Discussion in 'Fibromyalgia Main Forum' started by fight4acure, Jul 26, 2006.

  1. fight4acure

    fight4acure Member

    posted by joannla, thanks hon!

    ANN ARBOR, Mich., Sept. 27 -- The reason that opioids seem to fizzle for fibromyalgia may be because of reduced receptor activity in regions of the brain that process and dampen pain signals, researchers here found. Action Points

    Explain to interested patients that clinical experience has shown opioid pain medication to be less effective than in other patients with other diagnoses.

    This study affirms and provides a physiological explanation for the difference in efficacy.
    Reduced µ-opioid receptor-binding potential in fibromyalgia patients was also significantly correlated with depression and emotional components of pain, reported Richard E. Harris, Ph.D., of the University of Michigan, and colleagues, in the Sept. 12 issue of the Journal of Neuroscience.

    "Because these receptors are the target of opiate drugs," they wrote, "a profound reduction in the concentration or function of these receptors is consistent with a poor response of fibromyalgia patients to this class of analgesics, observed anecdotally in clinical settings."

    The researchers used PET with a selective µ-opioid receptor radiotracer to assess receptor availability differences between fibromyalgia patients and healthy pain-free individuals.

    Their study included 17 right-handed women with fibromyalgia (mean age 44.8, mean diagnosis duration 8.4 years) and 17 age- and sex-matched healthy controls who were part of an ongoing study of acupuncture treatment. The analysis was done on PET scans and other data collected at baseline.

    No participants were taking opioids or had a history of their use. Of the 17 fibromyalgia patients, 10 were taking antidepressant medication, either serotonin reuptake inhibitors or dual serotonin/norepinephrine reuptake inhibitors.

    The women reported "sensory" and "affective" characteristics of their pain on the Short Form of the McGill Pain Questionnaire immediately prior to undergoing the PET scan.

    Depressive symptoms were self-reported on the Center for Epidemiological Studies-Depression Scale, which is used to detect major or clinical depression.

    The PET scans showed significantly less opioid receptor-binding potential overall in fibromyalgia patients than in controls (P<0.01).

    Fibromyalgia patients also had significantly less opioid receptor availability in four specific regions of the brain, the left and right nucleus accumbens, the left amygdala, and the right dorsal anterior cingulate (all P<0.05).

    After controlling for global opioid receptor binding potential, the difference was still significant for the left (P<0.001) and right (P<0.05) nucleus accumbens and the amygdala (P<0.005). Activity in the dorsal anterior cingulate showed a similar trend (P<0.07).

    "All of these regions have previously been noted to play some role in nociception and pain," Dr. Harris and colleagues said.

    But, antidepressant use in the fibromyalgia group did not explain the opioid receptor abnormalities, the researchers said.

    Binding potential in these four brain regions was not significantly different in fibromyalgia patients taking serotonin reuptake inhibitors or dual serotonin/norepinephrine reuptake inhibitors than among those not taking drugs in this class (all P>0.35).

    Fibromyalgia patients also showed more depressive symptoms (P<0.05) with reduced opioid receptor binding within the amygdala, a region of the brain thought to modulate mood and the emotional dimension of pain.

    Among fibromyalgia patients, reductions in opioid receptor-binding in the left nucleus accumbens was correlated with significant increases in the emotional component of clinical pain (P<0.05) though not the sensory component (P>0.50). Controlling for antidepressant medication use did not change the association.

    The relative amount of emotional versus sensory pain varied between patients in correlation with differences in opioid receptor binding in the dorsal anterior cingulate (P<0.05), posterior cingulate (P<0.001), and right ventral putamen (P<0.05) with a trend for the anterior cingulate (P=0.09).

    "These results suggest that in fibromyalgia patients the affective quality of pain is associated with reduced µ-opioid receptor availability throughout the cingulate and other brain regions commonly associated with pain modulation," the researchers wrote.

    Alterations in central opioid neurotransmission in specific brain regions "suggest that these mechanisms, possibly as a consequence of persistent pain, are involved in the clinical presentation and even the perpetuation of symptoms in this illness," they added.

    Regardless of whether the mechanism is high endogenous opioids or downregulation of opioid receptors, the findings predict a poorer response to opioid painkillers for fibromyalgia patients, they concluded.

    The study was supported by grants from the Department of Army, the National Institutes of Health. Dr. Harris was supported by a National Center for Complementary and Alternative Medicine grant and another researcher was likewise supported by a National Institutes of Health grant. None of the researchers reported conflicts of interest.

    Additional Pain Management Coverage

    Primary source: The Journal of Neuroscience
    Source reference:
    Harris RE, et al "Decreased Central µ-Opioid Receptor Availability in Fibromyalgia" J Neurosci 2007;27:10000-10006.

  2. fight4acure

    fight4acure Member

    Update on Antiviral Medication and Comprehensive CFIDS Management - Notes from the Field

    by Dr. Dale Guyer, MD


    Dr. Guyer is a family physician and Director of The Advanced Medical Center in Indianapolis, Indiana,* where patients are offered a unique blend of traditional and integrative therapies for ME/CFS, Fibromyalgia, and a number of other health-related problems.

    Antiviral medications have generated considerable scientific attention in the primary and adjunctive treatment of CFIDS and FMS - in the subset of the population with a viral component as part of individual etiology.

    Through the years, I have noted a few good additive results with medications such as FamvirTM, ValtrexTM, and occasionally AcyclovirTM and AmantadineTM. Over the last year, thanks to the work of Dr. Jose Montoya at Stanford University, I have found that ValcyteTM offers another option that can really be the proverbial “icing on the cake” for many afflicted with CFIDS. Like other clinicians, my own experience with antiviral medications is that they are often very helpful with occasionally dramatic benefits, adding another viable alternative to the landscape of treatment options.

    Some years ago, I had doubts that antiviral meds could add significantly to the management of CFIDS. Retrospectively, the doubts stemmed largely from becoming accustomed to observing good results with therapeutic strategies I was already using.

    On many occasions, I have noted that comparatively simple treatments often deliver extraordinary results - Transfer Factor,1 oxidative therapies, Intravenous Vitamin (IV) therapy and vitamin B12 shots, to mention a few. Obviously, no protocol represents a “one size fits all” strategy. Clinicians are still required to find unique treatment strategies for unique patients.

    Recently, I followed two male high school students who were very physically active prior to development of severe cases of mononucleosis. Following the episodes over the next six months, I noted that both students exhibited the classic findings of CFIDS. Both also responded almost immediately to a cocktail of IV Therapy, Transfer Factor and broad-spectrum nutritional supplementation. One patient eventually competed in an international martial arts competition in Germany, while the other returned to twice daily football practice in the heat of the Indiana summer - a challenge even for those without CFIDS!

    In addition, my earlier opinions were based in large part on not observing impressive results with antiviral medications - at least not as good as I came to expect from other therapies.

    Along the way, a good friend - Kristin Loomis, who in addition to being very knowledgeable is also the Executive Director of the HHV-6 Foundation - encouraged me to continue to give antivirals a try. I must say she, as usual, proved correct. Last year, she introduced me to the research of Dr. Montoya2, a Stanford infectious disease specialist; and since then I have seen often very good success with Valcyte.

    In 2007, we began collecting data on the results of adding Famvir and Valcyte to individual treatment plans as clinically warranted. The formal results will be presented at the International College of Integrative Medicine meeting in Nashville in March 2008. In the meantime, I want to share observations that I have made over the last several months on very intriguing clinical findings that include the broad array of subjective improvements patients report while on antiviral therapy.

    n One interesting case involves a gentleman undergoing treatment for bipolar disorder for years. During his last office visit, he remarked that since starting Valcyte not only did the CFIDS symptoms reduce substantially, but he also noticed more motivation - for example, mowing the lawn and enjoying it, something he had not done in years. The patient reported that his lithium dose was reduced from 1200 mg daily to 300 mg daily.

    n Others have reported a restored sense of joy and humor - feelings absent for years, in addition to improved libido, decreased anxiety and depression, improvement in asthma and allergic symptoms, positive clinical changes in autoimmune disorders such as Crohn’s Disease, rheumatoid arthritis, and even one case of rare ALS type progressive motor neuron disease.

    As our clinical experience demonstrates, our evolving understanding of the pervasive role viral activity in human health expands. We are beginning to understand that chronic viral activity may be present in the population at levels higher than previously assumed and not just involved in the etiology of CFIDS.

    Can we predict which patients will do well with antiviral therapy?

