Current research in the field of emotions has demonstrated a strong causal correlation between stressful life events and clinical depression. The conceptual framework of this scientific study is taking into consideration the theoretical ideas developed by the laboratories of Alex Zautra, and Susan Folkman about the co-existence of positive and negative emotions during the experience of stress and depression. The principal purpose of this study is to report the convergent validity of the Multicultural State-Trait Depression Inventory, which supports the new direction in the psychometric assessment of clinical depression. Responses to the items of the state and trait scales were analyzed on a multicultural sample to determine the convergent validity and item analysis of the instrument. The results present empirical evidence that demonstrates a high degree of concurrent validity of the IMUDER subscalesand the reference instruments as shown by Pearson correlations. / Los estudios científicos de las emociones han demostrado concluyentemente una robusta relación causal entre eventos estresantes de la vida diaria y la depresión clínica. El marco conceptual del presente estudio toma en consideración los marcos teóricos de Alex Zautra y de Susan Folkman acerca de la coexistencia de emociones positivas y negativas en el proceso de estrés y depresión. El propósito de este estudio es reportar el análisis de ítems y la validez convergente del Inventario Multicultural de la Depresión, Estado-Rasgo (IMUDER). En base a una muestra multicultural, se realizó los análisis psicométricos en base al coeficiente de correlación de Pearson, a fin de determinar la validez convergente. Los resultados de dichos análisis realizados en forma separada para la escala estado y para la escala rasgo, nos indican un elevado nivel de asociación y validez convergente entre las escalas estado y rasgo del IMUDER, dimensiones de distres y eustres, y las pruebas de depresión utilizadas en este estudio. Estos datos indican que el IMUDER es un instrumento psicométrico que presentauna sólida validez convergente y propiedades psicométricas adecuadas.

O comportamento do escoamento supersônico no interior de bocais convergente-divergente retangulares é investigado numericamente, comparando-se quatro bocais com diferentes seções divergentes, com a mesma razão de aspecto AR=1.14 e mesma relação áreas da saída e da garganta dos bocais NAR=1.43. Os bocais são submetidos a diferentes pressões de admissão do fluido de trabalho, mantendo-se a relação entre a pressão de admissão e de descarga constante NPR=5. As simulações consideram o escoamento em regime permanente, compressível, viscoso, com abordagem baseada na massa específica (abordagem acoplada) , juntamente com o modelo de turbulência − /SST. A qualidade dos resultados é medida empregando-se três níveis de refino da discretização do domínio computacional, observandose a ordem de convergência e o índice de convergência de malhas GCI. Os resultados numéricos mostram que o número de Mach e a temperatura do fluido de trabalho independem da pressão de admissão, ao contrário do comportamento da pressão local e da massa específica. As propriedades do escoamento são fortemente dependentes da variação da geometria, e a variação do ângulo da seção divergente provoca uma mudança direta do número de Mach e inversa da pressão, da temperatura e da massa específica do escoamento no interior dessa seção. As simulações são comparadas com os resultados da teoria isentrópica e mostram que a linha sônica é deslocada do centro geométrico da garganta dos bocais para cada geometria simulada. A comparação com a teoria e com dados experimentais mostra desvios inferiores a 6x10-3 %. O uso do modelo de turbulência − / SST é capaz de resolver o escoamento com boa precisão, prevendo bem seu perfil de velocidades, as ondas de expansão de Prandtl-Meyer, juntamente com as interações dessas ondas com a camada limite. / The behavior of the supersonic flow inside rectangular convergent-divergent nozzle is investigated numerically by comparing four nozzles with different divergent sections, with a common aspect ratio AR=1.14, and the same nozzle exit-to-throat area ratios NAR=1.43. Nozzles are subject to several working fluid inlet pressures, maintaining a constant pressure ratio NPR=5. Simulations assume the flow in steady state, compressible, viscous, using a coupled approach with the turbulence model − /SST. The quality of results is measured by employing three refining levels of the computational domain discretization, observing the order of convergence and the grid convergence index GCI. Numerical results show that the Mach number and the temperature of the working fluid are independent of the inlet pressure, unlike the behavior of local pressure and the density. Flow properties are strongly dependent on the geometry variation, and the change on the angle of divergent section causes a direct effect on the Mach number and inverse on the pressure, the temperature and the density of the flow in this section. Simulations are compared to the results of the isentropic theory and show that the sonic line is offset from the geometric center of the throat nozzle, for each simulated geometry. Results from this work are compared to experimental and theoretical data and show deviations below 6x10-3 %. The − / SST turbulence model is able to solve the flow with good accuracy, and predicts its velocity profile, Prandtl-Meyer expansion waves, and their interactions with the boundary layer.

