distribution of the latest ME guidelines – the International Consensus Criteria. Every conference delegate will have a copy in their conference pack. We have also been UK distributor for the printed copies of the Canadian Consensus Criteria. Invest in ME (Charity Nr. 1114035) (May 2013) The charity tries to help people with ME and has been involved in a great deal of campaigning and lobbying to raise awareness and gain a more valid perception in the media and healthcare departments and by the public. The charity recently met with Dr Martin McShane – NHS Commissioning Board Authority, Director - Domain 2- Improving the quality of life for people with Long Term Conditions). This meeting was requested by the Prime Minister after a constituent and supporter, Alex Hall, met with the PM and passed on a letter from the charity. At the meeting Dr McShane heard directly from two parents of a severely affected young adult with ME. The parents spoke with dignity and passion about the treatment of their daughter and Dr McShane patiently heard the terrible story of how parents were blamed for this disease affecting their child, and how healthcare services had failed in their daughter’s case. Although not unique such direct imparting of knowledge to a prominent healthcare official of how severely affected patients with ME are managed and treated in UK is relatively rare in our experience. IiME also had proposals to Dr McShane which could be used to move things on. We suggested using this area (ME) as an example of a difficult area of medicine and use it as a model for nationwide services. We suggested an ME consultancy role for CCGs to be established. We proposed setting up clinical trials which could be initiated under the auspices of the local university's clinical trials team. As the NHS can participate and perform research so we suggested two such trials to begin with. IiME proposed setting up a trial of telemedicine, where severely affected patients could be treated by an ME consultant who would not have to be physically present, and where a GP or other professional could sit in and learn about ME. IiME suggested that a standard service model could be used for ME, and tested, in East Anglia. Other commissioning groups would be able to see the www.investinme.org Page 4 of 36 Journal of IiME Volume 7 Issue 1 effectiveness and efficacy of this model and it could be developed from there. This service model would be based on a biomedical approach to ME with a trained and knowledgeable consultant(s) and where training was emphasised. GPs could also learn from this and all would be aware of the biomedical research into ME which had been and was taking place. Common protocols could become established to enable a consistent approach to treating patients. The proposal for an examination and research facility in Norwich by IiME includes patients being correctly diagnosed and put forward for biomedical research, with results from the research being applied to patients as soon as possible. We needed an acceptance from the NHS that there was no one size fits all treatment/management option. Education of GPs was important as lack of knowledge permeates the NHS. So IiME proposed holding workshops with qualified physicians and the charity offered to arrange these as part of the introduction and trial of an appropriate service model, with the charity using its links to various researchers and clinicians here and abroad. Such workshops could educate healthcare staff and look at patients. We suggested these projects could serve as pilot projects for the NHS commissioning groups. Dr McShane identified three strands coming from our discussions. 1. Empathy and Respect (anger felt by patients and carers understandable) 2.Services (some in the country supportive) 3. Research The parents of the severely ill child added a 4th important strand - Medical practitioners are faced with a lot of conditions - instead of suspicion they should accept their limitations and show respect. Patient /carer experiences/expertise should be acknowledged. The outcomes from this meeting confirmed our views that we need to educate GPs; that research is correct way forward as IiME were proposing; and that we must continue to have to force through the necessary changes ourselves. So an independent charity and its supporters continue to crowd fund biomedical research, continue to crowd source ideas for ME research and continue to raise awareness of this disease – backed by an increasing number of supporters who, themselves, have ideas and are willing to make the enormous effort to make a difference. Prior to the conference the charity has organised an international collaborative meeting with researchers and clinicians from nine countries in attendance. Last year the collaborative two-day Clinical Autoimmunity Working Group (CAWG) meeting organised by Invest in ME and the Alison Hunter Memorial Foundation of Australia, in London, brought old and new researchers to the same table for two days of discussions. Initiatives came from this meeting and, perhaps, influenced the latest calls for research in the latest MRC highlight notice from last year - “There is now preliminary evidence supporting the view that inflammatory mechanisms in the brain and spinal cord may underlie the pathophysiology of some severe disease CFS/ME phenotypes.” Immune dysregulation: “There is evidence for a disturbance in innate and adaptive immunity in CFS/ME including alterations in cytokine profile, absolute and functional alterations in T cells and NK cells and occurrence of autoantibodies and allergic reactions that may explain some of the manifestations such as fatigue and flu-like symptoms. A number of infectious and (May 2013) Modern day terms for raising awareness and funding – crowd sourcing and crowd funding – are now used to describe efforts to maximise the potential of new technology for the benefit of patients. An increasingly more knowledgeable and determined patient population are forcing change and making things happen - making a difference - thanks to conferences and organisations highlighting ME research and to the immediacy and effects of social media. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 5 of 36

Journal of IiME Volume 7 Issue 1 environmental exposures have been associated as triggering these changes.” - UK Medical Research Council This developing recognition of the real disease in ME needs to be backed up with an appropriate response. The overwhelming need is for research - and essentially biomedical research into ME. We believe International collaboration is a necessity for research into ME. If we are seriously to have a way forward for proper research into ME then we need not just adequate funding, but correctly defined cohorts, standardisation on diagnostic criteria and a collaborative of researchers who will not blur science with politics. Research into ME needs a strategic approach - but it may be destined to fail completely by attempting to establish the way forward on foundations which include so much of what has been wrong in the past. So we need -  to establish homogeneous research cohorts  to adopt and endorse the latest ICC or CCC criteria for ME - for research and for diagnosis  to separate research into fatigue and chronic fatigue from ME  to establish transparent peer reviewing by professionals with the relevant experience and background For IiME our objectives over the next couple of years will be to attempt to fund more biomedical research using diagnostic criteria that are as good as we have in the current day. We will attempt to improve education of healthcare staff by facilitating training events with knowledgeable and experienced ME clinicians providing help, advice and education to GPs, nurses, researchers and patients. We will organise research meetings to bring the best researchers together. We will collaborate with those who are genuinely interested in progress in researching and treating and curing ME. This year we would also like to thank the Edward P. Evans Foundation for contributing to the costs of the conference. The Foundation is also a major funder of ME research with recent awards to OMI Merit and Griffith University showing a Invest in ME (Charity Nr. 1114035) www.investinme.org Page 6 of 36 (May 2013) We will support those initiatives which promise to make real progress. Our approach is to try to get a strategic research programme started here in the UK and build collaborations with trusted clinicians and researchers so that patients can get tested as part of research rather than having to spend vast amounts of money travelling to see doctors abroad. We need clinical trials to get evidence for treatments that work. We need better education about ME for healthcare staff. We need additional and long-term funding for biomedical research into ME. At our IIMEC8 conference we focus on ME now becoming a mainstream research area. We have representatives from most of the main biomedical research initiatives now occurring throughout the world. Our foundation biomedical research project will begin this year at a leading UK university. We are actively in discussion with a number of other projects and welcome the chance to work with other groups interested in biomedical research into ME. SPONSORS A word of thanks to the Irish ME Trust who, yet again, will be sponsoring one of the speakers to the conference. IMET have been a constant friend and supporter of IiME, and of ME patients. They have funded major research into ME and have been a leading member in the European ME Alliance. Journal of IiME Volume 7 Issue 1 commitment and vision which is to be welcomed as we try to facilitate international collaboration and sharing. And we would like thank our EMEA colleagues in Sweden. RME have kindly donated to help with the costs of the conference. We would like to thank Simmaron Research Foundation for generously sponsoring the tickets of two medical students from University of East Anglia. We would like to thank the presenters for coming to London to speak at IIMEC8 and all the delegates who attend in order to make this happen. We thank all of our supporters for their support in raising ME awareness, for their efforts in funding biomedical research and for their inspiration. The theme of the 8th Invest in ME International ME Conference 2013 in London on 31st May is Mainstreaming ME Research - an acceptance that, despite the past, research into ME is now joining the mainstream research area deserving of more funding and of the interest of top biomedical research institutions. The IIMEC8 conference will highlight the major biomedical research initiatives into ME now taking place. Enjoy the Journal. Enjoy the conference. Let’s do it for ME. Invest in ME ME QUOTES "The delayed responses starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS." Mella and Fluge, Haukeland University Hospital, Bergen, Norway http://bit.ly/10krfqn Invest in ME (Charity Nr. 1114035) London. The Biomedical Research into ME Collaborative (BRMEC) Meeting London on 30th May has attending almost 40 of the world’s experts and leading clinicians involved with ME. This meeting follows on from the cooperation and dedication of the Alison Hunter Memorial Foundation (Australia) and Invest in ME (UK). To raise awareness of ME, and promote collaboration, innovation and foundations for a clearer strategy of biomedical research into ME, Invest in ME and the Alison Hunter Memorial Foundation of Australia continue the collaboration which has been a feature for several years, and which established the Clinical Autoimmunity Working Group which met in London in May 2012. The extraordinary skill and experience which can be harnessed by meetings such as last year’s Clinical Autoimmunity Working Group meeting in London and this year’s BRMEC meeting, as well as the possibilities to progress further the understanding of the disease by “crowd sourcing” experience and ideas, promises to enable a unique contribution to understanding ME and suggest future research directions and perhaps treatments. Chairing the meeting was Dr Ian Gibson, former Dean of Biology at UEA and Professor Hugh Perry of Southampton University and Chair of the Medical Research Council Neurosciences Board. The objectives of the meeting were: 1. To present the status of some of the latest initiatives occurring in biomedical research into ME www.investinme.org Page 7 of 36 (May 2013) As part of the conference events this year Invest in ME have organised another researchers meeting in

Journal of IiME Volume 7 Issue 1 2. To discuss and explore the possibilities for collaboration and for funding for biomedical research into ME 3. To generate new ideas regarding research into ME and assess research strategies for ME research 4. Review experiences and expertise from other research areas in order to assist ME research 5. Review evidence for immunological derangement in ME 6. To discuss opportunities for extending clinical trials in multiple centres and possibly internationally 7. To plan future events Our hope for the meeting was to initiate new collaborations and generate new ideas for biomedical research into ME and help researchers support each other in the future. To achieve continued progress in understanding and treating this disease we must establish collaborations between biomedical researchers who can agree a clear strategy of biomedical research. BRMEC AGENDA ME QUOTES "ME/CFS is not uncommon in England and represents a significant burden to patients and society. The number of people with chronic Welcome and introductions Pathogen Discovery and Pathogenesis Retroviruses and ME Pathogen Discovery continued Gut Microbiota Study UEA Chaired Discussion Review of experience of Rituximab in ME Rituximab in autoimmune diseases Update on immunological derangement in ME Screening NK-, B- and T-cell phenotype and function in patients suffering from ME Chaired Discussion Update on ANS studies FDA Endpoints / Vistide OMI MERIT Strategy Discussion – As per objectives of meeting Funding Possibilities Ways to Continue Collaboration and Discovery Closing Summary and future directions. Briefing to Invest in ME Conference Invest in ME (Charity Nr. 1114035) fatigue who do not meet specific criteria for ME/CFS is higher still. Both groups have high levels of need for service provision, including health and social care. We suggest combining the use of both the CDC-1994 and Canadian criteria for ascertainment of ME/CFS cases, alongside careful clinical phenotyping of study participants. This combination if used systematically will enable international comparisons, minimization of bias, and the identification and investigation of distinct subgroups of patients with possibly distinct aetiologies and pathophysiologies, standing a better chance of translation into effective specific treatments." Nacul et al. BMC Med. 2011 Jul 28;9:91. doi: 10.1186/1741-7015-9-91. (May 2013) This demonstrates our view that forming a collaborative of biomedical researchers, including existing ME researchers and those new to the field, is the best way forward and promises the quickest and most efficient way to produce data and treatments and so benefit people with ME and their families – a Biomedical Research into ME Collaborative . Representatives from nine countries attended. Invest in ME and Alison Hunter Memorial Foundation continue to work together to raise awareness and promote sound biomedical research into ME through collaboration and innovation. The provisional agenda for the meeting is shown below. www.investinme.org Page 8 of 36 Journal of IiME Volume 7 Issue 1 (May 2013) IiME PROPOSAL FOR RESEARCH and EXAMINATION FACILITY At the IIMEC8 conference Dr Ian Gibson will announce news of the foundation research for ME project which the charity and its supporters will fund. It is a biomedical research project and will be carried out at the University of East Anglia. This follows three years of work by the charity and its supporters. It was at the 5th Invest in ME International ME Conference in London in May 2010 that Invest in ME announced that we had entered into discussions with the University of East Anglia to instigate a research facility for ME. Discussions continued after that conference and we decided to publicise our attempt to set up such a facility. We attached the research to a proposal for a centre of excellence for ME – something which the UK does not have today and which is required. Such a centre would allow proper examinations of people with ME, would allow patients to be put forward for trials, would allow the severely effected to be included in research, would facilitate translational biomedical research into ME to allow early results to be used for the benefit of patients, and would enable a database of results to be maintained. It may seem straightforward to get research carried out, to organise the necessary elements to treat patients properly, to initiate fundraising to carry this out. In practice it has not been so straightforward. During this time we have had setbacks. There have been walls put up, some understandable but others mendacious. We have encountered apathy and ignorance from some and lack of support from some. We have been affected by the effects of the government reforms to healthcare which affected everything in the NHS. Despite setbacks we have continued to try to get these necessary building blocks for a UK Centre of Excellence off the ground. Invest in ME are a small charity – Small charity BIG Cause has been our slogan. But we are determined and we have continued to lobby and to arrange and attend meetings. Our Invest in ME (Charity Nr. 1114035) fundraising efforts have continued and the inspiration given by the efforts of supporters has energised us to do more, and never give up. It does feel that we have been working on this project every single day – and that is close to the truth. A plain fact of life is that healthcare departments and organisations do not prioritise treatment of ME patients and the recent government healthcare reforms have seriously affected the timescale for implementing this – with a lot of preparatory work lost. The charity has had to spend much time trying to educate people about this disease. Though there have been a few surprises and disappointments along the way, thanks to wonderful support and help from fellow campaigners, we have managed to get there. Our work in attempting to set up a clinic, which is linked to the research, continues. IiME supporters can be truly proud of the fact that a top UK research university is preparing to perform high quality research into ME using sequencing facilities which already exist in Norwich Research Park. The foundation project looks very good. And so we build on this and continue. We have other ideas to supplement this and initiate new research. We will continue to try to have proper services for people with ME. Below is a summary of information relating to the proposal which was formulated by an Invest in ME steering group that was formed to oversee the setting up of this facility. It has taken a great deal of work and determination to pursue this proposal. But we hope this convinces anyone considering supporting our efforts that we are serious and will continue until we have a proper research base which can make a major contribution to understanding and treating this disease. www.investinme.org Page 9 of 36

Journal of IiME Volume 7 Issue 1 THE CHARITY PROPOSAL-THE BIG CAUSE With the objective of improving and promoting education about ME amongst healthcare staff and raising awareness of the disease the charity feels that the best way to make progress is to establish a national centre of excellence for ME. To this end we have established momentum and resources to begin work on establishing a base of research which could develop into a facility leading to a UK Centre of Excellence for Biomedical Research into ME. (May 2013) describing it as "SERIOUS or LIFE THREATENING", on a par with cancer or /heart failure (click here) and the UK government recognise ME as a chronic neurological illness. To download our poster please use this url - http://www.investinme.org/Documents/ME%20Aw areness/LBM%20Oct2012/Gut%20PROD%20A4.pdf BACKGROUND People with ME need early and correct diagnosis, proper treatment and advice. The current status of services for people with ME and their families in the UK is poor with little knowledge of biomedical research being applied and possible treatments not being made available to patients or healthcare staff. Simplistic and ineffectual, even damaging psychological therapies are offered in place of real treatments - wasting public money and doing nothing to help patients. This has resulted in ME patients having no real healthcare service and far too little progress in attracting new researchers or clinicians to study the disease. The dangers for people with ME having no proper clinical examination and no access to possible treatments is that the disease can develop into more severe forms with significant loss of functioning. There is also the danger of mis- or missed diagnosis – a common problem with people thought to suffer from ME. The USA Food & Drugs Agency (FDA) recently decided to re-categorise ME in "Immune Diseases - Invest in ME (Charity Nr. 1114035) THE AIMS and OBJECTIVES After five years of campaigning for awareness and promoting better education about ME the charity felt that the best way to make progress is to establish a national centre of excellence for ME. The Invest in ME Steering Group was formed - consisting of carers of people with ME and scientific advisors - to begin work on establishing a facility leading to a UK Centre of Excellence for Biomedical Research into ME. We believe that a change needs to be made in the way service provision for ME patients is carried out and is suggesting a simple but effective structure for providing services and instituting major biomedical research into this disease which will have profound effects on the way ME is treated in the UK and establish a hub of scientific and clinical excellence for ME within Europe. THE RESEARCH With the help of leading researchers the charity is proposing a number of initial projects which would help establish a research base and lead to further projects being initiated based on findings. It is not often realised that 60-70% of the immune system is located in the gut as a vast network of lymph tissue referred to as GALT (gut associated lymphatic tissue). The research highlighted in the proposal involves looking at gut microbiota, which is the latest thinking in how to go about research. In USA, renowned pathogen hunter Dr. Ian Lipkin and specialist clinician Dr. Nancy Klimas have all been suggesting a similar approach. The charity is keen to replicate the recent Norwegian Haukeland University findings using Rituximab as well as a number of new ideas being developed. The aim is to build on this but the research has to start somewhere and so the researchers will begin afresh with the best approach. This research proposal would build a strategy of research which would involve patients, clinicians and researchers working together. www.investinme.org Page 10 of 36 Journal of IiME Volume 7 Issue 1 THE PROPOSAL The charity proposes for a facility to be instigated with four main elements for diagnosis, treatment and research into ME – service commissioning, service provision with clinical diagnosis and examinations, translational biomedical research and a research database to allow for more research and improved training of healthcare staff. Figure 1 shows the elements of the model with patient care and treatment at the centre of the model. The proposal would be located around the Norwich Research Park in Norfolk. This area contains worldclass facilities with a leading university (the University of East Anglia (UEA)), leading research institutes and a modern university hospital (the Norfolk and Norwich University Hospital) - all of which complement the necessary biomedical research which would take place. (May 2013) from GPs. An important issue is for early and correct diagnosis to be determined. The service would include a clinical biomedical lead consultant who would perform correct diagnosis (using the international standard Canadian Consensus Guidelines or International Consensus Criteria), perform a full examination using a standard clinical protocol and, once patients have been formally diagnosed as having ME, administer possible treatments and participate in biomedical research into the disease. Using a standard diagnostic and clinical protocol the service would allow a model of care and appropriate care packages for people with severe presentations and would establish and co-ordinate a clinical network and disseminate best practice across that network. Follow-up examinations would be scheduled so that patients are provided with a service and possible treatments and results from any treatments would be fed back into a database which is administered between the university hospital and the university research faculty. GPs in the area with a special interest in ME would be used to assist and be trained in proper diagnosis and treatment of ME. Translational Biomedical Research A parallel but complementary element will be for translational biomedical research to be started by the university in association with other complementary research organisations. Figure 1 Service Commissioning Service commissioning would be performed by the local CCG or CCG Grouping (formerly the PCT). The service would require early and correct diagnosis, examination and treatment of ME using a clinical biomedical lead consultant with GPs with special interest being connected to the service. Diagnosis and Clinical Examinations The examinations of people with ME would be commissioned by the CCG. Referrals to the university hospital would be via existing methods The university would undertake biomedical research into ME using cohorts of patients from those being examined at the university hospital and provide possible recommendations for treatment. The university research would be used for more rapid provision of possible treatments for patients whilst at the same time building up the research database for ME and allowing fostering of new areas of cooperation with other biomedical research facilities. The research being proposed by the university would be of the most advanced possible – using virology and immunology as the key for examining patients. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 11 of 36

Journal of IiME Volume 7 Issue 1 An important aspect of the biomedical research is that properly defined and distinct patient cohorts are defined and maintained. The research would be oriented toward translational biomedical research, which allows results from research to be applied toward treatments for ME patients. Our initial proposal for research which has been discussed with researchers at the UEA, would aim to initiate studies using TGAC sequencing facility at the Norwich Research Park which would allow all known and unknown viruses present to be identified in a cohort of well defined patients. Allied to this would be biomedical research projects – the first of which would examine the possible link between ME and gut inflammation. A Research Database These initial and ongoing projects would enable a database to be established for use in further research. This research database will assist epidemiological studies, enhance research potential and provide patients with proper records of treatment. A research protocol will be established to outline all the study procedures, including data collection and planned data analysis. THE CURRENT INFRASTRUCTURE This proposal would make use of the existing infrastructure where patients are initially seen by GPs and referred to a consultant. Where it differs is that a specialist biomedical clinical lead would be used to perform diagnosis and provide treatment and would be working with a translational biomedical research facility at the university in order to deliver real improvement in patient care from scientific discovery THE BENEFITS The above proposal would lead to a facility with the following benefits –  Early and correct diagnosis of ME (May 2013)  the clinical lead consultant would assess and plan the development of future services in conjunction with commissioning CCGs  it would provide access to specialist assessment, diagnosis and advice on the clinical management, including symptom control and specific interventions, for both patients and health professionals  eventual provision of an ambulatory service and/or telemedical services for those severely ill patients who cannot be moved  development of a network of local multi-agency domiciliary services to support people who are more severely affected and who are unable to access hospital and primary care services  allow ME patients (including those severely affected) to participate in clinical trials, where novel research will be conducted, and where medical students can learn about this disease  facilitate training and education opportunities for healthcare staff to enhance their knowledge and skills in the diagnosis and management of ME  lead the development of services within primary and secondary care and support GPs and other health professionals in the care of patients with ME.  Healthcare staff would feel more comfortable with the diagnosis of ME being made  Undertake comprehensive assessments and provide a care package for each patient to include carer and family support  Savings on existing consultant referrals and staff by concentrating ME examination in one area. The benefits of this approach will, we are sure, save lives and could help restore or improve the lives of hundreds of thousands of patients and their families. TRAINING of HEALTHCARE STAFF The need for training in ME is one of the main areas of interest for the ISG. The proposed model would allow the GP network to have access to up to date information about ME including data on treatments and prognosis. Specialist advice for more complex cases across the country could be provided based on referrals from Invest in ME (Charity Nr. 1114035) www.investinme.org Page 12 of 36 Journal of IiME Volume 7 Issue 1 other CCGs. This in turn would complement the research database thus increasing knowledge and awareness of treatments. Models of care and appropriate care could be developed with packages for people with severe presentations. FUTURE DEVELOPMENTS This model would be developed in the future with an ambulatory service and/or tele-medical services being employed for those who are too ill to attend the hospital examination. Phlebotomy services would be provided for home visits to be made to allow the severely affected to participate in the research and allow treatments for these disenfranchised patients. We would seek to establish additional biomedical research projects to be undertaken by the university which would increase the knowledge about the disease and facilitate development of treatments for patients. In partnership with the charity more training courses would be arranged with visiting experts (researchers and clinicians) being able to share experiences and data and facilitate more education about the disease. Future developments would see the potential of referrals from other areas (and other countries) to be created thus generating income and helping to establish the translational research and treatment facility as the foremost facility in Europe for treating myalgic encephalomyelitis. Our aim is to build sustainable and developing collaborations with translational biomedical research at the heart of all research. FURTHER READING  University of East Anglia http://www.foh.uea.ac.uk  Institute of Food Research http://www.ifr.ac.uk  Norwich Research Park http://www.nrp.org.uk/cms.php?pageid=1  Norfolk and Norwich University Hospital http://www.nnuh.nhs.uk  TGAC - The Genome Analysis Centre http://www.tgac.bbsrc.ac.uk IiME BIOMEDICAL RESEARCH FUND Our long term objective is to establish a UK Centre of Excellence for Biomedical Research into ME. We will continue to campaign for this facility to be established. We welcome all support. Donations to the Invest in ME Biomedical Research Fund will be used to support the establishment of this facility. We hope to continue raising funds for other Invest in ME (Charity Nr. 1114035)  EDP News Story http://www.investinme.org/Medianewspapers. htm  MP Executive Summary September 2011 http://www.investinme.org/Documents/Biome dical%20Research%20Facility/MP%20Exec%20S ummary%20September%202011.pdf  FAQ September 2011 http://bit.ly/180Iod0 (May 2013) projects and until external research grants are available. http://bit.ly/qkjD5K HOW TO LEARN MORE Contact Invest in ME at info@investinme.org. SUPPORT US Help us by contributing to the Invest in ME Biomedical Research Fund for ME – http://tinyurl.com/ydh6whu Our JustGiving page is here - http://www.justgiving.com/investinm-e www.investinme.org Page 13 of 36

Journal of IiME Volume 7 Issue 1 (May 2013) Few who have any knowledge or experience of myalgic encephalomyelitis, whether from a personal or professional perspective, would dispute the urgent need for reliable bookmarkers for early and accurate diagnosis and provision of effective medical treatments for this organic chronic disease. Accurate information, guidance, education and training for patients, public, medical professionals, and other service providers, needs to be made available meanwhile to avoid unnecessary suffering. The Let's do it for ME campaign was launched by a small group of people with severe ME in July 2011 in support of the proposal by Invest in ME to establish a centre of excellence for ME based in East Anglia and the first of its kind in UK/Europe. We commend the forward-planning and joined up thinking to combine translational biomedical research with patient care and education and training for medical professionals, in collaboration with international researchers and like-minded ME organisations across the world, and the clear focus on infection and immunity. We are keen to help progress research and treatment, not only to benefit ourselves as patients, but also to avoid losing another generation to the ravages of this disease. We have no more time to lose. We wished to assist in a practical way by raising the £100k needed to fund the foundation project to get the research strategy underway in Norwich. We were delighted to receive supportive comments for our Guest book or by other means, from some of our MPs; the Countess of Mar, Chair of the Forward ME group; and Jane Colby, Executive Director of The Young ME Sufferers Trust. Empowerment is a key element driving the campaign and it has been very rewarding to see children and young people in particular, as well as the very severely affected, able to play a role in speaking out about their disabling illness and how it is viewed and treated by society and the medical profession, Invest in ME (Charity Nr. 1114035) whilst taking such positive steps to raise funds for the translational biomedical research required to bring realistic hope for their recovery, with support of well friends and family members. As we expect to reach the initial fund-raising target by the end of May or thereabouts, we will have raised £100k in under two years. This is no mean feat, starting from scratch from our homes and beds, with no campaign budget or publicity. Every penny raised goes to the IIME Biomedical Research Fund; any competition prizes or similar resources are donated. Every penny raised goes to the IIME Biomedical Research Fund We could not have achieved this without the tremendous efforts of a wide range of supporters, from very severely ill survivors to wonderful willing wellies. We are genuinely delighted and appreciative of any types and all levels of support, and there have been too many ingenious, innovative, creative, generous, courageous and inspiring ideas, events and contributions to highlight them all individually. Our supporters hail from all corners of the UK, Europe, USA, Australia, NZ, and over 3500 votes in April won IIME 1st prize of £2000 in The Big Break contest run by Direct Debit. Writer Jacqueline Rayner is a founder member of our planning group. She had been planning with her friends and colleagues at Big Finish Productions to produce a charity audio play for download in aid of IIME, based on the character of Bernice Summerfield: Many Happy Returns. Not content with that, producer Scott ran the Edinburgh Marathon for IIME, Simon donated funds www.investinme.org Page 14 of 36 Journal of IiME Volume 7 Issue 1 from his choir, and others have done more besides. At the same time, planning group member and writer Barnaby Eaton-Jones reworked his play, Running To Stand Still, in aid of our cause. Music artist Mama Chill decided to proactively support IIME in her awareness raising and by donating proceeds of downloads and joining the team. Her ME Awareness track is based on the original “I Can't Stand The Rain”, and her new track, “Don't Say Nuthin If It Ain't Worthwhile” was released for May Awareness. There are various other artists, writers, musicians, photographers, supporting IIME. Members of the planning group run the campaign websites and on-line shops; organise May Awareness events such as The Big Sleep for ME, designed to be accessible to people of all ages and levels of illness severity and launched in 2012, ongoing fundraisers such as the 1st of each month One Day-One Pound and Small Change to Change M.E, the Christmas card competition, calendars and summer quizzes, card sales, stalls, supermarket and church collections. We also proactively support other patient initiatives that include IIME such The Big Shave 2013 and Walk for ME. This is all done painstakingly between us over the course of days, weeks, months. Make ME Crafts exploded onto the scene last year and is proving hugely popular, with an ever-expanding team producing an impressive range of arts and crafts available all year round. A young contributor summed it up with this comment: “Big thankyou to Jon because you have brought the community together, its really positive, everyone is happy making and doing things they enjoy and its all going to hopefully find what is going on with our bodies !! Sooo happy to be a part of this XD xx” Invest in ME (Charity Nr. 1114035) (May 2013) Another member of our planning group featured alongside an advert placed by IIME to raise awareness of the foundation research project. Rosa had previously crocheted soft wool blue awareness wristbands for IIME and her grandparents hosted a coffee morning in aid of our cause. Following a decline in her health, Rosa was moved to a nursing home, and fed by nasojejunal tube. She chose to mark her 21st birthday by raising awareness and funds for our cause. The staff at the nursing home joined in with a pyjama day with all proceeds to Rosa's appeal. Goodwill messages were posted across the social networking sites and some people used Rosa's photo as their profile picture for the day. Her mother said that the appeal passed all their expectations. Having contracted ME at 8 years of age, Rosa's story epitomises the indomitable spirit of the majority of people of all ages with ME, as well as the spirit of our campaign. A 14 year old boy wrote: “Although it has been a year since I was in hospital due to M.E. I am still struggling with this awful misunderstood illness. I am still not in school and I want my life back as I knew it. I know many other children who are suffering with this illness too and I am in touch with them. They are also missing out on so many things like me. This is such a great cause, raising money to find a cure!!” We are grateful to IIME and to all those who are engaging with the international drive to instigate, fund, and conduct the kind of high quality scientific biomedical research that may be translated into long-awaited effective treatment options for this organic disease. www.investinme.org Page 15 of 36

Journal of IiME Volume 7 Issue 1 Wherever you are based and whatever role you play, be it front of stage or behind the scenes: we thank you for your support. Here follows just a few of the campaigns set up by supporters to raise awareness of ME and to raise funds for the IiME Biomedical Research Fund. Big Finish Productions is pleased to announce a very special release to celebrate the twentieth anniversary of archaeologist and adventurer Bernice Summerfield. Many Happy Returns will be a unique featurelength drama where every penny will go to supporting Invest in ME. (May 2013) Beckham on Channel 4′s Richard and Judy. This positive feedback encouraged her back into the studio where she worked with producer Shane Shanahan on her next album ‘Nobody wants to know ya when ya Nobody’. The Big Sleep for ME is an awareness and fundraising event initiated by Julia Cottam as part of the Let’s do it for ME effort to raise awareness and funds for biomedical research. Stacy Hart aka Rap/Hip Hop artist Mama Chill is an ME sufferer with real talent. When diagnosed with ME doctors told her that any chance of a music career was well and truly over but Stacy didn’t let this discourage her. While bedbound for two years she released 13 track home demo rap/hiphop album ‘RAW’ and also entered and won a competition to write a song for Victoria One Day One Pound encourages donations of £1 to be made on the 1st each month. If you would like to join us in creating a sea change by donating just £1 (or more if you wish) one day a month for Biomedical ME Research text the code ODOP99 £1 to 70070. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 16 of 36 Journal of IiME Volume 7 Issue 1 Make ME Crafts is a creative branch of the Let’s do it for ME campaign initiated and run by ME sufferer Jon Watson which sells handmade and unique items made by ME sufferers and their supporters crafting for charity. (May 2013) ‘Running To Stand Still’ is a charitable audio play with original songs. The central theme is the illness ME and, aside from giving information about the disease, it revolves around how it affects relationships and a sufferer’s life. It is in aid of Invest in ME and all the professional creatives involved have graciously given their time for free for this production. Advertisement Invest in ME (Charity Nr. 1114035) www.investinme.org Page 17 of 36

Journal of IiME Volume 7 Issue 1 Lili – Diane’s Story An ME Carer’s View I'm a carer for my adult daughter, Lili, who is completely bedbound with very severe myalgic encephalomyelitis. For Lili, M.E. didn't come slowly. It very rudely crashed into her life and very quickly stole her health, taking bigger and bigger chunks of it as she deteriorated. It all began when she experienced a gastric virus of a sort she had never experienced before because this time she never regained her health. A couple days later, she woke up with agonising head pain 'like her brain was on fire', with severe neck pain – she also couldn't move her neck, and her whole body was paralysed. She's not sure how long she stayed like this as she was in and out of consciousness but she truly felt that she was going to die because her body was undergoing an extreme crisis. To cut a long story short, it took a year to get a diagnosis during which time she literally dragged herself to doctors and hospital appointments to undergo tests and consultations (which were sometimes more like inquisitions from paid torturers). Although Lili was severely affected and completely housebound from day one, she forced herself to go because she so desperately wanted to know what was wrong with her so that she could have treatment and get on with her life again. However each visit and test pushed her body beyond its limits. She was gradually deteriorating. Every tiniest activity (physical, cognitive and sensory) from washing her hair to rubbish collection day, had devastating results. Sometimes she could recover in a few days, other times it would take months, but often the cumulative effects of the noisy, smelly, bright, sunny, loud, vibrational, fast, chemical based world we live in were all too much and disease progression with permanent damage resulted. Doctors always amaze me when they are puzzled by her severity and wonder why it's taking so long to 'pick up her bed and walk'. Invest in ME (Charity Nr. 1114035) Lili collapsed after her last hospital visit. She passed out with a seizure, her body violently shook, and paralysis spread throughout her body. It was an extreme reaction to the overload of physical, cognitive and sensory attack on her body during that year, but this last journey to the hospital was the straw upon the last straw that broke her body down. She never recovered. My beautiful daughter is totally bedbound. She has a diversity of symptoms that seem endless. (Most of the very severely affected have between 60+ and 100+ symptoms). The worst thing of all is the relentless, agonising pain. Widespread pain in every muscle, joint, and organ possible. She has not had one day free from pain since the illness began. Her whole life now is lived from her bed. Not her choice for she is a talented artist and photographer and she dreams of being in summer meadows photographing the dancing bees and butterflies and painting the colourful flowers. She dreams of baking cupcakes. She dreams of completing her geology degree. She dreams of paddling in the sea with her nephew. She dreams of putting on a pretty dress with her hair all beautified. Such simple dreams. Her dreams have been snatched from her by this awful disease that others misunderstand by thinking it's just about feeling tired or attention-seeking. The above are some of Lili's dreams but in reality, she would just love to be able to do some of the everyday things that others take for granted. Lili longs for simple pleasures such as having a bath, cleaning her own teeth, reading a book, eating a plate of solid food, emailing her friends, cuddling her nephew, having a conversation, going to the toilet rather than using a slipper-pan, and having a hug. When I hear people moaning about having to stand in a queue, I think 'my daughter would love to do that' (not the moaning bit)! To be able to get up, have a shower, get dressed, walk, travel, shop, interact with the environment, have a conversation, and stand in a queue are such blessings that people www.investinme.org Page 18 of 36 (May 2013) Journal of IiME Volume 7 Issue 1 forget they have. And to be able to do all this without unimaginable pain is a further blessing. My amazing daughter has such a positive view of life. I'm stunned that she's not depressed or angry. Although she sometimes has her low days, her courage and inner strength are immeasurable. Not a day passes without seeing one of her magical smiles which sometimes just breaks my heart. Her days are spent in a darkened room and in as much silence as the outside environment will allow. She is hypersensitive to light, noise, odour, vibration, touch, movement, chemicals, some foodstuffs, and medicinal drugs. She can hear a vacuum cleaner five houses down the road, smell the fabric softener on people's clothes and feel the vibration of a humming fridge. All these things can send her body into a crash at any time. She is unable to sit or stand due to being moribund with pain, orthostatic intolerance, paralysis, blackouts and much more and so her bed is her companion twenty-four hours a day. She is unable to chew and has swallowing difficulties so her food is liquid or puréed. She cannot tolerate touch as her skin is always 'on fire' like it's been grated with a cheese grater. Her description. I have to cut her pyjama tops off (when she can tolerate a change of tops) because any movement causes her indescribable pain. She has difficulty speaking sometimes and so asks me to be her voice... "My amazing daughter has such a positive view of life. I'm stunned that she's not depressed or angry. Although she sometimes has her low days, her courage and inner strength are immeasurable. Not a day passes without seeing one of her magical smiles which sometimes just breaks my heart." I do my best to protect her from noise, light, odour, vibration, movement etc within the house to minimise the damage to her health. I pick up the pieces after a visitor has long gone, desperately trying to create a place of healing safety for recovery to occur and to reduce her recovery time. However, I Invest in ME (Charity Nr. 1114035) (May 2013) am limited to protecting her from the outside world - aircraft, motorbikes, fireworks, DIY, sunshine, heat, barking dogs, roadworks, lawnmowers, parties, environmental smells...the list is endless. Another thing that I try to protect her from is people's attitudes towards her illness and therefore, towards her personally. Sometimes these misunderstandings and judgemental opinions come knocking at your door. Last year we had to move house. There was no choice. Lili and I knew that it would be a huge cost to her health and in the back of our minds, we knew (but didn't verbalise), it could have taken her life too. It didn't but it came very close. With a move comes new doctors. I registered us both at the local surgery straight away and booked a home visit. I won't go into details but the GP was an aggressive rude man who insulted Lili to such a degree that I wanted to throw him out. I remained polite but firm. The next time I called the surgery I requested a different GP. She came as if she had already prejudged us. The doctor was very keen for Lili to do GET. Lili declined stating her reasons. A couple of months later there was a knock at the door. It was a social worker. One of the doctors (who wished to remain anonymous) made an allegation of abuse/neglect. I was in a state of shock and felt sick to my stomach. To hear the words 'suspected of abusing your daughter' is something that will haunt me for the rest of my days. The accusing doctor said that Lili was 'being kept in the dark', 'not allowed to speak', 'nursed in bed for 24hrs for 3 years', 'denied hospital appointments'. The film, Whatever happened to Baby Jane?' springs to mind doesn't it! The case is still ongoing. Lili and I were hurled out of our safe world into the jaws of ignorance and betrayal. The bond of trust between patient and doctor had been shattered. It was obvious that the accusing doctor had no basic understanding of M.E. (let alone very severe M.E.). No understanding of light sensitivity and the fact that this group of patients are unable to get out of bed and so they certainly cannot travel to hospital appointments. The extent of this ignorance in a doctor is just frightening. The fact that they have not kept up their medical knowledge is cause for grave concern. The carer of an M.E. loved one is like no other carer. Not only is it imperative to learn about myalgic encephalomyelitis in order to give the specialist care required for M.E. (to avoid causing them further www.investinme.org Page 19 of 36

Journal of IiME Volume 7 Issue 1 harm), it is also necessary to become their protector. This serious illness is very misunderstood, even by doctors. Society as a whole has a very misguided view of M.E. and so the carer has to do all they can to keep this harmful ignorant tribal thinking from entering the world of the M.E. sufferer. They need to protect their healing space from influences, opinions and 'treatment' that will cause disease progression and maybe even death. But who protects the carer? In some ways the carer is as vulnerable as their loved one. If a doctor does not respect a patient's choice of treatment, they can send in the heavy mob – social services. It's not just children with M.E. that this happens to but adults too. Adults, like Sophia Mirza, who are completely of sound mind are threatened or taken away from the safety of their home and family. Another way to force the seriously ill person to tow-the-line is to go after their carer. A doctor can say anything they want. They are believed because of their social standing. People with M.E. don't seem to have the right to choose their treatment like other seriously ill people do. This can be a lonely and difficult journey for the M.E. person and their carer to travel. Together they travel, often feeling alone, often feeling vulnerable, feeling ignored and misunderstood, feeling isolated from a world they once knew. But this world no longer recognises them, no longer understands their plight, their sorrows, their torment, their daily struggle. They are outcasts. “Doctors and healthcare workers need to be reeducated, and the media and general public need correct and truthful information. People need to know... because M.E. isn't fussy who it attacks next." My hopes and prayers are that things will change for the better for the M.E. community and their carers. New M.E. biomedical centres with specialist training for healthcare workers would be a good start. I wholeheartedly support Invest in ME and their campaign to create a centre of excellence which is much needed not only for those with myalgic encephalomyelitis, but for society as a whole. Doctors and healthcare workers need to be reInvest in ME (Charity Nr. 1114035) (May 2013) educated, and the media and general public need correct and truthful information. People need to know... because M.E. isn't fussy who it attacks next. ME QUOTES Ann Epidemiol. 2013 Jun;23(6):371-376. doi: 10.1016/j.annepidem.2013.04.003. The adoption of chronic fatigue syndrome/myalgic encephalomyelitis case definitions to assess prevalence: a systematic review. Johnston S, Brenu EW, Staines DR, MarshallGradisnik S. Griffith Health Institute, School of Medical Sciences, National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Parklands, QLD, Australia. CONCLUSIONS: Advances in clinical case definitions during the past 10 years such as the Canadian Consensus Criteria have received little attention in prevalence research. Future assessments of prevalence should consider adopting more recent developments, such as the newly available International Consensus Criteria. This move could improve the surveillance of more specific cases found within CFS. http://www.ncbi.nlm.nih.gov/pubmed/23683713 ME QUOTES "It is of the greatest importance to keep in mind the goal toward which one works in science, but it is also of equal importance to simply explore and define the 'new' while keeping that mind well prepared for finding new treasures.It is only through such efforts that we believe the etiology of CFS will be finally illuminated." Steven Tracy and Nora Chapman, University of Nebraska Medical Center: http://bit.ly/11Xs9MA www.investinme.org Page 20 of 36 Journal of IiME Volume 7 Issue 1 GUIDELINES One of the basic problems with treatment of ME is the original diagnosis of the illness. Invariably it is too late and the current environment in the UK means that diagnosis may cover a broad range of illnesses with similar symptoms which are brought together under one diagnosis - ME - a deadend of a medical diagnosis by a medical community which cannot even agree on a name. In order to establish correct and early diagnosis there needs to be a standard clinical diagnosis method used throughout the country. This area is currently clouded with up to four sets of diagnostic criteria being available for use. When a doctor or paediatrician gives a diagnosis of myalgic encephalomyelitis then they do this currently by exclusion of other illnesses and by means of basic blood tests. Diagnostic guidelines are meant to be a means to assist in diagnosis. Another important distinction is If a diagnosis is given to a patient based on a different interpretation of an illness then the diagnosis may be flawed. Worse still patients might be misdiagnosed and a treatable illness may be missed for years in some cases. Invest in ME support the use of either the so called Canadian Consensus Criteria (CCC) or the later (May 2013) version of these guidelines the International Consensus Criteria (ICC). For some time Invest in ME have been responsible for distributing printed copies of the Canadian Consensus Guidelines in the UK. The charity earns nothing from this – we merely attempt to recover the cost of the original printing. The Canadian guidelines were recently endorsed by the US CFS Advisory Committee. between guidelines used for research and those used for clinical diagnosis. One may think these would always be the same. A clinician may treat a wide selection of patients but researchers need cohorts that are as homogeneous as possible. Invest in ME (Charity Nr. 1114035) More recently the International Consensus Guidelines (ICC) has been produced and is available in printed form from Invest in ME. Contact info@investinme.org to order. www.investinme.org Page 21 of 36

Journal of IiME Volume 7 Issue 1 (May 2013) Helping IiME – Sarah’s Story Invest in ME’s supporters have achieved an enormous amount over the years. One of the continually impressive ways of raising awareness of ME and of achieving fund raising to support biomedical research has involved use of our JustGiving pages. Continuing in the ethos of IiME and the methods of Let’s Do It for ME - to make progress and not build egos and to try to enjoy, as best one can, the events and ideas generated to support the charity – this nevertheless often masks some of the real tragedy being endured and the sacrifices people have had to make. So we have picked out just one story. Sarah-Louise Jordan is raising money for IiME and biomedical research. My Story There is so much I want to say! Before I became ill I hadn't even heard of M.E and the first twelve years of my life were magical and very English. Then I had a vaccination against meningitis c and my health very quickly began to fall apart. At first it was just all kinds of aches and pains, dizziness, forgetfulness, nausea, the occasional fainting spell and a lot more tiredness but within two years I had a constant migraine and I struggled to drag my legs around because they were so heavy. Soon I couldn’t walk at all and I began to 'freefall' until I was blind and had no memories. I lost all of my words and my ability to understand other people speaking. I was so exhausted even when I woke first thing that it felt like I was trying to lift buildings to try and move. I was housebound for a year and I by the end of it I could stand for 30 seconds and manage a few painful steps, but then I relapsed again and became bedbound. I didn’t sit up for four months, I barely moved and I couldn’t talk. I had no sense of touch and no strength in my body. I suddenly perked up in April 2004 and could sit up and read a little, I was so Invest in ME (Charity Nr. 1114035) excited. In July 2004 I woke up to find my whole body 'on fire'. So hot it felt like I was melting, so painful I wanted to scream and scream and scream. I honestly didn’t think I could bear it for one minute. So far I have been on fire for eight and a half years and counting.... At first the pain, the heat and the pressure-which made my head feel like it was gripped in a vice- was so intense that I couldn’t move or speak again. For six and a half years I was silent and still, simply enduring, my hearing was so sensitive that I had to wear headphones all the time. My parents added another door to my room and triple glazed the window. every noise was still excruciating. I had blackout blinds because the light made me physically sick. I released a strange chemical that smelt acidic and clung in clumps to my hair, pooling in white/brown patches on my skin. I woke one day to find my hands curled in fists, rigid, paralysed and I couldn’t open them. Nothing seemed to change until 2010 when they opened enough for me to be able to use my 'claws' and I began to be able to do little things despite the fire, like read and write and go online. I am still bedbound, although I had a little time when I could move around the house last year, and the fire has been particularly awful again this last year. I am 25 years old and I so want to live. I could write books worth on everything that has happened, but really all I need to say is, Invest in M.E are actually doing something to help people like me...and there are hundreds of thousands of us. We all fight the same dragon; we all want to beat it so we can be free. And I can’t even tell you how heroic my M.E friends are, what they go through and also how kind they are to other people! If you don’t know them, you are missing out! With them and the girls from my old schools, and other people I’ve met along the way, I feel that I have a life rich in people. But I am a young, free www.investinme.org Page 22 of 36 Journal of IiME Volume 7 Issue 1 spirit trapped in a body that will not work! Invest in ME want to change that. And, as to losing the 50 lb, it is something I really need to do, although I do not know who is going to keep Mr. Kipling in business without my help ;) Invest in ME’s JustGiving pages are here - http://www.justgiving.com/investinm-e (May 2013) Sarah’s JustGiving Page Sarah’s fundraising page is here - http://www.justgiving.com/Sarah-Louise-Jordan Thanks for taking the time to visit my JustGiving page. M.E is a horrible illness suffered by over 250,000 people in the UK and no cure or cause is currently known. I'm raising money for research into M.E as it's an illness that I and many of my close friends suffer from and I want to do my bit to help change that! I've taken the following information off the charity's website because I think it explains things better than I can: 'People with ME need early and correct diagnosis, proper treatment and advice. The current status of services for people with ME and their families in the UK is poor with little knowledge of biomedical research being applied and possible treatments not being made available to patients or healthcare staff. Simplistic and ineffectual psychological therapies are offered in place of real treatments - wasting public money and doing nothing to help patients. This has resulted in ME patients having no real healthcare service and far too little progress in attracting new researchers or clinicians to study the disease. The dangers for people with ME having no proper clinical examination and no access to possible treatments is that the disease can develop into more severe forms with significant loss of functioning. There is also the danger of mis- or missed diagnosis – a common problem with people thought to suffer from ME.' Donating through JustGiving is simple, fast and totally secure. Your details are safe with JustGiving – they’ll never sell them on or send unwanted emails. Once you donate, they’ll send your money directly to the charity. So it’s the most efficient way to donate – saving time and cutting costs for the charity. So please dig deep and donate now. Invest in ME (Charity Nr. 1114035) www.investinme.org Companies can also use JustGiving to support Invest in ME. The more awareness and funds we can raise the sooner there will be treatments for people such as Sarah. ME QUOTES "ME/CFS is disabling and has a greater impact on functional status and well being than other chronic diseases such as cancer. The emotional burden of ME/CFS is felt by lay carers as well as by people with ME/CFS. We suggest the use of generic instruments such as SF-36, in combination of other objective outcome measurements, to describe patients and assess treatments." Nacul et al. BMC Public Health 2011, 11:402 http://www.biomedcentral.com/14712458/11/402 ME QUOTES "After acute infections, enteroviruses can persist in patients resulting in manifestation of ME/CFS. Chronic enterovirus infection in an immunocompetent host may be an example of a stalemate between attenuated, intracellular viruses and an ineffective immune response.",Chia, Chia: EvMed Research, California, USA http://bit.ly/10krfqn Page 23 of 36

Journal of IiME Volume 7 Issue 1 (May 2013) PRESENTERS at the 8th INVEST in ME INTERNATIONAL ME CONFERENCE Bios and Abstracts from the presenters at IIMEC8 Conference Chair - Dr Ian Gibson recognize an outbreak of what is known as ME/Chronic Fatigue Syndrome (ME/CFS). He became a pioneering physician and researcher in understanding the biological characteristics and methods for diagnosing, managing and treating ME/CFS. He has also performed major studies of Ampligen as a treatment for ME/CFS, and studying the possible role of human herpes virus 6 (HHV-6) in CFS patients. See Wikipedia entry - click here http://en.wikipedia.org/wiki/Daniel_Peterson_(physi cian) Former Dean of Biological Sciences, UEA Dr Ian Gibson, former Labour MP for Norwich North, worked at University of East Anglia for 32 years, became Dean of the school of biological sciences in 1991 and was head of a cancer research team and set up the Francesca Gunn Leukaemia Laboratory at UEA. In 2011 Dr Gibson received an honorary doctorate of civil law from UEA. Key Note Speech: The Mainstreaming of ME Research Dr Daniel Peterson – Simmaron Research Foundation With over 25 years of medical practice, Dr Daniel L. Peterson has become a sought-after internist for diagnosing difficult and complex medical cases. When several patients in Incline Village became ill with symptoms that resembled persistent mononucleosis, Daniel Peterson was one of the first physicians to Invest in ME (Charity Nr. 1114035) Dr Andreas Kogelnik is the Founding Director of the Open Medicine Institute, a collaborative, community-based translational research institute dedicated to personalized medicine with a human touch while using the latest advances in medicine, informatics, genomics, and biotechnology. The Institute works closely with the Open Medicine Clinic and other clinics to conduct research and apply new knowledge back into clinical practice. Dr. Kogelnik received his M.D. from Emory University School of Medicine in Atlanta and his Ph.D. in bioengineering/bioinformatics from the Georgia Institute of Technology. Subsequently, he completed is residency in Internal Medicine and a Fellowship in www.investinme.org Page 24 of 36 Key Note Speech: Making ME Mainstream: Strategies for ME Research and Collaboration Dr Andreas Kogelnik Director of the Open Medicine Institute, USA Journal of IiME Volume 7 Issue 1 Infectious Diseases at Stanford University and its affiliated hospitals. Following his clinical training, he remained at Stanford with NIH funding to engage in post-doctoral research in microbiology, immunology and bioinformatics with Dr. Ellen Jo Baron and Dr. Stanley Falkow, where he explored host-response profiles in severely ill patients. Together with Dr. José Montoya, he was instrumental in the conception, design, and execution of the EVOLVE study - a placebo-controlled, double-blind study of a subset of chronic fatigue syndrome patients with evidence of viral infection. Dr. Kogelnik worked with Dr. Atul Butte in translational informatics to determine patterns that indicated a high risk for adverse events in paediatric patients at Lucille Packard Children's Hospital. He is the Medical Director of the Open Medicine Clinic - a communitybased research clinic focussed on chronic infectious diseases, neuroimmune disease, and immunology. Dr. Kogelnik has published numerous scientific papers and book chapters, is an Editor of Computers in Medicine and Biology, and is a Consulting Assistant Professor at Stanford University. With the Open Medicine Institute, he has led the formation of CFS and Lyme Registries and Biobanks as well as creating an infrastructure for providers to collect better data and implement clinical trials across a network of sites. Abstract: Not available at time of printing – but will be available on Invest in ME web site. The Role of the Brain and ME Rakib Rayhan (May 2013) Gulf War Illness (GWI), and Fibromyalgia (FM). Understanding pain perception, autonomic and cognitive dysfunction in relation to abnormal functional and structural changes within the brain in GWI has been Mr. Rayhan’s specific focus for the 2 past years. He has discovered that white matter alterations in the right inferior-frontal occipital fasciculus are strongly associated with the severity and perception of pain and fatigue. In addition, he has identified two unique phenotypes based upon autonomic and hyperalgesic changes in response to an exercisechallenge. Changes in symptoms were associated with distinct patterns in working memory cognitive networks and discrete regions of brain atrophy. These recent discoveries have substantiated GWI as a central nervous system disorder. He is actively engaged in further pursuing a systems biology approach to the neuroimaging research by examining genomics, proteomics and metabolomics. His desire is to identify potential biomarkers that provide objective support to disease criteria and that are then translated into new and affordable therapies leading to a better quality of life for patients. Abstract Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling and complex disease state characterized by profound fatigue, chronic pain, autonomic dysregulation, headaches, sleep disturbances, cognitive dysfunction, endocrine, immune and exertional exhaustion. ME/CFS is a part of a larger group of idiopathic interoceptive and nociceptive illnesses such as Gulf War Illness (GWI), Irritable bowel syndrome (IBS), migraines and Fibromyalgia (FM). Such syndromes greatly impair quality of life and have a high economic burden. Despite considerable research ME/CFS, GWI, and FM are diagnoses of exclusion that is further complicated by symptom severity, subphenotypes and a lack of quantifiable objective biomarkers. Rakib Rayhan works with Dr James Baraniuk at Georgetown University, Washington, and is deeply interested in symptomatic development and chronification of pain and fatigue in idiopathic illnesses such as Myalgic Encephalomyelitis (ME), Invest in ME (Charity Nr. 1114035) Exercise based paradigms have been useful models to show dynamic symptom alterations in CFS/ME and FM. This raised the question of whether increased susceptibility to stressor paradigms can elucidate objective evidence for the entire symptom complex. Utilizing both exercise provocation and functional magnetic resonance imaging (fMRI) technology, Dr. James Baraniuk has developed a novel paradigm to characterize the causality between inappropriate stressor response and www.investinme.org Page 25 of 36

Journal of IiME Volume 7 Issue 1 neurological dysfunction in GWI. GWI affects 25-30% of the one million military personnel who served in the 1991 Persian Gulf War. Veterans with GWI present with multifaceted symptom profiles similar to ME/CFS patients. In fact, overlap in symptoms often leads to co-morbid diagnosis. The data presented today provides the first direct evidence of i) white matter damage that is associated with the complaints of pain and fatigue ii) elucidation of two phenotypes in response to exercise stressors iii) neurological evidence of compensatory cognitive function iv) cortical, cerebellar, and brainstem damage associated with exercise induced phenotypes and v) cognitive alterations associated with abnormal energetics of lactate metabolism in the prefrontal cortex possibly linked to neuronal mitochondrial dysfunction. An important confounder is the use of different designation criteria to diagnose patients. This has created difficulties for clinicians to identify cases and also hindered meaningful collaboration between researchers. Current phenomenological case definitions have considerable consistency and functional overlap. What is clear is the need to shift focus from aetiology and "symptoms at rest" to the response of the CNS to physiological perturbations. Although heterogeneity in symptom complexes exists; it may be too subtle to elucidate true subphenotypes at baseline. This is due to the remarkable ability of the brain to recover function and hide the underlying insult. Pushing the CNS beyond its compensatory capabilities removes the phenotype dependent functional stopgap and leads to unchecked pathophysiological profiles that amplify subgroups that would otherwise go unnoticed. We propose that fMRI of patients before and after stressor protocols may provide the distinct advantage of a standardized top-down approach that will lead to biomarker discovery of subphenotypes, individual pathophysiology, and tailored therapies. Retroviruses and ME Professor Greg Towers Professor of Molecular Virology, Research Department of Infection, Div of Infection & Immunity, University College London, UK Research Activities: HIV,Host factors influencing viral tropism and antiviral innate immunity, Innate Invest in ME (Charity Nr. 1114035) (May 2013) Immunity, Retrovirus in gene therapy and xenotransplantation, Transcription and chromatin Abstract Greg J Towers and Stephane Hue Infection and Immunity, University College London Why do we think that XMRV is not a human pathogen? Xenotropic murine leukaemia virus related virus (XMRV) is a mouse gammaretrovirus. In 2006 XMRV was described as being present in prostate cancer samples using a new technique of virus discovery. Several labs began to study the association between XMRV and human disease. In 2009 XMRV was associated with samples from patients with ME/Chronic Fatigue. This study raised particular interest because it also found XMRV in samples from healthy controls suggesting that XMRV may be a new human pathogen infecting millions of individuals. Our interest in studying the life cycle of retroviruses led us to consider whether XMRV was truly a human pathogen. We found that patient derived XMRV sequences were almost identical to a mouse xenotropic gammaretrovirus found in a human prostate cancer cell line called 22Rv1. Using phylogenetic techniques we could show that the sequences in the cell line were more diverse and parental to those derived from patients. We also found that some XMRV sequences were identical to another known gammaretrovirus called Moloney MLV, a virus that is commonly used to study MLV and that cannot replicate in human cells. We concluded that XMRV sequences in patients could be explained by contamination, a recognised problem with very sensitive PCR based detection methods. We went on to show that human integration site junctions described as proving XMRV infection of human prostate samples could also most likely be explained by contamination. We also demonstrated that MLV sequences detected in patient samples by Shyh-Ching Lo and colleagues did not represent evolution of XMRV, rather www.investinme.org Page 26 of 36 Journal of IiME Volume 7 Issue 1 contamination of patient samples with different MLV sequences from mouse genomic DNA. We were unable to find XMRV sequences ourselves in HIV patients in the UK or within prostate cancer samples in the USA. In 2011 Vinay Pathak and colleagues described how XMRV is a recombinant virus that arose in the procedure in which the 22Rv1 cell line was derived by passage of human tumours in mice. The complex recombinant nature of XMRV and the lack of viral infection of tumour samples before exposure passage in mice convincingly demonstrated that the source of XMRV was contamination of PCR reactions with DNA from 22Rv1 cells or cloned XMRV encoding plasmid. These results and their implications for future retrovirus research in ME will be discussed. We are funded by the Wellcome Trust, the Medical Research Council and the UCL/UCLH National Institute of Health Research Biomedical Research Centre Pathogen Discovery in ME Professor Mady Hornig Associate Professor Mady Hornig, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health, New York, USA (May 2013) neuropsychiatric conditions, including autism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Mady Hornig, MA, MD is a physician-scientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health where she serves as Director of Translational Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, and toxic stimuli in the development of Invest in ME (Charity Nr. 1114035) www.investinme.org Page 27 of 36 Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Her work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project, one of the largest studies of immune factors in mood disorders and schizophrenia, examines the role of viruses and immune responses in the pathogenesis of these disorders. Abstract: Not available at time of printing – but will be made available on Invest in ME web site.

