New Horizons 2008 summary

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    pluis New Member

    New Horizons 2008: International Conference on ME/CFS Biomedical Research

    Hosted and organised by ME Research UK, and co-sponsored by the Irish ME Trust,
    the New Horizons 2008: International Conference on ME/CFS Biomedical Research
    took place on 6th May 2008 at the Wellcome Trust Conference Centre on the Genome
    Campus at Hinxton near Cambridge, UK, an outstanding custom-designed venue
    designed to attract the world's leading scientists to debate issues at the
    forefront of new scientific discovery.

    Building on the success of last year's conference at Heriot-Watt University,
    Edinburgh (read the report here), the day brought together researchers from
    around the world, healthcare professionals, representatives from local support
    groups, and delegates from ME/CFS charities. The full day's programme consisted
    of invited keynote lectures from scientists from Scotland, England, USA, Canada,
    Belgium, Sweden and Australia.


    Order your copy of the 4-DVD set (morning and afternoon) of the presentations by
    contacting our headquarters; the cost is 5 pounds (including P&P) for the
    four-DVD set. You can pay by cheque (made payable to 'ME Research UK'), and
    orders can also be taken by credit/dedit card over the phone.

    [Morning session]

    Roger Jefcoate

    Delegates were welcomed by Sue Waddle who was chairing the conference with Prof.
    Nancy Klimas and Bob McRae. The conference proper was opened formally by Roger
    Jefcoate CBE, co-founder of ME Research UK with Dr Vance Spence and Bob McRae,
    and a Patron of the charity. Roger explained that he felt greatly privileged to
    be welcoming delegates to such a prestigious event, and went on to describe how
    he came to be involved in ME and in funding research into the illness. For all
    of his working life, he has actively promoted technology for disabled people,
    including developing the world's first remote control system for severely
    disabled people at the National Spinal Injuries Centre, Stoke Mandeville
    Hospital, a system that is still freely available through the National Health
    Service, with thousands of happy users and carers nationwide. In 1983, he
    started a trust to fund adapted computers for severely disabled people, some of
    whom were housebound or even bedbound with ME; and in 1998 he was asked by Dr
    Vance Spence to fund a vital laser Doppler scanner for the ongoing biomedical
    research at Dundee University with Professor Jill Belch and Dr Faisel Khan. At
    nearly 30,000 pounds, this donation for the laser Doppler scanner remains the
    largest ever donation his charity has given.

    He continued: 'As you all well know, people with ME suffer grievously, often
    with little support or understanding, sometimes isolated and ignored by the very
    institutions that should be helping - such as the National Health Service and
    the Benefits Agency. Indeed, it is a matter of continuing astonishment to me
    that for so severe an illness, biomedical research is so underfunded, including
    by agencies such as the Medical Research Council which should be the first port
    of call. ME Research UK has become a beacon of hope for many patients, some of
    whom - I know from personal experience - have lived for many years in this sea
    of darkness and despair. It is heartening to see, therefore, the range of
    experts who have volunteered to come and share with us their efforts to explore
    the biomedical basis of the illness. A report to the Chief Medical Officer of
    England in 2002 said that a programme of research on all aspects of ME/CFS was
    urgently needed, and that improvement of health and social care was an urgent
    challenge. We hope that this conference will concentrate minds on scientific
    aspects of this illness.'

    Nancy Klimas

    The first keynote lecture was by Prof. Nancy Klimas of the University of Miami
    School of Medicine and the Miami VA Medical Center, who directs the UM/VAMC Gulf
    War and Chronic Fatigue Syndrome Research Center, which focuses on better
    understanding of the neuro-immune-endocrine interactions in both these complex
    disorders. Her presentation was entitled 'Clinical Aspects of ME/CFS', and her
    key initial emphasis was on the need to move beyond 'case definitional' issues
    of ME and CFS towards assessing patients (sub-grouping) on the basis of clinical
    tests and symptom clusters as outlined in the Canadian Consensus Definition of
    2003, of which she was a co-author. In her view, the post-exertional nature of
    symptoms are key, but it is also important to identify sleep anomalies, pain and
    autonomic dysfunctions which can be prevalent.

