and others, showing disproportionate complaints compared with observed behavior in fibromyalgia patients, unlike arthritis patients. Since pain-complaining behavior is likely related to effort (or lack thereof), “work capacity” may not be a valid way to compare fibromyalgia patients with other groups of patients with actual pathology. Finally, Dr. Romano’s unctuous advice about use of “terribly expensive” tests rings hollow, given his advocacy of SPECT in medical-legal fibromyalgia patients.32 Perhaps he justifies it based on his own uncontrolled research on “posttraumatic fibromyalgia syndrome” patients.35 I am afraid Dr. Long’s emotional personal testimonial doesn’t bear much comment. I t is largely based on faith and wishful thinking rather than science. Like Dr. Romano, he chose to ignore my comment in the editorial that Hubbard’s hypothesis of electromyographic trigger points has not been verified by reliable, acknowledged electromyographers. In fact, evidence contrary to Hubbard’s findings has been published? I thank Dr. Holmlund for his comments and endorse his suggestion.

[Clin Psychol Sci Prac 18: 311–324, 2011] Several reviews have concluded that graded exercise therapy (GET) and cognitive behavioral therapy (CBT) may be the most efficacious treatments for chronic fatigue syndrome (CFS). The current review extends the evidence for overall and outcome-specific effects of CBT and GET by directly comparing the treatments and addressing the methodological limitations of previous reviews. GET (n = 5) and CBT (n = 16) randomized controlled trials were meta-analyzed. Overall effect sizes suggested that GET (g = 0.28) and CBT (g = 0.33) were equally efficacious. However, CBT effect sizes were lower in primary care settings and for treatments offering fewer hours of contact. The results suggested that both CBT and GET are promising treatments for CFS, although CBT may be a more effective treatment when patients have comorbid anxiety and depressive symptoms.

We studied whether muscle fatigue, metabolism, or activation are abnormal in the chronic fatigue syndrome (CFS). Subjects performed both an intermittent submaximal and a sustained maximal voluntary isometric exercise protocol of the tibialis anterior muscle. The extent of fatigue, metabolic response, and changes in both M-wave amplitude and twitch tension during exercise were similar in patients and controls. The response to systemic exercise was also normal in the patients. However, voluntary activation of the tibialis was significantly lower in the patients during maximal sustained exercise. The results indicate that patients with CFS have (1) normal fatigability and metabolism at both the intracellular and systemic levels, (2) normal muscle membrane function and excitation-contraction coupling, and (3) an inability to fully activate skeletal muscle during intense, sustained exercise. This failure of activation was well in excess of that found in controls, suggesting an important central component of muscle fatigue in CFS.

