A prospective study on the dynamics of the clinical and immunological evolution of human Leishmania (L.) infantum chagasi infection in the Brazilian Amazon region

This prospective study was carried out from October 2003 to December 2005 and involved a cohort of 946 individuals of both genders, aged 1-89 years, from an endemic area for American visceral leishmaniasis (AVL), in Para State, Brazil. The aim of the study was to analyze the dynamics of the clinical and immunological evolution of human Leishmania ( L.) infantum chagasi infection represented by the following clinical-immunological profiles: asymptomatic infection (AI); symptomatic infection (SI = AVL); subclinical oligosymptomatic infection (SOI); subclinical resistant infection (SRI); and indeterminate initial infection (III). Infection diagnosis was determined by the indirect fluorescent antibody test and leishmanin skin test. In total, 231 cases of infection were diagnosed: the AI profile was the most frequent (73.2%), followed by SRI (12.1%), III (9.9%), SI (2.6%) and SOI (2.2%). The major conclusion regarding evolution dynamics was that the III profile plays a pivotal role from which the cases evolve to either the resistant, SRI and AI, or susceptible, SOI and SI, profiles; only one of the 23 III cases evolved to SI, while most evolved to either SRI (nine cases) or SOI (five cases) and eight cases remained as III. (C) 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

A cross-sectional study on the clinical and immunological spectrum of human Leishmania (L.) infantum chagasi infection in the Brazilian Amazon region

The objectives of this study were to identify individuals with symptomatic and/or asymptomatic infection due to Leishmania (L.) infantum chagasi; to study the two types of infection, both clinically and immunologically, and to determine the prevalence rate of infection at the beginning of the study. This was a cross-sectional study with a cohort of 946 individuals, of both genders, from the age of 1 year, living in the municipality of Barcarena, PA, Brazil, an area endemic for American visceral leishmaniasis (AVL). The leishmanin skin test (LST) and the indirect fluorescent test (IFAT), were used for the diagnosis of infection. One hundred and twenty cases of infection were diagnosed, with a prevalence rate of 12.6%; eight cases showed high seroreactivity (1280-10240, IgG) in IFAT and no LST reaction; four of these cases were typical AVL and four had subclinical oligosymptomatic infection. Using two immunological methods with a clinical examination of the infected individuals enabled the identification of five clinical-immunological profiles which may promote a better understanding of the interaction between L. (L.) i. chagasi and the human immune response: asymptomatic infection (AI) 73.4%; subclinical resistant infection (SRI) 15%; subclinicat oligosymptomatic infection (SOI) 3%; symptomatic infection (AVL) 3% and indeterminate initial infection (III) 5%. (C) 2009 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative

Context: There is limited information on the prevalence and correlates of bipolar spectrum disorder in international population-based studies using common methods. Objectives: To describe the prevalence, impact, patterns of comorbidity, and patterns of service utilization for bipolar spectrum disorder (BPS) in the World Health Organization World Mental Health Survey Initiative. Design, Setting, and Participants: Crosssectional, face-to-face, household surveys of 61 392 community adults in 11 countries in the Americas, Europe, and Asia assessed with the World Mental Health version of the World Health Organization Composite International Diagnostic Interview, version 3.0, a fully structured, lay-administered psychiatric diagnostic interview. Main Outcome Measures: Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) disorders, severity, and treatment. Results: The aggregate lifetime prevalences were 0.6% for bipolar type I disorder (BP-I), 0.4% for BP-II, 1.4% for subthreshold BP, and 2.4% for BPS. Twelve-month prevalences were 0.4% for BP-I, 0.3% for BP-II, 0.8% for subthreshold BP, and 1.5% for BPS. Severity of both manic and depressive symptoms as well as suicidal behavior increased monotonically from subthreshold BP to BP-I. By contrast, role impairment was similar across BP subtypes. Symptom severity was greater for depressive episodes than manic episodes, with approximately 74.0% of respondents with depression and 50.9% of respondents with mania reporting severe role impairment. Three-quarters of those with BPS met criteria for at least 1 other disorder, with anxiety disorders (particularly panic attacks) being the most common comorbid condition. Less than half of those with lifetime BPS received mental health treatment, particularly in low-income countries, where only 25.2% reported contact with the mental health system. Conclusions: Despite cross-site variation in the prevalence rates of BPS, the severity, impact, and patterns of comorbidity were remarkably similar internationally. The uniform increases in clinical correlates, suicidal behavior, and comorbidity across each diagnostic category provide evidence for the validity of the concept of BPS. Treatment needs for BPS are often unmet, particularly in low-income countries.

