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Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome. Cannon JG, Angel JB, Abad LW, Vannier E, Mileno MD, Fagioli L, Wolff SM, Komaroff AL. Department of Medicine, Tufts University-New England Medical Center, Boston, Massachusetts 02111, USA.

Chronic fatigue syndrome is a condition that affects women in disproportionate numbers, and that is often exacerbated in the premenstrual period and following physical exertion. The signs and symptoms, which include fatigue, myalgia, and low-grade fever, are similar to those experienced by patients infused with cytokines such as interleukin-1. The present study was carried out to test the hypotheses that (1) cellular secretion of interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-1 receptor type II (IL-1sRII) is abnormal in female CFS patients compared to age- and activity-matched controls; (2) that these abnormalities may be evident only at certain times in the menstrual cycle; and (3) that physical exertion (stepping up and down on a platform for 15 min) may accentuate differences between these groups. Isolated peripheral blood mononuclear cells from healthy women, but not CFS patients, exhibited significant menstrual cycle-related differences in IL-1 beta secretion that were related to estradiol and progesterone levels (R2 = 0.65, P < 0.01). IL-1Ra secretion for CFS patients was twofold higher than controls during the follicular phase (P = 0.023), but luteal-phase levels were similar between groups. In both phases of the menstrual cycle, IL-1sRII release was significantly higher for CFS patients compared to controls (P = 0.002). The only changes that might be attributable to exertion occurred in the control subjects during the follicular phase, who exhibited an increase in IL-1 beta secretion 48 hr after the stress (P = 0.020). These results suggest that an abnormality exists in IL-1 beta secretion in CFS patients that may be related to altered sensitivity to estradiol and progesterone. Furthermore, the increased release of IL-1Ra and sIL-1RII by cells from CFS patients is consistent with the hypothesis that CFS is associated with chronic, low-level activation of the immune system.

Immunologic Status Correlates with Severity of Physical Symptoms and Perceived Illness Burden in Chronic Fatigue Syndrome Patients Stacy E. Cruess, PhD; Nancy Klimas, MD; Michael H. Antoni, PhD; Lynn Helder, PhD; Kevin Maher, PhD; Robert Keller, MD; Mary Ann Fletcher, PhD Journal of Chronic Fatigue Syndrome, Vol. 7(1) 2000 pp. 39-52 Affiliations:Stacy E. Cruess and Michael H. Antoni are affiliated with the Department of Psychology, University of Miami. Michael H. Antoni is also with the Department of Psychiatry and Behavioral Sciences, University of Miami.Nancy Klimas, Kevin Maher and Mary Ann Fletcher are affiliated with the Department of Medicine, University of Miami.Lynn Helder and Robert Keller are affiliated with Biodoran Medical Center, Ft. Lauderdale, FL.Address correspondence to: Nancy Klimas, MD, 200 BMRC - Section 6D, c/o VA Medical Center, 1201 NW 16th Street, Miami, FL 33125.

ABSTRACT. The purpose of the present study was to investigate the relationship between immunologic status and physical symptoms in Chronic Fatigue Syndrome (CFS) patients. Twenty-seven patients diagnosed with CFS were included. Participants completed a questionnaire including selected subscales of the Sickness Impact Profile, the Cognitive Difficulties Scale, and frequency and severity of CFS-related physical symptoms. Cellular immune markers measured included number and percent of T-helper/inducer cells (CD3+CD4+), T-cytotoxic/ suppressor cells (CD3+CD8+), activated T-lymphocytes (CD26+CD2+ CD3+), activated T cytotoxic/suppressor cells (CD38÷HLA-DR+CD8+), and CD4/CD8 ratio. Spearman’s correlation coefficients revealed significant associations between a number of immunologic measures and severity of illness suggesting that the degree of cellular immune activation was associated with the severity of CFS-related physical symptoms, cognitive complaints, and perceived impairment secondary to CFS. Specifically, elevations in T-helper/inducer cells, activated T-cells, activated cytotoxic/suppressor T-cells, and CD4/CD8 ratio were associated with greater severity of several symptoms. Furthermore, reductions in T-suppressor/cytotoxic cells also appeared related to greater severity of some CFS-related physical symptoms and illness burden. Multiple regression analyses demonstrated that decreased percentage of CD3+CD8+ cells and increased number of CD38+HLA-DR+CD8+ cells were the strongest predictors of total illness burden and fatigue severity, accounting for almost 30% of the variance in these measures.

Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response Jo Nijs(a,b,*), Kenny De Meirleir(a,c), Mira Meeus(a), Neil R. McGregor(d,e), Patrick Englebienne(f,g) a Department of Human Physiology, Faculty of Physical Education and Physical Therapy Science, Vrije Universiteit Brussel (VUB), Brussel 1090, Belgium b Institute for Occupational and Physical Therapy, Department of Health Sciences, Hogeschool Antwerpen, Belgium c Chronic Fatigue Clinic, Vrije Universiteit Brussel (VUB), Belgium d Bio21, Institute of Biomedical Research, University of Melbourne, Parksville, Victoria 3000, Australia e Dental Clinical School, Westmead Hospital, Westmead, Australia f Department of Nuclear Medicine, Universit e Libre de Bruxelles (ULB), Belgium g RED Laboratories N. V., Zellik, Belgium * Corresponding author. Present address: Vakgroep MFYS/Sportgeneeskunde, AZ-VUB KRO gebouw - 1, Laarbeeklaan 101, 1090 Brussel, Belgium. Tel.: +32-2-477-4604; fax: +32-2-477-4607. E-mail address: jo.nijs@vub.ac.be Received 1 October 2003; accepted 9 November 2003 Source: Medical Hypotheses Vol 62, #5, pp 759-765 Date: April 2004 URL: http://www.sciencedirect.com/science/journal/03069877

Summary The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations. First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients. Second, the activation of the protein kinase R enzyme, a characteristic feature in atleast subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasidilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension. Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.

Mitochondrial abnormalities in the postviral fatigue syndrome. Behan WM, More IA, Behan PO Department of Pathology, University of Glasgow, Scotland. Acta Neuropathol 1991;83(1):61-5

We have examined the muscle biopsies of 50 patients who had postviral fatigue syndrome (PFS) for from 1 to 17 years. We found mild to severe atrophy of type II fibres in 39 biopsies, with a mild to moderate excess of lipid. On ultrastructural examination, 35 of these specimens showed branching and fusion of mitochondrial cristae. Mitochondrial degeneration was obvious in 40 of the biopsies with swelling, vacuolation, myelin figures and secondary lysosomes. These abnormalities were in obvious contrast to control biopsies, where even mild changes were rarely detected. The findings described here provide the first evidence that PFS may be due to a mitochondrial disorder precipitated by a virus infection.

Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry? Staines DR. Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Qld, Australia. don_staines@health.qld.gov.au

Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition. The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.

Clinical and Immunologic Effects of Autologous Lymph Node Cell Transplant in Chronic Fatigue Syndrome Nancy G. Klimas, MD; Roberto Patarca-Montero, MD, PhD; Kevin Maher, PhD; Mack Smith, RN, ARNP; Oliver Bathe, MD; Mary Ann Fletcher, PhD Journal of Chronic Fatigue Syndrome, Vol. 8(1) 2001, pp. 39-55 Nancy G. Klimas, Roberto Patarca-Montero, Kevin Maher, and Mary Ann Fletcher are Directors, E. M. Papper Laboratory of Clinical Immunology and Researchers at the Center for Behavioral Medicine Research, Miami Veterans Administration Medical Center, University of Miami School of Medicine, PO. Box 016960 (R-42), Miami, FL 33101. Mack Smith is Research Nurse at the Center for Behavioral Medicine Research.Oliver Bathe is affiliated with the Department of Surgery, Tom Baker Cancer Centre, University of Calgary, 1331/29th Street North West, Calgary, AB, T2N 4N2, Canada. Address correspondence to: Nancy G. Klimas at the above address (E-mail: Nancy.Klimas@med.va.gov ). This work was supported, in part, by a grant from the CFIDS Association of America, by NIH Center Grant 1UD1-AI 45940-02, and by funds from Neoprobe Corp. and Ciratech Corp.

ABSTRACT: An open labeled, phase 1, safety and feasibility study using lymph node extraction, ex vivo lymph node cell expansion, followed by autologous cell reinfusion was evaluated as a potential immunomodulatory treatment strategy in patients with chronic fatigue syndrome (CFS). The experimental therapy utilized the cells of the lymph node, activated and grown in culture with defined media, interleukin-2 (IL-2) and anti-CD3 to activate and enhance cellular immunological functions. This procedure was designed to change the cytokine pattern of the lymph node lymphocytes to favor expression of T -helper (Th)1.-type over Th2-type cytokines. The mixed population of ex vivo immune-enhanced cells were reinfused into the donor, who was carefully monitored for adverse events and possible clinical benefit. There were no adverse events. There were significant improvements in clinical status in association with a significant decrease in Th2-type cytokine production.

Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome.Kavelaars A, Kuis W, Knook L, Sinnema G, Heijnen CJ J Clin Endocrinol Metab 2000 Feb;85(2):692-6 Department of Pediatric Immunology, Wilhelmina Children's Hospital of the University Medical Center Utrecht, The Netherlands. a.kavelaars@wkz.azu.nl PMID: 10690878, UI: 20152737


The present study was designed to investigate the interaction between neuroendocrine mediators and the immune system in chronic fatigue syndrome (CFS). We
examined the sensitivity of the immune system to the glucocorticoid agonist dexamethasone and the beta2-adrenergic agonist terbutaline in 15 adolescent girls with CFS and 14 age- and sex-matched controls. Dexamethasone inhibits T-cell proliferation in healthy controls and in CFS patients. However, the maximal effect of dexamethasone on T-cell proliferation is significantly reduced in CFS patients as compared with controls. The beta2-adrenergic receptor agonist terbutaline inhibits tumor necrosis factor-alpha production and enhances interleukin-10 production by monocytes. Our data demonstrate that the capacity of a beta2-adrenergic agonist to regulate the production of these two cytokines is also reduced in CFS patients. We did not observe differences in baseline or CRH-induced cortisol and ACTH between CFS patients and controls. Baseline noradrenaline was similar in CFS and controls, whereas baseline adrenaline levels were significantly higher in CFS patients. We conclude that CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest CFS should be viewed as a disease of deficient neuroendocrine-immune communication.

Comparative Analysis of Lymphocytes in Lymph Nodes and Peripheral Blood of Patients with Chronic Fatigue Syndrome Mary Ann Fletcher, PhD; Kevin Maher, PhD; Roberto Patarca-Montero, MD, PhD; Nancy Klimas, MD Journal of Chronic Fatigue Syndrome, Vol. 7(3) 2000, pp. 65-75 Department of Medicine, University of Miami School of Medicine and the Miami VA Medical Center.
Address correspondence to: Mary Ann Fletcher, E.M. Papper Laboratory of Clinical Immunology - R-42, R.M.S.B. Room 8168, 1600 NW 10th Avenue, Miami, FL 33136 (E-mail: mfletche@med.miami.edu).

This work was supported, in part, by a grant from the CFIDS Association of America, by NIH Center Grant 1UDI-Al 45940-02, and by funds from Neoprobe Corporation and Ciratech Corporation.

ABSTRACT.
Blood and lymph node samples were obtained from patients with chronic fatigue syndrome (CFS) who had volunteered to undergo a lymph node biopsy while participating in a phase 1 clinical trial of a novel immunomodulatory therapy. The surface marker phenotypes of the peripheral blood and lymph node samples were examined using four-color flow cytometry and compared to published proportions of cells in peripheral blood and lymph nodes from control individuals. While a greater proportion of T lymphocytes from both lymph nodes and peripheral blood of control subjects are immunologically "naive" (CD45RA+), the proportions of lymphocytes with a "memory" phenotype predominate in lymph nodes and peripheral blood of CFS patients. CFS has been proposed to be a disease of autoimmune etiology and in this respect it is interesting to note that decreased proportions of CD45RA+ T ("naive") cells are also seen in the peripheral blood of patients with autoimmune diseases.

Detection of Immunologically Significant Factors for Chronic Fatigue Syndrome Using Neural-Network Classifiers. Hanson SJ, Gause W, Natelson B.Clin Diagn Lab Immunol 2001 May;8(3):658-662 Rutgers University, Newark, New Jersey. PMID: 11329477

Neural-network classifiers were used to detect immunological differences in groups of chronic fatigue syndrome (CFS) patients that heretofore had not shown significant differences from controls. In the past linear methods were unable to detect differences between CFS groups and non-CFS control groups in the nonveteran population.

An examination of the cluster structure for 29 immunological factors revealed a complex, nonlinear decision surface. Multilayer neural networks showed an over 16% improvement in an n-fold resampling generalization test on unseen data. A sensitivity analysis of the network found differences between groups that are consistent with the hypothesis that CFS symptoms are a consequence of immune system dysregulation. Corresponding decreases in the CD19(+) B-cell compartment and the CD34(+) hematopoietic progenitor subpopulation were also detected by the neural network, consistent with the T-cell expansion.

Of significant interest was the fact that, of all the cytokines evaluated, the only one to be in the final model was interleukin-4 (IL-4). Seeing an increase in IL-4 suggests a shift to a type 2 cytokine pattern. Such a shift has been hypothesized, but until now convincing evidence to support that hypothesis has been lacking.

