Toxic profile of marinobufagin from poisonous Amazon toads and antitumoral effects on human colorectal carcinomas.

ETHNOPHARMACOLOGICAL RELEVANCE: South Americans natives have extensively used the toad "kururu" to reduce/treat skin infections, cutaneous lesions and sores. They release secretions rich in bufadienolides, polyhydroxy steroids with well-documented cardiotonic and antiproliferative actions, but in vivo antitumoral evaluations in mammals are rare, and toxicological safety has been left in second place. AIMS OF THE STUDY: This investigation used in silico, in vitro and in vivo tools to evaluate acute and subacute toxic effects of marinobufagin and the anticancer action in tumor-bearing mice models. MATERIALS AND METHODS: Initially, in silico toxic predictions were performed, followed by in vitro assays using human and murine normal and tumor lines. Next, acute and subacute studies on mice investigated the behavior, hematological and intestinal transit profile and antitumoral activity of marinobufagin in sarcoma 180- and HCT-116 colorectal carcinoma-transplanted mice for 7 and 15 days, respectively. Ex vivo and in vivo cytogenetic assays in Sarcoma 180 and bone marrow cells and histopathological examinations were also executed. RESULTS: In silico studies revealed ecotoxicological effects on crustaceans (Daphnia sp.), fishes (Pimephales promelas and Oryzias latipes), and algae. A 24-h marinobufagin-induced acute toxicity included signals of central activity, mainly (vocal frenzy, absence of body tonus, increased ventilation, ataxia, and equilibrium loss), and convulsions and death at 10 mg/kg. The bufadienolide presented effective in vitro cytotoxic action on human lines of colorectal carcinomas in a similar way to ouabain and tumor reduction in marinobufagin-treated SCID-bearing HCT-116 heterotopic xenografts. Animals under subacute nonlethal doses exhibited a decrease in creatinine clearance with normal levels of blood urea, probably as a result of a marinobufagin-induced renal perfusion fall. Nevertheless, only minor morphological side effects were identified in kidneys, livers, hearts and lungs. CONCLUSIONS: Marinobufagin has in vitro and in vivo anticancer action on colorectal carcinoma and mild and reversible alterations in key metabolic organs without direct chemotherapy-induced gastrointestinal effects at subacute exposure, but it causes acute ataxia, equilibrium loss, convulsions and death at higher acute exposure.

Late onset neuromyelitis optica spectrum disorders (LONMOSD) from a nationwide Portuguese study: Anti-AQP4 positive, anti-MOG positive and seronegative subgroups.

INTRODUCTION: Several neuroimmunological disorders have distinct phenotypes according to the age of onset, as in multiple sclerosis or myasthenia gravis. It is also described that late onset NMOSD (LONMOSD) has a different phenotype. OBJECTIVE: To describe the clinical/demographic characteristics of the LONMOSD and distinguish them from those with early onset (EONMOSD). METHODS: From a nationwide Portuguese NMOSD study we analyzed the clinical/demographic characteristics of the LONMOSD. RESULTS: From the 180 Portuguese patients 45 had disease onset after 50 years old, 80% were female. 23 had anti-AQP4 antibodies (51.1%), 13 anti-MOG antibodies (28.9%) and 9 were double seronegative (20.0%). The most common presenting phenotypes in LONMOSD were transverse myelitis (53.3%) and optic neuritis (26.7%), without difference from EONMOSD (p = 0.074). The mean EDSS for LONMOSD was 6.0 (SD=2.8), after a mean follow-up time of 4.58 (SD=4.47) years, which was significantly greater than the mean EDSS of EONMOSD (3.25, SD=1.80)(p = 0.022). Anti-AQP4 antibodies positive LONMOSD patients had increased disability compared to anti-MOG antibodies positive LONMOSD (p = 0.022). The survival analysis showed a reduced time to use a cane for LONMOSD, irrespective of serostatus (p<0.001). CONCLUSIONS: LONMOSD has increased disability and faster progression, despite no differences in the presenting clinical phenotype were seen in our cohort.

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.

Variáveis sociodemográficas e sexuais associadas ao conhecimento sobre transmissão do vírus da imunodeficiência humana / Sociodemographic and sexual variables associated with knowledge about human immunodeficiency virus transmission

RESUMO Objetivo analisar a associação entre variáveis sociodemográficas e sexuais de mulheres em contexto de vulnerabilidade e seu conhecimento sobre as formas de transmissão do HIV. Métodos estudo transversal, analítico e exploratório ocorrido em Unidade de Atenção Primária à Saúde, com 221 mulheres. A coleta ocorreu com instrumentos contendo dados sociodemográficos, gineco-obstétricos, sexuais e mensuração do conhecimento acerca do HIV. Resultados o conhecimento sobre as formas de transmissão do HIV foi associado a faixa etária e escolaridade das entrevistadas. Conclusão a elevada prevalência de conhecimento inadequado quanto ao HIV foi explicada pela faixa etária mais jovem das mulheres, enquanto a redução deste desfecho foi verificada naquelas com maior escolaridade. Contribuições para a prática: os dados apresentados podem subsidiar novas abordagens e práticas assistenciais no campo da saúde sexual e reprodutiva a partir da análise proposta, objetivando a sensibilização quanto à realização de testagens, tratamento oportuno e quebra da cadeia de transmissão.

