Este trabalho descreve a ocorrência da doença meningocócica na região de abrangência da Divisão Regional de Saúde de Sorocaba-SP, no período de 1999 a 2008. Fundamentado em dados fornecidos pelo Instituto Adolfo Lutz e pelo Grupo de Vigilância Epidemiológica, a incidência e a letalidade foram calculadas, para toda a população e por faixa etária. Os valores obtidos foram comparados com os dados do Estado de São Paulo e do Brasil. Além disso, foram obtidas as distribuições de ocorrência por manifestação clínica e de critérios diagnósticos utilizados, permitindo a análise da situação epidemiológica da doença meningocócica, na região em estudo. Ao verificar os resultados relativos aos sorogrupos, sorotipos e soross ubtipos identificados, foi possível estabelecer o fenótipo das cepas que, predominantemente, causam a doença na região. Em relação à incidência, conclui-se que, durante praticamente todo o período em estudo, é maior do que os valores endêmicos encontrados nos países desenvolvidos. A faixa etária mais atingida, tanto do ponto de vista da incidência como da letalidade é a de 0 a 4 anos, indicando a necessidade de incremento e continuidade dos programas de vacinação relativos a esse grupo populacional. Em relação às cepas circulantes, os fenótipos B:4,7:P1.19,15 e C:23:P1.14-6 predominam, fato coerente com os resultados obtidos para a Grande São Paulo e Baixada Santista / This work describes the meningococcical disease occurrence in the area related to the Health Regional Division of Sorocaba-SP, between 1999 and 2008. Based on data available at Adolfo Lutz Institute and Epidemiological Vigilance Group, the incidence and the lethality were calculated, for the whole population and for age groups. The obtained values were compared with the data related to São Paulo State and Brazil. Besides, the clinical manifestation and diagnosis criteria distributions were obtained, allowing the analysis of the meningococcical disease epidemiological situation in the studied region. Verifying the results related to the identified serogroups, serotypes and serosubtypes, it was possible to establish the phenotype of the strains that, primarily, cause the disease in the region. Related to the incidence, it can be concluded that, in almost all the study period, it is greater than the endemic values found for developed countries. The more affected age group, concerning either incidence or lethality, is the 0 to 4 years old, indicating the necessity of increment and continuity of the vaccination programs. Related to the circulating strains, the phenotypes B:4,7:P1.19,15 e C:23:P1.14-6 are the more frequent, coherently with the obtained results for the Great São Paulo and Baixada Santista

Orientador: Antonio Carlos Paes / Resumo: Introdução: Os números relacionados à letalidade na lesão renal aguda (LRA) em cães e gatos de acordo com a etiologia são pouco conhecidas. Este é o primeiro estudo que avaliou as evidências disponíveis sobre a LRA para ajudar na tomada de decisões na prática clínica. Objetivos: Avaliar a letalidade da LRA em cães e gatos de acordo com a etiologia, infecciosa ou não infecciosa, e também em cães e gatos que estavam recebendo tratamento dialítico ou conservador. Métodos: Pesquisas em Medline, EMBASE e LILACS até julho de 2016 e revisão de listas de referências dos trabalhos incluídos. Os critérios de inclusão foram estudos em série de casos que avaliaram o tratamento de dialítico ou conservativo em cães e gatos com LRA independentemente da etiologia e letalidade por todas as causas relatada. A proporção agrupada e o intervalo de confiança (IC) são apresentados para cada resultado. A significância estatística foi definida com a não sobreposição dos intervalos de confiança de 95%, obtidos para cada intervenção. Resultados: Dezenove séries de casos envolvendo 1.233 animais foram elegíveis. As proporções agrupadas para a letalidade global, independentemente do tratamento e da etiologia, foram: gatos 52,6% e cães 45,0%. Os valores de letalidade de acordo com o tratamento foram numericamente maiores nos cães e gatos que receberam diálise quando comparado com o tratamento conservador. As diferenças significativas foram observadas devido à não-sobreposição das IC 95%, mostrando maiores... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Evidence related to lethality in acute kidney injury (AKI) in cats and dogs accordingly to the etiology are little known. This is the first study that evaluated the available evidence on AKI to allow decision-making in clinical practice. Objectives: To evaluate the lethality rate in cats and dogs with AKI accordingly to the etiology (i.e. infectious versus non-infectious), and the incidence of lethality in cats and dogs that were receiving either dialytic or conservative treatment. Methods: Searches of Medline, EMBASE, and LILACS to July 2016 and review of reference lists of previous review. Inclusion criteria were case series studies evaluating dialytic or conservative treatment in cats and dogs with AKI, regardless the etiology and all-cause lethality reported. The pooled proportion and the confidence interval (CI) are shown for each outcome. Statistical significance was defined if the 95% confidence intervals obtained for each intervention did not overlap. Results: 19 case series involving 1,233 animals proved eligible. The pooled proportions for overall lethality regardless the treatment and etiology were: cats 52.6% and dogs 45.0%.The rates of lethality accordingly the treatment were higher in the cats and dogs that receiving dialysis, regardless the etiology when comparing with conservative treatment, however there was no significant difference. Effect differences were seen due to the non-overlap of the 95% CIs showing higher proportions of mortality in AKI ... (Complete abstract click electronic access below) / Doutor

Este trabalho descreve a ocorrência da doença meningocócica na região de abrangência da Divisão Regional de Saúde de Sorocaba-SP, no período de 1999 a 2008. Fundamentado em dados fornecidos pelo Instituto Adolfo Lutz e pelo Grupo de Vigilância Epidemiológica, a incidência e a letalidade foram calculadas, para toda a população e por faixa etária. Os valores obtidos foram comparados com os dados do Estado de São Paulo e do Brasil. Além disso, foram obtidas as distribuições de ocorrência por manifestação clínica e de critérios diagnósticos utilizados, permitindo a análise da situação epidemiológica da doença meningocócica, na região em estudo. Ao verificar os resultados relativos aos sorogrupos, sorotipos e soross ubtipos identificados, foi possível estabelecer o fenótipo das cepas que, predominantemente, causam a doença na região. Em relação à incidência, conclui-se que, durante praticamente todo o período em estudo, é maior do que os valores endêmicos encontrados nos países desenvolvidos. A faixa etária mais atingida, tanto do ponto de vista da incidência como da letalidade é a de 0 a 4 anos, indicando a necessidade de incremento e continuidade dos programas de vacinação relativos a esse grupo populacional. Em relação às cepas circulantes, os fenótipos B:4,7:P1.19,15 e C:23:P1.14-6 predominam, fato coerente com os resultados obtidos para a Grande São Paulo e Baixada Santista / This work describes the meningococcical disease occurrence in the area related to the Health Regional Division of Sorocaba-SP, between 1999 and 2008. Based on data available at Adolfo Lutz Institute and Epidemiological Vigilance Group, the incidence and the lethality were calculated, for the whole population and for age groups. The obtained values were compared with the data related to São Paulo State and Brazil. Besides, the clinical manifestation and diagnosis criteria distributions were obtained, allowing the analysis of the meningococcical disease epidemiological situation in the studied region. Verifying the results related to the identified serogroups, serotypes and serosubtypes, it was possible to establish the phenotype of the strains that, primarily, cause the disease in the region. Related to the incidence, it can be concluded that, in almost all the study period, it is greater than the endemic values found for developed countries. The more affected age group, concerning either incidence or lethality, is the 0 to 4 years old, indicating the necessity of increment and continuity of the vaccination programs. Related to the circulating strains, the phenotypes B:4,7:P1.19,15 e C:23:P1.14-6 are the more frequent, coherently with the obtained results for the Great São Paulo and Baixada Santista

This thesis deals with the problems of cardiovascular diseases in Czech Republic and selected EU countries. Over the long term mortality in the Czech Republic there are changes in mortality rates. Largest fluctuations in the intensity of mortality were caused just cardiovascular diseases. These changes can be explained by the greater part of the changing economic and social factors, eating habits and decrease levels of some risk factors. On overall cardiovascular mortality in the long term the most involved two groups of diseases, ischemic heart diseases and cerebrovascular diseases. In international comparisons, the differences in the development of cardiovascular mortality between developed countries and the former socialist countries considerable.

