GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies.

Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.

Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia.

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.

Antileishmanial effects of Crotalaria spectabilis Roth aqueous extracts on Leishmania amazonensis.

Fifteen polar extracts from leaf, seed, pod, stem, flower and root of Crotalaria spectabilis were prepared using aqueous systems, based on the principles of green chemistry, and showed different protease inhibitor (PI) activities on trypsin, papain, pepsin and the extracellular L. amazonensis serine protease (LSPIII). The most pronounced inhibitory effect on LSPIII was observed in leaf (CS-P), root, stem, flower (CS-FPVPP) and pod (CS-VA) extracts. Crotalaria extracts exhibited low cytotoxicity on macrophages; however, they decreased the viability of L. amazonensis promastigotes and amastigotes, as observed in leaf (CS-AE, CS-P, CS-T and CS-PVPP), seed (CS-ST), flower and root (CS-RA) extracts. CS-P was chosen to study PI and secondary metabolites and a 10-12 kDa protein, analyzed by mass spectrometry, was identified as a serine PI homologous with papaya latex serine PI. Glycosylated flavonoids, such as quercetins, vitexin and tricin were the major secondary metabolites of CS-P. The presence of PIs in C. spectabilis is a new finding, especially in other organs than seeds since PIs have been reported only in seed legumes. Besides, this is the first report of antileishmanial activity of C. spectabilis extracts and the identification of serine polypeptide PI and glycosylated flavonoids from leaf.

Enhancing Dementia Knowledge and Self-Efficacy of In-Home Supportive Services Caregivers Through Online Training.

California's In-Home Supportive Services (IHSS) program provides vital home care to low-income consumers, some of whom live with Alzheimer's disease or related dementias (ADRD). Yet, most IHSS caregivers receive little or no training in dementia care. We present preliminary descriptive results of the IHSS + ADRD Training Project, a 10-week, competency-based, dementia training program, delivered online, for IHSS caregivers, in Alameda County. Increase in dementia knowledge and self-efficacy at training completion supports the importance of continuing and expanding this work.

Resultados Precoces do Procedimento de Norwood em um Centro de Referência no Brasil / Early Outcomes of the Norwood Procedure in a Reference Center in Brazil

Resumo Fundamento Apenas dois artigos abordam os resultados precoces de pacientes com síndrome do coração esquerdo hipoplásico (SHCE) submetidos à operação de Norwood, no Brasil. Objetivos Avaliamos pacientes com SHCE submetidos ao primeiro estágio da operação de Norwood para identificar os fatores preditivos de mortalidade precoce (nos primeiros 30 dias após a cirurgia) e intermediária (desde a sobrevida precoce até o procedimento de Glenn). Métodos Foram incluídos pacientes com SHCE submetidos em nosso serviço ao primeiro estágio da operação de Norwood de janeiro de 2016 a abril de 2019. Dados demográficos, anatômicos e cirúrgicos foram analisados. Os desfechos foram mortalidade precoce (nos primeiros 30 dias após a cirurgia), mortalidade intermediária (desde a sobrevida precoce até o procedimento de Glenn) e a necessidade de suporte pós-operatório com ECMO. Foram realizadas análises univariadas e multivariadas e calculados odds ratios, com intervalos de confiança de 95%. Um valor de p < 0,05 foi considerado estatisticamente significativo. Resultados Um total de 80 pacientes com SHCE foram submetidos ao primeiro estágio da operação de Norwood. A taxa de sobrevida em 30 dias foi de 91,3% e a taxa de sobrevida intermediária foi de 81,3%. Quatorze pacientes (17,5%) necessitaram de suporte com ECMO. Menor peso (p=0,033), estenose aórtica (vs atresia aórtica; p=0,036) e necessidade de suporte pós-operatório com ECMO (p=0,009) foram fatores preditivos independentes para mortalidade em 30 dias. A estenose da valva mitral ( vs atresia da valva mitral; p=0,041) foi um fator preditivo independente para mortalidade intermediária. Conclusão O presente estudo inclui a maior coorte brasileira de pacientes com SHCE submetidos ao primeiro estágio da operação de Norwood na era recente. Nossas taxas de sobrevida foram comparáveis às mais altas taxas de sobrevida relatadas globalmente. Baixo peso corporal, estenose valvar aórtica e necessidade de suporte pós-operatório com ECMO foram preditores independentes para mortalidade em 30 dias. A estenose da valva mitral foi o único fator preditivo independente para mortalidade intermediária.

