Les interactions avec les parents jouent un rôle formateur dans le développement et l’apprentissage du langage chez le jeune enfant. En effet, la quantité et le style de langage utilisés par les parents influencent la qualité de l’interaction et par là même la façon dont le langage de leur enfant évolue (Gallaway et Richards, 1999). Toutefois, cette évolution diffère selon les classes sociales et ce dès leur plus jeune âge (avant l’entrée à l’école élémentaire). D’un côté, les enfants de classe favorisée présentent une grande diversité lexicale car ils sont exposés à un discours riche en informations relatives à diverses situations. En revanche, les enfants, issus de classe défavorisée, présentent un retard en ce qui concerne les aptitudes langagières (Hoff, 2003 ; Feldman et al., 2000), car ils sont confrontés à des modèles d’apprentissages moins élaborés. En effet, les années préscolaires sont primordiales pour le développement lexical du jeune enfant d’autant plus, qu’à l’âge de 5 ans, il se prépare à entrer à l’école élémentaire. Il est donc nécessaire d’étudier l’influence de l’environnement scolaire et notamment l’interaction enseignant-enfant sur les performances verbales des enfants dans le but de leur garantir une meilleure intégration scolaire ensuite. Notre intérêt dans cette étude porte donc sur le rôle de l’école maternelle dont l’objectif majeur est la maîtrise du langage oral. Il apparaît opportun de prendre en compte, dans le cadre des apprentissages scolaires, les difficultés ainsi que les compétences de l’enfant pour l’aider à progresser (Florin, 2002). Notre recherche, réalisée auprès d’une population composée de 131 enfants âgés de 5 ans et de leurs 8 enseignantes, vise à comprendre si l’interaction enseignant-enfant a un impact sur les performances verbales des enfants et si cette interaction contribue à réduire les écarts de performances verbales langagières entre les enfants issus de classes sociales favorisée et défavorisée. / Interactions between the parents and the child have positive effects on the development and language learning amongst young children. The quality of interaction with the child is based on the amount and the quantity of the language style used by parents when addressing the child; which seems very important on language development (Gallaway et Richards, 1999).Children stemming from a privileged social class exhibit high lexical diversity. They are exposed to rich discourse information on various situations. Meanwhile, children from a disadvantaged social class are confronted-even before going to school-to different learning models and display a delay regarding language skills compared to their peers (Hoff, 2003 ; Feldman et al., 2000), even though the preschool years are important in the child lexical development. At age 5, the child is getting ready for elementary school, hence the importance of taking into account the influence of school environment, especially the interaction with the teacher on children verbal performance in order to ensure better school integration later.Our interest in this study focuses on the school environment whose major goal is to promote language proficiency, as it is a perquisite for school success. Hence, it seems appropriate to consider, in the context of school learning, the difficulty and the child’s skills in order to help them to progress (Florin, 2002). The main goal of our study, conducted among 131 5-year-old children and their eight teachers, is to underlie the importance of the school environment and particularly the interaction with the teacher on the development of the vocabulary at the preschooler age. Our goal is to determine if the teacher-child interaction has a positive impact on the child's verbal performance, and whether this interaction helps to reduce the gap on verbal achievement between children stemming from privileged and disadvantaged social classes.

A Lipodistrofia Parcial Familiar tipo 2 (FPLD2) é caracterizada pela perda do tecido adiposo em extremidades, adiposidade central, resistência insulínica e elevado risco cardiovascular. FPLD2 apresenta semelhanças clínicas com a síndrome de Cushing, tanto pelo padrão de distribuição adiposa quanto pelos distúrbios metabólicos que a acompanham, sugerindo a possibilidade do envolvimento dos glicocorticoides (GC) na patogênese das alterações metabólicas na FPLD2. Objetivos: Avaliar a heterogeneidade fenotípica e a sensibilidade aos GC em pacientes com FPLD2 portadores de duas diferentes mutações do gene LMNA: a p.R482W ou a p.R644C. Pacientes e Métodos: Estudo observacional analítico de caso-controle realizado no Hospital das Clínicas de Ribeirão Preto. Os portadores de FPLD2 (n=24) e indivíduos saudáveis (n=24) foram avaliados quanto a parâmetros antropométricos, composição corporal, perfil metabólico e níveis plasmáticos de adipocinas e citocinas plasmáticas. Cortisol plasmático e salivar foram dosados em condições basais e após três diferentes doses de dexametasona (DEX - 0,25; 0,5 e 1,0 mg) administrada às 23h. A expressão gênica das isoformas ? e ? dos receptores do glicocorticoide (GR) e da 11?-hidroxiesteróide desidrogenase tipo 1 e 2 (11?-HSD1 e 11?