ABSTRACT Objective to analyze the association between sociodemographic and sexual variables of women in a context of vulnerability and their knowledge about the ways of HIV transmission. Methods cross-sectional, analytical, and exploratory study conducted in a Primary Health Care Unit, with 221 women. The collection occurred with instruments containing sociodemographic, gynecological, and obstetric, sexual data and measurement of knowledge about HIV. Results knowledge about the ways of HIV transmission was associated with age and education of the interviewees. Conclusion the high prevalence of inadequate knowledge about HIV was explained by the younger age group of women, while the reduction of this outcome was seen in those with higher education. Contributions to practice: the data presented can subsidize new approaches and care practices in the field of sexual and reproductive health from the proposed analysis, aiming to raise awareness about testing, timely treatment and breaking the chain of transmission.

TyPed study: Natalizumab for the treatment of pediatric-onset multiple sclerosis in Portugal.

BACKGROUND: A significant proportion of pediatric-onset multiple sclerosis (POMS) patients do not respond to first-line disease-modifying therapies. Clinical trials showed that natalizumab is effective and safe in adults, but there are limited clinical trial data for children. Natalizumab is currently prescribed off-label for POMS. We aimed to characterize the effectiveness, safety and tolerability of natalizumab in all POMS cases treated in Portugal (from 2007 to 2018). METHODS: Data from clinical records were retrospectively collected for all POMS cases treated with natalizumab in Portugal. RESULTS: Twenty-one patients were included, 14 (67%) of which were female. The median age at POMS diagnosis was 13 years old. The median duration of treatment with natalizumab was 2 years and 3 months. Median Expanded Disability Status Scale score decreased from 1.5 to 1.0 after 24 months. The Annualized Relapse Rate decreased from 1.31 events/patient/year before treatment with natalizumab to 0 after 12 months of treatment and to 0.04 after 24 months. No gadolinium-enhancing lesions or new or enlarged T2 hyperintense lesions were observed in 8/8 patients (100%) after 12 months, and 4/5 (80%) after 24 months. There was one possible serious adverse event, which did not require dose adjustment. Five patients discontinued treatment due to positive anti-JCV (JC virus) antibody JC serostatus. CONCLUSION: Natalizumab may be an effective and safe disease-modifying therapy for POMS. Our results are in line with data published for the adult population, as well as with similar observational studies in pediatric populations in other regions.

Alemtuzumab outcomes by age: Post hoc analysis from the randomized CARE-MS studies over 8 years.

BACKGROUND: Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]). METHODS: Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years). RESULTS: Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22-0.24 vs. 0.38-0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%-92% vs. 62%-88%; achievement of 6-month confirmed disability improvement [CDI]: 20%-31% vs. 13%-25%), increased proportions free of MRI disease activity (70%-86% vs. 42%-63% per year), and slowed brain volume loss (BVL; -0.45% to -0.87% vs. -0.50% to -1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%-2.2% vs. >45 years: 8.1%) and deaths (0%-1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts. CONCLUSIONS: Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed.

Tumefactive demyelinating lesions spectrum disorders and the potential role of contemporary disease modifying treatments: a case report.

Marburg disease is a fulminant variant of multiple sclerosis (MS), in which the diagnosis may be particularly difficult and with high rates of mortality. We describe the case of a women with a clinical picture, radiographic features, and neuropathological findings consistent with the classical descriptions of Marburg disease. Initially, our patient did not improved with the acute phase treatments but later showed a good response to natalizumab (NTZ) treatment. This report highlights not only the utility of brain biopsy in the accurate diagnosis of this challenging condition but also the potential role of NTZ as an effective therapeutic option.

Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) is frequently diagnosed in women of reproductive age. Because the use of disease-modifying therapies (DMTs) early in the disease course is increasing, it is important to evaluate the safety of DMTs in pregnant women and their developing fetuses. Alemtuzumab, approved for the treatment of relapsing forms of MS, is administered as 2 courses of 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Alemtuzumab is eliminated from the body within approximately 30 days after administration; it is recommended that women of childbearing potential use effective contraception during and for 4 months after treatment. Here, we report pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years. METHODS: We followed 972 women who had alemtuzumab in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, and/or in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). In the extension studies, patients could receive additional alemtuzumab (12 mg/day on 3 days; ≥12 months apart) as needed for disease activity. All women who received alemtuzumab in the clinical development program were included. Pregnant or lactating patients were followed up for safety. RESULTS: As of November 26, 2018, 264 pregnancies occurred in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies, 233 (88%) were completed, 11 (4%) were ongoing, and 20 (8%) had unknown outcomes; 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion in alemtuzumab-treated patients (<35 years: 15%; ≥35 years: 37%; relative risk [RR], 2.46 [95% CI: 1.53-3.95], p=0.0002). Risk of spontaneous abortion was not increased in patients becoming pregnant ≤4 months versus >4 months since alemtuzumab exposure (19% vs 23%; RR, 1.08 [95% CI: 0.41-2.85], p=0.88). Autoimmune thyroid adverse events did not increase risk for spontaneous abortion (patients with vs without thyroid adverse events, 23.7% vs 21.3%; RR, 1.11 [95% CI: 0.69-1.80], p=0.75). Annualized relapse rate was 0.10 and 0.12 in the 2 years prior to pregnancy (post alemtuzumab), and was 0.22, 0.12, and 0.12 in each of the first 3 years postpartum, respectively. CONCLUSION: Normal live births were the most common outcome in women exposed to alemtuzumab 12 mg or 24 mg in clinical studies. Spontaneous abortion rate in alemtuzumab-treated patients was comparable with rates in the general population and treatment-naive MS patients, and was not increased in women with pregnancy onset within 4 months of alemtuzumab exposure. There was a minimal increase in postpartum relapses.

Epidemiological profile of congenital syphilis in the municipality of São Luís, 2008-2017 / Perfil epidemiológico da sífilis congênita no município de São Luís (MA), 2008­2017

Introduction: Congenital syphilis is a disease of great magnitude due to increasing numbers of new annual cases, affecting a large contingent of children, which translates into high incidence rates. The occurrence of syphilis cases evidences failures in health services, especially in prenatal care. Objective: To describe the epidemiological profile of congenital syphilis in the municipality of São Luís. Methods: Descriptive study with a quantitative approach. Congenital syphilis data recorded in SINAN from 2008 to 2017 were used. Results: The detection rate in the municipality shows a continuous increase. A total of 1,060 cases of congenital syphilis were diagnosed in neonates, 1,017 (96.0%) after the first week of life. Regarding the final diagnosis of cases, it was observed that 967 (91.2%) were classified as early congenital syphilis. The predominant maternal age range was 20 to 34 years, corresponding to 743 cases (70.1%). Regarding access to prenatal care, 802 (75.6%) mothers underwent prenatal care, while 219 (20.66%) did not. Among those who received prenatal care, 352 (33.0%) were diagnosed with syphilis during prenatal care, 481 (46.0%) were diagnosed at the time of delivery/curettage, and 59 (5.0%) were diagnosed after childbirth. Regarding the treatment regimen during pregnancy, 736 (70.0%) received inadequate treatment, 95 (8.0%) received no treatment and 62 (6.0%) received adequate treatment. Conclusion: The study contributed to the identification of possible losses in the stages of such care, and in obtaining qualified information that will guide decision-making and planning of health actions, supporting the epidemiological surveillance work in guiding managers and health teams.

Introdução: A sífilis congênita é uma doença de grande magnitude, pelos crescentes números de casos novos anuais, afetando grande contingente de crianças, que traduz elevadas taxas de incidência. A ocorrência dos casos de sífilis evidencia falhas dos serviços de saúde, principalmente na atenção pré-natal. Objetivo: Descrever o perfil epidemiológico da doença no município de São Luís. Métodos: Estudo descritivo com abordagem quantitativa. Utilizaram-se dados de sífilis congênita registrados no Sistema de Informação de Agravos de Notificação, no período de 2008 a 2017. Resultados: A taxa de detecção no município apresenta crescente aumento. Foram diagnosticados 1.060 casos em neonatos, sendo 1.017 (96%) após a primeira semana de vida. Quanto ao diagnóstico final dos casos, observou-se que 967 (91,2%) foram classificados como sífilis congênita recente. A faixa etária da mãe predominante era de 20 a 34 anos, correspondendo a 743 casos (70,1%). Quanto ao acesso ao pré-natal, 802 (75,6%) das mães fizeram prénatal, enquanto 219 (20,66%) não fizeram. Entre aquelas que fizeram, 352 (33%) tiveram diagnóstico de sífilis durante o pré-natal, 481 (46%) no momento do parto/curetagem e 59 (5%) após o parto. Em relação ao esquema de tratamento da gestante, 736 (70%) receberam tratamento inadequado, 95 (8%) não receberam tratamento e 62 (6%) receberam tratamento adequado. Conclusão: O estudo contribuiu para a identificação de eventuais perdas nas etapas desse cuidado e a obtenção de informações qualificadas, que irão nortear tomadas de decisão e planejamento das ações em saúde, subsidiando o trabalho da vigilância epidemiológica na orientação aos gestores e equipes de saúde.