Journal of IiME Volume 7 Issue 1 NHS Reforms: Implications for long term chronic conditions such as ME – for GPs and Patients (May 2013) Abstract Government NHS Reforms: Implications for long term chronic conditions such as ME – for GPs and Patients The Health and Social Care Act 2012 makes provisions for a number of changes to the English NHS – these changes became operational on 1 April 2013. Dr Clare Gerada, Chair of the Royal College of GPs, will present an overview of the NHS Reforms, and what changes in legislation mean in practice for GPs and their patients. Her talk will cover the structural changes, accountability, funding arrangements and commissioning. Dr Gerada will also outline the role of the Royal College of GPs, and ongoing work on long-term conditions. Dr Clare Gerada MBE MOM FRCP FRCGP Chair, Royal College of General Practitioners Dr Clare Gerada is a London-based GP and Chair of Council of the Royal College of General Practitioners. She is the first female Chair for over half a century. She has held a number of local and national leadership positions including Senior Medical Adviser to the Department of Health. She is Medical Director of the largest practitioner health programme in the country and she has published a number of academic papers, articles, books and chapters. Dr Gerada has been a GP since 1992, when she became a partner for the Hurley Clinic in South London. The practice started life in 1969 – and remains on its current site – on the ground floor of a 19-storey housing estate in Lambeth. Dr Gerada has a long involvement with the RCGP; she was previously Vice Chair of College Council and past Chair of the Ethics Committee. She established the RCGP’s groundbreaking Substance Misuse Unit and also led on the strategic and logistical delivery of the RCGP Annual National Conference. Prior to general practice, she worked in psychiatry at the Maudsley Hospital in South London, specialising in substance misuse. She was awarded an MBE for services to medicine and substance misuse. In 2012 Dr Gerada was presented with the National Order of Merit award in Malta for distinguishing herself in the field of health. Current Knowledge of Immunological Biomarkers in ME Professor Sonya Marshall-Gradisnik School of Medical Sciences, Griffith University, Australia Professor MarshallGradisnik is one of Australia's foremost researchers in the area of neuroimmunology and has been instrumental in establishing the Public Health and Neuroimmunology Unit (PHANU) at Bond University. Much of her work relates specifically to autoimmunity in Chronic Fatigue Syndrome sufferers and she is regularly asked to speak to community groups on behalf of Queensland Health and NSW Health. Her research in the area of exercise immunology has also contributed to the body of knowledge relating to the effect of doping in sport and she serves as Sports Medicine Australia's national spokesperson in this area. The vital research conducted by Professor Marshall has attracted more than $1 million in grant funding and she has produced 21 peer-reviewed papers, five Invest in ME (Charity Nr. 1114035) www.investinme.org Page 28 of 36 Journal of IiME Volume 7 Issue 1 book chapters and one provisional patent. In 2008 Dr Marshall was joint leader of the Bond University team responsible for developing the BioSMART program. The team was awarded a prestigious Australian Teaching and Learning Council Award (formerly known as the Carrick Award) for Outstanding Contribution to Student Learning and for the quality of student learning over a sustained period of time. Abstract: Immunological and molecular markers for defining Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis S.M. Marshall-Gradisnik1,2*, T.K. Huth1,2, K. Fuller1,2, M. Kapur1,2, S. Johnston1,2, S.B. Ramos1,2, D.R. Staines2, 3and E.W. Brenu1, 2 1. School of Medical Science, Griffith University, Gold Coast, Australia 2. The National Centre for Neuroimmunology and Emerging Diseases, Griffith Health Institute, Griffith University, Gold Coast, Australia. 3. Queensland Health, Gold Coast Public Health Unit, Robina, Australia Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is disorder with hallmarks of varying changes in immune cells and molecular related mechanisms. Decreased cytotoxic activity of innate and acquired immune cells together with increased CD4+,CD25+,FOXP3 regulatory T cells (Tregs) are consistent in CFS/ME patients, while cytokine profiles and immune cell phenotypes have produced equivocal results. MicroRNA and B cell investigations have also provided potential insight into additional immunological and genetic markers for CFS/ME. More recently investigations of NK phenotypes, dendritic cells (DCs), neutrophils, B cells, T cells, γδT cells and Tregs as well as cytotoxic activity, expression of cell surface receptors, adhesion molecules, intracellular proteins and cytokine secretion have been reported for CFS/ME patients. Collectively these studies are reviewed, suggesting comprehensive dysregulation of the immunological response in CFS/ME suggesting impaired immune functioning characterised by inadequacies in eliminating pathogens and restoring immune tolerance. (May 2013) Clinical Immunology and Research on B-cell Abnormalities in ME Patients Dr Amolak Bansal Consultant Clinical Immunology and Immunopathology, Epsom and St. Helier University Hospitals NHS Trust, Surrey, UK Dr. Bansal trained in immunology and allergy from 1989 to 1993 at St. Mary’s Hospital in Manchester and at Hope Hospital in Salford. From here he spent five years (1993-1997) as Senior Lecturer and Consultant in Clinical Immunology in the Department of Medicine at the Princess Alexandra Hospital in Brisbane, Australia. From 1997 to the present date Dr. Bansal has worked as a Consultant in Clinical Immunology and Immunopathology at Epsom and St Helier University Hospital. Dr Bansal’s key interests lie in allergy, autoimmunity, CFS/ME and immunodeficiency. Abstract: B and T cell dysregulation in patients with CFS/ME Bansal AS, Bradley AS, B. Ford B Sutton CFS Service and Department of Immunology, St. Helier University Hospital NHS Trust, Carshalton, Surrey, SM5 1AA. Low level autoimmunity is frequently evident in patients with CFS. However, CFS patients do not have the clinical features or the repertoire of autoantibodies seen in the commonly recognised systemic connective disorders or organ specific autoimmunity. Nonetheless, B cell depletion using Ritiximab has shown benefit in CFS. Furthermore Invest in ME (Charity Nr. 1114035) www.investinme.org Page 29 of 36

Journal of IiME Volume 7 Issue 1 autoimmunity to non-conventional self proteins has also been demonstrated. We sought evidence for B cell dysregulation as well as T cell dysfunction in 33 well characterised patients with mainly moderate CFS fulfilling all recognised criteria. B, T and NK cell enumeration was assessed using flow cytometry and NK cell cytotoxic function by K562 killing. Cytokines were analysed by multiplex technology. We found a significantly increased number of naïve and transitional B cells in addition to reduced plasmablasts in patients with CFS compared to healthy controls. The numbers of switched memory B cells were also reduced suggesting a dysregulation of B cell checking mechanism. CFS patients had significantly greater numbers of T helper memory effector cells and T helper and cytotoxic effector cells. They also had significantly reduced numbers of CD8+ lymph node homing naïve and memory T-cells suggesting either sequestration within lymph nodes or a reduction overall. While the levels of proinflammatory cytokines were no different between the CFS patients and the HC, the levels of IL12, IL21 and IL27 were reduced. These cytokines are particularly involved in regulating cellular immunity and specific antibody production within lymph node germinal centres. We did not find any significant difference in the circulating levels of NK cells or in NK cytotoxic function between patients with CFS and the HC. Taken as a whole our data suggest a subtle impairment of the immune system with T and B cell dysfunction geared towards autoimmunity and reduced anti-viral immunity. This was accompanied by altered lymph node germinal centre formation that is critical for specific antibody formation and the elimination of B cells with autoimmune tendency. We speculate on the cause of these changes in immune function which are likely to be multifactorial. Immunological Basis of ME Professor Carmen Scheibenbogen Professor for Immunology and Deputy Chair, Institute of Medical Immunology, Berlin Charité, Germany Group leader of a Tumour Immunology Laboratory and Attending Physician at the Dept. of Haematology, Oncology und Transfusionsmedizin, Invest in ME (Charity Nr. 1114035) www.investinme.org Page 30 of 36 (May 2013) CBF, Charité,,2/1997 Venia legendi for Internal Medicine "Habilitation",,1990 - 1998 Residency at the Med. Klinik und Poliklinik V, Hämatologie, Onkologie und Rheumatologie, Universität Heidelberg, 1988 - 1990 Postdoctoral fellowship at the Med. Klinik, Dept. of Hämatologie und, Onkologie, Universität Freiburg,1982 - 88 Medical school at the Universities of Bonn, Marburg and Denver Abstract: Diagnostic Markers in CFS One of the major problems in CFS is that the diagnosis is based on symptoms reported by patients. Diagnostic tests would be of great benefit for improving diagnostic uncertainness and the performance of clinical trials. A hallmark of CFS is immune dysregulation and immune activation. Both T cell activation and a skewed T cell type 1 / 2 profile can be detected in many patients with CFS. Regarding B cell function both diminished and elevated levels of immunoglobulins are found in subsets of patients. Further a skewed immune response against EBV is frequently found. Thus it should be possible to develop reliable diagnostic tests based on immune abnormalities. B-cell Depletion Therapy Using Rituximab in ME/CFS Professor Olav Mella Bergen University Hospital, Norway Professor Mella and Dr Fluge have published a paper "Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Journal of IiME Volume 7 Issue 1 Syndrome. A Double-Blind and Placebo-Controlled Study". Dr Øystein Fluge Bergen University Hospital, Norway (May 2013) the criteria defined in the randomized study. The main endpoint defining response was change in Fatigue score during the observation period, although improvements in fatigue were generally followed also by decrease in other ME-symptoms. Follow-up is a minimum of 28 mths in all patients. Two patients had serious allergic reactions and had to stop Rtx treatment (one responding patient given alternative B-cell depleting agent with new response). Two had repeated airway infections and were given antibiotics and eventually gamma globulin. Seven had transient ME-symptom increase shortly after Rtx infusion. Two had late onset neutropenia of short duration. Dr Øystein Fluge received medical degree in 1988 at the University of Bergen, and is a specialist in oncology since 2004. He has worked as a Research Fellow with support from the Norwegian Cancer Society and is now chief physician at the Cancer Department, Haukeland University Hospital. Doctoral work emanates from the Surgical Institute and Depart. of Molecular Biology, University of Bergen. Abstract: Intervention and maintenance treatment with the B-lymphocyte depleting monoclonal anti-CD20 antibody Rituximab in ME patients. A Phase II study. Fluge Ø, Mella O. Dept. of Oncology and Medical Physics, Haukeland University Hospital and University of Bergen, Norway. We have previously published a case series and a small double blind, placebo-controlled study using immune manipulation with the B-lymphocyte depleting, monoclonal anti-CD20 antibody Rituximab (Rtx). These studies showed that Rtx yielded clinically meaningful responses, with symptom alleviation, although usually transiently, in the majority of patients. Patients in the double-blinded study having received placebo were according to protocol offered inclusion into an open-label Phase II with Rtx treatment. This study pursued the concept of repeated Rtx infusions to see if responses were more durable than in the randomized study, and to estimate side effects of the drug including adverse effects of prolonged B-cell depletion. 28 patients (including 2 pilot patients) were treated with Rtx 500 mg/m2 day 1 and 15 (as in the randomized study) and with maintenance Rtx infusions at 3, 6, 10 and 15 mths. Patients in slow responses were offered additional infusions up to 24 mths. Study endpoints were predefined according to Invest in ME (Charity Nr. 1114035) 20 of the 28 patients had moderate or major response to treatment. 7 of the 9 placebo patients from the randomized study (without response) responded in the present study. Median selfestimated level of functioning, compared to completely healthy condition, was changed from 10% at baseline to 78% at 18-24 mths after inclusion in responders, and from 15 to 18% in nonresponders. Response durations were evidently longer than in the randomized study. However, later than 24 mths into the study, 9 of 20 responding patients have had ME-symptom recurrences. We conclude that the present Phase II study supports previous data on good clinical responses to immune manipulation with Rtx in ME-patients and that maintenance treatment seems to prolong responses. Based on the studies, we have sought financial support for a Norwegian multicenter, double-blinded and placebo-controlled study of Rtx given at day 1 and 15, and at 3, 6, 9 and 12 mths, with 24 mths observation time. This study will also include prospective analyses of bio bank material and physical tests to verify the subjective measures that are the prime endpoints. Parallel to the clinical studies, we have performed multiple analyses to get a better understanding of the mechanisms that trigger and maintain the symptoms in ME. Although preliminary, this has given us a candidate system we presently are investigating as a possible effector system in the body that may explain the symptoms and responses to interventions in ME-patients. What could be a possible link between such a system and the immune manipulation that Rtx induces? Dr. Fluge will cover this aspect of our studies in his presentation at the meeting. Supported by the Kavli Foundation and the Western Norway Health Authority. www.investinme.org Page 31 of 36

Journal of IiME Volume 7 Issue 1 (May 2013) OMI-MERIT INITIATIVE For a long time IiME has argued for a strategic approach to research into ME was necessary. But a translational research model also requires research to be connected to patient care – diagnosis, management, treatments, research integration, follow-up and so on. In such a model we also need researchers to work together. International collaboration is necessary and sharing of common database repositories and protocols. Local area GPs and consultants need to be involved and be able to share experiences. The use of digital technology also needs to be integrated in order to expedite and facilitate research and results. Using new technology also opens the way for severely affected patients to be integrated into research – thus enabling opportunities for them to be able to improve if treatments are found. The OMI-Merit Initiative offers to do all of this and create a surge of awareness which can finally make the urgent and long-overdue leap in progress which has been held back for a generation. Invest in ME wish to play a part in supporting this endeavour. The OMI-MERIT Initiative is a strategic initiative of the Open Medicine Institute and its collaborators to put the best science and people together in an organized, collaborative plan to discover and apply diagnostic and treatment solutions for ME/CFS. Led by the Open Medicine Institute and the MERIT Chair, Dr. Andreas Kogelnik (Open Medicine Institute/Private practice, US), the OMI-MERIT includes already many of the leading clinicians. Leading scientists and clinicians from around the globe with expertise in immunology, virology, genomics, informatics, molecular biology, epidemiology, infectious diseases, oncology, pathology, and clinical medicine – many presenting at IIMEC8 or BRMEC this year including Dan Peterson (Private practice, US), Olav Mella and Øystein Fluge (Haukeland University Hospital, Norway), Sonia Marshall-Gradisnik (Griffith Univ., Australia), Carmen Scheibenbogen (Charité Berlin, Germany), Rosamund Vallings (Private practice, New Zealand) and Mady Horning (Columbia Univ., US). The OMI-MERIT Priority Projects The OMI-MERIT initial projects are as follows – 1) Treatment: Phase 1: A large-scale, randomized, placebo-controlled trial of rituximab and valgancyclovir Goal: This rigorous, four-armed study will examine and further validate two of the most promising Invest in ME (Charity Nr. 1114035) therapies in the field by comparing: placebo, rituximab alone, valgancyclovir alone & combination therapy of valgancyclovir plus rituximab. Exceptional measurements of physiologic, genomic, virologic, and immunologic markers will be made throughout the course of the trial. Importance:A large-scale, rigorous trial is needed to confirm the initial findings of earlier smaller studies and move ME/CFS to molecularly trackable disease. Success of such a trial could move ME/CFS to a mainstream process for additional diagnostic and treatment trials. 2) An International Neuro Registry and BiobankPartially Funded. Goal:Supporting and expanding the largest and most comprehensive, longitudinal ME/CFS information source for research and collaboration will be the result of this project. We will collect longitudinal data and biological specimens from ME/CFS patients and controls and characterize the ME/CFS population by patient symptoms, laboratory and molecular profiles through crowd-sourced informatics and cutting edge tools in immunology, genomics and molecular biology. Comprehensive, standardized, sampling will include blood, CSF, urine, stool, brain/CNS, and other tissues. Samples will be available for additional studies in the MERIT list and beyond. Importance:There has been no large-scale, chronologic characterization effort across the ME/CFS population. The Registry and Biobank will help establish clinical and biologic clusters in the population, paving the way for diagnostic biomarkers and cluster specific treatments. In addition, this will provide a community resource for patients and is central to additional collaborative projects. 3) Protein Panel in Treatment and Naïve Patients Goal:Performing in-depth, cutting edge protein analysis of selected specimens from the Biobank to identify bacteria, viral, hormonal, antibody, cytokine and other protein-based substances that might be present in patient specimens. Specimens will be selected based on expected yield from clinical data and then discoveries confirmed in the larger patient population. Importance:This project aims to apply cutting-edge protein detection systems with specific, ultrasensitive ME/CFS related targets identified. Protein markers are key in identifying potential biomarkers and many new advanced technologies have never been applied to ME/CFS before. www.investinme.org Page 32 of 36 Journal of IiME Volume 7 Issue 1 4) Treatment: Phase 2: Other therapy mono and combination pilots Goal: To assess the effect of other touted treatments that are currently available in the field and establish immunologic and molecular parameters for measuring the efficacy of such treatments. Treatments assayed will include: Ampligen, Famvir, Etanercept, Rifaximin, Issentris, and possibly others. Importance:To determine a direction and baseline for other potential drug therapies in the field and assess which should receive additional allocation of funds for research. 5) Immunologic Biomarker Exploration Studies Goal:These exploratory studies will examine B-cell, Tcell and Natural Killer cell responses to disease and treatment groups using comprehensive, rigorous methods many of which have never before been applied to ME/CFS. It will seek to establish immunologic baselines and variants from that across the patient population. Importance:For a disease that appears to have a solid immunologic component to it, this study will provide the most advanced, longitudinal characterization of immune changes in critically implicated cells over selected treatment and control patients. 6) DNA Genetics-Funded Goal:Use the most advanced methods to sequence key areas of the human genome in a set of patients and controls and affected families and unrelated individuals. Utilizing advanced Human Genome Project technologies, this project will undertake HLA and other regional sequencing of areas of interest for selected patients and families. Importance:Establishing or refuting a role for genetics and potential heritable risk in ME/CFS. 7) Mass Spectroscopy/Environmental Measurements Goal:This exploratory study will search patient samples for unknown compounds, toxins, proteins and other substances that may be implicated in the genesis of the disease or otherwise contribute to immune dysfunction. Importance: This would be the first systematic examination of samples by the most reliable substance identification techniques to begin to establish an understanding of the contribution of nutritional and environmental factors to ME/CFS. 8) Comprehensive Viral Testing Goal:Establish a core of viral testing methodologies that are useful and could be useful clinically. Testing will include blood, urine, and saliva and other tissues where available for specific viruses such as EBV, HHV6, CMV, Parvovirus, HSV1, HSV2, and additional Invest in ME (Charity Nr. 1114035) (May 2013) panel type testing for novel viral identification and high throughput methods. Importance: This project will set the standard for clinical viral testing in ME/CFS and establish a guideline for evaluation and treatment directions for patients. Priority given to assays that have already yielded promising clinical results in partner labs. 9) Advanced Immunologic Biomarker Study 2 Goal: This secondary immune study will look at additional cell types that complement project #5 above, such as monocytes, macrophages and dendritic cells. Importance: This study extends our immunologic understanding of the disease and its extent. 10) Treatment: Phase 3: Natural and Over-theCounter substances-Moringa pilot funded Goal:Examine the potential benefit of several over the counter/natural therapies in a vetted scientific setting. Substances examined will include: Moringa oleifera, GcMAF, Vit B12, and Artemesinin. Importance:This project will be a first application of vetted scientific method and molecular science to non-pharmacologic substances that have had anecdotal benefits reported, thereby setting a standard for mainstream measurement of ME/CFS. Answers to inquiries: 1. The studies are listed in priority order, voted on by the OMI-MERIT group, however each study will start as soon as it’s funded. We have several donors that have specified which project they will fund. We will announce them as we are funded. 2. We have been fully funded for the OMI-MERIT, Project #6, DNA Genetics study and we have been partially funded for Project #10, a Moringa oleifera study, and partially funded for Project #2 the Registry and Biobank. 3. We will make announcements via Press Release, the OMF e-newsletter, the OMI Website & Facebook 4.The Open Medicine Institute (OMI) is a Community Benefits Corporation committed to applying a multidisciplinary, big data approach to the health care system to advance the understanding of “difficult” diseases and improve patient outcomes. 5.The Open Medicine Foundation (OMF) is a U.S. 501(c)(3) nonprofit with an aggressive mission: Invest in accelerating collaborative medical research to find effective treatments and diagnostic markers, current focus, ME/CFS. Keep the community informed by disseminating information on current research projects and results. Bring together thought leaders from around the world to brainstorm and participate in targeted initiatives. Encourage and engage the patient community to take an active role in their own health care. www.investinme.org Page 33 of 36

Journal of IiME Volume 7 Issue 1 8th Invest in ME International ME Conference 2013 31st May 2013, London Start Presenter 07.45-08.50 Registration 08.55 09:05 09:20 10:05 10:45 10.50 11:10 11:40 12:25 12.30 13:20 13:50 14:35 15:05 15.10 15:30 16:10 16:40 17:10 17.30 Dr Ian Gibson Dr Daniel Peterson Dr Andreas Kogelnik Rakib Rayhan Plenary Refreshment Break Professor Greg Towers Professor Mady Hornig Plenary Lunch Dr Clare Gerada Professor Sonya MarshallGradisnik Dr Amolak Bansal Plenary Refreshment Break Professor Carmen Scheibenbogen Professor Olav Mella Dr Øystein Fluge Plenary Adjourn Immunological Basis of ME B-cell Depletion Therapy Using Rituximab in ME/CFS - I B-cell Depletion Therapy Using Rituximab in ME/CFS - II Dr Ian Gibson - Questions Conference Agenda Presentation Welcome to the Conference Key Note Speech: The Mainstreaming of ME Research Key Note Speech: Making ME Mainstream: Strategies for ME Research and Collaboration The Role of the Brain and ME Questions Retroviruses and ME Pathogen Discovery in ME Questions Govt NHS Reforms: Implications for long term chronic conditions such as ME – for GPs and Patients Current Knowledge of Immunological Biomarkers Clinical Immunology and Research on B-cell Abnormalities in ME Patients Questions (May 2013) Support Biomedical Research into ME. Order our free newsletter. Distributed monthly via html, plain text or PDF http://bit.ly/14Q8VoP Invest in ME (Charity Nr. 1114035) www.investinme.org Invest in ME wristbands http://bit.ly/13gKHBp Page 34 of 36

The JOURNAL of IiME Volume 8 Issue 1 Published by Invest in ME Charity Nr. 1114035 www.investinme.org

Journal of IiME Volume 8 Issue 1 May 2014 IiME Conference DVDs The Invest in ME conference DVDs are professionally filmed and authored DVD sets consisting of four discs in Dolby stereo and in PAL (European) or NTSC (USA/Canada) format. They contain all of the presentations from Invest in ME International ME/CFS Conferences (2006 – 2014). Also included in the DVD sets are interviews with ME presenters, news stories and round-table discussions. The Invest in ME conference DVDs have been sold in over 20 countries and are available as an educational tool – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://www.investinme.org/DVD.html or via emailing Invest in ME at mailto:info@investinme.org Invest in ME (Charity Nr. 1114035) www.investinme.org Page 2 of 52 Journal of IiME Volume 8 Issue 1 May 2014 Welcome to the 9th Invest in ME International ME Conference 2014 in London – IIMEC9 Inside This Issue 3 Welcome to the Conference 8 9 Sponsors of IIMEC9 Extemporaneous Notes from IIMEC8 Severe ME 10 12 Invest in ME Research Grants LDIFME 13 A Biomarker in Predicting Clinical Response and Disease Activity 17 A Poem for ME Awareness 18 22 27 Crowd funding – 92 Tour Letter from America Importance of Basic Research 34 36 39 50 Perversely Dark Executive Summary for MPs Presenters at IiME Conference Conference Agenda Invest in ME PO BOX 561 Eastleigh SO50 0GQ Hampshire, UK E-mail: info@investinme.org www.investinme.org Member of European ME Alliance Disclaimer The views expressed in this Journal by contributors and others do not All content in the Journal of IiME is copyright to Invest in ME and the authors. Permission is required and requested from Invest in ME before republishing anything in this Journal. necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME was established in 2005 by Kathleen McCall and became a UK charity in 2006. The charity trustees are composed of ME patients and parents of children with myalgic encephalomyelitis - ME. The aim of the charity is to raise the profile of ME by improving the education of healthcare professionals about the disease, by raising awareness of the disease amongst the public and media and by facilitating and enabling an international strategy of biomedical research into the disease. Everyone working for and with the charity is a volunteer and nobody is paid a salary. At our last conference the theme was Mainstreaming ME Research –reflecting our view that after eight years of constant effort we could begin to see the change in emphasis about ME. Now even moribund establishment organisations are being forced to take ME more seriously. The IiME conferences have formed a crucial part of this education. Since our 2013 conference we have seen dramatic progress with our objectives. Our foundation project has begun at University of East Anglia and the Institute of Food Research. This three year studentship will analyse gut microbiota in ME patients. At the 2012 conference we stated that we were working on an attempt to set up a rituximab clinical trial. Following our Biomedical Research into ME Colloquium in London last year we have made rapid progress by partnering UCL in setting up the planned UK rituximab clinical trial. (continued..) Invest in ME (Charity Nr. 1114035) www.investinme.org Page 3 of 52

Journal of IiME Volume 8 Issue 1 May 2014 Thanks to the great proactivity of Professor Jonathan Edwards and Dr Jo Cambridge we have been able to develop the means to initiate the clinical trial and the initial B-cell preliminary study has now passed internal UCL checks and has gained ethical approval. IiME have now signed the contract with UCL. In addition we have been discussing with Dr Amolak Bansal a new study surrounding the hypothalamus. The charity is also planning on funding medical students to participate in research. In our ninth year as a charity we can say each year has been a stepping stone in breaking the mould and bringing ME into mainstream in research and media. Funding is scarce and the efforts of our supporters to make up what has been lacking from government agencies and research funding organisations have been awe-inspiring. Patients have worked tirelessly and imaginatively to raise funds for the research proposed by IiME and this has created a force for change. Currently Invest in ME and our supporters are actually initiating, organising and funding possibly the two most important ME research studies currently in the UK - the gut microbiome project at UEA and the IiME/UCL rituximab clinical trial. With the power of social media the charity and our supporters have been able to crowd source funding for these projects. Translational biomedical research - an iterative feedback of information between the basic and clinical research domains in order to accelerate knowledge translation from the lab to the bedside and back to the lab again - needs to be implemented to translate the findings of basic research more quickly and efficiently into medical practice. This will produce more meaningful health outcomes and facilitate the sharing of repositories and research-based facilities and laboratories. This is the model IiME are attempting to promote in the proposal for an examination and research facility. The change in the dynamics of research – certainly in the UK – has been affected by patients, those who have viewed with dismay the continued apathy to proper research which has been shown by establishment organisations. The success of the IiME/Let’s Do It For ME crowd sourcing campaigns has meant that patients can effectively enable the research that is required to be considered rather than research that unrepresentative establishment organisations decide they want. It is this that has forced progress. Progress is a fine word but change is its motivator – and people with ME and this charity have made that happen. Supporters have set up many Just Giving pages listing many imaginative ways of raising funds ranging from walking, running, cycling, swimming etc to dog sitting, crocheting, and cutting of hair A supporter’s song was put on iTunes. YouTube has been used for awareness videos. The Big Sleep has had an amazing range of ideas and events based around one theme. The ZZZ Factor Comedy Club used to humour to raise awareness. The 92 for ME football club tour was especially effective in getting publicity and reaching an entirely new audience and an article from the team’s leader, Mike Harley, appears in this Journal. There are close to 100 Just Giving pages set up to support Invest in ME in contrast just to a handful when we signed up to it with the help of a supporter paying the first year’s fee. The charity took part in Direct Debit competition again this year and won the first £2000 price – all of which has gone to funding biomedical research. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 4 of 52 Journal of IiME Volume 8 Issue 1 All of these ideas and events belie the crass misinformation about the disease which has been allowed to be propagated. IiME events all show patients and their families in a positive light – people who just wish to get better. The success in fundraising lies in active support from passionate volunteer fundraisers with the visionary Let’s Do it for ME team spearheading this change and leading the field. Yet even with all of the magnificent efforts of patients, carers, families and friends it is still a huge task to compete with the reserves of organisations such as the MRC – which ought to be accountable to patients but which has failed to develop any sensible or scientific approach to research into ME, until forced to do so. So just one slice of luck, a fortuitous coincidence or a benevolent act may be the difference between slow and rapid progress. As our poster states, One Event Can Change Everything. One such event has seen the charity receiving a £25,000 matched donation and later a further pledge of £200 000 in memory of the late Roger Heindry who sadly passed away in March 2013. This has enabled the charity to make a huge commitment to fund the rituximab clinical trial. So just one slice of luck, a fortuitous coincidence or a benevolent act may be the difference between slow and rapid progress. Social media has opened up new avenues of participation and publicity. It helps improve education – and also awareness. It also allows us to become aware of those who are no longer with us due to this awful disease. The loss of Robert Doyle 30, in July 2013 was a sad moment for many internet users as Rob was a well known and active member of the ME forum community. There are too many cases like this. The abuse of ME patients, based on ignorance and vested interests, extends beyond the UK – such has been the ability of some to fabricate and spin misinformation about ME. We continue to try to help where possible . Invest in ME have invited those in Denmark responsible for the treatment of Karina Hansen to the conference events and have written to the Danish health minister. We are also supporting other cases, in UK and Germany. In order to emphasise these situations and continue our commitment to help severely affected people with ME, we have invited Dr Nigel Speight to present our pre-conference dinner speech. Dr May 2014 Speight is a paediatrician who has been involved in helping many severely ill young people in the UK and abroad. Millions of patients are suffering around the world and the ratio of money being spent on this disease to the economic and societal losses it causes is at odds with any scientific, economic or moral viewpoint. It is organisations such as the MRC and the NIH in the USA that need to take most of the blame for this. It is the attitudes of people in these organisations that have been the problem. We actually agree with the remarks attributed to Professor Stephen Holgate of the MRC last year when he stated that we are bathing in a sea of ignorance regarding ME. It is rather disingenuous, though, of those who have been involved in controlling funding for ME research and have been aware of the lack of results from the psychosocial approach to ME to talk of ignorance. Organisations such as the MRC and the NIH have been filling the bath of research for ME patients for all these years and patients have been drowning in the effects of ignorance rather than bathing. How else can one explain the lack of funding for biomedical research especially into causes of ME? Experienced researchers such as Professors Ron Davis and Ian Lipkin are willing to study the disease but cannot get NIH funding. Surely the often-used excuse of lack of good quality research applications does not apply here. It is obvious that there has been, and still is something profoundly wrong with the peer reviewing system within these organisations regarding research applications from those who focus on biomedical into ME - something IiME has mentioned frequently over the years. It is vital that “We have all been frustrated over the years by the attitude of the MRC to CFS/ME.” these organisations address this as a matter of urgency. Perhaps it requires governmental select committee scrutiny to change things. The policies of these organisations seem to affect other countries also - and so we have situations like that of Karina Hansen, where blind ignorance of the effects of ME and a lack of proper research may endanger patients' lives. Professor Holgate himself has been head of the CFS/ME Programme at the MRC for many years and was also a member of recently demised CFS Research Foundation’s research committee. In a newsletter produced many years ago by the CFS Invest in ME (Charity Nr. 1114035) www.investinme.org Page 5 of 52

Journal of IiME Volume 8 Issue 1 Research Foundation the lack of action by the Medical Research Council was highlighted – “We have all been frustrated over the years by the attitude of the MRC to CFS/ME. They have assured us that they felt this was an important area of research, but grant applications were turned down. Dr (Jonathan) Kerr and the Foundation submitted three applications all of which went to the Neuroscience and Mental Health Board. These applications were dealing with neither neuroscience nor mental health. In spite of protests from the Foundation the MRC refused to remove our grant applications to a more appropriate board.” Indeed, the same newsletter spoke of Professor Holgate being chair of a forthcoming MRC panel for ME. That was 2008! In fact the newsletter went on to state – ’..it is anticipated by the end of 2008 that the MRC will have an agenda …’ In fact the response by the MRC lasted another five years and many years on from that article the sea of ignorance had been allowed to build into a tsunami. Now, belatedly and due to the example and the efforts and results of IiME supporters who are finding/funding a proper base of research, the MRC has actually been forced into at least appearing to act. Yet even their latest initiative, which proposes to join all researchers and organisations, no matter what their beliefs about ME or their interests, cannot agree on the basics – with no view or agreement on the correct way to diagnose ME nor even on the prevalence figure - with more than one MRC representative stating in the past year that the number of people suffering from ME was over 600,000, a magical and dramatic increase of 300% over previously assumed figures). If this really were the case then there certainly is an epidemic of ME which would warrant government intervention immediately. But this indicates the futility underlying this manoeuvring. And so the farcical continues. It is a strange policy to manipulate statistics in this way at a time when social media is liberating patients by allowing easier communication, more information, better education and the means to challenge the establishment PR organisations such as the Science Media Centre with robust and correct critiques of flawed science. Funding of research into ME is the key issue and it is a wonder to patients how key funding agencies can get it so wrong. May 2014 In reality it seems that there is no shortage of funds available for studies which fit government policy. And this shames those who issue statements talking of funding being available for high-quality studies or of ignorance about ME. It would indeed be a sad indictment of the society that we ourselves are paying for if what matters is who one knows rather than what one does when it comes to research funding granted for ME. So what of the real research required - the right stuff? As mentioned in our article which was published at the beginning of April research into ME needs a strategic approach - but it may be destined to fail completely by attempting to establish the way forward on foundations which include so much of what has been wrong in the past. ..a strange policy to manipulate statistics in this way at a time when social media is liberating patients by allowing easier communication, more information, better education and the means to challenge the establishment PR organisations such as the Science Media Centre with robust and correct critiques of flawed science. We have written in the past that we feel it is impossible to marry the views of those who believe in the deconditioning or behavioural/wrong illness belief model of ME with those from the biomedical side. The failed and flawed PACE Trial, for all the spin and waste of scarce funding, did prove one point emphatically - that the behavioural view of ME cannot deliver and should not continue to command more funding. There is another, better way forward for ME research - a clear case to be made for segregating the biomedical from the psychosocial. This could then force a separation of fatigue research from ME research. A strategy of biomedical research into ME with a research group being formed consisting of biomedical researchers, using resources and facilities across continents - hooked up to share research and data and crowd fund new research. Future research into ME must be based on collaboration - but not collaboration at any cost. It would seem quite meaningless to base the strategy on those failed policies and directions of the past - Invest in ME (Charity Nr. 1114035) www.investinme.org Page 6 of 52 Journal of IiME Volume 8 Issue 1 which have served patients so poorly and caused such suffering. This full day closed researcher meeting was designed to encourage collaboration and sharing of experience and to bring in new ideas and knowledge from outside the field of ME. A small charity with a BIG cause can achieve this. Colloquium Such is the meaning behind our Invest in ME Biomedical Research into ME Collaborative meetings which have been organised by Invest in ME and which precede our annual research conference. These aim to interest other researchers to the field of biomedical research into ME, assist those who are undertaking research or planning research into ME, and look for future collaborative projects and funding which could be generated by new ideas. This Colloquium, now in its fourth year and which has now attracted almost fifty delegates from ten countries, is a full day closed researcher meeting designed to encourage collaboration and sharing of experience and to bring in new ideas and knowledge from outside the field of ME. A small charity with a BIG cause can achieve this. The government, their organisations and the media have a lot of catching up to do. Listen to the patients is still a maxim to which politicians and the media should pay heed. Invest in ME Research Soon the charity will convert to CIO charity structure – something that has taken a lot of administrative effort over the past year. The name will become Invest in ME Research. But essentially everything continues. Our web address will remain, albeit with a new web design coming soon. Invest in ME Research will continue to lobby, raise awareness, facilitate, initiate and fund biomedical research into ME, and campaign to help patients and families to receive proper diagnosis, treatment and respect. Our commitment is to biomedical research into ME – something we will not compromise by merging all research into one big pot – a convenient but ill-fated philosophy. There is the wrong way and the right way to progress research into ME. We hope to change that in the future. For this version of the Journal we have included some interesting articles on other research areas as a way to help research into ME. So articles by Dr Jo Cambridge and Professor Steven Tracy will not specifically deal with ME but we hope, nonetheless, will be useful. From the USA columnist and producer Llewellyn King has contributed our letter from America article. Llewellyn’s comments the lack of action by governments and establishment organisations chime with ours. The Conference And so to the conference. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 7 of 52 May 2014 The Journal The Journal of IiME and forms part of each delegate’s conference pack at the 9th Invest in ME International ME/CFS Conference 2014. The Journal of IiME was created as a means of providing a broad spectrum of information on ME/CFS, combining biomedical research, information, news, views, stories and other articles relating to myalgic encephalomyelitis (ME/CFS). Our aim has been to distribute this for free four times a year. However, due to the resource and financial limitations of IiME we can only provide a snapshot of the wealth of experience which already exists and continues to increase and currently we are only able to publish a maximum of two copies a year.

Journal of IiME Volume 8 Issue 1 Our programme has always been planned so as to move the field forward and not just provide one presentation after another without thinking how they might join together or lead the field forward. This year we are very pleased to announce the presence a number of new presenters such as Professors Angela Vincent, Jonathan Edwards, Maureen Hanson, Jonas Blomberg and Drs Saul Berkowitz and Julian Blanco. We welcome again Professors Simon Carding, Mady Hornig, Sonya Marshall-Gradisnik, James Baraniuk, Julia Newton and Drs Amolak Bansal and Andy Kogelnik. It is a positive thing that we are able to interest researchers from outside the field of ME. The conference agenda is at the back of the Journal. We feel this is perhaps the best conference yet – reflecting a maturity which is beginning to develop in the field of ME research. We have at last managed to mainstream ME research – thus attracting new researchers, new funding and forcing established organisations into action in order not to appear outdated and redundant. Much of this change has been caused by patients – and although that should have been unnecessary it is, on all accounts, a salutary achievement showing courage, resilience and determination. May 2014 Dr Ian Gibson, former cancer researcher and Dean of Biological Sciences at UEA and MP, will be chairing this year’s conference. Dr Gibson has been instrumental in helping Invest in ME initiate negotiations to set up an examinations and research facility in Norwich using the excellent resources the Norwich Research Park has on offer. The conference is focal point for research and networking but there is a great deal of work behind the scenes. At the Invest in ME conferences there always seems to be a happy mixture of wanting, needing to learn, optimism and hope that things will improve. At the conference there will be researchers, clinicians, nurses, patient groups and patients, advocates and, we always hope, a sprinkling of politicians, journalists and others whom Invest in ME self-fund. The people working for and with Invest in ME are advocates of better education regarding ME. The IiME conference is not only a platform for proper, high-quality science – it is also a platform for the hopes of millions of people around the world. Let the Science Do The Talking. Enjoy the Journal. Enjoy the conference. Our Sponsors for IIMEC9 Invest in ME wish to thank the following organisations for helping by sponsoring the 9th Invest in ME International ME Conference 2014. Both organisations are fellow members of the European ME Alliance. The Irish ME Trust Norges ME Forening The Irish ME Trust has sponsored a speaker at all of our conferences and we would like to thank them for their continued support. Norway's ME Association (Norges ME Forening) is sponsoring the IIMEC9 conference. Norges ME Forening has been a long standing supporter of IiME we are very grateful for this kind donation. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 8 of 52 Journal of IiME Volume 8 Issue 1 Extemporaneous Notes from IIMEC8 Severe ME The situation of severely ill bedbound ME patients was discussed by some of the presenters at the 2013 Invest in ME International ME conference – IIMEC8. Dr Peterson said that the healthcare system is not geared for these types of patients. In the past these patients would have been cared for in hospitals with alimentary treatments but now the cost is prohibitive. Dr Staines said the situation is bizarre as normally the most severe patients in any illness get most attention and are hospitalized but in ME the situation seems to be reverse. The Australian Marshall-Gradisnik research group has included severe ME patients in their studies but have not found any differences in the immune system parameters in groups rated according to severity. Dr Staines pointed out that ME is, however, a multisystem illness and the immune system is only one part of it. The Griffiths University, where the MarshallGradisnik group is located, also has beds for patients so that they can include severely ill patients in their studies as well as monitor patients for 24 hours or more. This is something that should be possible elsewhere too. Doctors simply do not know what to do with these patients so there is an urgent need for education. After the conference Dr Bansal added the following especially for Invest in ME for a forthcoming news article (which subsequently was not used), explaining severe ME in the following way - “While it is presently very difficult for modern medicine to fully explain all severe ME symptoms, disordered neural function within the brain and spinal cord would come close. How this occurs is unknown but there are counterparts in certain newly described autoimmune conditions and viral infections of the nervous system. In addition to a direct stimulation of neurones in different parts of the brain and spinal cord there is also an impaired filtering function of the brain stem and a reduced threshold for neurones to fire off. This allows external stimuli such as movement, light, sounds, touch and sometimes even worrying thoughts to produce widespread neuronal activation with ultimate excitotoxic damage to these cells. The consequence is impaired activity of the brain generally but particularly the hypothalamus and prefrontal cortex leading to fatigue, disordered sleep, impaired memory, attention, faintness, palpitations, disordered respiration, temperature dysregulation etc. Outwardly many patients appear well and routine blood and other investigations are normal. Internally there are severe symptoms which, if unchecked, escalate leading ultimately to immobility and increasing pain and spasms in a proportion of patients. Clearly a greater understanding of this highly disabling condition is required with a greater focus on disrupted immune and neural pathways and not just psychosocial factors as has previously been the case.” ME STORY Rob had “asked that he didn't die in vain”. His sister Rachael created a JustGivingfundraising page and Fac ebook group and Rob's wonderful family, including sister Jo Ann, niece Lucy, and their friends set about a number of ways to raise funds for Invest in ME. This included selling the Christmas cards and calendars produced by our campaign in support of Invest in ME, wristbands, running raffles and collections at family events and, “anything else I can think of to make money for such a deserving cause, we just want to do something for others who suffer just like Rob” - Diane Invest in ME (Charity Nr. 1114035) www.investinme.org Page 9 of 52 May 2014

Journal of IiME Volume 8 Issue 1 May 2014 Invest in ME Research Grants Policy Invest in ME supports high quality, biomedical research into myalgic encephalomyelitis (ME). The following paragraphs detail our policy and procedures for applying for funding for such research. The charity welcomes applications for grants for projects of 6 months - 3 years duration. Anyone wishing to apply for a grant from the charity should use the form on the web site to apply (links are below), having first appraised oneself of the conditions for grant applications. It is emphasised that Invest in ME’s ethos is to initiate high-quality biomedical research into ME as an urgent requirement. Priority will be given to research which maximises the potential to find causality for ME and/or which promises to provide the greatest improvement for people with ME. Our priorities are steered by the unequivocal belief that ME is of organic origin and requiring a strategy of biomedical research with international collaboration. Our Research Priorities 1. Medical research into:  Research associated with Causality  Translational biomedical research to provide effective treatments for ME  Accurate and comprehensive diagnosis  Improved education of healthcare professionals about the disease  Telemedicine for use with and by ME patients and their physicians  Raising awareness amongst the public, the media and academia Collaboration Collaboration has been one of the central tenets of Invest in ME’s policy since our 2007 international ME conference in London. As a founding member of the European ME Alliance we work with international colleagues (advocates, researchers, research organisations and physicians) to make rapid progress in finding the cause of ME and providing treatments for all. Funding applications will be considered from outside of the UK though we do prefer to use collaborations with UK and European organisations and researchers. Our Research Funding Opportunities Invest in ME Research is committed to funding highquality biomedical research into myalgic encephalomyelitis (ME). This is a fundamental part of our strategy for ME which includes creating a UK/European Centre of Excellence for ME (CoE) [1]. The CoE influences our choice of looking for translational biomedical research which can discover causality and provide treatments – in a direct and expeditious way. This therefore means that we are looking for biomedical research applications – covering virology, immunology, and endocrinology with particular emphasis on autoimmunity. Invest in ME Research does not hold large unallocated amounts in a bank for research. We are not a membership charity as we believe ME patients should have access to free information and we try always to offer our products or services for free or at cost price. We campaign for the interests of patients and carers to try to ensure that those most vulnerable are not taken advantage of. We believe it is inappropriate and wasteful to store large amounts of funds which are unused and which just wait for applications. Instead we believe in identifying valid research which fulfils our strategic aims and then in initiating a funding campaign to attain the required funds. A list of current opportunities can be seen at this link. How Funding is Awarded Due to the way in which Invest in ME promotes research and seeks a strategic approach to research we prefer to request ideas for research projects or to identify them ourselves and then perform fundraising campaigns to raise the necessary funds. The way we promote the search for ideas is via our conferences, our researcher colloquiums and meetings and our newsletters. Academic institutions most likely to perform the sort of translational biomedical research into ME Invest in ME (Charity Nr. 1114035) www.investinme.org Page 10 of 52 Journal of IiME Volume 8 Issue 1 May 2014 Invest in ME Research Grants Policy that we require are invited to our research meetings and to our conferences. We also circulate our newsletter to many different academic institutions. In this way we believe we build awareness of our requirements and opportunities. With the gut microbiome research, which is our foundation project for a centre of excellence for ME, we directly sought support and assistance from University of East Anglia as that university plays an important role in the Norwich Research Park, which is the location for our proposed centre. Peer Reviewing The charity has a list of external reviewers whom we will ask to peer review any applications for funding and projects. We will assess all applications based on the relevance and usefulness of the research and in accordance with our research priorities, scientific merit, timescale and cost. How to Apply If potential researchers wish to first enquire informally about a project and grant request then please contact us using the contact details at the end of this article. Application Forms are available here – Word http://www.investinme.org/Documents/IIM E%20Grant%20Application%20Forms/IIME%20Rese arch%20Grant%20Application%20Form.docx PDFhttp://www.investinme.org/Documents/IIME%20Gr ant%20Application%20Forms/IIME%20Research%2 0Grant%20Application%20Form.pdf The award of any research grants will be according to Invest in ME’s terms and conditions and all decisions regarding acceptance or non-acceptance of research applications are the charity’s and will be final. Medical Ethics Projects funded by Invest in ME are to be conducted in accordance with the guidelines and principles described by the Declaration of Helsinki. It is expected that the research will be verified and approved by the appropriate research & development and ethics committees related to the research team. Dedicated Funds Invest in ME will maintain ring-fenced funds for those projects which require dedicated campaigns to support the fund-raising activities. Invest in ME also maintains a general Biomedical Research Fund which is used for many activities associated with biomedical research. Use of Animals in Medical Research The projects currently envisaged or being funded by Invest in ME are not, as far as we are aware, involving animals, and the charity currently has no plans to do so. Dissemination of results Results from Invest in ME-funded projects would be expected to be published in professional scientific journals. Invest in ME will expect frequent reports on progress of the research which would be disseminated though our web site, newsletter and Journal. ME FACTS “The hypothesis of the present study is that the appearance of cell-specific autoimmune antibodies may define subsets of (ME)CFS. (ME)CFS is clinically similar to several autoimmune disorders that can be diagnosed and characterised by autoantibody profiles. For this reason, we conducted an exhaustive evaluation of 11 ubiquitous nuclear and cellular autoantigens in addition to two neuronal specific antigens. Very few studies have evaluated the presence of autoantibodies in people with (ME)CFS. The findings of this study hint that evaluation of certain autoantibodies may give clues to ongoing pathology in subsets of (ME)CFS subjects. Among (ME)CFS subjects, those who had been sick longer had higher rates of autoantibodies” (S Vernon et al. Journal of Autoimmune Diseases May 25th, 2005:2:5). Invest in ME (Charity Nr. 1114035) www.investinme.org Page 11 of 52

Journal of IiME Volume 8 Issue 1 May 2014 What is Let’s Do It for ME? Let's do it for ME is a campaign to help raise awareness of the work of independent UK charity Invest in ME (Research) and funds for the biomedical research into myalgic encephalomyelitis that the charity is organising and/or funding. Let’s Do It for ME has its own website, Facebook page and blog and is playing a major part in raising funds for Invest in ME's biomedical research projects. During the ME Awareness month of May 2014 various events organised by Let’s Do It For ME and Invest in ME supporters created numerous ways of raising awareness with something to suit all ages, tastes and abilities. These included – International Event Page May 1st - 1 Day - £1 - 1st of the month to donate £1 to 1st class IiME research! LIGHT UP THE NIGHT FOR ME on May 12th – helping IiME have any public buildings lit up blue for ME Awareness on May 12th. Turn your body blue for M.E - anyone can take part - posting a photo of oneself or a body part in blue and donate to Julieann's JustGiving page. Selfie Facebook Fundraiser May 12th - based on the idea for cancer awareness - post pictures of yourself on your social networking sites and donate to Clare's JustGiving page. Sewber Moments Online Fundraising Raffle Sarah Mozer's Online Charity Fundraising Raffle The Big Sleep for ME – hugely successful – and fun - and now in its 3rd year and going global! Including - ° Where's Bear competition ° Poetry Competition ° T-shirt design competition - deadline for entries May 31st ° The Princesses and M.E - their first year and what a team! Fancy being a princess for a day? The Zzz...Factor for IiME Comedy Club - great entertainment in the comfort of your own home. Walk for ME in its second year with the first walk for IiME already completed. Walk for ME Isle of Man - wonderful team new on board for 2014 walking this coming weekend. Mass Observation Diary on May 12th - for the general public in UK but an ideal opportunity to raise ME Awareness given the date. #May12BlogBomb – for bloggers to write a guest blog for May 12th. Light a Candle to Remember M.E. A poignant event created on behalf our lovely Rosa Amor. A Vigil for International Awareness Day on May 12th in aid of Invest in ME Research Seren's 12hr Crochet Marathon for Invest in M.E. Seren is hoping to reach her £1000 target for IiME To get in gear for ME Awareness - visit our Shop for Biomedical ME Research Mama Chill's dizzyjam ME Awareness ranges with all proceeds to Invest in ME Click here for a variety of other ME Awareness materials. These events that anyone could take part in – emphasising the spirit of Let’s Do It For ME. Use this link to learn more - LDIFME website http://ldifme.org Invest in ME (Charity Nr. 1114035) www.investinme.org Page 12 of 52 Journal of IiME Volume 8 Issue 1 May 2014 A Biomarker in Predicting Clinical Response and Disease Activity in Patients with RA and SLE treated with Rituximab To investigate the potential of soluble CD23 as a biomarker in predicting clinical response and disease activity in patients with RA and SLE treated with Rituximab Aim: To determine whether a putative measure of B cell differentiation into memory cell phenotype can be used to inform on B cell kinetics and mechanisms of response and relapse during treatment with rituximab. Introduction: Removal of B cells with rituximab (RTX – a chimaeric monoclonal antibody recognising CD20 antigen)(1) induces clinical remission in a majority of seropositive patients with Rheumatoid arthritis (RA) (2). RTX is also used with reported success off-label in patients with SLE (3, 4). Although a randomised clinical trial in SLE did not provide clear evidence of clinical benefit, there are reasons to doubt the validity of these negative results (5). In both conditions, relapse can occur coincident with B cell return to the periphery, but in some patients may be delayed for many months (6, 7). Therefore, although B cell return precedes clinical relapse the time interval between B cell repopulation and clinical relapse is variable between patients, thus limiting the utility of B cell repopulation to accurately predict the timing of relapse. The clinical use of the B-cell depleting agent RTX in patients with RA was initiated by Professor Jonathan Edwards at UCL in 1998, with results of the first small open study published in 2001 (8). In 2006, RTX was licenced for refractory RA. Patients may be positively selected based on their serostatus as ‘good’ clinical responses (ACR>50%) are more predictable in patients with seropositive disease (2). Such an approach may limit the use of rituximab for seronegative RA, which may be better treated with alternative biological agents. Adequate B cell depletion in the peripheral blood, arbitrarily defined as CD19+ cells<5/μl, in patients with RA, and also when RTX is used off-label in SLE, is necessary for clinical response (9, 10). On the other hand, removal of the majority of peripheral B cells does not necessarily guarantee attaining a significant clinical benefit. When high sensitivity flow Geraldine Cambridge, PhD, Principal Investigator, University College London, UK Maria Leandro, MD PhD, Consultant Rheumatologist & Senior Lecturer, University College London, UK Venkat Reddy, MD, Consultant Rheumatologist, University College London, UK cytometry analysis was used (ie counting >100,000 cells), it was found that the level of depletion required to be even lower in some patients in order to achieve a ‘good’ clinical response. (11) Mechanisms underlying poor responses, in the face of good peripheral depletion, remain largely unexplored. In conjunction with studies of adequacy of peripheral B cell depletion, analysis of B cell phenotype showed that a persistence of memory B cells (usually CD27+) in peripheral blood in the weeks after rituximab therapy (12) correlated with impaired response rates in patients with RA. The analysis of B-cell phenotype has also been explored in order to suggest possible biomarkers to predict response. Several studies have now concluded that evolution of B cells towards an immunoglobulin-producing phenotype was related to whether the patient is going to respond well or not to rituximab and also whether periods of remission are going to be relatively short-lived (1315). In addition, higher percentages of switched memory B-cells in the circulation after rituximab have been associated with earlier relapse (15-17). This was supported by studies of the genetic phenotype which were possibly predictive for the strength of clinical response. In the REFLEX trial of rituximab in inadequate responders to anti-TNFα therapies, a 25% subgroup of treated subjects with elevated baseline mRNA levels of IgJ (a marker for antibody-secreting plasmablasts), showed reduced clinical response rates. There were no significant efficacy differences in the placebo arm subjects stratified by this marker. Prospective testing of IgJ, and strong IFNα signature pre-treatment in the DANCER and SERENE rituximab clinical trial cohorts confirmed the ability of these genetic markers to Invest in ME (Charity Nr. 1114035) www.investinme.org Page 13 of 52