We have developed a conceptual framework and a set of research guidelines for use in studies of the chronic fatigue syndrome. The guidelines cover the clinical and laboratory evaluation of persons with unexplained fatigue; the identification of underlying conditions that may explain the presence of chronic fatigue; revised criteria for defining cases of the chronic fatigue syndrome; and a strategy for dividing the chronic fatigue syndrome and other unexplained cases of chronic fatigue into subgroups. Background The chronic fatigue syndrome is a clinically defined condition [1-4] characterized by severe disabling fatigue and a combination of symptoms that prominently features self-reported impairments in concentration and short-term memory, sleep disturbances, and musculoskeletal pain. Diagnosis of the chronic fatigue syndrome can be made only after alternative medical and psychiatric causes of chronic fatiguing illness have been excluded. No pathognomonic signs or diagnostic tests for this condition have been validated in scientific studies [5-7]; moreover, no definitive treatments for it exist [8]. Recent longitudinal studies suggest that some persons affected by the chronic fatigue syndrome improve with time but that most remain functionally impaired for several years [9, 10]. Issues in Chronic Fatigue Syndrome Research The central issue in chronic fatigue syndrome research is whether the chronic fatigue syndrome or any subset of it is a pathologically discrete entity, as opposed to a debilitating but nonspecific condition shared by many different entities. Resolution of this issue depends on whether clinical, epidemiologic, and pathophysiologic features convincingly distinguish the chronic fatigue syndrome from other illnesses. Clarification of the relation between the chronic fatigue syndrome and the neuropsychiatric syndromes is particularly important. The latter disorders are potentially the most important source of confounding in studies of chronic fatigue syndrome. Somatoform disorders, anxiety disorders, major depression, and other symptomatically defined syndromes can manifest severe fatigue and several somatic and psychological symptoms and are diagnosed more frequently in populations affected by chronic fatigue [11-13] and the chronic fatigue syndrome [14, 15] than in the general population. The extent to which the features of the chronic fatigue syndrome are generic features of chronic fatigue and deconditioning due to physical inactivity common to a diverse group of illnesses [16, 17] must also be established. A Conceptual Framework for Studying the Chronic Fatigue Syndrome In the United States, 24% of the general adult population has had fatigue lasting 2 weeks or longer; 59% to 64% of these persons report that their fatigue has no medical cause [18, 19]. In one study, 24% of patients in primary care clinics reported having had prolonged fatigue ( 1 month) [20]. In many persons with prolonged fatigue, fatigue persists beyond 6 months (defined as chronic fatigue) [21, 22]. We propose a conceptual framework Figure 1 to guide the development of studies relevant to the chronic fatigue syndrome. In this framework, in which the chronic fatigue syndrome is considered a subset of prolonged fatigue ( 1 month), epidemiologic studies of populations defined by prolonged or chronic fatigue can be used to search for illness patterns consistent with the chronic fatigue syndrome. Such studies, which differ from casecontrol and cohort studies based on predetermined criteria for the chronic fatigue syndrome, will also produce much-needed clinical and laboratory background information. Figure 1. A conceptual framework of abnormally fatigued populations, including those with the chronic fatigue syndrome (CFS) and overlapping disorders. This framework also clarifies the need to compare populations defined by the chronic fatigue syndrome with several other populations in casecontrol and cohort studies. The most important comparison populations are those defined by overlapping disorders, by prolonged fatigue, and by forms of chronic fatigue that do not meet criteria for the chronic fatigue syndrome. Controls drawn exclusively from healthy populations are inadequate to confirm the specificity of chronic fatigue syndrome-associated abnormalities. Need for Revised Criteria To Define the Chronic Fatigue Syndrome The possibility that chronic fatigue syndrome study populations have been selected or defined in substantially different ways has made it difficult to interpret conflicting laboratory findings related to the chronic fatigue syndrome [23]. For example, the North American chronic fatigue syndrome working case definition [1] has been inconsistently applied by researchers [24]. This case definition is frequently modified in practice because some of the criteria are difficult to interpret or to comply with [25] and because opinions differ about the classification of chronic fatigue cases preceded by a history of psychiatric illnesses [26, 27]. Current criteria for the chronic fatigue syndrome also do not appear to define a distinct group of cases (28; Reyes M, et al. Unpublished data). For example, participants in the Centers for Disease Control and Prevention (CDC) chronic fatigue syndrome surveillance system [29] who met the chronic fatigue syndrome case definition did not substantially differ by demographic characteristics, symptoms, and other illness features from those who did not meet the definition (except by criteria used to place patients into one of our predetermined surveillance classification categories [Reyes M, et al. Unpublished data]). These findings indicate that additional subgrouping or stratification of study cases into more homogeneous groups is necessary for comparative studies. Need for Clinical Evaluation Standards Our experience suggests that fatigued persons often receive either inadequate or excessive medical evaluations. In the CDC chronic fatigue syndrome surveillance system, all participants were clinically evaluated by a primary physician before enrollment. Subsequently, 18% were found to have a preexisting medical condition that plausibly accounted for their chronic fatiguing illness (Reyes M, et al. Unpublished data). These medical conditions were identified either from a single battery of routine laboratory tests done on blood specimens obtained at enrollment or from review of available medical records. We believe that inappropriate tests are often used to diagnose the chronic fatigue syndrome in chronically fatigued persons. This practice should be discouraged. Need for a Comprehensive and Integrated Approach The complexities of the chronic fatigue syndrome and the existence of several obstacles to our understanding of it make a comprehensive and integrated approach to the study of the chronic fatigue syndrome and similar illnesses desirable. The purpose of the following proposed guidelines Figure 2 is to facilitate such an approach. Figure 2. Evaluation and classification of unexplained chronic fatigue. Guidelines for the Clinical Evaluation and Study of the Chronic Fatigue Syndrome and Other Illnesses Associated with Unexplained Chronic Fatigue Definition and Clinical Evaluation of Prolonged Fatigue and Chronic Fatigue Prolonged fatigue is defined as self-reported, persistent fatigue lasting 1 month or longer. Chronic fatigue is defined as self-reported persistent or relapsing fatigue lasting 6 or more consecutive months. The presence of prolonged or chronic fatigue requires clinical evaluation to identify underlying or contributing conditions that require treatment. Further diagnosis or classification of chronic fatigue cases cannot be made without such an evaluation. The following items should be included in the clinical evaluation. 1. A thorough history that covers medical and psychosocial circumstances at the onset of fatigue; depression or other psychiatric disorders; episodes of medically unexplained symptoms; alcohol or other substance abuse; and current use of prescription and over-the-counter medications and food supplements. 2. A mental status examination to identify abnormalities in mood, intellectual function, memory, and personality. Particular attention should be directed toward current symptoms of depression or anxiety, self-destructive thoughts, and observable signs such as psychomotor retardation. Evidence of a psychiatric or neurologic disorder requires that an appropriate psychiatric, psychological, or neurologic evaluation be done. 3. A thorough physical examination. 4. A minimum battery of laboratory screening tests including complete blood count with leukocyte differential; erythrocyte sedimentation rate; serum levels of alanine aminotransferase, total protein, albumin, globulin, alkaline phosphatase, calcium, phosphorus, glucose, blood urea nitrogen, electrolytes, and creatinine; determination of thyroid-stimulating hormone; and urinalysis. Routinely doing other screening tests for all patients has no known value [20, 30]. However, further tests may be indicated on an individual basis to confirm or exclude another diagnosis, such as multiple sclerosis. In these cases, additional tests or procedures should be done according to accepted clinical standards. The use of tests to diagnose the chronic fatigue syndrome (rather than to exclude other diagnostic possibilities) should be done only in the setting of protocol-based research. The fact that such tests are investigational and do not aid in diagnosis or management should be explained to the patient. In clinical practice, no additional tests, including laboratory tests and neuroimaging studies, can be recommended for the specific purpose of diagnosing the chronic fatigue syndrome. Tests should be directed toward confirming or excluding other etiologic possibilities. Examples of specific tests that do not confirm or exclude the diagnosis of the chronic fatigue syndrome include serologic tests for Epstein-Barr vi