Abstract Background Only two papers have addressed the early outcomes of patients with hypoplastic left heart syndrome (HLHS) undergoing the Norwood operation, in Brazil. Objectives We evaluated patients with HLHS undergoing the first-stage Norwood operation in order to identify the predictive factors for early (within the first 30 days after surgery) and intermediate (from early survival up to the Glenn procedure) mortality. Methods Patients with HLHS undergoing the stage I Norwood procedure from January 2016 through April 2019, in our service, were enrolled. Demographic, anatomical, and surgical data were analyzed. Endpoints were early mortality (within the first 30 days after surgery), intermediate mortality (from early survival up to the Glenn procedure) and the need for postoperative ECMO support. Univariate and multivariate analyses were performed, and odds ratios, with 95% confidence intervals, were calculated. A p-value <0.05 was considered statistically significant. Results A total of 80 patients with HLHS underwent the stage I Norwood procedure. The 30-day survival rate was 91.3% and the intermediate survival rate 81.3%. Fourteen patients (17.5%) required ECMO support. Lower weight (p=0.033), aortic stenosis (vs aortic atresia; p=0.036), and the need for postoperative ECMO support (p=0.009) were independent predictive factors for 30-day mortality. Mitral valve stenosis (vs mitral valve atresia; p=0.041) was an independent predictive factor for intermediate mortality. Conclusion The present study includes the largest Brazilian cohort of patients with HLHS undergoing the stage I Norwood procedure in the recent era. Our survival rates were comparable to the highest survival rates reported globally. Low body weight, aortic valve stenosis, and the need for postoperative ECMO support were independent predictors for 30-day mortality. Mitral valve stenosis was the only independent predictive factor for intermediate mortality.

Early Outcomes of the Norwood Procedure in a Reference Center in Brazil. / Resultados Precoces do Procedimento de Norwood em um Centro de Referência no Brasil.

BACKGROUND: Only two papers have addressed the early outcomes of patients with hypoplastic left heart syndrome (HLHS) undergoing the Norwood operation, in Brazil. OBJECTIVES: We evaluated patients with HLHS undergoing the first-stage Norwood operation in order to identify the predictive factors for early (within the first 30 days after surgery) and intermediate (from early survival up to the Glenn procedure) mortality. METHODS: Patients with HLHS undergoing the stage I Norwood procedure from January 2016 through April 2019, in our service, were enrolled. Demographic, anatomical, and surgical data were analyzed. Endpoints were early mortality (within the first 30 days after surgery), intermediate mortality (from early survival up to the Glenn procedure) and the need for postoperative ECMO support. Univariate and multivariate analyses were performed, and odds ratios, with 95% confidence intervals, were calculated. A p-value <0.05 was considered statistically significant. RESULTS: A total of 80 patients with HLHS underwent the stage I Norwood procedure. The 30-day survival rate was 91.3% and the intermediate survival rate 81.3%. Fourteen patients (17.5%) required ECMO support. Lower weight (p=0.033), aortic stenosis (vs aortic atresia; p=0.036), and the need for postoperative ECMO support (p=0.009) were independent predictive factors for 30-day mortality. Mitral valve stenosis (vs mitral valve atresia; p=0.041) was an independent predictive factor for intermediate mortality. CONCLUSION: The present study includes the largest Brazilian cohort of patients with HLHS undergoing the stage I Norwood procedure in the recent era. Our survival rates were comparable to the highest survival rates reported globally. Low body weight, aortic valve stenosis, and the need for postoperative ECMO support were independent predictors for 30-day mortality. Mitral valve stenosis was the only independent predictive factor for intermediate mortality.

