Sleep disturbance and kynurenine metabolism in depression.

OBJECTIVE: Although the interrelationships between sleep disturbance, inflammation, and depression have been found, molecular mechanisms that link these conditions are largely unknown. Kynurenine metabolism is hypothesized to be a key mechanism that links inflammation and depression. Inflammation activates the kynurenine pathway, leading to increases in 3-hydroxykynurenine (3HK) and quinolinic acid (QA), potentially neurotoxic metabolites, and decreases in kynurenic acid (KynA), a potentially neuroprotective compound. This relative neurotoxic shift in the balance of kynurenine metabolites has been associated with depression, but never been examined regarding sleep disturbance. We tested the association between sleep disturbance and this relative neurotoxic shift in 68 currently depressed, 26 previously depressed, and 66 never depressed subjects. METHODS: Sleep disturbance was assessed using the Pittsburgh Sleep Quality Index. Serum concentrations of kynurenine metabolites were measured using high performance liquid chromatography. Putative neuroprotective indices reflecting the relative activity of neuroprotective and neurotoxic kynurenine metabolites were calculated as KynA/QA and KynA/3HK (primary outcomes). RESULTS: Sleep disturbance was associated with reduced KynA/QA in the currently depressed group only (unadjusted beta -0.43, p<0.001). This association remained significant even after controlling for age, sex, analysis batch, body-mass index, and depressive symptoms in currently depressed subjects (adjusted beta -0.30, p=0.02). There was no significant association between sleep disturbance and KynA/3HK in any of the groups. Sleep disturbance was associated with increased C-reactive protein in currently depressed subjects only (unadjusted beta 0.38, p=0.007; adjusted beta 0.33, p=0.02). CONCLUSION: These data support the hypothesis that altered kynurenine metabolism may molecularly link sleep disturbance and depression.

A critical review of trials of transcranial direct current stimulation and trigeminal nerve stimulation for depression: the issue of treatment-emergent mania.

OBJECTIVE:: This study is a critical review analyzing occurrence of treatment-emergent mania (TEM) related to transcranial direct current stimulation (tDCS) and trigeminal nerve stimulation (TNS). METHOD:: We present a systematic review of the literature on TEM related to tDCS and TNS treatment for major depressive disorder (MDD), conducted in accordance with the recommendations from Cochrane Group and the PRISMA guidelines. RESULTS:: Our search identified few reported episodes of TEM in the literature. In fact, we found 11 trials focused on treatment of MDD (seven controlled trials of tDCS and four trials of TNS, three open label and one controlled). We highlight the need for safety assessment in clinical research settings to establish with precision and in larger samples the risks inherent to the technique under investigation. CONCLUSION:: Safety assessment is of fundamental importance in clinical research. TEM is a very important safety issue in MDD trials. Further and larger controlled trials will help to clarify both the safety and the clinical effects of combinations of pharmacotherapy and tDCS or TNS in daily clinical practice.

A critical review of trials of transcranial direct current stimulation and trigeminal nerve stimulation for depression: the issue of treatment-emergent mania / Revisão crítica da literatura de ensaios clínicos em estimulação transcraniana por corrente contínua e estimulação de nervo trigêmeo para depressão: o problema da mania tratamento-emergente

Abstract Objective: This study is a critical review analyzing occurrence of treatment-emergent mania (TEM) related to transcranial direct current stimulation (tDCS) and trigeminal nerve stimulation (TNS). Method: We present a systematic review of the literature on TEM related to tDCS and TNS treatment for major depressive disorder (MDD), conducted in accordance with the recommendations from Cochrane Group and the PRISMA guidelines. Results: Our search identified few reported episodes of TEM in the literature. In fact, we found 11 trials focused on treatment of MDD (seven controlled trials of tDCS and four trials of TNS, three open label and one controlled). We highlight the need for safety assessment in clinical research settings to establish with precision and in larger samples the risks inherent to the technique under investigation. Conclusion: Safety assessment is of fundamental importance in clinical research. TEM is a very important safety issue in MDD trials. Further and larger controlled trials will help to clarify both the safety and the clinical effects of combinations of pharmacotherapy and tDCS or TNS in daily clinical practice.