    Overall, it would appear that patients who fare better have a classic “viral” provoke history - i.e., they had a case of a “viral-like” illness, never got better, and over time keep going downhill. Duration of symptoms may be six months or 20 years. I have observed a few cases where these symptoms started after receiving a vaccine, such as the flu vaccine, and another case that appeared to begin after receiving a tetanus vaccine. In addition, patients will have consistent lab findings, including: depressed natural killer cells, low adrenal function, hormone deficiencies, elevated RNase-L3 levels, and elevated viral antibodies to Human Herpesvirus Six (HHV-6), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and occasionally other viruses.

    As a rule of thumb, individuals who experience milder symptoms of shorter duration [accompanied by elevated levels of] IgG (Immunoglobulin G) to EBV seem to do well with Famvir. However, patients more severely affected for a longer duration with antibodies more skewed to HHV-6 or CMV will often need Valcyte.

    Younger individuals with shorter duration of symptoms tend to get better faster, while people over 40 or those with several years of symptoms may need a few months to start getting back on track. Often even after six months of Valcyte or Famvir, we will maintain some individuals on a low dose of Famvir or Valcyte in the 50 mg range (a dose we compound because it is not commercially available).

    Another important issue is the necessity to take a comprehensive view of CFIDS.

    Often, physicians desire to treat CFIDS simplistically like we might address a sore throat - one cause, one solution. Undoubtedly, theories come and go relating to CFIDS, but in my experience, physicians who get optimal results evaluate all contributing factors, listen well, and integrate therapeutic support strategies to address contributing issues, such as: adrenal dysfunction, sub-clinical hypothyroidism, neurotransmitter imbalances, nutritional deficiencies, endocrine problems (depleted levels of DHEA, growth hormone, testosterone) - to name a few.

    In my experience, taking a more comprehensive approach accelerates the process of restoring health, while simultaneously diminishing the likelihood of feeling exhausted, depleted and miserable while taking antiviral medication.

    The inclusion of antiviral therapy in CFIDS has in my experience been a great addition. Like any stand-alone therapy, it may not offer the big difference we want to see; however, when combined with other supportive therapies, it offers a giant step forward in restoring wellness in individuals with CFIDS.

    * The Advanced Medical Center in Indianapolis, Indiana, was founded in 1997 by Dr. Guyer. New patients are welcome. For more information, including glossaries explaining some of the therapies, nutritionals and tests mentioned, visit (where you will need to download flash player) or call (317) 580-9355. To listen to a detailed lecture on CFIDS/FMS, log onto Dr. Guyer’s website.

    1. For more information on transfer factor, see recent articles in the Library such as "Transfer Factor and the Importance of a Healthy Immune System" by Aaron White, PhD, author of the highly rated new book A Guide to Transfer Factors & Immune System Health.

    2. To learn more about the HHV-6 Foundation, research relating to HHV-6 in ME/CFS, and Dr. Montoya’s continuing Valcyte research at Stanford, go to the HHV-6 Foundation website.

    3. RNase L is part of the body’s immune defense. When activated it puts a cell in the antiviral state – highly resistant to viral attacks, and ready to destroy viral RNA and ‘commit suicide’ if infected by a virus. For more about RNase L anomalies in ME/CFS patients, see “Dr. Kenny De Meirleir’s Breakthrough Research and Recommendations for CFS Testing & Treatment”

    Note: This information has not been evaluated by the FDA and is not meant to prevent, diagnose, treat, or cure any condition, illness, or disease. It is very important that you make no change in your healthcare plan or regimen without researching and discussing it in collaboration with your professional healthcare team.
  3. fight4acure

    fight4acure Member

    Insight into fibromyalgia

    Research out of the University of Michigan Health System is shedding new
    light on why people with the chronic pain condition fibromyalgia report
    that they do not respond to the types of medication that often relieves
    other people.

    U-M researchers say that may be because patients with fibromyalgia were
    found to have reduced binding ability of a type of receptor in the brain
    that is the target of opioid painkiller drugs such as morphine.

    The study included PET - positron emission tomography - scans of the
    brains of patients with fibromyalgia and a control group of people without
    the often-debilitating condition.

    'The finding is significant because it has been difficult to determine
    the causes of pain in patients with fibromyalgia, to the point that
    acceptance of the condition by medical practitioners has been slow,' said
    Richard E. Harris, research investigator in the Division of Rheumatology
    at the U-M Medical School's Department of Internal Medicine and a
    researcher at the U-M Chronic Pain and Fatigue Research Center.

    (c) 2007 Michigan Live LLC.
  4. fight4acure

    fight4acure Member

    Breaking news! Today, the CFIDS Association is pleased to announce the appointment of Suzanne Vernon, PhD, as scientific director, a brand-new post created to advance research in the field of CFS and accelerate progress in developing treatments for this illness. Read all about Dr. Vernon and the Association's campaign to raise one million dollars to fuel the program in the press release (PDF) issued today at

    Marcia Harmon
    Director of Communications
    CFIDS Association of America

  5. fight4acure

    fight4acure Member

    CFIDS Association Launches New Research Initiative for Chronic Fatigue
    Syndrome Today

    CHARLOTTE, N.C., Nov. 7 /PRNewswire/ -- The CFIDS Association of America today launched a new initiative to advance research in the field of chronic fatigue syndrome (CFS) and accelerate progress in developing treatments for this illness. The research initiative is designed to build
    a new model for bridging the gap between CFS science and medicine, and it includes a campaign to raise one million dollars over a one-year period to fuel the program. This is the largest CFS research campaign to date in the United States.

    "This new program represents a visionary approach to CFS research that has applications for many fields of science," says Dr. Suzanne Vernon, who will lead the program as the CFIDS Association's new scientific director. "There has been tremendous progress made by CFS researchers around the
    world in the last decade, and we now understand an enormous amount about the pathophysiology of CFS, and about the body systems that are broken or altered by this disease. But what is lacking is a mechanism for sharing this progress and information not only among investigators spread out
    across the globe who are working in disparate fields, but among health care professionals and patients."

    Vernon, who has 17 years of experience as a microbiologist at the Centers for Disease Control and Prevention (CDC), and who led the Molecular Epidemiology Program in the CDC's CFS research group from 1997 to 2007, says this mechanism isn't all that's been missing in the world of CFS science. A whole network is needed.

    "There has been no organization, academic institution or agency that has taken on the enormous task of bringing all this information together, connecting the dots and forging new collaborations across the globe," said Dr. Vernon. "Because of the enormous progress made in recent years, this is a critical time for determining CFS research needs and directions -- decisions that will have implications that will be felt for decades. The CFIDS Association is really on the cutting edge in recognizing the need to bridge the gap between CFS science and medicine, and for taking the leadership reins to start building the framework for that bridge in a way
    that has the potential to catapult the field forward."

    A million-dollar fund-raising campaign for CFS research is part of the new research initiative. "The pace of progress we're making is too slow and we need an infusion of funds to move the field forward faster," says Kimberly
    McCleary, president and CEO of the CFIDS Association.

    Specific elements of the new CFIDS Association research initiative include:
    - Revamping the Association's own research grants program, which has funded $4.8 million in research so far, in order to expedite progress in the search for biomarkers, treatments and a cure

    - Building strong collaborations with CFS researchers across the world to identify synergies, gaps and opportunities that warrant higher priority

    - Developing new opportunities for scientists to share ideas, knowledge and data to advance the field

    - Surveying other fields of research for findings and scientific approaches of potential relevance to CFS

    - Securing a new infusion of federal research funding for CFS

    - Attracting new investigators from a number of disciplines to the field of CFS research.

    Dr. Vernon believes that the research advances made in recent years should give all CFS patients hope, which has therapeutic value of its own. "But with this new initiative, within a few years we want to be able to offer
    more than hope to patients and their families, whose lives have been so altered by this debilitating illness. We want to be able to offer effective treatment interventions. Until we have a cure, that's the next important step."

    Benjamin Luft, MD, a professor and infectious disease specialist at SUNY at Stony Brook, said today that the CFIDS Association's research initiative and "the appointment of Suzanne Vernon to lead the program is a
    coup for both the Association and all who care about understanding and treating this elusive condition. Dr. Vernon's work at the CDC demonstrated a unique capacity to bring together various disciplines to understand
    chronic fatigue syndrome. This work serves as a paradigm for understanding diseases that are caused by a multiplicity of factors. Ultimately this knowledge is our best hope for effective therapy."

    About the CFIDS Association of America

    The CFIDS Association was founded in 1987 to stimulate high-quality CFS research, improve the ability of health care professionals to diagnose and manage the illness, secure a meaningful response to CFS from the federal government, provide educational information for patients and their
    families, and build widespread public awareness of CFS. The organization has invested more than $25 million in education, public policy and research and is the largest charitable funder and advocate of CFS research
    in the U.S.

