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Increased muscle mitochondria are largely responsible for the increased resistance to fatigue and health benefits ascribed to exercise training. However, very little attention has been given to the likely benefits of increased brain mitochondria in this regard. We examined the effects of exercise training on markers of both brain and muscle mitochondrial biogenesis in relation to endurance capacity assessed by a treadmill run to fatigue (RTF) in mice. Male ICR mice were assigned to exercise (EX) or sedentary (SED) conditions (n = 16-19/group). EX mice performed 8 wk of treadmill running for 1 h/day, 6 days/wk at 25 m/min and a 5% incline. Twenty-four hours after the last training bout a subgroup of mice (n = 9-11/group) were euthanized, and brain (brain stem, cerebellum, cortex, frontal lobe, hippocampus, hypothalamus, and midbrain) and muscle (soleus) tissues were isolated for analysis of mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α), Silent Information Regulator T1 (SIRT1), citrate synthase (CS), and mitochondrial DNA (mtDNA) using RT-PCR. A different subgroup of EX and SED mice (n = 7-8/group) performed a treadmill RTF test. Exercise training increased PGC-1α, SIRT1, and CS mRNA and mtDNA in most brain regions in addition to the soleus (P < 0.05). Mean treadmill RTF increased from 74.0 ± 9.6 min to 126.5 ± 16.1 min following training (P < 0.05). These findings suggest that exercise training increases brain mitochondrial biogenesis, which may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction.

Chronic fatigue (CF) in breast cancer survivors (BCSs) has been associated with increased serum C-reactive protein-levels (CRP), pro-inflammatory cytokines and cytokine gene single nucleotide polymorphisms (SNPs). Still, there are few studies on these topics, and due to small study-cohorts the possibility to adjust for other conditions related to inflammatory processes, e.g. depression, has been limited. In 302 BCSs, examined approximately four years after treatment for breast cancer stage II/III, data on high sensitivity (hs)CRP, leukocytes and mRNA interleukin (IL)1β and IL6R expression, depression and chronic fatigue were available. Three years thereafter, 236 BCSs were re-examined. The associations between fatigue and SNPs in inflammation-related genes; IL1β (rs16944), IL6 (rs1800795), IL6receptor (rs4129267, rs4845617, rs2228145), CRP (rs2794521, rs3091244) were investigated, together with the relations between SNPs in IL6R,IL1β and CRP genes and mRNA blood expression levels of IL6R and IL1β and serum hsCRP-levels, respectively. All analyses were repeated after exclusion of depressed individuals and separating BCSs with persistent fatigue from never-fatigued individuals. Even after exclusion of depressed individuals neither the SNPs nor the mRNA IL1β and IL6R expression levels were associated with chronic or persistent fatigue. In the subset of persistent fatigued and never-fatigued individuals the CRP SNP (rs3091244) was associated with hsCRP level (p=0.02). IL1β and IL6R mRNA expression levels were not related to the IL1β and IL6R genotypes. In a large cohort of BCSs the investigated SNPs in inflammation-related genes were not associated with fatigue, though subset analyses indicated an association between the CRP SNP (rs3091244) and serum hsCRP., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To examine phenotypic considerations in the study of fatigue and to explore significant issues affecting the extension of biobehavioral research of fatigue by the inclusion of genetic and genomic markers. THEORETICAL ORGANIZATION: Fatigue is a condition that has an adverse effect on quality of life that has been a focus of nursing inquiry. Yet, the study of fatigue has been stymied by the lack of phenotypic clarity. To expand the biobehavioral inquiry of fatigue, phenotypic clarity is needed. In addition, examining genomic factors associated with fatigue may help to elucidate the pathophysiology of fatigue and, in the future, lead to targeted interventions that address the molecular basis of fatigue., Conclusions: Given that nursing has been at the forefront of the study of fatigue, nurse scientists should consider enhancing phenotypic clarity by the development of a case-definition and use of a core measure of fatigue, one that can be augmented by condition- or population-specific measures as needed. Following the establishment of phenotypic clarity, the integration of genomics into biobehavioral research offers an opportunity for further clarity of phenotypes and for theoretical specification of the pathophysiology of conditions such as fatigue., Clinical Relevance: The development of targeted interventions for fatigue depend on a more precise definition of fatigue and a better understanding of the biologic processes that contribute to its development and persistence., (© 2011 Sigma Theta Tau International.)

Chronic fatigue is a common, poorly understood and disabling phenomenon in many diseases. We aim to provide an overview of fatigue in chronic autoimmune and inflammatory disease. Fatigue measurement, prevalence and confounding factors such as depression, sleep disorders and pain are reviewed in the first half of the article. In the second half of the article, we describe explanatory models of fatigue and fatigue signalling, with an emphasis on cytokines and sickness behaviour, oxidative stress, mitochondrial dysfunction and the impact of certain genes on fatigue.

Twin studies indicate substantial inherited components in cognitive abilities. One of the most extensively studied candidate genes of cognitive functioning is the dopamine D4 receptor gene (DRD4), which has been suggested to be related to attentional disorders. Based on reaction time data of 245 Caucasians participating in different cognitive tasks, slower responses characterized the group with the 7-repeat allele. This effect was present in both sexes and was not because of fatigue. To our knowledge, this is the first report on significant association (P = 0.0001) between the DRD4 variable number of tandem repeat (VNTR) polymorphism and response latencies in a non-clinical adult sample. Other studied dopaminergic polymorphisms did not show an association with reaction time. These results illustrate that speed-of-performance measures derived from multiple reaction time tasks using standardization procedures could be promising tools to detect unique genetic effects in the background of cognitive abilities., (© 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.)

Background: Somatic symptoms often co-occur with psychological symptoms but this overlap is poorly understood. Some aspects of this overlap differ in the South Asian context, but it is not clear whether this is a reporting effect or an underlying difference in experienced illness., Methods: Home interviews were administered to 4,024 twins randomly selected from a population-based twin register in the Colombo district of Sri Lanka (the CoTASS study). These included assessments of psychological, somatic and fatigue symptoms. The data were analyzed using factor analytic and quantitative genetic approaches., Results: Confirmatory factor analysis showed that the symptoms from the three scales represented three separate dimensions, rather than all tapping into a single dimension. However, familial correlations among the data were most consistent with a common pathway model. This implies that a portion of the underlying vulnerability is common across psychological, fatigue and somatic symptoms. There were sex differences in the etiology of this model, with shared environmental and genetic influences playing different roles in men and women., Conclusions: There is a complex etiological relationship between psychological, fatigue and somatic symptoms. This is similar in Sri Lanka to Western countries, but there may be a greater influence from the family environment, suggesting that care needs to be taken when generalizing research findings between countries. People who complain of certain fatigue or somatic symptoms may well also have psychological symptoms, or may have genetic or environmental vulnerabilities to such problems.

Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n=11) and non-fatigued controls (n=10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p<.05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: The goal of this paper is to discuss cancer-related fatigue (CRF) and address issues related to the investigation into potential biological and genetic causal mechanisms. The objectives are to: (1) describe CRF as a component of quality of life (QOL); (2) address measurement issues that have slowed progress toward an understanding of mechanisms underlying this symptom; (3) review biological pathways and genetic approaches that have promise for the exploration of causal mechanisms of CRF; and (4) offer directions for future research., Methods: Review, synthesis, and interpretation of the literature., Results: Until recently, CRF and QOL have been understood primarily as subjective patient-reported experiences. With increased understanding of human genetics, theories and research are being expanded to incorporate biological and genetic understandings of these subjective experiences. Proposed biological and genetic mechanisms of CRF that have been examined include cytokine dysregulation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, five hydroxy tryptophan (5-HT) neurotransmitter dysregulation, circadian rhythm disruption, alterations in adenosine triphosphate (ATP) and muscle metabolism, and vagal afferent activation. Approaches to the study of genetic mechanisms have also been addressed including candidate genes, genome-wide scanning, and gene expression. Based on the review and synthesis of the literature, directions for future research are proposed., Conclusions: Understanding the biological and genetic basis of CRF has the potential to contribute to a more complete understanding of the genetic determinants of QOL.

Objective: The human leukocyte antigen (HLA) DQB1*0602 allele is closely associated with narcolepsy, a neurologic disorder characterized by excessive daytime sleepiness, fragmented sleep, and shortened REM sleep latency. We evaluated whether DQB1*0602 was a novel marker of interindividual differences by determining its relationship to sleep homeostatic, sleepiness, and cognitive responses to baseline and chronic partial sleep deprivation (PSD) conditions., Methods: Ninety-two DQB1*0602-negative and 37 DQB1*0602-positive healthy adults participated in a protocol of 2 baseline 10 hours time in bed (TIB) nights followed by 5 consecutive 4 hours TIB nights. DQB1*0602 allelic frequencies did not differ significantly between Caucasians and African Americans., Results: During baseline, although DQB1*0602-positive subjects were subjectively sleepier and more fatigued, they showed greater sleep fragmentation, and decreased sleep homeostatic pressure and differentially sharper declines during the night (measured by non-REM EEG slow-wave energy [SWE]). During PSD, DQB1*0602-positive subjects were sleepier and showed more fragmented sleep, despite SWE elevation comparable to negative subjects. Moreover, they showed differentially greater REM sleep latency reductions and smaller stage 2 reductions, along with differentially greater increases in fatigue. Both groups demonstrated comparable cumulative decreases in cognitive performance., Conclusions: DQB1*0602 positivity in a healthy population may represent a continuum of some sleep-wake features of narcolepsy. DQB1*0602 was associated with interindividual differences in sleep homeostasis, physiologic sleep, sleepiness, and fatigue-but not in cognitive measures-during baseline and chronic PSD. Thus, DQB1*0602 may represent a genetic biomarker for predicting such individual differences in basal and sleep loss conditions.

Background: Most patients with major depression report problems in their sleep: insomnia, early morning awakenings and fatigue correlating with poor sleep quality. One of the key substances regulating sleep is adenosine. We hypothesized that variations in polymorphic sites of adenosine related genes may predispose to depression with sleep disturbances., Methods: We selected 117 single nucleotide polymorphisms from 13 genes and analyzed their association with depression and specific sleep problems (early morning awakenings and fatigue). Data were collected as part of the Health 2000 Study based on Finnish population and included 1423 adult subjects., Results: Our major finding herein was, among women, the association of SLC29A3 polymorphism rs12256138 with depressive disorder (p=0.0004, odds ratio=0.68, 95% CI 0.55-0.84, p<0.05 after Bonferonni correction for multiple testing). Only one gene showing any evidence for association was common to women and men (ADA)., Limitations: Relatively small size of the case samples., Conclusions: Our results suggest that compromised adenosine transport due to variation in nucleoside transporter gene SLC29A3 in women, could predispose to depression, and could suggest new directions in treatment research. The shortage of overlapping genes between the genders indicates that the genetics of mood regulation may vary between the sexes., (Copyright 2010 Elsevier B.V. All rights reserved.)

Context: Fatigue and sleep disturbance are common problems in oncology patients and their family caregivers (FCs). However, little is known about factors that contribute to interindividual variability in these symptoms or to their underlying biologic mechanisms., Objectives: An evaluation was done on whether genetic variation in a prominent proinflammatory cytokine, interleukin-6 (IL-6 c.-6101A>T [rs4719714]), was associated with mean ratings of evening fatigue, morning fatigue, and sleep disturbance, as well as with the trajectories of these symptoms., Methods: Over six months, participants completed standardized measures of fatigue and sleep disturbance. Linear regression was used to assess the effect of the IL-6 genotype and other covariates on mean fatigue and sleep disturbance scores. Hierarchical linear modeling was used to determine the effect of the IL-6 genotype on symptom trajectories., Results: Common allele homozygotes reported higher levels of evening fatigue (P=0.003), morning fatigue (P=0.09), and sleep disturbance (P=0.003) than minor allele carriers. Predictors of baseline level and trajectories of evening fatigue included age, gender, and genotype (intercepts) and baseline level of evening fatigue (slope). Predictors of baseline level and trajectories of morning fatigue included age and genotype (intercept) and age and baseline level of morning fatigue (slope). Predictors of baseline level and trajectories of sleep disturbance included age and genotype (intercept) and baseline level of sleep disturbance (slope)., Conclusions: Findings provide preliminary evidence of a genetic association between a functional promoter polymorphism in the IL-6 gene and severity of evening fatigue, morning fatigue, and sleep disturbance in oncology patients and their FCs., (Copyright © 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Background: Previous research has demonstrated that many lung cancer survivors report difficulties with symptom control and experience a poor quality of life (QOL). Although recent studies have suggested a relationship of single nucleotide polymorphisms (SNPs) in several cytokine genes with cancer susceptibility and prognosis, associations with symptom burden and QOL have not been examined. The current study was conducted to identify SNPs related to symptom burden and QOL outcomes in lung cancer survivors., Methods: All participants were enrolled in the Mayo Clinic Lung Cancer Cohort following diagnosis of lung cancer. A total of 1149 Caucasian lung cancer survivors completed questionnaires and had genetic samples available. The main outcome measures were symptom burden as measured by the Lung Cancer Symptom Scale and health-related QOL as measured by the Short-Form General Health Survey., Results: Twenty-one SNPs in cytokine genes were associated with symptom burden and QOL outcomes. Our results suggested both specificity and consistency of cytokine gene SNPs in predicting outcomes., Conclusions: These results provide support for genetic predisposition to QOL and symptom burden and may aid in identification of lung cancer survivors at high risk for symptom management and QOL difficulties., (Cancer 2010. (c) 2010 American Cancer Society.)