FUNDAMENTO: Apenas dois artigos abordam os resultados precoces de pacientes com síndrome do coração esquerdo hipoplásico (SHCE) submetidos à operação de Norwood, no Brasil. OBJETIVOS: Avaliamos pacientes com SHCE submetidos ao primeiro estágio da operação de Norwood para identificar os fatores preditivos de mortalidade precoce (nos primeiros 30 dias após a cirurgia) e intermediária (desde a sobrevida precoce até o procedimento de Glenn). MÉTODOS: Foram incluídos pacientes com SHCE submetidos em nosso serviço ao primeiro estágio da operação de Norwood de janeiro de 2016 a abril de 2019. Dados demográficos, anatômicos e cirúrgicos foram analisados. Os desfechos foram mortalidade precoce (nos primeiros 30 dias após a cirurgia), mortalidade intermediária (desde a sobrevida precoce até o procedimento de Glenn) e a necessidade de suporte pós-operatório com ECMO. Foram realizadas análises univariadas e multivariadas e calculados odds ratios, com intervalos de confiança de 95%. Um valor de p < 0,05 foi considerado estatisticamente significativo. RESULTADOS: Um total de 80 pacientes com SHCE foram submetidos ao primeiro estágio da operação de Norwood. A taxa de sobrevida em 30 dias foi de 91,3% e a taxa de sobrevida intermediária foi de 81,3%. Quatorze pacientes (17,5%) necessitaram de suporte com ECMO. Menor peso (p=0,033), estenose aórtica (vs atresia aórtica; p=0,036) e necessidade de suporte pós-operatório com ECMO (p=0,009) foram fatores preditivos independentes para mortalidade em 30 dias. A estenose da valva mitral ( vs atresia da valva mitral; p=0,041) foi um fator preditivo independente para mortalidade intermediária. CONCLUSÃO: O presente estudo inclui a maior coorte brasileira de pacientes com SHCE submetidos ao primeiro estágio da operação de Norwood na era recente. Nossas taxas de sobrevida foram comparáveis às mais altas taxas de sobrevida relatadas globalmente. Baixo peso corporal, estenose valvar aórtica e necessidade de suporte pós-operatório com ECMO foram preditores independentes para mortalidade em 30 dias. A estenose da valva mitral foi o único fator preditivo independente para mortalidade intermediária.

Extracorporeal Membrane Oxygenation After Norwood Surgery in Patients With Hypoplastic Left Heart Syndrome: A Retrospective Single-Center Cohort Study From Brazil.

Background: Extracorporeal membrane oxygenation (ECMO) is increasingly being used to support patients after the repair of congenital heart disease. Objective: We report our experience with patients with a single functional ventricle who were supported by ECMO after the Norwood procedure, reviewing the outcomes and identifying risk factors for mortality in these patients. Methods: In this single-center retrospective cohort study, we enrolled 33 patients with hypoplastic left heart syndrome (HLHS) who received ECMO support after the Norwood procedure between January 2015 and December 2019. The independent variables evaluated in this study were demographic, anatomical, and those directly related to ECMO support (ECMO indication, local of initiation, time under support, and urinary output while on ECMO). The dependent variable was survival. A p < 0.05 was considered statistically significant. Results: The ECMO support was applied in 33 patients in a group of 120 patients submitted to Norwood procedure (28%). Aortic atresia was present in 72.7% of patients and mitral atresia in 51.5%. For 15% of patients, ECMO was initiated in the operating room; for all other patients, ECMO was initiated in the intensive care unit. The indications for ECMO in the cardiac intensive care unit were cardiac arrest in 22 (79%) of patients, low cardiac output state in 10 (18%), and arrhythmia in 1 patient (3%). The median time under support was 5 (2-25) days. The median follow-up time was 59 (4-150) days. Global survival to Norwood procedure was 90.9% during the 30-day follow-up, being 33.3% for those submitted to ECMO. Longer ECMO support (p = 0.004) was associated with a higher risk of death in the group submitted to ECMO. Conclusions: The mortality of patients with HLHS who received ECMO support after stage 1 palliation was high. Patients with low urine output were related to worse survival rates, and longer periods under ECMO support (more than 9 days of ECMO) were associated with 100% mortality. Earlier ECMO initiation before multiorgan damage may improve results.