O comportamento do escoamento supersônico no interior de bocais convergente-divergente retangulares é investigado numericamente, comparando-se quatro bocais com diferentes seções divergentes, com a mesma razão de aspecto AR=1.14 e mesma relação áreas da saída e da garganta dos bocais NAR=1.43. Os bocais são submetidos a diferentes pressões de admissão do fluido de trabalho, mantendo-se a relação entre a pressão de admissão e de descarga constante NPR=5. As simulações consideram o escoamento em regime permanente, compressível, viscoso, com abordagem baseada na massa específica (abordagem acoplada) , juntamente com o modelo de turbulência − /SST. A qualidade dos resultados é medida empregando-se três níveis de refino da discretização do domínio computacional, observandose a ordem de convergência e o índice de convergência de malhas GCI. Os resultados numéricos mostram que o número de Mach e a temperatura do fluido de trabalho independem da pressão de admissão, ao contrário do comportamento da pressão local e da massa específica. As propriedades do escoamento são fortemente dependentes da variação da geometria, e a variação do ângulo da seção divergente provoca uma mudança direta do número de Mach e inversa da pressão, da temperatura e da massa específica do escoamento no interior dessa seção. As simulações são comparadas com os resultados da teoria isentrópica e mostram que a linha sônica é deslocada do centro geométrico da garganta dos bocais para cada geometria simulada. A comparação com a teoria e com dados experimentais mostra desvios inferiores a 6x10-3 %. O uso do modelo de turbulência − / SST é capaz de resolver o escoamento com boa precisão, prevendo bem seu perfil de velocidades, as ondas de expansão de Prandtl-Meyer, juntamente com as interações dessas ondas com a camada limite. / The behavior of the supersonic flow inside rectangular convergent-divergent nozzle is investigated numerically by comparing four nozzles with different divergent sections, with a common aspect ratio AR=1.14, and the same nozzle exit-to-throat area ratios NAR=1.43. Nozzles are subject to several working fluid inlet pressures, maintaining a constant pressure ratio NPR=5. Simulations assume the flow in steady state, compressible, viscous, using a coupled approach with the turbulence model − /SST. The quality of results is measured by employing three refining levels of the computational domain discretization, observing the order of convergence and the grid convergence index GCI. Numerical results show that the Mach number and the temperature of the working fluid are independent of the inlet pressure, unlike the behavior of local pressure and the density. Flow properties are strongly dependent on the geometry variation, and the change on the angle of divergent section causes a direct effect on the Mach number and inverse on the pressure, the temperature and the density of the flow in this section. Simulations are compared to the results of the isentropic theory and show that the sonic line is offset from the geometric center of the throat nozzle, for each simulated geometry. Results from this work are compared to experimental and theoretical data and show deviations below 6x10-3 %. The − / SST turbulence model is able to solve the flow with good accuracy, and predicts its velocity profile, Prandtl-Meyer expansion waves, and their interactions with the boundary layer.