Resumo Objetivo: O presente estudo consiste em uma revisão e análise crítica da ocorrência de mania tratamento-emergente (TEM) relacionada a estimulação transcraniana por corrente contínua (ETCC) e estimulação do nervo trigêmeo (TNS). Método: Apresentamos uma revisão sistemática de literatura sobre TEM relacionada a ETCC e TNS no tratamento de transtorno depressivo maior (TDM), conduzida de acordo com as recomendações do Grupo Cochrane e protocolo PRISMA. Resultados: A pesquisa identificou poucos relatos de TEM na literatura. Na verdade, foram encontrados 11 ensaios clínicos com foco no tratamento de TDM (sete estudos controlados de ETCC e quatro de TNS, sendo três abertos e um controlado). Destacamos a necessidade de avaliações de segurança em pesquisas clínicas para se estabelecer com maior precisão e em amostras maiores os riscos inerentes à técnica sob investigação. Conclusão: Avaliação de segurança é fundamental na pesquisa clínica. A TEM é um efeito adverso importante no tratamento do TDM. Maiores ensaios clínicos controlados ajudarão a esclarecer os efeitos clínicos e a segurança da combinação de psicotrópicos e ETCC ou TNS.

Fast Visual Field Progression Is Associated with Depressive Symptoms in Patients with Glaucoma.

PURPOSE: To evaluate the association between the rates of progressive visual field loss and the occurrence of depressive symptoms in patients with glaucoma followed over time. DESIGN: Prospective observational cohort study. PARTICIPANTS: The study included 204 eyes of 102 patients with glaucomatous visual field defects on standard automated perimetry (SAP). METHODS: All patients had Geriatric Depression Scale (GDS) questionnaires and visual field tests obtained over a mean follow-up time of 2.2±0.6 years. Change in depressive symptoms was assessed by calculating the difference between GDS scores at the last follow-up visit from those at baseline. Rates of visual field loss were assessed by SAP. An integrated binocular visual field was estimated from the monocular SAP tests, and rates of change in mean sensitivity (MS) over time were obtained from linear mixed models. Regression models were used to investigate the association between progressive visual field loss and changes in depressive symptoms, adjusting for potentially confounding clinical and socioeconomic variables. MAIN OUTCOME MEASURES: The association between rates of change in binocular SAP MS and change in GDS questionnaire scores. RESULTS: There was a significant correlation between change in the GDS scores during follow-up and change in binocular SAP sensitivity. Each 1 decibel (dB)/year change in binocular SAP MS was associated with a change of 2.0 units in the GDS scores during the follow-up period (P = 0.025). In a multivariable model adjusting for baseline disease severity, change in visual acuity, age, gender, race, Montreal Cognitive Assessment score, education, income, and comorbidity index, each 1 dB/year change in binocular SAP MS was associated with a change of 3.0 units in the GDS score (P = 0.019). CONCLUSIONS: Faster visual field progression was associated with the occurrence of depressive symptoms in patients with glaucoma.

Is Inflammation a Link Between Self-Reported Health and Infectious Disease Risk?

Self-reported health (SRH) has been consistently shown to predict morbidity and mortality. However, the mechanisms underlying this association are poorly understood. The study by Cohen and colleagues reported in this issue of Psychosomatic Medicine fills this gap by examining a potential biological mechanism: alteration of immune system functioning. The study shows that SRH predicted common cold after experimentally controlled virus inoculation in healthy individuals. More specifically, SRH predicted the cold-related illness expression as measured by objective clinical signs, whereas it did not predict the infection rates as measured by predefined increases in specific antibodies. This editorial discusses the significance of this study and the possibility that inflammation, an innate immune response, is a link between SRH and common cold risk. Because the illness expression of cold is generally attributed to increased local inflammation and SRH has been found associated with increased systemic inflammation, it is possible that SRH is a correlate of a heightened systemic inflammatory state and thus leads to increased local inflammatory responses after an exposure to a cold virus. SRH was also associated with well-known risk factors for inflammation in this study, such as overweight, perceived stress, and social isolation. Because of the strong predictive value of SRH for future morbidity and mortality and the simple low-cost tools that enable its assessment, SRH has the potential to identify high-risk individuals in various public health settings. Future research is needed to address the translational applicability of these findings and to further the mechanistic investigation in high-risk groups including older adults.

