L'objectif de cette thèse est de contribuer à une meilleure connaissance du marché du travail dans les économies en développement à dominante informelle. Le Mali est son cas d'étude. Dans la première partie, elle met en évidence la difficulté de comprendre le chômage au travers du statut ambigu des actifs de l'informel, oscillant entre le chômage et l'emploi. Nous y montrons que l'économie informelle exacerbe l'instabilité des frontières du chômage sans toutefois aliéner la rigidité des revenus salariaux à la baisse. A l'aide d'une courbe du salaire, nous appréhendons cette dernière et présentons ses causes. La seconde partie de la thèse pr'esente les dispositifs en matière d'emploi et montre que si, d'un côté, ils répondent pour une large part aux besoins du marché du travail et visent à corriger ses principales insuffisances - notamment en matière de financement et de formation -, de l'autre, leur mise en oeuvre se révèle profondément défaillante. Ceci explique les résultats mitigés de certaines mesures malgré plus de deux décennies d'application. Dans la troisième partie, l'attention est tournée vers l'offre de travail, à la faible connaissance de laquelle on peut attribuer une partie des échecs des dispositifs d'emploi. Nous y examinons le rôle de l'environnement familial dans la participation au marché du travail et dans la prospection d'emploi et montrons que plusieurs variables de cet espace peuvent contribuer à la formulation de meilleurs dispositifs / The aim of this thesis is to contribute to a better understanding of the labour market in informal-dominated developing economies. Mali is its study case. In the first part, it highlights the difficulty to approach unemployment through the ambiguous status of the informal workers, swinging between employment and unemployment. We show that the informal economy exacerbates the instability of the unemployment frontiers without alienating the wage stickiness, which we apprehend through a wage curve. The second part of the thesis presents the employment measures and shows that though, on one hand, they respond accurately to the labour market needs and aim to correct its shortcomings - particularly regarding the financing and training -, on the other hand, their execution is deeply dysfunctional. That explains the mitigated results of some measures, in implementation for over two decades. In the third part, the attention is turned to the labour supply, the weak knowledge of which can partially explain the failures of the employment policies. We examine the role of the household environment in the participation decision and the job search and shows that many variables of this environment can contribute to improving the measures.

Summary: Background: An increased risk for development of hereditary breast cancer is associated with germline mutations in BRCA1/2 and the influence of NBN mutations is also supposed. The aim of this study is to specify the frequency of recurrent mutations in BRCA1/2 in unselected breast cancer patients and the frequency of most common pathogenic mutations in NBN in Czech republic, to assess current criteria for genetic testing and to consider the addition of NBN to the tested genes. Methods: Screening for recurrent mutations 5382insC and 300T>G in BRCA1 was performed by RFLP, screening for mutations in exon 11 of BRCA1 was performed by PTT, screening for mutations in a selected region of exon 11 of BRCA2 by DHPLC, and screening for mutations in exon 6 of NBN by HRMA. All the mutations were confirmed by direct sequencing. Results: In 679 unselected breast cancer patients 7 carriers of 5382insC, 3 of 300T>G, and 4 of other mutations in BRCA1 were identified. 2 locally prevalent mutations were found in BRCA2. In 730 controls only one 5382insC BRCA1 mutation was identified. Out of 5 NBN mutations found in 600 high-risk patients two were 657del5 and one R215W. A total of 8 NBN mutation carriers were identified among 703 breast cancer patients, 2 of them 657del5 carriers and three R215W carriers. In 915...