Development of Lifetime Comorbidity in the World Health Organization World Mental Health Surveys

Context: Although numerous studies have examined the role of latent variables in the structure of comorbidity among mental disorders, none has examined their role in the development of comorbidity. Objective: To study the role of latent variables in the development of comorbidity among 18 lifetime DSM-IV disorders in the World Health Organization World Mental Health Surveys. Design: Nationally or regionally representative community surveys. Setting: Fourteen countries. Participants: A total of 21 229 survey respondents. Main Outcome Measures: First onset of 18 lifetime DSM-IV anxiety, mood, behavior, and substance disorders assessed retrospectively in the World Health Organization Composite International Diagnostic Interview. Results: Separate internalizing (anxiety and mood disorders) and externalizing (behavior and substance disorders) factors were found in exploratory factor analysis of lifetime disorders. Consistently significant positive time-lagged associations were found in survival analyses for virtually all temporally primary lifetime disorders predicting subsequent onset of other disorders. Within-domain (ie, internalizing or externalizing) associations were generally stronger than between-domain associations. Most time-lagged associations were explained by a model that assumed the existence of mediating latent internalizing and externalizing variables. Specific phobia and obsessive-compulsive disorder (internalizing) and hyperactivity and oppositional defiant disorders (externalizing) were the most important predictors. A small number of residual associations remained significant after controlling the latent variables. Conclusions: The good fit of the latent variable model suggests that common causal pathways account for most of the comorbidity among the disorders considered herein. These common pathways should be the focus of future research on the development of comorbidity, although several important pairwise associations that cannot be accounted for by latent variables also exist that warrant further focused study.

Twelve-Month Prevalence of and Risk Factors for Suicide Attempts in the World Health Organization World Mental Health Surveys

Objective: Although suicide is a leading cause of death worldwide, clinicians and researchers lack a data-driven method to assess the risk of suicide attempts. This study reports the results of an analysis of a large cross-national epidemiologic survey database that estimates the 12-month prevalence of suicidal behaviors, identifies risk factors for suicide attempts, and combines these factors to create a risk index for 12-month suicide attempts separately for developed and developing countries. Method: Data come from the World Health Organization (WHO) World Mental Health (WMH) Surveys (conducted 2001-2007), in which 108,705 adults from 21 countries were interviewed using the WHO Composite International Diagnostic Interview. The survey assessed suicidal behaviors and potential risk factors across multiple domains, including socio-demographic characteristics, parent psychopathology, childhood adversities, DSM-IV disorders, and history of suicidal behavior. Results: Twelve-month prevalence estimates of suicide ideation, plans, and attempts are 2.0%, 0.6%, and 0.3%, respectively, for developed countries and 2.1%, 0.7%, and 0.4%, respectively, for developing countries. Risk factors for suicidal behaviors in both developed and developing countries include female sex, younger age, lower education and income, unmarried status, unemployment, parent psychopathology, childhood adversities, and presence of diverse 12-month DSM-IV mental disorders. Combining risk factors from multiple domains produced risk indices that accurately predicted 12-month suicide attempts in both developed and developing countries (area under the receiver operating characteristic curve = 0.74-0.80). Conclusions: Suicidal behaviors occur at similar rates in both developed and developing countries. Risk indices assessing multiple domains can predict suicide attempts with fairly good accuracy and may be useful in aiding clinicians in the prediction of these behaviors. J Clin Psychiatry 2010;71(12):1617-1628 (C) Copyright 2010 Physicians Postgraduate Press, Inc.

