Reactive oxygen species (ROS) have been mainly viewed as unwanted byproducts of cellular metabolism, oxidative stress, a sign of a cellular redox imbalance, and potential disease mechanisms, such as in diabetes mellitus (DM). Antioxidant therapies, however, have failed to provide clinical benefit. This paradox can be explained by recent discoveries that ROS have mainly essential signaling and metabolic functions and evolutionally conserved physiological enzymatic sources. Disease can occur when ROS accumulate in nonphysiological concentrations, locations, or forms. By focusing on disease-relevant sources and targets of ROS, and leaving ROS physiology intact, precise therapeutic interventions are now possible and are entering clinical trials. Their outcomes are likely to profoundly change our concepts of ROS in DM and in medicine in general. A New Approach to Diabetes Mellitus and Reactive Oxygen Species Diabetes mellitus (DM) and its related end-organ damage, such as diabetic nephropathy, neuropathy, retinopathy, and cardiomyopathy, are major causes of death and long-term disability. Their underlying mechanisms are incompletely understood, which is why none of the current antidiabetic therapies target the underlying causes or are curative, but focus instead on normalizing surrogate parameters or risk factors such as blood glucose or hypertension [1]. Hence, our lack of mechanistic understanding of lifestyle change-resistant diabetic end-organ damage, together with the increasing prevalence of DM, represent a significant major unmet medical need. One mechanism that has been suggested for decades to cause pancreatic b cell dysfunction and diabetic end-organ damage is 'oxidative stress' (see Glossary), originally defined as an overproduction of reactive oxygen species (ROS). Antioxidants were considered the obvious therapeutic countermeasure but, clinically, have consistently disappointed [2]. Even worse, meta-analyses of clinical trials show that antioxidants may not only be ineffective, but harmful, and even increase mortality [2]. Recently, however, important conceptual breakthroughs in our understanding of ROS in general and DM in particular explain the failure of antioxidants and point towards entirely different mechanism-based and possibly curative therapeutic approaches. Our new understanding of ROS requires that many long-held misconceptions, such as the 'redox balance hypothesis' and the view that ROS are primarily stressors, disease triggers, and metabolic waste products, must be overcome. Instead, the many physiological roles of ROS and the existence of at least seven evolutionarily conserved ROS-producing enzymes (NOX1-5,

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This study aimed to investigate the association between exposure to different types of child maltreatment (CM) and the development of substance use disorders (SUDs) later in life. A systematic review was conducted: the PubMed, EMBASE and PsycINFO databases were searched for relevant papers and ten studies were identified for further analysis. Random effects meta‐analyses were performed for each type of maltreatment in order to estimate the odds ratio (OR) for SUD incidence, and meta‐regressions were performed to explore potential moderators. Individuals with a history of physical abuse during childhood had a 74 per cent increased risk for drug abuse later in life (OR = 1.74, 95% confidence interval (CI) = 1.362.18). The risk for drug abuse was also 73 per cent higher in individuals with a history of sexual abuse during childhood (OR = 1.73, 95% CI = 1.242.41). A meta‐regression found that gender has a moderating effect, with women at a greater risk of SUD incidence compared to men. Exposure to CM, such as physical and sexual abuse in childhood, increases the risk of further substance abuse. Understanding the interplay between the different factors associated with violence and abuse of psychoactive substances is of fundamental importance in designing prevention approaches and interventions for drug users. Key Practitioner Messages Child exposure to violence was associated with the development of substance use disorder. Exposure to violence affects men and women in a gender‐dependent manner, with females being at a higher risk. Understanding the interplay between the different factors associated with violence and drug abuse is of fundamental importance to design prevention approaches and interventions. Drug users have higher rates of child maltreatment and psychological suffering compared to the general population.

