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Co-Cure Weekly Digest of research and medical posts only - 15 Jan 2007 to 22 Jan 2007
Topics of the week:
2. RES: Fibromyalgia. Diagnostics - Disease Approach - Therapy
3. RES,NOT: Small trial stirs hope for PWCs
4. RES: Ca(2+) channel alpha(2)delta ligands: novel modulators of neurotransmission
5. RES: Why is the prevalence of chronic fatigue syndrome higher in women than in men?
7. RES: Growth Hormone Perturbations in Fibromyalgia: A Review
9. MED: The Role of Infection in Initiating ME/CFS
10. RES,NOT,URL: ME-NET will move soon
11. RES, MED, ACT, NOT: CDs and DVDs of the recent IACFS conference are available
12. RES: Sensitivity disturbances in patients with irritable bowel syndrome and fibromyalgia
13. RES,NOT: CDC launches First-Ever CFS Awareness Campaign
14. RES: CFS/ME & FM papers, published since December 2006
15. NOT,RES: An informal IACFS conference summary - first take
Copyright © 2007 Co-Cure
1. RES: A Pilot Study of the Efficacy of Heart Rate Variability (HRV) Biofeedback in Patients with Fibromyalgia
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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.
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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.
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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
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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.
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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
of chronic fatigue syndrome in Wichita, Kansas, Arch. Intern. Med. 163,
1530-6 (2003).
3. Steele, L., Dobbins, J.G., Fukuda, K. et al., The epidemiology of
chronic fatigue syndrome in San Francisco, Am. J. Med. 105 (3A), 83S-90S
(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).
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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.
Clin. Nutrit. 2004; 80:1611-1617.
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.
Genet. Part B, 2006; 141B: 947-956.
4. Van Konynenburg, R.A., Chronic fatigue syndrome and autism, Townsend
Letter for Doctors and Patients, October 2006, paper available at
http://www.findarticles.com/p/articles/mi_mOISW/is_279/ai_n16865315/print
5. Bhagavan, N.V., Medical Biochemistry, 4th edition, Harcourt Academic
Press, San Diego, CA, U.S.A. (2002), p. 356.
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
Biochimica Polonica (2004): 51 (2): 405-413.
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
biosynthesis, J. Biol. Chem. (2000); 275 (17): 12381-12387.
10. Bhagavan, N.V., Medical Biochemistry, 4th edition, Harcourt Academic
Press, San Dieago, CA, U.S.A. (2002), pp. 361-362.
11. Kim, S., Lim, I.K., Park, G.H., and Paik, W.K., Biological methylation
of myelin basic protein: enzymology and biological significance, Int. J.
Biochem. Cell Biol. (1997); 29 (5): 743-751.
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
syndrome, Biomed. Biochim. Acta (1989); 48 (2-3): S53-S57.
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
study of treatments of unexplained chronic fatigue, J. Clin. Psychiatry
(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
genes predict chronic fatigue syndrome, Pharmacogenomics (2006); 7 (3):
475-483.
67. Yeargin-Allsopp, M., Rice, C., Karapurkar, T., et al., Prevalence of
autism in a US metropolitan area, JAMA (2003); 289: 49-55.
68. Jason, L.A., Richman, J.A., Rademaker, A.W. et al., A community-based
study of chronic fatigue syndrome, Arch. Intern. Med. (1999); 159 (18):
2129-2137.
69. Reyes, M., Nisenbaum, R., Hoaglin, D. et al., Prevalence and incidence
of chronic fatigue syndrome in Wichita, Kansas, Arch. Intern. Med. (2003);
163: 1530-6.
70. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV), American Psychiatric Association, Washington, D.C. (1994).
71. Fukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., and
Komaroff, A., The chronic fatigue syndrome: a comprehensive approach to its
definition and study, International Chronic Fatigue Syndrome Study Group,
Ann. Intern. Med. (1994); 121 (12): 953-959.
