Pathogenesis Of Chronic Fatigue Syndrome Research Articles

Serological and virological investigation of the role of the herpesviruses EBV, CMV and HHV‐6 in post‐infective fatigue syndrome

Multiple previous studies have sought evidence for ongoing, active infection with, or reactivation of, Herpesviruses in patients with chronic fatigue syndrome (CFS), with conflicting results. This study aimed to clarify this by studying 20 patients enrolled in a well-characterized model of the onset and evolution of CFS, the prospective cohort of the Dubbo Infection Outcomes Study (DIOS). The patients selected for examination included five CFS patients with primary Epstein-Barr virus (EBV) infection; five CFS patients with acute viral infection not caused by EBV; and 10 matched controls with prompt resolution of primary EBV infection. Serum samples from three timepoints were assayed using a comprehensive range of serological assays for EBV, HHV-6, and CMV. Viral genomes were assessed using quantitative PCR assays. All patients were seropositive for HHV-6, and 10 were seropositive for CMV at infection baseline (five patients and five controls). Low titer CMV IgM antibodies were found at infection baseline in two of these cases and three control patients. HHV-6 IgG antibody titers were highest at infection baseline but did not differ between the CFS cases and the control patients. There were increases in EBV IgG VCA p18, EBNA-1 IgG, and EA IgG titers over time, but these did not differ between CFS cases and control patients. EBV and HHV6 DNA levels were at control levels in a minority of samples, and CMV was undetectable in all samples. These data do not support the hypothesis of ongoing or reactivated EBV, HHV-6, or CMV infection in the pathogenesis of CFS.

Fluctuation of serum vitamin E (α-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome

The etiology of chronic fatigue syndrome remains unknown. Oxidative stress may be involved in its pathogenesis. Vitamin E is a major endogenous lipid-soluble antioxidative substance, and is consumed during the lipid peroxidation process. We studied a population comprising 27 patients with chronic fatigue syndrome (10 men and 17 women, 29 +/- 6 years of age) and 27 age- and sex-matched control subjects. Serum vitamin E (alpha-tocopherol) concentrations were determined and expressed as mg/g total lipids (total cholesterol and triglyceride) to evaluate oxidative stress. Serum alpha-tocopherol concentrations (mg/g lipids) were significantly (P < 0.001) lower in the patients with chronic fatigue syndrome (2.81 +/- 0.73) than in the control subjects (3.88 +/- 0.65). The patients with chronic fatigue syndrome were re-examined during a follow-up interval. After 8 +/- 2 months, 16 patients exhibited a status that warranted re-examination during remission of the symptoms at a regular visit to our hospital (Group 1), while the remaining 11 did not (Group 2). The serum alpha-tocopherol levels were significantly elevated during remission as compared with those at baseline in Group 1 (2.71 +/- 0.62 --> 3.24 +/- 0.83, P < 0.001). The levels did not significantly change after the interval in Group 2 (2.97 +/- 0.86 --> 2.85 +/- 0.73, not significant). In conclusion, serum alpha-tocopherol concentrations were significantly lower in the patients with chronic fatigue syndrome as compared with the control subjects, suggesting increased oxidative stress in the former. The low level of serum alpha-tocopherol was ameliorated during the remission phase as compared with the exacerbation phase in the patients with chronic fatigue syndrome, suggesting that increased oxidative stress may be involved in the pathogenesis of chronic fatigue syndrome and might also be directly related to the severity of the symptoms of chronic fatigue syndrome.

Comment on “Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome”

Lombardi et al. (Reports, 23 October 2009, p. 585) reported detection of the human gammaretrovirus XMRV in the blood cells of patients with chronic fatigue syndrome (CFS). However, the patient description provided was incomplete. The inclusion of patients from a "CFS outbreak" previously linked with a viral infection, without confirmation in sporadic CFS cases, casts doubt on the role of XMRV in the pathogenesis of CFS.

