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Posted to Co-Cure Fri, 11 Aug 2000 21:59:21 -0700 by Melissa O'Toole

Characterization of pituitary function with emphasis on GH secretion in CFS

Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome.
Clin Endocrinol (Oxf) 2000 Jul;53(1):99-106
Moorkens G, Berwaerts J, Wynants H, Abs R
Departments of Internal Medicine; Endocrinology, University Hospital Antwerp; Department of Endocrinology, Middelheim Hospital Antwerp, Belgium.
PMID: 10931086, UI: 20389911

OBJECTIVE: Previous studies have revealed that hormonal disturbances may accompany the chronic fatigue syndrome (CFS). Changes in the secretion of the pituitary-adrenal axis have been demonstrated, as well as abnormalities in the GH-IGF-I axis. However, data have not always been well characterized and were sometimes conflicting. The small number of CFS patients investigated in earlier studies may have played a role in the interpretation of the results.

SUBJECTS AND DESIGN: Hormonal testing was performed in 73 nonobese CFS patients and nonobese 21 age-and gender-matched healthy controls. We investigated GH, ACTH and cortisol responses to insulin-induced hypoglycaemia. In a subgroup of patients arginine and clonidine stimulation for GH was also performed. Nocturnal secretion of GH, ACTH and cortisol were determined. Serum levels of IGF-I, prolactin, TSH, and free thyroxine were also measured. Visceral fat mass was assessed by CT scanning.

RESULTS: GH response to insulin induced hypoglycaemia assessed by peak value (17.0 +/- 13.1 &mgr;g/l vs. 22. 1 +/- 9.8 &mgr;g/l; P = 0.01) and by AUC (450.0 +/- 361.3 &mgr;g/l vs. 672.3 +/- 393.0 &mgr;g/l; P = 0.002) was significantly decreased in CFS patients vs. controls. Nocturnal GH secretion assessed by GH peak value (5.4 +/- 3.7 vs. 9.0 +/- 5.1 &mgr;g/l; P = 0.44) and by AUC (34.4 +/- 20.2 vs. 67.4 +/- 43.1; P = 0.045) was also significantly impaired in CFS patients. Arginine and clonidine administration showed no differences in GH secretion between CFS patients and controls. In the CFS group, GH peak values were significantly higher after ITT than after arginine (P = 0.017) or clonidine (P = 0.001). No differences in serum IGF-I levels were found between CFS patients and controls. Except for a significantly lower nocturnal cortisol peak value, no differences were found in ACTH and cortisol secretion between CFS patients and controls. Significantly higher serum prolactin levels (7.4 +/- 4.7 &mgr;g/l vs. 4.4 +/- 1.3 &mgr;g/l; P = 0.004) and significantly higher serum TSH levels (1.6 +/- 1.0 mU/l vs. 1.0 +/- 0.4 mU/l; P = 0.011) were found in CFS patients. Serum free thyroxine was comparable in both groups. Visceral fat mass was significantly higher in CFS patients (86.6 +/- 34.9 cm2 vs. 51.5 +/- 15.7 cm2; P < 0.001).

CONCLUSIONS: We observed a significant impairment of GH response during insulin-induced hypoglycaemia and a low nocturnal GH secretion in CFS patients. These changes did, however, not lead to different concentrations in serum IGF-I. The clinical expression of this inadequate GH secretion can thus be questioned, although the alteration in body composition may be related to this relative GH deficiency. Significantly increased prolactin and TSH levels were found when compared to controls. These findings give support to the hypothesis of a decreased dopaminergic tone in CFS. Further investigations are required in order to identify specific adaptations within the neurotransmitter system in CFS and to determine the clinical importance of the impaired GH homeostasis.

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Posted to Co-Cure Mon, 7 Aug 2000 10:26:55 +0200 by Jean Linn

CFS May Be Result of Childhood Non-paralytic Polio Infection

A layperson-accessible introductory article on this subject by Dr. Richard Bruno appears on-line at www.polionet.org/pen&ink/PI33-Sum00.htm#Childhood, in "Pen and Ink," an E-zine of the Polio Experience Network.

Some excerpts and notes:

"A childhood poliovirus infection may cause chronic fatigue in baby-boomers concludes a paper published in the January, 11, 2000, issue of the American Journal of Physical Medicine and Rehabilitation "Paralytic Versus 'Non-Paralytic' Polio: A Distinction without a Difference," by Dr. Richard L. Bruno, director of The Post-Polio Institute at New Jersey's Englewood Hospital and Medical Center and chairperson of the International Post-Polio Task Force."