72. Carruthers, B., Jain, A.K., De Meirleir, K.L., Peterson, D.L., Klimas,
N.G., Lerner, A.M., Bested, A.C., Flor-Henry, P., Joshi, P., Powles, A.C.,
Sherkey, J.A., and van de Sande, M.L., Myalgic encephalomyelitis/chronic
fatigue syndrome: clinical working case definition, diagnostic and
treatment protocols, J. Chronic Fatigue Syndrome (2003); 11 (1): 7-115.
73. Pangborn, J., Section 3: Molecular aspects of autism, in Pangborn, J.
and Baker, S.M., Autism: Effective Biomedical Treatments (2005), pp.
187-188, Autism Research Institute, 4182 Adams Avenue, San Diego, CA 92116,
U.S.A.
74. Geier, M.R., and Geier, D.A., The potential importance of steroids in
the treatment of autistic spectrum disorders and other disorders involving
mercury toxicity, Medical Hypotheses (2005); 64 (5): 946-954.
75. Geier, M.R., and Geier, D.A., An assessment of downward trends in
neurodevelopmental disorders in the United States following removal of
thimerosol from childhood vaccines, Med. Sci. Mon. (2006); 12 (6): CR231-CR239.
76. Van Konynenburg, R.A., Why is the prevalence of chronic fatigue
syndrome higher in women than in men?, poster paper, this Conference (2007).
77. Kim, S., Lim, I.K., Park, G.H., and Paik, W.K., Biological methylation
of myelin basic protein: enzymology and biological significance, Int. J.
Biochem. Cell Biol. (1997); 29 (5): 743-751.
78. Bursch, B., Ingman, K., Vitti, L., Hyman, P., and Zeltzer, L.K.,
Chronic pain in individuals with previously undiagnosed autistic spectrum
disorders, J. Pain (2004); 5 (5): 290-295.
79. Croonenberghs, J., Bosmans, E., Deboutte, D., Kenis, G., and Maes, M.,
Activation of the inflammatory response system in autism,
Neuropsychobiology (2002); 45 (1): 1-6.
80. Gupta, S., Aggarwal, S., Rashanravan, B., and Lee, T., Th1- and
Th2-like cytokines in CD4+ and CD8+ cells in autism, J. Neuroimmunol.
(1998); 85 (1): 106-109.
81. Warren, R.P., Foster, A., and Margaretten, N.C., Reduced natural killer
cell activity in autism, J. Am. Acad. Child Adolesc. Psychiatry (1987); 26
(3): 333-335.
82. Correia, C., Coutinho, A.M., Diogo, L., Grazina, M., Marques, C.,
Miguel, T., Ataide, A., Almeida, J., Borges, L., Oliveira, C., Oliveira,
G., and Vicente, A.M., Brief report: high frequency of biochemical markers
for mitochondrial dysfunction in autism: no association with the
mitochondrial aspartate/glutamate carrier SLC25A12 Gene, J. Autism Dev.
Disord. (2006); 36 (8): 1137-1140.
83. Filipek, P.A., Juranek, J., Nguyen, M.T., Cummings, C., and Gargus,
J.J., Relative carnitine deficiency in autism, J. Autism Dev. Disord.
(2004); 34 (6): 615-623.
84. Hoshino, Y., Ohno, Y., Murata, S., Yokoyama, F., Kaneko, M., and
Kumashiro, H., Dexamethasone suppression test in autistic children, Folia
Psychiatr Neurol Jpn (1984); 38 (4): 445-449.
85. White, J.F., Intestinal pathophysiology in autism, Exp. Biol. Med.
(Maywood) (2003); 228 (6): 639-649.
86. Liu, X., Hubbard, J.A., Fabes, R.A., and Adam, J.B., Sleep disturbances
and correlates of children with autism spectrum disorders, Child Psychiatry
Hum. Dev. (2006); 37 (2): 179-191.