    After reviewing the epidemiology - suggesting that there could be one million
    people with CFS in the USA - she described a model for the development of the
    illness. The model postulates a genetic predisposition (supported by past work
    on HLA DR haplotypes), which encounters a triggering event or infection, leading
    to the production of immune, endocrine or neuroendocrine mediators, resulting in
    a poor health outcome and persistence of illness. As she explained, chronic
    immune activation has long been thought to be a component of CFS, and
    T-lymphocytes appear to be chronically activated. Indeed, CD8 cells in patients
    typically demonstrate an increase in activation markers (CD38, HLA-DR) and a
    reduction in CD8 suppressor cells. Also, there is evidence that the homeostasis
    between the cell-mediated or T helper (Th1) immune response and the humoral
    (Th2) immune response is disrupted in CFS, as well as evidence of increased
    pro-inflammatory cytokine expression (TNF-a, IL1, IL6).

    Prof. Klimas reviewed the evidence for viral persistence and reactivation (e.g.,
    enterovirus, HHV6 and EBV), and then discussed the evidence for endocrine
    dysfunction, such as reduced cortisol output via several mechanisms (though many
    possible confounding factors such as deconditioning, sleep, and medication make
    final conclusions difficult). As regards autonomic dysfunction in ME/CFS, this
    has been measured as neurally mediated hypotension, orthostatic hypotension,
    parasympathetic dysfunction, sympathetic overactivation - and she indicated that
    Dr Julia Newton's presentation later in the day would go into these aspects in
    greater depth.

    Gene expression microarray data has become a highly productive tool for better
    understanding CFS research, and Prof. Klimas described recent studies, including
    the differential expression of 35 genes for T-cell activation, neuronal and
    mitochondrial regulatory abnormalities. Again, pre-post exercise challenge
    gene studies have indicated differences in genes that regulate ion transport and
    intracellular cell functions, and it may be that evaluation of gene expression
    profiles will allow for pathophysiologic subgrouping of patients. Advances in
    the field should result in targeted therapies to impact immune function, HPA
    axis regulation and persistent viral reactivation in CFS patients.

    Jo Nijs

    The next keynote lecture was given by Dr Jo Nijs, an academic physiotherapist
    with special interest in chronic pain and ME/CFS who works at the Vrije
    Universiteit Brussel, Belgium, and the University College of Antwerp where he is
    Head of the Division of Musculoskeletal Physiotherapy.

    Dr Nijs gave an overview of his recent paper on 'Intracellular immune
    dysfunction in ME/CFS: state-of-the-art and therapeutic implications' (published
    in Expert Opin Ther Targets 2008; 12:281-289), in which he examined the
    accumulating evidence in support of intracellular immune dysfunction in the
    illness. From an in-depth review of the scientific literature, he and his
    colleagues concluded that proteolytic cleavage of the native RNase L enzyme is
    characteristic of dysregulation of intracellular immunity in people with ME/CFS,
    although the origin of the dysregulation is unexplained at present. There is
    increasing evidence for upregulation of various aspects of the 2-5A synthetase/
    RNase L pathway and for immune cell apoptosis in ME/CFS. The dysregulation and
    upregulation of the 2-5A synthetase/RNase L pathway in ME/CFS are not just
    epiphenomena: evidence in support of their clinical importance has been
    provided. Conflicting data of the functioning of the PKR enzyme in blood cells
    of ME/CFS patients have been reported, possibly reflecting various stages of the
    illness or distinct subgroups. Intracellular immune impairments are related to
    poor exercise performance, but future research should reveal the exact nature of
    this association.

