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Ce projet de recherche a été effectué dans le but d'évaluer et de quantifier les boiteries chez les truies reproductrices. Pour ce faire, différentes méthodes ont été sélectionnées parmi les techniques utilisées pour évaluer la boiterie chez le porc et les autres espèces. Cinq méthodes dont la cinématique, la prise d'empreinte des pattes dans l'argile, l'évaluation des postures et du piétinement, l'observation du comportement de lever et l'évaluation des lésions des onglons ont été mises au point en station de recherche puis validées pour s'assurer de leur répétabilité. Parmi ces méthodes, l'analyse cinématique a démontré que les truies présentant une boiterie ont une vitesse de marche plus faible que les truies exemptes de boiterie ainsi qu'un temps de pose du pied plus long. L'évaluation des postures a révélé que les truies ayant des troubles locomoteurs passent moins de temps debout que les truies qui n'ont pas de boiterie.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

Les malformations cardiaques congénitales (CHM) représentent 28 % de toutes les malformations congénitales majeures et touchent 8 pour 1000 naissances à terme. Elles sont la cause de mortalité et de morbidité non infectieuse la plus fréquente chez les enfants de moins d’une année de vie. Les communications interventriculaires (VSD) forment le sous-type de CHM le plus fréquent et l’aggrégation familiale est extrêmement rare. Le but de cette étude était d’identifier les facteurs génétiques et les régions chromosomiques contribuant aux VSD. Une grande famille ségréguant diverses formes de pathologies septales, incluant des VSD, des anévrysmes du septum interventriculaire (VSA) et des communications interauriculaires (ASD), a été examinées et caractérisées cliniquement et génétiquement. Dix-huit membres de la famille, sur trois générations, ont pu être étudiés. (10 affectés : 4 VSD, 3 VSA, 2 ASD et une tétralogie de Fallot). L’analyse de liaison multipoint paramétrique démontre un logarithme des probabilités maximal (LOD) de 3.29 liant significativement le chromosome 10p15.3-10p15.2 aux traits observés dans cette famille. Le pointage LOD oriente vers une région pauvre en gènes qui a déjà été associée aux malformations du septum interventriculaire, mais qui est distincte de la région du syndrome de DiGeorge de type 2 sur le chromosome 10p. De plus, plusieurs scénarios d’analyse de liaison suggèrent que la tétralogie de Fallot est une phénocopie et qu’elle est donc génétiquement différente des autres pathologies du septum observées dans cette famille. En bref, cette étude associe une forme rare de VSD/VSA au chromosome 10p15 et permet d’étendre le spectre de l’hétérogénéité des pathologies septales. Mots-clés : Malformations cardiaques congénitales, malformations du septum, tétralogie de Fallot, analyse de liaison, chromosome 10p15, génétique moléculaire / Cardiac malformations represents 28 % of all major congenital malformation and affect 8 per 1000 live birth. They are the most frequent cause of non infectious mortality and morbidity in childen of less then 1 year of life. Although ventricular septal defects (VSD) are the most common congenital heart lesion, familial clustering has been described only in rare instances. The aim of this study was to identify genetic factors and chromosomal regions contributing to VSD. A unique, large kindred segregating various forms of septal pathologies—including VSD, ventricular septal aneurysms, and atrial septal defects (ASD)—was ascertained and characterized clinically and genetically. Eighteen family members in three generations could be studied, out of whom 10 are affected (2 ASD, 3 septal aneurysm, 4 VSD, and 1 tetralogy of Fallot). Parametric multipoint LOD scores reach significance on chromosome 10p15.3-10p15.2 (max. 3.29). The LOD score support interval is in a gene-poor region where deletions have been reported to associate with septal defects, but that is distinct from the DiGeorge syndrome 2 region on 10p. Multiple linkage analysis scenarios suggest that tetralogy of Fallot is a phenocopy and genetically distinct from the autosomal dominant form of septal pathologies observed in this family. This study maps a rare familial form of VSD/septal aneurysms to chromosome 10p15 and extends the spectrum of the genetic heterogeneity of septal pathologies. Fine mapping, haplotype construction, and resequencing will provide a unique opportunity to study the pathogenesis of septal defects and shed light on molecular mechanisms of septal development.

