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Introduction Alcohol Use Disorders are frequently comorbid with personality disorders. However, the heterogeneity of the prevalence estimates is high, and most data come from high income countries. Our aim is to estimate the prevalence and association between alcohol use outcomes and the three DSM-5 clusters of personality disorders in a representative sample of the São Paulo Metropolitan Area. Materials and methods A representative household sample of 2,942 adults was interviewed using the WHO Composite International Diagnostic Interview and the International Personality Disorder Examination Screening Questionnaire. Lifetime PD diagnoses were multiply imputed, and AUD diagnoses were obtained using DSM-5 criteria. We conducted cross-tabulations and logistic regression to estimate the associations between AUDs and PDs. Results and discussion Our study did not find significant associations of PDs with heavy drinking patterns or mild AUD. Cluster B PD respondents tended to show the highest conditional prevalence estimates of most alcohol use patterns and AUD, including its severity subtypes. When alcohol outcomes were regressed on all PD Clusters simultaneously, with adjustment for sex and age, only cluster B was significantly associated with past-year alcohol use (OR 3.0), regular drinking (OR 3.2), and AUDs (OR 8.5), especially moderate and severe cases of alcohol use disorders (OR 9.7 and 16.6, respectively). These associations between Cluster B PDs and these alcohol outcomes were shown to be independent of other PD Clusters and individuals´ sex and age. Conclusion The main finding of our study is that AUDs are highly comorbid with PDs. The presence of Cluster B PDs significantly increases the odds of alcohol consumption and disorders and of more severe forms of AUDs. Considering the local context of poor treatment provision, more specific prevention and intervention strategies should be directed to this population.

BACKGROUND: There are still few studies on predictors of smoking cessation in Brazilian samples. Experimentation with tobacco during adolescence (ETA) may be one of the important predictors. OBJECTIVE: This study aimed, within the context of a treatment-seeking group of subjects, to test the hypothesis that ETA negatively affects the outcome of smoking cessation during adulthood. DESIGN AND SETTING: Retrospective (historic) cohort study conducted at a psychosocial care center in São Paulo, Brazil, between 2007 and 2010. METHODS: Data on sociodemographics, smoking and medical profiles were obtained through self-report questionnaires that were completed at the baseline and at any follow-up appointment. Logistic regression models were constructed to describe factors associated with the outcome of smoking cessation, measured according to the self-reported four-week success rate among 367 outpatient smokers. RESULTS: ETA was found to be associated with not quitting smoking through the treatment (odds ratio = 0.57; 95% confidence interval = 0.33-0.96; P < 0.05), even after adjustment for dependence level, sociodemographics, nicotine patch use and number of years of smoking. CONCLUSIONS: Early exposure to nicotine may lead to higher risk of continuing smoking after treatment, in adulthood.

The implementation of early interventions stands out as an interesting approach to reduce harmful use of alcohol by focusing on the early recognition, diagnosis, and treatment across the full trajectory of alcohol use before more severe consequences occur. This chapter provides a brief overview of the literature on early intervention in harmful use of alcohol in Brazil—the largest middle-income country in Latin America, where alcohol use represents a significant burden. Though the scenario is rather worrisome, advances have been made in the past years: more research has been developed and public policies have been carried out to reduce such a burden. Early interventions focused on young people (underage and college students) should be given primarily, with a particularly growing concern on girls. There is robust evidence that screening and brief interventions (SBIs) can, in the short term, reduce problems related to alcohol use, at lower costs than more intensive treatments worldwide. In Brazil, the barriers for its implementation in primary care services seem to be related to integration and intersectional healthcare settings, and to training of professionals, the latter of which could initially be tackled through distance-learning approaches. Further research is still necessary to develop and evaluate SBI approaches addressing vulnerable populations. Finally, the reduction of harmful alcohol-use related consequences requires the joint effort of civil society, government, and the private sector, with special engagement of public health and research institutes to consolidate evidence-based strategies and measures.

PURPOSE: We estimate the proportion of psychotropic medication use (PMU) among adults in Sao Paulo Metropolitan Area, Brazil. We investigated whether socio-demographic factors, comorbidity, and disease severity influence PMU among individuals with psychiatric disorders. METHODS: Data are from the Sao Paulo Megacity Mental Health Survey, a cross-sectional, population-based study, the Brazilian branch of the World Mental Health Survey Initiative. Trained lay interviewers face-to-face assessed psychiatric disorders and PMU through the Composite International Diagnostic Interview. Respondents were asked about use of healthcare service and prescribed medications for mental disorders in the previous year. Information on PMU was collected for 2935 adult residents in the area and among those with disorders who received treatment. RESULTS: Around 6% of respondents reported PMU in the past year: hypnotics or sedatives were used by 3.7% and antidepressants by 3.5%. Among individuals with 12-month disorders, only 14% reported past year PMU. Gender, age, education, income, occupational status, comorbidity, and severity were significant predictors for PMU. Among those with 12-month DSM-IV disorders who obtained treatment in healthcare settings, almost 40% received medication only. Among those treated in specialty mental health service, around 23% received combination of medication and psychotherapy. CONCLUSION: Our study has pointed out that the recent trend of access to mental healthcare in Brazil depicts unmet needs, characterized by a low prevalence of PMU among individuals with psychiatric disorders. Policies that improve appropriate access to prescribed drugs for those most in need are urgent public health priority. Copyright © 2015 John Wiley & Sons, Ltd. Language: en