Trait sensitivity to social disconnection enhances pro-inflammatory responses to a randomized controlled trial of endotoxin.

UNLABELLED: One proposed mechanism for the association between social isolation and poor health outcomes is inflammation. Lonely or socially disconnected individuals show greater inflammatory responses, including up-regulation of pro-inflammatory gene expression, and people who are sensitive to cues of social disconnection (e.g., high levels of anxious attachment) exhibit greater inflammation in response to psychological stress. However, no studies have examined how sensitivity to social disconnection may influence pro-inflammatory responses to an inflammatory challenge. In the present study, we investigated the impact of sensitivity to social disconnection (a composite score comprised of loneliness, anxious attachment, fear of negative evaluation, and rejection sensitivity) on pro-inflammatory cytokines and gene expression in response to endotoxin, an inflammatory challenge, vs. placebo in a sample of one hundred and fifteen (n=115) healthy participants. Results showed that those who are more sensitive to social disconnection show increased pro-inflammatory responses (i.e., increased levels of tumor necrosis factor-alpha and interleukin-6) to endotoxin, as well as up-regulation of multiple genes related to inflammation. Furthermore, bioinformatics analyses revealed that those in the endotoxin group who are more sensitive to social disconnection exhibited a conserved transcriptional response to adversity (CTRA) regulatory profile, involving up-regulation of beta-adrenergic and pro-inflammatory transcription control pathways and down-regulation of antiviral transcription factors in response to endotoxin. These results may ultimately have implications for understanding the links between social isolation, inflammation, and health. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT01671150.

Plasma levels of soluble TNF receptors 1 and 2 after tDCS and sertraline treatment in major depression: Results from the SELECT-TDCS trial.

BACKGROUND: The cytokine hypothesis of depression postulates that the pathophysiology of this illness incorporates an increased production of pro-inflammatory cytokines, which leads to an over-activation of the hypothalamic-pituitary-adrenal axis as well as monoaminergic disturbances. Nevertheless, it remains unclear whether the amelioration of depressive symptoms could decrease cytokine levels. Notwithstanding antidepressant drug therapy might exert anti-inflammatory effects, the effects of non-invasive neuromodulatory approaches like transcranial direct current stimulation (tDCS) on pro-inflammatory cytokine networks are largely unknown. METHODS: We evaluated, in the Sertraline vs. Electric Current Therapy for Treating Depression Clinical Study (SELECT-TDCS) trial, whether the plasma levels of the soluble TNF receptors 1 and 2 (sTNFRs) changed after antidepressant treatment in a sample of 73 antidepressant-free patients with unipolar depressive disorder in an episode of at least moderate intensity. RESULTS: Although both tDCS and sertraline exerted antidepressant effects, the plasma levels of sTNFRs did not change over time regardless of the intervention and clinical response. Also, baseline sTNFRs levels did not predict antidepressant response. LIMITATIONS: Our negative findings could be a type II error, as this trial did not use an equivalence design. CONCLUSIONS: To conclude, in this novel placebo-controlled trial prospectively evaluating the changes of sTNFRs in depressed patients, we found that these molecules are not surrogate biomarkers of treatment response of tDCS, whose antidepressant effects occurred regardless of normalization of immunological activity.