Trinta e cinco pacientes com malformações arteriovenosas raquimedulares (MAVR) foram tratados por via endovascular. Foram analisados os tipos de MAVR, bem como os aspectos clínicos e angiográficos pré e pós-tratamento endovascular. As MAVR mais freqüentes foram as fístulas arteriovenosas durais (FAD), com 17 pacientes, seguidas das malformações arteriovenosas intramedulares (MAI), fístulas arteriovenosas perimedulares (FAVP) e malformações arteriovenosas metaméricas (MAVM). A avaliação do resultado do tratamento foi dividida em sucesso técnico e clínico, sendo que o primeiro foi subdividido em sucesso técnico do procedimento e do tratamento. O sucesso técnico do procedimento foi caracterizado como oclusão total da MAVR ao final de um procedimento endovascular. O sucesso técnico do tratamento foi caracterizado pela oclusão definitiva da MAVR, independentemente do número de procedimentos. A recidiva foi definida como o reaparecimento da MAVR, identificada na angiografia durante o seguimento dos pacientes, independentemente do quadro clínico apresentado. A recidiva implicava em insucesso do procedimento, mas não necessariamente do tratamento. O sucesso clínico do tratamento foi considerado como a melhora parcial ou total dos sintomas após um período mínimo de acompanhamento de 6 meses. Nas FAD, houve predomínio do sexo masculino e da faixa etária acima dos 36 anos. O tratamento endovascular das FAD mostrou sucesso do procedimento na maioria dos casos, porém com recidiva da lesão em 56,7% dos mesmos. Quando usadas partículas, observou-se recidiva em 73,3% dos procedimentos, porém com sucesso do tratamento em 66,7 dos pacientes. Quando utilizado o adesivo tissular (\"cola\"), houve recidiva em 11,1% dos procedimentos e sucesso do tratamento em 88,9% dos pacientes. A melhora clínica foi obtida em 64,7% dos pacientes. Dos 10 pacientes tratados com MAI, a faixa etária mais freqüente foi dos 19 aos 35 anos de idade e predomínio do sexo masculino. O tratamento endovascular das MAI mostrou sucesso do procedimento em 53,3% e recidiva da lesão em 6,7% dos pacientes. O sucesso do procedimento também foi superior quando usada cola, atingindo 63,6% dos procedimentos e apenas 25,0% com partículas. O sucesso do tratamento foi de 80,0% e a melhora clínica foi observada em 40,0% dos pacientes. Somente 1 paciente com MAVM foi tratado. O tratamento objetivou a embolização parcial da lesão para alívio dos sintomas, resultado que foi obtido com sucesso. Nas FAVP houve predomínio do sexo masculino e a faixa etária mais acometida foi dos 19 aos 35 anos. O tratamento endovascular das FAVP mostrou sucesso do procedimento em 75,0% dos pacientes e ausência de recidiva. O sucesso do tratamento foi de 85,7%, com melhora clínica em todos os pacientes. O nosso estudo mostrou que as MAVR podem ser tratadas de maneira eficiente e segura através da embolização. O seguimento dos pacientes tratados com cola mostrou menor índice de recidiva do que aqueles tratados com partículas. Após a embolização, houve melhora significativa no padrão da marcha nos pacientes com FAD e MAI / Endovascular treatment was used in 35 patients with spinal cord arteriovenous malformations (SCAVM). SCAVM types, along with clinical and angiographic features of pre-op and post-op endovascular treatments were analyzed. Seventeen patients had dural arteriovenous fístulas (DAVF), being this type the most frequent SCAVM, followed by intramedullary arteriovenous malformations (IAVM), perimedullary arteriovenous fístulas (PAVF) and metameric arteriovenous malformations (MAVM). Evaluation of treatment results was divided into technical and clinical success, being the first subdivided into technical success of the procedure and treatment. The procedural\'s technical success was characterized by total SCAVM occlusion at the end of an endovascular procedure. Technical success of the treatment was characterized by definitive occlusion of the SCAVM, independent of the number of procedures. Recurrence was defined as reappearance of SCAVM, identified on angiograms during patient follow up, independent of the observed clinical situation. Recurrence implied in an unsuccessful procedure but not necessarily in treatment failure. Treatment\'s clinical success was considered partial or total symptom improvement after a minimum 6 month period