WHAT IS IN OUR FUTURE - PART 2

Discussion in 'Fibromyalgia Main Forum' started by CelticLadee, Jan 19, 2003.

  1. CelticLadee

    CelticLadee New Member

    Jellybelly - I had copied your articles so here is Part 2:




    WHAT IS IN OUR FUTURE? part II 10/23/02 07:02 AM

    Oxidative Stress
    Oxidative stress has a central role to play in this illness. In a paper published by Prof. Richards from Newcastle, Australia, it has been shown that oxidative stress, as measured by methaemoglobin, malondialdehyde and 2,3 diphosphoglycerate levels, was significantly raised in CFS (ME) patients compared to controls. When comparing 33 patients against controls he found the following:

    Blood parameter Mean control values Mean CFS (ME) values P value
    Malondialdehyde 31.3 47.63 <0.006
    MetHb 0.62 1.45 <0.02
    2,3-DPG 5.07 5.73 <0.04
    Mean Red cell volume(MCV) 87.43 89.73 <0.02


    The amount of elevation correlated significantly with symptom expression in CFS (ME). His team felt that the mechanisms are similar to those found in rheumatoid arthritis. They also feel that bacterial toxins and Nitric Oxide can play a part in the elevated oxidative stress levels.

    Dr Fulle in Italy has shown that oxidative stress is present in the vastus lateralis muscle of patients with CFS (ME). Compared to age matched controls oxidative damage was detected to DNA and lipids, as well as increased activity of antioxidant enzymes. This again suggests an organic basis for this disorder. Fluidity and fatty acid composition were different in CFS (ME) to Fibromyalgia patients and controls.

    Professor Majid Ali from New York is a leading researcher in this field. He is a Professor of Pathology and Integrated Medicine. Most of his work has involved the use of a high magnification video microscope, magnifying up to x15, 000. Of course as a Pathologist he is already expert at standard medical microscopy.

    His hypothesis is that all of the co-factors described in this illness contribute to the total burden of oxidative stress. They are the causes of the oxidative stress or a direct result of oxidative stress.

    He calls CFS (ME) and Fibromyalgia, 'Oxidative - Dysoxygenative,' disorders. Oxygen is a double-edged sword. It is what sustains life. However, it is also what ages us. Oxidation in nature is spontaneous and requires no energy. It is the loss of an electron such as Fe2+ becoming Fe3+ in, e.g. iron to iron oxide. As we age we rust. The reverse process, reduction, does require energy. We derive this from nutrients and ultimately ATP.

    Utilising the technique of High Power Video Microscopy, and viewing freshly drawn live blood samples, (NOT FIXED or STAINED), it is possible to see many abnormalities in patients. These abnormalities cannot be seen until you reach x8,000 magnification, and then only with phase contrast and dark field illumination.

    They cannot be seen under direct illumination. I have one of these microscopes in my clinic and the abnormalities seen are shared in many chronic and inflammatory diseases.

    In hypercoagulable states microclots and plaques measuring from 2-3 microns to over 40 microns can be seen. Also evident are many fibrin spicules, which are platelet derived. Embedded in the clots are platelet clumps and bacteria, and yeast like forms. Mycoplasma can also be seen. There is a correlation between the amount of abnormality and disease severity. Red cell shape abnormalities abound. The appearances are, according to Prof. Ali, a direct result of increased oxidative stress. Soluble fibrin is easily seen on low power direct viewing, and in the oxidative stress model is produced by action of the sialidase enzyme, promoted by free radicals and bacterial neuraminidase. This enzyme acts on fibrinogen, but does not remove the A and B fibrinopeptide components. These appear to be relatively hydrophilic and thus fibrin becomes soluble fibrin. This other pathway is called The Bradford-Allen Coagulation pathway. As in David Berg's work, we see here a problem in the basic clotting and unclotting equilibrium secondary to oxidative stress. The abnormal anaerobic forms proliferate in this environment.

    The overall result is an oxidative coagulopathy, where the microcirculation is clogged up producing:

    1. Poor oxygen transport to cells 2. Poor oxidation in cells 3. The build up of organic acids causing acidosis

    He also postulates an oxidative lymphopathy, where the lymph channels become similarly blocked. This would fit in well with Raymond Perrin's observations that improvements are seen with lymphatic massage, which mechanically helps to unclog blocked channels.

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    I now move on to the controversial topic of yeasts. Yeast like organisms can clearly be identified through the video microscope. Again, only with phase contrast and magnifications greater than x8000. They appear generally after a few minutes and can be seen to spread across the field of view in yeast-like fashion. Majid Ali has extensively commented on the yeasts, their morphology and associations, with a detailed analysis of their growth patterns. There is a correlation between the amount of yeast and the rate of proliferation and severity of illness. Professor Ali performed the following study.

    Incidence of yeast forms in Peripheral Blood of 100 patients with Fibromyalgia and or CFS (ME) and 100 controls seen with High Resolution Phase Contrast Microscopy per 25 high power fields at 15,000x magnification

    Incidence <3 4-9 10-14 >15
    Patients 0% 12% 21% 67%
    Controls 37% 57% 6% 0%


    Frequency of Active Proliferation of yeast forms in peripheral blood of 100 patients with Fibromyalgia and/or CFS (ME) and 100 controls expressed as a percentage of those germinating per 25 HPFs.

    Germination rate <1 1-3 4-6 7 or more
    Patients 6% 13% 28% 53%
    Controls 7% 91% 2% 0%


    Obviously, the presence of these yeast forms is not diagnostic. They seem to be another co-factor. Prof. Ali feels they are there as a result of an 'Oxidative regression to a primordial cellular state', an interesting and plausible explanation for the development of chronic ill heath. The growth of the yeasts is a direct result of the anaerobic/glycolytic pathway dominance in these patients.

    Is there any evidence that the microbes seen are indeed yeasts/Candida type organisms? Majid Ali has done work correlating the severity of appearance under the microscope with increased urinary excretion of organic acids produced by yeasts, providing some evidence that these are real phenomena. One of these, Tartic acid, has also been shown to exhibit decreasing levels when patients are treated with anti-fungals. He has also labelled some of the samples positively with immunostains for Candida. Viewing the yeasts under dark field illumination, they appear transparent, due to the polysaccharide content of their cell walls, typical of yeasts. Also over many hours he has show them to behave like yeasts with budding and filament formation.

    When patients were treated with broad-based therapies, including anti-fungals, the following results were seen.

    Percentage detection rate of yeast forms before and after treatment in 100 patients

    No/25 high power fields 1-3 4-9 10-14 >
    15
    Pre Rx 0% 12% 21% 67%
    Post Rx 16% 56% 21% 7%


    He has also carried out a study that showed treatment with anti-fungals decreased the amount of yeast-like forms and improved symptoms. Symptom score 0 (no symptoms) to 4 (severe symptoms).