Les modes alternatifs de règlement des litiges en matière familiale se développent considérablement en droit français. Divers types ont pu être observés : médiation familiale, droit collaboratif, ou encore convention de procédure participative. Cette étude a pu mettre en évidence que le droit substantiel de la famille donne une consistance particulière aux modes alternatifs qui y sont concevables. Ils se détachent d’un droit commun des modes alternatifs pour s’émanciper et devenir autonome. Les modes alternatifs de règlement des litiges donnent un cadre structuré de négociation aux membres de la famille. Toutefois, il existe certaines normes impératives dont les individus ne peuvent s'écarter dans leurs conventions, des principes considérés comme fondamentaux qui imposent d’encadrer la volonté privée : le rôle du juge est irréductible en droit de la famille / Alternative forms of litigation settlement in familial matters have been considerably developing in French law. Several of them now exist: familial mediation, collaborative law, or participative procedure convention. This study has shown that substantial law of family gives particular consistency to the alternative forms that are subject to it. They detach themselves from common law alternative forms of settlement and have become autonomous. Alternative forms of litigation settlement give a structured framework to the negotiations between family members. However, individuals are not exempt from several imperative norms in their convention, principles that are considered as fundamental and which dictate that private will be ruled: the judge's role is irreducible in family law

Les inflammasomes sont des complexes protéiques intracellulaires qui ont un rôle majeur dans l'immunité innée. Leur activation conduit à la mort de la cellule dans un contexte hyperinflammatoire. Compte-tenu des effets potentiellement délétères, tissulaires et systémiques, les inflammasomes sont strictement régulés. A l'heure actuelle, la compréhension des mécanismes conduisant à leur activation et leur régulation reste partielle. Dans une première partie de cette thèse, nous avons utilisé une technique de biotinylation proximale (BioID) pour identifier les protéines interagissant avec l'inflammasome. Nous avons identifié 111 protéines dont la relation étroite avec l'inflammasome était vraisemblable. Parmi ces 111 protéines, 25% avaient d'ailleurs déjà été décrites comme des protéines interagissant avec le complexe. L'identification d'un adaptateur majeur de l'autophagie, p62/sequestosome-1 (p62), nous a conduit à focaliser notre attention sur son rôle dans la régulation de l'inflammasome. Nous avons d'abord démontré que l'interaction entre p62 et l'inflammasome existait, sur le plan biochimique. Par la suite, nous avons prouvé que p62 était un substrat du complexe et que l'activation de ce dernier entrainait le clivage de p62 au niveau d'un résidu aspartique en position 329. Enfin, nous avons caractérisé les conséquences fonctionnelles de ce clivage, en montrant que les fragments protéiques générés entrainaient une régulation positive ou négative du complexe. Nous avons alors émis l'hypothèse que p62 pourrait réguler l'inflammasome de manière différente selon le signal activateur. Dans une seconde partie, translationnelle, nous nous sommes intéressés aux conséquences des mutations dans la séquence de gènes codant les constituants de l'inflammasome ou des protéines régulatrices du complexe. Celles-ci sont à l'origine des maladies auto-inflammatoires monogéniques. Ces maladies sont caractérisées par des épisodes récurrents de fièvre associés variablement à d'autres symptômes systémiques. La plus fréquente est la fièvre méditerranéenne familiale (FMF), avec une prévalence estimée entre 1 et 5 pour 10 000 habitants en France. Les mutations du gène MEFV, codant la pyrine, sont à l'origine de la FMF. La pyrine peut induire la formation d'un inflammasome spécifique. Récemment, le mécanisme d'activation de l'inflammasome pyrine a été mieux caractérisé : certaines toxines (comme la toxine B du Clostridium difficile, TcdB) induisent l'activation de l'inflammasome pyrine. Nous avons utilisé ces nouvelles connaissances afin d'explorer les conséquences de l'activation de l'inflammasome pyrine par la TcdB dans les monocytes des patients atteints de FMF, comparés aux monocytes de donneurs sains. Nos résultats indiquent que ces mutations induisent un abaissement du seuil d'activation de l'inflammasome pyrine. Par ailleurs, les corrélations génotype/phénotype indiquent qu'il existe un effet de dosage génétique, en lien avec le nombre d'allèles mutés. Ces résultats ouvrent de nouvelles perspectives pour les patients atteints de FMF, tant dans la compréhension de la physiopathologie que dans la possibilité de mise au point de tests fonctionnels pour le diagnostic de la maladie / Inflammasomes are intracellular multiprotein complexes that have a