Veterans of Operation Desert Storm returned from the Persian Gulf Theater of Operations and developed multiple signs and symptoms characterized by disabling fatigue, arthralgia, intermittent fever, myalgia, impairments in short-term memory, headaches, skin rashes, diarrhea and additional symptoms that have defied a disease case definition but has been called Gulf War Illness (GWI). In a sampling of GWI patients and symptomatic family members (n=30) we have used the technique of Gene Tracking and have found evidence of mycoplasmal infections in the blood leukocytes of approximately one-half of these cases. Mycoplasma-positive patients can be successfully treated with several 6 week courses of doxycycline (200 mg/d) or other antibiotics. Of the 14/30 patients that were mycoplasma-positive, 11/14 completely recovered after multiple cycles of antibiotics and 3/14 are still undergoing antibiotic therapy and relapsing.

Using the blood of 100 CFS patients and forensic polymerase chain reaction we have found that a majority of Chronic Fatigue Syndrome (CFS) patients show evidence of multiple, systemic bacterial and viral infections (OR = 18.0, 95% CL 8.5-37.9, P < 0.001) that could play an important role in CFS morbidity. CFS patients had a high prevalence (51%) of one of four Mycoplasma species (OR = 13.8, 95% CL 5.8-32.9, P < 0.001) and often showed evidence of co-infections with different Mycoplasma species, Chlamydia pneumoniae (OR = 8.6, 95% CL 1.0-71.1, P < 0.01) and/or active Human Herpes Virus-6 (HHV-6) (OR = 4.5, 95% CL 2.0-10.2, P < 0.001). We found that 8% of the CFS patients showed evidence of C. pneumoniae and 31% of active HHV-6 infections. Since the presence of one or more chronic systemic infections may predispose patients to other infections, we examined the prevalence of C. pneumoniae and active HHV-6 infections in mycoplasma-positive and -negative patients. The incidence of C. pneumoniae or HHV-6 was similar in mycoplasma-positive and -negative patients, suggesting that such infections occur independently in CFS patients. Also, the incidence of C. pneumoniae in active HHV-6-positive and -negative patients was similar. Control subjects (N=100) had low rates of mycoplasmal (6%), active HHV-6 (9%) or chlamydial (1%) infections, and there were no co-infections in control subjects. Differences in bacterial and/or viral infections in CFS patients compared to control subjects were significant. The results indicate that a relatively large subset of CFS patients show evidence of bacterial and viral co- infections.