Evans syndrome in male lupus patient: case report / Síndrome de Evans em paciente lúpico do sexo masculino: relato de caso

ABSTRACT Evans syndrome (ES) is a rare autoimmune disease of unknown etiology. ES occurs when there is a combination of autoimmune hemolytic anemia (AIHA) with thrombocytopenia, whether or not accompanied by immune neutropenia. This syndrome fits into a special variable type of warm AHAI and may be related to rheumatic diseases, such as systemic lupus erythematosus (SLE). Its pathogenesis is still far away to be fully understood. Direct Coombs test results are positive in 98% of cases. ES treatment is required when the anemia due to hemolysis is intense, and corticotherapy is recommended initially. In refractory cases, splenectomy or rituximab therapy, as well as other immunosuppressants, such as azathioprine, may be used. In this study, we present the case of a 45-year-old patient, male, who was diagnosed with ES associated with active SLE. The patient was admitted to the emergency room presenting severe hemolytic anemia and onset of thrombocytopenia. He was treated with intravenous corticosteroid therapy, followed by azathioprine.

RESUMEN El síndrome de Evans (SE) es una enfermedad autoinmune rara de etiología desconocida; ocurre cuando hay combinación de anemia hemolítica autoinmune (AHAI) con trombocitopenia, acompañada o no de neutropenia inmune. Ese síndrome es un tipo variable especial de AHAI por anticuerpos calientes que puede se relacionar a enfermedades reumatológicas, como el lupus eritematoso sistémico (LES). Su patogénesis es aún compleja. La prueba de Coombs directa es positiva en 98% de los casos. El tratamiento del SE es necesario cuando la anemia secundaria a hemólisis es intensa, siendo indicado inicialmente el uso de corticosteroides. En casos refractarios se recomienda una esplenectomía o terapia con rituximab, además de otros inmunosupresores, como la azatioprina. En este trabajo, reportamos el caso de un paciente de 45 años, varón, que tuvo el diagnóstico de SE asociado a LES activo. Él fue admitido en la sala de urgencias con cuadro de anemia hemolítica severa y plaquetopenia. Fue tratado con corticoides por vía intravenosa, seguidos de azatioprina.

RESUMO A síndrome de Evans (SE) é uma doença autoimune rara de etiologia desconhecida; ocorre quando há combinação de anemia hemolítica autoimune (AHAI) com trombocitopenia, acompanhada ou não de neutropenia imune. Essa síndrome se enquadra em um tipo variável especial da AHAI a quente, podendo se relacionar com doenças reumatológicas, como lúpus eritematoso sistêmico (LES). Sua patogênese ainda é complexa. O Coombs direto é positivo em 98% dos casos. O tratamento da SE é necessário quando a anemia secundária à hemólise é intensa, sendo indicado inicialmente o uso de corticosteroides. Em casos refratários, pode-se optar pela esplenectomia ou terapia com rituximab, além de outros imunossupressores, como a azatioprina. Neste trabalho, relatamos o caso de um paciente de 45 anos, sexo masculino, com diagnóstico de SE associada a LES ativo. Foi admitido no pronto-socorro com quadro de anemia hemolítica severa e surgimento de plaquetopenia. O paciente foi tratado com corticoterapia intravenosa, seguida de azatioprina.

Marinobufagin, a molecule from poisonous frogs, causes biochemical, morphological and cell cycle changes in human neoplasms and vegetal cells.

Skin toad secretion present physiologically active molecules to protect them against microorganisms, predators and infections. This work detailed the antiproliferative action of marinobufagin on tumor and normal lines, investigate its mechanism on HL-60 leukemia cells and its toxic effects on Allium cepa meristematic cells. Initially, cytotoxic action was assessed by colorimetric assays. Next, HL-60 cells were analyzed by morphological and flow cytometry techniques and growing A. cepa roots were examined after 72 h exposure. Marinobufagin presented high antiproliferative action against all human tumor lines [IC50 values ranging from 0.15 (leukemia) to 7.35 (larynx) µM] and it failed against human erythrocytes and murine lines. Human normal peripheral blood mononuclear cells (PBMC) were up to 72.5-fold less sensitive [IC50: 10.88 µM] to marinobufagin than HL-60 line, but DNA strand breaks were no detected. Leukemia treaded cells exhibited cell viability reduction, DNA fragmentation, phosphatidylserine externalization, binucleation, nuclear condensation and cytoplasmic vacuoles. Marinobufagin also reduced the growth of A. cepa roots (EC50: 7.5 µM) and mitotic index, caused cell cycle arrest and chromosomal alterations (micronuclei, delays and C-metaphases) in meristematic cells. So, to find out partially targeted natural molecules on human leukemia cells, like marinobufagin, is an amazing and stimulating way to continue the battle against cancer.