A necessidade constante de desenvolvimento de competências individuais e organizacionais atrelada a projetos de educação a distância (EAD) expande a possibilidade de acesso a programas de treinamento, formação e qualificação profissionais ofertados por instituições de ensino superior (IES) e outras organizações do sistema produtivo. Nota-se um grande progresso tecnológico cada vez mais disseminado no recente campo da EAD. Porém, essa modalidade de ensino é muito carente de estudos sistemáticos. Variáveis relacionadas ao perfil da clientela necessitam ser mais investigadas, como é o caso dos Estilos de Aprendizagem, que necessita de uma definição mais apurada, especialmente para garantir a qualidade dos instrumentos que se propõem a medir esse construto. Muitas vezes o seu conceito está relacionado com o conceito de Estratégias de Aprendizagem, sem grandes diferenciações entre eles. Além disso, a literatura indica que tais variáveis de características da clientela podem estar relacionadas com a Evasão em cursos na modalidade EAD. Nesse sentido, a presente pesquisa objetivou construir e verificar evidências de validade de um instrumento de medida de Estilos de Aprendizagem, bem como realizar a validade convergente com o instrumento de Estratégias de Aprendizagem, além de propor uma discussão conceitual acerca dos Estilos de Aprendizagem. Ao final desse estudo, o instrumento de Estilos de Aprendizagem foi construído, passou por validação semântica, por juízes e foram verificadas evidências de validade estatística. Foi demonstrado também que os alunos que fizeram mais uso das Estratégias de Aprendizagem Autorregulatórias, bem como das Estratégias Comportamentais e valorizam mais os aspectos do ambiente no quais realiza os seus estudos (ou seja, possuem mais Preferências Ambientais) tendem a não abandonar o curso. A validação convergente entre os instrumentos de Estilos de Aprendizagem e Estratégias de Aprendizagem demonstraram que os instrumentos refletem o histórico de relacionamento entre esses conceitos. Muitos fatores de Estratégias de Aprendizagem se relacionam com o instrumento de Estilos de Aprendizagem. Os resultados também possibilitaram uma definição operacional de Estilos de Aprendizagem no campo da Psicologia Organizacional e do Trabalho (POT). Para pesquisas futuras, recomenda-se o uso de técnicas estatísticas mais robustas, como o uso de Análise Fatorial Confirmatória, bem como a Modelagem de Equações Estruturais, que poderiam mensurar com maior exatidão o quanto os Estilos e as Estratégias de Aprendizagem influenciam a Evasão em Ações Educacionais Ofertadas a Distância em contexto de IES. / The constant need to develop individual and organizational competences linked to e-learning projects expands the possibility of access to professional training and qualification programs offered by higher education institutions (HEIs) and other organizations of the productive system. A great technological progress is becoming increasingly widespread in this recent e-learning field. However, this type of education is very lacking in systematic studies. Variables related to the customer profile needs to be further investigated, like the Learning Styles variable. This last requires a more precise definition, especially to ensure the quality of the instruments used to measure this construct. The Learning Styles concept is often related to the Strategy Styles concept without mentioning the proper differences between them. Besides that, the literature indicates that such costumers characteristics variables may be related to the Evasion in e-learning courses. This research aimed to carry out the conceptual analysis of Learning Styles through the construction and verification of validity evidence of a measuring instrument and the convergent validity with Learning Strategies. The Learning Styles instrument was built, underwent semantic validation by judges and evidence of statistical validity were verified. It was also shown that students who made more use of Self-Regulatory Learning Strategies, as well as Behavioral Strategies and value the aspects of the environment in which they realize its studies (ie, have more Environmental Preferences) tend not to leave the course. The convergent validity between Learning Styles and Learning Strategies instruments showed that the instruments reflect the historical relationship between these concepts. Many aspects of Learning Strategies are also related to the Learning Styles aspects. The results showed an adequate definition of Learning Styles in the field of Organizational and Work Psychology (OWP). For future research, it is recommending the use of more consistent statistical techniques such the Confirmatory Factor Analysis as well as Structural Equation Modeling, which could measure more accurately how the Styles and Learning Strategies influence the Evasion in e-learning in the higher education institutions context.

[pt] Neste trabalho foi analisado o escoamento de fluidos não Newtonianos através de canais axisimétricos convergentes divergentes. A solução da conservação de massa e de conservação de momento foi obtida numericamente via volumes finitos utilizando o programa de computador Fluent. A equação constitutiva de fluidos Newtonianos generalizados foi utilizada para modelar o comportamento não Newtoniano, utilizando a equação constitucional de Shunk-Scriven para cálculo da viscosidade, que assume como sendo a média geométrica ponderada pelo classificador de escoamento R entre a viscosidade de cisalhamento e a viscosidade de extensão. Os resultados de perda de pressão e vazão são comparados com os resultados calculados pela relação simplificada proposta por Souza Mendes e Naccache, 2002 entre a perda de carga e vazão de fluidos viscoelásticos fluindo através do meio poroso, para analisar a sua performance. / [en] In this work, the flow of non-Newtonian fluids through axisimmetric convergingdiverging channels is analyzed. The solution of mass and momentum conservation equations is obtained numerically via finite volume technique using the Fluent software. The Generalized Newtonian Fluid constitutive equation was used to model the non- Newtonian fluid behavior, using the Shunk-Scriven model for the viscosity, where a weighted geometric mean by the flow classifier R between shear and extensional viscosities is assumed. The results of pressure drop and flow rate are compared to the ones predicted by a previously proposed simplified relation (Souza Mendes and Naccache, 2002) between pressure drop and flow rate, for viscoelastic fluids flow through porous media, in order to analyze its performance.

