Chronic Fatigue Syndrome: US Pacific Zone

Afari N, Buchwald D. · Department of Psychiatry, University of Washington, Seattle, USA. · Am J Psychiatry. · Pubmed #12562565 links to  free full text

Abstract: OBJECTIVE: Chronic fatigue syndrome is an illness characterized by disabling fatigue of at least 6 months, accompanied by several other symptoms. This review summarizes the current state of knowledge about chronic fatigue syndrome. METHOD: The case definition, prevalence, clinical presentation, evaluation, and prognosis of chronic fatigue syndrome are discussed. Research on the pathophysiology and treatment of chronic fatigue syndrome is reviewed. RESULTS: Chronic fatigue syndrome is diagnosed on the basis of symptoms. Patients with chronic fatigue syndrome experience significant functional impairment. Pathophysiological abnormalities exist across many domains, suggesting that chronic fatigue syndrome is a heterogeneous condition of complex and multifactorial etiology. Evidence also is beginning to emerge that chronic fatigue syndrome may be familial. Although chronic fatigue syndrome has significant symptom overlap and comorbidity with psychiatric disorders, several lines of research suggest that the illness may be distinct from psychiatric disorders. Patients' perceptions, attributions, and coping skills, however, may help perpetuate the illness. Treatment for chronic fatigue syndrome is symptom-based and includes pharmacological and behavioral strategies. Cognitive behavior therapy and graded exercise can be effective in treating the fatigue and associated symptoms and disability. CONCLUSIONS: Chronic fatigue syndrome is unlikely to be caused or maintained by a single agent. Findings to date suggest that physiological and psychological factors work together to predispose an individual to the illness and to precipitate and perpetuate the illness. The assessment and treatment of chronic fatigue syndrome should be multidimensional and tailored to the needs of the individual patient.

Miller RG. · Department of Neurology, California Pacific Medical Center, San Francisco, California 94115, USA. · Am J Phys Med Rehabil. · Pubmed #12409815 No free full text.

Abstract: New methods of examining both central and peripheral fatigue are now available. A broader understanding of the mechanisms of fatigue in healthy human subjects has begun to emerge. The mechanisms of fatigue in patients with various neuromuscular diseases are even more complex than in healthy persons. Examples of both central and peripheral fatigue in various neuromuscular diseases and other disorders are presented, including metabolic myopathy, chronic fatigue syndrome, postpolio syndrome, and amyotrophic lateral sclerosis.

Silver DS, Wallace DJ. · Division of Rheumatology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. · Rheum Dis Clin North Am. · Pubmed #12122927 No free full text.

Abstract: Most of the six million Americans with fibromyalgia have at least one associated syndrome which mandates specialized attention in addition to traditional therapeutic approaches. These include localized procedures, regional blocks, antiinflammatory or antimicrobial regimens, attention to non soft tissue sources of psychosocial distress, and classes of medicines not usually prescribed for fibromyalgia. The successful treatment of fibromyalgia-associated syndromes improves the symptoms, quality of life, and prognosis of fibromyalgia.

Pall ML, Satterlee JD. · School of Molecular Biosciences, Washington State University, Pullman 99164-4660, USA. · Ann N Y Acad Sci. · Pubmed #12000033 No free full text.

Abstract: Various types of evidence implicate nitric oxide and an oxidant, possibly peroxynitrite, in MCS and chemical intolerance (CI). The positive feedback loops proposed earlier for CFS may explain the chronic nature of MCS (CI) as well as several of its other reported properties. These observations raise the possibility that this proposed elevated nitric oxide/peroxynitrite mechanism may be the mechanism of a new disease paradigm, answering the question raised by Miller earlier: "Are we on the threshold of a new theory of disease?"

Monchamp T, Frishman WH. · Department of Medicine, University of California Los Angeles Medical Center, Los Angeles, California, USA. · Heart Dis. · Pubmed #11975842 No free full text.

Abstract: Chronic congestive heart failure is a clinical syndrome that affects nearly 5 million people in the United States alone. Patients with this condition have symptoms of dyspnea and exertional fatigue that often limit their daily activities and decrease their quality of life. There has recently been a paradigm shift in the management of congestive heart failure. Current strategies are focusing on improving the central cardiopulmonary abnormalities, such as decreased ejection fraction and increased capillary wedge pressure, and interventions aimed at improving the numerous peripheral changes that occur with congestive heart failure. Exercise as a treatment modality has been shown to affect many of these peripheral changes, specifically abnormalities in the skeletal muscle, peripheral blood flow, and neurohormonal milieu, which improve with appropriate exercise regimes. Exercise also reduces the symptoms of exertional fatigue, improves quality of life, and increases survival. This article reviews the current experience with exercise and congestive heart failure and discusses strategies used to implement an exercise program for patients.