follow up. Male and age over 36 years was preponderate in DAVF. Endovascular treatment in DAVF had procedural success in most cases, but with lesion recurrence in 56,7% of these patients. When particulate embolic agents were used, recurrence occurred in 73,3% of the procedures but with treatment success in 66,7% of these patients. When liquid tissue adhesive was used, there was 11,1% of recurrence and 88,9% in treatment success in these patients. Clinical improvement occurred in 64,7% of these patients. Male predominance and age between 19 to 35 years was more frequent in the 10 treated patients with IAVM. IAVM endovascular treatment was a procedural success in 53,3% and lesion recurrence in 6,7% of these patients. Procedural success was also superior when liquid tissue adhesive was used, up to 63,6% of these procedures and, only 25,0% with particulate embolic agents. Treatment success occurred in 80,0% and clinical improvement seen in 40,0% of these patients. Only 1 patient with MAVM was treated. Aim in treatment was partial lesion embolization to mitigate symptoms, which was successfully achieved. Male predominance and age between 19 to 35 years occurred in PAVF. PAVF endovascular treatment had procedural success in 75,0% and no recurrences in these patients. Treatment success occurred in 85,7% and clinical improvement in all patients. This study demonstrates that SCAVM can be treated efficiently and safely with endovascular embolization. Patient follow up revealed fewer recurrences in those treated with liquid tissue adhesive than in those with particulate embolic agents. After DAVF and IAVM embolization, patients had significant improvement in their gait

Dans le cadre du programme commun d’études pharmaco-épidémiologiques de la caisse nationale de l'assurance maladie et de l’agence nationale de sécurité du médicament, visant à évaluer l'impact sanitaire en France de l'exposition in utero à l’acide valproïque à partir des bases de données médico-administratives (BDMA) françaises, l’objectif de cette thèse était d’étudier l’utilisation des antiépileptiques pendant la grossesse et les risques de malformations congénitales et de troubles neuro-développementaux associés chez l’enfant. Le premier volet de cette thèse a consisté à formaliser et publier un algorithme d’identification des grossesses spécifiquement adapté aux BDMA françaises. L’application de cet algorithme à la description de l’utilisation des antiépileptiques pendant la grossesse a permis d’estimer à 6,7‰ la prévalence de l’utilisation des antiépileptiques pendant la grossesse et de montrer une baisse de l’utilisation des antiépileptiques de première génération, en particulier de l’acide valproïque, au bénéfice des antiépileptiques de deuxième génération entre 2007 et 2014. Dans le deuxième volet de cette thèse, l’exposition in utero à l’acide valproïque a été retrouvée associée à une augmentation du risque d’un grand nombre des malformations congénitales majeures (MCM) étudiées, avec une relation dose-effet pour les MCM les plus fréquentes, et l’exposition in utero au topiramate à une augmentation du risque de fentes oro-faciales. Des signaux relatifs à la prégabaline, au clonazépam et au phénobarbital ont aussi été identifiés. Dans le troisième volet de cette thèse, l’exposition in utero à l’acide valproïque a été retrouvée associée à une augmentation du risque de chacun des événements neuro-développementaux précoces étudiés versus lamotrigine, avec une relation dose-effet, à l’inverse des autres antiépileptiques. La réalisation d’études pharmaco-épidémiologiques à partir des BDMA françaises a permis aux autorités sanitaires de fournir rapidement des données sur l’utilisation des antiépileptiques pendant la grossesse en France. La réalisation de ces études a aussi permis de participer à l’enrichissement de la littérature observationnelle internationale sur les conséquences de l’exposition in utero aux antiépileptiques pour l’enfant à naitre. / The works of this thesis have been carried out within a programme of pharmacoepidemiological studies initiated by the National Agency of Medicine and Health Product Safety (ANSM) and the National Health Insurance fund (Cnam) in order to evaluate the public health situation in relation to prenatal exposure to valproic acid in France on the basis of the