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Co-Cure Weekly Digest of research and medical posts only - 15 Jan 2007 to 22 Jan 2007


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                                Date:    Tue, 16 Jan 2007 14:39:30 -0500
                                From:    "Bernice A. Melsky" <bernicemelsky verizon.net> 
                         
                                Subject: RES: A Pilot Study of the Efficacy of Heart Rate Variability  (HRV) Biofeedback in Patients with Fibromyalgia

                                A Pilot Study of the Efficacy of Heart Rate Variability (HRV) Biofeedback
                                in Patients with Fibromyalgia.

                                Appl Psychophysiol Biofeedback. 2007 Jan 12; [Epub ahead of print]

                                Hassett AL, Radvanski DC, Vaschillo EG, Vaschillo B, Sigal LH, Karavidas
                                MK, Buyske S, Lehrer PM.

                                Department of Medicine, Division of Rheumatology, University of Medicine
                                and Dentistry of New Jersey, Robert Wood Johnson Medical School
                                (UMDNJ-RWJMS), P.O. Box 19, MEB-484, New Brunswick, NJ, USA, <a.hassett umdnj.edu>.

                                PMID: 17219062


                                Fibromyalgia (FM) is a non-inflammatory rheumatologic disorder
                                characterized by musculoskeletal pain, fatigue, depression, cognitive
                                dysfunction and sleep disturbance. Research suggests that autonomic
                                dysfunction may account for some of the symptomatology of FM. An open label
                                trial of biofeedback training was conducted to manipulate suboptimal heart
                                rate variability (HRV), a key marker of autonomic dysfunction.

                                Methods: Twelve women ages 18-60 with FM completed 10 weekly sessions of
                                HRV biofeedback. They were taught to breathe at their resonant frequency
                                (RF) and asked to practice twice daily. At sessions 1, 10 and 3-month
                                follow-up, physiological and questionnaire data were collected.

                                Results: There were clinically significant decreases in depression and pain
                                and improvement in functioning from Session 1 to a 3-month follow-up. For
                                depression, the improvement occurred by Session 10. HRV and blood pressure
                                variability (BPV) increased during biofeedback tasks. HRV increased from
                                Sessions 1-10, while BPV decreased from Session 1 to the 3 month follow-up.

                                Conclusions: These data suggest that HRV biofeedback may be a useful
                                treatment for FM, perhaps mediated by autonomic changes. While HRV effects
                                were immediate, blood pressure, baroreflex, and therapeutic effects were
                                delayed. This is consistent with data on the relationship among stress, HPA
                                axis activity, and brain function.

                            [Return to top]

                                ------------------------------

                                Date:    Tue, 16 Jan 2007 14:42:16 -0500
                                From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
                                Subject: RES: Fibromyalgia. Diagnostics - Disease Approach - Therapy

                                [Fibromyalgia. Diagnostics - Disease Approach - Therapy.]
                                [Article in German]

                                Med Klin (Munich). 2007 Jan;102(1):23-29.

                                Lakomek HJ, Lakomek M, Bosquet-Nahrwold K.

                                Klinik fur Rheumatologie und Physikalische Medizin, Klinikum Minden,
                                Friedrichstrasse 17, 32427, Minden, Deutschland, <rheumatologie klinikum-minden.de>.

                                PMID: 17221348


                                Fibromyalgia is a complex of symptoms predominantly affecting females and
                                consisting of widespread pain.Etiology and pathogenesis are not
                                sufficiently known yet, however, there is the assumption that fibromyalgia
                                is looked at as being an illness with biological, psychological, and social
                                aspects. Therefore, the treatment of fibromyalgia calls for a multimodal
                                therapy approach.

                                The importance of fibromyalgia has been recognized within the German health
                                system by creating the new ICD code M79.70 and by assigning fibromyalgia
                                its own rheumatologic DRG (I79Z).In future research of fibromyalgia special
                                attention needs to be placed upon gender-specific problems.

                            [Return to top]

                                ------------------------------

                                Date:    Tue, 16 Jan 2007 23:34:35 +0100
                                From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
                                Subject: RES,NOT: Small trial stirs hope for PWCs

                                Source: Scientific American
                                Date:   January 14, 2007
                                Author: Toni Clarke
                                URL:    http://www.sciam.com/article.cfm?chanID=sa003&articleID=BBFAC18D2EDB930651D866F44FCFCB62


                                Small trial stirs hope for chronic fatigue patients
                                ---------------------------------------------------

                                BOSTON (Reuters) - Shortly after hiking the Grand Canyon with his wife in
                                1988, Michael Manson, the co-founder of PetSmart Inc., came down with what
                                felt like the flu. So did business partner Jim Dougherty. The illness changed
                                their lives.

                                In both men, the flu-like symptoms triggered a more debilitating condition
                                known as chronic fatigue syndrome for which there is no known cure, and no
                                known cause. Its symptoms range from fatigue and vertigo to nausea, pain and
                                cognitive confusion.

                                Many in the medical community don't believe chronic fatigue syndrome is a real
                                disease. There is no diagnostic test for it. Patients are often referred to
                                psychiatrists on the assumption that their symptoms are psychosomatic.

                                But for those who suffer its symptoms, including Manson and Dougherty, a
                                former marine who served twice in Vietnam, the condition is all too
                                devastatingly real.

                                "We've been fighting this for 18 years, and we've tried every possible
                                treatment, from wing of bat to eye of newt," said Manson, who has spent months
                                at a time too weak to walk more than a block or even get out of bed.


                                Nothing worked - until now.

                                Last June, Manson went to see Dr. Jose Montoya, associate professor of
                                medicine at Stanford University and a specialist in infectious diseases who
                                believes the disorder may be caused - at least in some cases, by one or more
                                viruses.

                                Montoya had presented anecdotal data earlier that year at a conference in
                                Barcelona, Spain, which suggested an antiviral drug called Valcyte, made by
                                Swiss drugmaker Roche Holding AG, could be helpful in treating certain CFS
                                patients.

                                Montoya now has data on 25 CFS patients, nearly all of whom had high levels in
                                their blood plasma of antibodies to the human herpes virus 6 (HHV-6) and the
                                Epstein-Barr virus.

                                The data - presented recently at a conference in Fort Lauderdale, Florida -
                                were remarkably consistent. Nearly every patient responded to the drug,
                                Montoya said, and most of the responses were dramatic.

                                "Scientists have suspected viruses for years but have never been able to prove
                                it," said Kristin Loomis, executive director of the HHV-6 Foundation, a
                                non-profit group which funds research into HHV-6.

                                Last year Manson began a six-month course of Valcyte, which is approved to
                                treat transplant patients to prevent viral infection. At first he felt worse.
                                Then, after a few weeks, he began to improve. He started walking, every day a
                                little more.

                                Now, nearly seven months later, he is walking two or three miles a day and
                                working out with light weights. And he is working on new business ideas.

                                "Not only is my physical ability returning but my cognitive ability has come
                                back too," Manson said.

                                Even so, Montoya stresses that the study is extremely small and the results
                                may not be replicated in bigger trials, the first of which he hopes to start
                                within the next few months.

                                "In a field that has been so stigmatized, and so full of false hopes, I think
                                the patients and the field deserve the best kind of trial, keeping an open
                                mind to the possibility that it won't work," he said.

                                Roche has agreed to put up $1.5 million to fund the next, 30-patient study

                                "Whether we put serious money behind this will all depend on the outcome of
                                this next study," said Nigel Pluck, Roche's clinical science leader for
                                Valcyte. "This is a somewhat contentious area for the medical profession in
                                that CFS is not a disease that you can test for. It's a diagnosis that you
                                come to by excluding everything else."

                                Even if results of further studies are positive they will probably apply only
                                to those patients with active HHV-6 and Epstein-Barr viruses, as indirectly
                                measured by the number of antibodies produced to fight them, Montoya said.

                                But for those who appear to fit the profile, like Manson, the benefits could
                                be enormous. "We are very excited and holding our breath," he said.

                                --------
                                (c) 2007 Scientific American

                            [Return to top]

                                ------------------------------

                                Date:    Wed, 17 Jan 2007 12:45:07 -0500
                                From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
                                Subject: RES: Ca(2+) channel alpha(2)delta ligands: novel modulators of neurotransmission

                                Ca(2+) channel alpha(2)delta ligands: novel modulators of neurotransmission.

                                Trends Pharmacol Sci. 2007 Jan 9; [Epub ahead of print]

                                Dooley DJ, Taylor CP, Donevan S, Feltner D.

                                Department of CNS Pharmacology, Pfizer Global Research and Development, Ann
                                Arbor, MI 48105, USA.

                                PMID: 17222465


                                The term 'Ca(2+) channel alpha(2)delta ligands' has recently been applied
                                to an evolving drug class that includes gabapentin (Neurontin((R))) and
                                pregabalin (Lyrica((R))), and reflects significant progress over the past
                                decade in elucidating the mechanism of action of these drugs: a novel,
                                specific action at one of the subunits constituting voltage-sensitive
                                Ca(2+) channels.

                                Binding of these ligands to the alpha(2)delta subunit is considered to
                                explain their usefulness in treating several clinical disorders, including
                                epilepsy, pain from diabetic neuropathy, postherpetic neuralgia and
                                fibromyalgia, and generalized anxiety disorder.

                                The evidence indicates a relationship between alpha(2)delta subunit binding
                                and the modulation of processes that subserve neurotransmission. This
                                modulation is characterized by a reduction of the excessive
                                neurotransmitter release that is observed in certain neurological and
                                psychiatric disorders.

                          [Return to top]

                                ------------------------------

                                Date:    Thu, 18 Jan 2007 14:23:10 -0500
                                From:    "Richard A Van Konynenburg PhD <richvank aol.com> via Co-Cure
                                         Moderators"
                                Subject: RES: Why is the prevalence of chronic fatigue syndrome higher in women than in men?

                                WHY IS THE PREVALENCE
                                OF CHRONIC FATIGUE SYNDROME
                                HIGHER IN WOMEN THAN IN MEN?

                                by

                                Richard A Van Konynenburg, Ph.D.
                                (Independent Researcher and Consultant)


                                8th International IACFS Conference on
                                Chronic Fatigue Syndrome, Fibromyalgia
                                and other Related Illnesses

                                Ft. Lauderdale, Florida, U.S.A.
                                January 10-14, 2007


                                Epidemiological studies have found that the prevalence of CFS is
                                significantly higher in women than in men.


                                Jason et al. (1) found a ratio of 1.8 (women to men) in a community-based
                                study in Chicago, IL, USA, that included over 28,000 adults.

                                Reyes et al. (2) found a ratio of 4.5 (women to men) in a study in Wichita,
                                KN, USA, that included nearly 24,000 households.

                                Other studies in San Francisco, CA, USA (3), the U.K. (4), Australia (5),
                                Sweden (6), Iceland (7) and the Netherlands (8) have also found
                                significantly higher prevalence of CFS or CFS-like illness in women.



                                Children have been found to have a lower rate of incidence of CFS than
                                adults, and there does not appear to be an effect of gender on the
                                incidence of CFS in childhood:


                                Carter and Marshall (1995) (9)

                                Jordan et al. (2000) (10)

                                Chalder et al. (2003) (11)

                                Means et al. (2004) (12)

                                Jones et al. (2004) (13)

                                Farmer et al. (2004) (14)

                                ter Wolbeek et al. (2006) (15)



                                This suggests that the transition to a higher relative rate of incidence of
                                CFS in females occurs during adolescence, and thus that it may be related
                                to increases in production of the female sex hormones, which occur at that
                                time.



                                Hypothesis

                                1.  Many people with CFS have polymorphisms in the genes that code for the
                                detox enzymes that metabolize the estrogens, and in particular the dominant
                                estrogen, estradiol.

                                2.  These polymorphisms can be expected to occur equally in males and
                                females, since these genes are autosomal (i.e. they are located on non-sex
                                chromosomes).  However, these polymorphisms would be particularly important
                                in women who are in their potentially reproductive years, because of the
                                higher production of estradiol in these women.

                                3.  One result of the presence of these polymorphisms would be to increase
                                the levels of semiquinones and quinones (16).

                                4.  Semiquinones and quinones react back and forth between each other in a
                                process that generates superoxide ions and is called redox cycling (17).

                                5.  This redox cycling would produce an additional contribution to
                                oxidative stress in these women that does not occur in men.  Men's bodies
                                produce much lower amounts of estradiol (by the action of aromatase on
                                testosterone), and the metabolism of the remainder of the testosterone
                                occurs by different pathways that do not involve redox cycling (18).

                                6.  According to the Glutathione DepletionMethylation Cycle Block
                                Hypothesis for the pathogenesis of CFS (19), oxidative stress depletes
                                glutathione, which leads to the onset of CFS.

                                7.  Therefore, women in their potentially reproductive years who have the
                                relevant polymorphisms would have an additional factor biasing them toward
                                onset of CFS that men do not have, and this would produce a higher
                                prevalence of CFS in women than in men.

                                (Note that this redox cycling mechanism is well established and has been
                                under study for several years because of its possible involvement in
                                carcinogenesis (16, 17).


                                Rates of Production of Estradiol in
                                Males and Females


                                PREPUBERTAL CHILDREN (20, 21):

                                         BOYS:  0.04 micrograms per day

                                         GIRLS:  0.3 micrograms per day



                                MEN:  50 micrograms per day (22)



                                WOMEN (by menstrual cycle stage) (22):

                                         Early follicular         36 micrograms per day
                                         Preovulatory             380 micrograms per day
                                         Midluteal                250 micrograms per day






                                Normal Metabolism of Estradiol by Detox Enzymes (23,24)

                                (See diagram http://www.co-cure.org/scan0004.bmp )

                                The metabolism of estradiol (and of the estrogens in general) is complex,
                                including a large number of alternative pathways and metabolites.


                                Most of the metabolism of estradiol occurs in the liver, while smaller
                                amounts occur in other organs, including breast, uterus, brain, kidneys and
                                ovaries.


                                Some estradiol is converted to estrone, and some is acted upon by various
                                CYP450 enzymes to form multiple hydroxylated metabolites.  Estradiol
                                itself, estrone and these hydroxylated metabolites can be conjugated by
                                other detox enzymes to form sulfates, glucuronides, or fatty acid
                                esters.  The various sulfate and glucuronide conjugates are the main
                                metabolites that are excreted in urine and stools. Only the major pathways
                                of estradiol metabolism are discussed in detail in the following.


                                The main hydroxylation reactions in the liver involve the CYP450 enzymes
                                CYP3A and CYP1A2, and their chief product is 2-hydroxyestradiol, which is a
                                catechol estradiol.


                                A smaller fraction of the total estradiol is metabolized by the enzyme
                                CYP1B1, located in organs other than the liver.  This reaction primarily
                                produces 4-hydroxyestradiol, another catechol estradiol.


                                Most of the catechol estradiols are O-methylated by the enzyme
                                catechol-O-methyltransferase (COMT) to form 2- and 4-methoxyestradiols,
                                which are excreted.


                                Some of the catechol estradiol molecules escape the COMT reaction and
                                instead are further oxidized by CYP1B1 to form semiquinones, which in turn
                                are oxidized to form quinones.  Normally, these are conjugated to
                                glutathione by the glutathione transferase (GST) superfamily of enzymes and
                                are excreted.



