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CO-CURE Medical & Research Posts Only Digest - 13 Nov 2006 to 20 Nov 2006 (#2006-52)
There are 15 messages totalling 1901 lines in this issue.

Topics of the week:
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                       This is a special digest of
                  Co-Cure Research & Medical posts only
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Date:    Wed, 15 Nov 2006 12:44:17 -0800
From:    Co-Cure moderators
Subject: NOT, ACT, RES: ME/CFS, Borreliosis and NICE

From Peter Kemp <counsellingme@xxxxx.xx.xx> :



In their Draught Guidelines for ME/CFS the National Institute for Health and
Clinical Excellence (NICE) include:

1.2.2.3 The following tests should not be done routinely.
. Serology testing for chronic bacterial infections (for example,
borelliosis)[sic] in the absence of any indicative history.

--------------------------------------
I have written a comment on the above statement which can be seen at: http://www.geocities.com/counsellingme/microscopy/comment.html I believe that NICE's statement displays a lack of awareness of current
research into Borreliosis (Lyme disease) and may effectively condemn many
thousands to lifelong illness that could be averted by timely diagnoses and
treatment for Borreliosis.

I have also written some webpages describing how I saw and filmed Borrelia
bacteria in a tiny blood drop with my own microscope, these can be seen at: http://www.geocities.com/counsellingme/microscopy/introduction.html Best Wishes,
Peter Kemp

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Date:    Wed, 15 Nov 2006 20:44:43 -0500
From:    Fred Springfield <fredspringfield@xxxxx.xxx> 
Subject: RES: A case control study of premorbid and currently reported physical activity levels in chronic fatigue syndrome

A case control study of premorbid and currently reported physical activity
levels in chronic fatigue syndrome.

Journal: BMC Psychiatry. 2006 Nov 13;6(1):53 [Epub ahead of print]

Authors: Smith WR, White PD, Buchwald D.

Address correspondence to Wayne R. Smith, Ph.D., 401 Broadway, Box 359797,
Seattle, Washington 98122, USA  E-Mail: <wrsmith@u.washington.edu> NLM Citation: PMID: 17101056


ABSTRACT:
BACKGROUND: Patients with chronic fatigue syndrome typically report high
levels of physical activity before becoming ill. Few studies have examined
premorbid and current activity levels in chronically fatigued patients.

METHODS: In a case-control study, 33 patients with chronic, unexplained,
disabling fatigue attending a university-based clinic specializing in
fatigue were compared to 33 healthy, age- and sex-matched controls.
Patients rated their activity levels before their illness and currently,
using scales designed for this purpose. Controls reported their level of
activity of 2 years previously and currently. Chi-square analyses, Students
t tests, and Wilcoxon signed rank tests were used in pair matched analyses.

RESULTS: Compared to healthy controls, patients with chronic, unexplained
fatigue rated themselves as more active before their illness (p less than
0.01) and less active currently (p less than 0.001). The patients also
reported they currently stood or walked less than the controls (median
[inter-quartile range] = 4 [2 - 5] versus 9 [7.5 - 12] hours, p less than
0.001), and spent more time reclining (median [inter-quartile range] = 12
[10 - 16] versus 8 [8 - 9.5] hours, p less than 0.001). These differences
remained significant for the subset of patients who met strict criteria for
chronic fatigue syndrome or fibromyalgia alone.

CONCLUSIONS: Patients with chronic, unexplained, disabling fatigue reported
being more physically active before becoming ill than healthy controls.
This finding could be explained by greater premorbid activity levels that
could predispose to illness, or by an overestimation of previous activity.
Either possibility could influence patients perceptions of their current
activity levels and their judgments of recovery. Perceived activity should
be addressed as part of management of the illness.


[Note: This is an Open Access article.  Its full text is available in PDF at http://www.biomedcentral.com/content/pdf/1471-244x-6-53.pdf 

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Date:    Wed, 15 Nov 2006 20:51:39 -0500
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> 
Subject: RES: The role of illness uncertainty on coping with  fibromyalgia symptoms

The role of illness uncertainty on coping with fibromyalgia symptoms.

Health Psychol. 2006 Nov;25(6):696-703.

Johnson LM, Zautra AJ, Davis MC.

Department of Psychology, Arizona State University, Tempe, AZ, US. lisajohnson@xxx.xxx.

PMID: 17100498


This study examined the role of illness uncertainty in pain coping among
women with fibromyalgia (FM), a chronic pain condition of unknown origin.

Fifty-one FM participants completed initial demographic and illness
uncertainty questionnaires and underwent 10-12 weekly interviews regarding
pain, coping difficulty, and coping efficacy. Main outcome measures
included weekly levels of difficulty coping with FM symptoms and coping
efficacy.

Multilevel analyses indicated that pain elevations for those high in
illness uncertainty predicted increases in coping difficulty. Furthermore,
when participants had more difficulty coping, they reported lower levels of
coping efficacy. Results were consistent with hypothesized effects.

Illness uncertainty accompanied by episodic pain negatively influenced
coping efficacy, an important resource in adaptation to FM.

((c) 2006 APA, all rights reserved).

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Date:    Thu, 16 Nov 2006 08:10:02 -0800
From:    "Neil Abbot <Neil.Abbot@xxxxx.xxx.xx>.......via Co-Cure moderators" 
Subject: RES, NOT: "New Horizons" International Conference on ME/CFS Biomedical Research 2007

International Conference on ME/CFS Biomedical Research 2007


Hosted and organised by ME Research UK, and co-sponsored by the Irish ME Trust www.imet.ie, the New Horizons: International Conference on ME/CFS Biomedical
Research will take place on Friday 25th May 2007, at the Edinburgh Conference
Centre, Heriot-Watt University, Edinburgh, UK. Building on the success of our
Colloquium earlier this year http://www.meresearch.org.uk/archive/colloquium.html we hope this will become
an annual international event, the location of which will vary from year to
year.

As ME/CFS biomedical research is very varied, spanning many scientific
disciplines and involving a wide range of healthcare professionals, this
research conference will provide the opportunity for researchers and
healthcare professionals within ME/CFS to present their latest work, share
ideas and identify key challenges for the future. The full day's programme,
which we are finalising at present, will consist of invited keynote lectures
and shorter research presentations, and will be of interest to a wide range of
professionals, people with ME, and observers alike.

The conference facilities are propose-built and disability-friendly, in an
attractive campus setting http://www.eccscotland.com/photogallery/cat17.html near the airport and just
outside the city centre, with free on-site parking. In addition, bed and
breakfast accommodation (approx £40 per night) is available on-campus near
the venue. Registration will be from 8.30 am, and the expected finish is 5 pm.
Included in the £60 registration fee are a delegate pack with detailed
lecture notes, finger buffet lunch, and morning and afternoon coffee/tea
breaks, served on-site.

You can download a conference flyer (pdf) here http://www.meresearch.org.uk/New%20Horizons%20Conference%20flyer.pdf This conference will be a key element of ME Awareness Month 2007 - an
important time for people with ME globally which is the reason Invest in ME http://www.investinme.org/index.htm and ME Research UK have been working
together to "energise ME Awareness" over the whole of May 2007, opening and
closing  it with an event to remember. The awareness-raising 2nd International
IiME ME Conference at Westminster http://www.investinme.org/IIME%20International%20ME%20Conference%202007%20Home.htm London on 2nd to 3rd May will OPEN the month, and the International Conference
on ME/CFS Biomedical Research at Heriot-Watt University in Edinburgh will
CLOSE the month. And in between, a lot of activity is planned.

To book your attendance at the International Conference on ME/CFS Biomedical
Research, please complete the registration form on the site, and send it by
post with your cheque to headquarters.

Dr Neil C. Abbot
Director of Operations
ME Research UK
The Gateway
North Methven St
Perth PH1 5PP, UK meruk@xxxxx.xxx.xx

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Date:    Thu, 16 Nov 2006 12:03:56 -0500
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> 
Subject: RES: Frequency of rheumatic diseases in patients with  autoimmune thyroid disease

Frequency of rheumatic diseases in patients with autoimmune thyroid disease.