French health care databases. The objective of this thesis was to study antiepileptic drug (AED) use during pregnancy and the risks of congenital malformations and neurodevelopmental disorders associated with prenatal exposure to these drugs. In a first study, we developed an algorithm to identify pregnancy episodes and related outcomes using the French health care claims databases and applied it to study AED use during pregnancy between 2007 and 2014. Over the study period, 6.7 per 1000 pregnancies were exposed to an AED. The use of newer AEDs increased concomitantly with the decreased use of valproic acid and the other older AEDs. In a second study, prenatal exposure to valproic acid was found to be associated with a wide range of malformations among those investigated, with a dose-response relationship for half of them, and prenatal exposure to topiramate with an increased risk of cleft lip with or without cleft palate. Signals concerning pregabalin, clonazepam and phenobarbital have also been identified. In a third study, prenatal exposure to valproic acid was found to be associated with increased risks of all early neurodevelopmental outcomes investigated compared with lamotrigine, with a dose-response relationship. Prenatal exposure to the other AEDs was not associated with an increased risk of any of these neurodevelopmental outcomes versus lamotrigine. Conducting pharmacoepidemiological studies based on the French health care databases enabled the health authorities to rapidly provide data on the use of AED during pregnancy in France. It also brought additional evidence to the international observational literature on the consequences of prenatal exposure to AEDs for the unborn child.

Des mutations hétérozygotes faux-sens dans le gène de la tubuline gamma TUBG1, ont été identifiées dans le contexte des malformations du développement cortical, associées à une déficience intellectuelle et à l'épilepsie. Ici, nous avons étudié par la technique d’électroporation in-utero et par des études in vivo, l’effet de quatre de ces variantes sur le développement cortical. Nous montrons que les mutations dans TUBG1 affectent le positionnement neuronal dans la plaque corticale, en perturbant la locomotion des neurones nouvellement nés, mais sans affecter la neurogenèse. Nous proposons que la γ-tubuline mutante affecte le fonctionnement global de ses complexes, et en particulier leur rôle dans la régulation de la dynamique des microtubules. De plus, nous avons développé un modèle de souris knock-in Tubg1Y92C/+ et évalué les conséquences de la mutation sur le développement cortical, les caractéristiques neuroanatomiques et le comportement. Les souris mutantes présentent une microcéphalie globale, des anomalies du néocortex et de l'hippocampe, des altérations du comportement et une susceptibilité épileptique. Ainsi, nous montrons que les souris Tubg1Y92C/+ miment au moins partiellement le phénotype humain et représentent donc un modèle pertinent pour d'autres investigations de la physiopathologie des malformations du développement cortical. / Missense heterozygous variants in the gamma tubulin gene TUBG1 have been linked to malformations of cortical development, associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning within the cortical wall, by a disrupting the locomotion of newly born neurons but without affecting neurogenesis. We propose that mutant γ-tubulin affects overall functioning of γ-tubulin complexes, and in particular their role in the regulation of microtubule dynamics. Additionally, we developed a knock-in Tubg1Y92C/+ model and assessed consequences of the mutation on cortical development, neuroanatomical features and behaviour. Mutant mice present with global microcephaly, neocortical and hippocampal abnormalities, behavioural alterations and epileptic susceptibility. Thus, we show that Tubg1Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of malformations of cortical development.