Panx1 knockout promotes preneoplastic aberrant crypt foci development in a chemically induced model of mouse colon carcinogenesis.

Colorectal cancer, which is the third leading cause of cancer-related deaths worldwide, is a multistep disease, featuring preneoplastic aberrant crypt foci (ACF) as the early morphological manifestation. The roles of hemichannel-forming transmembrane Pannexin 1 (Panx1) protein have not been investigated in the context of colon carcinogenesis yet, although it has contrasting roles in other cancer types. Thus, this study was conducted to examine the effects of Panx1 knockout (Panx1-/- ) on the early events of chemically induced colon carcinogenesis in mouse. Wild type (WT) and Panx1-/- female C57BL6J mice were submitted to a chemically induced model of colon carcinogenesis by receiving six intraperitoneal administrations of 1,2-dimethylhydrazine (DMH) carcinogen. Animals were euthanized 8 h (week 7) or 30 weeks (week 37) after the last DMH administration in order to evaluate sub-acute colon toxicity outcomes or the burden of ACF, respectively. At week 7, Panx1 genetic ablation increased DMH-induced genotoxicity in peripheral blood cells, malondialdehyde levels in the colon, and apoptosis (cleaved caspase-3) in colonic crypts. Of note, at week 37, Panx1-/- animals showed an increase in aberrant crypts (AC), ACF mean number, and ACF multiplicity (AC per ACF) by 56%, 57% and 20%, respectively. In essence, our findings indicate that Panx1 genetic ablation promotes preneoplastic ACF development during chemically induced mouse colon carcinogenesis, and a protective role of Panx1 is postulated.

Distribuição espaço-temporal da leishmaniose visceral no Brasil no período de 2007 a 2020 / Spatial-temporal distribution of visceral leishmaniasis in Brazil from 2007 to 2020 / Distribución espaciotemporal de la leishmaniasis visceral en Brasil en el período 2007-2020

RESUMO Objetivo. Analisar a dinâmica da distribuição espacial e temporal da leishmaniose visceral no Brasil no período de 2007 a 2020. Métodos. Este estudo ecológico do padrão espacial dos casos de leishmaniose visceral ocorridos no Brasil de 2007 a 2020 utilizou dados do Sistema de Informação de Agravos e Notificação (SINAN). As variáveis analisadas foram o coeficiente de incidência da leishmaniose visceral e o índice composto da leishmaniose visceral (ICLV), a partir das quais foram construídos mapas temáticos trienais. Foi calculado o índice de Moran global, para verificar a existência de autocorrelação espacial, e o índice de Moran local, para delimitar áreas de maior e menor risco para adoecimento por leishmaniose visceral no Brasil. Resultados. No período estudado, ocorreram 48 705 casos de leishmaniose visceral, com incidência de 25,53 casos/100 000 habitantes. Em todos os blocos trienais, houve autocorrelação espacial, havendo municípios das regiões Norte e Nordeste com incidência igual ou superior a 50 casos/100 000 habitantes. Com relação ao ICLV, houve aumento do número de municípios considerados de baixo risco de transmissão e presença crescente do número de capitais com classificação de risco muito intenso. Conclusão. A incidência de leishmaniose visceral variou ao longo dos triênios. A região de fronteira entre Tocantins, Maranhão e Pará, juntamente com o estado do Ceará, destacou-se na distribuição espacial da incidência da doença e na estratificação de risco pelo ICLV. Tais localidades devem ser prioritárias para ações e serviços voltados à vigilância e ao controle da doença.

ABSTRACT Objective. To analyze the dynamics of the spatial and temporal distribution of visceral leishmaniasis in Brazil from 2007 to 2020. Method. This ecological study focused on the spatial pattern of visceral leishmaniasis cases in Brazil from 2007 to 2020 using data from the Information System for Notifiable Diseases (SINAN). The variables analyzed were the incidence rate of visceral leishmaniasis and the visceral leishmaniasis composite indicator (VLCI), from which triennial thematic maps were constructed. The global Moran index was calculated to assess the existence of spatial autocorrelation, and the local Moran index was used to identify areas with higher and lower risk of visceral leishmaniasis in Brazil. Results. During the study period, there were 48 705 cases of visceral leishmaniasis, with an incidence rate of 25.53 cases per 100 000 population. There was spatial autocorrelation in all triennial blocks, with municipalities in the North and Northeast regions having an incidence equal to or greater than 50 cases per 100 000 population. Regarding the VLCI there was an increase in the number of municipalities classified as low risk for transmission, and a growing presence of state capitals with a classification of very high risk. Conclusion. The incidence of visceral leishmaniasis varied over the trienniums. The border region between the states of Tocantins, Maranhão, and Pará, along with the state of Ceará, stood out in the spatial distribution of the disease incidence and risk stratification by VLCI. These areas should be a priority for surveillance and control efforts for the disease.