                                What would happen to estradiol metabolism if there were polymorphisms in
                                the detox enzymes?

                                (See diagram http://www.co-cure.org/scan0004.bmp )


                                CYP3A4 AND CYP1A2:  Known polymorphisms that lower the activity of these
                                enzymes would decrease the fraction of estradiol that is metabolized by
                                them in the liver.   This would have the effect of increasing the fraction
                                of estradiol that is metabolized in other organs by CYP1B1.

                                CYP1B1:  Known polymorphisms that raise its activity would cause a greater
                                rate of production of 4-hydroxyestradiol, and would also cause more of this
                                to be oxidized to form semiquinones and quinones (16).

                                COMT:  Known polymorphisms that lower its activity would decrease the
                                fraction of 4-hydroxyestradiol that is methylated, leaving more to be
                                oxidized to semiquinones and quinones.

                                GST enzymes:  Known polymorphisms that lower the activity of members of
                                this superfamily of enzymes would decrease the rate of removal of
                                semiquinones and quinones, leaving more of them to carry on redox cycling
                                and to contribute to oxidative stress (25).


                                Have any of the detox enzymes that metabolize estradiol been found to have
                                these polymorphisms at higher frequencies in people with CFS?

                                Of these enzymes, so far the only one that has been reported to have been
                                studied in CFS is COMT.

                                Goertzel et al. (26) found that they could distinguish CFS cases from
                                controls with an accuracy of 75% by using combinations of polymorphisms of
                                only five genes.  They reported that of the nine genes containing a total
                                of 28 polymorphisms that they considered, the gene for COMT was among the
                                three most important genes for distinguishing CFS cases from
                                controls.  They considered six COMT polymorphisms in their study.  (This
                                result is remarkable in view of the facts that the entire human genome
                                contains about 25,000 genes and several million polymorphisms, and this
                                demonstrates the importance of elevated frequencies of COMT polymorphisms
                                in CFS.)

                                Two studies (27,28) have found the COMT Val 158 Met polymorphism to have
                                significantly higher frequencies in people with fibromyalgia than in
                                controls.  (This may be relevant because of the high comorbidity between
                                CFS and fibromyalgia.)


                                What about polymorphisms in the CYP and GST enzymes in CFS?  Have they been
                                observed at elevated frequencies?


                                Although no studies have yet been published about the frequencies of
                                polymorphisms in the CYP enzymes or the glutathione transferases in CFS
                                relative to controls, the author has received anecdotal reports from
                                several people with CFS who have had these polymorphisms characterized, and
                                trends in the data suggest high frequencies for these polymorphisms in CFS,
                                also.


                                Conclusions

                                This hypothesis is consistent with known biochemistry, and in combination
                                with the Glutathione DepletionMethylation Cycle Block Hypothesis for the
                                pathogenesis of chronic fatigue syndrome (19), it provides a plausible
                                explanation for the observed higher prevalence of CFS in women, a feature
                                that has heretofore not been explained.

                                This hypothesis is also consistent with available evidence concerning the
                                elevated frequencies of polymorphisms in catechol-O-methyltransferase
                                (COMT) in CFS.

                                Controlled study in people with CFS of the frequencies of polymorphisms in
                                the other enzymes involved in the metabolism of estradiol appears to be
                                warranted.  Such study would test this hypothesis.  It would also shed
                                light on the pathogenesis of CFS, and perhaps on the pathogeneses of other
                                disorders important in women's health.



                                References

                                1.  Jason, L.A., Richman, J.A., Rademaker, A.W. et al., A community-based
                                study of chronic fatigue syndrome, Arch. Intern. Med. 159 (18), 2129-2137
                                (1999).

                                2.  Reyes, M., Nisenbaum, R., Hoaglin, D. et al., Prevalence and incidence
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                                3.  Steele, L., Dobbins, J.G., Fukuda, K. et al., The epidemiology of
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                                (1998).

                                4.  Gallagher, A.M., Thomas, J.M., Hamilton, W.T. and White, P.D.,
                                Incidence of fatigue symptoms and diagnoses presenting in UK family care
                                from 1990 to 2001, J. Royal. Soc. Med. 97, 571-5 (2004).

                                5.  Lloyd, A.R., Hickie, I., Boughton, C.R. et al., Prevalence of chronic
                                fatigue syndrome in an Australian population, Med. J. Australia 153, 522-8
                                (1990).

                                6.  Evengard, B., Jacks, A., Pedersen, N. and Sullivan, P.F., The
                                epidemiology of chronic fatigue in the Swedish Twin Registry, Psych. Med.
                                35, 1317-26 (2005).

                                7.  Lindal, E., Stefansson, J.G., and Bergmann, S., The prevalence of
                                chronic fatigue syndrome in Icelanda national comparison by gender drawing
                                on four different criteria, Nordic J. of Psychiatry 56 (4), 273-7 (2002).

                                8.  Bazelmans, E., Vercoulen, J.H., Galama, J.M. et al., Prevalence of
                                chronic fatigue syndrome and primary fibromyalgia syndrome in the
                                Netherlands, Ned. Tijdschr. Geneeskd. 141 (31), 1520-3 (1997).

                                9.  Carter, B.D. and Marshall, G.S., New developments:  diagnosis and
                                management of chronic fatigue in children and adolescents, Current Problems
                                in Pediatrics 25, 281-93 (1995).

                                10. Jordan, K.M., Ayers, P.M., Jahn, S.C. et al., Prevalence of fatigue
                                syndrome-like illness in children and adolescents, J. Chronic Fatigue
                                Syndrome 6 (1), 3-21 (2000).

                                11. Chalder, T., Goodman, R., Wessely, S. et al., Epidemiology of chronic
                                fatigue syndrome and self reported myalgic encephalomyelitis in 5-15 year
                                olds; cross sectional study, BMJ 327, 654-5 (2003).

                                12. Mears, C.J., Taylor, R.R., Jordan, K.M. and Binns, H.J.,
                                Sociodemographic and symptom correlates of fatigue in an adolescent primary
                                care sample, J. Adolesc. Health 35, 528.e21-528.e26 (2004).

                                13. Jones, J.F., Nisenbaum, R., Solomon, L. et al., Chronic fatigue
                                syndrome and other fatiguing illnesses in adolescents: a population-based
                                study, J. Adolesc. Health 35 (1), 34-40 (2004).

                                14. Farmer, A., Fowler, T., Scourfield, J., and Thapar, A., Prevalence of
                                chronic disabling fatigue in children and adolescents, Brit. J. Psychiat.
                                184, 477-81 (2004).

                                15. ter Wolbeek, M., van Doornen, L.J., Kavelaars, A., and Heijnen, C.J.,
                                Severe fatigue in adolescents:  a common phenomenon?, Pediatrics 117 (6),
                                e1078-86 (2006).

                                16. Sissung, T.M., Price, D.K., Sparreboom, A. and Figg, W.D.,
                                Pharmacogenetics and regulation of human cytochrome P450 1B1:  implications
                                in hormone-mediated tumor metabolism and a novel target for therapeutic
                                intervention, Mol. Cancer. Res. 4 (3), 135-50 (2006).

                                17. Liehr, J.G. and Roy, D., Free radical generation by redox cycling of
                                estrogens, Free Radical Biol. & Med. 8, 415-23 (1990).

                                18. Bhagavan, N.V., Medical Biochemistry, fourth edition, Harcourt/Academic
                                Press, Burlington, MA (2002) pp. 785-6.

                                19. Van Konynenburg, R.A., Glutathione depletionmethylation cycle block
                                hypothesis for the pathogenesis of chronic fatigue syndrome, poster paper,
                                this Conference.
                                20.  Klein, K.O., Baron, J., Colli, M.J. et al., Estrogen levels in
                                childhood determined by an ultrasensitive recombinant cell bioassay, J.
                                Clin. Invest. 94, 2475-80 (1994).

                                21.  Andersson, A.M.  and Skakkebaek, N.E., Exposure to exogenous estrogens
                                in food:  possible impact on human development and health, Eur. J.
                                Endocrin. 140, 477-85 (1999).

                                22. Yen, S.S.C., Jaffe, R.B. and Barbieri, R.L., Reproductive
                                endocrinology, 4th ed. Saunders (1999), as cited in Ganong, W.F., Review of
                                medical physiology, twenty-second edition, New York, Lange Medical
                                Books/McGraw-Hill (2005), p. 441.

                                23. Tsuchiya, Y., Nakajima, M. and Yokoi, T., Cytochrome P450-mediated
                                metabolism of estrogens and its regulation in human, Cancer Letts. 227,
                                115-24 (2005).

                                24. Raftogianis, R., Creveling, C., Weinshilboum, R., and Weisz, J.,
                                Chapter 6:  Estrogen metabolism by conjugation, J. Nat. Cancer Inst.
                                Monographs No. 27, 113-24 (2000).

                                25. Hachey, D.L, Dawling, S., Roodi, N. and Parl, F.F., Sequential action
                                of phase I and II enzymes cytochrome P450 1B1 and glutathione S-transferase
                                P1 in mammary estrogen metabolism, Cancer Res. 63, 8492-9 (2003).

                                26. Goertzel, B.N., Pennachin, C., Coelho, L. de S., et al., Combinations
                                of single nucleotide polymorphisms in neuroendocrine effector and receptor
                                genes predict chronic fatigue syndrome, Pharmacogenomics 7 (3), 475-83 (2006).

                                27. Gursoy, S., Erdal, E., Herken, H. et al., Significance of
                                catechol-O-methyltransferase gene polymorphism in fibromyalgia, Rheumatol.
                                Intl. 23, 104-7 (2003).

                                28. Garcia-Fructuoso, F.J., Beyer, K., and Lao-Villadoniga, J.I., Analysis
                                of Val 159 Met genotype polymorphisms in the COMT locus and correlation
                                with IL-6 and IL-10 expression in fibromyalgia syndrome, J. Clin. Res. 9,
                                1-10 (2006).

                          [Return to top]

                                ------------------------------

                                Date:    Thu, 18 Jan 2007 15:01:27 -0500
                                From:    "Richard A Van Konynenburg PhD <richvank aol.com> via Co-Cure Moderators"
                                Subject: RES: Glutathione Depletion--Methylation Cycle Block: A Hypothesis for the Pathogenesis of Chronic Fatigue Syndrome

                                GLUTATHIONE DEPLETION--METHYLATION CYCLE BLOCK:
                                A HYPOTHESIS FOR THE PATHOGENESIS OF CHRONIC FATIGUE SYNDROME

                                by

                                Richard A Van Konynenburg, Ph.D.
                                (Independent Researcher and Consultant)


                                8th International IACFS Conference on
                                Chronic Fatigue Syndrome, Fibromyalgia
                                and other Related Illnesses

                                Ft. Lauderdale, Florida, U.S.A.
                                January 10-14, 2007
                                INTRODUCTION AND HYPOTHESIS


                                At the Seventh International Conference of the AACFS in 2004, the author
                                proposed and defended the hypothesis that glutathione depletion is an
                                important part of the pathogenesis of CFS (1).

                                In the conclusions of that paper it was noted that it seemed likely that
                                there are vicious circle mechanisms involved in CFS that prevent
                                glutathione repletion from being the complete answer for treating this
                                disorder.

                                Recent autism research (2,3) suggests that in that disorder a vicious
                                circle involving the methylation cycle apparently chronically holds down
                                the level of glutathione.

                                The present author has recently proposed (4) that this same mechanism is
                                active in many cases of CFS.  This model for CFS will be referred to as the
                                Glutathione DepletionMethylation Cycle Block (GD-MCB) Hypothesis.

                                This mechanism appears to be capable of explaining and drawing together
                                numerous features of CFS that have been reported in the peer-reviewed
                                literature.



                                What is the methylation cycle,
                                and what does it do?
                                (See diagram http://www.co-cure.org/scan0003.bmp )

                                The methylation cycle (also called the methionine cycle) (5) is a major
                                part of the biochemistry of sulfur and of methyl (CH3) groups in the
                                body.  It is also tightly linked to folate metabolism and is one of the two
                                biochemical processes in the human body that require vitamin B12 (the other
                                being the methylmalonate pathway, which enables use of certain amino acids
                                to provide energy to the cells).

                                This cycle supplies methyl groups for a large number of methylation
                                reactions, including those that methylate (and thus silence) DNA (6), and
                                those involved in the synthesis of a wide variety of substances, including
                                creatine (7), choline (7), carnitine (8), coenzyme Q-10 (9), melatonin
                                (10), and myelin basic protein (11).  Methylation is also used to
                                metabolize the catecholamines dopamine, norepinephrine and epinephrine
                                (12), to inactivate histamine (13), and to methylate phospholipids (14),
                                promoting transmission of signals through membranes.

                                The role of the methylation cycle in the sulfur metabolism is to supply
                                sulfur-containing metabolites to form a variety of important substances,
                                including cysteine, glutathione, taurine and sulfate, via its connection
                                with the transsulfuration pathway (5).

                                This cycle balances the demands for methylation and for control of
                                oxidative stress (15)
                                How is the methylation cycle dysfunctional in autism, and how is this
                                related to
                                glutathione depletion?


                                In autism the methylation cycle was found by James et al. (2,3) to be
                                blocked at methionine synthase, which is the step involving methylation of
                                homocysteine to form methionine (see diagram).

                                Two effects of this block that they measured are a significant decrease in
                                the level of plasma methionine and lowering of the ratio of
                                S-adenosylmethionine to S-adenosylhomocysteine.  The latter causes a
                                decreased capacity for promoting methylation reactions (16).

                                In addition, they found (2,3) that the flow through the transsulfuration
                                pathway (see diagram) was also decreased, resulting in lower plasma levels
                                of cysteine and glutathione and a lowered ratio of reduced to oxidized
                                glutathione, all of which they measured.  This lowered ratio reflects a
                                state of oxidative stress (17).

                                The block in the methylation cycle and the glutathione problem were found
                                to be linked, since supplements used to restore the methylation cycle to
                                normal operation (methylcobalamin, folinic acid and trimethylglycine) also
                                restored the levels of reduced and oxidized glutathione (2).

                                Do genetic factors contribute to producing this methylation cycle
                                dysfunction in autism?

                                It is known from studies of twins that genetics plays an important
                                predisposing role in autism (18).  The fact that the rate of incidence of
                                autism has increased dramatically in recent years is evidence that there is
                                also an important environmental component in the development of cases of
                                autism (3), since the population's genetic inheritance is relatively
                                constant over much longer periods.

                                James et al. (3) found that there are measurable genetic differences
                                between children with autism and healthy controls. The differences they
                                measured are associated with genes that encode enzymes and other proteins
                                impacting the methylation cycle, the folate metabolism and the glutathione
                                system.

                                In particular they found differences in allele frequency and/or significant
                                gene-gene interactions for genes encoding the reduced folate carrier (RFC),
                                transcobalamin II (TCN2), catechol-O-methyltransferase (COMT),
                                methylenetetrahydrofolate reductase (MTHFR), and one of the glutathione
                                transferases (GST M1).