major role in innate immunity. Their activation leads to hyperinflammatory cell death. In view of potentially deleterious effects, the inflammasomes are strictly regulated. At present, the understanding of the mechanisms leading to their activation and regulation remains partial. In a first part of this thesis, we used a technique of proximity-dependent biotinylation (BioID) to identify the proteins interacting with the inflammasome. We identified 111 proteins with a close relationship to the inflammasome. Among these 111 proteins, 25% had already been described as proteins interacting with the complex. The identification of a major adaptor of autophagy, p62/sequestosome-1 (p62), led us to focus our attention on its role in the regulation of inflammasome. We first demonstrated that the interaction between p62 and inflammasome was real, at the biochemical level. Subsequently, we proved that p62 was a substrate of the complex and that the activation of the latter led to the cleavage of p62 at the aspartate 329. Finally, we characterized the functional consequences of this cleavage and showed that the protein fragments generated led to a positive or negative regulation of the complex. We thus hypothesized that p62 could regulate the inflammasome differently according to the activator signal. In a second translational part, we looked at the consequences of mutations in the sequence of genes coding components of the inflammasome or proteins regulating it. These are the cause of monogenic auto-inflammatory diseases. These diseases are characterized by recurrent episodes of fever associated with other systemic symptoms. The most frequent is Familial Mediterranean Fever (FMF), with prevalence estimated at between 1 and 5 per 10 000 inhabitants, in France. Mutations of the MEFV gene, encoding pyrin, cause FMF. Pyrine may trigger the formation of a specific inflammasome. Recently, the mechanism of activation of the pyrin inflammasome has been better characterized: toxins (such as toxin B of Clostridium difficile, TcdB) induce the activation of the pyrin inflammasome. We used this new knowledge to investigate the consequences of TcdB on pyrin inflammasome activation in monocytes from FMF patients compared to monocytes from healthy donors. Our results indicate that these mutations induce a decreased threshold of activation of the pyrin inflammasome. In addition, genotype / phenotype correlations indicate a gene-dosage effect, related to the number of mutated alleles. These results open new perspectives for patients with FMF, in understanding the pathophysiology of the diseass and in developing functional diagnostic tests

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.

A hipercolesterolemia familiar (HF) é uma doença autossômica dominante caracterizada por níveis elevados de LDL-c e doença arterial coronária (DAC) precoce. Existem evidências de maior prevalência de aterosclerose subclínica nesta população avaliada pelo escore de cálcio (CAC) e pela espessura íntima-média carotídea (EIMC). O objetivo do nosso estudo foi avaliar aterosclerose subclínica por meio da angiotomografia de coronárias em portadores de HF sem aterosclerose manifesta, correlacionando os achados com parâmetros clínicos, laboratoriais, rigidez aórtica e carotídea e com a EIMC. Incluímos 102 HFs, (45±13 anos, 36% homens, LDL-c 280±54mg/dL) e 35 controles (46±12 anos, 40% homens, LDL-c 103±18mg/dL). O grupo HF apresentava maior carga de placa aterosclerótica representado por: maior número de pacientes com placa (48% versus 14%, p=0,0005), maior número de pacientes com estenose luminal acima de 50% (19% versus 3%, p=0,015), maior número total de segmentos com placas (2,0±2,8 versus 0,4±1,3, p=0,0016), maior número de segmentos com placas calcificadas (0,8±1,54 versus 0,11±0,67, p= 0,0044) e maior escore de cálcio pelo método de Agatston (55±129, mediana:0 versus 38±140, mediana:0; p=0,0028). Houve correlação positiva no grupo HF do número total de segmentos com placa com: idade (r=0,41, p<0,0001), escore de risco de Framingham (r=0,25, p=0,012), colesterol total (r=0,36, p<0,0002), LDL-c (r=0,27, p=0,005), HDL-c (r=0,24, p=0,017), apolipoproteína B (r=0,3, p=0,0032) e escore de cálcio (r=0,93, p<0,0001). Além disso, houve correlação negativa com: variação sísto-diastólica carotídea (r=-0,23, p=0,028) e percentual de distensão carotídeo (r=-0,24, p=0,014). A análise multivariada de determinantes da presença de placa aterosclerótica, revelou que idade (OR=1,105, IC95%: 1,049-1,164, p<0,001) e colesterol total (OR=1,013, IC95%:1,001-1,025) foram as variáveis associadas com a presença da mesma. A única variável associada com presença de obstrução luminal acima de 50% foi o escore de cálcio coronário (OR=1,004; IC95%:1,001-1,008; p=0,014). Em relação a determinantes da composição de placa, na análise multivariada a presença de placa não calcificada esteve associada com o sexo masculino (OR:15,45; IC95%: 