Sleep disturbance and longitudinal risk of inflammation: Moderating influences of social integration and social isolation in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Both sleep disturbance and social isolation increase the risk for morbidity and mortality. Systemic inflammation is suspected as a potential mechanism of these associations. However, the complex relationships between sleep disturbance, social isolation, and inflammation have not been examined in a population-based longitudinal study. This study examined the longitudinal association between sleep disturbance and systemic inflammation, and the moderating effects of social isolation on this association. The CARDIA study is a population-based longitudinal study conducted in four US cities. Sleep disturbance - i.e., insomnia complaints and short sleep duration - was assessed in 2962 African-American and White adults at baseline (2000-2001, ages 33-45years). Circulating C-reactive protein (CRP) was measured at baseline and follow-up (2005-2006). Interleukin-6 (IL-6) and subjective and objective social isolation (i.e., feelings of social isolation and social network size) were measured at follow-up. Sleep disturbance was a significant predictor of inflammation five years later after full adjustment for covariates (adjusted betas: 0.048, P=0.012 for CRP; 0.047, P=0.017 for IL-6). Further adjustment for baseline CRP revealed that sleep disturbance also impacted the longitudinal change in CRP levels over five years (adjusted beta: 0.044, P=0.013). Subjective social isolation was a significant moderator of this association between sleep disturbance and CRP (adjusted beta 0.131, P=0.002). Sleep disturbance was associated with heightened systemic inflammation in a general population over a five-year follow-up, and this association was significantly stronger in those who reported feelings of social isolation. Clinical interventions targeting sleep disturbances may be a potential avenue for reducing inflammation, particularly in individuals who feel socially isolated.

Impact of social isolation on behavioral health in elderly: Systematic review.

AIM: To examine and compare the effects of subjective and objective social isolation on behavioral health in elderly adults. METHODS: A systematic search of PubMed was performed for original research articles from peer-reviewed journals examining one of the following topics: "Social isolation and sleep disturbance", "social isolation and depression", or "social isolation and fatigue in older adults". Studies were selected following the criteria established based on the aim of this review. Data were extracted from the articles by two independent reviewers. Due to the heterogeneity in study designs and outcome measures of the included studies, qualitative and narrative analyses were conducted. RESULTS: The set criteria were used to select a total of 16 studies for the review. Of the 16, 13 were cross-sectional studies. The characteristics of study populations were identified as follows. A total of 12 studies randomly selected subjects irrespective of pre-existing health conditions. Consequently, an unspecified number of the study subjects had chronic diseases in the studies compared. In addition, cultural and ethnic backgrounds of studies in this review were diverse, and included subjects living in North America, South America, Asia, Europe, and Oceania. Both subjective and objective types of social isolation increased behavioral symptoms, such as sleep disturbance, depressive symptoms, and fatigue in older adults. Furthermore, a few recent studies reported stronger effects of subjective social isolation than objective social isolation on sleep disturbance and depressive symptoms. CONCLUSION: Social isolation affects behavioral health in older adults. Compared to the objective social isolation, subjective social isolation contributes more significantly to sleep disturbance and depression.

Effective gene delivery into human stem cells with a cell-targeting Peptide-modified bioreducible polymer.

Stem cells are poorly permissive to non-viral gene transfection reagents. In this study, we explored the possibility of improving gene delivery into human embryonic (hESC) and mesenchymal (hMSC) stem cells by synergizing the activity of a cell-binding ligand with a polymer that releases nucleic acids in a cytoplasm-responsive manner. A 29 amino acid long peptide, RVG, targeting the nicotinic acetylcholine receptor (nAchR) was identified to bind both hMSC and H9-derived hESC. Conjugating RVG to a redox-sensitive biodegradable dendrimer-type arginine-grafted polymer (PAM-ABP) enabled nanoparticle formation with plasmid DNA without altering the environment-sensitive DNA release property and favorable toxicity profile of the parent polymer. Importantly, RVG-PAM-ABP quantitatively enhanced transfection into both hMSC and hESC compared to commercial transfection reagents like Lipofectamine 2000 and Fugene. ∼60% and 50% of hMSC and hESC were respectively transfected, and at increased levels on a per cell basis, without affecting pluripotency marker expression. RVG-PAM-ABP is thus a novel bioreducible, biocompatible, non-toxic, synthetic gene delivery system for nAchR-expressing stem cells. Our data also demonstrates that a cell-binding ligand like RVG can cooperate with a gene delivery system like PAM-ABP to enable transfection of poorly-permissive cells.