    To learn more about CFS, visit

    (c) 2007 PR Newswire
  6. fight4acure

    fight4acure Member

    UW, Japanese Scientists Report Stem Cell Breakthrough
    Researchers Were Able To Make Ordinary Cells Operate Like Stem Cells (FOR MORE... READ WEBSITES ABOVE)

  7. fight4acure

    fight4acure Member

    Posted by Munch1958
  8. Debra49659

    Debra49659 New Member

    Thanks for the articles...will add some of my own at a later date. I have a few good ones.

  9. fight4acure

    fight4acure Member

    Low grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome.

    Clin Sci (Lond). 2007 Nov 21; [Epub ahead of print]
    Spence VA, Kennedy G, Belch JJ, Hill A, Khan F.
    PMID: 18031285

    Some of the symptoms reported by people with chronic fatigue syndrome (CFS) are associated with various cardiovascular phenomena. Markers of cardiovascular risk, including inflammation and oxidative stress, have been demonstrated in some CFS patients but little is known about the relationship of these and prognostic indicators of cardiovascular risk in this patient group.

    We sought to investigate the relationship between inflammation and oxidative stress and augmentation index, a measure of arterial stiffness, in 41 well characterised CFS patients and in 30 healthy subjects.

    The augmentation index, normalised for a heart rate of 75 beats per minute (AIx@75), was significantly greater in CFS patients than in control subjects (22.5 +/- 1.7 versus 13.3 +/- 2.3%, P=0.002). CFS patients also had significantly increased levels of C-reactive protein (2.58 +/- 2.91 versus 1.07 +/- 2.16 g/mL, P<0.01) and 8-iso-prostaglandin F 2alpha isoprostanes (470.7 +/- 250.9 versus 331.1 +/- 97.6 pg/mL, P<0.005).

    In CFS patients, AIx@75 significantly correlated with log C-reactive protein (r=0.507, P=0.001), isoprostanes (r=0.366, P=0.026), oxidised LDL (r=0.333, P=0.039) and systolic blood pressure (r=0.371, P=0.017).

    In a stepwise multiple regression model, (including systolic and diastolic blood pressure, body mass index, C-reactive protein, TNFalpha, IL-1, oxidised LDL, HDL cholesterol levels, isoprostanes, age and gender), AIx@75 was independently associated with log CRP (beta=0.385, P=0.006), age (beta=0.363, P=0.022), and female gender (beta=0.302, P=0.03) in CFS patients.

    The combination of increased arterial wave reflection, inflammation and oxidative stress may result in an increased risk of future cardiovascular events. Assessment of arterial wave reflection might be useful for determining cardiovascular risk in this patient group.
  10. fight4acure

    fight4acure Member

    Striatal grey matter increase in patients suffering from Fibromyalgia - a voxel-based morphometry study – Source: Pain, Dec 2007

    by T Schmidt-Wilcke, et al.


    [Note: ‘voxel-based morphometry’ is a neuroimaging analysis technique that allows “mapping” of differences in brain volume.]

    Fibromyalgia (FM), among other chronic pain syndromes, such as chronic tension type headache and atypical face pain, is classified as a so-called dysfunctional pain syndrome. Patients with Fibromyalgia suffer from widespread, "deep" muscle pain and often report concomitant depressive episodes, fatigue and cognitive deficits. Clear evidence for structural abnormalities within the muscles or soft tissue of Fibromyalgia patients is lacking.

    There is growing evidence that clinical pain in Fibromyalgia has to be understood in terms of pathological activity of central structures involved in nociception. We applied MR-imaging and voxel-based morphometry, to determine whether Fibromyalgia is associated with altered local brain morphology.

    We investigated 20 patients with the diagnosis of primary Fibromyalgia and 22 healthy controls. VBM revealed a conspicuous pattern of altered brain morphology in the right superior temporal gyrus (decrease in grey matter), the left posterior thalamus (decrease in grey matter), in the left orbitofrontal cortex (increase in grey matter), left cerebellum (increase in grey matter) and in the striatum bilaterally (increase in grey matter).

    Our data suggest that Fibromyalgia is associated with structural changes in the Central Nervous System of patients suffering from this chronic pain disorder. They might reflect either a consequence of chronic nociceptive input or they might be causative to the pathogenesis of Fibromyalgia. The affected areas are known to be both, part of the somatosensory system and part of the motor system.

    Source: Pain. 2007 Nov;132 Suppl 1:S109-16. PMID: 17587497, by Schmidt-Wilcke T, Luerding R, Weigand T, Jürgens T, Schuierer G, Leinisch E, Bogdahn U. Department of Neurology, Universitätsklinik Regensburg, Universitätsstrasse 84, D-93053 Regensburg, Germany. [E-mail: ]

  11. fight4acure

    fight4acure Member

    Please take some time to read this. It's about CFS and the 7 identifying genes present in those with CFS. It's more physical proof of this illness. Give this to your doctors and loved ones to read.

    Fight4acure! Fight2Educate!
  12. tansy

    tansy New Member

    James Sturcke and agencies Guardian Unlimited, Thursday December 13 2007

    The police were today ordered to reopen an investigation into Britain's worst water poisoning disaster following allegations of a cover-up.

    The pollution happened in 1988 when 20 tonnes of aluminium sulphate was delivered into the wrong tank at the water treatment works at Lowermoor on the edge of Bodmin Moor, which were run by the now defunct South West Water Authority.

    Since then, local people have complained of a range of health issues, from brain damage and memory loss to joint problems.

    The police investigation was ordered today by West Somerset coroner Michael Rose, who has opened inquests into the deaths of two women who lived in the Camelford area at the time of the pollution.

    One was Carole Cross, 58, who died in 2004 and was the wife of environmental scientist Doug Cross, a member of a government committee which has been investigating the medical effects of the incident.

    An autopsy revealed abnormally high levels of aluminium in the brain of his wife, who suffered from a neurological disease.

    Irene Neal, 91, lived in Rock, north Cornwall, at the time of the pollution and died in a nursing home in Buckfastleigh, Devon, in June this year.

    A brain autopsy on Neal, whose home was served by the Camelford water system, revealed an "unacceptable amount of aluminium in the brain", said her daughter, Pam Melville.

    The coroner said extensive tests, including pathology examinations, were undertaken by Professor Margaret Esiri at John Radcliffe hospital, Oxford, and by Chris Exley at Keele University, Staffordshire.

    "These tests have revealed there may be a connection between at least one of these deaths and the earlier incident," the coroner said.

    "In view of the serious allegations made in the media of a possible attempt to initially suppress the seriousness of the incident, I am asking the chief constable of Devon and Cornwall to hand me evidence gathered at the time of the original investigation."

    He also asked the chief constable to appoint a senior detective "to look into the allegations of a possible cover-up".

    The coroner said he would like to resume the inquest hearing once that information was available.

    A Devon and Cornwall police spokesman said today: "Following information contained within the coroner's press release, we have contacted him. He has not yet written to Devon and Cornwall police but, when he does, we will consider his request."

    Cross, who believes both deaths were linked to the pollution, today said there had been a cover-up from the beginning.

    "Probably the worst part has been that the medical establishment has hidden information which would have changed the course of the investigation. People would have been looked at and treated if possible," said Cross, who now lives in Cumbria.

    He served on the government's committee on toxicity, set up to look into the health effects of the pollution disaster, and claims it had been forbidden from looking at medical records and had to rely on anecdotal material.

    The final report of the committee has yet to be published.

    Cross and another member of the committee, Truro-based homeopath Peter Smith, claimed earlier this week that the Department of Health knew from the start that some people were at especially high risk from aluminium poisoning.

    But this

    Melville, who lives near Buckfastleigh, said today she was not in favour of wasting taxpayers' money on a police investigation, but felt there should be an automatic autopsy on anyone who died in the Camelford area.

    "There is enough anecdotal evidence to say there is a problem," she said.
    Lord Tyler, MP for North Cornwall between 1992 and 2005, described the coroner's announcement as "a case of 'better late than never'".

    "For nearly two decades, Lowermoor water poisoning victims have demanded a real, open investigation into the cover-up which followed the incident," he said.

    A draft report by the Lowermoor sub-group committee, published in 2005, said it was unlikely that the chemicals involved in the incident would have caused any persistent or delayed health effects.

    But the report, ordered by Michael Meacher, who was the environment minister at the time, recommended further research in a number of areas, including a study into those who did, and who did not, drink the water.