-HSD2 ) foi avaliada por qPCR. Resultados: Os portadores de FPLD2 apresentaram aumento de circunferência abdominal e cervical e redução da circunferência de quadril, das pregas cutâneas periféricas e da massa adiposa corporal. Os pacientes apresentaram elevados níveis de HOMA, triglicerídeos, TNF-?, IL-1?, IL-6 e IL-10, e redução dos níveis plasmáticos de adiponectina e leptina. Após 0,5 mg de DEX, o cortisol salivar apresentou-se menos supresso em portadores de FPLD2. As características clínicas e bioquímicas foram mais evidentes nos portadores da mutação p.R482W do LMNA em comparação aos portadores da mutação p.R644C. Não observamos diferenças quantoà expressão dos genes GR?, GR?, 11?-HSD1 e11?-HSD2 entre os grupos. Conclusões: A heterogeneidade fenotípica identificada entre os portadores de FPLD2 está associada ao local da mutação no gene LMNA. Observamos menor habilidade de supressão do eixo HPA após 0,5 mg DEX em portadores de FPLD2, sendo que essa dose foi a mais efetiva para a avaliação do espectro de sensibilidade aos GC entre os grupos. Em portadores de FPLD2, o estado pró-inflamatório está relacionado à redução da sensibilidade do eixo hipotálamo-hipófise-adrenal (HPA) aos GC. / Familial partial lipodystrophy type 2 (FPLD2) is characterized by insulin resistance, adipose atrophy of the extremities, and central obesity. Due to the resemblance with Cushing´s syndrome, we hypothesized a putative role of glucocorticoid (GC) in the pathogenesis of metabolic abnormalities in FPLD2. Objective: To evaluate the phenotypic heterogeneity and GC sensitivity in FPLD2 patients exhibiting the p.R482W or p.R644C LMNA mutations. Design, Setting and Participants: Prospective study with FPLD2 patients (n=24) and controls (n=24) at Ribeirao Preto Medical School University Hospital. Intervention and Main Outcome Measures: Participants underwent anthropometric, body composition, metabolic profile, plasma adipokines and cytokines measurements. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5, and 1.0 mg of dexamethasone (DEX) given at 2300h. Glucocorticoid receptor and 11?HSD isoforms expression were assessed by qPCR. Results: FPLD2 individuals presented increased waist and neck circumferences, decreased hip circumference, peripheral skinfold thickness, and fat mass. Patients presented increased HOMA and triglycerides, increased TNF-?, IL-1?, IL-6, and IL-10, and decreased plasma adiponectin and leptin levels. After 0.5mg DEX, salivary cortisol was less suppressed in FPLD2 patients. The clinical and biochemical phenotypes were more pronounced in patients harboring the p.R482W LMNA mutation. No differences were observed in the GR?, GR?, 11?-HSD1, and 11?-HSD2 expressions. Conclusions: FPLD2 patients exhibited phenotypic heterogeneity related to LMNA mutations. Patients showed less ability to suppress cortisol after 0.5 mg DEX, which was the most effective dose to expose the spectral HPA axis sensitivity among groups. Increased levels of proinflammatory cytokines might contribute to decreased GC sensitivity in FPLD2.

O receptor sensor do cálcio (CASR) desempenha um importante papel na manutenção da concentração plasmática do cálcio. Desde a sua descrição, mais de 200 mutações foram descritas podendo levar à perda ou ao ganho de função, resultando em situações de hiper ou hipocalcemia, respectivamente. Mutações inativadoras estão associadas à hipercalcemia hipocalciúrica familiar (HHF) e ao hiperparatireoidismo neonatal grave (HPTNG), enquanto que mutações ativadoras estão associadas à hipocalcemia autossômica dominante (HAD) e à Síndrome de Bartter tipo V. O objetivo deste estudo foi realizar o diagnóstico molecular, por meio da análise do gene CASR, em pacientes com HPTNG, HHF, hipocalcemia com PTH inapropriadamente normal ou baixo e hipoparatireoidismo idiopático com hipercalciúria na vigência de tratamento. Para cada criança (n = 2) com diagnóstico clínico e laboratorial de HPTNG, uma mutação \"nonsense\" em homozigose foi identificada na região codificadora do CASR (p.E519X e p.R544X). O estudo molecular dos pais das crianças mostrou tratar-se de casos herdados caracterizando-os como indivíduos com HHF e possibilitou o aconselhamento genético para estas famílias. Mutações pontuais em heterozigose na região codificadora do CASR (p.R25X, p.R69H, p.T627I) foram detectadas em três dos quatro pacientes selecionados com diagnóstico inicial de hiperparatireoidismo primário e bioquímica compatível com hipercalcemia hipocalciúrica. Estes achados constituem a base molecular da HHF e permitiram o rastreamento de outros casos de HHF nas respectivas famílias com impacto na abordagem terapêutica dos mesmos. Na paciente em que não foi detectada nenhuma mutação na região codificadora do CASR, o estudo prosseguiu com a pesquisa de alterações no número de cópias gênicas e de mutações nas regiões promotoras P1 e P2 como possíveis causas do fenótipo em questão. O resultado destas abordagens foi normal. Dos quatro pacientes selecionados com quadro de hipoparatireoidismo idiopático e hipercalciúria na vigência de tratamento, em apenas uma, a causa molecular foi definida por mutação \"missense\" em heterozigose na região codificadora do CASR (p.E767K) repercutindo positivamente no seu tratamento. Nos demais casos (n = 3), a pesquisa de alterações no número de cópias gênicas e de mutações nas regiões promotoras P1 e P2 também resultou normal. / The calcium sensing receptor (CASR) plays an important role in maintaining the plasma concentration of calcium. From its first description, more than 