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CO-CURE Medical & Research Posts Only Digest - 28 Aug 2006 to 4 Sep 2006 (#2006-41)

There are 22 messages totalling 2623 lines in this issue.

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Date:    Tue, 29 Aug 2006 16:31:10 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx>
Subject: RES,NOT: CFS Quackery web page updated

Today, the ME-NET page on CFS quackery has been updated.
   http://www.me-net.dds.nl/meweb/web4.10.html

The page now includes Medline links to 50-60 CFS papers published in quack
journals and a link to the 'Quackometer' to test CFS web pages for quackery.

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Date:    Tue, 29 Aug 2006 16:06:21 -0400
From:    Fred Springfield <fredspringfield@xxxxx.xxx>
Subject: RES: beta-Alanine and gamma-aminobutyric acid in chronic  fatigue syndrome

beta-Alanine and gamma-aminobutyric acid in chronic fatigue syndrome.

Journal: Clin Chim Acta. 2006 Jul 14; [Epub ahead of print]

Authors: Ulf Hannestad [a,*], Elvar Theodorsson [a] and Birgitta Evengård [b]

Affiliations:
[a] Faculty of Health Science, Division of Clinical Chemistry, Linköping
University, SE-581 85 Linköping, Sweden
[b] Department of Laboratory Medicine, Karolinska Institutet at Karolinska
University Hospital, Huddinge, SE-141 86 Stockholm, Sweden
[*] Corresponding author: Tel.: +46 13 223246; fax: +46 13 223240; E-Mail:
<ulf.hannestad@ibk.liu.se>

Received 7 June 2006;
revised 7 July 2006;
Available online 14 July 2006.

NLM Citation: PMID: 16934791


BACKGROUND: Due to the occurrence of sleep disturbances and fatigue in
chronic fatigue syndrome (CFS), an investigation was performed to examine
if there is an abnormal excretion of gamma-aminobutyric acid (GABA) and/or
its structural analogue beta-alanine in the urine from CFS patients. Both
GABA and beta-alanine are inhibitory neurotransmitters in the mammalian
central nervous system.

METHODS: The 24 h urine excretion of GABA and beta-alanine was determined
by isotope dilution gas chromatography mass spectrometry in 33 CFS patients
and 43 healthy controls. The degree of symptoms in both patients and
controls was measured by grading of three typical CFS symptoms using a
Visual Analogue Scale.

RESULTS: Men had a significantly higher excretion of both beta-alanine and
GABA than women. Comparing CFS patients with healthy controls showed no
significant difference in excretion of neither beta-alanine nor GABA. No
correlation was found between the excretion of beta-alanine or GABA and any
of the three characteristic CFS symptoms measured. However, two female and
two male CFS patients excreted considerably higher amounts of beta-alanine
in their 24 h urine samples than control subjects.

CONCLUSIONS: Increased excretion of beta-alanine was found in a subgroup of
CFS patients, indicating that there may be a link between CFS and
beta-alanine in some CFS patients.


Keywords: Chronic fatigue syndrome; ß-Alanine; ?-Aminobutyric acid;
Polyamines; Ornithine decarboxylase; Immunosuppression

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Date:    Tue, 29 Aug 2006 16:38:49 -0400
From:    Fred Springfield <fredspringfield@xxxxx.xxx>
Subject: RES: Long-chain polyunsaturated fatty acids and the  pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome)

Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic
encephalomyelitis (chronic fatigue syndrome).

Journal: J Clin Pathol. 2006 Aug 25; [Epub ahead of print]

Author: Basant K Puri [1,*]

Affiliation:
1 Hammersmith Hospital, United Kingdom

* To whom correspondence should be addressed. E-mail:
basant.puri@csc.xxx.xx.xx.

Accepted 31 July 2006

NLM Citation: PMID: 16935966


Evidence is put forward to suggest that myalgic encephalomyelitis, also
known as chronic fatigue syndrome, may be associated with persistent viral
infection. In turn, such infections are likely to impair the ability of the
body to biosynthesize n-3 and n-6 long-chain polyunsaturated fatty acids by
inhibiting the delta-6 desaturation of the precursor essential fatty acids
alpha-linolenic acid and linoleic acid. In turn, this would impair the
proper functioning of cell membranes, including cell signalling, and have
an adverse effect of the biosynthesis of eicosanoids from the long-chain
polyunsaturated fatty acids dihomo-a-linolenic acid, arachidonic acid and
eicosapentaenoic acid.

These actions might offer an explanation for some of the symptoms and signs
of myalgic encephalomyelitis. A potential therapeutic avenue may be offered
by bypassing the inhibition of the enzyme delta-6-desaturase by
administering both virgin cold-pressed non-raffinated evening primrose oil
and eicosapentaenoic acid. The former would supply gamma-linolenic acid and
lipophilic pentacyclic triterpenes. The gamma-linolenic acid can readily be
converted into dihomo-a-linolenic acid and thence arachidonic acid, while
triterpenes have important free radical scavenging, cyclooxygenase and
neutrophil elastase inhibitory activities.

Furthermore, both arachidonic acid and eicosapentaenoic acid are, at
relatively low concentrations, directly virucidal.


Key Words: Myalgic encephalomyelitis, eicosapentaenoic acid, long-chain
fatty acids

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Date:    Tue, 29 Aug 2006 20:36:56 -0400
From:    Fred Springfield <fredspringfield@xxxxx.xxx>
Subject: RES: Current research priorities in Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): disease mechanisms, a diagnostic  test and specific treatments

Current research priorities in Chronic Fatigue Syndrome / Myalgic
Encephalomyelitis (CFS/ME): disease mechanisms, a diagnostic test and
specific treatments.

Journal: J Clin Pathol. 2006 Aug 25; [Epub ahead of print]

Authors: Jonathan R Kerr [1*], Peter Christian [2], Andrea Hodgetts [2],
Paul R Langford [2], Lakshmi D Devanur [1], Robert Petty [1], Beverley
Burke [1], Lindsey I Sinclair [3], Selwyn CM Richards [4], Jane Montgomery
[4], Clare McDermott [4], Tim J Harrison [5], Paul Kellam [5], David J Nutt
[3] and Stephen T Holgate [6]

Affiliations:
[1] St George's University of London, United Kingdom
[2] Imperial College London, United Kingdom
[3] University of Bristol, United Kingdom
[4] Dorset CFS Service, Poole Hospital, United Kingdom
[5] University College London, United Kingdom
[6] University of Southampton, United Kingdom

[*] To whom correspondence should be addressed. E-mail: jkerr@xxxx.xx.xx.

Accepted 31 July 2006

NLM Citation: PMID: 16935968


Chronic fatigue syndrome (CFS) is an illness characterised by disabling
fatigue of at least 6 months duration which is accompanied by various
rheumatological, infectious and neuropsychiatric symptoms. A collaborative
study group has been formed in order to address the current areas for
development in CFS research, namely, to develop an understanding of the
molecular pathogenesis of CFS, to develop a diagnostic test, and to develop
specific and curative treatments.

Various groups have studied the gene expression in peripheral blood of CFS
patients and of those studies which have been confirmed using polymerase
chain reaction (PCR), it is clear that the most predominant functional
theme is that of immunity and defense. However, we do not yet know the
precise gene signature and metabolic pathways involved. Currently, this is
being addressed using a microarray representing 47,000 human genes and
variants, massive parallel signature sequencing (MPSS) and real-time PCR.

It will be important to ensure that once a gene signature has been
identified, that it is specific to CFS and does not occur in other diseases
and infections. A diagnostic test is being developed using
Surface-Enhanced, Laser-Desorption and Ionisation - Time of Flight
(SELDI-TOF) mass spectrometry following a pilot study in which putative
biomarkers were identified.

And, finally, clinical trials are being planned; novel treatments which we
believe are important to trial in CFS patients are interferon-a and one of
the anti-tumour necrosis factor-a drugs.


Key Words: Chronic Fatigue Syndrome, Myalgic encephalomyelitis, biomarkers,
gene expression, treatment

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Date:    Wed, 30 Aug 2006 08:59:00 -0400
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx>
Subject: RES: Cerebrospinal Fluid Corticotropin-Releasing Factor  Concentration is Associated with Pain but not Fatigue Symptoms in  Patients with Fibromyalgia

Cerebrospinal Fluid Corticotropin-Releasing Factor Concentration is
Associated with Pain but not Fatigue Symptoms in Patients with Fibromyalgia.

Neuropsychopharmacology. 2006 Aug 23; [Epub ahead of print]

McLean SA, Williams DA, Stein PK, Harris RE, Lyden AK, Whalen G, Park KM,
Liberzon I, Sen A, Gracely RH, Baraniuk JN, Clauw DJ.

1Department of Emergency Medicine, University of Michigan Medical Center,
Ann Arbor, MI, USA

PMID: 16936702


Previous studies have identified stress system dysregulation in
fibromyalgia (FM) patients; such dysregulation may be involved in the
generation and/or maintenance of pain and other symptoms.
Corticotropin-releasing factor (CRF) is the principal known central nervous
system mediator of the stress response; however, to date no studies have
examined cerebrospinal fluid (CSF) CRF levels in patients with FM.

The relationship between CSF CRF level, heart rate variability (HRV), and
pain, fatigue, and depressive symptoms was examined in patients with FM.

Among participants (n=26), CSF CRF levels were associated with sensory pain
symptoms (r=0.574, p=0.003) and affective pain symptoms (r=0.497, p=0.011),
but not fatigue symptoms. Increased HRV was also strongly associated with
increased CSF CRF and FM pain. In multivariate analyses adjusting for age,
sex, and depressive symptoms, the association between CSF CRF and sensory
pain symptoms (t=2.54, p=0.027) persisted. Women with FM who reported a
history of physical or sexual abuse had lower CSF CRF levels than women who
did not report such a history. CSF CRF levels are associated with both pain
symptoms and variation in autonomic function in FM.

Differences in CSF CRF levels among women with and without a self-reported
history of physical or sexual abuse suggest that subgroups of FM patients
may exist with different neurobiological characteristics. Further studies
are needed to better understand the nature of the association between CSF
CRF and pain symptoms in FM.

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Date:    Wed, 30 Aug 2006 12:12:44 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx>
Subject: RES,NOT: ME in Westminster: Journal of Clinical Pathology

Source: Journal of Clinical Pathology
        Preprint
Date:   October 2006
URL:    http://jcp.bmjjournals.com/future/preview.shtml
Rem:    More CFS papers in the next Journal of Clinical Pathology,
        - Kerr JR, Christian P, Hodgetts A, Langford PR, Devanur LD, Petty R,
          Burke B, Sinclair LI, Richards SC, Montgomery J, McDermott C,
          Harrison TJ, Kellam P, Nutt DJ, Holgate ST.
          Current research priorities in Chronic Fatigue Syndrome/Myalgic
          Encephalomyelitis (CFS/ME): disease mechanisms, a diagnostic test
          and specific treatments.
        - Hooper M.
          Myalgic Encephalomyelitis (ME): a review with emphasis on key
          findings in biomedical research.
        - Puri BK.
          Long-chain polyunsaturated fatty acids and the pathophysiology of
          myalgic encephalomyelitis (chronic fatigue syndrome).
        - Carruthers B.
          Definitions and aetiology of Myalgic Encephalomyelitis (ME): how
          the Canadian Consensus Clinical Definition of ME works.


[Editorial]

A new look at Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)
-------------------------------------------------------------------------
Gibson I.
House of Commons, United Kingdom.

It has been three years since the Chief Medical Office reported on CFS/ME
and the time has come for a thorough investigation by an All Party Group
drawn from the House of Commons and the House of Lords. We have received
many written submissions and are engaged in taking oral evidence in 2-hour
sessions, which we open to the public as well as interested groups. The
group has received a fantastic response to its requests for written
evidence over the last few months. Questions that arise for a government
response are the lack of provision and support for CFS/ME patients, the
issue of the clinical definition of CFS/ME, the need for a diagnostic test
for CFS/ME, effectiveness of the NICE guidelines, and criteria used to
decide which treatments are best for patients with CFS/ME.

-------
(c) BMJ Publishing group

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Date:    Wed, 30 Aug 2006 08:08:44 -0700
From:    "Jodi Basset <jodibassett@xxxxxx.xxx>................via Co-Cure moderator" 
Subject: NOT, MED: The effects of CBT and GET on M.E. patients

*permission to repost*

A new paper is available titled:

The effects of CBT and GET on M.E. patients

by Jodi Bassett, August 2006

This text looks at the level of safety and efficiency of treatments such as
CBT and GET in M.E. This is one of two papers I have been working on on the
subject of CBT and GET.

