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Rôle de la Protéine C, un anticoagulant naturel, dans l’association thrombose et cancer / Role of Protein C, a Natural Anticoagulant, in Thrombosis and Cancer AssociationBesbes, Samaher 30 September 2015 (has links)
Il est désormais admis que le caractère invasif d'une tumeur est lié, non seulement, au génotype des cellules cancéreuses, mais aussi à leurs interactions avec le microenvironnement tumoral (MT). Au sein du MT, une déstabilisation de la matrice stromale favorise la progression tumorale et la dissémination métastatique. Le remaniement de la matrice extracellulaire est souvent piloté par des enzymes protéolytiques. En revanche, les effets de l'inhibition de la formation de cette matrice sont peu étudiés. C’est dans cette optique que nous nous sommes intéressés à la protéine C (PC) et son récepteur endothélial (EPCR) et à leur rôle dans la tumorigenèse des leucémies et des cancers solides.L’EPCR est exprimé par un grand nombre de lignées cellulaires cancéreuses. Il est aussi détecté dans le compartiment tumoral chez des patients atteints de pathologie tumorale. Son gène est hautement conservé. Il possède cependant plusieurs polymorphismes. Un de ces SNPs (single nucleotide polymorphism) - 6936A/G - se traduit par la libération d'une forme soluble circulante de l'EPCR (EPCRs) résultant de la protéolyse de la forme membranaire. Chez des patients leucémiques, une fréquence élevée du SNP 6936A/G est observée et associée à la survenue de thrombose. D'autre part, l’EPCR est détecté in situ dans la majorité des biopsies tumorales testées et sécrété en grande quantité dans les ascites. La fixation de la PC sur l’EPCR et son activation augmentent la survie et le potentiel migratoire des cellules cancéreuses. Aussi, la PCA est capable de moduler, par communication paracrine, la sécrétion de plusieurs interleukines et cytokines. Ainsi, la stimulation de cellules du cancer de l'ovaire par la PCA induit la synthèse d'une thrombopoéïtine ovarienne fonctionnelle. Cette cytokine étant régulatrice de la production de plaquettes, la PCA semble être de nouveau à l'interface entre troubles de l'hémostase et pathologie cancéreuse. L’élucidation du rôle complexe de la PCA et de son récepteur endothélial dans la carcinogenèse permettrait non seulement de dégager de nouvelles approches thérapeutiques, mais aussi de prévenir le risque de thrombose associée au cancer et d’en réduire la morbidité. / It is now recognized that the invasiveness of tumor cells is not only related to the genotype of these cells but also to their interaction with tumor microenvironment (TM). Within the TM, stromal matrix destabilization promotes tumor progression and metastatic dissemination. The extracellular matrix remodeling is often driven by proteolytic enzymes. However, few studies have investigated the effects of an impairment of the matrix formation. Given these facts and circumstances, we were interested in protein C (PC) and its endothelial receptor (EPCR), as well as in their role in tumorigenesis in leukemia and solid cancers. EPCR is expressed by a wide range of cancer cell lines. It is also detected within the tumor compartment in patients with malignant diseases. EPCR gene is highly conserved but nevertheless contains polymorphisms. One of these SNPs (single nucleotide polymorphism) - 6936A/G – reflects – in the release of a soluble circulating form (EPCRs) resulting from the proteolysis of membrane-associated form. In leukemic patients a high incidence of 6936A/G SNP is observed and associated with thrombosis events. Moreover, EPCR is detected in the majority of tumor biopsies and is abundantly secreted in ascitic fluid. The PC attachment to EPCR and its activation promotes cell survival and migratory potential of tumor cells. Also, APC is able to modulate, by a paracrine manner, interleukins and cytokines secretion. Thus, ovarian cancer cells stimulation by APC induces the synthesis of a functional ovarian thrombopoietin. As this cytokine has a regulatory effect on platelet production, APC may be once again at the interface between hemostasis disorders and coagulation. The elucidation of the intricate role of APC and its endothelial receptor could permit not only to identify new therapeutic approaches but also to prevent cancer-associated thrombosis risk and to decrease morbidity in cancer patients.