Background: Fatigue is a common symptom in Western high-income countries but is often medically unexplained and little is known about its presentation in other populations., Aims: To explore the epidemiology and aetiology of fatigue in Sri Lanka, and of its overlap with depression., Method: A total of 4024 randomly selected twins from a population-based register in Sri Lanka (Colombo district) completed home interviews including the Chalder Fatigue Questionnaire., Results: The prevalence of fatigue was similar to that in other countries, although prolonged fatigue may be less common. There was substantial comorbidity with a screen for lifetime depression. Non-shared environmental factors made the largest contributions, although genetic/family factors also contributed. The aetiology appeared consistent across the spectrum of severity., Conclusions: The aetiology of fatigue is broadly similar in Sri Lanka and Western high-income countries. Abnormal experiences of fatigue appear to be the extreme form of more common fatigue, rather than representing independent entities with different genetic or environmental risk factors.

Objective: Inflammatory cytokines may influence both labile anger and depression. Both psychiatric conditions can occur during interferon alfa-based treatments. Evidence also indicates a central nervous system role for tumor necrosis factor alpha (TNF-alpha), whose expression may be increased by interferon alfa. A polymorphism in the promoter region of TNF-alpha has been associated with various inflammatory illnesses. We therefore hypothesized that this TNF-alpha polymorphism would influence susceptibility to psychiatric symptoms during interferon alfa therapy., Methods: One hundred five patients with hepatitis C, initially without active major depression (major depressive disorder), were treated with interferon alfa and then prospectively monitored using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the Beck Depression Inventory II, the Anger Irritability and Assault Questionnaire, and circulating TNF-alpha levels. The A-308G polymorphism (rs1800629) was determined using the 5'-nuclease assay. Repeated-measure mixed-effect analyses compared changes in symptoms over time., Result: Beck Depression Inventory II score increased during interferon alfa therapy (F = 6.2; P < 0.001), with 27% developing MDD. The TNF-alpha A allele was associated with worsened labile anger (F = 2.5; P < 0.05) and fatigue (F = 2.9; P < 0.05) during treatment but not with major depression incidence (chi = 0.0; P = 0.99) or increased Beck Depression Inventory II (F = 1.2; P = 0.31). Labile anger was not predicted by the serotonin transporter polymorphism (F = 0.8; P = 0.59)., Discussion: During treatment with an exogenous cytokine, vulnerability to worsening labile anger-distinct from major depression-is associated with genetic variability in TNF-alpha. This has implications both for patients being treated with interferon alfa and our understanding of genetic vulnerability for different subtypes of dysphoric and mood disorders.

Background: Dexamethasone contributes to high cure rates in paediatric acute lymphoblastic leukaemia (ALL) but significantly and adversely alters sleep and fatigue. Herein we explored three mechanisms (pharmacokinetics, serum albumin and pharmacogenetics) through which dexamethasone may cause debilitating fatigue and disrupted sleep., Methods: We enrolled 100 patients on a 10-d study: 5-d of no dexamethasone (OFF DEX) followed by 5-d of dexamethasone (ON DEX) during continuation chemotherapy. Sleep variables were collected with continuous actigraphy on days 1 through 5, both OFF DEX and ON DEX. On days 2 and 5 of each 5-d period, parents and patients 7 years of age and older completed a sleep diary and Fatigue Scale questionnaire. Blood was collected at 0 (pre-dexamethasone), 1, 2, 4 and 8 h after the first oral dexamethasone dose for pharmacokinetic analysis. Serum albumin concentration was retrospectively analysed in stored samples. Patient DNA was genotyped for 99 polymorphic loci in candidate genes associated with glucocorticoid metabolism., Results: Dexamethasone clearance was significantly greater in younger patients than in older ones and in lower risk patients. In multiple regression models, risk group was significantly related to pharmacokinetic parameters. We found that polymorphisms in three genes (AHSG, IL6, POLDIP3) were significantly associated with sleep measures but not with fatigue., Conclusion: Risk group had the most significant relationship with disrupted sleep in patients while on dexamethasone. Serum albumin levels had neither a direct relationship with sleep or fatigue variables nor an indirect relationship through systemic exposure to dexamethasone. We identified candidate genes that may help explain the adverse events of disrupted sleep in paediatric patients receiving dexamethasone., (Copyright 2010 Elsevier Ltd. All rights reserved.)

On the basis of the free radical and rate of living theories of aging, it has been proposed that decreased metabolism leads to increased longevity through a decreased production of reactive oxygen species (ROS). In this article, we examine the relationship between mitochondrial energy metabolism and life span by using the Clk mutants in Caenorhabditis elegans. Clk mutants are characterized by slow physiologic rates, delayed development, and increased life span. This phenotype suggests that increased life span may be achieved by decreasing energy expenditure. To test this hypothesis, we identified six novel Clk mutants in a screen for worms that have slow defecation and slow development and that can be maternally rescued. Interestingly, all 11 Clk mutants have increased life span despite the fact that slow physiologic rates were used as the only screening criterion. Although mitochondrial function is decreased in the Clk mutants, ATP levels are normal or increased, suggesting decreased energy utilization. To determine whether the longevity of the Clk mutants results from decreased production of ROS, we examined sensitivity to oxidative stress and oxidative damage. We found no evidence for systematically increased resistance to oxidative stress or decreased oxidative damage in the Clk mutants despite normal or elevated levels of superoxide dismutases. Overall, our findings suggest that decreased energy metabolism can lead to increased life span without decreased production of ROS.

Background: Vital exhaustion, a psychological state characterized by unusual fatigue, irritability, and feelings of demoralization, has been identified as a risk factor for cardiovascular diseases and linked to elevated levels of pro-inflammatory cytokines., Objective: The purpose of this study was to investigate the relationship between vital exhaustion and cytokine levels in patients with cardiovascular risk factors., Method: The entire cohort consisted of 356 primary-care patients with cardiovascular risk factors who participated in a study of early recognition of heart failure. All participants completed the Maastricht questionnaire (MQ) for assessing vital exhaustion. Cytokine serum levels were measured in all those subjects (N=178) who were assigned to the highest and lowest quartiles of the MQ, respectively., Results: We found that elevated serum concentrations of IL-6, TNFα, and IL-10, but not IL-1β or natriuretic peptides were associated with high MQ scores indicative of vital exhaustion. Using logistic regression analyses controlling for clinical variables and Type D personality, both TNFα (multivariate odds ratio [OR] =1.86; 95%-confidence interval [CI] =1.30-2.68; p=0.001) and IL-10(OR=1.62; 95%-CI=1.15-2.28; p=0.006), but not other cytokines significantly predicted vital exhaustion independently of other clinical and laboratory parameters examined [corrected]., Conclusion: The subjective state of vital exhaustion is linked to a substantial alteration in the pattern of secreted cytokines. Data suggest that a disturbance in the levels of both pro-inflammatory and anti-inflammatory mediators, rather than isolated stimulation by pro-inflammatory cytokines, is associated with the mental and physical changes of vital exhaustion.

