La lutte contre le cancer est certainement l’un des défis majeurs de ce 21ème siècle. Les résistances qui émergent contre les agents de thérapie ciblée présentent un aspect particulièrement épineux de cette problématique. La thèse présentée ici s’inscrit dans ce cadre. Elle vise à développer des molécules bioactives pouvant circonvenir les résistances apparues contre les traitements de certaines hémopathies malignes : la leucémie myéloïde chronique (LMC) et le syndrome myélodysplasique (SMD). Après avoir mis au point une méthodologie de synthèse monotope permettant de transformer un azoture en un 5-alcynyl-1,2,3-triazole, nous avons synthétisé deux séries de produits : nucléosidique et non nucléosidique. Pour chacune de ces séries, des relations structure-activité ont été établies. Après plusieurs cycles d’optimisation, trois composés lead très efficaces contre des lignées cellulaires résistantes de LMC et SMD, ont été sélectionnés. De surcroît, leur mode d’action s’est révélé très intéressant : il repose (partiellement ou entièrement, suivant le composé) sur un processus cellulaire qui connaît un véritable regain d’intérêt, à savoir l’autophagie. Une évaluation in vivo a été réalisée et a permis de valider l’activité prometteuse de notre composé lead nucléosidique. Par ailleurs, des études visant à déterminer la localisation intracellulaire et les cibles moléculaires de nos produits sont actuellement en cours / The fight against cancer is certainly one of the biggest challenges of the 21st century. Resistance that comes up against targeted therapy agents presents a particularly important aspect of this issue. The thesis presented here takes part within that framework. It aims at developing bioactive molecules able to circumvent resistance that have emerged against the treatment of certain hematological malignancies: chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS). Having developed a one-pot synthesis methodology that converts azides into 5-alkynyl-1,2,3-triazole, we synthesized two series of products: nucleosidic and non-nucleosidic. For each of these series, structure-activity relationships have been established. After running several cycles of optimization, three lead compounds particularly active on resistant cell lines of CML and MDS were selected. Further, their mode of action proved to be very interesting. It is based (partially or fully, depending on the compound) on a cellular process, which is experiencing a real renewed interest, the autophagy. An in vivo evaluation confirmed the promising activity of our nucleosidic lead compound. Moreover, studies aiming at determining the intracellular localization and molecular targets of our products are currently in progress

Cognitive impairment, “Chemofog”, has been well established as a negative outcome of otherwise successful medical radiation treatments. Mitigation of this negative feature would dramatically increase quality of life for those recovering from cancer treatment. There is currently no known intervention to protect or restore cognitive function of patients undergoing radiation treatments. Development of a multiple ingredient dietary supplement (MDS) is meant to offer a non-invasive therapy to help mitigate risk and decrease damage to individuals. The MDS was originally designed to off-set 5 key mechanisms associated with aging including oxidative damage, inflammation, impaired glucose metabolism, mitochondrial dysfunction and membrane deterioration. Radiation damage shares many of the same deficiencies that develop with age and supplementation with MDS would impact many of the same pathways. Changes in cytokine profile (inflammation markers), and biomarkers of behavioural functions, sensory functions, and oxidative damage provide preliminary evidence of MDS impacts. / Thesis / Bachelor of Science (BSc) / Cognitive impairment, “Chemofog”, has been well established as a negative outcome of otherwise successful medical radiation treatments. Mitigation of this negative feature would dramatically increase quality of life for those recovering from cancer treatment. There is currently no known intervention to protect or restore cognitive function of patients undergoing radiation treatments. Development of a multiple ingredient dietary supplement (MDS) is meant to offer a non-invasive therapy to help mitigate risk and decrease damage to individuals. The MDS was originally designed to off-set 5 key mechanisms associated with aging including oxidative damage, inflammation, impaired glucose metabolism, mitochondrial dysfunction and membrane deterioration. Radiation damage shares many of the same deficiencies that develop with age and supplementation with MDS would impact many of the same pathways.