    Dr Nijs explained that it seems plausible that decreased natural killer cell
    function, the presence of infections and intracellular immune dysfunctions are
    interrelated parts of the ME/CFS pathophysiology, but these potential
    interactions still need to be unravelled. More insight into the exact nature of
    these interactions is likely to come from well-designed drug treatment studies.
    Particularly needed are studies examining the effects of drug treatment in
    conjunction with exercise interventions. Since post-exertional malaise is one
    of the major problems with exercise therapy in ME/CFS, drugs might be able to
    diminish the side effects of exercise interventions, possibly leading to
    improved compliance and effectiveness.

    Gregor Purdie

    In the final presentation of the morning session, Dr Gregor Purdie, a general
    practitioner and GP Adviser to NHS Dumfries and Galloway, described service
    development and patient pathways from the perspective of the practising
    clinician. Dr Purdie has been actively involved in moves towards setting up a
    Scottish Clinical Network on ME/CFS, the outcome being 'responsive, empathetic,
    patient-centred care of high quality delivered by clinicians who have kept
    abreast of the latest research, with seamless working between primary, secondary
    and tertiary care'. As regards achieving such a network, he stressed that we
    need to ask ourselves who is to do this, when and how. At present in the pyramid
    of care most of the burden is taken up up by ME/CFS and other voluntary
    organisations at the base, but ideally it would be dispersed throughout the
    pyramid in a multidisciplinary approach involving consultants, primary care and
    healthcare support staff, with Centres of Excellence as a key aspect of the
    overall mix.

    Byron Hyde

    In the following session, Dr Byron Hyde, from Nightingale Research Foundation,
    Ottawa, Canada, outlined some of his conclusions from his years seeing ME and
    CFS patients. He explained that unlike physicians in other countries, he
    operates inside the Canadian healthcare system within which he can order any
    blood, urine or tissue test free of charge for any Canadian citizen, including
    MRI and SPECT imaging.

    His talk began by outlining myalgic encephalomyelitis which he described not as
    a syndrome but a disease process causing a diffuse measurable pathophysiological
    injury of the brain (CNS). He showed SPECT scans from his practice, and observed
    that they showed evidence of brain injuries. As regards the question of the
    triggers or causes of ME, he discussed epidemics, particularly the 1984-1992
    Ontario ME epidemic period during which enterovirus seemed to have an important
    role, concluding that it would be scientifically inexcusable not to consider
    that the enterovirus group was responsible for the diffuse brain damage noted in
    acute onset ME patients. As regards ME patients across the board, Dr Hyde's view
    is that the cause of the illness could be anything (virus, immunisation,
    physical trauma) that can cause a chronic diffuse injury of the CNS, hence the
    need for brain SPECT and brain PET imaging in evaluation.

    He highlighted sleep dysfunction as a prominent part of the illness. Indeed,
    when his Nightingale clinic in Ottawa studied 53 consecutive patients, only one
    had normal sleep; most patients had insufficient sleep or were blocked in stage
    1 and 2 non-restorative sleep, 31 had no stage 3 sleep, and 43 had insufficient
    or no stage 4 sleep. In a significant minority of these patients, mean oxygen
    saturation fell to low levels during the night. A copy of Dr Hyde's presentation
    to the conference can be found at the Nightingale Clinic website.

    Derek Enlander

    Dr Derek Enlander (Mount Sinai Medical School, New York; and New York ME/CFS
    Center, New York, USA) gave the next presentation which described his treatment
    of ME/CFS patients with a complex intramuscular injection, oral l-cystine,
    glutathione, methylcobalalmin, follinic acid and electrolytes. Based on
    treatment of approximately 800 patients over 15 years, he explained that he has
    developed a protocol which has helped 65% of patients, based on SF36 and other
    test criteria. Although the protocol originally started with weekly
    intramuscular kutapressin, results indicated that only approx 30% of patients
    were helped, so Dr Enlander has persisted over the past decade to better these
    results, adding (in stages) intramuscular magnesium sulphate, calphosan,
    methylcobalamin, folic acid, glutathione, trace zinc and molybdenum. This
    protocol seemed to be in line with a theory of a methylation cycle defect in
    ME/CFS. Although glutathione is poorly absorbed, Dr Enlander surmised that if
    glutathione was given by intramuscular and oral routes, a certain percentage
    will enter the circulation, so the protocol was extended to include daily oral
    capsules of glutathione and l-cystine, and daily oral capsules containing a
    range of vitamins. The addition of a potassium, sodium, magnesium and calcium
    combination seems to help muscle weakness and pain.

