Role of the cotransporter KCC2 in cortical excitatory synapse development and febrile seizure susceptibility

Le co-transporteur KCC2 spécifique au potassium et chlore a pour rôle principal de réduire la concentration intracellulaire de chlore, entraînant l’hyperpolarisation des courants GABAergic l’autorisant ainsi à devenir inhibiteur dans le cerveau mature. De plus, il est aussi impliqué dans le développement des synapses excitatrices, nommées aussi les épines dendritiques. Le but de notre projet est d’étudier l’effet des modifications concernant l'expression et la fonction de KCC2 dans le cortex du cerveau en développement dans un contexte de convulsions précoces. Les convulsions fébriles affectent environ 5% des enfants, et ce dès la première année de vie. Les enfants atteints de convulsions fébriles prolongées et atypiques sont plus susceptibles à développer l’épilepsie. De plus, la présence d’une malformation cérébrale prédispose au développement de convulsions fébriles atypiques, et d’épilepsie du lobe temporal. Ceci suggère que ces pathologies néonatales peuvent altérer le développement des circuits neuronaux irréversiblement. Cependant, les mécanismes qui sous-tendent ces effets ne sont pas encore compris. Nous avons pour but de comprendre l'impact des altérations de KCC2 sur la survenue des convulsions et dans la formation des épines dendritiques. Nous avons étudié KCC2 dans un modèle animal de convulsions précédemment validé, qui combine une lésion corticale à P1 (premier jour de vie postnatale), suivie d'une convulsion induite par hyperthermie à P10 (nommés rats LHS). À la suite de ces insultes, 86% des rats mâles LHS développent l’épilepsie à l’âge adulte, au même titre que des troubles d’apprentissage. À P20, ces animaux presentent une augmentation de l'expression de KCC2 associée à une hyperpolarisation du potentiel de réversion de GABA. De plus, nous avons observé des réductions dans la taille des épines dendritiques et l'amplitude des courants post-synaptiques excitateurs miniatures, ainsi qu’un déficit de mémoire spatial, et ce avant le développement des convulsions spontanées. Dans le but de rétablir les déficits observés chez les rats LHS, nous avons alors réalisé un knock-down de KCC2 par shARN spécifique par électroporation in utero. Nos résultats ont montré une diminution de la susceptibilité aux convulsions due à la lésion corticale, ainsi qu'une restauration de la taille des épines. Ainsi, l’augmentation de KCC2 à la suite d'une convulsion précoce, augmente la susceptibilité aux convulsions modifiant la morphologie des épines dendritiques, probable facteur contribuant à l’atrophie de l’hippocampe et l’occurrence des déficits cognitifs. Le deuxième objectif a été d'inspecter l’effet de la surexpression précoce de KCC2 dans le développement des épines dendritiques de l’hippocampe. Nous avons ainsi surexprimé KCC2 aussi bien in vitro dans des cultures organotypiques d’hippocampe, qu' in vivo par électroporation in utero. À l'inverse des résultats publiés dans le cortex, nous avons observé une diminution de la densité d’épines dendritiques et une augmentation de la taille des épines. Afin de confirmer la spécificité du rôle de KCC2 face à la région néocorticale étudiée, nous avons surexprimé KCC2 dans le cortex par électroporation in utero. Cette manipulation a eu pour conséquences d’augmenter la densité et la longueur des épines synaptiques de l’arbre dendritique des cellules glutamatergiques. En conséquent, ces résultats ont démontré pour la première fois, que les modifications de l’expression de KCC2 sont spécifiques à la région affectée. Ceci souligne les obstacles auxquels nous faisons face dans le développement de thérapie adéquat pour l’épilepsie ayant pour but de moduler l’expression de KCC2 de façon spécifique.

The collected works of W.H. Hudson.