Associations of serious mental illness with earnings: results from the WHO World Mental Health surveys

Background Burden-of-illness data, which are often used in setting healthcare policy-spending priorities, are unavailable for mental disorders in most countries. Aims To examine one central aspect of illness burden, the association of serious mental illness with earnings, in the World Health Organization (WHO) World Mental Health (WMH) Surveys. Method The WMH Surveys were carried out in 10 high-income and 9 low- and middle-income countries. The associations of personal earnings with serious mental illness were estimated. Results Respondents with serious mental illness earned on average a third less than median earnings, with no significant between-country differences (chi(2)(9)=5.5-8.1, P=0.5-0.79). These losses are equivalent to 0.3-0.8% of total national earnings. Reduced earnings among those with earnings and the increased probability of not earning are both important components of these associations: Conclusions These results add to a growing body of evidence that mental disorders have high societal costs. Decisions about healthcare resource allocation should take these costs into consideration.

AGE DIFFERENCES IN THE PREVALENCE AND CO-MORBIDITY OF DSM-IV MAJOR DEPRESSIVE EPISODES: RESULTS FROM THE WHO WORLD MENTAL HEALTH SURVEY INITIATIVE

Background: Although depression appears to decrease in late life, this could be due to misattribution of depressive symptoms to physical disorders that increase in late we. Methods: We investigated this issue by studying age differences in co-morbidity of DSM-IV major depressive episodes (MDE) with chronic physical conditions in the WHO World Mental Health (WMH) surveys, a series of community epidemiological surveys of respondents in 10 developed countries (n = 52,485) and 8 developing countries (n = 37,265). MDE and other mental disorders were assessed with the Composite International Diagnostic Interview (CIDI). Organic exclusion rules were not used to avoid inappropriate exclusion of cases with physical co-morbidity. Physical conditions were assessed with a standard chronic conditions checklist. Results: Twelve-month DSM-IV/CIDI MDE was significantly less prevalent among respondents ages 65+ than younger respondents in developed but not developing countries. Prevalence of co-morbid mental disorders generally either decreased or remained stable with age, while co-morbidity of MDE with mental disorders generally increased with age. Prevalence of physical conditions, in comparison, generally increased with age, while co-morbidity of MDE with physical conditions generally decreased with age. Depression treatment was lowest among the elderly in developed and developing countries. Conclusions: The weakening associations between MDE and physical conditions with increasing age argue against the suggestion that the low estimated prevalence of MDE among the elderly is due to increased confounding with physical disorders. Future study is needed to investigate processes that might lead to a decreasing impact of physical illness on depression among the elderly. Depression and Anxiety 27:351-364, 2010. (C) 2009 Wiley-Liss, Inc.

Treatment of suicidal people around the world

Background Suicide is a leading cause of death worldwide; however, little information is available about the treatment of suicidal people, or about barriers to treatment. Aims To examine the receipt of mental health treatment and barriers to care among suicidal people around the world. Method Twenty-one nationally representative samples worldwide (n=55 302; age 18 years and over) from the World Health Organization`s World Mental Health Surveys were interviewed regarding past-year suicidal behaviour and past-year healthcare use. Suicidal respondents who had not used services in the past year were asked why they had not sought care. Results Two-fifths of the suicidal respondents had received treatment (from 17% in low-income countries to 56% in high-income countries), mostly from a general medical practitioner (22%), psychiatrist (15%) or non-psychiatrist (15%). Those who had actually attempted suicide were more likely to receive care. Low perceived need was the most important reason for not seeking help (58%), followed by attitudinal barriers such as the wish to handle the problem alone (40%) and structural barriers such as financial concerns (15%). Only 7% of respondents endorsed stigma as a reason for not seeking treatment. Conclusions Most people with suicide ideation, plans and attempts receive no treatment. This is a consistent and pervasive finding, especially in low-income countries. Improving the receipt of treatment worldwide will have to take into account culture-specific factors that may influence the process of help-seeking.