200 mutations have been described leading to loss or gain of function, resulting in conditions of either hyper or hypocalcemia, respectively. Inactivating mutations are associated with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), whereas activating mutations are associated with autosomal dominant hypocalcemia (ADH) and type V Bartter\'s syndrome. The aim of this study was to perform the molecular diagnosis, by analyzing the CASR gene, in patients with NSHPT, FHH, hypocalcemia with inappropriately normal or low PTH and idiopathic hypoparathyroidism with hypercalciuria during treatment. In every child (n = 2) with clinical and laboratory diagnosis of NSHPT, a nonsense mutation in homozygosity was identified in the coding region of the CASR (p.E519X and p.R544X). The molecular analysis of the child\'s parents showed that they were inherited cases qualifying them as individuals with FHH and it enabled a genetic counseling for these families. Point mutations in heterozygosity in the coding region of the CASR (p.R25X, p.R69H, p.T627I) have been detected in three out of the four selected patients with an initial diagnosis of primary hyperparathyroidism and biochemistry compatible with hypocalciuric hipercalcemia. These findings are the molecular basis of FHH and allowed the screening of other FHH cases in these families impacting on their therapeutic approach. In patients where no mutation in the coding region of the CASR was detected, the study went on researching for changes in the number of gene copies and mutations in P1 and P2 promoter regions as possible causes to the phenotype in question. The result of these approaches has been normal. The molecular cause has been defined as missense mutation in heterozygosis in the coding region of the CASR (p.E767K) in only one out of the four selected patients with idiopathic hypoparathyroidism and hypercalciuria during treatment, with a positive impact on her treatment. In the other cases (n = 3), the search for changes in the number of gene copies and mutations in the P1 and P2 promoter regions was normal.

Confronter le lien familial au droit pénal peut sembler paradoxal. La contradiction s'efface cependant devant le caractère inéluctable et nécessaire de cette rencontre. L'étude de l'impact spécifique de la présence du lien de famille sur les règles répressives s'inscrit dans une perspective pluridisciplinaire et propose de mettre en présence deux objets dont les frontières évoluent constamment. À travers une double perspective d'observation et de prospection, cette recherche propose d'analyser le phénomène actuel de mutation de la protection pénale de la famille et de découvrir les principes qui lui sont propres, dans le but de mieux le saisir et de pouvoir en réorienter les applications futures. L'examen révèle l'existence d'un désintérêt répressif global à l'encontre du lien familial à l'endroit où sa prise en compte constitue un atout fondamental pour l'édification et la mise en œuvre cohérente des règles pénales. Cette étude propose d'analyser l'arsenal répressif existant et se donne pour objectif l'édification théorique d'une classification inédite des infractions familiales. La réalisation d'une typologie fonctionnelle de l'infraction familiale en droit pénal permet de pouvoir lui attribuer un outil de traitement procédural adapté à ses spécificités et d'aboutir à la mise en œuvre d'une politique pénale familiale spécifique. Cette ambition questionne la réalité du lien familial pénal et appelle, d'une part, à réinsérer le droit pénal dans le lien familial au stade de la classification des infractions familiales, et, d'autre part, à intégrer le lien familial dans le droit pénal au stade du traitement des infractions familiales. / Studying the family link from a criminal law perspective may seem paradoxical at first sight. Yet this is not the case since the confrontation between these two concepts is as ineluctable as is it necessary. The examination of the impacts of the family link on the repressive rules falls within a multidisciplinary approach and sheds light on two conceptions, whose limits are constantly changing. The purpose of this study is to analyse the current phenomenon of transformation in the criminal protection of families through observation and research; and to break down the principles governing it, so as to better grasp the situation and to give a new orientation towards future implementations. The study reveals the existence of an overall disinterest of the repressive field in the family link precisely where its consideration is a fundamental criterion in the construction and consistent implementation of criminal rules. The purpose of this research is to analyse the existing body of repressive laws and regulations currently in use as well as to establish an unprecedented classification of family offenses. The creation of a functional typology of family offenses in criminal law will make it possible to provide tailored legal tools to deal with this dilemma and to implement a specific criminal policy regarding the family. This endeavour challenges the very existence of the family link in criminal justice and demands not only that it be reintegrated into criminal law at the initial stage of classifying family offenses, but also that it be subsequently taken into consideration when dealing with these offenses.