RESUMEN Objetivo. Analizar la dinámica de la distribución espaciotemporal de la leishmaniasis visceral en Brasil en el período 2007-2020. Métodos. En este estudio ecológico del patrón de distribución espacial de los casos de leishmaniasis visceral ocurridos en Brasil en el período 2007-2020 se utilizaron datos del sistema de información de enfermedades de declaración obligatoria (SINAN). Las variables analizadas fueron el coeficiente de incidencia de leishmaniasis visceral y el índice compuesto de leishmaniasis visceral, a partir de los cuales se construyeron mapas temáticos trienales. Se calcularon el índice general de Moran para verificar la existencia de autocorrelación espacial, y el índice local de Moran para delimitar las zonas de mayor y menor riesgo de leishmaniasis visceral en Brasil. Resultados. En el período estudiado, hubo 48 705 casos de leishmaniasis visceral, con una incidencia de 25,53 casos por 100 000 habitantes. En todos los bloques trienales hubo una autocorrelación espacial, en la cual varios municipios de las regiones norte y nordeste registraron una incidencia de 50 casos por 100 000 habitantes o una tasa superior. En relación con el índice compuesto de leishmaniasis visceral, se observó un aumento del número de municipios considerados de riesgo bajo de transmisión y una tendencia ascendente del número de ciudades capitales con clasificación de riesgo muy alto. Conclusión. La incidencia de leishmaniasis visceral varió a lo largo de los períodos trienales. La región fronteriza entre Tocantins, Maranhão y Pará, junto con el estado de Ceará, se destacó en términos de la distribución espacial de la incidencia de la enfermedad y la estratificación del riesgo según el índice compuesto de leishmaniasis visceral. Es preciso dar prioridad a estos lugares en lo referente a las medidas y los servicios de vigilancia y control de esta enfermedad.

The Implications of Connexin 43 Deficiency during the Early Stages of Chemically Induced Mouse Colon Carcinogenesis.

Colorectal cancer (CRC), associated with an increased intake of processed red meats, saturated fats, and simple carbohydrates accompanied by low dietary fiber, fruits, and vegetables consumption, presents a high epidemiological burden. Connexin43 (Cx43) protein, which forms gap junctions or hemichannels, has tumor suppressor or oncogenic activities in a cancer type- and stage-dependent manner. Cx43 expression varies during colon carcinogenesis, and its functional role is not fully understood. Thus, we evaluated the implications of Cx43 heterologous deletion (Cx43+/-) during the early stages of a chemically induced model of colon carcinogenesis. Female C57BL/6J mice (wild-type or Cx43+/-) were submitted to a colon carcinogenesis model induced by 1,2 dimethylhydrazine (DMH). Mice were euthanized eight hours (week 7) or 30 weeks (week 37) after the last DMH administration to evaluate subacute colon toxicity outcomes or the burden of (pre)neoplastic lesions, respectively. At week 7, Cx43 deficiency inferred no alterations in the DMH-induced increase in systemic (peripheral blood), in situ (colonocytes) DNA damage, and apoptosis in the colonocytes. At week 30, Cx43+/- mice presented an increase in preneoplastic aberrant crypt foci (ACF) multiplicity, while no alterations were observed in colorectal adenoma (CRA) occurrence, multiplicity, volume, proliferation, growth, and ß-catenin immunoexpression. Similarly, an in silico analysis of human CRA showed decreased mRNA expression of Cx43 with no correlation with proliferation, apoptosis, and ß-catenin markers. These findings indicate the discrete role of Cx43 in the early stages of chemically induced mouse colon carcinogenesis.

Hepatocellular Carcinoma in a Free-Ranging Three-Toed Sloth (Bradypus variegatus).

The increasing interest of tumors in wildlife is important for biodiversity conservation and for monitoring environmental agents and/or contaminants with potential impact on human health. Here we described the occurrence of hepatocellular carcinoma (HCC) in noncirrhotic liver of a free-ranging three-toed sloth (Bradypus variegatus) from the Atlantic Forest biome in Brazil. The HCC showed a moderate mononuclear inflammatory infiltrate within the tumor tissue but with no inflammation and fibrosis in the adjacent liver tissue. Upon immunohistochemistry, neoplastic cells were diffusely positive for HepPar-1 and glutamine-synthetase presenting an irregular and random immunostaining pattern; ß-catenin was positive in the cytoplasmic membrane of malignant hepatocytes; and cytokeratin 19 immunostaining was restricted to bile duct epithelial cells. The liver tissue was negative for HBV-like and HCV-like viruses assessed by molecular tests. The potential similarity of pathogenesis may reinforce the need for research on environmental and/or infectious agents associated with HCC that may contribute to the understanding of cancer in wildlife.

Novel gammaherpesvirus associated with primary gastric T-cell lymphoma in a free-ranging giant armadillo in Brazil.