Rheumatol Int. 2006 Nov 11; [Epub ahead of print]

Soy M, Guldiken S, Arikan E, Altun BU, Tugrul A.

Department of Internal Medicine, Division of Rheumatology, Trakya
University Faculty of Medicine, 22300, Edirne, Turkey, msoy_2000@xxxxx.xxx.

PMID: 17102943


We aimed to investigate the frequency of rheumatic diseases in patients
suffering from autoimmune thyroid diseases (ATD).

Sixty-five patients (56 F, 9 M), who were followed by diagnosis of ATD,
were questioned and examined for the presence of rheumatic disease. Basic
laboratory tests and antithyroid antibodies, antinuclear antibody and
rheumatoid factor (RF) levels were also measured by appropriate methods.

Various rheumatic diseases were detected in 40 (62%) of patients with ATD.
The most frequent rheumatic conditions were fibromyalgia, recurrent
aphthous stomatitis, osteoarthritis, keratoconjunctivitis sicca and
xerostomia and carpal tunnel syndrome which were detected in 20 (31%), 13
(20%), 10 (15%), 9 (14%) and 8 (12%) of patients, respectively. Autoimmune
diseases, except Sjogren's syndrome, which were detected in ten patients
with ATD, are as follows-vitiligo: two; autoimmune hepatitis: two; oral
lichen planus: one, ulcerative colitis: one, inflammatory arthritis in four
patients (two of them had rheumatoid arthritis, one had psoriasis and
psoriatic arthritis and one had mixed collagen tissue disease). RF was
positive in two patients, one of them had rheumatoid arthritis and FANA was
positive in six (9%) patients; all of them had hypothyroidism.

The frequency of rheumatic diseases seems to be higher in patients
suffering from ATD. Initial evaluation and a regular checking for rheumatic
diseases in patients suffering from ATD were recommended.

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Date:    Sat, 18 Nov 2006 12:10:53 -0500
From:    Fred Springfield <fredspringfield@xxxxx.xxx> 
Subject: RES: The Use of D-Ribose in Chronic Fatigue Syndrome and Fibromyalgia: A Pilot Study

The Use of D-Ribose in Chronic Fatigue Syndrome and Fibromyalgia: A Pilot
Study.

Journal: J Altern Complement Med. 2006 Nov;12(9):857-862.

Authors: Teitelbaum JE, Johnson C, Cyr JS.

Affiliation: Fibromyalgia and Fatigue Centers, Dallas, TX.

NLM Citation: PMID: 17109576


Objectives: Fibromyalgia (FMS) and chronic fatigue syndrome (CFS) are
debilitating syndromes that are often associated with impaired cellular
energy metabolism. As D-ribose has been shown to increase cellular energy
synthesis in heart and skeletal muscle, this open-label uncontrolled pilot
study was done to evaluate if D-ribose could improve symptoms in
fibromyalgia and/or chronic fatigue syndrome patients.

Design: Forty-one (41) patients with a diagnosis of FMS and/or CFS were
given D-ribose, a naturally occurring pentose carbohydrate, at a dose of 5
g t.i.d. for a total of 280 g. All patients completed questionnaires
containing discrete visual analog scales and a global assessment pre- and
post-D-ribose administration.

Results: D-ribose, which was well-tolerated, resulted in a significant
improvement in all five visual analog scale (VAS) categories: energy;
sleep; mental clarity; pain intensity; and well-being, as well as an
improvement in patients' global assessment. Approximately 66% of patients
experienced significant improvement while on D-ribose, with an average
increase in energy on the VAS of 45% and an average improvement in overall
well-being of 30% (p < 0.0001).

Conclusions: D-ribose significantly reduced clinical symptoms in patients
suffering from fibromyalgia and chronic fatigue syndrome.

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Date:    Sat, 18 Nov 2006 14:08:46 -0500
From:    Fred Springfield <fredspringfield@xxxxx.xxx> 
Subject: RES: Sleep characteristics of persons with chronic fatigue  syndrome and non-fatigued controls: results from a population-based  study

Sleep characteristics of persons with chronic fatigue syndrome and
non-fatigued controls: results from a population-based study.

Journal: BMC Neurol. 2006 Nov 16;6(1):41 [Epub ahead of print]

Authors: William C. Reeves [1, *], Christine Heim [2], Elizabeth M Maloney
[1], Laura Solomon Youngblood [1], Elizabeth R Unger [1], Michael J. Decker
[3], James F Jones [1], David B. Rye [3]

Affiliations:
[1] Viral Exanthems & Herpesvirus Branch, Division of Viral & Rickettsial
Diseases, National Center for Infectious Diseases, Centers for Disease
Control & Prevention, Atlanta, GA, USA
[2] Department of Psychiatry and Behavioral Sciences, Emory University
School of Medicine, Atlanta, GA, USA,
[3] Dept. of Neurology, Emory University School of Medicine, Atlanta, GA, USA
[*] Corresponding author  E-Mail: <wcr1@cdc.gov> NLM Citation: PMID: 17109739


ABSTRACT:
BACKGROUND: The etiology and pathophysiology of chronic fatigue syndrome
(CFS) remain inchoate. Attempts to elucidate the pathophysiology must
consider sleep physiology, as unrefreshing sleep is the most commonly
reported of the 8 case-defining symptoms of CFS. Although published studies
have consistently reported inefficient sleep and documented a variable
occurrence of previously undiagnosed primary sleep disorders, they have not
identified characteristic disturbances in sleep architecture or a
distinctive pattern of polysomnographic abnormalities associated with CFS.

METHODS: This study recruited CFS cases and non-fatigued controls from a
population based study of CFS in Wichita, Kansas. Participants spent two
nights in the research unit of a local hospital and underwent overnight
polysomnographic and daytime multiple sleep latency testing in order to
characterize sleep architecture.

RESULTS: Approximately 18% of persons with CFS and 7% of asymptomatic
controls were diagnosed with severe primary sleep disorders and were
excluded from further analysis. These rates were not significantly
different. Persons with CFS had a significantly higher mean frequency of
obstructive apnea per hour (p=.003); however, the difference was not
clinically meaningful. Other characteristics of sleep architecture did not
differ between persons with CFS and controls.

CONCLUSIONS: Although disordered breathing during sleep may be associated
with CFS, this study generally did not provide evidence that altered sleep
architecture is a critical factor in CFS. Future studies should further
scrutinize the relationship between subjective sleep quality relative to
objective polysomnographic measures.


[Note: This is an Open Access article.  The complete text in PDF is
available for free at http://www.biomedcentral.com/content/pdf/1471-2377-6-41.pdf ]

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Date:    Sat, 18 Nov 2006 15:56:08 -0500
From:    "David Axford <david@axford.xxxxx.xx.xx> via Co-Cure Moderator" <ray@xxxxx.xxx> 
Subject: NOT,RES: ME & CFS References

 From David Axford <david@axford.xxxxx.xx.xx>:


ME & CFS References http://freespace.virgin.net/david.axford/me/me.htm Click on the:
"Medical Information" button, which is in the left-hand column.
You'll see the "Factsheet 2006" clearly marked 1st December 2006 in the
right hand frame. This has an "updated" graphic alongside. Click on the
button (microscope on top of the globe).

You may also find the article using the SEARCH button (identified with
Sherlock Holmes and magnifying glass) at bottom of page.

It is possible that your browser won't log on first time due to the large
number of people who are accessing the web-site. Please be patient and try
again at different times when it's less busy.


E-mail: david@axford.xxxxx.xx.xx 
Web: Home: http://freespace.virgin.net/david.axford/ 
ME/CFS: http://freespace.virgin.net/david.axford/me/me.htm 

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Date:    Sat, 18 Nov 2006 19:17:04 +0100
From:    Jan van Roijen <j.van.roijen@xxxxx.xx> 
Subject: med: D-ribose -Again

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


Send an Email for free membership
~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~
       >>>> Help ME Circle  <<<<
 >>>>  18 November 2006     <<<<
Editorship : j.van.roijen@xxxxx.xx Outgoing mail scanned by Norton AV
~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~



Dear Readers,


14 November I wrote a short message with the title: 
*D-ribose -warning* - 
see Co-Cure: http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0611b&L=co-cure&T=0&P=5296 
I never got so many responses before as about this subject.