Les Troubles du Spectre de l’Autisme (TSA) impliquent un pronostic développemental sensiblement différent dépendamment de leur sévérité et des troubles associés. Les difficultés relationnelles, les comportements inadaptés et les besoins spécifiques de l’enfant ont des répercussions sur le fonctionnement familial et affectent le vécu des parents. Cette situation génère un stress conséquent qui peut potentiellement mettre à mal la cohésion dans le couple parental, affecter les interactions parent-enfant, détériorer le sentiment de compétence parentale et entraîner une perception amoindrie de la qualité des relations familiales. L’écologie sociale du milieu familial permet de questionner le lien entre le climat familial perçu par les mères, évalué par l’IRF (LARIPE, 1989), et le stress maternel perçu, mesuré par l’ISP/FB (Bigras, LaFrenière, & Abidin, 1996), en tenant compte de la singularité de l’expression du handicap de leur enfant, soit la sévérité du trouble autistique, déterminée par l’EEAI (Rogé, 1989), et la coexistence d’un trouble du langage et/ou d’une déficience intellectuelle associée définit antérieurement à l’étude par le diagnostic médical.Le niveau langagier a un impact élevé, tant sur l’âge d’alerte pour les parents, que sur l’âge de diagnostic pour les professionnels, et se révèle fortement associé à l’évaluation de la sévérité des troubles autistiques (N=65). Dépendamment du niveau de stress maternel perçu, en recourant à une classification hiérarchique ascendante basée sur les dimensions de l’ISP/FB, la qualité des relations familiales diffère significativement. Les mères les plus stressées perçoivent le climat familial comme étant plus conflictuel. En considérant à six mois d’intervalle le vécu maternel au niveau écosystémique plutôt que dyadique, l’intervention écologique par l’intégration d’un chien d’assistance de la Fondation MIRA (Québec) dans le groupe familial (n=24) permet une diminution concomitante du stress maternel relatif à la gestion des comportements difficiles de l’enfant et de la sévérité des troubles autistiques. En l’absence de différence au premier temps de mesure avec les mères en attente de service (n=26), les mères des familles bénéficiant d’un chien présentent moins de stress, tant globalement, qu’en ce qui concerne les interactions et l’éducation de l’enfant autiste, et perçoivent également un climat relationnel plus favorable. Les résultats obtenus mettent en évidence la contribution de la médiation animale à l’amélioration de la qualité de vie de l’ensemble des membres du microsystème familial, notamment en ce qui concerne la facilitation des interactions intra et extrafamiliales. / Autism Spectrum Disorders (ASD) involve a significantly different developmental prognosis depending on severity and associated disorders. Relationship difficulties, inadequate behaviours and the specific needs of the child have implications on family functioning and affect parents' experiences. This situation generates significant stress that can potentially undermine parental cohesion, affect parent-child interactions, impair parenting, and lead to lessened perceptions of the quality of family relationships. Considering the social ecology of the family environment allows us to question the relationship between the family climate perceived by mothers, evaluated by the IRF (LARIPE, 1989), and the perceived maternal stress, measured by the ISP/FB (Bigras, LaFrenière and Abidin, 1996), taking into account the singularity of disability, namely autistic disorder severity, determined by the EEAI (Rogé, 1989), and the coexistence of a language disorder and/or an associated intellectual impairment defined by medical diagnosis realized prior to study.Language competence has a high impact, both on the age of parental alert and age of diagnosis by professionals, and is strongly associated with the severity of autistic disorders evaluation (N=65). Depending on the level of perceived maternal stress, using a cluster analysis based on the dimensions of ISP/FB, the quality of family relationships differs significantly. The most stressed mothers perceive the family climate as more confrontational. By considering maternal experience at the eco-systemic level rather than dyadic, an ecological intervention by integrating a MIRA Foundation (Quebec) assistance dog into the family group (n=24) produced a concomitant decrease for maternal stress related to management of child's difficult behaviours and for severity of autistic disorders. In absence of differences in the first measurement time with mothers waiting for service (n=26), mothers in families with a dog are less stressed both overall, than for interactions and for education of the autistic child. They also perceive a more favourable relationship climate. Results obtained highlight the contribution of animal mediation to improving the quality of life of all members in the microsystem, particularly on intra and extra-familial interactions facilitation.