The number of viral-associated neoplasms reported in wildlife has increased over the last decades, likely because of growing research efforts and a potentially greater burden of carcinogenic pathogens. Herein, we describe a primary gastric T-cell lymphoma in one free-ranging giant armadillo (Priodontes maximus) from Brazilian Pantanal infected by a novel gammaherpesvirus, proposed as Cingulatid gammaherpesvirus 1 (CiHV-1). By chromogenic in situ hybridisation against Epstein-Barr virus some neoplastic cells were labeled. Subsequently, a molecular screening was carried out to detect the occurrence of this pathogen in other giant armadillos in the same region. Overall, this novel virus was detected in 14.3% (3/21) of the tested giant armadillos. We suggest this herpesvirus, the first in Xenarthra, as a plausible aetiology of the neoplasm. The implications of CiHV-1 for this species are uncertain; while no outbreaks of disease have been recorded, the present study raises concerns. Further research is warranted to assess the real significance of CiHV-1 and its potential oncogenic role in this species.

Spatial analysis of AIDS in the state of Maranhão: an ecological study 2011-2018 / Análisis espacial del sida en el estado de Maranhão: un estudio ecológico 2011-2018 / Análise espacial da aids no estado do Maranhão: um estudo ecológico 2011-2018

ABSTRACT Objective: Analyze the spatio-temporal distribution of AIDS cases in Maranhão. Methods: Ecological study of AIDS cases in the Notifiable Diseases Information System, 2011-2018. Gross and adjusted incidences were calculated using the Baysean method; then, the Moran Global and Local Indices to observe the existence of spatial autocorrelation of the cases and for the delimitation of high and low risk clusters. Results: 6,349 cases were reported, which were distributed heterogeneously. There was an advance of cases to new areas and persistence in old areas, such as in the capital São Luís and its surroundings. The dissemination did not occur at random, with positive spatial autocorrelation, with evidence of the formation of clusters in the municipalities of São Luís, São José de Ribamar and Paço do Lumiar. Conclusion: High-risk areas have been identified and should be considered a priority for investment in health, management, and organization of health services.

RESUMEN Objetivo: Analizar la distribución espacio-temporal de los casos de SIDA en Maranhão. Métodos: Estudio ecológico de casos de SIDA en el Sistema de Información de Enfermedades de Notificación, 2011-2018. Las incidencias brutas y ajustadas se calcularon utilizando el método de Baysean; luego, los Índices de Moran Global y Local para observar la existencia de autocorrelación espacial de los casos y para la delimitación de aglomerados de Alto y Bajo Riesgo. Resultados: se notificaron 6.349 casos, los cuales se distribuyeron de forma heterogénea. Hubo un avance de casos a nuevas áreas y persistencia en áreas antiguas, como en la capital São Luís y sus alrededores. La diseminación no ocurrió al azar, con autocorrelación espacial positiva, con evidencia de la formación de aglomerados en los municipios de São Luís, São José de Ribamar y Paço do Lumiar. Conclusión: Se han identificado áreas de alto riesgo y deben considerarse una prioridad para la inversión en salud, gestión y organización de los servicios de salud.

RESUMO Objetivo: Analisar a distribuição espaço-temporal dos casos de aids no Maranhão. Métodos: Estudo ecológico dos casos de aids no Sistema de Informação de Agravos de Notificação, 2011-2018. Calcularam-se as incidências bruta e ajustada pelo método bayseano; em seguida, os Índices de Moran Global e Local para observar a existência de autocorrelação espacial dos casos e para delimitação de aglomerados de Alto e Baixo Risco. Resultados: Foram notificados 6.349 casos, que se distribuíram de forma heterogênea. Houve o avanço de casos para novas áreas e persistência nas áreas antigas, como na capital São Luís e seu entorno. A disseminação não ocorreu de forma aleatória, existindo autocorrelação espacial positiva, com evidência da formação de aglomerados nos municípios de São Luís, São José de Ribamar e Paço do Lumiar. Conclusão: Foram identificadas áreas de alto risco, devendo ser consideradas prioridade para o investimento em saúde, gestão e organização dos serviços de saúde.

In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.

Immunoexpression and Prognostic Significance of Multidrug Resistance Markers in Feline Mammary Carcinomas.

Feline mammary carcinomas (FMCs) are commonly characterized by high clinical aggressiveness and poor prognosis. FMCs share many features with the corresponding human disease, allowing the comparative investigation of tumour biology and therapeutic strategies, including multidrug resistance (MDR) mechanisms. Although transporting/binding proteins, including permeability glycoprotein (P-gp), lung resistance protein (LRP) and metallothionein (MT), are frequently associated with tumour aggressiveness and unresponsiveness to chemotherapy in human breast cancer, they have not been analysed in FMCs. We investigated the immunoexpression of P-gp, LRP and MT in FMCs and their correlation with clinicopathological parameters and overall survival (OS) time in 46 FMCs, with a median follow-up period of 289 days. These markers were co-expressed in 85% of tumours. P-gp was expressed in 93.4% of FMCs and was positively associated with tumour grade (P = 0.049). While unequivocally observed in all FMCs, LRP immunoexpression did not correlate with any clinicopathological parameters or OS. Expression of MT was significant in triple-negative basal- and normal-like molecular subtypes of FMCs (P = 0.023). The concurrent expression of MDR proteins indicates the potential existence of chemotherapy resistance-related mechanisms in FMCs. The positive association between P-gp and MT immunoexpression and aggressive phenotypes could open new therapeutic and translational strategies for FMCs.