Three-quarters of the people thought, that I became sick from
D-ribose, but that is not true.

After 4-5 days I felt some  better after using D-ribose.

I was so glad that I tried a yoga exercise: lying flat with my back
on the floor, I lifted my legs with my abdominal muscles for about
30 - 40 (?) sec.

And this short exercise made me very sick - NOT the D-ribose.

I'm now hoping that D-ribose will shorten the severe relapse;
which normally cost me weeks or months.

So my warning was not against the use D-ribose, but to be
careful with your energy, when you benefit from this supplement.


If I was not clear enough, please blame it on ME.


Jan van Roijen


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Date:    Sat, 18 Nov 2006 20:24:16 +0100
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx> 
Subject: RES,NOT: Gerberding's CFS memo to CDC staff

Source: Atlanta Journal-Constitution
Date:   November 17, 2006
Author: Alison Young
URL: http://www.ajc.com/news/content/news/stories/2006/11/17/1117meshcdcmemo.html Gerberding's memo to CDC staff
 -----------------------------

In the wake of news articles about problems with the Centers for Disease
Control and Prevention's response to Hurricane Katrina and serious animal
care issues in its laboratories, agency Director Julie Gerberding sent
this email memo to staff today...

---------- Forwarded message ----------
From: Gerberding, Julie M.D. (CDC/OD)
To: CDC All - CDC & ATSDR and non-CDC & non-ATSDR
Sent: Fri Nov 17 12:49:22 2006
Subject: Update

(...)

And when we launched the National Chronic Fatigue Syndrome awareness
campaign this month, we demonstrated what we can learn when we apply our
best epidemiologic and genomic science to a confusing illness like chronic
fatigue syndrome-credible evidence of a genomic and an environmental
basis for this condition.

(...)

Most importantly, we must learn from each other. I am certainly humbled
about how much I have learned from people at CDC as well as those outside
CDC who reflect our best as well as what we can do better.

Thank you for your commitment to excellence and the evidence of that all
over the world.

Best,

Jlg

--------
(c) 2006 Atlanta Journal-Constitution

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Date:    Sat, 18 Nov 2006 23:21:21 +0100
From:    Jan van Roijen <j.van.roijen@xxxxx.xx> 
Subject: res: Use of D-Ribose in ME/CFS & FM

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


Send an Email for free membership
~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~
       >>>> Help ME Circle  <<<<
 >>>>  18 November 2006     <<<<
Editorship : j.van.roijen@xxxxx.xx Outgoing mail scanned by Norton AV
~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~

On Sat, 18 Nov 2006 Fred Springfield posted the abstract of
*The Use of D-Ribose in Chronic Fatigue Syndrome and
Fibromyalgia: A Pilot Study* - Teitelbaum JE et al. 
Co-Cure: http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0611c&L=co-cure&T=0&P=4138 
as fair use I add the discussion section of this article



For Dutch readers:

A good and cheap address for D-ribose is:
Creanite - owner Jan de Heij - racing cyclist  and pharmacist: http://www.creanite.com/DaviWB/Pagina13.html ~jvr

```````````````````````````



DISCUSSION


Fibromyalgia and CFS are common, nonarticular, debilitating
syndromes that affect approximately 2%–4% of the population
worldwide. Patients with FMS and/or CFS generally
demonstrate reduced sustained exercise capacity, with lack of
muscular contractile force and endurance.11,12 Similar
conditions are frequently associated with abnormal metabolism.
Therefore, many FMS and/or CFS studies have investigated
potential alterations in muscle metabolism. 6,13,14–19

Adenosine triphosphate (ATP) is the primary energy source of
all living cells. In tissues subjected to metabolic stress, such as
hypoxia, ischemia, or known conditions of mitochondrial
dysfunction, ATP is catabolized with compromised metabolic
recovery. With ATP catabolism, adenosine diphosphate (ADP)
levels accumulate, forcing the cell to try to balance ATP/ADP
ratios in order to maintain energy stasis. However, these
reactions ultimately lead to an increased intracellular
concentration of adenosine monophosphate (AMP). In an effort
to try to control energy balance, the cell catabolizes AMP,
ultimately forming inosine, hypoxanthine, and adenine. These
catabolic end products are washed out of the cell, resulting in a
net loss of purines and an ultimate reduction in the total pool of
adenine nucleotides. Potentially, up to 90% of these produced
catabolites can be biochemically salvaged and recycled.
9,20,21

The rate of recovery of these energy substrates in metabolically
stressed cells is important for functional recovery of the cell,
including muscle.20,21–23 Therapeutic solutions that could try to
maintain a cell's energy stasis include either blocking the
degradation of adenine nucleotides or providing metabolic
supplementation to enhance nucleotide recovery via the salvage
or de novo pathways of purine synthesis.

The availability of 5-phosphoribosyl-L-pyrophosphate (PRPP) is
rate limiting in adenine nucleotide de novo synthesis and
salvage pathways, which is necessary to preserve or rebuild
cellular energy stores.9,20,21
5-Phosphoribosyl-Lpyrophasphate is formed through
pyrophosphorylation of ribose- 5-phosphate that is, itself,
synthesized from glucose via the pentose phosphate pathway
(PPP; or hexose monophosphate shunt). The rate-limiting
enzymes in the PPP, glucose- 6-phosphate dehydrogenase and
6-phosphogluconate dehydrogenase, are poorly expressed in
heart and muscle cells. As such, in skeletal muscle the PPP is
suppressed, limiting ribose availability as a substrate to drive
the purine nucleotide pathway and retarding purine nucleotide
synthesis during or following a metabolic insult.

The energy reserve, phosphorylation potential (PP), and the
ability to use oxygen (total oxidative capacity or Vmax) have
been determined using P-31 MRS in both normal and
fibromyalgic muscle.16 Both mean PP and Vmax values are
found to be significantly reduced in FMS.16 These findings are
consistent with reduced oxidative phosphorylation and ATP
synthesis, which translate clinically to muscle fatigue, soreness,
and stiffness.24 Impairment in mitochondrial oxidative
phosphorylation and potentially diminished glucose metabolism
impact ATP turnover, suggesting that the muscles of
fibromyalgia patients are energy starved. Further, decreased
ATP concentrations with accompanying changes in energy
metabolism have been found in the red blood cells of
fibromyalgia patients,25 suggesting that this energy deficiency
may be systemic.

Muscular metabolic abnormalities in fibromyalgia have been
proposed.6 Dysfunctional metabolism has been shown to lead
to cellular abnormalities6 that impact cellular function, producing
clinical symptoms. Muscle biopsies have shown that levels of
phosphocreatine (PCr) and ATP are significantly reduced (21%
and 17%, respectively) in muscle tissues of fibromyalgia
patients and the synthesis of PCr, an important store of cellular
high-energy phosphates, is deficient. Magnetic imaging of
skeletal muscle has shown that resting levels of ATP are 15%
lower in fibromyalgia patients than in normal controls and during
exercise PCr and ATP levels remain significantly low.14,16,19
During exercise there is an increase in metabolic breakdown
products of ATP (phosphodiesters) in fibromyalgic skeletal
muscle groups, indicating abnormal adenine nucleotide
metabolism and disruption of cell membranes, which are
common in other muscular diseases. There has been
speculation that these findings may be similar in patients
afflicted with CFS.16

It also has been shown that there are a decreased numbers of
capillaries within fibromyalgic muscle fibers, which can reduce
the oxidative capacity, leading to limited energy turnover, purine
pool depletion, and increased pain.24,26 Thickening of the
capillary endothelium also contributes to restricted oxygen
transport or delivery, further lowering oxygen tension in the
muscle, affecting energy metabolism and contributing to
functional fatigue and weakness. In general, the fibromyalgic
muscle has lower ATP concentrations than normal muscle.
Further, these factors can alter calcium and cellular ion stasis,
which, clinically can produce muscle soreness, stiffness, fatigue,
and diminished exercise capacity.

Patients with FMS and/or CFS may therefore have an alteration
in muscular energy use and metabolism. Fibromyalgic muscle
reaches anaerobic threshold earlier in exercise, thereby
potentially using less available energy-rich phosphate
metabolites at maximal work capacity. Patients with FMS may
have abnormal high-energy phosphate metabolism with
significantly lower levels of ATP and ADP in affected muscles as
compared to normal controls.24

The findings in this pilot study, using daily D-ribose, revealed an
increased improvement in the quality of life in patients afflicted
with FMS/CFS. However, there are several limitations noted in
this study. A major limitation centers on a lack of a placebo
group. This was, however, meant as an initial pilot study with
each patient acting as their own control. A follow-up RCT is, of
course, critical and currently under way using information (and
impetus) gained from this pilot study. In addition, as patients
were not seen in a clinic, initial assessment of each patient
relied on their own personal physician providing an accurate
clinical diagnosis of FMS/CFS. This pilot assessment was
designed as a clinically focused, community-based study, and
this reflects what occurs in most patients' cases.

Subjective outcome measures were only assessed in this study.
The diagnoses and effectiveness of therapies of FMS and CFS
are largely based on subjective symptoms. As no accepted
diagnostic laboratory tests are available to confirm the
diagnoses of and monitor progress in these syndromes, it is
reasonable to rely on subjective outcome measurements in this
clinical setting. Also, patients did not eliminate other stable
treatment modalities they had been on during the study.
However, patients were instructed not to make any changes in
their treatment regimen during the study. D-Ribose produced a
subjective beneficial outcome in these patients; therefore, the
addition of D-ribose may offer an added benefit to their
concurrent therapies.


CONCLUSIONS


This pilot study suggests that D-ribose may provide subjective
benefits in patients with FMS and/or CFS. Given the
biochemical benefits of D-ribose on increasing muscular energy
pools and reducing metabolic strain in affected muscles, the use
of this supplement may offer a valuable option for improving
quality of life in patients afflicted with FMS and/or CFS.