Fatigue is a common symptom and includes both physical and mental components. It can be associated with a variety of different syndromes and diseases, but in many cases is not associated with other comorbid conditions. Most humans have experienced acute fatigue in relation to different stressors. Acute fatigue typically decreases as the effect of the triggering factor is reduced and a normal homeostatic balance is restored. Fatigue that persists for 6 months or more is termed chronic fatigue. Chronic fatigue (CF) in combination with a minimum of 4 of 8 symptoms and the absence of diseases that could explain these symptoms, constitute the case definition for chronic fatigue syndrome. In spite of its prevalence, the biology of fatigue is relatively poorly understood and biological markers have not yet been identified. This literature search was performed in PubMed to identify research on the genetics and epigenetics of fatigue. Publications were included if fatigue was a major topic and the topic was combined with genetic and/or epigenetic measurements in adult humans. A total of 40 publications were identified. Although altered functioning in the hypothalamic-pituitary-adrenal axis, the serotonergic system, and associations with infectious agents have been identified, the search for genetic or epigenetic markers of fatigue, either in the context of CF or chronic fatigue syndrome (CFS) has been relatively unproductive or, in the case of epigenetics, nonexistent. Although several studies, both hypothesis-testing and hypothesis-generating, have been performed to search for biomarkers, they have mostly been underpowered, restricted by the heterogeneity of the phenotype, or limited by an unsystematic study design. To be able to confirm the hypothesis that risk for, or levels of, fatigue are influenced by the genetic or epigenetic background of an individual, studies need to be based on larger sample sizes with a more clearly defined phenotype. Studies need to focus not only on the influence of a single aspect such as single nucleotide polymorphisms (SNPs) or differential gene expression on disease risk or state, but also on the systems biology behind the disease in combination with information on environmental influences and validation of findings in functional studies., (Copyright (c) 2010 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Hugh Montgomery's discovery of the first of more than 239 fitness genes together with rapid advances in human gene therapy have created a prospect of using genes, genetic elements, and cells that have the capacity to enhance athletic performance (to paraphrase the World Anti-Doping Agency's definition of gene doping). This brief overview covers the main areas of interface between genetics and sport, attempts to provide a context against which gene doping may be viewed, and predicts a futuristic legitimate use of genomic (and possibly epigenetic) information in sport., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: There is very little genetically informative research identifying true environmental risks for psychiatric conditions. These may be best explored in regions with diverse environmental exposures. The current study aimed to explore similarities and differences in such risks contributing to depression and fatigue., Methods: Home interviews assessed depression (lifetime-ever), fatigue and environmental exposures in 4,024 randomly selected twins from a population-based register in the Colombo district of Sri Lanka., Results: Early school leaving and standard of living showed environmentally-mediated effects on depression, in men. In women, life events were associated with depression partly through genetic pathways (however, the temporal order is consistent with life events being an outcome of depression, as well as the other way around). For fatigue, there were environmentally mediated effects (through early school leaving and life events) and strong suggestions of family-environmental influences., Conclusions: Compared to previous studies from higher-income countries, novel environmentally-mediated risk factors for depression and fatigue were identified in Sri Lanka. But as seen elsewhere, the association between life events and depression was partially genetically mediated in women. These results have implications for understanding environmental mechanisms around the world.

Amphetamine is a stimulant drug that enhances attention and feelings of alertness. Amphetamine's effects are known to be modulated by endogenous cannabinoids, which are degraded by the enzyme fatty acid amide hydrolase (FAAH). In this study we investigated inter-individual differences in mood response to amphetamine in relation to four polymorphisms in the FAAH gene, including the FAAH missense variant rs324420C --> A (Pro129Thr), which was previously found to be associated with street drug use and addictive traits. One hundred and fifty-nine healthy Caucasian volunteers participated in a three-session, double-blind crossover study receiving either placebo or oral d-amphetamine (10 and 20 mg). Associations between individual genotypes and levels of self-reported Arousal (Profile of Mood States) after d-amphetamine ingestion were investigated using two-way ANOVAs/ANCOVAs. Association analyses for haplotypes were performed using the adaptive permutation approach implemented in PLINK. Genotypes at rs3766246 and rs2295633 were significantly associated with increased ratings of Arousal (p<0.05) and Fatigue (p<0.01) after the 10-mg dose. Fatigue levels were also found to be associated with the haplotypes CCC and TAT formed from rs3766246, rs324420, and rs2295633 (p<0.05). These data suggest that the endocannabinoid system influences variation in subjective response to amphetamine. This has important implications for understanding the role of endogenous cannabinoids in response to amphetamine, studies of poly-substance abuse, and understanding the genetic determinants of inter-individual differences in stimulant effects and risk of abuse.

Circadian disruption has been linked with inflammation, an established cancer risk factor. Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. Patients completed a questionnaire and provided a blood sample prior to undergoing a colonoscopy (n = 70). Adjusted mean serum cytokine concentrations (IL-6, TNF-alpha, gamma-INF, IL-1ra, IL-1-beta, VEGF) were compared among patients with high and low scores for fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory II), or sleep disruption (Pittsburgh Sleep Quality Index), or among patients with different Per3 clock gene variants. Poor sleep was associated with elevated VEGF, and fatigue-related reduced activity was associated with elevated TNF-alpha concentrations. Participants with the 4/5 or 5/5 Per3 variable tandem repeat sequence had elevated IL-6 concentrations compared to those with the 4/4 genotype. Biological processes linking circadian disruption with cancer remain to be elucidated. Increased inflammatory cytokine secretion may play a role.

Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the 'high IL-6' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.

Fatigue is one of the most frequent complaints among breast cancer survivors. However, mechanisms underlying persisting fatigue after end of treatment are poorly understood. To explore whether biological processes underlying persistent fatigue can affect gene expression of blood cells, genome-wide expression analyses were performed on whole blood samples from breast cancer survivors classified as chronic fatigued 2-6 years after diagnosis. Non-fatigued survivors served as controls. Several gene sets involved in plasma- and B-cell pathways differed between the chronic fatigued and the non-fatigued, suggesting that a dysregulation in these pathways is associated with chronic fatigue and that a B-cell-mediated inflammatory process might underlie fatigue. The chronic fatigued also had a higher level of leucocytes, lymphocytes and neutrophiles compared with the non-fatigued, thus further indicating that an activation of the immune system plays a role in the biology of chronic fatigue in breast cancer survivors.

Although fatigue and sleep disturbance are prevalent symptoms in oncology patients and their family caregivers, little is known about the factors that contribute to interindividual variability in symptom severity ratings as well as in their underlying biological mechanisms. In this study, we sought to determine whether a functional genetic variation in a prominent proinflammatory cytokine, tumor necrosis factor-alpha (TNFA-308G>A [rs1800629] promoter polymorphism) was associated with overall ratings of sleep disturbance and fatigue as well as with the trajectories of these symptoms. Over 6 months, participants completed standardized measures of sleep disturbance and fatigue. Multiple linear regression was used to assess the effect of the TNFA genotype and other covariates on mean sleep disturbance and fatigue scores. Hierarchical linear modeling was used to determine the effect of TNFA genotype on the trajectories of these symptoms. Common allele homozygotes reported higher levels of sleep disturbance (p=.09) and morning fatigue (p=.02) than minor allele carriers. Multivariate analyses demonstrated that age and genotype were predictors of both mean symptom scores and the trajectories of these symptoms. Findings provide preliminary evidence of an association between a functional promoter polymorphism in the TNFA gene and the severity of sleep disturbance and morning fatigue in oncology patients and their family caregivers.