Directions in Immunotherapy Roberto Patarca-Montero, MD, PhD The CFS Research Review, Winter 2001 University of Miami School of Medicine

In a subset of chronic fatigue syndrome (CFS) patients, the immune system is always activated. Although it is unknown why this happens, one hypothesis is that it is caused by a lingering infection or an infection that leaves an autoimmune sequelae.

Although the immune systems of some CFS patients are chronically activated, parts function poorly, particularly the T cells (the "generals" of the immune system army) and natural killer cells (destroyers of infected or cancerous cells). CFS patients' T cells have a decreased capacity to divide and generate new T cells, and their natural killer cells have significantly decreased cytotoxic activity.

Elevated Peroxynitrite as the cause of chronic fatigue syndrome: Other Inducers and Mechanisms of Symptom Generation Martin L Pall School of Molecular Biosciences, Washington State University, Pullman, WA. Source: J Chronic Fatigue Syndrome 2000; 7(4):45-58.

Abstract: In an earlier paper, I proposed that chronic fatigue syndrome (CFS) is caused by a response to infection, involving the induction of inflammatory cytokines which induce, in turn, the inducible nitric oxide synthase, producing elevated nitric oxide. Nitric oxide reacts with superoxide to form the potent oxidant, peroxynitrite. Six positive feedback loops were proposed by which peroxynitrite may stay elevated, acting to increase levels of both nitric oxide and superoxide, which react to form more peroxynitrite. This vicious cycle based on known biochemistry is proposed to be the central cause of CFS. The current paper discusses additional inducers which may act by increasing nitric oxide (physical or psychological trauma) or increasing superoxide (hypoxia) and the role of orthostatic intolerance, Ehlers-Danlos syndrome, excessive exercise, exercise intolerance and carbon monoxide in inducing hypoxia and consequently superoxide and peroxynitrite. The major symptoms of CFS can all be interpreted as relatively direct consequences of the pathophysiology predicted by the elevated peroxynitrite theory of CFS. Attractive mechanisms are proposed by which elevated peroxynitrite, nitric oxide and/or related physiological changes may induce CFS symptoms including fatigue, immune dysfunction, learning and memory dysfunction, multi-organ pain, exercise intolerance/postexertional malaise and orthostatic intolerance. Roles are discussed for six factors likely to influence the frequency of CFS induction in response to infection or other inducing events.

Prevalence of abnormal cardiac wall motion in the cardiomyopathy associated with incomplete multiplication of Epstein-barr Virus and/or cytomegalovirus in patients with chronic fatigue syndrome. Lerner AM, Dworkin HJ, Sayyed T, Chang CH, Fitzgerald JT, Beqaj S, Deeter RG, Goldstein J, Gottipolu P, O'Neill W. Department of Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA. lerner@cdimed.com

We reported unique incomplete herpesvirus (Epstein-Barr Virus (EBV) and/or nonstructural (HCMV) cytomegalovirus) multiplication in 2 distinct subsets of CFS patients. The CFS subsets were identified by: a) presence of IgM serum antibodies to HCMV nonstructural gene products p52 and CM2 (UL44 and UL57), and/or b) IgM serum antibodies to Epstein-Barr virus viral capsid antigen (EBV, VCA IgM). Diagnostic IgM serum antibodies were found in two independent blinded studies involving 49 CFS patients, but the same antibodies were absent in 170 control patients (p<0.05). Abnormal 24 Hr-electrocardiographic monitoring, tachycardias at rest and, in severe chronic cases, abnormal cardiac wall motion (ACWM) were seen in these same CFS patients. We now report a prospective consecutive case control study from 1987--1999 of cardiac dynamics as measured by radionuclide ventriculography in 98 CFS patients from 1987--1999. Controls were patients with various malignancies who were evaluated in protocols requiring radionuclide ventriculography before initiation of cardiotoxic chemotherapeutic agents. The prevalence of abnormal cardiac wall motion (ACWM) at rest in CFS patients was 10 out of 87 patients (11.5%). With stress exercise, 21 patients (24.1%) demonstrated ACWM. Cardiac biopsies in 3 of these CFS patients with ACWM showed a cardiomyopathy. Among the controls, ACWM at rest was present in 4 out of 191 patients (2%) (p=0.0018). A progressive cardiomyopathy caused by incomplete virus multiplication of EBV and/or HCMV in CFS patients is present.