    A year after the pollution incident, a government inquiry into health consequences considered it was unlikely that long-term health effects would occur, but a 1991 report referred to the possibility of "unforeseen late consequences".

    In 1999, an article in the British Medical Journal said it was "highly probable" that aluminium poisoning did cause brain damage in some people.

    After a trial at Exeter crown court in 1991, South West Water Authority was fined £10,000 with £25,000 costs for supplying water likely to endanger public health.

    Three years later, 148 victims of the incident reached an out-of-court settlement, with payments ranging from £680 to £10,000.
  13. DeborahLynn

    DeborahLynn Member

    I found this information on this board earlier today, and mentioned it on a post of one of Fight4acure's posts, and was asked to add it here. I just found it on ProHealth's CFS/FMS boards, so I can't take any credit for it:) I tried to find the post again so I could give credit to the one who originally posted it, but I couldn't find it.

    Here is a bit of good news about media coverage of ME/CFS in the UK, which hopefully helps fight against the stereotypes against ME/CFS.

    I wanted to share with you all a post I read earlier on this board about the government in UK and scandal regarding ME/CFS, with a web address for YouTube so you can see it yourself. It is:

    It even shows a ME/CFS researcher saying they are about a year from finding a cure for ME/CFS and another year from developing a diagnostic test. All this has come from privately funded research, because all the UK governmental research has been geared toward coping/counseling and psychiatric treatment.

    I thought you all might be glad to hear of some good research news! I was quite surprised to hear that they may be that close to finding a cure; here's hoping.

    (Update, 1-2-08 - I just found out that youtube segment is old news! Oh well, it's still very interesting. Here's to still hoping!)

    Love and prayers,


    [This Message was Edited on 01/01/2008]
    [This Message was Edited on 01/02/2008]
  14. fight4acure

    fight4acure Member

    (Originally posted by Mezombie. Thanks hon!)

    Seven genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): a detailed analysis of gene networks and clinical phenotypes

    Jonathan R Kerr,1,2 Beverley Burke,1* Robert Petty,1* John Gough,1,2 David Fear,3 Derek L
    Mattey,4 John S Axford,1,2 Angus G Dalgleish,1 David J Nutt.5
    1Department of Cellular & Molecular Medicine, St George’s University of London, London,UK; Sir Joseph Hotung Centre for Musculoskeletal Disorders; 3Dept of Asthma, Allergy and
    Respiratory Sciences, King’s College London, London, UK; 4Staffordshire Rheumatology Centre, Stoke on Trent, UK; 5Psychopharmacology Unit, Dept of Community Based Medicine,
    University of Bristol, Bristol, UK.
    *Robert Petty and Beverley Burke made equal contributions to this paper.
    JCP Online First, published on December 5, 2007 as 10.1136/jcp.2007.053553

    Chronic Fatigue Syndrome / myalgic encephalomyelitis (CFS/ME) is a multisystem disease,the pathogenesis of which remains undetermined. We have recently reported a study of gene expression which identified differential expression of 88 human genes in patients with CFS/ME. Clustering of QPCR data from CFS/ME patients revealed 7 distinct subtypes with distinct differences in SF-36 scores, clinical phenotypes and severity. In this study, for each CFS/ME subtype, we determined those genes whose expression differed significantly from that of normal blood donors, and then determined gene interactions, disease associations and molecular and cellular functions of those gene sets. Genomic analysis was then related
    to clinical data for each CFS/ME subtype. 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). It is particularly interesting that in these genomically derived subtypes, there were 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.


    Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) is a disease characterised by severe and debilitating fatigue, sleep abnormalities, impaired memory and concentration,and musculoskeletal pain.1 In the Western world, the population prevalence is estimated to be
    of the order of 0.5%.2,3 Research studies have identified various features relevant to the pathogenesis of CFS/ME such as viral infection, immune abnormalities and immune
    activation, exposure to toxins, chemicals and pesticides, stress, hypotension, lymphocyte abnormalities and neuroendocrine dysfunction. However, the precise underlying disease mechanisms and means by which these abnormalities inter-relate in CFS/ME patients, remain to be clarified.4,5

    We have previously described a study of 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. Genes showing differential expression were further analysed using quantitative PCR (QPCR) 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 distinct subtypes with distinct differences in SF-36 scores, clinical phenotypes and severity.6

    In this study, we have 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 =1.5, we have then determined those genes which are differentially expressed in each CFS subtype. For each subtype, we report respective gene functions / pathways gene interactions, and disease associations, and relate these to the clinical phenotype details of each.4


    Subjects and clinical characterisation Analyses in this paper are based upon clinical and genomic data from CFS/ME patients whose blood was used for QPCR confirmation of microarray data, as previously reported.6 In total, 55 such patients were enrolled from clinics in Dorset, UK; Bristol, UK; London, UK; and New York City, USA (one patient from Leicester, UK, was managed by a clinic in London). These cases were diagnosed according to the CDC diagnostic criteria for CFS/ME.1 Patients with psychiatric disease were excluded using the Minnesota International Neuropsychiatric Interview (MINI), thus ensuring that none of our patients was suffering from major psychiatric
    disease or abuse of alcohol or other drugs. In addition, patients who smoked in the previous year, or were currently taking (or were within 3 months of taking) antibiotics, steroids or antidepressants were excluded from the study.

    For all enrolled subjects, according to the recommendations of the International CFS Study
    Group,7 severity of physical and mental fatigue was assessed using the Chalder Fatigue Scale;8 level of disability was assessed using the Medical Outcomes Survey Short Form-36 (SF-36); accompanying symptoms were characterised using the Somatic and Psychological
    Health Report (SPHERE); sleep abnormalities were assessed using the Pittsburgh Sleep Questionnaire; and assessment of type and severity of pain was performed using the McGill
    Pain Questionnaire. For the CFS/ME patients, neurocognitive testing was performed using the Spatial Span (SSP) and Verbal Recognition Memory (VRM) modules of the Cantab software (Cambridge Cognition, UK), which showed abnormal results in CFS/ME.6,9 For each CFS patient, the severity of particular symptoms and level of function was taken from the above questionnaires.

    Then for each CFS subtype which was derived by clustering of QPCR data as previously described,6 mean values for each symptom and score were calculated and compared between the subtypes. Analysis of variance (ANOVA) was used to determine the significance of differences in individual SF-36 domain scores between CFS subtypes.
    Patients and controls gave written consent according to guidance of the Wandsworth Research Ethics Committee (approval number 05/Q0803/137). For the New York patients,
    approval of the local Institutional Review Board was obtained. The human experimentation guidelines of the US Department of Health and Human Services were followed in this study.

    Determination of differential expression of human genes in each CFS/ME subtype The threshold cycle (Ct) for each test gene in each sample was compared to a calibrator sample to calculate a ?Ct value. ?Ct values were then normalised to the Ct value for an endogenous control gene, lyceraldehyde-3-phosphate dehydrogenase (GAPDH) in respective samples to give the ??Ct values. Relative quantities (RQ) (2-??Ct) of each mRNA of interest were then calculated. Samples showing a difference between minimum and maximum RQ values of =100 (indicating poor replicate concordance) were excluded. The ttest was used to compare RQ values for the CFS/ME patients with those of the controls. Genes whose mean RQ values differed between the groups (at P=0.05) were included in our CFS/ME-associated gene signature.6 RQ values for all 88 CFS/ME-associated genes were
    were normalised and clustered using Genesis software.10

    For each CFS subtype, mean relative quantity (RQ) values were calculated. Then, for each gene, the mean RQ value for each CFS subtype was divided by the mean RQ value of the normal blood donors, to provide fold-difference values for each CFS subtype. For each subtype, genes were included for analysis assuming they showed fold-difference values (mean RQ in CFS subtype / mean RQ in Normal) in QPCR experiments of =1.5. Thus an 5 individual gene list was generated for each CFS subtype within the 88 gene signature for CFS. Mean fold-difference values were clustered using Cluster version 2.11 software (without
    normalization) and visualised using Treeview version 1.60 software.11

    Analysis of gene function and interaction in each CFS/ME subtype

    Each of these subtype-specific gene lists was analysed for gene function and interaction using Ingenuity Pathways Analysis (IPA) software (Ingenuity, Redwood City, CA, USA) in order to link CFS/ME-subtype-associated genes into networks based on recognised interactions, and to discern the top associated diseases and disorders, molecular and cellular functions, associated physiological system development and function and canonical pathways. 6


    Subjects and clinical characterisation Clinical and genomic data from a total of 55 CFS/ME patients fulfilling CDC diagnostic criteria were used for this study. Of these, 19 were male, and 36 were female, with an overall mean age of 41.6 years and a mean duration of disease of 3.2 years. Additional clinical details are provided elsewhere.6 This study included several CFS/ME patients whose disease was severe and necessitated bed rest for much of the day, and patients who were able to attend
    an out-patient clinic. Normal blood donors were used as a comparison group and clinical data for these is available elsewhere.6

    Genomic CFS/ME subtypes.