OBJECTIVES: To investigate the relative importance of common physical and mental disorders with regard to the number of days out-of-role (DOR; number of days for which a person is completely unable to work or carry out normal activities because of health problems) in a population-based sample of adults in the São Paulo Metropolitan Area, Brazil. METHODS: The São Paulo Megacity Mental Health Survey was administered during face-to-face interviews with 2,942 adult household residents. The presence of 8 chronic physical disorders and 3 classes of mental disorders (mood, anxiety, and substance use disorders) was assessed for the previous year along with the number of days in the previous month for which each respondent was completely unable to work or carry out normal daily activities due to health problems. Using multiple regression analysis, we examined the associations of the disorders and their comorbidities with the number of days out-of-role while controlling for socio-demographic variables. Both individual-level and population-level associations were assessed. RESULTS: A total of 13.1% of the respondents reported 1 or more days out-of-role in the previous month, with an annual median of 41.4 days out-of-role. The disorders considered in this study accounted for 71.7% of all DOR; the disorders that caused the greatest number of DOR at the individual-level were digestive (22.6), mood (19.9), substance use (15.0), chronic pain (16.5), and anxiety (14.0) disorders. The disorders associated with the highest population-attributable DOR were chronic pain (35.2%), mood (16.5%), and anxiety (15.0%) disorders. CONCLUSIONS: Because pain, anxiety, and mood disorders have high effects at both the individual and societal levels, targeted interventions to reduce the impairments associated with these disorders have the highest potential to reduce the societal burdens of chronic illness in the São Paulo Metropolitan Area.

OBJECTIVE: To investigate drinking patterns and gender differences in alcohol-related problems in a Brazilian population, with an emphasis on the frequency of heavy drinking. METHODS: A cross-sectional study was conducted with a probability adult household sample (n = 1,464) in the city of São Paulo, Brazil. Alcohol intake and ICD-10 psychopathology diagnoses were assessed with the Composite International Diagnostic Interview 1.1. The analyses focused on the prevalence and determinants of 12-month non-heavy drinking, heavy episodic drinking (4-5 drinks per occasion), and heavy and frequent drinking (heavy drinking at least 3 times/week), as well as associated alcohol-related problems according to drinking patterns and gender. RESULTS: Nearly 22% (32.4% women, 8.7% men) of the subjects were lifetime abstainers, 60.3% were non-heavy drinkers, and 17.5% reported heavy drinking in a 12-month period (26.3% men, 10.9% women). Subjects with the highest frequency of heavy drinking reported the most problems. Among subjects who did not engage in heavy drinking, men reported more problems than did women. A gender convergence in the amount of problems was observed when considering heavy drinking patterns. Heavy and frequent drinkers were twice as likely as abstainers to present lifetime depressive disorders. Lifetime nicotine dependence was associated with all drinking patterns. Heavy and frequent drinking was not restricted to young ages. CONCLUSIONS: Heavy and frequent episodic drinking was strongly associated with problems in a community sample from the largest city in Latin America. Prevention policies should target this drinking pattern, independent of age or gender. These findings warrant continued research on risky drinking behavior, particularly among persistent heavy drinkers at the non-dependent level.

The aim of the present study was to investigate the activation of rapid signaling events by 17β-estradiol in the rat uterus. 17β-Estradiol induced a rapid increase of total [3H]-inositol phosphate accumulation in the whole uterus and endometrium, but not in the myometrium. The effect of 17β-estradiol in the endometrium was blocked by phospholipase C (PLC) inhibitor (U73122), estrogen receptors antagonist (ICI 182,780), exportin CRM1 inhibitor (leptomycin B) and selective inhibitor of the SRC family of protein tyrosine kinases (PP2). Furthermore, a selective agonist of ESR1 (PPT) and a selective agonist of GPER (G-1) also induced a rapid increase of total [(3)H]-inositol phosphate accumulation in the endometrium. The G-1 effects were blocked by GPER antagonist (G-15). 17β-Estradiol and G-1 promoted an additive effect on total [3H]-inositol phosphate accumulation. In conclusion, the present results indicate that a rapid activation of the PLC-mediated phosphoinositide hydrolysis occurred in the rat endometrium after 17β-estradiol stimulation, and this effect was mediated by ESR1 that underwent nuclear export after hormone stimulation, and that GPER activation may play an additive role for this response. These rapid actions might be one of the key steps that mediate the estrogen-dependent activation of cellular events in the endometrium.

Estrogen plays a key role in maintaining the morphology and function of the efferent ductules. We previously demonstrated that the antiestrogen fulvestrant markedly affected gene expression in the rat efferent ductules. The mechanism of fulvestrant action to modulate gene expression may involve not only the blockade of ESR1 and ESR2 estrogen receptors, but also the activation of ESR1 and ESR2 when the receptors are tethered to AP-1 or SP1 transcription factors, or the activation of the G protein-coupled estrogen receptor 1. We therefore compared the effects of two strategies to interfere with estrogen action in the rat efferent ductules: treatment with fulvestrant or with the aromatase inhibitor anastrozole. Whereas fulvestrant markedly increased Mmp7 and Spp1, and reduced Nptx1 mRNA levels, no changes were observed with anastrozole. Fulvestrant caused changes in epithelial morphology that were not seen with anastrozole. Fulvestrant shifted MMP7 immunolocalization in the epithelial cells from the supranuclear to the apical region; this effect was less pronounced with anastrozole. In vitro studies of (35)S-methionine incorporation showed that protein release was increased, whereas tissue protein content in the efferent ductules of fulvestrant-treated rats was decreased. Although fulvestrant markedly affected gene expression, no changes were observed on AP-1 and SP1 DNA-binding activity. The blockade of ESRs seems to be the major reason explaining the differences between both treatments. At least some of the effects of fulvestrant appear to result from compensatory mechanisms activated by the dramatic changes caused by ESR1 blockade.