~~~~~~~~~~

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Date:    Sun, 19 Nov 2006 06:34:04 -0500
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx> 
Subject: RES: A Pilot Study of External Qigong Therapy for Patients  with Fibromyalgia

A Pilot Study of External Qigong Therapy for Patients with Fibromyalgia.

J Altern Complement Med. 2006 Nov;12(9):851-856.

Chen KW, Hassett AL, Hou F, Staller J, Lichtbroun AS.

Department of Psychiatry, University of Medicine and Dentistry of New
Jersey, Robert Wood Johnson Medical School, Piscataway, NJ., Center for
Integrative Medicine, University of Maryland School of Medicine, Baltimore,
MD, and University of Maryland School of Medicine, Baltimore, MD.

PMID: 17109575


Objectives: Although qigong is an important part of Traditional Chinese
medicine (TCM) based on a philosophy similar to acupuncture, few studies of
qigong exist in the Western medicine literature. To evaluate qigong therapy
as a modality in treating chronic pain conditions such as fibromyalgia
syndrome (FMS), we report a pilot trial of 10 women with severe FMS who
experienced significant improvement after external qigong therapy (EQT).

Design: Ten patients with FMS completed five to seven sessions of EQT over
3 weeks with pre- and posttreatment assessment and a 3-month follow-up.
Each treatment lasted approximately 40 minutes. Outcome measures: Tender
point count (TPC) and Fibromyalgia Impact Questionnaire (FIQ) were the
primary measures. McGill Pain Questionnaire (MPQ), Beck Depression
Inventory (BDI), anxiety, and self-efficacy were the secondary outcomes.

Results: Subjects demonstrated improvement in functioning, pain, and other
symptoms. The mean TPC was reduced from 136.6 to 59.5 after EQT treatment;
mean MPQ decreased from 27.0 to 7.2; mean FIQ from 70.1 to 37.3; and mean
BDI from 24.3 to 8.3 (all p < 0.01). Many subjects reported reductions in
other FMS symptoms, and two reported they were completely symptom-free.
Results from the 3-month follow-up indicated some slight rebound from the
post-treatment measures, but still much better than those observed at
baseline.

Conclusions: Treatment with EQT resulting in complete recovery for some FMS
patients suggests that TCM may be very effective for treating pain and the
multiplicity of symptoms associated with FMS. Larger controlled trials of
this promising intervention are urgently needed.

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Date:    Sun, 19 Nov 2006 15:29:51 -0500
From:    "David Axford <david@axford.xxxxx.xx.xx> via Co-Cure Moderator" <ray@xxxxx.xxx> 
Subject: NOT,RES: Latest ME Research

The latest ME & CFS References are now available at: <http://freespace.virgin.net/david.axford/melist.htm> 

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

Date:    Mon, 20 Nov 2006 09:45:15 +0100
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx> Subject: RES: CFS/ME & FM papers, published since October 2006

Source: NCBI PubMed
Date:   November 20, 2006
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi Topic=((chronic fatigue) OR (myalgic encephalomyelitis)) OR fibromyalgia
Ref:    In the update, you will only find journals that are indexed by
        Medline (PubMed).
        All scientific papers 1938-today, http://www.me-net.dds.nl/library/literature.html#publications Search scientific papers, http://www.me-net.dds.nl/library/literature.html#catalogue Figures computer analysis scientific papers: http://www.me-net.dds.nl/library/literature.html#figure All popular papers 1900-today, http://www.me-net.dds.nl/library/literature.html#popular CFS/ME & FM papers, published since October 2006
------------------------------------------------