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Trinta e cinco pacientes com malformações arteriovenosas raquimedulares (MAVR) foram tratados por via endovascular. Foram analisados os tipos de MAVR, bem como os aspectos clínicos e angiográficos pré e pós-tratamento endovascular. As MAVR mais freqüentes foram as fístulas arteriovenosas durais (FAD), com 17 pacientes, seguidas das malformações arteriovenosas intramedulares (MAI), fístulas arteriovenosas perimedulares (FAVP) e malformações arteriovenosas metaméricas (MAVM). A avaliação do resultado do tratamento foi dividida em sucesso técnico e clínico, sendo que o primeiro foi subdividido em sucesso técnico do procedimento e do tratamento. O sucesso técnico do procedimento foi caracterizado como oclusão total da MAVR ao final de um procedimento endovascular. O sucesso técnico do tratamento foi caracterizado pela oclusão definitiva da MAVR, independentemente do número de procedimentos. A recidiva foi definida como o reaparecimento da MAVR, identificada na angiografia durante o seguimento dos pacientes, independentemente do quadro clínico apresentado. A recidiva implicava em insucesso do procedimento, mas não necessariamente do tratamento. O sucesso clínico do tratamento foi considerado como a melhora parcial ou total dos sintomas após um período mínimo de acompanhamento de 6 meses. Nas FAD, houve predomínio do sexo masculino e da faixa etária acima dos 36 anos. O tratamento endovascular das FAD mostrou sucesso do procedimento na maioria dos casos, porém com recidiva da lesão em 56,7% dos mesmos. Quando usadas partículas, observou-se recidiva em 73,3% dos procedimentos, porém com sucesso do tratamento em 66,7 dos pacientes. Quando utilizado o adesivo tissular (\"cola\"), houve recidiva em 11,1% dos procedimentos e sucesso do tratamento em 88,9% dos pacientes. A melhora clínica foi obtida em 64,7% dos pacientes. Dos 10 pacientes tratados com MAI, a faixa etária mais freqüente foi dos 19 aos 35 anos de idade e predomínio do sexo masculino. O tratamento endovascular das MAI mostrou sucesso do procedimento em 53,3% e recidiva da lesão em 6,7% dos pacientes. O sucesso do procedimento também foi superior quando usada cola, atingindo 63,6% dos procedimentos e apenas 25,0% com partículas. O sucesso do tratamento foi de 80,0% e a melhora clínica foi observada em 40,0% dos pacientes. Somente 1 paciente com MAVM foi tratado. O tratamento objetivou a embolização parcial da lesão para alívio dos sintomas, resultado que foi obtido com sucesso. Nas FAVP houve predomínio do sexo masculino e a faixa etária mais acometida foi dos 19 aos 35 anos. O tratamento endovascular das FAVP mostrou sucesso do procedimento em 75,0% dos pacientes e ausência de recidiva. O sucesso do tratamento foi de 85,7%, com melhora clínica em todos os pacientes. O nosso estudo mostrou que as MAVR podem ser tratadas de maneira eficiente e segura através da embolização. O seguimento dos pacientes tratados com cola mostrou menor índice de recidiva do que aqueles tratados com partículas. Após a embolização, houve melhora significativa no padrão da marcha nos pacientes com FAD e MAI / Endovascular treatment was used in 35 patients with spinal cord arteriovenous malformations (SCAVM). SCAVM types, along with clinical and angiographic features of pre-op and post-op endovascular treatments were analyzed. Seventeen patients had dural arteriovenous fístulas (DAVF), being this type the most frequent SCAVM, followed by intramedullary arteriovenous malformations (IAVM), perimedullary arteriovenous fístulas (PAVF) and metameric arteriovenous malformations (MAVM). Evaluation of treatment results was divided into technical and clinical success, being the first subdivided into technical success of the procedure and treatment. The procedural\'s technical success was characterized by total SCAVM occlusion at the end of an endovascular procedure. Technical success of the treatment was characterized by definitive occlusion of the SCAVM, independent of the number of procedures. Recurrence was defined as reappearance of SCAVM, identified on angiograms during patient follow up, independent of the observed clinical situation. Recurrence implied in an unsuccessful procedure but not necessarily in treatment failure. Treatment\'s clinical success was considered partial or total symptom improvement after a minimum 6 month period follow up. Male and age over 36 years was preponderate in DAVF. Endovascular treatment in DAVF had procedural success in most cases, but with lesion recurrence in 56,7% of these patients. When particulate embolic agents were used, recurrence occurred in 73,3% of the procedures but with treatment success in 66,7% of