                                These genetic results, combined with the biochemical observations of
                                dysfunction in the methylation cycle, strongly suggest that variations in
                                genes associated with this cycle and its related biochemistry are involved
                                in the genetic predisposition to developing autism.


                                What evidence suggests that this same dysfunction and similar genetic
                                factors are also present in chronic fatigue syndrome?

                                1.  Methionine concentrations are reported to be below normal in both
                                plasma (19) and urine (20) in CFS patients.  Low methionine can be caused
                                by a methylation cycle block.


                                2.  Four magnetic resonance spectroscopy studies in CFS (21-24) have found
                                elevated choline-to-creatine ratios in various parts of the brain.  Both
                                choline and creatine arise partly from the diet and partly from synthesis
                                in the body.  Since the syntheses of these two substances are the main
                                users of methylation (7), a methylation deficit would be expected to
                                decrease the rate of synthesis of both of them, and hence to decrease their
                                levels in the cells.  When this occurred, it would be unlikely that their
                                ratio would remain the same, since the fractions of each supplied by
                                synthesis would not likely be the same, nor would the decrease in rates of
                                synthesis of these two substances likely to be proportional to their levels
                                in the cells. Since creatine synthesis is the greater user of methylation
                                (7), it might be expected that the choline-to-creatine ratio would
                                increase, as is observed.  It therefore appears that a methylation cycle
                                block could explain this well-replicated observation in CFS.

                                3.  Some substances that require methylation for their biosynthesis have
                                been found to be at below-normal levels in CFS patients, and/or patients
                                have been found to benefit by supplementing them.   This has been reported
                                in eleven of the studies in CFS of carnitine, beginning with the work of
                                Kuratsune et al. (25-34), both the studies of coenzyme Q10 (35, 36), a
                                study that included choline as phosphatidylcholine in a combination
                                supplement (37), and one recent study of melatonin (38) (though it should
                                be mentioned that earlier studies of melatonin in CFS found normal or
                                elevated levels, and/or did not find benefit from supplementation (see
                                review in ref. 39), suggesting that other issues in addition to the
                                methylation deficit might be involved in the case of melatonin.  See
                                "Magnesium depletion" later in this paper).

                                4.  Vitamin B12, which plays a key role in the methylation cycle and was
                                one of the supplements used to restore this
                                cycle in the autism work (2), has a long history (39,40) as one of the most
                                helpful of the essential nutrients in CFS when given in high-dosage
                                injections.  Lapp and Cheney (41, 42) found that in urine organic acids
                                testing of 100 CFS patients, 33% had elevated homocysteine, 38% had
                                elevated methylmalonate, and 13% had both (29,30).  The elevated
                                homocysteine implicates the methylation cycle,
                                What evidence suggests that this same dysfunction is also present in
                                chronic fatigue syndrome? (continued)

                                while the elevated methylmalonate indicates that the other pathway that
                                requires vitamin B12 showed deficiency as well.  Lapp and Cheney (42) found
                                that 50 to 80% of over 2,000 patients reported benefit from high-dose
                                vitamin B12 injections.  Evengard et al. (43) reported that vitamin B12
                                levels in the cerebrospinal fluid of 10 of 16 CFS patients were below their
                                detection limit of 3.7 pmol/L.  Regland et al. (44) found both low vitamin
                                B12 (in 10 out of 12 patients) and high homocysteine (in all 12 patients
                                studied) in the cerebrospinal fluid of CFS patients.  There were
                                significant correlations between these parameters and symptoms.

                                Regland et al. (45) performed an open trial in which they gave 1,000
                                microgram weekly injections of hydroxocobalamin for at least 3 months to
                                the 10 female patients from this study who had both low B12 and elevated
                                homocysteine.  They found that the treatment was significantly more
                                beneficial if the patient did not have the thermolabile allele of the
                                polymorphic gene for MTHFR.  They concluded that vitamin B12 deficiency was
                                probably contributing to the increased homocysteine levels.  They also
                                found that the effect of vitamin B12 supplementation was dependent on
                                whether the available methyl groups were further deprived by the existence
                                of thermolabile MTHFR.  This work implicated the methylation cycle in
                                What evidence suggests that this same dysfunction is also present in
                                chronic fatigue syndrome? (continued)

                                the pathogenesis of CFS, and it also pointed to the importance of a genetic
                                component, involving one of the same genes that have been implicated in
                                autism (3).

                                5.  Folinic acid was recently found to produce subjective improvement in
                                symptoms in 81% of 58 CFS patients tested (46).  This was also one of the
                                supplements used to restore the methylation cycle in the autism research (2).

                                6.  Many studies have reported evidence for oxidative stress in CFS (47-61).

                                7.  There have been several reports of depletion of reduced glutathione in
                                at least a substantial subset of CFS patients (49-51,
                                53,54,59,62).  Reduced glutathione augmentation is now widely used by CFS
                                clinicians, who have found that augmenting glutathione by various means has
                                been helpful to many of their patients (49,50,63-65).

                                8.  Polymorphisms in the gene coding for the COMT enzyme were found by
                                Goertzel et al. (66) to be some of the most important of those examined for
                                distinguishing CFS cases from controls.  As noted earlier, COMT is a
                                methyltransferase, associated with the methylation cycle.  In autism, the
                                COMT 472G>A polymorphism showed significant difference between cases and
                                controls (3).
                                If this same dysfunction is present in both autism and CFS, how can the
                                obvious differences between these two disorders be explained?

                                Major differences are seen in the gender ratio and in the symptoms of these
                                two disorders.
                                Autism is found primarily in boys, at a ratio of about 4 to1 (boys to
                                girls) (67), while CFS occurs mainly in adult women at a ratio measured at
                                1.8 to 1 (women to men) by Jason et al. (68) in one large epidemiological
                                study and 4.5 to 1 (women to men) by Reyes et al. (69) in another.
                                The most striking symptoms in autism involve the brain and are very
                                characteristic of this disorder.  They are described as follows by the
                                Diagnostic and Statistical Manual of Mental Disorders (70):
                                1. Qualitative impairment in social interaction, as manifested by at least
                                two of the following:
                                a. Marked impairment in the use of multiple nonverbal behaviors such as
                                eye-to-eye gaze, facial expression, body postures, and gestures to regulate
                                social interaction.
                                b. Failure to develop peer relationships appropriate to developmental level.
                                c. A lack of spontaneous seeking to share enjoyment, interests, or
                                achievements with other people (e.g., by a lack of showing, bringing, or
                                pointing out objects of interest).
                                d. Lack of social or emotional reciprocity.

                                2. Qualitative impairments in communication as manifested by at least one
                                of the following:
                                a. Delay in, or total lack of, the development of spoken language (not
                                accompanied by an attempt to compensate through alternative modes of
                                communication such as gestures or mime).
                                b. In individuals with adequate speech, marked impairments in the ability
                                to initiate or sustain a conversation with others.
                                c. Stereotyped and repetitive use of language or idiosyncratic language.
                                d. Lack of varied, spontaneous make-believe play or social imitative play
                                appropriate to developmental level.

                                3.    Restricted repetitive and stereotyped patterns of behavior,
                                interests, and activities, as manifested by at least one of the following:
                                a. Encompassing preoccupation with one or more stereotypic and restricted
                                patterns of interest that is abnormal either in intensity or focus.
                                b. Apparently inflexible adherence to specific, nonfunctional routines or
                                rituals.
                                c. Stereotypic and repetitive motor mannerisms (e.g., hand or finger
                                flapping or twisting, or complex whole-body movements).
                                d. Persistent preoccupation with parts of objects.
                                CFS involves a large variety of symptoms (71,72), the chief ones being
                                extreme fatigue, post-exertional malaise and/or fatigue, sleep dysfunction,
                                muscle pain, and symptoms involving the brain that are significant but less
                                profound than in autism (e.g. cognitive and memory difficulties).

                                The author proposes that these differences result at least in part from the
                                different ages at onset.  Autism develops early in life, before the brain
                                is completely developed and before puberty, while the onset of CFS occurs
                                after brain development is completed and (for the most part) after puberty.

                                Pangborn (73) has discussed five hypotheses that have been suggested to
                                explain the higher prevalence of autism in boys.  Of these, the one that
                                appears to be most consistent with the present author's hypothesis of a
                                common pathogenesis between CFS and autism is the one put forward by Geier
                                and Geier (74). Their hypothesis proposes
                                If this same dysfunction is present in both autism and CFS, how can the
                                obvious differences between these two disorders be explained? (continued)

                                that the higher prevalence of autism in boys results from the potentiation
                                of mercury toxicity by testosterone, while estrogen is protective.  There
                                is increasing evidence that mercury was a significant factor in the
                                etiology of many cases of autism, because mercury-containing thimerosol was
                                used as a preservative in vaccines given to them.  Since thimerosol was
                                removed from childhood vaccines, the number of new cases of
                                neurodevelopmental disorders, including autism, has been found to be
                                dropping (75).

                                The present author has proposed a hypothesis (76) to explain the higher
                                prevalence of CFS in women, involving an additional bias toward oxidative
                                stress due to redox cycling in the metabolism of estradiol when certain
                                polymorphisms are present.

                                With regard to symptoms, it seems likely that the role of methylation in
                                the formation of myelin basic protein (77) is at least part of the
                                explanation for the major problems in brain development in autism and the
                                symptoms that result from them.

                                Fatigue is not recognized to be a major feature of autism.  However, it
                                should be noted that the evaluation of fatigue is usually based on
                                self-report, which is not possible in children who are unable to
                                speak.  Also, it seems possible that fatigue may be manifested differently
                                in very young children as compared with adults.  Features such as
                                hyperactivity and irritability may reflect fatigue in these patients.

                                Chronic pain may also be difficult to identify and characterize in children
                                who do not have speech.  A recent paper suggests that chronic pain may be
                                the initial presenting symptom in cases of undiagnosed autism (78).

                                Many of the other phenomena found in CFS are also found in autism, but
                                historically they have not received as much attention in autism as the
                                brain-related symptoms, perhaps because the latter are so striking and
                                profound.  Some of the other phenomena that autism has in common with CFS
                                in addition to those already mentioned are elevated proinflammatory
                                cytokines (79), Th2 shift in the immune response (80), low natural killer
                                cell activity (81), mitochondrial dysfunction (82, 83), carnitine
                                deficiency (83), hypothalamus-pituitary-adrenal (HPA) axis dysfunction
                                (84), gut problems (85), and  sleep problems (86).



                                How does the Glutathione DepletionMethylation Cycle Block (GD-MCB)
                                Hypothesis explain other aspects of chronic fatigue syndrome?

                                Etiology:  According to the GD-MCB Hypothesis, CFS is caused by a
                                combination of two factors:
                                (1) a genetic predisposition (87), which is currently only partly known, and
                                (2) some combination of a variety of physical, chemical, biological and/or
                                psychological/emotional stressors, the particular combination differing
                                from one case to another (See Ref. 1 for a review.).

                                So far, polymorphisms in genes coding for the following proteins have been
                                found to be associated with CFS in general or with a subset:

                                         (1) Serotonin transporter (5-HTT) gene promoter (88)
                                         (2) Corticosteroid binding globulin (CBG) (89)
                                         (3) Tumor necrosis factor (TNF) (90)
                                         (4) Interferon gamma (IFN-gamma) (90)
                                         (4) Proopiomelanocortin (POMC) (91)
                                (5) Nuclear receptor subfamily 3, group C, member 1, glucocorticoid
                                receptor (66,91)
                                (6) Monoamine oxidase A (MAO A) (91)
                                (7) Monoamine oxidase B (MAO B) (91)
                                (8) Tryptophan hydroxylase 2 (TPH2) (66,91)
                                (9) Catechol-O-methyltransferase (COMT) (66)
                                How does the GD-MCB Hypothesis explain other aspects of chronic fatigue
                                syndrome?
                                (continued)

                                In addition, a COMT polymorphism has reported to be associated with
                                fibromyalgia (92, 93), and polymorphisms in the genes for the detoxication
                                enzymes CYP2D6 (cytochrome P450 2D6) and NAT2 (N-acetyl transferase 2) have
                                been found to be associated with multiple chemical sensitivities
                                (94).  These may be relevant to CFS because of its high comorbidities with
                                these two disorders.

                                All these proteins touch on the pathogenesis mechanism described in this
                                paper, which is what would be expected if this Hypothesis is valid.

                                With regard to the stressors found to precede onset of CFS, they are known
                                to raise cortisol secretion (prior to onset and early in the course of the
                                illness), to raise epinephrine secretion and to place demands on
                                glutathione, leading to oxidative stress (1).

                                According to this Hypothesis, when reduced glutathione is sufficiently
                                depleted and the oxidative stress therefore becomes sufficiently severe in
                                a person having the appropriate genetic predisposition, a block is
                                established at methionine synthase in the methylation cycle
                                (95,2,3).  Because the methylation cycle is located upstream of cysteine
                                and glutathione in the sulfur metabolism, these are further depleted, and a
                                vicious circle is formed.

                                Note that infectious pathogens are included among the possible biological
                                stressors that can contribute to the onset of CFS.  In particular, Borrelia
                                burgdorferi, the bacterium responsible for Lyme disease, has been found to
                                deplete glutathione in its host (96).  This may explain the very similar
                                pathophysiologies of chronic Lyme disease and CFS.  This may also explain
                                the epidemic clusters of CFS, which seem to have been produced by a
                                virulent infectious pathogen (or pathogens).  Perhaps the genetic factors
                                are less important in producing the onset if a very virulent pathogen is
                                present.

                                Epidemiology:  According to the GD-MCB Hypothesis, the prevalence of CFS is
                                determined by the frequency in the population of the combined presence of
                                certain genetic polymorphisms (yet to be completely identified) and of the
                                above described stressors occurring coincidentally in those having the
                                polymorphisms.  As noted earlier, the author has proposed that the higher
                                prevalence in women is a result of increased bias toward oxidative stress,
                                resulting from redox cycling in the metabolism of estradiol when certain
                                polymorphisms in detoxication enzymes are present (76).

                                Suppression of parts of the immune response:  Elevation of cortisol due to
                                long-term stressors causes a suppression of the cell-mediated immune
                                response and a shift to Th2 (97).

                                Depletion of reduced glutathione likewise causes a shift to Th2 (98, 99).

                                The elevation of cortisol prior to onset and in the early course of the
                                illness also (temporarily) suppresses inflammation (100).

                                The cytotoxicity of natural killer (NK) cells and CD8 T cells in CFS has
                                been found to be low, and Maher et al. found this to be associated with a
                                deficiency of perforin secretion (101).  According to the GD-MCB
                                Hypothesis, in CFS perforin secretion is inhibited by depletion of reduced
                                glutathione because glutathione is needed to form the disulfide bonds in
                                their proper configurations in secretory proteins (102).  Depletion of
                                glutathione therefore causes misfolding and recycle of perforin molecules,
                                which have twenty cysteine residues and thus ten disulfide bonds
                                (103).  This misfolding mechanism would affect other secretory proteins in
                                CFS that are synthesized in cells having glutathione depletion as well,
                                which may account for the observation of misfolded proteins in the spinal
                                fluid of CFS patients by Baraniuk et al. (104).