Tan EM, Sugiura K, Gupta S. · W.M. Keck Autoimmune Disease Center, The Scripps Research Institute, La Jolla, California 92037, USA. · J Clin Immunol. · Pubmed #11958593 No free full text.

Abstract: The 1994 case definition of chronic fatigue syndrome is widely used not only for diagnosis but also for clinical and laboratory-based observations of this clinical entity. The criteria for the 1994 case definition are based primarily on symptoms and not on physical signs or chemical or immunological tests. This situation has resulted in conflicting clinical and laboratory observations that in all likelihood is due to different populations of patients being studied in different centers. Based on some of the recent publications, there appears to be an emerging picture of this disease entity that we propose could be used to subgroup chronic fatigue syndrome into four different subclasses. These subclasses would consist of chronic fatigue with primarily nervous system disorders such as impaired memory or concentration and headache, chronic fatigue with primarily endocrine system disorders such as unrefreshing sleep and postexertional malaise, chronic fatigue with musculoskeletal system disorders such as muscle pain and joint pain, and chronic fatigue with immune system/infectious disorders such as sore throat and tender lymph nodes. It is suggested that if clinical and laboratory-based studies on chronic fatigue syndrome were conducted on more homogeneous subgroups of patients, the data from one center to the other might not be as conflicting and more insights can be shed on the nature of this clinical condition.

Barkhuizen A. · Department of Medicine (L329A), Oregon Health Sciences University and Portland VA Medical Center, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA. · Curr Pain Headache Rep. · Pubmed #11403739 No free full text.

Abstract: Fibromyalgia is a chronic syndrome characterized by widespread pain, unrefreshed sleep, disturbed mood, and fatigue. Until such time as we have a clearer understanding of the trigger and/or pathophysiologic mechanisms producing these symptoms, pharmacologic treatment should be aimed at individual symptoms. Such treatment should ideally be offered as part of a multidisciplinary treatment program using both pharmacologic and nonpharmacologic treatment modalities. Critical components of any successful fibromyalgia treatment program include addressing physical fitness, work and other functional activities, and mental health, in addition to symptom-specific therapies. The main symptoms that should be addressed include pain, sleep disturbances including restless leg syndrome, mood disturbances, and fatigue. Pharmacologic therapy should also be considered for syndromes commonly associated with fibromyalgia including irritable bowel syndrome, interstitial cystitis, migraine headaches, temporomandibular joint dysfunction, dysequilibrium including neurally mediated hypotension, sicca syndrome, and growth hormone deficiency. This article provides general guidelines in initiating a successful pharmacologic treatment program for fibromyalgia.

Aaron LA, Buchwald D. · Department of Medicine, Division of Internal Medicine, Harborview Medical Center, 325 Ninth Avenue, Box 359780, Seattle, WA 98104, USA. · Ann Intern Med. · Pubmed #11346323 No free full text.

Abstract: PURPOSE: Unexplained clinical conditions share features, including symptoms (fatigue, pain), disability out of proportion to physical examination findings, inconsistent demonstration of laboratory abnormalities, and an association with "stress" and psychosocial factors. This literature review examines the nature and extent of the overlap among these unexplained clinical conditions and the limitations of previous research. DATA SOURCES: English-language articles were identified by a search of the MEDLINE database from 1966 to January 2001 by using individual syndromes and their hallmark symptoms as search terms. STUDY SELECTION: Studies that assessed patients with at least one unexplained clinical condition and that included information on symptoms, overlap with other unexplained clinical conditions, or physiologic markers. Conditions examined were the chronic fatigue syndrome, fibromyalgia, the irritable bowel syndrome, multiple chemical sensitivity, temporomandibular disorder, tension headache, interstitial cystitis, and the postconcussion syndrome. DATA EXTRACTION: Information on authorship, patient and control groups, eligibility criteria, case definitions, study methods, and major findings. DATA SYNTHESIS: Many similarities were apparent in case definition and symptoms, and the proportion of patients with one unexplained clinical condition meeting criteria for a second unexplained condition was striking. Tender points on physical examination and decreased pain threshold and tolerance were the most frequent and consistent objective findings. A major shortcoming of all proposed explanatory models is their inability to account for the occurrence of unexplained clinical conditions in many affected patients. CONCLUSIONS: Overlap between unexplained clinical conditions is substantial. Most studies are limited by methodologic problems, such as case definition and the selection and recruitment of case-patients and controls.