This study proposed to investigate further the role of oestrogens during pubertal growth of rat ventral prostate, by analysing the effect of anti-oestrogen fulvestrant (ICI 182,780) on the expression of androgen (AR) and oestrogen receptors (ESR1 and ESR2), mitogen-activated protein kinase (ERK1/2) phosphorylation, and expression of Ki-67, a biomarker for cell proliferation. Ventral prostates were obtained from 90-day-old rats treated once a week for 2 months with vehicle (control) or ICI 182,780 (10 mg/rat, s.c.). Transcripts for AR, ESR1 and ESR2 were evaluated by quantitative real-time polymerase chain reaction. Expression of AR, ESR1, ESR2, total and phospho-ERK1/2 was analysed by Western blot or immunofluorescence. Ki-67-positive cells and myosin heavy chain were detected by immunohistochemistry. Cylindrical epithelial cells slightly taller, epithelial dysplasia and an increase in smooth muscle layer were observed in the ventral prostate from ICI 182,780-treated rats. ICI 182,780 did not change the mRNA, but decreased the protein levels for AR in the ventral prostate. The expression of ESR1 (mRNA and protein) was upregulated by ICI 182,780, but no changes were observed on ESR2 expression (mRNA and protein). ICI 182,780 decreased the phosphorylation state of ERK1/2, with no changes in total ERK1/2 levels. Ki-67-positive cells in the ventral prostate were also decreased by ICI 182,780. In conclusion, ICI 182,780 induces downregulation of AR expression and may block the translocation of ESR1 and ESR2 from the nucleus to the plasma membrane, decreasing ERK1/2 phosphorylation and prostatic epithelial cell proliferation. These findings provide a basis for physiological roles of oestrogen in the ventral prostate. Further studies with fulvestrant are necessary in benign prostate hyperplasia and prostatic cancer models.

The aim of the present study was to investigate the expression and signaling of the G protein-coupled estrogen receptor 1 (GPER) in cultured immature rat Sertoli cells—in which we have previously described the classical estrogen receptors (ESR1 and ESR2). Expression of GPER in cultured Sertoli cells from 15-day-old rats was detected by RT-PCR and immunoassays. Gper transcripts also were present in testes from 5-, 15-, and 120-day-old rats. Short-term treatment of Sertoli cells with 17beta-estradiol (E2), the GPER agonist G-1, or the ESR antagonist ICI 182,780 (ICI) rapidly activated MAPK3/1 (ERK1/2), even after down-regulation of ESR1 and ESR2, suggesting a role for GPER in the rapid E2 action in these cells. MAPK3/1 phosphorylation induced by ICI or G-1 was blocked by pertussis toxin, selective inhibitor of the SRC family of protein tyrosine kinases, metalloprotease inhibitor, MAP2K1/2 inhibitor, and epidermal growth factor receptor (EGFR) kinase inhibitor. Furthermore, E2, but not G-1, induced up-regulation of cyclin D1 in the Sertoli cells. This effect was blocked by ICI. E2 and G-1 decreased BAX and increased BCL2 expression and these effects were blocked by MAP2K1/2 inhibitor and EGFR kinase inhibitor. The pretreatment with ICI did not block the effect of E2. Taken together, these results indicate that in Sertoli cells 1) GPER-mediated MAPK3/1 activation occurs via EGFR transactivation through G protein beta gamma subunits that promote SRC-mediated metalloprotease-dependent release of EGFR ligands, which bind to EGFR and lead to MAPK3/1 phosphorylation; 2) E2-ESRs play a role in Sertoli cell proliferation; and 3) E2-GPER may regulate gene expression involved with apoptosis. ESR and GPER may mediate actions important for Sertoli cell function and maintenance of normal testis development and homeostasis.

Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans and rodents. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based compounds (e.g., bisphenols) may account for the recent declining fertility in men among developed countries by reducing sperm count and testis function. In this review, we critically discuss recent data in the field that have demonstrated the Cd-induced toxicity to the testis is probably the result of interactions of a complex network of causes. This is likely to involve the disruption of the blood-testis barrier (BTB) via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK). We also summarize current studies on factors that confer and/or regulate the testis sensitivity to Cd, such as Cd transporters and metallothioneins, the impact of Cd on the testis as an endocrine disruptor and oxidative stress inducer, and how it may disrupt the Zn(2+) and/or Ca(2+) mediated cellular events. While much work is needed before a unified mechanistic pathway of Cd-induced testicular toxicity emerges, recent studies have helped to identify some of the likely mechanisms and/or events that take place during Cd-induced testis injury. Furthermore, some of the recent studies have shed lights on potential therapeutic or preventive approaches that can be developed in future studies by blocking or minimizing the destructive effects of Cd to testicular function in men.

