Micelles polyioniques ternaires pour la libération intracellulaire d’oligonucleotides

Les oligonucléotides (ONs) antisens présentent un fort potentiel en tant qu’agents thérapeutiques. Toutefois, leurs propriétés physicochimiques limitent leur utilisation en thérapie génique. Pour pallier aux divers obstacles, des systèmes de vectorisation, tels que les micelles polyioniques (PICMs), ont été développés. Grâce à leur structure unique, les micelles protégent l’ON contre une dégradation prématurée et le couplage d’un ligand à leur surface augmente leur spécificité et leur internalisation. Dans d’autres systèmes, un polymère adjuvant aux propriétés pH-sensibles peut être ajouté pour faciliter la sortie de l’endosome et augmenter l’efficacité de l’ON. L’objectif général de ce mémoire était de mettre au point des PICMs ternaires ciblées pour l’administration d’ONs. Ces micelles assureraient à la fois l’internalisation cellulaire de leur cargaison en interagissant avec des récepteurs cellulaires et sa fuite de l’endosome grâce à un mécanisme de déstabilisation de la membrane endosomale. Pour cela, des PICMs composées d’un copolymère cationique de type poly(éthylène glycol)-bloc-poly(méthacrylate d’(alkylamino)éthyle) et d’un copolymère d’acide méthacrylique ont été préparées. Les propriétés physicochimiques de ces vecteurs ont démontré qu’ils permettaient une condensation efficace de l’acide nucléique et ce, indépendamment de la nature du polymère cationique et de l’acide nucléique. Finalement, une approche de couplage par pont disulfure a été développée afin de greffer au copolymère un fragment d’anticorps dirigé contre les récepteurs de la transferrine. En conclusion, ces travaux démontrent la versatilité et le potentiel des PICMs ternaires en tant que vecteurs d’acide nucléique, et proposent une méthodologie de couplage d’un ligand afin de formuler des PICMs ciblées.Antisens oligonucleotides (ONs) present great potential as therapeutic agents. However, their physicochemical properties hinder their use in gene therapy. Targeting systems, such as polyion complex micelles (PICMs), have been proposed to circumvent the main hurdles related to ON delivery. Their unique core/shell structure can protect the ON against premature degradation and the coupling of a ligand on their surface can increase their specificity and internalization. In other systems, a polymer with pH-sensitive properties can be added to facilitate the release of the ON from the endosome and increase its efficiency. The present work was aimed at optimizing ternary PICMs targeted for the delivery of antisens ON. Such systems would provide both cellular internalization of cargo by interaction with receptors on the surface of cell membranes and escape from the endosome through a mechanism of destabilization of the endosomal membrane. PICMs composed of cationic copolymers of poly(ethylene glycol)-bloc-poly((alkylamino)ethyl methacrylate) with a methacrylic acid copolymer adjuvant were prepared. Their physicochemical properties suggest that efficient complexation of nucleic acids was obtained, regardless of the nature of the cationic polymer and the nature of the nucleic acid. Finally, a synthetic approach was developed for the conjugation of an antibody fragment directed against the transferrin receptor via a labile disulfide bond at the end of the cationic copolymer. In conclusion, the work presented herein displays the versatility and potential of ternary PICMs as vehicles for the delivery of ONs and also provides a method for the conjugation of a ligand to generate targeted ternary PICMs

Arthroscopic Suprapectoral Biceps Tenodesis: The Best of Both Worlds

Biceps tendinopathy and superior labrum anterior posterior lesions are a common source of shoulder pain and disability and can be effectively treated with biceps tenodesis. There are a variety of open and arthroscopic tenodesis techniques, but no one technique has demonstrated superiority. Arthroscopic techniques often disregard the extra-articular portions of the biceps tendon as a potential source of pain. Open techniques address this concern; however, they can be associated with wound complications, increased blood loss, nerve injury, and disruptions to surgical workflow. Here, we describe an all arthroscopic tenodesis technique at the suprapectoral zone of the tendon. This method addresses extra-articular sources of pain, while limiting the potential pitfalls of open surgery

Effets d'agents biologiques, administrés localement, sur la formation des tissus calcifiés

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

Avaliação da suscetibilidade de falhas em estruturas metálicas de linhas de transmissão