To the Editor.— We read with interest the article by Gold et al. 1 We have recently reported the psychosocial attributes 2 and the clinical and immunologic characteristics 3 of a sample of 30 subjects. We noted frequent personality and cognitive abnormalities in the cohort, such as moderate to severe depression (as measured by the Hamilton Depression Rating Scale) seen in 79% of the subjects and frequent pathological personality disorders as defined by the Millon Clinical Multiaxial Inventory II. These subjects showed clear evidence of immunologic deficiency, the most notable being low natural killer-cell cytotoxicity (73%), low phytohemagglutinin and pokeweed mitogen response (63%), normal CD4 numbers but abnormal distribution of CD4 subsets, elevated CD8 and I 2 + CD8 + cells and low production of interferon-γ by mitogen-stimulated lymphocytes. Perhaps the explanation for the difference in our report and that by Gold et al lies in patient selection. All of the subjects

To observe the effects of Xiaopiyishen Herbal Extract Granule (XPYS-HEG) on the quality of life in people with fatigue-predominant subhealth (FPSH) and liver-qi stagnation and spleen-qi deficiency syndrome, the participants were allocated randomly to the treatment group (XPYS, n = 100) and the control group (placebo, n = 100) in this study. The study period was 18 weeks (6 weeks for the intervention and 12 weeks for followup). The results show that there were no differences between the two groups for the scores of eight factors on the SF-36 (Chinese version of the SF-36 universal quality-of-life scale) at baseline. Compared with the baseline score, intervention with XPYS-HEG led to a significant increase in scores for the factor of bodily pain at the end of the 6th week. Compared with the score at the end of the 6th week, the score for the factor of mental health in the XPYS group significantly increased at the end of the 18th week. Therefore, XPYS-HEG could partially improve the quality of life for people with FPSH and liver-qi stagnation and spleen-qi deficiency syndrome, which can ease bodily pain, stimulate a positive mood, and ease a negative mood.

To examine the role of delay in recovery of peripheral muscle function following exercise in the fatigue experienced by patients with the chronic fatigue syndrome (CFS) and to examine the influence of effort perception in limiting exercise performance in these patients, a study was carried out on a group of twelve patients with chronic fatigue syndrome and 12 sex and age-matched sedentary control subjects. Symptom limited incremental cycle exercise tests including measurements of perceived exertion were performed followed by examination of the contractile properties of the quadriceps muscle group for up to 48 hours. Muscle function was assessed by percutaneous electrical stimulation and maximum voluntary contractions. Muscle function at rest and during recovery was normal in CFS patients as assessed by maximum isometric voluntary contraction, 20:50 Hz tetanic force ratio and maximum relaxation rate. Exercise duration and the relationship between heart rate and work rate during exercise were similar in both groups. CFS patients had higher perceived exertion scores in relation to heart rate during exercise representing a reduced effort sensation threshold of 3.2 units on an unmodified Borg scale in CFS patients. Patients with chronic fatigue syndrome show normal muscle physiology before and after exercise. Raised perceived exertion scores during exercise suggest that central factors are limiting exercise capacity in these patients.

To evaluate the effect of cognitive behavioral intervention on chronic fatigue syndrome (CFS), we studied three patient groups: a CFS-treatment group (n = 22), a primary depression-treatment group (n = 20), and a no-treatment control group of subjects with CFS (n = 22). For the CFS-treatment group, a trend toward reduced depression-symptom scores was noted, but there were no significant changes in stress-related symptoms or fatigue severity. For the most depressed treated subjects with CFS, significant score reductions were observed in measures of depression, stress, fatigue severity, and fatigue-related thinking. In the depression group, significant reductions in depression, stress, and fatigue severity scores were found. No significant changes in any measure were observed in the CFS control group. A new fatigue-related cognitions scale, developed to assess cognitive and emotional reactions to fatigue, showed a significant reduction in such reactions in the CFS-treatment group, a finding suggesting that depression in this group was mediated by maladaptive thinking. The results suggest that a subset of CFS patients with cognition-related depressive symptomatology may respond to short-term behavioral intervention.