Aaron LA, Buchwald D. · Department of Medicine, Harborview Medical Center, 325 Ninth Avenue, Box 359780, Seattle, WA 98104, USA. · Curr Rheumatol Rep. · Pubmed #11286667 No free full text.

Abstract: Several unexplained clinical conditions frequently coexist with fibromyalgia; these include chronic fatigue syndrome, irritable bowel syndrome, temporomandibular disorder, tension and migraine headaches, and others. However, only recently have studies directly compared the physiological parameters of these conditions (eg, fibromyalgia vs irritable bowel syndrome) to elucidate underlying pathogenic mechanisms. This review summarizes data from comparative studies and discusses their implications for future research.

Friedlander AH, Walker LA, Friedlander IK, Felsenfeld AL. · Veterans Affairs Outpatient Clinic and Nursing Home, Sepulveda, Calif., USA. · J Am Dent Assoc. · Pubmed #10953534 links to  free full text

Abstract: BACKGROUND: Obstructive sleep apnea syndrome, or OSAS, is a common, but underdiagnosed, disorder that potentially is fatal. It is characterized by repetitive episodes of complete or partial upper airway obstruction leading to absent or diminished airflow into the lungs. These episodes usually last 10 to 30 seconds and result in loud snoring, a decrease in oxygen saturation, and chronic daytime sleepiness and fatigue. The obstruction is caused by the soft palate, base of the tongue or both collapsing against the pharyngeal walls because of decreased muscle tone during sleep. Potentially fatal systemic illnesses frequently associated with this disorder include hypertension, pulmonary hypertension, heart failure, nocturnal cardiac dysrhythmias, myocardial infarction and ischemic stroke. CLINICAL IMPLICATIONS: The classic signs and symptoms of OSAS may be recognizable by dental practitioners. Common findings in the medical history include daytime sleepiness, snoring, hypertension and type 2 diabetes mellitus. Common clinical findings include obesity; a thick neck; excessive fat deposition in the palate, tongue (enlarged) and pharynx; a long soft palate; a retrognathic mandible; and calcified carotid artery atheromas on panoramic and lateral cephalometric radiographs. CONCLUSIONS: Dentists cognizant of these signs and symptoms have an opportunity to diagnose patients with occult OSAS. After confirmation of the diagnosis by a physician, dentists can participate in management of the disorder by fabricating mandibular advancement appliances and performing surgical procedures that prevent recurrent airway obstruction.

Schatzberg AF. · Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Calif 94305-5548, USA. · J Clin Psychiatry. · Pubmed #10926050 No free full text.

Abstract: The second and third generation of antidepressants, i.e., the selective serotonin reuptake inhibitors, nefazodone, venlafaxine, and mirtazapine, are proving to be useful in a variety of seemingly diverse disorders, including most anxiety disorders. In addition to receiving approval from the U.S. Food and Drug Administration (FDA) for major depressive disorder, some of the newer antidepressants have received FDA approval for other disorders, e.g., generalized anxiety disorder (venlafaxine), bulimia nervosa (fluoxetine), obsessive-compulsive disorder (fluvoxamine, paroxetine, sertraline, and fluoxetine), social phobia (paroxetine), panic disorder (sertraline, paroxetine), and posttraumatic stress disorder (sertraline). In controlled studies, these agents have also shown usefulness in premenstrual dysphoric disorder, borderline personality disorder, obesity, smoking cessation, and alcoholism. This article describes the new and potential indications for recently developed antidepressants and the studies that suggested these indications.

