Influence of doxorubicin on model cell membrane properties : insights from in vitro and in silico studies

Despite doxorubicin being commonly used in chemotherapy there still remain significant holes in our knowledge regarding its delivery efficacy and an observed resistance mechanism that is postulated to involve the cell membrane. One possible mechanism is the efflux by protein P-gp, which is found predominantly in cholesterol enriched domains. Thereby, a hypothesis for the vulnerability of doxorubicin to efflux through P-gp is its enhanced affinity for the ordered cholesterol rich regions of the plasma membrane. Thus, we have studied doxorubicin's interaction with model membranes in a cholesterol rich, ordered environment and in liquid-disordered cholesterol poor environment. We have combined three separate experimental protocols: UV-Vis spectrophotometry, fluorescence quenching and steady-state anisotropy and computational molecular dynamics modeling. Our results show that the presence of cholesterol induces a change in membrane structure and doesn't impair doxorubicin's membrane partitioning, but reduces drug's influence on membrane fluidity without directly interacting with it. It is thus possible that the resistance mechanism that lowers the efficacy of doxorubicin, results from an increased density in membrane regions where the efflux proteins are present. This work represents a successful approach, combining experimental and computational studies of membrane based systems to unveil the behavior of drugs and candidate drug molecules.Peer reviewe

Cultivo de Saccharomyces cerevisiae adaptada em D-xilulose sob condições aeróbias e anaeróbias

O desenvolvimento de um processo para produção de etanol com uma alta produtividade a partir de D-xilulose é de grande interesse econômico. Esse processo pode agregar maior valor aos resíduos lignocelulósicos, além de promover um aproveitamento completo da biomassa, utilizando-se suas frações celulósica e hemicelulósica para a obtenção de etanol. O objetivo do presente trabalho foi estudar a assimilação de D-xilulose, o crescimento e a produção de etanol e xilitol em cultivo de levedura de panificação de Saccharomyces cerevisiae em condições aeróbias e anaeróbis. Os experimentos foram conduzidos em biorreator de bancada de 2L, utilizando meio mínimo contendo a mistura xilose-xilulose. Os cultivos foram realizados com colônia de levedura previamente selecionada a partir de experimentos de screening com mais de 20 colônias de isoladas de levedura comercial que apresentaram crescimento em meio mínimo contendo a mistura xilose-xilulose em condições anaeróbias. A fermentação da D-xilulose pela levedura na ausência de oxigênio resultou na produção de 4,2 g/L de etanol e 3,7 de xilitol. Já o crescimento da levedura em condições aeróbias forneceu como produto principal a biomassa, com formação de 8 g/L e como subproduto o xilitol, com concentração máxima de 2,0 g/L

Tabagismo na coorte de nascimentos de 1982: da adolescência à vida adulta, Pelotas, RS