___ Thomas MA, Smith AP.
       An investigation of the long-term benefits of antidepressant medication
       in the recovery of patients with chronic fatigue syndrome.
       Hum Psychopharmacol. 2006 Sep 18.
___ Smyth J, Nazarian D.
       Development and preliminary results of a self-administered intervention
       for individuals with fibromyalgia syndrome: a multiple case control
       report.
       Explore (NY). 2006 Sep;2(5):426-31.
___ Devanur LD, Kerr JR.
       Chronic fatigue syndrome.
       J Clin Virol. 2006 Sep 13.
___ Gillis ME, Lumley MA, Mosley-Williams A, Leisen JC, Roehrs T.
       The health effects of at-home written emotional disclosure in
       fibromyalgia: a randomized trial.
       Ann Behav Med. 2006 Oct;32(2):135-46.
___ Lotaif AC, Mitrirattanakul S, Clark GT.
       Orofacial muscle pain: new advances in concept and therapy.
       J Calif Dent Assoc. 2006 Aug;34(8):625-30.
___ Jamil H, Nassar-McMillan SC, Salman WA, Tahar M, Jamil LH.
       Iraqi Gulf War Veteran Refugees in the U.S.:PTSD and Physical Symptoms.
       Soc Work Health Care. 2006;43(4):85-98.
___ Arnold LM, Hudson JI, Keck PE, Auchenbach MB, Javaras KN, Hess EV.
       Comorbidity of Fibromyalgia and Psychiatric Disorders.
       J Clin Psychiatry. 2006 Aug;67(8):1219-1225.
___ Dinler M, Kasikcioglu E, Akin A, Sayli O, Aksoy C, Oncel A, Berker E.
       Exercise capacity and oxygen recovery half times of skeletal muscle in
       patients with fibromyalgia.
       Rheumatol Int. 2006 Sep 9.
___ Bonifazi M, Lisa Suman A, Cambiaggi C, Felici A, Grasso G, Lodi L,
       Mencarelli M, Muscettola M, Carli G.
       Changes in salivary cortisol and corticosteroid receptor-alpha mRNA
       expression following a 3-week multidisciplinary treatment program in
       patients with fibromyalgia.
       Psychoneuroendocrinology. 2006 Sep 6.
___ Wolfe F, Rasker JJ.
       The Symptom Intensity Scale, Fibromyalgia, and the Meaning of
       Fibromyalgia-like Symptoms.
       J Rheumatol. 2006 Sep 1.
___ Kool MB, Woertman L, Prins MA, Van Middendorp H, Geenen R.
       Low relationship satisfaction and high partner involvement predict
       sexual problems of women with fibromyalgia.
       J Sex Marital Ther. 2006 Oct-Dec;32(5):409-23.
___ El Maghraoui A, Tellal S, Achemlal L, Nouijai A, Ghazi M, Mounach A,
       Bezza A, Derouiche el M.
       Bone turnover and hormonal perturbations in patients with fibromyalgia.
       Clin Exp Rheumatol. 2006 Jul-Aug;24(4):428-31.
___ Alasehirli B, Demiryurek S, Arica E, Gursoy S, Demiryurek AT.
       No evidence for an association between the Glu298Asp polymorphism of
       the endothelial nitric oxide synthase gene and fibromyalgia syndrome.
       Rheumatol Int. 2006 Sep 2.
___ Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD,
       Reeves WC, Lloyd A; Dubbo Infection Outcomes Study Group.
       Post-infective and chronic fatigue syndromes precipitated by viral and
       non-viral pathogens: prospective cohort study.
       BMJ. 2006 Sep 16;333(7568):575.
___ Citak-Karakaya I, Akbayrak T, Demirturk F, Ekici G, Bakar Y.
       Short and long-term results of connective tissue manipulation and
       combined ultrasound therapy in patients with fibromyalgia.
       J Manipulative Physiol Ther. 2006 Sep;29(7):524-8.
___ Madden S, Sim J.
       Creating meaning in fibromyalgia syndrome.
       Soc Sci Med. 2006 Aug 30.
___ Betina Nishishinya M, Rivera J, Alegre C, Alejandra Pereda C.
       Non pharmacologic and alternative treatments in fibromyalgia [Spanish].
       Med Clin (Barc). 2006 Sep 2;127(8):295-9.
___ Karper WB, Jannes CR, Hampton JL.
       Fibromyalgia syndrome: the beneficial effects of exercise.
       Rehabil Nurs. 2006 Sep-Oct;31(5):193-8.
___ Blehm R.
       Physical therapy and other nonpharmacologic approaches to fibromyalgia
       management.
       Curr Pain Headache Rep. 2006 Oct;10(5):333-8.
___ Hwang E, Barkhuizen A.
       Update on rheumatologic mimics of fibromyalgia.
       Curr Pain Headache Rep. 2006 Oct;10(5):327-32.
___ Wood PB.
       A reconsideration of the relevance of systemic low-dose ketamine to the
       pathophysiology of fibromyalgia.
       J Pain. 2006 Sep;7(9):611-4.
___ Thorlacius S, Stefansson SB, Ranavaya MI, Walker R.
       Fibromyalgia and anxiety disorder [Icelandic].
       Laeknabladid. 2002 Nov;88(11):815-818.
___ McLean SA, Williams DA, Stein PK, Harris RE, Lyden AK, Whalen G, Park KM,
       Liberzon I, Sen A, Gracely RH, Baraniuk JN, Clauw DJ.
       Cerebrospinal fluid Corticotropin-Releasing factor concentration is
       associated with pain but not fatigue symptoms in patients with
       fibromyalgia.
       Neuropsychopharmacology. 2006 Aug 23.
___ 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.
       J Clin Pathol. 2006 Aug 25.
___ Hooper M.
       Myalgic Encephalomyelitis (ME): a review with emphasis on key findings
       in biomedical research.
       J Clin Pathol. 2006 Sep 1.
___ Puri BK.
       Long-chain polyunsaturated fatty acids and the pathophysiology of
       myalgic encephalomyelitis (chronic fatigue syndrome).
       J Clin Pathol. 2006 Aug 25.
___ Gibson I.
       A new look at Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/
       ME).
       J Clin Pathol. 2006 Aug 25.
___ Carruthers B.
       Definitions and aetiology of Myalgic Encephalomyelitis (ME): how the
       Canadian Consensus Clinical Definition of ME works.
       J Clin Pathol. 2006 Aug 25.
___ Hannestad U, Theodorsson E, Evengard B.
       Beta-Alanine and gamma-aminobutyric acid in chronic fatigue syndrome.
       Clin Chim Acta. 2006 Jul 14.
___ Guedj E, Taieb D, Cammilleri S, Lussato D, de Laforte C, Niboyet J,
       Mundler O.
       (99m)Tc-ECD brain perfusion SPECT in hyperalgesic fibromyalgia.
       Eur J Nucl Med Mol Imaging. 2006 Aug 25.
___ Eriksen W.
       Myalgic encephalopathy - an inexact report with doubtful conclusions
       [Norwegian].
       Tidsskr Nor Laegeforen. 2006 Aug 24;126(16):2144; author reply 2144-5.
___ Bennett R, Nelson D.
       Cognitive behavioral therapy for fibromyalgia.
       Nat Clin Pract Rheumatol. 2006 Aug;2(8):416-24.
___ Dadabhoy D, Clauw DJ.
       Therapy Insight: fibromyalgia - a different type of pain needing a
       different type of treatment.
       Nat Clin Pract Rheumatol. 2006 Jul;2(7):364-72.
___ Choy E.
       Comparing methods for the diagnosis of fibromyalgia.
       Nat Clin Pract Rheumatol. 2006 May;2(5):244-5.
___ Williams DA.
       Utility of cognitive behavioral therapy as a treatment for insomnia in
       patients with fibromyalgia.
       Nat Clin Pract Rheumatol. 2006 Apr;2(4):190-1.
___ Simon LS.
       Is milnacipran effective in treating pain in patients with fibromyalgia?
       Nat Clin Pract Rheumatol. 2006 Mar;2(3):126-7.
___ Staud R, Rodriguez ME.
       Mechanisms of disease: pain in fibromyalgia syndrome.
       Nat Clin Pract Rheumatol. 2006 Feb;2(2):90-8.
___ Clauw DJ.
       Does acupuncture help reduce pain in patients with fibromyalgia?
       Nat Clin Pract Rheumatol. 2005 Dec;1(2):76-7.
___ Komaroff AL.
       By the way, doctor. I would be most grateful for information concerning
       chronic fatigue syndrome, a disorder from which I have suffered for the
       past 10 years. Do you see any help on the horizon?
       Harv Health Lett. 2006 Aug;31(10):8.
___ Longley K.
       Fibromyalgia: aetiology, diagnosis, symptoms and management.
       Br J Nurs. 2006 Jul 13-27;15(13):729-33.
___ Osorio CD, Gallinaro AL, Lorenzi-Filho G, Lage LV.
       Sleep quality in patients with fibromyalgia using the pittsburgh sleep
       quality index.
       J Rheumatol. 2006 Sep;33(9):1863-5.
___ Gameiro GH, da Silva Andrade A, Nouer DF, Ferraz de Arruda Veiga MC.
       How may stressful experiences contribute to the development of
       temporomandibular disorders?
       Clin Oral Investig. 2006 Aug 22.
___ Okumus M, Gokoglu F, Kocaoglu S, Ceceli E, Yorgancioglu ZR.
       Muscle performance in patients with fibromyalgia.
       Singapore Med J. 2006 Sep;47(9):752-6.
___ Havermark AM, Langius-Eklof A.
       Long-term follow up of a physical therapy programme for patients with
       fibromyalgia syndrome.
       Scand J Caring Sci. 2006 Sep;20(3):315-22.
___ Singh SR, Levine MA.
       Natural health product use in Canada: analysis of the national
       poplulation health survey.
       Can J Clin Pharmacol. 2006 Summer;13(2):e240-50.
___ Lucas KE, Armenian HK, Petersen GM, Rowe PC.
       Familial aggregation of fainting in a case-control study of neurally
       mediated hypotension patients who present with unexplained chronic
       fatigue.
       Europace. 2006 Aug 18.
___ Bazzichi L, Giannaccini G, Betti L, Italiani P, Fabbrini L, Defeo F,
       Giacomelli C, Giuliano T, Rossi A, Uccelli A, Giusti L, Mascia G,
       Lucacchini A, Bombardieri S.
       Peripheral benzodiazepine receptors on platelets of fibromyalgic
       patients.
       Clin Biochem. 2006 Sep;39(9):867-72.