Le mouvement de la marche est un processus essentiel de l'activité humaine et aussi le résultat de nombreuses interactions collaboratives entre les systèmes neurologiques, articulaires et musculo-squelettiques fonctionnant ensemble efficacement. Ceci explique pourquoi une analyse de la marche est aujourd'hui de plus en plus utilisée pour le diagnostic (et aussi la prévention) de différents types de maladies (neurologiques, musculaires, orthopédique, etc.). Ce rapport présente une nouvelle méthode pour visualiser rapidement les différentes parties du corps humain liées à une possible asymétrie (temporellement invariante par translation) existant dans la démarche d'un patient pour une possible utilisation clinique quotidienne. L'objectif est de fournir une méthode à la fois facile et peu dispendieuse permettant la mesure et l'affichage visuel, d'une manière intuitive et perceptive, des différentes parties asymétriques d'une démarche. La méthode proposée repose sur l'utilisation d'un capteur de profondeur peu dispendieux (la Kinect) qui est très bien adaptée pour un diagnostique rapide effectué dans de petites salles médicales car ce capteur est d'une part facile à installer et ne nécessitant aucun marqueur. L'algorithme que nous allons présenter est basé sur le fait que la marche saine possède des propriétés de symétrie (relativement à une invariance temporelle) dans le plan coronal. / The gait movement is an essential process of the human activity and also the result of coordinated effort between the neurological, articular and musculoskeletal systems. This motivates why gait analysis is important and also increasingly used nowadays for the (possible early) diagnosis of many different types (neurological, muscular, orthopedic, etc.) of diseases. This paper introduces a novel method to quickly visualize the different parts of the body related to an asymmetric movement in the human gait of a patient for daily clinical. The goal is to provide a cheap and easy-to-use method to measure the gait asymmetry and display results in a perceptually relevant manner. This method relies on an affordable consumer depth sensor, the Kinect. The Kinect was chosen because this device is amenable for use in small, confined area, like a living room. Also, since it is marker-less, it provides a fast non-invasive diagnostic. The algorithm we are going to introduce relies on the fact that a healthy walk has (temporally shift-invariant) symmetry properties in the coronal plane.

No description available.

近年來，中華民國台灣地區國民所得不斷提高，行的品質逐漸受到重視，國內進口轎 車市場對量與質的需求均顯現出相當具有成長潛力的態勢，進口轎車代理商及貿易商 不斷引進各價位的轎車，且國產車業者亦不斷強化競爭利基以迎戰進口車，使得這個 市場的競爭日益激烈。 依分層抽樣原理，本研究以問卷訪問方式抽取台北市２０歲以上之５０６位消費者為 調查對象，期以對進口汽車之偏好態度為市場區隔的基礎，並結合潛在購買強度指標 及阻擾購車指標，藉以選擇其潛在目標市場，進而深入瞭解消費者之特性，據以研擬 開發潛在市場之有效行銷策略。 其次，本研究採用計量多元尺度法（Metric MDS）分別探討高、中、低三等價位共１ ５種品牌之進口轎車及３種品牌之國產車在市場上之競爭態勢，以作為業者引進車種 之參考。

Funding of services to residents in publicly funded long-term care (LTC) facilities has historically rested upon a list of physical needs. However, more than 60% of residents in nursing homes have dementia; a condition in which physical needs are only a part of the overall clinical picture. Since past funding formulas focused primarily on the physical characteristics of residents, the Ontario government has adopted the RUG (Resource Utilization Groups)-III (34 Group) for use in LTC facilities which follows the adoption of the Minimum Data Set (MDS) 2.0 assessment instrument. Some still question whether the newer formula adequately reflects the care needs of residents with dementia despite its validation in many countries. The purpose of this study was to determine the comprehensiveness of the RUG-III (34 Group) in addressing the needs of residents with dementia living in LTC. First, a critical systematic review of the literature was conducted to determine the needs of residents with dementia. Numerous electronic databases were searched for articles published between January 2000 and September 2010, and later cross-referenced. Second, needs identified from the literature were matched to the items of the RUG-III which are selected variables of the MDS 2.0. Third, the priority of the items in the RUG-III was analysed in accordance with the importance of the identified needs. The documented needs were taken from 68 studies and classified into 19 main categories. The needs most supported by the literature were the management of behavioural problems, social needs, the need for daily individualized activities/care and emotional needs/personhood. Among the needs identified, activities of daily living (ADLs), cognitive needs and general overall physical health met the most RUG-III items. These needs were found to be well represented within the system. Other needs of importance such as social needs are not thoroughly considered in the grouping methodology though matched to MDS variables. The fact that these needs are not well addressed in the RUG-III poses concerns. Future research is needed to validate the significance of these needs. Considerations should be made as to the adequacy of the funding system and the allocation of funding.