Werbach MR. · UCLA School of Medicine, California, USA. · Altern Med Rev. · Pubmed #10767667 links to  free full text

Abstract: Despite considerable worldwide efforts, no single etiology has been identified to explain the development of chronic fatigue syndrome (CFS). It is likely that multiple factors promote its development, sometimes with the same factors both causing and being caused by the syndrome. A detailed review of the literature suggests a number of marginal nutritional deficiencies may have etiologic relevance. These include deficiencies of various B vitamins, vitamin C, magnesium, sodium, zinc, L-tryptophan, L-carnitine, coenzyme Q10, and essential fatty acids. Any of these nutrients could be marginally deficient in CFS patients, a finding that appears to be primarily due to the illness process rather than to inadequate diets. It is likely that marginal deficiencies not only contribute to the clinical manifestations of the syndrome, but also are detrimental to the healing processes. Therefore, when feasible, objective testing should identify them and their resolution should be assured by repeat testing following initiation of treatment. Moreover, because of the rarity of serious adverse reactions, the difficulty in ruling out marginal deficiencies, and because some of the therapeutic benefits of nutritional supplements appear to be due to pharmacologic effects, it seems rational to consider supplementing CFS patients with the nutrients discussed above, along with a general high-potency vitamin/mineral supplement, at least for a trial period.

Kogelnik AM, Loomis K, Hoegh-Petersen M, Rosso F, Hischier C, Montoya JG. · Stanford University School of Medicine, Stanford, CA, USA. · J Clin Virol. · Pubmed #17276366 No free full text.

Abstract: BACKGROUND: Twelve patients with long-standing symptoms of central nervous system (CNS) dysfunction were found to have elevated antibody titres to human herpesvirus-6 (HHV-6) and Epstein-Barr virus (EBV). All patients had four or more of the following neurocognitive symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression. OBJECTIVES: We sought to determine whether elevated antibodies to EBV and HHV-6 indicated chronic viral activation in patients with CNS dysfunction and if their symptoms could be improved by suppressing viral activity with oral valganciclovir. STUDY DESIGN: Patients with high IgG antibody titers against HHV-6 and EBV who were suffering from central nervous system dysfunction and debilitating fatigue for more than one year (median 3 years, range 1-8 years) were treated with 6 months of valganciclovir in an open label study. RESULTS: Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activites. In the nine patients with a symptomatic response to treatment, EBV VCA IgG titers dropped from 1:2560 to 1:640 (p = 0.008) and HHV-6 IgG titers dropped from a median value of 1:1280 to 1:320 (p = 0.271). Clinically significant hematological toxicity or serious adverse events were not observed among the 12 patients. CONCLUSION: These preliminary clinical and laboratory observations merit additional studies to establish whether this clinical response is mediated by an antiviral effect of the drug, indirectly via immunomodulation or by placebo effect.

Vanness JM, Snell CR, Strayer DR, Dempsey L, Stevens SR. · University of the Pacific, Department of Sport Sciences, Stockton, CA 95211, USA. · Med Sci Sports Exerc. · Pubmed #12783037 No free full text.

Abstract: PURPOSE: The purpose of this study was to examine physiological responses of persons with chronic fatigue syndrome (CFS) to a graded exercise test. METHODS: Cardiopulmonary exercise tests were performed on 189 patients diagnosed with CFS. Based on values for peak oxygen consumption, patients were assigned to one of four impairment categories (none, mild, moderate, and severe), using American Medical Association (AMA) guidelines. A one-way MANOVA was used to determine differences between impairment categories for the dependent variables of age, body mass index, percentage of predicted [OV0312]O(2), resting and peak heart rates, resting and peak systolic blood pressure, respiratory quotient (RQ), and rating of perceived exertion. RESULTS: Significant differences were found between each impairment level for percentage of predicted [OV0312]O(2) and peak heart rate. Peak systolic blood pressure values for the "moderate," and "severe" groups differed significantly from each other and both other groups. The more impaired groups had lower values. The no impairment group had a significantly higher peak RQ than each of the other impairment levels (all P < 0.001). Peak [OV0312]O(2) values were less than predicted for all groups. Compared with the males, the women achieved actual values for peak [OV0312]O(2) that were closer to their predicted values. CONCLUSION: Despite a common diagnosis, the functional capacity of CFS patients varies greatly. Stratifying patients by function allows for a more meaningful interpretation of the responses to exercise and may enable differential diagnosis between subsets of CFS patients.

Guilleminault C, Palombini L, Poyares D, Chowdhuri S. · Stanford University Sleep Disorders Clinic, Stanford 94305, USA. · J Psychosom Res. · Pubmed #12127180 No free full text.