Gut inflammation in chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a debilitating disease characterized by unexplained disabling fatigue and a combination of accompanying symptoms the pathology of which is incompletely understood. Many CFS patients complain of gut dysfunction. In fact, patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome (IBS), a common functional disorder of the gut, and experience IBS-related symptoms. Recently, evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorder's pathogenesis.Studies examining the microecology of the gastrointestinal (GI) tract have identified specific microorganisms whose presence appears related to disease; in CFS, a role for altered intestinal microbiota in the pathogenesis of the disease has recently been suggested. Mucosal barrier dysfunction promoting bacterial translocation has also been observed. Finally, an altered mucosal immune system has been associated with the disease. In this article, we discuss the interplay between these factors in CFS and how they could play a significant role in GI dysfunction by modulating the activity of the enteric nervous system, the intrinsic innervation of the gut.If an altered intestinal microbiota, mucosal barrier dysfunction, and aberrant intestinal immunity contribute to the pathogenesis of CFS, therapeutic efforts to modify gut microbiota could be a means to modulate the development and/or progression of this disorder. For example, the administration of probiotics could alter the gut microbiota, improve mucosal barrier function, decrease pro-inflammatory cytokines, and have the potential to positively influence mood in patients where both emotional symptoms and inflammatory immune signals are elevated. Probiotics also have the potential to improve gut motility, which is dysfunctional in many CFS patients.

Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a debilitating disease of unknown etiology that is estimated to affect 17 million people worldwide. Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), in 68 of 101 patients (67%) as compared to 8 of 218 (3.7%) healthy controls. Cell culture experiments revealed that patient-derived XMRV is infectious and that both cell-associated and cell-free transmission of the virus are possible. Secondary viral infections were established in uninfected primary lymphocytes and indicator cell lines after their exposure to activated PBMCs, B cells, T cells, or plasma derived from CFS patients. These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS.

Epigallocatechin gallate ameliorates chronic fatigue syndrome in mice: Behavioral and biochemical evidence

Three decades after the coining of the term chronic fatigue syndrome, the diagnosis of this illness is still symptom based and the aetiology remains elusive. Chronic fatigue syndrome pathogenesis seems to be multifactorial and the possible involvement of immune system is supported. The present study was designed to evaluate the effects of the epigallocatechin gallate in a mouse model of immunologically induced chronic fatigue. On 19th day, after lipopolysaccharide/Brucella abortus administration, the mice showed significant increase in immobility period, post swim fatigue and thermal hyperalgesia. Behavioral deficits were coupled with enhanced oxidative–nitrosative stress as evident by increased lipid peroxidation, nitrite levels and decreased endogenous antioxidant enzymes (superoxide dismutase, reduced glutathione and catalase) and inflammation (increased levels of tumor necrosis factor-α and tissue growth factor-β). Chronic treatment with epigallocatechin gallate restored these behavioral and biochemical alterations in mice. The present study points out towards the beneficial effect of epigallocatechin gallate in the amelioration of chronic fatigue syndrome and thus may provide a new, effective and powerful strategy to treat chronic fatigue syndrome.

Association of peripheral inflammatory markers with chronic fatigue in a population-based sample

Alterations in the innate immune response may contribute to the pathogenesis of chronic fatigue syndrome (CFS). However, studies have been limited by small sample sizes, use of patients from tertiary care settings, inappropriate selection of controls, and failure to control for confounding demographic, medical and behavioral factors independently associated with immune activity. It is also not known whether specific symptoms account for observed associations between CFS and the innate immune response. To address these limitations, the current study examined plasma concentrations of high-sensitivity c-reactive protein (hs-CRP), white blood cell count (WBC) and a combined inflammation factor in a large population-based sample. Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with CFS ( n = 102) and in subjects with unwellness symptoms that did not meet diagnostic criteria for CFS (defined as “insufficient fatigue” [ISF]) ( n = 240) when compared to subjects who were well ( n = 115). Log transformed WBC was increased in ISF and was increased at a trend level in CFS. The combined inflammation factor was increased in both CFS and ISF. Subjects with CFS and ISF did not differ on any of the inflammation measures. In the entire subject population, the physical component summary score (PCS), but not the mental component summary score (MCS), from the Medical Outcomes Study Short Form-36 (SF-36) was negatively associated with each of the inflammation measures. Depressive symptoms were also associated with increased log hs-CRP. After adjustment for age, sex, race, location of residence, BMI, depressive status and immune-modulating medications, subjects classified as ISF continued to demonstrate increased log hs-CRP, WBC and elevations on the inflammation factor when compared to well controls; however, associations between CFS and log hs-CRP and the inflammation factor were no longer statistically significant. After adjustment, PCS score also remained independently associated with each of the inflammation measures. These findings support a role for innate immune activation in unexplained fatigue and unwellness, but do not suggest that immune activation is specific to CFS.

Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients

Chronic fatigue syndrome (CFS) is characterized by immune dysfunctions including chronic immune activation, inflammation, and alteration of cytokine profiles. T helper 17 (Th17) cells belong to a recently identified subset of T helper cells, with crucial regulatory function in inflammatory and autoimmune processes. Th17 cells are implicated in allergic inflammation, intestinal diseases, central nervous system inflammation, disorders that may all contribute to the pathophysiology of CFS. IL-17F is one of the pro-inflammatory cytokines secreted by Th17 cells. We investigated the association between CFS and the frequency of rs763780, a C/T genetic polymorphism leading to His161Arg substitution in the IL-17F protein. The His161Arg variant (C allele) antagonizes the pro-inflammatory effects of the wild-type IL-17F. A significantly lower frequency of the C allele was observed in the CFS population, suggesting that the His161Arg variant may confer protection against the disease. These results suggest a role of Th17 cells in the pathogenesis of CFS.

Traditional Chinese Medicine for Chronic Fatigue Syndrome

More and more patients have been diagnosed as having chronic fatigue syndrome (CFS) in recent years. Western drug use for this syndrome is often associated with many side-effects and little clinical benefit. As an alternative medicine, traditional Chinese medicine (TCM) has provided some evidences based upon ancient texts and recent studies, not only to offer clinical benefit but also offer insights into their mechanisms of action. It has perceived advantages such as being natural, effective and safe to ameliorate symptoms of CFS such as fatigue, disordered sleep, cognitive handicaps and other complex complaints, although there are some limitations regarding the diagnostic standards and methodology in related clinical or experimental studies. Modern mechanisms of TCM on CFS mainly focus on adjusting immune dysfunction, regulating abnormal activity in the hypothalamic-pituitary-adrenal (HPA) axis and serving as an antioxidant. It is vitally important for the further development to establish standards for ‘zheng’ of CFS, i.e. the different types of CFS pathogenesis in TCM, to perform randomized and controlled trials of TCM on CFS and to make full use of the latest biological, biochemical, molecular and immunological approaches in the experimental design.

Potential Drugs for Improving Chronic Fatigue Syndrome

Back to table of contents Previous article Next article LETTERFull AccessPotential Drugs for Improving Chronic Fatigue SyndromeSayed Shahabuddin Hoseini,Shahriar Gharibzadeh,Sayed Shahabuddin HoseiniSearch for more papers by this author,Shahriar GharibzadehSearch for more papers by this author,Published Online:1 Oct 2007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Chronic fatigue syndrome (CFS) is the current name for a disorder Characterized by debilitating fatigue and several associated physical, constitutional, and neuropsychological complaints. Specific symptoms reported by CFS patients are fatigue, difficult concentration, headache, sore throat, tender lymph node, muscle ache, joint ache, feverishness, and allergies. There are several hypotheses about its etiology, including postinfectious, immunological, neuroendocrine, neurological, and psychological ones. A CNS dysfunction brought about by abnormal cytokine release in response to antigenic challenge has been described. 1 Substantial evidences show a pivotal role for proinflammatory Cytokines (e.g., interleukin1, interleukin6, and tumor necrosis factor-α) in induction of CNS mediated responses such as fever, somnolence, and sickness behavior in acute infections. A significant elevation in serum levels of interleukin-1, and tumor necrosis factor-α in the patient with chronic fatigue syndrome have been reported. 2Recently, biological agents that bind and neutralize the tumor necrosis factor have become available: 1) Etanercept, a tumor necrosis factor type 2 receptor fused to IgG1, is assessed to be effective in psoriasis. 32) Infliximab, a chimeric mouse-human monoclonal antibody to the tumor necrosis factor, has shown successful trials for treating inflammatory bowel disease.3) Adalimumab, a fully human antibody to the tumor necrosis factor, is used in cutaneous sarcoidosis. 4) Thalidomide has immunomodulatory and anti-inflammatory effects including inhibition of synthesis of the tumor necrosis factor –α. It is effective for treating Behçets syndrome. 4 We suggest that these drugs, which are approved by FDA for some of the aforementioned diseases, can be useful in treating patients with chronic fatigue syndrome. Even modest improvement in symptoms can make an important difference in the patient’s degree of self-sufficiency and ability to appreciate life’s pleasures. 5 Surely, clinical trials should be done to assess the efficacy versus side effects of these drugs on affected patients. Faculty of Medicine, Medical Sciences/Tehran University, Tehran, IranNeuromuscular Systems Laboratory, Faculty of Biomedical Engineering, Amirkabir University of Technology, Tehran, IranReferences1 . Mihrshahi R, Beirman R: Etiology and pathogenesis of chronic fatigue syndrome: a review. N Z Med J 2005; 118:U1780Google Scholar2 . Tomoda A, Joudoi T, Rabab el-M, et al: Cytokine production and modulation: comparison of patients with chronic fatigue syndrome and normal controls. Psychiatry Res 2005; 134:101–104Google Scholar3 . Bos JD, de Korte J: Effects of etanercept on quality of life, fatigue, and depression in psoriasis. Lancet 2006; 367:6–7Google Scholar4 . Sayarlioglu M, Kotan MC, Topcu N, et al: Treatment of recurrent perforating intestinal ulcers with thalidomide in Behcet’s disease. Ann Pharmacother 2004; 38:808–811.Google Scholar5 . Straus SE: Chronic fatigue syndrome, in Harrison’s Textbook of Internal Medicine, 16th ed. New York, McGraw-Hill, 2005, pp 2545–2547Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 19Issue 4 Fall, 2007Pages 472-472 Metrics PDF download History Published online 1 October 2007 Published in print 1 October 2007