    AS previously reported, clustering of QPCR data revealed the presence of 7 genomic CFS subtypes with distinct profiles of gene expression within the 88-gene CFS gene signature.6 Fold-difference values (mean RQ in CFS / mean RQ in normal) for all CFS patients and for each CFS subtype are shown in Table 1. For each subtype, genes with fold-difference values of =1.5 were noted and used in further analysis. This resulted in the following numbers of
    differentially-expressed genes in each subtype; 58 (CFS subtype 1), 70 (CFS subtype 2), 48 (CFS subtype 3), 27 (CFS subtype 4), 66 (CFS subtype 5), 69 (CFS subtype 6), 71 (CFS subtype 7), respectively. In table 2, genes without values are those for which there was missing data for particular subtypes.

    Analysis of gene function in each CFS/ME subtype

    Using Ingenuity Pathways Analysis (IPA) software (Ingenuity, Redwood City, CA, USA), the gene list for each CFS subtype was analysed to determine the most important associated diseases and disorders, molecular and cellular functions, associated physiological system development and function and canonical pathways. The results of this analysis are shown in Table 2. As regards disease associations, analysis revealed some common (neurological,
    haematological, cancer) and some distinct (metabolic, endocrine, cardiovascular, immunological, inflammatory) disease associations among the subtypes.

    This was also true for cellular and molecular functions, and physiological system development and function analyses (Table 2). As regards the canonical pathways implicated in each subtype, there was more variation between subtypes than for the previous analyses, probably because these assignments are based on fewer genes per pathway. IL-6 signalling was implicated in subtypes 1, 2, 5, 6; B cell receptor signaling was implicated in subtypes 4, 6; oestrogen receptor signaling was implicated in subtypes 7; ephrin receptor signaling was implicated in subtypes 1, 2 and 7; and insulin receptor signaling was implicated in subtypes 3, 4 and 6 (Table 2).

    Analysis of gene interaction in each CFS/ME subtype

    Gene interaction was assessed for each subtype using IPA software. For each subtype, this analysis generated between 2 and 5 large networks (arbitrarily defined as containing 8 or more CFS-associated genes) based on published gene interactions (data not shown) and a
    variable number of smaller networks and single genes for which interactions were not known. For each subtype, all networks, large and small, were combined into a single network, indicating genes found to be upregulated and downregulated and then stratified to show the
    subcellular location of each (Figure 3, panels A-G).

    Clinical features of each CFS subtype Numbers of patients, mean age and male:female ratio for each subtype were as follows: subtype 1 (2; 27 years; 1:1), subtype 2 (5; 49 years; 4:1), subtype 3 (2; 32 years; 0:2), subtype 4 (19; 44.3 years; 8:11), subtype 5 (7; 51 years; 0:7), subtype 6 (14; 41.1 years; 6:8), subtype 7 (3; 47 years; 0:3). Subtypes 3, 5 and 7 were made up of females only; subtype 2
    was predominantly male and the remainder were mixed; age differences were less clearly demarcated. Mean questionnaire scores for each subtype are shown in Figure 1, panels A and B. Clinical symptom severity for each subtype is shown in Figure 1, panel C. CFS subtypes 1 and 7
    were the most severe, followed sequentially by subtypes 2, 4, 5 and 6 / 3.

    Analysis of variance testing revealed significant differences between groups for the SF36 total score (p = 0.016), social functioning (p = 0.03), and emotional role (p = 0.003), while the difference between groups approached significance for general health (p = 0.08) and mental health (p = 0.08). After adjusting for multiple comparisons significant associations were found between
    specific groups and clinical phenotypes. Subtype 7 had most pain, lowest SF-36 scores (along with subtype 1), most severe individual symptoms including swollen glands, sore throat, headaches, etc; subtype 1 had the worst cognition and mental health score, and poor sleep despite having the least pain; subtype 4 had moderate neurocognitive function and cognitive defects combined with moderate levels of bodily pain and sleep problems; subtype 5 had the best mental health but poor neurocognitive function, gastrointestinal complaints and
    the most marked muscle weakness and postexertional malaise; and subtype 2 had marked postexertional malaise, muscle pain and joint pain but poor mental health (Figure 1, panels A, B, C).

    Summary 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). It is particularly
    interesting that in these genomically derived subtypes, there were 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.

    As regards subtype associations with geographical location, subtypes 4 and 6 were predominant in Dorset; subtype 4 was predominant in London and New York, and subtype 5 was predominant in Bristol (Figure 1, panel D).

    CFS/ME associated genes which are specifically targeted by existing drugs Within the CFS gene signature, there were 5 human genes which are known to be targeted by one or more existing drugs which are designed or intended for use in other diseases. Based on the expression levels of these 5 genes, these drugs may be predicted to be beneficial for particular CFS subtypes. These genes, corresponding drugs and CFS subtypes are as follows: APP (AAB-001; subtypes 1, 2, 3, 4, 5, 6, 7); CXCR4 (JM1300; subtypes 5, 6); FNTA (lonafarnib, tipifarnib; subtypes 1, 2, 3, 5, 6); IL6ST (tocilizumab; subtypes 1, 2, 5, 6, 7); TNF (golimumab, adalimumab, etanercept, certolizumab pegol, infliximab; subtype 2).


    This study follows our paper describing differential expression of 88 human genes in CFS patients6 and its purpose is to expand upon the brief description of the genomic and phenotypic aspects of the CFS subtypes given in this earlier paper. It has long been recognized that subtypes of CFS/ME exist, and it has been believed that
    these subtypes may, at least in part, reflect particular aetiological factors.12 A symptom-based approach has had some success in identifying musculoskeletal, inflammatory and neurological subtypes,13 however, these groups had only minor differences in overall functional severity in contrast to those of the present study.

    It is intriguing that within our 88 gene signature, there are several genes with links to various aetiological triggering factors. For example, virus infection (EIF4G1, EBI2) and organophosphate exposure (Neuropathy Target Esterase (NTE)). EIF4G1 is an eukaryotic translation initiation factor which is bound and cleaved by a range of viruses, including enteroviruses, which both trigger and persistently infect CFS patients.14,15 Whistler and
    colleagues have also reported upregulation of EIF4G1 transcript variant 5 (the same variant as we report) in patients with CFS who have rapid (? triggered by virus infection) as compared with insidious onset.16 EIF4G1 is a component of the protein complex, EIF4F, which is crucial in translation.17 These viruses divert EIF4G1 from its utilisation by the cellular machinery to facilitate production of viral proteins.17 EIF4G1 is upregulated in CFS subtypes 1, 2, 3, 4, 6, 7 (Table 1; Figures 2 & 4, panels A, B, C, D, F, G).

    Various CFS-associated genes identified have previously been shown to be upregulated in EBV infection, namely NFKB1, EGR1, ETS1, GABPA, CREBBP, CXCR4, EBI2, HIF1A,
    JAK1, IL6R, IL7R, PIK3R1. This is very interesting as EBV is a recognized trigger of CFS and is known to reactivate upon stress.18 However, it is difficult to draw conclusions as to the interrelationship of these genes in the different subtypes (Figure 2). The EBV transcription factor BRLF1 was found to be over-represented in the original CFS gene signature, however, this was not tested by PCR.6 The EBV genes, BRLF1 and BZLF1, mediate the switch from latent to lytic phases of EBV infection and during this process they transactivate many human
    genes. It is interesting that the BRLF1 gene was identified as being over-represented in the transcription factor analysis, and that specific IgG to the Zebra protein (BZLF1 gene product) has been reported previously in CFS/ME patients.19 EBI2 is a gene which is upregulated 200-fold in EBV infected cells20 and is upregulated in
    subtypes 2, 3, 5, 6 and 7, but in none of the normal controls.6

    One subject with EBI2 upregulation was a 26 year old female whose CFS had been triggered by laboratorydocumented
    EBV infection and who had a chronic course with detectable EBV replication in blood for several years after the acute phase. This suggests the possibility that EBI2 may be
    a surrogate marker for ongoing EBV replication in CFS patients, although this remains to be clarified. If this is true, then this would be very useful to inform the decision as to which CFS patients should be treated with valganciclovir, which has been shown to be beneficial in