La voie de la polarité planaire cellulaire (PCP), aussi connue sous le nom de la voie non-canonique du Frizzled/Dishevelled, contrôle le processus morphogénétique de l'extension convergente (CE) qui est essentiel pour la gastrulation et la formation du tube neural pendant l'embryogenèse. La signalisation du PCP a été récemment associée avec des anomalies du tube neural (ATN) dans des modèles animaux et chez l'humain. Prickle1 est une protéine centrale de la voie PCP, exprimée dans la ligne primitive et le mésoderme pendant l'embryogenèse de la souris. La perte ou le gain de fonction de Prickle1 mène à des mouvements de CE fautifs chez le poisson zèbre et la grenouille. PRICKLE1 interagit directement avec deux autres membres de la voie PCP, Dishevelled et Strabismus/Vang. Dans notre étude, nous avons investigué le rôle de PRICKLE1 dans l'étiologie des ATN dans une cohorte de 810 patients par le re-séquençage de son cadre de lecture et des jonctions exon-intron. Le potentiel pathogénique des mutations ainsi identifiées a été évalué par des méthodes bioinformatiques, suivi par une validation fonctionnelle in vivo dans un système poisson zèbre. Nous avons identifié dans notre cohorte un total de 9 nouvelles mutations dont sept: p.Ile69Thr, p.Asn81His, p.Thr275Met, p.Arg682Cys et p.Ser739Phe, p.Val550Met et p.Asp771Asn qui affectent des acides aminés conservés. Ces mutations ont été prédites in silico d’affecter la fonction de la protéine et sont absentes dans une large cohorte de contrôles de même origine ethnique. La co-injection de ces variantes avec le gène prickle1a de type sauvage chez l’embryon de poisson zèbre a démontré qu’une mutation, p.Arg682Cys, modifie dans un sens négatif le phénotype du défaut de la CE produit par pk1 de type sauvage. Notre étude démontre que PK1 peut agir comme facteur prédisposant pour les ATN chez l’humain et élargit encore plus nos connaissances sur le rôle des gènes de la PCP dans la pathogenèse de ces malformations. / The planar cell polarity pathway (PCP) or the non-canonical Frizzled/Dishevelled pathway controls the morphogenetic process of convergent extension (CE) that is essential during embryogenesis for gastrulation and neural tube formation. Recently, PCP signalling was associated with neural tube defects (NTD) in humans and animal models. The core PCP protein, Prickle1, is expressed in the primitive streak and mesoderm during mouse embryogenesis. Both gain and loss of function of Prickle1 cause faulty CE movements in zebrafish and the frog. PRICKLE1 physically interacts with two other core PCP members, Dishevelled and Strabismus/Vang. In the present study we investigated the role of PRICKLE1 in the aetiology of NTDs in a large cohort of 810 patients through resequencing of its open reading frame and exon-intron junctions. The pathogenicity of the identified mutations was assessed through bioinformatics methods followed by a functional validation in a zebrafish system, in vivo. We identified in our cohort a total of nine novel mutations, of which seven affected conserved amino acids: p.Ile69Thr, p.Asn81His, p.Thr275Met, p.Arg682Cys, p.Ser739Phe, p.Val550Met and p.Asp771As. These mutations were predicted to affect the function of the protein in silico and were absent in a large cohort of ethnically-matched controls. Co-injection of these variants with the wild type pk1 in zebrafish oocytes revealed that one mutation, p.Arg682Cys, antagonized the CE phenotype induced by the wild-type zebrafish prickle1a in a dominant fashion. Our study demonstrates that PRICKLE1 can represent a predisposing factor for human NTDs and further expands our knowledge on the role that PCP genes in the pathogenesis of these malformations.