Objective: To characterize the clinical, psychological, and sleep pattern of idiopathic hypersomnia with and without long sleep time, and provide normative values for 24-hour polysomnography., Setting: University Hospital., Design: Controlled, prospective cohort., Participants: 75 consecutive patients (aged 34 +/- 12 y) with idiopathic hypersomnia and 30 healthy matched controls., Intervention: Patients and controls underwent during 48 hours a face-to-face interview, questionnaires, human leukocyte antigen genotype, a night polysomnography and multiple sleep latency test (MSLT), followed by 24-h ad libitum sleep monitoring., Results: Hypersomniacs had more fatigue, higher anxiety and depression scores, and more frequent hypnagogic hallucinations (24%), sleep paralysis (28%), sleep drunkenness (36%), and unrefreshing naps (46%) than controls. They were more frequently evening types. DQB1*0602 genotype was similarly found in hypersomniacs (24.2%) and controls (19.2%). Hypersomniacs had more frequent slow wave sleep after 06:00 than controls. During 24-h polysomnography, the 95% confidence interval for total sleep time was 493-558 min in controls, versus 672-718 min in hypersomniacs. There were 40 hypersomniacs with and 35 hypersomniacs without long ( > 600 min) sleep time. The hypersomniacs with long sleep time were younger (29 +/- 10 vs 40 +/- 13 y, P = 0.0002), slimmer (body mass index: 26 +/- 5 vs 23 +/- 4 kg/m2; P = 0.005), and had lower Horne-Ostberg scores and higher sleep efficiencies than those without long sleep time. MSLT latencies were normal (> 8 min) in 71% hypersomniacs with long sleep time., Conclusions: Hypersomnia, especially with long sleep time, is frequently associated with evening chronotype and young age. It is inadequately diagnosed using MSLT.

In order to test the "serotonin" hypothesis of the genesis of central fatigue, we studied association between genotype and fatigue (3-hour mental workload consisting of information processing and logical task solution) using analysis of variance for different indices (well-being, activity, mood, mental fatigue index). It was concluded that young men with serotonin deficit (LL genotype) and girls with serotonin excess (S genotype) were less tolerant to long-lasting mental workload. Thus, we confirmed that the degree of central fatigue depends on the function of the serotonin system and revealed gender differences in adaptive capacities of carriers of different variants of serotonin transporter.

Objectives: To determine, in a population-based sample of twin pairs, if extra-intestinal symptoms (EIS) are closely associated with both irritable bowel syndrome (IBS) and psychiatric disorders and whether such associations are explained on a genetic basis., Methods: A random sample of twins between the ages of 44 and 64 years enrolled in the Minnesota Twins Registry completed the Modified Mayo Clinic Bowel Disease Questionnaire, a questionnaire on extra-intestinal symptoms, and the Psychiatric Diagnostic Screening Questionnaire., Results: Of the 3,048 participants (51% response rate), 371 (12.2%) fulfilled Rome II criteria for IBS; 61 (16.4%) had a psychiatric disorder compared with 7.6% (n=204) of those without IBS (P<0.001). In regression analysis both IBS and psychiatric disorders were independently associated with the number of extra-intestinal symptoms (P<0.0005). Concordance rates for high EIS score were 30.0% for monozygote (MZ) twins and 16.7% in dizygote (DZ) twins (P=0.020) and the OR for concordance remained substantially higher for MZ than DZ twins after adjustment for psychiatric disorder and presence of IBS (6.82 (95% CI 4.45-10.45) and 2.71 (95% CI 1.69-4.37)). In MZ twins discordant for IBS, EIS and IBS were significantly associated (P=0.004) and psychiatric disorder and EIS were significantly associated (P=0.001)., Conclusions: Extra-intestinal symptoms are independently associated with both IBS and psychiatric disorders. There is evidence that there is a genetic basis to EIS, but the association with IBS and psychiatric disorders is not primarily explained by genetic influences.

Introduction: Some hypothyroid patients continue to have significant impairments in psychological well-being, despite adequate treatment with levothyroxine (LT4). T4 transport across the blood-brain barrier is one of the crucial processes for thyroid hormone action in the brain. OATP1C1, a thyroid hormone transporter expressed at the blood-brain barrier, is considered to play a key role in delivering serum T4 to the brain., Objective: To examine whether polymorphisms in OATP1C1 are determinants of well-being, neurocognitive functioning and preference for replacement therapy with a combination of LT4 and liothyronine (LT3)., Design and Participants: We studied 141 patients with primary autoimmune hypothyroidism, adequately treated with LT4 monotherapy and participating in a randomized clinical trial comparing LT4 therapy with LT4-LT3 combination therapy., Outcome Measurements: Different questionnaires on well-being and neurocognitive tests were performed at baseline. Serum thyroid parameters, OATP1C1-intron3C > T, OATP1C1-Pro143Thr and OATP1C1-C3035T polymorphisms were determined., Results: Allele frequencies of the OATP1C1 polymorphisms in patients with primary hypothyroidism were similar to those of healthy controls. Both the OATP1C1-intron3C > T and the OATP1C1-C3035T polymorphism, but not the OATP1C1-Pro143Thr polymorphism, were associated with symptoms of fatigue and depression. OATP1C1 polymorphisms were not associated with measures of neurocognitive functioning or preference for combined LT4-LT3 therapy., Conclusions: OATP1C1 polymorphisms are associated with fatigue and depression, but do not explain differences in neurocognitive functioning or appreciation of LT4-LT3 combination therapy. Future studies are needed to confirm these findings.

Converging evidence from basic and clinical studies suggests a role for proinflammatory cytokines in cancer-related fatigue, although the etiology of elevated inflammatory processes is unclear. We examined single nucleotide polymorphisms (SNPs) in the promoters of cytokine genes as genetic risk factors for cytokine-related fatigue in 33 fatigued and 14 non-fatigued breast cancer survivors, focusing on promoter sequence polymorphisms in IL1B and IL6 associated with differential expression of proinflammatory cytokines. Predictors of fatigue included presence of at least one cytosine at IL1B -511 (95%CI=0.91-16.6, p=.007) and homozygosity for either variant of the IL6 -174 genotype (G/G or C/C; 95%CI=1.12-17.9, p=.027). Associations between fatigue status and IL1B genotype remained significant after covariate adjustment for demographic, biobehavioral and treatment-related factors. These findings provide preliminary evidence that polymorphisms in IL1B may serve as a potential risk factor for persistent fatigue in the aftermath of cancer.