The first paper deals primarily with the financial and political motivations
behind the 'behavioural' model of M.E. (and ICD-CFS). The second paper (this
one) focuses almost entirely on the medical effects of CBT and GET on
patients, and the medical research which shows that exercise can be very
harmful for M.E.patients.


An excerpt:

'No evidence exists which shows that cognitive behavioural therapy (CBT) or
graded exercise therapy (GET) are appropriate, useful or safe treatments for
Myalgic Encephalomyelitis (or ICD-CFS) patients.

Studies involving miscellaneous psychiatric and non-psychiatric 'fatigue'
sufferers, and their response to these treatments, have no more relevance to
M.E. sufferers than they do to diabetes patients, cancer patients, patients
with multiple sclerosis or any other illness. Thus, patients with M.E. are
being prescribed these treatments on what amounts to a 'random' basis
medically and so the questions need to be asked:


What is the effect of graded exercise therapy (GET) on Myalgic
Encephalomyelitis (M.E.) patients?

As (bad) luck would have it, graded exercise programs are probably the
single most inappropriate treatment that a M.E. sufferer could be
recommended to undertake. This is because one of the unique features of
authentic M.E. is exercise intolerance - that patients worsen with even
trivial levels of activity or exercise.

Exercise or exertion intolerance is one of the many things which separates
Myalgic Encephalomyelitis so distinctly from various post-viral fatigue
states or other illnesses involving 'chronic fatigue' as the defining or
primary feature. People with M.E. do not improve with exercise. They cannot;
exercise intolerance is a large and essential part of what M.E. is. Veteran
M.E. expert Dr Ramsay explained that this unique characteristic: 'is
virtually a sheet-anchor in the diagnosis of Myalgic Encephalomyelitis and
without it a diagnosis should not be made.' (1986, [Online]).'


You can read the entire (6 page, fully referenced) article at:

www.ahummingbirdsguide.com/cbtandgeteffects.htm


Best wishes,
Jodi Bassett
--
A Hummingbirds Guide to Myalgic Encephalomyelitis:
www.ahummingbirdsguide.com
--
With the rapid development of technology and access to international
publication, the UK retained its reputation as a leading centre of ME/CFS
research and remained able to report clinical studies backed up by molecular
biology, brain imaging, sophisticated hormonal and other biochemical
studies.  At this point, with sound evidence of an infective cause, the way
in which such infection is spread and the pathogenisis of the disease, why
were we urged to adopt the "fatigue definitions" inflicted upon ME/CFS
sufferers by USA scientists? Redefinitions of ME - a 20th Century Phenomenon
by Dr Elizabeth Dowsett
--

[Return to top]

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Date:    Thu, 31 Aug 2006 13:15:50 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx>
Subject: RES,NOT: Polyunsaturated fatty acids in CFS

Source: Journal of Clinical Pathology
        Preprint
Date:   August 29, 2006
URL:    http://jcp.bmjjournals.com/cgi/content/abstract/jcp.2006.042424v1
Ref:    You can respond to this article at:
        http://jcp.bmjjournals.com/cgi/eletter-submit/jcp.2006.042424v1


Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic
encephalomyelitis (chronic fatigue syndrome)
-------------------------------------------------------------------------
BK Puri(*)
MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital,
London UK
* Correspondence to: Professor BK Puri, MRI Unit, Hammersmith Hospital, Du
  Cane Road, London W12 0HS, England, UK, basant.puri@csc.xxx.xx.xx


Abstract

Evidence is put forward to suggest that myalgic encephalomyelitis, also
known as chronic fatigue syndrome, may be associated with persistent viral
infection. In turn, such infections are likely to impair the ability of the
body to biosynthesize n-3 and n-6 long-chain polyunsaturated fatty acids by
inhibiting the delta-6 desaturation of the precursor essential fatty acids
alpha-linolenic acid and linoleic acid. In turn, this would impair the
proper functioning of cell membranes, including cell signalling, and have an
adverse effect of the biosynthesis of eicosanoids from the long-chain
polyunsaturated fatty acids dihomo-gamma-linolenic acid, arachidonic acid
and eicosapentaenoic acid. These actions might offer an explanation for some
of the symptoms and signs of myalgic encephalomyelitis. A potential
therapeutic avenue may be offered by bypassing the inhibition of the enzyme
delta-6-desaturase by administering both virgin cold-pressed non-raffinated
evening primrose oil and eicosapentaenoic acid. The former would supply
gamma-linolenic acid and lipophilic pentacyclic triterpenes. The gamma-
linolenic acid can readily be converted into dihomo-gamma-linolenic acid and
thence arachidonic acid, while triterpenes have important free radical
scavenging, cyclooxygenase and neutrophil elastase inhibitory activities.
Furthermore, both arachidonic acid and eicosapentaenoic acid are, at
relatively low concentrations, directly virucidal.

The aetiology of myalgic encephalomyelitis (chronic fatigue syndrome) is
currently not known. In this paper, evidence is adduced to show the key role
of certain long-chain polyunsaturated fatty acids in the pathophysiology of
this illness. First, evidence is provided which suggests a viral aetiology.
Second, the effects of such viral infections on the human biosynthetic
pathways for long-chain polyunsaturated fatty acids is considered. Third,
the subsequent effects on membrane phospholipids and the immune system are
described. Finally, therapeutic implications are outlined.


VIRAL AETIOLOGY

Several converging lines of evidence point to a viral aetiology for myalgic
encephalomyelitis.

First, many clinical features of epidemics of myalgic encephalomyelitis-like
illnesses such as the Los Angeles County Hospital epidemic of 1934 and the
Royal Free Hospital epidemic of 1955 are consistent with viral
infections.[1]

Second, immune system changes in myalgic encephalomyelitis tend to point to
reduced NK cell activity, reduced Th1 cell activity, increased Th2 cell
activity and increased Tc cell activity.[1-6] These findings are consistent
with a pre-existing long- term viral infection. Although these findings are
also consistent with an autoimmune response, there is little consistent
evidence to support this possibility in myalgic encephalomyelitis.

The third line of evidence relates to blood fatty acid levels. As we shall
see in the next two sections, viral infections can impair the ability of the
mammalian body to biosynthesize long-chain polyunsaturated fatty acids from
their short-chain precursors. In their baseline comparison of erythrocyte
membrane fatty acid levels between 63 patients (with what was then termed
postviral fatigue syndrome) and 32 normal volunteers, Behan et al. found
significantly lower levels of arachidonic acid and adrenic acid and of the
total n-6 polyunsaturated fatty acids.[7] A more recent study using the
Oxford Criteria for diagnosis found a significantly lower level of
eicosapentaenoic acid in patients with chronic fatigue syndrome.[8]

The fourth line of evidence comes from proton neurospectroscopy studies. As
we shall see in the next section, viral infections can prevent the body from
biosynthesizing long-chain polyunsaturated fatty acids. In turn, this
impairs the biosynthesis of membrane phospholipid molecules in the brain,
since long-chain polyunsaturated fatty acids are key components at the Sn2
position of these molecules. This leads to a reduced incorporation of the
polar head group choline in these molecules (at the Sn3 position). Hence we
should expect to see evidence of a raised level of free choline in the
brain, which can be assessed using proton neurospectroscopy.[9] This is
indeed the finding from the first two systematic proton neurospectroscopy
studies thus far published in myalgic encephalomyelitis or chronic fatigue
syndrome, namely the one by our group and that by the Glasgow group then
headed by Chaudhuri.[10,11] Furthermore, a Japanese case series of three
children with juvenile myalgic encephalomyelitis has also reported a raised
level of the choline peak on proton neurospectroscopy.[12]

The most recent evidence comes from an elegant study by Jonathan Kerr's
group.[13] They studied gene expression in peripheral blood mononuclear
cells in 25 patients with chronic fatigue syndrome compared with 25 normal
blood donors matched for age, gender and geographical location. One of their
findings was upregulation of the mitochondrial translation initiation factor
EIF4G1 transcript variant 5, a result which is consistent with a persistent
virus infection.


EFFECTS ON BIOSYNTHETIC PATHWAYS FOR LONG-CHAIN POLYUNSATURATED FATTY ACIDS

The first step in humans in the biosynthesis of n-6 long-chain
polyunsaturated fatty acids from the 18-carbon short-chain essential fatty
acid precursor linoleic acid is catalyzed by the enzyme
delta-6-desaturase.[1] Similarly, the biosynthesis of n-3 long- chain
polyunsaturated fatty acids from the 18-carbon short-chain essential fatty
acid precursor alpha-linolenic acid is also catalyzed by
delta-6-desaturase.[1] Back in 1935, Stoesser reported that acute viral
infections were associated with a reduction in the levels of long-chain
polyunsaturated fatty acids.[14] That the cause of this was the ability of
many viral species to inhibit the delta-6 desaturation of the precursor
short- chain essential fatty acids was discovered four decades later by
Dunbar and Bayley.[15,16].


EFFECTS ON MEMBRANE PHOSPHOLIPIDS AND THE IMMUNE SYSTEM

The fundamental building block of the lipid bilayers of outer cell membranes
and of many intracellular organelles is the phospholipid molecule. Based on
a three-carbon glycerol backbone, in normal membranes the middle carbon (the
Sn2 position) should have a long-chain polyunsaturated fatty acid attached
to it. This is usually either the n-6 long-chain polyunsaturated fatty acid
arachidonic acid or the n-3 long-chain polyunsaturated fatty acid
docosahexaenoic acid. Attached ultimately to the Sn3 position is a polar
head group, such as choline, ethanolamine, serine or inositol. As a result
of viral, or other, inhibition of delta-6-desaturase, an inadequate supply
of the long-chain polyunsaturated fatty acids is available for incorporation
into membrane phospholipid molecules. Thus the ratio of anabolism to
catabolism of membrane phospholipids can be expected to alter in an adverse
direction. In turn, so far as the brain is concerned, this may be expected
to have an unfavourable effect on neurotransmission; for example it has been
demonstrated that minor changes in fatty acid structure in a very small
proportion of membrane phospholipids can lead to profound changes in the
tertiary and quaternary structures of membrane proteins, and in the
functioning of such proteins.[17,18]

As mentioned above, changes in free choline can be measured in vivo using
proton neurospectroscopy. Changes in membrane phospholipid metabolism may
also be indexed using 31-phosphorus neurospectroscopy.[9]

In addition to the adverse effects on membrane structure and functioning
caused by delta-6-desaturase inhibition, there are also negative
consequences with respect to the biosynthesis of eicosanoids, such as
prostaglandins, leukotrienes and thromboxanes, since these require
long-chain polyunsaturated fatty acids such as arachidonic acid and
eicosapentaenoic acid as their precursors.[1] In turn, this can compromise
the functioning of the immune system.


THERAPEUTIC IMPLICATIONS

Inhibition of delta-6-desaturase can be bypassed by administering a
combination of evening primrose oil, which supplies the n-6 long-chain
polyunsaturated fatty acid gamma-linolenic acid, from which
dihomo-gamma-linolenic acid and arachidonic acid can be biosynthesized, and
the n-3 long-chain polyunsaturated fatty acid eicosapentaenoic acid.

A further advantage of giving this combination relates to the finding that
arachidonic acid and eicosapentaenoic acid, in addition to being precursors
of many eicosanoids, are also directly virucidal at relatively low levels,
for example inactivating lipid-enveloped viruses.[19,20] Furthermore, the
antiviral actions of interferon may also require its activation of the
conversion, catalyzed by cyclooxygenase, of dihomo-gamma-linolenic acid and
arachidonic acid into eicosanoids.[21]

If administering this regime, there are advantages in using virgin,
cold-pressed non-raffinated evening primrose oil rather than the more
commonly available refined preparation, as the former is rich in lipophilic
pentacyclic triterpenes, which have free radical scavenging, cyclooxygenase
and neutrophil elastase inhibitory properties.[22]


CONCLUSION

There is evidence that myalgic encephalomyelitis or chronic fatigue syndrome
may be associated with a persistent viral infection. Such an infection could
adversely impact on the biosynthesis of long-chain polyunsaturated fatty
acids and therefore on membrane structure and functioning and the production
of eicosanoids. Administration of long- chain polyunsaturated fatty acids
may offer a potential therapeutic route.