The efferent ductules express the highest amount of estrogen receptors ESR1 (ERalpha) and ESR2 (ERbeta) within the male reproductive tract. Treatment of rats with the antiestrogen fulvestrant (ICI 182,780) causes inhibition of fluid reabsorption in the efferent ductules, leading to seminiferous tubule atrophy and infertility. To provide a more comprehensive knowledge about the molecular targets for estrogen in the rat efferent ductules, we investigated the effects of ICI 182,780 treatment on gene expression using a microarray approach. Treatment with ICI 182,780 increased or reduced at least 2-fold the expression of 263 and 98 genes, respectively. Not surprisingly, several genes that encode ion channels and macromolecule transporters were affected. Interestingly, treatment with ICI 182,780 markedly altered the expression of genes related to extracellular matrix organization. Matrix metalloproteinase 7 (Mmp7), osteopontin (Spp1), and neuronal pentraxin 1 (Nptx1) were among the most altered genes in this category. Upregulation of Mmp7 and Spp1 and downregulation of Nptx1 were validated by Northern blot. Increase in Mmp7 expression was further confirmed by immunohistochemistry and probably accounted for the decrease in collagen content observed in the efferent ductules of ICI 182,780-treated animals. Downregulation of Nptx1 probably contributed to the extracellular matrix changes and decreased amyloid deposition in the efferent ductules of ICI 182,780-treated animals. Identification of new molecular targets for estrogen action may help elucidate the regulatory role of this hormone in the male reproductive tract.

The aim of the present study was to determine the mechanisms involved in estrogen actions in cultured rat Sertoli cells. RT-PCR detected transcripts for the estrogen receptors ESR1 and ESR2 in cultured immature Sertoli cells and in the testis of 15-, 28-, and 120-day-old rats. The expression of ESR1 and ESR2 was confirmed in Sertoli cells by immunofluorescence and Western blot. Immunohistochemistry with cryosections of testes from immature and adult rats revealed that ESR1 is present in Sertoli, Leydig, and some peritubular myoid cells, and ESR2 is present in multiple cell types, including germ cells. Treatment of Sertoli cells with 17beta-estradiol (E2) induced a translocation of ESR1 and ESR2 to the plasma membrane and a concomitant phosphorylation of MAPK3/1. Both effects reached a maximum after 10 min and were blocked by PP2, an inhibitor of the SRC family of protein tyrosine kinases, and by the antiestrogen ICI 182,780 (ICI). MAPK3/1 phosphorylation was also decreased in the presence of AG 1...

We estimate the proportion of psychotropic medication use (PMU) among adults in São Paulo Metropolitan Area, Brazil. We investigated whether socio-demographic factors, comorbidity, and disease severity influence PMU among individuals with psychiatric disorders.Data are from the São Paulo Megacity Mental Health Survey, a cross-sectional, population-based study, the Brazilian branch of the World Mental Health Survey Initiative. Trained lay interviewers face-to-face assessed psychiatric disorders and PMU through the Composite International Diagnostic Interview. Respondents were asked about use of healthcare service and prescribed medications for mental disorders in the previous year. Information on PMU was collected for 2935 adult residents in the area and among those with disorders who received treatment.Around 6% of respondents reported PMU in the past year: hypnotics or sedatives were used by 3.7% and antidepressants by 3.5%. Among individuals with 12-month disorders, only 14% reported past year PMU. Gender, age, education, income, occupational status, comorbidity, and severity were significant predictors for PMU. Among those with 12-month DSM-IV disorders who obtained treatment in healthcare settings, almost 40% received medication only. Among those treated in specialty mental health service, around 23% received combination of medication and psychotherapy.Our study has pointed out that the recent trend of access to mental healthcare in Brazil depicts unmet needs, characterized by a low prevalence of PMU among individuals with psychiatric disorders. Policies that improve appropriate access to prescribed drugs for those most in need are urgent public health priority.

Background: Given the recent launch of a new diagnostic classification (DSM-5) for alcohol use disorders (AUD), we aimed to investigate its dimensionality and possible measurement bias in a non-U.S. sample. Methods: The current analyses were restricted to 948 subjects who endorsed drinking at least one drink per week in the past year from a sample of 5037 individuals. Data came from São Paulo Megacity Project (which is part of World Mental Health Surveys) collected between 2005 and 2007. First, exploratory factor analysis (EFA) was carried out to test for the best dimensional structure for DSM-5-AUD criteria. Then, item response theory (IRT) was used to investigate the severity and discrimination properties of each criterion of DSM-5-AUD. Finally, differential criterion functioning (DCF) were investigated by socio-demographics (income, gender, age, employment status, marital status and education). All analyses were performed in Mplus software taking into account complex survey design features. Results: The best EFA model was a one-dimensional model. IRT results showed that the criteria “Time Spent” and “Given Up” have the highest discrimination and severity properties, while the criterion “Larger/Longer” had the lowest value of severity, but an average value of discrimination. Only female gender had DCF both at criterion- and factor-level, rendering measurement bias. Conclusion: This study reinforces the existence of a DSM-5-AUD continuum in the largest metropolitan area of South America, including subgroups that had previously higher rates of alcohol use (lower educational/income levels). Lower DSM-5-AUD scores were found in women.