                                Proliferation of T lymphocytes is inhibited by the block in the folate
                                cycle, which inhibits production of new RNA and DNA (105).

                                Viral and intracellular bacterial reactivation:  According to the GD-MCB
                                Hypothesis, depletion of reduced glutathione is the trigger for the
                                reactivation of latent viral and intracellular bacteria in CFS.  The
                                infections found initially in a case of CFS are usually due to those
                                pathogens that are capable of residing in the body in the latent state,
                                suggesting that these infections arise by reactivation (106). In general,
                                intracellular glutathione depletion is associated with the activation of
                                several types of viruses (1, 107-111) as well as Chlamydia (112), and it
                                may account for reactivation of other latent intracellular bacteria as
                                well.  In herpes simplex type 1 viral infection, raising the glutathione
                                concentration inhibits viral replication by blocking the formation of
                                disulfide bonds in glycoprotein B (111).  Since glycoprotein B appears to
                                be present in all herpes virus types (113), it is likely that glutathione
                                depletion is responsible for reactivation of Epstein-Barr virus,
                                cytomegalovirus and HHV-6 in CFS.

                                The Coxsackie B3 virus genome is known to code for glutathione peroxidase,
                                a selenium-containing enzyme (114). Taylor has suggested (115) that such
                                viruses suppress the immune system of the host by depleting its selenium,
                                thus inhibiting the host's use of glutathione peroxidase.  Since
                                glutathione peroxidase makes use of glutathione, depletion of reduced
                                glutathione itself would therefore assist this virus in its mechanism of
                                infection.

                                Populations more deficient in selenium would be expected to be more
                                vulnerable to Coxsackie B3 infection.  It is interesting to note that
                                nearly all the studies of Coxsackie virus in CFS have come from the
                                UK.  The population there has become more deficient in selenium since the
                                1970s, when major sources of grain in the diet were changed to areas with
                                selenium-deficient soils (116).

                                Immune activation:  This occurs when the immune system detects the
                                reactivation of pathogens (117).

                                Activation of 2-5A, RNase-L pathway (118):  This pathway is activated by
                                interferon and double stranded RNA as part of the cellular response to
                                viral reactivation. According to the GD-MCB Hypothesis, RNase-L remains
                                activated in CFS because of the suppression of the cell-mediated immune
                                response and the consequent failure to defeat the viral infection (See
                                "Suppression of parts of the immune response," above.)

                                Mitochondrial dysfunction and the onset of physical fatigue:  As
                                hypothesized by Bounous and Molson (119), competition between the oxidative
                                skeletal muscle cells and the immune system for the decreased supply of
                                glutathione and cysteine causes depletion of reduced glutathione in the
                                skeletal muscles.  According to the GD-MCB Hypothesis, this inhibits the
                                glutathione peroxidase reaction and allows hydrogen peroxide to build
                                up.  This in turn probably exerts product inhibition on the superoxide
                                dismutase reaction, which allows superoxide, produced as part of normal
                                oxidative metabolism, to rise in the mitochondria of the oxidative skeletal
                                muscle cells.  Superoxide reacts with nitric oxide to produce
                                peroxynitrite, as Pall (120) has pointed out.  Superoxide also interacts
                                with aconitase in the Krebs cycle to inhibit it (121), and peroxynitrite
                                can cause partial blockades in the Krebs cycle and also the respiratory
                                chain (120, 122).  These reactions lower the rate of production of ATP, and
                                this constitutes mitochondrial dysfunction.  Since ATP is needed to power
                                muscle contraction, lack of it produces physical fatigue.

                                RNase-L cleavage, leading to formation of the low molecular weight version
                                (123):  Depletion of reduced glutathione removes inhibition of the activity
                                of calpain (124), which is located in the cytosol with RNase-L, and calpain
                                cleaves RNase-L (125).  (Elastase, the other enzyme found by Englebienne et
                                al. (125) to be able to cleave RNase-L in the laboratory, is confined to
                                granules and vesicles inside living cells (126), and thus is not in contact
                                with RNase-L.)

                                Failure to defeat viral and intracellular bacterial infections and
                                continuing immune activation:  According to the GD-MCB Hypothesis, these
                                occur because of depletion of reduced glutathione (127) and also because
                                the folate metabolism block prevents production of new DNA and RNA for
                                proliferation of T lymphocytes (105).

                                Depletion of magnesium:  There is a long history showing depletion of
                                magnesium in CFS and benefits of supplementation, both orally and by
                                injection (See review in Ref. 39).  Magnesium depletion may be responsible
                                for a variety of symptoms that are found in CFS (128), including
                                mitochondrial dysfunction, muscle twitching, muscle pain, sleep problems
                                and cardiac arrhythmia.  In connection with sleep problems, Durlach et al.
                                have found that magnesium depletion is associated with abnormalities in the
                                level of melatonin and dysregulation of biorhythms (129). Manuel y Keenoy
                                et al. (54) found that the subset of CFS patients that was resistant to
                                repletion of magnesium in their clinical study also showed glutathione
                                depletion.  It has also been found that glutathione depletion causes
                                magnesium depletion in red blood cells (130).  According to the GD-MCB
                                Hypothesis, the depletion of intracellular magnesium in CFS is another
                                result of depletion of reduced glutathione.

                                Buildup of toxins:  Glutathione depletion allows toxins, including heavy
                                metals, to build up, because there is not enough glutathione to conjugate
                                these toxins as rapidly as they enter the body.  Mercury is of particular
                                concern, because the population in general has considerable exposure to it
                                from dental amalgams, fish consumption, and environmental sources such as
                                nearby coal-fired power plants.  There is considerable clinical experience
                                of mercury buildup in CFS patients (1).  Immune testing has also shown
                                evidence that the immune system has responded to elevated mercury in CFS
                                patients (131-133).

                                Solidification of the vicious circle:  After the vicious circle has
                                developed involving the methylation cycle block and the depletion of
                                glutathione, another factor must come into play to lock in this situation
                                chronically.  It seems likely that buildup of toxins is the factor
                                responsible for this, by blocking the formation of methylcobalamin and thus
                                the activity of methionine synthase.  It has been shown that one of the
                                important roles of glutathione normally is to protect the very much smaller
                                (by six orders of magnitude) concentrations of cobalamins from reaction
                                with toxins by forming glutathionylcobalamin (134).  Without this
                                protection, cobalamins are vulnerable to reaction with a variety of
                                toxins.  An example is mercury.  It has been found that very small
                                concentrations of mercury are required to block the methionine synthase
                                reaction (135).  Because of this additional factor, attempts simply to
                                correct the glutathione depletion and the oxidative stress after the
                                cobalamins have reacted with toxins in most cases will not restore normal
                                function of the methylation cycle (1).

                                Neurotransmitter dysfunction:  The production of melatonin from serotonin
                                as well as the metabolism of the catecholamines require methylation, as
                                noted earlier, and according to the GD-MCB Hypothesis, they are inhibited
                                because of the decreased methylation capacity.  Also, genetic polymorphisms
                                involving enzymes in the neurotransmitter system have been found to be more
                                frequent in at least some subsets of CFS patients, as noted earlier.  These
                                factors cause dysfunction of the neurotransmitters.

                                Further development of mitochondrial dysfunction:  As the course of the
                                illness progresses, it is likely that other factors that result from
                                glutathione depletion and the methylation cycle block come into play and
                                further suppress the operation of the mitochondria.  These include the
                                buildup of toxins and infections, depletion of magnesium, and damage to the
                                phospholipid membranes of the mitochondria by oxidizing free radicals
                                (136).  Because the essential fatty acids in these membranes are
                                polyunsaturated, they are the most vulnerable to oxidation (137), and they
                                become depleted, at least in some CFS patients (See review in Ref. 39).


                                HPA axis blunting (138):  According to this Hypothesis, glutathione
                                depletion in the pituitary gland inhibits production of proopiomelanocortin
                                (POMC) (which has two disulfide bonds in its N-terminal fragment (139)),
                                and hence secretion of ACTH (which is part of POMC), by the same mechanism
                                as inhibition of perforin synthesis (102) (See "Suppression of parts of the
                                immune response," above.).  This results in the lowering of cortisol
                                secretion by the adrenal glands, which is a late finding in the course of
                                the illness (140).  As noted earlier, genetic polymorphisms in POMC may
                                also be involved in a subset of CFS patients (91).

                                Diabetes insipidus (excessive urination, thirst, decrease in blood volume):
                                According to this Hypothesis, glutathione depletion inhibits production of
                                arginine vasopressin (141), which has one disulfide bond (142), by the same
                                biochemical mechanism by which it inhibits perforin and ACTH synthesis
                                (102).  It is likely that the secretion of oxytocin, which also has one
                                disulfide bond and is also synthesized in the hypothalamus, is also
                                inhibited.  Measurements of oxytocin in CFS have not been reported, but
                                there is evidence that it is low in some fibromyalgia patients (143), which
                                may be relevant because of the high comorbidity of CFS and fibromyalgia.  A
                                clinician has reported benefit from oxytocin injections in fibromyalgia
                                patients (144).
                                How does the GD-MCB Hypothesis explain other aspects of chronic fatigue
                                syndrome? (continued)


                                Low cardiac output (145):  According to this Hypothesis, this occurs
                                because depletion of reduced glutathione in the heart muscle cells lowers
                                the rate of production of ATP, as in the skeletal muscle cells.  This
                                produces diastolic dysfunction as observed by Cheney (146, 147).  Both low
                                blood volume (see Diabetes insipidus, above), which produces low venous
                                return, and diastolic dysfunction, which decreases filling of the left
                                ventricle, produce low cardiac output.  In addition, in some cases, as
                                observed by Lerner et al., viral infections produce cardiomyopathy
                                (148).  According to the GD-MCB Hypothesis, this is a result of depletion
                                of reduced glutathione and suppression of cell-mediated immunity.  This is
                                another factor that can decrease cardiac output in CFS.

                                Orthostatic hypotension and orthostatic tachycardia (149):  According to
                                this Hypothesis, these occur because of low blood volume, low cardiac
                                output and HPA axis blunting (See Diabetes insipidus, Low cardiac output,
                                and HPA axis blunting, above.).

                                Loss of temperature regulation:  As pointed out by Cheney (146), this
                                occurs because of low cardiac output (see Low cardiac output, above), which
                                causes the autonomic nervous system to decrease blood flow to the
                                skin.  This removes the ability to regulate the rate of heat loss from the
                                skin.
                                How does the GD-MCB Hypothesis explain other aspects of chronic fatigue
                                syndrome?
                                (continued)


                                Hashimoto's thyroiditis (150) and elevated incidence of thyroid cancer
                                (151):  According to this Hypothesis, Hashimoto's thyroiditis occurs in CFS
                                because depletion of reduced glutathione  in the thyroid gland allows
                                damage to thyroglobulin by hydrogen peroxide, as proposed by Duthoit et al.
                                (152). In addition, hydrogen peroxide damage to DNA in the thyroid gland
                                may be responsible for the elevated incidence of cancer there.   Hydrogen
                                peroxide is produced normally by the thyroid to oxidize iodide in the
                                process of making thyroid hormones (153).

                                Increasing variety of infections (154) and inflammation (155):  According
                                to this Hypothesis, viral, intracellular bacterial and fungal infections
                                accumulate over time because the cell-mediated immune response is
                                dysfunctional (See "Suppression of parts of the immune response,"
                                above.).  Inflammation becomes more severe because of the decreased
                                secretion of cortisol later in the course of the illness (See "HPA axis
                                blunting," above), and because of the rise in histamine as a result of lack
                                of sufficient methylation capacity to deactivate it (156).

                                Slow gastric emptying (157) and gastroesophageal reflux:  According to this
                                Hypothesis, in CFS these result from mitochondrial dysfunction in the
                                parietal cells of the stomach, due to depletion of reduced glutathione,
                                which results in low production of stomach acid.  (Anecdotally, many CFS
                                patients have reported absence of eructation after ingestion of sodium
                                bicarbonate solution on an empty stomach, suggesting low stomach acid
                                status.) A slower rate of gastric emptying was found to be associated with
                                higher pH, i.e. lower acid status (158).

                                Gut problems: According to this Hypothesis, several of the above factors
                                converge to produce problems in the gut in CFS, often referred to as
                                irritable bowel syndrome (IBS).  These factors include glutathione
                                depletion, low cardiac output, immune suppression, low stomach acid
                                production, neurotransmitter dysfunction (note that serotonin plays a major
                                role in gut motility), and increasing variety of infections and inflammation.

                                The degree of abnormality of a lactulose breath test (indicating small
                                intestinal bacterial overgrowth) in fibromyalgia patients was found by
                                Pimentel et al. to be greater than in IBS patients without fibromyalgia
                                (159).  In addition, they found that the abnormality was correlated with
                                somatic pain (159).  (This may be relevant because of the high comorbidity
                                of CFS with fibromyalgia.)

                                Brain-related problems:  According to this Hypothesis, several of the above
                                factors also converge to produce problems in the brain.  These include
                                glutathione (and cysteine) depletion, low cardiac output, failure to defeat
                                infections and continued immune activation, neurotransmitter dysfunction,
                                decreased methylation capacity to maintain myelin, and increasing variety
                                of infections and inflammation.

                                Relapsing (Crashing) (160):  Many CFS patients have chronically low
                                glutathione levels. According to this Hypothesis, when the level of
                                stressors is temporarily increased, the levels of reduced glutathione
                                become more severely depleted, and this produces the so-called crashing
                                phenomenon. After a period of rest, reduced glutathione levels are
                                increased to the chronically low levels that existed prior to the increased
                                stressors.

                                Alcohol intolerance (161):  According to this Hypothesis, because of
                                mitochondrial dysfunction, the skeletal muscles of CFS patients depend more
                                than normal on glycolysis for ATP production.  Increased use of glycolysis
                                requires increased use of gluconeogenesis by the liver to convert lactate
                                and pyruvate back to glucose (Cori cycle).  In CFS, this is hampered by low
                                cortisol levels.  The metabolism of ethanol by the liver further inhibits
                                gluconeogenesis,
                                producing hypoglycemia and lactic acidosis.  This accounts for the alcohol
                                intolerance reported by many CFS patients.

                                Weight gain: According to this Hypothesis, the weight gain often seen in
                                CFS results from the inability to metabolize
                                carbohydrates and fats at normal rates, because of partial blockades in the
                                Krebs cycle produced by depletion of reduced glutathione.  Excess
                                carbohydrates are cycled back to glucose by gluconeogenesis, and ultimately
                                are converted to stored fat.

                                Low serum amino acid levels (19):  According to this Hypothesis, these
                                result from the burning of amino acids as fuel at higher rates than
                                normal.  Amino acids are able to enter the Krebs cycle by anaplerosis,
                                downstream of the partial blockades, so they can be used as fuel in place
                                of carbohydrates and fats.

                                The pathogenesis of CFS becomes increasingly complex as it proceeds,
                                because of the interactions and feedback loops that develop.  For this
                                reason, determining the cause-effect relationships for all the aspects of
                                the resulting pathophysiology is a problem that is exceedingly
                                difficult.  Nevertheless, understanding the etiology and early pathogenesis
                                provides a basis for developing a more effective treatment approach.