REFERENCES

 1. Puri BK. Chronic fatigue syndrome. London: Hammersmith Press, 2005.
 2. Caligiuri M, Murray C, Buchwald D, et al. Phenotypic and functional
    deficiency of natural killer cells in patients with chronic fatigue
    syndrome. J Immunol 1987;139:3306-3313.
 3. Klimas NG, Salvato FR, Morgan R, et al. Immunologic abnormalities in chronic
    fatigue syndrome. J Clin Microbiol 1990;28:1403-1410.
 4. Tirelli V, Pinto A, Marotta G, et al. Clinical and immunologic study of 205
    patients with chronic fatigue syndrome: a case series from Italy. Arch
    Intern Med 1993;153:116-120.
 5. Visser J, Blauw B, Hinloopen B, et al. CD4 T lymphocytes from patients with
    chronic fatigue syndrome have decreased interferon-gamma production and
    increased sensitivity to dexamethasone. J Infect Dis 1998;177:451-454.
 6. Skowera A, Cleare A, Blair D, et al. High levels of type 2 cytokine-producing
    cells in chronic fatigue syndrome. Clin Exp Immunol 2004;135:294-302.
 7. Behan PO, Behan WMH, Horrobin D. Effect of high doses of essential fatty
    acids on the postviral fatigue syndrome. Acta Neurol Scand 1990;82:209-216.
 8. Warren G, McKendrick M, Peet M. The role of essential fatty acids in chronic
    fatigue syndrome. Acta Neurol Scand 1999;99:112-116.
 9. Puri BK. Proton and 31-phosphorus neurospectroscopy in the study of
    membrane phospholipids and fatty acid intervention in schizophrenia,
    depression, chronic fatigue syndrome (myalgic encephalomyelitis) and dyslexia.
    Int Rev Psychiatry 2006;18:145-147.
10. Puri BK, Counsell SJ, Zaman R, et al. Relative increase in choline in the
    occipital cortex in chronic fatigue syndrome. Acta Psychiatr Scand
    2002;106:224-226.
11. Chaudhuri A, Condon BR, Gow JW, et al. Proton magnetic resonance
    spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport
    2003;14: 225-228.
12. Tomoda A, Miike T, Yamada E, et al. Chronic fatigue syndrome in childhood.
    Brain Dev 2000;22:60-64.
13. Kaushik N, Fear D, Richards SCM, et al. Gene expression in peripheral blood
    mononuclear cells from patients with chronic fatigue syndrome. J Clin Pathol
    2005;58:826-832.
14. Stoesser AV. Effect of acute infection on iodine number of serum fatty acids.
    Proc Soc Exp Biol Med 1935;32:1326-1327.
15. Dunbar IM, Bayley JM. Enzyme deletions and essential fatty acid metabolism in
    cultured cells. J Biol Chem 1975;250:1152-1154.
16. Bayley JM. Lipid metabolism in cultured cells. In: F Snyder (ed.) Metabolism
    in Mammals, Volume II. Plenum Press, New York 1977, pp. 352-364.
17. Witt MR, Nielsen M. Characterisation of the influence of unsaturated free
    fatty acids on brain GABA/benzodiazepine receptor binding in vitro. J
    Neurochem 1994;62:1432-1439.
18. Cordero-Erausquin M, Marubio LM, Klink R, et al. Nicotinic receptor function:
    new perspectives from knockout mice. Trends Pharmacol Sci 2000;21:211-217.
19. Sands J, Auperin D, Snipes W. Extreme sensitivity of enveloped viruses,
    including herpes simplex, to long-chain unsaturated monoglycerides and
    alcohols. Antimicrob Agents Chemother 1979;15:67-73.
20. Horowitz B, Piet MP, Prince AM, et al. Inactivation of lipid-enveloped viruses
    in labile blood derivatives by unsaturated fatty acids. Vox Sang 1988;54:
    14-20.
21. Karmazyn M, Horrobin DF, Manku MS, et al. Interferon fever. Lancet 1977;
    2:307.
22. Puri BK. The clinical advantages of cold-pressed non-raffinated evening
    primrose oil over refined preparations. Med Hypotheses 2004;62:116-118.

The Corresponding Author has the right to grant on behalf of all authors and
does grant on behalf of all authors, an exclusive licence (or non-exclusive
for government employees) on a worldwide basis to the BMJ Publishing Group
Ltd and its Licensees to permit this article (if accepted) to be published in
JCP and any other BMJPGL products to exploit all subsidiary rights, as set out
in our licence.

--------
(c) 2006 BMJ Publishing Group Ltd

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

Date:    Thu, 31 Aug 2006 12:40:13 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx>
Subject: RES,NOT: Research priorities in CFS

Source: Journal of Clinical Pathology
        Preprint
Date:   August 29, 2006
URL:    http://jcp.bmjjournals.com/cgi/content/abstract/jcp.2006.042374v1
Ref:    You can respond to this article at:
        http://jcp.bmjjournals.com/cgi/eletter-submit/jcp.2006.042374v1


Current research priorities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
(CFS/ME): disease mechanisms, a diagnostic test and specific treatments
---------------------------------------------------------------------------------
JR Kerr,(1) P Christian,(2) A Hodgetts,(2) PR Langford,(2) LD Devanur,(1)
R Petty,(1) B Burke,(1) LI Sinclair,(3) SCM Richards,(4) J Montgomery,(4)
C McDermott,(4) TJ Harrison,(5) P Kellam,(6) DJ Nutt,(3) ST Holgate,(7) and
the Collaborative Clinical Study Group.*
1 Dept of Cellular & Molecular Medicine, St George's University of London;
2 Dept of Paediatric Infectious Diseases, Imperial College London;
3 Psychopharmacology Unit, University of Bristol;
4 Dorset CFS Service, Poole Hospital, Dorset; Depts of
5 Medicine and
6 Infection, University College London;
7 MRC Dept of Immunopharmacology, University of Southampton.
* Collaborative Clinical Study Group
  D Honeybourne (Birmingham Heartlands Hospital), AP Smith (Cardiff University),
  M Thomas (Cardiff University), JG Ayres (University of Aberdeen), J Main
  (Imperial College London), T Daymond (University of Sunderland), A Bansal
  (St Helier Hospital, Surrey), BK Puri (Hammersmith Hospital), R Morgan
  (Imperial College London), RC Peveler (University of Southampton), JS Axford
  (St George's University of London), W Weir (Harley Street, London),
  D Enlander (New York CFS Association, Fifth Avenue, New York, NY), JK Chia
  (ID Med, Torrance, CA).
Correspondence to: Dr Jonathan R Kerr, Sir Joseph Hotung Senior Lecturer in
Inflammation, Dept of Cellular & Molecular Medicine, St George's University
of London, Cranmer Terrace, London SW17 0RE, United Kingdom. Tel: 0208 725
5276. Fax: 0208 725 5260. Email: jkerr@xxxx.xx.xx.


Abstract

Chronic fatigue syndrome (CFS) is an illness characterised by disabling
fatigue of at least 6 months duration which is accompanied by various
rheumatological, infectious and neuropsychiatric symptoms. A collaborative
study group has been formed in order to address the current areas for
development in CFS research, namely, to develop an understanding of the
molecular pathogenesis of CFS, to develop a diagnostic test, and to develop
specific and curative treatments. Various groups have studied the gene
expression in peripheral blood of CFS patients and of those studies which
have been confirmed using polymerase chain reaction (PCR), it is clear that
the most predominant functional theme is that of immunity and defense.
However, we do not yet know the precise gene signature and metabolic
pathways involved. Currently, this is being addressed using a microarray
representing 47,000 human genes and variants, massive parallel signature
sequencing (MPSS) and real-time PCR. It will be important to ensure that
once a gene signature has been identified, that it is specific to CFS and
does not occur in other diseases and infections. A diagnostic test is being
developed using Surface-Enhanced, Laser- Desorption and Ionisation ­ Time of
Flight (SELDI-TOF) mass spectrometry following a pilot study in which
putative biomarkers were identified. And, finally, clinical trials are being
planned; novel treatments which we believe are important to trial in CFS
patients are interferon- and one of the anti-tumour necrosis factor- drugs.


Introduction

Chronic fatigue syndrome (CFS) is an illness characterised by disabling
fatigue of at least 6 months duration which is accompanied by various
rheumatological, infectious and neuropsychiatric symptoms.1 The prevalence
of CFS is 0.5% and it is more common in women than in men. The diagnosis is
clinical and there is no laboratory test and no specific treatment. CFS is
now accepted as a valid disease is its own right, and this, along with the
urgent need to elucidate its pathogenesis, and to develop strategies for
diagnosis and treatment, was emphasised in the recent report to the Chief
Medical Officer (CMO), 'A report of the CFS/ME Working Group'.2
Epidemiological studies have revealed that many CFS patients give a history
of an illness consistent with virus infection which precedes the development
of fatigue,3 and CFS has been shown to follow acute infection with various
infectious agents. CFS patients have been shown to have evidence of immune
activation. However, despite considerable research, the causative and
perpetuating disease mechanisms remain unknown.

In 2001, a Collaborative Study Group was formed to specifically investigate
the molecular pathogenesis of CFS, to develop a diagnostic test, and to take
this knowledge forward into development of new, specific treatments, which
are not available at present. The members of this group were also concerned
at the trivialisation of CFS and the labelling of patients as sufferers of
psychiatric, psychological or somatoform disease. To address the problem, a
pilot study was performed to see if there was any evidence that the white
blood cells of CFS patients exhibited a specific gene signature, as has been
shown for several other immune- mediated diseases. This pilot study provided
clear support for the hypothesis that abnormalities of gene regulation occur
in CFS.4 Following this, further funding was awarded by the CFS Research
Foundation, Hertfordshire, UK (http://www.cfsrf.com), to continue with the
research and to expand upon the pilot study. Currently, the total support is
approximately 1 million pounds from the CFS Research Foundation, UK, and the
purpose of this review is to outline how this money is being spent, what
will be gained from this research, and what are the future priorities for
research in the area of CFS.

The principal goals are to gain a clear understanding of those genes which
are associated only or mainly with CFS, and also to identify protein
biomarkers in the serum of CFS patients which can be used to develop a test
designed to assist doctors in the clinical diagnosis of CFS in hospitals and
clinics. In addition to these, and based on those genes that have been shown
to be associated with CFS, clinical trials will be performed of new and
established pharmaceutical drugs in CFS patients in order to identify one or
more treatments which will cure most cases of the disease.


Which genes occur at abnormal levels in patients with CFS?

Information generated by sequencing of the human genome along with advances
in manufacture of automated chips and data analysis has provided the
potential to correlate the genome of an organism with its biological
functions. Analysis of gene expression in peripheral blood white blood cells
has become a standard methodological approach to study of the pathogenesis
of many human diseases. In CFS, blood has been shown to be a good choice
because it is accessible, because it has been shown that most genes are
found to be expressed in the white blood cells and as it has been shown by
various groups that the white blood cells of CFS patients exhibit
reproducible alterations in gene expression as compared with normal controls
(Table 1).4-8 Unfortunately, some studies on gene expression in CFS suffer
the serious flaw of not confirming microarray analyses with real-time
PCR.5,9-20 The genes identified by such studies using unconfirmed microarray
data cannot be relied upon due to the known lack of specificity in
microarray analyses, and so interpretation of these studies is extremely
difficult. Considering PCR-confirmed studies only,4-8 (Kerr et al,
unpublished), the genes identified in CFS suggest a complex picture but most
prominent within which is 'immunity and defense'. This supports previous
findings on the role of the immune system in the maintenance of this
disease.

In our own pilot study,4 total RNA in the circulating white blood cells was
examined in 25 CFS patients and 25 age and sex-matched normal blood donors
for gene expression using a microarray representing 9,522 human genes. After
confirmation of the results using taqman real-time polymerase chain reaction
(PCR), 16 genes were shown to be expressed at very different levels in the
cases compared with the controls. These genes were involved in several
processes, including immunity and defense, the mitochondrion, and
transcriptional and translational regulation. Although this study provides
proof that CFS patients exhibit significant and reproducible differences in
gene expression compared with controls, the particular profile of genes
identified indicates that the picture is complex.

