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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:1. NOT, ACT, RES: ME/CFS, Borreliosis and NICE
2. RES: A case control study of premorbid and currently reported physical activity levels in chronic fatigue syndrome
3. RES: The role of illness uncertainty on coping with fibromyalgia symptoms
4. RES, NOT: "New Horizons" International Conference on ME/CFS Biomedical Research 2007
5. RES: Frequency of rheumatic diseases in patients with autoimmune thyroid disease
6. RES: The Use of D-Ribose in Chronic Fatigue Syndrome and Fibromyalgia: A Pilot Study
7. RES: Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study
8. NOT,RES: ME & CFS References
9. med: D-ribose -Again
10. RES,NOT: Gerberding's CFS memo to CDC staff
11. res: Use of D-Ribose in ME/CFS & FM
12. RES: A Pilot Study of External Qigong Therapy for Patients with Fibromyalgia
13. NOT,RES: Latest ME Research
14. RES: CFS/ME & FM papers, published since October 2006
15. RES,NOT: Cortisol and CFS
[Return to digest index] --------------------------------------------- This is a special digest of Co-Cure Research & Medical posts only --------------------------------------------- ---------------------------------------------------------------------- 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 [Return to top] ------------------------------ 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 [Return to top] ------------------------------ 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). [Return to top] ------------------------------ 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 [Return to top] ------------------------------ 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. [Return to top] ------------------------------ 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. [Return to top] ------------------------------ 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 ] [Return to top] ------------------------------ 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.xxWeb: Home: http://freespace.virgin.net/david.axford/ME/CFS: http://freespace.virgin.net/david.axford/me/me.htm [Return to top] ------------------------------ 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=5296I 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 [Return to top] ------------------------------ 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 [Return to top] ------------------------------ 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=4138as 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. ~~~~~~~~~~ [Return to top] ------------------------------ 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. [Return to top] ------------------------------ 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> Click on the: "Latest Research" button which is in the left-hand column. You'll then see the "ME/CFS References " clearly marked 1st December 2006 in the right hand frame. This has a "NEW" graphic alongside. Click on the button (microscope on top of the globe). You may also find the article using the SEARCH tool which is on the home 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 (PGP Public Key Available) ICQ: 51628739 Yahoo! ID: david_axford Web: Home: http://freespace.virgin.net/david.axford/ ME/CFS: http://freespace.virgin.net/david.axford/me/me.htm [Return to top] ------------------------------ 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 [Return to top] ------------------------------ 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. 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