Genetic variants of BRCA1 and BRCA2 genes in cats with mammary gland carcinoma.

Mammary tumours are the first and third most incident neoplasm in women and cats, respectively. Approximately 85% of feline mammary gland tumours are malignant and aggressive, especially the triple-negative and HER-2+ molecular subtypes. Triple-negative basal-like feline mammary carcinomas (FMCs) are considered suitable models due to the clinical and morphological similarities with human basal-like triple-negative breast cancer (TNBC). In women, TNBC has a poor prognosis and is often associated with mutations in the tumour suppressor genes BRCA1 and BRCA2. In light of this, the aim of the present investigation was to screen somatic and germline variants of BRCA1 and BRCA2 in nine female cats bearing FMCs. Matched whole blood and FMC samples were obtained for genetic analysis. Additional tumour samples were obtained for histopathological and immunohistochemical evaluation. Genomic DNA was isolated and 27 exonic regions of BRCA1 and BRCA2 genes were amplified and screened by next-generation sequencing. A somatic variant with high functional impact was found in exon 11 of BRCA2 at a frequency of 4.34% in one FMC-bearing cat. Four germline variants with moderate impact were detected in three of the nine FMC-bearing cats and were restricted to exon 9 of BRCA1. It is concluded that the germline genetic variants found in one-third of FMC-bearing animals might be associated with a higher risk of hereditary mammary carcinogenesis.

Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) affects around 25% of the worldwide population. Non-alcoholic steatohepatitis (NASH), the more progressive variant of NAFLD, is characterized by steatosis, cellular ballooning, lobular inflammation, and may culminate on hepatic stellate cell (HSC) activation, thus increasing the risk for fibrosis, cirrhosis, and HCC development. Conversely, the antifibrotic effects of sorafenib, an FDA-approved drug for HCC treatment, have been demonstrated in 2D cell cultures and animal models, but its mechanisms in a NAFLD-related microenvironment in vitro requires further investigation. Thus, a human 3D co-culture model of fatty hepatocytes and HSC was established by culturing hepatoma C3A cells, pre-treated with 1.32 mM oleic acid, with HSC LX-2 cells. The fatty C3A/LX-2 spheroids showed morphological and molecular hallmarks of altered lipid metabolism and steatosis-induced fibrogenesis, similarly to the human disease. Sorafenib (15 µM) for 72 hours reduced fatty spheroid viability, and upregulated the expression of lipid oxidation- and hydrolysis-related genes, CPT1 and LIPC, respectively. Sorafenib also inhibited steatosis-induced fibrogenesis by downregulating COL1A1, TGFB1, PDGF, and TIMP1 and by decreasing protein levels of IL-6, TGF-ß1, and TNF-α in fatty spheroids. The demonstration of the antifibrotic properties of sorafenib on steatosis-induced fibrogenesis in a 3D in vitro model of NAFLD supports its clinical use as a therapeutic agent for the treatment of NAFLD/NASH patients.

Prevalence and factors associated with locomotive syndrome in community-dwelling older adults / Prevalencia y factores asociados al síndrome locomotor en adultos mayores de la comunidad / Prevalência e fatores associados à síndrome locomotora em idosos comunitários

ABSTRACT Objective: to analyze prevalence and the factors associated with locomotive syndrome in community-dwelling older adults. Method: a cross-sectional study, developed in a municipal center for the care of older adults in Teresina, Piauí, Brazil. The sample was for convenience and comprised 204 older adults aged 60 years or more, of both genders and with preserved cognitive capacity, according to parameters of the Mini Mental State Examination. Data collection occurred from March to November 2018, by applying a form for sociodemographic, clinical and falls occurrence characterization and the 25-item Geriatric Locomotive Function Scale. To measure the strength of the associations between the variables, odds ratios and 95% confidence intervals were adopted. The statistical significance level was set at 5% for the analyses. Results: the prevalence of locomotive syndrome found was 37.2%. The factors associated with the presence of locomotive syndrome were individual monthly income (p=0.005); existence of one of the following comorbidities: systemic arterial hypertension (p=0.039), osteoporosis (p=0.016), arthrosis (p<0.001) or obesity (p=0.014); and history of hospitalization in the last year (p=0.007). Conclusion: the prevalence of locomotive syndrome found in this study was low and presented higher levels in older adults, with an individual monthly income of two to three minimum wages; who reported having hypertension, osteoporosis, arthrosis or obesity; and with a history of hospitalization in the last year. The health condition investigated showed to be related to aging, with significant repercussions on functionality.