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) The role of oestrogens in epididymal function is still unclear. Knockout of the oestrogen receptor ESR1 (Esr1-/-) or treatment with the anti-oestrogen Fulvestrant affect epididymal milieu and sperm motility. We investigated the effect of in vivo treatment of rats with Fulvestrant on: (i) expression of genes that may be important for the architecture and function of the epididymal epithelium: prominins 1 and 2, metalloproteinase 7, claudin 7, beta-catenin and cadherin 13, and (ii) levels of oestradiol and testosterone, and expression of oestrogen and androgen receptors, in the initial segment (IS), caput, corpus and cauda epididymis. Fulvestrant (i) reduced gene expression of prominin 1 (variant 1) in the caput, reduced prominin 1 protein content in the caput epididymis and in the efferent ductules, and increased the localization of prominin 1 in microvilli of the caput and corpus; (ii) reduced gene expression of prominin 2 in the corpus and cauda epididymis; (iii) increased the metalloproteinase 7 content in the apical region of principal cells from IS/caput; (iv) reduced in the corpus epididymis, but increased in the efferent ductules, the cadherin 13 mRNA level; (v) reduced testosterone but increased oestradiol levels in the corpus and cauda; (vi) increased the androgen receptor protein content in all regions of the epididymis, and the oestrogen receptor GPER in the corpus and cauda epididymis. in conclusion, treatment with Fulvestrant induced regional-specific changes in hormonal and steroid receptor content, and affected expression of proteins important for epithelial organization and absorption/secretion. the mechanisms of oestrogen action may differ among epididymal regions, which may contribute to determine region-specific sperm functions. Universidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, BR-04044020 São Paulo, Brazil Univ Illinois, Dept Comparat Biosci, Urbana, IL 61801 USA Univ Fed Minas Gerais, Dept Morphol, Belo Horizonte, MG, Brazil Universidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, BR-04044020 São Paulo, Brazil FAPESP: 2008/56564-1 Web of Science

BACKGROUND: Research conducted in high-income countries has investigated influences of socioeconomic inequalities on drinking outcomes such as alcohol use disorders (AUD), however, associations between area-level neighborhood social deprivation (NSD) and individual socioeconomic status with these outcomes have not been explored in Brazil. Thus, we investigated the role of these factors on drink-related outcomes in a Brazilian population, attending to male-female variations. METHODS: A multi-stage area probability sample of adult household residents in the Sao Paulo Metropolitan Area was assessed using the WHO Composite International Diagnostic Interview (WMH-CIDI) (n = 5,037). Estimation focused on prevalence and correlates of past-year alcohol disturbances [heavy drinking of lower frequency (HDLF), heavy drinking of higher frequency (HDHF), abuse, dependence, and DMS-5 AUD] among regular users (RU); odds ratio (OR) were obtained. RESULTS: Higher NSD, measured as an area-level variable with individual level variables held constant, showed an excess odds for most alcohol disturbances analyzed. Prevalence estimates for HDLF and HDHF among RU were 9% and 20%, respectively, with excess odds in higher NSD areas; schooling (inverse association) and low income were associated with male HDLF. The only individual-level association with female HDLF involved employment status. Prevalence estimates for abuse, dependence, and DSM-5 AUD among RU were 8%, 4%, and 8%, respectively, with excess odds of: dependence in higher NSD areas for males; abuse and AUD for females. Among RU, AUD was associated with unemployment, and low education with dependence and AUD. CONCLUSIONS: Regular alcohol users with alcohol-related disturbances are more likely to be found where area-level neighborhood characteristics reflect social disadvantage. Although we cannot draw inferences about causal influence, the associations are strong enough to warrant future longitudinal alcohol studies to explore causal mechanisms related to the heterogeneous patterns of association and male-female variations observed herein. Hopefully, these findings may help guide future directions for public health. Language: en

Background: We aimed to identify different categorical phenotypes based upon the DSM-V criteria of alcohol use disorders (AUD) among alcohol users who had at least one drink per week in the past year (n = 948). Methods: Data are from the São Paulo Megacity Mental Health Survey collected in 2005–2007, as part of the World Mental Health Survey Initiative. A latent class analysis of the 11 DSM-5-AUD criteria was performed using Mplus, taking into account complex survey design features. Weighted logistic regression models were used to examine demographic correlates of the DSM-5-AUD latent classes. Results: The best latent-class model was a three-class model. We found a “non-symptomatic class” (69.7%), a “use in larger amounts class” (23.2%), defined by high probability (>70%) of the “use in larger amounts” criterion only, and a “high-moderate symptomatic class” (7.1%), defined by high-moderate probability of all the 11 AUD criteria. Compared to those in the non-symptomatic class, individuals in the “high-moderate symptomatic class” were more likely to have been married, have lower educational attainment and to be unemployed or in non-regular/informal employment. Those on the “use in larger amounts class” were more likely to have been married or never married. Conclusion: The two symptomatic classes clearly represented the dimensionality of the new proposed AUD criteria, and could be more specifically targeted by different prevention or treatment strategies. DSM-5-AUD has the advantage of shedding light on risky drinkers included in the “use in larger amounts class”, allowing for preventive interventions, which will reach a large number of individuals.