16Unphysiological reactive oxygen species (ROS) formation is considered an important 17 pathomechanism for several disease phenotypes with high unmet medical need. Therapeutically, 18 antioxidants have failed multiple times. Instead, focusing on only disease-relevant, enzymatic 19sources of ROS appears to be a more promising and highly validated approach. Here the family of 20 five NADPH oxidases (NOX) stands out as drug targets. Validation has been restricted, however, 21 mainly to genetically modified rodents and is lacking in other species including human. It is thus 22 unclear whether the different NOX isoforms are sufficiently distinct to allow selective 23 pharmacological modulation. Here we show for five of the most advanced NOX inhibitors that 24 indeed isoform selectivity can be achieved. NOX1 was most potently (IC 50 ) targeted by ML171 (0.1 25 µM); NOX2, by VAS2870 (0.7 µM); NOX4, by M13 (0.01 µM) and NOX5, by ML090 (0.01 µM). 26Conditions need to be carefully controlled though as previously unrecognized non-specific 27 antioxidant and assay artefacts may limit the interpretation of data and this included, surprisingly, 28 one of the most advanced NOX inhibitors, GKT136901. As proof-of-principle that now also 29 pharmacological and non-rodent target validation of different NOX isoforms is possible, we used a 30 human blood-brain barrier model and NOX inhibitor panel at IC 50 concentrations. The protective 31 efficacy pattern of this panel confirmed the predominant role of NOX4 in stroke from previous 32 genetic models. Our findings strongly encourage further lead optimization efforts for isoform-33 selective NOX inhibitors and clinical development and provide an experimental alternative when 34 genetic validation of a NOX isoform is not an option. 35 [2][3][4]. This paradox was initially explained by these compounds being underdosed, thereby not 41 reaching efficacy. It is now understood, however, that ROS are not only harmful metabolic by-42 products, but also serve important protective, metabolic and signaling functions, such as the 43 regulation of cell proliferation, differentiation, migration and survival, innate immune response, 44 vascular tone, neuronal signaling as well as inflammation [5][6][7][8]. Anti-oxidants are likely to 45 simultaneously interfere with both qualities of ROS, the physiological and pathophysiological ones 46 with overall neutral or even deleterious outcomes. Thus, ROS should not be modulated in a 47

Trends in Psychiatry and Psychotherapy Review ArticleResumo Objetivo: Prejuízos envolvendo o controle inibitório têm sido considerados déficits centrais em usuários de substâncias psicoativas, contudo parece haver disfunções específicas de acordo com a droga de escolha. Este artigo teve por objetivo revisar os achados recentes sobre alterações do controle inibitório em amostras de usuários de cocaína e/ou crack. Método: A pesquisa foi realizada nas bases de dados PubMed, PsycINFO e Web of Knowledge, em duas etapas, de acordo com os critérios de elegibilidade: inicialmente foi feita uma pesquisa nas bases de dados com análise dos títulos e resumos; após, os artigos foram lidos na íntegra. Os critérios de inclusão foram: artigos empíricos publicados em inglês, português ou espanhol, nos últimos 10 anos e que tenham avaliado o controle inibitório em usuários de cocaína e/ou crack. Resultados: Do total de 3.796 resultados, 56 títulos foram selecionados, sendo 20 excluídos. Como resultado, 36 artigos foram incluídos na revisão. Em 90% dos estudos revisados, foi relatada a presença de déficits de controle inibitório, verificados através de prejuízos no processamento cognitivo e no monitoramento de respostas, além de níveis elevados de impulsividade, independentemente do padrão de consumo de cocaína e/ou crack (uso recreativo ou crônico). Usuários em abstinência apresentaram níveis elevados de impulsividade, mesmo após longos períodos sem uso da droga. Conclusão: Usuários de cocaína e/ou crack podem apresentar prejuízos de controle inibitório apesar dos diferentes padrões de consumo. Níveis elevados de impulsividade podem constituir fator de vulnerabilidade para o uso de drogas e para a recaída. Descritores: Drogas, avaliação, inibição, cognição. AbstractObjective: Impairments involving inhibitory control have been considered central deficits in drug users, but it appears that dysfunctions may be specific to users' drug of choice. This article aims to review recent findings on inhibitory control impairment in samples of crack and/or cocaine users. Methods: Searches were conducted on the PubMed, PsycINFO, and Web of Knowledge databases in two stages according to eligibility criteria. Initially, databases were searched and the titles and abstracts of results were analyzed and then selected articles were read in full. Inclusion criteria were: empirical articles written in English, Portuguese, or Spanish, published in the last ten years and involving the assessment of inhibitory control in crack and/or cocaine users. Results: The database searches returned a total of 3,796 titles, 56 of them were selected initially and then a further 20 were excluded. Thirty-six articles were included in this review. In 90% of the studies reviewed the presence of inhibitory control deficits was reported, verified by impaired cognitive processing and response monitoring, as well as high levels of impulsiveness, regardless of the pattern of crack and/or cocaine consumption (recreational or chronic). Former users showed high levels of impulsi...