To evaluate our clinical impression that patients with the chronic fatigue syndrome (CFS) did not walk normally, we assessed gait kinematics at slow walking speeds (i.e., 0.45, 0.89 and 1.34 m/sec) and 30 m run time speeds on CFS patients and on a comparison group of sedentary controls. Run time was significantly slower for CFS than control subjects (p < 0.001). There was a significant interaction (p < 0.01) between group and speed for maximum hip angle during stance and swing phase with hip angle being significantly larger at 1.34 m/sec for CFS than controls subjects for both cases (p < 0.05). Knee flexion during stance and swing phases was significantly larger for controls than CFS subjects at 0.45 m/sec (p < 0.01). Ratio of stride length divided by leg length was significantly larger for the control subjects than for the CFS subjects with differences occurring at 0.45 and 0.89 m/sec (p < 0.01) but not 1.34 m/sec. The data indicate that CFS patients have gait abnormalities when compared to sedentary controls. These could be due to balance problems, muscle weakness, or central nervous system dysfunction; deciding which will require further research. Evaluation of gait may be a useful tool to measure outcome following therapeutic interventions.

To estimate the economic impact of chronic fatigue syndrome (CFS) on the individual, the government, and the community.

To attempt to replicate the syndrome-like structure identified by exploratory factor analysis of symptom reports from 249 Gulf War veterans of a Naval reserve battalion (the developmental sample), we administered Haley's original symptom questionnaire to 335 Gulf War veterans who served primarily in active-duty US Army units living in North Texas (the validation sample). On the basis of recently validated goodness-of-fit criteria (SRMR<or=0.08, RMSEA<or=0.06, and CFI>or=0.95), a structural equation model (Model 1) with four symptom scales loading on each of three first-order latent syndrome factors fit both the developmental and validation samples well and was invariant across both samples. Additional models validated a higher-order latent factor (a single Gulf War syndrome) explaining the variances and covariances of the first-order factors, four additional symptom scales loading on the higher-order factor, and four possible secondary factor loadings that also fit the data well. All structural models were invariant across cohorts of the validation sample surveyed before and after intense publicity following publication of the case definition. These findings suggest that the apparent syndrome structure of a single Gulf War syndrome with three variants may be found widely and justify a confirmatory sample survey of Gulf War-era veterans.

This study examined the effects of Hurricane Andrew on physical symptoms and functional impairments in a sample of chronic fatigue syndrome (CFS) patients residing in South Florida.In the months after Hurricane Andrew (September 15-December 31, 1992), 49 CFS patients were assessed for phychosocial and physical functioning with questionnaires, interviews, and physical examinations. This sample was made up of 25 CFS patients living in Dade county, a high impact area, and 24 patients in Broward and Palm Beach counties, areas less affected by the hurricane. Based on our model for stress-related effects on CFS, we tested the hypothesis that the patients who had the greatest exposure to this natural disaster would show the greatest exacerbation in CFS symptoms and related impairments in activities of daily living (illness burden). In support of this hypothesis, we found that the Dade county patients showed significant increases in physician-rated clinical relapses and exacerbations in frequency of several categories of self-reported CFS physical symptoms as compared to the Broward/Palm Beach county patients. Illness burden, as measured on the Sickness Impact Profile, also showed a significant increase in the Dade county patients. Although extent of disruption due to the storm was a significant factor in predicting relapse, the patient's posthurricane distress response was the single strongest predictor of the likelihood and severity of relapse and functional impairment. Additionally, optimism and social support were significantly associated with lower illness burden after the hurricane, above and beyond storm-related disruption and distress responses. These findings provide information on the impact of environmental stressors and psychosocial factors in the exacerbation of CFS symptoms.