No description available.

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

As síndromes mielodisplásicas (SMD) se caracterizam por terem uma hematopoese displásica, citopenias e pelo risco de progressão para leucemia mielóide aguda. O diagnóstico baseia-se na clínica e nos achados citomorfológicos da medula óssea (MO) e citogenéticos. Na fase inicial ou quando a MO é hipocelular o diagnóstico é difícil e a citogenética frequentemente é normal. A imunofenotipagem (IMF) tem sido cada vez mais utilizada nos casos de SMD em adultos e pouco explorada na SMD pediátrica. Os nossos objetivos foram: estudar os casos de SMD e doenças correlatas (LMA relacionada à SMD: LMA-rMD; leucemia mielomonocítica crônica: LMMC e leucemia mielomonocítica juvenil: LMMJ) em adultos e crianças, associando os dados clínicos e laboratoriais aos obtidos pela IMF, que utilizou um painel de anticorpos monoclonais para as várias linhagens medulares. No período compreendido entre 2000 e 2010 foram estudados 87 pacientes (64 adultos e 23crianças) oriundos do HUPE/UERJ e IPPMG/UFRJ e 46 controles (23 adultos e 20 crianças). Todos os doentes realizaram mielograma, biópsia óssea, citogenética, citoquímica e estudo imunofenotípico. Segundo os critérios da OMS 50 adultos foram classificados como SMD, 11 como LMA-rMD e 3 LMMC. Entre as crianças 18 eram SMD, 2 LMA e 3 LMMJ. Os pacientes adultos com SMD foram divididos em alto risco (n = 9; AREB-1 e AREB-2) e baixo risco (n=41; CRDU, CRDM, CRDM-SA, SMD-N e SMD-5q-). As crianças com SMD em CR (n=16) e AREB (n = 2). Anormalidades clonais recorrentes foram encontradas em 22 pacientes adultos e em 7 crianças. Na análise da IMF foi utilizada a metodologia da curva ROC para a determinação dos valores de ponto de corte a fim de identificar os resultados anormais dos anticorpos monoclonais nos pacientes e nos controles, permitindo determinar a sensibilidade e especificidade desses em cada linhagem. A IMF foi adequada para a análise em todos os pacientes e 3 ou mais anormalidades foram encontradas. A associação da IMF aumentou a sensibilidade da análise morfológica na linhagem eritróide de 70 para 97% nos adultos e de 59 para 86% nas crianças; na linhagem granulocítica de 53 para 98% nos adultos e de 50 para 100% nas crianças. Nos monócitos, onde a morfologia não foi informativa, mostrou uma sensibilidade de 86% nos adultos e 91% nas crianças. Enquanto que na linhagem megacariocítica, não analisada pela IMF, a morfologia mostrou uma sensibilidade de 95% nos adultos e 91% nas crianças. Na população de blastos foi expressiva a ausência de precursores linfóide B (em 92% dos adultos e em 61% das crianças). Os resultados observados nas crianças com SMD foram semelhantes aos encontrados nos adultos. Em conclusão, nossos resultados mostraram que a IMF é um método complementar ao diagnóstico da SMD e doenças correlatas tanto em adultos quanto em crianças podendo contribuir para o reconhecimento rápido e precoce dessas enfermidades, devendo ser incorporado aos procedimentos de rotina diagnóstica. / As síndromes mielodisplásicas (SMD) se caracterizam por terem uma hematopoese displásica, citopenias e pelo risco de progressão para leucemia mielóide aguda. O diagnóstico baseia-se na clínica e nos achados citomorfológicos da medula óssea (MO) e citogenéticos. Na fase inicial ou quando a MO é hipocelular o diagnóstico é difícil e a citogenética frequentemente é normal. A imunofenotipagem (IMF) tem sido cada vez mais utilizada nos casos de SMD em adultos e pouco explorada na SMD pediátrica. Os nossos objetivos foram: estudar os casos de SMD e doenças correlatas (LMA relacionada à SMD: LMA-rMD; leucemia mielomonocítica crônica: LMMC e leucemia mielomonocítica juvenil: LMMJ) em adultos e crianças, associando os dados clínicos e laboratoriais aos obtidos pela IMF, que utilizou um painel de anticorpos monoclonais para as várias linhagens medulares. No período compreendido entre 2000 e 2010 foram estudados 87 pacientes (64 adultos e 23crianças) oriundos do HUPE/UERJ e IPPMG/UFRJ e 46 controles (23 adultos e 20 crianças). Todos os doentes realizaram mielograma, biópsia óssea, citogenética, citoquímica e estudo imunofenotípico. Segundo os critérios da OMS 50 adultos foram classificados como SMD, 11 como LMA-rMD e 3 LMMC. Entre as crianças 18 eram SMD, 2 LMA e 3 LMMJ. Os pacientes adultos com SMD foram divididos em alto risco (n = 9; AREB-1 e AREB-2) e baixo risco (n=41; CRDU, CRDM, CRDM-SA, SMD-N e SMD-5q-). As crianças com SMD em CR (n=16) e AREB (n = 2). Anormalidades clonais recorrentes foram encontradas em 22 pacientes adultos e em 7 crianças. Na análise da IMF foi utilizada a metodologia da curva ROC para a determinação dos valores de ponto de corte a fim de identificar os resultados anormais dos anticorpos monoclonais nos pacientes e nos controles, permitindo determinar a sensibilidade e especificidade desses em cada linhagem. A IMF foi adequada para a análise em todos os pacientes e 3 ou mais anormalidades foram encontradas. A associação da IMF aumentou a sensibilidade da análise morfológica na linhagem eritróide de 70 para 97% nos adultos e de 59 para 86% nas crianças; na linhagem granulocítica de 53 para 98% nos adultos e de 50 para 100% nas crianças. Nos monócitos, onde a morfologia não foi informativa, mostrou uma sensibilidade de 86% nos adultos e 91% nas crianças. Enquanto que na linhagem megacariocítica, não analisada pela IMF, a morfologia mostrou uma sensibilidade de 95% nos adultos e 91% nas crianças. Na população de blastos foi expressiva a ausência de precursores linfóide B (em 92% dos adultos e em 61% das crianças). Os resultados observados nas crianças com SMD foram semelhantes aos encontrados nos adultos. Em conclusão, nossos resultados mostraram que a IMF é um método complementar ao diagnóstico da SMD e doenças correlatas tanto em adultos quanto em crianças podendo contribuir para o reconhecimento rápido e precoce dessas enfermidades, devendo ser incorporado aos procedimentos de rotina diagnóstica.

