(AACFS Seventh International Conference Madison, Wisconsin, October 8-10, 2004)
WHAT IS GLUTATHIONE? [Refs. 1--5]
• A tripeptide composed of the amino acids glutamic acid,
cysteine, and glycine. Its molecular weight is 307.33 Da.
• Found in all cells in the body, in the bile, in the
epithelial lining fluid of the lungs, and, at much smaller
concentrations, in the blood.
• The predominant nonprotein thiol (molecule containing an S-H
or sulfhydryl group) in cells.
• Its active form is the chemically reduced form, called “GSH.”
• GSH is compartmentalized, with concentrations ranging from
0.5 to 10 millimolar in various organs and cell types.
• GSH serves as a substrate for enzymes, including the
glutathione peroxidases and the glutathione-S-transferases.
• When oxidized, two glutathione molecules join together via a
disulfide bond to form “oxidized glutathione,” or “glutathione
disulfide,” referred to as “GSSG.”
• Inside cells, the concentration of GSSG is normally
maintained at less than 1% of total glutathione by the enzyme
glutathione reductase, which is powered by NADPH, produced by the
pentose phosphate shunt, part of carbohydrate metabolism.
WHAT ARE SOME OF THE FUNCTIONS OF GLUTATHIONE (GSH)? [Refs. 1--5]
• Maintains proper oxidation-reduction (redox) potential
inside cells. Redox affects the oxidation state of sulfur in
enzymes, and thus affects the rates of biochemical reactions in
cells.
• Scavenges peroxides and oxidizing free radicals directly and
also serves as the basis for the antioxidant network.
• Performs Phase II detoxication of heavy metals (such as
mercury), organophosphate pesticides, chlorinated hydrocarbon
solvents, estradiol, prostaglandins, leukotrienes, acetaminophen,
and other foreign and endogenous toxins.
• Stores and transports cysteine throughout the body.
• Transports amino acids into cells, especially cystine into
kidney cells.
• Regulates the cell cycle, DNA and protein synthesis and
proteolysis, and gene _expression.
• Regulates signal transduction.
• Participates in bile production.
• Protects thyroid cells from self-generated hydrogen peroxide.
By means of several of the above functions, GSH plays very important
roles in (1) maintaining mitochondrial function and integrity, (2)
regulating cell proliferation, and (3) supporting the immune
system.
James - August 25th, 2008
This article is excerpted with permission from Dr. Mark J. Pellegrino’s highly praised book, Fibromyalgia: Up Close and Personal.
Dr. Pellegrino, an international leader in FM treatment and himself an FM patient since childhood.
Article at ProHealth
James - August 20th, 2008
Our next meeting will be held on the coming Monday August 11, from 12:30 to 2;30pm, at our usual venue, a meeting room off the hall behind St Judes Church, Freyberg Street, Lyall Bay.
This will be a “between ourselves” meeting, when we can catch up on each other’s news, welcome new members or visitors and raise any topics we would like to discuss.
James - August 7th, 2008
The ME Association is pleased to announce that we have been informed by the Royal College of General Practitioners (RCGP) that they will now remove their classification of CFS as a mental health disorder.
James - July 24th, 2008
Cognitive behaviour therapy is effective in treating the symptoms of chronic fatigue syndrome, according to a recent systematic review carried out by Cochrane Researchers.
The researchers looked at data from 15 studies involving a total of 1,043 patients with CFS. The studies compared the effects of CBT with those of usual care and other psychological therapies and suggest that in both cases CBT is more effective at reducing the severity of symptoms, provided patients persist with treatment.
James - July 19th, 2008
The July issue of the Journal of Midwifery & Women’s Health offers an outstanding guide for female ME/CFS patients and their healthcare teams – on pregnancy-related issues from preconception to postpartum support (“Chronic Fatigue Syndrome: Implications for Women and their Health Care Providers During the Childbearing Years”). More broadly, though, the guide is prefaced on perhaps the most complete and up-to-date summary of the science on chronic fatigue syndrome (ME/CFS) offered to date.