Caracterização de atores e práticas de Redução de Danos na região Sul do país / Characterization of actors and practices of Harm Reduction in the South region of Brazil

Resumo O uso de conceitos e práticas de Redução de Danos (RD) na atenção às pessoas que usam drogas foi iniciado no Brasil nos anos 1990, como resposta preventiva à propagação do HIV/aids. Ao longo dos anos, ganhou espaço em outros campos de ação, como a saúde mental e a proteção social. Em 2019, com as mudanças no governo federal, esta prática foi retirada da definição da política sobre drogas. Com foco nos reflexos dessas mudanças, este estudo visou caracterizar quem atua e quais ações são desenvolvidas junto às pessoas que usam drogas, sob a perspectiva da RD, em municípios da região Sul do Brasil (RS, SC e PR). Trata-se de um estudo exploratório descritivo e transversal, que usou um questionário virtual composto por questões abertas, fechadas e métodos mistos de análise de dados. Os participantes foram recrutados por meio do método Snowball Sampling, de forma virtual, alcançando 72 questionários validados. Foi desenvolvida uma análise exploratória dos dados quantitativos. Para as respostas qualitativas foi usada a Análise Textual Discursiva e o software NVivo (versão 12). Os resultados demonstraram o perfil dos profissionais; mudanças ao longo dos anos e a necessidade de ampliar investimentos em pesquisas sobre RD.

Abstract Harm Reduction (HR) concepts and practices in the care of people who use drugs stared being used in Brazil in the 1990s, as a preventive response to the spread of HIV/AIDS. Over the years, it gained space in other fields, such as mental health and social protection. In 2019, with changes in the federal government, this practice was removed from the definitions of the drug policy. Focusing on the consequences of these changes, this study aimed to characterize who works and what actions are developed with the people who use drugs, in the HR perspective, in the southern region of Brazil. This is a descriptive and cross-sectional exploratory study, which used an online questionnaire with open and closed questions, and mixed methods of data analysis. Participants were recruited using the Snowball Sampling method, by virtual means, reaching 72 validated questionnaires. An exploratory analysis of the quantitative data was developed. For the qualitative data, the Discursive Textual Analysis and NVivo software (version 12) were used. The results showed the profile of professionals; the changes over the years; and the need to expand investments in HR research.

Monocyclic Nitro-heteroaryl Nitrones with Dual Mechanism of Activation: Synthesis and Antileishmanial Activity.

5-Nitro-furan nitrones (1) and 5-nitro-thiophene nitrones (2) were synthesized in one step. Compounds 1a-c had the most potent leishmanicidal activity against intracellular amastigote forms of Leishmania amazonensis and L. infantum (from 0.019 to 2.76 µM), with excellent selectivity (from 39 to 5673). The comparison of the leishmanicidal activity in promastigotes of wild type L. donovani with those overexpressing nitroreductases NRT1 or NRT2 shows that 1a,b are activated by both, which could slow the development of resistance. Their redox potential (E redox) obtained by cyclic voltammetry (-0.67 and -0.62 V) shows that the reduction of the nitro group is modulated by the nitrone group. Oral administration of 1b to mice infected by L. infantum reduced the parasite load on the spleen by 76.6 and 95.0% with doses of 50 and 100 mg/kg, respectively, administered twice a day, for 5 days. In the liver, the parasite load suppression was above 75% with either treatment.

Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis.

Translational studies involving the reuse and association of drugs are approaches that can result in higher success rates in the discovery and development of drugs for serious public health problems, including leishmaniasis. If we consider the number of pathogenic species in relation to therapeutic options, this arsenal is still small, and each drug possesses a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. In the search for new drugs, we performed a drug screening of L. amazonensis promastigotes and intracellular amastigotes of fifty available drugs belonging to several classes according to their pharmacophoric group. Spironolactone, a potassium-sparing diuretic, proved to be the most promising drug candidate. After demonstrating the in vitro antileishmanial activity, we evaluated the efficacy on a murine experimental model with L. amazonensis and L. infantum. The treatment controlled the cutaneous lesion and reduced the parasite burden of L. amazonensis significantly, as effectively as meglumine antimoniate. The treatment of experimental visceral leishmaniasis was effective in reducing the parasite load on the main affected organs (spleen and liver) via high doses of spironolactone. The association between spironolactone and meglumine antimoniate promoted better control of the parasite load in the spleen and liver compared to the group treated with meglumine antimoniate alone. These results reveal a possible benefit of the concomitant use of spironolactone and meglumine antimoniate that should be studied more in depth for the future possibility of repositioning for leishmaniasis co-therapy.