Les leucémies aiguës myéloïdes (LAM) représentent un groupe d’hémopathies malignes agressives, de pronostic sombre en dépit des traitements intensifs actuellement proposés. Malgré une grande hétérogénéité clinique et moléculaire, les cellules de LAM sont caractérisées par l’activation de voies de signalisation essentielles à leur prolifération et leur survie, comme par exemple celle du complexe mTORC1 (mammalian target of rapamycin complex 1). Cependant, l’utilisation clinique d’inhibiteurs tels que la rapamycine ou des inhibiteurs catalytiques s’est avérée décevante, ce qui suggère qu’il n’y a pas d’addiction oncogénique à mTORC1 dans les LAM. Au cours de ce travail, nous avons démontré que l’activation de mTORC1 est au contraire une condition nécessaire à l’induction de la mort cellulaire en réponse à l’activation d’AMPK (AMP-activated protein kinase), établissant une relation de létalité synthétique entre ces deux voies. Pour cela, nous avons utilisé un nouveau composé activateur spécifique d’AMPK, le GSK621. En invalidant la sous-unité catalytique AMPKα1 par ARN interférence ou par le système CRISPR/Cas9, nous avons démontré que les effets antileucémiques de ce composé sont bien dépendants de l’activation d’AMPK. Nous avons observé que ce composé favorise l’autophagie, et que ce processus est impliqué dans la mort des cellules leucémiques puisque l’inhibition des protéines ATG5 ou ATG7 a un effet protecteur sur les cellules leucémiques. Les effets antileucémiques du composé GSK621 ont été confirmés sur des cellules primaires, ainsi que sur un panel de vingt lignées de LAM, et dans un modèle murin de xénogreffe. De façon intéressante, l’activation d’AMPK pourrait également compromettre la survie des cellules souches leucémiques, comme en atteste l’atténuation du potentiel clonogénique en méthylcellulose de cellules murines transformées par MLL-ENL ou FLT3-ITD. Nous avons observé que le composé GSK 621 n’avait pas de toxicité envers les progéniteurs hématopoïétiques normaux, ouvrant ainsi une fenêtre thérapeutique intéressante. Comme l’activation d’AMPK conduit dans de nombreux modèles cellulaires à l’inhibition de mTORC1, et comme l’activation de mTORC1 est observée dans les cellules de LAM mais pas dans les progéniteurs hématopoïétiques normaux, nous avons proposé l’hypothèse que le niveau d’activation de mTORC1 déterminait les effets de l’activateur d’AMPK. Pour cela, nous avons inhibé mTORC1 dans les cellules leucémiques d’une part, et activé mTORC1 dans les progéniteurs normaux d’autre part. De façon inattendue, mTORC1 échappe au contrôle d’AMPK dans les LAM, et nous avons observé que l’activation de mTORC1 est une condition nécessaire et suffisante pour que le composé GSK621 entraîne la mort des cellules. Le substrat moléculaire de cette létalité synthétique est le facteur de transcription proapoptotique ATF4, dont la transcription est favorisée par mTORC1, et la traduction par AMPK via la phosphorylation d’eIF2A. Ces travaux proposent donc que malgré l’absence d’addiction oncogénique, l’activation de mTORC1 dans les LAM représente une opportunité thérapeutique originale via une relation de létalité synthétique avec l’activation d’AMPK. Ils constituent un rationnel au développement clinique d’activateurs d’AMPK dans les LAM, voire dans d’autres cancers ayant une activation constitutive de mTORC1. / Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis despite intensive treatments. Virtually all recurrent molecular alterations in AML functionally converge to cause signal transduction pathway dysregulation that drives cellular proliferation and survival. The mammalian target of rapamycin complex 1 (mTORC1) is a rapamycin-sensitive signaling node defined by the interaction between mTOR and raptor. Constitutive mTORC1 activity is nearly universal in AML. However, pharmacologic inhibition with rapamycin or second-generation mTOR kinase inhibitors has shown limited anti-leukemic activity in both preclinical models as well as in clinical trials, suggesting that addiction to this oncogene is not a recurrent event in AML. Here we report that sustained mTORC1 activity is nonetheless essential for the cytotoxicity induced by pharmacologic activation of AMP-activated protein kinase (AMPK) in AML. Our studies employed a novel AMPK activator called GSK621. Using CRISPR/Cas9 and shRNA-mediated silencing of the AMPKa1 catalytic subunit, we showed that AMPK activity was necessary for the anti-leukemic response induced by this agent. GSK621-induced AMPK activation precipitated autophagy, and blocking autophagy via shRNA-mediated knockdown of ATG5 or ATG7 protected AML cells from cytotoxicity resulting from treatment with GSK621, suggesting that autophagy promotes cell death in the context of active AMPK. GSK621 cytotoxicity was consistently observed across twenty different AML cell lines, primary AML patient samples and AML xenografts in vivo. GSK621-induced AMPK activation also impaired the self-renewal capacity of MLL-ENL- and FLT3-ITD-induced murine leukemias as measured by serial methylcellulose replating assays. Strikingly, GSK621 did not induce cytotoxicity in normal CD34+ hematopoietic progenitor cells. We hypothesized that the differential sensitivity to GSK621 could be due to the difference in amplitude of mTORC1 activation between AML and normal CD34+ cells. In contrast to most reported cellular models in which AMPK inhibits mTORC1, sustained mTORC1 activity was seen following GSK621-induced AMPK activation in AML. Inhibition of mTORC1 either pharmacologically (using rapamycin) or genetically (using shRNAs targeting raptor and mTOR) abrogated AMPK-induced cytotoxicity in AML cells, including primary AML patient samples. The same synthetic lethality could be recapitulated in normal CD34+ progenitors by constitutive activation of mTORC1 using a lentivirally-transduced myrAKT construct. We further observed that the level of ATF4 protein is under a transcriptionnal control by mTORC1 and a translational control by AMPK (through eIF2A), and explains the synthetic lethal relationship between AMPK and mTORC1. Taken together, these data show that the magnitude of mTORC1 activity determines the degree of cytotoxicity triggered by AMPK activation. Our results therefore support AMPK activation as a promising therapeutic strategy in AML and other mTORC1-active malignancies which warrants further investigations in clinical trials.