Potential Drugs for Improving Chronic Fatigue Syndrome

Back to table of contents Previous article Next article LETTERFull AccessPotential Drugs for Improving Chronic Fatigue SyndromeSayed Shahabuddin Hoseini,Shahriar Gharibzadeh,Sayed Shahabuddin HoseiniSearch for more papers by this author,Shahriar GharibzadehSearch for more papers by this author,Published Online:1 Oct 2007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Chronic fatigue syndrome (CFS) is the current name for a disorder Characterized by debilitating fatigue and several associated physical, constitutional, and neuropsychological complaints. Specific symptoms reported by CFS patients are fatigue, difficult concentration, headache, sore throat, tender lymph node, muscle ache, joint ache, feverishness, and allergies. There are several hypotheses about its etiology, including postinfectious, immunological, neuroendocrine, neurological, and psychological ones. A CNS dysfunction brought about by abnormal cytokine release in response to antigenic challenge has been described. 1 Substantial evidences show a pivotal role for proinflammatory Cytokines (e.g., interleukin1, interleukin6, and tumor necrosis factor-α) in induction of CNS mediated responses such as fever, somnolence, and sickness behavior in acute infections. A significant elevation in serum levels of interleukin-1, and tumor necrosis factor-α in the patient with chronic fatigue syndrome have been reported. 2Recently, biological agents that bind and neutralize the tumor necrosis factor have become available: 1) Etanercept, a tumor necrosis factor type 2 receptor fused to IgG1, is assessed to be effective in psoriasis. 32) Infliximab, a chimeric mouse-human monoclonal antibody to the tumor necrosis factor, has shown successful trials for treating inflammatory bowel disease.3) Adalimumab, a fully human antibody to the tumor necrosis factor, is used in cutaneous sarcoidosis. 4) Thalidomide has immunomodulatory and anti-inflammatory effects including inhibition of synthesis of the tumor necrosis factor –α. It is effective for treating Behçets syndrome. 4 We suggest that these drugs, which are approved by FDA for some of the aforementioned diseases, can be useful in treating patients with chronic fatigue syndrome. Even modest improvement in symptoms can make an important difference in the patient’s degree of self-sufficiency and ability to appreciate life’s pleasures. 5 Surely, clinical trials should be done to assess the efficacy versus side effects of these drugs on affected patients. Faculty of Medicine, Medical Sciences/Tehran University, Tehran, IranNeuromuscular Systems Laboratory, Faculty of Biomedical Engineering, Amirkabir University of Technology, Tehran, IranReferences1 . Mihrshahi R, Beirman R: Etiology and pathogenesis of chronic fatigue syndrome: a review. N Z Med J 2005; 118:U1780Google Scholar2 . Tomoda A, Joudoi T, Rabab el-M, et al: Cytokine production and modulation: comparison of patients with chronic fatigue syndrome and normal controls. Psychiatry Res 2005; 134:101–104Google Scholar3 . Bos JD, de Korte J: Effects of etanercept on quality of life, fatigue, and depression in psoriasis. Lancet 2006; 367:6–7Google Scholar4 . Sayarlioglu M, Kotan MC, Topcu N, et al: Treatment of recurrent perforating intestinal ulcers with thalidomide in Behcet’s disease. Ann Pharmacother 2004; 38:808–811.Google Scholar5 . Straus SE: Chronic fatigue syndrome, in Harrison’s Textbook of Internal Medicine, 16th ed. New York, McGraw-Hill, 2005, pp 2545–2547Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 19Issue 4 Fall, 2007Pages 472-472 Metrics PDF download History Published online 1 October 2007 Published in print 1 October 2007