--------
(c) 2006 NCBI PubMed

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

Date:    Mon, 20 Nov 2006 16:15:56 +0100
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx> 
Subject: RES,NOT: Cortisol and CFS

Source: Psychosomatic Medicine
        Vol 68, #4, 578-582
Date:   July/August 2006
URL: http://www.psychosomaticmedicine.org/contents-by-date.0.shtml 
http://www.psychosomaticmedicine.org/cgi/content/abstract/68/4/578 
Urinary Cortisol and Cortisol Metabolite Excretion in Chronic Fatigue Syndrome
------------------------------------------------------------------------------
Walid K. Jerjes, BSc, Norman F. Taylor, PhD, MrCPath, Timothy J. Peters, PhD,
FrCP, FrCPath, Simon Wessely, MD, FrCP, PFCPsych, and Anthony J. Cleare,
MrCPsych, PhD
  From the Department of Clinical Biochemistry, Guy's, King's and St.
  Thomas' School of Medicine, King's College London, UK (W.K.J., N.F.T.,
  T.J.P.); and the Section of Neurobiology of Mood Disorders (A.J.C.) and
  General Hospital Psychiatry (S.W.), Department of Psychological Medicine,
  Institute of Psychiatry, King's College, London, UK.
  Address correspondence and reprint requests to Walid K. Jerjes, BSc,
  Department of Clinical Biochemistry, King's College Hospital, Denmark Hill,
  London Se1 9rx, U.K. E-mail: walid.jerjes@kcl.ac.uk Received for publication May 28, 2005; revision received January 7, 2006.


Objectives
Reduced basal hypothalamic-pituitary-adrenal (HPA) axis output in chronic
fatigue syndrome (CFS) has been inferred from low cortisol levels in blood,
saliva, and urine in some studies. Because >95% of cortisol is metabolized
before excretion, we assessed cortisol output by assay of both cortisol
metabolites and free cortisol in 24-hour urine collections and also
investigated sex differences in these between CFS and control groups.

Method
We calculated total urinary cortisol metabolites (TCM) and cortisol
metabolite ratios from individual steroid data in 40 patients (20 males and
20 females) with CFS who were free of medication or comorbid psychiatric
disorder likely to influence the HPA axis. Results were compared with those
of 40 healthy volunteers (20 males and 20 females) well matched for age and
body mass index. Data for free cortisol was obtained on 28 of the patients
and 27 of the controls.

Results
The mean of TCM and cortisol metabolite ratios was not significantly
different between patients and controls for either sex (p>.05 for all
parameters). Previously established sex differences were confirmed in our
controls and were found to be similar in CFS for TCM and the ratios
11OH/11OXO, 5alpha/5beta THF, and 20OH/20OXO (see text) (p.005, p<.05,
p<.05, and p<.005, respectively). Urinary free cortisol values were
numerically (but not statistically) lower in patients with CFS than
controls, and correlated inversely with fatigue levels in patients.
Conclusion: The finding of normal urinary cortisol metabolite excretion in
patients with CFS is at variance with earlier reports that CFS is a
hypocortisolemic state. If serum and saliva cortisol levels are lower in
CFS, this would suggest that metabolic clearance of cortisol is faster in
patients with CFS than controls. This study also demonstrates that sex
differences must be taken into account when interpreting results in patients
with CFS.

Key words
chronic fatigue syndrome, cortisol metabolites, cortisol metabolite ratios,
excretion, sex differences, hypoadrenalism.

Abbreviations
HPA = hypothalamic-pituitary-adrenal; UFC = urinary free cortisol; DSM-IV =
Diagnostic and Statistical Manual of Mental Disor-ders, Fourth Edition; CDC
= Centers for Disease Control and Prevention; CBG = cortisol binding
globulin; 11beta HSD = 11beta hydroxysteroid dehydrogenase activity; TCM =
total urinary cortisol metabolites; THE = tetrahydrocortisone; THF =
tetrahydrocortisol; 5alpha THF = allo-tetrahydrocortisol; alpha-Cort =
alpha-cortolone; beta&beta = beta-cortolone and beta-cortol; alpha-cortol =
alpa-cortol.
------------------------------------------------------------------------------

INTRODUCTION

Chronic fatigue syndrome (CFS) is a controversial condition of uncertain
etiology that is characterized by debilitating fatigue and associated with
myalgia, sleep disturbance, cognitive symptoms, anxiety, and low mood. Some
of these symptoms are shared with Addison's and Cushing's diseases (1),
which initially led to the suggestion of an abnormality in the hypothalamic-
pituitary-adrenal axis (HPA) in patients with CFS. Reduced HPA axis activity
in CFS is indicated by various approaches, but not all studies permit this
conclusion. Demitrack et al. (2) and Cleare et al. (3) demonstrated low
basal serum cortisol levels based on evening and morning samples,
respectively. Because there is a circadian variation of serum cortisol,
careful attention to timing of collection is required, and there is a risk
that differing sleep-wake cycles in CFS and control groups might render
comparisons invalid.

Salivary concentrations of cortisol may be a more reliable indicator
of HPA activity (4), and this approach facilitates multiple sampling. The
concentration in saliva reflects the free fraction in blood but is
approximately 50% of blood levels as a result of 11beta-hydrosteroid
dehydrogenase (11beta-HSD) activity in the parotid gland (5). Findings in
CFS include lower levels in the evening (6) and a blunted early morning rise
(7). Our group recently found reduced salivary free cortisol in CFS
throughout a 15-hour daytime period (8) with no phase difference, whereas
others using less frequent sampling found no change (9,10).

Urinary free cortisol (UFC) in 24-hour samples has been widely used to
assess basal cortisol secretion and has the theoretical advantage of being
unaffected by possible cortisol circadian rhythm differences. Of six studies
to date, four have reported reductions in CFS (11). However, UFC may provide
an unreliable indicator of HPA axis activity, because assays have a large
variability at the lower part of the analytical range (12), are subject to
interference (13), and UFC represents only 2% to 3% of the daily adrenal
cortisol output.

A more promising, novel approach is the measurement of 24-hour urinary
total cortisol metabolite (TCM) excretion. The principal metabolites of
cortisol, generated primarily in the liver, account for >95% of cortisol
excretion. This potentially offers a more sensitive means of detecting
changes in rates of cortisol secretion than UFC and lessens the possibility
of confusion resulting from differences in circadian rhythm of cortisol
secretion or metabolism (14). It has enabled, for example, detection of
subtle reduction in cortisol production in asthmatics treated with inhaled
glucocorticoid (15). Our group has previously noted an increase of TCM in
patients with major depression (16), a finding that is consistent with many
other studies of the HPA axis in this disorder.

Cortisol metabolism begins with reduction of the A ring to form
tetrahydrocortisol and allotetrahydrocortisol through action of beta- and
alpha-reductases followed by 3alpha- and 3beta-hydroxysteroid dehydrogenases
(3-HSDs). Cortisone, produced from cortisol through the action of 11
beta-HSD, similarly gives rise through 5beta reduction to tetrahydrocortisone.
Further reduction of tetrahydrocortisol and tetrahydrocortisone by 20alpha-
and 20beta-HSD results in the formation of alpha and beta cortols and alpha
and beta cortolones, respectively. These metabolites are excreted in the
urine predominantly as glucosiduronates with smaller amounts as sulfates
(17).