Dr. Bruno notes that L. Jason's recent CFS prevalence study, published in the October 11, 1999 issue of Archives of Internal Medicine (available on-line at: archinte.ama-assn.org/issues/v159n18/full/ioi90161.html), found that baby-boomers have a higher incidence of CFS:

"Potentially half of those diagnosed today with CFS may in fact have had Summer Grippe or undiagnosed non-paralytic polio as children in the years before the polio vaccine became available," said Dr. Bruno. "They may also have brain activating system damage that causes chronic fatigue."

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Posted to Co-Cure Sun, 6 Aug 2000 15:48:28 +0200 by Dr. Marc-Alexander Fluks

Enhanced sensitivity of the peripheral cholinergic vascular response

Source: American Journal of Medicine
(Elsevier ScienceDirect)
Volume 108, Issue 9, Pages 695-782
Date: 15 June 2000

Enhanced sensitivity of the peripheral cholinergic vascular response in patients with chronic fatigue syndrome
Vance A. Spence PhDa, Faisel Khan PhD, and Jill J. F. Belch MDa
Section of Vascular Medicine and Biology, University Department of Medicine, Ninewells Hospital and Medical School, Dundee, Scotland, UK
Received 19 July 1999; revised 1 March 2000; accepted 1 March 2000. Available online 27 July 2000.

Article Outline

Patients with chronic fatigue syndrome have a variety of clinical symptoms, with associated physical, psychological, and social disability. The syndrome is poorly understood; the etiology and pathophysiology are not known.

Cholinergic mechanisms are important in the control of peripheral skin perfusion [1 and 2] and, in part, are regulated by endothelial cells [3]. We have developed a method for assessing endothelial function in which acetylcholine is delivered transdermally across intact skin using iontophoresis [4], and the vascular responses are measured by laser Doppler imaging [5]. These techniques have been used in many patients with cardiovascular disease, in whom endothelial dysfunction and impaired vasodilatation are common. We have now applied this methodology to investigate cholinergic activity in patients with chronic fatigue syndrome to see if the reported evidence of central nervous system cholinergic sensitivity in these patients [6] is widespread.

Subjects and methods

Patients were randomly selected from 420 members of a local chronic fatigue syndrome/myalgic encephalomyelitis self-help group. We enrolled 22 patients (7 men and 15 women; mean [p/m SD] age 45 p/m 9 years, range 26 to 59) who fulfilled the Centers for Disease Control criteria for chronic fatigue syndrome [7]. All patients had a principal complaint of fatigue, exacerbated by physical and mental activity, for more than 6 months (illness duration 8 p/m 5 years, range 1 to 15). No other medical cause of fatigue was identified, and none of the patients had a history of vascular disease. We also enrolled 22 age-matched (p/m 1 year) and sex-matched control subjects. None of the control subjects and 13 of the patients with chronic fatigue syndrome took medications. Four patients with chronic fatigue syndrome were taking amitryptilline (10 mg to 20 mg at night for pain control), 3 were taking low doses of a serotonin reuptake inhibitor, and 7 were taking nonsteroidal anti-inflammatory drugs (which were stopped for at least 10 days before the study date). All participants gave written informed consent. The local committee on medical research ethics approved the study.

MEASUREMENT OF SKIN BLOOD FLOW AND DRUG DELIVERY

We used a laser Doppler imager (Moor Instruments, Axminster, United Kingdom) that scans a low-power laser beam over the skin surface. The scanner was set to a spatial resolution of 100x100 pixels and a scan speed of 4 ms/pixel. Moving blood in the microvasculature causes a Doppler shift, which is processed to build a color image of blood flow (termed "erythrocyte flux") in arbitrary perfusion units.

Iontophoresis was used to transport drugs in solution across intact skin. We used a protocol similar to that used in our previous studies [4 and 8]. In brief, a circular iontophoresis electrode (inner diameter 20 mm) was attached midway on the volar aspect of the forearm. A reference electrode was placed around the wrist to complete the circuit. Both electrodes were connected to an iontophoresis controller, which provided a direct current for drug delivery.