James - July 16th, 2008
Sleep problems are one of the cardinal symptoms of ME/CFS (and fibromyalgia), and if you’ve been “tired but wired” one too many nights, I strongly recommend a smart, eye-opening new book, Insomniac, by Gayle Greene.
James - July 16th, 2008
The question as to whether fibromyalgia and ME/CFS (’chronic fatigue syndrome’) are the same illness, closely related illnesses, or completely different illnesses has been debated by physicians and scientists for many years.
Some feel FM and ME/CFS are different facets of the same illness, while others believe they are distinct disorders that share several common symptoms. To further complicate the situation, 70 percent of people who have been diagnosed with one are also diagnosed with the other.
A new paradigm put forth several years ago by Muhammad B. Yunus, MD, suggests that FM and ME/CFS, along with a number of other conditions like irritable bowel syndrome, migraines, and multiple chemical sensitivities, are part of a larger group he terms “Central Sensitivity Syndromes.” The uniting factor that all of these illnesses have in common is central sensitization – an exaggerated response of the central nervous system to stimuli.
James - July 16th, 2008
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.
James - July 10th, 2008
On 6/5/08 I attended the International conference on ME/CFS Biomedical Research at Hinxton, Cambridge, UK. 130 people attended and cutting edge research was presented from around the globe. The conference was sponsored jointly by ME Research UK and the Irish ME Trust. Sadly, Vance Spence, who had organised the conference and was going to give an introductory overview, was too ill to attend.
The conference was formally opened by one of the Patrons, Roger Jefcoate, CBE, and he described ME Research UK as a world leader in Biomedical Research in ME/CFS, which presented a signal of hope for sufferers and those taking care of them.
The first presentation was given by Prof Nancy Klimas (Florida, USA) with an overview on behalf of Vance Spence, followed by her own presentation reviewing the clinical aspects of ME/CFS. She explained how we needed to get away from clinical case definitions towards biomedical subgrouping. She described the Canadian definition as more clinical by including autonomic, neuroendocrine and immune dysfunction. She feels the most important symptom of all is post-exertional relapse. She stressed the importance now of having a paediatric case definition. Children can have a diagnosis made after 3 months of illness. Various other symptoms are included, such as rhythm disturbances of sleep as well as non restoration, more widespread and migratory pain, and the inclusion of 2 or more neurocognitive manifestations, and inclusion of symptoms of an autonomic, neuroendocrine or immunological nature.
A number of overlapping conditions such as Fibromyalgia, Gulf War Syndrome and Multiple Chemical Sensitivity were also mentioned..
Epidemiologically, this illness in the USA has an incidence of 522 per 100,000 females and 291 per 100,000 males. This leads to a 50% reduction in household income, and a 9$ billion US loss in productivity. There are probably 1,000,000 sufferers in the USA of an illness which can be as severe as congestive heart failure. In the UK, 44% of physicians lack confidence in making the diagnosis and those that do make the diagnosis more readily usually have had a family member with the illness.
The pathogenesis involves a combination of genetic susceptibility coupled with a trigger event and/or infection, whence mediators (immune, endocrine, neuroendocrine, psychological) lead to a health outcome and persistence. A slide then showed the interaction between the various body systems implicated, to explain the many and varied symptoms. The length of the illness tends to lead to an overlap and change in symptoms over time, one area affecting another.
In this illness there is an immune cascade leading to chronic immune activation, with a shift from Th1 to Th2 dominance. The immune activation leads to functional defects. The level of severity depends on the pro-inflammatory cytokines.