But the ultimate goal in all of these studies has not yet been achieved;
namely to identify with complete certainty those genes whose over- or
under-expression occurs in patients with CFS, but not in either normal
persons or in patients with other diseases. In addition, such research must
be comprehensive enough to identify particular metabolic pathways that are
involved in CFS. Therefore, we must use methods that look at all known genes
and then be able to group the genes together so that we have knowledge of
the pathways involved.

Another interesting development is the suggestion that standard microarrays
may not be adequate as their design depends on prior knowledge of the gene
sequences that are looked for in the samples, as described above. The study
of Powell et al,6 is particularly interesting in this regard, because it is
the only published study of significant size, to date, that used an entirely
open-ended screening method (differential display) and found that 4 of 12
PCR- confirmed, CFS-associated, transcripts could not be matched to known
genes in either the Celera or NCBI genomics databases (as of December 2005),
and suggests the involvement of novel sequences in CFS. We have taken this
phenomenon very seriously and are reproducing our 2005 pilot study using a
combination of both microarrays (representing 47,000 human genes and
variants) and massive parallel signature sequencing (MPSS).

MPSS is a new method that precisely quantifies all mRNA species and has the
potential to detect entirely new human genes as well as viral and other
genes. The method utilises microbeads which are bound to signature sequences
which bind genes in the sample. Then, those signature sequences that have
bound gene attached to them are sequenced while they are still attached to
the bead, and used to generate precise numbers of each signature sequence
present in the sample. Therefore, all genes are detected and precise gene
copy numbers generated for each. Our strategy is to identify genes which are
significantly differentially expressed between CFS and normal groups in
microarray and MPSS studies, and to confirm these using real-time PCR. This
is critical due to the known lack of specificity of gene arrays and other
such sensitive screening methods.

In a Phase 2 study the genes in our CFS-associated gene signature will be
tested for in many more CFS patients, patients whose disease fits criteria
for CFS except for duration of disease (for example, 3-6 months duration of
illness), normal controls with a degree of fatigue on the day of sampling,
and disease controls (for example, rheumatoid arthritis, osteoarthritis,
endogenous depression, etc). This will exclude some genes identified in the
first phase, but the genes that are left can be taken to be specific to the
disease process(es) in CFS.

In a Phase 3 study a small subset of CFS patients will be examined who are
typical in terms of their disease phenotype (or symptoms) and CFS-associated
gene signature, at 13 time points over one year at intervals of one month.
Clinical symptoms and their severity will be recorded and gene levels
determined, and an attempt made to associate particular abnormalities of
gene expression with the presence and severity of particular symptoms which
occur in CFS.

The MPSS signature sequences have also been used to indicate virus
infections in our patients as compared with controls, and currently 28
possible viral candidates are being tested for in the white blood cells of
our study subjects.


Development of a diagnostic test to be used in clinical laboratories

Progress is also being made towards identifying biomarkers in the serum of
patients with CFS. A biomarker is a protein that occurs at different levels
in the serum of patients as compared with normal people and patients
suffering from other diseases. This work is being done using a technique
called Surface-Enhanced, Laser-Desorption and Ionisation ­ Time of Flight
(SELDI-TOF) mass spectrometry (http://www.ciphergen.com).

In this technique, minute amounts of serum are spotted onto the surface of
aluminium chips which are then subjected to an ionisation current. This
method combines chromatographic separation, achievable due to the presence
of biochemically active chip surfaces, with mass spectrometry. Based on the
time of flight, the mass/charge (m/z) ratio for each molecule is
determined. The method is able to determine the mass and relative amount of
each individual molecule in complex protein mixtures. Analysis of mass
spectra from cases as compared with controls, identifies peaks (or proteins)
the presence or absence of which can reliably distinguish between the two
groups. It is these proteins (or combinations of them) which can then be
used as biomarkers in a diagnostic test, assuming they are shown to be
specific to patients with CFS.


Protein Biomarker Pilot Study

We have performed a pilot study of this approach at Imperial College London
which has identified statistically significant protein biomarkers in the
blood of CFS patients (P Christian, A Hodgetts, P Langford, JR Kerr). In
this study, serum samples from 30 cases of CFS and 30 normal blood donors
(age and sex-matched) were examined. Each serum was tested using CM10 and
Q10 chips using a matrix consisting of a saturated solution of sinapic acid
in 50% acetonitrile and 0.5% trifluoroacetic acid. Pooled sera from each
group (10 pools each of 3 sera for each group) were then anionically
fractionated using resin by a standard protocol and analysed using NP20
chips. This resulted in collection of 6 fractions containing eluants of
flow-through with pH9, pH7, pH5, pH4, pH3 and acid-organic solvent. These
fractions were analysed using the SELDI-PC NP20 arrays and the spectra were
analysed using Ciphergen Express Data Manager (CEDM) software. Biomarkers
were found which differentiated the groups and some of these were found to
be reproducible (Figure 1), thus confirming the hypothesis that such
differences occur between patients with CFS and normal persons. Larger-scale
studies must now take place to confirm and further detail these promising
results. This work is currently being performed using adult and paediatric
blood samples, as a collaboration between Imperial College London and St
George's University of London.

This work is being performed quite separately from the gene expression work.
The reason for this is that it is well recognised that genes that are
differentially expressed in a particular disease state may be detected as
differentially expressed at the protein level in only 30-70% of cases.
Therefore, it seems that many factors may influence the relationship between
the white blood cell transcript level and the respective serum protein
level. In view of this, these studies are performed independently of each
other, but on the same populations in order to clarify this relationship.


Clinical trials of pharmaceutical drugs in patients with CFS

Knowledge of how a disease is caused leads directly to design and
utilisation of treatments which correct the abnormal processes and,
hopefully, lead to improvement or cure of the disease. In the context of
genomic research, many treatments have been designed in this way. For
example, a range of so-called 'biologic' treatments are now available for
immune- mediated diseases.

On the basis of the results of gene expression studies, funded by the CFS
Research Foundation, UK, a clinical trial of interferon-beta (IFN-beta) is
planned at St George's University of London. We envisage that this will be
first of several clinical trials that are based on our gene expression
findings, using the novel gene approach outlined above.

Interferon-beta (IFN-beta) is involved in the regulation of humoral immune
responses and immune responses against virus infections. IFN-beta increases
expression of HLA class I antigens and blocks the expression of HLA class 2
antigens. IFN-beta stimulates the activity of NK cells, which are accepted
to be inefficient in CFS patients. IFN-beta selectively inhibits the
expression of some mitochondrial genes which are implicated by gene studies
in CFS patients,4 (Kerr et al, unpublished). IFN-beta inhibits the
proliferation of a number of cancer cell lines.21 Evidence for T cell
activation has been documented in CFS patients,4 (Kerr et al, unpublished).
Virus infection is known to trigger CFS and various studies suggest that
ongoing virus infection is a feature of CFS. Finally, IFN-beta is a
licensed treatment for multiple sclerosis (MS) in which it has resulted in
reduction of fatigue. It is thought that the pathogenesis of fatigue in MS
may be cytokine- mediated,22 as has been demonstrated in the CFS. A trial of
IFN-beta has not been performed previously in CFS patients. As CFS patients
are unusually sensitive to drugs and chemicals, a reduced dose may need to
be used to avoid side effects.

The TNF-alpha inhibitors are another group which may provide benefit in CFS.
This group of drugs has been shown to lead to dramatic improvement in
patients with rheumatoid arthritis, Crohn's disease, psoriasis and other
diseases including asthma. One TNF-alpha inhibitor (Etanercept) has been
used with significant benefit in the treatment of 6 CFS patients in a pilot
study (Lamprecht et al, 2001). Unfortunately, this trial was not published
as a paper, but only as a meeting abstract. The use of TNF-alpha inhibitors
in CFS is strongly supported by scientific data on the immune responses in
CFS, epidemiological data, and now data from gene expression studies,6 (Kerr
et al, unpublished). It is also an urgent priority to repeat this work and
perform a larger clinical trial of etanercept in CFS patients.


Conclusion

In the near future, we can expect a diagnostic test for CFS, an
understanding of the mechanisms of the disease, and treatments that will
work in most cases of this tragic and all- too-common illness.


Acknowledgements

We thank the CFS Research Foundation (http://www.cfsrf.com) for funding.


Figure Caption

Figure 1. Potential biomarker of CFS at 17899 Da which eluted in the
acid/organic wash from the anionic exchange fractionation. p=0.0052


Table

Table 1. Gene expression studies in CFS. Only the microarray results of studies shown in grey have been confirmed
         using PCR.
----------------------------------------------------------------------------------------------------------------------
Author & year        Ref. No.   No.   Gene expression      PCR  Purpose of study             Main functional themes
                     No.  CFS   normal  screening method   used                              pathogenesis of CFS*
                          cases controls
----------------------------------------------------------------------------------------------------------------------
Vernon et al, 2002    5    5   17     Filter array         No   To identify gene expression  Immunity & defence
                                      (1764 genes)              correlates of CFS
Powell et al, 2003    6    7    4     Differential display Yes  To identify gene expression  Immunity & defence
                                                                correlates of CFS
Whistler et al, 2003  9   23    0     Microarray           No   To identify gene expression  Not applicable
                                      (3,800 genes)             correlates of CFS phenotypes
Whistler et al, 2005 10    5    5     Microarray           No   To identify gene expression  Not applicable
                                      (3,800 genes)             correlates of exercise
Grans et al, 2005     7   20   14     Microarray           Yes  To identify gene expression  Not applicable
                                      (30,000 genes)            correlates of CFS
Kaushik et al, 2005   4   25   25     Microarray           Yes  To identify gene expression  Immunity & defence
                                      (9,522 genes)             correlates of CFS
Gow et al, 2005      12    8    7     Microarray           No   To identify gene expression  Immunity & defence
                                      (33,000 genes)            correlates of CFS
Grans et al, 2006     8   30   36     Not applicable       Yes  To determine oestrogen       Reduced ERbeta levels
                                                                receptor (ERbeta) levels     - consistent with
                                                                                             immunomodulation
Carmel et al, 2006   13   40   37     Microarray           No   To identify gene expression  Not applicable
                                      (19,760 genes)            correlates of CFS phenotypes
Whistler et al, 2006 11   40   37     Microarray           No   To identify gene expression  Energy metabolism,
                                      (19,760 genes)            correlates of CFS phenotypes signal transduction, cell
                                                                                             proliferation, apoptosis
Broderick et al, 2006 14  40   37     Microarray           No   To identify illness          Not applicable
                                      (19,760 genes)            parameters in fatiguing
                                                                illness
Fang et al, 2006     16   40   37     Microarray           No   To identify gene expression  Immune response,
                                      (19,760 genes)            correlates of CFS phenotypes apoptosis, ion-channel,
                                                                                             reg. of cell growth,
                                                                                             neuronal activity
Fostel et al, 2006   17   40   37     Microarray           No   To identify gene expression  Immune response,
                                      (19,760 genes)            correlates of CFS            androgen receptors, P450,
                                                                                             cytoskeleton, signalling
Kerr et al,               47   74     Microarray           Yes  To identify gene expression  Immunity & defence
unpublished                           (47,000 genes)            correlates of CFS
                                      & MPSS*
----------------------------------------------------------------------------------------------------------------------
*MPSS, massive parallel signature sequencing.