--[15] The purple land; being the narrative of one Richard Lamb's adventures in the Banda Orientál in South America, as told by himself.--[16] A shepherd's life; impressions of the South Wiltshire Downs.--[17] Adventures among birds.--[18] Far away and long ago; a history of my early life.--[19] Birds in town & village.--[20] Birds of La Plata.--[21] The book of a naturalist.--[22] A traveller in little things.--[23] A hind in Richmond Park.--[24] Dead man's plack, An old thorn, & Miscellenea.

The valley of shadows,

"This book is not a novel, but the recollections of scenes and episodes of my early life in Illinois and Missouri."--Pref. to Boston ed., 1909.

Beauties selected from the writings of Thomas De Quincey.

De Quincey's early life.--Dreams.--Narratives.--Essays.--Critiques and reminiscences.--Detached gems.

Short plays about famous authors,

Introduction.--A mistake at the manor ["based on an incident in the early life of Oliver Goldsmith"]--When Heine was twenty-one.--Miss Burney at court.--A Christmas eve with Charles Dickens.--The fairies' plea; an interlude for Shakespeare day. Adapted from Thomas Hood's "Plea of the midsummer fairies."

Sir Robert Peel. From his private papers.

Vol. 1 also issued under title: Sir Robert Peel. In early life, 1788-1812; as Irish Secretary, 1812-1818; and as Secretary of State, 1822-1827.

The neurodevelopmental hypothesis of schizophrenia: a review of recent developments

The neurodevelopmental hypothesis (NDH) of schizophrenia suggests that a disruption of brain development during early life underlies the later emergence of psychosis during adulthood. The aim of this review is to chart the challenges and subsequent refinements to this hypothesis, with particular reference to the static versus progressive nature of the putative neurobiological processes underlying the NDH. A non-systematic literature review was undertaken, with an emphasis on major review papers relevant to the NDH. Weaknesses in the explanatory power of the NDH have led to a new generation of more refined hypotheses in recent years. In particular, recent versions of the hypothesis have incorporated evidence from structural neuroimaging which suggests changes in brain volumes after the onset of schizophrenia. More detailed models that incorporate progressive neurobiological processes have replaced early versions of the NDH, which were based on a 'static encephalopathy. In addition, recent models have suggested that two or more 'hits' are required over the lifespan rather than only one early-life event. Animal models are providing important insights into the sequelae of disturbed early brain development. The NDH has provided great impetus to the schizophrenia research community. Recent versions of the hypothesis have encouraged more focused and testable hypotheses.

Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle

There is growing evidence that 1,25-dihydroxyvitamin D-3 is involved in normal brain development. The aim of this study was to examine the impact of prenatal and postnatal hypovitaminosis D on prepulse inhibition (PPI) of acoustic startle in adult rats. We compared six groups of rats: control rats with normal vitamin D throughout life and normal litter size (Litter); control rats with normal vitamin D but with a reduced litter size of two (Control); offspring from reduced litters of vitamin D deplete mothers who were repleted at birth (Birth), repleted at weaning (Weaning) or remained on a deplete diet until 10 weeks of age (Life); or control rats that were placed on a vitamin D-deficient diet from 5 to 10 weeks of age (Adult). All rats were tested in acoustic startle chambers at 5 and 10 weeks of age for acoustic startle responses and for PPI. There were no significant group differences at 5 weeks of age on the acoustic startle response or on PPI. At 10 weeks of age, rats in the Life group only had impaired PPI despite having normal acoustic startle responses. We conclude that combined prenatal and chronic postnatal hypovitaminosis D, but not early life hypovitaminosis D, alters PPI. (C) 2004 Elsevier Inc. All rights reserved.