Relationships of cognitive difficulties to immune measures, depression and illness burden in CFS. Lutgendorf S, Klimas NG, Antoni M, Brickman A, Fletcher MA University of Miami School of Medicine, Miami, Florida, USA. Journal of Chronic Fatigue Syndrome 1995; 1(2): 23-41.

Abstract: OBJECTIVE. We related the subjective assessment of cognitive difficulties with lymphocyte phenotypes, cell-mediated immunity (CMI), cytokine and neopterin levels in patients with chronic fatigue syndrome (CFS), in order to determine if CFS patients complaining of greater cognitive difficulties would show greater impairments in cell-mediated immunity and a greater degree of immune system dysregulation, and to determine if these cognitive difficulties would correlate with the other non-affective measures of CFS-associated illness burden. We also assessed whether these relationships would hold independent of depression in two ways, by statistically covarying depression severity scores and by comparing subsets of CFS patients with and without a concurrent diagnosis of major depressive disorder. DESIGN. A case series of CFS patients. SETTING. Outpatient tertiary referral clinic at the University of Miami School of Medicine, Miami, FL. PATIENTS. Consecutive sample of 65 patients who were referred as CFS to the University of Miami Diagnostic Immunology Clinic, who met the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of CFS and consented to participate. MAIN MEASURES. Self-assessment of cognitive difficulties, depression and illness burden, clinician-assessed depression and CFS symptoms, lymphocyte phenotype, proliferative response to mitogens, serum levels of cytokines and neopterin. RESULTS. Among CFS patients, high Cognitive Difficulty Scale (CDS) scores were significantly related to lower lymphocyte proliferative responses to mitogens, higher neopterin levels, and higher CD4 and lower CD8 lymphocyte counts. These relationships, with the exception of T cell subset percentages, were maintained when depression severity was used as a co-variate. High CDS scores were also significantly related to lower Karnofsky scores, and greater illness burden as measured by the Sickness Impact Profile. Evidence is presented that CFS patients with higher cognitive difficulty scores have more immune and clinical dysfunction than those with less cognitive difficulty, and that these relationships are independent of depression . These observations provide support for the concept that although both cognitive difficulties and immunologic abnormalities, such as immune activation and impaired cell-mediated immunity, may represent secondary sequelae to the same event(s), they are not likey to be secondary sequelae to depression.

Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA Vojdani A; Ghoneum M; Choppa PC; Magtoto L; Lapp CW Immunosciences Laboratory Inc., Beverly Hills, California, USA. J Intern Med 1997 Dec;242(6):465-78 (ISSN: 0954-6820)

OBJECTIVES: A prominent feature of chronic fatigue syndrome (CFS) is a disordered immune system. Recent evidence indicates that induction of apoptosis might be mediated in a dysregulated immune system by the upregulation of growth inhibitory cytokines. Therefore, the purpose of this study was to evaluate the apoptotic cell population, interferon-alpha (IFN-alpha) and the IFN-induced protein kinase RNA (PKR) gene transcripts in peripheral blood lymphocytes (PBL) of CFS individuals, as compared to healthy controls. SUBJECTS AND METHODS: PBL were isolated from CFS (n = 29) and healthy control individuals (n = 15) and subjected to quantitative analysis of apoptotic cell population and cell cycle progression by flow cytometry. Quantitative competitive polymerase chain reaction (Q/C PCR) and Western blot analysis were used to assess the levels of PKR mRNA and protein in control and CFS individuals. In addition, circulating IFN-alpha was measured by ELISA assay. RESULTS: Increased apoptotic cell population was observed in CFS individuals, as compared to healthy controls (26.6 +/- 12.9% and 9.9 +/- 4.2%, respectively). The increased apoptotic subpopulation in CFS individuals was accompanied by an abnormal cell arrest in the S phase and the G2/M boundary of the cell cycle as compared to the control group (8.6 +/- 1.2 to 22.8 +/- 2.4 and 3.6 +/- 0.82 to 24.3 +/- 3.4, respectively). In addition, CFS individuals exhibited enhanced PKR mRNA and protein levels (mean basal level 3538 +/- 1050 and 2.7 +/- 0.26, respectively) as compared to healthy controls (mean basal level 562 +/- 162 and 0.89 +/- 0.18, respectively). In 50% of the CFS samples (n = 29) treated with 2-aminopurine (2-AP) (a potent inhibitor of PKR) the apoptotic population was reduced by more then 50%. CONCLUSIONS: PKR-mediated apoptosis in CFS individuals may contribute to the pathogenesis and the fatigue symptomatology associated with CFS.

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