Étude fonctionnelle de l'apolipoprotéine D humaine en situations de stress

L'apolipoprotéine D (apoD) est une glycoprotéine sécrétée dont l'expression est modulée dans une multitude de situations incluant les cancers de différents tissus, les désordres métaboliques et les maladies neurodégénératives. Bien que la liste des conditions présentant une augmentation de l'apoD s'allonge chaque jour, les facteurs provoquant le déclenchement de son expression, de même que la fonction de celle-ci, restent inconnus. Les travaux présentés dans cette thèse ont permis de jeter un peu de lumière sur ces deux aspects. Dans un premier temps, ces travaux ont permis de déterminer que l'apoD est une protéine de stress spécifique et que son expression est déclenchée par des stress ayant une forte composante oxydante ou inflammatoire. Cependant, alors que l'expression de l'apoD en réponse au stress oxydatif est associée à un arrêt de croissance, en condition inflammatoire, elle est accompagnée d'une stimulation de la prolifération. De plus, ces stress modifient non seulement le niveau d'expression, mais aussi la localisation intracellulaire de l'apoD. L'apoD, qui est normalement sécrétée, est réinternalisée et s'accumule dans le cytoplasme et le noyau. L'entrée de l'apoD dans la cellule influence, de plus, la prolifération cellulaire. Ces travaux ont ensuite permis de mieux cerner le rôle de cette modulation de l'apoD en situations de stress chez l'animal. Pour cela, nous avons soumis des souris surexprimant l'apoD humaine dans leur système nerveux ou n'exprimant pas l'apoD à des conditions neurodégénératives. Nous avons ainsi établi que l'apoD serait impliquée dans les mécanismes régulant la protection contre diverses atteintes neurodégénératives, incluant le stress oxydatif et l'inflammation, favorisant donc la survie suite à ces atteintes. Ainsi, l'apoD joue un rôle dans la fonction neuronale basale tel que déterminé grâce à des tests comportementaux. De plus, l'apoD limite la peroxydation lipidique lors de l'exposition au paraquat, un générateur de stress oxydatif. De façon similaire, l'apoD contrôle la production de cytokines et de phospholipase A2, réduit l'infiltration de cellules T et induit l'activation gliale en réponse à l'infection par le coronavirus humain OC43, un modèle d'inflammation aiguë. Par ailleurs, la surexpression de l'apoD humaine chez la souris favorise l'accumulation de lipides dans le foie et les muscles, favorisant ainsi le développement de la résistance à l'insuline accompagnant souvent le vieillissement physiologique. Cette accumulation de lipides a été associée à une stimulation de gènes impliqués dans la synthèse d'acides gras. Les travaux présentés dans cette thèse contribuent donc à établir l'apoD comme un facteur bénéfique favorisant la survie suite à une atteinte cellulaire. Ils suggèrent aussi l'importance de contrôler les niveaux physiologiques de l'apoD afin de maintenir l'homéostasie métabolique. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Apolipoprotéine D, Arrêt de croissance, Inflammation, Lipocaline, Résistance à l'insuline, Stress oxydatif

The antisense protein of HTLV-2 positively modulates HIV-1 replication

International audienc

Oseltamivir compounding in the hospital pharmacy during the (H1N1) influenza pandemic

AIMS: Pandemics impose large demands on the health care system. The supply of appropriate chemotherapeutic agents, namely oseltamivir solution, presented a serious challenge in the recent influenza pandemic. This study reports on the rational series of pharmacotechnical steps that were followed to appropriately handle bulk oseltamivir powder to meet the increased demand. METHODS: During a six-week period in August and September of 2009, a task force was created in the Central Pharmacy of Hospital das Clínicas to convert imported oseltamivir phosphate into ready-to-use solution for utilization by physicians and public health authorities. The protocol included dissolution, physico-chemical tests and the bottling of a liquid microdose formulation for emergency room and outpatient dispensing with adequate quality control during all phases. RESULTS: The successful production routine was based on a specially designed flowchart according to which a batch of 33210 g of oseltamivir powder was converted into 32175 solution units during the aforementioned period with a net loss of only 2.6%. The end products were bottles containing 50 ml of 15 mg/mL oseltamivir solution. The measured concentration was stable and accurate (97.5% - 102.0% of the nominal value). The drug was prescribed as both a prophylactic and therapeutic agent. DISCUSSION: Hospital pharmacies are conventionally engaged in the manipulation of medical prescriptions and specialty drugs. They are generally responsible for only small-scale equipment used for manufacturing and quality-control procedures. The compounding of oseltamivir was a unique effort dictated by exceptional circumstances. CONCLUSION: The shortage of oseltamivir solution for clinical use was solved by emergency operationalization of a semi-industrial process in which bulk powder was converted into practical vials for prompt delivery