The anti-inflammatory cytokine interleukin (IL)-10 is important for regulating inflammation in the periphery and brain, but whether it protects against infection- or age-related psychomotor disturbances and fatigue is unknown. Therefore, the present study evaluated motor coordination, time to fatigue, and several central and peripheral proinflammatory cytokines in male young adult (3-mo-old) and middle-aged (12-mo-old) wild-type (IL-10(+/+)) and IL-10-deficient (IL-10(-/-)) mice after intraperitoneal injection of lipopolysaccharide (LPS) or saline. No age-related differences were observed; therefore, data from the two ages were pooled and analyzed to determine effects of genotype and treatment. LPS treatment increased IL-1beta, IL-6, and TNFalpha mRNA in all brain areas examined in IL-10(+/+) and IL-10(-/-) mice, but to a greater extent and for a longer time in IL-10(-/-) mice. Plasma IL-1beta and IL-6 were increased similarly in IL-10(+/+) and IL-10(-/-) mice 4 h after LPS but remained elevated longer in IL-10(-/-) mice, whereas TNFalpha was higher in IL-10(-/-) mice throughout after LPS treatment. Motor performance and motor learning in IL-10(+/+) mice were not affected by LPS treatment; however, both were reduced in IL-10(-/-) mice treated with LPS compared with those treated with saline. Furthermore, although LPS reduced the time to fatigue in IL-10(+/+) and IL-10(-/-) mice, the effects were exacerbated in IL-10(-/-) mice. Thus the increased brain and peripheral inflammation induced by LPS in IL-10(-/-) mice was associated with increased coordination deficits and fatigue. These data suggest that IL-10 may inhibit motor deficits and fatigue associated with peripheral infections via its anti-inflammatory effects.

The Human Genome Project and HapMap have led to a better appreciation of the importance of common genetic variation in determining cancer risk, created potential for predicting response to therapy, and made possible the development of targeted prevention and therapeutic interventions. Advances in molecular epidemiology can be used to explore the role of genetic variation in modulating the risk for severe and persistent symptoms, such as pain, depression, and fatigue, in patients with cancer. The same genes that are implicated in cancer risk might also be involved in the modulation of therapeutic outcomes. For example, polymorphisms in several cytokine genes are potential markers for genetic susceptibility both for cancer risk and for cancer-related symptoms. These genetic polymorphisms are stable markers and easily and reliably assayed to explore the extent to which genetic variation might prove useful in identifying patients with cancer at high-risk of symptom development. Likewise, they could identify subgroups who might benefit most from symptom intervention, and contribute to developing personalized and more effective therapies for persistent symptoms.

Chronic fatigue syndrome (CFS) is a debilitating disorder of unknown etiology with no known lesions, diagnostic markers or therapeutic intervention. The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality. A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined in 137 clinically evaluated subjects (40 CFS, 55 with insufficient fatigue, and 42 non-fatigued, NF, controls) derived from a population-based CFS surveillance study in Wichita, Kansas. Of the polymorphisms examined, three markers (-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of -1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. Further, in silico analysis revealed that the -1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 to the A allele but not the G allele at this locus. These data indicate that sequence variation in HTR2A, potentially resulting in its enhanced activity, may be involved in the pathophysiology of CFS.

Prolonged fatigue equal to or greater than 1 month duration and chronic fatigue equal to or greater than 6 months duration are both commonly seen in clinical practice, yet little is known about the etiology or epidemiology of either symptom. Chronic fatigue syndrome (CFS), while rarer, presents similar challenges in determining cause and epidemiology. Twin studies can be useful in elucidating genetic and environmental influences on fatigue and CFS. The goal of this article was to use biometrical structural equation twin modeling to examine genetic and environmental influences on fatigue, and to investigate whether these influences varied by gender. A total of 1042 monozygotic (MZ) twin pairs and 828 dizygotic (DZ) twin pairs who had completed the University of Washington Twin Registry survey were assessed for three fatigue-related variables: prolonged fatigue, chronic fatigue, and CFS. Structural equation twin modeling was used to determine the relative contributions of additive genetic effects, shared environmental effects, and individual-specific environmental effects to the 3 fatigue conditions. In women, tetrachoric correlations were similar for MZ and DZ pairs for prolonged and chronic fatigue, but not for CFS. In men, however, the correlations for prolonged and chronic fatigue were higher in MZ pairs than in DZ pairs. About half the variance for both prolonged and chronic fatigue in males was due to genetic effects, and half due to individual-specific environmental effects. For females, most variance was due to individual environmental effects.

The effect of a disrupted immune system on the neuromuscular system is poorly characterized. We compared the strength and fatigue of RAG2(-/-) mice, which lack T-cells and B-cells, with immune intact controls. RAG2(-/-) mice demonstrated fatigue with shorter inverted hang-times (HT) and voluntary wheel-running (VWR) distance and total run times; they increased body weight more slowly but had proportionally normal forelimb grip strength (FGS) and VWR speed. Medial rectus femoris histopathology showed no change in fiber type proportions, no variation in type 2b fiber diameter, and no change in the percentage of central nuclei. There was no change in serum creatine kinase (CK) levels. Thus, in RAG2(-/-) mice body weight and fatigue were directly affected by a hypoactive immune system. Whether these effects were centrally or peripherally mediated is unknown. This model may help to explain fatigue in human conditions in which the immune system is suppressed or absent.

Chronic fatigue syndrome (CFS) is a significant public health problem of unknown etiology, the pathophysiology has not been elucidated, and there are no characteristic physical signs or laboratory abnormalities. Some studies have indicated an association of CFS with deregulation of immune functions and hypothalamic-pituitary-adrenal (HPA) axis activity. In this study, we examined the association of sequence variations in the glucocorticoid receptor gene (NR3C1) with CFS because NR3C1 is a major effector of the HPA axis. There were 137 study participants (40 with CFS, 55 with insufficient symptoms or fatigue, termed as ISF, and 42 non-fatigued controls) who were clinically evaluated and identified from the general population of Wichita, KS. Nine single nucleotide polymorphisms (SNPs) in NR3C1 were tested for association of polymorphisms and haplotypes with CFS. We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (P < 0.05) and found similar associations with quantitative assessments of functional impairment (by the SF-36), with fatigue (by the Multidimensional Fatigue Inventory) and with symptoms (assessed by the Centers for Disease Control Symptom Inventory). Subjects homozygous for the major allele of all associated SNPs were at increased risk for CFS with odds ratios ranging from 2.61 (CI 1.05-6.45) to 3.00 (CI 1.12-8.05). Five SNPs, covering a region of approximately 80 kb, demonstrated high linkage disequilibrium (LD) in CFS, but LD gradually declined in ISF to NF subjects. Furthermore, haplotype analysis of the region in LD identified two associated haplotypes with opposite alleles: one protective and the other conferring risk of CFS. These results demonstrate NR3C1 as a potential mediator of chronic fatigue, and implicate variations in the 5' region of NR3C1 as a possible mechanism through which the alterations in HPA axis regulation and behavioural characteristics of CFS may manifest.