Studies were performed in a temperature-controlled room (22 C to 23 C). Following a 20-minute equilibration period, baseline skin perfusion was measured at the volar aspect of the dominant forearm over the iontophoresis electrode. Using a 0.1-mA anodal current, a 1% solution of acetylcholine chloride (Sigma Chemical, St. Louis, Missouri) was iontophoresed for 10 seconds to achieve a dose of 1 mC/cm2. The duration was increased to 20 seconds for a dose of 2 mC/cm2, to 40 seconds for a dose of 4 mC/cm2, and to 80 seconds for a dose of 8 mC/cm2. Scans were performed for 2 minutes between doses. At a different site, we used a 0.1-mA cathodal current to iontophorese sodium nitroprusside (David Bull Laboratories, Warwick, United Kingdom) to give doses of 1, 2, 4, and 8 mC/cm2. Scans were performed for 4 minutes between doses.

All measurements and data analyses were blinded to patient status and were performed by a researcher who was unaware whether the subject was a patient or a control.

STATISTICAL ANALYSIS

Results are expressed as mean SD. Differences between patients with chronic fatigue syndrome and control subjects were compared using two-way analysis of variance (ANOVA) for repeated measures. The null hypothesis was rejected at P <0.05.

Results

Baseline skin erythrocyte flux was similar in patients with chronic atigue syndrome (22 p/m 7 perfusion units) and control subjects (20 p/m 5 perfusion units, P = 0.23). The vascular responses to acetylcholine were significantly greater in patients with chronic fatigue syndrome than in control subjects at all 4 doses (P = 0.01, ANOVA; Figure 1). In contrast, the vascular responses to sodium nitroprusside (Figure 2) were not significantly different between the groups of subjects.

Excluding the 4 patients taking amitryptilline did not alter the results. The vascular response to acetylcholine was still significantly greater in the patients with chronic fatigue syndrome (22 p/m 7, 60 p/m 26, 105 p/m 28, 127 p/m 23, and 141 p/m 21 perfusion units) than in the control subjects (19 p/m 5, 37 p/m 24, 69 p/m 36, 95 p/m 35, and 112 p/m 30 perfusion units, P = 0.001).

Discussion

The results of this study show enhanced cholinergic activity in the peripheral microcirculation of patients with chronic fatigue syndrome. This enhancement was specific for acetylcholine; the vascular responses to sodium nitroprusside were similar in patients with chronic fatigue syndrome and in control subjects.

We could not determine why the patients with chronic fatigue syndrome have acetylcholine supersensitivity in the skin microcirculation. Recent evidence in mice treated with cholinesterase inhibitors suggests that cholinergic stimulation promotes changes in the genes regulating acetylcholine metabolism [9] and that such changes are facilitated by stress [10]. Whether such changes of cholinergic tone apply to the metabolism of acetylcholine in vascular endothelium, however, remains speculative. There are several ways that the acetylcholine-endothelial pathway could account for cholinergic supersensitivity. Acetylcholine produces vasodilatation through a sequence of events beginning with its binding to muscarinic receptors on the endothelial cell surface. This activates G proteins, promoting the conversion of l-arginine to nitric oxide, which diffuses into the smooth muscle cells and stimulates guanylate cyclase to produce cyclic GMP, thereby causing relaxation. As vascular responses to sodium nitroprusside were not enhanced in patients with chronic fatigue syndrome, we suggest that the enhanced vasodilator activity to acetylcholine is situated at the muscarinic M3 receptor or along the muscarinic receptor/vascular smooth muscle pathway.

Many of the symptoms of chronic fatigue syndrome, such as temperature sensitivity, gastrointestinal difficulties, problems with sleep, and orthostatic intolerance, are consistent with altered cholinergic activity. Our findings of enhanced cholinergically-mediated vasodilatation are related only to the vasoactive properties of acetylcholine within the endothelium, which are distinct from its action as a neurotransmitter. Nevertheless, the response of skin microvessels to acetylcholine is typical of blood vessels elsewhere in the body. Thus, our findings might have important implications for features of chronic fatigue syndrome that involve vascular integrity.

The patients in this study were heterogeneous and had a diverse range of symptoms and severity of presentation. We did not examine the potential effects of duration of illness or overall health at the time of testing. A study that used more specific criteria might identify differences in cholinergic sensitivity among different groups of patients with chronic fatigue syndrome, as has been seen for immune function [11 and 12].

Acknowledgements
We are grateful to the Myalgic Encephalomyelitis Association Moray Firth group and Tenovus Scotland for their support. We thank Jenny Cooper for her technical assistance.