Prevalência e características dos eventos adversos a medicamentos no Brasil / Prevalencia y características de los eventos adversos con medicamentos en Brasil / Prevalence and characteristics of adverse drug events in Brazil

Resumo: O presente trabalho tem como objetivo descrever a prevalência e fatores associados a eventos adversos a medicamentos (EAM) referidos por usuários de medicamentos no Brasil. Trata-se de um estudo transversal de base populacional, realizado no período de setembro de 2013 a fevereiro de 2014, com dados coletados na Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos (PNAUM). Foram consideradas todas as pessoas que referiram o uso de medicamentos; entre elas, foram identificadas as que referiram pelo menos um problema com o uso do medicamento. Realizou-se uma análise descritiva para estimar a prevalência e os intervalos de 95% de confiança (IC95%) de EAM entre as variáveis estudadas, e foram calculadas as razões de prevalência bruta e ajustada, pela regressão de Poisson, na investigação dos fatores associados aos EAM. A prevalência de EAM no Brasil foi de 6,6% (IC95%: 5,89-7,41), sendo maior e estatisticamente significante após a realização da análise multivariada, entre pessoas do sexo feminino; residentes nas regiões Centro-oeste e Nordeste; que consumiam maior número de medicamentos; que percebiam seu estado de saúde como "ruim"; e que se automedicavam. Os EAM foram mais relatados para os medicamentos fluoxetina, diclofenaco e amitriptilina. Os EAM mais referidos pelos entrevistados foram sonolência, dor epigástrica e náuseas. Os EAM mais referidos pelos entrevistados foram de natureza leve, considerados evitáveis e estiveram associados a medicamentos de uso frequente pela população. Em razão desse estudo, foi possível conhecer a dimensão do problema ocasionado pelo uso de medicamentos no Brasil.

Resumen: El presente trabajo tiene como objetivo describir la prevalencia y factores asociados a eventos adversos con medicamentos (EAM), informados por usuarios de medicamentos en Brasil. Se trata de un estudio transversal de base poblacional, realizado durante el período de septiembre de 2013 a febrero de 2014, con datos recogidos en la Encuesta Nacional sobre el Acceso, Utilización y Promoción del Uso Racional de Medicamentos en Brasil (PNAUM). Se consideraron a todas las personas que informaron del uso de medicamentos; entre ellas, se identificaron a las que informaron de por lo menos un problema con el uso del medicamento. Se realizó un análisis descriptivo para estimar la prevalencia y los intervalos de confianza a 95% (IC95%) de EAM entre las variables estudiadas, y se calcularon las razones de prevalencia bruta y ajustada, por la regresión de Poisson, en la investigación de los factores asociados a los EAM. La prevalencia de EAM en Brasil fue de un 6,6% (IC95%: 5,89-7,41), siendo mayor y estadísticamente significante tras la realización del análisis multivariado, entre personas del sexo femenino; residentes en las regiones Centro-Oeste y Nordeste; que consumían un mayor número de medicamentos; que percibían su estado de salud como "malo"; y que se automedicaban. Se informaron de más EAM en medicamentos como: fluoxetina, diclofenaco y amitriptilina. Los EAM más referidos por los entrevistados fueron somnolencia, dolor epigástrico y náuseas. Los EAM más referidos por los entrevistados fueron de naturaleza leve, considerados evitables y estuvieron asociados a medicamentos de uso frecuente por la población. Con motivo de este estudio, fue posible conocer la dimensión del problema ocasionado por el uso de medicamentos en Brasil.

Abstract: The aim of this study was to describe the prevalence of adverse drug events (ADEs) and associated factors reported by users of medicines in Brazil. This was a cross-sectional population-based study conducted from September 2013 to February 2014 with data from the Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines (PNAUM). The study included all individuals that reported the use of medicines and identified, among them, all those reporting at least one problem with the medicine's use. A descriptive analysis was performed to estimate ADE prevalence and 95% confidence intervals (95%CI) among the target variables. Crude and adjusted prevalence ratios were calculated using Poisson regression to investigate factors associated with ADEs. Overall ADE prevalence in Brazil was 6.6% (95%CI: 5.89-7.41), and after multivariate analysis, higher prevalence was associated with female gender, residence in the Central and Northeast regions, consumption of more medicines, "bad" self-rated health, and self-medication. The drugs most frequently reported with ADEs were fluoxetine, diclofenac, and amitriptyline. The most frequent ADEs were somnolence, epigastric pain, and nausea. Most reported ADEs were mild, avoidable, and associated with medicines used frequently by the population. The study provided knowledge on the size of the problem with use of medicines in Brazil.