    Relief of symptoms in 100 patients with CFS+/- FM
    with anti-yeast therapies
    Symptom Pre-Treatment After Treatment
    Fatigue 3.5 2
    Myalgia 3 2
    Cognitive difficulties 3.5 0.5
    Malaise 3 1


    Where they originate from is not known. They may come from the gastrointestinal tract, via or from the oral cavity, and there is increasing evidence that this may happen. He suggests they also may be endogenous. Cultures will need to be made to mimic the conditions on the microscope slide to grow the yeasts, and work on this is underway.

    As stated above he calls the ecological terrain existing in CFS (ME) and Fibromyalgia an 'Oxidative regression to primordial cellular ecology.' In this state he feels we favour the overgrowth of latent microbes such as mycoplasma and chlamydia, as well as yeasts. They seem to be associated with erythrocytes. We already know that yeasts like Candida will use haemoglobin as a source of Fe. In summary they are only seen when oxidative stress exists.

    If we suspect the yeasts seen on video microscopy to be yeast/Candida, do we have any evidence for Candida and human interactions? Prof. Vojdani looked at serum from clinical cases, based on seronegativity or seropositivity for IgG, IgM and IgA autoantibodies against thyroid, adrenal and ovarian tissue. He then tested each sample for the presence of Candida antibodies. Expressed as a percentage expressing Candida antibody overall:

    Seropositive for autoantibodies - 60% had Candida antibodies
    Seronegative for autoantibodies -7.5% had Candida antibodies
    Controls - 10% had Candida antibodies
    P<0.001 for IgG and IgM
    P<0.01 for IgA


    Confirmatory evidence came from the fact that when antibody positive tissue was treated with rabbit anti-Candida antibodies and human positive sera, it produced a reduction in thyroid autoantibody levels. It would be interesting to see if there is an increase in anti-Candida antibodies in people with other autoimmune and hypercoagulable conditions, such as the Antiphospholipid Antibody Syndrome.

    Another interesting angle to this is the question of heat shock proteins. These proteins are part of the family of stress proteins, the others being glucose regulated proteins and ubiquitin. They were first discovered when cells were exposed to thermal stress. However, they are produced in response to other stressors, e.g. cold, alcohol and heavy metals such as lead, cadmium, mercury and oxidants. They are also of value in the absence of stress and in modifying the response to repeated stressors. They may be considered as 'universal folding assist' proteins. Some of their functions include:

    1. Assisting in the folding of newly formed proteins.
    2. During stress they hold denatured proteins and thereby prevent irreversible denaturation and allow proteins to return to a normal configuration after the stress is removed.
    3. Assisting in chromosome replication and transcription, mRNA splicing and ribosome assembly.
    4. The transport of unfolded proteins via microtubules to their destination within the cell.


    However, an excess of hsp's can have deleterious effects. Too many inhibit protein folding and increased levels may be seen as dangerous or foreign antigens by the immune system. Studies in the past have shown that because all hsp's are very similar genetically, they can trigger autoimmune states, such as in leprosy, TB and Histoplasmosis by cross reactivity between the infective agent hsp's and human hsp's.

    Candida produces several hsp's. The important ones in this story are hsp 47, 90 and 70. These Hsp's are involved in hormone action. They are required to fold steroid hormone receptors until the steroid hormone binds to the receptor. But, in candidiasis, an excess of hsp 47 effectively blocks this action. People who survive deep-seated Candidiasis make a lot of antibodies against hsp 47. Also, plasminogen activator production is steroid dependent. Inhibition of its production will lead to a failure of fibrinolysis. This is common in systemic Candida infections, leading to DIC, a mild form being the clot/unclot dysequilibrium seen in chronic fatigue states. Robert Bradford and Henry Allen have proposed these two factors before.

    When discussing upregulation of the 2-5 Synthetase/RNase L system you will recall Vojdani showing that this can be induced by MTBE and benzenes in the presence of hsp 70. Is it therefore, the cross reactivity between hsp from the yeasts, and human hsp's with the immune system that is contributing to the clinical picture? The more yeasts seen on microscopy, the sicker you are. It would help to explain not only the upregulation of the RNase L enzymes, be they normal or low molecular weight, but the hypercoagulable state found in patients, and also steroid hormone resistance, which I see a lot of. Many patients, who appear almost Addisonian, and have low salivary free fraction hormone levels, do not improve on physiological replacement doses. This always puzzled me. As well as GH/IGF-1 deficiencies, maybe an excess of hsp's is the answer.

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    Th1/Th2 balance
    A Th2 cytokine shift, as has been reported in many patients.
    T Helper cells produce cytokines in response to immune insults. Cytokines were named for their immunomodulatory effects, but they also penetrate the blood brain barrier, act as neuromodulators, and produce both acute and chronic changes in the brain. This is particularly in the regions associated with cognition and endocrine activity.

    Th1 cytokines are preferentially produced when there is immune activation because of the presence of viruses, bacteria or protozoa. The so-called cell mediated immune response. The cytokines produced include Interferon-gamma, IL-2, IL-12 and TNF alpha, although the latter is also expressed to a lesser degree in the Th2 cytokine response.

    Th2 cytokines are produced when there is a requirement for optimal antibody production for an antigen specific immune response. This may be in toxin exposure, parasitic infections, atopy, allergy and autoimmune states. These include IL-1Ra, sIL-1Ra, IL-4, IL-6, and IL-10.

    The inter-relationship between these two is complex. It is not as simple as a pure shift from one to the other. Studies looking at the levels of various cytokines produce different results and there are many reasons for this. Microbial exposure favours Th1 cytokines and seems to predominate early on in the illness. However Mycoplasma stimulates a Th2 response. Chemical induction and vaccinations, including those against neurotoxins, such as those given to USA/UK soldiers in the Gulf War favours Th2. Interestingly not the French soldiers, who were given the older Th1 cytokine inducing type of vaccines. They have less chronic fatigue problems.

    Chronic stress and illness, such as in chronic sympathetic stimulation, favours Th2 cytokines. Noradrenaline fulfils the criteria for a neurotransmitter/ neuromodulator in lymphoid tissue. It is released from sympathetic nerve terminals in these tissues. Through stimulation of the beta2-adrenoreceptor-cAMP-protein kinase A pathway it inhibits the TH-1 cytokine response systemically. This is to protect the body against the pro-inflammatory cytokines and other activated macrophage products.

    The presence of parasites in the upper gastrointestinal tract may favours Th2, with IgE stimulation. This is important because many patients have parasites such as Blastocystis Hominis, Dientamoeba and Giardia in the gut. Also relevant is whether or not the patients are atopic, or have allergies pushing them towards Th2 patterns.