    Gavin Spickett

    The role of the ME/CFS Clinic in the UK as regards clinical assessment and
    service delivery was described in a presentation by Dr Gavin Spickett
    (Consultant Clinical Immunologist, Royal Victoria Infirmary, Newcastle upon
    Tyne). There are now 13 Clinical Network Co-ordinating Centres (CNCC in the UK -
    see the CFS/ME Service Investment Programme 2004-2006 Programme Report - and Dr
    Spickett is Clinical Champion for Northern ME/CFS CNCC in Newcastle.

    His presentation discussed the care pathways adopted in clinical practice in the
    North of England - recently described in the Nice Guideline 2007 - including the
    key role of medical assessment which aims to undertake a detailed clinical
    evaluation (after GPs have already performed routine tests, including
    pre-screening bloods) to identify alternative diagnoses that may present with
    fatigue to ensure that patients receive appropriate treatment for these.
    Evidence from studies in the clinics has shown that experienced clinicians are
    able to make alternative diagnoses in a significant percentage of patients
    referred from primary care with suspected ME/CFS, and that education programmes
    directed at primary care, as well as strict referral guidelines, do not seem to
    have reduced the prevalence of alternative diagnoses. For example, an audit of
    the Newcastle clinic in 1998 showed that 17% of patients referred could be given
    alternative diagnoses, and a recent re-audit in 2007 showed that in the first
    three years of the new service ME/CFS was confirmed in only 56% of referrals,
    with the remainder consisting of alternative diagnoses (28%), sleep apnoea (9%),
    and depression and anxiety (7%). He explained that with the advent of the NICE
    Guideline 2007 and its encouragement of earlier diagnosis, the proportion of
    alternative diagnoses might be expected to rise.

    Dr Spickett (pictured left, with Prof. Malcolm Hooper) emphasised that it is
    essential both for the subsequent therapeutic intervention and for the
    development of research cohorts that, in the absence of specific confirmatory
    tests, a clear diagnosis, according to International Criteria can be made for
    each patient. For those with a diagnosis of ME/CFS, the NICE-based management
    approaches consist of interventions based around models used for the chronic
    pain team (biopsychosocial model) including activity-based approaches (pacing,
    graded exercise, sleep hygene), lifestyle management, CBT, and physio and
    occupational therapy. An important aspect of the work of the clinical service is
    the provision of help with benefits, and the provision of letters to the
    Department of Work and Pensions to support the maintenance of benefits for
    patients attending the clinic.

    Dr Spickett presented preliminary data on outcomes of the management approach
    above for a small number of patients (n=7 or 8) using the Minimum Dataset;
    these showed mixed results on the Chalder fatigue score (42%/42%/14% improved/
    unchanged/worsened, respectively), pain score (28%/28%/28%, respectively), and
    SF36 quality of life score (0/28%/57%). As he explained, the numbers available
    for analysis are very small as yet, but in the future there will be a need to
    identify those patients not benefiting from the interventions on offer, who
    might need to be offered a different therapeutic approach.

    Julia Newton

    The morning session was brought to a close by Prof. Julia Newton (Senior
    Lecturer, Institute of Cellular Medicine, Newcastle University) who spoke of
    her work on the autonomic nervous system and its dysfunction in ME/CFS. Prof.
    Newton explained how the autonomic nervous system is responsible for
    subconscious activities that occur in the human body, such as respiration,
    bladder and bowel function. It is also integral to the maintenance of
    cardiovascular functions such as maintenance of heart rate and blood pressure.
    Autonomic dysfunction and particularly low blood pressure (hypotension) are a
    frequent finding in people with the symptom of 'fatigue' generally, and her
    programme of research is directed towards understanding the role of autonomic
    dysfunction and developing interventions that target autonomic nervous system