Viral persistence and reactivation was discussed with references to studies on HHV6, Enterovirus and EBV. In HHV6 studies, 79% of patients were found to have HHV6 activity (compared to 22-54% of controls) and 28 out of 144 were found to have HHV6 in the spinal fluid, and 7 out of 35 in another group. Clearing the spinal fluid led to great improvement in 5 out of 8 people, but the antiviral agents used are potent and toxic. Enterovirus was found in 13% of muscle biopsies and in 60% of gastric biopsies in those with gastric symptoms. In EBV the dUTPase is seen as an immune modulator up-regulating the cytokines.
Endocrinologically, there is reduced cortisol output due to various mechanisms, such as heightened negative feedback, heightened receptor function and impaired ACTH and cortisol responses to challenge. There is a possibility of DHEA abnormality.
There are many symptoms of autonomic dysfunction. These occur as a result of parasympathetic dysfunction with sympathetic overactivation. Neurally mediated hypotension, orthostatic hypotension, slow gastric emptying, heart rate variability, haemodynamic instability (shown on tilt table), decline in cognitive function after treadmill, abnormal perfusion in cerebellum, reduced perfusion in mid cerebral region, and a drop in BP causing relapse are among the many effects.
In the central nervous system, tryptophan abnormalities in the cerebrospinal fluid result from abnormalities in levels of serotonin and its precursors. PET scans have shown that 5HTP binding is reduced. There is pronounced reduction of serotonic transporters in the anterior cingulate. Reduction of grey matter in the more severely affected is evident. There is utilization of more extensive regions of the brain to process tasks than normal. This has been shown using fMRI and mPASAT. It has been shown that “practice makes perfect” and it is in fact possible to rewire the brain.
Sleep is usually abnormal with intrusion of alpha waves, altered hormonal releases and lowering of NK cell count. There is also a decrease in exercise induced pain threshold.
Gene studies are very exciting. 35 genes have been differentially expressed, which relate to T cell activation, and neuronal and mitochondrial regulatory abnormalities. Up to 6 subgroups have been identified. ME/CFS is a complex illness and the subgroups must be further defined.
Many treatments were discussed:
Immunomodulatory: Ampligen
Isoprinosine,thalidomide,antiTNFα, monoclonal antibodies.
Autologous lymphocyte study
Antimicrobial: Antivirals such as foscanet, valganciclovir
Endocrine: Florinef (failed when used alone)
Erythropoietin (very modest benefit)
Autonomic: Beta-blockers to regulate the pump
HPA drugs (not particularly useful)
Sleep: Sleep routine
Tricyclics
Sodium oxybate (must have sleep study to eliminate apnoea)
Pregabilin
Melatonin (mixed results)
Cell metabolism
CNS directed medication
Nutrition: CoQ10. αlipoic acid, NADH etc
Reconditioning: Short 5 minute spells of upright exercise, followed by 5 minutes of flat flexibility work can be more manageable
Exercises to increase flexibility and muscle bulk should be encouraged.
Studies of gene expression using micro-array techniques will help direct us to which drugs will be suitable for which sub group, with the eventual aim being a preventative approach. Quality of life is improved with a multidisciplinary approach and compassionate care.
Dr Jo Nijs (Brussels) then gave an overview of intracellular immune dysfunction in ME/CFS. He described dysregulation of intracellular immunity and upregulation of the RNaseL pathway (due to proteolytic cleavage of native RNaseL), and immune cell apoptosis. The virus in a cell leads to release of interferon, with change in the activity of the host cell, affecting the enzymes, (PKR, RNaseL). Apoptotic neutrophils are increased, leading to cell suicide, which is overactive in ME/CFS. TNFα receptors are increased, RNaseL cleavage is equivalent to caspase activity and there is G-actin cleavage. There is an interplay between NK cells and infections. Conflicting data of the functioning of the PKR enzyme in the blood cells may reflect stages of the illness or distinct subgroups.