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Complexes de nickel caméléons : exploration de tous ses degrès d'oxydation pour la formation de liaisons C-C et C-CF3 / Cameleonic nickel complexes : study of its oxidation states for C-C and C-CF3 bond formationD'accriscio, Florian 23 February 2017 (has links)
Ce projet de recherche porte sur l’étude de complexes de nickel à différents degrés d’oxydation (de 0 à +IV) dans le but de promouvoir la formation de liaisons C–C et C–CF3. Dans une première partie, l’étude porte sur l’utilisation de complexes de nickel à basse valence en tant que catalyseurs pour les réactions de couplage croisé de Negishi et de Suzuki-Miyaura. Si la formation de liaisons C–C est une réaction parfaitement maîtrisée au palladium, l’emploi de complexes de nickel comme catalyseurs est plus difficile à appréhender d’un point de vue mécanistique. Dans ce travail, l’utilisation d’un ligand bis-phosphine a permis de synthétiser et d’isoler des complexes de nickel(0). Une étude mécanistique complète alliant expériences et calculs DFT démontre que la réaction de Negishi fonctionne uniquement sur un régime Ni(0)/Ni(II). Des études préliminaires montrent en revanche que le mécanisme est tout autre lorsqu’on s’intéresse à la réaction de Suzuki-Miyaura. Dans une deuxième partie, l’objectif est la formation de liaisons C–CF3 en utilisant des complexes de nickel à haute valence. La formation de ces liaisons à partir de métaux de transition reste un défi puisque les méthodologies utilisées à ce jour au niveau industriel nécessitent l’utilisation de conditions drastiques et conduisent à la formation de composés nocifs pour l’environnement. Ce n’est que très récemment que des travaux de recherche ont porté sur l’utilisation du nickel comme support à la formation de liaisons C–CF3. Ce projet décrit la synthèse de complexe de nickel(III) portant deux groupements CF3 et l’utilisation d’un complexe dimérique de nickel(III) comme plateforme pour l’accès à d’autres complexes [NiIII(CF3)2]. Si ces complexes ne permettent pas de former de liaisons C–CF3, une espèce de nickel(IV) permet la formation de telles liaisons. Il s’agit de plus du premier complexe de nickel(IV) portant deux atomes de fluor et deux groupements CF3 capable de promouvoir l’activation de liaisons C–H. / This research project aims at the study of nickel complexes in different oxidation states (from 0 to +IV) in order to promote C–C and C–CF3 bond formation. In a first part, low-valent nickel complexes are used as catalysts to perform Negishi and Suzuki-Miyaura cross-coupling reactions. If the C–C bond formation is a well-known reaction using palladium catalysts, the use of nickel complexes as catalysts is more complicated to understand in the mechanistic aspect. In this work, the key point is the use of a bis-phosphine ligand which allows the synthesis and isolation of nickel(0) complexes. A full mechanistic study via stoichiometric reactions as well as DFT calculations confirms that the Negishi cross-coupling works only on a Ni(0)/Ni(II) catalytic cycle. Surprisingly, preliminary studies on the Suzuki-Miyaura cross-coupling reactions show that the mechanism pathway is completely different. In a second part, our interest is focused on the C–CF3 bond formation using high-valent nickel complexes. In chemical industries, the C–CF3 bond formation requires harsh conditions and also produces toxic waste for the environment. This mainly explains why the use of transition metals is still challenging in this topic. However in the last few years, the interest for the use of nickel complexes as coupling agent for C–CF3 bond formation has grown. This work deals with the synthesis of nickel(III) complexes bearing two CF3 substituents and the use of a dimeric nickel(III) complex as a building block for the formation [NiIII(CF3)2] type complexes. If these species do not promote the C–CF3 cross coupling, a nickel(IV) complex shows its ability to create this bond. Moreover, this is the first nickel(IV) species bearing both fluorine and CF3 substituents at the same metal center and promoting C–H bond activation.