    The presence of a co-existent autoimmune process favours a Th2 shift. How well people feel when they are sampled and how old they are is important. The older they are, the more they seem to be pushed towards a Th2 pattern. These Th1/Th2 shifts may need to be determined when considering therapies.

    It has also been postulated that a generalised excess of cytokines could cause a sustained increase in peroxynitrite levels. This is a potent free radical. The mechanism would involve cytokine induction of nitric oxide synthetase. This then causes an increase in nitric oxide levels, which reacts with the free radical Superoxide to generate peroxynitrite. Multiple amplification and feedback then occurs. This mechanism may be one reason for the high oxidative stress seen in this illness.

    Following on from this is the important fact that peroxynitrite inhibits our anti-oxidant enzymes, Superoxide dismutase, Glutathione peroxidase and Catalase, again increasing oxidative stress. Also, another very important fact is that peroxynitrite has been shown to be a strong stress to human monocytes, leading to a dose dependent increase in hsp 70.

    It is suggested that this increase in oxidative stress could cause damage to the hypothalamus and account for all the hormone problems. Also, high peroxynitrite and nitric oxide levels could account for the sodium channelopathies seen in this group of syndromes. Finally these high free radical levels would favour uncoupling of Krebs cycle oxidative phosphorylation in mitochondria. This could also lead to the abnormalities in urinary organic and amino acids as seen by McGregor.

    In Gilbert's syndrome, i.e. unconjugated hyperbilirubinaemia, there is a four fold increased incidence in sufferers. This also independently increases oxidative stress as well as having an impact on cellular uptake of thyroid hormones.

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    Treatments
    What are the most effective treatment protocols to date? Having collaborated with Michelle Ranaghan, Action for ME's former Research Officer, on the large literature search, I have read a lot of studies. I feel the studies, with the fewest side effects and prolonged results on follow up, are those using Integrated Medicine Protocols. Crucially all the problems identified above are treated simultaneously. Treatment is not only with conventional drugs, but also with hormones, antioxidants and minerals, herbal preparations, nutritional advice and sensible guidelines on rest and activity. Psychological problems are also addressed.

    One of these was by Dr. Jacob Teitelbaum who published an open study showing promising results and followed this up with a very well constructed double blind placebo controlled trial, which has now been accepted for publication in the Journal of Chronic fatigue Syndromes. I feel this approach would be the easiest to apply on the NHS.

    72 Fibromyalgia patients, 70 of whom also fulfilled the CDC criteria for ME, were divided into two groups and treated either with placebo therapies or active treatment by a unified, simultaneous approach for three months. Patients were treated based on clinical symptoms and/or lab testing for:

    1. Subclinical thyroid, adrenal (cortisol and DHEA), and gonadal hormone imbalances or deficiencies.
    2. Disordered sleep (Zolpidem,Trazadone, Amitriptyline, Clonazepam, Melatonin or herbs such as Valerian root).
    3. Suspected neurally mediated hypotension with fludrocortisone and increased fluids.
    4. Opportunistic infections e.g. common parasites such as Blastocystis hominis, Giardia and Dientamoeba, Clostridia, and fungal overgrowth with conventional antimicrobials and herbs.
    5. Suspected nutritional deficiencies (multivitamins, magnesium glycinate/malic acid, B12 and Iron).

    32 patients in each group completed the study. Using a combination of patient and physician assessments, FMS Impact questionnaire, Analogue scores and Tender Point Indices, the results were, with p< 0.0001

    Much worse Worse Same Better Much better
    Active group 1 0 2 13 16
    Control group 3 9 11 6 3


    The conclusion was that significantly greater benefits were seen in the treatment, as opposed to placebo group, for all primary outcomes. After one year, improvements had been maintained in the treated group. Further details can be found at www.endfatigue.com

    The second impressive study was by Professor Majid Ali. This was an Open prospective study on 150 Fibromyalgia/CFS (ME) patients. The study was based on the results of clinical, biochemical and video microscopy findings. The programme involved nutritional education, intravenous and oral nutritional supplements, redox restoring substances, such as glutathione and taurine, hormonal support, probiotic and herbal bowel therapies, nasal and other oxidative therapies, gentle stretching and non-competitive exercise, and training in self-regulation and stress reduction. No attempt was made to limit the number of therapies patients received. Neither was any attempt made to blind the study, as this would have been impossible to do, given the comprehensive and holistic therapies involved.

    The patients were divided into three groups according to duration of illness:

    Group 1 < 3 years
    Group 2 3-6 years
    Group 3 > 6 years


    Again, as with the Teitelbaum's study, standard clinical evaluations were used.

    Outcome Poor Fair Good Excellent
    Overall 10% 5.3% 19.3% 65.4%
    Group 1 (n=56) 7.1% 7.2% 10.7% 75%
    Group 2 (n=26) 3.9% 7.7% 19.2% 69.2%
    Group 3 (n=68) 14.7% 2.9% 26.5% 55.9%


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    Further information is available at www.majidali.com

    In conclusion, we have direct evidence from good sources that these groups of syndromes share common factors, and that there is proof for their organic basis. There exists a chronically activated immune system, which may result from microbial, or toxin overload or a summation of the two. As a result hypercoagulability exists, causing problems in both blood and lymph microcirculation's. This hypercoagulability may arise from a combination of hereditary, immune mediated and oxidative stress pathways. We have chronic sympathetic system activation, from many causes. We then have a situation where the body is subject to a high degree of oxidative stress, probably the most damaging state in biology. Multiple subtle endocrine changes are also present, both quantitatively in terms of hormone levels, and also qualitatively, with loss of circadian rhythmicity. Given the bi-directional flow of information between the nervous, endocrine and immune systems, we are presented with a perfect example of Chaos Biology. This results in a failure of homeostasis and homeodynamics. Simply stated, a body that cannot respond to any form of biological stress, be it environmental, infective, physical or psychological.

    Although some of the ideas I have presented are novel and controversial, I believe the overall hypothesis has a sound base in science. We must remember that all explanations for these groups of illnesses are at present speculative. However, the studies demonstrating pathophysiology are not and neither are the results of treatment programmes. I am afraid that as a profession, it seems we have shot ourselves in the foot again, and have assumed psychological causation, because of our lack of knowledge. Medical history is littered with illnesses that were thought to be psychogenic e.g. Tuberculosis and Hypothyroidism. We need to act quickly to repair the damage and work for funding for patients on the NHS.