1,72-138,23, p=0,014), a placa mista com antecedente familiar de DAC precoce (OR=4,90; IC95%:1,32-18,21, p=0,018) e placa calcificada a menor chance com o sexo masculino (OR=0,21; IC95%: 0,05-0,84, p=0,027). Conclusões: Os pacientes portadores de HF apresentam maior carga de placa avaliada pela angiotomografia em comparação aos controles; idade e colesterol total associaram-se a presença de placas no grupo HF; o escore de cálcio associou-se a presença de estenose luminal acima de 50%. / Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by high LDL-c levels and premature coronary artery disease (CAD) onset. There is evidence of greater prevalence of subclinical atherosclerosis in this population evaluated by coronary calcium score (CCS) and carotid intima-media thickness (IMT). The aim of our study was to assess subclinical atherosclerosis by computed tomography coronary angiography (CTCA) in patients with FH without manifest atherosclerosis and correlate the findings with clinical and laboratory parameters, aortic and carotid stiffness and IMT. We included 102 FHs (45 ± 13 years, 36% men, LDL-c 280 ± 54mg/dL) and 35 controls (46 ± 12 years, 40% men, LDL-c 103 ± 18mg/dL). The FH group had a greater atherosclerosis plaque burden represented by: higher number of patients with coronary plaque (48% versus 14%, p = 0.0005) and with luminal stenosis greater than 50% (19% versus 3% p = 0.015), higher total number of segments with plaques (2.0 ± 2.8 versus 0.4 ± 1.3, p = 0.0016), higher number of segments with calcified plaques (0.8 ± 1.54 versus 0.11 ± 0.67, p = 0.0044) and higher CCS by the Agatston method (55 ± 129, median: 0 vs. 38 ± 140, median = 0, p = 0.0028). There were positive correlations of total number of segments with plaque in FH group with the following variables: age (r=0.41, p<0.0001), Framingham risk score (r =0.25, p=0.012), total cholesterol (r=0.36, p<0.0002), LDL-c (r=0.27, p=0.005), HDL-c (r=0.24, p=0.017), apolipoprotein B (r=0,3, p=0.0032) and CCS (r=0.93, p<0.0001). In addition there was a negative correlation with: carotid systo-diastolic variation (r=- 0.23, p=0.028) and percentage of carotid distension (r=- 0.24, p=0.014). After multivariate analysis, the determinants of plaque presence were age (OR=1.105, 95% CI=1.049-1.164, p<0.001) and total cholesterol (OR=1.013, 95% CI:1.001-1.025). The only variable associated with presence of luminal stenosis greater than 50% was CCS (OR = 1.004, 95% CI: 1.001-1.008, p=0.014). After multivariate analysis, the presence of non-calcified plaque was associated with male gender (OR: 15.45, 95% CI 1.72-138.23, p = 0.014), mixed plaque with family history of early CAD (OR = 4.90, 95%:1.32-18.21, p=0.018) and calcified plaque negatively with males (OR = 0.21, 95% CI: 0.05-0.84, p = 0.027). Conclusions: FH subjects have higher plaque burden assessed by CTCA compared to controls; age and total cholesterol were associated with the presence of coronary plaque in the FH subjects; CCS was associated with luminal stenosis greater than50%.

A hipercolesterolemia familiar (HF) é uma doença de herança genética autossômica dominante caracterizada pela elevação dos níveis séricos de colesterol total e das lipoproteínas de baixa densidade (LDL- c). Conhecida por estar estreitamente relacionada ao processo aterosclerótico, a HF pode determinar o desenvolvimento de lesões obstrutivas precoces em distintos leitos arteriais. Nesse contexto, a HF também tem sido proposta como um fator de risco para a doença arterial periférica (DAP). Avaliamos assim de forma sistemática por meio de um estudo transversal e observacional, a prevalência de DAP em uma população brasileira de portadores de HF. Estudamos também sua associação com diversos fatores de risco cardiovascular, incluindo sexo, idade, hipertensão arterial sistêmica, diabetes mellitus, tabagismo, perfil lipídico, níveis séricos de glicemia e creatinina. Avaliou-se também a associação da DAP com histórico prévio de doença cardiovascular (DCV) bem como sua associação com marcadores de aterosclerose subclínica representados pela angiotomografia coronariana e escore de cálcio coronário. Foram estudados 212 portadores de HF, sendo que em 86% foi comprovada presença de mutação do receptor da LDL e um grupo de comparação composto por 524 indivíduos normolipidêmicos. O rastreamento da DAP foi realizado por dois avaliadores treinados, pela medida do índice tornozelo-braquial (ITB) avaliado em repouso na posição supina, com Doppler vascular portátil. Houve maior prevalência de DAP definida por ITB <= 0,90 em portadores de HF comparados aos controles (17,5% vs. 2,3%, respectivamente; p < 0,001). As variáveis que se associaram independentemente com a alteração dos valores do ITB nos grupos estudados foram, a idade, antecedente prévio de doença cardiovascular e o indivíduo ser portador de HF (OR= 5,77 IC 95% 2,83-11,77, p < 0,001). Na população de HF as variáveis que se