                                CONCLUSIONS

                                There is abundant and compelling evidence that the glutathione
                                depletionmethylation cycle block mechanism is an important part of the
                                pathogenesis for at least a substantial subset of chronic fatigue syndrome
                                patients.

                                A pathogenesis hypothesis based on this mechanism is capable of explaining
                                and unifying many of the published observations regarding chronic fatigue
                                syndrome, and it provides a basis for developing a more effective treatment
                                approach.



                                KEY TO DIAGRAM (See http://www.co-cure.org/scan0003.bmp )


                                The diagram shows the methylation cycle at the top right, the folate cycle
                                at the top left, and the transsulfuration pathway at the bottom right.

                                The enzymes that catalyze the reactions are shown in boxes:

                                BHMT                  Betaine homocysteine methyltransferase
                                CBS                      Cystathionine beta synthase
                                CDO                     Cysteine dioxygenase
                                CGL                     Cystathionine gamma lyase
                                GCL                     Glutamate cysteine ligase
                                GS                        Glutathione synthase
                                MAT                    Methionine adenosyltransferase
                                MS                       Methionine synthase
                                MSR                     Methionine synthase reductase
                                MTase                  Methyltransferase (a class of enzymes)
                                MTHFR               Methylene tetrahydrofolate reductase
                                SHT                      Serine hydroxymethyltransferase
                                TS                        Thymidylate synthase

                                Most of the metabolites are spelled out.  The ones that are abbreviated are
                                as follows:

                                DMG                              Dimethylglycine
                                SAH                      S-Adenosylhomocysteine
                                SAM                     S-Adenosylmethionine
                                THF                     Tetrahydrofolate
                                TMG                    Trimethylglycine (betaine)

                                The cofactor and coenzyme are as follows:

                                P5P                      Pyridoxal phosphate, the active form of
                                                                        Vitamin B6
                                B12                       Methylcobalamin, one of the active forms of
                                                                        Vitamin B12
                                REFERENCES

                                1.  Van Konynenburg, R.A., Is glutathione depletion an important part of
                                the pathogenesis of chronic fatigue syndrome? poster paper, Seventh
                                International AACFS Conference, Madison, WI, USA, October 2004, paper
                                available at http://www.phoenix-cfs.org/GluAACFS04.htm or at
                               
                               
http://www.personalconsult.com/articles/glutathioneandchronicfatigue.html.

                                2.  James, S.J., Cutler, P., Melnyk, S., Jernigan, S., Janak, L., Gaylor,
                                D.W., and Neubrander, J.A., Metabolic biomarkers of increased oxidative
                                stress and impaired methylation capacity in children with autism, Am. J.
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                                3.  James, S.J., Melnyk, S., Jernigan, S., Cleves, M.A., Halsted, C.H.,
                                Wong, D.H., Cutler, P., Bock, K., Boris, M., Bradstreet, J.J., Baker, S.M.,
                                and Gaylor, D.W., Metabolic endophenotype and related genotypes are
                                associated with oxidative stress in children with autism, Am. J. Med.
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                                4.  Van Konynenburg, R.A., Chronic fatigue syndrome and autism, Townsend
                                Letter for Doctors and Patients, October 2006, paper available at
                               
                               
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                                5.  Bhagavan, N.V., Medical Biochemistry, 4th edition, Harcourt Academic
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                                6.  Brenner, C., and Fuks, F., DNA Methyltransferases:  facts, clues,
                                mysteries, Curr. Top. Microbiol. Immunol. (2006); 301: 45-66.

                                7.  Brosnan, J.T., Jacobs, R.L., Stead, L.M., and Brosnan, M.E.,
                                Methylation demand:  a key determinant of homocysteine metabolism, Acta
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                                8.  Bhagavan, N.V., Medical Biochemistry, 4th edition, Harcourt Academic
                                Press, San Diego, CA, U.S.A. (2002), pp. 367-368

                                9.  Jonassen, T., and Clarke, C.F., Isolation and functional expression of
                                human COQ3, a gene encoding a methyltransferase required for ubiquinone
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                                10. Bhagavan, N.V., Medical Biochemistry, 4th edition, Harcourt Academic
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                                11. Kim, S., Lim, I.K., Park, G.H., and Paik, W.K., Biological methylation
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                                12. Bhagavan, N.V., Medical Biochemistry, 4th edition, Harcourt Academic
                                Press, San Diego, CA, U.S.A. (2002), p. 763.

                                13. Bhagavan, N.V., Medical Biochemistry, 4th edition, Harcourt Academic
                                Press, San Diego, CA, U.S.A. (2002), p. 362.

                                14. Hirata, F., and Axelrod, J., Phospholipid methylation and biological
                                signal transmission, Science (1980); 209 (4461): 1082-1090.

                                15. Mosharov, E., Cranford, M.R., and Banerjee, R., The quantitatively
                                important relationship between homocysteine metabolism and glutathione
                                synthesis by the transsulfuration pathway and its regulation by redox
                                changes, Biochemistry (2000); 39 (42): 13005-13011.

                                16. Weir, D.G., and Scott, J.M., The biochemical basis of the neuropathy in
                                cobalamin deficiency, Baillieres Clin. Haematol. (1995); 8 (3): 479-497.

                                17. Nemeth, I., and Boda, D., The ratio of oxidized/reduced glutathione as
                                an index of oxidative stress in various experimental models of shock
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                                18.  Bailey, A., Le Couteur, A., Gottesman, I., Bolton, P., Simonoff, E.,
                                Yuzda, E., and Rutter, M., Autism as a strongly genetic disorder:  evidence
                                from a British twin study, Psychol. Med. 1995; 25: 63-77.

                                19. Bralley, J.A., and Lord, R.S., Treatment of chronic fatigue syndrome
                                with specific amino acid supplementation, J. Appl. Nutrit. 1994; 46 (3): 74-78.

                                20. Eaton, K.K. and Hunnisett, A., Abnormalities in essential amino acids
                                in patients with chronic fatigue syndrome, J. Nutrit. Environ. Med. 2004;
                                14 (2): 85-101.

                                21. Tomoda, A., Miike, T., Yamada, E., Honda, H., Moroi, T., Ogawa, M.,
                                Ohtani, Y., and Morishita, S., Chronic fatigue syndrome in childhood, Brain
                                & Development (2000); 22: 60-64.

                                22. Puri, B.K., Counsell, S.J., Saman, R., Main, J., Collins, A.G., Hajnal,
                                J.V. and Davey, N.J., Relative increase in choline in the occipital cortex
                                in chronic fatigue syndrome, Acta Psychiatr. Scand. (2002); 106: 224-226.

                                23. Chaudhuri, A., Condon, B.R., Gow, J.W., Brennan, D. and Hadley, D.M.,
                                Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue
                                syndrome, NeuroReport 2003; 14 (2): 225-228.

                                24. Levine, S., Cheney, P., Shungu, D.C. and Mao, X., Analysis of the
                                metabolic features of chronic fatigue syndrome (CFS) using multislice 1H
                                MRSI, abstract, conference syllabus, Seventh International AACFS Conference
                                on Chronic Fatigue Syndrome, Fibromyalgia and Other Related Illnesses,
                                Madison, WI, U.S.A., October 8-10, 2004.

                                25. Kuratsune, H, Yamaguti, K, Takahashi, M., Misaki, H., Tagawa, S., and
                                Kitani, T., Acylcarnitine deficiency in chronic fatigue syndrome, Clinical
                                Infectious Diseases (1994); 18(Suppl.): S62-S67.

                                26. Plioplys, A.V. and Plioplys, S., Serum levels of carnitine in chronic
                                fatigue syndrome:  clinical correlates, Neuropsychobiology (1995); 32: 132-138.

                                27. Majeed, T., De Simone, C., Famularo, G., Marcelline, S. and Behan,
                                P.O., Abnormalities of carnitine metabolism in chronic fatigue syndrome,
                                Eur. J. Neurol. (1995); 2: 425-428.

                                28. Grant, J.E., Veldee, M.S. and Buchwald, D., Analysis of dietary intake
                                and selected nutrient concentrations in patients with chronic fatigue
                                syndrome, J. Am. Dietet. Assn. (1996); 96: 383-386.

                                29. Plioplys, A.V. and Plioplys, S., Amantadine and L-carnitine treatment
                                of chronic fatigue syndrome, Neuropsychobiology (1997); 35: 16-23.

                                30. Kuratsune, H., Yamaguti, K, Lindh, G., Evengard, B., Takahashi, M.,
                                Machii, T. et al., Low levels of serum acylcarnitine in chronic fatigue
                                syndrome and chronic hepatitis type C, but not seen in other diseases,
                                Intl. J. Molec. Med. (1998); 2: 51-56.

                                31. Vermeulen, R.C., Kurk, R.M., and Scholte H.R., Carnitine,
                                acetylcarnitine and propionylcarnitine in the treatment of chronic fatigue
                                syndrome, abstract, Proceedings of the Third International Clinical and
                                Scientific Meeting on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
                                (2001), Alison Hunter Memorial Foundation, P.O. Box 2093, BOWRAL, NSW 2576,
                                Australia.

                                32. Vermeulen, R.C. and Scholte, H.R., Exploratory open label, randomized
                                study of acetyl- and propionylcarnitine in chronic fatigue syndrome,
                                Psychosom. Med. (2004); 66 (2): 276-282.

                                33. Li, Y.J., Wang, D.X., Bai, X.L., Chen, J., Liu, Z.D., Feng, Z.J., and
                                Zhao, Y.M., Clinical characteristics of patients with chronic fatigue
                                syndrome:  analysis of 82 cases, Zhonghua Yi Xue Za Zhi (2005); 85 (10):
                                701-704.

                                34. Vermeulen, R.C., and Sholte, H.R., Azithromycin in chronic fatigue
                                syndrome (CFS), an analysis of clinical data, J. Translat. Med. (2006); 4: 34.

                                35. Langsjoen, P.H., Langsjoen, P.H. and Folkers, K., Clin. Investig.
                                (1993); 71(8 Suppl): S140-S144.

                                36. Bentler, S.E., Hartz, A.J., and Kuhn, E.M., Prospective observational
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                                (2005); 66 (5): 625-32.

                                37. Nicolson, G.L., and Ellithorpe, R., Lipid replacement and antioxidant
                                nutritional therapy for restoring mitochondrial function and reducing
                                fatigue in chronic fatigue syndrome and other fatiguing illnesses, J.
                                Chronic Fatigue Syndrome (2006); 13 (1): 57-68.

                                38. van Heukelom, R.O., Prins, J.B., Smits, M.G. and Bleijenberg, G.,
                                Influence of melatonin on fatigue severity in patients with chronic fatigue
                                syndrome and late melatonin secretion, Eur. J. Neurol. (2006); 13 (1): 55-60.

                                39. Van Konynenburg, R. A., Chapter 27:  Nutritional approaches, Handbook
                                of Chronic Fatigue Syndrome, L. A. Jason et al., eds, John Wiley and Sons,
                                Hoboken, NJ, U.S.A. (2003), pp. 580-653.

                                40. Werbach, M.R., Nutritional strategies for treating chronic fatigue
                                syndrome, Alternative Medicine Review (2000); 5 (2): 93-108.

                                41. Lapp, C. W. and Cheney, P. R., The rationale for using high-dose
                                cobalamin (vitamin B-12), CFIDS Chronicle Physicians' Forum (Fall, 1993):
                                19-20, CFIDS Assn. of America.

                                42. Lapp, C.W., Using vitamin B-12 for the management of CFS, CFIDS
                                Chronicle (1999); 12 (6): 14-16, CFIDS Assn. of America.

                                43. Evengard, B., Nilsson, C.G., Astrom, G., Lindh, G., Lindqvist, L.,
                                Olin, R. et al., Cerebral spinal fluid vitamin B12 deficiency in chronic
                                fatigue syndrome, abstract, Proceedings of the American Association for
                                Chronic Fatigue Syndrome Research Conference, San Francisco, CA, U.S.A.
                                (October 13-14, 1996).

                                44. Regland, B., Andersson, M., Abrahamsson, L., Bagby, J., Dyrehag, L.E.,
                                and Gottfries, C.G., Increased concentrations of homocysteine in the
                                cerebrospinal fluid in patients with fibromyalgia and chronic fatigue
                                syndrome, Scand. J. Rheumatol. (1997); 26: 301-307.

                                45. Regland, B., Andersson, M., Abrahamson, L., Bagby, J., Dyrehag, L.E.,
                                and Gottfries, C.G., One-carbon metabolism and CFS, abstract, Proceedings
                                of the 1998 Sydney Chronic Fatigue Syndrome Conference, Alison Hunter
                                Memorial Foundation, P.O. Box 2093, BOWRAL NSW 2576, Australia.

                                46. Lundell, K., Qazi, S., Eddy, L., and Uckun, F.M., Clinical activity of
                                folinic acid in patients with chronic fatigue syndrome,
                                Arzneimittelforchung (2006); 56 (6): 399-404.

                                47. Ali, M., Ascorbic acid reverses abnormal erythrocyte morphology in
                                chronic fatigue syndrome, abstract, Am. J. Clin. Pathol. (1990); 94:515.

                                48. Ali, M., Hypothesis: chronic fatigue is a state of accelerated
                                oxidative molecular injury, J. Advancement in Med. (1993); 6 (2): 83-96.

                                49. Cheney, P.R., Evidence of glutathione deficiency in chronic fatigue
                                syndrome, American Biologics 11th International Symposium (1999), Vienna,
                                Austria, tape no. 07-199, available from Professional Audio Recording, P.O.
                                Box 7455, LaVerne, CA, 91750, U.S.A. (phone 1-800-227-4473).

                                50. Cheney, P.R., Chronic fatigue syndrome, lecture presented to the CFIDS
                                Support Group of Dallas-Fort Worth, Euless, TX, on May 15, 1999, video tape
                                obtained from Carol Sieverling, 513 Janann St., Euless, TX 76039, U.S.A.

                                51. Richards, R.S., Roberts, T.K., Dunstan, R.H., McGregor, N.R. and Butt,
                                H.L., Free radicals in chronic fatigue syndrome: cause or effect?, Redox
                                Report (2000); 5 (2/3): 146-147.

                                52. Richards, R.S., Roberts, T.K., McGregor, N.R., Dunstan, R.H., and Butt,
                                H.L., Blood parameters indicative of oxidative stress are associated with
                                symptom expression in chronic fatigue syndrome, Redox Report (2000); 5 (1):
                                35-41.

                                53. Fulle, S., Mecocci, P., Fano, G., Vecchiet, I., Vecchini, A.,
                                Racciotti, D., Cherubini, A., Pizzigallo, E., Vecchiet, L., Senin, U., and
                                Beal, M.F., Specific oxidative alterations in vastus lateralis muscle of
                                patients with the diagnosis of chronic fatigue syndrome, Free Radical Biol.
                                and Med. (2000); 29 (12): 1252-1259.