Secretaria de Segurança Pública of the State of São Paulo, Brazil United States National Institutes of Mental Health John D. and Catherine T. MacArthur Foundation Pfizer Foundation US Public Health Service Fogarty International Center (FIRCA) Pan American Health Organization Eli Lilly Company Foundation Ortho-McNeil Pharmaceutical, Inc. GlaxoSmithKline Bristol-Myers Squibb Shire Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background: World population growth is projected to be concentrated in megacities, with increases in social inequality and urbanization-associated stress. São Paulo Metropolitan Area (SPMA) provides a forewarning of the burden of mental disorders in urban settings in developing world. the aim of this study is to estimate prevalence, severity, and treatment of recently active DSM-IV mental disorders. We examined socio-demographic correlates, aspects of urban living such as internal migration, exposure to violence, and neighborhood-level social deprivation with 12-month mental disorders.Methods and Results: A representative cross-sectional household sample of 5,037 adults was interviewed face-to-face using the WHO Composite International Diagnostic Interview (CIDI), to generate diagnoses of DSM-IV mental disorders within 12 months of interview, disorder severity, and treatment. Administrative data on neighborhood social deprivation were gathered. Multiple logistic regression was used to evaluate individual and contextual correlates of disorders, severity, and treatment. Around thirty percent of respondents reported a 12-month disorder, with an even distribution across severity levels. Anxiety disorders were the most common disorders (affecting 19.9%), followed by mood (11%), impulse-control (4.3%), and substance use (3.6%) disorders. Exposure to crime was associated with all four types of disorder. Migrants had low prevalence of all four types compared to stable residents. High urbanicity was associated with impulse-control disorders and high social deprivation with substance use disorders. Vulnerable subgroups were observed: women and migrant men living in most deprived areas. Only one-third of serious cases had received treatment in the previous year.Discussion: Adults living in São Paulo megacity had prevalence of mental disorders at greater levels than similar surveys conducted in other areas of the world. Integration of mental health promotion and care into the rapidly expanding Brazilian primary health system should be strengthened. This strategy might become a model for poorly resourced and highly populated developing countries. Univ São Paulo, Sch Med, Dept & Inst Psychiat, Sect Psychiat Epidemiol LIM 23, São Paulo, Brazil Universidade Federal de São Paulo, Dept Prevent Med, São Paulo, Brazil Univ Michigan, Inst Social Res, Ann Arbor, MI USA Michigan State Univ, Coll Human Med, Dept Epidemiol, E Lansing, MI 48824 USA Univ São Paulo, Sch Med, Dept & Inst Psychiat, Lab Neurosci LIM 27, São Paulo, Brazil Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA Universidade Federal de São Paulo, Dept Prevent Med, São Paulo, Brazil FAPESP: 03/00204-3 United States National Institutes of Mental Health: R01MH070884 US Public Health Service: R13-MH066849 US Public Health Service: R01-MH069864 US Public Health Service: R01 DA016558 Fogarty International Center (FIRCA): R03-TW006481 Web of Science

Aims: To evaluate sociodemographic correlates associated with transitions from alcohol use to disorders and remission in a Brazilian population. Methods: Data are from a probabilistic, multi-stage clustered sample of adult household residents in the Sao Paulo Metropolitan Area. Alcohol use, regular use (at least 12 drinks/year), DSM-IV abuse and dependence and remission from alcohol use disorders (AUDs) were assessed with the World Mental Health version of the Composite International Diagnostic Interview. Age of onset (AOO) distributions of the cumulative lifetime probability of each alcohol use stage were prepared with data obtained from 5037 subjects. Correlates of transitions were obtained from a subsample of 2942 respondents, whose time-dependent sociodemographic data were available. Results: Lifetime prevalences were 85.8% for alcohol use, 56.2% for regular use, 10.6% for abuse and 3.6% for dependence; 73.4 and 58.8% of respondents with lifetime abuse and dependence, respectively, had remitted. The number of sociodemographic correlates decreased from alcohol use to disorders. All transitions across alcohol use stages up to abuse were consistently associated with male gender, younger cohorts and lower education. Importantly, low education was a correlate for developing AUD and not remitting from dependence. Early AOO of first alcohol use was associated with the transition of regular use to abuse. Conclusion: The present study demonstrates that specific correlates differently contribute throughout alcohol use trajectory in a Brazilian population. It also reinforces the need of preventive programs focused on early initiation of alcohol use and high-risk individuals, in order to minimize the progression to dependence and improve remission from AUD.

Environmental toxicants, such as cadmium and bisphenol A (BPA) are endocrine disruptors. In utero, perinatal or neonatal exposure of BPA to rats affect the male reproductive function, such as the blood-testis barrier (BTB) integrity. This effect of BPA on BTB integrity in immature rats is likely mediated via a loss of gap junction function at the BTB, failing to coordinate tight junction and anchoring junction function at the site to maintain the immunological barrier integrity. This in turn activates the extracellular signal-regulated kinases 1/2 (Erk1/2) downstream and an increase in protein endocytosis, destabilizing the BTB. The cadmium-induced disruption of testicular dysfunction is mediated initially via its effects on the occludin/ZO-1/focal adhesion kinase (FAK) complex at the BTB, causing redistribution of proteins at the Sertoli-Sertoli cell interface, leading to the BTB disruption. The damaging effects of these toxicants to testicular function are mediated by mitogen-activated protein kinases (MAPK) downstream, which in turn perturbs the actin bundling and accelerates the actin-branching activity, causing disruption of the Sertoli cell tight junction (TJ)-barrier function at the BTB and perturbing spermatid adhesion at the apical ectoplasmic specialization (apical ES, a testis-specific anchoring junction type) that leads to premature release of germ cells from the testis. However, the use of specific inhibitors against MAPK was shown to block or delay the cadmium-induced testicular injury, such as BTB disruption and germ cell loss. These findings suggest that there may be a common downstream p38 and/or Erk1/2 MAPK-based signaling pathway involving polarity proteins and actin regulators that is shared between different toxicants that induce male reproductive dysfunction. As such, the use of inhibitors and/or antagonists against specific MAPKs can possibly be used to "manage" the illnesses caused by these toxicants and/or "protect" industrial workers being exposed to high levels of these toxicants in their work environment.