This study was designed firstly to compare this approach with UFC in 24-hour
urine collections from patients with CFS selected by rigorous criteria;
second, to provide a more reliable test of the hypothesis that there is
reduced activity of the HPA axis in CFS compared with healthy volunteers;
third, to investigate possible abnormalities in cortisol metabolism in
patients with CFS; and finally, to investigate whether the gender differences
in urinary cortisol metabolites we have previously established in normal
volunteers (14) are present in CFS.


MATERIALS AND METHODS

Subjects

Forty adult patients with CFS (20 males and 20 females) were recruited
through the specialist CFS clinic at King's College Hospital (KCH). All
patients met the 1994 Centers for Disease Control and Prevention (CDC)
criteria for diagnosis of CFS (18) and were interviewed using the
semistructured format of Sharpe et al. (19). All patients were interviewed by
two psychiatrists (A.C. and S.W.) at KCH to check for the presence of any
exclusionary psychiatric disorder as per the CDC criteria. As well as this
categorical delineation, we obtained a dimensional measure of the severity of
fatigue using the Chalder fatigue scale (20), scored using the Likert method,
to give a range of 0 to 33. Further inclusion criteria stipulated the age
range 25 to 55 years and the absence of any history of neurologic, endocrine,
or cardiovascular disorders. To obtain as accurate a measure of HPA axis
activity as possible, we tested only patients who were not taking any
psychotropic medication or other medication that might affect the HPA axis
and had been free of such medication for at least 2 months. Although the
modifications in 1994 of the original CDC diagnostic criteria permitted
inclusion of patients with comorbid major depression or anxiety disorders,
patients with a current major depressive episode or anxiety disorder as
defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition (DSM-IV) criteria were excluded from this study because of their
potential impact on the HPA axis.

Forty healthy subjects (20 males and 20 females) were recruited among the
staff and student body at KCH and were well matched for age, sex, and body
mass index (BMI) with the patients with CFS. They were all assessed by a
research nurse to be in good health without any serious medical illness or
history of psychiatric disorder. All had normal dietary habits, taking
breakfast, lunch, and dinner at about the same time. All subjects habitually
went to bed between 11:30 PM and 12:30 AM and got up between 7:00 AM and 8:00
AM. All subjects gave written, informed consent and ethical approval for the
study was obtained from the local research ethics committee. Urine samples
for controls and CFS subjects were based on collections from January 1997 to
January 2001.


Urinary Collections

Subjects were provided with a standard container for 24-hour urine collection
and given clear instructions on how to complete the collection. They were
told to start each collection at 9:00 AM, having emptied their bladder just
before 9:00 AM. Thereafter, they were to collect all the urine they passed
into the bottle, and at 9:00 AM the next day, they were to empty their
bladder into the bottle to complete the collection. On receipt of the
specimen at the laboratory, the volume was noted, and after vigorous shaking,
two 20-mL aliquots were taken for freezing at -40C before subsequent
analysis.


Urinary Free Cortisol Measurements

Urine cortisol was extracted into dichloromethane and dried extracts were
analyzed by radioimmunoassay using Guildhay sheep anticortisol antiserum (HPS
631-1G) and cortisol-3CMO-histamine-[125-I] as tracer (21). Interassay CV%
was less than 12% for cortisol concentrations over 50 nmol/L.


Cortisol Metabolite Measurements

Urinary steroid profile analysis was carried out by high-resolution gas
chromatography of methyloxime-trimethylsilyl ether (MO-TMS) derivatives as
previously described (22). The intra- and interassay CVs were 7.1% to 21.1%
and 11.2% to 21.9%, respectively, for individual metabolites and 8.8% and
13.6%, respectively, for TCM. The major cortisol metabolites were assayed and
calculated as mug/24 hours. Derived sums were as previously reported (22).
These were: TCM, sum (tetrahydrocortisone [THE] + tetrahydrocortisol [THF] +
allotetrahydrocortisol [5alpha THF] + alpha-cortolone [alpha-cort] +
beta-cortolone and beta-cortol [beta&beta] + alpha-cortol [alpha-Cortol];
11-OH/11-OXO, [THF + allo-THF beta&beta/2] + alpha-cortol)/(THE +
alpha-cortolone beta&beta/2). 5alpha/5beta THF, 5alpha THF/THF; 20OH/20OXO:
(alpha-cortol + beta&beta + alpha-cortolone))/(THE + THF + 5alpha THF). The
ratio of 11OH/11OXO was calculated as an index of total net
11beta-hydroxysteroid dehydrogenase activity. The ratio 5alpha/5beta THF was
calculated as an index of 5alpha versus 5beta reduction and 20OH/20OXO as an
index of net 20-hydroxysteroid dehydrogenase activity.


Statistical Analyses

Comparisons were made by nonparametric test (Mann-Whitney test) (using SPSS
for Windows version 11), because both controls and CFS subjects showed
significant deviations from a normal distribution. Results are given using
median and interquartile ranges. The coefficient of correlation between
fatigue score and steroid levels was calculated by the general linear
regression method.


RESULTS

There was no difference between mean age and BMI between patients with CFS
and controls (mean age [years], 34.0 p/m 1.6 and 32.6 p/m 1.5, p=.30) and BMI
(kg/m2) (23.6 p/m 0.7 and 23.7 p/m 0.7 respectively, p=.8). The CFS
subjects reported high mean scores for fatigue on the Chalder fatigue scale
compared with controls (24.4 p/m 2.9; 7.6 p/m 2.3, p<.0001). The mean
duration of illness for patients with CFS was 2.1 p/m 0.1 years.


Cortisol Metabolites

TCM excretion in patients was not different from controls for either males or
females (Table 1). None of the cortisol metabolite ratios were significantly
different in either males or females with CFS compared with controls. There
were signif- icant sex differences for TCM and all the cortisol metabolite
ratios in both controls and patients with CFS (Table 1).


Urinary Free Cortisol

For technical reasons, urinary free cortisol data were only available for 28
patients and 27 controls. The median UFC (and interquartile range) was 57.5
(37.8-97.3) nmol/24 hours in CFS and 76 (55-107) nmol/24 hours in controls
(Mann-Whitney U=297, p=.17). Values for males and females are shown in Table
1. Although these were numerically lower in patients with CFS than controls,
there was no statistically significant difference in male, female, or the
combined group comparisons. Values were higher in males than females but this
only reached significance in controls.


Correlation With Clinical Measures

There was a significant negative correlation between fatigue score and UFC
(r=0.55, p<.005), but a negative relationship for fatigue score and TCM did
not reach significance (r=-0.18, p=.07).


DISCUSSION

This study found that neither urinary TCM nor the ratios of cortisol
metabolites were different between patients with CFS and the control group.
There are no comparable findings in the literature. UFC levels, whereas lower
in the CFS group, were also not statistically different but did show a
negative correlation with fatigue score. Of six published studies of urinary
free cortisol in CFS, four (including those with the largest sample sizes)
found a low basal 24-hour UFC (2,23-25), whereas two found no change.

Several causes for the apparent divergence of findings between TCM and UFC
may be suggested. First, results for UFC may be subject to interference (13).
Higher levels in normals might thus be the result of higher levels of
crossreacting substances. The concentration of cortisol binding globulin
(CBG) is higher in CFS (2) and may negatively influence urinary free cortisol
excretion.

Second, this sample of patients may not have had the same degree of
hypocortisolism as patients in other studies. We have previously suggested
this might result from either population differences or because the etiology
of the HPA axis dysfunction in CFS is itself multifactorial and variable (4).
Nevertheless, in the present study, we used very similar patient selection
criteria to our previous studies in which we did find significant reductions
in UFC and other indicators of HPA axis dysfunction. Our previous study
focusing on UFC had a larger sample, and the difference between patients with
CFS and controls was 26.5 nmol/24 hours (24), not dissimilar to that obtained
here, which was 20.5 nmol/24 hours for the males and females combined. It is
not certain, therefore, whether this sample in fact did not have
hypocortisolism or that the degree of hypocortisolism present was too small
to be detected statistically given the power of this reduced sample size.