Oseltamivir compounding in the hospital pharmacy during the (H1N1) influenza pandemic

AIMS: Pandemics impose large demands on the health care system. The supply of appropriate chemotherapeutic agents, namely oseltamivir solution, presented a serious challenge in the recent influenza pandemic. This study reports on the rational series of pharmacotechnical steps that were followed to appropriately handle bulk oseltamivir powder to meet the increased demand. METHODS: During a six-week period in August and September of 2009, a task force was created in the Central Pharmacy of Hospital das Clínicas to convert imported oseltamivir phosphate into ready-to-use solution for utilization by physicians and public health authorities. The protocol included dissolution, physico-chemical tests and the bottling of a liquid microdose formulation for emergency room and outpatient dispensing with adequate quality control during all phases. RESULTS: The successful production routine was based on a specially designed flowchart according to which a batch of 33210 g of oseltamivir powder was converted into 32175 solution units during the aforementioned period with a net loss of only 2.6%. The end products were bottles containing 50 ml of 15 mg/mL oseltamivir solution. The measured concentration was stable and accurate (97.5% - 102.0% of the nominal value). The drug was prescribed as both a prophylactic and therapeutic agent. DISCUSSION: Hospital pharmacies are conventionally engaged in the manipulation of medical prescriptions and specialty drugs. They are generally responsible for only small-scale equipment used for manufacturing and quality-control procedures. The compounding of oseltamivir was a unique effort dictated by exceptional circumstances. CONCLUSION: The shortage of oseltamivir solution for clinical use was solved by emergency operationalization of a semi-industrial process in which bulk powder was converted into practical vials for prompt delivery

ApoD, a Glia-Derived Apolipoprotein, Is Required for Peripheral Nerve Functional Integrity and a Timely Response to Injury

Producción CientíficaGlial cells are a key element to the process of axonal regeneration, either promoting or inhibiting axonal growth. The study of glial derived factors induced by injury is important to understand the processes that allow or preclude regeneration, and can explain why the PNS has a remarkable ability to regenerate, while the CNS does not. In this work we focus on Apolipoprotein D (ApoD), a Lipocalin expressed by glial cells in the PNS and CNS. ApoD expression is strongly induced upon PNS injury, but its role has not been elucidated. Here we show that ApoD is required for: (1) the maintenance of peripheral nerve function and tissue homeostasis with age, and (2) an adequate and timely response to injury. We study crushed sciatic nerves at two ages using ApoD knock-out and transgenic mice over-expressing human ApoD. The lack of ApoD decreases motor nerve conduction velocity and the thickness of myelin sheath in intact nerves. Following injury, we analyze the functional recovery, the cellular processes, and the protein and mRNA expression profiles of a group of injury-induced genes. ApoD helps to recover locomotor function after injury, promoting myelin clearance, and regulating the extent of angiogenesis and the number of macrophages recruited to the injury site. Axon regeneration and remyelination are delayed without ApoD and stimulated by excess ApoD. The mRNA and protein expression profiles reveal that ApoD is functionally connected in an age-dependent manner to specific molecular programs triggered by injury.2015-09-1

Concentração e distribuição do rendimento por raça no Brasil

O objetivo do trabalho é estudar a concentração racial do rendimento e analisar a distribuição do rendimento no interior das categorias de raça/cor no Brasil em 2001, a partir dos microdados da Pesquisa Nacional por Amostra de Domicílios do IBGE. Apesar do mito da democracia racial, o rendimento no Brasil está concentrado na categoria não negra da população, que inclusive aufere rendimento maior que os negros, mesmo quando controlado o nível de escolaridade dos trabalhadores. Embora o rendimento entre negros seja relativamente melhor distribuído que o rendimento para não-negros e para o Brasil como um todo, essa melhor distribuição é pouco significativa quando comparada a indicadores internacionais. Neste sentido, a má distribuição do rendimento no Brasil extrapola a questão racial e se manifesta também no interior das categorias de raça/cor.