Die autosomal-dominant vererbte Familiäre Hypercholesterinämie ist durch eine exzessive Erhöhung der LDL-Serumcholesterinspiegel gekennzeichnet und bedingt aufgrund einer prämaturen Atherosklerose den frühzeitigen Tod der Patienten. Da ursächlich ein defekter LDL-Rezeptor (LDL-R) zugrundeliegt, der durch Mutationen im Bereich des LDL-R-Gens hervorgerufen wird, kommt der Gentherapie als potentieller Behandlungsmöglichkeit ein besonderer Stellenwert zu. Diese Arbeit untersuchte den Einfluß einer Virusdosiseskalation auf Cholesterinsenkung und Langzeitexpression im adenoviral vermittelten LDL-R-Gentransferversuch im Kaninchenmodell. Hierfür wurden 7 Watanabe Heritable Hyperlipidemic Kaninchen, welche an einer vergleichbaren kongenitalen Hypercholesterinämie durch einen LDL-R-Defekt leiden, mit unterschiedlichen Dosierungen eines Adenovirus des Serotyps 5 therapiert, der die Gensequenz für den humanen LDL-R enthielt. Vor und nach Therapie wurden Bestimmungen der Serumcholesterinkonzentrationen und LDL-Stoffwechselkinetiken mit 125I-LDL sowie semiquantitative szintigraphische Auswertungen durch 111In-LDL-Scans durchgeführt. Hierbei mußte festgestellt werden, dass die adenoviral vermittelte transgene Expression des LDL-R durch die Bestimmung des Serumcholesterins nicht korrekt wiedergegeben wird. Denn zum einen konnte bei der Bestimmung des Serumcholesterins ein dosisabhängiger Effekt beobachtet werden, dieser zeigte sich bei den Stoffwechselkinetiken mit 125I-LDL und bei den Scanuntersuchungen mit 111-In-LDL jedoch nicht. Zum anderen kam es innerhalb von 12-18 Tagen nach Gentransfer zu einem Wiedererreichen der Serumcholesterinausgangswerte, wohingegen die in vivo-Stoffwechselkinetiken eine erhöhte Abbaurate radiomarkierter LDL und die Szintigraphie eine LDL-R-Expression über die gesamte Dauer des Experimentes von 120 Tagen belegten. / Familial hypercholesterolemia is an autosomal dominantly inherited disease characterized by an exzessive elevation of serum LDL cholesterol which leads to premature atherosclerosis and an early death of the patients. As the reason is a defective LDL receptor (LDLR) caused by mutations in the gene encoding LDLR, gene therapy plays an increasingly important role as a treatment possibility. This paper examined the influence of an escalation of the virus dose on the cholestorol reduction and long-term expression in the adenovirally mediated LDLR gene therapy experiment using a rabbit animal model. To facilitate this 7 Watanabe Heritable Hyperlipidemic rabbits, suffering from an equivalent congenital hypercholesterolemia due to a LDLR defect, were treated with different doses of a serotype 5 adenovirus which contained the gene sequence of the human LDLR. Pre and post gene therapy measurements of the serum cholesterol levels and kinetics of LDL metabolism with 125I-LDL were performed, as well as semiquantitative scintigraphic analysis of 111In-LDL scans. The finding was that the adenovirally mediated transgene expression of the LDLR was not correctly reflected by the measurement of the serum cholesterol levels. This was because of a dose dependant effect concerning the measurements of the serum LDL cholesterol levels, which did not appear regarding the kinetics of LDL metabolism with 125I-LDL and the scans with 111In-LDL. Moreover, the serum cholesterol levels reached their initial value within 12-18 days post gene transfer whilst the in vivo-kinetics of LDL metabolism showed an increased catabolic rate of radiolabeled LDL and the scintigraphy indicated a LDLR expression for the whole period of the experiment lasting 120 days.

A osteoporose é uma doença de alta prevalência na população geral, e a ocorrência de fraturas se associa a grande morbi-mortalidade e impacto econômico. Na maioria dos indivíduos afetados, a osteoporose tem etiologia multifatorial, com herdabilidade estimada entre 50 e 85%, atribuível a um conjunto de variantes genéticas de pequeno efeito individual. Raramente, há casos de osteoporose associada a síndromes monogênicas, decorrentes de defeitos genéticos de grande impacto. Postula-se que indivíduos com quadros extremos de osteoporose não sindrômica possam ter causa genética mono- ou oligogênica, atribuível a variantes de impacto intermediário sobre o fenótipo, ainda pouco reconhecidas. Nos últimos anos, o avanço das tecnologias de sequenciamento permitiu o reconhecimento de novos genes associados à fragilidade óssea e atualmente possibilita a análise simultânea de múltiplos genes. Neste contexto, os objetivos deste projeto de pesquisa foram: 1) buscar genes candidatos para fragilidade óssea previamente associados a doenças Mendelianas com alto impacto na resistência óssea, fenótipos extremos de osteoporose e estudos de associação genética em escala genômica (GWAS) para osteoporose; e 2) pesquisar a presença de variantes alélicas patogênicas