Incidência de Chlamydia trachomatis em gestantes diagnosticadas com sífilis / Chlamydia trachomatis incidence on syphilis diagnosed pregnant women

De acordo com a Organização Mundial da Saúde, a cada ano, mais de 376 milhões de pessoas são infectadas pelas doenças sexualmente transmissíveis, das quais 127,2 milhões são por Chlamydia trachomatis. As infecções genitais não tratadas na gestação, principalmente as assintomáticas, podem acarretar complicações, tais como: endometrite puerperal e síndrome de Fitz-Hugh-Curtis. A pesquisa científica foi realizada com o objetivo de identificar a presença de Chlamydia trachomatis na secreção endocervical de gestantes sifilíticas, estabelecendo o perfil das gestantes a partir de informações dos possíveis sinais e sintomas durante a gravidez e hábitos gestacionais. Adotou-se como caminho metodológico a pesquisa quantitativa, descritiva, bibliográfica e laboratorial. Como resultados finais, 54% das gestantes foram diagnosticadas com Chlamydia trachomatis e 67% eram assintomáticas. Correlacionamos também que as altas taxas de infecção estão associadas com a falta de conhecimento sobre infecções sexualmente transmissíveis e suas formas de prevenção.(AU)

According to the World Health Organization, each year, more than 376 million people are infected with sexually transmitted diseases, of which 127.2 million are Chlamydia trachomatis, it is a asymptomatic disease, meaning there are no symptoms. Genital infections can lead to complications such as: puerperal endometritis and Fitz-Hugh- -Curtis syndrome. The scientific research was carried out to identify the presence of Chlamydia trachomatis in the endocervical secretion of syphilitic pregnant women. This research established a profile of pregnant women infected with Chlamydia trachomatis using information about possible signs and symptoms during pregnancy and gestational habits. It provides a methodological way to quantify and describe the laboratory research. The results showed, 54% of the pregnant women were diagnosed with Chlamydia trachomatis of which 67% were asymptomatic. We also correlate that high rates of Chlamydia trachomatis infection are associated with lack of knowledge about sexually transmitted infections and their forms of prevention.(AU)

Gênero e transgeracionalidade: uma (des)construção / Gender and transgeneration: a (de)construction / Genre et transgénérationnalité: une (dé)construction / Género y transgeneracionalidad: una (de)construcción

Resumo Este estudo buscou investigar e compreender a transmissão e manutenção transgeracional de perspectivas de gênero a partir de entrevistas semiestruturadas realizadas com 10 jovens, com idades entre 20 e 27 anos. Identificou-se que as novas gerações buscam ressignificar questões transmitidas por suas famílias, objetivando uma sociedade equitativa, embora as mudanças percebidas nas dinâmicas familiares ainda não sejam suficientes para a desconstrução de paradigmas históricos e culturais. Esses jovens, embora possuam posicionamento social crítico e busquem desconstruir valores estereotipados e preconceituosos relacionados ao gênero, deixam transparecer em seus discursos que as desigualdades políticas, econômicas e sociais ainda afetam profundamente as mulheres. Um dos principais motivos que levaram à desconstrução transgeracional foi o acesso à informação e a potente inserção em grupos que motivam a militância, embora poucos dos entrevistados ultrapassem as barreiras da internet em suas atuações.

Abstract This study analyzed the transgenerational transmission and maintenance of gender perspectives with use of semi-structured interviews with 10 young adults aged between 20 and 27 years. The new generations were found to re-signify issues transmitted by their families aiming for a fair society, although the perceived changes in family dynamics are not enough to reflect on the deconstruction of historical and cultural paradigms. Although these individuals have a critical social stance and seek to deconstruct stereotypical and prejudiced gender values, their discourses showed that political, economic and social inequalities still profoundly affect women. One of the main reasons that led to this transgenerational deconstruction was the access to information and the powerful insertion in groups that motivate militancy, although few of the interviewees overcome the internet barriers in their actions.