RESUMEN Objetivo: analizar la prevalencia y los factores asociados al síndrome locomotor en adultos mayores de la comunidad. Método: estudio de tipo transversal, desarrollado en un centro de atención para adultos mayores de Teresina, Piauí, Brasil. La muestra fue por conveniencia y estuvo compuesta por 204 adultos mayores de 60 o más años de edad, de ambos sexos y con capacidad cognitiva preservada, según parámetros del Mini Examen de Estado Mental. Los datos se recolectaron entre marzo y noviembre de 2018 aplicando un formulario para la caracterización sociodemográfica, clínica y de caídas y la Escala Geriátrica de la Función Locomotora de 25 ítems. Para medir la fuerza de las asociaciones entre las variables, se adoptaron odds ratios e intervalos de confianza del 95%. El nivel de significancia estadística se estableció en 5% para los análisis. Resultados: la prevalencia del síndrome locomotor fue del 37,2%. Los factores asociados a la presencia del síndrome locomotor fueron los siguientes: ingreso mensual individual (p=0,005); presencia de una de las comorbilidades: hipertensión arterial sistémica (p=0,039), osteoporosis (p=0,016), artrosis (p<0,001) u obesidad (p=0,014); y antecedentes de internación en el último año (p=0,007). Conclusión: la prevalencia del síndrome locomotor que se encontró en este estudio fue baja y demostró ser superior en adultos mayores, con ingresos mensuales individuales de de dos a tres salarios mínimos; que indicaron sufrir hipertensión, osteoporosis, artrosis u obesidad; y con antecedentes de internación en el último año. La condición de salud investigada demostró estar relacionada con el envejecimiento, con repercusiones significativas sobre la funcionalidad.

RESUMO Objetivo: analisar a prevalência e os fatores associados à síndrome locomotora em idosos comunitários. Método: estudo do tipo transversal, desenvolvido em núcleo de atenção ao idoso, em Teresina, Piauí, Brasil. A amostra foi por conveniência e constituída por 204 idosos com idade igual ou superior a 60 anos, de ambos os sexos, com capacidade cognitiva preservada, segundo parâmetros do Mini Exame do Estado Mental. A coleta de dados ocorreu de março a novembro de 2018, por meio da aplicação de um formulário para caracterização sociodemográfica, clínica e de ocorrência de quedas e da Escala Geriátrica da Função Locomotora de 25 itens. Para aferição da força das associações entre as variáveis, adotaram-se razão de chances e intervalos de confiança de 95%. Nível de significância estatística estabelecido de 5% para as análises. Resultados: a prevalência da síndrome locomotora encontrada foi de 37,2%. Os fatores associados à presença da síndrome locomotora foram renda mensal individual (p=0,005); existência de uma das comorbidades: hipertensão arterial sistêmica (p=0,039), osteoporose (p=0,016), artrose (p<0,001) ou obesidade (p=0,014); e histórico de hospitalização, no último ano (p=0,007). Conclusão: a prevalência da síndrome locomotora encontrada no presente estudo foi baixa e apresentou-se maior em idosos, com renda mensal individual de dois a três salários mínimos; que referiram ter hipertensão, osteoporose, artrose ou obesidade; e com histórico de hospitalização, no último ano. A condição de saúde investigada se mostrou relacionada ao envelhecimento, com repercussões significativas sobre a funcionalidade.

The combination of coffee compounds attenuates early fibrosis-associated hepatocarcinogenesis in mice: involvement of miRNA profile modulation.

Aberrant microRNA expression implicates on hepatocellular carcinoma (HCC) development. Conversely, coffee consumption reduces by ~40% the risk for fibrosis/cirrhosis and HCC, while decaffeinated coffee does not. It is currently unknown whether these protective effects are related to caffeine (CAF), or to its combination with other common and/or highly bioavailable coffee compounds, such as trigonelline (TRI) and chlorogenic acid (CGA). We evaluated whether CAF individually or combined with TRI and/or CGA alleviates fibrosis-associated hepatocarcinogenesis, examining the involvement of miRNA profile modulation. Then, male C3H/HeJ mice were submitted to a diethylnitrosamine/carbon tetrachloride-induced model. Animals received CAF (50 mg/kg), CAF+TRI (50 and 25 mg/kg), CAF+CGA (50 and 25 mg/kg) or CAF+TRI+CGA (50, 25 and 25 mg/kg), intragastrically, 5×/week, for 10 weeks. Only CAF+TRI+CGA combination reduced the incidence, number and proliferation (Ki-67) of hepatocellular preneoplastic foci while enhanced apoptosis (cleaved caspase-3) in adjacent parenchyma. CAF+TRI+CGA treatment also decreased hepatic oxidative stress and enhanced the antioxidant Nrf2 axis. CAF+TRI+CGA had the most pronounced effects on decreasing hepatic pro-inflammatory IL-17 and NFκB, contributing to reduce CD68-positive macrophage number, stellate cell activation, and collagen deposition. In agreement, CAF+TRI+CGA upregulated tumor suppressors miR-144-3p, miR-376a-3p and antifibrotic miR-15b-5p, frequently deregulated in human HCC. CAF+TRI+CGA reduced the hepatic protein levels of pro-proliferative EGFR (miR-144-3p target), antiapoptotic Bcl-2 family members (miR-15b-5p targets), and the number of PCNA (miR-376a-3p target) positive hepatocytes in preneoplastic foci. Our results suggest that the combination of most common and highly bioavailable coffee compounds, rather than CAF individually, attenuates fibrosis-associated hepatocarcinogenesis by modulating miRNA expression profile.