nestes genes candidatos em indivíduos com osteoporose grave, familiar ou idiopática. A partir de revisão sistemática, 128 genes candidatos foram selecionados para compor um painel de sequenciamento paralelo em larga escala. O sequenciamento incluiu todos os éxons e 25 pares de bases das junções íntron-éxon. Foram consideradas variantes genéticas de interesse aquelas raras (frequência alélica < 1%) e com predição de alto impacto sobre a proteína codificada. Trinta e sete indivíduos (7 famílias e 21 casos isolados) foram selecionados seguindo critérios clínicos, laboratoriais e densitométricos restritivos, excluindo-se pacientes com causas secundárias de osteoporose. A coorte foi composta por homens em 54%, a mediana de idade ao diagnóstico foi 44 anos e 86% tinham histórico de fratura. Dentre os 28 casos índices, foram identificadas 33 variantes de interesse. Após análise de segregação familiar, foi possível excluir patogenicidade de cinco destas variantes, restando 28 variantes potencialmente patogênicas, presentes em 71% da coorte. Todas as variantes foram encontradas em heterozigose, sendo 26 variantes de ponto não-sinônimas, uma deleção de 9 pares de bases, e uma grande deleção envolvendo o único éxon codificador do gene candidato GPR68. Foi encontrada uma associação de variantes em genes diferentes em 21% da coorte, incluindo uma mulher jovem com osteoporose grave e variantes em WNT1, PLS3 e NOTCH2. A análise de segregação familiar neste caso sugeriu um efeito patogênico aditivo das variantes. Vinte e cinco porcento das variantes potencialmente patogênicas foram identificadas em genes candidatos bem estabelecidos (WNT1, PLS3, COL1A1, COL1A2), e 57% se localizam em novos genes candidatos identificados inicialmente por GWAS, como NBR1 e GPR68, também associados à alteração da remodelação óssea em modelos animais. Os resultados deste trabalho dão relevância a novos genes na fisiologia da resistência óssea e indicam um papel proeminente de interações digênicas/oligogênicas em casos de osteoporose grave, familiar ou idiopática. O reconhecimento de novas vias associadas à fragilidade óssea pode levar ao desenvolvimento de novos tratamentos, e a identificação de variantes patogênicas associadas à osteoporose pode, futuramente, permitir um manejo clínico personalizado de pacientes e seus familiares / Osteoporosis is a highly prevalent disorder resulting in fragility fractures and incurring in great morbi-mortality and economic burden. In most cases, osteoporosis has a multifactorial etiology, with an estimated heritability of 50-85% attributable to a combination of several low-impact genetic variants. Rarely, cases of syndromic osteoporosis due to high-impact genetic defects are seen. It is therefore hypothesized that severe/idiopathic cases of otherwise inconspicuous osteoporosis may have a monoor oligogenic etiology due to genetic variants with an intermediate effect. During the past years, advances in molecular sequencing have revealed novel candidate genes for bone fragility, and have enabled simultaneous sequencing of multiple genes. In this context, the objectives of this research project were: 1) to identify candidate genes for bone fragility, as previously reported in association to Mendelian disorders with high impact on bone resistance, idiopathic or familial osteoporosis, and genome-wide association studies (GWAS) for bone mineral density and fragility fractures; and 2) to perform molecular analysis of these candidate genes in patients with severe, familial or idiopathic osteoporosis. Through a systematic review, 128 candidate genes were identified and included in a panel for massively parallel sequencing. Coding regions and 25-bp boundaries were captured and sequenced. Rare variants (allele frequency < 1%), with a predicted high impact on protein function were initially selected as variants of interest. Thirty-seven subjects (21 sporadic cases and 7 families) were included according to stringent criteria based on clinical and densitometric evaluation, excluding individuals with secondary osteoporosis. Males represented 54% of the cohort, median age at diagnosis was 44 years, and 84% of subjects had a history of fractures. Thirtythree variants of interest were identified initially. After familial segregation analysis, 5 variants were considered as benign in regard to bone fragility, resulting in 28 potentially pathogenic variants, all heterozygous, present in 71% of the cohort. Of these variants, 26 were nonsynonymous, there was one 9-bp deletion and one large deletion involving the only coding exon of candidate gene GPR68. An association of two or more variants in different genes was present in 21% of the cohort, including a young woman with severe osteoporosis and variants in WNT1, PLS3 and NOTCH2. Familial segregation in this case suggested an additive pathogenic effect