    She explained to a rapt audience that her research group has recently shown that
    89% of those with ME/CFS experience symptoms on standing (orthostatic
    intolerance) and autonomic nervous system symptoms are frequently present in
    those with ME/CFS, the degree of which correlates with fatigue severity and is
    comparable to the symptom burden seen in a range of fatigue-associated chronic
    diseases (click here for a more exhaustive discussion of this work). Again, her
    studies examining haemodynamic responses to standing have shown that 27% (n=63)
    of ME/CFS patients have Positional Orthostatic Tachycardia Syndrome, and that
    cardiovascular parameters correlate with increasing fatigue. Recent preliminary
    results from a series of MRI scans in her unit have shown impaired proton
    removal from muscle during exercise in 16 patients with ME/CFS compared with
    matched controls, leading to the hypothesis that fatigue arises due to impaired
    pH run off from muscle during exercise, which is influenced either entirely or
    at least in part by the degree of autonomic dysfunction. As Julia explained in
    questions chaired by Bob McRae (pictured), research is now focusing on
    techniques to help patients with their autonomic symptoms, and one of these -
    orthostatic (tilt) training - is to be further assessed for ME/CFS patients; it
    might be that a (self-managed) tilt training program could be helpful
    symptomatically. Prof. Newton has recently received a large grant from ME
    Research UK to continue her important investigations on ME/CFS patients from the
    Newcastle clinic over the next two years.

    [Afternoon session]

    Dan Peterson

    The afternoon session began with an overview of the Whittemore Peterson
    Institute for NeuroImmune Disease, University of Nevada, by Dr Dan Peterson one
    of the co-founders, who also discussed some of the work currently underway or
    planned. The aim of the Institute is to be a comprehensive medical research
    facility devoted to patients with neuro-immune diseases such as ME/CFS, atypical
    multiple sclerosis, fibromyalgia, and other similarly presenting illnesses which
    account for billions in lost wages and increased healthcare costs yet receive
    relatively little attention or funding at the National Institutes of Health or
    the CDC. At present, the institute is under construction within the Center for
    Molecular Medicine on the campus of the University of Nevada, Reno, School of
    Medicine, and is scheduled to open formally in late summer 2010. This $70
    million project brings basic researchers, clinical doctors and patients together
    to facilitate the exchange of new ideas and better communication.

    Since its inception, the Institute has focused on research into the pathogenesis
    and aetiology of a subset of ME/CFS patients manifesting primarily neurological
    symptoms and concomitant laboratory abnormalities of the innate immune system.
    Additionally, translational studies have been instituted with respect to
    techniques to determine functionality and to explore promising therapeutic
    agents. In addition, as ME/CFS is a significant contributor to the financial
    burden, as well as functional disability, of the society at large, new
    approaches with respect to patient management are being encouraged and a
    structure to implement these patient-centred cost-effective approaches are being
    designed and implemented.

    Dr Peterson explained that disability carriers, as well as pharmaceutical
    companies, are seeking objective endpoints to determine the extent of disability
    and measure improvement in patients undergoing therapeutic strategies. Exercise
    tolerance testing with expired gas exchange has been widely published as a
    technique that is useful diagnostically, as well as for establishing therapeutic
    endpoints. A recent study done in collaboration with the University of the
    Pacific documented significant changes in a unique fashion in a sequential
    exercise tolerance test performed over a two-day interval. Additional studies to
    reproduce this finding and determine utility in therapeutic trials are currently
    being planned.

    A subset of patients severely affected with ME/CFS with evidence of viral
    reactivation has been documented to demonstrate a gamma T-cell clonal
    rearrangement. Studies are currently underway to determine the monoclonality and
    antigen specificity of this unusual T-cell rearrangement, as well as intensive
    studies into the possible role of viruses in development of neoplastic disorders
    in a subset of chronically affected ME/CFS patients. Again, perturbations of the
    RNase L/2-5A synthetase antiviral pathway have been widely reported in a subset
    of patients, and RNase L studies are currently underway to further characterise
    this previously described abnormality and its significance to symptom
    development in people with ME/CFS.