    Treatment Plan
    Ideally, I think that any patient with a fatiguing illness of more than one month needs urgent assessment. The CDC definition of an illness greater than six months duration makes no sense. Most of the damage may be done early in the illness. We do not know enough about our molecular biology to guarantee that some changes are not reversible. I suspect some permanent damage does occur and is a major cause of treatment resistance. Having tried out almost all the treatments on my patients, both conventional and complementary, I am convinced that a multi-disciplinary approach is essential. As a result of all that I have discussed, what practical measures are to be taken with patients? The therapeutic options outlined below form the basis for treatment. The list of therapies is not complete and I have excluded many nutritional and IV therapies from this basic plan, but they can be utilised in special circumstances. I suggest we use an Integrated approach with collaboration between the following.

    Clinician
    There is no reason why this could not be the GP with training and a colleague with expertise available via phone / fax / email. The planned introduction of GP specialists would be and appropriate. The best place to treat patients may be in Primary Care. There are no designated Consultants in chronic fatigue syndromes at present.

    Osteopath/Physiotherapist/Chiropractor
    Trained in lymphatic massage techniques. Information on the methods used by Raymond Perrin can be obtained through his clinic, where he sees patients privately, or through the Osteopathic Information Service. I consider this essential. At least an assessment should be made to confirm or rule out lymphatic drainage problems clinically. Any osteopath can learn the techniques. More and more NHS osteopaths are now available.

    Raymond Perrin
    83 Whittaker Lane
    Prestwich
    Manchester
    M25 1ET, UK
    Tel: 0161 773 0123

    Osteopathic Information Service
    Osteopathy House
    176 Tower Bridge Rd
    London
    SE1 3LU, UK
    Tel: 0207 357 6655

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    Nutritionist/Dietician
    Food choices are very important. In general, a glycaemic diet should be followed (a protein to carbohydrate ratio of 1:2 by weight or calorie counting as they are calorie equivalent), with good quality proteins and slowly digested carbohydrates. Organic food is preferable, but still expensive.

    Psychological input
    Through a clinical psychologist, (or specially trained health professional), if there are emotional problems because of the illness. These may be health related, social or financial. Battling with the DSS is enough to make anyone depressed.

    Dentist (see below)
    There are an increasing number of Dental Practitioners who have expertise in this field. I can supply details of how to find a suitable dentist.

    Specific therapies
    Patients often ask if any of the therapies outlined below are available through their GP on a normal prescription, instead of on a private prescription. Some of them are, and I have indicated this with a *. I know this because I write them on an FP10 for my own General Practice Patients. However I always tell patients the following:


    Although all the therapies have been used in successful trials of one kind or another, they are not yet established medical practice
    Some of the therapies are used out of licence, or a licence is not applicable
    As a GP, you take legal responsibility for the prescription you issue. Although the therapies are safe, well tolerated, free from major side effects, and usually in physiological doses only, the possibility of individual iatrogenic reactions are there.
    Lack of familiarity with some of the medications is a reason not to prescribe,
    If your doctor refuses to prescribe for any reason, then you must not take it in anyway to mean that they do not care about you, or have no compassion for your situation.
    However I am happy to discuss problems and advise any GP/Hospital Doctor/ Health Professional on prescribing issues.

    The basic idea is to remove as many stressors as possible. Initial investigations and consultation with all members of the above team will identify many. However, don't forget hidden stressors like H. Pylori and other gut parasites, or inadvertent toxin exposure such as handling pet flea collars. I have not included common drugs such as analgesics and antidepressants as they are covered elsewhere, except to say high analgesic doses are often required, even using opiates and low doses of Tricyclics and SSRI's should be tried initially, as side effects are common.

    Vitamins / Minerals and Nutritional Supplements
    Here, we are not using the Recommended Daily Allowances, which are primarily aimed at preventing deficiency syndromes and maintaining good health. When you have an 'oxidative fire', as in these illnesses, your requirements change. We are using them therapeutically.

    1. A good antioxidant /mineral mixture
    There are many products available OTC from Pharmacies, Health food shops and Independent distributors. They should contain a balance of both fat and waters soluble vitamins, include selenium, and be taken all the time. Forceval* is a prescribable option. Oxidative stress can be measured using blood methaemoglobin, or Vespro's Free Radical Test kit which measures urinary malondialdehyde levels. This is an easy to use kit based on a visual colormetric scale. Supplement levels should be adjusted until normal ranges are achieved. These should be checked periodically at around monthly intervals. It is particularly important to get this right before anti-fungals are taken to prevent die-off reactions.

    2. B Vitamins*
    Poor functional levels of B Vitamins have been reported by Heap et al using AST, glutathione reductase, and transketolase as markers of pyridoxine, riboflavin and thiamine respectively. (P< .001). Compounds with up to 50mgs of each per day can be used. An alternative is Strong Vitamin B Co* 2-4 / day Low levels of B12 are found in the cerebrospinal fluid of patients, reflecting poor neuro-axis levels. High CSF levels of homocysteine are also found. B12 deficiency causes deficient remethylation of homocysteine. Indeed Low brain levels have been associated with many degenerative neurological disorders. It is thought that B12 couples with environmental toxins in an attempt to detoxify the brain. Rarely, it may also occur as a result of enzymatic problems, or changes in blood-brain barrier permeability. Therefore, amine neurotransmitter levels suffer, as B12 is required for this. It is safe and can be given as an IM injection. I use 1000mcgs hydroxycobalmin once or twice a week, but workers in the USA have used up to 30,000mcgs per week It is available as a sublingual preparation and is prescribable in that form. The dose required may in part be due to genetic factors. In a Swedish study, people with low levels of reductase needed higher doses. The use of the active form i.e. already methylated is being investigated. A more generalised methylation disorder may account for many of the functional vitamin deficiencies

    3. Magnesium malate*
    1000mgs once a day - used in the Teitelbaum study. This is good for muscle physiology. Also, Dr. David Dowson published a double blind study in 1991 showing low red cell magnesium levels in CFS (ME) patients which improved with treatment, as did symptoms in patients. IM 2mls 2% Mg SO4 as weekly injections does help some patients. Experienced workers use dilute IV preparations. Magnesium deficiencies lead to lower total antioxidant capacity and glutathione levels. Interestingly Magnesium malate is used in Anorexia nervosa patients to promote weight gain.

    4. Folic acid* 5mg once daily.

    5. Oral NADH (Enada)
    Recommended dose is 5-10 mgs / day. The reduced form is absorbable orally. Nicotinamide adenine dinucleotide is used in ATP production. In a double blind crossover study, 26 patients were given oral NADH at a dose of 10 mgs per day. On active treatment 31% responded favourably against 8% on taking placebo. I do not routinely use it because of its high cost, but feel it has a place. Some people need up to six a day. High levels of pre-treatment urinary 5-HIAA seem to indicate whether or not treatment will be successful.