OBJETIVO: Evaluar la prevalencia de tabaquismo en adolescentes y adultos jóvenes pertenecientes a una cohorte de nacimientos de base poblacional. MÉTODOS: Estudio prospectivo de cohorte de los nacidos en 1982 en la ciudad de Pelotas, RS, entrevistados en 1997, 2000-1 y 2005. El desenlace estudiado fue el tabaquismo, definido como consumo de al menos un cigarro en la última semana en los acompañamientos de 1997 y 2000-1. En el seguimiento de 2005, la variable dependiente fue tabaquismo actual. El análisis ajustado fue realizado por medio de regresión de Poisson. RESULTADOS: Las prevalencias de tabaquismo entre hombres fueron de 5,9%, 20,2% y 27,6% en los seguimientos de 1997, 2000-1 y 2005, respectivamente. Los respectivos valores para las mujeres fueron 9,3%, 27,5% y 23,6%. La edad promedio de inicio de fumar fue de 15,1 años (dp=2,5). En el análisis multivariable, menor escolaridad materna, baja renta familiar en 1982, haber sido pobre durante todo el período acompañado y el fumar de la madre durante el embarazo estuvieron significativamente asociados con mayores prevalencias de fumar en ambos sexos. El color de la piel no blanca se asoció con mayor riesgo de fumar entre las mujeres. El amamantamiento no mostró asociación con el tabaquismo. En las mujeres, el fumar estuvo inversamente asociado con el peso al nacer en el análisis bruto, pero perdió la significancia en el ajustado. CONCLUSIONES: La mayor concentración de tabaquismo en los grupos más pobres sugiere que conductas como el combate al fumar en la gestación y el aumento de precio del cigarro podrían tener importante impacto poblacional.OBJETIVO: Avaliar a prevalência de tabagismo em adolescentes e adultos jovens pertencentes a uma coorte de nascimentos de base populacional. MÉTODOS: Estudo prospectivo de coorte dos nascidos em 1982 na cidade de Pelotas, RS, entrevistados em 1997, 2000-1 e 2005. O desfecho estudado foi o tabagismo, definido como consumo de pelo menos um cigarro na última semana nos acompanhamentos de 1997 e 2000-1. No acompanhamento de 2005, a variável dependente foi tabagismo atual. A análise ajustada foi realizada por meio de regressão de Poisson. RESULTADOS: As prevalências de tabagismo entre homens foram de 5,9%, 20,2% e 27,6% nos acompanhamentos de 1997, 2000-1 e 2005, respectivamente. Os respectivos valores para as mulheres foram 9,3%, 27,5% e 23,6%. A idade média de início do fumo foi de 15,1 anos (dp=2,5). Na análise multivariável, menor escolaridade materna, baixa renda familiar em 1982, ter sido pobre durante todo o período acompanhado e fumo materno na gravidez estiveram significativamente associados com maiores prevalências de fumo em ambos os sexos. A cor da pele não branca associou-se com maior risco de fumo apenas entre as mulheres. A amamentação não mostrou associação com tabagismo. Nas mulheres, o fumo esteve inversamente associado com o peso ao nascer na análise bruta, mas perdeu a significância na ajustada. CONCLUSÕES: A maior concentração de tabagismo nos grupos mais pobres sugere que condutas como o combate ao fumo na gestação e o aumento do preço do cigarro poderiam ter importante impacto populacional.OBJECTIVE: To assess smoking prevalence in adolescents and young adults of a population-based birth cohort. METHODS: Prospective birth cohort study of infants born in 1982, in the city of Pelotas, Southern Brazil, and interviewed in 1997, 2000-2001 and 2005. In the 1997 and 2000-2001 follow-up visits, the outcome studied was smoking, defined as the consumption of at least one cigarette in the previous week. In the 2005 follow-up visit, the dependent variable was current smoking. Adjusted analysis was performed using Poisson regression. RESULTS: Smoking prevalences among males were 5.9%, 20.2% and 27.6% in the 1997, 2000-2001 and 2005 follow-up visits, respectively. Among females, respective values were 9.3%, 27.5% and 23.6%. Mean age of smoking onset was 15.1 years (SD=2.5). In the multivariate analysis, lower maternal level of education, low income level in 1982, poverty during the follow-up period and maternal smoking were significantly associated with higher smoking prevalences in both sexes. Being non-white was associated with higher risk of smoking among females exclusively. Breastfeeding was not associated with smoking. Among females, smoking was inversely associated with birth weight in the crude analysis, but lost its significance in the adjusted analysis. CONCLUSIONS: Higher incidence of smoking in poorer groups suggests that behavior such as avoiding smoking during pregnancy and increasing cigarette prices can have an important population impact

COVID-19 and social distancing among children and adolescents in Brazil

OBJECTIVE To estimate the prevalence of SARS-CoV-2 antibodies and the adherence to measures of social distancing in children and adolescents studied in three national surveys conducted in Brazil between May–June 2020. METHODS Three national serological surveys were conducted in 133 sentinel cities located in all 27 Federative Units. Multistage probability sampling was used to select 250 individuals per city. The total sample size in age ranges 0–9 and 10–19 years old are of 4,263 and 8,024 individuals, respectively. Information on children or adolescents was gathered with a data collection app, and a rapid point-of-case test for SARS-CoV-2 was conducted on a finger prick blood sample. RESULTS The adjusted prevalence of antibodies was 2.9% (2.2–3.6) among children 0–9 years, 2.2% (1.8–2.6) among adolescents 10-19 years, and 3.0% (2.7–3.3) among adults 20+years. Prevalence of antibodies was higher among poor children and adolescents compared to those of rich families. Adherence to social distancing measures was seen in 72.4% (71.9–73.8) of families with children, 60.8% (59.6–61.9) for adolescents, and 57.4% (56.9–57.8) for adults. For not leaving the house except for essential matters the proportions were 81.7% (80.5–82.9), 70.6% (69.6–61.9), and 65.1% (64.7–65.5), respectively. Among children and adolescents, social distancing was strongly associated with socioeconomic status, being much higher in the better-off families. CONCLUSIONS The prevalence of antibodies against SARS-CoV-2 showed comparable levels among children, adolescents, and adults. Adherence to social distancing measures was more prevalent in children, followed by adolescents. There were important socioeconomic differences in the adherence to social distancing among children and adolescents