Abstract: OBJECTIVE: The question addressed here is: Can a discrete sleep disordered breathing (SDB) play a role in the insomnia complaint of postmenopausal chronic insomniacs? To respond to the query, two groups of individuals derived from a cohort of postmenopausal chronic insomniacs recruited mostly from the community were enlisted in a treatment protocol. These subjects were all individuals identified with normal breathing (n=68) and all those recognized with Upper Airway Resistance Syndrome (UARS) (n=62) pooled from a cohort of 349 postmenopausal insomniacs. TREATMENT PROTOCOL: The 62 UARS were allocated to either treatment of chronic insomnia by behavioral approaches or treatment of SDB. Based on ENT evaluation, health professionals in charge of patients selected either treatment with nasal CPAP or treatment of nasal turbinates. A stratification correction was performed to obtain a near equal number of both treatment modalities in each of the two subgroups. The 68 individuals with normal breathing were randomly allocated to immediate behavioral treatment of insomnia or delay treatment of insomnia. The delay treatment received a list of 10 sleep hygiene recommendations by mail. METHODOLOGY: Questionnaires, visual analog scales (VAS), Epworth Sleepiness Scale (ESS), clinical interviews, clinical evaluation with oto-laryngologic clinical assessment of a presence/absence of narrow upper airway and location of narrowing. Actigraphy and polysomnography (PSG) with pressure transducer/and nasal cannula system and esophageal manometry. DATA ANALYSES: All recording data were scored blind to patient's condition. RESULTS: Two subjects in the SBD-CPAP treated group (Group B) and two subjects in the delayed treatment group (Group D) dropped out. Total sleep time was improved compared to baseline in all groups, including the delayed treatment group. One group was significantly better (ANOVA, P=.05) with a more important delta score compared to baseline, and this was the behaviorally treated non-SDB. Sleep latency was significantly decreased in the behaviorally treated group (with or without SBD), P=.05, compared to SBD-treated and delayed treatment groups. Sleep latency was, however, improved in all groups. VAS for "quality of sleep" was higher at 6 months in all the groups when compared to "baseline" values. VAS for "daytime fatigue" showed significant differences among the four groups (ANOVA, P=.01); the overall score at the end of treatment was significantly better in the SDB-treated group than the other three groups. SBD was treated either by radio frequency on nasal turbinate or by nasal CPAP. CPAP-treated patients had a lower VAS score than nasal turbinate treatment, but the difference was only a trend. The delta improvement (6-month baseline condition) in "daytime fatigue" of each subgroup was calculated and compared within and between groups. Despite the small number of subjects, the turbinate-treated subgroup was significantly different from Groups B, C and D (ANOVA, P=.05). When a similar comparison was made with the nasal CPAP group, there was only a nonsignificant trend when compared to Groups B, C and D. CONCLUSION: Abnormal breathing during sleep significantly enhanced complaints of daytime fatigue in postmenopausal chronic insomniacs and this complaint improved with SDB treatment. This improvement is significantly better compared to SDB insomniacs treated with a behavioral regimen. Behavioral treatment, however, gave the best response in the non-SDB chronic insomnia group and improved better long sleep latency even in the SDB group. These results suggest the need to find an appropriate treatment for SBD even if mild and to recognize the role of SDB in relation to symptoms seen with chronic insomnia.

Bell IR, Szarek MJ, Dicenso DR, Baldwin CM, Schwartz GE, Bootzin RR. · Department of Psychology, The University of Arizona, Tucson 85721, USA. · Int J Neurosci. · Pubmed #10681117 No free full text.

Abstract: Previous studies indicate that low level chemical intolerance (CI) is a symptom of several different controversial conditions with neuropsychiatric features, e.g., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and "Persian Gulf Syndrome". Prior studies suggest that limbic and/or mesolimbic sensitization may contribute to development of CI. The purpose of this report was to document the waking electroencephalographic (EEG) patterns of individuals with CI during chemical exposures presented over repeated sessions. Three groups of adult subjects who were recruited from the community participated in the study: self-reported CI who had made associated lifestyle changes due to their intolerance (CI/ LSC), self-reported CI who had not made such changes (CI), and normal controls without self-reported CI. Subjects underwent two sessions involving one-minute EEG recordings during exposures to low level chemical odors (a probe for limbic activation). The CI, but not the CI/ LSC, subjects had increased absolute delta power after the chemical exposures during the second, but not the first, session. The findings support the neural sensitization hypothesis for intolerance to low levels of environmental chemicals in vulnerable individuals. As in human studies of stimulant drug sensitization, those with the strongest past history with sensitizing agents may not show-term sensitization to low level exposures in the laboratory.

