O nosso objetivo foi de avaliar evolutivamente a perda da força muscular e das habilidades motoras, bem como a progressão da distribuição da fraqueza muscular nos diferentes segmentos dos membros superiores em pacientes com distrofia muscular de Duchenne em corticoterapia. Selecionamos seguintes testes de fácil aplicação: Teste de força Manual Muscular Escala Medical Research Council; Teste ABC provas de coordenação visual-motora e fatigabilidade provas n° 1, 3, 7 e 8; Grau funcional de Brooke; Índice de Barthel. Os testes foram aplicados em 40 pacientes com idades entre 5 e 15 anos, deambulantes e não deambulantes, os quais foram avaliados três vezes, com intervalos de seis meses entre cada avaliação. Os resultados mostraram que a progressão da distribuição da força muscular nos membros superiores ocorreu dos segmentos proximais para os distais em todos os pacientes e foi maior nos pacientes não deambulantes e com maior idade. O ato de escrever (pegada no lápis e/ou caneta) não foi influenciado pela progressão; no entanto, o aumento da fatigabilidade foi um fator limitante contribuindo para a redução do ritmo e da qualidade da escrita. O grau funcional de Brooke confirmou a variação das medidas de força muscular e nas atividades de vida diária o nível de dependência foi maior nos pacientes com maior idade, acontecendo nestes compensações funcionais importantes que lhes permitiram realizar a atividade de forma adaptada. / Our aim was to analyze the progression of the involvement of muscle strength and functional motor hability as well as the progression of the weakness pattern in the upper limbs of children with Duchenne muscular dystrophy who were receiving steroid therapy. We evaluated 40 patients with DMD, aged 5-15 years, by using the following simple tests: MRC score based on the upper limbs muscles; ABC tests number 1, 3, 7 and 8 for assessing visual motor coordination and fatigability; Brooke functional ability scale and modified Barthel index. All boys were evaluated every 6 months along a period of 18 months. The loss of muscular strength showed a proximal to distal progression and was greater in non- ambulant and in older patients. The act of writing (to hold pencil or pen) was not influenced by the progression; however, the fatigability increased and was a limiting factor for the speed and the quality of the hand writing. The Brooke functional ability scale confirmed the changes in the muscular strength. The performance in daily activities showed a greater dependence in the older patients who adopted functional compensations for performing the activities in an adapted way.

Les techniques de criblage actuelles (in vitro et in silico) sont dépendantes des efforts menés en biologie médicinale pour identifier des cibles biologiques pertinentes ; cibles difficiles à définir pour les maladies génétiques dites "perte de fonction". De plus, les composés issus de ces cribles s'avèrent souvent inefficaces et/ou toxiques une fois confrontés à la complexité physiologique d'un organisme entier. Pour contourner ce problème, nous proposons d'utiliser le nématode C. elegans, notamment pour des maladies répondant aux critères suivants : i) physiopathologie complexe et/ou mal comprise excluant le développement à court terme de médicaments sur une base rationnelle, ii) peu d’espoir de thérapie génique/cellulaire à court terme, iii) conservation chez C. elegans du gène relié à la maladie humaine et induisant un phénotype exploitable une fois inactivé. Nous démontrons ici que ce petit nématode permet de tester, à moindre coût, un grand nombre de composés chimiques tout en conservant la complexité physiologique d'un animal entier. De plus, la souplesse génétique de cet animal permet d'apporter rapidement des informations sur le mode d'action des composés identifiés. Ainsi, en plus du but initial visant à identifier des molécules bioactives à intérêt thérapeutique, cette approche peut permettre de dégager de nouvelles cibles moléculaires utiles pour l'industrie chimique, et cruciales pour la recherche de traitements contre les maladies perte de fonction. Finalement, nous présentons comment mettre en place une telle stratégie, notamment pour la myopathie de Duchenne, l'amyotrophie spinale et le syndrome de Schwartz-Jampel. Enfin, nous présentons les résultats obtenus lors des différentes campagnes de criblage, les validations des molécules les plus prometteuses et les travaux effectués pour tenter de comprendre leur mode d'action chez le nématode. / Current high-throughput screening methods for drug discovery rely on the existence of targets. Moreover, most of the hits generated during screenings turn out to be invalid after further testing in animal models. To by-pass these limitations, efforts are now being made to screen chemical libraries on whole animals. One of the most commonly used animal model in biology is the murine model Mus musculus. However, its cost limits its use in large-scale therapeutic screening. In contrast, the nematode Caenorhabditis elegans is gaining momentum as screening chemical tool. This tiny worm combines genetic amenability, low cost, and culture conditions that are compatible with large-scale screens. Its main advantage is to allow high-throughput screening in a whole-animal context. Moreover, its use is not dependent on the prior identification of a target and permits the selection of compounds with an improved safety profile. Here, we introduce this approach with the Duchenne Muscular Dystrophy, the Spinal Muscular Dystrophy and the Schwartz-Jampel syndrome. We present the methodology used with each model to screen up to 7,000 compounds and the results of these screening campaigns. We further present the validation of our best hits and try to understand their mechanism of action.