Les anomalies du tube neural (ATN), incluant l'anencéphalie et le spina-bifida, représentent un groupe de malformations congénitales très fréquentes chez l'homme. Ces anomalies sont causées par un défaut partiel ou complet de la fermeture du tube neurale au cours de l'embryogenèse. Les ATN ont une étiologie complexe et multifactorielle impliquant des facteurs environnementaux et génétiques. La voie de signalisation non-canonique du Frizzled (Fz)/Dishevelled (Dvl) contrôle la polarité cellulaire planaire (PCP) et le processus morphogénétique appelé l’extension convergente qui est essentiel pour la gastrulation et la fermeture du tube neural. Très important, des mutations des gènes de cette voie étaient fortement associées aux ATN chez la souris et l’humain. Scribble est un gène de la voie PCP qui cause une sévère ATN chez la souris Circletail. Notre étude vise à analyser le rôle de SCRIBBLE1 dans les ATN humains par des analyses de séquence de son cadre de lecture et ses jonctions exon-introns. Notre étude comporte 396 patients recrutés au Centre Spina Bifida de l’hôpital Gaslini en Gènes, Italie et 83 patients recrutés au Centre Spina Bifida de l’hôpital Sainte Justine. Les patients sont affectés par plusieurs formes d’ATN. Nous avons identifié neuf mutations rares et non synonymes chez 10 patients, p.Asp93Ala (c. 435G>A), p.Gly145Arg (c. 278A>C), p.Gly263Ser (c. 786C>A), p.Gly469Ser (c. 1405G>A), p.Pro649His (c. 1946C>A), p.Gln808His (c. 2424G>T), p.Val1066Met (c. 3196G>A), p.Arg1150Gln (c. 3480G>A) et p.Thr1422Met (c. 4266C>T). Cinque mutations, p.Gly263Ser, p.Pro649His, p.Gln808His, p.Arg1150Gln, p.Thr1422Met, étaient absentes dans les contrôles analysés et prédites d’être pathogéniques in silico. Cette étude montre que des mutations rares dans SCRIB1 pourraient augmenter le risque des ATN dans une fraction des patients. L’identification des gènes prédisposant aux ATN nous aidera à mieux comprendre les mécanismes pathogéniques impliqués dans ces maladies. / Neural tube defects (NTDs), including anencephaly and spina bifida, represent a group of very common birth defects in humans. These anomalies are caused by a partial or complete failure of neural tube closure during embryogenesis. NTDs have a multifactorial etiology involving environmental and genetic factors. The non-canonical signaling pathway Frizzled (Fz) / Dishevelled (Dvl) controls the planar cell polarity (PCP) and the morphogenetic process called convergent extension (CE) which is essential for gastrulation and neural tube closure. Importantly, mutations in genes of this pathway were strongly associated with NTDs in mice and humans. Scribble is a PCP gene that causes a severe NTD mouse Circletail. Scribble binds to another PCP protein, Stbm / Vang, and they cooperate together for the stability of the PCP pathway. Our study aims at investigating the role of SCRIBBLE1 in human NTDs by sequence analyses of its open reading frame and exon-intron junctions. The cohort included in this study consisted of 396 patients recruited at the Spina Bifida Centre of Gaslini Hospital in Genoa, Italy, and 83 patients recruited at the Spina Bifida Center of the Sainte Justine Hospital, Montreal, Canada. Patients were affected by several forms of NTDs. We identified nine non-synonymous and rare mutations in 10 patients: p.Asp93Ala (c. 435G>A), p.Gly145Arg (c. 278A>C), p.Gly263Ser (c. 786C>A), p.Gly469Ser (c. 1405G>A), p.Pro649His (c. 1946C>A), p.Gln808His (c. 2424G>T), p.Val1066Met (c. 3196G>A), p.Arg1150Gln (c. 3480G>A) and p.Thr1422Met (c. 4266C>T). Five of those mutations, p.Gly263Ser, p.Pro649His, p.Gln808His, p.Arg1150Gln, p.Thr1422Met, were absent in all controls analyzed and were predicted to be pathogenic using bioinformatics. Our study demonstrates that rare mutations in SCRIB1 could predispose to NTDs in a fraction of patients. The identification of genes that predispose to ATN will help us better understand the pathogenic mechanisms involved in these diseases.