87. Sullivan, P.F., Genetics, chapter 5 in Handbook of Chronic Fatigue
Syndrome, L.A. Jason et al., eds., (2003) John Wiley and Sons, Hoboken, NJ,
U.S.A., pp. 89-107.
88. Narita, M., Nishigami, N., Narita, N., Yamaguti, K., Okado, N.,
Watanabe, Y., and Kuratsune, H., Association between serotonin transporter
gene polymorphism and chronic fatigue syndrome, Biochem. Biophys. Res.
Commun. (2003); 311 (2): 264-266.
89. Torpy, D.J., Bachmann, A.W., Gartside, M., Grice, J.E., Harris, J.M.,
Clifton, P., Easteal, S., Jackson, R.V., Whitworth, J.A., Association
between chronic fatigue syndrome and the corticosteroid-binding globulin
gene ALA SER224 polymorphism, Endocr. Res. (2004); 30 (3): 417-429.
90. Carlo-Stella, N., Badulli, C., De Silvestri, A., Bazzichi, L.,
Martinetti, M., Lorusso, L., Bombardieri, S., Salvaneschi, L., and Cuccia,
M., A first study of cytokine genomic polymorphisms in CFS: positive
association of TNF-857 and IFNgamma 874 rare alleles, Clin. Exp. Rheumatol.
(2006); 24 (2): 179-182.
91. Smith, A.K., White, P.D., Aslakson, E., Vollmer-Conna, U., and
Rajeevan, M.S., Polymorphisms in genes regulating the HPA axis associated
with empirically delineated classes of unexplained chronic fatigue,
Pharmacogenomics (2006); 7 (3): 387-394.
92. Gursoy, S., Erdal, E., Herken, H. et al., Significance of
catechol-O-methyltransferase gene polymorphism in fibromyalgia, Rheumatol.
Intl. (2003); 23: 104-7.
93. 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.
(2006); 9: 1-10.
94. McKeown-Eyssen, G., Baines, C., Cole, D.E., Riley, N., Tyndale, R.F.,
Marshall, L., and Jazmaji, V., Case-control study of genotypes in multiple
chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON2 and MTHFR, Int. J.
Epidem. (2004); 33: 971-978.
95. Lertratanangkoon, K., Orkiszewski, R.S., and Scimeca, J.M.,
Methyl-donor deficiency due to chemically induced glutathione depletion,
Cancer Research (1996); 56: 995-1005.
96. Pancewicz, S.A., Skrzydlewska, E., Hermanowska-Szpakowicz, T.,
Zajkowska, J.M., and Kondrusik, M., Role of reactive oxygen species (ROS)
in patients with erythema migrans, an early manifestation of Lyme
borreliosis, Med. Sci. Monit. (2001); 7 (6): 1230-1235.
97. Elenkov, I.J., Glucocorticoids and the Th1/Th2 balance, Ann. N.Y. Acad.
Sci. (2004); 1024: 138-146.
98. Peterson, J.D., Herzenberg, L.A., Vasquez, K., and Waltenbaugh, C.,
Glutathione levels in antigen-presenting cells modulate Th1 versus Th2
response patterns, Proc. Natl. Acad. Sci. U.S.A. (1998); 95: 3071-3076.
99. Murata, Y., Shimamura, T., and Hamuro, J., The polarization of Th1/Th2
balance is dependent on the intracellular thiol redox status of macrophages
due to the distinctive cytokine production, Internat. Immunol. (2002); 14
(2): 201-212.
100. Katler, E., and Weissmann, G., Steroids, aspirin and inflammation,
Inflammation (1977); 2 (4): 295-307.
101. Maher, K.J., Klimas, N.G. and Fletcher, M.A., Chronic fatigue syndrome
is associated with diminished intracellular perforin, Clin. Exp. Immunol.
(2005); 142 (3): 505-511.
102. Chakravarthi, S. and Bulleid, N.J., Glutathione is required to
regulate the formation of native disulfide bonds within proteins entering
the secretory pathway, J. Biol. Chem. (2004); 279 (38): 39872-39879.