High prevalence of dementia among older adults from poor socioeconomic backgrounds in Sao Paulo, Brazil

Background: The aim of this study was to determine the prevalence of dementia in a socioeconomically disadvantaged population of older adults living in the city of Sao Paulo, Brazil. Methods: A cross-sectional one-phase population-based study was carried out among all residents aged >= 65 in defined census sectors of an economically disadvantaged area of Sao Paulo. Identification of cases of dementia followed the protocol developed by the 10/66 Dementia Research Group. Results: Of 2072 individuals in the study, 105 met the criteria for a diagnosis of dementia, yielding a prevalence of 5.1%. Prevalence increased with age for both men and women after age 75 years, but was stable from 65 to 74 years. Low education and income were associated with increased risk of dementia. Conclusions: The prevalence of dementia among older adults from low socioeconomic backgrounds is high. This may be partly due to adverse socioeconomic conditions and consequent failure to compress morbidity into the latter stages of life. The increasing survival of poorer older adults with dementia living in developing countries may lead to a rapid increase in the prevalence of dementia worldwide.

Regulation of type 17 helper T-cell function by nitric oxide during inflammation

Type 17 helper T (Th17) cells are implicated in the pathogenesis many of human autoimmune diseases. Development of Th17 can be enhanced by the activation of aryl hydrocarbon receptor (AHR) whose ligands include the environmental pollutant dioxin, potentially linking environmental factors to the increased prevalence of autoimmune disease. We report here that nitric oxide (NO) can suppress the proliferation and function of polarized murine and human Th17 cells. NO also inhibits AHR expression in Th17 cells and the downstream events of AHR activation, including IL-22, IL-23 receptor, and Cyp1a1. Conversely, NO did not affect the polarization of Th17 cells from mice deficient in AHR. Furthermore, mice lacking inducible nitric oxide synthase (Nos2(-/-)) developed more severe experimental autoimmune encephalomyelitis than WT mice, with elevated AHR expression, increased IL-17A, and IL-22 synthesis. NO may therefore represent an important endogenous regulator to prevent overexpansion of Th17 cells and control of autoimmune diseases caused by environmental pollutants.

IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy

Objectives Interleukin 33 (IL-33) is a new member of the IL-1 family of cytokines which signals via its receptor, ST2 (IL-33R), and has an important role in Th2 and mast cell responses. This study shows that IL-33 orchestrates neutrophil migration in arthritis. Methods and results Methylated bovine serum albumin (mBSA) challenge in the knee joint of mBSA-immunised mice induced local neutrophil migration accompanied by increased IL-33R and IL-33 mRNA expression. Cell migration was inhibited by systemic and local treatments with soluble (s) IL-33R, an IL-33 decoy receptor, and was not evident in IL-33R-deficient mice. IL-33 injection also induced IL-33R-dependent neutrophil migration. Antigen- and IL-33-induced neutrophil migration in the joint was dependent on CXCL1, CCL3, tumour necrosis factor a (TNF alpha) and IL-1 beta synthesis. Synovial tissue, macrophages and activated neutrophils expressed IL-33R. IL-33 induces neutrophil migration by activating macrophages to produce chemokines and cytokines and by directly acting on neutrophils. Importantly, neutrophils from patients with rheumatoid arthritis successfully treated with anti-TNF alpha antibody (infliximab) expressed significantly lower levels of IL-33R than patients treated with methotrexate alone. Only neutrophils from patients treated with methotrexate alone or from normal donors stimulated with TNF alpha responded to IL-33 in chemotaxis. Conclusions These results suggest that suppression of IL-33R expression in neutrophils, preventing IL-33-induced neutrophil migration, may be an important mechanism of anti-TNF alpha therapy of inflammation.

Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection

Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options(1,2). Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33-treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (T(H)1) to T(H)2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection(3). Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration(4). We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors(5,6). Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsis.