Infection and vaccination in chronic fatigue syndrome: Myth or reality?

Chronic fatigue syndrome (CFS) is characterized by severe disabling fatigue lasting for more than 6 months associated with physical and mental disturbances such as headache, arthralgia, myalgia, memory impairment, sore throat and tender lymph nodes. The exact pathogenesis is still unknown. Several models were proposed to explain its etiology including chronic infection, endocrine dysfunction, autonomic imbalance, depression, decreased immunity states and an aberrant reaction to infection. No convincing evidence was found to support any of the suggested pathogenic mechanisms. The current concept is that CFS pathogenesis is a multi factorial condition in which an infective agent cause an aberrant immune response characterized by a shift to Th-2 dominant response. When the response fails to be switched-off, a chronic immune activation occurs and clinically expressed as the symptomatology of CFS.Vaccinations are used in order to stimulate the immune system to induce a persistent immunity against the favorable antigens. Several syndromes that contain chronic fatigue as one of their symptoms, such as “Gulf war syndrome” and macrophagic myofasciitis were related to vaccinations.Can vaccinations induce the aberrant immune response of CFS? Little is known about this issue. There are some reports on CFS occurring after vaccination, but few prospective and retrospective studies failed to find such an association.A working group of the Canadian Laboratory Center for Disease Control (LCDC) that was founded in order to examine the suspected association between CFS and vaccinations concluded that there is no evidence that relates CFS to vaccination. Further studies are requested to examine this issue since it is very conceivable that if infection can lead to CFS, vaccination may also lead to it in the same immune-mediated pathogenesis.

Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome

Background Human herpesvirus 6 (HHV-6) and 7 (HHV-7) have been suggested as possible triggering agents for chronic fatigue syndrome (CFS). Objectives To determine the possible association of HHV-6 and HHV-7 infections with CFS. Study design The prevalence of latent/persistent and active viral infections by nPCR, characteristic of HHV-6 variants using restriction endonuclease analysis and changes of lymphocyte subsets in peripheral blood by laser flow-cytometry in 17 CFS patients was examined. In addition, 12 patients with unexplained chronic fatigue and 20 blood donors (BD) were studied. Results No difference in prevalence of latent/persistent single viral infections between the patients and BD was found but dual infection rate was significantly higher in CFS patients. Active HHV-6 and dual (HHV-6 + HHV-7) infections were detected in CFS patients only and frequency of HHV-7 reactivation was also significantly higher in these patients. HHV-6 variant B was predominant in CFS patients (12/13). The changes of immunological parameters in CFS patients with active dual infection were characterized by significant decrease of CD3+ and CD4+ T cells, significant increase of CD95+ cells and decrease of CD4+/CD8+ ratio. Conclusions HHV-6 and HHV-7 may be involved in the pathogenesis of CFS and reactivation of both viruses may provoke changes in the phenotype of circulating lymphocytes.

Erythrocyte Oxidative Damage in Chronic Fatigue Syndrome

It has been hypothesized that a link exists between erythrocyte metabolism (particularly redox metabolism) and erythrocyte shape and that both are related to erythrocyte deformability. The aim of this research is to confirm the results of earlier studies and to investigate a correlation between erythrocyte morphology and erythrocyte oxidative damage in chronic fatigue syndrome (CFS). Reduced glutathione (GSH), malondialdehyde (MDA), methemoglobin (metHb) and 2,3-diphosphoglyceric acid (2,3-DPG) were measured in 31 patients suffering from CFS and 41 healthy control subjects. Scanning electron microscopic studies of the erythrocytes from both groups were also carried out. There was evidence of oxidative damage in CFS with statistically significant increases in 2,3-DPG (p < 0.05), metHb (p < 0.005) and MDA (p < 0.01). The CFS patients in this study also had significantly more stomatocytes in their blood than the normal subjects (p < 0.005). There is a strong likelihood that the increase in erythrocyte antioxidant activity is associated with the presence of stomatocytes. The results of this study provide further evidence for the role of free radicals in the pathogenesis of CFS and a link between erythrocyte metabolism and erythrocyte shape.