Journal of IiME Volume 8 Issue 1 predict poor response to anti-CD20 therapy (18, 19). In patients with SLE, we have shown that high serum BAFF levels and possession of autoantibodies with ENA specificity indicated shorter clinical response(<6 months) to RTX (20). Thus, current evidence suggests that tracking of memory B celland plasma cell activity are both important in predicting clinical relapse/response. Whereas serum immunoglobulin levels including autoantibody levels are used to identify plasma cell activity there are no biomarkers that may predict the formation of memory B cells. Our early studies of the kinetics of autoantibody levels following RTX showed a correlation with the ‘delayed’ onset of clinical response (often approximately 1-2 months after B cell depletion induced), characteristic of RTX treatment in patients with RA. Studies by Immunohistochemical studies of synovial biopsies after RTX by Thurlings and colleagues (21) showed that the reduction of plasma cells at 16 weeks post-RTX was the best predictor of clinical improvement at 24 week followup. Although B cell numbers in synovium were also reduced at 16 weeks, they were not correlated with response. The results from studies of biopsied joints following RTX therefore supported our hypothesis that the clinical response to RTX was due at least in part to an indirect effect on plasmablasts/plasma cells associated with autoantibody production (22). Rituximab was therefore possibly working by preventing recruitment of activated autoreactive B cells into secondary lymphoid tissue and to joints by removing circulating B cells. Re-establishment of disease involves the reengagement of pro-inflammatory pathways, which are absent or greatly diminished during the period of B-cell depletion. Relapse after RTX has been found to follow B cell return to the periphery in patients with RA, but this relationship is less clear in patients with SLE. B cell return after RTX mirrors ontogeny with transitional and naïve B cells, many expressing CD5, exiting the bone marrow and expanding in the periphery. Recovery of B cell numbers to within the normal range varies enormously between patients and can be very protracted. Maturation to memory phenotype, and restoration of the normal ratio between naïve and memory B cell compartments is not often achieved for many months or even years in either condition(23, 24). Differentiation towards memory phenotype after B cell return, most commonly associated (but not always) with gaining CD27+ status (25), may however herald relapse (14). Our May 2014 observations also suggest that rises in IgM-RhF are closely associated with impending relapse (26). Therefore, relatively long periods of B cell depletion in the peripheral blood (6-9 months in patients with RA) are associated with reduction in symptoms after RTX. The trigger for relapse can either coincide with, or follow by periods of some months, the exit of new B cells from the bone marrow. The time-course and B cell kinetics during the RTX treatment cycle therefore suggest that pathogenic plasmablasts/plasma cells are mostly short-lived and their removal is necessary for induction of remission. The strong association of rises in autoantibodies, rather that B cell numbers, with clinical relapse, suggests that naïve B cells or resistent memory B cell populations (perhaps expanded by by-stander help as a consequence of T cell dependent or independent pathways), are differentiating into Ig-producing cells. Studies leading to this project: Preliminary studies in our laboratory suggested that the measurement of a serum factor released from B cells as they undergo differentiation to memory phenotype (soluble CD23) , may be a useful surrogate of a) relative rate of differentiation of naïve B cells to a memory phenotype (CD27+) following RTX (Cambridge et al, submitted 2013) and b) a potential biomarker for depletion/response to RTX in RA and SLE patients (preliminary data, Figure 1 attached). Briefly, we found that in 23 RA patients treated with RTX, baseline levels of serum sCD23 were generally within normal limits, decreasing to below the normal range at depletion, demonstrating that most serum sCD23 was derived from B cells. It has previously been shown that sCD23 levels may correlate with disease activity in patients with SLE and SS (27, 28). CD23, the low affinity FcεR, is expressed on mature naïve B cells, lost from germinal centre cells and is expressed only on a low proportion of IgD+ memory B cells and possibly some transitional B cells (29). Expression of CD27 following antigen encounter induces cleavage of CD23 and the soluble receptor, sCD23 is released into the circulation. CD23 and CD27 expression appears to be virtually mutually exclusive; with both antigens possibly only transiently expressed on the same cell. sCD23 is released from the membrane expressed molecule by the action of endogenous αdisintegrin and metalloprotease10. Cleavage from the cell surface can be induced following stimulation in vitro with IL4 and CD40-L. Serum levels above normal limits (>2000ng/ml) in vivo are associated with allergy and atopy. It has recently Invest in ME (Charity Nr. 1114035) www.investinme.org Page 14 of 52 Journal of IiME Volume 8 Issue 1 been shown that the soluble molecule can positively control IgE synthesis (30, 31). Therefore, sCD23 levels would serve as a potential biomarker of memory cell formation, the detection of which in peripheral circulation is predictive of clinical relapse. Experimental plan: RA: As the relationship between B cell kinetics and relapse after RTX is highly variable between patients, we identified 4 key time points in each cycle for analysis: Baseline (pre-RTX in each cycle); when B-cell depleted (CD19+Breturn (CD19+B(ΔDAS28>1.2). SLE: The relationship between B cell return and disease flare is also highly variable in these patients and the kinetics of the clinical response differs from RA. We will therefore use length of time to flare after treatment either (<6 months) and between 612 months to determine efficacy of treatment, as we have previously described (32, 33). Therefore we will include samples collected at baseline (prior to RTX) and at 3, 6, 9 and 12 month intervals. Determination of disease activity and flare will be assessed by BILAG2004(34). Protocol Patients: Stored serum samples are available from patients treated with RTX over the last 12 years (from our cohorts of >250 patients with RA; 100 patients with SLE). Clinical data will be collected retrospectively and samples from the same patients tested concurrently. Levels of soluble CD23 will be measured using ELISA (R and D systems). Isotypes of Rheumatoid factors (RhF) and anti-cyclic citrullinated peptides (CCP) will be measured using ELISA kits (from Axis Sheild, Dundee, UK). We aim to include samples from 30 patients with RA and 20 with SLE. Differences between time points will be assessed following log transformation and T-test with significance level set at 1%. Correlations between variables (sCD23, autoantibodies) will be by linear regression. Multivariate analysis will be used to determine relationships between serum sCD23 levels, levels of autoantibodies and duration of clinical response, assessed by EULAR response criteria for RA patients; flare< or ≥ 6 months; and SLE responder index for SLE. References 1. Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy May 2014 in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. 1997;90(6):2188-95. 2. Khan A, Scott D. Rituximab after methotrexate failure in rheumatoid arthritis: evaluation of the SERENE trial. Expert opinion on biological therapy. 2011;11(11):1515-8. 3. Leandro MJ, Edwards JC, Cambridge G, -cell Ehrenstein MR, Isenberg DA. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis and rheumatism. 2002;46(10):2673-7. 4. Diaz-Lagares C, Croca S, Sangle S, Vital EM, Catapano F, Martinez-Berriotxoa A, et al. Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmunity reviews. 2012;11(5):357-64. 5. Isenberg DA. Rituximab-it was the best of times, it was the worst of times. Autoimmunity reviews. 2012;11(11):790-1. 6. Popa C, Leandro MJ, Cambridge G, Edwards JC. Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 yrs. Rheumatology (Oxford). 2007;46:626-30. 7. Anolik JH, Barnard J, Owen T, Zheng B, Kemshetti S, Looney RJ, et al. Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. Arthritis and rheumatism. 2007;56(9):3044-56. 8. Edwards JC, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology (Oxford). 2001;40(2):205-11. 9. Vital EM, Rawstron AC, Dass S, Henshaw K, Madden J, Emery P, et al. Reduced-dose rituximab in rheumatoid arthritis: efficacy depends on degree of B cell depletion. Arthritis and rheumatism. 2011;63(3):603-8. 10. Vital EM, Dass S, Buch MH, Henshaw K, Pease CT, Martin MF, et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis and rheumatism. 2011;63(10):3038-47. 11. Dass S, Rawstron AC, Vital EM, Henshaw K, McGonagle D, Emery P. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthritis and rheumatism. 2008;58(10):2993-9. 12. Nakou M, Katsikas G, Sidiropoulos P, Bertsias G, Papadimitraki E, Raptopoulou A, et al. Rituximab therapy reduces activated B cells in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cells correlates with clinical response. Arthritis research & therapy. 2009;11(4):R131. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 15 of 52

Journal of IiME Volume 8 Issue 1 13. Teng YK, Verburg RJ, Verpoort KN, Diepenhorst GM, Bajema IM, van Tol MJ, et al. Differential responsiveness to immunoablative therapy in refractory rheumatoid arthritis is associated with level and avidity of anti-cyclic citrullinated protein autoantibodies: a case study. Arthritis research & therapy. 2007;9(5):R106. 14. de la Torre I, Moura RA, Leandro MJ, Edwards J, Cambridge G. B-cell-activating factor receptor expression on naive and memory B cells: relationship with relapse in patients with rheumatoid arthritis following B-cell depletion therapy. Annals of the rheumatic diseases. 2010;69(12):2181-8. 15. Moller B, Aeberli D, Eggli S, Fuhrer M, Vajtai I, Vogelin E, et al. Class-switched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis. Arthritis research & therapy. 2009;11(3):R62. 16. in patients with rheumatoid arthritis: predictors of response and B cell subset regeneration after repeated treatment. Arthritis and rheumatism. 2008;58(6):1566-75. 17. Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis and rheumatism. 2006;54(2):613-20. 18. Owczarczyk K, Lal P, Abbas AR, Wolslegel K, Holweg CT, Dummer W, et al. A plasmablast biomarker for nonresponse to antibody therapy to CD20 in rheumatoid arthritis. Science translational medicine. 2011;3(101):101ra92. 19. Raterman HG, Vosslamber S, de Ridder S, Nurmohamed MT, Lems WF, Boers M, et al. The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. Arthritis research & therapy. 2012;14(2):R95. 20. Cambridge G, Isenberg DA, Edwards JC, Leandro MJ, Migone TS, Teodorescu M, et al. B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response. Annals of the rheumatic diseases. 2008;67(7):10116. 21. Thurlings RM, Vos K, Wijbrandts CA, Zwinderman AH, Gerlag DM, Tak PP. Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response. Annals of the rheumatic diseases. 2008;67(7):917-25. Epub 2007/10/30. 22. rheumatoid arthritis and other autoimmune May 2014 diseases. Nature reviews Immunology. 2006;6(5):394-403. 23. Muhammad K, Roll P, Einsele H, Dorner T, Tony HP. Delayed acquisition of somatic hypermutations in repopulated IGD+CD27+ memory B cell receptors after rituximab treatment. Arthritis and rheumatism. 2009;60(8):2284-93. 24. Iwata S, Saito K, Tokunaga M, Tanaka Y. Persistent memory B cell down-regulation after 6year remission induced by rituximab therapy in patients with systemic lupus erythematosus. Lupus. 2013;22(5):538-40. 25. Wei C, Anolik J, Cappione A, Zheng B, PughBernard A, Brooks J, et al. A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus. J Immunol. 2007;178(10):6624-33. 26. Cambridge G, Leandro MJ, Edwards JC, Roll P, Dorner T, Tony HP. Anti-CD20 therapy Ehrenstein MR, Salden M, Bodman-Smith M, et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis and rheumatism. 2003;48(8):2146-54. 27. Bansal A, Roberts T, Hay EM, Kay R, Pumphrey RS, Wilson PB. Soluble CD23 levels are elevated in the serum of patients with primary Sjogren's syndrome and systemic lupus erythematosus. Clinical and experimental immunology. 1992;89(3):452-5. 28. Chomarat P, Briolay J, Banchereau J, Miossec P. Increased production of soluble CD23 in rheumatoid arthritis, and its regulation by interleukin-4. Arthritis and rheumatism. 1993;36(2):234-42. 29. Bohnhorst JO, Bjorgan MB, Thoen JE, Natvig JB, Thompson KM. Bm1-Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sjogren's syndrome. J Immunol. 2001;167(7):3610-8. 30. Lachaux A, Grosjean I, Bonnefoy JY, Kaiserlian D. Soluble serum CD23 levels and CD23 molecule expression on intestinal epithelial cells in infants with reaginic and non reaginic cow's milk allergy. European journal of pediatrics. 1996;155(10):918. 31. Cooper AM, Hobson PS, Jutton MR, Kao MW, Drung B, Schmidt B, et al. Soluble CD23 controls IgE synthesis and homeostasis in human B cells. J Immunol. 2012;188(7):3199-207. 32. Cambridge G, Leandro MJ, Teodorescu M, Edwards JC, Cambridge G. B-cell targeting in Manson J, Rahman A, Isenberg DA, et al. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody Invest in ME (Charity Nr. 1114035) www.investinme.org Page 16 of 52 Journal of IiME Volume 8 Issue 1 profiles. Arthritis and rheumatism. 2006;54(11):3612-22. 33. May 2014 Cambridge G, Stohl W, Leandro MJ, Migone TS, Hilbert DM, Edwards JC. Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis and rheumatism. 2006;54(3):723-32. 34. Romero-Diaz J, Isenberg D, RamseyGoldman R. Measures of adult systemic lupus erythematosus: updated version of British Isles Lupus Assessment Group (BILAG 2004), European Consensus Lupus Activity Measurements (ECLAM), A Poem for ME Awareness Month by a severely affected young person with ME Systemic Lupus Activity Measure, Revised (SLAM-R), Systemic Lupus Activity Questionnaire for Population Studies (SLAQ), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI2K), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Arthritis care & research. 2011;63 Suppl 11:S37-46. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 17 of 52

Journal of IiME Volume 8 Issue 1 May 2014 The world of ME has many hurdles for patients - one of the greatest being isolation. It is too infrequent an occurrence for friends, and sometimes even relatives of someone with ME to stay in contact, let alone actively do something to help. Many ME patients can feel isolated and abandoned by their friends and even family members due to the ignorance and effects of the disease. So Invest in ME were amazed at the reaction and spirit of a group of four friends who created a scheme to visit all 92 English Football League Stadiums in under 92 hours in support of Invest in ME and in order to raise money and awareness for the Rituximab Trial. They did this to help their friend who has ME. On 16th of April 2014, my wife, Cat, and two good mates; Mike and Raz started a six day challenge to drive to all 92 English Football League Grounds in under 92 travelling hours for Invest In ME. I wanted to do something to raise funds and awareness for ME sufferers as one of my best friends from school in Cornwall, Ian, has suffered from ME for over 7 years and been unable to work or lead a normal life. Throughout this period he has always amazed me with his positivity about one day recovering and he told me about the Rituximab trial and its success in Norway. From hearing about it and doing some research online it appears that the drug could represent a very real breakthrough for treating and hopefully curing the illness and I was determined to get involved and do as much as The event lasted six days in April 14. The charity and our supporters are indebted to this group of four who are did such an amazing job of raising awareness for ME. Football clubs, hotels, TV companies helped in building huge interest and this positive way of raising awareness and funds for ME has increased the exposure of the work the charity is trying to do. The blog of the event is here http://92in92.blogspot.co.uk and one can still make donations to support the amazing event The charity had a flag especially made for the tour and this was shown in photographs made at every football ground and used for photo opportunities at all of the clubs. we could to support bringing it to the UK. Ian and I have always talked for hours about football (him being a Liverpool fan, myself being a Man Utd fan) and once we’d come up with the idea to visit all 92 clubs it became really obvious that this could be a huge event in raising awareness. We began writing off to all of the clubs for support, football magazines, over 150 newspapers UK wide and various radio/TV to try and get as much attention as possible. In the end over 70 clubs pledged their support for the challenge which was pretty amazing and over 30 newspapers began calling me for info and agreeing to feature us. The challenge itself had been done by 3 other groups in the weeks running up to its start date so we found that a lot of the clubs were unable to support us with Invest in ME (Charity Nr. 1114035) www.investinme.org Page 18 of 52 Journal of IiME Volume 8 Issue 1 donations or signed items. We changed tactics therefore and asked them for a small feature in their match day programmes which we hoped would be seen by thousands of supporters per game and also their websites and social media. We were in effect giving them free content and asking them to promote us and themselves with the view of raising awareness which for the most part they were more than happy to do. This meant that we acquired hundreds of followers and an army of supporters who in turn wrote off to their local clubs and media demanding support! In some cases we were able to secure signed items which we are due to auction very soon including match tickets, signed pennants and other items but the most important aspect of the trip was to try and dispel the myth that ME is purely a psychological/non-physical condition and required funded biological research. We had fantastic support from Invest In ME who not only helped with emailing the clubs but were influential in creating flyers which we handed out at the grounds and working with us to design our huge flag which we took to be photographed with at all of the stadiums. We wrote off to local hotels to stop at during the trip and were given some fantastic discounts mainly from the Holiday Inn and also secured a cash donation from Enterprise Rent-acar who would play a key part in our success later on in the story…. Taking to the road we stopped at Plymouth the night before and visited Plymouth Argyle where I met the Chief Executive of the club who told me that he himself had overcome ME –he’d come in on his day off to support us and opened up the ground for us to be filmed for ITV which was a fantastic May 2014 gesture. Donations and requests for information began to flood in and we began the event in high spirits with a real feeling that we’d be able to change people’s perceptions of ME and make a difference. Day one was eventful and although we got caught up in heavy holiday traffic we made it to our final club at 10pm with pitch side photos at Plymouth, Exeter, Yeovil, Bristol Rovers, Cardiff and Swansea under our belts. Twitter support from these clubs and web features also came in which further increased our followers and sponsorship. Day two was a huge one, beginning in Bournemouth, going along to Brighton and then up into the 12 London clubs was always going to be tough at the start of the bank holiday weekend. But luckily we had some amazing support from Arsenal who ushered us onto the pitch for photos and put us in two match day programmes! Another pitch side photo at Tottenham and some great support from the other London clubs followed and we were humbled by the support that we had from some ME sufferers who met us at the grounds and wished us well. Day three was extremely hard as we arrived at Colchester just before the kick off for their home game and my clutch gave out. The staff and police at the ground were fantastic and Invest In ME helped us secure an Enterprise hire car to finish the leg as I travelled with the car back to Bristol on a very slow recovery truck. I hopped in another car and drove through the night to Milton Keynes ready to start the fourth day back with the team. As our car lay stationary in the car park outside the ground we had what is now infamously being called ‘The Colchester Silence’ –a two minute pause as reality sunk in that we might not complete the event. Don’t worry this and much Invest in ME (Charity Nr. 1114035) www.investinme.org Page 19 of 52

Journal of IiME Volume 8 Issue 1 more has all been captured on video which we are furiously editing ready for view! The team met with Richard from Invest In ME who had been such a huge help and we had another fantastic food parcel! With a man down and a midnight finish we decided that there was no way we wanted to let everyone down and no matter the cost or effort, we were going to finish the event. Day four was actually pretty enjoyable despite covering a huge distance and over 24 clubs. These including pitch side photos at Aston Villa and with yet more club and paper support but we had become a well-oiled machine running on a diet of ghastly energy drinks and service station sandwiches. It was tough physically and mentally to keep going with just two drivers and the ‘media team’ in the back trying to keep up with messaging and posting to our social media which had become such an important part of the event. We met up with James Smith at Burton Albion whose mum suffers from ME and he came with us onto the pitch just before kick off at their home game and with one of their players we were photographed for the local papers –this was again another huge highlight for us and his mum baked us some delicious cakes! After a feature on Radio 5Live a lady from Scunthorpe drove over to the ground especially to make a donation which again was simply an amazing feeling for us. May 2014 actually opened up the ground bringing one of the players along for a photo as well as featuring us on their website and match day programme. We moved on towards Bradford and met one of our supporters whose partner suffers from ME and he came along especially with the local newspaper to give us a cash donation. Again we were incredibly moved and meet-ups like this really kept us going. Later in the day Manchester United not only allowed us onto the pitch but their fantastic staff showed us the dressing rooms and players lounge which was a fantastic bonus. More programme features, papers and twitter support followed as we broke through the £3K mark. Ending up in Carlisle at 10pm we knew that the final day would be a lot easier with just 7 clubs left to go. On day six we met up with Paul Kayes from ‘Lets Do It For ME’ at Middlesbrough and he was a real inspiration to us (as he had been throughout the entire project) as well as other ME sufferers we met there who had contacted the club to open their doors to us. A fantastic welcome from the club and another signed pennant as we left for our final two clubs. We finally finished at Leicester City (which we had moved from day four) and were thoroughly shattered but enormously delighted to have completed the challenge in what was just over 80 travelling hours. It’s an incredibly unfair and seemingly indiscriminate condition and we’re all passionately behind any event that sees a move towards a cure or better treatment. We targeted ourselves on reaching an audience of 10 million people which with the help of being featured on ITV news in 10 regions, BBC Radio 5 Live, the 30+ newspapers and over 70 clubs we feel that we have more than achieved this. Day five included a start at York City where someone at the club got wind of the club’s initial refusal to support us and he contacted us to apologise, taking matters into his own hands he The sheer volume of anonymous donations that have come in prove that there is a real clamour to get this illness properly researched and a Invest in ME (Charity Nr. 1114035) www.investinme.org Page 20 of 52 Journal of IiME Volume 8 Issue 1 cure/prevention found. We have another event to raise awareness in the pipeline (top secret) and we’ll do everything we can to support Invest In ME and bring the Rituximab trial to the UK. Just by the trial even happening we hope that it will open the door to more trials and biological research which can only be a good thing for Ian and the other 250,000 we hope will one day benefit. May 2014 If you’d like to find out more about our event please go to www.92in92.blogspot.co.uk –all photos, football club support and media features can be found here. To sponsor us please visit www.justgiving.com/teams/strobl “We’re pretty happy with the reach that we had with regard to highlighting the need for clinical research and feel that if we inspire just 100 people to select the charity as the beneficiary for their next sponsored event then that will be a fantastic achievement. What struck us as we recovered from the lack of sleep and rehydrated ourselves was that we’re all fit and well, the people that have supported us throughout the run up to the challenge and throughout all still have ME and need our help. The young children we met who suffered from the illness have left a lasting impression on all of us.” Invest in ME (Charity Nr. 1114035) www.investinme.org Page 21 of 52

Journal of IiME Volume 8 Issue 1 Letter from I consider this a manifesto for the ME/CFS community. These are my thoughts, after nearly five years of watching the anguish and the neglect that surrounds this disease. The manifesto states what I think should be done now. And “now” is an important word. There is a story that Winston Churchill, when he was very old and sick, summoned the gardener at his beloved country home in Kent, Chartwell, and asked him to plant an oak tree in an open space. The gardener, looking at his enfeebled employer, swallowed and said, “But, sir, an oak tree takes a hundred years to grow.” “Then you'd better plant it now, hadn't you?” said Churchill. During World War II, Churchill used this same execution imperative approach to work. Churchill used to stick little, pre-printed notes — long before the days of Post-it notes -- on his paperwork for staff that read, “Action This Day.” One of the first things that struck me about ME/CFS, when I started writing and broadcasting on the subject, was how slow the pace of progress was, even as the suffering suggested the need for immediate action. The second was how stingy public and private funding for research was then and is now. I want my friends and loves, who are in the grip of a relentless affliction, whose days are torn from the calendar of hell, to be cured in my lifetime -and I am 74. I want to be able to hold them as whole happy people; the people they were before they were struck down by an enemy they did not provoke, a monster they do not deserve, an unseen captor, a malicious jailer that takes daily life and makes it into a tool of torture and punishment. One year, the CFIDS Association of America was able to declare proudly that it had raised $2 million. The National Institutes of Health, a federal agency that should be pushing research, granted a paltry $5 million for ME/CFS in 2013. By comparison, in that same year, I learned that a consortium of foundations was sponsoring a green power marketing initiative at $6 million a year. I have spent nearly 50 years writing about federal funding for energy, science and technology, and the sums of money spent has been in the tens of billions of dollars. One company gets more than Invest in ME (Charity Nr. 1114035) www.investinme.org Page 22 of 52 America ME/CFS Manifesto Llewellyn King A ME/CFS Manifesto Invest in ME contacted Llewellyn King to ask for permission to republish this article – as it chimes so well with the views of the charity regarding progress, obstructions to progress, and the need begin sowing the seeds of change. Llewellyn King is executive producer and host of “White House Chronicle” on PBS, a columnist for the Hearst-New York Times Syndicate and a commentator on SiriusXM Satellite Radio. He is the co-host of ME/CFS Alert on YouTube. king@kingpublishing.com May 2014 Journal of IiME Volume 8 Issue 1 Letter from America $60 million year-in a year-out for nuclear fusion research -- and I see nothing wrong with that. But when I look at the federal funding for ME/CFS research, I am aghast: It is not funded at a level that can be expected to produce results. It is, to my mind, a crime against the sick; morally, if not criminally, indictable. To allow the scale of suffering that attends ME/CFS, without making research on the disease a national priority, is close to wilful neglect; an abrogation of the high purposes of Hippocrates' calling. Other governments are not free of guilt for the suffering – and the United Kingdom stands out among the many offenders. These governments have been seduced by the fraudulent blandishments of the psychiatric lobby. If a ME/CFS patient refuses to accept a psychiatric diagnosis, he or she can either be imprisoned or forced to suffer the insinuation that they are not physically sick, even if they cannot get out of bed. There are cases in Europe where patients refusing the prescribed psychiatric treatment have been imprisoned, as happened most recently to Karina Hansen in Denmark. The United States is experiencing a boom in natural gas production and the deployment of solar panels on rooftops. These successes are the manifestation of substantial research money committed in the 1970s, and sustained since then. Science needs certainty of support, both political and financial, to triumph. The key is sustained funding; a splash here and a dash there just won't do -- it won't do anything. ME/CFS researchers need to concentrate on their work, wherever that work takes them, free from the stress of insecure funding. ME/CFS deserves the level of effort that might lead to success. It is not getting it now, and it never has had it. It is appalling that Dr. Ian Lipkin, the highly respected virus hunter, is trying to raise $1.27 million through crowd funding to investigate the role of microbiome in ME/CFS. What we are seeing is a scientist forced to beg. Yet this fundamental research, with application for diseases beyond ME/CFS, is at the frontier of biomedical science. If we, as a nation, are to believe that we are in the forefront of science, we must be in the forefront of biomedical research as well as the forefront of computers, telecommunications, materials and physics. We almost humbled polio, and developed powerful drug therapies for AIDS. Other governments are not free of guilt for the suffering – and the United Kingdom stands out among the many offenders. We can transplant vital organs and gave hope to the leper. The advances came neither cheaply nor easily, but they have saved lives beyond counting and eased suffering beyond enumeration. Why not for ME/CFS? Why not? There is eloquence in the voices of the community. But they are widely distributed and, sadly, they fall mostly on ears of those who already know them — the sick, their families and their advocates. The voices need to be heard widely, need to be channelled and need to be focused. A million points of light won't do it. A laser, a great beam, will do it. There are three principal reasons why these voices are not heard by those who need to hear them: 1. ME/CFS is a hard story for the media to grasp. 2. ME/CFS has no celebrity doing what Elizabeth Taylor did for AIDS, what Jerry Lewis did for Multiple Sclerosis, or what Michael J. Fox is doing for Parkinson's Disease. 3. ME/CFS has no presence in Washington. Of the three, the last is the most critical to act on, and it is the one that would produce the most measurable result. Simply stated: Being on the ground in Washington every day is the essential step the community has to take. May 2014 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 23 of 52

Journal of IiME Volume 8 Issue 1 Letter from America To get results in Washington, you need to-see-andbe-seen in the daily life there. Letters and petitions do not have nearly the impact as a Washington denizen talking to a decision-maker in person. Happily this would amount to one very visible person, who strolls the halls of Congress, lunches at the clubs and restaurants, like the Cosmos or Metropolitan clubs, or the Monocle Restaurant on Capitol Hill. Once, I was mentioned in the Wonkette blog because I was spotted entering Bistro B, a favourite restaurant of the powerful, and those who think they are powerful. If your children attend one of the power schools, like St. Alban's or Sidwell Friends, contacts can be made and deals can be done at the events. A friend of mine enlisted President Bill Clinton's help for a cause because their children went to the same school. It may strike you as banal, but it is the Washington political game. Learn to play it. Washington is a society of people who are impressed with each other. It is important to be known. If you are invited to the annual White House Correspondents' Association or Alfalfa Club dinners, you are known. The next step is to be known for ME/CFS advocacy. Once known, the perfect advocate/lobbyist will morph into a resource, a voice for others in Washington: a source of information for congressional aides trying to understand the budget requests of agencies, and a source of information for reporters writing about diseases of the immune system. A voice in Washington puts pressure on government agencies to do the right thing, and on members of Congress to authorize and appropriate money. The advocate/lobbyist can learn, through the hearing process, about the diligence and transparency of the agencies and the quality of their operations; to see if they are doing the job or treading water, to see how transparent their operations are and the quality of professionals operating programs. Another salutary source of pressure in Washington is the press corps. It covers not just politics but also the functioning of government. The pinnacle of power in the corps are still The Washington Post, The New York Times and The Wall Street Journal. But the news agencies, The Associated Press, Bloomberg and Reuters, followed by a veritable media army that cover politics and programs, including Politico, The Hill, Roll Call, National Journal, and the specialized medical publications also play important roles. Fifty years ago, the center of media activity was New York. Now it is Washington. A professional advocate for ME/CFS needs to cultivate the media and to be comfortable with the currency of Washington and to trade in it. That currency is information. Washington is a great information market. The successful lobbyist/advocate is, by the nature of the city and its functioning, an information broker. The sums of money that will be needed to accelerate research cannot be calculated and could be very substantial. Research funding, above all, needs to be sustained at predictable levels. The pharmaceutical industry figures that a new drug can cost upwards of $1.2 billion. I mention it only to hint at the vast amount of money needed for drug research and development. How much ME/CFS will need and for how long is an existential question? Money stimulates research, attracts new young minds to the field and leads to success. Right now, there is so little money funding so few researchers in ME/CFS. In the United States, that success may be a long time in coming – too long for those for whom today will be a living hell, as yesterday was and tomorrow will be. I figure that for as little as $1 million, a start toward a Washington presence can be made. That would Invest in ME (Charity Nr. 1114035) www.investinme.org Page 24 of 52 May 2014 Journal of IiME Volume 8 Issue 1 Letter from America cover one advocate/lobbyist, one office and one assistant for one year; not a smidgeon of attention from a giant lobbying firm, but a dedicated ME/CFS standard-bearer. Funding should grow within a year, as the ME/CFS cause comes out of the shadows. I operated a small business in Washington for 33 years, and I am confident that a new ME/CFS presence there will reverse the disease's funding fortunes at NIH, increase media awareness, and cause the big foundations to sit up and take notice. It would give ME/CFS the kind of presence that other diseases with active advocates – COPD, ALS, MS and others -- have in Washingon and the nation. If this is not done the government will continue to ignore the case for ME/CFS. Worse, the new billionaires who are beginning to throw real money into biomedical research will not know about ME/CFS. It will be hidden in plain sight much as it has been from the wider public. ME/CFS needs a place on the national agenda if it is to be understood and cured in reasonable time, and if the very best minds are to be attracted to the task and to stay with it. That Churchill oak needs to be planted now, and in sight of the U.S. Capitol. May 2014 Can I Tell you about ME/Chronic Fatigue Syndrome? This is a book by Jac Rayner. IiME chairman Kathleen McCall has reviewed the book for the publisher and included the following comments - "This book is very clear and easy to read. It is a great resource that can be used by ME patients and their carers to explain and inform others what it is like to be affected by ME/CFS. Not only children but adult relatives, friends and teachers would learn a great deal from this book." Available on Amazon at this link http://www.amazon.co.uk/tellabout-Chronic-Fatigue-Syndrome/dp/1849054525 Jac's book is also to be translated into Norwegian. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 25 of 52

Journal of IiME Volume 8 Issue 1 May 2014 Arctic Marathon - Fundraising for Invest in ME Marathons are no mean feat to accomplish - for anyone. An extreme way of raising awareness of ME and much-needed funding for biomedical research into ME has now been set in motion by Mike Shepherd. Mike is taking on the North Pole Marathon. As Mike writes on his web site -This is the challenge of a lifetime and it is the result of my daughter having ME since September 2008. I have seen first hand how damaging ME can be to a person's life, their prospects and their family http://www.shepherdfitness.co.uk Donations and sponsorship can be made/discussed with Mike using the web link above. MY A-Z OF M.E. (Myalgic Encephalomyelitis) by Ros Lemarchand Do you feel that no one understands you? Do you feel alone with this illness? Do you find it hard to express how you feel? Ros Lemarchand's book of poems about life with M.E. is a must for you. MY A-Z OF M.E. (Myalgic Encephalomyelitis) is available in both Kindle and paperback editions http://www.amazon.co.uk/.../dp/1492735116/ref=sr_1_6 Ros also has a YouTube video about the book - http://www.youtube.com/watch?v=4GotabFQVjI Invest in ME (Charity Nr. 1114035) www.investinme.org Page 26 of 52 Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes by Steven Tracy1 Following on from our 2009 article by the same author Illustrating the complexities of translating basic research into clinical practice For some years now Invest in ME has been trying to interest other researchers to work within the areas of ME – partly to mainstream ME research and allow it to overcome the misinformation that has been allowed to be propagated over a generation, but also partly to use the great experience from other research which must be brought in and applied to ME research in order for progress to be made. The link between enteroviruses and ME has existed for many years but the lack of funding from establishment organisations has forced this to be banished to the sidelines, with just the work of Dr John Chia keeping alive the research in this area. Invest in ME has had Dr. Chia presenting at many of our conferences. We have also had Dr Nora Chapman from University of Nebraska presenting at our conference. Professor Steven Tracy is an expert on diabetes and enteroviruses. He wrote an article for IIME – Human Enteroviruses and Chronic Infectious Disease He has kindly given us permission to reproduce this article in our Journal. This is a good article to illustrate the amount of research that has gone into understanding the role of enteroviruses in T1D. We could not agree more with the conclusion of this article. Type1 Diabetes Our laboratories have been working with the CVB since the early 1980s to understand how the viruses induce human inflammatory heart disease (myocarditis). It was therefore a natural extension of our work to examine the putative connection between CVB infection and type 1 diabetes (T1D) onset. We use the nonobese diabetic (NOD) mouse as the animal model in which to study T1D onset. This is a well-established model used throughout the world for T1D research and one which is very useful for studying aspects of the virus-host relationship. Female NOD mice develop T1D at an incidence of between 70-100% of mice by 6 months of age: this means that for every 10 mice studied, 7-10 will naturally develop T1D by 6 months of age. Examination of the pancreatic islets in these mice shows that when mice are very young, no insulitis is apparent but by 6-8 weeks of age, insulitis has started to develop. Insulitis is inflammation of the islets, the places in the pancreas where beta cells are found. Beta cells produce insulin. When enough beta cells are destroyed, T1D occurs. Islet Invest in ME (Charity Nr. 1114035) www.investinme.org Page 27 of 52 1 Professor Steven Tracy Ph.D. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha NE 68198-6495; stracy@unmc.edu; 402-559-7747 Primary research interest: Molecular biology and pathogenesis of the group B coxsackieviruses since the early 1980s http://www.unmc.edu/pathology/type 1_diabetes.htm

Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes inflammation is autoimmune, which is to say, it is a naturally occurring inflammation that targets the host itself. By 12-15 weeks, insulitis is extensive in nearly every islet and it is at this age that the mice begin to develop outright T1D. This is easily observed by measuring the level of glucose (sugar) in the mouse' urine: when normal, there is no glucose detectable but once diabetic, the mice shed more than 20 grams per liter of urine (equal to about an ounce per quart). tube, then resurrect infectious virus in cell cultures, and use such viruses to study their biologies. This is a technique called reverse genetics and uses another key technique, molecular cloning. We have discovered several new aspects of the virus/T1D relationship using the mouse model, all of which are consistent with that which is known from others' human studies. (A picture of a NOD mouse pancreatic islet that is dying due to the infiltration of autoimmune lymphocytes. The pathogenic lymphocytes are the dark cells surrounding the interior, lighter area, which is the remaining intact islet, still able to produce insulin. But not for long...) Our laboratory has a collection of different CVB strains for its studies. A serotype of CVB classifies a group of CVB; we use predominantly the CVB3 because we have spent most of our research characterizing this specific serotype. However, many different enteroviruses are likely able to cause T1D in humans, not just the CVB. It is often mentioned that only CVB4 causes T1D: this is simply not true. Now, within any CVB serotype, there are numerous strains of viruses, which all differ genetically from each other. You can think of a virus strain as a variation on a single theme. Our use of the CVB3 strains has permitted a deeper understanding of how relatively minor variations in the viral genetics can have huge impact on the outcomes of virus infections. We have derived molecular clones of several CVB3 genomes so that we can manipulate the viral genetic stuff in the test 1. The CVB protect diabetes prone mice from developing T1D. Because the CVB are often mentioned as primary infectious causes of human T1D, we asked the simple question: if we inoculate the virus into young, healthy NOD mice, what happens? Does T1D immediately occur? The answer? No! Such CVB-inoculated mice enjoyed a significantly diminished chance of developing T1D compared to control mice (mice which were not inoculated with virus and develop T1D normally)[1]. In some cases following CVB inoculation, no mice developed T1D through 10 months of life. This finding showed that there is no simple link between these viruses and T1D. The NOD mouse is very prone to developing T1D: these data showed, however, that a common virus infection, one linked to human T1D onset, could actually protect these mice. There is the criticism that nearly any treatment of NOD mice will suppress T1D and in large part, this is true. However, this criticism ignores the important fact that alone of all the treatments experimentally used in NOD mice to suppress T1D, inoculation with CVB represents a test of an agent suspected to be the cause - not the cure - of T1D. Our work demonstrated that, in effect, we can vaccinate NOD mice so that they do not develop T1D. This in turn suggests the intriguing possibility that one might be able to be vaccinated against developing T1D. Indeed, we strongly believe that T1D was rare in humans before about 100-200 years ago, simply because humans were commonly exposed naturally to numerous enterovirus infections as a natural part of growing up in a world of contaminated water and poor or absent hygiene [1]. [This was recently reviewed: Enteroviruses, type 1 diabetes, and hygiene: a complex relationship. S. Tracy et al., Reviews in Medical Virology 20:106-116, 2010.] Invest in ME (Charity Nr. 1114035) www.investinme.org Page 28 of 52 Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes 2. The CVB do not invade and destroy islet cells of healthy mice. Viruses generally destroy cells by direct infection: viruses enter a cell, take it over, replicate themselves and in the process, kill the cell, releasing newly-created progeny virus to repeat this process. If enteroviruses such as the CVB are to be considered causes of T1D, then - most simply - the viruses must be able to destroy the insulin-producing beta cells in the pancreatic Islets of Langerhans. We observed that no virus was detectable within the islets of young, healthy NOD mice, even though we could detect the receptor protein that the CVB uses to gain entrance to cells. Receptors are like doors to rooms: a virus has to have a receptor in order to gain entrance to a host cell. Thus, even though we showed the receptor is present in islets, the 'door' appears somehow barred to effective CVB entry. This observation was consistent with our failure to observe that CVB cause T1D in young, healthy mice: if the virus cannot kill islet cells, then one would suspect the virus cannot induce T1D, either. In fact, this is what we observed. mechanism called the innate immune response and production of specific antiviral protein molecules called interferons. Using a CVB3 strain that we developed in the laboratory which was bioengineered to produce a mouse immune protein (cytokine) called interleukin-4 (or IL-4), we showed that this virus did gain entry to islets in young, healthy NOD mice. This experiment was important for two reasons. One, it showed that the expression of the virus receptor meant that CVB could gain access to islet cells. While this was logical, it had not been shown before in the mouse itself, only in a special condition (cell culture). Secondly, it showed that by changing the local microenvironment of the islet by the virus-induced production of IL-4, the virus could replicate successfully in the islets. We also noticed two more things of importance. One, this type of virus infection caused no insulitis: the virus which produced IL-4 did not induce the mouse to attack the islets with its anti-viral immune response. Two, mice inoculated with this strain of virus had a better chance of never developing T1D than mice which did not get the virus infection. This surprising finding meant that despite intraislet replication of this bioengineered virus, this group of mice developed fewer cases of T1D than did mice without the virus injection. This observation showed that in some cases, virus infection of islets does not lead to more T1D or rapid onset T1D and therefore, the story was not quite so simple [2]. (This is a picture of a human pancreatic islet that was stained for the expression of a protein, called CAR, the receptor which the coxsackie B viruses require in order to enter a cell to replicate. The dark brown is the islet to which an antibody against CAR is bound. Clearly, human islets, like mouse islets, express CAR and so, should be able to be infected under the right circumstances.) 3. However, if the islet microenvironment is altered in specific ways, CVB can enter the islets. Other workers have suggested that the islets defend themselves against virus entry through a Islets in older NOD mice naturally become massively inflamed with autoimmune lymphocytes. This kills beta cells and the islet then loses the ability to produce insulin. Here you can see the residual small areas in such an islet in which Invest in ME (Charity Nr. 1114035) www.investinme.org Page 29 of 52

Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes coxsackie B virus is replicating (shown by the brown color in the upper left corner primarily). The light blue in the remaining area are pathogenic autoimmune lymphocytes. Virus only replicates in the remaining healthy tissue, thus speeding T1D onset by killing insulin-producing beta cells. 4. CVB infection of older, prediabetic mice can, however, trigger T1D, an event linked to the alteration of the islet microenvironment. Older, pre-diabetic mice show massive insulitis in nearly every islet and not surprisingly, soon begin to become sick with T1D due to loss of insulin production. This naturally occurring, genetically driven autoimmune disease kills cells in the islets, including the beta cells, a process that leads to loss of insulin production and thus, T1D onset. This inflammation of islets represents a real change in the biology of the islet, a massive naturallyoccurring change in the islet microenvironment. We therefore asked another simple question: if CVB does not trigger T1D in young mice but instead, protects them, what happens in mice that are about to develop T1D anyway? We knew that IL-4 could let virus replicate in islets: would inflammation permit the same? The answer was yes! Young NOD mice are analogous to humans who are genetically predisposed to developing autoimmune T1D but have yet to do so: they may have little or no insulitis present, just like young NOD mice. Based on our results, we suggest that humans with little or no insulitis, are at low risk from CVBinduced T1D. This is because we have shown that CVB (or in humans, we believe other enteroviruses as well) need to have insulitis in place in order to be able to successfully replicate in islets. However, it is quite difficult to say how advanced insulitis is in a human being; even presuming one knows that one is at risk. Humans are not like mice in a key respect: these mice are highly inbred and so, their own genes drive them to develop T1D in a regular, predictable fashion (the very thing that makes them so useful for this research). Every human is genetically distinct and has a different schedule for developing autoimmune insulitis (if indeed they ever do and of course, by far most do not). By modeling this situation in mice, we mimic the case in humans where a virus infection occurs at a time closely prior to the time when that person would develop T1D anyway from his/her own autoimmune disease. In mice, this is a specific age; in humans, it could be any time. What we found was that pre-diabetic mice - i.e., mice with ongoing insulitis - when inoculated with a virulent strain of CVB, rapidly developed T1D, much faster than the rate of development observed in the control mice in which it is controlled only by the autoimmune disease. When we examined the islets of such mice, we discovered the presence of virus (as shown above). That virus was found replicating within the islets and associated with beta cells prior to the onset of T1D meant that the virus replication was denuding the mouse of intact beta cells, consequently causing early onset T1D[2]. (Stained bright red is an isolated mouse pancreatic islet. It is still associated with some residual pancreatic tissue.) 5. Findings in mice and how they relate to human T1D: connecting the dots. The very great majority of enterovirus infections in humans never trigger T1D, even though enterovirus infections are common in the US from spring through the summer into the fall months and enteroviruses are encountered worldwide. So, if human enteroviruses are causes of human T1D, how is this explained? Using information we have gained by asking key questions of our mouse model and correlating clinical reports of enterovirus-linked T1D, we suggest that there are several reasons. It is very likely that only certain enteroviruses can induce T1D or for that matter, act to protect one from developing T1D. Clearly in NOD mice, the CVB can either protect mice from developing autoimmune T1D (when they are exposed to the virus when young) or CVB can rapidly trigger T1D Invest in ME (Charity Nr. 1114035) www.investinme.org Page 30 of 52 Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes onset (when older mice with insulitis are exposed to the virus). The CVB belong to one of four human enterovirus species, denoted A-D. Only human enteroviruses of the B species (or HEV-B), and this includes the CVB, have been associated with T1D onset. Poliovirus, for example, which is a species C enterovirus and to which nearly everyone in the world has been exposed (mostly now by clinical inoculations but prior to this due to wild-type infections), has had no impact on T1D incidence. Thus, we propose that the HEV-B species are the key players. Now, for an enterovirus to 'suddenly' trigger T1D (when T1D occurs shortly after or during, for example, a 'cold' or 'flu-like' illness), we believe the islets have to already be significantly experiencing extensive insulitis through one's own autoimmune disease. That is to say, insulitis has to be present. This might normally, in time, lead to T1D onset or it might not. From the NOD mouse model, we know that islets in young mice that are not inflamed cannot be normally infected by CVB. This does not have to do with the virus receptor, the protein on the cell surface which the virus uses to enter cells. The CVB receptor is well expressed in young and older mice. So, when mice are young and have no insulitis yet, the islets cannot be infected, but when the mice are older and are developing insulitis, CVB can infect remaining healthy islet tissue and if the viral damage is sufficient, T1D ensues shortly after the virus infection. However, the overwhelming majority of people do not have insulitis. Therefore, we postulate that because most enterovirus infections in humans do not induce T1D, by far most people do not have insulitis. Therefore, this is consistent with the observation that the very great majority of enterovirus infections do not trigger T1D onset. The host (humans or mice) have to "work" with the virus to cause T1D. That is to say, without hostdriven (genetically determined) insulitis, the enterovirus cannot replicate productively in beta cells and cause T1D. Viruses are opportunists and will replicate wherever they can. In the case of a normal (not inflamed) islet in the mouse pancreas, CVB can enter cells (because the receptor is present) but cannot successfully replicate. We hypothesize that this is also the case in human beings. Only when the islet is attacked by the host's autoimmune disease do islets' defenses fall, permitting the virus to replicate productively in and kill islet cells. We know this happens in mice and we postulate this is the case in human beings. But this is a contested point. Human islets, isolated from pancreas and placed in culture, can replicate enteroviruses: such infections can kill beta cells in these cultured islets. This observation suggests that human islets might be infectable in the body, whether or not they are inflamed due to the autoimmune process. Currently, this remains an open question. We also know from our work in mice, that the enterovirus infection has to be due to a strain that replicates quickly in the pancreas. Just like some humans can run faster than others, some virus strains can replicate faster than others (that is, some virus strains make more progeny virus in a shorter length of time than others). We have characterized strains (or variants) of CVB serotypes that replicate more rapidly and to higher titers, than other strains. To initiate T1D in NOD mice, we have shown that as few as 50 virus particles of a rapidly replicating strain of CVB3 can induce T1D, whereas more than 1 million virus particles of a slowly replicating strain are needed to induce T1D. Therefore, the average dose needed to successfully infect a mouse and to cause T1D with a rapidly replicating strain is far lower than for other strains. However, these rapidly replicating strains of enterovirus (which are generally termed 'virulent' strains, due to their capacity to induce disease easily in disease models) which are capable of causing severe disease, circulate relatively rarely. Most CVB strains, for example, do not cause serious disease such as myocarditis when assayed in mice. And even though all CVB strains replicate well in pancreas (thereby showing that these viruses have a predilection for replicating in pancreas tissue), this does not mean, that all are capable of replicating sufficiently well in islets to trigger T1D. The bottom line is this: the average (usual) enterovirus infection is due to a poorly virulent strain at a low dose, two factors that along with the requirement for ongoing insulitis, lower the odds dramatically for a T1D-inducing islet infection. We also know that enterovirus infections induce protective antiviral immunity in people. This is the same principle by which the poliovirus vaccines have worked so well: inoculation with the vaccine strains of poliovirus induce an immunity that Invest in ME (Charity Nr. 1114035) www.investinme.org Page 31 of 52

Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes dramatically suppresses the replication of polioviruses when the human again is infected, thereby keeping that individual safe from crippling polio. There are more than 100 known enterovirus serotypes and each serotype induces immunity in a person that will protect that person from disease caused by future exposure to that same serotype. This means that if one has already experienced an infection by a specific serotype, for example CVB3, one is immune to disease from all variations (strains) of CVB3 when next one may encounter it. However, type-specific immunity does not protect one from infection by a different serotype; protection is serotype-specific. To continue this example, therefore, CVB3 immunity will not protect one against infection by a strain of CVB1 or CVB4, for instance. Therefore, in order to trigger T1D in humans, an ebterovirus must infect a person who has no pre-existing immunity to that specific virus. So in addition to everything else discussed above, one must also experience a new enterovirus infection, against which one has no immunity, in order for T1D to be triggered. From this argument -knowing the various requirements which we can postulate to exist based on our current knowledge - one can see that having T1D initiated by a enterovirus infection such that it 'suddenly' occurs, would be a rare event. In order for T1D to be triggered by a enterovirus infection, therefore, a variety of specific conditions have to be met all at the same time: (1) the right enterovirus species (not all can do this, insulitis needs to be present (and most people likely have none), (2) the virus strain should be one that replicates rapidly (because the average natural infectious dose is very low, the virus has to generate enough progeny virus to cause the damage before the host immune response suppresses the infection), (3) the virus infection must be one never before encountered by the person (otherwise, that person is immune to the virus), and (4) the person's islets must have insulitis ongoing (in order to create the environment that supports productive enterovirus replication in the islets). If T1D onset triggered by an enterovirus requires all these requirements, one can understand why the disease is rarely caused by an enterovirus. 6. What does all of this mean for a cure for T1D? Finding a cure for existing T1D or a preventive measure against as-yet-to-occur T1D are two vital missions. Current work suggests that newly diagnosed T1D patients may profit from an antibody treatment that reduces pathogenic T cells, permitting the patient's own regulatory (good) T cells to expand in number to protect the islets from damage. This is wonderful news. However, we must also stay focused on the issue of preventing T1D completely. We know the value of vaccines: polio, rabies, measles, mumps, rubella and more, all are diseases readily countered and suppressed by vaccine development. Properly designed vaccines work. However, the relationship between enterovirus infections and T1D biology is complex as the foregoing arguments have shown. We can largely prevent T1D in NOD mice with a single injection of CVB at an early age. This means we can prevent the host's own autoimmune disease from killing the beta cells and causing T1D - in most cases. There are those who argue that NOD mice are not a good platform for designing approaches to counteract or suppress T1D, and in most cases, this criticism is valid: nearly every approach that has functioned well in NOD mice does not function in humans. However, human enteroviruses are human viruses and we know they are involved in human T1D. That they mimic much of what we know or surmise occurs when studied in the NOD mouse, is strongly inferential data in support of the hypothesis that certain human enteroviruses can either protect from, or induce, T1D. Enteroviruses are 'a bird in the hand' argument: we know they are involved in human T1D. So while we wait for clinical studies to produce lists of potential infectious candidates involved in the T1D etiology, we ought to be moving ahead to understand how enteroviruses are involved in the disease process. In the final analysis, no matter what list of potential pathogens that are found to be suspected of causing T1D, the human enteroviruses will be at the top of the list. Waiting is not an option anymore, now that we know this story. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 32 of 52 Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes Can a vaccine be created against enteroviruses which will eliminate T1D and perhaps all other enteroviral diseases as well? Good question. Vaccines usually target at most a few viruses; the polio vaccines targeted three types of poliovirus, for example. A major developmental problem for T1D is that at present, we do not know which enteroviruses cause T1D: there are at least 100 known and many more uncharacterized human enteroviruses. This is far too many to target for a vaccine, especially if some or many play no role in the disease. For a classical vaccine approach to be considered, we must determine which enteroviruses cause T1D, and determine how the viruses cause the disease. That enteroviruses in species B are likely the key players, suggests the relevant field has been winnowed significantly already. Research on this topic should be actively encouraged. Of course, there is also the question of how many cases of T1D are indeed caused by enteroviral infections. If enteroviruses do not cause many cases, no company would ever make a vaccine because the market would be so small. That is a hard fact: cures are dependent upon the free market. We know that CVB and other species B enteroviruses are involved in T1D induction. However, work is required to identify the viruses that are found in the pancreas tissue of diabetic humans. That said, we have been speaking so far about a classical vaccine: one which develops protective antiviral immunity against specific virus(es) serotypes that protects one against disease caused by subsequent exposure to the same virus(es) serotypes. There are potentially other approaches to vaccination, ones which may not involve the generation of protective immunity but instead, a generic or pan-enterovirus immunity. The possibility exists that one can induce the immune system to recognize enteroviruses in general, such that when it comes up against an actual virus infection, the immune response will be much more rapid. That may be all that is required and that would be rather readily accomplished. Such an approach is not a "silver bullet" like, for example, the polio vaccines; such an approach would offer a much better chance at suppressing a potentially T1D-causing infection but might protect all people. This, too, is worthy of research support because of its immense potential, not only for T1D but for viral diseases in general. In fact, we now have a large amount of data demonstrating that we can actually vaccinate NOD mice in this way and protect them not only from their own autoimmune T1D but also from CVB-induced T1D later in life. Therefore, we believe that the potential for this approach is huge. In one scenario, using standard and wellunderstood (from the poliovirus vaccine experience) technologies, a safe, protective antienteroviral vaccine could be devised. While it would not completely protect the individual from virus disease in the same manner that the polio vaccines prevent poliomyelitis, such an approach could slow the infection sufficiently so that the immune response would have a vital few extra days to respond and clear the infection. Again, data from the mouse model indicates this slowing of new infections is tightly linked to lowering the chance of developing virus-induced T1D. The goal should always be to eradicate the disease, while an acceptable compromise is to greatly reduce the incidence of the disease. To focus primarily on treating people with the disease is unacceptable. 7. The importance of basic research to help find the cure to T1D. That which we understand about human enteroviruses and their impact upon T1D development has been derived from basic research. As scientists and citizens, we are driven by the need for a cure, but we must temper our approach as we know that if we chase off down a promising but blind alley, we will waste valuable time. Ignoring basic research while emphasizing only clinical palliative efforts will never eradicate or suppress the disease. The goal should always be to eradicate the disease, while an acceptable compromise is to greatly reduce the incidence of the disease. To focus primarily on treating people with the disease is unacceptable. 1. Tracy et al. 2002 J Virology 76:12097-12111 2. Drescher et al. 2004 Virology 329: 381-394 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 33 of 52

Journal of IiME Volume 8 Issue 1 PERVERSELY DARK May 2014 A new film from Norway – about severe ME – from Pål Winsents. It is perverse that many formerly able bodied persons have to lie in complete darkness and isolation. And, indefinitely so. In each of their respective rooms, in two different places around the greater Oslo, Norway area, lie ME/CFS patients Kristine and Bjørnar sequestered in protective total darkness. In both cases, the tiniest amount of mental, social, or physical effort is detrimental and can completely overwhelm their bodies’ minimal energy reserves and function. Consequently, only health care assistants and immediate family are permitted whispered access into their isolation in order to feed, medicate, and tend them. Film maker Pål Winsents and Fenomen Film remarkably were given access into these patients’ dark realms and permitted to ‘syphon’ some of Kristine and Bjørnar’s stories and their precious infinitesmal life energy for the making of this important and unusual film. While medical experts in Norway and internationally debate and test their many theories in attempts to understand and discover a cure for ME/CFS in order to get its patient group up and out into light and life again, many such lives whither way as the many years roll by. During the six years of filming Kristine and Bjørnar, the Fenomen Film crew was astounded by these patients’ non-despairing fortitude, courage, and level of intellectual reflection despite the lack of proper stimuli or external battery life recharging them when confined to be in the dark with a great unknown. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 34 of 52 Journal of IiME Volume 8 Issue 1 Without giving away too much, Perversely Dark is also a film about love, perseverance soccer, presents, and Christmas songs, as well as a human transformation one would not believe it if not seen with one’s own eyes. Director and film company Perversely Dark, the documentary film by director Pål Winsents from Norway and Fenomen Film, recently premiered at Victoria Movie Theaters in Oslo, Norway on May 12 with 350 people. And the premiere was one of the headlines on National TV Broadcaster the same evening. Perversely Dark follows the somber sequestered lives of two ME/CFS patients and their survival struggle to regain health and activity. Perversely Dark is Pål Winsents’ ninth documentary film and his second thematic ME/CFS May 2014 film uniquely exploring the lives of this little known patient group while bringing their stories and voices into society’s light. His first ME/CFS themed film Få Meg Frisk (Heal Me!) featured partially functioning Anette Gilje, ME/CFS patient and former General Secretary of the Norwegian ME Association, through her desperate journey for treatment and proactive steps. In Perversely Dark Pål Winsents ventures even further and captures the anguishing worse case stories of two fulltime ME/CFS bed ridden patients and their families’ struggles over a six year period in which time ME/CFS patients flounder in the unknown about what is happening to their bodies while without treatment or cure available. The film will have English subtitles added. http://www.syktmorkt.no/ Invest in ME (Charity Nr. 1114035) www.investinme.org Page 35 of 52

Journal of IiME Volume 8 Issue 1 IiME Research Projects UK Centre of Excellence Executive Summary for MPs This is a summary of the current status regarding Invest in ME’s proposal for a Centre of Excellence for ME Research and Treatment STATUS UPDATE May 2014 Background ° Seriously inadequate standard of medical care for ME patients in UK ° Very little funded UK biomedical research into condition ° Confusion between ME and chronic fatigue has led to unscientific research and ineffective treatment regimes ° NHS resources focus on symptom management therapies whilst underlying condition left untreated ° Medical professionals lack understanding of and training in ME -serious risk of mis-diagnosis and missed diagnoses ° International research has revealed much about biomedical basis of ME ° ME now identified as both highlighted area and high priority by MRC ° ME is leading cause of long-term absence from school due to sickness for students and teachers ° ME is recognised by the Department of Health as a chronic neurological illness Project Outline Biomedical research and treatment institute for ME in East Anglia, based in Norwich within the Norwich Research Park utilising and based on university and institute facilities and resources Hub of scientific and clinical excellence for ME within Europe Research arm to be funded initially by private/charitable donations leading to applications to major public research funding bodies such as the NIHR, NIH, MRC etc. Clinical diagnosis and treatment arm to be funded by CCGs (formerly agreed with Norfolk PCT) Service Commissioning ° GP referral, via normal NHS channels ° Consultant physician to diagnose patients according to international scientific criteria ° Based at Norfolk and Norwich University Hospital, subject to agreement ° GPs with special interest to be linked to Institute ° Treatment of patients based on up to date biomedical research findings ° Hub and spoke model: dissemination of expert knowledge to GPs and ME clinics nationwide ° Out of area referrals included ° Correctly identified patient cohorts considered for Institute research projects ° Training opportunities for medical students and other consultants, nurses etc. Invest in ME ° UK charity campaigning for biomedical research and treatment of ME ° Founder member and current Chair of European ME Alliance ° Organises annual international CPD-accredited international ME conference ° Organises annual international research colloquium ° Allied to a patient led campaign called Let’s Do it for ME to raise funds for Invest in ME research ° Has initiated UK gut microbiome project to study ME as well as a UK rituximab clinical trial ° Holds worldwide contacts with ME organisations, physicians and researchers Research ° Based at Norwich Research Park, including University of East Anglia and Institute of Food Research and utilizing other institutes such as The Genome Analysis Centre ° Advanced fundamental research, initially using virology and immunology ° Key component: accurate definition of patient cohort, giving scientific validity to results ° Translational research -potential for direct patient benefit Invest in ME (Charity Nr. 1114035) www.investinme.org Page 36 of 52 May 2014 Journal of IiME Volume 8 Issue 1 ° Dovetails with national identification of ME as priority area (NIH initiatite and MRC highlight notice) ° Initial projects: “A role for a leaky gut and the intestinal microbiota in the pathophysiology of myalgic encephalomyelitis” The majority of the immune system can be found in the gut and it is therefore highly desirable to study the gut microbiota in ME patients. The gastrointestinal tract contains a microbiota consisting of a vast number of bacteria and viruses ° Includes cooperation with other national/international research facilities (network already in place) Benefits ° Unique opportunity to establish European hub of scientific and clinical excellence ° Attraction of international interest and research funding to East Anglia ° Early and correct diagnosis ° Establishment of clinical trials ° Development of effective treatments, leading to highly significant public savings ° Hub and spoke. model to address seriously inadequate levels of clinical service for ME in East Anglia and nationwide ° Development of network of domiciliary services to support severely affected patients (currently seriously neglected) ° Savings on existing consultant referrals and staff -ME examination focused in one area ° Financially viable – Institute can start small and grow as further funding becomes available Current status ° All elements of the Institute model are ready to be put in to place with the exception of Norfolk May 2014 and Norwich University Hospital, which has previously declined to provide a service locally as they do not feel that they “can provide a satisfactory high quality service on the basis proposed” – despite offering no service currently to ME patients ° The healthcare reforms have removed the promise made by Norfolk PCT to perform full examinations on ME patients by a qualified consultant. This now has to be renegotiated with CCGs ° The charity met with one CCG head and Dr Martin McShane – NHS Commissioning Board Authority, Director for Improving the quality of life for people with Long Term Conditions ° Dr Amolak Bansal from Epsom and St Helier CFS clinic in Surrey is providing accurately diagnosed patients for research purposes. He is involved already in the research funded by the charity ° The Foundation project at IFR/UEA examining the gut microbiota in ME patients started in October 2013 ° We have been discussing with a paediatrician at N&NUH to become involved in ME and gut microbiota research at IFR/UEA and the charity is exploring that possibility Expansion of Scope In order to augment the concept of a Centre of Excellence for ME the charity has initiated other research to expand the scope of research and form a strategy of international collaboration in biomedical research of ME. Rituximab Clinical Trial Following the charity’s research meetings and cooperation with European ME groups and researchers, especially the Norwegians, an intent was made in 2012 The beginnings of a clinical trial of the rituximab drug for ME where a multi-centre study is about to begin. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 37 of 52