Persistent sleep disturbance: a risk factor for recurrent depression in community-dwelling older adults.

STUDY OBJECTIVES: The objective of this study was to examine the associations between the temporal and severity characteristics of sleep disturbance and subsequent depression in community-dwelling older adults. DESIGN: A prospective cohort study with assessment of sleep disturbance and depression at baseline and across 2 years of follow-up. SETTING: Three urban communities in the United States. PARTICIPANTS: Community-dwelling older adults in whom prior depression (n = 145), current depression (n = 68), or never mentally ill (n = 206) were diagnosed at the baseline assessment. MEASUREMENTS AND RESULTS: Major depression at year 2, defined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders. Among patients with either a depression history or current depression at baseline, persistent sleep disturbance throughout year 1 was associated with persistent or recurrent depression at year 2, after adjustment for group status, antidepressant and hypnotic sedative use, severity of depressive symptoms, chronic medical burden, and sociodemographic variables (adjusted odds ratio = 5.20, 95% confidence interval [CI] = 1.16 to 23.29). Among those who were not depressed at year 1, persistent sleep disturbance throughout year 1 predicted depression recurrence during year 2 (adjusted hazards ratio = 16.05, CI = 1.21 to 213.06), independent of the severity of sleep disturbance. None of the older adults who were never mentally ill developed a depression. CONCLUSIONS: Persistent sleep disturbance during a year-long period is associated with depression the following year. Among older adults with prior depression, identification of those with persistent sleep disturbance may optimize the efficacy of sleep related interventions to improve depression remission and/or prevent late-life depression.

Early life stress and inflammatory mechanisms of fatigue in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Fatigue is highly prevalent and causes serious disruption in quality of life. Although cross-sectional studies suggest childhood adversity is associated with adulthood fatigue, longitudinal evidence of this relationship and its specific biological mechanisms have not been established. This longitudinal study examined the association between early life stress and adulthood fatigue and tested whether this association was mediated by low-grade systemic inflammation as indexed by circulating C-reactive protein (CRP) and interleukin-6 (IL-6). In the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based longitudinal study conducted in 4 US cities, early life stress was retrospectively assessed in 2716 African-American and white adults using the Risky Families Questionnaire at Year 15 examination (2000-2001, ages 33-45 years). Fatigue as indexed by a loss of subjective vitality using the Vitality Subscale of the 12-item Short Form Health Survey was assessed at both Years 15 and 20. While CRP was measured at both Years 15 and 20, IL-6 was measured only at Year 20. Early life stress assessed at Year 15 was associated with adulthood fatigue at Year 20 after adjustment for sociodemographic characteristics, body-mass index, medication use, medical comorbidity, smoking, alcohol consumption, physical activity, current stress, pain, sleep disturbance as well as Year 15 fatigue (adjusted beta 0.047, P=0.007). However, neither CRP nor IL-6 was a significant mediator of this association. In summary, early life stress assessed in adulthood was associated with fatigue 5 years later, but this association was not mediated by low-grade systemic inflammation.

Gender, obesity and repeated elevation of C-reactive protein: data from the CARDIA cohort.