Resumo: Linhas de transmissão aéreas estão expostas a diversos riscos associados ao meio, às alterações de características construtivas e às variações climáticas. Muitas vezes, estes riscos podem trazer sérios danos, incorrendo em quedas de estruturas. A queda de uma estrutura pode causar a interrupção do fornecimento de energia de uma localidade por longo período, bem como gera custos associados na reconstrução de trechos do sistema elétrico, no lucro cessante da concessionária e em indenizações decorrentes da falta de energia. Devido à importância das linhas aéreas, uma análise quantitativa de suas características com o intuito de identificá-las e mitigá-las tem muito a contribuir para o planejamento, operação e manutenção de linhas. Portanto, este trabalho tem como objetivo avaliar a suscetibilidade das estruturas quanto a quedas a partir da análise de bancos de dados de estruturas e de informações sobre as que sofreram danos utilizando a Teoria de Conjuntos Aproximados (Rough Sets) e o Método de Regressão Logística. A partir da aplicação destas técnicas, pretendese extrair conhecimento sobre quais parâmetros e variáveis influenciam o comportamento mecânico das linhas em operação e podem ser utilizados para diagnosticar possíveis quedas de torres. Estas informações podem se tornar uma base para direcionar os investimentos de reforço de estruturas, evitando a ocorrência de longos desligamentos e altos custos por decorrência de danos em torres de linhas de transmissão. Os resultados são obtidos utilizando o histórico de duas mil estruturas metálicas atualmente em operação no estado do Paraná, a partir das quais se geram regras a fim de identificar a suscetibilidade das estruturas quanto a quedas. A partir dos resultados encontrados é possível fazer uma comparação entre os métodos e concluir sobre sua capacidade de apresentar dados suficientes para a realização de projetos de melhorias nas estruturas apontadas

Distribution maps of twenty-four Mediterranean and European ecologically and economically important forest tree species compiled from historical data collections

Species distribution maps are often lacking for scientific investigation and strategic management planning at international level. Here, we present the range-wide, natural distribution maps of twenty-four Mediterranean and European forest-tree species of key ecological and economic importance in the Mediterranean basin. Data on the geographic distribution of the twenty-four tree species were compiled from over one hundred published sources, making this contribution one of the most extensive resource available from historical data. Dataset can be accessed at: https://doi.org/10.5281/zenodo.822953. Associated metadata can be accessed at: http://www.fao.org/geonetwork/srv/en/metadata.show?id=56996. These data provide key spatial information to further investigate species occurrence-environment relationships, provide a baseline to assess the future impact of climate change, identify marginal populations with specific genetic resources, among other possible applications

Restricciones físicas en mayores institucionalizados. Prevalencia, factores asociados e impacto sobre la funcionalidad del anciano