Determinantes do óbito infantil no Vale do Jequitinhonha e nas regiões Norte e Nordeste do Brasil

OBJECTIVE This study aims to identify the social and demographic determinants, in addition to the determinants of reproductive health and use of health services, associated with infant mortality in small and medium-sized cities of the North, Northeast and Southeast regions of Brazil. METHODS This is a case-control study with 803 cases of death of children under one year and 1,969 live births (controls), whose mothers lived in the selected cities in 2008. The lists of the names of cases and controls were extracted from the Sistema de Informação sobre Mortalidade (SIM – Mortality Information System) and the Sistema de Informação sobre Nascidos Vivos (SINASC – Live Birth Information System) and supplemented by data obtained by the research of “active search of death and birth”. Data was collected in the household using a semi-structured questionnaire, and the analysis was carried out using multiple logistic regression. RESULTS The final model indicates that the following items are positively and significantly associated with infant mortality: family working in agriculture, mother having a history of fetal and infant losses, no prenatal or inadequate prenatal, and not being associated to the maternity hospital during the prenatal period. We have observed significant interactions to explain the occurrence of infant mortality between race and socioeconomic score and between high-risk pregnancy and pilgrimage for childbirth. CONCLUSIONS The excessive number of home deliveries and pilgrimage for childbirth indicates flaws in the line of maternity care and a lack of collaboration between the levels of outpatient and hospital care. The study reinforces the need for an integrated management of the health care networks, leveraging the capabilities of cities in meeting the needs of pregnancy, delivery and birth with quality.OBJETIVO Identificar os determinantes sociais, demográficos, da saúde reprodutiva e de utilização dos serviços de saúde associados ao óbito infantil em municípios de pequeno e médio porte das regiões Norte, Nordeste e Sudeste do Brasil. MÉTODOS Trata-se de um estudo caso-controle com 803 casos de óbito de menores de um ano e 1.969 nascidos vivos (controles), cujas mães residiam em 2008 nos municípios selecionados. As listas nominais dos casos e do controles foram extraídas do Sistema de Informação sobre Mortalidade e do Sistema de Informação sobre Nascidos Vivos e completadas por dados obtidos pela pesquisa de “busca ativa de óbito e nascimento”. A coleta de dados foi realizada em domicílio por meio de questionário semiestruturado, e a análise, por meio de regressão logística múltipla. RESULTADOS O modelo final indicou que estão associadas positivamente e significativamente ao óbito infantil: a família trabalhar na agricultura, a mãe ter tido história de perdas fetais e infantis, não ter feito pré-natal ou ter tido um pré-natal inadequado e não estar vinculada à maternidade durante o pré-natal. Foram observadas interações significativas para explicar a ocorrência do óbito infantil entre cor de pele e escore socioeconômico e entre gestação classificada como de risco e peregrinação para o parto. CONCLUSÕES O número excessivo de partos domiciliares e de peregrinação para o parto indica falhas na linha de cuidado da gestante e desarticulação entre os níveis de atenção ambulatorial e hospitalar. O estudo reforça a necessidade de uma gestão integrada das redes de atenção à saúde, potencializando as capacidades municipais em atender, com qualidade, à gestação, ao parto e ao nascimento

Experimental Pharmacology in Transgenic Rodent Models of Alzheimer’s Disease

This Mini Review discusses the merits and shortfalls of transgenic (tg) rodents modeling aspects of the human Alzheimer’s disease (AD) pathology and their application to evaluate experimental therapeutics. It addresses some of the differences between mouse and rat tg models for these investigations. It relates, in a condensed fashion, the experience of our research laboratory with the application of anti-inflammatory compounds and S-adenosylmethionine (SAM) at the earliest stages of AD-like amyloid pathology in tg mice. The application of SAM was intended to revert the global brain DNA hypomethylation unleashed by the intraneuronal accumulation of amyloid-β-immunoreactive material, an intervention that restored levels of DNA methylation including of the bace1 gene. This review also summarizes experimental pharmacology observations made in the McGill tg rat model of AD-like pathology by applying “nano-lithium” or a drug with allosteric M1 muscarinic and sigma 1 receptor agonistic properties (AF710B). Extremely low doses of lithium (up to 400 times lower than used in the clinic) had remarkable beneficial effects on lowering pathology and improving cognitive functions in tg rats. Likewise, AF710B treatment, even at advanced stages of the pathology, displayed remarkable beneficial effects. This drug, in experimental conditions, demonstrated possible “disease-modifying” properties as pathology was frankly diminished and cognition improved after a month of “wash-out” period. The Mini-Review ends with a discussion on the predictive value of similar experimental pharmacological interventions in current rodent tg models. It comments on the validity of some of these approaches for early interventions at preclinical stages of AD, interventions which may be envisioned once definitive diagnosis of AD before clinical presentation is made possible