References
1. F. Khan and J.D. Coffman, Enhanced cholinergic cutaneous vasodilation in Raynaud's phenomenon. Circulation 89 (1993), pp. 1183-1188.
2. J.D. Coffman and R.A. Cohen, Cholinergic vasodilator mechanism in human fingers. Am J Physiol 252 (1987), pp. H594-H597.
3. J.G. Parnavelis, W. Kelly, G. Burnstock et al., Ultrastructural localisation of ChaT in vascular endothelial cells in rat brain. Nature 316 (1985), pp. 724-725.
4. F. Khan, S.J. Litchfield, M. McLaren et al., Oral L-arginine supplementation and cutaneous vascular responses in patients with primary Raynaud's phenomenon. Arthritis Rheum 40 (1997), pp. 352-357.
5. F. Khan, I.R. Greig, D.J. Newton et al., Skin blood flow after transdermal S-nitrosothio-acetylglucose. Lancet 350 (1997), pp. 410-411.
6. A. Chaudhuri, T. Majeed, T. Dinan and P.O. Behan, Chronic fatigue syndrome: a disorder of central cholinergic transmission. J Chron Fatigue Synd 3 (1997), pp. 3-16.
7. International Chronic Fatigue Syndrome Study Group, K. Fukuda, S.E. Strauss, I. Hickie et al., The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 121 (1994), pp. 953-959.
8. F. Khan, N.C. Davidson, R.C. Littleford et al., Cutaneous vascular responses to acetylcholine are mediated by a prostacyclin-dependent mechanism in man. Vasc Med 2 (1997), pp. 82-86.
9. D. Kaufer, A. Friedman, S. Seidman and H. Soveq, Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature 393 (1998), pp. 373-377.
10. R.M. Salposky, The stress of Gulf War syndrome. Nature 393 (1998), pp. 308-309.
11. I.S. Hassan, B.A. Bannister, A. Akbar et al., A study of the immunology of chronic fatigue syndrome: correlation of immunologic parameters to health dysfunction. Clin Immunol Immunopathol 87 (1998), pp. 60-67.
12. A.C. Mawle, R. Nisenbaum, J.G. Dobbins et al., Immune responses associated with chronic fatigue syndrome: a case control study. J Infect Dis 175 (1997), pp. 136-141.

Correspondence should be addressed to Faisel Khan, PhD, Section of Vascular Medicine and Biology, University Department of Medicine, Ninewells Hospital and Medical School, Dundee, DD1 9SY Scotland, United Kingdom

________________
(c) 2000 ScienceDirect - an Elsevier Science B.V. registered trademark.

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Posted to Co-Cure Sat, 5 Aug 2000 18:19:56 EDT by Bernice Melsky

Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways

Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways.
Pain 2000 Aug 1;87(2):201-211
Larson AA, Giovengo SL, Russell IJ, Michalek JE
Graduate Program in Neuroscience, 295 Animal Science/Veterinary Medicine Building, University of Minnesota, 1988 Fitch Avenue, MN 55108, St. Paul, USA
PMID: 10924813

Substance P (SP), a putative nociceptive transmitter, is increased in the CSF of patients with fibromyalgia syndrome (FMS). Because excitatory amino acids (EAAs) also appear to transmit pain, we hypothesized that CSF EAAs may be similarly involved in this syndrome. We found that the mean concentrations of most amino acids in the CSF did not differ amongst groups of subjects with primary FMS (PFMS), fibromyalgia associated with other conditions (SFMS), other painful conditions not exhibiting fibromyalgia (OTHER) or age-matched, healthy normal controls (HNC). However, in SFMS patients, individual measures of pain intensity, determined using an examination-based measure of pain intensity, the tender point index (TPI), covaried with their respective concentrations of glutamine and asparagine, metabolites of glutamate and aspartate, respectively. This suggests that re-uptake and biotransformation mask pain-related increases in EAAs. Individual concentrations of glycine and taurine also correlated with their respective TPI values in patients with PFMS. While taurine is affected by a variety of excitatory manipulations, glycine is an inhibitory transmitter as well as a positive modulator of the N-methyl-D-asparate (NMDA) receptor. In both PFMS and SFMS patients, TPI covaried with arginine, the precursor to nitric oxide (NO), whose concentrations, in turn, correlated with those of citrulline, a byproduct of NO synthesis. These events predict involvement of NO, a potent signaling molecule thought to be involved in pain processing. Together these metabolic changes that covary with the intensity of pain in patients with FMS may reflect increased EAA release and a positive modulation of NMDA receptors by glycine, perhaps resulting in enhanced synthesis of NO.
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Posted to Co-Cure Fri, 4 Aug 2000 17:54:54 -0700 by Melissa O'Toole

Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium

Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium.
J Am Coll Nutr 2000 Jun;19(3):374-82
Manuel y Keenoy B, Moorkens G, Vertommen J, Noe M, Neve J, De Leeuw I
Laboratory of Endocrinology, University of Antwerp, Belgium.
PMID: 10872900, UI: 20329301

OBJECTIVE: Magnesium deficiency and oxidative stress have both been identified as pathogenic factors in aging and in several age-related diseases. The link between these two factors is unclear in humans although, in experimental animals, severe Mg deficiency has been shown to lead to increased oxidative stress.

METHODS: The relationship between Mg body stores, dietary intakes and supplements on the one hand and parameters of the oxidant-antioxidant balance on the other was investigated in human subjects.

RESULTS: The study population consisted of 93 patients with unexplained chronic fatigue (median age 38 years, 25% male, 16% smokers and 54% with Chronic Fatigue Syndrome (CFS). Mg deficient patients (47%) had lower total antioxidant capacity in plasma (p=0.007) which was related to serum albumin. Mg deficient patients whose Mg body stores did not improve after oral supplementation with Mg (10 mg/kg/day) had persistently lower blood glutathione levels (p=0.003). In vitro production of thiobarbituric acid reactive substances (TBARS) by non-HDL lipoproteins incubated with copper was related to serum cholesterol (p<0.001) but not to Mg or antioxidants and did not improve after Mg supplementation. In contrast, velocity of formation of fluorescent products of peroxidation (slope) correlated with serum vitamin E (p<0.001), which was, in turn, related to Mg dietary intakes. Both slope and serum vitamin E improved after Mg supplementation (p<0.001).

CONCLUSIONS: These results show that the lower antioxidant capacity found in moderate Mg deficiency was not due to a deficit in Mg dietary intakes and was not accompanied by increased lipid susceptibility to in vitro peroxidation. Nevertheless, Mg supplementation was followed by an improvement in Mg body stores, in serum vitamin E and its interrelated stage of lipid peroxidation.

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Posted to Co-Cure Thu, 3 Aug 2000 22:14:08 -0700 by Melissa O'Toole

Self-reported sensitivity to chemical exposures in five clinical populations and healthy controls

Self-reported sensitivity to chemical exposures in five clinical populations and healthy controls.
Psychiatry Res 2000 Jul 24;95(1):67-74
Nawab SS, Miller CS, Dale JK, Greenberg BD, Friedman TC, Chrousos GP, Straus SE, Rosenthal NE
Section on Biological Rhythms, National Institute of Mental Health, 10 Center Drive, Bldg. 10, Rm. 3S-231, 20892-1390, Bethesda, MD, USA
PMID: 10904124

Two hundred and twenty-five subjects, including normal volunteers and patients with previously documented seasonal affective disorder (SAD), chronic fatigue syndrome (CFS), Cushing's syndrome, Addison's disease and obsessive-compulsive disorder (OCD), completed a self-rated inventory of reported sensitivity to various chemical exposures.

Patients with CFS, Addison's disease and SAD self-reported more sensitivity to chemical exposures than normal controls. In addition, women reported more sensitivity than men.

This report suggests that chemical sensitivity may be a relevant area to explore in certain medical and psychiatric populations. A possible relationship between reported chemical sensitivity and hypothalamic-pituitary-adrenal (HPA)-axis functioning is discussed.

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Posted to Co-Cure Wed, 2 Aug 2000 15:55:34 -0400 by Ray Colliton

Genetic Predisposition to Chronic Fatigue Syndrome and Fibromyalgia?

Genetic Predisposition to Chronic Fatigue Syndrome and Fibromyalgia?
by Tamara Schuit
ImmuneSupport.com

08-01-2000 - New research using twins may point to a genetic predisposition to CFS and FM.

Both identical and fraternal female twins were examined at the University of Washington. In Phase One of a two-phase study, several interesting results were found.

Read the article

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Note: All abstract summaries, unless otherwise noted, were prepared by Margaret Bailey.


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