Antecedentes: Hay una gran variabilidad de datos sobre la prevalencia y los factores que se asocian al uso de restricciones físicas en el medio institucional. Estos dispositivos son utilizados habitualmente para garantizar la seguridad de los ancianos o la integridad física de residentes y trabajadores. A pesar de su supuesta finalidad protectora, su aplicación puede originar consecuencias negativas tanto a nivel físico como psicológico, aumentando el riesgo de lesiones graves e incluso la muerte. Objetivos: Describir la prevalencia de restricciones físicas en los ancianos institucionalizados en 5 residencias de la provincia de Valencia, los factores asociados al uso de restricciones y el impacto de las mismas sobre la funcionalidad, el estado cognitivo, el riesgo de caídas, el riesgo de úlceras y el estado nutricional de los residentes. Material y método: Se realizó un estudio observacional, longitudinal, retrospectivo, de cohortes, con seguimiento de los ancianos institucionalizados en 5 residencias durante el periodo mayo de 2008 a enero de 2013. Se recogió información de 1.634 residentes. El seguimiento se realizó cada 6 meses. La variable principal fue la prevalencia y los descriptivos muestrales incluyeron la edad, sexo, tipo de residentes, estado al alta, bajas voluntarias y tiempo de ingreso en años. Se distingueron dos grupos, uno formado por residentes con restricciones y otro sin restricciones. Se utilizaron los resultados de 5 escalas de valoración (Barthel, MEC, Norton, Tinetti y MNA) para evaluar la funcionalidad, el estado cognitivo, el riesgo de úlceras por presión, el riesgo de caídas y el estado nutricional de los residentes y, a través del análisis de la varianza, se comparó el estado físico y cognitivo de los residentes y su evolución (longitudinal), primero en función del uso de restricción física, y segundo del tiempo de estancia. Resultados: La muestra con información basal estuvo formada por 1.257 residentes, mayoritariamente mujeres (66 %), y con una edad media de 80 años. La prevalencia de restricción física obtenida fue de 23,8 %. Los residentes con restricción tuvieron una edad media de 81 años y la prevalencia entre sexos a nivel basal fue equiparable. Las restricciones físicas más utilizada fueron las de silla (cinturones pélvicos y chalecos), seguidas por las de silla asociadas a las restricciones de cama (cinturones y sábanas de sujeción) y por las de cama (solas). La prevalencia de uso de restricción de los residentes dados de baja por defunción fue de 31 %, con una correlación alta y significativa entre la relación uso de restricción y las defunciones. Las restricciones físicas se aplicaron mayoritariamente en el primero año de ingreso (86 %) y el principal motivo de su aplicación fue la prevención de caídas (87 %). En la comparación entre grupos de residentes con y sin restricción, hubo una asociación estadísticamente significativa entre el uso de restricciones y la baja funcionalidad, el deterioro cognitivo severo, el riesgo de úlceras por presión, el riesgo de caídas y el mal estado nutricional de los residentes. Además, se realizó un seguimiento del estado de 201 participantes de los que se tenía información de al menos 36 meses. En la evolución en función del tiempo, hubo diferencias estadísticamente significativas para la funcionalidad, riesgo de úlceras y riesgo de caídas (p<0.05). No hubo diferencias significativas en las interacciones tiempo-grupos (p>0.05). Conclusiones: La prevalencia del uso de restricciones físicas en las residencias analizadas coincide con los resultados de otros estudios nacionales, pero es alta si comparada con estudios de otros países. Este estudio evidencia la asociación entre el uso de restricciones y el deterioro avanzado de los residentes con relación a su funcionalidad, estado cognitivo, riesgo de úlceras, riesgo de caídas y estado nutricional.Background: There is great variability of data on the prevalence and factors associated with the use of physical restraints in nursing homes. These devices are commonly used to ensure the safety of the elderly or the physical integrity of residents and workers. Despite the intended protective purpose, its application can have negative consequences both physically and psychologically, increasing the risk of serious injury and even death. Objectives: To describe the prevalence of physical restraints, as well as factors associated with their use, in the institutionalized elderly in five nursing homes in the province of Valencia, Spain. The impact of these restraints on functionality, cognitive status, risk of falls, risk of ulcers, and the nutritional status of residents were also considered. Materials and methods: A retrospective, longitudinal, observational, cohort study was performed with tracking of the institutionalized elderly in five nursing homes during the period May 2008 to January 2013. Baseline information was collected from 1,634 with follow-ups occurring every 6 months. The primary variable was the prevalence of physical restraints, and the demographic of the subjects including age, sex, type of residents (internal/external), state at discharge voluntary leave, and time elapsed from admission in years. Two groups were distinguished; one consisting of residents with restraints and another with no restraints. The results were assessed on 5 scales, Barthel, MEC, Norton, Tinetti, and MNA aimed at assessing the level of dependency, the cognitive condition, the risk of ulcers and falls as well as the nutritional state. Through analysis of the variance of the results, the physical and cognitive status of the residents and their (longitudinal) evolution was compared, first depending on the use of physical restraint, and second, on the length of stay. Results: The baseline information was collected from 1,257 residents, mostly women (66%) with an average age of 80 years old. The prevalence of physical restraints obtained was 23.8%. Residents living with restraints were on average 81 years in age and the prevalence between the sexes at the baseline was similar. The most commonly used physical restraints were chair restraints (pelvic belts and waistcoats), followed by a combination of chair restraints and bed restraints (belts and restraint sheets), and sole bed restraints. The prevalence in usage of restraints among residents who deceased during the study was 31%, with a statistically significant difference between the ratio of use of restraints and deaths. The physical restraints were applied mainly in the first year of admission (86%) primarily for the prevention of falls (87%). In comparing between groups of residents with and without restraints, there was a statistically significant association between the use of restraints and low functionality, severe cognitive impairment, risk of pressure ulcers, risk of falls, and poor nutritional status of the residents. In addition, a follow-up was carried-out on the status of 201 participants whom information was taken during 36 months. During the time period of this study, there were statistically significant differences in the functionality, risk of ulcers and risk of falls (p <0.05). There were no significant differences in time-group interactions (p> 0.05). Conclusions: The prevalence of the use of physical restraints in the nursing homes analyzed coincides with the results of other national studies, but it is high when compared with studies in other countries. This study shows the association between the use of restraints and the deterioration of the residents' functionality, cognitive impairment, risk of pressure ulcers, risk of falls, and nutritional status

HTTPS Traffic Classification

Network Machine Learning Research Group (NMLRG), Internet Research Task Force (IRTF), Buenos Aires, Argentina, April 2016HTTPS Traffic Classificatio