of these variants. Twenty-five percent of potentially pathogenic variants were identified in well-established candidate genes (WNT1, PLS3, COL1A1, COL1A2), and 57% located to novel candidate genes initially identified by GWAS, such as NBR1 and GPR68, which have been previously associated to changes in bone remodeling in mouse models. These results support the involvement of GWAS genes in the pathophysyiology of osteoporosis, and indicate a prominent role for digenic/oligogenic interactions in cases of severe, familial or idiopathic osteoporosis. Recognition of new molecular pathways in the determination of bone fragility may lead to the development of new drugs, and the identification of pathogenic variants associated to osteoporosis may allow individualized clinical management of patients and their relatives

Made available in DSpace on 2016-08-10T10:32:15Z (GMT). No. of bitstreams: 1 HELOIZA ALVES RIBEIRO.pdf: 1313749 bytes, checksum: 3b3e9f568efcb5c959c8490eef6a6aad (MD5) Previous issue date: 2014-04-03 / In this dissertation the analysis is focused on the study case of a research developed during a Master´s Degree course in Social Sciences Studies at PUC Goiás, which was aimed on the theoretical, conceptual, and socio-historical references that scientifically validate the principle of social familial matrix system, adopted by PNAS/SUAS. It consist in analyzing the conceptual and practice developed by the professionals, at the Social Assistance Reference Center (CRAS) in Goiania, through interventions done in the basic social protection field, aimed at the qualifying of the services and the effectiveness of social rights. The research was conducted in a quantitative and qualitative basis. The first dimension was configured in a bibliographical revision over the work produced in the Social Services area, in the policies of social assistance, family, the social familial matrix system, and other complementary areas. The main sources were: national and international literature, as well as documental and historical bibliographic registers, also in the implantation and implementation processes of social assistance policies in Goiania. Data was collected from the Municipal Secretariat of Social Assistance (SEMAS) of Goiania. The field research was performed at the working site of the professionals (CRAS). This study is corroborated with the analysis which recognizes that the social assistance policies are not, by themselves, resolving, and, therefore, there are enormous challenges to be overcome, from their formulation to the socio-care actions, which means to recognize the existing tensions in the working process in this field. The result of this process may express the level of theoretical appropriation and ethical-political positioning of the professional, aimed at his/her identification with a specific social project that is equalitarian and emancipator, grounded a logic of rights, or not. / Na presente dissertação a análise recai sobre o objeto de estudo da pesquisa desenvolvida durante o Mestrado em Serviço Social na PUC Goiás que, à luz das referências teórico-conceituais e sócio-históricos que cientificam o princípio de matricialidade sociofamiliar adotado pela PNAS/ SUAS, analisam a concepção e a prática desenvolvidas pelos (as) profissionais nos Centros de Referência de Assistência Social (CRAS), em Goiânia. Foram priorizadas as intervenções realizadas no campo da proteção social básica, com vistas à qualificação dos serviços e efetivação de direitos sociais. A condução da pesquisa foi de natureza qualitativa e quantitativa. A primeira dimensão configurou-se na revisão bibliográfica sobre as produções na área do Serviço Social, da política de assistência social, da família, da matricialidade sociofamiliar e outras áreas complementares. As principais fontes foram: literatura nacional e internacional, bem como pesquisa documental e bibliográfica dos registros históricos, como também o processo de implantação e implementação da política de assistência social em Goiânia, município em que foi realizada a pesquisa. Foram coletados dados da Secretaria Municipal de Assistência Social (SEMAS) de Goiânia. A pesquisa de campo foi realizada nos locais de trabalho dos profissionais, ou seja, nos CRAS. Neste estudo corrobora-se com as análises que reconhecem que a política de assistência social não é por si só resolutiva e, por isso, há grandes desafios a serem superados, desde sua formulação à execução das ações socioassistenciais, o que significa reconhecer as tensões existentes no processo de trabalho nesse campo. O resultado desse processo deverá expressar o nível de apropriação teórica e o posicionamento éticopolítico do (a) profissional, tendo em vista, sua identificação com um determinado projeto societário que seja igualitário e emancipador, ancorado na lógica do direito, ou não.