Tuberculose em idosos no Maranhão: contribuição para o programa de controle / Tuberculosis in the elderly in Maranhão: contribution to the control program / Tuberculosis en ancianos en Maranhão: contribución al programa de control

Objetivo: Analisar o perfil e identificar os fatores associados à tuberculose em idosos no Maranhão no período de 2010 a 2015. Métodos: Estudo transversal analítico com os casos de tuberculose em idosos no estado do Maranhão. Foram utilizados dados secundários do SINAN, disponíveis no Datasus. Para identificar as associações entre o desfecho (tuberculose em idosos) e as variáveis independentes, utilizou-se a regressão de Poisson. Resultados: Após o ajuste do modelo, a escolaridade < 8 anos de estudo, ter encerramento por não cura, exame anti HIV não realizado e ter diabetes apresentaram­se como fatores que aumenta a chance da ocorrência de tuberculose em idosos. As demais variáveis apresentaram-se como fator protetor. Conclusão: Foi observada alta prevalência de tuberculose em idosos no estado (16,6%). Há necessidade de se adotarem estratégias de acompanhamento dessa clientela

Objective: To analyze the profile and identify the factors associated with tuberculosis in the elderly in Maranhão from 2010 to 2015. Methods: An analytical cross-sectional study with cases of tuberculosis in the elderly in the State of Maranhão. Secondary data from SINAN, available on Datasus, were used. To identify the associations between the outcome (tuberculosis in the elderly) and the independent variables, Poisson regression was used. Results: After adjustment of the model, schooling < 8 years of study, closure due to non-cure, unrecovered HIV test and diabetes had a factor that increases the chance of tuberculosis occurring in the elderly. The other variables were presented as protective factor. Conclusion: A high prevalence of tuberculosis in the elderly was observed in the State (16.6%). There is a need to adopt strategies to follow up this clientele

Objetivo: Analizar el perfil e identificar los factores asociados a la tuberculosis em ancianos en Maranhão en el período de 2010 a 2015. Métodos: Estudio transversal analítico con los casos de tuberculosis en ancianos en el Estado de Maranhão. Se utilizaron datos secundarios del SINAN, disponibles en Datasus. Para identificar las asociaciones entre el desenlace (tuberculosis en ancianos) y las variables independientes se utilizó la regresión de Poisson. Resultados: Después del ajuste del modelo la escolaridad < 8 años de estudio, tener cierre por no cura, examen anti VIH no realizado y tener diabetes se presentaron como factor que aumenta la probabilidad de la ocurrencia de tuberculosis en ancianos. Las demás variables se presentaron como factor protector. Conlusión: Se observó una alta prevalencia de tuberculosis en ancianos en el Estado (16,6%). Hay necesidad de adoptar estrategias de acompañamiento de esa clientela

Fatores associados à coinfecção tuberculose/HIV no período 2001-2011 / Tuberculosis/HIV coinfection associated factors regarding the 2001-2011 timeframe

Objetivo: Analisar os fatores associados à coinfecção tuberculose/HIV e determinar a prevalência máxima e mínima da positividade do teste anti-HIV entre casos de tuberculose no Maranhão, no período de 2001 a 2011. Métodos: Estudo transversal realizado mediante consulta aos dados do Sistema de Informação de Agravos de Notificação. Para identificar associações, utilizou-se a regressão de Poisson com ajuste robusto da variância. Resultados: A prevalência da coinfecção tuberculose/HIV foi de 15,1%. Na análise bruta, as associações significativas para coinfecção foram sexo masculino, faixas etárias de 20 a 39 anos e de 40 a 59 anos, escolaridade inferior a oito anos, entrada por transferência e encerramento por abandono/óbito. Na análise ajustada, sexo masculino, faixa etária de 29 a 30 anos, escolaridade inferior a oito anos e encerramento por abandono/óbito permaneceram associados à coinfecção. Conclusão: Foi observada alta taxa de coinfecção tuberculose/HIV no estado do Maranhão e associações com diversos fatores relacionados à saúde