    Three patients had markedly raised levels of NTE, while all normal controls had uniformly low levels; CFS subtypes with significantly raised NTE levels were 1, 2, 5 and 7, of which subtypes 1, 2 and 7 were the most severely affected subtypes. We have previously documented upregulation of NTE in CFS.22 NTE is the primary site of action of organophosphate (OP) compounds, such as sarin, which cause axonal degeneration and paralysis resulting from inactivation of its serine esterase activity23 and in the adult chicken nervous system, OP-modified NTE initiates neurodegeneration. Exposure to OP compounds
    may trigger CFS/ME24 and Gulf War Illness (GWI).25
    IL10RA is a gene which is critical for T cell activation and immune system homeostasis as polymorphisms in it have been shown to be associated with development of lymphoma,
    COPD, autoimmunity, severity of hepatitis C infection, and multiple sclerosis.26-30 In the present study it was upregulated,6 although we have previously found it to be downregulated in CFS patients.22

    There were more subjects in our pilot study19 that were bed-bound than in the present study,6 and IL10RA levels appear to be a marker of severity in CFS (as they are
    closely correlated with SF-36 general health score), with lower levels reflecting increasing severity (data not shown). It is interesting that disease associations identified in the various subtypes are mostly those
    which are already recognised in CFS. However, for any one disease association, there are important variations between the subtypes. For example, for ‘neurological disease’, which applies to all subtypes, the number of genes in this category varies from subtype to subtype
    (Table 2). Assuming differential expression of these genes reflects, at least in part, the pathogenesis of CFS, the gene contribution to each disease association presumably affects the final phenotype and risk of complications, for example, lymphoma.31,32 It is also interesting that these genomically derived subtypes represent distinct clinical syndromes and that those which were most severe were also those suffering from anxiety / depression, as would be
    expected in a disease with a biological basis. Oestrogen receptor signalling is implicated in CFS subtype 7.

    Interestingly, it has previously been reported that CFS patients exhibit a downregulation of oestrogen receptor beta.36,37 Oestrogen is an immunomodulator and has multiple effects on the immune system and on other hormones which can themselves affect the immune response.38
    Following repeat testing, and confirmation of these findings, it will be important to find a means by which we can determine the subtype of individual CFS patients. For the purpose of subtype diagnosis, use of an 88-gene QPCR-derived signature is cumbersome and so it will be important to determine the most predictive genes within this signature, whose up or downregulation reliably predicts subtype-status. Using this approach, and depending on further research, we may then be able to use a shortlist of 10-20 CFS-associated genes to subtype
    individual patients in clinical settings.

    We believe these 88 genes to reflect real biological features of these CFS patients, and this is supported by the fact that differential expression of 16 of these genes has been reported previously by our group.22 If these findings are confirmed, there are various options for clinical trials using existing therapies which have been shown to be safe, based on targetting of key genes in patients of different CFS subtypes, namely, IL6ST, TNF, CXCR4, APP, FNTA.

    Interestingly, one anti-TNF drug (etanercept) has already been trialled using an 8 week regimen in 6 CFS patients with reported clinical benefit in fatigue and pain in all subjects. Although this was not published as a paper, it was presented by Kristin Lamprecht and colleagues from Minnesota at the International Association for CFS (IACFS) Meeting in Seattle in 2001 ( Unfortunately, this was not followed up because the Peterson group moved out of CFS research around this time (Phil Peterson, personal communication).

    In conclusion, we report in detail the genomic and phenotypic differences in 7 genomically defined subtypes of CFS. Further work is required to validate these findings, and this work is underway in our laboratory.10


    We thank Sir Joseph Hotung for funding of the salaries of JK and BB, and CFS Research Foundation, Hertfordshire, UK for generous funding of this project. There are no competinginterests for any author.

    [This Message was Edited on 01/01/2008]
  15. fight4acure

    fight4acure Member

    Death caused by CFS/ME. They tested the spinal cord and found illness present, clear evidence of disease, proving this is not a mental illness.

    Fight4acure! Fight2Educate!
  16. msbsgblue

    msbsgblue Member

    Just bookmarking for my profile and bumping!
  17. fight4acure

    fight4acure Member

    Urinary markers of altered collagen metabolism in fibromyalgia patients.

    Scand J Rheumatol. 2007 Nov-Dec;36(6):470-7.

    Ribel-Madsen S, Christgau S, Gronemann ST, Bartels EM,
    Danneskiold-Samsøe B, Bliddal H.

    The Parker Institute, Department of Rheumatology, Frederiksberg Hospital, Capital Region of Denmark.

    PMID: 18092271

    Objective: To assess the metabolism of collagen in fibromyalgia (FM) patients, and to compare the occurrence of collagen metabolism markers to the severity of FM symptoms.

    Methods: Morning urine was collected from 27 FM women fulfilling the American College of Rheumatology (ACR) criteria for FM, and from seven controls. FM patients completed the Fibromyalgia Impact Questionnaire (FIQ). Bone mineral density (BMD), isokinetic muscle strength in knee and elbow, and hand-grip strength were measured. Urinary concentrations of collagen type I cross-linked C-telopeptide (CTX-I) and collagen type II cross-linked C-telopeptide (CTX-II) were determined by enzyme-linked immunosorbent assay (ELISA). Pyridinoline (Pyd) and deoxypyridinoline (Dpd) were determined by liquid chromatography, and hydroxyproline (Hyp) by spectrophotometry. All concentration data were normalized to creatinine.

    Results: Mean values in the FM group and the control group,
    respectively, were: urinary CTX-I 246.8 and 337.5 microg/mmol (p = 0.060); CTX-II 110.4 and 185.1 ng/mmol (p = 0.035); Pyd 56.1 and 52.3 nmol/mmol (NS); Dpd 15.1 and 14.0 nmol/mmol (NS); Pyd : Dpd ratio 4.05 and 3.96 (NS); Hyp 26.1 and 21.1 micromol/mmol (NS). Significant inverse correlations were seen between CTX-I and the intensity of fatigue, and between CTX-II and anxiety. An inverse correlation between CTX-I and muscle strength was apparent, but relied on extreme values from one patient, and no significant correlation was found between CTX-I or CTX-II and tender points or BMD in the FM group.

    Conclusions: Low urinary concentrations of CTX-II and CTX-I and normal levels of Pyd and Dpd were found in FM, but their relationship to the intensity of FM symptoms was unclear.
  18. fight4acure

    fight4acure Member
  19. fight4acure

    fight4acure Member

    An INTERVIEW with
    Dr. I. Jon Russell

    n the interview below, Special Topics correspondent Myrna Watanabe talks with Dr. I. Jon Russell about his highly cited fibromyalgia research. In our analysis of this field, Dr. Russell’s work ranks at #5, with 26 applicable papers cited a total of 610 times. Three of these papers are included on the lists of the most-cited papers in this field over the past decade and over the past two years.
    Dr. Russell is an associate professor of medicine in the Department of Medicine, Division of Clinical Immunology at the University of Texas Health Science Center in San Antonio. He also is director of the University Clinical Research Center in San Antonio. He trained as a biochemist and earned his Master’s and Ph.D. degrees in biochemistry from University of Nebraska in Lincoln, later attending medical school at Loma Linda University in Loma Linda, California, from which he received his M.D. degree.

    Dr. Russell is an internist with a subspecialty in rheumatology. His research interest is the fibromyalgia syndrome, which he helped to classify, along with his long-time collaborator Dr. Fred Wolfe. Dr. Russell’s background in biochemistry has been helpful in identifying several chemical abnormalities in fibromyalgia. He notes that despite his highly cited papers, as indicated in Essential Science Indicators, fibromyalgia has been a controversial diagnosis.

    His research on fibromyalgia has ranged from early characterization of fibromyalgia syndrome patients, research classification of the condition, its epidemiology, its biochemical pathogenesis, and, more recently, its pharmacological management. Dr. Russell is a consultant to many pharmaceutical and investment companies, including Pfizer, Eli Lilly, Society of Industry Leaders, Shearson-Lehman, and many others.

    Your most-cited paper in the last 10 years, which had been cited 109 times at the time of our analysis, is, "Health status and disease severity in fibromyalgia—Results of a six-center longitudinal study," (Arthritis and Rheumatism 40:1571-9, 1997). Why has this paper been cited so often?

    Fred Wolfe (from the Arthritis Research Center in Wichita, Kansas, and the University of Kansas School of Medicine) was the mastermind of this project, but five other investigators across the country submitted fibromyalgia syndrome patients to be monitored every six months for many years. The essence of this paper was a comparative analysis of a cross-section of fibromyalgia syndrome patients all across the United States using the same assessment instruments for all. It was coupled with a study of national costs associated with the syndrome. Together, these papers have provided the knowledge base upon which national and international decisions could be made regarding how to plan for and deal with this condition.