Toxoplasmosis-associated IRIS involving the CNS: a case report with longitudinal analysis of T cell subsets

Background: HIV-infected patients may present an unforeseen clinical worsening after initiating antiretroviral therapy known as immune reconstitution inflammatory syndrome (IRIS). This syndrome is characterized by a heightened inflammatory response toward infectious or non-infectious triggers, and it may affect different organs. Diagnosis of IRIS involving the central nervous system (CNS-IRIS) is challenging due to heterogeneous manifestations, absence of biomarkers to identify this condition, risk of long-term sequelae and high mortality. Hence, a deeper knowledge of CNS-IRIS pathogenesis is needed. Case presentation: A 37-year-old man was diagnosed with AIDS and cerebral toxoplasmosis. Anti-toxoplasma treatment was initiated immediately, followed by active antiretroviral therapy (HAART) 1 month later. At 2 months of HAART, he presented with progressive hyposensitivity of the right lower limb associated with brain and dorsal spinal cord lesions, compatible with paradoxical toxoplasmosis-associated CNS-IRIS, a condition with very few reported cases. A stereotactic biopsy was planned but was postponed based on its inherent risks. Patient showed clinical improvement with no requirement of corticosteroid therapy. Routine laboratorial analysis was complemented with longitudinal evaluation of blood T cell subsets at 0, 1, 2, 3 and 6 months upon HAART initiation. A control group composed by 9 HIV-infected patients from the same hospital but with no IRIS was analysed for comparison. The CNS-IRIS patient showed lower percentage of memory CD4(+) T cells and higher percentage of activated CD4(+) T cells at HAART initiation. The percentage of memory CD4(+) T cells drastically increased at 1 month after HAART initiation and became higher in comparison to the control group until clinical recovery onset; the percentage of memory CD8(+) T cells was consistently lower throughout follow-up. Interestingly, the percentage of regulatory T cells (Treg) on the CNS-IRIS patient reached a minimum around 1 month before symptoms onset. Conclusion: Although both stereotactic biopsies and steroid therapy might be of use in CNS-IRIS cases and should be considered for these patients, they might be unnecessary to achieve clinical improvement as shown in this case. Immunological characterization of more CNS-IRIS cases is essential to shed some light on the pathogenesis of this condition.Portuguese Foundation for Science and Technology (FCT; PIC/IC/83313/2007) and co-financed by the Portuguese North Regional Operational Program (ON.2 - O Novo Norte) under the National Strategic Reference Framework (QREN) through the European Regional Development Fund (FEDER). A FCT fellowship was attributed to RRS (PD/BD/106047/2015; Inter-University Doctoral Program in Ageing and Chronic Disease) and to CN [SFRH/BPD/65380/2009; Programa Operacional Potencial Humano (POPH) through the Fundo Social Europeu (FSE)]info:eu-repo/semantics/publishedVersio

A genome-wide association study in Hispanics/Latinos identifies novel signals for lung function: the Hispanic Community Health Study/Study of Latinos

Rationale:: Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome-wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in cohorts of European ancestry. Objectives: Perform a GWAS of COPD-phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations. Methods: :GWAS of lung function and COPD in Hispanic/Latino participants from a population-based cohort. We performed replication studies of novel loci in independent studies. Measurements and Main Results: Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for forced expiratory volume in one second (FEV1) in ZSWIM7 (rs4791658; p=4.99×10-9) replicated. A rare variant (MAF=0.002) in HAL (rs145174011) was associated with FEV1 to forced vital capacity (FEV1/FVC) (p=9.59×10-9) in a region previously identified for COPD-related phenotypes; it remained significant in conditional analyses but did not replicate. Admixture mapping identified a novel region, with a variant in AGMO (rs41331850), associated with Amerindian ancestry and FEV1, which replicated. A novel locus for FEV1 identified among ever smokers (rs291231; p=1.92×10-8) approached statistical significance for replication in admixed populations of African ancestry and a novel SNP for COPD in PDZD2 (rs7709630; p=1.56×10-8) regionally replicated. Additionally, loci previously identified for lung function in European samples were associated in Hispanic/Latino participants in HCHS/SOL at the genome-wide significance level. Conclusions: We identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing togenetic etiologies of COPD