Funding of services to residents in publicly funded long-term care (LTC) facilities has historically rested upon a list of physical needs. However, more than 60% of residents in nursing homes have dementia; a condition in which physical needs are only a part of the overall clinical picture. Since past funding formulas focused primarily on the physical characteristics of residents, the Ontario government has adopted the RUG (Resource Utilization Groups)-III (34 Group) for use in LTC facilities which follows the adoption of the Minimum Data Set (MDS) 2.0 assessment instrument. Some still question whether the newer formula adequately reflects the care needs of residents with dementia despite its validation in many countries. The purpose of this study was to determine the comprehensiveness of the RUG-III (34 Group) in addressing the needs of residents with dementia living in LTC. First, a critical systematic review of the literature was conducted to determine the needs of residents with dementia. Numerous electronic databases were searched for articles published between January 2000 and September 2010, and later cross-referenced. Second, needs identified from the literature were matched to the items of the RUG-III which are selected variables of the MDS 2.0. Third, the priority of the items in the RUG-III was analysed in accordance with the importance of the identified needs. The documented needs were taken from 68 studies and classified into 19 main categories. The needs most supported by the literature were the management of behavioural problems, social needs, the need for daily individualized activities/care and emotional needs/personhood. Among the needs identified, activities of daily living (ADLs), cognitive needs and general overall physical health met the most RUG-III items. These needs were found to be well represented within the system. Other needs of importance such as social needs are not thoroughly considered in the grouping methodology though matched to MDS variables. The fact that these needs are not well addressed in the RUG-III poses concerns. Future research is needed to validate the significance of these needs. Considerations should be made as to the adequacy of the funding system and the allocation of funding.