Bufadienolides from amphibians: A promising source of anticancer prototypes for radical innovation, apoptosis triggering and Na+/K+-ATPase inhibition.

Amphibians present pharmacologically active aliphatic, aromatic and heterocyclic molecules in their skin as defense against microorganisms, predators and infections, such as steroids, alkaloids, biogenic amines, guanidine derivatives, proteins and peptides. Based on the discovered bioactive potential of bufadienolides, this work reviewed the contribution of amphibians, especially from members of Bufonidae family, as source of new cytotoxic and antitumor molecules, highlighting the mechanisms responsible for such amazing biological potentialities. Bufonidae species produce bufadienolides related to cholesterol through the mevalonate-independent and acidic bile acid pathways as polyhydroxy steroids with 24 carbons. In vitro antitumor studies performed with skin secretions and its isolated components (specially marinobufagin, telocinobufagin, bufalin and cinobufagin) from Rhinella, Bufo and Rhaebo species have shown remarkable biological action on hematological, solid, sensitive and/or resistant human tumor cell lines. Some compounds revealed higher selectivity against neoplastic lines when compared to dividing normal cells and some molecules may biochemically associate with Na+/K+-ATPase and there is structural similarity to the digoxin- and ouabain-Na+/K+-ATPase complexs, implying a similar mechanism of the Na+/K+-ATPase inhibition by cardenolides and bufadienolides. Some bufadienolides also reduce levels of antiapoptotic proteins and DNA synthesis, cause morphological changes (chromatin condensation, nuclear fragmentation, cytoplasm shrinkage, cytoplasmic vacuoles, stickiness reduction and apoptotic bodies), cell cycle arrest in G2/M or S phases, mitochondrial depolarization, PARP [poly (ADPribose) polymerase] and Bid cleavages, cytochrome c release, activation of Bax and caspases (-3, -9, -8 and -10), increased expression of the Fas-Associated protein with Death Domain (FADD), induce topoisomerase II inhibition, DNA fragmentation, cell differentiation, angiogenesis inhibition, multidrug resistance reversion, and also regulate immune responses. Then, bufadienolides isolated from amphibians, some of them at risk of extinction, emerge as a natural class of incredible chemical biodiversity, has moderate selectivity against human tumor cells and weak activity on murine cells, probably due to structural differences between subunits of human and mice Na+/K+-ATPases.

Counteracting effects on free radicals and histological alterations induced by a fraction with casearins.

Casearia sylvestris Swartz is a medicinal plant widely distributed in Brazil. It has anti-inflammatory, antiulcer and antitumor activities and is popularly used to treat snakebites, wounds, diarrhea, flu and chest colds. Its leaves are rich in oxygenated tricyclic cis-clerodane diterpenes, particulary casearins. Herein, we evaluated the antioxidant activities of a fraction with casearins (FC) isolated from C. sylvestris and histological changes on the central nervous system and livers of Mus musculus mice. Firstly, in vitro studies (0.9, 1.8, 3.6, 5.4 and 7.2 µg/mL) revealed EC50 values of 3.7, 6.4 and 0.16 µg/mL for nitrite, hydroxyl radical and TBARS levels, respectively. Secondly, FC (2.5, 5, 10 and 25 mg/kg/day) was intraperitoneally administered to Swiss mice for 7 consecutive days. Nitrite levels in the hippocampus (26.2, 27.3, 30.2 and 26.6 µM) and striatum (26.3, 25.4, 34.3 and 27.5 µM) increased in all treated animals (P < 0.05). Lower doses dropped reduced glutathione, catalase and TBARS levels in the hippocampus and striatum. With the exception of this reduction in TBARS formation, FC displayed only in vitro antioxidant activity. Animals exhibited histological alterations suggestive of neurotoxicity and hepatotoxicity, indicating the need for precaution regarding the consumption of medicinal formulations based on Casearia sylvestris.