Journal of IiME Volume 8 Issue 1 ° Jonathan Edwards, Emeritus Professor of Connective Tissue Medicine at UCL became the charity’s clinical trial advisor in July 2013 ° A study looking at B cells in ME patients is ready to start at UCL in London ° Fundraising is ongoing for a clinical trial to treat ME patients with rituximab, a monoclonal antibody used to treat certain types of cancer. ° Over £300K has been raised so far of the initial target of £350K and UCL has expressed interest in performing such a trial ° Professor Edwards has been working with the Norwegian Bergen researchers and the charity set up a visit to Bergen in September 2013 Hypothalamus Study ° A study looking at antibodies binding hypothalamus has been accepted to be performed by Dr Bansal at St Helier and Epsom NHS Trust Hospital Invest in ME is therefore asking Norfolk MPs to engage actively with this project with a view to securing this final, and vital, elements of the project. Further details: Invest in ME email: info@investinme.org FURTHER READING University of East Anglia http://www.foh.uea.ac.uk Institute of Food Research http://www.ifr.ac.uk Norwich Research Park http://www.nrp.org.uk/cms.php?pageid=1 Norfolk and Norwich University Hospital http://www.nnuh.nhs.uk TGAC - The Genome Analysis Centre http://www.tgac.bbsrc.ac.uk EDP News Story http://www.investinme.org/Medianewspapers.htm FAQ September 2011 http://bit.ly/180Iod0 One of Sue's sons has been severely affected by M.E. and other related conditions for many years. Her book has ISBN code 978-0-9574948-0-0. Sue was interviewed by Kath, at Wythenshawe local radio, on her programme, 'Disability Matters'. As a result of her suggestion, I contacted the Royal National Institute for the Blind, who are now making a large-print version of the book, and when funds allow, a Braille version! Sue's MATRIX slot is here - click here May 2014 Rafi Brown and the Candy Floss Kid Sue Stern has raised over £1000 by taking a MATRIX slot and donating proceeds to IiME from sales of her children's novel last year - just a year ago. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 38 of 52 Journal of IiME Volume 8 Issue 1 May 2014 PRESENTERS at the 9th INVEST in ME INTERNATIONAL ME CONFERENCE Bios and Abstracts from the presenters at IIMEC9 Conference Chair - Dr Ian Gibson Former Dean of Biological Sciences, UEA Dr Ian Gibson, former Labour MP for Norwich North, worked at University of East Anglia for 32 IIMEC9 Abstract - Key Note Speech People with ME may rightly feel that their illness has been neglected by science. However, this ‘neglect’ may in part simply reflect just how difficult a scientific problem ME poses. To get a foothold, science needs both reproducible objective findings and well enough structured hypotheses to choose the right questions to ask in further experiments. For ME these have been hard to pin down. years, became Dean of the school of biological sciences in 1991 and was head of a cancer research team and set up the Francesca Gunn Leukaemia Laboratory at UEA. In 2011 Dr Gibson received an honorary doctorate of civil law from UEA. Professor Jonathan Edwards Emeritus Professor of Connective Tissue Medicine University College London (UCL) Professor Jonathan Edwards, of UCL's Department of Medicine, announced a highly original new treatment for rheumatoid arthritis in October 2000. His team has conducted trials of a new combination of drugs on patients who have suffered from rheumatoid arthritis for as long as 20 years; all but two of the 22 patients have so far shown marked improvements in their symptoms of the disease. More information - http://www.ucl.ac.uk/medicine/research The recent finding of a response to rituximab in ME patients indicates that at least a proportion of cases may have an autoimmune basis. This suggests that lessons learned in the study of conditions such as rheumatoid arthritis, which led to the initial use of rituximab for autoimmunity, may provide clues for research into ME. The story of how rituximab came to be used in RA, and the pitfalls encountered both in terms of finding objective disease markers and in formulating a hypothesis for disease mechanism, will be discussed. Key steps in that process were the recognition that in autoimmune disease external trigger factors may be less important than spontaneous errors within the immune regulatory mechanism itself and that B cell tolerance of self may fail independently of T cell tolerance. It also became clear that there are many ways in which autoantibodies can cause disease and that one should not expect to find a 100% match between traditional antibody findings and disease. Moreover, the use of rituximab has itself proved to be a powerful tool in studying details of disease mechanism and perhaps the same may prove true for ME. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 39 of 52

Journal of IiME Volume 8 Issue 1 Professor Angela Vincent Emeritus Professor of Neuroimmunology, University of Oxford Professor Vincent is Emeritus Professor of Neuroimmunology at the University of Oxford, and an Emeritus Fellow of Somerville College. She holds an Honorary Consultant position in Immunology and runs the Clinical Neuroimmunology service which is an international referral centre for the measurement of antibodies in neurological diseases. Together with colleagues she collaborates with neurologists worldwide. She was formerly Head of Department of Clinical Neurology (2005-2008), and is a Past President of the International Society of Neuroimmunology, and an Associate Editor of Brain. She was a co-applicant and group leader of OXION, the Wellcome Trust-funded Integrative Physiology Initiative "Ion channels and Diseases of Electrically Excitable Cells". She is a member of Faculty of 1000 (Neuroscience, Neurobiology of Disease and Regeneration) Her major interest is in the role of autoimmunity in neurological diseases, including multiple sclerosis and auto-antibody mediated ion channel and receptor disorders. Recent advances have included (a) the discovery that maternal antibodies to different fetal proteins can cause rare neuromuscular disorders, and may be involved in some forms of autism or other neurodevelopmental disorders; (b) the definition and characterisation of a new form of myasthenia gravis associated with antibodies to a receptor tyrosine kinase, MuSK, that performs an important maintenance role at the neuromuscular junction; and (c) the recognition that some central nervous system disorders, involving memory loss, seizures, movement disorders, can be caused by antibodies to potassium ion channels and to various receptor proteins. In these, and several other conditions, new ways are being devised to measure the pathogenic May 2014 antibodies for better clinical diagnosis, and establishing model in vitro and in vivo systems for investigation of the pathophysiology of the diseases. Her group also works, in collaboration with Profs David Beeson and Nick Willcox, on the genetics of myasthenia and the factors that determine autoimmune responses to the main target, the acetylcholine receptor. More information - http://www.clneuro.ox.ac.uk/team/principalinvestigators/angela-vincent #IIMEC9 - Autoantibodies in different forms of neurological disease: relevance for ME? Autoantibodies to a variety of receptors and ion channels on cells of the nervous system can be identified in children and adults with newly acquired neurological diseases. Most of the patients have classical features of myasthenia gravis or central nervous system diseases including loss of memory, seizures, confusion or bizarre movements. The diseases improve with immunotherapies that reduce the levels of the “pathogenic” antibodies. The field is still developing and some antibodies are now being detected in patients with other conditions including first episode psychosis, unexplained epilepsy, sleep disorders or pain. But the relevance of the antibodies in these disorders is not yet established and some findings may be entirely incidental. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 40 of 52 Journal of IiME Volume 8 Issue 1 Professor Jonas Blomberg Emeritus Professor of Clinical Virology, Department of Medical Sciences, Uppsala University, Sweden Professor Jonas Blomberg is an MD and PhD, graduating at the University of Gothenburg. Has worked with Lipids at the department of Medical Biochemistry 1965-1972 as a Clinical Virologist in Gothenburg 19721979 and as a postDoc at John Stephensons Lab at NCI Frederick on retroviruses 19791981. He then worked as a Clinical Virologist in Lund, Sweden 1981-1995 and then as a professor of Clinical Virology in Uppsala 1996- to the present. His main fields of interest are: Retrovirology, Bioinformatics, Clinical Virology and broadly targeted and multiplex methods for detection of microbial nucleic acid. He also is interested in evolution and Infection biology. Professor Blomberg is on the editorial board of Journal of Virology http://jvi.asm.org/site/misc/edboard.xhtml #IIMEC9 Abstract: Infection-induced autoimmunity in ME Not available at time of printing – but will be made available on Invest in ME web site. Professor Mady Hornig Associate Professor Mady Hornig, Center for Infection and Immunity (CII), Columbia University Mailman School of Public Health, New York, USA Mady Hornig, MA, MD is a physician-scientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health where she serves as Director of Translational May 2014 Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, and toxic stimuli in the development of neuropsychiatric conditions, including autism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 41 of 52

Journal of IiME Volume 8 Issue 1 Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Her work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project, one of the largest studies of immune factors in mood disorders and schizophrenia, examines the role of viruses and immune responses in the pathogenesis of these disorders. #IIMEC9 Abstract: Pathogen Discovery in ME Not available at time of printing – but will be made available on Invest in ME web site. Professor Carmen Scheibenbogen Professor for Immunology and Deputy Chair, Institute of Medical Immunology, Berlin Charité, Germany Group leader of a Tumour Immunology Laboratory and Attending Physician at the Dept. of Haematology, Oncology und Transfusionsmedizin, CBF, Charité,,2/1997 Venia legendi for Internal Medicine "Habilitation",,1990 - 1998 Residency at the Med. Klinik und Poliklinik V, Hämatologie, Onkologie und Rheumatologie, Universität Heidelberg, 1988 - 1990 Postdoctoral fellowship at the Med. Klinik, Dept. of Hämatologie und, Onkologie, Universität Freiburg,1982 - 88 Medical school at the Universities of Bonn, Marburg and Denver #IIMEC9 Abstract: Role of EBV and ME/CFS Carmen Scheibenbogen, Madlen Löbel, Sandra Bauer, Agnes Mooslechner, Leif Hanitsch, Patricia Grabowski, Kirsten Wittke, Ulf Reimer, Maren Eckey, Klemens Ruprecht, Hans-Dieter Volk Institute for Medical Immunology and Neurology, Charité, and JPT Peptide Technologies, Berlin Late first Epstein-Barr virus (EBV) infection is a frequent trigger of Chronic Fatigue Syndrome (CFS). About 20% of patients have serological or PCR evidence of EBV reactivation. A deficient EBVMay 2014 specific immune response became evident in more than half of our patients when specific B cell and T cell memory responses were analysed (Löbel M. et al., Plos One, January 2014). By analysing the spectrum of EBV-specific antibodies against various proteins we observed a pattern of EBV-specific antibody responses, which could distinguish CFS from healthy controls and patients with multiple sclerosis (Ruprecht K. et al., J. Neuroimmunology, April 2014). When comparing EBV load in blood immune cells, we found more frequently low but detectable levels of EBER-DNA in CFS patients compared to healthy controls. However, no evidence of lytic EBV reactivation was observed indicating that no severe defect in T- and NK cell control of EBV exists. In line with this observation we found normal NKG2D expression on NK cells, which is important for killing of EBV-infected B cells. There is accumulating evidence that B cells are dysregulated in CFS. Many patients have alterations of immunoglobulin levels and those with diminished levels often suffer from recurrent respiratory tract infections. Both B cell depletion and high dose immunoglobulin therapy is effective in a subset of patients. Our current research focuses on the detailed characterisation of B cells and the EBVinduced regulation of B cell genes in CFS. Taken together, our findings give evidence for a deficient or dysregulated EBV-specific immune response in many CFS patients. Our data may point to an impaired ability to control early steps of EBV reactivation. Professor Simon Carding Professor of Mucosal Immunology at University of East Anglia and Institute of Food Research. Following his PhD at London he held postdoctoral positions at New York University School of Medicine, New York and at Yale University School of Medicine, New Haven, USA. He then moved to the University of Pennsylvania, Philadelphia, USA as Assistant and Invest in ME (Charity Nr. 1114035) www.investinme.org Page 42 of 52 Journal of IiME Volume 8 Issue 1 later Associate Professor. He joined University of Leeds as Professor of Molecular Immunology in the Institute of Molecular and Cellular Biology in 1999. His scientific interests are in understanding how the immune response in the gut functions and in particular, is able to distinguish between the commensal microbes that reside in the gut and environmental microbes that cause disease, and in the mechanisms by which the body's immune system no longer ignores or tolerates commensal gut bacteria and how this leads to immune system activation and inflammatory bowel disease. #IIMEC9 Abstract: A role for a leaky gut and the intestinal microbiota in the pathophysiology of myalgia encephalomyelitis/ chronic fatigue syndrome? Simon R Carding1,2, Tom Wileman1, Daniel Vipond1,2, Bharat Harbham1, Eleanor Cottam3 and Amolak Bansal4 1Norwich Medical School, University of East Anglia, 2Gut Health and Food Safety Research Programme, Institute of Food Research, Norwich Research Park, Norwich, 3The Pirbright Institute, Woking, 4Dept. Immunology, St. Helier NHS Trust, Carshalton. Recent studies point to a link between autoimmunity and myalgic encephalomyelitis (ME) raising the possibility that the neuro-inflammation seen during ME may be triggered by systemic infections. The gastrointestinal tract contains a vast population of resident microbes (the microbiota) consisting primarily of bacteria and fungi, yeasts and viruses. The microbiota influences intestinal barrier function and host defences against microbial challenge with microbial dysbiosis leading to both local and systemic chronic inflammation. The microbiota may also influence cognitive function and behaviour. It is known that gut infections can cause anxiety, depression and cognitive dysfunction; and microbefree, germfree mice that have no intestinal microbiota display alterations in stress-responsivity, central neurochemistry and behaviour indicative of a reduction in anxiety. Many ME patients have gastrointestinal disturbance, are more likely to develop irritable bowel syndrome, and may have increased intestinal permeability (a “leaky” gut”). Together these observations suggest that changes in intestinal barrier integrity, which may be driven May 2014 by or are a consequence of intestinal dysbiosis, as a result, for example, of a gut infection could contribute to ME by driving systemic inflammation and/or influencing the microbiota-gut-brain axis. With support from Invest in ME we have initiated a project to address the hypothesis that alterations in intestinal barrier integrity and the resulting influx of luminal antigens triggers and perpetuates a state of chronic inflammation both locally and systemically that contributes to the pathophysiology of CFS/ME. The aim of this three-year, multi-centre collaborative project therefore is to determine if alterations in the intestinal barrier integrity and microbiota composition and function exist in CFS patients. Professor Sonya MarshallGradisnik School of Medical Sciences, Griffith University, Australia Professor Marshall-Gradisnik is one of Australia's foremost researchers in the area of neuroimmunology and has been instrumental in establishing the Public Health and Neuroimmunology Unit (PHANU) at Bond University, and now at Griffith University. Much of her work relates specifically to autoimmunity in Chronic Fatigue Syndrome sufferers and she is regularly asked to speak to community groups on behalf of Queensland Health and NSW Health. Her research in the area of exercise immunology has also contributed to the body of knowledge relating to the effect of doping in sport and she serves as Sports Medicine Australia's national spokesperson in this area. The vital research conducted by Professor Marshall has attracted more than $1 million in grant funding Invest in ME (Charity Nr. 1114035) www.investinme.org Page 43 of 52

Journal of IiME Volume 8 Issue 1 and she has produced 21 peer-reviewed papers, five book chapters and one provisional patent. In 2008 Dr Marshall was joint leader of the Bond University team responsible for developing the BioSMART program. The team was awarded a prestigious Australian Teaching and Learning Council Award (formerly known as the Carrick Award) for Outstanding Contribution to Student Learning and for the quality of student learning over a sustained period of time. Professor Marshall-Gradisnik is also leading The National Centre for Neuroimmunology and Emerging Diseases (NCNED), a research team situated at Griffith University on the Gold Coast. The team focuses on Myalgic Encephalomyelitis. #IIMEC9 Abstract: Innate and Adaptive Immune Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Brenu EW1, Hardcastle SL, Huth, T, Johnston S, Nguyen, T., Ramos SB, Staines DR, MarshallGradisnik SM. National Centre for Neuroimmunology and Emerging Diseases, Griffith Health Institute, Griffith University, Parklands, Queensland, Australia. Queensland Health, Gold Coast Public Health Unit, Robina, Gold Coast, Queensland, Australia. Immunological abnormalities are consistent in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients, namely reduced Natural Killer (NK) cell cytotoxic activity. However, reports on other basic immune cell parameters are inconsistent in CFS/ME, possibly related to the heterogeneity or variation in severity of the illness. The purpose of this research was to assess innate and adaptive immune cells that have not been previously examined in CFS/ME in cohorts of both moderate and severely affected patient severities. CFS/ME patients were assessed using the 1994 CDC Case Definition for CFS/ME. Health, mobility and quality of life questionnaires were used to assess all participants and also to further distinguish CFS/ME participants as either moderately or severely affected. Using flow cytometric assays, NK cells, neutrophils, monocytes, T regulatory cells (Tregs), iNKT cells, B cell phenotypes and dendritic cells (DCs) were examined each of these groups. DC, B, neutrophil and Treg phenotypes were significantly different between the CFS/ME and nonMay 2014 fatigued controls. NK cytotoxic activity was significantly reduced in CFS/ME patients compared to controls and was further reduced in severely affected patients. The severe CFS/ME patients also demonstrated significantly increased DC, B, iNKT and NK phenotypes when compared to both the moderate CFS/ME patients and healthy controls. These results have confirmed previous reports that NK cell cytotoxic activity is consistently reduced in CFS/ME. This data has further suggested that further immune cells, including DCs, B, Tregs and iNKT cells have immune perturbations related to cytotoxic activity and phenotypes in CFS/ME and this may be contributing to the overall immune profile demonstrated in this illness and other autoimmune disorder. Professor James Baraniuk Professor of Medicine at Georgetown University Medical Centre James N. Baraniuk was born in Alberta, Canada, south of Banff. He earned his honours degree in chemistry and microbiology, medical degree, and unique bachelor's degree in medicine (cardiology) at the University of Manitoba, Winnipeg, Canada. Thereafter, he moved to Akron, OH, USA, for his internship and internal medicine residency at St Thomas Hospital. After another year of internal medicine residency at Duke University Medical Center, Durham, NC, he trained with Dr C.E. Buckley, III, in allergy and clinical immunology. He moved to the laboratory of Dr Michael Kaliner at the National Institute of Allergy and Infectious Diseases, Bethesda, MD, and there began his longstanding collaboration with Dr Kimihiro Ohkubo. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 44 of 52 Journal of IiME Volume 8 Issue 1 After 2 years studying neuropeptides, he joined Dr Peter Barnes' laboratory at the National Heart and Lung Institute, Brompton Hospital, London, UK. Dr Baraniuk returned to Washington, DC, and Georgetown University, where he is currently Associate Professor with Tenure in the Department of Medicine. #IIMEC9 Abstract: Brain Imaging and ME Not available at time of printing – but will be made available on Invest in ME web site. Professor Julia Newton Clinical Professor of Ageing and Medicine, Institute for Ageing and Health, Newcastle University and Honorary Consultant Physician, Royal Victoria Infirmary, UK Professor Newton's research programme focuses upon the integrity of the autonomic nervous system in health and disease, specifically the role of autonomic dysfunction in the pathogenesis of fatigue and its clinical consequences, namely cognitive impairment. Examining the integrity of the ANS in humans is established in her physiology laboratory using relatively simple, inexpensive, non-invasive technologies that allow evaluation of a wide range of parameters that will within the foreseeable future be readily transferable into therapeutic interventions for patients. #IIMEC9 Abstract: ANS and ME Autonomic Dysfunction & ME The autonomic nervous system controls all of those functions that go on in the human body outside conscious control. Studies have confirmed that problems with the autonomic nervous system (autonomic dysfunction (AD)) are a common occurrence in those with ME, with almost 90% of sufferers describing postural dizziness, syncope (blackouts) and a range of other autonomic symptoms. Formal testing has confirmed the presence of objectively measured autonomic May 2014 dysfunction in ME with conditions such as neurally mediated hypotension and positional tachycardia syndrome recognised at significantly increased prevalence compared to matched control populations. The underlying cause of this frequently found AD is as yet not understood. Studies will be described confirming muscle, cardiac and brain abnormalities the severity of which associates with the underlying AD. Professor Maureen Hanson Liberty Hyde Bailey Professor, Cornell University Maureen Hanson is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, NY. Previously she was on the faculty of the Department of Biology at the University of Virginia in Charlottesville and an NIH NRSA postdoctoral fellow at Harvard, where she also completed her Ph.D. degree. While most of her prior research has concerned cell and molecular biology in plant cells, she began a research program on ME/CFS after noting at a 2007 IACFS meeting the paucity of molecular biologists studying the illness. Her lab was part of the 2012 multicenter study organized by Ian Lipkin's group at Columbia University to assess the actual role of XMRV in ME/CFS. Dr. Hanson has a current project to examine the microbiome of ME/CFS patients and controls, in collaboration with Dr. Ruth Ley (Cornell Microbiology) and Susan Levine, M.D. (Manhattan, NY). Dr Levine is also collaborating with Dr. Hanson on an immune cell gene expression project that involves Dr. Fabien Campagne and Dr. Rita Shaknovich at Weill Cornell Medical School in New York City. Dr. Hanson's third project concerns analysis of blood samples from individuals performing a twoInvest in ME (Charity Nr. 1114035) www.investinme.org Page 45 of 52

Journal of IiME Volume 8 Issue 1 day cardiopulmonary exercise test at Ithaca College under the supervision of Dr. Betsy Keller. #IIMEC9 Abstract: Markers of Post-exertional Malaise 1Maureen R. Hanson, 1Ludovic Giloteaux, 2Xiaojing Lu, 2Jason W. Locasale, 3Betsy A. Keller 1Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA 2Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA 3Department of Exercise & Sport Sciences, Ithaca College Ithaca, NY, USA ME/CFS patients often report an increase in symptoms following levels of physical or cognitive activity that would not be challenging to healthy subjects, a problem which is termed post-exertional malaise. Reports have demonstrated that healthy subjects, as well as subjects with heart or renal failure or lung diseases, are able to reproduce their maximum oxygen consumption (VO2max) and/or VO2 at ventilatory threshold (VT) when they undergo repeated cardiopulmonary exercise tests (CPET). In contrast, detrimental effects of an exercise challenge on the physiology of individuals with ME/CFS can be documented by objective measures obtained during two CPETs. Because subjects cannot willfully alter the maximum amount of oxygen they inhale nor the amount of carbon dioxide they exhale, measurement of these parameters provides an objective indicator of an individual’s physiological function that cannot be explained by deliberate malingering or by psychiatric illness. After induction of post-exertional malaise by an initial CPET, ME/CFS patients often exhibit abnormal physiological and/or autonomic nervous system responses and are usually unable to repeat either their VO2max and/or VT, which is a measure of the anaerobic threshold, or they show symptoms of autonomic dysfunction. Anaerobic threshold is the exercise intensity at which metabolism transitions to anaerobic energy production, which is less efficient and results in accumulation of lactic acid. We have observed patients with ME/CFS who become prematurely “anaerobic” at low work levels. After an exercise challenge, even modest activities, such as lying quietly while watching television or sitting and eating, require some patients to use anaerobic metabolism. Other patients exhibit Metabolic Equivalent of Task (MET) May 2014 levels at maximal exertion of 4.0 or less, while 4.0 METs are required to do such simple activities as hanging laundry, sweeping a sidewalk or climbing stairs slowly. A simple strategy can be used to discern biochemical and metabolic abnormalities in individuals experiencing post-exertional malaise. By collecting blood samples before an exercise challenge and 24 hours afterwards, assays can be performed to determine which molecules have changed in concentration. We will discuss the data that is currently available about exercise-induced changes in amounts of plasma molecules. Dr Andreas Kogelnik Director of the Open Medicine Institute, USA Dr Andreas Kogelnik is the Founding Director of the Open Medicine Institute, a collaborative, communitybased translational research institute dedicated to personalized medicine with a human touch while using the latest advances in medicine, informatics, genomics, and biotechnology. The Institute works closely with the Open Medicine Clinic and other clinics to conduct research and apply new knowledge back into clinical practice. Dr. Kogelnik received his M.D. from Emory University School of Medicine in Atlanta and his Ph.D. in bioengineering/bioinformatics from the Georgia Institute of Technology. Subsequently, he completed is residency in Internal Medicine and a Fellowship in Infectious Diseases at Stanford University and its affiliated hospitals. Following his clinical training, he remained at Stanford with NIH funding to engage in post-doctoral research in microbiology, immunology and bioinformatics with Dr. Ellen Jo Baron and Dr. Stanley Falkow, where he explored host-response profiles in severely ill patients. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 46 of 52 Journal of IiME Volume 8 Issue 1 Together with Dr. José Montoya, he was instrumental in the conception, design, and execution of the EVOLVE study - a placebocontrolled, double-blind study of a subset of chronic fatigue syndrome patients with evidence of viral infection. Dr. Kogelnik worked with Dr. Atul Butte in translational informatics to determine patterns that indicated a high risk for adverse events in paediatric patients at Lucille Packard Children's Hospital. He is the Medical Director of the Open Medicine Clinic - a community-based research clinic focussed on chronic infectious diseases, neuroimmune disease, and immunology. Dr. Kogelnik has published numerous scientific papers and book chapters, is an Editor of Computers in Medicine and Biology, and is a Consulting Assistant Professor at Stanford University. With the Open Medicine Institute, he has led the formation of CFS and Lyme Registries and Biobanks as well as creating an infrastructure for providers to collect better data and implement clinical trials across a network of sites. #IIMEC9 Abstract: Diagnosis/Treatments and ME in USA An update of OMI collaborative projects current and planned will be given, including the Population Survey of Cognition in ME/CFS, The effect of the MTHFR gene on the treatment of ME/CFS, and the OpenMedNet longitudinal survey study. The Population Survey of Cognition and ME/CFS is a large-scale survey of scientific measures of cognitive function across the spectrum of ME/CFS with subgroups being evaluated before and after treatment (n=4000). The MTHFR study is evaluating the effect of treatment of ME/CFS patients with MTHFR gene abnormalities with methyl folate and methyl B12 (n=120). OpenMedNet Survey study is giving us insight into the distribution of the disease and natural course of disease (n=100,000). We will summarize upcoming directions and how the ME/CFS community can participate. May 2014 Dr Amolak Bansal Consultant Clinical Immunology and Immunopathology, Epsom and St. Helier University Hospitals NHS Trust, Surrey, UK Dr. Bansal trained in immunology and allergy from 1989 to 1993 at St. Mary’s Hospital in Manchester and at Hope Hospital in Salford. From here he spent five years (1993-1997) as Senior Lecturer and Consultant in Clinical Immunology in the Department of Medicine at the Princess Alexandra Hospital in Brisbane, Australia. From 1997 to the present date Dr. Bansal has worked as a Consultant in Clinical Immunology and Immunopathology at Epsom and St Helier University Hospital. Dr Bansal’s key interests lie in allergy, autoimmunity, CFS/ME and immunodeficiency. #IIMEC9 Abstract: Diagnosis/Treatments and ME in UK The diagnosis of CFS/ME is often challenging as the symptoms do not fit commonly encountered conditions and there are no diagnostic tests currently. It is therefore a diagnosis of exclusion. However, the delayed post-exertion malaise after physical and mental overactivity as well as the hypersensitivity to sounds and lights and the neurocognitive dysfunction are rarely if ever seen collectively in any other condition. Unfortunately, the precise mechanism for these highly disabling symptoms remains unclear. The criteria used to confirm CFS/ME in research and particularly the operationalisation of these criteria has been the subject of much controversy. The deficits in the early criteria appear to have been eliminated but at the expense of additional complexity. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 47 of 52

Journal of IiME Volume 8 Issue 1 The need to assess the frequency and severity of each of the symptom sets is an important step forward and will hopefully improve the diagnostic certainty for primary and secondary care physicians. The Sutton CFS/ME service has used a diagnostic scoring system for the last 6 years which has been found easy to use and reliable. This will be discussed in the broader context of the various diagnostic CFS/ME criteria and certain unusual clinical findings noted by this service. Dr Saul Berkowitz Royal London Hospital for Integrated Medicine, London, UK Dr Berkowitz is one of two full-time consultants at the Royal London Hospital for Integrated Medicine. He graduated from Fitzwilliam College, Cambridge in 1989, and from Charing Cross and Westminster Medical School in 1993. He was the first doctor in the UK to complete a joint training program in both orthodox and complementary medicine, and have recognised postgraduate qualifications in Alllergy, Western herbal medicine (phytotherapy), acupuncture and homeopathy. Dr Berkowitz treats patients with a wide range of mostly chronic medical problems. May 2014 Dr Julian Blanco Leader of the Irsi Caixa Research Institute's Cell Virology and Immunology Research Group, Barcelona, Spain The IrsiCaixa Institute for AIDS Research IRSI Caixa works alongside the most prestigious international research centres, and its publications are among those with the most impact in their field. Dr Blanco has vast experience in HIV related research but has also been involved in ME/CFS research as in 2013 his group published the paper , Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome, Curriu et al. Journal of Translational Medicine 2013, 11:68. #IIMEC9 Abstract: External View of ME Research Strategy When ME/CFS knocked the door of biomedical research, most teams were already working in other life threatening diseases, and little attention was paid to this disease. Reversing this situation to take advantage of the massive work and exceptional advances that biomedical research has made in the last decade, should be a major goal. The advances in the clinical definition of ME, the undeniable data on the prevalence of the disease are major players contributing to push ME towards the frontline of biomedical research. What will ME/CFS find in the current research landscape? Most of diseases can now be approached from a completely different scientific perspective that could be approached ten years ago. New technologies and new analysis tools generating and managing million of data are now available. This information will inform us on the genetic basis of the disease and the implication of intestinal microbiota or the immune system in its pathophysiology. However all this powerful arsenal of technology will be useless in the absence of a proper choice of patients. Clinical efforts in diagnosis and in the definition of clinical trials will be therefore determinant to achieve the final goal. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 48 of 52 Journal of IiME Volume 8 Issue 1 May 2014 The Invest in ME/UCL Rituximab Clinical Trial An International Event When Invest in ME announced in June 2013 that we were planning a UK trial of rituximab for ME there was a great deal of interest raised. The rituximab trial follows the exciting work which has been, and is being performed in Norway by the Haukeland University hospital researchers Professor Olav Mella and Dr Oystein Fluge. The response from around the world emphasises how great the need is for high-quality biomedical research into ME. This has been sorely lacking for a generation with funding mostly being squandered on psychological interventions which have no hope of finding cause or making available effective long term or permanent treatments. The research work in Norway was backed up by impressive and dedicated patient advocacy by the Norwegian ME Forening which has raised the profile of ME in Norway and throughout the world. Their tireless work encouraged IiME as did the more recent success of the fantastic Norwegian ME and You campaign to raise funds for the Norwegian research. These efforts have created a real sense of hope amongst patients. Our wonderful supporters have risen to the occasion and their efforts have validated the decision to initiate the UK trial with UCL. The imaginative Let’s Do It For ME campaign has continued to produce ideas to raise funds and awareness and The MATRIX is an example of a unique method of achieving both. We have had donations from around the world, ranging from £1 to £3,000. A very generous foundation has donated £25,000 already and pledged £200,000 toward the clinical trial. This was in memory of the late Roger Heindry who sadly passed away in March 2013. We are very grateful for this extraordinarily generous offer from the donating foundation. It was an amazing gesture from compassionate and caring people who want to make a difference. It allows the hopes of many patients to become a reality – allows a vision to be maintained that there is a future for ME patients and that we, patients and families and supporters, can make a difference. A few good people can change things. One event can change everything. As such, IiME and our supporters have managed to initiate and organise something which many thought was not possible. This is an international event and is followed and funded by many around the world. Our objective is to ensure that a clinical trial of rituximab is allowed to be performed by the best researchers possible and to ensure that this trial makes a valuable contribution to the collective ME research pool. We have stated before that we believe in achieving results by the most direct method, where possible. For IiME the issue of making rapid progress in ME research is important, it is personal. The need is here - the need is now. We continue our efforts to raise the remaining funds. We thank all those who are supporting this trial and we will continue to provide information on the status of the trial as we progress. Please contact IiME directly if you or your organisation would like to assist or contribute. If anyone would like to ask any questions about the UK rituximab trial then please use the Contact form on the rituximab web site. With this trial we can take a huge leap forward in ME research. Let’s Do Research! Let’s Do It For ME! Invest in ME (Charity Nr. 1114035) www.investinme.org Page 49 of 52

Journal of IiME Volume 8 Issue 1 9th Invest in ME International ME Conference 2014 30th May 2014, London Start 07.45 Presenter Registration 08.55 Welcome to IIMEC9 09:05 09:35 10:10 10.40 Break 11:00 11:40 12:10 12.35 13:25 14:05 14:45 15.15 15:35 16:10 16:25 16:40 17.00 17:20 17.30 Professor Mady Hornig Pathogen Discovery in ME Professor Carmen Scheibenbogen EBV and ME/CFS Professor Simon Carding Lunch Professor Sonya Marshall-Gradisnik Current Knowledge of Immunological Biomarkers in ME Professor James Baraniuk Professor Julia Newton Coffee/tea Break Prof Maureen Hanson Dr Amolak Bansal Dr Andreas Kogelnik Dr Andreas Kogelnik Dr Amolak Bansal Dr Saul Berkowitz Dr Julian Blanco Dr Ian Gibson A framework for future fMRI characterizations in ME Patients ANS and ME Markers of Post-Exertional Malaise Diagnosis/Treatments for ME within NHS Diagnosis/Treatments for ME in USA Panel Discussion External View of ME Research Strategy Plenary Session Adjourn (Note that the agenda, format and times are subject to change) Support Biomedical Research into ME. Order our free newsletter. Distributed monthly via html, plain text or PDF http://bit.ly/14Q8VoP Invest in ME wristbands http://bit.ly/13gKHBp Gut Microbiota and ME/CFS Dr Ian Gibson Professor Jonathan Edwards Professor Angela Vincent Professor Jonas Blomberg Lessons for ME Research from Rheumatoid Arthritis Research Finding Antibodies in Neorological Diseases Infection-induced autoimmunity in ME Conference Agenda Presentation May 2014 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 50 of 52 o M o M

Journal of IiME Volume 9 Issue 1 May 2015 Journal of IiME IIMEC10 – 10 YEARS IIME Conferences M.E. and ME Invest in ME – 10 Years On How To Get Trials Reported ME: The Last and Next Ten Years ME/CFS – Through The Eyes of a Young Researcher Better from America? The True Battle with CFS Anna’s Story Matchstick Campaign for ME Speakers at IIMEC10 Agenda IIMEC10 3 8 9 10 12 17 22 24 34 39 43 44 54 As Invest in ME enters its tenth year as a UK charity then our tenth annual international conference – IIMEC10 – heralds perhaps the realisation of many patients and their families long held wish – that ME has finally entering a stage where sensible and credible research is being planned. That this is mainly due to the work and will of patients illustrates how much there is still to do – but the hard work of Invest in ME’s supporters is beginning to shape a better future. DISCLAIMER The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. Invest in ME was established in 2005 and became a UK charity in 2006. The charity trustees are composed of ME patients and parents of children with myalgic encephalomyelitis - ME. When the charity was formed the aim was to make a difference – to change the way ME was perceived by the society at large and researched by academic institutions, by campaigning for patients’ rights and providing a platform for better education about ME and the sparse research which was occurring. This has gradually evolved to include the objective to facilitate and initiate high quality biomedical research in top research institutions. Raising the profile of ME by improving the education of healthcare professionals about the disease, by raising awareness of the disease amongst the public and media and by facilitating and enabling an international strategy of biomedical research into the disease, has been a full time job for the charity trustees – despite it being performed when time permits, in evenings and weekends and holidays, and when the illness itself allows. Our conferences started in 2006, the same year that conference chairman, Dr Ian Gibson, produced the so called Gibson Report where a group of parliamentarians chaired by Dr Gibson Invest in ME (Charity Nr. 1114035) www.investinme.org Page 3 of 57 INVEST in ME COMMENT IIMEC10 - 10 YEARS

Journal of IiME Volume 9 Issue 1 looked at evidence about ME from a wide range of sources. Our conference facilitated the hearing of Drs Byron Hyde and Bruce Carruthers. The Gibson report is still a very valuable historical document and if some of the recommendations from the report had been acted upon then people with ME and their families might well be in a different (and better) position today. This year the US Institute of Medicine produced a report for US diagnostic purposes. Three of the speakers at this year’s conference were involved with the report. Professor Betsy Keller was one of the group members and Professor Maureen Hanson and Dr Dan Peterson were among the reviewers. The IOM working group looked at the published research as well as the so called grey literature in a systematic way and what they found was the shocking fact that little replicable or validated research existed compared to the number of people affected by this disease. The numerous definitions being used have complicated all research and the lack of some common and agreed protocols and standards has affected diagnosis and therefore treatment. Samples need to be shared so that different research groups can make sure they are finding the same thing and areas of expertise are being utilised effectively. Such sharing is taking place with IiME funded researchers at UCL and IFR/UEA and some of the research will be presented at the conference. Amongst the speakers at the Invest in ME Biomedical Research into ME Colloquium 5 (BRMEC5 – taking placed on the two days prior to the IIMEC10 conference) is Dr Luis Nacul and the rest of the UK biobank team who have also worked on standardising protocols to make sure the samples they collect are as representative of the patient population as possible in the absence of objective biomarkers. From Haukeland University hospital in Bergen Dr Oystein Fluge and Professor Olav Mella return to present at the Invest in ME conference once again to talk about their current research. May 2015 In 2012 Dr Don Staines, co-Chair of the Invest in ME/Alison Hunter Memorial Foundation BRMEC2 Clinical Autoimmunity Working Group, and now professor and co-director at the N.C.N.E.D., stated - ‘The recent discovery from researchers in Norway that an anti- CD20 B cell- depleting drug had a marked benefit in the treatment of ME/CFS has sent a clear message to scientists and medical practitioners around the world that this disease may have an autoimmune origin. The findings of Drs Fluge and Mella and their coworkers are consistent with theories previously published that ME/CFS may be an autoimmune disease. Despite compelling evidence that this disease is linked epidemiologically to infection and the disorder possibly being a post-infection disturbance of the immune system, little funding has gone into studies of autoimmunity. This is clearly a multi-system illness which has been badly managed in terms of the research agenda.’ While the clinicians who made the discovery, Dr Oystein Fluge and Dr Olav Mella, and coworkers, remain guarded in drawing unwarranted conclusions from the study published in PLoS late in 2011, a large multicentre study is now underway. We are delighted to welcome them back to the IIME conference. We now can see more progress being made. The Chronic Fatigue Initiative funded by the Hutchins Family Foundation has produced research that has been noticed by the media. Drs Mady Hornig and Dan Peterson are among the authors of papers from this initiative. One study published in Science Advances, looked at plasma immune signatures and the other one published in Molecular Psychiatry, looked at cytokines in spinal fluid of ME/CFS patients. These research results may help in finding biomarkers to aid diagnostics. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 4 of 57 Journal of IiME Volume 9 Issue 1 This year we are also welcoming back Dr John Chia who is the only ME clinician/researcher concentrating on enteroviruses and ME. The late Dr John Richardson did a considerable amount of work into enteroviruses and ME in the UK and his work and legacy has been carried on by Dr Spurr and Professor Malcolm Hooper – who both participate in BRMEC5. We are delighted to welcome some new presenters to the conference proceedings. Professor Ian Charles has taken on leadership of the Institute of Food Research (IFR) in Norwich and we are honoured that he is opening the tenth Invest in ME conference. His track record is impressive and we hope his vision and innovation will help with ME research in the future as the research base for ME at UEA/IFR in Norwich Research Park has enormous potential in finding the cause(s) of ME. The charity first proposed its centre of excellence in 2010 and with the help of the Let’s Do It For ME team of volunteers funds were raised for the foundation research project which began at University of East Anglia and the Institute of Food Research in October 2013. This three year studentship is analysing gut microbiota in ME patients. Daniel Vipond is the PhD student taking on this project under the leadership of Professors Simon Carding and Tom Wileman. The patients are selected from Dr Amolak Bansal’s CFS clinic at Epsom and St Helier hospital. Invest in ME want proper education about ME to begin at medical school and one of the best ways is for medical students to intercalate in their course and play a part in the research projects. So fourth year medical students from the University of East Anglia (UEA), Bharat Harbham and Navena Navaneetharaja are also involved in the IFR/UEA gut microbiota May 2015 research. The charity has for a long while stated the importance of international collaboration and we are pleased that Professor Maureen Hanson enabled Navena to spend over three months at Cornell University in Itacha USA to learn about their gut microbiota research. Meanwhile Bharat is currently working intensely with Professor Angela Vincent in her laboratory at Oxford University. This is the essence of the IiME approach to research. Finding the cause, working in collaboration, using opportunities for international collaboration, bringing new expertise into studying ME and facilitating the education of healthcare staff. At the 2012 conference we stated that we were working on an attempt to set up a rituximab clinical trial. Following our Biomedical Research into ME Colloquium 3 in London in 2013 we made rapid progress with our partners UCL. ●● ● “The charity has for a long while stated the importance of international collaboration…” ●● ● Dr Bansal along with Dr Saul Berkowitz UCLH is also involved in this, the second IiME funded project which is looking at B cell biology in ME patients as the foundation for a clinical trial of rituximab. This work is being performed by Fane Mensah under the expert leadership of Dr Jo Cambridge. Professor Jonathan Edwards is also involved as an advisor. All of the students involved with IiME funded research projects will be in a panel discussion at the conference – satisfying a long held objective to highlight the next generation of researchers at our conference. Also being presented in the IiME London research meetings this year is fascinating research from new speakers to the IIME conference/colloquium. Markers to aid in diagnostics may be found from the visual research performed by Dr Claire Hutchinson and her team. Dr Neil Harrison’s work on immune brain communication is very relevant Invest in ME (Charity Nr. 1114035) www.investinme.org Page 5 of 57

Journal of IiME Volume 9 Issue 1 for understanding ME and Professor Jonas Bergquist has been studying the CSF of a Swedish ME/CFS patient cohort. This year’s conference sees the progression of the spectrum of research into ME which is now being realised and we expect this to continue. As per the title of our 2013 conference ME is now “mainstreamed” into scientific research – and we hope it stays there. We believe we are on the verge of significant breakthroughs once research such as the IiME-funded projects are underway. Preceding the IIMEC10 conference is our annual 2-day research colloquium (BRMEC5) with over 60 biomedical researchers from thirteen countries participating. In an atmosphere of collaboration we hope to make more progress which will lead to change for the benefit of people with ME and their families. BRMEC5 has taken a lot of effort to set up but we believe it is the way forward. Our aim over the last nine years has been to ensure that ME is researched properly in an international collaborative way. As we enter our tenth year as a charity we feel our strategy for research is succeeding. Our objective is not to exist as a charity for the sake of it – but to make real progress to understand and eventually overcome ME. With a little more support and some help our proposal for a centre of excellence can be realised. With colleagues and friends across the world, and dedicated and able researchers working with us to make progress, these agents for change are making a difference in how ME is researched, perceived and treated. We have felt a change is underway, despite resistance to progress from some quarters. Even the recent IOM report has finally conceded what patients have been fighting to make known for a generation – to governments, research councils, health services, the media and the public – Invest in ME (Charity Nr. 1114035) www.investinme.org Page 6 of 57 Our Sponsors Invest in ME would like to thank those organisations who have sponsored part of the IIMEC10 conference. We would like to thank Vitae Natural Nutrition who have become a sponsor of the May 2015 “It is clear from the evidence compiled by the committee that ME/CFS is a serious, chronic, complex, multisystem disease that frequently and dramatically limits the activities of affected patients.” For Invest in ME education and research are the key to progress, and hence change. The IiME conferences have formed a crucial part of this education and our research colloquia form a crucial and productive part of the research. We may not have the most funding or resources – but we feel we are currently funding and facilitating some of the best research possible and have ideas and plans that can change things forever. Welcome to IIMEC10. Journal of IiME Volume 9 Issue 1 IIMEC10 pre-conference dinner. Vitae Natural Nutrition is a laboratory that develops natural products based on Science and nutraceutical technology, designed to activate, improve and regulate the biological processes of the body maintaining and extending its functions. Following the vision of a healthier world to live in, Vitae have made important progress in the food supplement field and have generated results. The goal of the team is to invest in progress, seeking more natural solutions through innovation. The cornerstone of the research team is to find more efficient natural solutions through the use of innovation. Vitae have a number of reputable research partners and team members including: Qualified scientists Multifaceted Professionals Strong partnerships with Health Centers, Hospitals, and endorsements from Universities. We would also like to thank three of our European ME Alliance colleagues for their great support in sponsoring the conference. The Irish ME Trust, who have supported all our conferences, deserve a special mention. Our European ME Alliance partners in Sweden and Norway have proven to be also contributed to the conference costs. The Swedish RME group and Norges ME Forening have both generously donated to the conference costs. We are very proud to have received such wonderful support from our European ME Alliance colleagues. May 2015 Our Research IMET and RME Sweden also recently donated to the Invest in ME Biomedical Research Fund (BRF) to help us in progressing our base of highquality biomedical research in Europe. Our two major areas of research currently revolve around the gut microbiota studies and the rituximab/B-cell research - a solid foundation of biomedical research which is being augmented with new collaborations. The donations help us with the work being performed by the IFR/UEA in collaboration with Angela Vincent at Oxford University as she has expertise and interest in the role of autoimmunity in neurological diseases, including multiple sclerosis and auto-antibody mediated ion channel and receptor disorders. This is very topical in light of the clues from the Norwegian rituximab trials as well as recent research that has come from the Chronic Fatigue Initiative funded by the Hutchins Family Foundation. These studies published by Hornig et al include a serum and a cerebrospinal fluid study. The abstract of the cerebrospinal fluid (CSF) study states – "Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity."• These new donations have consolidated the research efforts at the Norwich Research Park where we now have a unique opportunity to establish, for good, our Centre of Excellence for ME using high-quality biomedical research and state-of-the-art research and treatment facilities. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 7 of 57

Journal of IiME Volume 9 Issue 1 May 2015 IiME CONFERENCES – 10 Years Professor Malcolm Hooper Professor Malcolm Hooper Emeritus Professor of Medicinal Medicine at Sunderland University. The 10th Annual IiME Conference is a remarkable achievement of the human spirit and deserves the strongest applause and recognition for 10 years of very hard work and the way in which the energy and commitment of the ME community has been harnessed in the interests of patents, carers, scientists and clinicians. Patients and carers have found reliable information about the illness and been given hope in their demanding and often ignored situations. A string of eminent and ground breaking international scientists and doctors have addressed the IiME Conferences and reported on their work and accepted the challenge of communicating it without dumbing it down. This has made the Conferences invaluable in disseminating reliable and up to date information that specialists as well as parents and careers have found encouraging and revitalising. All who attended gained much with some experts making a commitment to engage with the illness and face the challenge of ME, a serious, multi-system biomedical illness that can Malcolm Hooper, via his advocacy and championing of human rights for ME patients, was instrumental in the formation of UK charity Invest in ME not to be dismissed or superficially engaged with by the ideological stance of both Government, Insurance Agencies, DWP and NICE - an unholy alliance that is using the now utterly discredited PACE trial to support their stance. The recent draft P2P report has exposed the inadequacies of the somatoform / psychiatric / psychological approach that has sought to resist all the biomedical evidence presented at conference after conference. The P2P draft report states: 1. the Oxford Criteria (designed and used by psychiatrists) should be retired since they result in a confused and confusing mixture of patients from which only confused and confusing data can be measured which cannot be reliably analysed. Reliable and objective measurement is noticeable by its absence in many of these studies. 2. Any studies using the Oxford Criteria should not be used to direct treatment (CBT and GET). The vast number of papers produced by the Invest in ME (Charity Nr. 1114035) www.investinme.org Page 8 of 57 Journal of IiME Volume 9 Issue 1 “Wessely Scool” particularly the PACE Study are null and void and CBT/GET with ir without antidepressants are comprehensively rejected leaving only the biomedical science to help understanding and guide treatment. Everything must now change - Government, NICE, DWP and the Insurance industry - if evidence-based medicine is accepted. If it is not the P2P judgement stands against them as charlatans, tricksters who no longer recognise truth , scientific or otherwise when it meets them. This is the greatest triumph of IiME whose support and commitment to truth have been vindicated. Invest in ME have enjoyed the support of many ME sufferers and carers. They merit the greatest thanks and credit for their vision and enormous amount of work which has been carried out over the last nine years. Congratulations to all who work so hard often behind the scenes to make the IiME conferences the success they are. The development of the Research Programmes and Colloquiums marked a new and impressive extension of the Conferences and is now bearing much good fruit and further enhancing the vision that was inaugurated with the original Conference. It is a pleasure and a joy to be associated with their vision and work the ME community owes them a great debt - long may they and the IiME conferences flourish. Malcolm Hooper ME PATIENT “Kaylah is going to do a sponsored horse ride. for IiME because she has struggled with ME since the age of 5!” – Claire from IiME’s JustGiving pages https://www.justgiving.com/investinm-e/ May 2015 M.E. and ME I ran, I swam, it’s who I am I laughed, had fun, enjoyed the sun. I was doing such when this begun. Felt a chill on a good warm day Aches and pains that won’t go away Like the flu, I heard it said But arms and legs are made of lead. Can’t remember what I was about to say Simple words have gone astray Can’t make a choice between two simple things Someone else is pulling my strings. I try to read, but it only drains Focussing harder, just scrambles my brains The dark clouds descend, lead to despair The weight of three men sinks into my chair No outward sign to give a clue No bandage, mark, no black and blue Strange, it seems I always look well Look from this side, then you could tell Remove the mask for a day to see The evil face of this beast called M.E. Like a thief in the night it takes away Your hope, your strength, your friends Your likes, your loves your chance to play And never makes amends All we want is to be believed And trusted when we say Hey GP, can’t you see We didn’t ask to be this way This is real, a real big deal As big as the ‘popular’ ills It needs to be taught, given some thought Not just a bundle of pills We don’t have a choice, we need a real voice Give us some hope TODAY So don’t be doubting, we’re gonna keep shouting We’re just not going away. By Bill Clayton Invest in ME (Charity Nr. 1114035) www.investinme.org Page 9 of 57

Journal of IiME Volume 9 Issue 1 May 2015 Invest in ME – 10 Years On Ros Vallings The first ME/CFS conference I attended was in Dublin in 1994. I had been involved in a small research project with patients with ME/CFS, and that conference sparked my interest further. Research into the illness was just beginning to tick over and I remember a presentation by Mary Ann Fletcher on the role of the immune system – citing NK cells and cytokines – a new language for me, as a GP seeing a few patients with the illness – already acknowledged as some sort of “expert” in NZ as I had actually heard of the illness (dubbed Royal Fee disease when I was a student in London). From then on I was caught, and since then have attended many International ME/CFS conferences including many of the previous nine organised by Invest in ME, headed by Kathleen McCall. I have gradually learnt the “language” which seems to grow by the year, and I am sure what I have learnt can have only increased my understanding of this complex illness, and hopefully benefitted my patients. At that first Invest in ME conference we heard of the work of Jonathan Kerr identifying genomic changes – an exciting development. Dr Ros Vallings Dr. Rosamund Vallings has over three decades experience in the field of CFS / ME and is one of New Zealand’s leading authority on the disease. She was recognized by the Queen in the 2008 New Year’s Honours when awarded the New Zealand Order of Merit (MNZM). Dr. Vallings has served voluntarily for over 27 years as President of the ANZMES and latterly as Medical Advisor and Committee Member Invest in ME is a remarkable organization. From small beginnings and hard fundraising, it has grown to be internationally acknowledged as a unique leader, both in conference organization and spreading information worldwide about ME/CFS. The conferences have become particularly special with the inclusion of closed symposia for over 80 invited attendees ahead of the conference itself. This year will be the 5th such addition and will spread over 2 days. These symposia/colloquia are unique in that, as well as specially invited top ME/CFS researchers and clinicians, invitees have included researchers from other disciplines with potential Invest in ME (Charity Nr. 1114035) www.investinme.org Page 10 of 57 Journal of IiME Volume 9 Issue 1 for interest in the field. This gives the researchers an opportunity to discuss ideas and network among themselves. As a result the planned idea of collaborative research encompassing many fields of medicine has emerged. The symposia have been then followed by the more traditional one day conferences with a range of invited speakers – the leaders in their fields of research. Attendees have included patients, clinicians, research scientists and supporters. There is always a buzz of anticipation and no-one is ever disappointed. Work presented is always backed by reliable research. Having attended a number of these meetings now, I feel I have learnt a lot watching the growth of research, acknowledgement of the illness and clinical management. From the small beginnings when we knew this illness was real and in some way tied in with the immune system, I have watched the research evolve to encompass every system of the human body. Science has grown alongside, so that many investigative interventions are now possible, including in depth evaluation of the immune system, microbiological and biochemical studies, advanced brain scanning techniques etc. The search for a biomarker and potential treatment options provide much hope for the future. Inevitably there have been hiccups over the years, with new ideas such as XMRV disappointingly thwarted, but that happens in every branch of medicine. Drugs are now being trialled, and particular inspiration has come from the work of our Norwegian colleagues. Many countries around the world are now involved in research into ME/CFS and clinicians worldwide are better informed. These IiME conferences and symposia have also provided a wonderful opportunity for clinicians and researchers (some of whom are often quite isolated in their own setting) to get to know May 2015 each other well, and have ongoing communication and peer support. So what of the future? I think that our growing understanding of the immune system and its complexity is holding many answers. We know now that the workings of the immune system are interspersed throughout the whole body and involve brain, gastrointestinal tract and many other organs. This helps us understand why this illness is so widespread. Muscle pathology and issues associated with auto-immunity hold promise. This is a multisystem illness, with many potential causes, including likely genetic vulnerability. Finding a biomarker will give credibility to the illness, but what patients need is more specific treatment. At present we can offer management strategies and medication based on individual needs. Drug trials are underway looking at autoimmunity, anti-viral agents etc. Paediatric issues are being addressed by a committee set up to provide guidelines for children with ME/CFS. Those with very severe illness have very special needs too. Invest in ME provides an ongoing forum for development of greater understanding of this complex illness. So much has been clarified from what seemed so complicated to me in the early days. Medicine is never static and we will all go on learning, particularly due to the supreme efforts of organisations such as Invest in ME. Thank you, Kathleen and all at IiME for your work in producing these conferences, so that gradually the answers for our many patients will be forthcoming. ROSAMUND VALLINGS, MNZM Invest in ME (Charity Nr. 1114035) www.investinme.org Page 11 of 57

Journal of IiME Volume 9 Issue 1 How to Get All Trials Reported: Audit, Better Data, and Individual Accountability Editorial comment: Although Invest in ME share little in common with this author’s views on ME we do feel this article about the publication of research data is useful and would be interesting if applied to the publicly funded PACE Trial, where data has been refused to be released to the public despite Freedom of Information requests. In this week’s PLOS Medicine, the World Health Organization (WHO) publishes a landmark position statement, requiring all trials to make their methods and results available [1]. This represents important progress on a longstanding and global structural problem that has a clear, negative impact on patient care. The best currently available evidence shows that the methods and results of clinical trials are routinely withheld from doctors, researchers, and patients [2–5], undermining our best efforts at informed decision making. From this point forward, whenever the methods and results of a trial are withheld, doctors, patients, researchers, campaigners, and health care providers will be able to point at an unambiguous statement from WHO. Delivering definitive change, however, will require more than positive statements and good intentions. The first quantitative data demonstrating publication bias in clinical trials—and clear call for trial registries—was published in 1986 [6]. Anyone withholding the methods and results of a clinical trial is already in breach of multiple codes and regulations, including the Declaration of Helsinki, various promises from industry and professional bodies, and, in many cases, the United States Food and Drug Administration (FDA) Amendment Act of 2007. Indeed, a recently published cohort study of trials in clinicaltrials.gov found that more About the Author Ben Goldacre Senior Clinical Research Fellow, Centre for EvidenceBased Medicine, Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom Research Fellow, Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom DOI: 10.1371/journal.pmed.1001821 Citation: Goldacre B (2015) How to Get All Trials Reported: Audit, Better Data, and Individual Accountability. PLoS Med 12(4): e1001821. doi:10.1371/journal.pmed.1001821 Published: April 14, 2015 Copyright: © 2015 Ben Goldacre. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Funding: No specific funding was received for this work. BG is currently funded by the Wellcome Trust and the Laura and John Arnold Foundation. Competing interests: BG is a co-founder of AllTrials.net, which campaigns internationally for all trials to be registered with their full methods and results available. BG receives academic funding from the Wellcome Trust, and the Laura and John Arnold Foundation, to work on various problems, including publication bias. BG receives income from popular science books and public speaking on problems in science, including publication bias. Provenance: Commissioned; not externally peer reviewed Invest in ME (Charity Nr. 1114035) www.investinme.org Page 12 of 57 May 2015 Journal of IiME Volume 9 Issue 1 than half had failed to post results; and even though the FDA is entitled to issue fines of $10,000 a day for transgressions, no such fines have ever been levied [3]. In the face of such slow progress, this commentary sets out some practical suggestions for auditing, performance tables, accountability, codes of conduct, and better data that should help to drive up standards and prevent trial reports being withheld from those who need them most. What Should Trials Transparency Look Like, and How Do We Achieve It? The WHO statement calls for summary results to be both posted on a registry and submitted to a journal within 12 months. However, it is worth noting that academic journal publication may ultimately prove to be a red herring, as an indicator of transparency. Academic publishing decisions can be arbitrary, and introduce lengthy delays in access to knowledge. Furthermore, there is a growing body of evidence demonstrating that journals often fall short of the basic expected standards for reporting of clinical trials. It is commonplace to find that primary outcomes have been switched, for example [7]; findings are routinely “spun” [8]; and compliance with reporting standards such as CONSORT is highly variable. When compared with the long and formal structured Clinical Study Reports created for all industrysponsored trials, academic papers have been shown to be incomplete and inconsistent [9]. However, since all clinical trials are fundamentally similar—when compared, for example, with the myriad study designs in molecular biology—it has been possible to develop reporting standards and operationalise these. Reporting results onto a structured database, such as the results tab of clinicaltrials.gov [10], has many preferable features: there is minimal delay, there is compulsory reporting of features that are required; and there is no possibility to switch pre-specified outcomes or other forms of May 2015 reporting misconduct. Put simply, there is a box to report the pre-specified primary outcome, and it has to be filled. Recent research has shown that academic journal reports are inconsistent with those on clinicaltrials.gov [2] and contain less complete information on methods, results, and adverse events [11]. Furthermore, International Committee of Medical Journal Editors (ICMJE) member journals have explicitly stated that they will not reject trial reports on the grounds that the results have already appeared on clinicaltrials.gov, and that they do not regard registry results reporting as prior publication [12]. Lastly, clinicaltrials.gov is clear that they will accept results on any trial, from any era, on any treatment, from any territory. This negates a key defence commonly cited by trialists and sponsors when facing calls for greater transparency: that journals reject “negative” results. All trials can now be reported, immediately, using clinicaltrials.gov as a first or last resort, if the trialist is willing. The question remains: how can we ensure this is done? The Need for Audit One key element is likely to lie in medicine’s most basic research tool. Audits are routinely conducted on local service issues, such as infection rates, or waiting times, but rarely on broader structural issues such as publication bias, even though the impact of the latter on patient care is likely to be greater and global. Indeed, it is peculiar that for many years trial registration was considered an end in itself, when in reality registration is only of value as the raw material for publication audit. The basic structure for a routine ongoing audit of results reporting is simple: using a register, identify trials that completed more than 12 months ago; establish, through whatever means, whether results from the trial have been reported; and post the date of results appearing to the register. From this, it is trivial to derive performance metrics for individual companies, Invest in ME (Charity Nr. 1114035) www.investinme.org Page 13 of 57