    Collaborative studies are ongoing, utilising a standardised viral array with the
    goal of identifying potentially treatable subsets of patients with a common
    virally induced aetiology that may be amenable to specific antiviral therapy.
    Cytokines have widely been implicated as mediators of symptomatology, both in
    the CNS and peripherally in patients suffering from ME/CFS. Dr Peterson
    explained that large-scale studies will be carried out to explore the presence
    of a variety of cytokines and functionality in patients and a large number of
    controls to further characterise potential patterns that may be useful
    diagnostically and potentially therapeutically. Recently, the specialised field
    of informatics has been utilised to analyse and manage complex
    inter-relationships involving multiple variables longitudinally; a model for
    applying informatics to mine data and reset the paradigm for ME/CFS has been

    Faisel Khan

    Dr Faisel Khan (The Institute of Cardiovascular Research, University of Dundee)
    described how his keynote lecture represented the work of a very active group
    which has uncovered a range of findings on ME/CFS patients in scientific papers
    from 2003 to 2007. These include increased oxidative stress, abnormally
    sensitive acetylcholine metabolism, and increased neutrophil apoptosis -
    specifically a larger proportion of dying (apoptotic) cells than in healthy
    subjects - consistent with an activated inflammatory process which is possibly
    the consequence of a past or present infection.

    Dr Khan described his specific work on vascular function, and began by
    explaining the accumulating evidence that many patients have associated
    cardiovascular symptoms such as autonomic dysfunction, and attenuated heart rate
    and blood pressure regulation with increased vasomotor tone and loss of
    beat-to-beat heart rate control; such symptoms can contribute to destabilisation
    of blood pressure and orthostatic intolerance and, in the more severe CFS cases,
    a reduced cardiac output. Endothelial function is an important regulator of
    vascular function and is a well established marker of future cardiovascular

    He explained how the group at Dundee had previously studied the vascular
    response in the forearm skin microcirculation to an endothelium-dependent
    vasodilator (acetylcholine, ACh) and found that CFS patients exhibited
    significantly enhanced vascular responses to ACh compared with control subjects.
    In a further study, they have demonstrated that the ACh sensitivity may be
    explained by prolonged action of the vascular response to ACh. Enhanced
    sensitivity to ACh is not normally consistent with elements of endothelial
    dysfunction and increased cardiovascular risk. ACh sensitivity in CFS patients
    may be a consequence of a free radical attack on acetylcholinesterase expression
    on the vascular endothelium giving rise to a reduced expression of the enzyme,
    resulting in the prolongation of the ACh response.

    Dr Khan explained that his recent work concerned arterial stiffness, and the
    fact that the results showed arterial stiffness to be significantly elevated in
    CFS patients compared with control subjects (click here for a more exhaustive
    discussion of this work). The degree of 'stiffness' was associated with levels
    of serum C-reactive protein (CRP), pointing to a role of low grade inflammation
    and oxidative stress. Thus the combination of augmented arterial stiffness and
    increased inflammation and oxidative stress may result in unfavourable
    haemodynamics. Increased arterial stiffness and inflammation might be regulated
    by levels of vitamin D, and the group are currently exploring the possible
    association between vitamin D and vascular function in these patients. In
    addition, the group is testing both focal endothelial function in the brachial
    artery and global endothelial function in smaller pre-resistance arteries, and
    also coronary flow reserve.