Prevalencia de nacimientos pre-termino por peso al nacer: revision sistematica

OBJETIVO Estimar a prevalência de nascimentos pré-termo por faixas de peso ao nascer e obter uma equação para correção de estimativas. MÉTODOS Revisão sistemática da literatura nacional, de 1990 a 2012, para identificar estudos com coleta primária de informações sobre peso ao nascer e idade gestacional. Foram selecionados 12 que contribuíram com tabulações da prevalência de nascimentos pré-termo para faixas de 100 g de peso ao nascer. Os resultados desses estudos foram combinados pelo método de polinômios fracionais, sendo obtidas curvas separadas para meninos e meninas, comparadas com os resultados do Sistema de Informações sobre Nascidos Vivos para os anos 2000, 2005, 2010 e 2011. RESULTADOS As estimativas da prevalência de nascimentos pré-termo, obtidas a partir dos estudos primários, foram superiores às do Sistema de Informações sobre Nascidos Vivos para praticamente todas as faixas de peso ao nascer. A prevalência relatada pelo Sistema de Informações sobre Nascidos Vivos foi de 7,1% em 2010, cerca de 38% menor do que a estimativa de 11,7% obtida com a equação de correção. CONCLUSÕES Os dados do Sistema de Informações sobre Nascidos Vivos quanto à prevalência de nascimento pré-termo não refletem a verdadeira dimensão da prematuridade no Brasil. Assim sendo, para sua utilização, será necessária a aplicação do fator de correção, conforme proposto.OBJETIVO Estimar la prevalencia de nacimientos pre-término por rangos de peso al nacer y obtener una ecuación para corrección de estimaciones. MÉTODOS Revisión sistemática de la literatura nacional, de 1990 a 2012, para identificar estudios con colecta primaria de informaciones sobre peso al nacer y edad de gestación. Se seleccionaron 12 que contribuyeron con tabulaciones de la prevalencia de nacimientos pre-término para grupos de 100 g de peso al nacer. Los resultados de estos estudios fueron combinados por el método de polinomios fraccionales siendo obtenidas curvas separadas para niños y niñas, comparadas con los resultados del Sistema de Informaciones sobre Nacidos Vivos para los años 2000, 2005, 2010 y 2011. RESULTADOS Las estimaciones de la prevalencia de nacimientos pre-término, obtenidas a partir de los estudios primarios, fueron superiores a las del Sistema de Informaciones sobre Nacidos Vivos para prácticamente todos los grupos de peso al nacer. La prevalencia relatada por el Sistema de Informaciones sobre Nacidos Vivos fue de 7,1% en 2010, cerca de 38% menor que la estimativa de 11,7% obtenida con la ecuación de corrección. CONCLUSIONES Los datos del Sistema de Informaciones sobre Nacidos Vivos sobre prevalencia de nacimiento pre-término no reflejan la verdadera dimensión de la prematuridad en Brasil. Siendo así, para su utilización, será necesaria la aplicación del factor de corrección, conforme propuesto.OBJECTIVE To estimate the prevalence of preterm birth by categories of birth weight, and to obtain an equation to correct the estimates. METHODS Systematic review of the Brazilian literature published from 1990 to 2012, to identify studies with primary collection of data on birth weight and gestational age. Twelve studies were selected and contributed for tabulations of preterm prevalence according to 100 g birth weight categories. These results were combined using sex-specific fractional polynomial equations and the resulting curves were compared with results from the Live Birth Information System for the years 2000, 2005, 2010 and 2011. RESULTS For all birth weight categories, preterm prevalence estimates based on primary studies had a higher prevalence than those of the the Live Birth Information System. The prevalence reported by the Live Birth Information System was of 7.2% in 2010, about 38.0% lower than the estimated prevalence of 11.7% obtained with the correctional equation. CONCLUSIONS Information reported by the Live Birth Information System on preterm prevalence does not reflect the true magnitude of the problem in Brazil, and should not be used without the correction factors proposed in the present analyses