Les techniques de criblage actuelles (in vitro et in silico) sont dépendantes des efforts menés en biologie médicinale pour identifier des cibles biologiques pertinentes ; cibles difficiles à définir pour les maladies génétiques dites "perte de fonction". De plus, les composés issus de ces cribles s'avèrent souvent inefficaces et/ou toxiques une fois confrontés à la complexité physiologique d'un organisme entier. Pour contourner ce problème, nous proposons d'utiliser le nématode C. elegans, notamment pour des maladies répondant aux critères suivants : i) physiopathologie complexe et/ou mal comprise excluant le développement à court terme de médicaments sur une base rationnelle, ii) peu d'espoir de thérapie génique/cellulaire à court terme, iii) conservation chez C. elegans du gène relié à la maladie humaine et induisant un phénotype exploitable une fois inactivé. Nous démontrons ici que ce petit nématode permet de tester, à moindre coût, un grand nombre de composés chimiques tout en conservant la complexité physiologique d'un animal entier. De plus, la souplesse génétique de cet animal permet d'apporter rapidement des informations sur le mode d'action des composés identifiés. Ainsi, en plus du but initial visant à identifier des molécules bioactives à intérêt thérapeutique, cette approche peut permettre de dégager de nouvelles cibles moléculaires utiles pour l'industrie chimique, et cruciales pour la recherche de traitements contre les maladies perte de fonction. Finalement, nous présentons comment mettre en place une telle stratégie, notamment pour la myopathie de Duchenne, l'amyotrophie spinale et le syndrome de Schwartz-Jampel. Enfin, nous présentons les résultats obtenus lors des différentes campagnes de criblage, les validations des molécules les plus prometteuses et les travaux effectués pour tenter de comprendre leur mode d'action chez le nématode.

Author: Bc. Antonín Mařík Title: Capture of the abduction contracture of the hip joint as a biomechanical cause of idiopathic scoliosis The theme of the thesis is based on lectures and numerous publications by Professor Tomasz Karski, MD, PhD from Lublin, published in international journals (from the 1990s to the present). The work is based on the biomechanical cause of the "so-called idiopathic" scoliosis, the cause of which is considered primarily the restriction of adduction in the right hip joint - so-called an abduction contracture. This contracture is one of the symptoms of "Syndrome of Contracture" according to Prof. Hans Mau (Tübingen, Germany). The years-long prevailing "standing easy" attitude on the right lower limb is a manifestation of the abduction contracture in the right hip joint and the cause of scoliosis in two groups and three types of classification of "biomechanical" scoliosis according to Karski. The main object of the thesis is an objective assessment of the relationship between the abduction contracture of the right hip joint and the idiopathic scoliosis (IS) of the spine in the examined set of probands. Clinical and anthropological examinations were performed in a group of 20 patients with idiopathic scoliosis and 16 control probands, including specialized tests on the...

Author: Bc. Antonín Mařík Title: Capture of the abduction contracture of the hip joint as a biomechanical cause of idiopathic scoliosis The theme of the thesis is based on lectures and numerous publications by Professor Tomasz Karski, MD, PhD from Lublin, published in international journals (from the 1990s to the present). The work is based on the biomechanical cause of the "so-called idiopathic" scoliosis, the cause of which is considered primarily the restriction of adduction in the right hip joint - an abduction contracture. This contracture is one of the symptoms of "contractures and deformity syndrome" according to Prof. Hans Mau (Tübingen, Germany). The years-long prevailing "standing easy" attitude on the right lower limb is a manifestation of the restriction of abduction - the abduction contracture in the right hip joint and the cause of scoliosis in two groups and three types of classification of "biomechanical" scoliosis according to Karski. The main object of the thesis is an objective assessment of the relationship between the abduction contracture of the right hip joint and the idiopathic scoliosis of the spine in the examined set of probands. The thesis focuses, among other things, on the recent overview of the knowledge about idiopathic scoliosis, especially on diagnostics and...

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