    6. Undenatured whey proteins (Immunocal* Imuplus* Immune Pro *Solgars Whey To Go*)
    Basically, these are milk-derived products, which are very close biochemically to human breast milk. They have anti-viral, bacterial and possibly fungal action. They contain two cysteine molecules bound together, which is a requirement for absorption. This is an essential precursor for glutathione. Low glutathione levels are seen in patients, particularly in white cells. It has been shown to raise glutathione levels and therefore it is important to try to take one of these products. Some people cannot tolerate these products. Personal communication with Professor Hubbard, Clinical Biochemist in California, suggests an alternative way of raising glutathione:

    N-Acetyl Cysteine caps - 1 three times a day
    Q10- 30mgs twice a day
    Evening primrose oil 1-2gms twice daily

    7.For Sleep - Tricyclics*, Zolpidem* and certain benzodiazepines* e.g. clonazepam in sleep difficulties with restless leg syndrome. Valerian root, lemon balm and passiflora are all useful herbs for sleep.

    Other products may apply in selected cases. For example, people often have low butyric acid levels, a fuel source for the bowel. This can be estimated using faecal test kits (Great Smokies CDSA kit). Occasionally, digestive enzymes are required as gross sympathetic activation inhibits digestion. Pro-biotics are useful to replace normal bowel flora if deficient on testing or caused by antibiotic treatment.

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    Hormones
    I prescribe physiological doses of hormones after testing using saliva estimations. These are reflective of free-fraction levels and therefore bioactive levels. They are easy for the patient to do at home and prove useful for looking at both total levels and problems with circadian rhythmicity.

    1. Hydrocortisone*
    This is converted into cortisol directly. Dose range is 2.5 mg (Corlan Pellet*) to 15 mg in divided doses, (4mg of hydrocortisone = 1mg of prednisolone). Safety studies have been carried out which indicate that up to 25 mgs does not suppress endogenous ACTH.

    2. DHEA*
    For women use10 mg bd., and in men 25mg bd. Conversion of DHEA to extra oestrogen and testosterone does not occur significantly until > 50 mgs daily.

    4. Melatonin
    Use 0.5mg at 8-9pm. This helps to initiates sleeps via the Histamine-Interleukin-Prostaglandin system. Melatonin is the 'molecular manifestation of darkness'. It may be possible to reset the internal body clock with about 4-6 months treatment.

    4. Thyroid replacement*
    This is useful in clinically hypothyroid patients with low/borderline levels, and especially if autoantibodies are present. Aim to keep T4 and T3 within the reference interval. TSH may be unreliable in chronic illness. The usual thyroxine range is 25-125 mcgs. Some people are poor converters of T4 to T3. Occasionally, I use Liothyronine (T3) 10 mgs. Sometimes it is best to use a combination. Some organs prefer to get thyroxine hormones as T4, e.g. the brain, whilst others prefer T3, e.g. the kidney. Liothyronine (Tetroxin) is best given as a bd. dose because of its short half-life. A combined American compound is available containing a physiological mixture of T4 and T3 and is sometimes useful. Armour/USP thyroid measured in grains. Average dose is ½ to 2 grains (about 40-160 mcgs T4).

    5. For neurally mediated hypotension
    Extra plain fluids, totalling about 2-3 pints per day, on top of normal intake can help. A pinch of sea salt in fluids, twice a day, can also help. In severe cases, with dizziness and syncope, fludrocortisone* 100 mcgs ¼ a tab /day. Dr David Bell and his colleagues have done much of the work in this field. Certainly delayed orthostatic hypotension and / or tachycardia are common. They seem to be due to a combination of excessive gravitational pooling in the lower limbs and subnormal circulating erythrocyte volumes in some patients. A study recently done by Streeten, Thomas and Bell showed that military anti-shock trousers would help these problems. Fludrocortisone as an isolated therapy has recently been shown to be no better than placebo. Normal saline infusions at the same time as Tilt Testing have abolished abnormal responses.

    6. Peri-menstrual exacerbation of fatigue is a problem
    Some women with severe dysoestrogenism need help with hormones, but this is a difficult area requiring some experience. Women tend to have lowish progesterones, dissociated from oestrogen. Oestrogen dominance is evident in the luteal phase on saliva testing. You can use hormones, but they tend to need individual tailoring after testing, using multiple point collections of saliva over a monthly cycle. Indolplex* is an oestrogen receptor modulator derived from plants, containing Diindolalyamine. It can be very useful, (it has no intrinsic hormone activity). No trial work is available for this product in CFS (ME). The botanical Agnus castus can also help PMT symptoms.

    7. IGF-1 levels As discussed above some patients have problems with GH/IGF-1 levels, and therefore, problems with anabolic/catabolic balance. IGF-1 hormone can now be measured in saliva. Apart from using the actual hormones, Growth hormone secretagogues, which modulate Growth hormone, and therefore, IGF-1 levels can be used. They increase both IGF-1 and DHEA levels. They do not stimulate supra physiological levels. They work as an adaptogen on stored GH in the pituitary. Dr Salvato in Texas used Somatomed*, from Vespro, in a study. She gave this secretagogue to 200 CFS (ME) patients for three months and found the following -

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    Objective
    Body cell mass increase of one pound or more in 63% of patients
    Weight loss secondary to a decrease in body fat in 82% of patients
    Weight gain of 5-11pounds in 18% of patients
    IGF-1 levels increased by over 20% in 59% of patients
    Natural killer cell numbers increased by 30% or more in 59% of patients


    Subjective
    Sleep markedly improved in 79% of patients
    Cognitive functioning improved in 78% of patients
    Myalgia improved in 52% of patients
    Fatigue improved in 68% of patients


    Side effects
    Transient increase in muscle and joint pain was reported in 28% of patients
    Mild oedema was experienced by 31% of patients
    It is interesting to note that significant improvements were found
    in patients who did not obtain increases in IGF- 1 levels
    Somatomed has been shown previously to increase IGF-1 levels and DHEA.

    Anti-microbials

    1. Anti-fungals*
    These can help, especially in most cases. I normally use a combination approach. Nystatin* can help in gastrointestinal Candida, and in cases where a leaky gut is suspected, at a dose of 1 or 2 tablets four times a day for two to six weeks. I use Fluconazole* 50gs once daily for one week with Terbinafine* 250 mgs per day for two weeks initially, although this can be extended. I also have patients who take Dioxychlor, one to twenty drops twice a day, at the same time. This is a naturopathic remedy Also useful is Paraguard* 2 caps three times a day. This product contains many anti-fungal and anti-parasite herbs which are effective against common gut pathogens in CFS (ME), such as Blastocystis. It should be taken for 8- 12 weeks with a suitable probiotic.