Objective: To analyze the factors associated with Tuberculosis/HIV coinfection and to determine the maximum and minimum prevalence of HIV test positivity among tuberculosis cases in Maranhão from 2001-2010. Methods: Cross-sectional study of data from the Notifiable Diseases Information System. Poisson regression was used with robust variance adjustment to identify associations. Results: Tuberculosis/ HIV coinfection prevalence was 15.1%. In the raw analysis, the significant associations for coinfection were male sex, age groups from 20-39 years and from 40-59 years, schooling less than 8 years, entry by transfer and closure by abandonment/death. In the adjusted analysis, male gender, age range of 29 to 30 years, schooling less than 8 years and closure due to abandonment/death remained associated with coinfection. Conclusion: Tuberculosis/HIV coinfection rate was high in the state of Maranhão and associations with several factors related to health

Objetivo: Analizar los factores asociados a la coinfección TB/VIH y determinar la prevalencia máxima y mínima de la prueba del VIH positiva entre los casos de TB en Maranhao, de 2001 a 2011. Métodos: Estudio transversal, realizado en consulta con los datos del Sistema de Información de Agravios y Notificaciones. Para identificar asociaciones, se utilizó regresión de Poisson con ajuste robusto de la varianza. Resultados: La prevalencia de la coinfección TB/VIH fue del 15,1%. En el análisis crudo, asociaciones significativas para la coinfección fueron sexo masculino, edades de 20-39 años y 40-59 años, educación menos de ocho años y cierre de la entrada por abandono/muerte. En el análisis ajustado, sexo, edad 29-30 años, educación menos de 8 años y final por abandono/ muerte se mantuvo asociado con la coinfección. Conclusión: Hubo una alta tasa de coinfección TB/VIH en el estado de Maranhão y asociaciones con diversos factores relacionados a la salud

Fibrosis-associated hepatocarcinogenesis revisited: Establishing standard medium-term chemically-induced male and female models.

Hepatocellular carcinoma causes ~10% of all cancer-related deaths worldwide, usually emerging in a background of liver fibrosis/cirrhosis (70%-90% of cases). Chemically-induced mouse models for fibrosis-associated hepatocarcinogenesis are widely-applied, resembling the corresponding human disease. Nonetheless, a long time is necessary for the development of preneoplastic/neoplastic lesions. Thus, we proposed an early fibrosis-associated hepatocarcinogenesis model for male and female mice separately, focusing on reducing the experimental time for preneoplastic/neoplastic lesions development and establishing standard models for both sexes. Then, two-week old susceptible C3H/HeJ male and female mice (n = 8 animals/sex/group) received a single dose of diethylnitrosamine (DEN, 10 or 50 mg/Kg). During 2 months, mice received 3 weekly doses of carbon tetrachloride (CCl4, 10% corn oil solution, 0.25 to 1.50 µL/g b.wt.) and they were euthanized at week 17. DEN/CCl4 protocols for males and females displayed clear liver fibrosis, featuring collagen accumulation and hepatic stellate cell activation (α-SMA). In addition, liver from males displayed increased CD68+ macrophage number, COX-2 protein expression and IL-6 levels. The DEN/CCl4 models in both sexes impaired antioxidant defense as well as enhanced hepatocyte proliferation and apoptosis. Moreover, DEN/CCl4-treated male and female developed multiple preneoplastic altered hepatocyte foci and hepatocellular adenomas. As expected, the models showed clear male bias. Therefore, we established standard and suitable fibrosis-associated hepatocarcinogenesis models for male and female mice, shortening the experimental time for the development of hepatocellular preneoplastic/neoplastic lesions in comparison to other classical models.

Acidentes de trânsito com idosos: demandas e responsabilidades sociais e governamentais / Traffic accidents with elderly people: social and governmental demands and responsibilities / Accidentes de tránsito con adultos mayores: demandas y responsabilidades sociales y gubernamentales

Reflexão teórica na qual se buscou refletir sobre as demandas e responsabilidades da sociedade e do poder público frente aos altos índices de acidentes de trânsito envolvendo idosos. Percebeu-se que, para a melhor compreensão desse agravo, é preciso necessário que sejam repensadas as transformações inerentes ao processo de envelhecimento e suas influências no indivíduo como pedestre e/ou condutor, bem como a infraestrutura e a logística de trânsito capazes de agravar ou minimizar a vulnerabilidade desse grupo aos acidentes. A sociedade civil e o poder público são responsáveis pela garantia da saúde e da segurança da população, com destaque para os idosos, especialmente em relação à sua mobilidade. Nesse sentido, fazem-se necessários o planejamento e a execução de obras de acessibilidade que respeitem as particularidades da pessoa idosa, bem como a fiscalização e penalização das infrações por parte do poder público. A sociedade civil, por sua vez, tem como grande responsabilidade assumir e cumprir com o papel social na construção de um trânsito sem violência e mais seguro para as pessoas idosas.