Gordon R, Michalewski HJ, Nguyen T, Gupta S, Starr A. · Department of Neurology, University of California, Irvine, Med. Surge I, Room 154, Irvine, CA 92697-4290, USA. · Int J Mol Med. · Pubmed #10534571 No free full text.

Abstract: Premovement, sensory, and cognitive brain potentials were recorded from patients with Chronic Fatigue Syndrome (CFS) in four tasks: i) target detection, ii) short-term memory, iii) self-paced movement, and iv) expectancy and reaction time (CNV). Accuracy and reaction times (RTs) were recorded for tasks i, ii, and iv. Results from CFS patients were compared to a group of healthy normals. Reaction times were slower for CFS patients in target detection and significantly slower in the short-term memory task compared to normals. In target detection, the amplitude of a premovement readiness potential beginning several hundred milliseconds prior to stimulus onset was reduced in CFS, whereas the poststimulus sensory (N100) and cognitive brain potentials (P300) did not differ in amplitude or latency. In the memory task, a negative potential related to memory load was smaller in CFS than normals. The potentials to self-paced movements and to expectancy and RT (CNV) were not different between groups. The findings in CFS of slowed RTs and reduced premovement-related potentials suggest that central motor mechanisms accompanying motor response preparation were impaired in CFS for some tasks. In contrast, measures of neural processes related to both sensory encoding (N100) and to stimulus classification (P300) were normal in CFS.

Stahl SM. · Department of Psychiatry, University of California, San Diego, CA, USA. · Hum Psychopharmacol. · Pubmed #19479906 No free full text.

Abstract: Fibromyalgia is a syndrome of widespread chronic pain associated with sleep disorders, depressed mood, cognitive impairment and fatigue. Its etiology and pharmacopathology are poorly understood but it is thought to result from a dysfunction of central pain processing mechanisms leading to generalised pain sensitisation. Pain perception is the result of a bidirectional process of ascending and descending pathways. Nociceptive input from peripheral afferent neurons is sent via the dorsal horn of the spinal cord to the higher brain centres involved in pain perception. Some descending inhibitory projections to the spinal cord attenuate the nociceptive effects. Numerous neurotransmitters including serotonin, dopamine, noradrenaline and substance P are involved in these processes. In other neuronal pathways in the brain, the same neurotransmitters are involved in mood control, sleep regulation and cognitive function providing a neurochemical substrate for the wide range of symptoms seen in fibromyalgia. Attenuation of neuronal hyperactivity through ligands acting at the alpha2-delta subunits of voltage-dependent calcium channels and increased inhibitory activity of the descending pathways by inhibition of serotonin and noradrenaline reuptake are two mechanisms that are currently exploited by new medication for the treatment of fibromyalgia.

Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, Palmer RH. · Seattle Rheumatology Associates, 1101 Madison Street, Suite 1000, Seattle, WA 98104, USA. · J Rheumatol. · Pubmed #19132781 No free full text.

Abstract: OBJECTIVE: To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM). METHODS: A 27-week, randomized, double-blind, multicenter study compared milnacipran 100 and 200 mg/day with placebo in the treatment of 888 patients with FM. Two composite responder definitions were used to classify each patient's individual response to therapy. "FM responders" concurrently satisfied response criteria for improvements in pain (visual analog scale 24-h morning recall), patient global impression of change (PGIC), and physical functioning (SF-36 Physical Component Summary); while "FM pain responders" concurrently satisfied response criteria for improvements in pain and PGIC. RESULTS: At the primary endpoint, after 3-month stable dose treatment, a significantly higher percentage of milnacipran-treated patients met criteria as FM responders versus placebo (milnacipran 200 mg/day, p = 0.017; milnacipran 100 mg/day, p = 0.028). A significantly higher percentage of patients treated with milnacipran 200 mg/day also met criteria as FM pain responders versus placebo (p = 0.032). Significant pain reductions were observed after Week 1 with both milnacipran doses. At 15 weeks, milnacipran 200 mg/day led to significant improvements over placebo in pain (realtime, daily and weekly recall; all measures, p < 0.05), PGIC (p < 0.001), fatigue (p = 0.016), cognition (p = 0.025), and multiple SF-36 domains. Milnacipran was safe and well tolerated by the majority of patients during 27 weeks of treatment; nausea and headache were the most common adverse events. CONCLUSION: Milnacipran is safe and effective for the treatment of multiple symptoms of FM.