Although alteration to peripheral systems at the skeletal muscle level can contribute to one's ability to sustain endurance capacity, neural circuits regulating fatigue may also play a critical role. Previous studies demonstrated that increasing brain serotonin (5-HT) release is sufficient to hasten the onset of exercise-induced fatigue, while manipulations that increase brain dopamine (DA) release can delay the onset of fatigue. These results suggest that individual differences in endurance capacity could be due to factors capable of influencing the activity of 5-HT and DA systems. We evaluated possible differences in central fatigue pathways between two contrasting rat groups selectively bred for high (HCR) or low (LCR) capacity running. Using quantitative in situ hybridization, we measured messenger RNA (mRNA) levels of tryptophan hydroxylase (TPH), 5-HT transporter (5-HTT), 5-HT1A and 5-HT1B autoreceptors, dopamine receptor-D2 (DR-D2) autoreceptors and postsynaptic receptors, and dopamine receptor-D1 (DR-D1) postsynaptic receptors, in discrete brain regions of HCR and LCR. HCR expressed higher levels of 5-HT1B autoreceptor mRNA in the raphe nuclei relative to LCR, but similar levels of TPH, 5-HTT, and 5-HT1A mRNA in these areas. Surprisingly, HCR expressed higher levels of DR-D2 autoreceptor mRNA in the midbrain, while simultaneously expressing greater DR-D2 postsynaptic mRNA in the striatum compared to LCR. There were no differences in DR-D1 mRNA levels in the striatum or cortex between groups. These data suggest that central serotonergic and dopaminergic systems may be involved in the mechanisms by which HCR have delayed onset of exercise-induced fatigue compared to LCR.

Background: Medically unexplained disabling fatigue in young people is familial and frequently associated with depressed mood., Aims: To examine the degree of sharing of genetic and environmental influences on the symptoms of depression and fatigue in this age group., Method: The parents of twins aged 8-17 years, derived from a population-based register, completed a questionnaire regarding lifetime-ever disabling fatigue in both twins. Twins aged 11 years or over completed the Mood and Feelings Questionnaire. The genetic and environmental influences on fatigue and the relationship with depression were examined using bivariate genetic analysis., Results: Parent-rated data were obtained for 1468 twin pairs (65%) and self-rated data from 930 older twin pairs (58%). Bivariate analysis of fatigue and depression suggested that genetic and environmental influences on disabling fatigue were mainly specific to fatigue., Conclusions: Unexplained disabling fatigue in childhood is substantially familial and has mainly an independent aetiology from depression.

In a group of 465 patients diagnosed as having chronic mercury toxicity (CMT), 32.3% had severe fatigue, 88.8% had memory loss, and 27.5% had depression. A significant correlation was found between CMT and the Apo-lipoprotein E4 genotype (p=0.001). An investigation into an additional 864 consecutively seen general practice patients, resulted in 30.3% having evidence consistent with CMT, and once again a significant correlation was found with the APO-E4 genotype (p=0.001). Removal of amalgam mercury fillings when combined with appropriate treatment resulted in a significant symptom reduction (p<0.001) to levels reported by healthy subjects.

Aim: By genechip cDNA microarray, the genes expressions of Stearoyl-coenzyme A desaturase (Scd-2) and brain fatty acid-binding protein (B-FABP) were studied in the central nervous system (CNS) of the mice to discuss the mechanism of exercise-induced fatigue., Methods: Building the model of fatigued animal and using the genechip cDNA microarray, the genes expressions were analyzed between the control group and fatigue group mice., Results: The genes expression of Scd-2 and B-FABP were obvious different in the brain of fatigued group mice than of control group., Conclusion: Exercise-induced nerve center fatigue is correlated with genes expressions of lipid metabolism.

Objective: Sustained psychological stress may result in a state operationalized as "vital exhaustion." Exhaustion predicted coronary artery disease (CAD) events whereby increased inflammatory activity might mediate this link. Moreover, there is an emerging importance of gene-environmental interactions in CAD. We investigated the effect of exhaustion severity on plasma levels of C-reactive protein (CRP) and whether exhaustion might regulate CRP levels via the -308G/A polymorphism of the tumor necrosis factor (TNF)-alpha gene., Methods: We assessed exhaustion in 275 industrial employees (mean age +/- SD, 41 +/- 9 years, 88% men) using the Maastricht Questionnaire. Subjects were stratified as per exhaustion severity: none (N = 80), moderate (N = 128), and severe (N = 67). The TNF-alpha polymorphism was determined by real-time polymerase chain reaction, and plasma CRP levels were measured by a high-sensitivity immunoassay., Results: There was a significant interaction between exhaustion and the TNF-alpha polymorphism, explaining 4.5% in the variance of plasma CRP values (F(5,271) = 2.47, p =.033); the result held after controlling for classic cardiovascular risk factors. Adjusted mean CRP levels across exhaustion strata in GA (N = 70) and AA (N = 3) carriers combined were 0.91 mg/l (none), 1.78 mg/l (moderate), and 2.61 mg/l (severe) as compared with 1.24 mg/l, 1.61 mg/l, and 1.36 mg/l for the GG wild-type (N = 202)., Conclusion: The findings suggest that the A allele of the TNF-alpha -308 G/A polymorphism may mediate inflammation with exhaustion in a dose-response relationship, while with the GG wild-type exhaustion severity seems unrelated to CRP levels. The finding provides a rationale for gene-environmental interactions by which psychosocial factors may promote atherosclerosis and CAD.

Background: Fatigue is one of the most common disabling symptoms in patients with multiple sclerosis (MS), but the putative role of proinflammatory cytokines remains to be elucidated., Methods: Thirty-seven patients (27 women, 10 men) with relapsing remitting (n = 29) and secondary progressive (n = 8) MS, aged 41.0 +/- 10.2 years, were studied. Fatigue was assessed by Krupp's Fatigue Severity Scale (FSS). Cytokine mRNA expression for interferon (IFN)-gamma tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were measured by real time RT PCR. Autonomic function was evaluated by standard tests for parasympathetic and sympathetic function, as well as by serum levels of norepinephrine and epinephrine., Results: Median levels of TNF-alpha mRNA expression were significantly higher in MS patients with (FSS > or = 4.0 and > or = 5.0, n = 26 and n = 14, respectively) than in those without fatigue (FSS < 4.0, n = 11). No differences were seen for IFN-gamma and IL-10 mRNA expression. Cytokine levels were not correlated to autonomic tests or to serum catecholamine levels., Conclusions: These results suggest that TNF-alpha, as a principal proinflammatory mediator, is associated with MS-related fatigue. This is in support of a pathogenic role of the MS-related inflammatory process in the development of fatigue.