Made available in DSpace on 2016-04-04T18:27:34Z (GMT). No. of bitstreams: 1 EDSON OLIVEIRA.pdf: 495828 bytes, checksum: 142be76be6b90a5bcd810994694833f6 (MD5) Previous issue date: 2004-12-21 / Searching to appoint the paper of the desprotection in the occurrences of domestic sexual abuse, proceeded it the descriptive analysis from found these occurrences in findings of psychological studies carried through by judiciary psychologists, members of the team technique s judiciary psychology of one of the circumscriptions of the Court s Justice of the S?o Paulo s State. In elapsing of the analysis one was identified 34 victims and one chose 16 class of information, from which was possible according to the duration period of the domestic sexual abuse. Getting 9 domestic sexual abuse of only episode; 9 in a short period and 16 in a drawn out period. One proved that the prolongation of the abuse is an indicating insurance of the occurrence of the maternal connivance, however, not if it could affirmed that this is essential so that the abuse if draws out. It can be proven that the maternal connivance happens correlated with the interests and concerns of the mother with the family s preservation and the children s sustenance, however, its understanding cannot do without the collective s recognition of the indignification of the separate woman and with children and of the single woman with children. One identified three correlated groupality s familial configuration with the occurrences of domestic sexual abuse, being common integration relations between them. It is pointed the dignification of the separate woman with children and of the single woman with children as a psicossocial intervention to able to stimulate the revelation and to prevent the occurrences of domestic sexual abuse. / Buscando apontar o papel da desprote??o nas ocorr?ncias de abuso sexual dom?stico, procedeu-se ? an?lise descritiva de tais ocorr?ncias em laudos de estudos psicol?gicos. Os laudos foram produzidos por psic?logos judici?rios, membros da equipe t?cnica de psicologia judici?ria de uma das circunscri??es do Tribunal de Justi?a do Estado de S?o Paulo. No decorrer de an?lise descritiva identificou-se 34 v?timas e elegeu-se 16 classes de informa??es, a partir das quais foi poss?vel agrupar as vitimiza??es segundo o per?odo de dura??o. Obtendo-se 9 vitimiza??es de epis?dio ?nico; 9 de per?odo curto e 16 de per?odo prolongado. Comprovou-se que o prolongamento do abuso ? um indicador seguro da ocorr?ncia da coniv?ncia materna, entretanto, n?o se p?de afirmar que esta seja imprescind?vel para que o abuso se prolongue. Pode-se comprovar que a coniv?ncia materna acontece correlacionada a interesses e preocupa??es da m?e com a preserva??o da fam?lia e com o sustento dos filhos, entretanto, sua compreens?o n?o pode prescindir do reconhecimento da indignifica??o coletiva da mulher separada e com filhos. Identificou-se tr?s configura??es da grupalidade familiar correlacionadas ?s ocorr?ncias de abuso sexual dom?stico, sendo comum rela??es de complementariedade entre elas. Aponta-se a dignifica??o da mulher separada e com filhos como uma interven??o psicossocial capaz de estimular a revela??o e de prevenir as ocorr?ncias de abuso sexual dom?stico.

A hipercolesterolemia familiar (HF) é uma alteração de origem genética comum que pode se manifestar clinicamente desde o nascimento e provoca um aumento nos níveis plasmáticos de LDL-colesterol (LDL-c), xantomas e doença coronária prematura. Sua detecção e tratamento precoce reduzem a morbidade e mortalidade coronária. A identificação e rastreamento em cascata familiar usando níveis de LDL-c e detecção genética é a estratégia mais aconselhável e rentável para descoberta de novos casos. O tratamento crônico com estatinas reduz o risco cardiovascular da população em geral, contudo, estudos clínicos com estatinas revelam risco cardiovascular residual mesmo após correção das concentrações de LDL-c. Com o surgimento de novas drogas e mais recentemente um inibidor da enzima pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9), este estudo enfatizou na investigação específica para aqueles acometidos com defeitos genéticos nessa enzima, por ser de frequência ainda mais rara e pouco estudada, necessitando de melhor investigação na população em estudo a fim de rastrear a ocorrência de mutações patológicas na PCSK9. O objetivo desse estudo foi identificar e caracterizar mutações e/ou deleções patológicas no gene PCSK9 em pacientes com Hipercolesterolemia Familiar provenientes do Hospital das Clínicas de Ribeirão Preto da FMRP/USP selecionados para o teste genético. Foi feito o rastreamento de mutações pelo método Hight Resolution Melting (HRM), de forma prática, rápida e eficiente, onde mutações detectadas foram seqüenciadas. Foram identificadas 7 mutações não patogênicas, caracterizando que a população estudada não apresenta Hipercolesterolemia Familiar associada a mutações no gene PCSK9, fato que não exclui o diagnóstico por outros defeitos genéticas associados a doença. / Familial hypercholesterolemia (FH) is an alteration of common genetic origin that can manifest clinically from birth and which causes an increase in the LDL-cholesterol plasma levels (LDL-c), xanthomas and premature coronary disease. Its early detection and treatment reduce morbidity and coronary mortality. The identification and tracking in familial cascade using levels of LDL-c and genetic detection is the most advisable and profitable strategy to find new cases. The chronic treatment with statins reduces the cardiovascular risk in the population in general. However, clinic studies on statins show a residual cardiovascular risk even after the correction of LDL-c concentrations. With the appearance of new drugs and, more recently, of a proprotein convertase subtilisin/kexin type 9 enzyme inhibitor (PCSK9), this study highlighted the specific investigation for those stricken by genetic defects in this enzyme, once it is even rarer and understudied and needs further investigation in the study\'s population aiming at tracking the occurrence of a pathological mutation in the PCSK9. This study aimed at identifying and characterizing mutations and/or pathological deletions in the PCSK9 gene in patients with Familial Hypercholesterolemia from the RPMS/USP Ribeirão Preto Clinical Hospital which were selected for the genetic test. We performed the mutation tracking by using the High Resolution Melting (HRM) method in a practical, fast and efficient way, where the mutations detected were sequenced. We identified 7 non-pathogenic mutations, showing that the population studied does not present Familial Hypercholesterolemia associated to mutations in the PCSK9 gene, which doesn\'t exclude the diagnosis by other genetic defects associated to the disease.