Parrish BP, Zautra AJ, Davis MC. · Department of Psychology, Arizona State University. · Health Psychol. · Pubmed #19025264 links to  free full text

Abstract: OBJECTIVE: The current study tested whether daily interpersonal events predicted fatigue from one day to the next among female chronic pain patients. DESIGN: Self-reported fatigue, daily events, pain, sleep quality, depressive symptoms, and functional health across 30 days were assessed in women with rheumatoid arthritis (RA: n = 89), Osteoarthritis (OA: n = 76), and Fibromyalgia syndrome (FM: n = 90). MAIN OUTCOME MEASURES: Self-report fatigue measured on a 0 to 100 scale and fatigue affect from PANAS-X (Watson & Clark, 1994). RESULTS: Multilevel analyses showed that both higher average levels of and daily increases in negative events predicted more fatigue, whereas daily increases in positive events predicted less fatigue. Across all pain conditions, increases in negative events continued to predict higher fatigue on the following day. Moreover, for participants with FM or RA, increases in positive events also predicted increased fatigue the following day. Daily increases in fatigue, in turn, predicted poorer functional health on both the same day and the next day. CONCLUSION: These results indicate that both on average and on a daily basis, interpersonal events influence levels of fatigue beyond common physical and psychological correlates of chronic pain and highlight differences between chronic pain groups.

Presson AP, Sobel EM, Papp JC, Suarez CJ, Whistler T, Rajeevan MS, Vernon SD, Horvath S. · Biostatistics, University of California, Los Angeles, CA, USA. · BMC Syst Biol. · Pubmed #18986552 links to  free full text

Abstract: BACKGROUND: Systems biologic approaches such as Weighted Gene Co-expression Network Analysis (WGCNA) can effectively integrate gene expression and trait data to identify pathways and candidate biomarkers. Here we show that the additional inclusion of genetic marker data allows one to characterize network relationships as causal or reactive in a chronic fatigue syndrome (CFS) data set. RESULTS: We combine WGCNA with genetic marker data to identify a disease-related pathway and its causal drivers, an analysis which we refer to as "Integrated WGCNA" or IWGCNA. Specifically, we present the following IWGCNA approach: 1) construct a co-expression network, 2) identify trait-related modules within the network, 3) use a trait-related genetic marker to prioritize genes within the module, 4) apply an integrated gene screening strategy to identify candidate genes and 5) carry out causality testing to verify and/or prioritize results. By applying this strategy to a CFS data set consisting of microarray, SNP and clinical trait data, we identify a module of 299 highly correlated genes that is associated with CFS severity. Our integrated gene screening strategy results in 20 candidate genes. We show that our approach yields biologically interesting genes that function in the same pathway and are causal drivers for their parent module. We use a separate data set to replicate findings and use Ingenuity Pathways Analysis software to functionally annotate the candidate gene pathways. CONCLUSION: We show how WGCNA can be combined with genetic marker data to identify disease-related pathways and the causal drivers within them. The systems genetics approach described here can easily be used to generate testable genetic hypotheses in other complex disease studies.

Boorom KF, Smith H, Nimri L, Viscogliosi E, Spanakos G, Parkar U, Li LH, Zhou XN, Ok UZ, Leelayoova S, Jones MS. · Blastocystis Research Foundation, 5060 SW Philomath Blvd, #202, Corvallis, OR 97333, USA. · Parasit Vectors. · Pubmed #18937874 links to  free full text

Abstract: ABSTRACT: Blastocystis is a prevalent enteric protozoan that infects a variety of vertebrates. Infection with Blastocystis in humans has been associated with abdominal pain, diarrhea, constipation, fatigue, skin rash, and other symptoms. Researchers using different methods and examining different patient groups have reported asymptomatic infection, acute symptomatic infection, and chronic symptomatic infection. The variation in accounts has lead to disagreements concerning the role of Blastocystis in human disease, and the importance of treating it. A better understanding of the number of species of Blastocystis that can infect humans, along with realization of the limitations of the existing clinical laboratory diagnostic techniques may account for much of the disagreement. The possibility that disagreement was caused by the emergence of particular pathogenic variants of Blastocystis is discussed, along with the potential role of Blastocystis infection in irritable bowel syndrome (IBS). Findings are discussed concerning the role of protease-activated receptor-2 in enteric disease which may account for the presence of abdominal pain and diffuse symptoms in Blastocystis infection, even in the absence of fever and endoscopic findings. The availability of better diagnostic techniques and treatments for Blastocystis infection may be of value in understanding chronic gastrointestinal illness of unknown etiology.