    Our 1990 paper on the research classification of the fibromyalgia syndrome (Wolfe F, et al., "The American College of Rheumatology 1990 criteria for the classification of fibromyalgia," Arthritis and Rheumatism 33[2]:160-72, 1990) would probably be our most cited work because it provided a uniform framework upon which international research about this condition could be based. This paper allowed investigators around the world to be confident of their fibromyalgia syndrome diagnosis so patients entered into research studies would be uniform. Every research paper that reports an investigation about the fibromyalgia syndrome would be expected to quote this paper.

    Acceptance of the fibromyalgia syndrome by physicians is growing in proportion to the large numbers of published studies that provide objective support for allodynia, central sensitization, neurochemical abnormalities, and well-tolerated, effective therapy.

    Through the years, Fred Wolfe and I have had many papers together. Another important paper in this series reported on the prevalence of the fibromyalgia syndrome in the general population of the United States (Wolfe F, et al., "The prevalence and characteristics of fibromyalgia in the general population." Arthritis and Rheumatism, Volume 38[1]:19-28, 1995). I think this paper has been critical to progress regarding the fibromyalgia syndrome because it paved the way for estimating the magnitude of the problem in the United States and the cost of the disorder to the national economy. With these data it was possible to project the potential benefits to the pharmaceutical industry if companies were to invest in the development of medications with known mechanisms of action that would really improve the quality of patients’ lives. Many exploratory market surveys were conducted during this time.

    Your highly cited papers seem to be moving from description of the syndrome to biochemical mechanisms of the disease and potential drugs to treat the condition. Is this a natural progression of your interest or are there specific reasons for these changes?

    Before we knew how to consistently diagnose the fibromyalgia syndrome, it was impossible to conduct meaningful biochemical research studies. Therefore, I assisted with clinical presentation studies, epidemiology studies, and cost-of-care studies. Whenever time and financial support allowed, I would conduct a biochemical study. In most of those studies, we were fortunate to have chosen directions that were fruitful. Much of this occurred and was published before 1996, prior to the time frame for this Special Topics analysis.

    Together, the classification criteria and the study to determine the prevalence of the disorder in the general population prepared the way for biochemical studies. For several years, I had studied the levels of serotonin and its metabolites in the blood and urine from people with fibromyalgia and normal controls. One day, Fred Wolfe asked, "Why don’t you do serotonin levels on the serum samples that I’ve collected from fibromyalgia syndrome patients?" (Wolfe F, et al., "Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. Journal of Rheumatology 24[3]:555-9, 1997).

    Our transition to the study of spinal fluids is an interesting story. I proposed to our Institutional Review Board that I draw spinal fluid from fibromyalgia syndrome and healthy normal controls to examine the levels of selected neurochemicals known to be involved in the process of nociception. The answer was no. The explanation was that it is inappropriate to perform a test with potential adverse effects on patients who have nothing wrong with them.

    I changed my approach and wrote to a friend, Dr. Henning Vaerøy in Norway, who had already done a study of spinal fluid substance P in fibromyalgia syndrome. I proposed that he come on a speaking tour to San Antonio but his "ticket" was to be an aliquot of each of his spinal fluids that we could analyze in our laboratory. The resultant study was successful in documenting low levels of biogenic amines in people with the fibromyalgia syndrome (Russell IJ, et al., "Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis," Arthritis and Rheumatism 35[5]:550-6, 1992). With that finding in hand, I again approached the Institutional Review Board, and this time, they approved both a spinal fluid collection and a sample bank for the long-term storage of samples collected from fibromyalgia syndrome patients and appropriate controls.

    Back in about 1994, our San Antonio group published our second paper on examination of spinal fluid in fibromyalgia syndrome (Russell IJ, et al., "Elevated cerebrospinal fluid levels of substance P in patients with fibromyalgia syndrome," Arthritis and Rheumatism 37[11]:1593-1601, 1994). We confirmed and expanded upon the earlier finding by Vaerøy that spinal fluid substance P levels are dramatically elevated in people with the fibromyalgia syndrome. This finding has now been confirmed by two other research groups studying three different ethnic groups.

    So then, our question was, "Why do we have elevated substance P levels in the spinal fluid of fibromyalgia syndrome patients?" I recruited a world-class neuroscientist, Dr. Alice Larson, from the veterinary school in Saint Paul, Minnesota. We talked about this problem of how substance P was produced and she proposed that nerve growth factor might be responsible. I sent her spinal fluids, and Dr. Susan Giovengo, who was working in Dr. Larson’s laboratory, assayed them for nerve growth factor. We already knew that substance P levels were high in patients with primary fibromyalgia syndrome, but were numerically less so in secondary fibromyalgia syndrome when it was associated with rheumatoid arthritis. Dr. Giovengo’s assay of nerve growth factor demonstrated that it was very high in people with primary fibromyalgia syndrome but was not elevated in those with secondary fibromyalgia syndrome (Giovengo SL, Russell IJ, Larson AA, "Increased concentrations of nerve growth factor (NGF) in cerebrospinal fluid of patients with fibromyalgia," J. Rheumatol. 26[7]:1564-9, 1999).

    The next step was to ask about the excitatory amino acids, such as glutamate and aspartate, which are released in the dorsal horn of the spinal cord in the process of afferent pronociception. Again it was Dr. Alice Larson who did the measurements on our San Antonio spinal fluids (Larson AA, et al., "Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways," Pain 87[2]:201-11, 2000). The result was that the levels in the fibromyalgia syndrome spinal fluids were not significantly different from normal controls but that there were intercorrelations between neurochemicals that suggested an active pain process in the patients with fibromyalgia.

    Together, these findings set the stage for interpretation of the fibromyalgia syndrome as an objective disorder in which the patients’ perception of pain and allodynia appeared to be correct.

    Probably the next most important piece of information comes from our more recent directions. In collaboration with several other centers under funding from the National Institutes of Health, we explored the genetic basis of the fibromyalgia syndrome among people in families who had at least two affected immediate family members. There were two chromosomal loci that related highly [Lod score] with two separate subgroups of fibromyalgia syndrome patients (Iyengar SK, et al., "Genetic linkage of fibromyalgia syndrome to the serotonin receptor 2A region on chromosome 13 and the HLA region on chromosome 6," Submitted to Genes and Immunity, in review, 2005). A full genome scan is underway using the samples from this study.

    Is there any one study, paper, or group of related papers you have written or co-authored that you believe have been most influential in your field? If so, which?

    I think the aforementioned substance P paper was probably the most influential, but it probably should have been paralleled by the one on biogenic amines in the spinal fluid of fibromyalgia syndrome patients.

    Were there problems in convincing your colleagues that fibromyalgia was a real condition?

    Over the past 10 years, people have been "discovering" the fibromyalgia syndrome. Suddenly, drug companies, insurance companies, government agencies, and a variety of investigators have been concluding that fibromyalgia is here to stay and that it can be very expensive. It was then that the fibromyalgia syndrome acquired a very powerful foe, the insurance industry in the United States and Canada, who were loath to pay for claims of injuries sustained during falls or motor vehicle accidents that seemed to be temporally related to the onset of the fibromyalgia syndrome symptoms.

    Some of our medical colleagues are also hesitant to espouse the disorder, but that is changing. Acceptance of the fibromyalgia syndrome by physicians is growing in proportion to the large numbers of published studies that provide objective support for allodynia, central sensitization, neurochemical abnormalities, and well-tolerated, effective therapy.

    What other contributions have you made to the field?

    Considering all of this, I felt that the important contribution for me to offer was to find objective evidence from the laboratory that the fibromyalgia syndrome is a biologic disorder. That has been the impetus for many of our other papers. It is gratifying, therefore, to observe that many of the medicinal agents that have proven beneficial for managing the symptoms are known to fix abnormalities that we have described. For these reasons, I have also felt good about my efforts to assist the pharmaceutical industry in studying promising new medications. It is satisfying to administer a medication that has a known mechanism of action that would be predicted to help the fibromyalgia syndrome symptoms and see the benefit come to life.

    For example, the drug tramadol (Ultram) was the first neurochemical therapeutic agent to achieve a statistic of p=0.001 for the management of pain in the fibromyalgia syndrome. I was pleased to lead the research team in writing the manuscript for that study (Russell IJ, et al., "Efficacy of tramadol in treatment of fibromyalgia," J. Clin. Rheumatol. 6[5]:250-7, 2000).