Estrogen plays a key role in maintaining the morphology and function of the efferent ductules. We previously demonstrated that the antiestrogen fulvestrant markedly affected gene expression in the rat efferent ductules. The mechanism of fulvestrant action to modulate gene expression may involve not only the blockade of ESR1 and ESR2 estrogen receptors, but also the activation of ESR1 and ESR2 when the receptors are tethered to AP-1 or SP1 transcription factors, or the activation of the G protein-coupled estrogen receptor 1. We therefore compared the effects of two strategies to interfere with estrogen action in the rat efferent ductules: treatment with fulvestrant or with the aromatase inhibitor anastrozole. Whereas fulvestrant markedly increased Mmp7 and Spp1, and reduced Nptx1 mRNA levels, no changes were observed with anastrozole. Fulvestrant caused changes in epithelial morphology that were not seen with anastrozole. Fulvestrant shifted MMP7 immunolocalization in the epithelial cells from the supranuclear to the apical region; this effect was less pronounced with anastrozole. In vitro studies of (35)S-methionine incorporation showed that protein release was increased, whereas tissue protein content in the efferent ductules of fulvestrant-treated rats was decreased. Although fulvestrant markedly affected gene expression, no changes were observed on AP-1 and SP1 DNA-binding activity. The blockade of ESRs seems to be the major reason explaining the differences between both treatments. At least some of the effects of fulvestrant appear to result from compensatory mechanisms activated by the dramatic changes caused by ESR1 blockade.

A substantial advance in our understanding on the estrogen signaling occurred in the last decade. Estrogens interact with two receptors, ESR1 and ESR2, also known as ERα and ERβ, respectively. ESR1 and ESR2 belong to the nuclear receptor family of transcription factors. In addition to the well established transcriptional effects, estrogens can mediate rapid signaling, triggered within seconds or minutes. These rapid effects can be mediated by ESRs or the G protein-coupled estrogen receptor GPER, also known as GPR30. The effects of estrogen on cell proliferation, differentiation and apoptosis are often mediated by growth factors. The understanding of the cross-talk between androgen, estrogen and growth factors signaling pathways is therefore essential to understand the physiopathological mechanisms of estrogen action. In this review we focused on recent discoveries about the nature of the estrogen receptors, and on the signaling and function of estrogen in the male reproductive system. Durante a última década, ocorreu um avanço substancial no conhecimento da sinalização do estrógeno. Estrógenos interagem com dois receptores, ESR1 e ESR2, também conhecidos como ERα e ERβ, respectivamente. ESR1 e ESR2 pertencem à família de receptores nucleares, que funcionam como fatores de transcrição. Além dos bem estabelecidos efeitos transcricionais, os estrógenos medeiam a sinalização rápida, desencadeada dentro de segundos ou minutos. Esses efeitos rápidos podem ser mediados por ESRs ou pelo receptor de estrógeno acoplado à proteína G, GPER, também conhecido como GPR30. Os efeitos de estrógenos sobre a proliferação celular, diferenciação e apoptose são, muitas vezes, mediados por fatores de crescimento. Portanto, a compreensão da interação entre as vias de sinalização de andrógeno, estrógeno e fatores de crescimento é essencial para entender os mecanismos fisiopatológicos envolvidos na ação estrogênica. Nesta revisão, foram abordadas descobertas recentes sobre a estrutura dos receptores, a sinalização e a função do estrógeno no sistema reprodutor masculino.

In mammals, at least five different muscarinic acetylcholine receptor subtypes (mAChRs; M(1)-M(5)) are known to be widely expressed and distributed in different tissues from different species. They mediate distinct physiological functions according to their location and receptor subtype. Multiple events are associated with the regulation of intracellular signaling by mAChRs, and a coordinated balance of the molecular mechanisms governing receptor signaling, desensitization, resensitization, and mitogenic signaling is known to occur in various cell types. Most of the actions of acetylcholine (ACh) in the male reproductive tract are induced by its effects on mAChRs, but the role of specific mAChR subtypes on male reproductive function and fertility are still not well understood. The rat efferent ductules and epididymis are androgen-dependent tissues of the male reproductive tract, with important roles in the process to form a viable and fertile sperm. In the present study, aspects of the expression, localization, and potential function of mAChR subtypes in rat efferent ductules and epididymis are reviewed. Furthermore, evidences for the implication of mAChRs in the regulation of protein synthesis and secretion in these tissues are presented. Taken together, the studies contribute to our understanding about physiological aspects of mAChR and mechanisms by which the cholinergic system affects male reproduction.

National Institute of Child Health and Human Development National Institutes of Health Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) In mammalian testes, such as rats, the mechanism(s) that regulate blood-testis barrier (BTB) restructuring at stages VIII-IX of the seminiferous epithelial cycle of spermatogenesis to facilitate the transit of preleptotene/leptotene spermatocytes is not known. This is due to the lack of information on the regulatory proteins at the BTB. Herein, focal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase, is shown to structurally interact with occludin and ZO-1 to form a functional protein complex at the BTB. Its expression at the BTB in the seminiferous epithelium is stage specific, being lowest at stage VIII-IX tubules, analogous to the expression pattern of occludin. Using primary Sertoli cells cultured in vitro with an established tight junction (TJ) permeability barrier that mimics the BTB in vivo, the knockdown of FAK by RNAi led to a transient disruption of the TJ barrier. This was accompanied by a loss of association between occludin and ZO-1, likely the result of reduced occludin phosphorylation at Tyr and Ser residues, but not Thr, which in turn led to a redistribution of occludin at the Sertoli-Sertoli cell interface, moving from cell membrane into cell cytosol, thereby disrupting the BTB. These findings suggest that a similar mechanism is in place in the testis in vivo to regulate BTB restructuring to facilitate the transit of primary spermatocytes. Furthermore, FAK was shown to be a molecular target of cadmium because its knockdown would desensitize Sertoli cells to cadmium-induced TJ barrier disruption. in summary, FAK is a unique regulator of BTB dynamics in the testis. Populat Council, Ctr Biomed Res, New York, NY 10065 USA Universidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, BR-04044020 São Paulo, Brazil Universidade Federal de São Paulo, Dept Pharmacol, Sect Expt Endocrinol, BR-04044020 São Paulo, Brazil National Institute of Child Health and Human Development: R01 HD056034 National Institute of Child Health and Human Development: R03 HD051512 National Institute of Child Health and Human Development: U54 HD029990 FAPESP: 06/51281-6 Web of Science