The clinical importance of this is a reduction in quality of life and a reduction in exercise capacity, both of which are affected by intracellular activity. Elastase over- activity maybe an important consideration and neutrophil elastase inhibitors may prove useful, as elastase may only be important and needed when the body is fighting massive infection. Drug trials are needed in combination with exercise intervention, as drugs may diminish the side effects of exercise intervention, leading to improved effectiveness. Drugs to fight exercise-induced oxidative stress and subsequent post-exertional malaise may prove useful. Drugs targeting the 2.5A synthetase/RNaseL pathway in combination with careful exercise intervention may also be of future interest.
Dr Gregor Purdie (Scotland) as a GP advisor to the NHS, looked at the development of clinical services for those with ME/CFS. He stressed that knowledge comes from patient contact. There has been some positive progress this year. There is still a great need for clinical services, education and training. Research should be supported and translated into clinical tools. We need to ask ourselves who is to do this, when and how? In the current “pyramid of care”, with primary care at the bottom and specialist tertiary care at the top, most effort is currently seen at the bottom rung, with much of the work being done by voluntary organizations. Work needs to be done at all levels: local, regional, national and international. The personnel involved should include a multidisciplinary approach with specialist consultants, GPs, nurses, physios, OTs etc. All have a niche role and the eventual aim should be for specialist Centres of Excellence for this perplexing and difficult illness.
Dr Byron Hyde (Ottawa, Canada) looked at various patient-centred research and clinical aspects and presented his view that ME and CFS are not the same thing. He described ME as resulting from chronic brain injury, usually as a result of infection, often during an epidemic. The injury is measurable and most often in the limbic area. He demonstrated with a number of brain scans.
The long viral phase of herpes and EBV has been studied and he feels these are not likely to be the primary cause of the illness. Echo viruses maybe more important. Echo viruses have been recovered in some patients up to 3 years after falling ill. In another study in 2008, he found that Hepatitis B vaccination led to 22% of cases of ME. Mention was made of the high incidence of enteroviruses in China now. In another study, he found that mercury, lead, zinc, copper and aluminium were elevated in 11 out of 53 patients.
Generally patients suffered poor sleep, which led to poor short term memory and inadequate production of human growth hormone. Only 1 out of 53 of patients had a normal sleep pattern with resultant normal brain scan. Brain oxygen saturation was generally low at 88% or less.
He concluded with a case study of an Olympic athlete who seemed to have classical ME, and was eventually found to have a tumour in the atrium. He used this as an illustration of the importance of thorough investigation.
Dr Derek Englander (New York) looked at treatments targeting the methylation cycle. The methylation cycle is complex and a part of general metabolism. He presented a most complicated slide to demonstrate to us just how complex is the biochemistry associated with this illness. His team has developed a protocol over the past 15 years after treating 800 patients, 65% of whom have benefitted. Initially weekly IM injections of kutapressin were used. It was subsequently theorized that there was a defect in the methylation cycle, which maybe due to a genome defect. A wider protocol has now been developed using glutathione, B vitamins, zinc, magnesium, and a number of amino acids.
Dr Gavin Spickett (Newcastle upon Tyne) discussed the care pathways adopted in clinical practice in the North of England. This is based on medical assessment and therapeutic intervention. The NICE guidelines are used for referral, but there is no preferred treatment model, which is to be regularly reviewed. The diagnosis is one of exclusion, looking at other causes of fatigue, such as infection, connective tissue disease, auto-immune disease, sleep problems and organic brain disease. There is overlap with IBS, POTS, FM, overtraining etc. Everything is being stored on a database. Medically experienced physicians are needed as are specific treatment protocols. There is a referral pathway for GPs and there is encouragement to refer children early (at 6 weeks). Pre-screening blood tests are recommended to eliminate other causes, such as coeliac disease, which has been found to be common. Despite this, 17% patients are still found to have other conditions. Older, retired patients need more intensive investigation looking for other conditions.
To increase awareness a number of GP training days were set up and there was no uptake initially, but now these are heavily subscribed.
Of note, 57% of patients relapsed with graded exercise.