    2. Antibiotics*
    If I have evidence of Mycoplasma or Chlamydia, and other means do not work, I would use Doxycycline 100 mgs twice a day for 12 weeks or Erythromycin 1gm twice a day for 12 weeks. Some doctors cycle round antibiotics for up to one year. Prof. Nicholson says 85% relapse if the treatment is less than 12 weeks. Patients can feel worse before they improve. They use 3 - 6 monthly cycles of the above plus Ciproxin. For upper gut parasites like Giardia, I use Tinidazole 500 gms twice daily for 10-14 days. Whether or not antibiotics are useful in a chronically activated immune system, to suppress the production of aberrant mRNA, remains to be seen.

    Anti coagulation*
    (All the usual contra-indications apply)

    1. For low dose Heparin therapy, a pre-treatment FBC also needs checking. Do remember that your standard coagulation tests will be normal. Check for thrombocytopaenia at 7 and 14 days with a FBC. Using porcine heparin this occurs in < 0.3% for the more serious type 2 thrombocytopaenia. Also, electrolytes need checking in high risk groups such as diabetics and those on potassium sparing diuretics. The dose recommended by Dr. Berg is 4000 units of plain heparin, s/c twice daily, for less than 70Kg patients, and 5000 units, twice daily, for patients above this weight. Some patients need up to 15 000 units. Patients need to be instructed in self-administration. It should be tried for a month to assess response. Hopefully, once the oxidative stress is under control, there will be less need for this therapy. In the USA, therapy is given for up to six months. It is a prophylactic dose of Heparin, i.e. pre surgery dose. The BNF states that this dose does not need routine monitoring, but I feel it should be monitored as doses are continued, and also until coagulation studies, as used by Dr. Berg, are available. This dosing schedule is used safely in the Antiphospholipid Antibody Syndrome already. Long term use can cause osteoporosis and this should be considered and preventative measures taken in high risk patients. I suspect that until further trials are performed, the use of heparin will be limited in the UK, although all the evidence is that it is safe. David Berg gives doxycycline routinely with it in the USA. The main point to remember is that the doses suggested simply take people from a hypercoagulable state to a normal state.

    2. Another option is low dose aspirin* +/- heparin. A 75mg dose has a side effect profile similar to placebo. 60% of patients have platelet activation.

    3. Again, with or without the above, the plant derived substance Bromelain*, found in pineapples, is suggested by Dr. Berg, in a dose of 500mgs, twice daily. Available on an FP10 as Solgars Bromelain*. Omega - 3 fish oils have been used at a dose of around 100-200mgs per day. Maxepa* 1 cap bd. is useful.

    The first three have been used safely together, but I have no data on all four together.

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    Dr. Berg switches to oral anticoagulation after 3-6 months. He also uses Transfer Factor, but this is very expensive. Low molecular weight heparins are an alternative. With the advent of oral heparin, a lot of the problems of bd. s/c injections will be solved. It is true of course, that we routinely give far more 'risky' drugs all the time in a wide range of less disabling illnesses, e.g. NSAID's, steroids and immunosuppressants.

    Obviously, patients who smoke should be strongly advised and given help to quit. The basic regime should be tried for three months and then reviewed. Generally, between 3 to 6 months, people can be weaned off a lot of therapies and maintained eventually on a minimum of therapies.

    I have specifically not discussed the Dental Aspects of these illnesses. This is outside my area of expertise. I hope to coerce a dental colleague to write a short review paper to be added to this. I am convinced though, that this is an important area of research and treatment. Dental work prior to becoming ill was identified in AfME's research as a co-factor. The oral cavity provides a portal for a whole host of significant interactions. Mercury is, of course, a well-researched heavy metal toxin, peripherally and centrally. It combines with anaerobic microbes in chronic dental sepsis to form the very toxic thiols, which are neurotoxins. Yeasts are capable of converting mercury to methylmercury, which is incredibly toxic.

    The above protocol is derived from the work of many doctors and has been shown to be effective and safe. I expect that until research funds become available from central sources, a controlled trial of all the above will not happen. However, as stated above, all the therapies have been tried, with a few exceptions, in clinical trials. I can think of no reason why any part should be antagonistic to another. The trials are based on the treatment of adults. No trials of an integrated approach have been carried out on children. However, as CFS (ME) is now the commonest cause of long term absence from school, serious consideration needs to be given to their plight.

    All the above treatment plans have been described by other people and studied individually - I have simply put them together. I hope they will especially help the 15% or so of patients who do not improve, whatever treatment they have received up to now. This group of patients are often house / bed bound, and most of the above therapies could be undertaken at home. It may be that the massage was missing, or anticoagulation, or whatever. I strongly suspect that this is the case.

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    Dedication
    Although this document is not of book size and maybe doesn't warrant a dedication, I would nevertheless like to dedicate it to all those patients who insisted, and keep on insisting, that they really are sick. Also, to all the health professionals who believed them. I would also like to thank Dr.'s Pat Shipley, Derek Pheby, Betty Dowsett, Ian Hyams, Ellen Goudsmit and especially Michelle Ranaghan. Their conversations, individual experiences, knowledge and support over the past few years have been vital. Most of the advances in the field of 'Chronic Fatigue' medicine have been due to individual efforts. It really is time for government sponsored research, trials and treatments. As a parting shot, I am extremely concerned that patients with such a variety of pathophysiologies are at high risk of developing other chronic illnesses, secondary to factors such as high levels of oxidative stress. We need to address their problems now. I hope all those involved in the care of patients realise this.

    This document may be freely distributed by any means to any interested party as long as my name remains on it.

    © Dr. Andrew John Wright - 3rd February 2001.

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    Selected References

    Action for ME
    PO Box 1302
    Wells
    Somerset
    BA5 1YE, UK
    Tel 01749 670799 www.afme.org.uk

    CHROME is a charity attempting to identify all the severely disabled sufferers and follow their progress over ten years. This will provide invaluable information for further research.

    CHROME
    3 Britannia Rd
    London
    SW6 2HJ, UK
    Tel: 0207 736 3511
    www.ds.dial.pipex.com

    Epidemiology
    Various sources, especially AfME and CHROME databases and previous written submissions by Dr. Betty Dowsett, Hon. Consultant Virologist, South Essex Health Authority and Dr. Derek Pheby, Director, Cancer Epidemiology Unit, University of Bristol.