Made available in DSpace on 2016-04-04T18:27:35Z (GMT). No. of bitstreams: 1 GLAUCIA MITSUKO ROCHA.pdf: 493337 bytes, checksum: 75d110b5c61b2396ceab94011e243e75 (MD5) Previous issue date: 2002-12-18 / Considering the evidence of reliability and validity of the Escala Diagn?stica Adaptativa Operacionalizada-Redefinida (EDAO-R) when applied to adults, and the necessity to expand the range of tools and procedures available for the assessment of the elderly people, the main goal of this study is to estimate EDAO-R s reliability and convergent validity applied to the elderly people. Ss were 80 older persons (60 years old or more), of both genders (85% of women), who attend to third age groups. The majority (66,25%) was in the young-old group (60-69 years old), was either married (42,5%) or widowed (40%), having son (83,75%), catholic (75%), retired (61,25%), with many different professions, living in their own home (83,75%), alone (28,75%) or with husband / wife (27,5%), and of middle class (61,3%). EDAO-R is a clinical assessment, and then the reliability was taken from an interrater coefficient (Cohen s kappa) between two independent judges. The convergent validity was taken across assessment instruments, Ferrans and Power s Quality of Life Index (IQV) and the Geriatric Depression Scale (GDS-15), as external criterion. The results showed statistically significant interaction, taken through the Spearman s correlation test, between EDAO-R and age (rs= -0,261, p<0,01) and, through the Contingency test between EDAO-R and the person s occupational conditions (C=0,468, p<0,05). The sample tended to the best adaptive levels when assessment through EDAO-R, as to the best scores when assessment through IQV and GDS-15. The reliability for the adaptive efficacy was ? =0,503. When analyzed by EDAO-R s sectors, the Affective-Relational had k=0,551; Productivity had k=0,459; Organic had k=0,612 and the Social-Cultural had k=0,650, which are considered from fair to good. Statistically significant interactions were observed through Spearman s correlation test, between EDAO-R and IQV (rs=-0,449, p<0,01) and between EDAO-R and GDS-15 (rs=0,397, p<0,01). The results are discussed considering the socio-demographic profile of the sample, and indicate that EDAO-R is a reliable and valid measure of the adaptive efficacy when applied to the elderly people who attend to third age groups. Besides that, considering the used operational assessment categories, it s possible to obtain good agreement scores between independent judges. / Considerando as evid?ncias de precis?o e validade da Escala Diagn?stica Adaptativa Operacionalizada-Redefinida (EDAO-R) quando aplicada a adultos e a necessidade de se ampliar o leque de instrumentos e procedimentos dispon?veis para a avalia??o da pessoa idosa, este estudo teve como objetivos estimar a precis?o e a validade convergente da EDAO-R, aplicada a pessoas idosas. Foram avaliadas 80 pessoas, com 60 anos ou mais de idade, de ambos os sexos, predominantemente mulheres (85%), freq?entadoras de grupos da terceira idade, com idades entre 60 e 69 anos (66,25%), casadas (42,5%) ou vi?vas (40%), tendo filhos (83,75%), de religi?o cat?lica (75%), aposentadas (61,25%), com profiss?es diversificadas, residindo em moradia pr?pria (83,75%), sozinhas (28,75%) ou com o c?njuge (27,5%), e de classe m?dia (61,3%). Por se tratar de avalia??o cl?nica, a precis?o foi estimada atrav?s de coeficiente de acordo (kappa de Cohen) entre dois ju?zes independentes. A validade convergente foi estimada utilizando-se o ?ndice de Qualidade de Vida (IQV), de Ferrans e Powers c a Geriatric Depression Scale (GDS-15), como crit?rios externos. Obteve-se associa??es estatisticamente significantes, atrav?s do teste de correla??o de Spearman, entre a EDAO-R e idade (rs= -0,261, p<0,01) e, atrav?s do teste de Conting?ncia, entre a EDAO-R e a condi??o ocupacional da pessoa (C=0,468, p<0,05). A amostra tendeu aos melhores n?veis adaptativos, quando avaliada pela EDAO-R, assim como aos melhores escores, quando avaliada pelo IQV e pela GDS-15. O coeficiente de precis?o obtido para a efic?cia adaptativa geral foi te=0,503. Avaliada por setores, o Afetivo- Relacional obteve k=0,551; o da Produtividade, te=0,459; o Org?nico, k=0,612 e o S?cio-Cultural k=0,650, coeficientes considerados de moderados a bons. Foram observadas associa??es estatisticamente significantes, atrav?s do teste de correla??o de Spearman, entre a EDAO-R e o IQV (rs=-0,449, p<0,01 e entre a EDAO-R e a GDS-15 (rs=0,397, p<0,01). Os resultados s?o discutidos em fun??o do perfil s?cio-demogr?fico da amostra e indicam que a EDAO-R ? uma medida precisa e v?lida da efic?cia adaptativa quando aplicada a pessoas idosas que freq?entam atividades em grupos da terceira idade. Al?m, disto, em fun??o da boa operacionaliza??o das categorias de avalia??o, ? poss?vel obter-se bons ?ndices de acordo entre avaliadores independentes.