References

 1. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The
    chronic fatigue syndrome: a comprehensive approach to its definition and
    study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med.
    1994 Dec 15;121(12):953-9.
 2. Report of the CFS/ME Working Group. Department of Health, January 2002.
    (http://www.doh.gov.uk/cmo/cfsmereport).
 3. Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry.
    2003 Feb;160(2):221-36. Review.
 4. Kaushik N, Fear D, Richards SC, McDermott CR, Nuwaysir EF, Kellam P,
    Harrison TJ, Wilkinson RJ, Tyrrell DA, Holgate ST, Kerr JR. Gene expression
    in peripheral blood mononuclear cells from patients with chronic fatigue
    syndrome. J Clin Pathol. 2005 Aug;58(8):826-32.
 5. Vernon SD, Unger ER, Dimulescu IM, Rajeevan M, Reeves WC. Utility of the
    blood for gene expression profiling and biomarker discovery in chronic
    fatigue syndrome. Dis Markers. 2002;18(4):193-9.
 6. Powell R, Ren J, Lewith G, Barclay W, Holgate S, Almond J. Identification
    of novel expressed sequences, up-regulated in the leucocytes of chronic
    fatigue syndrome patients. Clin Exp Allergy. 2003 Oct;33(10):1450-6.
 7. Grans H, Nilsson P, Evengard B. Gene expression profiling in the chronic
    fatigue syndrome. J Intern Med. 2005;258(4):388-90.
 8. Grans H, Nilsson M, Dahlman-Wright K, Evengard B. Reduced levels of
    oestrogen receptor beta mRNA in Swedish patients with chronic fatigue
    syndrome. J Clin Pathol. 2006 May 26; [Epub ahead of print].
 9. Whistler T, Unger ER, Nisenbaum R, Vernon SD. Integration of gene
    expression, clinical, and epidemiologic data to characterize Chronic
    Fatigue Syndrome. J Transl Med. 2003 Dec 1;1(1):10.
10. Whistler T, Jones JF, Unger ER, Vernon SD. Exercise responsive genes
    measured in peripheral blood of women with chronic fatigue syndrome and
    matched control subjects. BMC Physiol 2005;24;5(1):5.
11. Whistler T, Taylor R, Craddock RC, Broderick G, Klimas N, Unger ER. Gene
    expression correlates of unexplained fatigue. Pharmacogenomics 2006;7(3):
    395-405.
12. Gow JW, Cannon C, Behan WMH, Herzyk P, Keir S, Riboldi-Tunnicliffe G, Behan
    PO, Chaudhuri A. Whole-Genome (33,000 genes) Affymetrix DNA Microarray
    Analysis of Gene Expression in Chronic Fatigue Syndrome. International
    Conference on Fatigue Science, Karuizawa, Japan. February 2005. Abstract
    S7-03/P2-19.
13. Carmel L, Efroni S, White PD, Aslakson E, Vollmer-Conna U, Rajeevan MS. Gene
    expression profile of empirically delineated classes of unexplained
    chronic fatigue. Pharmacogenomics 2006;7(3):375-86.
14. Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N, Unger ER.
    Identifying illness parameters in fatiguing syndromes using classical
    projection methods. Pharmacogenomics 2006;7(3):407-19.
15. Craddock RC, Taylor R, Broderick G, Whistler T, Klimas N, Unger ER.
    Exploration of statistical dependence between illness parameters using the
    entropy correlation coefficient. Pharmacogenomics 2006;7(3):421-8.
16. Fang H, Xie Q, Boneva R, Fostel J, Perkins R, Tong W. Gene expression
    profile exploration of a large dataset on chronic fatigue syndrome.
    Pharmacogenomics 2006;7(3):429-40.
17. Fostel J, Boneva R, Lloyd A. Exploration of the gene expression correlates
    of chronic unexplained fatigue using factor analysis. Pharmacogenomics
    2006;7(3):441-54.
18. Lin SM, Devakumar J, Kibbe WA. Improved prediction of treatment response
    using microarrays and existing biological knowledge. Pharmacogenomics 2006;
    7(3):495-501.
19. Waltman P, Pearlman A, Mishra B. Interpreter of maladies: redescription
    mining applied to biomedical data analysis. Pharmacogenomics 2006;7(3):
    503-9. Review.
20. Shoemaker J. Statistical challenges with gene expression studies.
    Pharmacogenomics 2006;7(3):511-9.
21. Arnason BG. Long-term experience with interferon beta-1b (Betaferon)in
    multiple sclerosis. J Neurol. 2005 Sep;252 Suppl 3:iii28-iii33.
22. Heesen C, Nawrath L, Reich C, Bauer N, Schulz KH, Gold SM. Fatigue in
    multiple sclerosis: an example of cytokine mediated sickness behaviour?
    JNNP 2006;77:34-9.
23. Lamprecht K, et al. Pilot study of etanercept treatment in patients with
    Chronic Fatigue Syndrome. Meeting of the American Association of Chronic
    Fatigue Syndrome (AACFS), Seattle, 2001.
    http://www.cfsresearch.org/cfs/conferences/14.htm

The Corresponding Author has the right to grant on behalf of all authors and
does grant on behalf of all authors, an exclusive licence (or non-exclusive
for government employees) on a worldwide basis to the BMJ Publishing Group
Ltd and its Licensees to permit this article (if accepted) to be published in
JCP and any other BMJPGL products to exploit all subsidiary rights, as set out
in our licence."

--------
(c) 2006 BMJ Publishing Group Ltd

[Return to top]

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

Date:    Thu, 31 Aug 2006 13:21:14 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx>
Subject: RES,NOT,URL: Clinical Trials: CFS and FM

Clinical Trials: Chronic Fatigue Syndrome
http://www.centerwatch.com/patient/studies/cat336.html

Clinical Trials: Fibromyalgia
http://www.centerwatch.com/patient/studies/cat218.html

[Return to top]

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

Date:    Fri, 1 Sep 2006 12:46:19 -0400
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx>
Subject: RES: A reconsideration of the relevance of systemic low-dose ketamine to the pathophysiology of fibromyalgia

A reconsideration of the relevance of systemic low-dose ketamine to the
pathophysiology of fibromyalgia.

J Pain. 2006 Sep;7(9):611-4.

Wood PB.

Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.

PMID: 16942946


Fibromyalgia is a common disorder characterized by chronic widespread pain
that affects an estimated 2% of the general population. Recent advances
have shed insight on this mysterious disorder, leading to the growing
conclusion that disturbances of pain-related processes within the central
nervous system, termed central sensitization, represent its most likely
source.

The phenomenon of central sensitization depends on plasticity in function
of N-methyl-D-aspartate (NMDA) subtype glutamate receptors. Earlier studies
implicated increased sensitivity of central NMDA receptors as playing a
primary role in fibromyalgia, as evidenced by a significant reduction in
symptoms among a large subset of patients in response to low doses of
ketamine, a noncompetitive NMDA receptor antagonist.

However, recent insights into the pharmacology of this drug cast doubt on a
direct contribution of NMDA receptors and add credence to a model of the
disorder that suggests that the primary pathology of fibromyalgia is a
suppression of the normal activity of dopamine-releasing neurons within the
limbic system. The implications for future therapies for fibromyalgia, and
indeed many other chronic pain conditions, are discussed in light of these
insights.

PERSPECTIVE: The current lack of a demonstrable pathology underlying the
pain of fibromyalgia has hampered progress toward adequate treatment of
this mysterious disorder. Accumulating evidence suggests that fibromyalgia
may represent a dysregulation of dopaminergic neurotransmission, which may
provide insights to guide both rational clinical interventions as well as
system-specific research models.

[Return to top]

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

Date:    Fri, 1 Sep 2006 13:17:25 -0400
From:    Kimberly Hare <Kimberly_ohare@xxxxx.xxx>
Subject: RES: Definitions and aetiology of Myalgic Encephalomyelitis (ME): how the Canadian Consensus Clinical Definition of ME Works

Definitions and aetiology of Myalgic Encephalomyelitis (ME): how the Canadian Consensus
Clinical Definition of ME Works

Journal: J. Clin. Pathol. published online 25 Aug 2006; doi:10.1136/jcp.2006.042754

Author:  Bruce Carruthers


Abstract
A perspective on the various definitions of ME and the process of discovering its aetiology has
been taken. The importance of clinical guidelines has been emphasised to encourage clinicians to
provide the clear descriptions of their individual patients required for proper clinical activity;
diagnosis, estimation of severity of impact, prognosis, treatment, and rehabilitation. This individual
knowledge is informed by general and (hopefully) publicly confirmed knowledge resulting from
scientific research during the second person interaction which lies at the core of the clinical
encounter. Both types of knowledge are essential.

Definitions of a medical disorder must serve two divergent functions; both necessary, yet mutually
exclusive because of their fundamentally different observational contexts - one dealing with groups
of patients who can be approached scientifically and the other with individuals in a clinical context.
Research definitions (1-3) provide researchers with (relatively) homogenous groups of patients to
allow meaningfully isolated and controlled observations as they follow various hypotheses in the
hope of confirming/refuting them. In the context of research all knowledge is under review; both
what is explicitly in doubt and what is supposed to have been confirmed. Thus the observational
context is one of general uncertainty, but grounded in trust that the scientific method can generate
reliable (third-person) knowledge, and one has to start somewhere. As each patient must be
viewed as a member of a selected set, methodologically they cannot be viewed as individuals.

At the risk of exhibiting anecdotage , I would like to argue that another context of observation is
critical to the clinical endeavour, one that depends on the anecdotal, viewpoint-including, firstperson
experience of a patient. This is not merely consideration of a list of symptoms. It uses what
is regarded as established third-person medical knowledge (graded into several categories of
certainty/uncertainty), and matches this knowledge with that being provided by the individual
patient, in the certainty of her/his illness experience. These two types of (what is regarded to be)
certain knowledge meet in a second-person interchange between physician and patient involving
the basic clinical activities of individual diagnosis, individual prognosis, individual treatment and
individual prevention (4), also including an assessment of its impact on the patient s individual life
(degree of dis-ease and dis-ability, or deviation from the state of ease and ability which we call
health).

The observational context of clinical activity is thus more complex and begins from the first-person
viewpoint generated by the deictic (5,6) co-ordinates of the individual patient, which then meet the
observational and empathic skills of the physician, as well as the generalised third-person coordinates
of established public knowledge backed by various forms of evidence, in the doctor-
patient relationship within a second-person interaction. This knowledge then must be reapplied
within the deictic co-ordinates of the individual patient, viewpoints and all. But this is anecdotal
certainty, and hence irrelevant to science. But, however anecdotal, this clinical work is essential as
the patient s unique clinical entity must be identified by being observed accurately and adequately
within its proper context. The relevant variables to follow within the entity must be sorted out from
the irrelevant ones, and similarly with those in its background. The symptoms and signs
expressing this dynamic entity must be observed minutely to see how their qualitative and
quantitative changes are developing. Interactions within and without the entity must be observed in
order to find consilient and causal chains to assign symptom priority. The individual effects of
treatments must be observed and such effects may trump the statistical results of evidence based
treatments within the clinical context.

A primary clinical entity cannot be a static object. It is necessarily subjective in part (since it
observes at least itself), and like the primary illness experience that participates in it, is an
undivided, in-dividual, as yet unnamed whole, and of the nature of a real process, not to be
confused with the set of concepts used to name and describe it (see problem of
realism/nominalism(7)). Note that all of these clinical practices depend to a large extent on the
assumption of the accuracy and adequacy of the patient s experience of illness as it unfolds under
the observation of the physician. If the observational discipline of Western painting is based on the
disavowal of deictic reference (8), then it is no wonder that clinical observation skills are
atrophying. But it is the dynamic clinical entity, of necessity both subjective and objective, which
orients the field of clinical activity, if clearly and adequately observed.

If such clarity and adequacy are not achieved, several types of smudging may result. In other
words, if the generalisations from the medical model are too generic, they have no chance of
adequately meeting the patients illness experience, and much relevant data may be overlooked
and/or misinterpreted. Thus the move from a more specific clinical concept such as ME or
Fibromyalgia to a more generic concept such as Chronic Fatigue Syndrome or Chronic Pain
Syndrome entails missing a lot of the information that makes the syndrome as a name match the
syndrome as an experience. The syndrome as an experience is a coherent entity whose parts run
together as a process - as the word syndrome indicates etymologically - and whose causal
interactions are sensed directly in the mode of causal efficacy (9). This entity arises against a
background which is treated as a nonentity for the purposes of the observation. Thus the attempt
to organise clinical activity around a nonentity, such as in Somatization Disorder and Munchausen
Syndrome(10,11), where diagnosis depends on the absence of an entity, may interfere with proper
clinical activity by importing a misplaced forensic attitude towards a patient s illness experience,
discounting or distorting its relevance. The move towards ignoring the distinctions between primary
and secondary which designate sensed causal directions within a clinical entity, whether applied to
depression, anxiety, infection or fibromyalgia, add to the confusion and impede the elucidation of a
properly dynamic clinical entity. The widespread use of the holistic biopsychosocial model of
disease(12-14) without any distinction between a clinical entity and its background encourages the
drowning of clinical entities by risk factors which can proliferate endlessly in a nominalist fury
without orientation as to their state of relevance or lack thereof with respect to a real entity (7).