This is a theoretical reflection about the demands and responsibilities of society and of the public power in view of the high rates of traffic accidents involving elderly people. It was noticed that, in order to better understand this problem, it is necessary to rethink the transformations inherent in the aging process and its influences on the individuals as pedestrians and/or drivers, as well as the infrastructure and traffic logistics capable of aggravating or mitigating the vulnerability of this group to accidents. Civil society and public authorities are responsible for guaranteeing the health and safety of the population, with particular emphasis on the elderly, especially in relation to their mobility. In this sense, it is necessary to plan and execute accessibility works that respect the particularities of elderly people, as well as the supervision and punishment of infractions by the public power. Civil society, on the other hand, has a major responsibility to assume and fulfill its social role in non-violent and safer traffic for the elderly.

Fatores associados ao retratamento da tuberculose nos municípios prioritários do Maranhão, Brasil / Factors associated with tuberculosis retreatment in priority districts of Maranhão, Brazil

Resumo Este estudo investigou os fatores associados aos casos de retratamento de tuberculose por recidiva e por reingresso após abandono. Trata-se de um estudo transversal tipo analítico dos casos notificados no Sistema de Informação de Agravos de Notificação em municípios prioritários do Estado do Maranhão, de janeiro de 2005 a dezembro de 2010. Para identificar as associações foi utilizado o modelo de regressão logística. Os pacientes com idade entre 40 e 59 anos (OR = 1,49; p = 0,029) e com a forma clínica pulmonar (OR = 2,79; p = 0,016) apresentaram maior chance para recidiva. Os reingressos após abandono tiveram maior chance nos indivíduos do sexo masculino (OR = 1,53; p = 0,046), com idade entre 20 e 39 anos (OR = 1,65; p = 0,007), com menos de oito anos de estudo (OR = 2,01; p = 0,037) e dependentes de álcool (OR = 1,66; p = 0,037), os quais apresentaram maior chance de novo abandono (OR = 5,96; p < 0,001). Esses dados reforçam a necessidade de estratégias direcionadas a esse grupo, como a ampliação do tratamento supervisionado, intensificação da busca ativa, acompanhamento pós-alta e ações de educação em saúde.

Abstract This study investigated factors associated with cases of tuberculosis retreatment due to relapse and readmission after treatment abandonment. This is an analytical cross-sectional study type of cases reported in the Information System for Notifiable Diseases in priority municipalities in the State of Maranhão, from January 2005 to December 2010. A logistic regression model was used to identify the association. Patients aged between 40 and 59 years (OR = 1.49, p = 0.029) with a pulmonary clinical form (OR = 2.79, p = 0.016) were more likely to incur relapse. Readmissions after abandonment were more likely in males (OR = 1.53, p = 0.046), aged between 20 and 39 years (OR = 1.65, p = 0.007), with less than eight years of schooling (OR = 2.01, p = 0.037) and with alcohol dependence (OR=1.66, p = 0.037), which showed a higher probability of another abandonment (OR = 5.96, p < 0.001). These data reinforce the need for strategies aimed at this group, such as increased supervised treatment, intensified active search, post-discharge follow-up and health education action.

Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice.

While gap junctions mediate intercellular communication and support liver homeostasis, connexin hemichannels are preferentially opened by pathological stimuli, including inflammation and oxidative stress. The latter are essential features of non-alcoholic steatohepatitis. In this study, it was investigated whether connexin32 and connexin43 hemichannels play a role in non-alcoholic steatohepatitis. Mice were fed a choline-deficient high-fat diet or normal diet for 8 weeks. Thereafter, TAT-Gap24 or TAT-Gap19, specific inhibitors of hemichannels composed of connexin32 and connexin43, respectively, were administered for 2 weeks. Subsequently, histopathological examination was carried out and various indicators of inflammation, liver damage and oxidative stress were tested. In addition, whole transcriptome microarray analysis of liver tissue was performed. Channel specificity of TAT-Gap24 and TAT-Gap19 was examined in vitro by fluorescence recovery after photobleaching analysis and measurement of extracellular release of adenosine triphosphate. TAT-Gap24 and TAT-Gap19 were shown to be hemichannel-specific in cultured primary hepatocytes. Diet-fed animals treated with TAT-Gap24 or TAT-Gap19 displayed decreased amounts of liver lipids and inflammatory markers, and augmented levels of superoxide dismutase, which was supported by the microarray results. These findings show the involvement of connexin32 and connexin43 hemichannels in non-alcoholic steatohepatitis and, simultaneously, suggest a role as potential drug targets in non-alcoholic steatohepatitis.

Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice.

Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficacy of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5h. Sampling was performed 3, 6, 24 and 48h following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.