Journal of IiME Volume 9 Issue 1 funders, drugs, disease areas, institutions, and investigators. This is highly specific and accountable information that can be used for practical good. Firstly, the very act of creating such data would allow us to name and shame poor performers, and also to reward best practice. Furthermore, those falling behind can identify and learn from those who are successfully meeting their obligations to patients. The results of the audit can also be used to inform medical decision making. While it is unwise for doctors to use their prescription pads to pursue political goals, transparency metrics for an individual drug company are valuable context for interpreting data on the benefits of their products. For example, suppose there are two treatments of apparently equal benefit in meta-analysis, but one is made by a company with a proven track record of complete transparency, with 95% of all information available, while the other is made by a company with clear record of withholding information. The clinically cautious approach is to prescribe the treatment for which the results are more reliable, from the company that is more transparent. May 2015 ●● ● “Withholding the results of clinical trials is unethical and harms patients. Those guilty of such misconduct could be banned from Professional bodies and professional regulators, similarly, can now incorporate the WHO guidance into their codes of conduct and create mechanisms to ensure it is acted upon, for example by opening formal investigations when contacted over concerns around results being withheld by individual researchers or clinicians, and triggering disciplinary action whenever audit shows that the codes have been broken. It is rare, in professional regulation, to have data on transgressions created so rapidly and so unambiguously; it would be wrong to neglect this opportunity to improve standards. Patient groups, lastly, could write open letters to all companies and researchers withholding methods and results of trials on treatments taken by their members, represent their constituencies by holding individuals to reasonable account, and again help improve compliance. conducting further trials on patients” ●● ● The Practicalities of Audit Such audit can be conducted locally, centrally, or ideally, both. Since the recent rejuvenation in policy discussion in the United Kingdom on withheld trials, there have been small local audits Audit data can also be used by ethics committees and institutional review boards (IRBs). Withholding the results of clinical trials is unethical and harms patients. Those guilty of such misconduct could be banned from conducting further trials on patients until their previous trials have been made available. Indeed, even in the absence of such audit data, it would be trivial for all IRBs to ask one simple question of all those applying to conduct a trial: “Have you been involved in any clinical trial, which completed more than 12 months ago, for which the results remain inaccessible?” conducted by various bodies, including sections of the Health Research Authority (as yet unpublished); the National Institute of Health Research (as yet unpublished); the Medical Research Council (to produce an estimate of publication bias for a 2012 UK parliamentary inquiry into trials transparency [13], but as yet unpublished); and an ongoing audit, on which I am a collaborator, covering trials in the University of Oxford. For the latter, alongside our findings, we also plan to publish our practical experiences of conducting the audit, with a boilerplate protocol that can be used by others in order to help make local audits simpler and produce comparable data. Such audits could and should be conducted and published routinely by all government research funders, Invest in ME (Charity Nr. 1114035) www.investinme.org Page 14 of 57 Journal of IiME Volume 9 Issue 1 industry sponsors, and institutions, to help ensure that all trials are reported. Central audit is also desirable, and can be readily worked into existing trial registry workflows. At present, a completed trial without an associated results report on a registry may represent a transgression, but it may also represent an administrative failure. Publishing performance data and acting upon it will incentivise trialists to update their records. Worse still, it is currently impossible to establish on clinicaltrials.gov whether a completed trial has successfully requested an extension for reporting (whatever one might think of such exemptions), because this information is not posted; if data fields on such exceptions are routinely and transparently posted in public onto the database, compliance and transparency rankings can be automatically generated at no cost. When discussing efficiencies, it is important to be clear, however, that the cost of even manual audit is trivial in comparison to the cost of conducting a randomised trial. Producing accessible knowledge for clinical decision making is the key purpose of a trial. Once a trial has been conducted—at great cost—and left unreported, then the small and final marginal cost of making its results available represents better value for money than almost any other step in the research process. What to Do about Past Trials The emphasis by WHO on having access to all trials, from the past as well as the future, is particularly important and welcome. It is clinically highly relevant because the overwhelming majority of prescriptions today are for treatments that came onto the market— and were therefore researched—over the preceding decades rather than the past five years. The question, however, is how to May 2015 ●● ● “We cannot make truly informed decisions when vitally important prioritise access to such information, since there is no sense in resources being deployed on sharing evidence that is no longer relevant to current practice. There are many options. One is to proactively release information, prioritising by some metric of clinical need, such as the number of patients affected; or usage, such as the number of prescriptions issued for that class of treatments; or even a complex model built around power calculations and the likelihood of the withheld data changing the conclusions of the best current systematic review. information on the methods and results of clinical trials is routinely withheld” ●● ● A simpler option, however, is for thorough retrospective registration of clinical trials to act as a “menu” from which doctors, researchers, and patients can request further disclosure of full methods and results, with appropriate transparency around the request and adjudication process. This is an attractive option since registration is low cost, but it does present one previously undocumented challenge. Through the AllTrials.net campaign, we are currently conducting an audit of companies’ policies on trials transparency, to create a Trials Transparency Index. In doing so, we have met a large number of individual companies to ask about gaps in their policies. One recurring theme, on the issue of retrospective registration, is that registries often require detailed administrative information (such as an IRB approval number) that is not readily traceable 20 years after a trial was completed. It may therefore be pragmatic to take a more permissive approach to completeness of certain data fields, with missing items replaced by an explanatory note where absolutely necessary, in preference to a trial not being retrospectively registered at all. Conclusion The position statement from WHO is powerful and welcome, but previous calls for registration were not enough to fix publication bias, and Invest in ME (Charity Nr. 1114035) www.investinme.org Page 15 of 57

Journal of IiME Volume 9 Issue 1 positive statements require practical implementation. The solution is likely to lie in simple audit, providing better data for individual accountability. This can be delivered at low cost through a routine audit cycle to identify completed but unreported trials on all registries, with public performance tables that will incentivise trialists to ensure their registry entries reflect their compliance. Local audit will facilitate data-checking and ensure local accountability. As with all audit cycles throughout clinical practice this data must be acted on, with those who are guilty of research misconduct in withheld trials exposed to public scrutiny and local performance management; investigations automatically triggered by their professional regulators; and denied access to further trial participants. Lastly, doctors and patients can act on withheld data exposed by audit and consider avoiding treatments—or indeed whole companies—where there is clear evidence that the data on those interventions is comparatively unreliable. These are simple processes that should have been integrated into the information ecosystem of evidence-based medicine from the outset. We cannot make truly informed decisions when vitally important information on the methods and results of clinical trials is routinely withheld, and yet we have tolerated this simple, fixable, pervasive flaw in evidence-based medicine for many decades. The doctors and patients of the future may well look back on this phenomenon with amazement, much as we look back on mediaeval bloodletting. Author Contributions Wrote the paper: BG. Agrees with manuscript results and conclusions: BG. BG has read, and agrees that he meets, ICMJE criteria for authorship. References 1.Moorthy VS, Karam G, Vannice KS, Kieny M-P. Rationale for WHO's New Position Calling for Prompt Reporting and Public Disclosure of Interventional Clinical Trial Results. PLoS Med. May 2015 2015 Apr 14; 12(4): e1001819. doi: 10.1371/journal.pmed.1001819. 2.Hartung DM, Zarin DA, Guise J-M, McDonagh M, Paynter R, Helfand M. Reporting discrepancies between the ClinicalTrials.gov results database and peer-reviewed publications. Ann Intern Med. 2014 Apr 1;160(7):477–83. doi: 10.7326/M13-0480. pmid:24687070 3.Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J, Califf RM. Compliance with Results Reporting at ClinicalTrials.gov. N Engl J Med. 2015 Mar 12;372(11):1031–9. doi: 10.1056/NEJMsa1409364. pmid:25760355 4.Ross JS, Tse T, Zarin DA, Xu H, Zhou L, Krumholz HM. Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis. BMJ. 2012;344:d7292. doi: 10.1136/bmj.d7292. pmid:22214755 5.Jones CW, Handler L, Crowell KE, Keil LG, Weaver MA, Platts-Mills TF. Non-publication of large randomized clinical trials: cross sectional analysis. BMJ. 2013 Oct 29;347:f6104. doi: 10.1136/bmj.f6104. pmid:24169943 6.Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol. 1986 Oct 1;4(10):1529–41. pmid:3760920 7.Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P. Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials. JAMA. 2009 Sep 2;302(9):977–84. doi: 10.1001/jama.2009.1242. pmid:19724045 8.Boutron I, Dutton S, Ravaud P, Altman DG. Reporting and Interpretation of Randomized Controlled Trials With Statistically Nonsignificant Results for Primary Outcomes. JAMA. 2010 May 26;303(20):2058–64. doi: 10.1001/jama.2010.651. pmid:20501928 9.Wieseler B, Wolfram N, McGauran N, Kerekes MF, Vervölgyi V, Kohlepp P, et al. Completeness of Reporting of Patient-Relevant Clinical Trial Outcomes: Comparison of Unpublished Clinical Study Reports with Publicly Available Data. PLoS Med. 2013 Oct8;10(10):e1001526. doi: 10.1371/journal.pmed.1001526. pmid:24115912 10.Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials. gov results database—update and key issues. N Engl J Med. 2011;364(9):852–60. doi: 10.1056/NEJMsa1012065. pmid:21366476 11.Riveros C, Dechartres A, Perrodeau E, Haneef R, Boutron I, Ravaud P. Timing and Completeness of Trial Results Posted at ClinicalTrials.gov and Published in Journals. PLoS Med. 2013 Dec3;10(12):e1001566. doi: 10.1371/journal.pmed.1001566. pmid:24311990 12.ICMJE. ICMJE | About ICMJE | Clinical Trials Registration. 2014.http://www.icmje.org/about-icmje/faqs/clinical-trialsregistration/. Accessed 20 March 2015. 13.House of Commons Science and Technology Select Committee. Inquiry into Clinical Trials Transparency, note 305. 2013. http://www.publications.parliament.uk/pa /cm201314/cmselect/cmsctech/104/10407.htm#note305. Accessed 20 March 2015. From http://www.plosmedicine.org/article/comments/info%3Adoi% 2F10.1371%2Fjournal.pmed.1001821 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 16 of 57 Journal of IiME Volume 9 Issue 1 May 2015 ME: The Last and The Next Ten Years What a difference a decade makes in medicine - - or does it? The two camps in the ME/CFS “battle” remain as far apart as ever, to the continuing detriment of patients and also to the State’s limited resources: it is currently claimed that the cost of “CFS” to the UK economy is up to £3.5 billion per annum. One camp consists of biomedical scientists and clinicians whose research shows that ME is an organic multi-system neuro-immune disorder with protean symptomatology; some consider it likely to be an autoimmune disease with the target organ being the vascular endothelium. The other camp consists of a small but influential group of UK psychiatrists and insurance doctors (known colloquially as the “Wessely School”) who remain convinced that what they refer to as “CFS/ME” is a psychogenic condition where reported symptoms result not from organic disease but from patients' maladaptive beliefs and behaviour, and that the condition can be fully reversed by graded exercise and cognitive behavioural therapy. Currently we are at a tipping point, because the “behavioural” camp is slowly but surely being unseated. In the last ten years the quintessence of the ME battleground in the UK has been the focus on pseudoscience, but there is at last a transition underway from pseudoscience to scientific medicine. Here are some facts, all easily verifiable: Since 2005, ME has been included in the UK National Service Framework for long-term neurological conditions. On 30th January 2006 the then Health Minister, Lord Warner, said on the record: “There is only one World Health Organisation International Classification of Diseases code for chronic fatigue syndrome/myalgic encephalomyelitis, which is G93.3” (HL3612). About the Author Margaret Williams has been a prolific writer on the subject of ME over the last two decades or more. Her thorough and meticulous commentaries on the inaccuracies, bias and often farcical claims of the psychosocial lobby have aided the ME community in destroying the myths and spin which has been allowed to foster by establishment organisations. A great debt is owed to Margaret Williams for her dedication and professional input to science for the benefit of all people with ME and their families On 2nd June 2008 the Parliamentary UnderSecretary of State, Department of Health (Lord Darzi of Denham) stated: “My Lords, the Government accept the World Health Organisation’s classification of CFS/ME as a neurological condition….My Lords, I have acknowledged that CFS/ME is a neurological condition” (HLPQ: Health: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis). On 21st November 2011 Lord Freud, Minister for Welfare Reform, confirmed in a letter to the Countess of Mar that the Department for Work and Pensions does not consider ME/CFS to be a mental disorder. The letter was unequivocal: “The Department of Health has indicated that they have ‘always relied on the definition set out by the World Health Organisation in its International Classification of diseases (ICD) under ICD code G93.3, subheading other disorders of the brain’. The DWP is in agreement with this view. Therefore, for the avoidance of doubt, I can be clear that the Department does not classify CFS/ME as a mental health disorder”. Despite Ministers’ clear pronouncements, given that key members of the “behavioural” camp have acquired formidable powers and have Invest in ME (Charity Nr. 1114035) www.investinme.org Page 17 of 57

Journal of IiME Volume 9 Issue 1 secured established positions as advisors on “CFS/ME” to UK Departments of State, including the Department of Health and the Department for Work and Pensions, and also to bodies such as the Medical Research Council (MRC) and NICE (the National Institute for Health and Care Excellence), it is their behavioural modification interventions (ie. “brain-washing”) that prevail throughout the NHS, with the risk of serious iatrogenic harm to patients with ME/CFS. Many informed observers believe that within the next ten years this situation will be seen for what it is – a truly appalling medical scandal of astounding proportions, but it is a scandal that (via the auspices of the Science Media Centre and the UK media) many UK luminaries, have condoned without question, (http://www.sciencemediacentre.org/film/); (http://www.meactionuk.org.uk/The-SMC-andits-campaign-against-MECFS.htm). The “evidence” of the “behavioural” camp The PACE trial (Pacing, Activity, and Cognitive behavioural therapy, a randomised Evaluation) is by far the most contentious clinical research study conducted in the field in the last ten years. Conceived and executed by psychiatrists Professors Peter White and Michael Sharpe, assisted by a behaviour therapist, Professor Trudie Chalder, it was funded by the MRC, the Scottish Chief Scientist’s Office, the Department of Health and the Department for Work and Pensions. The PACE Trial is the only clinical trial that the DWP has ever funded and it did so because it was assured that cognitive “restructuring” would successfully remove people with ME/CFS from claiming State benefits. Recruiting began in 2004 and finished in November 2008. Problems with the PACE trial were legion, a particular one being that CBT and GET participants (but not those in other arms of the trial) were instructed to ignore their symptoms. May 2015 Such advice has previously been described as “dangerous” in a Witness Statement for the High Court (http://www.meactionuk.org.uk/Statements-ofConcern-for-High-Court.htm). After the trial had started the Principal Investigators abandoned the protocol-defined thresholds for fatigue and physical function required for a "positive outcome" and "recovery" and replaced them with far less demanding criteria. These changes were such that it became possible to leave the trial with greater fatigue and worsened physical function and still meet the newly-defined thresholds of “the normal range” (this is not the same as normal health, but the media was encouraged to report it as synonymous with “recovery”). The recalculation and construction of “the normal range” allowed the claim that participants had “recovered”: “This study confirms that recovery from CFS is possible and that CBT and GET are the therapies most likely to lead to recovery” (PD White et al: Psychological Medicine: 2013: doi:10.1017/S0033291713000020). ●● ● “Numerous FOIA requests for the raw data (which does not belong to the Investigators but to UK taxpayers) to be released have been refused on entirely spurious grounds” ●● ● The Investigators initially claimed that the PACE trial was to study “CFS/ME” but after publication in The Lancet of selective results in February 2011, the Chief Principal Investigator (Professor Peter White) wrote to the editor in March 2011 saying that the PACE trial “does not purport to be studying CFS/ME but CFS simply defined as a principal complaint of fatigue”. This was a cause for concern, because funding and ethical approval had been sought and obtained on the basis that the Investigators would be studying “CFS/ME”, not “fatigue”. The PACE trial cost UK taxpayers over £5 million and, despite desperate and increasingly ludicrous attempts to proclaim its success, it is widely acknowledged to have failed (http://www.bmj.com/content/350/bmj.h227/rapi Invest in ME (Charity Nr. 1114035) www.investinme.org Page 18 of 57 Journal of IiME Volume 9 Issue 1 d-responses) and, far from reducing claims for benefits, participants’ claims for benefits due to illness or disability actually increased from baseline to follow-up (McCrone et al PLoS ONE 7(8): e40808. doi:10.1371/journal.pone.0040808). Numerous FOIA requests for the raw data (which does not belong to the Investigators but to UK tax-payers) to be released have been refused on entirely spurious grounds, lending yet more support to the widespread opinion that release would conclusively demonstrate the failure of CBT and GET as vehicles for recovery from ME/CFS, indicating that their proponents have spent their professional lives in a null field. Given that there is an acknowledged nationwide lack of basic services for ME patients and that most have no access to NHS consultants and never get to see a neurologist, immunologist, endocrinologist or vascular specialist and even have profound difficulty in seeing a GP, the claim that the cost to the UK economy of “CFS” alone is £3.5 billion per annum is questionable (J Psychosom Res. 2012;72:242–7). Patients with ME/CFS experience real difficulty in seeing a GP: not only do many GPs refuse to accept that it is a legitimate disorder, but after the BMJ ran a campaign to list “non-existent” diseases that are best left untreated, in which ME features along with big ears and freckles (BMJ 2002:324:883885) patients with ME were removed from GPs’ lists, being tersely informed that: “This practice does not treat non-existent diseases”. The two major US institutions that -- despite the glowing reports of the PACE trial’s claimed success -- have revised their position on ME/CFS are the NIH and the CDC. (1) The US National Institutes of Health, one of the world’s foremost medical research centres, convened a Pathways to Prevention working group which in December 2014 published its draft Statement entitled “Advancing the Research on Myalgic Encephalomyelitis / Chronic Fatigue Syndrome”. It is an important document, as it signifies a major change in attitude towards ME/CFS and casts further May 2015 doubt on the claimed success of the PACE Trial. The NIH Statement is unambiguous that the Oxford criteria (formulated by the Wessely School themselves and used in the PACE trial) are flawed and lack reliability, thereby confounding the ability to interpret results drawn from studies which used them to select cohorts and noting that use of the Oxford criteria may impair progress and cause harm. This being so, it can be surmised that all previous psychiatric “research” on ME/CFS that used the Oxford criteria (not just the PACE trial) used groups of people who were not properly characterised and thus those results also lack scientific credibility. The following quotations from the NIH are particularly significant: “ME/CFS exists. “The Oxford criteria (published in the Journal of the Royal Society of Medicine in February 1991) are flawed and include people with other conditions, confounding the ability to interpret the science. “Often, patients with ME/CFS are labelled as lazy, deconditioned, and disability-seeking; this hampers scientific progress. Both society and the medical profession often treat patients with ME/CFS with disdain, suspicion, and disrespect. Patients are frequently treated with psychiatric and other inappropriate drugs that may cause harm. “There is reproducible evidence of neurocognitive dysfunction with abnormalities in functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies. Strong evidence indicates immunologic and inflammatory pathologies, neurotransmitter signalling disruption, microbiome perturbation, and metabolic or mitochondrial abnormalities in ME/CFS. “This is not a psychological disease in aetiology. “Existing treatment studies (CBT and GET)…(have) not translated to improvements in quality of life. Thus, they are not a primary treatment strategy. “The focus on exercise programmes has further stigmatised and discouraged research participation. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 19 of 57

Journal of IiME Volume 9 Issue 1 “Many patients with ME/CFS are misdiagnosed and treated erroneously with potentially toxic therapies that may cause harm. “Current research has neglected many of the biological factors underlying ME/CFS onset and progression. “ME/CFS is a chronic, complex condition…with no cure…..Nothing has improved the lives of the patients. “fMRI and imaging technologies should be further studied as diagnostic tools and as methods to better understand the neurologic dysfunction of ME/CFS. The Conclusions of the draft report reiterate key findings: “Specifically, continuing to use the Oxford definition may impair progress and cause harm…Thus, for needed progress to occur we recommend that the Oxford definition be retired”. May 2015 ●● ● there are new rules of consent and doctors are legally accountable for informing patients of any material risks in any recommended medical interventions (BMJ 2015:350:h1481). This means that psychiatrists who recommend graded exercise therapy for people with ME/CFS must warn them of the potential risks of deterioration with exercise, or be in breach of the law. To many people, it also means that having to inform patients with ME/CFS of the risks of GET (because of the increased cardiovascular risk, which would have to be explained to patients) invalidates the belief that patients are suffering from a behavioural as opposed to a physical disorder. “psychiatrists who recommend graded exercise therapy for people with ME/CFS must warn them of the potential risks of deterioration with exercise, or be in breach of the law” ●● ● https://prevention.nih.gov/docs/programs/mecfs /ODP-MECFS-DraftReport.pdf Since such strong doubts have been raised about the Oxford criteria, the question again arises about the validity and safety of the NICE Clinical Guideline on ME/CFS (CG53) which relies so heavily on Oxford criteria-based research and which promotes directive (not supportive) CBT and GET as the primary intervention for those with ME/CFS. In the light of current knowledge, whether or not clinicians should rely on the NICE Guideline has become ever more imperative, especially in the light of the recent UK Supreme Court ruling that overturned the long-held Bolam principle (a test used to assess medical negligence; it held that a doctor was not negligent if his actions would be supported by a responsible body of medical opinion; indeed, the accused doctor needed only to find an expert who would testify to having done the same thing). This has now changed: The latest NIH draft Statement confirms the long-held belief that the NICE Guideline on ME/CFS should be withdrawn because, as many have claimed from the time it was published in August 2007, it was never fit for purpose, and further doubt must now arise as to how safe it is. Indeed, this has now been acknowledged: in June 2014 Professor Mark Baker, Director of the Centre for Clinical Practice at NICE, said at the Forward-ME Meeting at the House of Lords that the NICE Guideline was no longer meeting the needs of people with ME/CFS and should be replaced. (2) After publication on 10th February 2015 of the Institute of Medicine’s Committee’s report (Beyond ME/CFS: Redefining an Illness), the US Centres for Disease Control decided to archive its CFS Toolkit that recommended CBT and GET as interventions for ME/CFS. The conclusion of the IOM Report states: “It is clear from the evidence compiled by the committee that ME/CFS is a serious, chronic, complex, and multisystem disease that frequently and dramatically limits the activities of affected patients” (http://www.cdc.gov/cfs/toolkit/archived.html). The “behavioural” school continues to ignore the evidence (not hypotheses) documented for ME/CFS. The evidence is now so strong that Invest in ME (Charity Nr. 1114035) www.investinme.org Page 20 of 57 Journal of IiME Volume 9 Issue 1 ME/CFS is a serious multi-system neuroimmune disorder that it becomes intellectually embarrassing for anyone to continue to consider it to be a behavioural disorder. Recent research from the US posits that true ME (as distinct from ubiquitous chronic “fatigue”) is an autoimmune disorder: “Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift towards an allergic or T-helper type-2 pattern associated with autoimmunity….Profiles of ME/CFS subjects also differed from those of MS subjects, with ME/CFS cases showing a markedly greater degree of central nervous system immune activation as compared with those with MS” (M. Hornig et al; Molecular Psychiatry 31st 2015: doi:10.1038/mp.2015.29). March Dr Oystein Fluge and Professor Olav Mella from Haukeland, Norway, have conducted several studies of the cancer drug rituximab (a monoclonal antibody that targets and destroys the body’s B cells, which recover once treatment ceases) on ME/CFS patients. Their theory is that ME/CFS is a variant of an autoimmune disease that affects the body’s ability to control blood flow. World-class experts like Fluge and Mella would not use anti-cancer drugs like methotrexate, cyclophosphamide and rituximab, all of which carry a black box warning, if they believed ME/CFS to be a behavioural disorder; the difference between Fluge and Mella and the “behavioural” psychiatrists is that the former actually listen to their patients whilst the latter prefer to impose their own beliefs and control their patients’ behaviour. The above are merely illustrations of some of the many important biomedical research findings published on ME/CFS in the last ten years. After almost 30 years of UK health care providers’ dismissal and mistreatment patients with ME/CFS are aware that finally, a paradigm shift is occurring and the psychiatrists’ May 2015 stranglehold over their disease is being loosened. That this is so is thanks to charities like Invest in ME who, quietly but resolutely, have done so much to bring about that paradigm change. During the next ten years, it is likely that the link between the immune defects found in ME/CFS and an infectious or environmental trigger will be discovered and, without doubt, ME/CFS will be added to the long list of organic disorders (including epilepsy, myasthenia gravis, MS, diabetes, migraine, pernicious anaemia, ulcerative colitis, gastric ulcer and Parkinsons) which psychiatrists forcefully asserted were psychogenic until medical science proved otherwise. ME PATIENT “A fellow member of the Let's Do It For ME fundraising team for IIME has written this on my behalf as I am too ill to do it myself. I have very severe ME. I got ME at the age of 8. I am now 23. Like some other serious illnesses, ME can fluctuate in severity. You can see from the photos in the picture gallery that whenever well enough, I was out being involved and enjoying life to the best of my ability. My health took a bad turn for the worse in 2012. I went into hospital and then to a nursing home, fed by naso-jejunum tube. The staff helped me and my family to celebrate my 21st birthday there by raising awareness and funds for Invest in ME to help them set up a UK centre of excellence for research and hopefully treatment. People like me with ME desperately need this. I am being cared for at home now and can listen to audio books for about 15 minutes in the morning and cuddle my guinea pig in the evening. That is all the daily activity I can do with my current level of illness severity. I am asking you to sponsor me to listen to audio books. Thank you for helping me to help IIME.” Rosa from IiME’s JustGiving pages https://www.justgiving.com/investinm-e/ Invest in ME (Charity Nr. 1114035) www.investinme.org Page 21 of 57

Journal of IiME Volume 9 Issue 1 May 2015 ME/CFS – Through The Eyes of a Young Researcher Before I start I would like to introduce myself. I am a 24-year-old researcher (student). I am originally from the Netherlands where I completed a Masters degree in Infection and Immunity. I came to work with Dr. Cambridge because we share the same interest in B cells, their development, functioning and relation within diseases. She told me that she was going to work on a project on ME/CFS, a disease I had heard of, but did not know the details from. The only thing I was told was that it is a disease with unknown aetiology with possible involvement of white blood cells called B cells. To learn more about the disease I started reading papers on what was known before I started the research. Quite quickly I came to the conclusion that it really was a difficult disease to talk about with people, not to mention actually being involved in research. So I just told myself, to get involved in the study and that will hopefully clarify the phenomena of the disease (I hope). So we formed our small ME/CFS Research Team with the collaboration of Dr. Saul Berkovitz (Consultant Neurologist, UCLH), Dr. Amolak Bansal (Consultant Immunologist, St Helier Hospital), Dr. Arti Sharma (Research coordinator), Dr. Cambridge and myself. We made a plan of how to collect the samples needed, organized ourselves and solved the many logistic issues for the project in a few very busy months. Fane Mensah University College London The process was relatively straightforward; ME/CFS patients who had been seen and assessed by the two Consultants were invited for an appointment with Dr. Sharma and myself. I saw these appointments as a great opportunity to educate myself and see with my own eyes what ME/CFS really involves. After a few appointments and some formal discussions with patients (and family members) ME/CFS started to make sense to me. Not the scientific immunological or neurological part (which was my main task), but the part of how this disease affects people who used to be healthy (young or old, at the beginning of a career or just in the middle) and now became patients of a disease without a clear diagnostic pattern and no biomedical therapeutic strategy. Before I went into the lab to perform the research with the group, I already knew that I now wanted to explore this rare, but so *affecting disease. Not just to perform B cell analysis in these patients, but also because of my interest in this condition and my wish to really try and understand the disease. Patients (ME/CFS) rely on researchers and doctors to provide them with answers to their questions (something they expect from us), but something that has been often ignored by GPs and even in some cases specialists. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 22 of 57 Journal of IiME Volume 9 Issue 1 This is not an easy situation, because we cannot always give answers to things we are not certain of. But what we can do is educate ourselves by performing research, instead of ignoring the disease or giving false answers. Luckily, there are groups who try to solve the phenomena behind ME/CFS and funders like Invest in ME who play a really important role in this. I mention the words “education” and “research”, simply because it is an important area which has to be paid attention to! A lot of papers have been published in the last few years, something, which keeps fundraisers, patients and researchers positive. Although, it is still difficult to fully assess the implication or the interpretation of the findings related to ME/CFS (based on virology, immunology, psychology etc.). Due to the heterogeneity in the environment amongst other things, (which make comparisons between different groups of patients a problem) research is often difficult to reproduce. Another issue is the comparison of ‘healthy controls’ with ME/CFS Patients. Just like ME/CFS patients, healthy controls are also heterogeneous (as we all know everyone is different). The big difference between ME/CFS and other diseases is that in other diseases we have a clear symptom-based ‘biomarker’, for example, swollen joints, skin rashes etc. and also diagnostic markers in the blood (antibodies, a clear infection, inflammation etc.), which we can compare with a healthy, if heterogeneous, control group. This could also be a reason why results are not easily reproduced. Therefore, it could be possible to focus on the group of ME/CFS patients as a whole and see if we can compare different sub-groups within ME/CFS similarly to how we want to compare healthy controls with May 2015 ME/CFS patients. I am not saying that we should ignore the results with healthy individuals; we should still use this as measurement for clear differences. Significance may thus not lie in the whole population (patients or even HC) but in a sub-group. Important findings so far describe abnormalities in the immune system and as a result this might affect the nervous system (fatigue and other symptoms), underlying the immune system as an important factor. Instead of thinking of the effect of the immune system on the nervous system, we could also think of an effect or functioning of the nervous system to restore the dysregulated immune homeostasis. It is really important to focus in different areas and systems, because that is where ME/CFS resides “in different areas”. The collaborative board initiated by Invest in ME, combines different groups from over the world in all these different areas. Extending and strengthening relationships and collaborations will bring us closer to answering those questions we and especially the patients want the answer to. ME PATIENT “I've had M.E. for six years now, and it’s an ongoing daily struggle. Not just because it sucks being ill 24 hours a day and having no quality of life but because there is no treatment, minimal support and little medical understanding of this illness. Invest in M.E. are a charity trying to change this.” - Leanne from IiME’s JustGiving pages https://www.justgiving.com/investinm-e/ Invest in ME (Charity Nr. 1114035) www.investinme.org Page 23 of 57

Journal of IiME Volume 9 Issue 1 Better from America? An Analysis of P2P and IOM Reports on ME May 2015 Recently two American institutions have commented on ME – treatment, research and other issues. These reports not only affect US citizens – they can also affect and influence other countries in the way they diagnose and treat peopled with ME or CFS across the world. The significance of these reports is due to the large amount of time and resource invested in analysing diagnostic criteria, past and current research into ME, funding for ME research and other areas associated with the way this disease has been treated and perceived over the last generation. As such it was very interesting to compare the views of these bodies and those which Invest in ME have been advocating during the last nine years. The NIH Pathways to Prevention (P2P) Workshop Report: Advancing the Research on Myalgic Encephalomyelitis / Chronic Fatigue Syndrome was formed to create a research agenda for ME. Invest in ME submitted a full response to the National Institute for Health after reading the full report. Invest in ME urged the NIH to make a bold move and substantially increase funding for biomedical research into ME. A summary of Invest in ME’s comments on the P2P report - Summary ► It proved useful for an outside group of experts to get an overview of ME/CFS research. But it is clearly not possible to do this successfully by just using a scoring method that works for a well-established disease that everyone agrees upon without any knowledge of the underlying history. ► It does not help that research into ME/CFS has had two opposite viewpoints and the P2P document consequently tried to facilitate both. This is a major mistake and is contrary to any common sense or logic. It repeats the calamitous mistakes of the MRC in the UK ► If the statement is made that ME/CFS is a physical disease then recommendations should follow logically from that statement. ► If there are co-morbidities they should be dealt with in the same way as one would do with co-morbidities in MS, cancer or Parkinson’s disease or any other disease. ► We commented that it was, at times, difficult to comprehend what the real objective of this workshop was and we hoped that this was not yet another paper exercise to keep Invest in ME (Charity Nr. 1114035) www.investinme.org Page 24 of 57 Journal of IiME Volume 9 Issue 1 the patient community seemingly happy whilst the authorities do nothing concrete to remedy the current situation ( a tactic used extensively by the establishment for the last ten years). ► It would be well for the NIH NOT to follow the UK example where an insincere effort to change is portrayed as real progress but just results in wasted years. ► The mediocrity in terms of provision of correct and up to date definitions and guidelines, scientific research and development of treatments and perception of ME was a direct result, and failure, of the policies of the past. ► We found the first part of this report described what needs to be done – but there were some incomprehensible references to using treatments which have contributed to the abysmal situation in which ME/CFS patients find themselves. ► We believe research into ME needs a strategic approach - but it is meaningless, and destined to fail completely, if it attempts to establish the way forward on foundations which include so much of what has been wrong in the past. ► For a way forward with proper research into ME then we need not just funding, but correctly defined cohorts, standardisation on diagnostic criteria and a collaborative of researchers who will not blur science with politics. ► The NIH have a unique possibility to be bold, to fix this problem once and for all. Invest in ME suggested the following actions for the NIH to take –  The NIH finally and totally abandon all links to the psychosocial model with regard to ME research funding May 2015  Instead of relying on alternative funding streams elsewhere the NIH should take responsibility themselves for ME/CFS  The NIH should invest $50 million per year for the next five years in biomedical research into ME/CFS, and provide correct and current education into the disease which will, in turn, raise appropriate awareness.  This would mean an investment of $250 million over 5 years. This amount will still be less than the documented annual cost of ME/CFS of $1 billion as noted in line 6.  This will –  create scores of biomedical research projects, lots of potential international collaboration, new ideas and new skills to enter the ME/CFS research area  facilitate the harnessing of the full potential of academic and research institutes  attract new, young researchers into the field of ME/CFS – this the charity has proven already with our BCell/rituximab project with UCL where a young researcher is drawn into this exciting area of research  galvanise science and eventually form pockets of expertise which will create the centres of excellence for the future.  We suggested trying this for a 5 year period  With a yearly review of progress can inform every one of the status.  After 5 years of such funding a new conference/workshop/committee can be convened and progress can be examined.  This will provide the best chance possible for resolving this illness to the benefit of patients.  Our guess is that so much progress will have been made in research, in perception and possibly in treatments during that period that the money will be recouped with the Invest in ME (Charity Nr. 1114035) www.investinme.org Page 25 of 57

Journal of IiME Volume 9 Issue 1 added benefit of giving some people their lives back.  The stigma attached to ME as mentioned in the report – which is actually, in our opinion, just ignorant prejudice created by corrupt organisations and individuals - would be swept away. $50 million per year is really not much. After 5 years it will probably have built so much momentum that it could carry on by itself through savings in welfare, through new discoveries and, yes, through private donations/funding. Invest in ME suggested a beginning by inviting NIH to be represented at our fifth Biomedical Research into ME Colloquium in London on 2728th May 2015 and look the major research initiatives underway or planned. We invited the NIH to be represented there in London – in order to join our international collaboration effort to resolve this illness in a way that brings hope to patients, brings responsible and proper science to the research area and brings a raising of awareness that will obliterate the monstrous distortions about ME/CFS which have poisoned all chance of making progress in the last generation. We received no response. IOM “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness” Invest in ME looked at the full report from the USA Institute of Medicine (IOM). There was no public consultation as happened in the P2P or UK NICE guidelines. The IOM concluded with what has been obvious to patients for a generation – but which has for too long been ignored by governments, research councils, health services and the media “It is clear from the evidence compiled by the committee that ME/CFS is a serious, May 2015 chronic, complex, multisystem disease that frequently and dramatically limits the activities of affected patients.” We summarise below our observations after reading through the full report that we feel are worth noting - ► IOM is a respected and influential institute This means that the good points from this report can be quoted elsewhere to aid convincing other healthcare authorities that ME needs to be treated seriously as a systemic disease. ► IOM performed an extensive literature review. This means that the good points from this report can be quoted elsewhere to aid convincing other ► The proposed new diagnostic criteria are clinical criteria for the US healthcare system and there was only one European (and no UK reviewers) involved - so it remains to be seen whether the UK and other European health care authorities will adopt this report ► The IOM criteria allow co-morbidities which seems sensible for clinical purposes as anyone can have more than one disease. ► Care should be taken to avoid misdiagnoses and this is why specialists are needed to oversee diagnosis ► Post-Exertional Malaise (PEM) is obligatory, not optional, for diagnosis and this is the one Invest in ME (Charity Nr. 1114035) www.investinme.org Page 26 of 57 Journal of IiME Volume 9 Issue 1 defining symptom that patients say was missing from CDC Fukuda ► Both the IOM report and the P2P draft report call for more research and highlight the serious lack of research into this area of medicine compared to the numbers of patients involved ► “Literature on mortality associated with ME/CFS is sparse.” ► Also subgrouping was a task to be analysed by the IOM committee but due to the sparcity of research that was not possible. ► The implicit result of the above commentary is a direct condemnation of the research and funding policies of the UK Medical Research Council and US National Institute for Health ► This report is essentially far better than the UK CFS/ME NICE guidelines which were heavily biased toward CBT and GET and did not encourage, for example, further investigation into the promising IVIG paediatric research (Rowe, 1997) which the IOM does ► The IOM committee declared unequivocally that ME/CFS is a physical illness, a disease ► The IOM definition and the name goes against treatments such as CBT and GET and contradicts the P2P report in that respect. ► The report states that ME/CFS is a diagnosis to be made and provides good suggestions for asking questions and eliciting medical history as well as assessing supportive symptoms such as sleep disturbance and pain. ► There needs to be extensive medical education to make more doctors confident in making the diagnosis but we need centres of excellence (such as proposed by IiME) and experienced consultants to oversee the education. May 2015 ► Diagnosing patients according to them fitting in the diagnostic criteria rather than by exclusion of other illnesses is good. ► One of the committee’s most important conclusions is that a thorough history, physical examination, and targeted work-up are necessary and often sufficient for diagnosis of ME/CFS (a point often emphasized by clinicians speaking at IiME conferences). ► It is also all the more important to invest in fundamental research that can come up with objective and easily implemented tools for aiding diagnostic accuracy. ► “First and foremost, listening to patients and taking a careful history are key diagnostic tools.” ► Patients who have not yet been symptomatic for 6 months should be followed over time to see whether they meet criteria for ME/CFS at a later time. ► The report mentions objective tests such as CPET or tilt test being useful for gaining social security but not necessarily for diagnosis due to risk for worsening the patient's condition ► The report calls for research into biomarkers and acknowledged there being sufficient evidence for immune dysfunction despite there not being reliable markers for clinical use yet ► The report recognises that most patients never regain their pre-illness levels of health or functioning ► The report recognises inappropriate removal of children from their families in some extreme cases – though perhaps more common in the backward UK environment ► The report rejects childhood trauma and somatisation as being part of paediatric cases ► The IOM recognise the adverse impact on education from this disease for children. 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Journal of IiME Volume 9 Issue 1 The isolation for children affected by this disease in school years is a major factor which society needs to address and for which schools need to be criticised due to their lack of knowledge of the disease and their apathy in keeping children linked in some way to their school class. ► The report recognises the negative impact on employment and education ► The report stated that the term CFS is not appropriate. This aligns with the P2P report The committee determined that the name “chronic fatigue syndrome” has done a disservice to many patients. ► The report rejected the long established name myalgic encephalomyelitis (ME) stating there not being enough evidence to justify the correctness of the name and that the name “myalgic encephalomyelitis” does not accurately describe the major features of the disease. This is something Invest in ME disagrees with. Even if one believed the above IOM statement to be correct, it seems to ignore the fact that there are other diseases with incorrect names such as malaria and hay fever and they have not been changed. The UK MRC states that there is now evidence of neuroinflammation in some severe cases of ME. This is no different from, for example, poliomyelitis where the mild cases may appear unremarkable and go even unnoticed. ► In place of ME the committee proposes SEID “systemic exertion intolerance disease” as a name that more fully captures the full scope of this disorder. We feel this is not a progressive decision and provides a name not so dissimilar from the ineffectual and inappropriate CFS ► Both the P2P report and the IOM report fail to move away from the association of ME May 2015 with fatigue as the main symptom. That ought to have been addressed. They should have recommended dropping CFS and used ME until more is known as ME is well established in the name and even US researchers and clinicians have started to use ME instead of CFS in recent years. ► SEID is a clumsy acronym albeit better than CFS. The use of a potentially misunderstood fatigue-associated word means that this will be bound to retain the implication of ME/CFS being a fatigue illness ► Systemic and Disease are easy to accept but Exertion Intolerance will not be well understood by the general public and will be confused with exercise (physical) intolerance only. ► It was not totally clear if the recommendation for a name change was to replace CFS or ME or both. ► The criteria are more specific than the CDC Fukuda but wider than CCC or ICC. This may lead to an influx of patients for the few US specialists. Is that the intent? Or is there a plan to train more specialists? ► Is there sufficient infrastructure in place to deal with the large percentage of undiagnosed patients that this report refers to? ► We wondered who would take responsibility for the follow up work or will this expensive report end up like the UK CMO, 2003 report whose recommendations were not acted upon? ► If CFS and ME have traditionally had different criteria as stated in the report and the IOM report used ME/CFS as in the CCC then it was somewhat unclear whether this report meant to combine the two definitions into one ► Most ME, CFS or ME/CFS research has been performed using the CDC criteria and more Invest in ME (Charity Nr. 1114035) www.investinme.org Page 28 of 57 Journal of IiME Volume 9 Issue 1 recently the CCC or the combination of CDC and CCC and hardly any research has been performed using the ICC or the Ramsay Criteria. The ICC is based on research that has used CCC or CDC criteria. This just goes on to show that researchers use various criteria and then it is used as evidence for any of the acronyms of CFS, ME/CFS or ME depending on the users and it would be sensible to use criteria that are inclusive for diagnosis but allows for specific phenotypes to be selected for research. ► The IOM panel included ICC signatories Drs Lucinda Bateman and Nancy Klimas. The ICC 2011 states that the panel recommended the use of myalgic encephalomyelitis for patients who meet the ICC criteria because a distinctive disease entity should have one name. So does this mean that the ICC should be used for ME and the IOM report for SEID? ► Less than one-third of medical schools include ME/CFS-specific information in the curriculum ► For years ME and CFS patients have been let down by the disbelieving medical profession and hopefully this report benefits patients rather than cause yet more problems ► The few doctors/researchers that have believed in patients have been let down by their colleagues and research funding bodies and we hope that the HHS and NIH now take ME and SEID seriously and allocate funding based on them being physical diseases ► The report acknowledges high societal costs and recommends that the guidelines are revisited in no more than five years to allow new research findings to be taken into account ► “Ideally, experienced individuals without significant conflicts of interest should conduct a May 2015 systematic literature review to address the key questions.” “Members of this group should clearly disclose their potential conflicts of interest, and the conveners of the group should try to limit the number of members with significant conflicts, who should in no case represent a majority of the group’s membership.” ► “There is no adequate evidence to enable comment on the manifestations of ME/CFS across the life course.” ► This is an acknowledgement which NICE and the MRC have never made in the UK where vested interests continue to affect what is funded or reported. In Conclusion - Going Forward ► Despite “Patients, advocates, researchers, and clinicians expressed strong opposition to the study, arguing that the IOM lacks the expertise to develop clinical case definitions” the IOM insisted on continuing this exercise. They therefore set up a unique opportunity to make things better. ► Will this report promote the prompt diagnosis of patients with this complex, multisystem, and often devastating disorder; enhance public understanding; and provide a firm foundation for future improvements in diagnosis and treatment? ► After so long a period where governments, medical research councils, health departments and some of those supporting organisations completely abrogated their responsibilities to patients with this disease then it might be too optimistic to expect one report to overturn all that has been allowed to be wrong with the research into, perception and treatment of ME. ► But a start has to be made. 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Journal of IiME Volume 9 Issue 1 ► In the absence of anything else one must take what one can and build upon it. And there are many good points in the report. ► If the intent to improve the situation for people with ME and their families is honest then elements from this and the P2P report can change the way healthcare professionals treat the disease. ► The good points from this report ought to force and demand a radical rethink of Health Institutes’ and Research Councils’ policies – something long overdue. ► To exact a greater morality amongst research funders might be one benefit from this. Name ► Unfortunately, however many good points there may be in this report the name will be something which many will interpret and then relate to their perception of the disease. ► We believe the suggested name is ill thought-out and needs to be rethought. ► Whilst it is obviously logical and correct to remove the term CFS and Chronic Fatigue we feel it is not a sensible strategy to change the name to the suggested SEID at this point. ► Even if the intent was honourable the name will still influence how this disease is treated. ► Just as with food the contents in the tin may be completely ignored due to poor labelling. ► By deciding to tinker with the name of this disease one is also obliged to examine the history and politics behind it and understand why such a name change could offend, discriminate, confound, disappoint or just enrage some patients. ► Playing with the name and using exertion – however the correctness in medicine may be different from lay perception – will still invoke an initial response of this is being a fatigue illness rather than a systemic disease. May 2015 ► So we suggest retaining Myalgic Encephalomyelitis (ME) until enough current data is found to support or otherwise. ME (itis) is already in the WHO, it does not stop research, it removes the rather useless CFS denigration and still allows a correct view to be presented. Criteria ► Whilst it may be good that a set of simplified criteria are produced there is the concern that the criteria listed by the IOM report may be too broad. The criteria also need to be validated first to see if they really capture the right kind of patients. At the Invest in ME conferences there have been calls for the need for simple diagnostic criteria. ► However, the committee also added a table with many more symptoms which could be used to support the diagnosis. ► It will require education of doctors to make them able to identify the disease and avoid incorporating misdiagnoses into the assessment. The multiple comments within the IOM report relating to lack of belief from healthcare staff are evidence that this education is important. Distribution ► An obvious point – but one which needs reaffirming for any diagnostic criteria used - ► “The criteria proposed here will not improve the diagnosis and care of patients unless health care providers use them” ► Apart from the name the distribution of the other sensible points from the IOM report needs to be managed, monitored and followed-up in order that uptake of ME being a real systemic disease in ensured. ► In the UK the CMO report of 2002 [10] produced seven recommendations. It would be a disaster if the IOM report ended up like the CMO report in the UK where none of the Invest in ME (Charity Nr. 1114035) www.investinme.org Page 30 of 57 Journal of IiME Volume 9 Issue 1 recommendations were implemented and the psychiatric lobby who refused to sign the report went on take charge of the fatigue clinics and obtained all of the public research funding. ► At that time the participating psychiatrists should have been left out. But what has transpired is that they have still been allowed to control the debate in the UK. ► We would urge the US authorities to avoid a repeat of that. ► The report makes a major point - “Key to this effort will be the continued positioning of ME/CFS as a legitimate disease that occurs in both children and adults and should be properly diagnosed and treated.” May 2015 ► then this would also mean that the name SEID would have to be revisited and almost certainly changed. ► The toolkit for screening and diagnosis is an important part of the process. If this is not done properly then it is no good of having all of these recommendations. ► Again, there is a need for centres of excellence such as IiME have proposed [11] and experienced clinicians that can oversee this work. Research ●● ● ““Clearly a dramatic and immediate increase in funding for biomedical research needs to be made.,IiME ► What can be very helpful is if the information emphasises ME/CFS as a serious physical illness and that in itself leads to health care providers taking a correct attitude toward these patients despite there being no cure or effective treatment being available yet. Just informing patients to avoid overexertion in the early stages of the disease can make a huge difference in the outcome of the disease. - suggested $250 million dollars over the next five years” IiME Recommendation to IOM” ●● ● ► The report has underlined a core message from the earlier P2P report – namely how mediocre has been the research to date on such a serious disease; The IOM report is a major indictment of negligent MRC/NIH/CDC policies, highlighting the way that research and treatment and information about ME have been totally misrepresented ► It is good that the committee recommends continuing surveillance of the evidence and revisiting the criteria in no more than five years. But if ► “The committee recognizes that new and accumulating evidence will likely enable refinement of the diagnostic criteria proposed in this report and possibly define subtypes of the disease or even distinct entities” over the last generation by false funding policies, flawed research and vested interests. What a waste of life has been allowed to occur by governments from their failure to monitor progress or listen to continuing and mounting patient concerns; how corrupt and immoral has been the attitude of those leading the organisations which use public funding of ME research, given mainly to researchers who consider ME/CFS a psychosomatic illness? Our overriding feeling is that the IOM report highlights the complete lack of any strategy to research this disease properly by those entrusted with the responsibility to do just that. The aim now should be to find a speciality that owns ME/CFS or make ME/CFS a speciality in its own right – and this will not be psychiatry. 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Journal of IiME Volume 9 Issue 1 The onus is on the IOM and NIH to honour those good points from these reports – and to translate these into action. Clearly a dramatic and immediate increase in funding for biomedical research needs to be made. IiME suggested $250 million dollars over the next five years. This will be a long haul. Those in NIH and CDC – as well as those in UK MRC - and the respective government health ministers who have been responsible for ME research and funding and guidelines over the last generation have been incompetent, or worse. So lessons have to be learned from these past failures to ensure the same fatal mistakes are not made again. We ended our P2P report evaluation thus - Words are fine and Progress is a fine word – but change is its motivator – and it is action that delivers change. To make progress we need not mere words and a slow, undeliberate action plan. To make progress with this illness we need to make a bold changes. The task now is to implement the good points of this new acceptance of ME as being the real disease that patients already know it is. And we stated to the NIH the following - This is urgent, lives are dependent on it – Treat it as being urgent! Invest in ME is a small charity with a BIG cause. If such a small charity and its supporters can organise ten international conferences with delegates from 20 countries, if it can organise 5 biomedical research colloquiums attracting participants from top research organisations in a dozen countries, if it can initiate possibly the two most important research projects for ME in the UK then the NIH should be able to do far, far better – and in a far shorter period of time. May 2015 The reports vindicated all that Invest in ME has been trying to achieve these last nine years. And, after reading and commenting on these recent reports, we are frustrated that we do not have the means to correct much of what has been wrong over the last generation. With more support and the means to change things we can make more rapid progress and overcome these establishment obstacles. Recently the charity has initiated and funded important new research projects in the UK for ME [III]. After some success we only wish it were possible for the MRC in the UK to provide some of their squandered funding instead to IiME. To paraphrase Winston Churchill – Give Us The Money And We Will Finish The Job. In the meantime we will progress the research foundation we have begun as quickly as possible because, as our advisor Dr Ian Gibson stated – “Things do not have to be the way they are – we can change things.” Links I Invest in ME Response to NIH Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Draft Executive Summary http://www.investinme.org/IIME-Newslet-150101.htm II Invest in ME Response to Institute of Medicine “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness” http://www.investinme.org/IIME-Newslet-150302.htm III Invest in ME research http://www.investinme.org/research Invest in ME (Charity Nr. 1114035) www.investinme.org Page 32 of 57 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 33 of 57

Journal of IiME Volume 9 Issue 1 May 2015 THE TRUE BATTLE WITH CHRONIC FATIGUE SYNDROME by Dena Graham For an illness that boasts such a myriad of symptoms, you might think that the Chronic Fatigue Syndrome battle starts and finishes there. Each day is a challenge – some more than others. And just when there seems to be a glimmer of light, a temporary ‘remission’ of symptoms (or at least a waning of them), it rears its ugly head again. The first year, for many, is taken up with visiting GPs and specialists, trying to find answers. Surely it’s not normal to be so ill, so often. And then, when the diagnosis of CFS (sometimes also known as Myalgic Encephalomyelitis (ME)) comes back, there’s the inevitable temptation to take to the internet, trying to understand this complaint and find a ‘cure’. All this when, some days, you can barely lift your head off the pillow. That should be battle enough. Except, for many CFS sufferers, the true battle begins when it comes to other people’s perceptions of it. To be so ill, yet dismissed by so many, is a harsh blow. Worse when it comes from people who you think ought to know you better. The battle begins I can’t say exactly how long I’ve suffered from CFS – it certainly pre-dates any diagnosis and has gone on for at least three years; starting with recurrent throat and ear infections that became more frequent; and the after-effects of which lasted longer. I used to say to my mother that it felt as though there was something ‘evil’ inside me. I didn’t mean this in any paranormal manner – but I wasn’t using it as a metaphor either. I simply felt as if there was a something insidious creeping through my body, wreaking havoc. It wasn’t normal to feel like your life force was ebbing; and then reach a point where you actually wished you were dead, just so the pain and exhaustion went away. I finally received a diagnosis about two years ago, after seeing a number of specialists. For anyone who believes that CFS sufferers are malingerers, actively seeking such an unspecified diagnosis, I can assure you that this isn’t the case. Not for me, nor for the majority of CFS sufferers. Of course, that’s not to say that a handful of people aren’t (in the same way that some people may fake whiplash for their own personal means). However, for most people with CFS, that diagnosis is not a positive one. It’s an answer without a solution. I wanted, desperately, to be told there was a problem with my thyroid; a sinus issue; there was even a point, God help me, when I wished to be diagnosed with a minor, treatable form of cancer – because at least then there would be the hope of a cure. When I received the CFS diagnosis, I was told to go away and accept it. The consultant, who specialised in this area, had seen enough patients to realise that this is not the diagnosis people want, nor accept lightly. It leaves them foundering without any medical direction and they inevitably continue to look for answers. Once that diagnosis comes in, you’re on your own essentially. Not because the consultants don’t believe it exists – but because they don’t have anything to offer in the way of treatment. And so begins a long road of medical denial and frantic research. You try one route after another in the hope of vanquishing this unfathomable complaint. For me, that began with cutting out meat; cutting out dairy; cutting out sodas and only drinking water or herbal tea; whipping up green smoothies; Beta Glucans; Amitriptyline; Chi Machines; Allicin; salt pipes. Believe me, the list was endless – and continues to this day. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 34 of 57 Journal of IiME Volume 9 Issue 1 Meanwhile, since the array of symptoms is so splendid and wide ranging, I battered my private medical insurance looking for another answer. Because, and I’ll say it again, I didn’t want to be ill with CFS. It was impacting hugely on my life. I had to take seven months off work, dropping my wage (forcing my husband and I to move out of our home). I had to call on all my reserves to try and ‘hide’ as much of my illness as possible from my 3 year old daughter – struggling with the guilt of knowing I couldn’t do the things I wanted to do with her. I was missing out on her life. I was missing out on my life. Days went by in a blur of pain and frustration. During this time, a third consultant ran more blood analysis and discovered that I was testing off the chart for the Epstein Barr virus. That was a high point. Why? Because it proved that something had caused this. Glandular Fever, Lyme Disease, Epstein Barr . . . these are just a few conditions that can trigger CFS. And this diagnosis validated me, even if it didn’t help the symptoms. So why was it that important to be validated? Because, by then, I was aware that many people just didn’t ‘get’ this condition – and many others didn’t believe it existed. People who I thought were good friends didn’t bother keeping in touch to see how I was. I knew that if it had been any other complaint, which didn’t carry the CFS stigma, I would have had their sympathy. CFS – Clearly Fake Symptoms Even now, having returned to work (again, most CFS sufferers want to work. They don’t want their lives to be put on hold. They are not using it as an excuse to opt out or take the easy route) I still face the flack – more so, because people assume that if you’re working you’re ‘cured’. So I often hide how I’m feeling – not wanting to bore people. May 2015 On days when I tell people that I feel bad, I’ve had comments along the lines of ‘Oh, I feel like that too’. Or ‘I think I might have CFS’. No, you don’t. CFS isn’t feeling exhausted because you’ve had a late night or it’s four days into the week and you’re ready for the weekend. It’s not feeling like you’re getting older and could do without a commute now. It’s unrelenting bonecrunching fatigue, combined with headaches, aching limbs, a low-grade sore throat most of the time, the inability to plan ahead (even for nice things) because you don’t know how you’re going to feel this time tomorrow. It’s keeping everything crossed that you’ll be able to attend a friend’s wedding. It’s giving up socialising. It’s no holidays for three years (even though your addled body could do with a week on a beach) because you couldn’t even take the journey to the airport, far less the plane ride itself. It’s going to bed early, waking up and still feeling as though you haven’t slept. It’s climbing out of bed bent double because you can’t straighten up. It’s either missing taking your child to the park, or going but feeling like death – watching her through tear-filled eyes as you realise that this is time you’ll never get back but simply can’t enjoy. It’s rushing bedtime stories because, some days, you can barely keep your head up. It’s not watching your favourite programs when you’re off work sick – because this isn’t a cosy-up and ‘enjoy’ kind of ill – it’s an obliterating type of illness. It’s feeling that every day’s a battle and there’s no knowing if or when that battle’s going to end. But the worst part of it all is the endless lack of understanding. People who are supposed to be friends don’t even bother to see how you are when you’re ill. Why? Because they believe that you’re malingering? That you’re faking your symptoms? Using CFS as an excuse to work from home? Because they think that, surely, you must be exaggerating and nobody could be ill for that long? I don’t have the answers – all I know is what the reactions are. The only bright spot is that my employers have taken this on Invest in ME (Charity Nr. 1114035) www.investinme.org Page 35 of 57