    Jonathan Kerr

    In his keynote lecture, Dr Jonathan Kerr (Department of Cellular and Molecular
    Medicine, St George's University of London) described the background to the
    molecular studies that he has been conducting over the past four years. In
    previous work, he characterised gene expression in peripheral blood from 25
    patients with ME/CFS, and 50 normal blood donors using the Affymetrix U133+2
    microarray. Genes showing differential expression were further analysed using
    quantitative polymerase chain reaction in 55 patients with ME/CFS and 75 normal
    blood donors. Differential expression was confirmed for 88 genes, 85 of which
    were upregulated and three downregulated. Highly represented functions were
    haematological disease and function, immunological disease and function, cancer,
    cell death, immune response and infection. Clustering of data from patients with
    ME/CFS revealed seven distinct subtypes with distinct differences in Medical
    Outcomes Survey Short Form-36 scores, clinical phenotypes and severity.

    In the most recent study which he described, the group determined for each CFS
    subtype the fold difference of each of the 88 CFS-associated genes compared with
    normal persons. Using a fold-difference cut-off of greater than 1.5, those genes
    that were differentially expressed in each CFS subtype were determined. As Dr
    Kerr (pictured right with Dr Enlander) explained, genomic analysis revealed
    some common (neurological, haematological, cancer) and some distinct (metabolic,
    endocrine, cardiovascular, immunological, inflammatory) disease associations
    among the subtypes. Subtypes 1, 2 and 7 were the most severe, and subtype 3 was
    the mildest. Clinical features of each subtype were as follows: subtype 1
    (cognitive, musculoskeletal, sleep, anxiety/depression); subtype 2
    (musculoskeletal, pain, anxiety/depression); subtype 3 (mild); subtype 4
    (cognitive); subtype 5 (musculoskeletal, gastrointestinal); subtype 6
    (postexertional); subtype 7 (pain, infectious, musculoskeletal, sleep,
    neurological, gastrointestinal, neurocognitive, anxiety/depression).

    Dr Kerr explained that it was particularly interesting that there was evidence
    that the seven genomically derived subtypes were associated with distinct
    clinical syndromes, and that those which were most severe were also those with
    anxiety/depression, as would be expected in a disease with a biological basis.
    It remains to be determined what these subtypes represent, as they appear to be
    biologically meaningful, and to discover their natural history and possibilities
    for treatment. The team have already begun a study to develop a test based on
    human single nucleotide polymorphisms (SNPs) (read more here) which could
    reliably determine subtype status in individuals.

    Birgitta Evengard

    Prof. Birgitta Evengard (Clinic Infectious Diseases, Umeå University, Sweden)
    gave the pentultimate lecture of the day on the role of the Swedish twin
    registry in searching for a biomarker for the illness. She described the ongoing
    work on characterising the epidemiological patterns and the role of genes and
    environment in the most severe phenotype of fatigue illnesses, the chronic
    fatigue syndrome (CFS), in a representative sample of the Swedish population. In
    the project, collection of epidemiological data, clinical and biological data,
    psychological and socio-demographic data are included, all evaluated with a
    gender perspective. The aim is to describe the prevalence of conditions
    characterised by chronic fatigue and their risk factors in patients and affected
    twins, the latter compared to their healthy co-twins. The population-based
    design enables the possibility of evaluating the validity of the CFS definition
    and, through molecular epidemiology, identify biological determinants of
    potential value for diagnosis.

    The registry assesses twins aged 42 to 65 years old (n=31,406) for chronic
    fatigue from a telephone-based interview with the aim of identifying candidate
    twin pairs for further clinical, psychometric and biological sampling. To date,
    the team have collected and thoroughly reviewed all available medical records
    (n=2,489) for 1,779 individual twins with the strongest complaints of fatigue.
    Also, a web-based questionnaire for the age-group 18 to 42 years identified
    possibly discordant monozygotic twin pairs. In all, 33 pairs of monozygotic twin
    pairs discordant for CFS have been identified, and most have undergone medical
    examination, blood chemistry (sedimentation rate, white blood cell count, liver
    and renal function, thyroid hormones), serum proteomics, and screening of
    cerebrospinal fluid for molecular virus. In addition, mRNA-expression is under
    analysis as is the testing for virus and the cytokine array. To date, two known
    viruses have been detected in the cerebrospinal fluid through the molecular
    virus screening.