Background: Inappropriate coping with chronic stress may result in a state of "vital exhaustion" that has been associated with coronary artery disease. Impaired fibrinolysis due to an increase in type 1 plasminogen activator inhibitor (PAI-1) might mediate this link. Genetic and environmental factors both regulate the plasma PAI-1 levels. We investigated the contribution of the PAI-1 4G/5G gene polymorphism to the plasma levels of PAI-1 in exhaustion., Methods: The study participants were 258 (mean age 40.9 +/- 9.1 years) apparently healthy subjects of an airplane manufacturing plant in Germany who completed the Shortened 9-item Maastricht Vital Exhaustion Questionnaire. A median split was performed on exhaustion scores rendering two groups of exhausted and non-exhausted subjects. The PAI-1 4G/5G polymorphism in the promoter region of the PAI-1 gene and several variables related to the insulin resistance syndrome known to affect plasma PAI-1 levels were assessed., Results: Across all subjects, exhausted individuals had higher PAI-1 antigen levels than non-exhausted subjects (46.6 +/- 20.7 vs 38.3 +/- 21.4 ng/ml, p = 0.002). There were no significant differences in the PAI-1 antigen levels between exhausted and non-exhausted individuals with both the 4G/4G and the 4G/5G polymorphism. With the 5G/5G polymorphism, however, exhausted subjects had higher PAI-1 antigen levels than non-exhausted subjects (44.9 +/- 22.9 vs 31.2 +/- 13.1 ng/ml, p = 0.017). These results did not change when controlling for the variables of insulin resistance., Conclusions: The findings suggest that the PAI-1 4G/5G gene polymorphism might affect the plasma PAI-1 levels related to exhaustion severity. With the 5G/5G polymorphism, exhausted subjects might have less fibrinolytic capacity than non-exhausted subjects.

Objective: Proinflammatory changes are thought to link vital exhaustion with adverse cardiovascular outcomes. Monocytes play a central role in the pathogenesis of atherosclerotic lesions and are a major source of circulating cytokines. We hypothesized that vital exhaustion may alter the regulation of monocyte activity, as measured by lipopolysaccharide (LPS)-stimulated and glucocorticoid inhibited release of the proinflammatory cytokine interleukin-6 (IL-6)., Methods: In 166 middle-aged apparently healthy men, vital exhaustion was measured by the Shortened Maastricht Exhaustion Questionnaire. Subjects in the highest quartile (highly exhausted, N= 38) were compared with those in the second and third quartiles (moderately exhausted N= 89) vs. those in the lowest quartile (nonexhausted, N= 39) in terms of plasma C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha) levels, and as to IL-6 release after LPS stimulation in vitro. Inhibition of IL-6 release was determined by coincubation with increasing concentrations of dexamethasone. Monocyte glucocorticoid sensitivity was defined as the dexamethasone concentration inhibiting IL-6 release by 50%., Results: Highly exhausted individuals had higher CRP levels than nonexhausted subjects (p=.008). LPS-stimulated IL-6 release was not significantly different between groups. However, in highly exhausted participants, dexamethasone was less able to inhibit IL-6 release (p=.010), and the glucocorticoid sensitivity was lower (p=.003) than in nonexhausted subjects., Conclusions: In highly exhausted individuals, glucocorticoids exert less suppressive action on monocyte IL-6 release than in nonexhausted subjects. This finding points to altered regulation of monocyte cytokine production as one possible pathway linking exhaustion with atherosclerosis.

Objective: Abnormal corticosteroid-binding globulin (CBG) is an extremely rare condition and only three mutations have been described in four families. The molecular basis of an abnormal CBG in a Brazilian family was studied and correlations between genotype and serum cortisol, cortisol binding capacity (CBC) and CBG levels were determined., Subjects: All 10 family members, comprising three generations, and nine healthy volunteers were studied., Measurements: Genomic DNA was extracted from white blood cells from all family members. The human cbg exons 2-5 were amplified by PCR, submitted to automatic sequencing. Cortisol and CBG levels in serum were measured by radioimmunoassay (RIA). CBC in serum was determined using tritiated cortisol and other cortisol binding parameters were calculated through Scatchard analysis., Results: A missense mutation in exon 5 of cbg (1254G --> A; Asp367Asn), recently described as CBG Lyon, was found in all family members. The proband and one sister were homozygous whereas all other family members, including parents, were heterozygous for this mutation. Cortisol levels in the only two homozygotes were lower than in heterozygotes and both were significantly lower as compared to controls (69 and 182 nmol/l vs. 267 +/- 129 nmol/l vs. 459 +/- 195 nmol/l, respectively, P < 0.05). CBC was decreased in the two homozygotes as compared to heterozygotes and in both groups as compared to controls (< 90 and 114 nmol/l vs. 305.0 +/- 81.4 nmol/l vs. 594.8 +/- 59.5 nmol/l, respectively, P < 0.05). CBG levels were lower in homozygotes as compared to heterozygotes and in both as compared to controls (325 and 375 nmol/l vs. 496.75 +/- 50.75 nmol/l vs. 647.25 +/- 87.50 nmol/l, respectively, P < 0.05)., Conclusions: An abnormal CBG resulting from a missense mutation and known as CBG Lyon was found in this Brazilian kindred. This abnormal CBG has decreased affinity for cortisol and results in low or low normal serum cortisol levels in homozygous and heterozygous subjects. Although relative hypotension and fatigue have recently been associated with CBG deficiency in a family with two CBG mutations (null and Lyon), the two homozygous subjects in this kindred were both normotensive and only the proband presented with fatigue.

The unexplained underperformance syndrome (UPS), previously known as the overtraining syndrome (OTS), has been defined as a persistent decrement in athletic performance capacity despite 2 weeks of relative rest. It has been proposed that UPS may be caused by excessive cytokine release during and following exercise causing a chronic inflammatory state and 'cytokine sickness'. This article extends that hypothesis by proposing that time-dependent sensitisation could provide a model through which the aetiology of UPS may be explained. In this model, the principal abnormal factors in UPS are an increased production of and/or intolerance to interleukin (IL)-6 during exercise. Strategies to attenuate the IL-6 response to exercise that may also reduce an athlete's susceptibility to UPS are proposed.

Objective: Gender differences in the symptoms of major depression have received limited research attention. The aim of this study was to explore these differences in male-female twin pairs., Method: Telephone interviews were conducted to determine the lifetime history of major depression in 1,404 complete pairs of opposite-sex dizygotic twins identified through a population-based registry. From these, the authors selected 201 pairs in which both twins fulfilled the DSM-III-R criteria for lifetime major depression. Dichotomous symptom variables were analyzed by using McNemar's chi-square. For continuous variables, conditional logistic regression was used., Results: Female twins reported experiencing significantly more fatigue, hypersomnia, and psychomotor retardation during the most severe major depressive episode, whereas male twins reported more insomnia and agitation., Conclusions: In this group of matched twins, gender differences in the symptoms of major depression were seen in the areas of sleep, psychomotor changes, and fatigue. Gender significantly modifies some clinical features of major depression.