C-reactive Protein (CRP) measurements above 10 mg/L have been conventionally treated as acute inflammation and excluded from epidemiologic studies of chronic inflammation. However, recent evidence suggest that such CRP elevations can be seen even with chronic inflammation. The authors assessed 3,300 participants in The Coronary Artery Risk Development in Young Adults study, who had two or more CRP measurements between 1992/3 and 2005/6 to a) investigate characteristics associated with repeated CRP elevation above 10 mg/L; b) identify subgroups at high risk of repeated elevation; and c) investigate the effect of different CRP thresholds on the probability of an elevation being one-time rather than repeated. 225 participants (6.8%) had one-time and 103 (3.1%) had repeated CRP elevation above 10 mg/L. Repeated elevation was associated with obesity, female gender, low income, and sex hormone use. The probability of an elevation above 10 mg/L being one-time rather than repeated was lowest (51%) in women with body mass index above 31 kg/m(2), compared to 82% in others. These findings suggest that CRP elevations above 10 mg/L in obese women are likely to be from chronic rather than acute inflammation, and that CRP thresholds above 10 mg/L may be warranted to distinguish acute from chronic inflammation in obese women.

Psychometric analysis of the Korean version of the Disgust Scale-Revised.

OBJECTIVE: Disgust is a basic emotion associated with feelings of revulsion and withdrawal behaviors from dangerous situations. The aim of this study was to examine the psychometric properties of the Disgust Scale--Revised (DS-R), a tool designed to measure individuals' responses to various disgust-provoking situations, among Korean populations. METHODS: A sample of 1117 healthy volunteers completed self-report questionnaires containing the 27-item DS-R. A subsample (n = 231) completed the Temperament and Character Inventory (TCI), Eysenck Personality Questionnaire (EPQ), and State-Trait Anxiety Inventory (STAI). Principal component analysis using a varimax rotation was conducted. Construct validity was assessed using Pearson correlation analysis for the TCI, EPQ, and STAI. To examine differences in responses on the DS-R among populations, patients with obsessive-compulsive disorder were compared with healthy subjects who were matched with respect to age and sex. RESULTS: The Cronbach α estimates for total items and the 3 original subscales of the DS-R, including: core disgust, animal reminder disgust, and contamination-based disgust, were 0.86, 0.77, 0.80, and 0.55, respectively. Principal component analysis identified 5 factors, which accounted for 48% of the total variance of the scale. The 5 newly developed dimensions were labeled as core disgust-touch, core disgust-dirt, contamination-based disgust, animal reminder disgust, and social intolerance disgust. The Cronbach α coefficients were 0.79, 0.64, 0.46, 0.77, and 0.34, respectively, for these subscales. The DS-R was correlated positively with harm avoidance from the TCI, neuroticism from the EPQ, and the anxiety scores of STAI. Furthermore, the contamination-based disgust scores for patients with obsessive-compulsive disorder were higher than those of normal controls. CONCLUSION: The DS-R may be a reliable, valid, and acceptable tool to measure disgust sensitivity among Korean populations. The psychometric properties of the Korean version of the DS-R and the original DS-R are discussed.

Prior depression history and deterioration of physical health in community-dwelling older adults--a prospective cohort study.

OBJECTIVE: Depression worsens outcomes of physical illness. However, it is unknown whether this negative effect persists after depressive symptoms remit in older adults. This study examined whether prior depression history predicts deterioration of physical health in community-dwelling older adults. DESIGN: Prospective cohort study. SETTING: Three urban communities in the United States. PARTICIPANTS: Three hundred fifty-one adults aged 60 years or older-145 with a history of major or nonmajor depression in full remission and 206 concurrent age- and gender-matched comparison subjects with no history of mental illness. MEASUREMENTS: Participants were assessed at baseline, 6 weeks, 1 year, and 2 years for physical health functioning (the Physical Component Summary of the 36-Item Short-Form Health Survey) and chronic medical burden (the Chronic Disease Score). Given the repeated nature of measurements, linear mixed model regression was performed. RESULTS: Both physical functioning and chronic medical burden deteriorated more rapidly over time in the group with prior depression history compared with comparison subjects, and these changes were independent of the measures of mental health functioning, depressive symptoms, and sleep quality. Similar results were observed when those who developed depressive episodes during follow-up were excluded. CONCLUSION: A prior history of clinical depression is associated with a faster deterioration of physical health in community-dwelling older adults, which is not explained by current levels of depressive symptoms and mental health functioning or by recurrence of depressive episodes. Careful screening for a history of depression may identify those older adults at greatest risk for physical declines and chronic medical burden.