Dr Julia Newton (Newcastle) discussed clinical studies focusing on autonomic issues, with particular reference to heart rate and BP regulation. Autonomic dysfunction is strongly associated with fatigue in many ME/CFS patients. There is a problem of synchronicity between the sympathetic and parasympathetic systems. 90% ME/CFS patients have Orthostatic Intolerance (OI). The higher the OI score, the greater is the fatigue. 52% patients experience a drop in BP on tilt table. MRI scans have shown that there is impaired proton removal from muscle during exercise in patients, so it is hypothesized that the fatigue arises due to impaired pH run-off from muscle during exercise., which maybe influenced by the autonomic dysfunction. Research is now focusing on how to help patients reset the parasympathetic/sympathetic balance.
Annette Whittemore, (Nevada,USA) who is president of the Whittemore-Petersen Institute for Neuro-immune Disease was unable to be present, so her address was given on her behalf by Dr Dan Petersen (Nevada). This exciting development is to be a centre of excellence comprising 80,000 sq ft at a cost of 78million$US. It will be a comprehensive patient-friendly research facility devoted to patients with neuro-immune diseases such as ME/CFS, FM, atypical MS and other similar presenting illnesses. Location is within the Centre for Molecular Medicine, University of Nevada. Research is already being established and currently looking for bio-immune markers which could lead to more effective treatments , and also looking at those ME/CFS patients who go on to develop cancer.
Dr Dan Petersen then gave an overview of the current research taking place in Nevada. He began by telling us that in the US 10% of the patients consume 70% of the healthcare dollars, and chronic disease diagnosis and management accounts for a significant proportion. Patient-centred, cost effective approaches are being designed and implemented.
Oxidative impairment is evident in ME/CFS and there is a need to demonstrate this to insurers. Exercise tolerance testing with expired gas exchange is widely recommended, but paired tests are needed as performance is significantly decreased on the second test over a 2-day interval. Other research to be furthered will be identifying subsets, looking at the role of viruses in the development of neoplasia in chronically affected patients, looking at bone marrow as a reservoir for HHV6 as PBMCs rarely show HHV6, and collaborative studies utilizing viral array to identify potential patients who may be amenable to specific antiviral therapy will be undertaken.
One study presented analysed cytokines and chemokines in a controlled trial and found chemokines dramatically high with Th1/Th2 dysregulation. These patterns may prove useful diagnostically and potentially therapeutically. The specialized field of Informantics is being utilized to analyse and manage complex inter-relationships involving multiple variables longitudinally.
Vascular and inflammatory aspects of ME/CFS were presented by Dr Faisel Khan (Dundee). There is increasing evidence that ME/CFS patients have associated cardiovascular symptoms. Endothelial function is an important regulator of vascular function and a well established marker of cardiovascular events. ME/CFS patients have significantly enhanced vascular responses to acetylcholine (ACh) compared with control subjects. This may be a consequence of 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.
Arterial stiffness is also significantly elevated in ME/CFS compared to controls, and this is associated with elevation of CRP, pointing to low grade inflammation and oxidative stress. All this may result in unfavourable haemodynamics and increased risks of cardiovascular events in ME/CFS patients. Increased arterial stiffness and inflammation maybe regulated by levels of Vitamin D. Other risk factors for ME/CFS patients may be a tendency to lower HDL cholesterol and higher LDL.
Isoprostane is a marker for oxidative stress, and in ME/CFS this goes up with exercise intolerance. Oxidative stress can lead to endothelial damage.
Dr Jonathon Kerr (London) gave a review of the molecular studies in ME/CFS at his centre. 88 genes have been identified of which only 3 were down-regulated – the others were all up-regulated. The highly represented functions were haematological disease and function, immunological disease and function, cancer, cell death, immune response and infection. 13 transcription factors were over-represented. Data from ME/CFS patients revealed 7 subtypes with distinct differences in SF-36 scores, clinical phenotypes and severity. 12 genes have been linked with EBV. It is now important to determine what these subtypes represent as they appear to be biologically meaningful. Possibilities for treatment with 5 potential drugs to target these genes should provide rationale for treatment. The study needs to be confirmed and replicated, and specificity of the genes needs to be tested. Eventual diagnostic test subtyping should be possible.