The Canadian consensus case definition and diagnostic protocol for ME (15) has been influenced
by the clinical method of Sydenham (16), which is to provide a fuller and richer framework to fit the
patient's illness experience into a framework that is specific and complete enough to match the
patient's experience, yet consonant with the large body of public and confirmed results that have
been obtained by the research activity stimulated by earlier definitions. It tries to be more adequate
to the clinical activity that each patient's unique clinical situation demands. It facilitates a precise
and adequate observation of the unique clinical entity arising in a patient in contrast to its
contextual background. This is necessary to orient clinical activities, to guide the quantification of
the events, both syndromal and contextual, which may be of particular relevance, as well as
sorting out their causal direction and priority. It tries to remain close enough to be adequate to the
illness experience of the patient and thus invariant to the changes in interpretation of this
experience as science evolves over the years (16). Unless a disease entity is eliminated by better
understanding and better technology, it will continue to require clinical attention, whatever we
hypothesize its natural kind to be.

To improve clinical observation, the Canadian definition and diagnostic protocol lays out a number
of regions of patho-physiological dysfunction, as necessary components of the syndrome of ME,
but the particular expression of symptoms within each region is contingent between individuals,
and their specific pattern is left open to be decided by clinical observation of the individual and
later diagnostic classification. These component regions include fatigue, which must be severe
and prolonged and of a certain dynamic pattern (delayed, prolonged reactive), and significant
dysfunction must be observed in the following realms - sleep, pain, neurological/cognitive, and at
least one of the following 3 realms - autonomic nervous system, neuroendocrine, and immune
system. This approach facilitates the identification of the patient s individual clinical entity or
syndrome, how its parts fit together and interact, as well as its impact on the patient s life - seen as
dis-ability and dis-ease - and leading to a more accurate and adequate diagnosis. It allows
estimates of the clinical course and prognosis, decisions regarding treatment, estimation of the
treatment effects, and search for successful preventive and rehabilitative strategies. With its
flexible combination of necessary and optional features, the definition allows the diagnosis to fit the
patient rather than the other way around (as with Procrustes, an innkeeper from Greek mythology
who stretched the guests to fit his bed!).

The possible aetiology of ME is under scientific observation. This is done by experiment and by
controlled observation. Many observers are following various lines of investigation and observation
as to the aetiology of ME, which we are all following with interest.

There are some problems. A hypothesis is a cognitive structure necessary to organise one's
experimental efforts. When rigorously tested independently and often enough, your hypothesis can
be regarded as tentatively confirmed. But within the context of research, you should work to
disprove your hypothesis. As noted by Sydenham (16), to arrange reality to save it can cause
much error. I quote In writing the history of a disease, every philosophical hypothesis whatsoever,
that has previously occupied the mind of the author, should lie in abeyance. This being done, the
clear and natural phenomena of the disease should be noted - these and these only. They should
be noted accurately, and in all their minuteness;......No man can state the errors that have been
occasioned by these physiological hypotheses. Writers, whose minds have taken a false colour
under their influence, have saddled diseases with phenomena which existed in their own brains
only; but which would have been clear and visible to the whole world had the assumed hypotheses
been true.

The opposite problem of importing a context of doubt into the clinical arena, which is heavily
dependant on deictic certainties, can result in the disruption of the second person clinical
observation structure and subsequent clinical practices, as observed with the smudge diagnoses
mentioned earlier.

The problem of cultivating a holistic view without adequately structuring the field with a proper
clinical entity can lead to great confusions of relevance, where contextual and syndromal features
are confounded with no way of clinically quantifying their relative impacts. Choose the right kind of
entity or you may end up only considering background factors with no clinical entity left that they
are the background of - see the fate of the Cheshire cat in Alice in Wonderland, where the cat
fades, leaving only the smile! (17)

References
1.Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition.
Ann Intern Med. 1988;108(3):387-9.
2.Sharpe MC, Archard LC, Banatvala JE, et al. A report - chronic fatigue syndrome: guidelines for
research. J R Soc Med. 1991;84(2):118-21.
3.Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue
syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue
Syndrome Study Group. Ann Intern Med. 1994 Dec 15;121(12):953-9.
4.McDermott W. Evaluating the Physician and His Technology. In Doing Better and Feeling
Worse: Health in the United States , ed, Knowles JH. Norton, New York, 1977, pp.142-156.
5.Tallis R. The Raymond Tallis Reader. Ed, Grant M. Palgrave Macmillan, New York, 2000.
6.Bryson N. Vision and Painting. Yale University Press, New Haven, 1983, p.87.
7.Hacking I. The Social Construction of What? Harvard University Press, Cambridge, 1999, pp.80-
84; 96-99; 174; 205-6.
8.Bryson N. Vision and Painting. Yale University Press, New Haven, 1983, p.89.
9.Whitehead AN. Symbolism. Capricorn Books, New York, 1927, pp.30-59.
10. Hollifield, MA. Somatoform Disorders. In: Kaplan and Sadock s Comprehensive Textbook of
Psychiatry. Eds. Sadock BJ and Sadock VA, 8th ed. Baltimore: Lippincott, Williams and Wilkins,
2004, pp.1800-1828.
11. Wang D, Nadiga DN and Jenson, JJ. Factitious Disorders. In: Kaplan and Sadock s
Comprehensive Textbook of Psychiatry. Eds. Sadock BJ and Sadock VA, 8th ed. Baltimore:
Lippincott, Williams and Wilkins, 2004, pp.1829-1843.
12. Engel GL. The clinical application of the biopsychosocial model. Am J Psychiatry
1980;137:535-44.
13.Dilts SL. Models of the Mind. Brunner Routledge, Philadelphia, 2000.pp13-16.
14.Wessely S, Hotopf M, Sharpe MC. Chronic Fatigue and its Syndromes. Oxford University
Press, Oxford, 1998, pp.363-5.
15.Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic encephalomyelitis / Chronic Fatigue
Syndrome: clinical working case definition, diagnostic and treatment protocols. Journal of Chronic
Fatigue Syndrome 2003;11:7-115.
16.Sydenham T. Medical observations concerning the history and the cure of acute diseases.
Preface to the 3rd edition, section 9, p14. (First Edition, 1676, The works of Thomas Sydenham,
MD. Classics of Medicine Library, 1979).
17.Carroll L. Alice in Wonderland. Collins, London, undated, pp.67-80.