Résumé Cette étude visait à étudier et à comprendre la transmission transgénérationnelle et le maintien des perspectives de genre à partir d'entretiens semi-structurés menés auprès de 10 jeunes, âgés de 20 à 27 ans. Il a été identifié que les nouvelles générations cherchent à redéfinir les aspects transmis par leurs familles visant une société équitable, bien que les changements perçus dans la dynamique familiale ne soient pas suffisants pour réfléchir à la déconstruction des paradigmes historiques et culturels. Bien que ces jeunes aient une position sociale critique et cherchent à déconstruire des valeurs de genre stéréotypées et préjugées, ils preuves par leurs discours que les inégalités politiques, économiques et sociales affectent profondément les femmes. L'une des principales raisons qui ont conduit à la déconstruction transgénérationnelle était l'accès à l'information et l'insertion puissante dans des groupes qui motivent le militantisme, bien que peu de personnes interrogées dépassent les barrières d'Internet dans leurs actions.

Resumen Este estudio buscó investigar y comprender la transmisión transgeneracional y mantenimiento de las perspectivas de género a partir de entrevistas semiestructuradas realizadas con 10 jóvenes, con edades entre 20 y 27 años. Se identificó que las nuevas generaciones buscan resignificar cuestiones transmitidas por sus familias apuntando a una sociedad equitativa, aunque los cambios percibidos en la dinámica familiar no son suficientes para reflexionar sobre la deconstrucción de paradigmas históricos y culturales. Aunque estos jóvenes tienen una posición social crítica y buscan deconstruir valores de género estereotipados y prejuiciosos relacionados al género, dejan claro en sus discursos que las desigualdades políticas, económicas y sociales aún afectan profundamente a las mujeres. Una de las principales razones que llevaron a la deconstrucción transgeneracional fue el acceso a la información y la inserción en grupos que motivan la militancia, a pesar de que pocos de los entrevistados superan las barreras de la internet en sus acciones.

Falam de paz onde não há: representações da vida em comunidade entre jovens residentes em um Território de Paz / Speaking of peace where there is none: representations of community life among young people living in a peaceful territory / Ils parlent de paix lorsquil ny a pas: représentations de la vie communautaire chez les jeunes vivants dans un territoire de paix / Hablan de la paz donde no hay: representaciones de la vida comunitaria entre los jóvenes residentes en un territorio de paz

Resumo Estudo de cunho etnográfico que visou compreender os efeitos do projeto Território de Paz sobre o cotidiano, as vivências comunitárias e os projetos de vida de jovens do bairro Guajuviras, localizado em Canoas (RS), e marcado pelo tráfico de drogas, pela violência e pelo estigma. Serão focalizados os resultados da análise de conteúdo das entrevistas semiestruturadas feitas com 34 jovens (entre 18 e 29 anos) residentes no bairro sobre os temas relacionados a trabalho, estudo, lazer e percepções sobre o bairro e sobre o projeto Território de Paz. O estudo apontou para a importância do trabalho em políticas públicas de forma sensível aos modos de vida das juventudes ao assinalar que a maioria dos entrevistados teve sua vida afetada pela violência e não percebe como efetiva sua diminuição após a implantação do projeto que os tinha como principal público-alvo.

Abstract This ethnographic study verified the effects of the Território da Paz project on the daily life, community experiences and life projects of adolescents and young adults in the Guajuviras, Canoas, RS, marked by drug trafficking, violence and stigma. Content analysis was conducted on semi-structured interviews with 34 young individuals (18 and 29 years old) living in the region regarding topics related to work, study, leisure, and their perceptions about the neighborhood and the project. This study pointed to the importance of working in public policies while taking into account youths' ways of life, as the majority of respondents had their lives affected by violence and did not perceive the project's effectiveness after its implementation despite being the main target audience.