103. Li, F., Zhou, X., Qin, W., and Wu, J., Full-length cloning and
3'-terminal portion expression of human perforin cDNA, Clinica Chimica Acta
(2001); 313: 125-131.
104. Baraniuk, J.N., Casado, B., Maibach, H., Clauw, D.J., Pannell, L.K.,
and Hess, S.S., A chronic fatigue syndrome-related proteome in human
cerebrospinal fluid, BMC Neurol. (2005); 5: 22.
105. Dhur, A. Galan, P. and Hercberg, S., Folate status and the immune
system, Prog. Food Nutr. Sci. (1991); 15 (1-2): 43-60.
106. Komaroff, A.L., and Buchwald, D.S., Chronic fatigue syndrome: an
update, Annual Reviews of Medicine (1998); 49:1-13.
107. Roederer, M., Raju, P.A., Staal, F.J.T., Herzenberg, L.A.,
and Herzenberg, L.A., acetylcysteine inhibits latent HIV expression in
chronically infected cells, AIDS Research and Human Retroviruses (1991); 7:
563-567.
108. Staal, F.J.T., Roederer, M., Israelski, D.M., Bubp, J., Mole, L.A.,
McShane, D., Deresinski, S.C., Ross, W., Sussman, H., Raju, P.A., Anderson,
M.T., Moore, W., Ela, S.W., Herzenberg, L.A., and Herzenberg, L.A.,
Intracellular glutathione levels in T cell subsets decrease in HIV-infected
individuals, AIDS Research and Human Retroviruses (1992); 8: 305-311.
109.. Ciriolo, M.R., Palamara, A.T., Incerpi, S., Lafavia, E., Bue, M.C.,
De Vito, P., Garaci, E., and Rotilio, G., Loss of GSH, oxidative stress,
and decrease of intracellular pH as sequential steps in viral infection, J.
Biol. Chem. (1997); 272 (5): 2700-2708.
110. Cai, J., Chen, Y., Seth, S., Furukawa, S., Compans, R.W., and Jones,
D.P., Inhibition of influenza infection by glutathione, Free Radical
Biology & Medicine (2003); 34 (7): 928-936.
111. Palamara, A.T., Perno, C.-F., Ciriolo, M.R., Dini, L., Balestra, E.,
D'Agostini, C., Di Francesco, P., Favalli, C., JRotilio, G, and Garaci, E.,
Evidence for antiviral activity of glutathione: in vitro inhibition of
herpes simplex virus type 1 replication, Antiviral Research (1995); 27:
237-253.
112. Azenabor, A.A., Muili, K., Akoachere, J.F., and Chaudhry, A.,
Macrophage antioxidant enzymes regulate Chlamydia pneumoniae
chronicity: evidence of the effect of redox balance on host-pathogen
relationship, Immunobiology (2006); 211 (5): 325-339.
113. Norais, N., Tang, D., Kaur, S., Chamberlain, S.H., Masiarz, F.R.,
Burke, R.L., and Marcus, F., Disulfide bonds of Herpes simplex virus type 2
glycoprotein gB, J. Virology (1996); 70 (11): 7379-7387.
114. Taylor, E. W., Nadimpalli, R.G., and Ramanathan, C.S., Genomic
structures of viral agents in relation to the biosynthesis of
selenoproteins, Biol. Trace Elem. Res. (1997); 56 (1): 63-91.
115. Taylor, E.W., Selenium and viral diseases: facts and hypotheses, J.
Orthomolec. Med. (1997); 12 (4): 227-239.
116. Broadley, M.R., White, P.J., Bryson, R.J., Meacham, M.C., Bowen, H.C.,
Johnson, S.E., Hawkesford, M.J., McGrath, S.P., Zhao, F.J., Breward, N.,
Harriman, M., and Tucker, M., Biofortification of UK food crops with
selenium, Proc. Nutr. Soc. (2006); 65 (2): 169-81.