                                54. Manuel y Keenoy, B., Moorkens, G., Vertommen, J., Noe, M., Neve, J.,
                                and De Leeuw, I., Magnesium status and parameters of the
                                oxidant-antioxidant balance in patients with chronic fatigue: effects of
                                supplementation with magnesium, J. Amer. Coll. Nutrition (2000); 19 (3):
                                374-382.

                                55. Manuel y Keenoy, B., Moorkens, G., Vertommen, J., and De Leeuw, I.,
                                Antioxidant status and lipoprotein peroxidation in chronic fatigue
                                syndrome, Life Sciences (2001); 68: 2037-2049.

                                56. Vecchiet, J., Cipollone, F., Falasca, K., Mezzetti, A., Pizzigallo, E.,
                                Bucciarelli, T., De Laurentis, S., Affaitati, G., De Cesare, D.,
                                Giamberardino, M.A., Relationship between musculoskeletal symptoms and
                                blood markers of oxidative stress in patients with chronic fatigue
                                syndrome, Neuroscience Letts. (2003); 335: 151-154.

                                57. Smirnova, I.V., and Pall, M.L., Elevated levels of protein carbonyls in
                                sera of chronic fatigue syndrome patients, Molecular and Cellular Biochem.
                                (2003); 248: 93-95.

                                58. Jammes, Y., Steinberg, J.G., Mambrini, O., Bregeon, F., and Delliaux,
                                S., Chronic fatigue syndrome: assessment of increased oxidative stress and
                                altered muscle excitability in response to incremental exercise, J. Intern.
                                Med. (2005); 257 (3): 299-310.

                                59. Kennedy, G., Spence, V.A., McLaren, M., Hill, A., Underwood, C. and
                                Belch, J.J., Oxidative stress levels are raised in chronic fatigue syndrome
                                and are associated with clinical symptoms, Free Radic. Biol. Med. (2005);
                                39 (5): 584-589.

                                60. Maes, M., Mihaylova, I. and Leunis, J.C., Chronic fatigue syndrome is
                                accompanied by an IgM-related immune response directed against neopitopes
                                formed by oxidative or nitrosative damage to lipids and proteins, Neuro
                                Endocrinol. Lett. (2006); 27 (5): 615-621.

                                61. Richards, R.S., Wang, L., and Jelinek, H., Erythrocyte oxidative damage
                                in chronic fatigue syndrome, Arch. Med. Res. (2007); 38 (1): 94-98.

                                62. Kurup, R.K., and Kurup, P.A., Hypothalamic digoxin, cerebral chemical
                                dominance and myalgic encephalomyelitis, Intern. J. Neurosci. (2003); 113:
                                683-701.

                                63. Salvato, P., CFIDS patients improve with glutathione injections, CFIDS
                                Chronicle (Jan./Feb. 1998).  CFIDS Assn. of America.

                                64. Foster, J.S., Kane, P.C., and Speight, N., The Detoxx Book:
                                Detoxification of Biotoxins in Chronic Neurotoxic Syndromes, Doctor's Guide
                                (2003), available from http://www.detoxxbox.com.

                                65. Enlander, D., CFS Handbook, second edition, N.Y. CFIDS Assn., Comp
                                Medica Press, Medical Software Co., New York (2002), available from author
                                at 860 Fifth Avenue, New York, NY 10021, U.S.A.

                                66. Goertzel, B.N., Pennachin, C., Coelho, L. de S., et al., Combinations
                                of single nucleotide polymorphisms in neuroendocrine effector and receptor
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                                Yaqob, A., Mayer, W., Bieger, W., and Lindh, U., Metal-specific
                                lymphocytes: biomarkers for sensitivity in man, Neuroendocrinol. Lett.
                                (1999); 20 (5): 289-298.

                                132. Sterzl, I., Prochazkova, J., Hrda, P., Bartova, J., Matucha, P., and
                                Skejskal, V.D., Mercury and nickel allergy:  risk factors in fatigue and
                                autoimmunity, Neuroendocrinol. Lett. (1999); 20 (3-4): 221-228.

                                133. Marcusson, J.A., The frequency of mercury intolerance in patients with
                                chronic fatigue syndrome and healthy controls, Contact Dermatitis (1999);
                                41 (1): 60-61.

                                134. Watson, W.P., Munter, T., and Golding, B.T., A new role for
                                glutathione:  protection of vitamin B12 from depletion by xenobiotics,
                                Chem. Res. Toxicol. (2004); 17: 1562-1567.

                                135. Waly, M., Oltenau, H., Banerjee, R., Choi, S-W., Mason, J.B., Parker,
                                B.S., Sukumar, S., Shim, S., Sharma, A., Benzecry, J.M., Power-Charnitsky,
                                V-A., and Deth, R.C., Activation of methionine synthase by insulin-like
                                growth factor-1 and dopamine: a target for neurodevelopmental toxins and
                                thimerosol," Molec. Psychiat. (2004); 9: 358-370.

                                136.  Personal communication with Dr. Sarah Myhill of Wales, UK (2006),
                                based on laboratory analysis of Dr. John McLaren Howard of Biolab Medical
                                Unit in London, UK.  To be published.

                                137. Levine, S.A. and Kidd, P.M., Antioxidant adaptation: its role in free
                                radical pathology, Allergy Research Group, San Leandro, CA, U.S.A. (1986).

                                138. Demitrack, M.A., Dale, J.K., Straus, S.E., Laue, L., Listwak, S.J.,
                                and Kruesi, M.J., Evidence for impaired activation of the
                                hypothalamic-pituitary-adrenal axis in patients with chronic fatigue
                                syndrome, J. Clin. Endocrinol. Metab. (1991): 73 (6): 1224-1234.

                                139. Bennett, H.P., Seidah, N.G., Benjannet, S., Solomon, S., and Chretien,
                                M., Reinvestigation of the disulfide bridge arrangement in human
                                pro-opiomelanocortin N-terminal segment (hNT 1-76), Int. J. Pept. Protein
                                Res. (1986); 27 (3): 306-313.

                                140. Demitrack, M.A., Neuroendocrine correlates of chronic fatigue
                                syndrome: a brief review, J. Psychiatric Research (1997); 31 (1): 69-82.

                                141. Bakheit, A.M., Behan, P.O., Watson, W.S., and Morton, J.J., Abnormal
                                arginine-vasopressin secretion and water metabolism in patients with
                                postviral fatigue syndrome, Acta Neurol. Scand. (1993); 87 (3): 234-238.

                                142. Greenspan, F.S. and Gardner, D.G., Basic & Clinical Endocrinology,
                                seventh edition, Lange Medical Books/McGraw-Hill, New York (2004), p. 116.

                                143. Anderberg, U.M., and Uvnas-Moberg, K., Plasma oxytocin levels in
                                female fibromyalgia syndrome patients, Z. Rheumatol. (2000); 59 (6): 373-379.

                                144. Flechas, J., Oxytocin in the treatment of fibromyalgia, lecture
                                (2004), available from
                               
http://www.brodabarnes.org/audio_visual.htm, order number A126.

                                145. Peckerman, A., LaManca, J.J., Dahl, K.A., Chemitiganti, R., Qureishi,
                                B., and Natelson, B.H., Abnormal impedance cardiography predicts symptom
                                severity in chronic fatigue syndrome, Am. J. Med. Sci. (2003); 326 (2): 55-60.

                                146. Cheney, P.R., CFS & Diastolic Cardiomyopathy, lecture (June 18, 2005),
                                video tape obtained from Dallas-Fort Worth CFIDS Support Group, 513 Janann
                                St., Euless, TX 76039, U.S.A.

                                147. Cheney, P.R., Chronic fatigue syndrome:  the heart of the matter,
                                lecture (September 2006), DVDs obtained from Dallas-Fort Worth CFIDS
                                Support Group, 513 Janann St., Euless, TX 76039, U.S.A.

                                148. Lerner, A.M., Dworkin, H.J., Sayyed, T., Chang, C.H., Fitzgerald,
                                J.T., Begaj, S., Deeter, R.G., Goldstein, J., Gottipolu, P., and O'Neill,
                                W., Prevalence of abnormal cardiac wall motion in the cardiomyopathy
                                associated with incomplete multiplication of Epstein-Barr Virus and/or
                                cytomegalovirus in patients with chronic fatigue syndrome, In Vivo (2004);
                                18 (4): 417-424.

                                149. Stewart, J.M., Orthostatic intolerance, chapter 13, Handbook of
                                Chronic Fatigue Syndrome, L. A. Jason et al., eds, John Wiley and Sons,
                                Hoboken, NJ, U.S.A. (2003), pp. 245-280.

                                150. Wikland, B., Lowhagen, T., and Sandberg, P.O.. Fine-needle aspiration
                                cytology of the thyroid in chronic fatigue, Lancet (2001); 357 (9260): 956-957.

                                151. Hyde, B., paper at this Conference.  (The present author's review of
                                Dr. Hyde's 2004 preconference talk, in which he also discussed this topic,
                                can be found at either of the following
                                websites:                                
 
 
  

                                      http://phoenix-cfs.org/AACFS04Hyde.htm   or
                               
                               
http://www.pahealthsystems.com/archive308-2004-11-192561.html

                                152. Duthoit, C., Estienne, V., Giraud, A., Durand-Gorde, J.M., Rasmussen,
                                A.K., Feldt-Rasmussen, U., Carayon, P., and Ruf, J.,  Hydrogen
                                peroxide-induced production of 40 kDa immunoreactive thyroglobulin fragment
                                in human thyroid cells:  the onset of thyroid autoimmunity?, Biochem. J.
                                (2001); 360 (Pt 3): 557-562.

                                153. Ekholm, R. and Bjorkman, U., Glutathione peroxidase degrades
                                intracellular hydrogen peroxide and thereby inhibits intracellular protein
                                iodination in thyroid epithelium, Endocrinology (1997); 138: 2871-2878.

                                154. Nicolson, G.L., Gan, R., and Haier, J., Multiple co-infections
                                (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue
                                syndrome patients:  association with signs and symptoms, APMIS (2003); 111
                                (5): 557-566.

                                155. Buchwald, D., Werner, M.H., Pearlman, T., and Kith, P., Markers of
                                inflammation and immune activation in chronic fatigue and chronic fatigue
                                syndrome, J. Rheumatol. (1997), 24 (2): 372-376.

                                156. Bhagavan, N.V., Medical Biochemistry, fourth edition, Harcourt
                                Academic Press, San Diego, CA, U.S.A. (2002) p. 352.

                                157. Burnet, R.B., and Chatterton, B.E., Gastric emptying is slow in
                                chronic fatigue syndrome, BMC Gastroenterology (2004); 4: 32.

                                158. Emerenziani, S., and Sifrim, D., Gastroesophageal reflux and gastric
                                emptying, revisited, Curr. Gastroenterol. Rep. (2005); 7 (3): 190-195.

                                159. Pimentel, M., Wallace, D., Hallegua, D., Chow, E., Kong, Y., Park, S.,
                                and Lin, H.C., A link between irritable bowel syndrome and fibromyalgia may
                                be related to findings on lactulose breath testing, Ann. Rheum. Dis.
                                (2004); 63 (4): 450-452.

                                160. Nisenbaum, R., Jones, J.F., Unger, E.R., Reyes, M., and Reeves, W.C.,
                                A population-based study of the clinical course of chronic fatigue
                                syndrome, Health Qual. Life Outcomes (2003); 1 (1): 49.

                                161. Woolley, J., Allen, R., and Wessely, S., Alcohol use in chronic
                                fatigue syndrome, J. Psychosom. Res. (2004): 56 (2): 203-206.

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                                Date:    Thu, 18 Jan 2007 16:24:30 -0500
                                From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
                                Subject: RES: Growth Hormone Perturbations in Fibromyalgia: A Review

                                Growth Hormone Perturbations in Fibromyalgia: A Review.

                                Semin Arthritis Rheum. 2007 Jan 12; [Epub ahead of print]

                                Jones KD, Deodhar P, Lorentzen A, Bennett RM, Deodhar AA.

                                Assistant Professor of Nursing and Medicine, Oregon Health & Science
                                University School of Nursing and School of Medicine (Division of Arthritis
                                & Rheumatic Diseases), Portland.

                                PMID: 17224178


                                OBJECTIVE: Fibromyalgia (FM) is a syndrome characterized by chronic
                                widespread pain, fatigue, disrupted sleep, depression, and physical
                                deconditioning. In this article, we review the literature on the normal
                                activity of the hypothalamic-pituitary-growth hormone-insulin-like growth
                                factor-1 (HP-GH-IGF-1) axis and its perturbations in FM subjects.

                                METHODS: Studies included in this review were accessed through an English
                                language search of Cochrane Collaboration Reviews. Keyword MeSH terms
                                included "fibromyalgia," "growth hormone" (GH), or "insulin-like growth
                                factor-1" (IGF-1).

                                RESULTS: Twenty-six studies enrolling 2006 subjects were reviewed. Overall,
                                low levels of IGF-1 were found in a subgroup of subjects. Growth hormone
                                stimulation tests often revealed a suboptimal response, which did not
                                always correlate with IGF-1 levels. No consistent defects in pituitary
                                function were found. Of the 3 randomized placebo controlled studies, only 9
                                months of daily injectable recombinant GH reduced FM symptoms and
                                normalized IGF-1.

                                CONCLUSIONS: These studies suggest that pituitary function is normal in FM
                                and that reported changes in the HP-GH-IGF-1 axis are most likely
                                hypothalamic in origin. The therapeutic efficacy of supplemental GH therapy
                                in FM requires further study before any solid recommendations can be made.

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                                Date:    Thu, 18 Jan 2007 16:28:57 -0500
                                From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
                                Subject: RES: Autonomic activation and pain in response to low-grade mental stress in fibromyalgia and shoulder/neck pain patients

                                Autonomic activation and pain in response to low-grade mental stress in
                                fibromyalgia and shoulder/neck pain patients.

                                Eur J Pain. 2007 Jan 13; [Epub ahead of print]

                                Nilsen KB, Sand T, Westgaard RH, Stovner LJ, White LR, Bang Leistad R,
                                Helde G, Ro M.

                                Norwegian University of Science and Technology, Department of
                                Neurosciences, N-7489 Trondheim, Norway; St. Olavs Hospital Trondheim
                                University Hospital, N-7489 Trondheim, Norway.

                                PMID: 17224287


                                OBJECTIVE: Psychosocial stress is a risk factor for musculoskeletal pain,
                                but how stress affects musculoskeletal pain is poorly understood. We wanted
                                to examine the relationship between low-grade autonomic activation and
                                stress-related pain in patients with fibromyalgia and localised chronic
                                shoulder/neck pain.

                                METHODS: Twenty-three female patients with fibromyalgia, 29 female patients
                                with chronic shoulder-neck pain, and 35 healthy women performed a stressful
                                task lasting 60min. With a blinded study design, we recorded continuous
                                blood pressure, heart rate, finger skin blood flow and respiration
                                frequency before (10min), during (60min) and after (30min) the stressful
                                task. The physiological responses were compared with subjective reports of
                                pain.

                                RESULTS: The increase in diastolic blood pressure and heart rate in
                                response to the stressful task were smaller in fibromyalgia patients
                                compared with the healthy controls. Furthermore, fibromyalgia patients had
                                reduced finger skin blood flow at the end of the stressful task compared to
                                healthy controls. We also found an inverse relationship between the heart
                                rate response and development and recovery of the stress-related pain in
                                fibromyalgia patients.