Les anomalies du tube neural (ATN), incluant l'anencéphalie et le spina-bifida, représentent un groupe de malformations congénitales très fréquentes chez l'homme. Ces anomalies sont causées par un défaut partiel ou complet de la fermeture du tube neurale au cours de l'embryogenèse. Les ATN ont une étiologie complexe et multifactorielle impliquant des facteurs environnementaux et génétiques. La voie de signalisation non-canonique du Frizzled (Fz)/Dishevelled (Dvl) contrôle la polarité cellulaire planaire (PCP) et le processus morphogénétique appelé l’extension convergente qui est essentiel pour la gastrulation et la fermeture du tube neural. Très important, des mutations des gènes de cette voie étaient fortement associées aux ATN chez la souris et l’humain. Scribble est un gène de la voie PCP qui cause une sévère ATN chez la souris Circletail. Notre étude vise à analyser le rôle de SCRIBBLE1 dans les ATN humains par des analyses de séquence de son cadre de lecture et ses jonctions exon-introns. Notre étude comporte 396 patients recrutés au Centre Spina Bifida de l’hôpital Gaslini en Gènes, Italie et 83 patients recrutés au Centre Spina Bifida de l’hôpital Sainte Justine. Les patients sont affectés par plusieurs formes d’ATN. Nous avons identifié neuf mutations rares et non synonymes chez 10 patients, p.Asp93Ala (c. 435G>A), p.Gly145Arg (c. 278A>C), p.Gly263Ser (c. 786C>A), p.Gly469Ser (c. 1405G>A), p.Pro649His (c. 1946C>A), p.Gln808His (c. 2424G>T), p.Val1066Met (c. 3196G>A), p.Arg1150Gln (c. 3480G>A) et p.Thr1422Met (c. 4266C>T). Cinque mutations, p.Gly263Ser, p.Pro649His, p.Gln808His, p.Arg1150Gln, p.Thr1422Met, étaient absentes dans les contrôles analysés et prédites d’être pathogéniques in silico. Cette étude montre que des mutations rares dans SCRIB1 pourraient augmenter le risque des ATN dans une fraction des patients. L’identification des gènes prédisposant aux ATN nous aidera à mieux comprendre les mécanismes pathogéniques impliqués dans ces maladies. / Neural tube defects (NTDs), including anencephaly and spina bifida, represent a group of very common birth defects in humans. These anomalies are caused by a partial or complete failure of neural tube closure during embryogenesis. NTDs have a multifactorial etiology involving environmental and genetic factors. The non-canonical signaling pathway Frizzled (Fz) / Dishevelled (Dvl) controls the planar cell polarity (PCP) and the morphogenetic process called convergent extension (CE) which is essential for gastrulation and neural tube closure. Importantly, mutations in genes of this pathway were strongly associated with NTDs in mice and humans. Scribble is a PCP gene that causes a severe NTD mouse Circletail. Scribble binds to another PCP protein, Stbm / Vang, and they cooperate together for the stability of the PCP pathway. Our study aims at investigating the role of SCRIBBLE1 in human NTDs by sequence analyses of its open reading frame and exon-intron junctions. The cohort included in this study consisted of 396 patients recruited at the Spina Bifida Centre of Gaslini Hospital in Genoa, Italy, and 83 patients recruited at the Spina Bifida Center of the Sainte Justine Hospital, Montreal, Canada. Patients were affected by several forms of NTDs. We identified nine non-synonymous and rare mutations in 10 patients: p.Asp93Ala (c. 435G>A), p.Gly145Arg (c. 278A>C), p.Gly263Ser (c. 786C>A), p.Gly469Ser (c. 1405G>A), p.Pro649His (c. 1946C>A), p.Gln808His (c. 2424G>T), p.Val1066Met (c. 3196G>A), p.Arg1150Gln (c. 3480G>A) and p.Thr1422Met (c. 4266C>T). Five of those mutations, p.Gly263Ser, p.Pro649His, p.Gln808His, p.Arg1150Gln, p.Thr1422Met, were absent in all controls analyzed and were predicted to be pathogenic using bioinformatics. Our study demonstrates that rare mutations in SCRIB1 could predispose to NTDs in a fraction of patients. The identification of genes that predispose to ATN will help us better understand the pathogenic mechanisms involved in these diseases.