Sintomas e fatores de risco para asma entre escolares piauienses / Síntomas y factores de riesgo para el asma entre escolares piauienses / Symptoms and risk factors for asthma among piauiense schoolchildren

OBJETIVOS: Analisar a prevalência de sintomas de asma entre escolares de seis a sete anos do município de Picos-PI; e identificar fatores de risco associados à doença. MÉTODOS: Estudo transversal realizado com crianças de 6 e 7 anos de Picos em novembro de 2010 a maio de 2011. Para coletar os dados, foi utilizado um formulário adaptado do Internacional Study of Asthma and Allergies in Childhood. Os dados foram analisados com base na estatística descritiva e analítica. RESULTADOS: Dentre as 234 crianças da amostra estudada, 56% eram do gênero feminino. A prevalência de diagnóstico médico de asma foi de 7,7%. Os seguintes fatores de risco apresentaram relação estatisticamente significante com a ocorrência de asma (p < 0,05): sibilos após a realização de exercício físico, tosse seca à noite sem estar gripado, bronquite, e ter pais asmáticos. CONCLUSÃO: Observou-se o subdiagnóstico da asma e há necessidade de que novos trabalhos sejam realizados com uma amostra maior, para analisar de modo mais amplo a situação da asma em crianças no município de Picos - PI.

OBJECTIVES: To assess the prevalence of asthma symptoms among schoolchildren aged six to seven years in the municipality of Picos-PI; and to identify risk factors associated with the disease. METHODS: A cross-sectional study with children aged six and seven from Picos, in November 2010 and May 2011. To collect data, we used an adapted form of the International Study of Asthma and Allergies in Childhood. Data were analyzed using descriptive and analytical statistics. RESULTS: Among the 234 children in the study sample, 56% were female. The prevalence of the medical diagnosis of asthma was 7.7%. The following risk factors presented a statistically significant relationship with the occurrence of asthma (p <0.05): wheezing after physical exercise, dry cough at night without having a cold, bronchitis, and having parents with asthma. CONCLUSION: We observed an underdiagnosis of asthma; there is a necessity for further work to be conducted with a larger sample, to examine more broadly the situation of asthma in children in the municipality of Picos - PI.

OBJETIVOS: Analizar la prevalencia de síntomas de asma entre escolares de seis a siete años del municipio de Picos-PI; e identificar factores de riesgo asociados a la enfermedad. MÉTODOS: Estudio transversal realizado con niños de 6 y 7 años de Picos en noviembre de 2010 a mayo de 2011. Para recolectar los datos, se utilizo un formulario adaptado del Internacional Study of Asthma and Allergies in Childhood. Los datos fueron analizados con base en la estadística descriptiva y analítica. RESULTADOS: De los 234 niños de la muestra estudiada, el 56% era del género femenino. La prevalencia del diagnóstico médico de asma fue de 7,7%. Los siguientes factores de riesgo presentaron relación estadísticamente significativa con la ocurrencia de asma (p < 0,05): sibilancias después de la realización del ejercicio físico, tos seca por la noche sin estar agripado, bronquitis, y tener padres asmáticos. CONCLUSIÓN: Se observó el subdiagnóstico del asma y hay necesidad de que nuevos trabajos sean realizados con una muestra mayor, para analizar de modo más amplio la situación del asma en niños en el municipio de Picos - PI.

A alma exterior em Machado de Assis: um olhar psicanalítico / The exterior soul in Machado de Assis: a psychoanalytic view / El alma exterior en Machado de Assis: una mirada psicoanalítica / L'âme exterior de Machado de Assis: un regard psychanalytique

A noção de alma exterior perpassa toda a obra de Machado de Assis, indicando a importância atribuída ao olhar do outro sobre o eu. Os temas da ascensão social, hierarquia, títulos, aparência e status social estão relacionados a essa noção e formam um conjunto de aspectos que reiteradamente aparecem em romances e contos machadianos. O objetivo deste artigo é relacionar a noção de alma exterior aos seguintes conceitos freudianos: Eu, Ideal do Eu/Supereu e Narcisismo, buscando demonstrar que há uma afinidade entre tais conceitos e a noção trazida por Machado de Assis. Tanto os conceitos freudianos quanto a noção de alma exterior são discutidos em seu potencial de trazer luz à relação existente entre subjetividade e sociedade. A constituição do Eu implica a introjeção dos objetos, em um processo de identificação com os pais pelo qual não apenas estes, mas os valores da sociedade passam a se constituir como instâncias permanentes da subjetividade. A noção de alma exterior tem a propriedade de relacionar a interioridade e a exterioridade para o ser humano, pois ela é ao mesmo tempo alma, que poderia ser chamada de psíquico ou subjetividade, e exterior, por estar vinculada ao que no indivíduo pode ser visto, avaliado ou admirado pelos outros.