Journal of IiME Volume 9 Issue 1 board; without their support, enabling me to continue working, I would have lost yet another part of my life. Try telling the man whose leg is hanging off it’s not ‘real’ pain Recently, my husband overheard a conversation at his work. A colleague, who has MS, was speaking to someone and they were clarifying – ME or MS? The reply was, ‘No, the real one, MS’. This hit my husband hard. He is the one who lives with me. It hasn’t just impacted on my life, but his too. Meanwhile, his colleague gets injections for her MS and is able to enjoy a pretty normal life. He’s heard stories of her going out drinking; socialising with friends; enjoying a tipple with lunch, and he knows I can’t do any of that. She was able to go to her work’s Christmas party. I wasn’t able to go to mine. Yet, when her work duties are restricted, nobody bats an eyelid – despite the fact that she’s still managing to maintain a social life. He’s sat with me as I’ve cried tears of pain and frustration – he can see how ‘real’ it all is. I’m not living a normal life. I’m getting by, clinging to each day by my fingertips. So to hear someone dismiss ME/CFS as a condition that’s ‘not real’ is insulting in the extreme. If we take symptoms alone as a mark of illness severity and put them on a sliding scale, then it’s entirely possible for someone with CFS to be living a far more restricted, pain-filled life than someone with MS (I’m using this as an example simply because the issue was raised about that being ‘real’ and the other not being real). And let’s not forget, people with CFS don’t have any medical interventions to help either. Some forms of cancer can have less impact on the body. I don’t say this to undermine cancer, in any of its manifestations (it’s the worst thing someone can be told they have) – I simply highlight it to demonstrate that, symptomatically, there are people who are treated for cancer and go on to live full, healthy, pain-free lives. As Llewellyn King – executive producer and host of the White May 2015 House Chronicle – commented, ‘The world of CFS is dark indeed — an abysmal place of unmediated pain, disability, hopelessness, financial ruin and sometimes suicide. One doctor told me that if she were to have to choose for herself between CFS and cancer, she would choose cancer. “At least for cancer, there are treatments; if they fail, you die. With CFS you are the living dead.” ’ Indeed, there are people with CFS who are wheelchair-bound, then bed-bound and, in severe cases, do lose their lives – either through the illness or due to the aforementioned suicide. By the same token, there are a host of recognised diseases and complaints that present with few symptoms and which are eminently treatable. A broken leg might be excruciating but it’s fixable. The one thing that can definitively be said about CFS is that it’s all about the symptoms. In fact, it’s probably one of the few conditions that is so symptom-heavy and solution-light. Consequently, if I had to hazard a guess why people are so dismissive of CFS, it’s possibly because it’s been a victim of its name. ‘Fatigue’ doesn’t get anywhere close to summing up the array of symptoms that present. We associate fatigue with tiredness, lethargy, apathy; things that aren’t entirely positive. It’s easy to simply dismiss someone as lacking get-up-and-go. It leaves out the recurrent viruses, aching limbs, visual flickers and many other lesser-known symptoms. Unfortunately, the name is vague because nobody fully understands it yet. Even the more medical-sounding Myalgic Encephalomyelitis has been shortened to ME – which carries its own negative connotations and harks back to ‘yuppie flu’. I suspect though, when it’s eventually pinned down and given a specific medical label, it will then be recognised as one of those handful of conditions nobody wants to have the misfortune of contracting. That said, this shouldn’t be a competition of diseases. Whenever anyone is ill, with anything, that person deserves to be treated with Invest in ME (Charity Nr. 1114035) www.investinme.org Page 36 of 57 Journal of IiME Volume 9 Issue 1 empathy, consideration and respect. Not to be told that their condition isn’t ‘real’. So let’s talk about those real symptoms I, and thousands of others, can tell you that CFS symptoms aren’t made up or imagined. In fact, I was ticking the CFS symptom boxes before I even knew what they were. I assure you that my muscle pain is very real – and I say this as someone who went through labour without any form of pain intervention. The headaches are real, as is the frequent dizziness that comes with a crash. The recurrent throat flare-ups (and ongoing low-level sore throat that never seems to disappear entirely), they’re real too. The burning feeling in the face; the tingling in the extremities; the leaden limbs; the crawling skin; the insomnia; the anxiety; the brain fog; the visual flickering; the neck pain; the regular bone-crunching exhaustion (think jet lag combined with running a marathon and a bout of flu). All these things (and more) are real. And you know what – CFS is such a giving condition that, sometimes, you experience a plethora of symptoms all at once. I can guarantee you that most CFS sufferers are facing at least two or three symptoms even on a good day. In fact, ‘good’ days are when you only have a few symptoms at a low level. Our good days would be your bad days. And let’s not even talk about what happens to your body if you get a common cold – it can wipe you out for weeks. In three years there have been a handful of days when I’ve felt normal. Entirely normal. Free from pain, awake, energised. I have felt like I’m walking on air – happy, positive and vital. Yes, your body cries, I remember now, this is how it feels to be well. And then it all comes to a screeching halt. If it’s all in the head, a lot of people are sharing one brain Recently, I found a GP who is prescribing Low Dose Naltrexone to help alleviate the symptoms of CFS. I did well on this for a while – it was the May 2015 first thing to ever make me feel relatively normal. However, about three months in, I had a huge crash. I called him and told him that, oddly, since I’d increased the dose it didn’t seem to be helping as much. He commented that he’d been hearing this a lot from patients. He said this is yet another reason why he knows that CFS is a genuine complaint – the very fact that the increased dosage is having the same effect on numerous people. Nobody who calls him knows this. Ergo, it proves that something is happening. In the 1980s, CFS was referred to as ‘Yuppie flu’ – although it’s been around far longer than that. There was an unexplained outbreak among nurses at the Royal Free Hospital in 1955. So either a large group of nurses suddenly came down with a fit of the vapours at the same time, or something’s at work here that we still don’t understand. Indeed, there was also an outbreak of these symptoms at the Los Angeles County General Hospital in 1934. And as far back as 1750, Sir Richard Manningham reported a syndrome referred to as ‘febricula’ (little fever). There have also been suggestions in the Lancet and the British Medical Journal that, upon returning from the Crimean War, Florence Nightingale spent years housebound, too fatigued to take visitors. Now she’s not the type of woman who strikes me as having been a malingerer. In fact, many consultants will tell you that ME often affects those people who are the most driven – workaholics; people who’ve studied for degrees; those who have a can-do attitude. Certainly, the medical profession now recognises CFS as a real condition – even if they don’t know what causes it or how to treat it. The most recent evidence indicates that there’s a difference in the brain scans of those suffering from CFS http://www.webmd.com/chronicfatigue-syndrome/news/20141030/brain-scansyield-clues-to-chronic-fatigue-syndrome. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 37 of 57

Journal of IiME Volume 9 Issue 1 Furthermore, it’s acknowledged that the disability rates of chronic fatigue syndrome patients are on a level with those who have lupus; MS; rheumatoid arthritis and a range of other serious conditions. In some cases, patients are housebound for years, while others have died of the complaint. And let’s debunk another myth. CFS patients are not hypochondriacs. In fact, I now ignore a lot of symptoms, assuming they’re part of the CFS bundle. I’ve had an ongoing ear pain for 12 days that would have sent most other people to the GP. Instead, I’ve lived with it – as I live with all the other symptoms. So, if I had to put one message out there to those who are fortunate enough not to have to do daily battle with their bodies – it’s to please, please not give CFS/ME/Fibromyalgia sufferers something else to battle. Namely a negative, unsympathetic, dismissive, disbelieving attitude. Nobody wants to feel this way. If there is somebody at your work who seems to be getting ‘preferential’ treatment in terms of hours or home working; just consider the fact that they’re May 2015 still trying to work, despite the hurdles they face. And if a friend is housebound or you haven’t seen them in a while, consider the fact that they may need your support. They aren’t choosing to opt out of life. Because until CFS gains the same sympathetic recognition as other illnesses, you are sidelining a huge group of people – and this is a condition that can strike anyone at any time. Including the naysayers. ME PATIENT We are raising money for Invest in ME a great charity that funds research into ME, a disabling illness that affects my wife Susan, many dear friends and hundreds of thousands of people in this country. I have managed to regain my health from this illness but many sufferers remain chronically unwell and I am taking this opportunity to raise funds for something very close to my heart.” Steven from IiME’s JustGiving pages https://www.justgiving.com/investinm-e/ Invest in ME (Charity Nr. 1114035) www.investinme.org Page 38 of 57 Journal of IiME Volume 9 Issue 1 May 2015 Anna’s story It is with sadness that I realized that I would be unable to attend the Invest in ME conference this year, but in trading e-mails with IiME, they kindly asked if I could submit a short piece on ME. Well, I stuttered around the house wondering what I could possibly write about until I had to get ready for Anna’s graduation. And there it was right in front of me: Anna’s story, one of the best stories possible, one that brings tears to my eyes even now. And every word of it is true. I first met Anna when she was thin and frail, being carried into my office by her father because she could not walk. It would have been about twelve years ago, she was just thirteen. Anna had been through a difficult time by then, with a lifetime’s worth of pain and insults. There are many aspects of her story that bring anger because of the callousness of the medical profession, and joy because there are some patients that medical malpractice cannot injure. It is very likely that Anna’s illness began with Histoplasmosis. This part is a little sketchy because I did not know her at that time, but in retrospect, Histoplasmosis is very likely. She was treated by the infectious disease group at the University of Rochester, a group that was of world renown in Pediatric Infectious Diseases. In reviewing the records the evidence was somewhat flimsy for Histo. Antibodies were +/and Anna had never been to an area where this illness was prevalent. But whatever it was, it was severe. Exhaustion and tiredness were present from day one, along with weakness, intestinal dysmotility, generalized pain and killer headaches. She had been ill for about a year before she had come to my office, but in retrospect post-exertional malaise had always been present. Exertional May 2015 Dr David Bell Dr. David Bell graduated from Harvard College and gained an MD degree at Boston University. Post doctoral training in paediatrics was completed with subspecialty training in Paediatric Behavior and Developmental Disorders. In 1978 he began work at the University of Rochester and then began a private practice in the town of Lyndonville, New York. In 1985 nearly 220 persons became ill with an illness subsequently called chronic fatigue syndrome in the communities surrounding Lyndonville, New York. This illness cluster began a study of the illness which continues today. Dr. David Bell is the author or coauthor of numerous scientific papers on CFS, and, in 2003 was named Chairman of the Advisory Committee for Chronic Fatigue Syndrome of the Department of Health and Human Services. Publications include A Disease of A Thousand Names, (1988) and The Doctor's Guide to Chronic Fatigue Syndrome, (1990). David S. Bell MD 1 Dunbridge Heights Fairport, NY 14450 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 39 of 57

Journal of IiME Volume 9 Issue 1 intolerance, as in Systemic Exertional Intolerance Disease (SEID) as some are calling it now. After a two hour visit I made the diagnosis of ME/CFS as she was classic in all respects except that she was more severe than most. Because of the nausea, she was unable to eat and had lost weight, almost 50 pounds. She could not walk and had to be carried to the bathroom by her parents. She had killer headaches. I was happy to take her on as a patient. The first steps in her treatment were very straightforward: I had to undo the damage done by previous medical personnel. This part of the story is well known to most young persons with ME/CFS. She was said to be anorexic, and that if she did not begin to eat, she could starve to death. All her GI tests were normal except the motility studies. She was admitted to the behavioral units where she had to walk to the bathroom or pee her pants. And it was not certain that anyone would help her change clothes. The constant message given to her was that there was nothing medically wrong with her, and that her symptoms were a desperate cry for attention due to mental illness. Unravelling this damage was not difficult. She had been an A student and an athlete, two factors that argued against school phobia. She was socially outgoing and had good friends, the majority of whom were dropping away, another strike against behavior disorder. Her parents were wonderful people, with good communication and absence of scapegoating, an abnormal dynamic that can exacerbate behavior disorders within families. At first, Anna did not trust me at all, which was a healthy response to the medical abuse she had May 2015 been subjected to. But after a while the doubts began to fall away. She came to understand her condition which is essential to managing it long term. We talked about brain blood flow, orthostatic intolerance, autonomic nervous system dysmotility, and about the need to have a thick skin. I have always insisted on complete honesty with young persons with ME/CFS. If they are neurotic, they need to see that neurosis from another point of view. Confrontation with support is the classic technique. I once told a 14 year old boy that he had ME/CFS, but he did not need to limp to show others that he was ill. Although I confronted him, I said nothing to imply that the rest of his symptoms were bogus – but the limp was. He did well and never limped again. ●● ● I wrote notes saying that Anna was ill, but the teachers did not believe me. I went to her school and argued for home tutoring. The school refused, saying that she had school phobia. I went back to the school and said that Anna had an illness recognized by the CDC, and if they wished to practice medicine without a license, I would take them to court. They agreed to two one hour tutoring visits per week. ●● ● A thick skin is necessary. The world is full of evil and everyone comes in contact with it every day. I suggest to everyone to listen carefully to all criticism. If there is any truth to it, try to make changes. If there is no truth to it, discard it, but only after thinking about it carefully. If someone calls you a hypochondriac, as happened to Anna, consider the possibility. Thinking about it will do no harm. Pile up evidence for and against. Putting together that evidence was the next step for Anna. I have never been a great fan of the Centers for Disease Control (CDC). But they put together a terrific paper which demonstrated that the likelihood of CFS after an infection was related to the seriousness of the infection at the beginning1 . Invest in ME (Charity Nr. 1114035) www.investinme.org Page 40 of 57 Journal of IiME Volume 9 Issue 1 Anna said something that caught my attention, “If the CDC says it is a real illness, why does everyone think that I am making up my symptoms?” This was one of the many questions that Anna stumped me with. One of the things I used to say to my patients and their parents was that the severity of the beginning of the illness was an indicator of the long term prognosis. Because Anna could not walk for over a year was bad news; it implied that she would not do very well in the long term. Of course there were school issues. I wrote notes saying that Anna was ill, but the teachers did not believe me. I went to her school and argued for home tutoring. The school refused, saying that she had school phobia. I went back to the school and said that Anna had an illness recognized by the CDC, and if they wished to practice medicine without a license, I would take them to court. They agreed to two one hour tutoring visits per week. Obviously, this amount of tutoring is negligible. But it taught Anna several things. First it taught her that I was committed to her and would not put up with discrimination. Secondly it taught her about the exertion intolerance. The post-exertion malaise is not just after physical exertion, it occurred after mental exertion as well. And it taught her about orthostatic intolerance. If she had her tutoring session sitting up at the kitchen table, she could not do well. But she did better if she was lying down. This observation of Anna’s stimulated our office to do a small study, never published. If you ask healthy persons in what position they read, they almost invariably say that they read sitting up in an armchair, May 2015 except at bedtime. Ask someone with ME/CFS and they say they always read lying down. Blood flow to the brain, orthostatic intolerance. And when she came to understand that, she no longer paid attention to people calling her a hypochondriac. We did a “poor-man’s tilt table test” where Anna would stand quietly next to the bed while we monitored her blood pressure and pulse. A healthy adolescent can stand for ninety minutes, although that would cause leg discomfort. Anna had three abnormalities on this test. Her pulse rate went up to 140 beats per minute after ten minutes of quiet standing, meaning that she had Postural Orthostatic Tachycardia Syndrome (POTS). Her pulse pressure – the difference between the upper and lower number of her blood pressure went down to 10 mmHg, called orthostatic narrowing of the pulse pressure. And at ten minutes she passed out, almost. Her blood pressure went to zero. ●● ● One specialist wanted to operate on her brain saying that she had Histoplasma meningitis, but the others said not to operate. Doctors. ●● ● to school. She did her homework, and despite saying that she was having trouble thinking and reading, she got good grades. Some days she would use her wheelchair which the insurance company did not want to provide for her. Some medicines helped a little. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 41 of 57 Paula in our office is very good at predicting when this is about to happen and helped her to lie down. In her case she had three very good reasons to have orthostatic intolerance and reduction of blood flow to the brain. The years passed. Anna was able to get up and walk around the house a bit, and on good days she was able to get

Journal of IiME Volume 9 Issue 1 Headaches were the worse symptom now by far. She went to a specialized headache clinic in Philadelphia. One specialist wanted to operate on her brain saying that she had Histoplasma meningitis, but the others said not to operate. Doctors. By 2008 Anna decided to go to college. She had learned a neat trick. If she took six hours of classes Monday, Wednesday and Friday, she would spend Tuesday, Thursday, Saturday and Sunday in bed. And it worked. She did not have much of a social life, and it took six years to get through, but she was getting by. She was succeeding. We had long talks about life. I said that teenage dating and sex were way over-rated. And yesterday she graduated. She had two majors and graduated summa cum laude in both. We cried together at her graduation party. She has done better than very well, she has done fantastic. IiME Conference DVDs The Invest in ME conference DVDs are professionally filmed and authored DVD sets consisting of four discs in Dolby stereo. They contain all of the presentations from Invest in ME International ME/CFS Conferences (2006 – 2015). Also included in the DVD sets are interviews with ME presenters, news stories, round-table discussions or pre-conference dinner presentations. The Invest in ME conference DVDs have been sold in over 20 countries and are available as an educational tool – useful for healthcare staff, researchers, scientists, educational specialists, media, ME support groups and people with ME and their carers/parents. Full details can be found at - http://www.investinme.org/DVD.html or via emailing Invest in ME at mailto:info@investinme.org Invest in ME (Charity Nr. 1114035) www.investinme.org Page 42 of 57 May 2015 She is still not well, but she is getting by. I was wrong with my poor prediction due to the severity of her illness, but I’m OK with that. Why did she do so well? I have no idea. But she is smart; she does not feel sorry for herself; she is stubborn; she learned long ago that most of what people say, they know little about; she is forging her own road through life, and I am happy for her. The only sadness I feel is for the medical providers who have never experienced this type of joy treating their patients. 1. Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon S, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006; 333. Journal of IiME Volume 9 Issue 1 May 2015 Using Art to Raise Awareness of ME Art has the power to inspire, to evoke reflection, to see things differently, to force change. An image can capture a thousand words and express views and feelings and convey a sentiment often far better than several pages of words. Wolfgang Stiller is an award-winning German artist who currently lives and works in Berlin. Wolfgang has kindly given permission for his matchstick images to be used for raising awareness of ME. Wolfgang's original and inspired art now allows us to launch the Matchstick Campaign for ME Awareness. Janet Smart and the Let's Do It For ME team have added a slogan for each image and, in turn, IiME has developed a brochure featuring these images and describing what the charity and our supporters are doing. Wolfgang has used a common, everyday item which is often ignored, used and discarded Invest in ME (Charity Nr. 1114035) www.investinme.org Page 43 of 57 by most people, and turned it into a message which makes one pause and think. These striking images are used to highlight the situation in which people with ME have found themselves. The parallels with the way ME patients have been treated over the years are obvious. To continue to raise awareness throughout the year these wonderful and searching images will hopefully cause people to reflect on the waste of life which has been, and is occurring with regard to this disease. Yet they will also offer hope that things will change, will improve and serve to highlight that from the ashes of ignorance and apathy will come a better time and patients will regain their health. Each of the images carries a message - and this message has been related to the work that Invest in ME (Research) and supporters are carrying out. Copies of brochure and posters available from Invest in ME – info@investinme.org

Journal of IiME Volume 9 Issue 1 May 2015 PRESENTERS at the 10th INVEST in ME INTERNATIONAL ME CONFERENCE Bios and Abstracts from the presenters at IIMEC10 Dr Ian Gibson Conference Chair Dr Ian Gibson, former Labour MP for Norwich North, worked at University of East Anglia for 32 years, became Dean of the school of biological sciences in 1991 and was head of a cancer research team and set up the Francesca Gunn Leukaemia Laboratory at UEA. In 2011 Dr Gibson received an honorary doctorate of civil law from UEA. Professor Ian Charles Keynote Speech: Solving ME/CFS: What a Research Park Has to Offer in Resolving a Chronic Disease Such as ME Professor Ian Charles joins the Institute of Food Research in May 2015 to lead the programme to develop the UK’s new Centre for Food & Health to be based at the Norwich Research Park. Professor Charles is returning to the UK from Australia where he was Director of the ithree institute, University of Technology, Sydney. Professor Charles has over 30 years’ experience in academic and commercial research. His academic career has included being a founding member of The Wolfson Institute for Biomedical Research at University College London, one the UK’s first institutes of translational medicine. He has also worked in the pharmaceutical industry at Glaxo Wellcome, and has been founder and CSO of biotech companies in the area of infectious disease, including Arrow Therapeutics, sold to AstraZeneca, and Auspherix a venture capital backed company founded in 2013. His current research interests include infectious diseases as well as the microbiome and its impact on health and wellbeing. The new Centre for Food & Health will provide a step change for food and *health research, and the translation of science by industry, to benefit society and the UK economy. The Centre will be located at the Norwich Research Park, one of Europe’s largest single-site concentrations of research in Food, Health and Environmental sciences. The multidisciplinary Centre aims to bring together the Institute of Food Research and aspects of the University of East Anglia’s Faculty of Science and the Norwich Medical School with the regional gastrointestinal endoscopy facility at the Norfolk and Norwich University Hospital. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 44 of 57 Journal of IiME Volume 9 Issue 1 With a unique integration of diet, health, nutrition and medicine under one roof, linking closely to world class plant and crop research at the John Innes Centre and bioinformatics at The Genome Analysis Centre (both also located on the Norwich Research Park), it will have the potential to deliver clinically validated strategies to improve human health and wellbeing. Abstract: Sufferers of M.E., carers, family and friends, all want to know what causes M.E. in order to determine how the condition can be prevented, treated and cured. We need to better understand the biological, physiological and psychological mechanisms that determine how nutrition, food choice and individual dietary patterns contribute to lifelong health and disease. We also need to know how differences in dietary needs and responses between individuals and population groups at different stages of human life. Expanding knowledge in these areas we believe will be important to understanding a range of issues including ME. The science of food, nutrition and health is immensely complicated. Future science has to take an interdisciplinary approach to effectively understand how all these interconnected factors act together. With over 3000 scientists at the Norwich Research Park, consisting of 4 world leading research institutes, a university and a teaching hospital, it is one of Europe’s largest single-site concentrations of research in Food and Health and Environmental sciences. Having academic excellence across a range of diverse, but related fields, in one location is a very powerful way to deliver a step-change in potential outcomes across a number of health issues. Importantly, the new centre for food and health, due to open at the end of 2017 at the Norwich Research Park, takes co-location to a new level as it uniquely integrates academic excellence with clinical expertise; by bringing together the Institute of Food Research with May 2015 aspects of the University of East Anglia’s medical school and science faculty with the Norfolk and Norwich University Hospitals' gastrointestinal endoscopy facility, working alongside industry. The new Institute will provide a novel holistic, systematic and integrated approach to deliver faster innovation as well as helping to inform government policy on a range of gut and diet related issues including M.E. The development of this new centre, together with the other expertise and facilities located at the Norwich Research Park, puts it in a very good position to lead a UK and European Centre of Excellence for biomedical research for M.E. to provide possible prevention and solutions. Professor Jonas Bergquist Proteomics in ME/CFS Professor Begquist has a background as MD, Associate Professor of Clinical Neuroscience , Sahlgrenska University Hospital and the University of Gothenburg. Since 1999 , he has been a researcher in Uppsala, Sweden, and in 2005 was appointed professor of analytical chemistry and neurochemistry at the Department of Chemistry - BMC , Uppsala University. From 2011 he worked also as an adjunct professor of pathology at the University of Utah, Salt Lake City, Utah, USA. Abstract: Not available at time of printing – but will be made available on Invest in ME web site. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 45 of 57

Journal of IiME Volume 9 Issue 1 Professor Mady Hornig Markers of Immunity and Metabolism in ME Mady Hornig, MA, MD is a physicianscientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health New York, USA where she serves as Director of Translational Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, and toxic stimuli in the development of neuropsychiatric conditions, including autism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and May 2015 inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Her work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project, one of the largest studies of immune factors in mood disorders and schizophrenia, examines the role of viruses and immune responses in the pathogenesis of these disorders. Abstract: Markers of immunity and metabolism in ME/CFS Mady Hornig, MA, MD A diverse range of microbial and immune stimuli has been hypothesized to trigger the onset of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To date, however, no single factor is clearly implicated, leaving the majority of cases of disease unexplained. The absence of diagnostic biomarkers seriously curtails the capacity to identify individuals affected by the disorder and to distinguish Invest in ME (Charity Nr. 1114035) www.investinme.org Page 46 of 57 Journal of IiME Volume 9 Issue 1 them from those who have other fatiguing illnesses. Under the auspices of the Hutchins Family Foundation-supported Chronic Fatigue Initiative, we recently found evidence of differences in plasma immune signatures in patients with ME/CFS who have recent onset of illness as compared with patients who have been ill for longer periods, and as compared with matched controls. We are currently investigating whether these stage-specific immune profiles are also correlated with altered metabolites in blood as well as with the bacteria of the gut and oropharyngeal microbiome that help to shape these metabolomic patterns. This work is beginning to elucidate candidate biomarkers for ME/CFS that may both facilitate early diagnosis and promote our capacity to tailor interventions to the specific stage of illness. Dr Luis Nacul Epidemiological Evidence on ME/CFS: Current status and implications for research and service delivery Dr Luis Nacul is Clinical Senior Lecturer at London School of Hygiene and Tropical Medicine Abstract: The reported prevalence of ME/CFS varies 100-fold, with the best estimates between 0.2% and 0.7%. The most likely explanations for these variations relate to methodological differences in studies, including in data collection procedures and case definitions used, in addition to differences May 2015 in population studied. Methodological limitations also restrict the interpretation of findings on risk factors, mechanism of disease and treatment. The distribution and disabling nature of the disease and lack of specific treatment owes to a high burden and economic impact to individuals and society. The presentation will discuss epidemiological evidence on ME/CFS and their limitations, and how they can be used to guide research and services planning. Dr Amolak Bansal Diagnosis and Differential Diagnosis of ME/CFS Dr Amolak Bansal is Consultant, Clinical Immunology and Immunopathology, Epsom and St. Helier University Hospitals NHS Trust, Surrey, UK Dr. Bansal trained in immunology and allergy from 1989 to 1993 at St. Mary’s Hospital in Manchester and at Hope Hospital in Salford. From here he spent five years (1993-1997) as Senior Lecturer and Consultant in Clinical Immunology in the Department of Medicine at the Princess Alexandra Hospital in Brisbane, Australia. From 1997 to the present date Dr. Bansal has worked as a Consultant in Clinical Immunology and Immunopathology at Epsom and St Helier University Hospital. Dr Bansal’s key interests lie in allergy, autoimmunity, CFS/ME and immunodeficiency. Abstract: Diagnosing CFS/ME Fatigue is a feature of many common illnesses but is the main and overwhelming problem in Invest in ME (Charity Nr. 1114035) www.investinme.org Page 47 of 57

Journal of IiME Volume 9 Issue 1 Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The latter is poorly understood and accompanied by several additional symptoms that suggest a subtle immunoendocrine dysfunction accompanied by viral reactivation and complicated in some cases by alterations in mood and sleep. The differential diagnosis of CFS/ME is large and includes primary sleep problems, endocrine dysfunction, alterations of mood, systemic autoimmunity, certain chronic infections and specific neurological disorders. However, CFS/ME may be confidently diagnosed on the basis of specific clinical criteria combined with normality of specific routine blood tests including those that assess inflammation, autoimmunity, endocrine dysfunction and gluten sensitivity. An early confident diagnosis is important as it can reduce patient anxiety, encourage early intervention and prevent expensive unnecessary investigations. May 2015 Professor Jo Edwards) approximately 10 years ago for the treatment of rheumatoid arthritis), exploring more precisely how the technique works and trying to explain the marked variation in response between different patients Abstract: The newly initiated research into ME/CFS at UCL stemmed from our awareness of the studies of Drs Fluge and Mella showing clinical efficacy of the B cell depleting drug, Rituximab, in a double blind placebo controlled trial in Norway. Rituximab therapy for non-malignant diseases was introduced by Professor Jo Edwards, initially for Rheumatoid arthritis patients at UCL, in 1998. Secondly, Professor Edwards has emphasised the enormous unmet clinical need for patients diagnosed with this condition and encouraged me to become involved in order to explore possible mechanisms underlying ME/CFS which may be modified or even stopped by removing B cells from these patients. Dr Geraldine (Jo) Cambridge B cells, Rituximab and ME/CFS Dr Jo Cambridge is Principal Research Fellow Inflammation, Div of Medicine Faculty of Medical Sciences, UCL Her group focuses its interests on B cell depletion (an idea which they introduced (with the At UCL, I have been conducting clinicallybased research involving patients with a number of different diseases treated with rituximab and other B-cell targeting drugs. Our aim is to maximize the efficiency of their use and to predict imminent relapse in order to allow more rapid intervention before worsening of symptoms. As a newcomer to ME/CFS, the first thing that struck me from published literature and the age and sex distribution of ME/CFS was the hypothesis of an infectious trigger for the condition but with an ‘unbalanced’ response of the immune system which may subsequently not resolve. This does not mean that the infectious agent needs to persist. There are a number of ways that B cells could contribute to this. With the appointment of Fane Mensah, our PhD student in 2014, we have been exploring B cell biology in patients with ME/CFS. His Invest in ME (Charity Nr. 1114035) www.investinme.org Page 48 of 57 Journal of IiME Volume 9 Issue 1 tenacity has already produced some tantalizing results. I will outline some of the ways we are approaching the very subtle ways that B cells may be functioning differently in patients and also between patients which will hopefully complement the other research in ME/CFS which we are hearing about at the BRMEC5 Colloquium and IIMEC10 conference. Dr Neil Harrison Immune-Brain Communication and Relationship to Inflammation Dr Neil Harrison is Honorary Consultant Neuropsychiatrist, Brighton & Sussex Medical School, UK Dr Harrison's' work in the laboratory focuses on understanding how infection or inflammation in the body interacts with the brain. For most these symptoms are usually short lived and relatively mild. However, when the immune system is activated for long periods, such as in people suffering from rheumatoid arthritis, they can become extremely debilitating or even life-threatening. Understanding how the immune system interacts with the brain is a crucial first step that will form the foundations for future development of novel therapies targeting these common and disabling symptoms. Most of his studies utilise a combination of functional brain imaging (e.g. fMRI, FDG-PET, EEG, polysomnography), experimental models of inflammation, custom cognitive tasks and diverse measures of peripheral immune status. Abstract: Immune-Brain Communication and Relationship to Inflammation Until recently the brain was considered an Œimmune-privileged¹ site, isolated from changes in immune activity. However, recent evidence has challenged this and demonstrated clear bi-directional communication between the brain and immune system. Interestingly, activation of one of these pathways has been shown to predict the amount of fatigue experienced after experimental inflammation. In this talk I will review the mechanisms through which inflammation in the body can be communicated to the brain and discuss our current understanding of how this relates to changes in mood, motivation and fatigue. Professor Sonya MarshallGradisnik Immunological Biomarkers in ME Professor MarshallGradisnik is one of Australia's foremost researchers in the area of neuroimmunology and was instrumental in establishing the Public Health and Neuroimmunology Unit PHANU) at Bond University. (Much of her work relates specifically to autoimmunity in Chronic Fatigue Syndrome sufferers and she is regularly asked to speak to community groups on behalf of Queensland Health and NSW Health. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 49 of 57 May 2015

Journal of IiME Volume 9 Issue 1 Her research in the area of exercise immunology has also contributed to the body of knowledge relating to the effect of doping in sport and she serves as Sports Medicine Australia's national spokesperson in this area. The vital research conducted by Professor Marshall has attracted more than $1 million in grant funding and she has produced 21 peerreviewed papers, five book chapters and one provisional patent. In 2008 Dr Marshall was joint leader of the Bond University team responsible for developing the BioSMART program. The team was awarded a prestigious Australian Teaching and Learning Council Award (formerly known as the Carrick Award) for Outstanding Contribution to Student Learning and for the quality of student learning over a sustained period of time. Abstract: Not available at time of printing – but will be made available on Invest in ME web site. Dr John Chia ME and chronic enterovirus infection: An Update on pathogenesis Dr Chia is an infectious disease specialist practicing in Torrance, California, USA and has published research recently (Chronic fatigue syndrome associated with chronic enterovirus infection of the stomach) on the role of enteroviruses in the aetiolgy of ME/CFS – an area which has been implicated as one of the triggers by a number of studies. There are more than 70 different types of enteroviruses that can affect the central nervous system, heart and muscles, all of which is consistent with the symptoms of ME/CFS. May 2015 By analysing samples of stomach tissue from 165 patients with CFS, Dr. Chia's team discovered that 82% of these individuals had high levels of enteroviruses in their digestive systems. Dr Chia's research may result in the development of antiviral drugs to treat the debilitating symptoms of ME/CFS. Dr Chia is President of the Enterovirus Foundation and Assistant Professor at the UCLA School of Medicine. Abstract: Not available at time of printing – but will be made available on Invest in ME web site. Dr Claire Hutchinson Biomarkers: Visual Processing and ME/CFS Dr Claire Hutchinson is a lecturer in the College of Medicine, Biological Sciences and Psychology at the University of Leicester. As a vision scientist the majority of her work is concerned with how visual sensory information is encoded by the human visual system. Her research includes healthy visual perception, age-related visual decline, and visual markers of 'non-visual' illnesses. It is this latter strand of research that led her to study vision-related problems in ME/CFS. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 50 of 57 Journal of IiME Volume 9 Issue 1 Abstract: People with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) report a number of vision-related symptoms associated with their condition. These include difficulties with depth perception and focussing on objects, hypersensitivity to light, eyestrain, painful, itchy or dry eyes, problems with visual attention and vision-related headaches. Despite these vision-related complaints, there has been very little research systematically examining their characteristics and causes. We have shown that the severity of vision problems in ME/CFS is correlated with their impact on patients’ everyday lives and have provided experimental evidence to support the results of questionnaire studies. Here, I will discuss this work examining visual markers of ME/CFS. I will present a snapshot of our experimental evidence and discuss how particular visual deficits can be mapped onto different stages of the visual processing pathway. Finally, I will discuss the utility of our work for people with ME/CFS and those treating them with particular reference to how our findings: (1) may be useful in clinical diagnosis and (2) provide insight into the origin (e.g. the eye, the cortical visual pathways, cognitive control of visual processing) of vision-related problems in ME/CFS. Professor Betsy Keller Activity guidelines to avoid symptom flares Department of Exercise & Sport Sciences, Ithaca College Ithaca, NY, USA May 2015 Professor Keller is Professor Ithaca College, Dept. of Exercise and Sport Sciences, Ithaca, NY. Since 2003 Professor Keller has tested persons ill with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) for purposes of research and/or to provide an objective assessment of functional capacity and ability to perform and recover from physical work. Often, these individuals seek an objective indication of illness status to apply for disability benefits. A two-day exercise test protocol has shown to be instrumental in delineating abnormal responses to and recovery from exercise in ME/CFS patients. Her report of test results and interpretation has been successful in many cases to support an argument for disability coverage. There are only a few researchers in the USA who have performed and interpreted the twoday exercise test protocol on ME/CFS patients, and therefore have observed first-hand the anomalous multisystem responses of these patients 24 hours post-exercise. Professor Keller continues to expand the small body of peer-reviewed evidence of the abnormal recovery response to physical activity in ME/CFS so that most, if not all clinicians, researchers, health insurers and patient family members also understand the deleterious impact of this illness. To that end, she has collaborated on an NIH R21 grant with PI, Maureen Hanson, from Cornell University to study the effects of exercise in ME/CFS on parameters of Invest in ME (Charity Nr. 1114035) www.investinme.org Page 51 of 57

Journal of IiME Volume 9 Issue 1 physiological and immune function. Together they continue to analyze this data and other data collected to better understand how to help those with ME/CFS. Abstract: Post exertion malaise (PEM) is an exacerbation of the symptom profile of an ME patient following physical, cognitive or emotional stress. Physical stress that exceeds the physiologic threshold of aerobic metabolism necessitates energy production from anaerobic metabolism to meet energy demands of work. Energy production via anaerobic metabolism is fast acting and important to meet immediate and short-term energy demands, but produces metabolites that contribute to physiologic fatigue. A dependency on anaerobic energy production for longer duration activities (> 2 min) will exceed a physiologic threshold of aerobic energy production (aka anaerobic threshold) and contribute to fatigue. In healthy individuals, the physiologic consequence of exceeding anaerobic threshold is a reduction in work to an intensity at which aerobic metabolism can supply the preponderance of energy. The reduction in work also enables recovery of anaerobic energy-producing processes. In contrast, exercise studies of ME patients reveal an impaired ability of aerobic metabolism to facilitate recovery following anaerobic work. In this case, the ME patient will rely predominantly on anaerobic metabolism to power even low-level activities that would not normally provoke fatigue. The altered metabolism will also exacerbate the profile of ME symptoms that are specific to the patient, possibly causing new symptoms to emerge. With judicious management of physical activity intensity, duration, and recovery, it is easier to avoid post-exertion symptom exacerbation (PEM) than it is to recover from it. May 2015 Strategies and guidelines for physical activity management will be discussed with goals of avoiding symptom flares and improving movement efficiency, and with hope for enhancing overall well-being. Professor Olav Mella / Dr Øystein Fluge Multi-centre Rituximab Clinical Trial for ME/CFS Dr Øystein Fluge received medical degree in 1988 at the University of Bergen, and is a specialist in oncology since 2004. He has worked as a Research Fellow with support from the Norwegian Cancer Society and is now chief physician at the Cancer Department, Haukeland University Hospital. Doctoral work emanates from the Surgical Institute and Department of Molecular Biology, University of Bergen. Professor Mella has performed clinical trials to test the benefit of B-cell depletion therapy using rituximab in ME/CFS patients. Dr. Olav Mella of Haukeland University Hospital in Bergen, Norway began his investigation of rituximab’s effects on CFS after treating several Hodgkin’s Lymphoma patients who had long standing cases of CFS prior to developing cancer. In 2011 Professor Mella and Dr Fluge published a paper "Benefit from BLymphocyte Depletion Using the Anti-CD20 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 52 of 57 Journal of IiME Volume 9 Issue 1 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and PlaceboControlled Study" Abstract: Rituximab: a multicenter, double blind, placebo-controlled study of rituximab induction and maintenance treatment in ME/CFS Øystein Fluge and Olav Mella, Haukeland University Hospital, for the Norwegian cooperative study group (Haukeland University Hospital, Oslo University Hospital Notodden Hospital, St. Olav University Hospital, University Hospital of Northern Norway). ME is a debilitating disease, often long-lasting, with a high sickness burden and a low quality of life, in addition to costing the patients, their families and society vast amounts of money. There is no established or generally accepted drug treatment. Based on observation of a patient with ME with marked symptom improvement when she was treated for lymphoma with cytotoxic drugs, we did a case study, followed by a small, double blind, placebo-controlled study with the anti-CD20, monoclonal antibody rituximab, that acts by depleting B-lymphocytes. These positive studies were followed by a phase II study of rituximab in 29 patients, exploring rituximab induction followed by maintenance rituximab up to 15 months, with 36 months observation time. That study confirmed that B-cell depletion with rituximab resulted in clinical responses in 2 of 3 patients and that about half of the patients still experienced sustained responses at the end of the observation. Based on these studies, there is from September 2014 an on ongoing, Norwegian multicenter study of rituximab induction and maintenance. The study is double blind, placebo (saline and May 2015 albumin) controlled, and has by May 2015 recruited more than 120 of the projected 152 patients. The patients fulfill the Canadian criteria, with sickness duration from 2-15 years. The study is block randomized by treatment center, with a predetermined number of included patients in each center. Induction is with rituximab 500mg/m2 day 1 and 15, maintenance with 500mg flat dose at 3, 6, 9 and 12 months. Observation time is 24 months. The primary end points are temporal development of self-reported fatigue score, and number of patients reaching predetermined, clinical criteria for response. Secondary endpoints are quality of life measured by SF36, levels of physical activity registered by electronic armbands for 7 consecutive days before and after intervention, total level of self-reported function at 6, 12, 18 and 24 months, and number of patients still in response at 24 months. Toxicity will be analyzed. Based on the assumption that declined ability for blood flow regulation is an important element in symptom maintenance in ME, substudies to investigate endothelial dysfunction in large arteries (flow-mediated vasodilation) before and after intervention will be performed in Bergen and Notodden, microcirculatory changes in addition in Bergen. Ergo-spirometry day 1 and 2 before and after intervention will be done in Bergen, Oslo and Notodden in patients sufficiently well to perform ramp bicycle exertion. In Bergen, patients with gastrointestinal symptoms are offered a gastroenterology sub-study before and after intervention. The study will be unblinded for analysis when the last recruited patient has been observed for 24 months, hopefully in early autumn 2017. Throughout the study, systematic blood tests are drawn for a central biobank with the aim of elucidating molecular mechanisms behind the symptom maintenance in ME. This part of the Invest in ME (Charity Nr. 1114035) www.investinme.org Page 53 of 57

Journal of IiME Volume 9 Issue 1 study is supported by the Kavli Foundation. The clinical study is supported the Norwegian Research Council, the Norwegian Department of Health, the Regional Health Authorities, MEandYou crowd-funding, and the Norwegian ME Association. Finally, we will briefly report on a recently initiated phase II study exploring pulse infusions of another immune-modulating drug, cyclophosphamide, in three groups of totally 40 patients: the largest group consists of patients not previously in our intervention studies, another is non-responders to rituximab, and finally patients with response to rituximab and subsequently recurring. May 2015 ME PATIENT “The reason I’m so proud of one of the charities I support, Invest in ME, is because it is run entirely by a few volunteers who themselves either suffer with the illness or are parents of children with ME. There are no salaries; every penny that’s raised goes where it should go and alongside the Lets Do It For ME team who are also voluntary, what they have achieved is nothing short of phenomenal." - Stacy Hart, Watford Observer Invest in ME (Charity Nr. 1114035) www.investinme.org Page 54 of 57 C10 Conference DVD The IIMEC10 ConferenceDVD contains 4 discs and is in PAL format- and contains the full presentations from the 2015 conference plus plenary sessions, and the pre-conference dinner keynote speech by Mike Shepherd. Order it here http://www.investinme.eu/IIMEC10.shtml#dvd _____________________________________________ Check the IIMEC10 Conference Trailer Journal of IiME Volume 9 Issue 1 10th Invest in ME International ME Conference 2015 29th May 2015, London Start 07.45 Presenter Registration 08.55 Welcome to IIMEC10 09:05 Professor Ian Charles Dr Ian Gibson Solving ME: What a Research Park Has to Offer in Resolving a Chronic Disease Such as ME 09:30 Professor Mady Hornig Markers of Immunity and Metabolism in ME 10:00 Professor Jonas Bergquist Proteomics in ME 10.25 Coffee/Tea Break 10:50 Dr Luis Nacul Conference Agenda Presentation May 2015 Epidemiological Evidence on ME/CFS: Current Status and Implications for Research and Service Delivery 11.15 Dr Amolak Bansal 11:45 Professor Sonya MarshallGradisnik 12.15 UEA / IFR / UCL Researcher/Students 12.35 Lunch 13.40 Dr Jo Cambridge 14:05 Dr Neil Harrison 14:30 Dr John Chia 14:55 Dr Claire Hutchinson 15.15 Coffee/Tea Break 15:50 Professor Betsy Keller 16.15 Dr Oystein Fluge/ Professor Olav Mella 17.10 Plenary Session Diagnosis and Differential Diagnosis of ME Immunological Markers in ME The Next Generation – Panel discussion with Professor Simon Carding B-cell biology and ME Immune-Brain Communication and Relationship to Inflammation ME and Chronic Enterovirus Infection Biomarkers: Visual Processing and ME Activity guidelines to avoid symptom flares Multi-centre Clinical Trial of Rituximab Will ME Be Treatable/Cured? 17.30 Adjourn (Note that the agenda, format and times are subject to change) Invest in ME (Charity Nr. 1114035) www.investinme.org Page 55 of 57

Journal of IiME Volume 9 Issue 1 May 2015 Running 28 European Marathons - in the name of Friendship Mike Harley is raising awareness of ME and raising funds for Invest in ME’s biomedical research fund by running a marathon in every EU country (currently 28 in total). His first challenge was the Prague marathon that took place on Sunday 3rd May. Then on to Helsinki in the summer. Mike is doing this because one of his oldest friends, Ian, has been suffering from ME for over 7 years and has been unable to work or lead a normal life. This is a great example of friendship. And this is not the only occasion Mike has supported his friend in this way. Last year Mike, with a group of friends, took part in a very different challenge for the charity (92 football grounds in 92 hrs - http://www.92in92.blogspot.co.uk/) managing to reach over 10 million people (through TV, Press and the football community) and raising nearly £5K for the IiME Rituximab trial fund - Invest in ME (Charity Nr. 1114035) www.investinme.org Page 56 of 57 http://www.ukrituximabtrial.org/IIMEUKRT%2 0Donate.htm. Throughout this project Mike met and talked to ME sufferers and their families and this has had a very profound effect on his decision to attempt this new challenge. Mike will be taking the flag below with him around Europe. Mike’s JustGiving page is https://www.justgiving.com/mikeseumarathons /

A New Decade of Invest in ME – Research www.investinme.org

Science, Politics and ME a book by Dr Ian Gibson Dr Gibson led an inquiry into ME in 2006. Without official funding, at a time when unbiased and independent analysis of ME by establishment organisations and the media was lacking, Dr Gibson provided a checkpoint which attempted to get publicity and change which would help ME patients S MP http://tinyurl.com/hl644uh E http://www.investinme.eu/IIMEC11-DVD.shtml Journal of IiMER Volume 10 Issue 1 Journal of IiMER Welcome to IIMEC11 10 Years of Biomedical Research 10 Years One Stupid Dot Letter from America 1 QUADRAM C of E for ME EMERG EMEA NEWS Mike’s EU Marathons for IiME Letter from America 2 4 8 10 19 20 24 26 29 30 33 43 Tackling ME/CFS in New Zealand 46 It’s a Funny Old World Speakers at IIMEC11 Agenda IIMEC11 56 60 75 Invest in ME - Research (UK Charity Nr. 1153730) PO BOX 561 Eastleigh SO50 0GQ Hampshire, UK Tel: 02380 643736 07759 349743 E-mail: info@investinme.org Web: www.investinme.org DISCLAIMER The views expressed in this Journal by contributors and others do not necessarily represent those of Invest in ME. No medical recommendations are given or implied. Patients with any illness are recommended to consult their personal physician at all times. https://secure.thebiggive.org.uk/charity/view/6239 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 3 of 77 June 2016 Invest in ME Research Invest in ME Research (transitioning from Invest in ME) is an independent UK charity facilitating and funding a strategy of biomedical research into Myalgic Encephalomyelitis (ME) and promoting better education about the disease. The charity is run by volunteers - patients or parents of children with ME – but on a professional basis with a passion for developing a scientific foundation for research into ME. We do not receive, and have never received funding from government or government organisations. The charity decided early on that biomedical research into ME was crucial in order to make progress in treating this disease. We also decided that education of healthcare staff, the media, government departments, patient groups and patients was to be a priority. Our conferences and, later, our research colloquiums, were organised from the beginning in order to provide a platform for research and a means of facilitating education about ME. In order to bring the best research to bear on ME and to bring the best education to healthcare and patients we welcome your support.

Journal of IiMER Volume 10 Issue 1 Welcome from the June 2016 about this disease and to biomedical research which is the only way that the cause of ME will ultimately be found. A decade of commitment to research, education and awareness has finally succeeded in opening up new areas of research. Chairman IIMEC11: 11 YEARS A NEW DECADE OF RESEARCH In 2015 Invest in ME arranged its TENTH international ME conference - an event bringing together many of the world's most renowned scientists and researchers to London to meet with healthcare professionals and patients. In May of 2016 the charity reached its 10th year anniversary as a charity. By necessity Invest in ME (Research) have had to create and take opportunities in order to make progress. Ten years ago Invest in ME was formed to make a change in how Myalgic Encephalomyelitis was perceived and treated in the media, by health departments and by healthcare professionals, and to educate, publicise and lobby regarding ME and the urgent requirement for public funding for biomedical research. A decade of biomedical research conferences achieved - all underlining the charity's commitment to education After ten years as a charity there are good signs of real progress and, with enough support, we can make this permanent. A strategy of high-quality biomedical research has broken the mould of the past and a new decade now brings new and possibly decisive projects which will finally overturn the barren landscape of ME research which had been allowed to exist for too long. Ten years ago the ME research landscape was different - no platform for regularly showcasing or encouraging biomedical research - no funding and no recognition of the need to fund biomedical research into this disease. Yet now real progress is underway – thanks to the last ten years of effort by IiME’s supporters which has forced real change. These have been the foundations upon which we can build a sensible policy toward research into ME. The charity has two major high-quality research projects underway – probably the two most important research projects for the future of ME research in the UK - and is building a foundation for translational biomedical research into ME – a Centre of Excellence for ME. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 4 of 77 Journal of IiMER Volume 10 Issue 1 This strategy has been augmented with education of, and participation in our research projects by, medical students - enhancing theirs and their peers’ education about ME and building a base for the next generation of researchers. We have for many years also been introducing new areas of research and new researchers into the field of ME – a new idea initiated by the charity to mainstream research into ME. Last year the charity proposed and facilitated the establishment of the European ME Research Group - a group of top European researchers who will collaborate and establish multi-site international biomedical research projects which will overturn decades of miserly funding being directed to ME research and which has discouraged good research to be formulated or performed. The charity is at the heart of European cooperation with its participation in the formation of the European ME Alliance involving 13 countries in Europe and with the potential to achieve. The Invest in ME strategy of bringing in researchers from other fields to help and improve biomedical research into ME has been successful and well worth the effort and cost. June 2016 Our conferences bring together patients, researchers, clinicians and healthcare staff and allow knowledge and experiences to be shared – and has been doing so for eleven years. Our research colloquiums are bringing together high-calibre international researchers – concentrating on biomedical research - that can help us understand the cause/s and pathomechanisms of ME. The charity's proposal for a Centre of Excellence for ME is possible to achieve and it has set a target which can be reached if enough support is given. Our supporters deserve recognition for all their support and efforts to bring change to the landscape of ME research and perception. Due to imaginative and positive support such as the Let’s Do It for ME campaign and thanks to dedicated supporters the charity enters a new decade which promises to transition all the efforts of the past ten years into benefits for all patients and their families - and also for healthcare staff. All of this brings momentum which then spawns changes elsewhere - by influencing others, by interesting scientists and researchers in new research areas and establishing a change in how ME is perceived. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 5 of 77

Journal of IiMER Volume 10 Issue 1 As we approach our tenth year as a charity we may look back to some progress and a good deal of change occurring due to the efforts and determination of the charity and its supporters. As we look forward we will continue to seek change. If a disease is well understood then all aspects of patient care may improve whilst cures and treatments are being developed. Understanding of ME and finding the cause/s and pathomechanisms can only be achieved if research takes a clear stand of ME being a physical illness as a starting point and everything else is consequential. There are now enough clues, well presented over the ten years of IiME conferences that need to be followed up. Clinical trials such as the phase III rituximab trial in Norway and the UK rituximab trial project funded by Invest in ME Research give patients hope and make healthcare professionals take ME more seriously even before the trials have begun or results have been published. Even the awareness of ME patients being part of proper mainstream clinical trials makes a huge difference to the perception of this disease. This we have witnessed already. Invest in ME Research have never had any doubt of ME being anything other than a physical illness and we do not believe there is sense or reason for mixing flawed psychosocial views of the June 2016 disease with biomedical views under one umbrella. We hope that our ten years of focused approach and engaging with researchers that have the skills to help solve ME is beginning to bring results and will continue. Dear Kathleen, I just wanted to thank you all for setting up the charity and all the hard work that you have done over the last 10 years. I became ill in 2005 and you set up the charity around the same time. Your charity has given me such hope that some proper biomedical research is being done. There is a lot of positive momentum now in ME and I know the fruits of your labour over these 10 years will soon pay off big time! Kind regards – H (ME patient) By necessity Invest in ME (Research) have had to create and take opportunities in order to make progress. After ten years as a charity there are good signs of real progress and, with enough support we can make this permanent. This is a good time to be involved in ME research as we are at the beginning of making discoveries. We are optimistic for the future as patient power has made Invest in ME (Charity Nr. 1114035) www.investinme.org Page 6 of 77 Journal of IiMER Volume 10 Issue 1 it possible for patients to show the types of research they want and need. We believe we can look forward, and expect even more rapid progress in the future – directed by agents of change which have been or are being created. The IIMEC11 conference and BRMEC6 research colloquium provide unique opportunities to begin this new decade of conferences with an intent to resolve ME once and for all. And for so many patients and their families this will not have come a moment too soon. Welcome to IIMEC11 and BRMEC6 Kathleen McCall CHAIRMAN INVEST IN ME -RESEARCH June 2016 IiMER chairman Kathleen McCall thanks our sponsors of IIMEC11 events Invest in ME (Charity Nr. 1114035) www.investinme.org Page 7 of 77

Journal of IiMER Volume 10 Issue 1 June 2016 10 Years of Biomedical Research - Invest in ME Dr Leonard A Jason and Zachary Siegel CENTER FOR COMMUNITY RESEARCH, DEPAUL UNIVERSITY, CHICAGO, USA Leonard A. Jason is a professor of clinical and community psychology at DePaul University, director of the Center for Community Research, and the author of Principles of Social Change. - See more at: http://blog.oup.com/2015/02/diseas e-name-chronic-fatigue-syndromeme/#sthash.OYrlnLJU.dpuf 10 years of Invest in ME’s dedication to advocate for a marginalized group and the determination to allocate funds in a neglected field needs to be acknowledged and applauded. This organization has been working in the trenches of ME, and it has been a notable and significant contribution to the field. Invest in ME has been able to increase awareness and disseminate knowledge to scientists, clinicians, and patients within the ME community. With limited resources, but unlimited creativity and imagination, these patients and their supporters have showed the world what can be done. They are an inspiration for the world. Stigma is still associated with too many patients with ME, and this might be partly due to our society’s infatuation with unlimited energy, Zachary Siegel is a research assistant at DePaul University's Center for Community Research. He is also a freelance writer. stamina, and endurance, and in fact, these entities are more alluring than money. Patients with ME continue to encounter scepticism, and this is regrettable, as patients first endure a devastating illness and then they are further victimized by our society’s reaction to them. Far too many scientists and health care workers have been part of the problem, and this has to change. The status quo is not acceptable for patients with ME. It’s only by us collectively being involved in action that the situation will change. And it has changed for many other illness groups, such as people with HIV/AIDS, who demonstrated that it is possible to bring about a sea change in the treatment and respect for people with Invest in ME (Charity Nr. 1114035) www.investinme.org Page 8 of 77 Journal of IiMER Volume 10 Issue 1 this illness. To bring about this type change is going to involve not just the patients who have ME, but also their friends and family members who do not have this illness. The future of this field is in connecting the many patient and scientific groups into one larger body that is united for change. We welcome youth groups, civic organizations, and not-for-profits to get involved in one of the truly neglected areas needing structural changes in the way patients are treated and their availability to quality care. In order to push forward, we need research that involves multidisciplinary efforts that will bring together scientists from different disciplines including virologists, epidemiologists, individuals who study the autonomic nervous system, genetics, computer science, immunology, and many other disciplines. This illness represents a great challenge to medicine, and one from which we will all learn the intricacies and systems of the human body. In addition to the massive amounts of funding that are needed to better understand this complex illness, patients living in every country need the best that medicine can offer. The key to success is a team of health care providers working closely with patients, using services that meets all of their needs. I continue to believe that learning how to pace and stay within the energy envelope is the key to having a better quality of life. But we need Support Biomedical Research into ME. Invest in ME Research wristbands http://www.investinme.org/IiMEWristbands.htm Invest in ME (Charity Nr. 1114035) www.investinme.org Page 9 of 77 June 2016 much more basic research to find ways to cure this illness, and one day it will be possible, just as it has with other diseases that have had adequate funding for research. ME received considerable media attention over the last year, and we now need to use this momentum to bring about the changes that are so desperately needed. There is nothing as important for our field as seeing patients as true collaborators in service programs and research that focus on better understanding this illness, and their voices and vision need to play an instrumental role in setting the agenda for the future. By Dr. Leonard A. Jason and Zachary A. Siegel