                                CONCLUSION: We found abnormal cardiovascular responses to a 60min long
                                stressful task in fibromyalgia patients. Furthermore, we found a negative
                                association between the heart rate response and the pain which developed
                                during the stressful task in the fibromyalgia group, possibly a result of
                                reduced stress-induced analgesia for fibromyalgia patients.

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                                Date:    Thu, 18 Jan 2007 19:24:11 -0500
                                From:    Co-Cure Moderator <ray CO-CURE.ORG>
                                Subject: MED: The Role of Infection in Initiating ME/CFS

                                The Role of Infection in Initiating ME/CFS
                                by Dr. David S. Bell, MD

                                12-13-2006


                                This is a draft excerpt from ME/CFS expert Dr. David S. Bell's new book in
                                progress.* It outlines the role of various infectious agents in initiating
                                ME/CFS. Later chapters will discuss "how the infection sets off the
                                abnormal vascular and energy production problems that cause the symptoms."

                                It's a reasonable guess that 75 percent of all persons with ME/CFS were
                                previously healthy people who developed an infection and then never got
                                better, says Dr. Bell. "But does the infection that starts ME/CFS go away
                                after initiating a process - a 'hit and run' onset - or is the illness due
                                to a persisting infection?" It may be both.

                                Read this excerpt at 
                               
http://www.immunesupport.com/library/showarticle.cfm?id=7581

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                                ------------------------------

                                Date:    Fri, 19 Jan 2007 15:00:15 +0100
                                From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
                                Subject: RES,NOT,URL: ME-NET will move soon

                                ME-NET will move soon...

                                The new site already works so please update your links.

                                +-----------------------------------------------------+
                                |                      Home page                      |
                                +------+-------------------vvvvvv---------------------+
                                | Old  | http://www.me-net.dds.nl                     |
                                | New  | http://www.me-net.combidom.com               |
                                +------+-------------------^^^^^^^^^^^^---------------+
                                .                          |
                                +--------------------------+--------------------------+
                                |          Deep Link Transformation Protocol          |
                                +------+-------------------vvvvvv-----------vvvv------+
                                | Old  | http://www.me-net.dds.nl/path/file.html      |
                                | New  | http://www.me-net.combidom.com/path/file.htm |
                                +------+-------------------^^^^^^^^^^^^-----------^^^-+

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                                ------------------------------

                                Date:    Fri, 19 Jan 2007 12:27:35 -0500
                                From:    Rich Van Konynenburg <richvank AOL.COM>
                                Subject: RES, MED, ACT, NOT: CDs and DVDs of the recent IACFS conference are available

                                The recent 8th biennial conference of the International Association for
                                Chronic Fatigue Syndrome (Ft. Lauderdale, Florida, USA, January 10-14,
                                2007) was professionally taped this time for the
                                first time. It was done by Instatapes in Idaho. Their phone number is 1-
                                800-669-8273, and their fax number is 1-888-346-8273. Their address is
                                Insta-Tapes Media, P.O. Box 908, Coeur d'Alene, Idaho 83816-0908 USA.
                                They are offering three options: (1) audio CDs, (2) Mp3 audio, and (3)
                                DiGiVision DVD Rom. The third option is a video that shows the speaker
                                on half the screen and the Power Point slides on the other half, and of
                                course has the audio with them. The program order code for this
                                conference is CFS-061/062. They are offering recordings of either the
                                patient conference or the research conference or both, in all three of these
                                recorded options. Check with Insta-Tapes for the prices.
                                At the conference, they promised delivery within 10 days for the third
                                recorded option, and within 30 days for the other two options.

                                Rich Van Konynenburg, Ph.D.

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                                ------------------------------

                                Date:    Fri, 19 Jan 2007 12:43:29 -0500
                                From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
                                Subject: RES: Sensitivity disturbances in patients with irritable bowel syndrome and fibromyalgia

                                Sensitivity disturbances in patients with irritable bowel syndrome and
                                fibromyalgia.

                                Am J Gastroenterol. 2006 Dec;101(12):2782-9.

                                Caldarella MP, Giamberardino MA, Sacco F, Affaitati G, Milano A, Lerza R,
                                Balatsinou C, Laterza F, Pierdomenico SD, Cuccurullo F, Neri M.

                                Department of Medicine and Aging Sciences, Section of Internal Medicine and
                                Gastroenterology, Centre for the Study of Aging (Ce.S.I.), "Gabriele
                                D'Annunzio" University and Foundation, Chieti, Italy.

                                PMID: 17227524


                                BACKGROUND: Although visceral hypersensitivity is a common feature among
                                patients with irritable bowel syndrome (IBS), studies on somatic
                                sensitivity have given controversial results.

                                AIM: To assess visceral sensitivity in response to isotonic rectal
                                distensions and somatic sensitivity at different layers of the body wall
                                (skin, subcutis, and muscle) in patients with IBS and fibromyalgia (FM),
                                within and outside the area of abdominal pain referral.

                                MATERIALS AND METHODS: We studied 10 patients with IBS, 5 patients with FM,
                                9 patients with IBS+FM, and 9 healthy controls. Rectal distensions were
                                performed by increasing tension at 4 g steps up to 64 g or discomfort. Pain
                                thresholds to electrical stimulation were measured within and outside the
                                areas of abdominal pain referral.

                                RESULTS: Patients with IBS and IBS+FM demonstrated rectal hypersensitivity
                                in comparison to controls. The threshold of discomfort was 44  5 g in
                                IBS and 36  5 in IBS+FM patients, while patients with FM and healthy
                                controls tolerated all distensions without discomfort. In the areas of pain
                                referral, pain thresholds of all three tissues of the body wall were lower
                                than normal in all patients groups (p < 0.001). In control areas, the pain
                                thresholds were normal in skin, and lower than normal in subcutis and
                                muscle in IBS (p < 0.001). FM and IBS+FM demonstrated somatic
                                hypersensitivity at all sites (p < 0.001 vs healthy).

                                CONCLUSION: Our observations seem to indicate that, although sharing a
                                common hypersensitivity background, multiple mechanisms may modulate
                                perceptual somatic and visceral responses in patients with IBS and FM.

                          [Return to top]

                                ------------------------------

                                Date:    Fri, 19 Jan 2007 22:58:25 +0100
                                From:    "Dr. Marc-Alexander Fluks" <fluks@COMBIDOM.COM>
                                Subject: RES,NOT: CDC launches First-Ever CFS Awareness Campaign

                                Source: CDC News
                                Date:   November 22m 2006
                                URL:    http://www.cdc.gov/about/news/2006_11/cfs.htm
                                       
                                Photographs:    
         
                               
       
       
        http://www.cdc.gov/about/news/2006_11/images/gerberding_cfs_1.jpg
                                       
                                http://www.cdc.gov/about/news/2006_11/images/gerberding_cfs_2.jpg


                                [CDC News]

                                Launches First-Ever Chronic Fatigue Syndrome Awareness Campaign
                                ---------------------------------------------------------------

                                In 2004, the Centers for Disease Control and Prevention (CDC) created the
                                National Center for Health Marketing (NCHM) as part of its strategic
                                restructuring to confront urgent 21st-century health threats. For the
                                800,000 Americans who suffer from chronic fatigue syndrome but remain
                                undiagnosed CDC's pledge to translate its impeccable science into
                                accessible health information means they can now make more sound health
                                decisions.

                                Health marketing is vital in translating scientific data into usable
                                information and creating health messages that help Americans take a more
                                active role in making their health decisions. To convey these messages,
                                NCMH has championed several public awareness campaigns by developing
                                customer-centered and science-based strategies to protect and promote the
                                health of diverse populations.

                                NCHM's most recent effort makes available information and resources for
                                people affected by an illness that affects more than 1 million Americans
                                – 80 percent of whom have not been diagnosed. First recognized in the
                                mid-1980s and medically defined in 1988, Chronic Fatigue Syndrome (CFS) is
                                a debilitating illness that can be challenging to diagnose and treat.

                                After nearly 20 years of CDC and National Institutes of Health research, in
                                November the NCHM launched the first-ever CFS Public Awareness Campaign
                                designed to educate the American public and health care professionals about
                                who is at risk, the symptoms of the illness, treatment and management
                                options, the importance of seeking diagnosis and treatment, and the impact
                                of the illness on both patients and family members.


                                Get Informed. Get Diagnosed. Get Help.

                                The CFS Public Awareness Campaign kicked off November 3 during a press
                                briefing at the National Press Club in Washington, D.C. In launching the
                                campaign to target patients and health care professionals, CDC Director,
                                Julie L. Gerberding, M.D., M.P.H., was joined by Health and Human Services
                                Assistant Secretary of Health, John Agwunobi, M.D., and by CDC's leading
                                CFS researcher, William C. Reeves, M.D.

                                "As we continue to learn more and more about this illness, we want
                                clinicians as well as people who suffer from CFS to know about current
                                treatments which rely on a combination of strategies to deal with the most
                                problematic symptoms," said Dr. Gerberding. "Working together, patients and
                                health care professionals can achieve positive improvements in function and
                                quality of life at all stages."

                                To help achieve these improvements, the campaign provides public service
                                announcements for radio and television illustrating the impact of the
                                illness, educating people about how to recognize symptoms and referring
                                people to resources that can help. In addition the campaign features a
                                national photo exhibit and targets key stakeholder and partnership
                                development. It also includes a CFS Toolkit for Health Care Professionals
                                that provides fact sheets on symptoms, diagnosis and treatment options, as
                                well as patient brochures.

                                NCHM has also launched a comprehensive new Web site, http://www.cdc.gov/cfs,
                                with up-to-date information on CFS to provide easy to understand,
                                downloadable education tools for patients, their families and health care
                                professionals. By visiting the Web site, patients and caregivers can learn
                                basic facts about CFS, possible causes, "how to talk to you doctor" and
                                stay abreast on new knowledge and publications.

                                "It is important that health care providers be addressed not only through
                                medical industry channels, but through mass media venues to maximize
                                productive communication between providers and their patients," said NCHM
                                Director, Jay Bernhardt, PhD, MPH. "A coordinated campaign using consistent
                                messages and visual images will increase the impact of awareness efforts."


                                Working Together

                                "CDC has a large multidisciplinary research group that collaborates
                                internationally and is very committed to finding meaningful answers that
                                will ultimately help CFS patients," said Dr. Reeves. "CDC is really quite
                                serious about this research."

                                "Get Informed, Get Diagnosed and Get Help is something that [CDC] is very
                                proud to support in conjunction with the Chronic Fatigue and Immune
                                Dysfunctions Syndrome Association of America and the network of patients,
                                advocates and scientists across the [agency] and United States," said Dr.
                                Gerberding.

                                Strong partnerships and the creation of the NCHM have allowed CDC to extend
                                the reach of essential public health services and health promotions such as
                                the CFS campaign. These efforts have also contributed to CDC's readiness to
                                confront 21st-Century health threats while emerging as a modern, flexible,
                                goal-oriented agency entrusted to protect lives and improve health.

                                To learn more about how CDC has reorganized to face 21st century health
                                threats, visit:
                                 
                               
  
  
   http://www.cdc.gov/about/news/2006_10/reorg_facts.htm
                                
                                To learn more about CFS, visit:
                                 
                               
  
  
   http://www.cdc.gov/cfs/
                                
                                
                                To learn more about CDC's National Center for Health Marketing, visit:
                                 
                               
  
  
   http://www.cdc.gov/healthmarketing/
                                
                                --------
                                (c) 2006 CDC

                          [Return to top]

                                ------------------------------

                                Date:    Sat, 20 Jan 2007 10:47:54 +0100
                                From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
                                Subject: RES: CFS/ME & FM papers, published since December 2006

                                Source: NCBI PubMed
                                Date:   January 20, 2007
                                URL:    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
                                        Topic=((chronic fatigue) OR (myalgic encephalomyelitis)) OR fibromyalgia
                                Ref:    In the update, you will only find journals that are indexed by
                                        Medline (PubMed).
                                        All scientific papers 1938-today,
                                       
          
          
           http://www.me-net.combidom.com/library/literature.htm#publications
                                        Search scientific papers
                                       
          
          
           http://www.me-net.combidom.com/library/literature.htm#catalogue
                                        Figures computer analysis scientific papers,
                                       
          
          
           http://www.me-net.combidom.com/library/literature.htm#figure
                                        All popular papers 1900-today,
                                        http://www.me-net.combidom.com/library/literature.htm#popular


                                CFS/ME & FM papers, published since December 2006
                                -------------------------------------------------