Prof Birgitta Evengard presented her team’s work with the Swedish Twin registry looking for a biomarker. 31.406 individual twins, comprising 12,407 complete pairs, responded to a telephone interview and 1 in 5 claimed to be tired. 2.36% had fatigue with symptoms suggestive of CFS of at least 6 months duration. 33 pairs of monozygotic twins discordant for CFS were identified. 1779 individual twins were identified for ongoing study. There was no sex difference in symptoms, but the females had more severe symptoms. There was no association with age, education or occupation. The mean number of symptoms was 2.4. The commonest symptoms were sleep difficulties, cognitive impairment, myalgia and joint pain.
Estrogen may be the key regulator. It is a regulator of growth and differentiation in the reproductive tract, breasts, CNS` and skeletal system. Alpha and beta Estrogen (ERα and ERβ) receptors are implicated in several diseases. There was reduced expression of ERβ in patients consistent with immune mediated pathogenesis in CFS. There was also HPA axis disturbance, immune dysfunction (with abnormal cytokine dynamics), abnormal blood/brain communication and a background of infection. 75% improved with valganciclovir. Genes were identified in 20 of the women and 2 more viruses were detected (orphan viruses).
Q fever, Rickettsia and CFS was the topic discussed by Dr Stephen Graves (NSW, Australia). Rickettsia are gram negative bacteria transmitted by arthropod vector. They were named after Ricketts the microbiologist, and are nothing to do with rickets due to malnutrition. Patients respond in different ways:
Death
Infection, then recovery
Auto-immune illness
Chronic Fatigue Syndrome.(10-20%)
Illness due to Rickettsia honei and Q fever caused by Coxiella burnetii both have similar sequelae.
CFS is largely a post-infectious condition, and Q fever and Rickettsia can be precipitants. The microbial antigen may persist. These bacteria have an intracellular lifestyle. Post Q fever the microbial antigen persists in the bone marrow and PBMCs. The microbe C,burnetii is not viable because a cell mediated response has killed it, but it may persist as undegraded cells with some DNA. The antigen is only found in the more virulent form. The persistence of the microbial antigen appears to cause dysregulation of the cytokine cascade leading to ongoing fatigue in a genetically predisposed subpopulation. The relevance of this could mean that Q` fever vaccination could have a positive impact on the incidence of CFS in Australia.
As always when a conference ends, there is a sense of sadness saying goodbye to old friends again, but innevitably a great sense of excitement and hope at the progress and new ideas. Thank you to Vance Spence and Neil Abbott, and their Irish counterparts for the brilliant organization of this wonderful event, which I felt privileged to attend in such a lovely English setting. And, many thanks also to ANZMES for enabling me to participate.
Rosamund Vallings MNZM, MB BS
James - July 9th, 2008
Individuals views expressed in Brainstorm (The Web Site) do not necessarily reflect those of the Wellington ME/CFS Support Group.
Any information provided is not intended for use as, or to replace professional medical/diagnostic advice. If you have medical issues you should consult a physician.
Brainstorm (The Web Site) and the Wellington ME/CFS Support Group assumes no responsibility for the choice or outcome of any treatment by its readers.
Everybody is welcome to join Gerda every Friday between 12:30-2:30 at 27 Mexted Terrace, Linden, Tawa (Tawa Art and Craft Society Inc building)
Fine art, painting, poems, craft, scrapbooking, artist trading cards etc. It is about creating something with people to whom you don't have to explain about ME/CFS. Bring your art project or come a long and get some ideas what to do. If you just want to pop in for a coffee you are most welcome to.
For more information email the group, or contact Gerda.
Download the Groups information leaflet.
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