Journal of IiMER Volume 10 Issue 1 June 2016 10YEARs studies for undertaking epidemiological research on CFS/ME in the UK. In 2006 Invest in ME was formed as a charity by patients and carers of children with ME. There were no funds let alone paid staff but lots of passion to put things right due to too much emphasis having been put on psychosocial paradigms following on from the 2002 CMO report. The MRC annual report from 2002/03 stated “Chronic Fatigue Syndrome/ME (CFS/ME): following the publication of a Report of the Chief Medical Officer’s Independent Working Group in January 2002, and at the request of the DoH in England, the MRC convened an independent CFS/ME Research Advisory Group to develop a broad strategy for advancing biomedical and health services research on CFS/ME. The research strategy was published on 1 May 2003, when the MRC issued a highlight notice welcoming research proposals (investigator-initiated) covering the spectrum of research into CFS/ME. In addition, the MRC will investigate usefulness of existing longitudinal The MRC’s Council agreed the funding of two clinical trials of treatments for CFS/ME in March 2003. A trial led by Dr Alison Wearden (University of Manchester) will evaluate pragmatic rehabilitation, a nurse-led self-help intervention in the treatment of CFS patients in primary care, against supportive listening or treatment as usual. Dr Peter White (St Bartholomew’s Hospital, London) will undertake a randomised controlled trial of cognitive behaviour therapy, graded exercise therapy, and adaptive pacing against usual medical care for patients with CFS. This latter study is funded in partnership with the DoH, the Department of Work and Pensions, and the Chief Scientist’s Office of the Scottish Executive.” Since the CMO’s report of 2002 the debacle over the disastrous PACE Trial is the clearest illustration of the failure and the negligence shown by those who have been responsible for funding ME research. Much of the charity’s early and continued work was concerned with Invest in ME (Charity Nr. 1114035) www.investinme.org Page 10 of 77 Journal of IiMER Volume 10 Issue 1 protesting the public funding policy of favouring behavioural research over biomedical one. We held our first conference in Westminster, London in 2006 in the hope that politicians and other healthcare decision makers could easily attend. Dr Ian Gibson, MP for Norwich North at the time, opened the first conference. He has been the charity’s supporter and advisor ever since. We worked with ITV Meridian and Norway’s Puls programme to allow their excellent reporting on severe ME in the UK and Norway to be seen. These programs were made available for our first 2006 conference DVD set and formed a powerful and realistic statement on how disabling ME can be to patients and their families. The 2007 we trialled a two-day public conference format in London. Dr Ian Gibson was joined by another Norfolk MP Mr Norman Lamb who opened the second day. We also started producing the Journal of IiME, a mixture of science, education and politics and as we had no funds these were printed by ourselves using a standard, slow home printer - tedious as well as time and ink consuming all that work was. June 2016 We believe that everyone who attended the 2007 conference left not only with an enhanced knowledge gained from the conference but also with renewed hope for the future. There were early signs of things to come from Norway when Ellen Piro and Eva Stormørken gave their presentation explaining the reasons for the Norwegian ME Association saying a firm NO to the Norwegian NICE guidelines. Their presentation received a great ovation as it resonated with patients and carers in the UK. Invest in ME contributed to the review of the UK NICE Guidelines (both the draft version and the final version). We found both documents unsatisfactory due to emphasis on psychiatric paradigms to manage/treat ME/CFS. Invest in ME produced a 52-page response that followed our 38,000-word response to the draft guidelines. The charity visited the CMO’s office to meet with Dr Bill Kirkup, Deputy CMO at the time. We requested that ME be treated as a notifiable illness in schools - but this was rejected. Invest in ME have written to past and current ministers at the Department of Health and to the Medical Research Council in order to encourage more funding to be allocated for biomedical research into ME. The chief executive of the MRC contributed an article for our Journal for the 2007 conference. Invest in ME took over distribution of the Canadian ME/CFS Guidelines in the UK on a not-for-profit basis. The guidelines are now a basic requirement for any Invest in ME (Charity Nr. 1114035) www.investinme.org Page 11 of 77

Journal of IiMER Volume 10 Issue 1 service model being developed for diagnosis, management and treatment of ME. They are widely used in research such as the Invest in ME funded B cell study at UCL and gut microbiota at IFR/UEA. The Norwegian phase III rituximab trial selects patients fulfilling these criteria also. We translated into English the Norwegian documents describing the exciting news of the Norwegian government’s intentions (MP Laila Dåvøy was instrumental in initiating this work in 2006-2007) to treat ME more seriously and with a more strategic approach, including creation of centres of excellence for ME. From 2008 Invest in ME began participating in the All Party Parliamentary Group discussions and sent in many submissions. Sadly, the health ministers at the time, Mr Alan Johnson and Mrs Ann Keen, both declined to take responsibility for the situation with ME and declined invitations to our conferences – demonstrating a point which has been consistent over the years – that apathy toward ME patients has no party political borders. The charity was instrumental in forming the European ME Alliance in 2008 – a grouping of charities and patient organisations within Europe who came together to tackle issues around ME affecting European patients and their families. June 2016 In 2009 the charity published and distributed the unique book on ME, Lost Voices from a hidden illness, which was compiled by Natalie Boulton and highlighted the situation of those severely affected by ME and their families. This book has been ordered by patients, support groups, healthcare staff and researchers in twenty countries. It was also ordered for inclusion in the syllabus by Chicago University, USA. Numerous research activities to support TV, radio and newspaper coverage of ME were performed and IiME contributed to the consultation and review of the NICE Guidelines for CFS/ME. The charity began its Biomedical Research Fund to allow donations to research projects to be made. IiME organised and hosted the fourth annual Invest in ME International ME conference in London in 2009. The focus of this conference was Severe ME, an attempt to raise more awareness of patients with severe ME - a group of patients who were not represented in research trials and completely misunderstood by healthcare services. Prior to the conference Invest in ME arranged for the American journalist, Hillary Johnson, to visit London and give a pre-conference presentation on the evening before the conference to an audience of researchers, clinicians, patients and media people. Hillary’s presentation concerned the USA CDC’s Invest in ME (Charity Nr. 1114035) www.investinme.org Page 12 of 77 Journal of IiMER Volume 10 Issue 1 influence on ME research throughout the world. Invest in ME submitted responses to the published 5-year plan for CFS (ME) from the USA Centres for Disease Control. The charity also submitted responses to the UK All Party Parliamentary Group on ME. In 2010, tired with continually sitting in meetings with the NHS to discuss services for ME - yet with no progress being made, Invest in ME formulated a proposal for biomedical research to be based at a research and examination facility in the Norwich Research Park in Norfolk – a Centre of Excellence for ME. The Norwich Research Park includes multiple institutes and companies, including the University of East Anglia, Institute of Food Research and the Norfolk and Norwich University hospital as well as the Genome Analysis Centre (TGAC). Our proposal envisaged performing translational biomedical research into ME by researchers at the university using a patient cohort which had been diagnosed by an experienced clinician using appropriate diagnostic guidelines. Invest in ME formed a steering group to initiate our proposal and entered discussions with the university and hospital and with a renowned clinician. We had been in discussions with Norfolk Primary Care Trust (PCT) also and had secured a promise to fund the patient June 2016 examinations. These discussions and promotion of our proposal as one of the best ways forward for securing proper research and treatments for people with ME in the UK and Europe continued. IiME organised and hosted the fifth annual Invest in ME International ME conference in London. This had the theme of “A New Era in ME/CFS Research” to reflect the new awareness and acceptance that only biomedical research will allow treatments and cures to be found for ME. The 5th IiME conference (IIMEC5) was as usual CPD accredited and a platform for biomedical research. Invest in ME continued its criticism of the NICE Guidelines for CFS/ME which we viewed as lacking in any usefulness for physicians or patients. We also continued to criticise the PACE trial as flawed science and a huge waste of public money – money which could have been far better utilised if allocated for biomedical research into ME. From 2011 we were joined and supported in our quest for a Centre of Excellence with a new and visionary fundraising initiative – Let’s Do It For ME - formed by three house/bedbound patients. Together we quickly raised almost £10000 for our foundation project to study the gut microbiota in ME patients. For the charity this was a great deal in terms of the usual budget. This was a turning point in encouraging people with ME and their friends and families to actively fundraise for ME as they do in many other illnesses. There is still a long way to go to get to the level of MS, cancer, heart disease etc. but it was a good start and has continued to grow. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 13 of 77

Journal of IiMER Volume 10 Issue 1 IiME organised and hosted its sixth annual Invest in ME International ME/CFS conference. This had the theme of “The Way Forward for ME – A Case for Clinical Trials” to reflect the need for clinical trials of treatments for ME which could make a difference to the lives of patients. The 6th IiME conference (IIMEC6) was the first time that Professor Mella and Dr Fluge presented on ME/CFS in public. They made a lasting impression on us and we knew straight away that these two fine Norwegian gentlemen and their research were something special and worth keeping an eye on. We are honoured to have had the chance to follow their progress year after year. The charity organised the first Biomedical Research into ME Colloquium in 2011 – named the Corridor Conference – bringing together researchers from different continents to discuss and share knowledge about ME – and also some researchers new to the ME field. BRMEC1 was a new and unique addition to IiME’s conference events. For the first and only time the British Medical Journal (BMJ) accepted an invitation to the conference and their representative participated in the panel discussion. Prior to the conference the charity arranged a special meeting of the APPG in parliament and took along a number of our researchers who we had brought June 2016 to London for the IIMEC6 conference. This allowed MPs to be given true facts about the disease and the research required. Invest in ME continued to tackle the unjust media portrayal of ME and made an official complaint to the Press Complaints Commission after a series of unsubstantiated and biased articles appeared in major newspapers in a seemingly coordinated media attack on sick and vulnerable patients. Although, predictably, the PCC did not rule in the charity’s favour the bias and inaccurate reporting in these misleading and orchestrated articles and the unprofessional and flawed editorial control were clearly shown by Invest in ME to be present in the media – something which would be symptomatic of poor journalism shown later by the so called Leveson Inquiry. We also wrote to the Lancet about the PACE trial and continued to argue that flawed theories should not be funded by the public. In 2012 the three areas which have needed attention and which formed the basis of our work in order to benefit the public and society have been - funding for biomedical research, education about ME and campaigning/lobbying to ensure that ME is taken seriously and that patients receive care from healthcare staff who actually understand the disease. To this end the 2011-2012 was a year where the charity did much work to support our objectives. Many of these Invest in ME (Charity Nr. 1114035) www.investinme.org Page 14 of 77 Journal of IiMER Volume 10 Issue 1 activities performed by the charity overlap. An example was the premiere screening in the UK of a film about ME, Voices from the Shadows, which allowed a debate to be initiated about past treatment of ME patients with a message relating to the damage being inflicted on families by flawed and biased research. Invest in ME organised the first two showings – one in Norwich and one at the British Library in London. In Norwich the Mayor of Norwich attended along with the media, patients, and family members. In London the British Library provided an imposing setting for a serious debate on this disease which the film allowed to be initiated. Dr Nigel Speight spoke at the screening on a panel which included a local London councillor. Our continued criticism of the PACE Trial showed how badly wrong research can go and how much money is being wasted on deleterious and flawed approaches to this disease by organisations that are unaccountable. June 2016 NHS services, GP training, press complaints made by the charity and other activities which the charity had conducted. The charity had also written to various organisations in order to clarify errors and misinformation in publications. Invest in ME continued with its annual conference events. In May 2012 our seventh Invest in ME International ME CPD accredited Conference (IIMEC7) took place in London along with the Clinical Autoimmunity Working Group (CAWG) which was a 2-day research meeting, the BRMEC2 Colloquium, that IiME organised in collaboration with the Alison Hunter Memorial Foundation of Australia – working together for over six months on designing this research meeting. The CAWG was an extraordinary meeting with world-renowned experts in different fields, not just ME and laid the foundations for our future colloquiums. On the evening before the conference Invest in ME arranged and hosted the pre-conference dinner and the charity was delighted to have Norwegian journalist Jørgen Jelstad Invest in ME had been invited to be an observer at the All Party Parliamentary Group (APPG) for ME. The charity provided input to meetings on points concerning welfare reform, research, presenting his speech “Words Matter”. Jørgen has closely followed ME research and his presentation provided a great deal of food for thought. At the end of the 2012 conference we announced our intention to try to set up a clinical trial in the UK of rituximab for ME patients. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 15 of 77

Journal of IiMER Volume 10 Issue 1 As part of our strategy to initiate highquality biomedical research into ME that looked at causality of ME the charity was finally able to fund its first research project in 2013, the gut microbiota study at IFR/UEA involving a three year PhD studentship. This followed many years of effort and fundraising and was greatly assisted by the charity’s advisor Dr Ian Gibson. The charity and its supporters contributed to the appeal by the Australian Alison Hunter Memorial Foundation and Australian PHANU for a flow cytometer to be purchased to assist research there. The charity organised and held its 8th annual international research conference – with the sub-title of Mainstreaming ME Research – reflecting our view that ME was now entering the mainstream research activities being considered by research establishments. We also organised our third international research colloquium in order to encourage ME research. These events established a core working group of researchers and facilitated many new collaborations – which was the intention of the meetings. This also underlined the charity’s conviction that a strategy of biomedical research into ME is possible, is sensible and will be the only way to June 2016 find treatments/cures for ME. As part of the charity’s attempt to mainstream ME research into research agendas and discussions of major organisations we invited the chair of the Royal College of GPs to speak at our 8th International ME conference. Dr Gerada’s talk led to a lively discussion with some surprising statements. Following the colloquium/conference the charity announced the beginning of its rituximab clinical trial project. We also announced that our advisor on the project would be Emeritus Professor Jonathan Edwards of UCL. During 2013 the charity organised a video conference call with Dr Martin McShane - NHS Commissioning Board Authority, Director – in an attempt to influence DoH policy on ME. In the discussion were the parents of a severely affected young adult who had themselves been victimised by the social services due to complete ignorance about ME. We feel our strategy of biomedical research with collaboration between international biomedical researchers is bringing change and a real prospect of continued progress. As we stated in our newslett – our motives “are to make rapid progress in translational biomedical research into ME which will benefit ME patients and their families and provide hope that something is being done for them, that there truly is a promise of better times Invest in ME (Charity Nr. 1114035) www.investinme.org Page 16 of 77 Journal of IiMER Volume 10 Issue 1 June 2016 ahead and not just further delaying tactics to waste more years” By 2014 we could say that the charity’s work had made an impact. After a year of attempting to gain interest in setting up a clinical trial of the drug rituximab, following promising results from the Norwegian Fluge et al. study, the charity initiated a project for the trial and related B cell research in association with University College London. We began a fundraising campaign with the help of the Let’s Do It For ME team of volunteers. An initial target amount of £350 000 was set and we thus started a crowdfunding project into ME which had not been tried before in the UK. This was a daunting task but not one the charity thought impossible to achieve – and IiME's supporters rose to the challenge with positive campaigns which raised funds and awareness for this disease. The supporters of the charity have been a credit to the community of ME patients and carers and have demonstrated the resilience of this population of sick people. We were privileged and grateful to the Hendrie Foundation who agreed to pledge funding toward the rituximab trial. This allowed patients and carers renewed hope in tackling this disease and is now an international project – both in the crowdfunding aspect and in the research itself. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 17 of 77

Journal of IiMER Volume 10 Issue 1 The charity has received donations and support from many different countries around the world. After an impressive campaign lasting a year, in August 2014 the charity secured the initial target amount (with pledges) of £350,000. To allow the promising B-cell study into ME to continue, and as part of the overall research portfolio that Invest in ME has with UCL and the consultants from Epsom and St Helier University Hospital and UCLH, the charity committed itself to fund a new PhD studentship at UCL that began in 2015. The charity organised and held its 9th annual international research conference – with the sub-title of Synergising Research into ME – illustrating the objectives of the charity in organising and facilitating international collaboration in research into ME. Following the IIMEC9 international conference the charity agreed in principle to fund further PhD students at UEA/IFR and also two intercalating medical students who would assist in the research underway at UEA/IFR. One student spent time at Cornell University with Professor Maureen Hanson and one at Oxford University under the guidance of Professor Angela Vincent. The charity also formed an Advisory Board to help the charity plan a strategy for research and provide advice on what research to fund. We are very pleased to have renowned researchers from UEA, IFR, Oxford and UCL in our Advisory Board. In 2015 the charity made submissions for the NIH Pathways to Prevention Report (P2P). We also made an analysis of the Institute of Medicine June 2016 (IOM) “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness” report. We continued our advocacy and support for people with ME by formally complaining to the BBC regarding poorly researched and unbalanced reporting. The BBC to its shame failed to respond to any of the complaints made – underlining the fact that although we had begun to change the research landscape it was still difficult to change the practices of a publicly-funded establishment organisation that is unaccountable regarding the truth. One can bring a horse to water but the horse has to be thirsty to drink. 2015 saw the fifth international biomedical research Colloquium and our tenth international ME conference. And both events were the best to date. A landmark achieved. Over ten years only a small proportion of the work that the charity and its supporters has performed can be mentioned. And in truth we never imagined that it would take so much effort to make the changes now being seen. Yet we enter a new decade of Invest in ME research – better equipped than ten years ago, more knowledgeable of the disease itself and as passionate as ever to produce a solution which will finally see an end to the misery which people with ME and their families have been forced to endure for the last two decades or more. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 18 of 77 Journal of IiMER Volume 10 Issue 1 One Stupid D ٜt Stacy Hart aka @MamaChill hip hop/rap artist, diagnosed with M.E. in 1991. Stacy still has M.E., 24 years after being diagnosed. June 2016 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 19 of 77

Journal of IiMER Volume 10 Issue 1 June 2016 By Zaher Nahle PhD, MPA, Vice President for Research and Scientific Programs Solve ME/CFS Initiative – Los Angeles, California Within the spectrum of human diseases, ME/CFS is “…one of the most challenging.” That is how the Director of the National Institutes of Health (NIH), Dr. Francis S. Collins, described this disease in a press release in late 2015 when he announced efforts to bolster ME/CFS research at the NIH. Collins, as the head of a $32 billion research agency investigating hundreds of complex diseases, has a unique perspective on medical challenges worldwide, which makes his characterization of ME/CFS especially telling. But why is this disease so challenging, “most challenging” in fact? The answer is not simple yet the challenges can be classified in two categories. “Humanmade” challenges resulting from inept policies and a lack of leadership and “nature-made” challenges stemming from the complex, multifactorial nature of the disease itself: First, solving medical mysteries historically, particularly stubborn ones, has been proportional to investment in clinical investigations and basic research. Lessons from polio to HIV have taught us that repeatedly. It is, therefore, consequential that the meager research spending on ME/CFS to date continues to sustain, if not fuel, the challenging attributes of this disease. Second, there is no US national strategy yet to tackle the disease in a focused, comprehensive way. Such strategy would create an aggregate mass of scientists, including the necessary infrastructure, for studying this incredibly stimulating area of science. Elements of such strategy would include: (i) Making ME/CFS a viable career path for investigators by funding federal grant opportunities in this area; (ii) Supporting clinical and research mentorship programs in ME/CFS; (iii) Developing centers for excellence dedicated to ME/CFS clinical and basic research; (iv) Fast tracking FDA approvals of promising drug candidates; and (iv) Redefining the illness as one of the “most challenging” diseases in medical school curricula and other medical education platforms, including those associated with influential federal agencies such as the CDC. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 20 of 77 Journal of IiMER Volume 10 Issue 1 Third, the serious deficit in comprehending the natural history of the disease is another key challenge. Case in point are statements in the February 2015 Institute of Medicine (IOM) report indicating that the committee “was unable to define subgroups of patients or even to clearly define the natural history of the disease” recommending that “Studies aimed at assessing the natural history of the disease and its temporal characteristics (onset, duration, severity, recovery, and functional deficits) are essential for a better understanding of ME/CFS and also are important to further refine the diagnostic criteria proposed in this report.” Fourth, the reluctance of most pharmaceutical companies to invest in the ME/CFS field absent reliable biomarkers is a challenge. In effect, this virtually eliminates the bulk of the financial and technological contributions from the private sector. Therefore, clever public/private partnerships to stimulate such endeavors are needed. These four issues define the “humanmade” impediments to solving this disease. The complex nature of the disease is a challenge itself; the biological pathways associated with ME/CFS pathophysiology are hard to investigate since by all indications they affect systems that are pleotropic by nature, i.e., regulating multiple interweaved networks and targets. Let’s illustrate this last point with an example: Take Cortisol, which is now being studied in depth at the CDC through its ME/CFS clinical multi-site program. It is a critical steroid hormone regulator within neuroendocrine signaling but also regulates a myriad of key components in the cellular energy production machinery (i.e., bioenergetics) and influences essential genes of inflammatory cytokines as well, hence altering our energetics capacity June 2016 alongside our immunity and inflammation status. Clearly, a singular factor can potentially control complex functions and systems that are intertwined and interconnected. When it goes awry, the consequences become multifactorial. One can list many more examples associated with ME/CFS, from mitochondrial dysfunction, to pathogenic factors to neurological abnormalities to autonomic deregulations that are all, by design, complex, pan-disciplinary elements crucial for our cognitive and physical functioning. At our organization, the Solve ME/CFS Initiative (SMCI) and under the leadership of Carol Head, SMCI president, we work to mitigate these challenges in several ways: I. One, we continue to put resources into projects that accelerate the discovery process. We promote this function by: i. Supplying any investigator studying ME/CFS the research materials (specimens) they need, using our Solve CFS BioBank; Our BioBank and Patient Registry™ holds a repository of physical samples from ME/CFS patients to supports the work of qualified researchers. This important aspect of services that our organization provides to researchers, also represents our efforts to link patients directly to researchers and facilitate the use of human materials in the process of investigating ME/CFS. ii. Funding meritorious grants through a competitive peer-review process to identify innovative technologies, Invest in ME (Charity Nr. 1114035) www.investinme.org Page 21 of 77

Journal of IiMER Volume 10 Issue 1 concepts and biomarkers. This program is named the Ramsay Research Grant Award Program in honor of the Myalgic Encephalomyelitis pioneer Dr. A. Melvin Ramsay, who was the recognized authority in ME from 1955 until his death in 1990. His sound descriptions of the disease have stood the test of time. This grant program part of our organization’s overall research strategy to encourage participatory investigations, accelerate new discoveries and reduce barriers for entry into the challenging yet rewarding field of ME/CFS. The Ramsay program has three main objectives: • INVEST in original ideas that will clarify the nature, progression and root causes of the disease. • CREATE environments through these pilot grants to help awardees generate preliminary data and compete for long-term federal grants with the hope of retaining these researchers in the ME/CFS field. • FACILITATE collaboration among individuals committed to solving this challenging medical issue through our organization’s network. II. Two, we engage with government leaders and policy makers. This engagement in advocacy is driven by two fundamental beliefs: one, that it is the responsibility of the government to find cures for the up to 2.5 million ME/CFS patients in the US alone and not the other way around; and two, that major breakthroughs will be accelerated June 2016 with significant funding from the federal government, most importantly NIH and CDC. These discussions with key government officials, which we consider essential to our core mission, establish a healthy partnership with national and public health organizations while simultaneously maintaining the pressure aimed at finding real solutions to our disease. III. Three, we are taking the lead in developing a national registry that can clarify the natural history of the disease. This is done in partnership with Genetic Alliance PEER program and the Robert Wood Johnson Foundation, as well as the ME/CFS community. Such initiative will also facilitate performing longitudinal and cross sectional studies, informing clinical trial design, sharing information with organizations and researchers for educational and research purposes, collecting demographic, epidemiological, genetic, social sciences, health disparity, comorbidity and treatment outcome data, conducting relevant and targeted surveys and creating an information hub that will benefit the ME/CFS community as a whole. IV. Four, we maintain vigilance against misleading information and poorly designed studies and disseminate information through our multi-communication channels (e.g., e-newsletter, print publication, social media) to refute suspect science and keep the community up to date on current Invest in ME (Charity Nr. 1114035) www.investinme.org Page 22 of 77 Journal of IiMER Volume 10 Issue 1 affairs. We also bring thought leaders from government, academia and the private sector to our patient community through regular webinars and forums. V. Five, we developed an investigation framework of highpriority targeted research initiatives focusing on original research. Initiated this year, this program leverages in-house expertise to help close the knowledge gaps in our organization’s three key research focus areas: bioenergetics, neuroendocrine biology and immune dysfunction. We conduct these targeted initiatives through well-defined projects initiated at our organization, either independently or in collaboration with researchers or medical centers. Projects are typically high risk/high reward and likely to generate information useful to the broader medical and scientific ME/CFS community. Results of these initiatives will be shared with the community to spark further studies. Currently, we have several targeted initiatives in the areas of bioenergetics, metabolomics, functional genomics, immune-senescence and RNA interference that were developed with commercial entities like Metabolon, research centers like Memorial Sloan Kettering Cancer Center and individual academic laboratories at leading medical centers nationwide. To achieve all these ambitious goals, we leverage other key assets at the organization including: Invest in ME (Charity Nr. 1114035) www.investinme.org Page 23 of 77 June 2016  a Research Advisory Council made up of highly respected experts drawn from diverse fields  a broad-based network of patients as partners  deeply committed board members, each of whom has a personal connection to the disease. We work to add value in our research endeavors by pursuing the most innovative applications and ideas in the ME/CFS field to make this disease understood, diagnosable and treatable. We are always looking for collaborations and partnerships in the United States and abroad. -----The Solve ME/CFS Initiative (SMCI), based in Los Angeles, is the major nonprofit, US-based organization focused on the debilitating disease Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) since its founding in 1987 (then under the name of CIFDS Association of America). SMCI’s mission is to serve ME/CFS patients through making the pathophysiology of the ME/CFS understood, diagnosable and treatable. With emphasis on transparency and rigor, the organization pursues its work in a number of ways, including grant making, bio-banking and patient registry support, the design and implementation of research programs in the basic and translational sciences as well as national advocacy, engagement and multi-channel communications on the most pressing and current ME/CFS affairs.

Journal of IiMER Volume 10 Issue 1 June 2016 Norwich to be Home to the Quadram Institute The Quadram Institute is a new centre for food and health research to be located on the Norwich Research Park. Under one roof the Quadram Institute will integrate research teams from the current Institute of Food Research (IFR) and University of East Anglia’s (UEA) Faculty of Science and Norwich Medical School with the Norfolk and Norwich University Hospital’s (NNUH) gastrointestinal endoscopy facility. The Quadram Institute is the name of the new hub for food and health research to be located at the heart of the Norwich Research Park, one of Europe’s largest single-site concentrations of research in food, health and environmental sciences. Building of a new facility to house the Quadram Institute began in February 2016, with an anticipated opening in 2018. The Quadram Institute’s mission is to develop solutions to worldwide challenges in human health, food and disease. The opening of the new building will be in 2018 quadram.ac.uk The initial investment for the Quadram Institute is being provided by the Biotechnology and Biological Sciences Research Council (BBSRC) together with its three Norwich-based partners: the Institute of Food Research (IFR); the Norfolk and Norwich University Hospitals NHS Foundation Trust (NNUH); and the University of East Anglia (UEA). The Quadram Institute will integrate research teams from the IFR and UEA’s Faculty of Science and Norwich Medical School with the NNUHs’ gastrointestinal endoscopy facility under one roof. To be led by Professor Ian Charles, currently Director of the IFR, the Quadram Institute’s mission will be to develop solutions to worldwide challenges in human health, food and disease. The concept for the institute is to enable a step-change in food and health science research by providing new insights and accelerating innovation that will deliver new foods and treatments as well as proactive health and lifestyle interventions, for the benefit of society and the bio-economy. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 24 of 77 Journal of IiMER Volume 10 Issue 1 The creation of the Quadram Institute underlines the collaboration of the four founding partners and reflects its strategy to work across four research themes: the gut and the microbiome (the gut flora); healthy ageing; food innovation; and food safety. These research themes will link closely to the world-class plant and crop research at the John Innes Centre and bioinformatics at The Genome Analysis Centre, both also located at the Norwich Research Park, creating a powerful plant-food-health pathway to deliver clinically-validated strategies to improve human nutrition, health and wellbeing. The Quadram Institute will work closely with the food industry, healthcare and allied sectors to transfer its scientific knowledge into practice. “There is a unique set of resources and expertise at the Norwich Research Park enabling the new Quadram Institute to be a world-leading innovation hub across our areas of interest, namely the gut, microbes, food and health. This is an exciting time to have the opportunity to be truly at the forefront of an emerging new discipline of health and food research. Recent understanding of how food and our gut flora interact is creating a fundamental shift in the way we will understand and address the impact of food on health. We will be engaged in fundamental and translational research, alongside clinical studies and endoscopy and our goal is to become recognised globally for research excellence and clinical expertise, and impact on patient care and outcomes” said Professor Charles. Professor Melanie Welham, BBSRC Director of Science said, “The UK is a recognised leader in bioscience research, with Norwich being well known for its strengths in food and plant Invest in ME (Charity Nr. 1114035) www.investinme.org Page 25 of 77 June 2016 sciences, as well as microbiological and gastrointestinal research. The Quadram Institute will enable us to bring together world-leading scientists in custom-built facilities to develop an integrated approach to food, diet and health research. The challenges these scientists will be tackling are some of the most important for people around the world, socially and economically.” UEA Vice-Chancellor Professor David Richardson said: "The Quadram Institute will be a unique multidisciplinary hub for world-leading research in the important fields of food, diet and health. This partnership will give Norwich Research Park researchers the opportunity to make cutting-edge contributions at the forefront of this emerging discipline.”

Journal of IiMER Volume 10 Issue 1 A Centre of Excellence for ME An Opportunity for Major Progress in Diagnosis, Treatment and Research into Myalgic Encephalomyelitis Since 2010 Invest in ME have been promoting the concept of a Centre of Excellence for ME and we have been steadily building a foundation of research that can be the basis for such a Centre. Our Executive Summary for MPs has been updated and is here – http://www.investinme.org/Documents/C ofE/Invest%20in%20ME%20Research% 20UK%20Centre%20of%20Excellence%2 0for%20ME%20Executive%20Summary %20for%20MPs%20Status%20June%2 02016.pdf This is a summary of the current status regarding the Invest in ME Research proposal for a Centre of Excellence for ME Research and Treatment based in Norwich, UK. Background  A seriously inadequate standard of medical care exists for ME patients in UK  Very little and fragmented biomedical research into the condition Invest in ME (Charity Nr. 1114035) www.investinme.org Page 26 of 77  Confusion between ME and chronic fatigue has led to unscientific research and ineffective treatments  Medical professionals lack understanding of, and training in ME – a serious risk of mis-diagnosis and missed diagnoses exists  Medical students are taught from a curriculum which uses flawed or out of date information about ME  ME identified as both highlighted area and high priority by MRC – yet MRC has continually failed to fund adequate biomedical research into ME  ME is leading cause of long-term absence from school due to sickness for students and teachers  ME is recognised by the Department of Health as a chronic neurological illness yet official guidance and management are aimed at mainly changing patients’ “false illness beliefs”  In 2015 The USA Institutes of Medicine (IOM) recognised ME as a serious, chronic disease June 2016 Journal of IiMER Volume 10 Issue 1 Our Objective A Centre of Excellence for ME in East Anglia, within the Norwich Research Park, utilising and based on existing facilities and resources would provide a hub of scientific and clinical excellence for ME within Europe The research arm would be funded initially by private/charitable donations but these preliminary research projects, coordinated in a strategy, would lead to grant applications to major public research funding bodies The clinical diagnosis and treatment arm would be funded eventually by the NHS - a key objective is that treatments are made available for all. Service Commissioning Current status A GP referral, via normal NHS channels to a consultant-led service that links with GPs with special interest. Treatment of patients would be based on sound scientific evidence A hub and spoke model would exist which would allow dissemination of expert knowledge to GPs and/or ME clinics nationwide and internationally. Out of area referrals would generate income. Training opportunities for medical students and other consultants, nurses etc. would exist. A unique training establishment would be possible Benefits Our proposal is a unique opportunity to establish European hub of scientific and clinical excellence in Norwich Research Park Early and correct diagnosis of patients would apply for all UK patients. Several medical students funded by IiMER have been intercalating in their medical degrees and we will continue to do this with more already planned More plans exist to develop a strategy of research involving international collaboration Invest in ME (Charity Nr. 1114035) www.investinme.org Page 27 of 77 All elements of the centre model exist and are ready to be integrated, with the exception of a lead ME consultant that the charity is progressing in discussions with relevant parties. The Foundation project at IFR/UEA examining the gut microbiota in ME patients started in October 2013. In the autumn of 2016 there will be two more PhDs starting and a further PhD student funded by IiME is currently being advertised. B-cell research as part of a rituximab clinical trial project began at UCL in 2014 and continues with a PhD currently working and a student being funded later in the year. June 2016 The establishment of standard protocols for effective diagnosis and clinical trials would be complemented by development of effective treatments, leading to highly significant public savings. The hub and spoke model would address seriously inadequate levels of clinical service for ME in East Anglia and nationwide The development of a network of domiciliary services to support severely affected patients (currently seriously neglected by the health service and previously left out of research into ME). Savings on existing consultant referrals and staff - ME examination focused in one area The project is financially viable – the Centre can start small and grow as further funding becomes available

Journal of IiMER Volume 10 Issue 1 The inaugural meeting of The European ME Research Group (EMERG) – initiated and funded by the charity - has opened the possibility of a Europeanwide collaboration which seeks national and EU funding. The charity is actively looking at complimentary projects which will increase the research knowledge base and translate research into treatments. The foundations are therefore already set to establish a Centre which can act as a hub for UK and European research and work with other academic organisations and researchers, as well as other Centres of Excellence in Europe and USA, Canada and Australia and New Zealand. LET’s C Research – A C of E for ME Now the charity is launching a campaign to raise awareness of the possibilities with the Centre of Excellence and gain more support for the firm establishment of this biomedical research and treatment facility for ME. So we ask supporters to begin getting major support from MPs, GPs, media, celebrities, schools, businesses, research organisations, families, friends. Our logo will appear everywhere. We are having t-shirts made for events in which our supporters raise funds and awareness. A web page will be set up for this shortly and progress will be published as and when possible. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 28 of 77 Our Big Give page is here – https://secure.thebiggive.org.uk/projects/ view/9169 June 2016 Already it is good to see some early support for this campaign - Our Twitter hashtags are and Journal of IiMER Volume 10 Issue 1 June 2016 Creating a New Vision of Research into ME in Europe For a long time it has been the objective of Invest in ME to forge international collaborations between researchers. IiME is a member of the European ME Alliance (EMEA) and recently EMEA has joined the European Federation of Neurological Associations in order to promote ME in Europe. With our EMEA colleagues we also had discussions on forming a European Advisory Board which would allow EMEA to discuss, initiate and fund biomedical research into ME. This led to further development of the idea. During the Invest in ME BRMEC5 Colloquium in May 2015 discussions with European researchers were conducted about the future of ME research and how better to coordinate and link together research activity in several European countries. Based upon these conversations there appeared to be overwhelming support and enthusiasm from the group of researchers whom IiME/EMEA have brought together to work cooperatively and more effectively. Forming a group or consortium of European researchers represents a very progressive step in not only helping to establish new collaborations and cement on-going ones but also in developing new research ideas and Invest in ME (Charity Nr. 1114035) www.investinme.org Page 29 of 77 priorities and bidding for funds that would allow us to work together on joint projects. This is the genesis of EMERG - The European ME Research Group IiME convened the inaugural meeting in London in October 2015 to bring this together in the hope that rapid and lasting progress can be made in the research, treatment and cure for myalgic encephalomyelitis. EMERG has a vision of working collaboratively to increase biomedical research into myalgic encephalomyelitis (ME) in order to find cause(s), treatment(s) and understanding about the disease. This provides a powerful combination of campaigning and raising of awareness, building new research and accumulation of data based on collaboration and sharing of experiences and knowledge, which will allow rapid progress in the building up a strategy of high-quality research into ME.

Journal of IiMER Volume 10 Issue 1 The European ME Alliance (EMEA) is now composed of thirteen countries in Europe – working together to create change. RISK OF SUICIDE DUE TO NEGLECT AMONGST PEOPLE LIVING WITH MYALGIC ENCEPHALOMYEILITIS/CHRONIC FATIGUE SYNDROME IN SPAIN: FIRST SPANISH STUDY LigaSFC May 12, 2016 “We will not be a just, advanced nor democratic country as long as there are people who have Myalgic Encephalomyelitis who continue being ignored and INVISIBLE” - Juan Jimenez-Ortiz Another International Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Day is here. But do people with ME/CFS in Spain Have we anything to celebrate? No, it does not seem so. That is why the Spanish association of PWME (people with Myalgic Encephalomyelitis), LigaSFC, is launching this very important study by Juan Jimenez-Ortiz on the effects of neglect, mistreatment and lack of proper medical and social care which people with ME/CFS in Spain live with. For several decades, PWME in Spain, their associations and their lawyers, have been denouncing that this very serious neuroimmune illness, which affects one in 200 people, live with a great number of social and political factors which, added to their illness, severely reduce their quality of life and put them at risk of suicide (see the numerous articles by the Collectiu Ronda Lawyer’s Cooperative in Barcelona). These factors include, mainly, a lack of access to relevant medical care and a precarious economic situation due the lack of pensions and other help which people too sick to work are entitled to in Spain. Also the lack of proper care of this illness by the health administrations results in a general lack of social support for PWME. PWME in Spain have spent decades saying that all they want is what other people who are ill with other pathologies have. But they don’t seem to be listened to. Socially aware and concerned Spanish psychologist, Juan Jimenez-Ortiz, has carried out a research study (for his PhD thesis by the University of Valladolid) with the title: “Depression, hopelessness Invest in ME (Charity Nr. 1114035) www.investinme.org Page 30 of 77 June 2016 Journal of IiMER Volume 10 Issue 1 in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Risk factors and protection” (2016). The results of this research study are highly worrisome. The high level of risk of suicide, depression and hopelessness in these patients is much higher than in the rest of the Spanish population due to, mostly, the lack of relevant health care services. STUDY AND RESULTS Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is one of the Central Sensitivity Syndromes (CSS). Although there are still some questions regarding its etiology, the research done up to now attributes it to a significant alteration in the Central Nervous System which affects the immune and the endocrine systems. This produces severe symptoms of fatigue that is not solved by resting, immune dysfunction, cognitive problems, inflammations, and many more organic alterations. Due to these dysfunctions and symptoms, PWME’s lives are severely disrupted. All activities of daily life are affected. Many studies, including this one by Jimenez-Ortiz, show that the effects of this illness as well as the institutional abandonment (health care and social care), added to the losses that such an illness produces (work, family and social relations) are related to depression, hopelessness and risk of suicide. June 2016 The objectives of this study by JimenezOrtiz were the following: To measure the incidence of depression, hopelessness and risk of suicide in a sample of Spanish PWME. To identify which sociodemographic variables or circumstances were related to suffering depression, hopelessness and risk of suicide. Concretize which variables could be modified to reduce the incidence of depression, hopelessness and risk of suicide. Propose a model of probability of depression, hopelessness and risk of suicide amongst PWME. Jimenez-Ortiz proposed the following hypothesis: There is an incidence amongst PWME higher than the rest of the population of depression, hopelessness and risk of suicide. There is significant sociodemographic and clinical data (circumstances) regarding depression, hopelessness and risk of suicide amongst PWME. There are variables which can affect in a positive manner these circumstances. In this study, 205 Spanish people participated, all of them diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 187 women and 18 men, between 27 and 71 years of age. The participants were from the following Spanish Regions: 7 from Andalucia, 1 from Aragon, 1 from Asturias, 5 from the Canary Islands, 4 from Castilla La Mancha, 15 from Castilla y Leon, 102 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 31 of 77

Journal of IiMER Volume 10 Issue 1 from Catalonia, 7 from Galicia, 22 from Madrid, 1 from Murcia, 14 from Navarra, 5 from the Basque Country, 3 from La Rioja and 18 from Valencia. The most significant result in this study is the incidence, amongst PWME, of risk of suicide which is 12.75%, compared to the incidence in the general Spanish population which is 2.3%. The incidence of depression amongst these PWME is 57.25%, compared to the incidence in the general Spanish population which is 4%. And the incidence of hopelessness amongst these PWME is 66.85% (there are no studies of hopelessness in the general Spanish population). Some of the reasons which have been found to be associated in a significant manner to depression, hopelessness and risk of suicide amongst PWME, include: To risk of suicide: Not having medical care. Having ME/CFS affect their capacity to earn a living and the worsening of the economic situation of their family unit. Having to turn to family members for help with activities of daily life. Not being listened to by doctors. To depression and hopelessness: Having been put down and not treated properly by the health care system. Not having regular medical follow-up. Having been sent for psychological or psychiatric treatment and been labelled as “rebellious patient”. Having lost their job. Having lost friendships due to the illness. June 2016 Not being believed when mentioning the effects on their health of chemical agents (chemical sensitivities). Having had their intimate (sexual) relationships affected by ME/CFS. Having had ME/CFS affect their economic situation. CONCLUSIONS AND RECOMMENDATIONS The results of this study are very important because they show that: PWME have the most significant areas of their lives affected by this illness. PWME feel invisible in all aspects of their daily life. The disruption crated by the symptoms of ME/CFS added to the negative experiences lived by PWME are related, in a very significant manner, to depression, hopelessness and to risk of suicide. Spanish PWME have higher levels of depression, hopelessness and risk of suicide than the rest of Spanish society. Some of the Preventive Measures that the author, Juan Jimenez-Ortiz, proposes are: The abandonment and neglect that Spanish PWME live with from the health care system, from the employment world and from their social and family lives has to be denounced and taken seriously. This abandonment and neglect generates suffering among these PWME. There is an urgent need to organize and carry out educational and training activities about ME/CFS for health care workers, families and society in general. FOR MORE INFORMATION: info@ligasfc.org Invest in ME (Charity Nr. 1114035) www.investinme.org Page 32 of 77 Journal of IiMER Volume 10 Issue 1 June 2016 My name is Mike Harley; I’m from Bristol and I’m about to run my 6th of 28 planned EU marathons for charity, that’s one in every member state. On Saturday 4th June 2016 I’m heading out to run the Stockholm Marathon before another 2 marathons this year: Gdansk in Poland and Toulouse in France. I want to raise the profile of ME all over Europe and connect charities, researchers and patients together to share resources and lobby their governments for biomedical research and progress. Ultimately I want to help affect a change in the UK/across Europe but also a real shift in the perception of this awful, indiscriminating illness. The icing on the cake for me would be to make it through all the marathons in one piece and see some of my friends well on the road to full recovery. I hadn’t heard of ME really before my friend Ian came down with it over 9 years ago. Ian is one of my oldest mates and even though for much of the last decade he’s been too ill to work and lost some of the best years of his life to ME, he’s always been the same positive person throughout. After a few years of no real improvement and not seeing him as much as before, I wanted to find out a bit more about what was making him ill and what could be done. He’s taught me a lot about the inconsistencies in treatment, both the lack of up-to-date knowledge from GPs and funding for biomedical research from governments not just in the UK. It wasn’t until he told me about Invest in ME and the work they’re doing with the top scientists and researchers that I started to learn more about ME and how ‘well folk’ can potentially help them to find a cure. Around the time that I got involved with fundraising, Invest In ME were already on the way to crowd-funding enough to set-up a Rituximab trial, B-Cell research and beginning to finalise plans to create a UK ME treatment and research centre in Norwich drawing upon their strong ties with some of the best researchers and scientists from around the world. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 33 of 77

Journal of IiMER Volume 10 Issue 1 I was very impressed with what they had achieved given the fact that the work is done entirely on a voluntary/nonsalaried basis; compared to other charities they seemed to be the only ones doing anything really pro-active to help people get better. It’s not my first sponsored challenge for biomedical ME research; I led a team to visit 92 football grounds in 92 hours in 2014 on a trip where we raised over £4000, were featured in 11 TV regions, BBC radio and over 70 football club matchday programmes. It was on this trip that we felt a huge wave of support from ME patients and their families, not just on social media where they really kept us going, but also when they turned up at the grounds to wish us well, often with food, sponsorship and their stories to tell. We met sufferers in wheelchairs, really ill young children, people of all ages and severities. It really was a life-changing experience: they were all such nice people who through no fault of their own were ill and weren’t getting any help. When the challenge was done, I felt that I really couldn’t just leave things there. Most weren’t well enough to fight for funding and attention themselves and with very few people around to stand up for them I had to find something bigger and carry on; I think the injustice of their June 2016 situation really angered me (and still does) if I’m honest. On to this challenge and I can tell you that I’ve done 5 so far: London (UK), Prague (Czech Rep), Helsinki (Finland), Dublin (Ireland) and Thessaloniki (Greece). I’ve met with charities, media and patients and it’s been an incredible experience; everyone has been really receptive and super-friendly. Since I started the challenge last May, I’ve acquired over 1000 followers, £3200 in donations and clocked up nearly 2000 miles in training. I’m not a natural runner by any stretch, I’m short, not very sporty and pretty ignorant when it comes to technique (mental and physical). But like all good underdogs, as with the people I run for and represent, I’m determined and up for the challenge despite the cost, lifestyle change and commitment required. I’m driven by the good wishes and support from the friends I’ve made within the community as well as the gross injustice that I’m seeing with regards to the treatment of ME patients. The support I’ve had makes it really easy to carry on. Having done the UK previously (I may well do it again at the end to wrap things up!), my 1st race and return to running was in Prague. Prior to the race I met the family of an ME patient there with connections to their leading ME charity. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 34 of 77 Journal of IiMER Volume 10 Issue 1 I had patients come to cheer me on in the race and I found the same sense of frustration and injustice that I had read about in the UK. I met patients and ME charity representatives in Finland and Ireland also and interviewed an ME patient of 25 years from Greece; all were the same –their governments classified ME as a psychological problem and refuse to support biological research. I’m always keen to write a blog where I find out more about the treatment and perception of ME in each country. These pieces are by far and away the most viewed posts; patients and their families are really keen to see what is happening in other countries and join together in solidarity. The people that I interview have explained that they need to remain relatively anonymous and not to publish their names as they fear investigation by social security/insurance companies who might claim that they are ‘working’. It’s a desperate situation in my view when patients aren’t able to publicly fight for their right to treatment. The UK PACE trial and its legacy clearly has had a huge impact on the rest of Europe and the way ME is viewed and (not) treated. I’ve tried hard to raise awareness of ME on the challenge so far. I’ve had blogs published and interviews on Running Bug (300K followers), BBC Radio and regional newspapers. It has been difficult though. ME sadly still seems to be viewed with suspicion and huge ignorance by national media –perhaps the government agenda of neglect and denial is being adhered to there too. June 2016 One national newspaper approached me to write a piece on the challenge but have failed to publish it despite claiming to be happy with the quality. In any case, I’m here to do everything I can to help Invest in ME. I’m strongly urging anyone who is doing a sponsored event to pick them as their charity, we all know someone with ME and biomedical research is the way that you can help them. Big thanks to everyone who has supported and sponsored me so far, I’m really enjoying the challenge and feeling that I’m doing something worthwhile to help my new friends and, of course, my good friend Ian. Find me on Twitter @mikesEUmaras If you’d like to sponsor me, text ‘IIME82’ and £5 to 70070 I can also be found at www.justgiving.com/mikeseumaratho ns and at www.mikeseumarathons.eu and on Facebook at www.facebook.com/mikeseumaratho ns Invest in ME (Charity Nr. 1114035) www.investinme.org Page 35 of 77

Journal of IiMER Volume 10 Issue 1 June 2016 www.justgiving.com/mikeseumarathons Page 36 of 77 Invest in ME (Charity Nr. 1114035) www.investinme.org News from N orway On 10th of April the Norwegian Research Council announced that they would be inviting mainly patients and family members but also healthcare practitioners to submit suggestions for research topics into ME. The deadline for these submissions was 3rd May. The Research Council acknowledges that there are different names being used such as CFS and ME and considers it a serious and fairly common condition with or without pain. The cause/s are unknown, biomarkers for the condition have not been found yet and there is disagreement on the symptom based criteria. As a consequence there are no effective treatments. The Norwegian Health Directorate estimates that there are between 10 000 and 20 000 patients with CFS/ME in Norway. Many experience considerable health problems over a long period of time and feel that they are badly served by the healthcare system. The research activity has increased over the last few years, both in amount and approaches, but the need for research and better understanding of CFS/ME is still extensive. Why this approach? There are many ways of identifying the knowledge requirement. The health programmes within the Norwegian Research Council now trial an approach which has been named ‘needs identified research’. It will be research that gathers knowledge that is particularly called for by healthcare users, and which can provide benefit in a relatively short time period. The Research Council therefore invited participation to identify research areas that can form a basis for new research projects.

News from N What happens after 3rd May? The Norwegian Research Council will set up a broad based user panel that consists of patients, family members, healthcare professionals, healthcare authorities and researchers who will advise on the research need and type of research that would be useful for patients with CFS/ME. This will be achieved through a three stage process toward prioritising concrete research projects. The first task of the user panel would be to evaluate proposals or research questions that have been received by the 3rd May deadline (stage 1). Based on the user panel’s prioritisation of proposals the Research Council will send out a call for researchers to respond to. In the first instance researchers are invited to send in a simple application with a short project description (stage 2). The user panel evaluates and grades the applications on the basis of how they answer the need and expected benefit set out in the call. A selection of researchers who have sent in applications will be then invited to send in full applications (stage 3). These applications will be treated in a similar manner as ordinary applications to the health programmes. The planned deadline for a simplified application will be 7th September and for the full application 23rd November 2016. The Research Council will publish a short general report on the research proposals that have been received. The announcement and invitation for a simplified application (stage 2) is scheduled to be published on the Research Council’s website in June. None of the user panel members can submit or be involved in an application for a research project. Names of the panel members will be announced in early May. o rway News from N rway The Norwegian ME Association works to improve the condition for MEpatients through informing both patients and health care workers, health authorities and politicians about ME and about new research on ME. The association also arranges talks and conferences as well as informal meetings where patients can meet other in the same situation. The association has local chapters in almost all counties. During 2016 the Norwegian ME Association has responded to calls for input regarding new laws concerning child protection services, services for disabled persons and education for disabled children. In January the association published the report from a large survey of ME patients experience with Nav. NAV administers a third of the national budget through schemes such as unemployment benefit, work assessment allowance, sickness benefit, pensions, child benefit and cash-for-care benefit. Many ME patients report that they find it difficult to get the benefits to which they are entitled. The report showed that the treatment of patients varies wildly between offices, and that there is little knowledge of ME within Nav. Since the report was published, the association has been invited to present it at several Nav offices, and we hope to go to many others. We are very pleased to see a growing interest in ME as experienced by the patients. Representatives for the association has also talked at ME conferences, both arranged by patients and by the health authorities The Norwegian ME Association is often asked to provide background information for articles in magazines and newspapers. Representatives for the association has also been on the news on national radio several times. The association has a large website filled with information on ME. The website is updated regularly, both with research news, and “human interest” stories. A guest blog has become very popular. Recently, the Research Council of Norway invites patients to tell them what research into ME was needed. They received more than 700 replies. A board of researchers and patient representatives, two from the ME Association, will soon start to look through the ideas and identify projects.