Résumé Étude ethnographique visant à comprendre les effets du projet Territoire de Paix sur la vie quotidienne, les expériences communautaires et les projets de vie des jeunes du quartier Guajuviras, situé à Canoas / RS et marqué par le trafic de drogue, la violence et la stigmatisation. Les résultats ont été recueilli de l'analyse du contenu des entretiens semi-structurés avec 34 jeunes (âgés de 18 à 29 ans) vivant dans le quartier. Les interviews ont porté sur des thèmes liés au travail, aux études, aux loisirs et aux perceptions du quartier et du projet Territoire de Paix. Les résultats souligne l'importance de construire les politiques publiques d'une manière qui soit sensible aux modes de vie des jeunes, soulignant que la plus part des répondants avaient été victimes de violence et ne percevaient pas l'efficacité des actions après la mise en œuvre du projet qui les avait comme leur principal public cible.

Resumen Este estudio etnográfico tuvo como objetivo comprender los efectos del proyecto Territorio de la Paz en la vida cotidiana, las experiencias comunitarias y los proyectos de vida juvenil en el barrio de Guajuviras, ubicado en Canoas (RS, Brasil), y marcado por el tráfico de drogas, la violencia y el estigma. El estudio se centrará en los resultados del análisis de contenido de las entrevistas semiestructuradas con 34 jóvenes (entre 18 y 29 años de edad) que viven en el barrio en cuanto a temas relacionados con el trabajo, el estudio, el ocio y las percepciones sobre el vecindario y el proyecto Territorio de la Paz. Se apunta la importancia del trabajo con políticas públicas de una manera que sea sensible a las formas de vida de los jóvenes al señalar que la mayoría de los encuestados tuvieron sus vidas afectadas por la violencia y no percibieron su efectividad después de la implementación del proyecto que los tuvo como público objetivo.

Oral pentamidine-loaded poly(d,l-lactic-co-glycolic) acid nanoparticles: an alternative approach for leishmaniasis treatment.

Leishmaniasis is a group of diseases caused by a protozoa parasite from one of over 20 Leishmania species. Depending on the tissues infected, these diseases are classified as cutaneous, mucocutaneous and visceral leishmaniasis. For the treatment of leishmaniasis refractory to antimony-based drugs, pentamidine (PTM) is a molecule of great interest. However, PTM displays poor bioavailability through oral routes due to its two strongly basic amidine moieties, which restricts its administration by a parenteral route and limits its clinical use. Among various approaches, nanotechnology-based drug delivery systems (nano-DDS) have potential to overcome the challenges associated with PTM oral administration. Here, we present the development of PTM-loaded PLGA nanoparticles (NPs) with a focus on the characterization of their physicochemical properties and potential application as an oral treatment of leishmaniasis. NPs were prepared by a double emulsion methodology. The physicochemical properties were characterized through the mean particle size, polydispersity index (PdI), zeta potential, entrapment efficiency, yield process, drug loading, morphology, in vitro drug release and in vivo pharmacological activity. The PTM-loaded PLGA NPs presented with a size of 263 ± 5 nm (PdI = 0.17 ± 0.02), an almost neutral charge (-3.2 ± 0.8 mV) and an efficiency for PTM entrapment of 91.5%. The release profile, based on PTM dissolution, could be best described by a zero-order model, followed by a drug diffusion profile that fit to the Higuchi model. In addition, in vivo assay showed the efficacy of orally given PTM-loaded PLGA NPs (0.4 mg kg-1) in infected BALB/c mice, with significant reduction of organ weight and parasite load in spleen (p-value < 0.05). This work successfully reported the oral use of PTM-loaded NPs, with a high potential for the treatment of visceral leishmaniasis, opening a new perspective to utilization of this drug in clinical practice.