The influence of aerobic fitness and fibromyalgia on cardiorespiratory and perceptual responses to exercise in patients with chronic fatigue syndrome

To investigate cardiorespiratory and perceptual responses to exercise in patients with chronic fatigue syndrome (CFS), accounting for comorbid fibromyalgia (FM) and controlling for aerobic fitness. Twenty-nine patients with CFS only, 23 patients with CFS plus FM, and 32 controls completed an incremental bicycle test to exhaustion. Cardiorespiratory and perceptual responses were measured. Results were determined for the entire sample and for 18 subjects from each group matched for peak oxygen consumption. In the overall sample, there were no significant differences in cardiorespiratory parameters between the CFS only group and the controls. However, the CFS plus FM group exhibited lower ventilation, lower end-tidal CO2, and higher ventilatory equivalent of carbon dioxide compared with controls, and slower increases in heart rate compared with both patients with CFS only and controls. Peak oxygen consumption, ventilation, and workload were lower in the CFS plus FM group. Subjects in both the CFS only group and the CFS plus FM group rated exercise as more effortful than did controls. Patients with CFS plus FM rated exercise as significantly more painful than did patients with CFS only or controls. In the subgroups matched for aerobic fitness, there were no significant differences among the groups for any measured cardiorespiratory response, but perceptual differences in the CFS plus FM group remained. With matching for aerobic fitness, cardiorespiratory responses to exercise in patients with CFS only and CFS plus FM are not different from those in sedentary healthy subjects. While CFS patients with comorbid FM perceive exercise as more effortful and painful than do controls, those with CFS alone do not. These results suggest that aerobic fitness and a concurrent diagnosis of FM are likely explanations for currently conflicting data and challenge ideas implicating metabolic disease in the pathogenesis of CFS.

Reduced levels of oestrogen receptor β mRNA in Swedish patients with chronic fatigue syndrome

Background: Chronic fatigue syndrome (CFS) is an illness with unknown aetiology and pathophysiology. The difference in incidence by sex observed for CFS indicates a role for oestrogen and oestrogen receptors...

Exploration of Statistical Dependence Between Illness Parameters using the Entropy Correlation Coefficient

The entropy correlation coefficient (ECC) is a useful tool for measuring statistical dependence between variables. We employed this tool to search for pairs of variables that correlated in the chronic fatigue syndrome (CFS) Computational Challenge dataset. Highly related variables are candidates for data reduction, and novel relationships could lead to hypotheses regarding the pathogenesis of CFS. Data for 130 female participants in the Wichita (KS, USA) clinical study [1] was coded into numerical values. Metric data was grouped using Gaussian mixture models; the number of groups was chosen using Bayesian information content. The pair-wise correlation between all variables was computed using the ECC. Significance was estimated from 1000 iterations of a permutation test and a threshold of 0.01 was used to identify significantly correlated variables. The five dimensions of multidimensional fatigue inventory (MFI) were all highly correlated with each other. Seven Short Form (SF)-36 measures, four CFS case-defining symptoms and the Zung self-rating depression scale all correlated with all MFI dimensions. No physiological variables correlate with more than one MFI dimension. MFI, SF-36, CDC symptom inventory, the Zung self-rating depression scale and three Cambridge Neuropsychological Test Automated Battery (CANTAB) measures are highly correlated with CFS disease status. Correlations between the five dimensions of MFI are expected since they are measured from the same instrument. The relationship between MFI and Zung depression index has been previously reported. MFI, SF-36, and Centers for Disease Control and Prevention (CDC) symptom inventory are used to classify CFS; it is not surprising that they are correlated with disease status. Only one of the three CANTAB measures that correlate with disease status has been previously found, indicating the ECC identifies relationships not found with other statistical tools. The ECC is a useful tool for measuring statistical dependence between variables in clinical and laboratory datasets. The ECC needs to be further studied to gain a better understanding of its meaning for clinical data.