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

Date:    Sat, 2 Sep 2006 04:36:10 +0200
From:    Jan van Roijen <j.van.roijen@xxxxx.xx>
Subject: res: Post-infective & CFS precipitated by viral & non-viral pathogens

~~~~~~~~~~~~~~~~~~~~~~~~~~~~


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BMJ, doi:10.1136/bmj.38933.585764.AE (published 1
September 2006)


RESEARCH



Post-infective and chronic fatigue syndromes
precipitated by viral and non-viral pathogens:
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
prospective cohort study




Ian Hickie 1, Tracey Davenport 1, Denis Wakefield 2, Ute
Vollmer-Conna 3, Barbara Cameron 2, Suzanne D Vernon 4,
William C Reeves 4, Andrew Lloyd 2*, for the Dubbo Infection
Outcomes Study Group


1 Brain and Mind Research Institute, Sydney University, Sydney,
    NSW 2050, Australia
2 School of Medical Sciences, University of New South Wales,
    Sydney, NSW 2052
3 School of Psychiatry, University of New South Wales
4 Division of Viral and Rickettsial Diseases, Centers for
    Disease Control and Prevention, Atlanta, GA 31033, USA

* Correspondence to: a.lloyd@unsw.xxx.xx.



Objective

To delineate the risk factors, symptom patterns, and longitudinal
course of prolonged illnesses after a variety of acute infections.

Design

Prospective cohort study following patients from the time of
acute infection with Epstein-Barr virus (glandular fever), Coxiella
burnetii (Q fever), or Ross River virus (epidemic polyarthritis).

Setting

The region surrounding the township of Dubbo in rural Australia,
encompassing a 200 km geographical radius and 104 400
residents.

Participants

253 patients enrolled and followed at regular intervals over 12
months by self report, structured interview, and clinical
assessment.

Outcome measures

Detailed medical, psychiatric, and laboratory evaluations at six
months to apply diagnostic criteria for chronic fatigue syndrome.
Premorbid and intercurrent illness characteristics recorded to
define risk factors for chronic fatigue syndrome. Self reported
illness phenotypes compared between infective groups.

Results

Prolonged illness characterised by disabling fatigue,
musculoskeletal pain, neurocognitive difficulties, and mood
disturbance was evident in 29 (12%) of 253 participants at six
months, of whom 28 (11%) met the diagnostic criteria for chronic
fatigue syndrome. This post-infective fatigue syndrome
phenotype was stereotyped and occurred at a similar incidence
after each infection. The syndrome was predicted largely by the
severity of the acute illness rather than by demographic,
psychological, or microbiological factors.

Conclusions

A relatively uniform post-infective fatigue syndrome persists in a
significant minority of patients for six months or more after
clinical infection with several different viral and non-viral
micro-organisms. Post-infective fatigue syndrome is a valid
illness model for investigating one pathophysiological pathway
to chronic fatigue syndrome.


(Accepted 2 August 2006)


~jvr: the full article in pdf format can be found at:

http://bmj.bmjjournals.com/cgi/rapidpdf/bmj.38933.585764.AEv1

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

Date:    Sat, 2 Sep 2006 10:32:34 -0400
From:    "Rich Van Konynenburg <Richvank@xxx.xxx> [via Co-Cure Moderators" 
Subject: RES: Latest Dubbo results and the glutathione depletion--methylation cycle, block hypothesis for CFS

Today another paper from the Dubbo, Australia, infection outcomes study
was published (Hickie, I, et al.,"Post-infective and chronic fatigue
syndromes precipitated by viral and non-viral pathogens: preospective
cohort study," BMJ,doi:10.1136/bmj.38933.585764.AE).

As you may know, this study is involved with following people who
develop infectious diseases over time to try to understand why some of
them do not recover, but instead continue to be ill with a disorder
that meets the criteria for chronic fatigue syndrome.

This paper compared the percentage of people who had cases of
mononucleosis (glandular fever), Q fever, and Ross River virus,
respectively, who later met the criteria for chronic fatigue syndrome.
It's interesting to note that Q fever is caused by an intracellular
bacterium, while the other two are viral diseases.

The authors found that the percentage who went on to have CFS was the
same for the three infectious diseases (11% at 6 months).  This common
result is very significant, because it suggests that the reason these
people develop CFS is not associated with the particular pathogen, but
rather with their host response.

Here's a quotation from the paper: "Examination of outcomes after the
three distinctive acute infections reported here strongly implicates
aspects of the host response to infection (rather than the pathogen
itself) as the likely determinants of post-infective fatigue syndrome,
as the case rates after infection with Epstein--Barr virus (a DNA
virus), Ross River virus (an RNA virus), and C. burnetii (an
intracellular bacterium) were comparable, and the symptom
characteristics progressively merged over time."

I would like to submit that this is the type of result that would be
predicted by the glutathione depletion--methylation cycle block
hypothesis for the pathogenesis of chronic fatigue syndrome.  This
hypothesis holds that CFS onset is caused by a combination of a genetic
predisposition (a set of polymorphisms) that particular people are born
with, and a sufficient load of stressors to lower the glutathione level
enough to trigger a vicious circle mechanism, involving the methylation
cycle, and facilitated by the genetic predisposition.  One of the
classes of possible stressors is the biological stressors, and
infectious agents are one category of these biological stressors.
According to this model, it does not matter what the particular
infectious agent is.  What matters is whether the infection (combined
with any other stressors that might be present in the particular
person) is sufficient to lower the glutathione level enough to trigger
the vicious circle mechanism.  It seems clear that the results of this
study confirm that this is the way onset of CFS behaves when triggered
by pathogens.

Please note that this study does not tell us what needs to be done for
treatment, only what the characteristics are of the category of CFS
that is post-infectious in origin.

Rich Van Konynenburg, Ph.D.

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Date:    Sat, 2 Sep 2006 17:23:59 -0400
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx>
Subject: RES: Update on rheumatologic mimics of fibromyalgia

Update on rheumatologic mimics of fibromyalgia.

Curr Pain Headache Rep. 2006 Oct;10(5):327-32.

Hwang E, Barkhuizen A.

Oregon Health and Science University,3181 SW Sam Jackson Park Road, OP09,
Portland, OR 97239, USA. hwange@xxxx.xxx.

PMID: 16945247


Fibromyalgia is a common disorder of diffuse musculoskeletal pain. Several
rheumatic diseases can mimic fibromyalgia, and a clinician would not want
to miss these diagnoses because of their potential long-term sequelae, such
as progressive joint damage or life- or organ-threatening disease if they
remain untreated.

This paper discusses the typical clinical presentations of selected
rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis,
ankylosing spondylitis, polymyalgia rheumatica, and osteoarthritis) then
highlights the key features in history, laboratory testing, and
radiographic imaging that aid the clinician in differentiating between
fibromyalgia and these rheumatic diseases.

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

Date:    Sun, 3 Sep 2006 09:42:00 -0400
From:    "Garth Nicolson <gnicolson@xxx.xxx> [via Co-Cure Moderators" 
Subject: RES:Glutathione depletion--methylation cycle, block hypothesis for CFS - similar conclusions

[Moderator's note: Prof. Nicholson sent this information in connection
with Rich Van Konynenburg's post “RES: Latest Dubbo results and the
glutathione depletion--methylation cycle, block hypothesis for CFS”
(http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0609a&L=co-cure&P=971]
----------------------------------------


Dear Rich and interested parties,

We actually published a paper (Nicolson GL, Gan R, Haier J.
Multiple co-infections (Mycoplasma, Chlamydia, Human Herpesvirus-6)
in blood of chronic fatigue syndrome patients: association with signs
and symptoms. Acta Pathol Microbiol Immunol Scand 2003; 111: 557-566 )
that came to similar conclusions with CFS patients who were tested for
multiple co- infections.  The number of bacterial or viral co-infections
found (and we only looked for a few) in CFS patients correlated
with the severity of signs and symptoms but not the type of infection.

Thus a similar outcome would be expected independent of the infection
type, if the infection caused morbidity in genetically susceptible
individuals.

The more infections found--the more severe the signs and symptoms or the
more signs/symptoms found.  I would guess that the more infections--the
greater the oxidative stress (more ROS/RNS) and the lower the
concentrations of the cellular antioxidants, such as glutathione and other
antioxidants.

When certain infections are present, and the list is growing, in CFS
patients, they need to be addressed and adequately suppressed in order
to reduce and important source of oxidative stress.

Oxidative stress is becoming more important than previously thought
in a variety of chronic diseases, from type 2 diabetes, cardiovascular
diseases to neurodegenerative diseases.

Garth

Prof. Garth Nicolson
The Institute for Molecular Medicine
www.immed.org

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

Date:    Sun, 3 Sep 2006 15:28:30 +1000
From:    Alexa McLaughlin <alexa@xxxx.xxx.xx>
Subject: RES: Latest Dubbo results and the psychiatric hypothesis

At a presentation in Canberra, Australia, for Science Week on 20
August 2006, one of the authors of this study, infectious diseases
specialist Professor Andrew Lloyd, stated that post-infective CFS
(using the Fukuda definition) is NOT a psychiatric disorder. He
advised the audience that this was going to be demonstrated by an
upcoming BMJ article, which is presumably the latest Dubbo paper.

The PowerPoint presentation of Professor Lloyd's talk is at:

http://www.mecfscanberra.org.au/actmecfs/act_science%20week.htm

Post-infective and chronic fatigue syndromes precipitated by viral
and non-viral pathogens: prospective cohort study. Ian Hickie, Tracey
Davenport, Denis Wakefield, Ute Vollmer-Conna, Barbara Cameron,
Suzanne D Vernon, William C Reeves, Andrew Lloyd, for the Dubbo
Infection Outcomes Study Group

The URL for the latest paper is:

http://bmj.bmjjournals.com/cgi/rapidpdf/bmj.38933.585764.AEv1

The authors state: "Importantly, premorbid and intercurrent
psychiatric disorder did not show predictive power for post-infective
fatigue syndrome at any time point." and "suggesting that severity of
the acute illness rather than the specific pathogen may be the major
determinant of post-infective fatigue syndrome."

On the other hand, this study required the "strict application of the
diagnostic criteria for chronic fatigue syndrome with exclusion of
alternative medical and psychiatric disorders, including through the
recommended laboratory investigations1 (not required in some studies29 30)."

"In combination with the predominantly self limiting natural history
of post-infective fatigue syndrome recorded here, these risk factors
and demographic characteristics indicate that patients with
postinfective fatigue syndrome constitute a distinguishable subset
within the broad diagnostic category of chronic fatigue syndrome.
This is consistent with the recognised heterogeneity in patient
groups identified within the label of chronic fatigue syndrome.32"

In the conclusion they say: "we propose that alternative
neurobiological mechanisms triggered during the severe, acute illness
and sustained in the absence of ongoing peripheral inflammation
underpin the persistent symptom domains of post-infective fatigue
syndrome." This was also stated at the end of an earlier paper:

Cameron B, Bharadwaj M, Burrows J, Fazou C, Wakefield D, Hickie I, et
al. Prolongex illness following infectious mononucleosis is associated with altered
immunity but not elevated viral load. J Infect Dis 2006;193:664-71.

In the media release in Australia relating to the Cameron paper:

http://www.unsw.edu.au/news/pad/articles/2006/feb/Hit_and_run.html

Professor Lloyd stated:

"Our findings reveal that neither the virus nor an abnormal immune
response explain the post-infective fatigue syndrome. We now suspect
it's more like a hit and run injury to the brain.

"We believe that the parts of the brain that control perception of fatigue
and pain get damaged during the acute infection phase of glandular fever. If
you're still sick several weeks after infection, it seems that the symptoms
aren't being driven by the activity of the virus in body, it's happening in
the brain."

The media release continues with: " The research team comprising of
scientists from the University of New South Wales, the University of
Sydney and the Queensland Institute of Medical
Research plan to test their 'brain injury' hypothesis by doing
neurological tests on the study participants."

Interestingly, the lead author of the latest paper is psychiatrist
Professor Ian Hickie, who has in the past been strongly associated
with the psychiatric hypothesis of Wesseley et all .


[Return to top]

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

Date:    Sun, 3 Sep 2006 11:26:37 -0700
From:    Melissa O'Toole <m_otoole2@xxxxx.xxx>
Subject: MED: Flexible Joints a Curious Clue to Chronic Fatigue Syndrome

Flexible Joints a Curious Clue to Chronic Fatigue Syndrome
Children with the condition often have hyperflexible joints, researchers find

By Ross Grant
HealthDay Reporter

SUNDAY, Sept. 3 (HealthDay News) -- Chronic fatigue syndrome has been accepted
as a medical condition for almost 20 years. Once passed off as a series of
sometimes ambiguous complaints about pain in the joints and a general malaise
-- primarily by females -- the condition was confirmed by medical researchers
as bona fide in 1988.

But classifying a painful physical condition as real doesn't necessarily mean
that there is a specific treatment to make it better. What follows is a good
example:

The young girl had been receiving treatment for chronic fatigue syndrome for
three years before anyone at the Johns Hopkins Children's Center noticed her
special condition.

In evaluating the girl's condition, Dr. Peter Rowe thought he had looked at
everything. Then, a lab clinician made an offhand observation that the girl
also had joints that could bend and twist much more than normal.

"I was chagrined that my physical examination had not included that. So, we
decided to look into it," said Rowe, a professor of pediatrics.

What he and other researchers found was puzzling, to say the least.

Sixty percent of the 60 children and teens they treated for chronic fatigue
syndrome also had hypermobility in at least four of their joints. Only 20
percent of the general public has a single hyperflexible joint, such as being
able to bend a pinkie 90 degrees backward, touch the thumb to the forearm, or
bend at the waist and rest both hands flat on the ground.

"It was a surprise," Rowe said of the discovery. "Some of the kids would be
able to put their leg behind their head in a seated position. Others could do
the splits. Once we saw this over and over, we thought it was something that
needed more study."

Their findings, which appeared in The Journal of Pediatrics, added a vexing
wrinkle to the current thinking on chronic fatigue syndrome.

In the past, some doctors regarded the syndrome as a psychosomatic byproduct of
depression. And those who saw it as a legitimate illness could find few
physiological signs of it.

"In the past, you had a tremendous amount of skepticism about [the syndrome],
which created a certain amount of stigma for people who have it," said Leonard
Jason, a professor of psychology and director of the Center for Community
Research at DePaul University in Chicago.

The recent study, he added, "could ultimately lead to us understanding the
physiology of this condition."

The syndrome affects four adults per 1,000, but fewer children. To be diagnosed
with it, a person must have a sudden onset of fatigue that lasts at least six
months. There must also be four of the following eight symptoms: impaired
memory, sore throat, tender neck or tender lymph nodes in the arm pit, muscle
pain, joint pain, new headaches, troubled sleep and a feeling of malaise after
exertion.

Rowe emphasized that having hyperflexible joints doesn't mean a person will
have the syndrome. Just how the two are related is little more than a guess,
Rowe and Jason agreed.

Children develop joint mobility in their early years, while the syndrome
doesn't generally show itself until puberty. It is difficult to find a causal
relationship between the two, because not everyone who has the syndrome also
has joint hypermobility, Rowe said.

Still, he wondered whether flexible joints may stress the peripheral nerves in
the arms and legs, thereby fatiguing the entire nervous system, or the
excessive range of motion may indirectly cause the syndrome.

"For example, if you're prone to injury because of your joints, you might
decrease your activity, which studies have shown can lead to [the syndrome],"
Rowe said.

To find better treatments for chronic fatigue syndrome, Rowe wants to study
hyperflexible joints in greater depth, and test whether they are also more
common in adults with the syndrome.

Jason, though, said research should be aimed at genetics.

"I think there may be some genetic factors. We really should look at the
parents. There could very well be a number of things passed on that make kids
more prone to [the syndrome]," Jason said.

More information

For more about chronic fatigue syndrome, visit the U.S. National Institutes of
Health at http://www.niaid.nih.gov/factsheets/cfs.htm


SOURCES: Peter Rowe, M.D., professor, pediatrics, Johns Hopkins Children's
Center, Baltimore; Leonard Jason, Ph.D., professor, psychology, and director,
Center For Community Research, DePaul University, Chicago; September 2002, The
Journal of Pediatrics

Copyright © 2006 ScoutNews, LLC. All rights reserved

___________________________

Date:    Sun, 3 Sep 2006 23:43:08 +0000
From:    Mary Schweitzer <marymsch@xxxxx.xxx>
Subject: Re: MED: Flexible Joints a Curious Clue to Chronic Fatigue Syndrome

As I understand it, the link between overly flexible joints and NMH/POTS is the hereditary condition Ehlers-Danlos 
Syndrome (EDS).  EDS is a connective tissue disorder that causes tissues to stretch - the theory is that SOME FORMS 
OF EDS (not all) cause veinous pooling of blood when patients stand a long time, which causes NMH/POTS or 
vasodepressor syncope.  So that is where the relationship to us would come in.

Patients interested in EDS might want to look at the home website of the Ehlers-Danlos National Foundation:

http://www.ednf.org/

And click on the first question under "knowledge" on the left - "What is EDS?"

My sister and my niece have both been diagnosed with EDS, and my brother was also diagnosed with a connective tissue 
disorder.  As it runs in families, I am supposed to get genetic testing to see if I have it, or if my daughter does.

Two examples of the type of flexibility in SOME kinds of EDS (not all) would be being able to touch your forearm with 
your thumb (same arm, of course - hey, it's hard enogh for us to try it with the other arm ...), and the children's 
party trick of being able to turn your eyelids inside-out.

NOTE:  I can't do either, but I'm still supposed to get the genetic testing, as I do have NMH/POTS.  My daughter can do both.

According to the website:
"What are the symptoms of EDS?

"Clinical manifestations of EDS are most often joint and skin related and may include:

"Joints: joint hypermobility; loose/unstable joints which are prone to frequent dislocations and/or subluxations; 
joint pain; hyperextensible joints (they move beyond the joint's normal range); early onset of osteoarthritis.

"Skin: soft velvet–like skin; variable skin hyper-extensibility; fragile skin that tears or bruises easily 
(bruising may be severe); severe scarring; slow and poor wound healing; development of molluscoid pseudo tumors 
(fleshy lesions associated with scars over pressure areas).

"Miscellaneous/Less Common: chronic, early onset, debilitating musculoskeletal pain (usually associated with the 
Hypermobility Type); arterial/intestinal/uterine fragility or rupture (usually associated with the Vascular Type); 
Scoliosis at birth and scleral fragility (associated with the Kyphoscoliosis Type); poor muscle tone (associated with 
the Arthrochalasia Type); mitral valve prolapse; and gum disease."

There are six major types of EDS, so if you suspect you have it, go to the website to check the different combinations of symptoms.

Mary Schweitzer

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

Date:    Sun, 3 Sep 2006 22:46:23 +0200
From:    Jan van Roijen <j.van.roijen@xxxxx.xx>
Subject: res: mitochondrial dysfunction associated with fatigue- after  EBV infection