Crack cocaine users frequently report difficulties regarding having healthy and rewarding relationships. Factors other than the use of crack cocaine itself may be at play when it comes to being able to develop healthier connections with partners, adult relatives and close friends. To verify which factors, including demographics, substance abuse related factors and psychiatric comorbidities could be markers for a higher severity of problems in interpersonal relationships of crack cocaine users seeking for treatment. This was a cross-sectional study, conducted between April 2011 and November 2012. Participants were 407 crack cocaine users seeking treatment in specialized public facilities of six Brazilian capitals. The relationship of severity of problems in the family/social area and the prevalence of psychiatric disorders, exposure to stressful events, substance use related factors and practice of illicit activities were explored through multivariate analyses. Number of days using crack cocaine in the last 30 days, age of first time using alcohol and feeling its effects, a diagnosis of alcohol abuse, posttraumatic stress disorder, antisocial personality disorder and attention-deficit/hyperactivity disorder were significantly associated with a higher severity of problems in interpersonal relationships with partners, adult relatives and friends. Problems in interpersonal relationships are strongly related to specific psychiatric comorbidities and the frequency of crack cocaine use. Factors identified by this study can make the paths to recovery more challenging. These results support psychosocial interventions that focus in the improvement of interpersonal relationships of crack cocaine users.

Objective: Many studies correlate characteristics of family functioning and the development of drug addiction. This study sought to evaluate and compare the family environment styles of two groups of psychoactive substance users: 1) alcohol-only users and 2) crack-cocaine users. Methods: Three hundred and sixty-four users of alcohol, crack-cocaine, and other drugs, recruited from research centers in four Brazilian capitals participated in this study. Subjects were evaluated through the Family Environment Scale and the Addiction Severity Index, 6th version (ASI-6). ASI-6 t-scores were compared by analysis of variance (ANOVA) and post-hoc tests. A final model was obtained using a logistic regression analysis. All analyses were adjusted for partner, age, and psychiatric t-score. Results: We found a significant difference between groups in the cohesion subscale (p = 0.044). The post-hoc test revealed a difference of 1.06 points (95%CI 0.11-2.01) between groups 1 (6.4560.28) and 2 (5.3860.20). No significant between-group differences were observed in the other subscales. However, categorical analyses of variables regarding family dynamic showed that crack users more often reported that sometimes people in their family hit each other (30.4% vs. 13.2%, p = 0.007) and that people in their family frequently compared each other regarding work and/or school achievement (57.2% vs. 42.6%, p = 0.041). Conclusion: These results suggest that families of crack-cocaine users are less cohesive than families of alcohol users. This type of family environment may affect treatment outcome, and should thus be adequately approached.

This study offers important information regarding the relationship of mental health personnel with their work. Care providers within this sample reported an overall high level of job satisfaction, while perceived burden differed by type of service and educational attainment. To our knowledge, this is the first study with a sample of mental health professionals working with substance users across five Brazilian states.