    The preliminary results indicate little difference between affected and
    unaffected twins as regards age, education or occupation. Sleep difficulties,
    cognitive impairment, myalgia and joint pain seem to be the most common
    symptoms. Interestingly, oestrogen may be important, as expression of one of the
    oestrogen receptors was reduced in patients. In addition, an HPA axis
    disturbance has been observed.

    Stephen Graves

    In the final presentation of the day, Dr Stephen Graves (Director, Australian
    Rickettsial Reference Laboratory, New South Wales, Australia) shared with the
    audience his wide experience of 'Q Fever' (Coxiella burnetii), 'Flinders Island
    Spotted Fever' (Rickettsia honei strain marmionii) and their possible
    relationship to CFSCFS. He explained that a period of fatigue after an
    infectious disease is a well-recognised phenomenon, which when it lasts for
    months and is referred to as 'post-infectious chronic fatigue'. The Q-fever
    research group hypothesise that many cases of CFS are really 'post-infectious
    chronic fatigue' and that a proportion of these cases are sequelae arising from
    Q Fever (infection with Coxiella burnetii) or Flinders Island Spotted Fever
    (infection with Rickettsia honei, strain marmionii). These two bacteria have an
    obligate, intracellular life style (as do viruses), passing between eukaryotic
    cells of vertebrates (bush mammals, reptiles, humans) and invertebrates (ticks).
    Post-typhus chronic fatigue Flinders Island Spotted Fever was first reported in
    Australia in 1940 but recent data (2008) shows the persistence of rickettsiae in
    peripheral blood mononuclear cells of affected patients.

    Post-Q Fever chronic fatigue was first reported in Australia in 1996 and has now
    been confirmed by others. Antigen from C. burnetii persists in the patient's
    bone marrow and peripheral blood mononuclear cells. The persistence of the
    microbial antigens in the patient appears to cause a dysregulation of the
    cytokine cascade leading to ongoing fatigue in a genetically predisposed
    subpopulation. If the group's hypothesis is correct, public health measures to
    reduce rickettsial infections (e.g., by enhanced Q Fever immunisation) may have
    a positive impact on the incidence of CFS.

    In a poster presentation accompanying the talk, Dr Graves with the Adelaide Q
    fever Research Group and collaborators explored further the issue of
    post-infection fatigue states of varying duration, which are familiar after
    viral, bacterial and protozoal infections. Of interest was a subgroup observed
    after infection with a range of obligate or facultative intra-cellular, or
    cell-dependent bacteria - especially the macrophage pathogens. During the period
    1993 to the present, studies of Q fever yielded the following conclusions: that
    post-Q fever Fatigue Syndrome follows about 10 to 20% of clinically overt cases
    of acute primary Q fever and matches the standard CFS definitions; that patients
    with post-Q fever Fatigue Syndrome exhibit significant variant patterns of
    cytokine responses (IL-6, IFN gamma and IL-2) compared with various controls,
    when their peripheral blood mononuclear cells are stimulated with Q fever and
    control antigens in short term cell culture; that immunogenetic studies have
    shown significant frequency differences (i.e., gene polymorphisms), between
    post-Q fever Fatigue Syndrome on the one hand, and on the other hand, Q fever
    endocarditis, asymptomatic Q fever convalescents and unexposed population
    control panels. Overall, precipitating factors appear to be overt not
    subclinical infection (perhaps reflecting heavy seeding with coxiella

    Our thanks go to Regina Clos for some of the photos of the day, and the complete
    selection of her photos, including of the beautiful town of Cambridge, can be
    found at her website CFS-aktuell. But our most grateful thanks go to the 130
    delegates who came a long way to attend, and who - judging by the overwhelmingly
    positive feedback forms - found the experience educational and most importantly
    great fun!

    You can order your copy of the 4-DVD set of the presentations by contacting our
    headquarters; the special 'Energising ME Research' price is 5 pounds (P&P
    included) for the set, and please make cheques out to 'ME Research UK'. We can
    also take credit/dedit card orders over the phone.

    (c) 2008 ME Research UK

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