THE INFLUENCE OF VIBRISSAL SOMATOSENSORY PROCESSING IN RAT SUPERIOR COLLICULUS ON PREY CAPTURE

The lateral part of intermediate layer of superior colliculus (SCI) is a critical substrate for successful predation by rats. Hunting-evoked expression of the activity marker Fos is concentrated in SCI while prey capture in rats with NMDA lesions in SCI is impaired. Particularly affected are rapid orienting and stereotyped sequences of actions associated with predation of fast moving prey. Such deficits are consistent with the view that the deep layers of SC are important for sensory guidance of movement. Although much of the relevant evidence involves visual control of movement, less is known about movement guidance by somatosensory input from vibrissae. Indeed, our impression is that prey contact with whiskers is a likely stimulus to trigger predation. Moreover, SCI receives whisker and orofacial somatosensory information directly from trigeminal complex, and indirectly from zona incerta, parvicelular reticular formation and somatosensory barrel cortex. To better understand sensory guidance of predation by vibrissal information we investigated prey capture by rats after whisker removal and the role of superior colliculus (SC) by comparing Fos expression after hunting with and without whiskers. Rats were allowed to hunt cockroaches, after which their whiskers were removed. Two days later they were allowed to hunt cockroaches again. Without whiskers the rats were less able to retain the cockroaches after capture and less able to pursue them in the event of the cockroach escaping. The predatory behaviour of rats with re-grown whiskers returned to normal. In parallel, Fos expression in SCI induced by predation was significantly reduced in whiskerless animals. We conclude that whiskers contribute to the efficiency of rat prey capture and that the loss of vibrissal input to SCI, as reflected by reduced Fos expression, could play a critical role in predatory deficits of whiskerless rats. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

P2X4 receptors interact with both P2X2 and P2X7 receptors in the form of homotrimers

BACKGROUND AND PURPOSE The P2X receptor family consists of seven subunit types - P2X1-P2X7. All but P2X6 are able to assemble as homotrimers. In addition, various subunit permutations have been reported to form heterotrimers. Evidence for heterotrimer formation includes co-localization, co-immunoprecipitation and the generation of receptors with novel functional properties; however, direct structural evidence for heteromer formation, such as chemical cross-linking and single-molecule imaging, is available in only a few cases. Here we examined the nature of the interaction between two pairs of subunits - P2X2 and P2X4, and P2X4 and P2X7. EXPERIMENTAL APPROACH We used several experimental approaches, including in situ proximity ligation, co-immunoprecipitation, co-isolation on affinity beads, chemical cross-linking and atomic force microscopy (AFM) imaging. KEY RESULTS Both pairs of subunits co-localize upon co-transfection, interact intimately within cells, and can be co-immunoprecipitated and co-isolated from cell extracts. Despite this, chemical cross-linking failed to show evidence for heteromer formation. AFM imaging of isolated receptors showed that all three subunits had the propensity to form receptor dimers. This self-association is likely to account for the observed close interaction between the subunit pairs, in the absence of true heteromer formation. CONCLUSIONS AND IMPLICATIONS We conclude that both pairs of receptors interact in the form of distinct homomers. We urge caution in the interpretation of biochemical evidence indicating heteromer formation in other cases.

Modulation of effective connectivity during emotional processing by Delta(9)-tetrahydrocannabinol and cannabidiol

Cannabis sativa, the most widely used illicit drug, has profound effects on levels of anxiety in animals and humans. Although recent studies have helped provide a better understanding of the neurofunctional correlates of these effects, indicating the involvement of the amygdala and cingulate cortex, their reciprocal influence is still mostly unknown. In this study dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to explore the effects of pure compounds of C. sativa [600 mg of cannabidiol (CBD) and 10 mg Delta(9)-tetrahydrocannabinol (Delta(9)-THC)] on prefrontal-subcortical effective connectivity in 15 healthy subjects who underwent a double-blind randomized, placebo-controlled fMRI paradigm while viewing faces which elicited different levels of anxiety. In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not Delta(9)-THC disrupted forward connectivity between these regions during the neural response to fearful faces. This is the first study to show that the disruption of prefrontal-subocrtical connectivity by CBD may represent neurophysiological correlates of its anxiolytic properties.