associaram independentemente à alteração dos valores de ITB foram a idade e a presença de histórico de tabagismo ativo ou passado. Houve uma associação univariada entre o histórico de doença cardiovascular e o diagnóstico de doença arterial periférica nesta população (OR= 3,20 IC 95% 1,53-6,67, p=0,001), porém tal associação não se manteve significativa quando ajustada por variáveis de confusão. Da mesma forma não se encontrou associação entre os valores alterados de ITB e a presença de placa coronariana e sua gravidade, bem como com o escore de cálcio coronário. Os dados sugerem dissociação entre o desenvolvimento da aterosclerose em diferentes leitos arteriais .Em conclusão, nossos resultados indicam que a DAP é mais frequente na HF do que em indivíduos normolipidêmicos e que outros fatores de risco potencializam o colesterol para sua presença. Não foi encontrada associação independente da alteração do ITB com manifestação de DCV prévia e com a aterosclerose coronária subclínica. Contudo, mais estudos são necessários para determinar o papel do uso do ITB como ferramenta para avaliação do risco de eventos cardiovasculares nessa população / Familial hypercholesterolemia (FH) is a genetic disease of autosomal dominant inheritance characterized by elevated serum levels of total and low density lipoprotein ( LDL - c ) cholesterol. FH is associated to atherosclerosis and can determine the early development of obstructive lesions in different arterial beds. In this context, FH has also been proposed as a risk factor for peripheral arterial disease (PAD). In a cross-sectional observational study the prevalence of PAD in a Brazilian population of patients with FH was determined . We also study its association with several cardiovascular risk factors, including gender, age , hypertension , diabetes mellitus , smoking , lipid profile , serum glucose and creatinine. The association of PAD with previous manifestations of cardiovascular disease (CVD) and with markers of subclinical coronary atherosclerosis detected by computed tomography coronary angiography and coronary calcium score was also evaluated. We studied 212 patients with FH, of which 86% had a confirmed diagnosis by the presence of LDL receptor mutations, and a comparison group consisting of 524 normolipidemic subjects . PAD diagnosis was made by 2 trained evaluators, by the ankle-brachial index ( ABI ) measured at rest in the supine position. There was a higher prevalence of PAD defined as ABI <= 0.90 in patients with HF compared with controls (17.5 % vs . 2.3% , p < 0.001 ) . The variables that were independently associated with altered ABI values in both groups were age, previous history of CVD and the diagnosis of FH (OR = 5.77 95% CI 2.83 to 11.77 , p < 0.001). In FH subjects variables independently associated with altered ABI values were age and the presence of current or past smoking history. There was a univariate association between CVD history and the diagnosis of PAD in this population (OR = 3.20 95% CI 1.53 to 6.67 , p = 0.001), but this association did not remain significant when adjusted for confounders . Likewise, no association was found between the values of altered ABI and the presence of coronary plaque and its severity, as well with the coronary calcium score. The data suggest that there is a dissociation of atherosclerosis development in different arterial beds. In conclusion, our results indicate that PAD is more common in FH than in normolipidemic subjects and that other risk factors potentiate cholesterol to determine its presence. No independent association was found between the alteration of ABI values with manifestations of prior CVD, as well as with the presence of subclinical coronary atherosclerosis. More studies are needed to determine the role of ABI use as a tool for assessing the risk of cardiovascular events in FH

Made available in DSpace on 2017-07-10T18:56:28Z (GMT). No. of bitstreams: 1 KellyMoreira.pdf: 759694 bytes, checksum: 509b4918a43fada8abb1c6b443abd0ed (MD5) Previous issue date: 2011-03-01 / This work, entitled: The decline of the house, the shade of the death and the fall of the Meneses masks, aims to analyze the relation between the finance decline and the ethical and moral degradation of the Meneses family, the main characters of the novel: Crônica da casa assassinada (1959), written by Lúcio Cardoso. The main points analyzed are: the importance of space as a category in the narrative construction, the tragic female condition, the disease and death of the character Nina, the relation between the cancer, which destroys her, the fall of the house and the ethical and moral ruin of the family. The tragedy of the Meneses family is a result of their inability of adaptation to their historical time, wath implicates in their decline. Inside of this decadent familiar context we have the female characters, united by ties of envy, hatred, pity and death. Gilberto Freyre (2000), Rita Felix Fortes (2010), Simone de Beauvoir (1980), Phillipe Áries (2003), José Carlos Rodrigues (1993), and other s principles will be used to base this analysis. / No presente estudo, intitulado: A decadência da casa, a sombra da morte e o cair das máscaras Meneses, objetiva-se analisar a relação entre a decadência financeira e a desagregação ética e moral da família Meneses, protagonista do romance Crônica da casa assassinada (1959), do escritor Lúcio Cardoso. Os principais aspectos abordados são: a importância do espaço como categoria na construção da narrativa; a trágica condição feminina; a doença e morte da personagem Nina e a relação entre o câncer que a destrói, a queda da casa e a ruína ética e moral da família. A tragédia da família Meneses decorre de sua incapacidade de se adaptar ao seu tempo histórico, o que implica sua decadência. Dentro desse contexto familiar decadente, encontram-se as personagens femininas, unidas por laços de inveja, ódio, compaixão, e morte. Para fundamentar esta análise serão utilizados os postulados de Gilberto Freyre (2000), Rita Félix Fortes (2010), Simone de Beauvoir (1980), Phillipe Áries (2003), José Carlos Rodrigues (1993), dentre vários outros.

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 2014-08-20T13:46:35Z (GMT). No. of bitstreams: 1 Heron_Ungaretti_Vaz_Dissertacao.pdf: 1341982 bytes, checksum: 5612e547b57f9399e92fd61d3ebc6617 (MD5) Previous issue date: 2010-09-10 / The present work deals with the social-productive organization of the family farm in the district of Palmas, municipality of Bagé, state of Rio Grande do Sul, with the objective to verify the existence of a differentiation in the territorial configuration of the municipality above from the analyze of the rural property of familial character. Thereby, it was attempted to analyze the territorial organization in the meridional campaign region from a historical perspective of the land property and from the review of concepts of the social category of family farming, investigating the origin of the Brazilian political-legal order and the instruments of land property acquisition. Therefore, it is aimed to comprehend the reproduction strategies of the family farmers living in the municipality of Bagé, from the comparison of the theory that underlies the family farming, property and territory concepts and the empiric reality observed in the district of Palmas. It was concluded that family farmers adopt specific strategies of social reproduction, as the using of familial workforce, production for self consumption, the pursuit of autonomy in the process of commercialization, yet the livestock and crop production diversification. The land property for the family farmer consists not only in a heritage land of material character, but in a symbolic living space that keeps the memory of the family group and reproduces it for the future generations. Moreover, by the realized research it was proved that the governmental actions that aim the straightening of familial family farming are extremely necessary to (re)organize the physical and social-productive basis of the familial rural property and to promote the territorial development / O presente trabalho trata da organização socioprodutiva da agricultura familiar presente no distrito de Palmas, município de Bagé, Estado do Rio Grande do Sul, com o objetivo de verificar a existência de uma diferenciação na configuração territorial do referido município, a partir da análise da propriedade rural de caráter familiar. Desse modo, buscou-se analisar a organização territorial, na região da Campanha Meridional, a partir de uma perspectiva histórica da propriedade da terra e da revisão dos conceitos da categoria social da agricultura familiar, investigando a origem do ordenamento político-jurídico brasileiro e os instrumentos de aquisição da propriedade da terra. Assim, almeja-se compreender as estratégias de reprodução dos agricultores familiares existentes no município de Bagé, a partir do cotejo da teoria que embasa os conceitos de agricultura familiar, propriedade e território e a realidade empírica observada no distrito de Palmas. Concluiu-se que os produtores familiares adotam estratégias específicas de reprodução social como a utilização da mão de obra familiar, a produção para o autoconsumo, a busca da autonomia no processo de comercialização, além da diversificação da produção animal e vegetal. A propriedade da terra, para o produtor familiar, constitui tanto um patrimônio fundiário de caráter material, quanto um espaço de vida simbólico que guarda a memória do grupo familiar e a reproduz para as gerações futuras. Ainda, ficou evidenciado, pela pesquisa realizada, que as ações governamentais que visem ao fortalecimento da agricultura familiar são extremante necessárias para (re)organizar as bases físicas e socioprodutivas da propriedade rural familiar e para promover o desenvolvimento territorial