La voie de la polarité planaire cellulaire (PCP), aussi connue sous le nom de la voie non-canonique du Frizzled/Dishevelled, contrôle le processus morphogénétique de l'extension convergente (CE) qui est essentiel pour la gastrulation et la formation du tube neural pendant l'embryogenèse. La signalisation du PCP a été récemment associée avec des anomalies du tube neural (ATN) dans des modèles animaux et chez l'humain. Prickle1 est une protéine centrale de la voie PCP, exprimée dans la ligne primitive et le mésoderme pendant l'embryogenèse de la souris. La perte ou le gain de fonction de Prickle1 mène à des mouvements de CE fautifs chez le poisson zèbre et la grenouille. PRICKLE1 interagit directement avec deux autres membres de la voie PCP, Dishevelled et Strabismus/Vang. Dans notre étude, nous avons investigué le rôle de PRICKLE1 dans l'étiologie des ATN dans une cohorte de 810 patients par le re-séquençage de son cadre de lecture et des jonctions exon-intron. Le potentiel pathogénique des mutations ainsi identifiées a été évalué par des méthodes bioinformatiques, suivi par une validation fonctionnelle in vivo dans un système poisson zèbre. Nous avons identifié dans notre cohorte un total de 9 nouvelles mutations dont sept: p.Ile69Thr, p.Asn81His, p.Thr275Met, p.Arg682Cys et p.Ser739Phe, p.Val550Met et p.Asp771Asn qui affectent des acides aminés conservés. Ces mutations ont été prédites in silico d’affecter la fonction de la protéine et sont absentes dans une large cohorte de contrôles de même origine ethnique. La co-injection de ces variantes avec le gène prickle1a de type sauvage chez l’embryon de poisson zèbre a démontré qu’une mutation, p.Arg682Cys, modifie dans un sens négatif le phénotype du défaut de la CE produit par pk1 de type sauvage. Notre étude démontre que PK1 peut agir comme facteur prédisposant pour les ATN chez l’humain et élargit encore plus nos connaissances sur le rôle des gènes de la PCP dans la pathogenèse de ces malformations. / The planar cell polarity pathway (PCP) or the non-canonical Frizzled/Dishevelled pathway controls the morphogenetic process of convergent extension (CE) that is essential during embryogenesis for gastrulation and neural tube formation. Recently, PCP signalling was associated with neural tube defects (NTD) in humans and animal models. The core PCP protein, Prickle1, is expressed in the primitive streak and mesoderm during mouse embryogenesis. Both gain and loss of function of Prickle1 cause faulty CE movements in zebrafish and the frog. PRICKLE1 physically interacts with two other core PCP members, Dishevelled and Strabismus/Vang. In the present study we investigated the role of PRICKLE1 in the aetiology of NTDs in a large cohort of 810 patients through resequencing of its open reading frame and exon-intron junctions. The pathogenicity of the identified mutations was assessed through bioinformatics methods followed by a functional validation in a zebrafish system, in vivo. We identified in our cohort a total of nine novel mutations, of which seven affected conserved amino acids: p.Ile69Thr, p.Asn81His, p.Thr275Met, p.Arg682Cys, p.Ser739Phe, p.Val550Met and p.Asp771As. These mutations were predicted to affect the function of the protein in silico and were absent in a large cohort of ethnically-matched controls. Co-injection of these variants with the wild type pk1 in zebrafish oocytes revealed that one mutation, p.Arg682Cys, antagonized the CE phenotype induced by the wild-type zebrafish prickle1a in a dominant fashion. Our study demonstrates that PRICKLE1 can represent a predisposing factor for human NTDs and further expands our knowledge on the role that PCP genes in the pathogenesis of these malformations.