Incidence of contralateral cervical metastasis in laryngeal tumors

Introduction: Through the knowledge of the metastatic pathways of the Squamous Cell Carcinoma (SCC) of the larynx, the lymph node level with a higher probability of involvement can be predicted. The surgeon uses this knowledge to determine the extension of neck dissection to perform. However, the longer the surgery, the greater the morbidity for the patient. When the metastatic risk is >20%, neck dissection of that cervical level is necessary. In cases of clinically evident (cN+) metastasis, uni or bilaterally, comprehensive neck dissection is determinant for the treatment, however there is no consensus about neck dissection for contralateral clinically negative neck (cN-). Objective: To evaluate if patients with laryngeal SCC homolateral cN+ and contralateral cN- should be submitted to bilateral neck dissection. Methods: The team reviewed medical records from 135 patients with a diagnosis of laryngeal malignancy between March/2009 and September/2017, analyzing gender, age, tobacco and alcohol comsumption, primary tumor site, neck dissection laterality, clinical and pathological contralaterality, staging, tumor recurrence or late metastasis and survival Results: We observed that 40.74% were pN+ on at least one side after neck dissection, which 87.27% performed bilateral neck dissection. Of these, 66.67% did not have contralateral metastasis, 87.5% had no previously clinically evident metastasis. Conclusion: Patients contralateral cN- have a risk <20% for occult metastasis and should not routinely go through bilateral neck dissection.

Leishmanicidal Activity of Withanolides from Aureliana Fasciculata var. Fasciculata.

Leishmaniasis is the generic denomination to the neglected diseases caused by more than 20 species of protozoa belonging to the genus Leishmania. The toxic and parenteral-delivered pentavalent antimonials remain to be the first-line treatment. However, all the current used drugs have restrictions. The species Aureliana fasciculata (Vell.) Sendtner var. fasciculata is a native Brazilian species parsimoniously studied on a chemical point of view. In this study, the antileishmanial activity of A. fasciculata was evaluated. Among the evaluated samples of the leaves, the dichloromethane partition (AFfDi) showed the more pronounced activity, with IC50 1.85 µg/ml against promastigotes of L. amazonensis. From AFfDi, two active withanolides were isolated, the Aurelianolides A and B, with IC50 7.61 µM and 7.94 µM, respectively. The withanolides also proved to be active against the clinically important form, the intracellular amastigote, with IC50 2.25 µM and 6.43 µM for Aurelianolides A and B, respectively. Furthermore, withanolides showed results for in silico parameters of absorption, distribution, metabolism, excretion, and toxicity (ADMET) similar to miltefosine, the reference drug, and were predicted as good oral drugs, with the advantage of not being hepatotoxic. These results suggest that these compounds can be useful as scaffolds for planning drug design.

Safety and efficacy of recanalization therapy in pediatric stroke: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Safety and efficacy of intravenous (IV) thrombolysis and endovascular therapy in children with acute ischemic stroke (AIS) are unknown to date. We aimed to review and synthesize currently available evidence on these acute recanalization therapies in pediatric stroke patients. METHODS: We performed a systematic review and meta-analysis of all available data on safety and efficacy of acute treatment including thrombolysis and endovascular therapy in pediatric AIS patients aged <18 years. We searched the electronic databases Medline and Cochrane Library for eligible studies published from the earliest date available until August 31, 2016. Safety outcomes included intracerebral hemorrhage (ICH) post-treatment and in-hospital mortality. Efficacy outcomes included functional outcome 3-6 months after index stroke. RESULTS: We identified 222 records, of which 3 studies with a total of 16,987 pediatric stroke patients met our eligibility criteria of whom 181 received IV thrombolysis. No data exists from randomized trials and no data is available on endovascular thrombectomy. Risk of any ICH was increased in children receiving thrombolysis (risk ratio = 3.48, 95%CI: 1.66-7.29; p = 0.001) compared with controls, with no evidence of heterogeneity (I2 = 0%). None of the included studies reported complete data on symptomatic ICH. In-hospital mortality was similar between pediatric stroke patients treated with thrombolysis and controls (risk ratio = 1.44, 95%CI: 0.39-5.40; p = 0.586), with evidence of heterogeneity (I2 = 62%). Efficacy of revascularization therapies could not be analyzed due to lack of outcome data. CONCLUSIONS: Our analyses demonstrate a substantial lack of data on efficacy and safety of acute recanalization therapies in children with AIS. PROSPERO REGISTRATION INFORMATION: URL: http://www.crd.york.ac.uk/PROSPERO. Unique identifier: CRD42016047140.