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Réactivité des glyconitriles vis-à-vis d’organométalliques : accès à des céto-C-glycosides précurseurs de C-glycoconjugés / Reactivity of glyconitriles towards organométallics : acces to C-glycosides precursors of C-glycoconjugatesElla Obame, Idriss 19 July 2016 (has links)
Les glycoconjugués constituent une classe de molécules organiques importante car ils sont impliqués dans de nombreux processus biologiques à savoir l'inflammation, la transmission du signal, la fécondation, l'adhérence cellule-cellule et bactérie-cellule, la reconnaissance virus-cellule et la défense immunitaire… L'utilisation de ce type de molécules comme principe actif peut être limitée par l'instabilité de la liaison glycosidique en milieu physiologique et de ce fait la préparation de C-glycoconjugués plus stables, non sensibles aux hydrolyses acides et enzymatiques constitue un enjeu en synthèse organique. Cette thèse décrit un nouvel accès à des C-glycoconjugués via des précurseurs céto-C-glycosides. La majeure partie du travail a consisté à la mise au point d’une nouvelle voie d’accès à des céto-C-glycosides à partir de glyconitriles issus du glucose, du galactose ou du mannose. Dans un premier temps, la réactivité de glyconitriles totalement protégés sous forme d’éthers benzyliques vis-à-vis d’organozinciques activés a été étudiée permettant d’isoler différentes cétones fonctionnalisées C-glycosylés. Lorsque ces substrats sont opposés à des organomagnésiens, un mélange de composé attendu et de glycal issu de l’élimination du benzyloxy en position 2 est observé. Afin de limiter la formation des glycals, des glyconitriles comportant un groupe hydroxyle en position 2 ont été préparés. L’addition de réactifs de Grignard ou d’organolithiens sur ces glyconitriles ont conduit à divers céto-C-glycosides. Ainsi, il a été montré que l’addition des organolithiens était plus efficace en termes de rendement.Ayant en main ces dérivés cétoniques, une étude de fonctionalisation de la fonction cétonique (formation de méthylène, de gem-difluoré, réduction en alcool…) a été entreprise, sur un substrat modèle, acquis qui pourra être transposé aux acyl-C-glycosides plus complexes. De plus, l’application de la méthodologie de synthèse à des C-glycoconjugués originaux appartenant à trois familles de composés différentes, inhibiteurs potentiels de SGLT-2 ou de glycogène phosporylase, nouvelles cibles thérapeutiques dans le traitement du diabète de type 2, a été validée. / Glycoconjugates, an important series of organic molecules, are fundamental to many important biological processes such as inflammation, signal transduction, fertilization, bacterial-cell or cell-cell adhesion, virus-cell recognition and immune response…The use of such compounds as drug is limited by the significant hydrolysis occurring in physiological medium or in acidic conditions. Thus, more stable C-glycoconjugates syntheses have to be developed.A new strategy for the synthesis of C-glycoconjugates via acyl-C-glycosides precursors is described from gluco-, galacto- or manno-nitriles. First, the reactivity of O-perbenzylated glyconitriles towards various activated organozinc reagents led to various functionalized keto-C-glycosides. However, with Grignard reagents, a mixture of the corresponding compound along with glycal occurring from the elimination of benzyloxy group located in position 2 is observed. To prevent such elimination, 2-hydroxyglyconitrile was prepared. With organomagnesium or organolithium reagents, these glyconitriles led to various glyconitriles in good yieds. It is noteworthy that organolitium reagents were more efficient, leading to better yields in glucose and galactose series.With these keto derivatives in hands, the transformation of the keto group into methylene, gem-difluorine, alcool…. was performed on a galatose-derived ketone as a model for the preparation of more complex C-glycosides. Moreover, the application of the methodology was applied to the synthesis of original C-glycoconjugates as potential SGLT-2 or glycogen phosphorylase inhibitors, thereby validating the synthetic strategy.
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Prestandautvärdering av koppling mellan C#.NET och Pitch Runtime InfrastructureLarsson, Adam January 2014 (has links)
Denna rapport dokumenterar arbetet med att utreda hur C# och Pitch RTI fungerar tillsammans, och vilka prestandaeffekter som resulterar av denna koppling. Motiveringen kommer från att kunder till företaget Pitch har efterfrågat stöd för C# som programmeringsspråk när de använder Pitch RTI. Metoden gick ut på att successivt lära sig använda de tekniker som finns tillgängliga, för att sedan implementera lösningar på hur kopplingen ska ske. Resultaten visar hur övergången går till och prestandan som uppnåddes med hjälp av indexnotation. Tekniken IKVM hade högre prestandaindex och gick snabbare att komma igång med jämfört med tekniken C++/CLI. Men C++/CLI passar bättre ur ett distributionsperspektiv. Slutsatsen blev att Pitch som företag med hjälp av denna rapport är bättre förberett på framtida utredningar och implementationer som skulle använda de utvärderade teknikerna.