Journal of IiMER Volume 10 Issue 1 June 2016 From Norway Haukeland University Hospital: Brief status of the Project on Genetic Predisposition to ME / CFS A published study shows a clear genetic predisposition to ME (Albright et al, 2011). This was a population-based study in which risk of ME was 2.7 times higher in first-degree relatives of CFS patients, 2.3 times higher in second degree relatives, and 1.93 times higher in cubic relatives, compared with the risk of ME in the general population. Our research group at the Department of Oncology, Haukeland University Hospital, has in recent years been contacted by several independent families with striking incidence of ME and they all have wanted us to do further analysis on mapping of genetic predisposition. We believe mapping of gene changes in affected patients will be an important step forward in the understanding of disease mechanisms. We conducted exome sequencing from both CFS patients and healthy family members, where all the coding regions of the genome, including the flanking intro regions were characterized. This technique is considered experimental diagnostic / research and is not considered a full investigation of all genetic variants that exist in a human. Initially we will only answer the question of what is the molecular genetic predisposition to ME disease in our patients. Exome that constitutes the coding parts of genes including the flanking intron portions, is approximately 1.5% of the total DNA of a human cell, but about 85% of all known mutations is still located therein. We imagine that some families may have genetic variants of immune genes such as HLA genes, where it is known that specific HLA types are correlated with various autoimmune diseases. HLA genes in ME are being examined in a specific project at OUS, led by Benedicte Lie, Marthe Viken and Torstein Egeland. At Haukeland Hospital, we are most concerned about families with significant incidence of ME disease, often with multiple siblings with onset relatively early age, often with a relatively severe illness, and preferably with ME disease in successive generations. We believe some such families may have genetic variants directly in the "effector system" for symptoms (which symptoms are created), and where the detection of such variants can tell us about disease mechanisms. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 40 of 77 Journal of IiMER Volume 10 Issue 1 We have completed exome sequencing in a total of 18 people, from two different families with significant incidence of ME disease among first and second degree relatives. We have started analysing a third family. Regarding the two families for whom we have completed exome sequencing and subsequent analysis, we have several relevant gene variants that are being investigated further. Currently we have focused on an interesting genetic variation (mutation) that all the sick persons in one family have, and which occurs in approximately 2/1000 of a European general population. The variant also occurs in a few of the patients included in our clinical trial. We focus our efforts towards this variation now and have taken skin biopsies (all cells in the affected have the same gene variant) for cultivating cell cultures and closer examination of energy metabolism. We have created cells in which the mutation is "inserted" by means of gene transfection, and where we can "turn up" the expression of the mutated variant significantly, and see the implications for the cells. We believe the version we're dealing with now may be relevant to the disease, and data so far fits in well with the work we otherwise perform now, to identify disease mechanisms of ME closer. 04/15/16 Øystein Fluge Olav Mella Ove Bruland June 2016 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 41 of 77

Journal of IiMER Volume 10 Issue 1 http://me-forskning.no/oppdateringfra-haukeland-om-prosjektet-pagenetisk-predisposisjon/ 10 May 2016 Update, RituxME study Multi-centre study RituxME completed enrolment of all 152 participants in September 2015. By the summer holidays, all patients in Bergen, Trondheim, Notodden and Oslo will have completed their course of treatment, and study centre in Tromsø provides final treatment in September. As known RituxME is a double blind study, meaning that neither the patient nor treating personnel know whether the individual patient is receiving active medication or placebo. Blinding is maintained until the last participant has finished one year of follow-up after stopping treatment, and we will therefore be able to break the code in September 2017. The results of RituxME study will be published in a scientific paper during 2018. Research biobank at Haukeland University Hospital has been expanded with blood tests before treatment from all participants, and together with samples from previous studies and the ongoing cyclophosphamide study, these blood samples form a unique source for research on disease mechanisms and a possible biomarker. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 42 of 77 June 2016 There is currently a lot going on in the laboratory at Haukeland, and there is collaboration with several national and international institutions on studies such as autoantibodies, immune signatures, cell metabolism and genetics, where samples from the biobank are being used. We continue to collect samples for the Biobank at fixed time points during the trial, right until the last patient has completed follow-up. Kari Sørland Programme coordinator http://me-forskning.no/oppdateringfra-haukeland-om-rituxme-studien/ Journal of IiMER Volume 10 Issue 1 June 2016 When the hoof beats are zebras By Maureen Hanson An analysis by Johns Hopkins researchers claims that a third of all deaths in the US annually are due to medical errors. This finding not only calls for better reporting of such errors, but also for better medical training to prevent them. But death is not the only outcome of medical errors—instead, unnecessary patient suffering can result. Anyone who binge-watches the TV show Discovery Life: Mystery Diagnosis will soon detect a pattern, one that demonstrates the need for improvements in medical training. A typical show might have a young woman suddenly taken violently ill with an apparent stomach flu. But instead of getting better, she continues feeling nauseated and weak. She has to drop out of college. At home she develops a myriad of symptoms—such as night sweats, sore throat, swollen glands, and difficulty reading and speaking. She visits a doctor, who tells her she has strep throat. Despite antibiotics, she doesn’t get better, then goes to an internist, who tells her she should see a psychiatrist. Professor Maureen Hanson is Professor of Molecular Biology and Genetics at Cornell University and conducts NIH-supported research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. She is with The OpEd Project’s Public Voices Fellowship at Cornell. This continues on for several more scenes—sometimes several years in the life of the ill person whose story is being told—as one after another wrong diagnosis is made. The mistaken doctors are always played by actors, as no doctor who gave the incorrect diagnosis would like to be identified. Finally, a smart doctor figures out what is wrong, and is identified by name and appears on the show. The grateful young woman now has a diagnosis, and sometimes a treatment, often leading to a happy ending. Such could be a show made to describe Laura Hillenbrand’s journey to a diagnosis of chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis, as described in her vivid, and often shocking, New Invest in ME (Charity Nr. 1114035) www.investinme.org Page 43 of 77

Journal of IiMER Volume 10 Issue 1 Yorker article. But while she eventually did receive the correct diagnosis, she didn’t get a happy ending. For there is no effective treatment for most victims of the disease, and she remains ill and rarely able to leave her house. As a researcher who surveys CFS patients who volunteer as experimental subjects, I have learned that a long journey to be diagnosed with chronic fatigue syndrome is not unusual. In fact, it is common for individuals with symptoms of CFS to go through multiple years of misdiagnoses, most seeing an average of 4-6 doctors or more, often being told they have a psychiatric disorder, before they find a doctor who has learned enough about CFS to identify the disease. The Centers for Disease Control estimates that fewer than 20% of Americans who have CFS have been diagnosed. Part of the blame for this problem lies in medical training, in which students are told the famous adage: “If you hear hoofbeats, think horses, not zebras.” In other words, if symptoms appear to fit a common disease, then that is the best diagnosis. This idea, when not applied properly, is the origin of many of the errors chronicled by the Mystery Diagnosis TV show. Because though some diseases are less common than others, that doesn’t mean they don’t exist—every rare disease has its victims. Another lesson from the show’s episodes: advocating for yourself can save your life. A striking number of the patients or their caregivers came to a suspected diagnosis or consulted a knowledgeable physician through researching their own symptoms on the web or in the library. June 2016 Standard blood tests are given to someone who arrives complaining of long-lasting fatigue, malaise, and muscle pain. But no abnormalities are seen in such tests of patients with CFS. This leads to the favorite diagnosis of doctors who don’t want to spend time dealing with a patient with unexplained symptoms: depression. Indeed, some CFS patients do become depressed—after being ill for years, losing their jobs, being maligned by friends and family, and repeatedly being told that there is nothing physically wrong with them. But not all CFS patients become depressed, and even those who have psychological problems also have a physical illness of unknown origin. More sophisticated tests, ones more often found in research labs rather than medical testing labs, have revealed immunological and neurological abnormalities in CFS patients. But these are difficult to translate into a simple, easily administered test. Why is a diagnosis important, given that there is no effective treatment for most CFS victims that can restore their prior functioning? Because recommended therapies for misdiagnosed illnesses often can do harm, increasing the severity of CFS. Inappropriate drugs or lifestyle changes—such as types of exercise harmful to people with CFS— can causes patients to become worse, sometimes with long-term detrimental effects. Improved training of physicians about CFS is needed if patients are not going to continue being unwilling characters in real-life episodes of Mystery Diagnosis. A 2010 survey of medical textbooks revealed that only 40% even mentioned CFS. Until recently, little has been done to dispel early and Invest in ME (Charity Nr. 1114035) www.investinme.org Page 44 of 77 Journal of IiMER Volume 10 Issue 1 stubbornly persistent notions of the psychological basis of the illness. Fortunately, the National Institute of Medicine undertook a year-long study of the scientific literature, and concluded that that CFS is a “serious, chronic, complex, and systemic disease that frequently and dramatically limits the activities of affected patients.” The report provided a simple set of diagnostic criteria that could be applied by a physician in general practice or any speciality to determine whether a patient should be diagnosed with CFS. June 2016 A Clinician’s Guide the Institute produced should reduce the time to diagnosis—and help knowledgeable patients advocate for themselves. Originally printed in THE HILL http://thehill.com/blogs/congressblog/healthcare/279089-when-thehoofbeats-arezebras From IT's A FUNNY OLD WORLD - MEDICINE and ME http://www.investinme.org/IIME-Cartoons-2013-01.htm Invest in ME (Charity Nr. 1114035) www.investinme.org Page 45 of 77

Journal of IiMER Volume 10 Issue 1 June 2016 Within its population of 4.5 million, New Zealand has an estimated 2000025000 ME/CFS patients1. An advantage of this nationwide number is that a significant proportion of these have been evaluated and diagnosed by a single general health practitioner, Dr Rosamund Vallings, of our team who specialises in ME/CFS in her Auckland medical practice. Moreover, with her specialised clinical knowledge of this illness and international role her patient contact extends nationwide and she facilitates training for other health practitioners throughout the country. There is also an effective national ME/CFS organisation, ANZMES, and various regions within the country have their own support groups that are invaluable for affected patients. This means for study purposes in depth information is available for at least a proportion of New Zealand patients. For this patient group variables beyond Warren P. Tate1, Eiren C. Sweetman1, Alex J. K. Noble1, Christina D. Edgar1, Grace Bateman1, Angus Mackay1, Margaret M. Ryan2, Lynette D. Hodges3 & Rosamund Vallings4 1Department of Biochemistry, 2Department of Anatomy, University of Otago, Dunedin & Brain Health Research Centre and Brain health New Zealand, 3School of Sport and Exercise, Massey University, Palmerston North, & 4Howick Health and Medical Centre, Auckland the design of a study, like ethnicity, that can confound subsequent evaluations can be managed by careful selection of patients. Our New Zealand environment brings into play the concept of ‘precision medicine’ where intense study of a small number of Invest in ME (Charity Nr. 1114035) www.investinme.org Page 46 of 77 Journal of IiMER Volume 10 Issue 1 patients can balance the disadvantage of having only a limited base number of patients available for recruitment. ‘Precision medicine’ is being applied to ‘rare diseases’ internationally where patient numbers are naturally small, and yet intense molecular studies are starting to reveal new biological insights into these illnesses2. Despite the advantages of a small wellcharacterised patient group, those health practitioners in New Zealand who understand that most ME/CFS patients do not recover from their illness, are often reluctant to take more than a very small number of such patients into their practices. Additionally, until very recently, medical students received no formal training in ME/CFS, and so graduated without the necessary knowledge to assist their professional response when confronted with a potential ME/CFS patient. There are still pockets of practitioners who remain sceptical of the validity of ME/CFS as a distinct illness. This often leads to frustrated patients looking constantly for an empathetic health practitioner in their own town or city who has some knowledge and understanding of their illness. The confusing and conflicting publicity in 2015 from opposite sides of the Atlantic on the nature of ME/CFS has not helped this situation in New Zealand. On the one hand, the Institute of Medicine of the National Academy of Sciences in the United States published a report in February3 that emphasised the serious and chronic nature of the illness. The authors expressed regret that many practitioners had not taken patients June 2016 more seriously. It further concluded the disease needed a new name to replace the name used in the United States, Chronic Fatigue Syndrome (CFS). The well-meant suggestion of Systemic Exercise Intolerance Disease (SEID), emphasising post exertional malaise as the key characteristic of the illness, Professor Warren Tate however, would be unlikely to add more gravitas to perceptions of the disease from either the public or the health profession. On the other hand, a conflicting Lancet Psychiatry report was published in October, updating4 the PACE study of 20115 arising from Oxford University, which together with associated publicity advocated exercise and positive thinking as the best mix for alleviating ME/CFS symptoms Invest in ME (Charity Nr. 1114035) www.investinme.org Page 47 of 77

Journal of IiMER Volume 10 Issue 1 For those chronically affected patients here in New Zealand who have tried everything possible to manage their ME/CFS over a long term of the illness, the additional apparent quotes in the publicity surrounding the follow up PACE study article from the authors - that it was a minority who thought ME/CFS was a chronic illness and was caused by a virus - were not well received. Indeed, many believe their illness to have been triggered by a viral infection - often Epstein Barr-mediated glandular fever. Such ME/CFS patients have often used highly innovative ways to achieve a constructive life despite the serious restrictions to their life choices because of the symptoms of the illness. Post activity malaise has been a real part of these debilitating effects. As discussed in one of our pilot studies below, this can be documented after exercise by physiological testing. Ironically, medical students in training, and the wider group of health professionals in New Zealand, regard the Lancet as an iconic fount of medical knowledge, and have enormous respect for Oxford as a research University. Therefore, those who rely on such sources, and have no prior contact with ME/CFS patients or appreciation of the often lifetime debilitating features of the illness, will be left with a distorted view of ME/CFS not helpful to the management of their patients. Despite this confusion, the situation in 2016 in New Zealand is looking promising for New Zealand patients. Now, at the University of Otago Medical School, in a module on unexplained diseases, teaching and discussion on the topic of ME/CFS is facilitated by WPT to what has proven to be a highly June 2016 responsive young audience of 3rd year medical students. The most common question asked, albeit with some anxiety by the medical students in their sessions on ME/CFS is ‘How do I respond to an ME/CFS patient?’ My (WPT) simple response has been ‘Acknowledge that the patient is ill and needs your empathy and help - while you are determining whether their illness is consistent with the clinical guidelines for ME/CFS’. They, and all General Practitioners in New Zealand now receive the 2014 edition of the international ‘Primer for Clinical practitioners’6 to which Dr Vallings contributed as part of the international writing panel. In addition, Dr Vallings has written two excellent books, one for adult patients and their practitioners7, and one for teenagers8 bewildered by an ME/CFS mediated dramatic change in their health status. It is anticipated the situation for ME/CFS patients countrywide will improve as tomorrow’s young doctors graduate and spread throughout the workforce. The students were surprised that, despite the lack of general community knowledge and understanding of ME/CFS, the number of New Zealand patients is about half of those diagnosed with Alzheimer’s disease in New Zealand9. In common with ME/CFS, Alzheimer’s disease still has no simple molecular diagnostic test, and as yet no effective therapies. ME/CFS however, receives much less publicity, less national and international focus, and considerably less research funding than Alzheimer’s disease, and so there is critical need for better knowledge and a higher public profile. However, despite ongoing confusion as to the nature of ME/CFS, much new exciting global research and Invest in ME (Charity Nr. 1114035) www.investinme.org Page 48 of 77 Journal of IiMER Volume 10 Issue 1 serendipitous observations have been made in the 4- 5 years since the unfortunate focus on the retrovirus XMRV10, a false lead that appeared at the time to be so promising. The Norwegian trials of rituximab as an antibody therapy for lymphoma that serendipitously gave ME/CF patients a period of remission is an exciting observation that can direct our focus to better understand the disease11. Recent important ME/CFS studies on plasma cytokines12, and on miRNAs in plasma13 and Natural Killer cells14, as well as a miRNA study for a biomarker signature in the related disease, fibromyalgia15, have added valuable information. Given the environment described above in New Zealand, we have initiated a research programme on ME/CFS that is patient focussed, and is leaning towards the principles of precision medicine for understanding each patient, by using comprehensive molecular studies in the hope that this paradigm might reveal new information on the illness that is of national and global significance. An illustration how a detailed molecular focus on individual patients - precision medicine - can provide valuable information for such an unexplained disease as ME/CFS was starkly illustrated by the personal intense molecular study published in Cell in 201216 with over 40 authors by a Stanford University medical geneticist Michael Snyder. He followed his own molecular profile over ~ 2 years and related it to relatively minor illnesses such a common cold and an upper respiratory infection. The title of the paper was ‘Personal omics profiling reveals dynamic molecular and medical and phenotypes’. Apart from June 2016 determining the sequence of his genome, Snyder carried out complex analyses like exome sequencing, transcriptome sequencing, small RNA sequencing, shotgun proteome sequencing and metabolome analysis repeatedly through the 2 year period on samples of plasma and blood cells, and these were linked with clinical tests. Informative changes in gene expression profiles were revealed in response to the viral illnesses and they could be related to specific molecular pathways that were affected. Such a profound longitudinal study and analysis is beyond what can be done even with a small group of ME/CFS patients because of cost alone. Nevertheless, a distilled down study is possible that could still provide valuable information. Changes in the expression of genes, proteins and plasma metabolites in a chronic disease like ME/CFS that has acute, steady state, and relapsing phases might be highly informative to reveal a deeper layer of understanding. The costs of genome sequencing have plummeted to ~$2000 - $5000 per genome depending on whether detailed analysis of the results is included, and while providing valuable information it seems as yet not to provide compelling data that would immediately improve the situation for individual ME/CFS patients. In line with these concepts, we are now in the data collection stage for two small pilot studies, each with 10 patients, recruited in two separate regions of New Zealand. They are matched by age/gender with healthy controls, with one of the studies having Invest in ME (Charity Nr. 1114035) www.investinme.org Page 49 of 77

Journal of IiMER Volume 10 Issue 1 a comparative cohort of multiple sclerosis (MS) patients, as an example of a ‘fatigue illness’ distinct from ME/CFS. Our goal is to examine and correlate changes in plasma cytokines and miRNAs, with the cellular transcriptome, and the proteome in purified immune cells. In the second study we are planning to link these molecular analyses to an exercise regime that measures physiological parameters before and after exercise. These two pilot studies in turn are preliminary to a planned larger study with 40 carefully evaluated patients from Dr Vallings health practice. To understand the disease mechanism of ME/CFS in our NZ cohort at a molecular level, June 2016 coding, small and large noncoding RNAs, and initiating a study of the proteome. We have become acutely aware that the key to validating results from small patient studies, whether it be for rare diseases or the pilot studies we are conducting, are appropriate biostatistical analyses. This is a dynamic field and new ways of analysing data are constantly being developed that can extract richer information from low numbers of patients, providing random variables outside the study design can be controlled. It is sobering a comprehensive analysis has been undertaken in an initial pilot study group. Peripheral blood samples were taken from the study participants and plasma, lymphocytes and neutrophils extracted. From the plasma and lymphocyte immune cells total RNA (including small RNAs) was isolated using a mirVana™ PARIS™ RNA and Native Protein Purification Kit. Total protein was also obtained from the lymphocyte and neutrophil cells for western and proteome analysis. So far we have obtained and analysed data on both cytokines and microRNAs from plasma in one of our pilot studies, and are awaiting the results of analyses on the transcriptome encompassing that of the 750 000 studies that have suggested statistically significant leads for therapy development only a handful have stood up to rigorous testing and development17. That is a challenge for us in taking a ‘precision medicine’ approach to these studies. In consultation with an experienced biostatistician we are exploring a number of mainstream statistical approaches in an attempt to ensure apparent molecular differences between ME/CFS patients and controls have validity. There is an advantage in having two independent statistical tests so that if an effect is found with one test it can be confirmed with the other. Since our studies are discovery tests, Invest in ME (Charity Nr. 1114035) www.investinme.org Page 50 of 77 Journal of IiMER Volume 10 Issue 1 the ability to confirm a result derived from one patient cohort with the other cohort of our second pilot study supports further analysis. MicroRNAs are of great interest as potential disease biomarkers since they are present and highly stable in virtually all biofluids, and appear to be acutely sensitive to changes in various physiological processes 18-19. They have emerged as important biomarkers and modulators of numerous pathophysiological processes. Our approach, guided by the ‘precision medicine’ methodology aims to investigate any correlation between circulating cytokines and miRNAs in plasma samples from individual patients within our two study groups. In our ME/CFS pilot studies for example, we have found differences between multiple cytokines and a particular microRNA. This implies a connection between these cytokines with the microRNA. Of interest for our initial results is a recent study by Su et al. 201520 where two cytokines were shown to induce a microRNA in macrophages in chronic inflammation. Recently, perhaps relevant to ME/CFS a number of dysregulations in microRNAs have been reported in patients suffering from pain - in complex regional pain syndrome, cystitis-induced chronic pain, and irritable bowel disorder, both in the affected tissues, and reflected in the circulation. Such microRNAs are implicated functionally in pain processing based on studies in animal models of inflammatory and neuropathic pain, and in vivo studies have found dysregulated microRNAs influence the post-transcriptional June 2016 modulation of genes implicated in pain generation and maintenance21. Several clinical studies have highlighted the potential of plasma microRNAs to be biomarkers for complex regional pain syndrome and for fibromyalgia. For example, Orlova et al. (2011)22 used whole blood samples from 41 patients with complex regional pain syndrome and 20 controls in a study analysing miRNA, cytokines and correlations with numerous clinical parameters. Unsurprisingly, expected cytokines such as VEGF were elevated in the disease group compared to controls and a miRNA-signature was evident. Extensive correlation analyses revealed that 4 miRNAs were positively correlated with disease-associated pain level, one other was correlated with the occurrence of migraine within the patient cohort and an extensive array of miRNAs was found to correlate with the levels of circulating cytokines22. A similarly designed 2013 study investigated the miRNA profile of the cerebrospinal fluid in fibromyalgia patients23, a disease with many commonalities to ME/CFS, identified 10 miRNAs differentially expressed between affected patients and healthy controls. Most notably, the study found that decreased levels of miR-145-5p in the CSF were associated with reported symptomatology such as pain intensity and fatigue24. To investigate changes in miRNA expression, we used TaqMan® Array MicroRNA cards to assay for 754 human miRNAs in the plasma samples. Megaplex™ RT Primers complement the assays on the cards Invest in ME (Charity Nr. 1114035) www.investinme.org Page 51 of 77

Journal of IiMER Volume 10 Issue 1 and were used to convert the miRNA to cDNA. To improve assay sensitivity and account for the limited abundance of some miRNAs, a preamplification step using Megaplex™ PreAmp Primers was included. Data was assessed using the BioC/R package HTqPCR (high-throughput qPCR)25. MiRNAs with ‘undetermined’ ct values or ct values >35 were removed from the analysis. A norm rank invariant method was used to normalise the data. The two study groups have initially been compared using a nonparametric Mann Whitney U test to determine statistically significant miRNAs. To complete our molecular study of the pilot study group we are also completing full transcriptome and proteome analyses of the ME/CFS and healthy control individuals. At present, as stated above, transcriptome analysis of the 20 participants in our first pilot study is underway. Total RNA was extracted from lymphocytes purified from the original blood samples, using the same extraction kit as for the miRNA analysis. We are investigating by HiSeq analysis both small RNA (NEXTflex small RNA libraries), including miRNA, and total RNA (TruSeq stranded total RNA libraries (ribozero human/rat/mouse). The proteome analysis will analyse total protein extracts from the patient and control subject’s lymphocyte cells. Samples will be compared by sensitive global proteomics profiling using the mass spectrometry facilities in the Centre for Protein Research, University of Otago. The approach will allow for a semi-quantitative comparison of protein profiles using for example spectral counts or extracted peak intensities. It will be of significant interest to see if the results of these June 2016 analyses correlate in any way with our miRNA and cytokine investigations to suggest disease mechanisms or pathways. Invest in ME (Charity Nr. 1114035) www.investinme.org Our second pilot study conducted by exercise physiologist, Dr Lynette Hodges at Massey University, aims to link exercise performance with molecular analyses. The exercise part of the study has examined differences in fatigue parameters among three study groups, ME/CFS patients, MS patients and healthy controls. Each group performs repeated incremental exercise tests separated by 24 hours. Incremental exercise tests utilised an increased power requirement each minute and measured oxygen consumption, carbon dioxide production, respiratory exchange ratio, and power output, among other parameters. Each incremental exercise test was followed by a steady state 5 min exercise test conducted at the anaerobic threshold, measuring cardiac output. In contrast to the other two groups ME/CFS patients uniquely had lower power output on the day 2 reexercise test, consistent with the reported characteristic of the disease, post-exertional malaise. Cytokine analysis data on plasma samples from these subjects have just been collected. Applying miRNA analysis in this collaborative exercise study is appealing; it has been shown that circulating miRNA-signatures are distinct enough to enable discrimination between eccentric and concentric exercise23 and so they also may provide valuable indicators of the post-exertional malaise experienced by ME/CFS sufferers. It is hoped that we can also add data on the expression of coding genes, and of small and larger noncoding RNAs, together with altered protein profiles to give a more Page 52 of 77 Journal of IiMER Volume 10 Issue 1 comprehensive understanding of the compromised physiology in ME/CFS relating to this post exercise malaise. ME/CFS lends itself to longitudinal intensive molecular study to understand fluctuating health through relapse and recovery and steady state health periods, just as the Snyder study described above monitored molecular changes through compromised health episodes with viral illnesses. The precision medicine approach can be used to analyse what is happening in individual ME/CFS patients, and determine whether there are common mechanisms behind the relapses in each member of a small cohort of patients. Additionally, pregnancy in some women ME/CFS patients can lead to a significant alleviation in symptoms, perhaps because of increased blood suppression volume, of allergic responses, and their changed hormonal profile. Understanding what dysregulated pathways are reversed in this situation through molecular analysis may give further insight into the nature of ME/CFS. Additionally, new technology is now available that can assess mitochondrial functions in isolated blood cells and that may be additional information that can be added. We work towards a goal of providing a diagnosis that combines multiple molecular biomarkers linked to References 1) Welcome to ANZMES. The Associated New Zealand ME Society Inc, Auckland, New Zealand. http://www.anzmes.org.nz 2) Newman SK, Jayanthan RK, Mitchell GW, Carreras Tartak JA, Croqlio MP, Suarez A, Liu AY, Razzo BM, Oveniran E, Ruth JR, Fajgenbaum DC (2015) Taking Control of Castleman Disease: Leveraging Precision Medicine Technologies to Accelerate Rare Invest in ME (Charity Nr. 1114035) www.investinme.org Disease Page 53 of 77 June 2016 dysregulated biologically plausible pathways, and understanding the compromised physiology and can lead to more effective treatments for the heterogeneous symptomology of the ME/CFS patient group, not only aiding clinicians in choosing treatment options, but perhaps also helping in the stratification of patients in clinical trials. Acknowledgements: We are grateful for support from ANZMES the national ME/CFS group of New Zealand, Lottery Health Fund of New Zealand, H S and J C Anderson Charitable Trust, a private bequest.

Journal of IiMER Volume 10 Issue 1 Research The Yale Journal of Biology and Medicine 88:383-388. 3) Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. (2015) Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US). Available from: http://www.ncbi.nlm.nih.gov/books/NB K274235/ doi: 10.17226/19012 4) Sharpe M, Goldsmith KA, Johnson AL, Chalder T, Walker K, White PD (2015). Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial. Lancet Psychiatry 2: 1067–1074. 5) White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 377: 823 – 836. 6) Friedberg F, Bateman L, Bested AC, Davenport T, Friedman KJ, Gurwitt A, Leonard LA, Lapp CW, Stevens SR, Underhill RA, Vallings R (2014) ME/CFS: A Primer for Clinical Practitioners. Chicago, International Association for Chronic Fatigue Encephalomyelitis. 7) Vallings R (2012) Chronic Fatigue Syndrome M.E. Symptoms, Diagnosis & Management Calico Publishing Ltd, New Zealand, edited by Linda Cassells, pp1-350. Syndrome/Myalgic 9) Dementia Economic Report 2012. Alzheimers New Zealand. http://www.alzheimers.org.nz/newsand-events/nz-information/dementiaeconomic-report-2012 10) Lombardi VC, Ruscetti FW, Das Gupta J, Pfost JD, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, PetrowSadowski C, Gold B, Dean M, Silverman RH, Mikovits JA (2009) Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 326: 585–589. 11) Fluge Ø1, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O (2011) Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A doubleblind and placebo-controlled study. PLoS One. 6(10):e26358. doi:10.1371/journal.pone.0026358. 12) Brenu EW1, van Driel ML, Staines DR, Ashton KJ, Hardcastle SL, Keane J, Tajouri L, Peterson D, Ramos SB, Marshall-Gradisnik SM (2012) Longitudinal investigation of natural killer cells and cytokines in chronic fatigue USA: encephalomyelitis. Translational Medicine 9:88. doi: 10.1186/1479-5876-10-88. 13) Brenu EW, Ashton KJ, Batovska J, Staines DR, Marshall-Gradisnik SM (2014) High-throughput sequencing of plasma microRNA in chronic fatigue syndrome/myalgic encephalomyelitis. PLoS One 9: e102783 Invest in ME (Charity Nr. 1114035) www.investinme.org Page 54 of 77 June 2016 8) Vallings R (2015) Managing ME CFS A Guide for Young People. Calico Publishing Ltd, New Zealand edited by Linda Cassells, pp1-145. syndrome/myalgic Journal Journal of IiMER Volume 10 Issue 1 14) Petty RD, McCarthy NE, Le Deiu R, Kerr JR (2016) MicroRNAs hsa-miR99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) cells of patients with Chronic Fatigue Syndrome (CFS)/Myalgic Encephalomyelitis (ME). PLoS One 11: e0150904 15) Cerdá-Olmedo G, Mena-Durán AV, Monsalve V, Oltra E (2015) Identification of a microRNA signature for the diagnosis of fibromyalgia. PLoS One 10: e0121903 16) Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam HYK, Chen R, Miriami E, Karczewski KJ, Hariharan M, Dewey FE, Cheng Y, Clark MJ, Im H, Habegger L, Balasubramanian S, O’Huallachain M, Dudley JT, Hillenmeyer S, Haraksingh R, Sharon D, Euskirchen G, Lacroute P, Bettinger K, Boyle AP, Kasowski M, Grubert F, Seki S, Garcia M, Whirl-Carrillo M, Gallardo M, Blasco MA, Greenberg PL, Snyder P, Klein TE, Altman RB, Butte AJ, Ashley EA, Gerstein M, Nadeau KC, Tang H, Snyder M (2012) Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes. Cell 148 :1293–1307. 17) Manning A (2016) Precision Medicine and Autoimmune diseases - presentation 18) Jung M., Schaefer A., Steiner I., Kempkensteffen C., Stephan C., Erbersdobler A., Jung K. (2010) Robust microRNA stability in degraded RNA preparations from human tissue and cell samples. Clinical Chemistry 56, 998–1006. 19) Tomaselli S., Panera N., Gallo A., Alisi A. (2012) Circulating miRNA profiling to identify biomarkers of Invest in ME (Charity Nr. 1114035) www.investinme.org Page 55 of 77 June 2016 dysmetabolism. Biomarker Medicine 6, 729–742. 20) Su S, Zhao Q, He C, Huang D, Liu J, Chen F, Chen J, Liao JY, Cui X, Zeng Y, Yao H, Su F, Liu Q, Jiang S, Song E (2015) MiR-142-5p and miR130a-3p are regulated by IL-4 and IL13 and control profibrogenic macrophage Communications. doi:10.1038/ncomms9523. 21) Anderson HH, Duroux M, Gazerani P (2014) MicroRNAs as modulators and biomarkers of inflammatory and neuropathic pain conditions. Neurobiology of Disease 71, 159–168. 22) Orlova IA, Alexander GM, Qureshi RA, Sacan A, Graziano A, Barrett JE, Schwartzman RJ, Ajit SK (2011) MicroRNA modulation in complex regional pain syndrome. Journal Translational Medicine 9, 195. doi: 10.1186/1479-5876-9-195. 23) Bjersing JL, Lundborg C, Bokarewa MI, Mannerkorpi K (2013) Profile of cerebrospinal microRNAs in fibromyalgia. PLoS One 8, e78762. http://dx.doi.org/10.1371/journal.pone. 0078762. 24) Banzet S, Chennaoui M, Girard O, Racinais S, Drogou C, Chalabi H, Koulmann N (2013) Changes in circulating microRNAs levels with exercise modality. Journal of Applied Physiology 115, 1237-1244. 25) Dvinge H, Bertone P (2009) HTqPCR: High - throughput analysis and visualization of quantitative real - time PCR data in R. Bioinformatics 25: 3325. program. Nature 6:8523.

Journal of IiMER Volume 10 Issue 1 June 2016 It's a Funny Old World #thingsdoctorssaytopeoplewithME With a disease such as ME humour can sometimes help in balancing the absurdity of the patient’s situation with hope for a better way forward. When the establishment organisation responsible for using public funding to research diseases such as ME has failed consistently (influenced by vested interests), where the Department of Health and Chief Medical Officer avoid taking any responsibility for treating the disease with any serious action and where successive health ministers do not even register the disease on their worklist of important subjects – then what is left for a patient or his/her family to do? All of the above, of course, influences how many healthcare professionals still continue to view and treat the disease – sometimes showing an immense talent for ignorance and insensitivity that might be candidates for some record book, were it not for the negligence that it so clearly illustrates. Hopefully conferences such as IIMEC11 and the resulting DVD can dispel some of this ignorance and neglect – and increased knowledge and education are weapons that the patient community can use to counter this. But humour can help one deal with it. So here, thanks to Ali Head and Invest in ME (Charity Nr. 1114035) www.investinme.org Page 56 of 77 friends, are a selection of quotes from patients who have been on the receiving end of some awkward, some ridiculous, some incomprehensible and some just downright stupid observations from healthcare staff – and others. “well, I'm going to have to give you the CFS diagnosis. But no employer will want you.” “well if you don't follow your GET/CBT plan it means you want to keep yourself ill” GP: "ALL my patients complain of tiredness". - Exactly. Doctors & patients need diagnostics for this disease "there's no such thing as CFS" After neg bloodwork: "I've tested you for everything I can treat." - Infectious Disease Specialist “Oh dear you must be very tired...” Journal of IiMER Volume 10 Issue 1 Follow up with Gastroenterologist 'U need to take a step back and address your mental state' "Well a lot of that will be because of your weight" At cardiologist for myocarditis, cardiomyopathy, POTS, - ''so you're here because you're fatigued? 3x week sport will cure you!” Psychotherapist when challenged "WE think it's something in your PERSONALITY that keeps you ill" (tied to 'benefits' situation) GP: “I don’t think there is anything wrong with your heart, You Just have ME GP: but I don’t believe in ME” “finally going to GP due to worsening symptoms from consistently overdoing it& being referred for GET for deconditioning” 'No illness could be that complicated - you must have imagined it!"" - I wish . . . . ! ! Doctors attributing any new symptom to your ME diagnosis, making them miss other ailments/illnesses f.ex. breast cancer Apparently my fibromyalgia is caused by childhood trauma, according to ME clinic psych. At ME clinic with psych. I told of woman who died from ME. She replied "no one dies from fatigue” My GP often dismisses my symptoms and labels me with health anxiety. who wouldn't want answers to symptoms? June 2016 I asked about poss POTS diagnosis, GP told me no point in testing as it’s just another label with no cure. Why don't you just go for a run around the block! In a consultation with my GP, she said: "Shall I pray for you? We could do it now!" “You just have an atypical depression” “The death of your boyfriend is probably holding you back to full recovery.” “I suffer with Fibromyalgia & M.E. One Dr told me it doesn't exist.” "I can try you on these new meds and if they help you I can try them on my other ME patient". “Part of it is that you're getting older too! (Thanks, I'm 53 not 73. I see old people more fit than I am.)” “You def have a fatigue/pain syndrome but I don't want to label you. (Thanks, my boss will love that)” "u either choose2get better or continue2live like this. Rheumy said this2me.I have ME&fibro” “So how is your relationship with your parents?” "I am completely baffled by your symptoms" one of the more honest Drs. “Do you believe in ME?” – Psychiatrist Invest in ME (Charity Nr. 1114035) www.investinme.org Page 57 of 77

Journal of IiMER Volume 10 Issue 1 "It's mind over matter". If only I'd known, I'd have thought myself better years ago! "Well ME and Fibro are all just terms for pain and fatigue that is unexplained, I can't help you"- neuro!!” "Everyone gets tired. You need to push through it." Went from moderate to severe within weeks... "I've never heard of ME. I'll google it" Medical Assessment Unit doc trained in Ireland.” When asking if anything could with excessive sweating. "No it's just the chronic fatigue" "You need to see a psychiatrist" Went to psychiatrist, got clean bill of MH "It was psychotherapist I meant" Neurologist; "FM? That doesn't exist, neither does that other thing what do you call it? ME?" "People who work here think it’s a mental illness" (CFS clinic) "The only thing I know about ME is Graded Exercise Therapy" Said by neurologist 2016 After 29+ yrs of ME I have great life, great job, boyfriend, I just don't feel well; "Cause of her CFS is depression" “I'm not sure how to help you.... Why don't we try antidepressants??” - But I'm not depressed "Oh I don't like to refer people with ME or fibro for wheelchairs as I believe it makes them lazy" A UK specialist told me to "Get a boyfriend and an active sex life, if you want a cure" - NHS have left me to rot for 12 yrs! 'You have the right attitude to get over M.E' I've still got the same 'attitude' years later, I'm still ill “I don't "do" fatigue, I hope you grow out of it” - consultant immunologist "you’re listening to your body too much” " you’ve had glandular fever but you’re well over it now " I was seeing a specialist for something else and I mentioned it and he said " oh come on don't give me that" “Why don't you try actually going to the gym.” “When are you going to pull yourself together get off antidepressants and get back to work” Invest in ME (Charity Nr. 1114035) www.investinme.org Page 58 of 77 June 2016 “Having ME might be "inconvenient" but there is really nothing I can do” “No, no children get ME” ...suggesting it's a psychosomatic adult illness.. ”go home and do some exercise.” Journal of IiMER Volume 10 Issue 1 “Come back and see me when your head is spinning and you're spitting blood like in operas” “There’s no such thing as me/cfs it’s just another fancy word for tiredness an that’s what u have go” 'If blood tests don’t show anything we'll assume you have ME’ "I'm old school. I don't believe in these new mumbo jumbo illnesses, you're lazy and want time off work" “When you feel a bit tired you mustn't give in to it. GP after I'd had ME for years and had to give up work” Very recently: “No one at the Surgery is experienced with dealing with it (CFS) because it's a rare condition” “None of the GPs in this practice are interested in taking you on as a patient because you say you have ME” "Have you tried any exercise?" (The stairs?? And once a week a bath I nearly die after) "You have a high heart rate but we don't know why" One GP I saw said to me get a full time job and a husband and you will be fine!!!! So in my head I leapt across the table and bitch slapped her! “It's all stress related work, on your inner issues” (only stress was no answer or help being seriously ill)"It's anxiety" (No it's really NOT) "You have caused your condition of CFS by choosing to lie in bed for years" Invest in ME (Charity Nr. 1114035) www.investinme.org Page 59 of 77 June 2016 'all teenagers get tired and you're probably lazy too, there's nothing wrong with you' “At age 16, "have a baby, a good shake up of your hormones should sort it." I had a baby in my late 20's guess what - it didn't sort it.” “6 years ago, (10 years into having M.E.), I had a bad relapse, bedridden. Doctor was called for a home visit; it was the doctor who had given me my initial diagnosis. He said "oh, I thought you were better, M.E. usually goes away by itself after 2 years" ....It took almost 2 years before I received the diagnosis, did he think once he'd told me what it was it'd go away? Doh!! Needless to say, I've since changed doctors.” "Probably just an adolescent pre occupation with health" "What do you expect, you ARE middle aged?" I was 38 DWP Doctor in 1994 "Were you attending church when you developed ME?"

Journal of IiMER Volume 10 Issue 1 June 2016 IIMEC11 PRESENTERS Dr Ian Gibson – Conference Chair Dr Ian Gibson, former Labour MP for Norwich North, worked at University of East Anglia for 32 years, became Dean of the school of biological sciences in 1991 and was head of a cancer research team and set up the Francesca Gunn Leukaemia Laboratory at UEA. In 2011 Dr Gibson received an honorary doctorate of civil law from UEA. Dr Vicky Whittemore Program Director in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health in the United States. Dr. Whittemore is a Program Director in the Synapses, Channels and Neural Circuits Cluster. Her interest is in understanding the underlying mechanisms of the epilepsies including the study of genetic and animal models of the epilepsies. The major goal is to identify effective treatments for the epilepsies and to develop preventions. Dr. Whittemore received a Ph.D. in anatomy from the University of Minnesota, followed by post-doctoral work at the University of California, Irvine, and a Fogarty Fellowship at the Karolinska Institute in Stockholm, Sweden. She was on the faculty of the University of Miami School of Medicine in The Miami Project to Cure Paralysis prior to working with several non-profit organizations including the Tuberous Sclerosis Alliance, Genetic Alliance, Citizens United for Research in Epilepsy (CURE), and the National Coalition for Health Professional Education in Genetics (NCHPEG). She also just completed a four-year term on the National Advisory Neurological Disorders and Stroke Council. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 60 of 77 Journal of IiMER Volume 10 Issue 1 June 2016 IIMEC11 PRESENTERS ABSTRACT: Not available at time of going to press – to be added later. Professor Olli Polo Chief of the Department of Pulmonary Medicine, Tampere University Hospital, Finland ABSTRACT: Not available at time of going to press – to be added later. Professor Carmen Scheibenbogen Professor for Immunology and Deputy Chair Institute of Medical Immunology Berlin Charite, Germany Head of the Outpatient Clinic for Adult Immunodeficiency. Clinical Training in Hematology and Oncology. Research interest in CFS/ME, Immunodeficiency, Cancer Immunology. ABSTRACT Autoantibodies to adrenergic and acetylcholine receptors in CFS/ME Carmen Scheibenbogen, Institute of Medical Immunology, Charité, Berlin Autoantibodies directed against neurotransmitter receptors are causing various types of autoimmune diseases. Recently we were able to demonstrate elevated antibodies against beta2 adrenergic receptors and muscarinic acetylcholine Invest in ME (Charity Nr. 1114035) www.investinme.org Page 61 of 77

Journal of IiMER Volume 10 Issue 1 IIMEC11 June 2016 PRESENTERS receptors in a subset of patients with CFS/ME. Patients with elevated autoantibodies frequently had increased IgG levels, ANA titers and/or T cell activation. We therefore suspect that the autoantibodies can activate immune cells carrying these receptors by imitating adrenaline/ acetylcholine stimulation. Various other symptoms of CFS/ME could be explained by an overstimulation of the sympathetic/parasympathetic nervous system. In patients who were treated with rituximab in the Norway trials elevated autoantibodies normalized. Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, Meisel C, Reinke P, Volk HD, Fluge Ø, Mella O, Scheibenbogen C. Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. 52: 32-39, 2016. Dr Geraldine (Jo) Cambridge B cells, Rituximab and ME/CFS Dr Jo Cambridge is Principal Research Fellow Inflammation, Div of Medicine Faculty of Medical Sciences, UCL Her group focuses its interests on B cell depletion (an idea which they introduced (with the Professor Jo Edwards) approximately 10 years ago for the treatment of rheumatoid arthritis), exploring more precisely how the technique works and trying to explain the marked variation in response between different patients ABSTRACT B cell biology and Rituximab treatment in Patients with ME/CFS G. Cambridge and F. Mensah Centre of Rheumatology Research, Division of Medicine, University College of London Invest in ME (Charity Nr. 1114035) www.investinme.org Page 62 of 77 Journal of IiMER Volume 10 Issue 1 IIMEC11 June 2016 PRESENTERS Use of Rituximab: Before the use of rituximab, the strongest accepted evidence for an association between B-cells and systemic autoimmune diseases such as lupus and rheumatoid arthritis, was that clinical disease was associated with serum autoantibodies. The ability to remove B-cells with rituximab (given in 2 injections 1 week apart) has revealed factors that are important for both inducing remission and resumption of symptoms. Firstly, we found that our patients with high levels of autoantibodies had a significantly more pronounced and predictable clinical response to rituximab than patients with no autoantibodies. Secondly, B cells are killed very quickly by Rituximab – within a week of the infusions - but the kinetics of the clinical response (taking from 1- 5 months after depletion), suggest that it is a constantly generated B-cell product (?autoantibody) and not B-cells themselves that need to be reduced for remission to occur. Thirdly, a considerable proportion of B cells are not depleted, being resident in protective niches in lymphoid and inflamed tissues, and autoantibody levels can often remain raised, in the presence of considerable improvement of clinical symptoms. Taken together, this would suggest that only a proportion of parent B cells and autoantibodies are actually directly ‘pathogenic’. However, as patients eventually do relapse, the autoimmune response underlying the pathogenesis of disease must be self-sustaining. Patients are thus not ‘cured’ by Rituximab and symptoms can worsen again when the peripheral B cell compartment begins regenerating (6-9 months after infusion of rituximab), although some patients can have extended remission even after B cell return. Side-effects are rare and although reductions in serum total antibody levels can occur, effects on protective immunity are mild and serious infections rare. We have therefore learned much about how rituximab works in autoimmune rheumatic diseases but in ME/CFS patients, we are just beginning. As ME/CFS is such a heterogenous disease, our research is focussed on investigating B cell biology in these patients in order to qualify differences from healthy individuals and thus to identify those patients most likely to respond to rituximab and related therapies. B cell Research into ME/CFS: Fatigue is a major component of many systemic autoimmune rheumatic diseases where it is usually associated with the presence of inflammation and cytokine production. After rituximab, a marked reduction in fatigue indices has been reported, possibly due to reducing cytokine (usually interferon-α) production through removal of activating autoantibody containing immune complexes. The fatigue and other symptoms experienced by patients with ME/CFS differs in that no frank inflammatory site has been identified and the fatigue and other symptoms seems to be induced by both physical and mental stressors. We have hypothesized that dysregulation of metabolic re-programming in B cells may influence normal differentiation to appropriate (?Auto?) antibody secretion and memory B cell generation. Rituximab would therefore work by stopping the production of as yet only tentatively identified pathogenic antibodies. Following on from our already published data on B cells which showed that a certain marker, Invest in ME (Charity Nr. 1114035) www.investinme.org Page 63 of 77

Journal of IiMER Volume 10 Issue 1 June 2016 IIMEC11 PRESENTERS CD24 was up-regulated or retained by newly generated B cells, we have been using cells from patients and controls to follow B cell development patterns in response to certain stimuli. We have also established an in vitro system in which we can compare the metabolic function of B cells in ME/CFS patients with healthy controls. This system can also be used to examine the effect of soluble factors such as cytokines and antibodies and agonists/antagonists binding receptors shared between the immune and nervous systems. G. Cambridge, PhD, Principal Investigator. Professor Tom Wileman Professor of Infection and Immunity & Director at Biomedical Research Centre at University of East Anglia, Norfolk, UK Professor Wileman is Professor of Infection and Immunity & Director and Director at Biomedical Research Centre at Univ. of East Anglia. He was Head of Dep. Immunology and Pathology and Virus Cell Biology Group at Institute of Animal Health; Assistant Professor at Dep. Medicine at Harvard Medical School and Claudia Adam's Barr Investigator in Cancer Research, Dept. Molecular Immunology, Dana Farber Cancer Institute, Harvard Medical School; Fellow of the Parker Francis Pulmonary Research Foundation, Dept. Cell Biology, Washington Univ. Medical School. ABSTRACT: Tom Wileman The human virome contains eukaryotic viruses that infect host cells and prokaryotic viruses that infect bacterial communities within the microbiota. The virome of healthy individuals interacts with the microbiota and the host immune system to set an inflammatory threshold that can influence susceptibility to many diseases Invest in ME (Charity Nr. 1114035) www.investinme.org Page 64 of 77 Journal of IiMER Volume 10 Issue 1 IIMEC11 June 2016 PRESENTERS including diabetes, cardiovascular disease and the metabolic syndrome. Modulation of the immune system can also stimulate bystander resistance to pathogens. Human prokaryotic viromes are relatively stable but they can be altered by diet and disease and this can influence the diversity of the microbiota. Changes in prokaryotic virus populations can lead to gene transfer able to influence microbial antibiotic resistance, virulence and metabolism. Recent work shows that the diversity of the enteric virome increases during inflammatory bowel disease and that this can reduce the diversity of microbial communities leading to dysbiosis and inflammation. We have developed methods to study the enteric virome of patients with chronic fatigue syndrome/ME to see if similar changes occur during the development of this debilitating disease. Professor Don Staines The National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffiths University, Australia Dr Staines is a public health physician at Gold Coast Population Health Unit. He has worked in health services management and public health practice in Australia and overseas. His interests include collaborative health initiatives with other countries as well as cross-disciplinary initiatives within health. Communicable diseases as well as post infectious fatigue syndromes are his main research interests. A keen supporter of the Griffith University Medical School, he enjoys teaching and other opportunities to promote awareness of public health in the medical curriculum. ABSTRACT: Not available at time of going to press – will be added later. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 65 of 77

Journal of IiMER Volume 10 Issue 1 June 2016 IIMEC11 PRESENTERS Professor Simon Carding Leader, Gut Health and Food Safety Programme Institute of Food Research, Norwich Research Park, UK Professor Simon Carding Professor of Mucosal Immunology at University of East Anglia and Institute of Food Research. Following his PhD at London he held postdoctoral positions at New York University School of Medicine, New York and at Yale University School of Medicine, New Haven, USA. He then moved to the University of Pennsylvania, Philadelphia, USA as Assistant and later Associate Professor. He joined University of Leeds as Professor of Molecular Immunology in the Institute of Molecular and Cellular Biology in 1999. His scientific interests are in understanding how the immune response in the gut functions and in particular, is able to distinguish between the commensal microbes that reside in the gut and environmental microbes that cause disease, and in the mechanisms by which the body's immune system no longer ignores or tolerates commensal gut bacteria and how this leads to immune system activation and inflammatory bowel disease. ABSTRACT: Despite excellent ME/CFS research being carried out in several centers and groups across Europe it remains fragmented and uncoordinated. With the support of the UK-based charity Invest in ME - Research EMERG has been established with the aim of developing a coordinated programme of European-based research to identify the underlying causes of ME/CFS and to develop more effective forms of treatment that can be supported by trans-national and national funders. Journal of IiMER Volume 10 Issue 1 IIMEC11 June 2016 PRESENTERS Professor Mady Horning Markers of Immunity and Metabolism in ME Mady Hornig, MA, MD is a physician-scientist in the Center for Infection and Immunity (CII) at the Columbia University Mailman School of Public Health New York, USA where she serves as Director of Translational Research and is an associate professor of epidemiology. Her research focuses on the role of microbial, immune, and toxic stimuli in the development of neuropsychiatric conditions, including autism, PANDAS (Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection), mood disorders and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She is widely known both for establishing animal models that identify how genes and maturational factors interact with environmental agents to lead to brain disorders and for her work clarifying the role of viruses, intestinal microflora and xenobiotics in autism and other neuropsychiatric illnesses that may be mediated by immune mechanisms. Under her direction, proteomic analyses of umbilical cord samples are identifying potential birth biomarkers for autism in a prospective study in Norway, the Autism Birth Cohort (ABC). She established that there was no association between intestinal measles virus transcripts and autism, and, with Brent Williams and W. Ian Lipkin at CII, has found altered expression of genes relating to carbohydrate metabolism and inflammatory pathways and differences in the bacteria harboured in the intestines of children with autism. She also leads projects examining the influence of immune molecules on brain development and function and their role in the genesis of schizophrenia, major depression, and cardiovascular disease comorbidity in adults, and directs the Chronic Fatigue Initiative Pathogen Discovery and Pathogenesis Project at CII. In 2004, Dr. Hornig presented to the Institute of Medicine Immunization Safety Review Committee and testified twice before congressional subcommittees regarding the role of infections and toxins in autism pathogenesis. Her work in ME/CFS is establishing immune profiles and helping to identify pathogens that may be linked to disease. Her work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project, one of the largest studies of immune factors in mood disorders Invest in ME (Charity Nr. 1114035) www.investinme.org Page 67 of 77

Journal of IiMER Volume 10 Issue 1 June 2016 IIMEC11 PRESENTERS and schizophrenia, examines the role of viruses and immune responses in the pathogenesis of these disorders. ABSTRACT: Not available at time of going to press – will be added later. Professor Maureen Hanson Liberty Hyde Bailey Professor, Department of Molecular Biology and Genetics, Cornell University, New York, USA Maureen Hanson is Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University in Ithaca, NY. Previously she was on the faculty of the Department of Biology at the University of Virginia in Charlottesville and an NIH NRSA postdoctoral fellow at Harvard, where she also completed her Ph.D. degree. While most of her prior research has concerned cell and molecular biology in plant cells, she began a research program on ME/CFS after noting at a 2007 IACFS meeting the paucity of molecular biologists studying the illness. Her lab was part of the 2012 multicenter study organized by Ian Lipkin's group at Columbia University to assess the actual role of XMRV in ME/CFS. Dr. Hanson has a current project to examine the microbiome of ME/CFS patients and controls, in collaboration with Dr. Ruth Ley (Cornell Microbiology) and Susan Levine, M.D. (Manhattan, NY). Dr Levine is also collaborating with Dr. Hanson on an immune cell gene expression project that involves Dr. Fabien Campagne and Dr. Rita Shaknovich at Weill Cornell Medical School in New York City. Dr. Hanson's third project concerns analysis of blood samples from individuals performing a two-day cardiopulmonary exercise test at Ithaca College under the supervision of Dr. Betsy Keller ABSTRACT: The Search for Biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Maureen R. Hanson (presenter), Ludovic Giloteaux, Julia Goodrich, Anthony Walters, Susan Levine, Ruth Ley Invest in ME (Charity Nr. 1114035) www.investinme.org Page 68 of 77 Journal of IiMER Volume 10 Issue 1 June 2016 IIMEC11 PRESENTERS Biological markers (biomarkers) are objective measures of biological phenomena. Among possible biomarkers are the physical appearance of an organism or its components, amounts of molecules or cell types, responses of cells or tissue to a stimulus, enzyme activities, gene sequences, or level of interactions of one molecules with another. Many potential biomarkers for the identification of victims of ME/CFS have been measured in the past in the hope of understanding the pathophysiology of the disease. Such studies have revealed abnormalities in function, population and gene expression in immune cells, disturbances in brain morphology and operation, abnormal gas exchange parameters in exercise physiology, discordant levels of plasma signaling proteins, and atypical autonomic function. While these abnormalities have provided some hints about the biological basis of the disease, much more information is needed to understand its underlying cause. Furthermore, the existing biomarkers are cumbersome to implement in a medical office setting, not available to be performed typical medical testing labs, and are not able to identify all patients that can be diagnosed with the disease by an experienced ME/CFS physician. We explored the possibility that levels of inflammatory proteins in the blood, in conjunction with bacterial species abundance in the gut microbiome, might serve as biomarkers for diagnosis if the intestinal microbiome is disturbed in ME/CFS. We examined the bacterial microbiome in 48 ME/CFS patients in 39 healthy controls by sequencing regions of DNA that allow identification of the different types of bacteria that are present. We found that ME/CFS patients had reduced diversity in bacterial types in comparison to healthy individuals, a finding that has also been reported in Crohn’s disease and ulcerative colitis. While there is no set of species detected that is present in ME/CFS patients that is absent from healthy individuals, we identified a number of taxonomic groups that were represented in different abundance between ME/CFS patients and controls. By applying a statistical method to the blood analyses and the bacterial compositions, we were able to classify 83% of the subjects correctly as either patients or healthy individuals. Our results are consistent with an ongoing damage to the gut that leads to greater microbial translocation into the blood, which could then have adverse effects on the immune system. The difference in population structure of the microbial community may be contributing to some ME/CFS symptoms and to their severity. However, there is no evidence that the disturbance in the gut microbiome is a cause of the disease rather than being one of its symptoms. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 69 of 77

Journal of IiMER Volume 10 Issue 1 IIMEC11 Professor Elisa Oltra Professor Elisa Oltra is a professor of Cell and Molecular Biology at the Universidad Católica de Valencia “San Vicente Mártir” where she also works as a researcher in the area of stem-cell and cancer Dr. Elisa Oltra is a professor of Cell and Molecular Biology at the Universidad Católica de Valencia “San Vicente Mártir” where she also works as a researcher in the area of stem-cell and cancer. She obtained an M.S. degree in Biochemistry at the Universidad de Valencia (Spain) and later earned her PhD in Biochemistry, Cell and Molecular Biology at the University of Miami, FL (USA) where she stayed for her post-doctoral training and later, as Senior Scientist till 2006 when she moved back to Spain. During her studies at the University of Miami she identified alternative 5´UTR sequences involved in regulating cell-cell communication through mechanisms of differential connexin43 expression in the heart. She also isolated a novel essential protein (Ini) and demonstrated its participation in mechanisms of transcription and splicing. In 2009 she started a project to investigate the molecular basis of Fibromyalgia having identified at present irregularities in RNAseL expression and miRNAs profile changes in the participating patients which could lead to a deeper understanding of the disease. In 2012 she joined the IVP Valencian Institute of Pathology, also at the Universidad Católica de Valencia where she is currently studying a specific type of vesicles: the exosomes, as mediators of stem-cell based therapies. She is also academic director of the first officially accredited Master degree in Biobanking in Europe in collaboration with the Spanish Network of Biobanking at Invest in ME (Charity Nr. 1114035) www.investinme.org Page 70 of 77 June 2016 PRESENTERS Journal of IiMER Volume 10 Issue 1 IIMEC11 June 2016 PRESENTERS the Instituto de Salud Carlos III, Madrid (Spain). From https://publons.com/author/361418/elisa-oltra#profile ABSTRACT: Molecular Biomarkers of Myalgic Encephalomyelitis Elisa Oltra, Jaime Cuquerella, Armando V. Mena-Durán, Vicente Monsalve and Germán Cerdá-Olmedo School of Medicine, Catholic University of Valencia (Spain) Summary At present no objective diagnostic method for ME or related diseases exists. A lack of reliable markers not only leads to misdiagnosis but limits the possibility of finding effective treatments and/or preventive actions as well. MicroRNAs, also called miRNAs or miRs, are a set of small molecules that work as important modulators of gene expression in tissue-specific physiologic pathways, in response to environmental cues and in disease. Their high stability in body fluids has already shown the use of these small nucleic acids in the diagnosis and prognosis of certain type of cancers and other diseases, appearing as attractive biomarker candidates for the development of precision medicine programs. Encouraged by the idea that miR profiling must be altered in ME patients and related diseases, we and other researchers have pursued the analysis of miRs in blood and other body fluids finding alterations that need to be understood. In our initial study, we performed a genome-wide expression profiling of these miRs in Peripheral Blood Mononuclear Cells (PBMCs) of patients with chronic fatigue and fibromyalgia comorbidities (N=11) and population-age-matched controls (N=10) using human v16-miRbase 3D-Gene microarrays (Toray Industries, Japan). This analysis led to the identification of a miRNA signature of 5 of these small nucleic acids that showed marked down-regulation (6-fold or higher). In addition, the low levels of the hsa-miR223-3p, hsa-miR451a, hsa-miR338-3p, hsa-miR143-3p and hsa-miR1455p could be validated by real-time quantitative PCR amplification (qPCR), an alternative method for measuring the expression levels of these molecules. At present, we are extending this study to a larger cohort of participants presenting a more varied symptom profiling than those that participated in our pilot study with the aim of unveiling symptom and symptom-severity-associated miR profiles. We are including additional body fluids and sub-fractions in our analysis to determine the most appropriate sample to use for a liquid biopsy-based diagnostic method of ME and related diseases. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 71 of 77

Journal of IiMER Volume 10 Issue 1 June 2016 IIMEC11 PRESENTERS Professor James Baraniuk Professor of Medicine at Georgetown University Medical Centre, Washington, USA James N. Baraniuk was born in Alberta, Canada, south of Banff. He earned his honours degree in chemistry and microbiology, medical degree, and unique bachelor's degree in medicine (cardiology) at the University of Manitoba, Winnipeg, Canada. Thereafter, he moved to Akron, OH, USA, for his internship and internal medicine residency at St Thomas Hospital. After another year of internal medicine residency at Duke University Medical Center, Durham, NC, he trained with Dr C.E. Buckley, III, in allergy and clinical immunology. He moved to the laboratory of Dr Michael Kaliner at the National Institute of Allergy and Infectious Diseases, Bethesda, MD, and there began his long-standing collaboration with Dr Kimihiro Ohkubo. After 2 years studying neuropeptides, he joined Dr Peter Barnes' laboratory at the National Heart and Lung Institute, Brompton Hospital, London, UK. Dr Baraniuk returned to Washington, DC, and Georgetown University, where he is currently Associate Professor with Tenure in the Department of Medicine. ABSTRACT: Not available at time of going to press – will be added later. Professor Ron Davis Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California, USA Ronald W. Davis, Ph.D., is a Professor of Biochemistry and Genetics at the Stanford School of Medicine in Stanford, California. He is a world leader in the development of biotechnology, especially the development of recombinant DNA and genomic methodologies and their application to biological systems. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 72 of 77 Journal of IiMER Volume 10 Issue 1 June 2016 At Stanford University, where he is Director of the Stanford Genome Technology Center, Dr. Davis focuses on the interface of nano-fabricated solid state devices and biological systems. He and his research team also develop novel technologies for the genetic, genomic, and molecular analysis of a wide range of model organisms as well as humans. The team's focus on practical application of these technologies is setting the standard for clinical genomics. ABSTRACT: Big Data Approach: Severely ill ME Patient Cohort Our first major effort with multiple patients was to collect a large number of molecular observations on patients with ME/CFS. Once published these data could serve as the basis for a large number of hypotheses that NIH and other government agencies might fund. The cost of this type of study will be very expensive per patient. In order to reduce the overall cost it was recommended by the OMF Scientific Advisory committee to study severely ill patients because they should show the largest molecular signature. With a larger signal fewer patients can be used and still achieve statistical significance. This study has been called the Big Data Study of Severely Ill CFS Patients. These patients are bed bound so do not visit clinics and have not been studied. We send a medical team to each home in the San Francisco Bay Area to collect blood, urine, saliva, tears, and stool. We will be collecting more molecular data on each patient at one time point than has ever been collected in any study in history. While we were seeking funding for the Big Data Study we tested some of the technologies on a few severe and not severe CFS and healthy control patients. We discovered that the metabolome (the small metabolites found in the blood and urine) of the serium gave clear indication of metabolic abnormalities. Preliminary results indicated that glycolysis may be impaired with glucose being routed to fatty acid synthesis. Possibly more important, the metabolites in the citric acid cycle in the mitochondria were lower than in healthy controls and some almost undetectable. This cycle generates most of the energy (ATP) for the body. It makes it clear that this is no psychosomatic disease. From preliminary analysis it would appear that not only ATP is low but also ADP, AMP, GTP and in some cases uracile. These cofactors are involved in hundreds of molecular reactions in the body including in the brain. Their decrease would cause a large number of body functions to be abnormal. We don’t know which cells in the body are being affected (possible all cells) and are currently studying the various white and red cells with a variety of commercial and custom technologies. Invest in ME (Charity Nr. 1114035) www.investinme.org Page 73 of 77

Journal of IiMER Volume 10 Issue 1 June 2016 Sufferers of M.E., carers, family and friends, all want to know what causes M.E. in order to determine how the condition can be prevented, treated and cured. ….. With over 3000 scientists at the Norwich Research Park, consisting of 4 world leading research institutes, a university and a teaching hospital, it is one of Europe’s largest single-site concentrations of research in Food and Health and Environmental sciences. Having academic excellence across a range of diverse, but related fields, in one location is a very powerful way to deliver a step-change in potential outcomes across a number of health issues. Importantly, the new centre for food and health, due to open at the end of 2017 at the Norwich Research Park, takes co-location to a new level as it uniquely integrates academic excellence with clinical expertise; by bringing together the Institute of Food Research with aspects of the University of East Anglia’s medical school and science faculty with the Norfolk and Norwich University Hospitals' gastrointestinal endoscopy facility, working alongside industry. The new Institute will provide a novel holistic, systematic and integrated approach to deliver faster innovation as well as helping to inform government policy on a range of gut and diet related issues including M.E. The development of this new centre, together with the other expertise and facilities located at the Norwich Research Park, puts it in a very good position to lead a UK and European Centre of Excellence for biomedical research for M.E. to provide possible prevention and solutions. - Professor Ian Charles Director of Institute of Food Research IMEC10 conference Together Under the Umbrella Invest in ME are members of European ME Alliance (EMEA) – who are members of the European Federation of Neurological Alliances (EFNA). The Together Under the Umbrella campaign will lead to an increase in public, political and scientific support for all brain and brain-related disorders, resulting in reduced stigma. http://undertheumbrella.eu Invest in ME (Charity Nr. 1114035) www.investinme.org Page 74 of 77 Conference Agenda Start Presenter 07.45 Registration 08.55 IiME 09:00 Dr Ian Gibson 09:10 Dr Vicky Whittemore 09:35 Professor Olli Polo 10:00 Professor Carmen Scheibenbogen Presentation Welcome to IIMEC11 10 years – Looking Back, Looking Forward Keynote Speech: NIH Research into ME Clinical Diagnosis of Myalgic Encephalomyelitis Autoantibodies to adrenergic and acetylcholine receptors in CFS/ME 10.30 Coffee/Tea Break in the Great Hall 11:00 Dr Jo Cambridge B cells, Rituximab and ME/CFS 11.25 Professor Tom Wileman Gut Virome in ME 11:50 Dr Don Staines Update from NCNED: Receptor identification and intracellular signalling 12.30 Professor Simon Carding European ME Research Group 12.45 Lunch in the Great Hall 13.45 Professor Mady Hornig Pathogen Discovery in ME 14:25 Professor Maureen Hanson 14:55 Professor Elisa Oltra The Search for Biomarkers in ME Molecular Biomarkers of Myalgic Encephalomyelitis 15.25 Coffee/Tea Break in the Great Hall 15:55 Professor James Baraniuk Exercise testing and orthostatic tachycardia 16.20 Professor Ron Davis Big Data Approach: Severely ill ME Patient Cohort 17.10 Dr Ian Gibson Plenary Session Status of ME Research 17.30 Adjourn (Note: the agenda, format and times are subject to change) Invest in ME (Charity Nr. 1114035) www.investinme.org Page 75 of 77

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