    De Becker P - Exercise capacity in Chronic Fatigue Syndrome - Arch Intern Med 2000 Nov 27;160(21):3270-7
    Jason LA - Chronic fatigue syndrome: sociodemographic subtypes in a community based study - Eval Health Prof 2000 Sep;23(3):243-63
    Deale A -Diagnosis of psychiatric disorder in clinical evaluation of chronic fatigue syndrome J R Soc Med 2000 Jun; 93(6):3 10-2

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    Immunology
    Ablashi - Ampligen inhibits human herpes - 6 in vitro- In Vivo 1994 Jul-Aug:8 (4):587-91
    De Meirleir K- Levels of LMWRNase L in patients-Conference report 2nd World Conference on CFS and Related Disorders, Brussels, 9-12 Sept 1999
    De Meirleir K - A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome - Am J Med 2000 Feb; 108(2):99-105
    Elenkov IJ - Stress, cytokine patterns and susceptibility to disease - Ballières Best Pract Res Clin Endocrinol Metab 1999 Dec; 13(4):583-95
    Maes M - The effect of psychological stress on humans and a Th1 response in stress related anxiety-Cytokine 1998 Apr; 10(4):313-8
    Morel PA - Crossregulation between Th1 and Th2 cells - Crit Rev Immunol1998; 18(4);275-303
    Moss RB - TNF-alpha and chronic fatigue syndrome - J Clin Immunol 1999 Sep; 19(5):3 14-6
    Patora R - Dysregulated expression of TNF in CFS-Clin Infect Dis 1994 Jan; 18(1):5 14-53
    Strayer D - Treatment of CFS with Ampligen J of CFS 1(1):35, 92
    Strayer D - Durability of therapeutic benefit with Ampligen as measured by the Karnofsky Performance score - presented at the Am Assoc of CFS Conference Oct 1998
    Suhadolnik R - Identification of a subset of people with low mol wt RNase L- Clin Infect Dis 1994:18, 596- 604
    Suhadolnik R - Changes in the 2-5 Synthetase/ RNase L pathway in a controlled clinical trial with poly(1)-poly(C12U) in CFS - In Vivo 1994 Jul-Aug: 8 (4):599-604.
    Suhadolnik R - Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome - J Interferon Res Jul;17(7):377-85
    Vojdani A - RNase L inhibitor levels - J Clin Immunol 1998:50 (1):1-16

    Immunotoxicology
    Behan PO - Chronic fatigue syndrome as a delayed reaction to chronic low dose Organophosphate exposure - J of Environ Medicine (1996) 6: 341-350
    Bell IR - Illness from low levels of environmental chemicals: relevance to CFS - AJM 1998 Sep 28(3a): 74s-82s
    Dunstan RH - A preliminary investigation into Organochlorine levels in CFS - Med J Aust 1996 Feb 19; 164(4):251
    Urnovitz HB - RNAs in the sera of Persian Gulf War Veterans have segments homologous to chromosome 22q11.2- Clinical Microbiol Rev 1996 Jan:9(1):72-99
    Urnovitz HB - Human endogenous retrovirus: nature, occurrence, and clinical implications in human disease - Clinic Microbiol Review 1996;(1):72-99
    Vojdani A - Interferon induced proteins are elevated in blood of patients with biochemical or viral induced CFS - Immunopharmacol Immunotoxicol 1999 May:21 (2):175-202
    Vojdani A - Abnormal apoptosis in cell cycle progression in humans exposed to MTBE and benzene - Human Exp Toxins 1997 Sep;16(9) 485-94

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    Endocrinology
    Allain TJ - Changes in GH/IGF's, and IGF-1 in CFS - Biol Psych 1997 Mar 1;41(5):567-73
    Baerwaerts J - Secretion of GH in patients with CFS - GH/IGF research 1998:8 supp B 127-9
    Beckett and Wilkinson - Thyroid hormone metabolism and thyroid function tests in non-thyroidal illness - Bulletin Clinical Biochemistry Vol1 No1 1998
    Bennett AL - IGF-1 levels in patients with CFS - J Psychiatric Res 1997 Jan-Feb;31(1):91-6
    Bennett RM - A randomised double blind controlled study of GH in the treatment of Fibromyalgia - Am J Medicine 1998 Mar;104(3):227-231
    Buchwald D - IGF-1 levels in CFS and FM - J Rheumatol 1996 Apr;23(4):739-42
    Buckingham JC - Cytokines, glucocorticoids and neuroendocrine function - Pharmacol Res 1994 Jul :35-42
    Cleare AJ - Integrity of the GH/IGF system is maintained in patients with CFS - J Clin Endocrinol Metab 2000 Apr;85(4):1433-9a
    Irwin M - Stress-induced immune suppression. Role of the autonomic nervous system - Ann N Y Acad Sci 1993 Oct 29; 697:203-18
    Karatsune H - Dehydroepiandosterone sulfate deficiency in chronic fatigue syndrome- Int J Mol Med 1998 Jan:1 (1) :143-6
    Knook L - High nocturnal melatonin levels in adolescents with CFS - J Clin Endocrinol Metab 2000 Oct 85(10):3690-2
    Korszun A - Melatonin in females with Fibromyalgia and CFS - J Rheumatol 1999 Dec;26(12):2675-80
    Leal-Cerro A - The GH-GHRH-IGF-1 axis in patients with Fibromyalgia syndrome. - J Clin Endocrinol Metab 1999 Sep;84(9):3378-81
    McGregor - Urinary organic and amino acids in CFS - Conference report 2nd World Congress on CFS and Related Disorders Brussels 9-12 September 1999
    Moorkens G - Effect of GH treatment in patients with CFS - GH/IGF research 1998;8 Supp B 131-3
    Moorkens G - Characterisation of pituitary function with emphasis on GH secretion in CFS - Clin Endocrinol 2000 Jul;53(1):99-106
    Rowe PL - fludrocortisone acetate to treat neurally mediated hypotension in CFS: A randomised control trial - JAMA 2001 Jan 3; 285(1):52-9
    Savino W - Immunoneuroendocrine connectivity: the paradigm of the thymus- hypothalamus / pituitary axis- Neuroimmunomodulation 1999 Jan-April :6 (1-2):126-36
    Scott L - The Role of the HPA axis in Chronic Fatigue Syndrome (1997 PhD Thesis) - The British Library.
    Scott LV - Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and health - J Affect Disord 1999 Jul; 54 (1-2):129-37
    Skinner G - Clinical response to thyroxine sodium in clinically hypothyroid but biochemically euthyroid patients - J of Nut & Environ Med (2000) 10, 115-124
    Smith EM - IL-10 as a mediator in the HPA axis and the brain - J Neuroimmunol 1999 Dec:100(1-2):140-8


    Nervous System / Spine
    Brooks JC - Proton Magnetic Resonance spectroscopy of the hippocampus in CFS - Br J Radiol 2000 Nov;73(875):1206-8
    Cohen H - Autonomic dysfunction in patients with Fibromyalgia: application of power spectral analysis of heart rate variability- Semin Arthritis Rheum 2000 Feb; 29(4): 217-27
    Elenkov IJ - The sympathetic nerve-An integrative interface between two supersystems: the brain and the immune system - Pharmacol Rev 2000 Dec; 52(4):595-638
    Perrin R - Effectiveness of osteopathic treatment on symptoms associated with ME - J of Med Eng & Tech; Vol 22 , number 1 Jan/Feb 1998 1-12.
    Rosner MJ - Spinal Stenosis in Fibromyalgia patients - conference report Oct 1997 Portland USA.
    Yunus MB - Genetic linkage analysis of multicase families with FM syndrome-Immune support.com 02-02-1999