    Over a period of about seven years, I worked on clinical studies to test the anticonvulsant drug pregabalin (eventually released as Lyrica), and helped to author the first published manuscript on this topic (Crofford LJ, et al., "Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial," Arthritis Rheum. 52[4]:1264-73, 2005).

    I also worked for about three years on another worthy agent, duloxetine (Cymbalta), which is the first real member of the serotonin-norepinephrine reuptake inhibitors. I predict that there will be others in this class before long. (I was an investigator, but not an author, on the key publications.)

    Another agent that I have been pleased to study has been sodium oxybate, which I class as a strong sedative and inducer of restorative sleep. I am helping to prepare the manuscript for that agent’s debut in the field of fibromyalgia syndrome studies (Russell IJ, Perkins T, Michalek JE, Xyrem® for Fibromyalgia Syndrome Research Group, "Sodium oxybate [Xyrem®] relieves pain and improves sleep in patients with the fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multi-center clinical trial," in preparation).

    What I want to portray here is this: even though I think of myself as a biochemist with clinical training, the clinical studies were critical. They helped to prepare the way to finding biochemical mechanisms for which medications could be developed to help the patients.

    What else are you involved in?

    I felt that it was important for us to develop an educational program for patients and physicians. We started with what we called the "Primer for Fibromyalgia." It was a six-page brochure explaining the syndrome and listing other resources. We gave it away free to anyone who requested it. The Arthritis Foundation listed our "Primer" among its approved resources for fibromyalgia syndrome patients. We were printing about 1,000 copies of the "Primer" per quarter for at least three years. Since there was no specific funding for that effort, it got so we could no longer afford to support it.

    I then helped to write a book for a lay audience that was published and has sold over 150,000 copies (Fransen J, Russell IJ, The Fibromyalgia Help Book: Practical Guide to Living Better with Fibromyalgia, St. Paul, MN: Smith House Press, 1996).

    With funding from the RGK Foundation of Austin, Texas, we produced a Nova-like video production to educate patients and help clinicians and patients understand the disorder better. Between 3,000 and 4,000 copies of that video were distributed to patients and support groups.

    Then there was the issue that physicians wanted to learn about the fibromyalgia syndrome. In 1993, I started a journal for physicians who are interested in this field, the Journal of Musculoskeletal Pain, for which I continue to serve as the editor. The journal is now finishing its 15th year of continuous publication.

    We worked with others of like interests to start a series of meetings that were eventually named MYOPAIN. In 1995, we started the International MYOPAIN Society. I helped develop the bylaws and served as its first president. The organization has now grown to over 700 members in about 40 countries and has an international meeting every three years, alternating between the U.S. and a European country. That, I think, is quite a successful effort because physicians who were involved in this field felt they were isolated, and this society has given them a way to maintain their social and academic ties with active research in the field.

    What are you working on now?

    We just submitted a paper—Kuan TS, et al., "Discrimination of fibromyalgia patients from normal controls using the levels of cerebrospinal chemicals," (submitted to Pain, 2006)—in which we show that we can identify spinal fluid from people with the fibromyalgia syndrome based on three biochemical tests for substance P, nerve growth factor, and 5-hydroxyindole acetic acid. When we plug the concentrations of the three neurochemicals into a formula we developed, it distinguishes fibromyalgia syndrome spinal fluid from that of healthy normal controls with an accuracy of 90%.

    This year, we presented an abstract at the American Pain Society which reports that there is a G protein-coupled receptor that is dysfunctional in fibromyalgia. The interesting thing about this was that this measurement was made on peripheral blood lymphocytes. The most important impact should have been on the central nervous system, but it seems to have affected all the cells of the body. There is a dysfunctional G protein complex on the surface of cells, and that could be an important reason why fibromyalgia syndrome patients have so many symptoms.

    Is there anything about your papers or your career that you think would be important for our readers?

    The concept that I would most want to get across is that all of my efforts in this regard have been intended to provide a variety of kinds of support for fibromyalgia syndrome patients and to educate physicians so they are better prepared to help the patients.

    Since 1982, I have lectured about the fibromyalgia syndrome to physicians at least once in nearly every state of the union and at least once in 15 countries. I’ve given about 300 continuing medical education lectures to physicians and patient groups with the goal of providing information resources about the disorder. With regard to the patients, these lectures have helped them to regain confidence in themselves. When patients are repeatedly told that there is nothing wrong with them, they begin to doubt themselves. The information provided in the lectures about objective abnormalities documented in the fibromyalgia syndrome give them support for their own psyches.

    Back in the 1980s, at the American College of Rheumatology national meetings, there were only five or six of us meeting together each year to talk about the fibromyalgia syndrome. Sometimes, our wives came along to fill a few more chairs. There are lots of good advocates now. In 1990, we were fortunate to come up with 20 people who believed enough in the fibromyalgia syndrome to participate in the criteria study. If you look at the number of publications on fibromyalgia, there were about 15 a year until 1990, when the American College of Rheumatology criteria paper was published. Thereafter, the number of papers went up to about 120 a year, and has stayed at that level or higher ever since. Based on the temporal relationship of the criteria to change in publications, I would conclude either that the 1990 ACR classification criteria paper was a critical publication, or that a critical time was reached, or both.

    I have been grateful in the last five years to be invited to write the fibromyalgia syndrome chapters in both of the world’s main textbooks of pain (Loeser JD, et al., Bonica's Management of Pain, 3rd edit., Philadelphia: Lippincott Williams & Wilkins, 2001 and McMahon S, Koltzenburg M, Wall and Melzack’s Textbook of Pain, 5th edit., Oxford: Churchill Livingstone, 2005). In addition, I was asked by David Simons, M.D., who bears the legacy of Janet Travell, M.D., in advocating for the myofascial pain syndrome, to write a fibromyalgia syndrome chapter in his Trigger Point Manual and in another book called Muscle Pain with David Simons, M.D., and Sigfried Mense, M.D., Ph.D., in each case to facilitate having the reader make comparisons with the myofascial pain syndrome.

    It is clear now that the movement to recognize, research, and manage the fibromyalgia syndrome is well grounded and will continue to progress with many young people taking the lead from those of us who now have limited time to contribute.

    I. Jon Russell, Ph.D., M.D.
    University of Texas Health Science Center
    San Antonio, TX, USA

  20. fight4acure

    fight4acure Member

    posted originally by joynoel:

    Valcyte (valganciclovir) and CFS
    Use of valganciclovir (Valcyte) in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. Journal of Clinical Virology 2006;37:S33-38

    Montoya et al at Stanford University treated chronic fatigue syndrome patients with 6 months of valganciclovir (Valcyte) if they had elevated IgG tests for HHV-6 and EBV and had at least 4 of the following symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression. Nine of the twelve treated patients (75%) “experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activities.” In the nine patients with a symptomatic response to treatment, EBV VCA IgG and HHV-6 IgG titers significantly declined.

    This is not a new finding, as previous studies as far back as 1997 have demonstrated significant improvement with similar antivirals.1,2,3 This study has, however, been much more publicized. We have been using Valcyte in our center for the treatment of chronic fatigue syndrome for over 4 years and have found it to be effective, especially in patients with the flowing: flu-like symptoms or having symptoms that started with a flu-like illness; elevated IgG or EA against Epstein bar virus, cytomegalovirus and/or HHV-6; low natural killer cell activity; high RNAse-L activity; high ACE (>35); coagulation activation; high tumor necrosis factor (TNF); low melanocyte stimulation hormone (MSH); high interleukin-6 (IL-6); low WBC; increased 1-25 vitamin D/25 vitamin D ratio and/or elevated or decreased total IgA, IgM or IgG levels.

    This study contributes more confirmatory evidence that IgM antibodies are not typically elevated in chronic reactivating infections so most patients are incorrectly told they do not have an active infection based on such testing. High IgG levels are diagnostic for an active infection in these patients, which is not what is taught in medical school and contrary to the belief of most physicians, including infectious disease specialists. This study also demonstrated the lack of sensitivity of standard PCR testing.

    1. Lerner AM, Zervos M and Dworkin HJ et al. New cardiomyopathy: A pilot study of intravenous ganciclovir in a subset of the chronic fatigue syndrome. Infectious Diseases In Clinical Practice 1997;6:110-117.

    2. Lerner AM, Zervos M and Chang CH et al. A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome. Clinical Infectious Diseases. 2001;32:1657-58.

    3. Lerner AM, Beqaj SH, and Deeter RG et al. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs of Today. 2002;38:549-561.