Exploration of the Gene Expression Correlates of Chronic Unexplained Fatigue using Factor Analysis

To identify biomarkers of chronic fatigue syndrome (CFS) and related disorders through analysis of microarray data, pathology test results and self-report symptom profiles. To empirically derive the symptom domains of the illnesses, factor analysis was performed on responses to self-report questionnaires (multidimensional fatigue inventory, Centers for Disease Control and Prevention (CDC) symptom inventory and Zung depression scale) before validation with independent datasets. Gene expression patterns that distinguished subjects across each factor dimension were then sought. A four-factor solution was favored, featuring 'fatigue' and 'mood disturbance' factors. Scores on these factors correlated with measures of disability on the Short Form (SF)-36. A total of 57 genes that distinguished subjects along each factor dimension were identified, although the separation was significant only for subjects beyond the extreme (15th and 85th) percentiles of severity. Clustering of laboratory parameters with expression of these genes revealed associations with serum measurements of pH, electrolytes, glucose, urea, creatinine, and liver enzymes (aspartate amino transferase [AST] and alanine amino transferase [AST]); as well as hematocrit and white cell count. CFS is a complex syndrome that cannot simply be associated with changes in individual laboratory tests or expression levels of individual genes. No clear association with gene expression and individual symptom domains was found. However, analysis of such multifacetted datasets is likely to be an important means to elucidate the pathogenesis of CFS.

Orthostatic instability in a population-based study of chronic fatigue syndrome

Purpose Autonomic nervous system dysfunction has been suggested as involved in the pathophysiology of chronic fatigue syndrome. This population-based case control study addressed the potential association between orthostatic instability (one sign of dysautonomia) and chronic fatigue syndrome. Subjects and methods Fifty-eight subjects who fulfilled criteria of the 1994 chronic fatigue syndrome research case definition and 55 healthy controls participated in a 2-day inpatient evaluation. Subjects had been identified during a 4-year population-based chronic fatigue syndrome surveillance study in Wichita, Kan. The present study evaluated subjects’ current medical and psychiatric status, reviewed past medical/psychiatric history and medication use, used a stand-up test to screen for orthostatic instability, and conducted a head-up tilt table test to diagnose orthostatic instability. Results No one manifested orthostatic instability in the stand-up test. The head-up tilt test elicited orthostatic instability in 30% of eligible chronic fatigue syndrome subjects (all with postural orthostatic tachycardia) and 48% of controls (50% with neurally mediated hypotension); intolerance was present in only nonfatigued (n = 7) subjects. Neither fatigue nor illness severity were associated with outcome. Conclusions Orthostatic instability was similar in persons with chronic fatigue syndrome and nonfatigued controls subjects recruited from the general Wichita population. Delayed responses to head-up tilt tests were common and may reflect hydration status. These findings suggest reappraisal of primary dysautonomia as a factor in the pathogenesis of chronic fatigue syndrome.

A preliminary epidemiological study and discussion on traditional Chinese medicine pathogenesis of chronic fatigue syndrome in Hong Kong

Our purpose is to conduct an epidemiological study of chronic fatigue syndrome (CFS) and its syndrome types and symptoms of traditional Chinese medicine (TCM) among adults (20-50 years old) in Hong Kong, and to discuss the TCM pathogenesis. Cross-sectional questionnaire survey. Demographic data, CDC (1994) CFS diagnostic criteria, Trudie Chalder fatigue scale, and China national standard for TCM syndrome types criteria. Twenty to fifty years old adults by convenient sampling. One thousand and thirteen subjects were successfully interviewed. Five hundred and eighty-five subjects (57.8%) had different levels of fatigue. Sixty-five subjects (6.4%) met CFS diagnostic criteria. In terms of TCM syndrome types, blood stasis due to qi deficiency had the highest prevalence (35.7%) among CFS. In the 54 symptoms investigated in total, the first eight symptoms in order of appearing rates were soreness of loins and weakness in knees, poor spirit, lassitude, pain, insomnia, forgetting, vessels blood stasis, vertigo and dazzle. The mostly appeared tongue figures were pale and corpulent or pale dim tongue proper, white and white greasy tongue coating, and the mostly appeared pulse figure was sunken-thin. The point prevalence of CFS among adults of 20 to 50 years old was found to be 6.4%. The most prevalent TCM syndrome type was blood stasis due to qi deficiency. The TCM pathogenesis of CFS was deficiency of origin, mainly deficiency of qi and kidney, with excess of superficiality.