Inhibition of 19-kDa C-terminal region of merozoite surface protein-1-specific antibody responses in neonatal pups by maternally derived 19-kDa C-terminal region of merozoite surface protein-1-specific antibodies but not whole parasite-specific antibodies

Immunizing pregnant women with a malaria vaccine is one approach to protecting the mother and her offspring from malaria infection. However, specific maternal Abs generated in response to vaccination and transferred to the fetus may interfere with the infant's ability to respond to the same vaccine. Using a murine model of malaria, we examined the effect of maternal 19-kDa C-terminal region of merozoite surface protein-1 (MSP1(19)) and Plasmodium yoelii Abs on the pups' ability to respond to immunization with MSP1(19). Maternal MSPI,g-specific Abs but not A yoelii-specific Abs inhibited Ab production following MSP1(19) immunization in 2-wk-old pups. This inhibition was correlated with the amount of maternal MSP1(19) Ab present in the pup at the time of immunization and was due to fewer specific B cells. Passively acquired Ab most likely inhibited the development of an Ab response by blocking access to critical B cell epitopes. If a neonate's ability to respond to MSP1(19) vaccination depends on the level of maternal Abs present at the time of vaccination, it may be necessary to delay immunization until Abs specific for the vaccinating Ag have decreased.

The effects of pre-weaning undernutrition on the expression levels of free radical deactivating enzymes in the mouse brain

A mild degree of undernutrition brought about by restricting the amount of food in the diet is known to alter the life span of an animal. It has been hypothesised that this may be related to the effects of undernutrition on an animals anti-oxidant defense system. We have therefore, used real-time PCR (rt-PCR) techniques to determine the levels of mRNA expression for manganese superoxide dismutase (MnSOD), copper/zinc superoxide dismutase (Cu/ZnSOD), glutathione peroxidase 1 (GPx 1) and catalase in the brains of Quackenbush mice undernourished from conception until 21-post-natal days of age. It was found that 21- and 61-day-old undernourished mice had a deficit in the expression of Cu/ZnSOD in both the cerebellum and forebrain regions compared to age-matched controls. The expression of MnSOD was found to be greater in the cerebellum, but not the forebrain region, of 21-day-old undernourished mice. There were no significant differences in the expression of GPx 1 and catalase between control and undernourished or previously undernourished mice. Our results confirm that undernutrition during the early life of a mouse may disrupt some of the enzymes involved in the anti-oxidant defense systems.

Developmental Vitamin D-3 deficiency alters the adult rat brain

There is growing evidence that Vitamin D-3 (1,25-dihydroxyvitamin D-3) is involved in brain development. We have recently shown that the brains of newborn rats from Vitamin D-3 deficient dams were larger than controls, had increased cell proliferation, larger lateral ventricles, and reduced cortical thickness. Brains from these animals also had reduced expression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor. The aim of the current study was to examine if there were any permanent outcomes into adulthood when the offspring of Vitamin D-3 deficient dams were restored to a normal diet. The brains of adult rats were examined at 10 weeks of age after Vitamin D-3 deficiency until birth or weaning. Compared to controls animals that were exposed to transient early Vitamin D-3 deficiency had larger lateral ventricles, reduced NGF protein content, and reduced expression of a number genes involved in neuronal structure, i.e. neurofilament or MAP-2 or neurotransmission, i.e. GABA-(alpha 4). We conclude that transient early life hypovitaminosis D-3 not only disrupts brain development but leads to persistent changes in the adult brain. In light of the high incidence of hypovitammosis D-3 in women of child-bearing age, the public health implications of these findings warrant attention. (c) 2005 Elsevier Inc. All rights reserved.

Polymorphisms in the vitamin D receptor and their associations with risk of schizophrenia and selected anthropometric measures

The association between vitamin D levels and skeletal growth has long been recognized. However, exposure to low levels of vitamin D during early life is also known to alter brain development, and is a candidate risk factor for schizophrenia. This study examines the association between four polymorphisms in the vitamin D receptor (VDR) and 1) risk of schizophrenia, and 2) three anthropometric variables (height, head size, and head shape). Four single-nucleotide polymorphisms (SNPs; rs10735810/FokI, rsl544410/BsmI, rs7975232/ApaI, and rs731236/TaqI) in the VDR gene were genotyped in 179 individuals with schizophrenia and 189 healthy controls. No significant associations were detected between any of the four VDR SNPs and risk of schizophrenia. Patients were slightly but significantly shorter compared to controls. Of the four SNPs, only rs10735810/FokI was associated with any of the anthropometric measures: the M4 isoform of this SNP was significantly associated with larger head size (P = 0.002). In light of the evidence demonstrating a role for vitamin D during brain development, the association between polymorphisms in VDR and brain development warrants closer scrutiny.