Prospective association between C-reactive protein and fatigue in the coronary artery risk development in young adults study.

BACKGROUND: Fatigue is highly prevalent and causes serious disruption in quality of life. Although the underlying biological mechanism is unknown, increases in inflammation have been implicated. This prospective study examined the association between C-reactive protein (CRP), a biomarker of systemic inflammation, and fatigue 5 years later. METHODS: The Coronary Artery Risk Development in Young Adults (CARDIA) study is a population-based longitudinal study conducted in four U.S. cities. Highly sensitive CRP concentration and fatigue were measured in 2983 African American and white adults at both year 15 (2000-2001, ages 33-45 years) and year 20 (2005-2006) examinations. Fatigue was assessed using the vitality subscale of the 12-item Short Form Health Survey. RESULTS: Plasma CRP concentration at baseline (i.e., CARDIA year 15) was a significant predictor of fatigue level 5 years later (unadjusted beta = .126, p < .001). After adjustment for potential confounders, this association remained significant (adjusted beta = .044, p = .033). Additionally, baseline CRP independently predicted fatigue in the subgroup of participants without medical comorbidity (adjusted beta = .051, p = .039). Fatigue was associated with a persistent elevation of CRP at both examinations but not with a transient elevation of CRP at only one of the examinations. CONCLUSIONS: This is the first study to demonstrate a prospective association between an inflammatory marker and fatigue in a general population. Furthermore, the association between low-grade systemic inflammation and fatigue seems primarily driven by persistent immune activation and not explained by the presence or development of medical comorbidity.

To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers.

Behavioral scientists have increasingly included inflammatory biology as mechanisms in their investigation of psychosocial dynamics on the pathobiology of disease. However, a lack of standardization of inclusion and exclusion criteria and assessment of relevant control variables impacts the interpretation of these studies. The present paper reviews and discusses human biobehavioral factors that can affect the measurement of circulating markers of inflammation. Keywords relevant to inflammatory biology and biobehavioral factors were searched through PubMed. Age, sex, and hormonal status, socioeconomic status, ethnicity and race, body mass index, exercise, diet, caffeine, smoking, alcohol, sleep disruption, antidepressants, aspirin, and medications for cardiovascular disease are all reviewed. A tiered set of recommendations as to whether each variable should be assessed, controlled for, or used as an exclusion criteria is provided. These recommendations provide a framework for observational and intervention studies investigating linkages between psychosocial and behavioral factors and inflammation.

Comparative epidemiology of chronic fatigue syndrome in Brazilian and British primary care: prevalence and recognition.

BACKGROUND: Although fatigue is a ubiquitous symptom across countries, clinical descriptions of chronic fatigue syndrome have arisen from a limited number of high-income countries. This might reflect differences in true prevalence or clinical recognition influenced by sociocultural factors. AIMS: To compare the prevalence, physician recognition and diagnosis of chronic fatigue syndrome in London and São Paulo. METHOD: Primary care patients in London (n=2459) and São Paulo (n=3914) were surveyed for the prevalence of chronic fatigue syndrome. Medical records were reviewed for the physician recognition and diagnosis. RESULTS: The prevalence of chronic fatigue syndrome according to Centers for Disease Control 1994 criteria was comparable in Britain and Brazil: 2.1% v. 1.6% (P=0.20). Medical records review identified 11 diagnosed cases of chronic fatigue syndrome in Britain, but none in Brazil (P<0.001). CONCLUSIONS: The primary care prevalence of chronic fatigue syndrome was similar in two culturally and economically distinct nations. However, doctors are unlikely to recognise and label chronic fatigue syndrome as a discrete disorder in Brazil. The recognition of this illness rather than the illness itself may be culturally induced.