Third, a possible factor of relevance is duration of illness. The duration in
our patients was relatively short, at 2.1 years, in comparison to most
studies of CFS in the literature. It may be that HPA axis activity is more
diminished later in the course of CFS (31). Patients reported by Demitrack et
al. (2) had an average duration of 7.2 years associated with reduced basal
serum cortisol, whereas there was no difference in the basal cortisol levels
in patients reported by Young et al. (9) and Scott et al. (32,33) with a mean
duration of illness of 2.5 years and 4.8 years, respectively. Duration of
illness has been correlated with the degree of impairment in the
adrenocorticotrophic hormone response to the insulin stress test (34). The
large cohort studies necessary to test this theory prospectively have not yet
been undertaken.

Fourth, patients with CFS judged to be hypocortisolemic by single blood or
saliva assays may have a different cortisol rhythm than normals so that
differences might result when serum or saliva cortisol values are compared at
specified times. There are inconsistencies in the literature on the circadian
rhythm in patients with CFS based on serial samples. There are reports of a
flattened circadian rhythm in CFS (26,35), whereas other studies, including
one of ours, based on saliva, have not found a significant change in cortisol
rhythm (8,9,36). Because our data on UFC and TCM were obtained in the same
24-hour collections, circadian rhythm considerations cannot explain our
divergent findings.

Lastly, it might be that patients with CFS clear cortisol faster than
controls. No direct measures of cortisol clearance have been undertaken in
CFS to date. An increase in cortisol metabolite levels coupled with an
increased metabolic clearance rate of cortisol has been demonstrated in
patients with obesity (27) and apparent cortisone reductase deficiency (28),
whereas our group found high levels of TCM in patients with polycystic ovary
syndrome (29). There was a decrease in the 11OH/11OXO ratio, and we proposed
that increased cortisol oxidation had resulted in enhancement of the cortisol
metabolic clearance rate. Others have proposed an increase of 5alpha-
reduction to explain this phenomenon (30). We found no such alterations in
cortisol metabolism in this study, but, as noted, free cortisol in urine
represents only 2% to 3% of the urinary cortisol metabolites (14) so that a
metabolic shift too small to detect by our methodology might still be
sufficient to decrease UFC significantly. The ratio of 11OH/11OXO represents
an index of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity: the
type I is predominant in the liver and acts as a reductase (cortisone to
cortisol (37)), whereas type II is predominantly renal and acts as a
dehydrogenase (cortisol to cortisone (38)). We have found increases of
11OH/11OXO ratio in females but not males with major depression so that the
gender difference was abolished (16), whereas Poor et al. (39) found an
increase of 11OH/11OXO ratio in both de- pressed men and women. We have also
demonstrated increases in 5alpha/5beta THF ratio in both males and females
with major depression (40,41). None of these changes was found in the present
group of nondepressed patients with CFS.

Sex differences were present for TCM and for all urinary cortisol metabolite
ratios in the controls in line with our previous publication (14) and all
these differences were also found in the CFS group. Similarly, published
higher values for UFC in normal males (42,43) are supported by our data. Sex
differences for UFC in CFS have not been previously exam- ined. A larger
sample size might have confirmed a sex differ- ence for the CFS group as
well. These findings reinforce the need to be aware that quantification of
cortisol and cortisol metabolites in urine collections may be misleading if
gender is not taken into account.

Despite the still conflicting results on HPA axis changes in CFS, reports of
symptom improvement during glucocorticoid treatment (44,45) suggest that
cortisol deficiency plays some part in the symptom profile of CFS. Our
finding that patients with higher fatigue scores have lower urinary free
cortisol is consistent with this. Mineralocorticoids, on the other hand, do
not produce benefit in CFS (46-48).

There are some limitations to this article. We did not use dynamic measures
of HPA axis function nor make comparisons with salivary or serum cortisol
levels. It may be helpful in the future to take several of these measures
concurrently. Regarding the urinary assessments, although we standardized the
procedure as much as possible between patients and controls (e.g., time of
meals and sleeping pattern), other factors that may affect the HPA axis could
not be standardized such as the level of physical activity. The volumes of
urine collected were not significantly different between groups, indi- cating
a similar degree of compliance with our instructions. Also, although our
sample size of 40 patients with CFS and 40 controls represents one of the
largest in the literature on the HPA axis in CFS, our power to detect small
differences between groups was obviously limited by this. A preliminary power
calculation based on our results suggests that at 5% significance, we had 80%
power to detect a medium effect size difference of TCM between groups (i.e.,
a difference between groups of approximately 2000 mug/24 hours, representing
an effect size of approximately 0.6). We would not have been able to detect a
difference representing a small effect size between groups. A final issue
relates to psychiatric comorbidity. Depression is associated with HPA axis
overdrive and hypercortisolism in approximately 50% of cases and because
approximately half of patients with CFS have a concurrent depressive illness,
comorbid depression might cancel out any hypocortisolism resulting from CFS
itself. In our sample, the possibility that depressive symptomatology
contributed to an elevation of cortisol level in our patients with CFS
appears slight, because none met the criteria for major depression. Many
patients with CFS have a history of depression, because this is one of the
most consistently identified risk factors for developing CFS (49), and we did
not attempt to tease out any contribution of this to the findings in the
present study. Although previous depression may confer long-term alterations
to the HPA axis, when we compared urinary free cortisol in over 120 patients
with CFS, we found no difference between those with and without a psychiatric
history (24). Nevertheless, accurate retrospective ascertainment of
depression is fraught with difficulty (50).


CONCLUSION

Urinary cortisol metabolite assay provides no new evidence that in CFS, the
symptoms of fatigue result from a reduction of cortisol secretion, although
hypocortisolemic states are claimed to be common in patients with CFS.
Patients with CFS may have a faster clearance of cortisol than controls, but
our finding of normal proportions of cortisol metabolites provides no
positive support for this. On the other hand, lower free cortisol­the
biologically active fraction­is correlated with higher fatigue levels. The
present study clearly demonstrates sex differences in cortisol metabolite
excretion between CFS males and females, which are similar to those in normal
subjects.


We are grateful to Dorothy Blair and members of the Chronic Fatigue Research
and Treatment Unit, King's College Hospital, for help in recruiting subjects
and collecting urine specimens. The following funding bodies provided partial
support for this research: The Linbury Trust, The Psychiatry Research Trust,
and The Kings College Hospital Joint Research Trust.


TABLE

Table 1. Excretion of Urinary Cortisol (UFC) and Cortisol Metabolites (TCM) and Their Metabolite Ratios for
         Patients With Chronic Fatigue Syndrome (CFS) and Control Subjects Over 24 Hours
------------------------------------------------------------------------------------------------------------
                  Controls (n=40)                               Patients With CFS (n=40)
                  --------------------------------------------  --------------------------------------------
                  Males                  Females                Males                  Females
                  (n=20)^a               (n=20)^b               (n=20)^b               (n=20)^b
------------------------------------------------------------------------------------------------------------
TCM ( g/24h)      7468    (5837-10,410)  3777    (2383-7059)**  8975    (5430-10,928)  4897    (3238-5993)**
11OH/11OXO           0.78 (0.64-0.89)       0.66 (0.60-0.70)*      0.77 (0.66-0.90)       0.72 (0.56-0.81)*
5alpha/5beta THF     0.74 (0.53-1.40)       0.56 (0.39-0.78)*      0.94 (0.73-1.36)       0.67 (0.43-0.98)*
20OH/20OXO           0.29 (0.27-0.34)       0.32 (0.27-0.43)*      0.27 (0.23-0.30)       0.32 (0.27-0.46)**
UFC (nmol/24h)      99    (71-130)         59    (41-78)*         69    (50-107)         51    (29-87)
------------------------------------------------------------------------------------------------------------
^a - except UFC, n=13;
^b - except UFC, n=14.
Values are expressed as median and interquartile ranges in the group. Within each group, asterisks show
significant sex differences: * p<.05, ** p<.005.
Between the two groups (CFS vs. controls): p>.05 for all parameters.


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(c) 2006 American Psychosomatic Society

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