Pall ML. · School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4234, USA. · Med Hypotheses. · Pubmed #18667279 No free full text.

Abstract: Post-radiation syndrome is proposed to be chronic fatigue syndrome (CFS) or a chronic fatigue syndrome-like illness, initiated by exposure to ionizing radiation. This view is supported by the nitric oxide/peroxynitrite (NO/ONOO-) cycle mechanism, the putative etiologic mechanism for CFS and related illnesses. Ionizing radiation may initiate illness by increasing nitric oxide levels via increased activity of the transcription factor NF-kappaB and consequent increased synthesis of the inducible nitric oxide synthase. Two types of components of the nitric oxide/peroxynitrite cycle have been studied in post-radiation syndrome patients and shown to be elevated. The symptoms and signs of post-radiation syndrome and its chronicity are similar or identical to those of chronic fatigue syndrome and can be explained as being a consequence of nitric oxide/peroxynitrite cycle etiology. While the data available to test this view are limited, it provides for the first time a comprehensive explanation for post-radiation syndrome.

Turk Charles S, Gatz M, Kato K, Pedersen NL. · Department of Psychology, University of California, Irvine, CA 92697-7085, USA. · Health Psychol. · Pubmed #18624602 No free full text.

Abstract: OBJECTIVE: Neuroticism, a personality trait related to distress and emotional stability, is often correlated with physical symptoms and disease presence. Theorists have posited that chronic emotional instability creates physiological changes detrimental to health, yet most findings are based on cross-sectional analyses. The objective of the current study was to examine neuroticism assessed in 1973 and the likelihood of reporting physical conditions 25 years later. DESIGN: Participants included 21676 adult twins (n = 8143 intact twin pairs) ranging from 15 to 47 years old in 1973 who were assessed again between 1998 and 2002. MAIN OUTCOME MEASURES: Thirteen physical conditions, including chronic fatigue syndrome, ulcers, and coronary heart disease, were selected based on their prior theoretical and empirical links to personality traits. RESULTS: Results indicate that the likelihood of having a physical condition is related to higher levels of prior neuroticism, with some associations attenuated when controlling for familial similarity. CONCLUSION: Familial influences are most pronounced for conditions most related to systemic pain, suggesting genetic pathways between neuroticism and these pain experiences.

Hokama Y, Empey-Campora C, Hara C, Higa N, Siu N, Lau R, Kuribayashi T, Yabusaki K. · Department of Pathology, University of Hawaii-Manoa, Honolulu, HI 96822, USA. · J Clin Lab Anal. · Pubmed #18348309 No free full text.

Abstract: This study examined 328 CFS sera in a study with 17 CCFP, 8 Gulf War Veterans (GWV), 24 Prostate Cancer (PC), and 52 normal sera in the modified Membrane Immunobead Assay (MIA) procedure for CTX. Three hundred and twenty-eight CFS patients' sera were examined by the modified MIA with purified MAb-CTX and 91.2% gave a titre > or =1:40. 76% of the 17 CCFP sera samples and 100% of the 8 GWV sera samples also had a titre > or =1:40. 92.3% of 52 normal sera showed titres of 1:20 or less, while 4 gave titres of > or =1:40. In addition, 41 sera were examined for Anti-Cardiolipin (aCL) by a commercial ELISA procedure with 87.8% demonstrating IgM, IgM+IgA, or IgM+IgG aCL antibodies. These results showed mostly the IgM aCL antibody alone in the sera samples. In addition, 41 serum samples were examined for aCL, with 37 showing positive for aCL, representing 90.2% positive for the three disease categories examined: CFS, CCFP and GWV. Examination for antiMitochondrial-M2 autoantibody (aM-M2) in 28 patients (CFS (18), CCFP (5), and GWV (5)) was negative for aM-M2. Inhibition analysis with antigens, CTX, CFS "Acute Phase Lipids", commercial Cardiolipin (CL) and 1,2-Dipalmitoyl-sn-Glycero-3-[Phospho-L-Serine] (PS) and antibodies, MAb-CTX and aCL from patients' serum show that the phospholipids in CL and CTX are antigenically indistinguishable with antibodies MAb-CTX and CFS-aCL. Preliminary chemical analyses have shown the lipids to be phospholipids associated with CL of the mitochondria. We designate this "Acute Phase Lipid" comparable to "Acute Phase Proteins" (C-reactive protein (CRP) and Serum Amyloid A (SAA)) in inflammatory conditions.