117. Janeway, C.A., Jr., Travers, P., Walport, M. and Shlomchik, M.J., T
Cell-Mediated Immunity, chapter 8 in Immunobiology, 6th edition, Garland
Science, New York (2005), pp. 319-365.
118. Bastide, L., Demettre, E., Martinand-Mari, C., and Lebleu, B.,
Interferon and the 2-5A/Pathway, chapter 1 in Englebienne, P., and De
Meirleir, K., Chronic fatigue syndrome--a biological approach, CRC Press,
Boca Raton, FL, U.S.A. (2002), pp. 1-15.
119. Bounous, G., and Molson, J., Competition for glutathione precursors
between the immune system and the skeletal muscle: pathogenesis of chronic
fatigue syndrome, Med. Hypotheses (1999); 53 (4): 347-349.
120. Pall, M., Elevated, sustained peroxynitrite levels as the cause of
chronic fatigue syndrome, Med. Hypotheses (2000); 54 (1): 115-125.
121. Fridovich, I., Superoxide radical and superoxide dismutases, Annu.
Rev. Biochem. (1995); 64: 97-112.
122. Radi, R., Cassina, A., Hodara, R., Quijano, C., and Castro, L.,
Peroxynitrite interactions and formation in mitochondria, Free Radic. Biol.
Med. (2002); 33 (11); 1451-1464.
123. Suhadolnik, R.J., Peterson, D.L., O'Brien, K., Cheney, P.R., Herst,
C.V.T., Reichenbach, N.L., et al., Biochemical evidence for a novel low
molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome, J.
Interferon Cytokine Research (1997); 17: 377-385.
124. Englebienne, P., Herst, C.V., Roelens, S., D'Haese, A., El Bakkouri,
K., De Smet, K., Fremont, M., Bastide, L., Demettre, E. and Lebleu, B.,
Ribonuclease L: overview of a multifaceted protein, chapter 2 in
Englebienne, P., and De Meirleir, K., Chronic fatigue syndrome--a
biological approach, CRC Press, Boca Raton, FL, U.S.A. (2002), pp. 17-54.
125. Rackoff, J., Yang, Q., and DePetrillo, P.B., Inhibition of rat PC12
cell calpain activity by glutathione, oxidized glutathione and nitric
oxide, Neurosci. Lett. (2001); 311 (2): 129-132.
126. Baggiolini, M., Schnyder, J., Bretz, U., Dewald, B., and Ruch, W.,
Cellular mechanisms of proteinase release from inflammatory cells and the
degradation of extracellular proteins, Ciba Found. Symp. (1979); 75: 105-121.
127. Droge, W., and Breitkreutz, R., Glutathione and immune function, Proc.
Nutr. Soc. (2000); 59: 595-600.
128. Seelig, M.S., Review and hypothesis: might patients with the chronic
fatigue syndrome have latent tetany of magnesium deficiency?, J. Chronic
Fatigue Syndrome (1998); 4 (2): 77-108.
129. Durlach, J., Pages, N., Bac, P., Bara, M., Guiet-Bara, A., and
Agrapart, C., Chronopathological forms of magnesium depletion with
hypofunction or with hyperfunction of the biological clock, Magnes. Res.
(2002); 15 (3-4): 263-268.
130. Barbagallo, M., Dominguez,L.J., Taglimonte, M.R., Resnick, L.M. and
Paolisso, G., Effects of glutathione on red blood cell intracellular
magnesium: relation to glucose metabolism, Hypertension (1999); 34 (1): 76-82.
131. Stejskal, V.D., Danersund, A., Lindvall, A., Hudecek, R., Nordman, V.,
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.
[Return to top]
------------------------------
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.
[Return to top]
------------------------------
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.
[Return to top]
------------------------------
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
[Return to top]
------------------------------
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 |
+------+-------------------^^^^^^^^^^^^-----------^^^-+
[Return to top]
------------------------------
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.
[Return to top]
------------------------------
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
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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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Last Revision: April 20, 2007
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