This review summarizes the symptoms and signs seen in patients with chronic fatigue syndrome (CFS). It is based on the authors' experience with two cohorts of approximately 510 patients with chronic debilitating fatigue and on the reported experience of other investigators with similar patients. The most characteristic symptoms of CFS are the sudden onset of an infectious-type illness, the subsequent chronic and debilitating fatigue, and postexertional malaise; many patients also have recurrent fevers, pharyngitis, adenopathy, myalgias, sleep disorders, and cognitive impairment.

This review explores the epidemiological evidence for the relationship between depression and cardiovascular disease from a mechanistic standpoint. It is important to examine the biological, behavioral and social mechanisms to improve outcomes for depressed cardiac patients. A number of plausible biobehavioral mechanisms linking depression and cardiovascular disease have been identified. Tricyclic antidepressants have various effects on the cardiovascular system, while selective serotonin reuptake inhibitors are not associated with adverse cardiac effects and should, therefore, be the preferred choice for the treatment of most patients with comorbid depression and cardiovascular disease.

This paper provides an overview of the evidence addressing the impairments of the 2'-5' oligoadenylate (2-5 A) synthetase/RNase L pathway in Chronic Fatigue Syndrome (CFS) patients. The 2-5A synthetase/RNase L pathway in CFS patients appears to be both up-regulated (i.e. increased levels of bioactive 2-5A synthetase and increased activity of the RNase L enzyme) and deregulated (elastase and calpain initiate 83 kDa RNase L proteolysis, generating two major fragments with molecular masses of 37 and 30 kDa, respectively). The deregulation of the 2-5A synthetase/RNase L pathway in CFS accompanies decreased NK-function and deregulation of apoptotic pathways. Since various components of the pathway appear to be related to performance during a graded exercise stress test, some evidence supportive of the clinical importance of the impaired pathway in CFS patients has been provided. Studies addressing the treatment of the deregulation of the 2-5A synthetase/RNase L pathway in CFS are warranted.

This article uses data from patients recruited using the 1994 case definition of chronic fatigue syndrome (CFS) to contrast those meeting criteria for the Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) Canadian case definition with those that did not meet these criteria. The study also contrasts those meeting criteria for Myalgic Encephalomyelitis (ME) based on criteria from Ramsay and other theorists with those that did not meet the ME criteria. The ME/CFS case definition criteria identified a subset of patients with more functional impairments and physical, mental, and cognitive problems than the subset not meeting these criteria. The ME subset had more functional impairments, and more severe physical and cognitive symptoms than the subset not meeting ME criteria. When applied to a population meeting the 1994 CFS case definition, both ME/CFS and ME criteria appear to select a more severe subset of patients.

There is no doubt that the symptoms of fatigue are costly for both society and for the individual. Fatigue is found in a spectrum of diseases and illnesses caused by pathology in biological systems, but also by environmental factors which directly or indirectly influence biological systems in the human body. Although it has been known for a long time that more women than men suffer from this group of illnesses, little research has focused on the influence of gender, e.g., the circumstances which women and men live under, on the outcome of fatigue-related health problems. The complex interaction between different regulatory systems connecting body, soul, and mind is clearer today as molecular techniques are being developed. Data on a genetic linkage to chronic fatigue have also been established.

There have been many epidemiological and clinical researches on chronic fatigue (CF) and chronic fatigue syndrome (CFS) since the 1990s, but such studies have been quite limited in Korea. The aim of this study was to investigate the point prevalence of CF and CFS in patients who visited community-based eight primary care clinics in Korea. The study subjects were 1,648 patients aged 18 yr and over who visited one of eight primary care clinics in Korea between the 7th and 17th of May 2001. The physicians determined the status of the subjects through fatigue-related questionnaires, medical history, physical examination, and laboratory tests. The subjects were categorized into no fatigue, prolonged fatigue, CF and then CF were further classified to medically explained CF (Physical CF and Psychological CF) and medically unexplained CF (CFS and idiopathic chronic fatigue). The point prevalence of CF and CFS were 8.4% (95% CI 7.1-9.7%) and 0.6% (95% CI 0.2-1.0%). Medically explained CF was 80.5% of CF, of which 57.1% had psychological causes. The clinical characteristics of CFS were distinguished from explained CF. CF was common but CFS was rare in community-based primary care settings in Korea.