COOPERATIVA DE TRABALHO COMO OPÇÃO DE INCLUSÃO SOCIAL: O CASO AMIGOS DO LIXO

O movimento de cooperativas populares vem crescendo exponencialmente nós últimos anos. Como forma de organização alternativa à crise do desemprego, as cooperativas atendem não só às camadas de base popular, mas também a um contingente expressivo de trabalhadores qualificados e com um bom padrão de vida. O estudo de caso foi realizado em numa cooperativa popular Amigos do Lixo , localizada na cidade de Guaratinguetá SP. A metodologia utilizada foi o estudo de caso único, como técnicas de coleta de dados, observação direta, análise de documentos e entrevistas com cooperados e gestor. O objetivo geral foi analisar se a Cooperativa de Trabalho citada atua como geradora de trabalho e renda. Procurou-se descrever os principais conceitos que definem a Economia Solidária e a Cooperativa de trabalho. A questão foi analisada por meio da investigação das percepções das condições de vida dos cooperados antes e após o ingresso nas respectivas cooperativas.

A GESTÃO DE RECURSOS HUMANOS: PERFIL ESTRATÉGICO OU OPERACIONAL?

Este trabalho tem como objetivo examinar o estágio atual do processo de desenvolvimento da função de Recursos Humanos (RH) e se esses papéis, ainda requeridos ou já existentes, atendem às expectativas dos diversos estratos envolvidos, auxiliando na busca de melhores resultados para as empresas e os que nelas trabalham. Nesse contexto, baseou-se na premissa de que as crescentes alterações sócio-culturais e o constante avanço tecnológico experimentado no mundo, além das modificações das condições de vida, permeiam e alteram as condições de trabalho e expectativas de convivência entre as pessoas e suas organizações, exigindo que a função Recursos Humanos busque alternativas de ação para alinhar suas estratégias às das organizações onde atua e fazendo com que o sistema de gestão de pessoas seja fonte de vantagem competitiva sustentável. Buscou-se analisar se o que uma organização faz e como o faz é fator que a distingue das demais, se sua especialização e habilidades deixam-na mais capaz, se é essa capacidade que a torna essencialmente mais competente e técnica e se, nesse quadro, o posicionamento postural de Recursos Humanos é adequado. Também procurou analisar a atuação de diversos públicos de interesse, como os envolvidos nas atividades trabalhistas-sindicais e se os novos elementos da governança corporativa são definidores de atuação estratégica para os profissionais da área estudada. Dentro dos conceitos acima, verificaram-se teorias e fatos, além de pesquisa, que resumissem e explicassem o que se sabe sobre o objeto estudado, classificando-os e sistematizando-os conforme apresentados na realidade empírica e selecionando aqueles a serem estudados, na tentativa de buscar e prever novas caracterizações dos papéis desempenhados por Recursos Humanos, que melhor os clarifiquem. A análise dos levantamentos teóricos realizados reforçou a importância das vantagens competitivas para o sucesso empresarial e a necessidade de que pessoas de conhecimento tornem-se mais produtivas na busca dessas vantagens, além de constatar que essas pessoas devem estar preparadas para atuar em contextos exigentes e complexos e o alerta de que a atuação estratégica de RH é fundamental na solidificação desse novo perfil dos empregados. As diversas funções operacionais atribuídas a Recursos Humanos, entre elas a administração da infra-estrutura e o gerenciamento da contribuição dos funcionários, devem complementar-se, agora, com as chamadas funções estratégicas, geradoras de valor, destacando-se o auxílio na definição das estratégias empresariais e sua tradução em ações de transformação e mudança. Mais do que isso se verificou a crescente preocupação de autores em aliar os recentes conceitos de governança corporativa a essa função estratégica de Recursos Humanos.(AU)