                                ___ Caldarella MP, Giamberardino MA, Sacco F, Affaitati G, Milano A, Lerza R,
                                       Balatsinou C, Laterza F, Pierdomenico SD, Cuccurullo F, Neri M.
                                       Sensitivity disturbances in patients with irritable bowel syndrome and
                                       fibromyalgia.
                                       Am J Gastroenterol. 2006 Dec;101(12):2782-9.
                                ___ [No authors listed]
                                       New recommendations for fibromyalgia relief. Heated pool therapy,
                                       certain medications among new treatments.
                                       Health News. 2006 Nov;12(11):8-9.
                                ___ Nilsen KB, Sand T, Westgaard RH, Stovner LJ, White LR, Bang Leistad R,
                                       Helde G, Ro M.
                                       Autonomic activation and pain in response to low-grade mental stress
                                       in fibromyalgia and shoulder/neck pain patients.
                                       Eur J Pain. 2007 Jan 13.
                                ___ Jones KD, Deodhar P, Lorentzen A, Bennett RM, Deodhar AA.
                                       Growth Hormone Perturbations in Fibromyalgia: A Review.
                                       Semin Arthritis Rheum. 2007 Jan 12.
                                ___ Dooley DJ, Taylor CP, Donevan S, Feltner D.
                                       Ca(2+) channel alpha(2)delta ligands: novel modulators of
                                       neurotransmission.
                                       Trends Pharmacol Sci. 2007 Jan 9.
                                ___ Lakomek HJ, Lakomek M, Bosquet-Nahrwold K.
                                       Fibromyalgia. Diagnostics - Disease Approach - Therapy [German].
                                       Med Klin (Munich). 2007 Jan;102(1):23-29.
                                ___ Hassett AL, Radvanski DC, Vaschillo EG, Vaschillo B, Sigal LH,
                                       Karavidas MK, Buyske S, Lehrer PM.
                                       A Pilot Study of the Efficacy of Heart Rate Variability (HRV)
                                       Biofeedback in Patients with Fibromyalgia.
                                       Appl Psychophysiol Biofeedback. 2007 Jan 12.
                                ___ Dreyer L, Mellemkjaer L, Kendall S, Jensen B, Danneskiold-Samsoe B,
                                       Bliddal H.
                                       Increased cancer risk in patients referred to hospital with suspected
                                       fibromyalgia.
                                       J Rheumatol. 2007 Jan;34(1):201-6.
                                ___ Bach GL, Clement DB.
                                       Efficacy of Farabloc as an analgesic in primary fibromyalgia.
                                       Clin Rheumatol. 2007 Jan 11.
                                ___ Kim SH.
                                       Skin biopsy findings: Implications for the pathophysiology of
                                       fibromyalgia.
                                       Med Hypotheses. 2007 Jan 8.
                                ___ Goudsmit EM.
                                       The language of health care: Chronic fatigue syndrome.
                                       J R Soc Med. 2007 Jan;100(1):7.
                                ___ Katafuchi T, Kondo T, Take S, Yoshimura M.
                                       Brain Cytokines and the 5-HT System during Poly I:C-Induced Fatigue.
                                       Ann N Y Acad Sci. 2006 Nov;1088:230-7.
                                ___ Johnson EO, Kostandi M, Moutsopoulos HM.
                                       Hypothalamic-Pituitary-Adrenal Axis Function in Sjogren's Syndrome:
                                       Mechanisms of Neuroendocrine and Immune System Homeostasis.
                                       Ann N Y Acad Sci. 2006 Nov;1088:41-51.
                                ___ Hampton T.
                                       Chronic fatigue syndrome answers sought.
                                       JAMA. 2006 Dec 27;296(24):2915.
                                ___ Mayhew E, Ernst E.
                                       Acupuncture for fibromyalgia - a systematic review of randomized
                                       clinical trials.
                                       Rheumatology (Oxford). 2006 Dec 19.
                                ___ Stuifbergen AK, Phillips L, Voelmeck W, Browder R.
                                       Illness perceptions and related outcomes among women with fibromyalgia
                                       syndrome.
                                       Womens Health Issues. 2006 Nov-Dec;16(6):353-60.
                                ___ Wingenfeld K, Wagner D, Schmidt I, Meinlschmidt G, Hellhammer DH, Heim C.
                                       The low-dose dexamethasone suppression test in fibromyalgia.
                                       J Psychosom Res. 2007 Jan;62(1):85-91.
                                ___ Buskila D, Sarzi-Puttini P, Ablin JN.
                                       The genetics of fibromyalgia syndrome.
                                       Pharmacogenomics. 2007 Jan;8(1):67-74.
                                ___ Prins MA, Woertman L, Kool MB, Geenen R.
                                       Sexual functioning of women with fibromyalgia.
                                       Clin Exp Rheumatol. 2006 Sep-Oct;24(5):555-61.
                                ___ Morgan RM, Parry AM, Arida RM, Matthews PM, Davies B, Castell LM.
                                       Effects of elevated plasma tryptophan on brain activation associated
                                       with the Stroop task.
                                       Psychopharmacology (Berl). 2006 Dec 19.
                                ___ Carta MG, Cardia C, Mannu F, Intilla G, Hardoy MC, Anedda C, Ruggero V,
                                       Fornasier D, Cacace E.
                                       The high frequency of manic symptoms in fibromyalgia does influence
                                       the choice of treatment?
                                       Clin Pract Epidemol Ment Health. 2006 Dec 19;2(1):36.
                                ___ Wearden AJ, Chew-Graham C.
                                       Managing chronic fatigue syndrome in U.K. primary care: challenges
                                       and opportunities.
                                       Chronic Illn. 2006 Jun;2(2):143-53.
                                ___ Rona RJ, Fear NT, Hull L, Wessely S.
                                       Women in novel occupational roles: mental health trends in the UK
                                       Armed Forces.
                                       Int J Epidemiol. 2006 Dec 15.

                                --------
                                (c) 2007 NCBI PubMed

                          [Return to top]

                                ------------------------------

                                Date:    Sat, 20 Jan 2007 11:37:08 -0500
                                From:    "Pat Fero <bp.fero verizon.net> via Co-Cure Moderator" <ray CO-CURE.ORG>
                                Subject: NOT,RES: An informal IACFS conference summary - first take

                                An informal IACFS conference summary - first take.

                                Pat Fero, MEPD
                                WISCONSIN


                                I attended the 5 day IACFS conference, January 9 - 14 in Ft. Lauderdale,
                                and in many ways it was amazing. I am attempting, in general terms, to
                                describe what I heard. I can no longer take notes and listen, so I will
                                miss important things plus I show bias for my own personal interests.
                                Additionally, it is impossible to attend 5 days of presentations. Please
                                look for other conference summaries that will be extensive. You might
                                consider ordering the IACFS conference syllabus for $15 or choosing audio
                                and/or video options.  Call Insta-Tapes Media at 1 888 346 8273 for
                                ordering and pricing information.

                                Research findings and ideas:
                                   In general terms, many studies looked at exercise intolerance to try to
                                define what happens in the body.  The researchers and clinical scientists
                                are developing methods to measure cardiovascular, and cardiopulmonary
                                health in CFS patients. This relates to oxygen consumption. Several papers
                                in the main session and in the poster sessions showed that CFS patients
                                ability to do work (bike, treadmill)  is impaired if one measures how much
                                oxygen is used for the task. It's a mathematical computation based on
                                (age?) and body weight. Control groups varied. Normal, deconditioned and
                                those patients with primary depression were compared to CFS patients. One
                                interesting study showed that CFS patients will show extreme abnormalities
                                in a next day, second session of exercise. CFS patients do not recover in
                                24 hours =  intolerance.


                                Patients understand "overdoing" and "payback," but in research it is
                                wonderful to see US and international scientists defining methods to show
                                what we experience. Over and over again, I heard...THIS is a very abnormal
                                finding. In addition, one study showed that both mental and physical energy
                                expended can cause impairment.


                                What to do about it? Graded exercise therapy is ill advised. If a patient
                                has abnormal oxygen consumption, muscles will not have enough O2. If you
                                push yourself, this will start a cascade of events that lead to
                                relapse.  Yet, any kind of movement helps the body maintain some activity
                                tolerance and allows those chemicals recycled in muscle contraction to be
                                stimulated.


                                Along the same lines, it was hopeful to see several studies on cardiac
                                involvement and CFS. This would include work on viruses that seem to target
                                heart tissue (Martin Lerner), Inflammation and Arterial stiffness in
                                patients predictive of cardiovasular risk (Vance Spence), and the complex
                                lecture by Paul Cheney on "Diastolic Dysfunction in the Chronic Fatigue
                                Syndrome enhanced by Tilt-echocardiography."


                                Immunology/Infectious disease studies are back!  One researcher new to CFS,
                                presented a wonderful explanation of MD training and the infectious disease
                                model. Jose Montoya, Stanford University School of Medicine, said that
                                traditional training wraps around a short course disease model. A person
                                gets very ill, is treated if possible, then lives or dies.  Disease with an
                                infectious onset resulting in long term, chronic illness is not common and
                                is not emphasized in medical school training.


                                So why chronic illness with infectious onset?  Scientists need to look at
                                gene variance and to try to find abnormalities and commonalities in CFS
                                patients to see the disease process.  Montoya also discussed the changing
                                view of viruses. It was thought that one virus = one type of illness.(EBV
                                causes mononucleosis.) Apparently, with much more study on viral infection,
                                viruses in general, and the discovery of new viruses, we know that several
                                kinds of viruses or a combination can cause very similar illnesses. Viruses
                                mutate, and viruses adapt to the host. (That would be you and me.)


                                Genetics/Proteomics. How is the variability of the host reaction to viral
                                infection related to genetics? Again, investigations in this area surge
                                forward in all countries. Because the information is very technical and I
                                have no background, I cannot address this. However, the surge represents
                                keys unlocking doors for people with CFS.


                                Proteomics focuses on the structural and functional properties of proteins
                                and their expression. One investigation poses that a specific CFS related
                                proteome (like a profile) suggests a common pathophysiology for CFS, FM and
                                Persian Gulf War Illness. This research is a collaboration among three
                                academic institutions, Federal Institute of Technology, Zurich,
                                Switzerland, University of Michingan, Ann Arbor and Georgetown University
                                (PI James Baraniuk).


                                Medical Technology. I want to emphasize that thinking about fatigue in
                                scientific terms is changing and is cutting edge.   One session was called,
                                "New Methods for Evaluating the Fatigue State." A patient might think...oh
                                no...here we go again. However, the presentations that followed showed a
                                leap in how to think about fatigue.  -  "Spectroscopic diagnosis of Chronic
                                Fatigue Syndrome by visible and near-infrared spectroscopy in serum
                                samples."  - This complex presentation from Japanese researchers at the
                                Fatigue Clinical Center in Osaka, Japan, concluded that "Vis-NIR
                                spectroscopy for sera combined with chemometrics analysis could provide a
                                promising tool to objectively diagnose CFS." The team was able to determine
                                through blood, a "complete separation"  of 77 CFS patients from 71 healthy
                                controls


                                You knew you were sick!

                                New methods in viral studies using refined technology show further
                                abnormalities in subsets of CFS patients. I missed an entire session on
                                Sunday afternoon devoted to this, but smaller sessions from Wednesday
                                through Sunday, highlighted the work. With the support of the HHV6
                                Foundation, the founders, Kristin Loomis and Annette Whittemore and their
                                scientific advisor, Dr. Dharam Ablashi who discovered HHV6, interest is
                                renewed and generated in viral CFS investigations.


                                Case Definition and Epidemiology. Several sessions were devoted to the
                                various research and clinical case definitions of CFS. As with new medical
                                equipment that enables researchers to look more carefully at donor samples
                                to find a biological marker for CFS, establishing a criteria that works in
                                the doctors office is a much needed diagnostic tool. Unless MD's use  the
                                Canadian ME/CFS criteria or use their own gleaned from years of clinical
                                practice, they have no standard to use when trying to discover if a patient
                                has CFS. So, with much lively discussion about including this or that
                                symptom, scientists are trying to find something practical, so we do not
                                have to go to 10 MD's before finding a diagnosis.


                                A new Pediatric case definition was introduced by a panel of international
                                researchers. This is in the development stages, but it looked very good to
                                me. The longer document includes the definition and a preliminary
                                questionairre that can be used for parents and for a child who might have
                                CFS. My thought was THANKS to Dr. Leonard Jason who spearheaded this effort
                                and to all the MD's who have been seeing kids for 20 years. AND...IT IS
                                ABOUT TIME. How can we begin to look at how common CFS is in kids unless we
                                have a way to define what the beast looks like in this population?


                                Brain Function. Seven investigators presented in this 2 hour session. (I
                                missed the entire session.) As I look at abstracts, I see that increased
                                use of instruments like MRI, SPECT, PET and fMRI, and use of these in an
                                innovative way, show some of the abnormalities in functioning that patients
                                experience on a daily basis. These may not have practical application if a
                                patient cannot have this testing done, but there are other ways to find
                                loss of functional abilities.


                                In one study, the Van Hoof Elke (Belgium), patients performed a
                                standardized exercised stress test, neurocognitive tests and filled out a
                                questionnaire on their functional abilities. The results showed that
                                functional status could be predicted by both the exercise stress test and
                                by testing cognitive abilities. This Belgium team concluded that use of
                                these very common tools to define occupational disability seems valid.


                                Years ago, a Deluca study showed that CFS patients have deficiencies in
                                speed of information processing. At the time, it was one of a few studies
                                confirming what patients say about their loss of thinking skills. At this
                                2007 conference, several studies furthered our understanding . The Japanese
                                and Swedish research teams collaborated on comprehensive look at a
                                neuro-molecular mechanism leading to chronic fatigue. They conclude that
                                CFS is not only a functional disorder, but also an organic disorder.


                                Now that I am looking at the abstract book, I find many interesting
                                studies. Perhaps I will write a second summary. I did not even mention
                                advocacy issues that were addressed for 2 days and simmered for 5 days. You
                                know, after I returned from the first Ft. Lauderdale conference in 1994, I
                                devoted a 90 minute support group meeting to summarizing the research. We
                                had 40 people attending! Now, I could not do that because there is far more
                                research in many more areas and we no longer have a Madison support group.
                                The dynamics are so different.....


                                I know I will post about NIH funding. I have 2 new FOIA's. The bottom line
                                on these is... YES, we have 7 new CFS grants = the possibility of renewing
                                7 grants, so the situation is better. The down side is that The NIH
                                budgeted 6 million dollars, the "new money" offered the possibility of 4
                                million dollars, so one would think that we would have 9  to 10 million
                                dollars spent on CFS in 2006. I would take 8 million. However, it appears
                                to be the same 6 million dollars we have had for years. The FOIA documents
                                are on the WI website at www.wicfs-me.org.


                                The conference was delightful and perplexing. PANDORA people worked many
                                long hours and far into the morning the night before the patient conference
                                which had about 300 attendees. For me, meeting patients cements my
                                commitment to work on CFS issues a long as I am able. What a joy!!!


                                The scientists and MD's (about 300?) are committed to CFS research. It's
                                neither a high profile career in science, nor do they gain great wealth
                                from researching an underfunded, misunderstood, cutting edge illness. When
                                the MD's go home, they do not have support circles of colleagues that
                                admire their work and share stories. The ICONS in our community show wear
                                and tear and holes in their shoes just like us. I am pleased to have been a
                                part of the 8th IACFS conference and I am looking forward to the next event.


                                Dietary supplements/prescriptions. We still have few treatment studies for
                                CFS. Several companies exhibited products and their studies showed the
                                positive effects of supplements in CFS and FM patients.


                                P

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                                Date:    Sat, 20 Jan 2007 14:44:42 -0500
                                From:    Fred Springfield <fredspringfield VERIZON.NET>
                                Subject: RES: An experimental study of the influence of individual  participant characteristics on formal consensus development

                                An experimental study of the influence of individual participant
                                characteristics on formal consensus development.

                                Journal: Int J Technol Assess Health Care. 2007 Winter;23(1):108-15.

                                Authors: Carpenter J, Hutchings A, Raine R, Sanderson C.

                                Affiliation: London School of Hygiene & Tropical Medicine.

                                NLM Citation: PMID: 17234024

                                Objectives: The aim of this study was to examine the influence of
                                participants' characteristics on the results produced by formal consensus
                                methods.

                                Methods: The approach was an experimental study of 346 participants in 20
                                groups rating the appropriateness of four mental health interventions for
                                the treatment of chronic fatigue syndrome, irritable bowel syndrome, and
                                chronic back pain. There were four factors in the design: systematic
                                literature review provided or not, decisions made under realistic or
                                "ideal" resource assumptions, clinically mixed (general practitioners and
                                mental health professionals) or homogenous group (general practitioners
                                only), convened or mail-only group. A group's rating was defined as the
                                median of participants' ratings. The influence of participants'
                                characteristics (age, sex, and specialty) was examined using multilevel models.

                                Results: The largest differences were between the GPs and mental health
                                professionals, both in their initial ratings of the different
                                interventions, and in how much they altered their ratings between rounds.
                                There were smaller but statistically significant (p<.05) differences
                                between specialty and age groups in initial ratings for the treatment (by
                                whatever means) of different conditions, and for certain conditions women
                                increased their ratings more than men. Women rated intervention more
                                favorably when assuming "ideal" rather than realistic levels of resources,
                                but men did not.

                                Conclusions: Our findings support the practice of treating professional
                                specialty as an important determinant of the results in consensus panels.


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End of Co-Cure Weekly Digest of research and medical posts only - 15 Jan 2007 to 22 Jan 2007

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