The notion of exterior soul is a notion that frequently appears in the works of Machado de Assis, indicating the importance given to the look of the other on the ego. The themes: social mobility, social hierarchy, titles, appearance and social status relate to the exterior soul notion and also frequently appear in the novels and short stories of Machado de Assis. This paper aims to relate Machado de Assis exterior soul and some Freud concepts: ego, ideal ego/superego and narcissism, in order to demonstrate their affinity with the notion brought by Machado de Assis. Both, Freudian concepts and the exterior soul notion are discussed in the perspective of their potential to clarify the relationship between subjectivity and culture. Ego's formation requires introjections of objects through a mechanism of identification with the parents, when not only the parents values, but also, social values are converted in permanent parts of subjectivity. The exterior soul notion has the property of relating interior and exterior in human beings, as it is, at the same time, soul, which can be named psychic or subjectivity, and exterior, once it is related to something in the individual that can be observed, analyzed or appreciated by the others.

La noción de alma exterior impregna toda la obra de Machado de Assis e indica la importancia que tiene la mirada del Otro sobre el Yo. Los temas de la movilidad social, jerarquía, títulos, apariencia y condición social están relacionados a esta noción y forman un conjunto que aparece repetidamente en las novelas y cuentos de Machado de Assis. El objetivo de este trabajo es relacionar la noción de alma exterior a los siguientes conceptos freudianos: Yo, el Ideal del Yo / Superyó y Narcisismo, tratando de demostrar que existe una afinidad entre estos conceptos y la idea presentada por Machado de Assis. Los conceptos freudianos y la noción machadiana de alma exterior tienen potencial para arrojar luz sobre la relación entre la subjetividad y la sociedad. La formación de Yo implica la introyección de los objetos en un proceso de identificación con los padres y no solamente ellos, sino que son los valores de la sociedad a constituirse como órganos permanentes de la subjetividad. La noción de alma exterior tiene la propiedad de relacionar la interioridad y la exterioridad en los seres humanos, ya que es, a un tiempo, alma, lo que se podría denominar subjetividad, y externa, pues vinculase a lo que en el individuo se puede ver, ser valorado o admirado por los demás.

La notion de l'âme extérieure imprègne toute l'oeuvre de Machado de Assis et indique l'importance attachée au regard dautrui sur le Moi. Les thèmes relatifs a la mobilité sociale, la hiérarchie, des titres, lapparence et le statut social sont liés à cette notion et forment un ensemble qui apparaissent à plusieurs reprises dans les romans et contes de Machado de Assis. Le but de cet article est relier la notion de lâme exterieure aux concepts freudiens (Moi, Idéal du Moi/Surmoi et Narcisisme) cherchant à démontrer qu'il existe une affinité entre ces concepts et la notion apportée par Machado de Assis. Les concepts freudiens et la notion machadienne sont discutés en ce qui concerne à éclairer la relation entre la subjectivité et la culture. La formation de le Moi implique l'introjection d'objetsdans un processus d'identification avec les parents selon lequel non seulement ceux-ci, mais les valeurs de la société doivent être constitués en organes permanents de la subjectivité. La notion de l'âme extérieure a la propriété de l'intériorité et l'extériorité se rapportent à l'homme car il est à la fois l'âme qui pourrait être appelée psychique ou la subjectivité, et à l'extérieur, d'être liée à ce que l'individu peut être vu, valorisé ou admiré par les autres.

Significados e sentidos das casas estudantis e a dialética inclusão-exclusão / Significados y sentidos de las casas estudiantiles y la dialéctica inclusión-exclusión / The meaning and the sense of the student’s dwellings by young college students and the inclusion-exclusion dialetic

O objetivo deste artigo é discutir a relação entre os significados e os sentidos (Vigotski, 2001) das casas estudantis para seus moradores, jovens universitários, apontando os processos de inclusão e exclusão vividos por esses sujeitos. Foi realizada uma pesquisa com os moradores de casas estudantis, em Goiânia, utilizando os seguintes procedimentos: aplicação de questionário, consulta a documentos, realização de grupos focais com estudantes selecionados, além de observação não sistemática durante as visitas feitas às casas. As informações colhidas demonstram que os significados tendem a enaltecer as casas estudantis, e os sentidos, expressões mais singulares, indicam que a experiência de ser morador é vivida como sofrimento e sacrifício. À luz da dialética exclusão-inclusão (Sawaia, 2001), são analisadas as contradições entre os significados e os sentidos.

The purpose of this article is to discuss the relationship between the meanings and the senses (Vigotski, 2001) of the student dwellers, young college students, from their point of view, as well as to investigate the processes of inclusion and exclusion they experienced. The research was accomplished with dwellers of the student dwelling of Goiânia-GO, making use of the following procedures: questions applied to the dwellers, reading of papers related to the student dwelling, focal groups and direct observation in the student dwelling during the visits to the dwellers. The results show that the meanings given by the student dweller tend to give value to and to elevate the experience of being a dweller, and that meanings that come from singular expressions indicate that the student dwelling is experienced as a sacrifice and suffering by the students. By means of the exclusion-inclusion dialectic (Sawaia, 2001), such contradiction was analyzed.