~~~~~~~~~~~~~~~~~~~~~~~~~~~~


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BMC Infectious Diseases


Research article


Preliminary evidence of mitochondrial
dysfunction associated with post-infective
fatigue after acute infection with Epstein Barr Virus
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~


Suzanne D Vernon*1, Toni Whistler1, Barbara Cameron2, Ian B
Hickie3, William C Reeves1 and Andrew Lloyd2

Address: 1Centers for Disease Control and Prevention, 1600
Clifton Road, Atlanta, Georgia 30333, USA, 2University of New
South Wales, Sydney 2052, Australia and 3Brain and Mind
Research Institute, University of Sydney, New South Wales,
Sydney 2006, Australia

Email: Suzanne D Vernon* - svernon@xxx.xxx; Toni Whistler -
taw6@xxx.xxx; Barbara Cameron - b.cameron@unsw.xxx.xx;
Ian B Hickie - ianh@med.usyd.xxx.xx; William C Reeves -
wcr1@xxx.xxx; Andrew Lloyd - a.lloyd@unsw.xxx.xx

* Corresponding author


Abstract
```````````


Background:

Acute infectious diseases are typically accompanied by
non-specific symptoms including fever, malaise, irritability and
somnolence that usually resolve on recovery. However, in some
individuals these symptoms persist in what is commonly termed
post-infective fatigue. The objective of this pilot study was to
determine the gene expression correlates of post-infective
fatigue following acute Epstein Barr virus (EBV) infection.

Methods:

We followed 5 people with acute mononucleosis who developed
post-infective fatigue of more than 6 months duration and 5
HLA-matched control subjects who recovered within 3 months.
Subjects had peripheral blood mononuclear cell (PBMC)
samples collected at varying time points including at diagnosis,
then every 2 weeks for 3 months, then every 3 months for a year.
Total RNA was extracted from the PBMC samples and
hybridized to microarrays spotted with 3,800 oligonucleotides.

Results:

Those who developed post-infective fatigue had gene
expression profiles indicative of an altered host response during
acute mononucleosis compared to those who recovered
uneventfully. Several genes including ISG20 (interferon
stimulated gene), DNAJB2 (DnaJ [Hsp40] homolog and CD99),
CDK8 (cyclin-dependent kinase 8), E2F2 (E2F transcription
factor 2), CDK8 (cyclindependent kinase 8), and ACTN2
(actinin, alpha 2), known to be regulated during EBV infection,
were differentially expressed in post-infective fatigue cases.
Several of the differentially expressed genes affect
mitochondrial functions including fatty acid metabolism and the
cell cycle.

Conclusion:

These preliminary data provide insights into alterations in gene
transcripts associated with the varied clinical outcomes from
acute infectious mononucleosis.


``````

Background
````````````````

Acute viral diseases such as infectious mononucleosis typically
present clinically with a cluster of non-specific symptoms
including; fever, an increased need to sleep, disease-fighting
strategy mediated by the action of proinflammatory cytokines
[4-8]. In general, acute sickness behavior resolves in parallel
with clearance or control of the infecting agent.

However, some individuals exhibit prolonged illness with fatigue,
mood changes and cognitive impairment. Such prolonged
illness following infectious mononucleosis has been recognized
for at least half a century [9].

Recent studies of infectious mononucleosis due to EBV
infection demonstrated that fatigue, sore throat and malaise
persisted for up to two months in approximately 40% of patients
and for six or more months in approximately 10% [10,11]. The
risk factors for and pathophysiology of this post-infective fatigue
syndrome following EBV infectious mononucleosis have not
been identified. It remains unclear whether post-infective fatigue
reflects chronic effects of persistent EBV (e.g., viralmediated) or
whether acute EBV infection functions as a stressor that triggers
an altered host response to the virus leading to ongoing
symptoms.

The objective of this pilot study was to assess patients' gene
transcription patterns in the peripheral blood following acute
infectious mononucleosis due to EBV and to determine whether
those who recovered uneventfully had different gene expression
profiles than those who developed post-infective fatigue. To do
this, a small cohort of HLA-matched individuals was followed
over one year after infectious mononucleosis. We found that
individuals who suffered from post-infective fatigue had a distinct
gene expression profile during acute illness compared to those
whose illness resolved. Evaluation of the gene expression profile
over the course of the year implicated an altered host response
to EBV and mitochondrial dysfunction in those who developed
post-infective fatigue.

These data provide insight into alterations in gene transcripts
associated with the varied clinical outcomes from
EBV-associated mononucleosis.



BMC Infectious Diseases 2006, 6:15



~jvr:  the full text in pdf format can be found at:
http://www.biomedcentral.com/content/pdf/1471-2334-6-15.pdf

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

Date:    Sun, 3 Sep 2006 18:17:53 -0400
From:    "Rich Van Konynenburg PhD <richvank@xxx.xxx> via Co-Cure Moderators"
Subject: MED: Recuperat-ion and Lyme disease

Here's a response I posted to Paula Carnes on another list, that I think
might be of interest to people here. She asked me why I think Recup
is helping her, a person with Lyme disease.

Rich Van Konynenburg, Ph.D.


Hi, Paula.

Here is something to consider:

Mark London noted the high citrate content of Recup, and that citrate
produces alkalinization, and this has gotten me thinking. I want to
comment on it a little, and suggest a possible mechanism for how
Recup could be helping you.

First, it's true that in a person whose citric acid cycles are
operating normally, if citrate is ingested, it will be utilized by the
citric acid cycle in the cells and will be burned as fuel. Probably
the cells of the gut will burn most of it, because they get first
access. So long as the citric acid cycle (Krebs cycle) is operating
well, this should happen. Since citrate is an anion (negatively
charged ion), it must come into the body with a cation (positively
charged ion) to balance the charge. In Recup, the cation is sodium.
Being an elemental mineral, sodium survives in the body as sodium, and
the excess is excreted in the urine. Since sodium is a cation, in the
urine it must be balanced with an anion, and the body takes care of
this by dissociating water molecules into hydrogen ions and hydroxide
ions, and matching up the excreted sodium with hydroxide. The result
is that the pH of the urine rises, i.e. becomes more alkaline. So
that's why taking a citrate causes alkalinization of the urine, and
that's what happens in a person who has normally operating Krebs
cycles. I suspect that your Krebs cycles are operating more or less
normally, so that this is what happens in your body when you ingest
Recup. I'll get back to your case (Lyme disease) again below, but
first I want to talk about cases in which the citric acid cycle is
not operating normally.

In many PWCs (I expect not in you, but I don't have urine organic
acids test results for you, so I can't be positive in your case) it
is found that citrate is elevated in the urine. I think this means
that there is a partial blockade in the citric acid cycle beyond the
location of citrate. I have argued that the partial blockade is at
aconitase, and is produced by a rise in superoxide in response to
glutathione depletion and consequenct product inhibition of the superoxide
dismutase reaction. If people who have this partial blockade ingest
citrate, I don't believe their bodies will be able to metabolize it
well, and the excess will be excreted in the urine. To the degree
this happens, the ingestion of citrate will probably not alkalinize
their urine to the degree it does in a person with normally operating
citric acid cycles. This may explain why Recup doesn't work well for
some PWCs. This could be checked by urine organic acids testing and
correlation with response to Recup. Also, by the, way, in these
people, the ingestion of citrate will not help to raise their
magnesium and calcium, as Mark suggested, because citrate is a good
chelator for the +2 ions, and will tend to take them out in the
urine.

Now, back to your case, Paula. We know that you have tested positive
for Lyme disease, and we also know that your HLA typing shows that
your immune system is not able to recognize and destroy Lyme disease
toxin. We know from Dr. Shoemaker's work that Borrelia produce an
anion toxin, because he has been able to bind it with cholestyramine,
which is an anion exchange resin. I'm going to guess that this anion
toxin acts as a weak acid. What that means is that it binds hydrogen
ions fairly well, and doesn't give them up and become ionized as an
anion unless the pH of the environment is fairly high. This is the
case in bile (pH 7.5 in the liver, pH 6 in the gall bladder), and
that would explain why the Lyme toxin is able to be in anion form when it
is excreted into the duodenum in the bile, and hence, why it can be
bound with an anion exchange resin.

Now, move with me to the field of clinical toxicology. In this field,
one of the ways used to cause certain toxins to be excreted faster is
to alkalinize the urine, usually by the injection of bicarbonate.
However, ingesting sodium citrate will also alkalinize the urine,
provided that the Krebs cycles can burn the citrate, as I discussed
above. The reason alkalinization is used for detox of certain
substances is that if they behave as weak acids, the elevation of pH
will cause them to become ionized, and then they are more likely to
remain in solution and be excreted in the urine than to be resorbed
in the kidney tubules and be retained in the body. In clinical
toxicology, this is referred to as "ion trapping."

So I suggest that in your case what's happening is that taking Recup
is raising the pH of your urine to a level where the Lyme toxin is
ionized and thus is excreted more readily.

This hypothesis can be tested. One of the simplest things you could
do would be to get some pH paper at a drugstore and check the pH of
your urine when you have been taking Recup. I would guess that it
will be on the high side, say pH 6 or higher. Many people, especially
if their diet is high in meat and low in vegetables, have a lower pH
than this. If your urine pH is lower than about six and Recup is
helping you, then I would say that this hypothesis is not valid for
your case. If it's pH 6 or higher, I would say that this hypothesis
still has a chance.

Another test would be to try taking a significant amount of sodium
bicarbonate orally instead of Recup, and see if that also gives a
benefit. Of course, this will tend to make you burp a lot if you have
normal stomach acid leves, but it's all for the sake of science, and
you do want to know why Recup helps you, right?(:-) If the bicarb
also helps you, then I think the alkalinization-of-urine idea may be
valid in your case.

Rich Van Konynenburg

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


Date:    Mon, 4 Sep 2006 21:59:24 -0400
From:    "Annie-Danielle <dan_artlover@xxxxx.xx.xx> [via Co-Cure Moderators" 
Subject: MED: Flexible Joints a Curious Clue to Chronic Fatigue Syndrome - Another Persepctive

Overly flexible joints (hypermobiles or hyperlax) are indeed a part of
Ehlers-Danlos Syndrome, but exists also in a syndrome of it's own.
EDS is a serious condition and has often very rare and severe skin
condition associated with it, as well as important cardiovascular troubles.
Many people have major joint hypermobility problems but do not fit the
diagnosis criteria of any of the EDS types. (I know most people
suffering from CFS suffer from some skin or cardiovascular troubles
also, but rarely the same type as the ones described in the definition
of EDS. In those case, the skin and cardiovascular troubles are probably
just caused by CFS...)

In those cases, where there is indeed a joint hypermobility problem and
a very bad one, but if it's not Ehler Danhlos Syndrome, maybe what they
have is what is called Benign Joints Hypermobility Syndrome (BJHS).

I've been diagnosed with that illness well before being diagnosed with
CFS. As you can learn on the Hypermobility Syndrome Association website
http://www.hypermobility.org/ , many people live with joints
hypermobility and most never have a problem with that, they're just very
flexible (and often have fun with it). It can be in only one or some of
your joints, or in most or all of them. (In my case, it's in all of them).
It usually is present at birth, but of course, you don't always notice
it! You usually do when it develops...
It becomes a problem when you begin to injure yourself, (sprains,
luxations, etc.), you usually injure yourself more and more as time
passes (and more and more easily and in silly manners, like picking up
your cat or lifting up the garage door, as your ligaments grow fainter
and tear) and then you begin to hurt even when you're not injured
(because of micro-traumatisms your joints have suffered, or because of
tears they've suffered over time), and finally with all this stress the
joints have faced, your body develops ostheoarthritis.

It's a fact : whatever the syndrome, a link seems to have been
established with hypermobility and CFS... Let's hope it'll give a clue
to research!
In the meantime, I just wanted people to know there was another syndrome
(BJHS) existing for those that didn't fit the diagnosis criteria of
Ehlers-Danlos Syndrome but were suffering as much. It's sadly another of
those : no treatment except for symptom relief kind of thing... but yet
again, to put a name on what you have is so much better!

Annie-Danielle Grenier

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

End of CO-CURE Medical & Research Posts Only Digest - 28 Aug 2006 to 4 Sep 2006 (#2006-41)

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