Several integral membrane proteins that constitute the blood-testis barrier (BTB) in mammalian testes, in particular rodents, are known to date. These include tight junction (TJ) proteins (e.g. occludin, junctional adhesion molecule-A, claudins), basal ectoplasmic specialization proteins (e.g. N-cadherin), and gap junction proteins (e.g. connexin43). However, the regulators (e.g. protein kinases and phosphatases) that affect these proteins, such as their interaction with the cytoskeletal actin, which in turn confer cell adhesion at the TJ, remain largely unknown. We report herein that focal adhesion kinase (FAK) is a putative interacting partner of occludin, but not claudin-11 or junctional adhesion molecule-A. Immunohistochemistry and fluorescence microscopy studies illustrated that the expression of FAK in the seminiferous epithelium of adult rat testes was stage specific. FAK colocalized with occludin at the BTB in virtually all stages of the seminiferous epithelial cycle but considerably diminished in stages VIII-IX, at the time of BTB restructuring to facilitate the transit of primary leptotene spermatocytes. Using Sertoli cells cultured in vitro with established TJ-permeability barrier and ultrastructures of TJ, basal ectoplasmic specialization and desmosome-like junction that mimicked the BTB in vivo, FAK was shown to colocalize with occludin and zonula occludens-1 (ZO-1) at the Sertoli-Sertoli cell interface. When these Sertoli cell cultures were treated with CdCl(2) to perturb the TJ-barrier function, occludin underwent endocytic-mediated internalization in parallel with FAK and ZO-1. Thus, these findings demonstrate that FAK is an integrated regulatory component of the occludin-ZO-1 protein complex, suggesting that functional studies can be performed to study the role of FAK in BTB dynamics., link_to_OA_fulltext

The efferent ductules express the highest amount of estrogen receptors ESR1 (ERalpha) and ESR2 (ERbeta) within the male reproductive tract. Treatment of rats with the antiestrogen fulvestrant (ICI 182,780) causes inhibition of fluid reabsorption in the efferent ductules, leading to seminiferous tubule atrophy and infertility. To provide a more comprehensive knowledge about the molecular targets for estrogen in the rat efferent ductules, we investigated the effects of ICI 182,780 treatment on gene expression using a microarray approach. Treatment with ICI 182,780 increased or reduced at least 2-fold the expression of 263 and 98 genes, respectively. Not surprisingly, several genes that encode ion channels and macromolecule transporters were affected. Interestingly, treatment with ICI 182,780 markedly altered the expression of genes related to extracellular matrix organization. Matrix metalloproteinase 7 (Mmp7), osteopontin (Spp1), and neuronal pentraxin 1 (Nptx1) were among the most altered genes in this category. Upregulation of Mmp7 and Spp1 and downregulation of Nptx1 were validated by Northern blot. Increase in Mmp7 expression was further confirmed by immunohistochemistry and probably accounted for the decrease in collagen content observed in the efferent ductules of ICI 182,780-treated animals. Downregulation of Nptx1 probably contributed to the extracellular matrix changes and decreased amyloid deposition in the efferent ductules of ICI 182,780-treated animals. Identification of new molecular targets for estrogen action may help elucidate the regulatory role of this hormone in the male reproductive tract.

The expression of muscarinic acetylcholine receptor (mAChR) subtypes (M(1)-M(5)) was studied in the rat efferent ductules and epididymis at the mRNA and protein levels. The relative abundance of each mAChR transcript subtype differed depending on the tissue and the epididymal region analyzed. The M(1) mAChR mRNA level was more abundant in the efferent ductules than in the caput and cauda of the epididymis. The M(2) mAChR mRNA level was similar between the efferent ductules and caput of the epididymis and higher in the cauda region. The M(3) mAChR mRNA level was low in the efferent ductules and caput of the epididymis, but high levels were detected in the cauda region. mRNAs for M(4) and M(5) mAChRs were not detected in these tissues. Our studies indicated a variable degree of immunostaining for each mAChR subtype in a cell-type and tissue-specific pattern. M(1) mAChR was detected over the efferent ductule epithelium. M(2) and M(3) mAChRs were observed in the apical region of the ciliated cells. Apical and narrow cells of the initial segment showed distinct staining by M(1) antibody, whereas a supranuclear reaction was noted in the principal cells of the caput of the epididymis. In addition, staining for M(1) and M(2) mAChRs was visible in the apical membrane of some epithelial cells of the cauda region. M(3) mAChR was detected in the peritubular smooth muscle of the efferent ductules and epididymis. Functional studies suggested the involvement of this subtype in epididymal tubule contraction. Thus, the cell-specific expression of the various mAChR subtypes in the efferent ductules and epididymis suggests that these receptors play a role in the modulation of luminal fluid composition and smooth muscle contraction.