these patients. When liquid tissue adhesive was used, there was 11,1% of recurrence and 88,9% in treatment success in these patients. Clinical improvement occurred in 64,7% of these patients. Male predominance and age between 19 to 35 years was more frequent in the 10 treated patients with IAVM. IAVM endovascular treatment was a procedural success in 53,3% and lesion recurrence in 6,7% of these patients. Procedural success was also superior when liquid tissue adhesive was used, up to 63,6% of these procedures and, only 25,0% with particulate embolic agents. Treatment success occurred in 80,0% and clinical improvement seen in 40,0% of these patients. Only 1 patient with MAVM was treated. Aim in treatment was partial lesion embolization to mitigate symptoms, which was successfully achieved. Male predominance and age between 19 to 35 years occurred in PAVF. PAVF endovascular treatment had procedural success in 75,0% and no recurrences in these patients. Treatment success occurred in 85,7% and clinical improvement in all patients. This study demonstrates that SCAVM can be treated efficiently and safely with endovascular embolization. Patient follow up revealed fewer recurrences in those treated with liquid tissue adhesive than in those with particulate embolic agents. After DAVF and IAVM embolization, patients had significant improvement in their gait

Introdução: As malformações arteriovenosas são lesões congênitas caracterizadas por uma rede capilar malformada (nidus) que comunica o sistema arterial e venoso em um mecanismo de shunt arteriovenoso não irrigando tecido normal. Devido ao shunt arteriovenoso as MAVs apresentam alto fluxo sanguíneo, podem ser assintomáticas ou sintomáticas dependendo de sua localização. O tratamento das MAV busca a exclusão circulatória completa do nidus o que pode ser alcançado por meio de ressecção cirúrgica, radiocirurgia ou embolização endovascular. Objetivo: descrição técnica de uma série de dois casos de MAVs de localização periférica (fora do sistema nervoso central), que foram tratadas através da embolização com uso de cateter-balão de duplo lúmen. Materiais e métodos: Trata-se de estudo retrospectivo que avaliou os pacientes submetidos a embolização com cateter-balão de duplo lúmen para o tratamento das MAVs periféricas pelo Setor de Radiologia Intervencionista do HCFMRP-USP. Resultados: Os achados encontrados foram consistentes com a literatura atual demonstrando altas taxas de sucesso técnico e clínico, sem complicações inerentes ao procedimento. Conclusão: O uso destes dispositivos se mostrou mais eficaz em obliterar completamente o nidus deste tipo de lesão, além de reduzir o tempo de procedimento, a exposição à fluoroscopia. Neste estudo foi obtida a exclusão angiográfica completa das MAV em uma única sessão de embolização e não foram descritas complicações relacionadas ao tratamento. / Introduction: Arteriovenous malformations are congenital lesions characterized by a malformed capillary network (nidus) that communicates the arterial and venous system in an arteriovenous shunt mechanism and does not irrigate normal tissue. Due to the arteriovenous shunt AVMs present high blood flow, they may be asymptomatic or symptomatic depending on their location. The AVM treatment seeks the complete circulatory exclusion of the nidus which can be achieved by means of surgical resection, radiosurgery or endovascular embolization. Objectives: A technical description of a series of two cases of peripheral AVMs that were treated through embolization using a dual-lumen balloon catheter. Materials and methods: This is a retrospective study that evaluated patients undergoing embolization with a double-lumen balloon catheter for the treatment of peripheral AVMs by the Interventional Radiology Sector of HCFMRP-USP. Results: The findings were consistent with the current literature demonstrating high rates of technical and clinical success, without complications inherent to the procedure. Conclusion: The use of these devices has been shown to be more effective in completely obliterating the nidus of this type of lesion, in addition to reducing the procedure time, exposure to fluoroscopy. In this study complete angiographic exclusion of AVM was obtained in a single embolization session and no complications related to treatment were described.