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    Hypercoagulability
    Ang YS - Randomised comparison or unfractionated heparin with corticosteroids in severe chronic Inflammatory Bowel Disease - Aliment Pharmacol Ther 2000 Aug; 14(8): 1015-22
    Berg D- CFS/FM as a variation of the Antiphospholipid Antibody syndrome - Blood Coag & Fibrinolysis 1999, 10: p 1-4
    Bradford R- Oxidology 2nd Edition pg. 658-669

    Hannan KL- activation of the coagulation system in Gulf War Illness: a potential pathophysiologic link with chronic fatigue syndrome. A laboratory approach to diagnosis - Blood Coag and Fibrinolysis 2000 Oct; 11(7):673-8

    Mycoplasma
    Vojdani A - Detection of Mycoplasma genus by PCR in patients with CFS- FEMS Immunol Med Microbiol 1998 Dec; 22(4):355-65
    Vojdani A - Multiplex PCR for the detection of M fermentans, M hominis, and M penetrans in patients with CFS, FM, RA and Gulf War illness - J of CFS 1999;5:187-197
    Nicholson GL - Chronic infections as a common aetiology for many patients with CFS, FM and GWI - Intern J of Med 1998;1:42-46
    Nicholson GL - Identification and treatment of chronic infections in CFIDS, Fibromyalgia and RA - CFIDS Chronicle 1999;12(3):19-21
    Nicholson GL - Role of Mycoplasma infections in Fatigue Illnesses - J Chronic Fatigue Syndr 2000;6(3/4):23-39

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    Oxidative Stress
    Adrie C - Contrasting effects of NO and peroxynitrite on hsp70 expression and apoptosis in human monocytes - J Am Physiol Cell Physiol 2000 Aug;279(2): c452-60
    Fulle S - Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome - Free Radical Biol Med 2000 Dec 15;29(12):1252-9
    Grzelak A- Inactivation of antioxidant enzymes by peroxynitrite-Scan J Clinic Lab Invest 2000 Jul(4):253-8
    Manuel y Keenoy B - Magnesium status and parameters of oxidative stress- J Am Coll Nutrit 2000 Jun;19(3):35-41
    Pall ML- Elevated Peroxynitrite as the cause of chronic fatigue syndrome-Med Hypotheses 2000 Jan; 54(1):115-25
    Richards RS - Blood Parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome-Redox Report 2000;5(1):35-41

    Heat shock proteins / Candida
    Ashman RB - Production and function of cytokines in natural and acquired immunity to Candida - Microbiol review 1995 Dec;59(4):646-72
    De Maio A - Heat shock proteins: facts, thoughts and dreams - Shock 1991 Jan;11(1):1-12
    Eroles - The cloning of a fragment encoding part of a 70kDa hsp protein of C. albicans - FEMS Microbiol Letters 1995 April 15;128(1):95-100
    Leung FS - The immunology of heat shock proteins - J Ivest Allerg Clin Immunol 1991 Feb;1:23-30
    Matthews R - Stress proteins in fungal disease - Med Mycol 1998; 36 Suppl 1:45-51
    Moseley P- Stress proteins and the immune response - Immunopharmacology 2000 Jul 25;48(3):299-302
    Matthews R - The cloning of a DNA sequence of a major fragment of the 47 kDa hsp of C. albicans - FEMS Microbiol letters 1989 Jul 1;51(1): 25-30
    Nakagawa Y - The expression of C. albicans catalase gene in response to hydrogen peroxide - Microbiol Immunol 1999;43(7): 645-51
    Rajapandi T - The molecular chaperones hsp 90 and 70 are both necessary and sufficient to activate glucocorticoid receptors- J Biol Chem 2000 Jul 21;275(29):22597-604
    Rokutan K - Implications of hsp proteins for health and disease - J Med Invest 1998 Feb; 44(3-4):137-47
    Wick G - Atherosclerosis as an autoimmune disease due to an immune reaction against hsp 60-Herz 2000 Mar;25(2): 87-90
    Yannai S - Transformation of inorganic mercury by C albicans - App and Environ Microbiol Jan 1991 p 245-47

    Treatment
    Ali M - Efficacy of an Ecologic approach for the reversal of Fibromyalgia - J of Integrative Medicine Vol 3 1999 No 1 p 48-64
    Ali M - Oxidative regression to Primordiol Cellular Ecology (ORPEC) - J of Integrative Medicine Vol 2 no 1 spring 1998 p 4-56
    Cox, Campbell and Dowson D - Red Cell Mg in CFS (ME) - Lancet1991 Mar 30;337(8744): 757-60
    Forsyth LM - Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome - Ann Allergy Asthma 1999 Feb; 82(((2): 185-91
    Forsyth LM - The measurement of 5-HIAA urinary concentrations as a predictive marker of efficacy in chronic fatigue syndromes - presented at the Oct 1998 Am Ass of CFS Conference
    Heap LC - Vitamin B status in patients with CFS - J R Soc. Med Apr; 92(4): 183-5
    Manuel y Keenoy B - Magnesium status and parameters of the oxidant-antioxidant balance in patients with CFS - J Am Coll Nutr 2000 Jun;19(3):374-82
    Regland - Increased concentrations of homocysteine in the CFS of patients with Fibromyalgia and CFS- Scand J Rheumatol 1997; 26(4): 301-7
    Salvato P - A clinical trial of Somatomed in persons with Chronic Fatigue
    Syndrome - data on file Bayou City Medical Centre Texas - awaiting publication J of CFS.
    Streeten DH - The roles of orthostatic hypotension, orthostatic tachycardia and subnormal erythrocyte volume in the pathogenesis of chronic fatigue syndrome - Am J Med Sci 2000 Jul: 320(1):1-8
    Teitelbaum J - Effective treatment in severe chronic fatigue states - J of Musculoskeletal Pain - Feb 1996
    Teitelbaum J - A double blind study looking at effective treatment for CFS (ME) / Fibromyalgia - accepted for publication Journal Of Chronic Fatigue Syndromes

    Dr AJ Wright
    57 Chorley New Road
    Bolton
    BL1 4QR
    Phone 01204 366101
    Fax 01204 366112
    chronobiologyuk@yahoo.com


























  2. Mikie

    Mikie Moderator

    This is very comprehensive info and I appreciate your sharing it with us.

    Love, Mikie