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Studies in the manuscript tradition of the "Ranae" of Aristophanes /Eberline, Charles N. January 1980 (has links)
Texte remanié de: Diss.--Littérature--Urbana-Champaign, 1976. / Bibliogr. p. 175-184. Index.
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Dinâmica do carbono durante a decomposição de palha de trigo marcada com 13c e dejetos líquidos de suínos / Carbon dynamics during decomposition of 13c-labelled wheat straw and pig slurryLuz, Laura Patrícia da 11 May 2007 (has links)
In no-tillage areas, the pig slurry is applied on the cultural residues, as much as cover or commercial crops. A few research information exists involving the soil carbon dynamics with this modality of pig slurry application. A better understanding of soil carbon dynamics during the decomposition of pig slurry and cultural residues is necessary, as much of the environmental point of view as of the maintenance and improvement of soil quality. This
work was carried out in laboratory conditions, with the objective of evaluating the dynamics of the carbon during the decomposition of 13C-labelled wheat straw and pig slurry, used separately or mixed, with and without soil incorporation. In a Hapludalf soil and using an entirely randomized design were evaluated the following treatments, with four replications: T1 - Soil; T2 - Soil + straw in surface; T3 - Soil + incorporated straw; T4 - Soil + pig slurry in surface; T5 - Soil + pig slurry incorporated; T6 - Soil + pig slurry incorporated + straw in surface; T7 - Soil + pig slurry incorporated + incorporated straw; T8 - Soil + straw in surface + pig slurry in surface. The soil humidity was adjusted for 100% of the field capacity and the incubation was carried out for 95 days with temperature kept in 25ºC. The C-CO2 evolution and its isotopic 13C excess were evaluated continually and, periodically, the amounts of remaining C straw and C soil, with their respective 13C isotopic excess. The apparent C
mineralization of pig slurry didn't increased with its soil incorporation, which just favored the straw C mineralization. In the treatments with wheat straw, with and without pig slurry, the apparent C mineralization (C-CO2) of straw in 95 days was, on average, of 58,4%, while the real C straw mineralization (13C-CO2) was of 45,8%, evidencing the occurrence of positive "priming effect." Despite of the high C/N (65,2) of wheat straw, its C mineralization just increased when was maintained in soil surface and the pig slurry were applied on the straw. In
this condition, where the contact of straw with the soil is deficient, the presence of N mineral of pig slurry favored the heterotrophic microbial population, responsible for straw decomposition. With the higher contact of the straw with the soil, for its incorporation, the microorganisms supplied their N needs for biosynthesis from straw and soil organic matter mineralization, independently of N from pig slurry application. At the end of the experiment, the balance of 13C (13C-straw + 13C-soil + 13C-CO2), indicated that, in the average of all
treatments, about 24% of the applied 13C with the straw were not recovered, probably for the incomplete capture of the 13C-CO2 liberated and for the difficulty in recovering the straw completely, in the treatments in that it was incorporated to the soil / Em áreas de plantio direto, os dejetos de suínos são aplicados sobre os resíduos culturais, tanto de plantas de cobertura de solo como das culturas comerciais. Existem poucas
informações de pesquisa envolvendo a dinâmica do carbono no solo com esta modalidade de aplicação dos dejetos. Uma melhor compreensão da dinâmica do carbono durante a
decomposição de dejetos de suínos e resíduos culturais é fundamental, tanto do ponto de vista ambiental quanto da manutenção e melhoria da capacidade produtiva do solo. Este trabalho foi conduzido, em condições de laboratório, com o objetivo de avaliar a dinâmica do carbono durante a decomposição de palha de trigo enriquecida com 13C e dejetos líquidos de suínos, utilizados isoladamente ou misturados, com e sem incorporação ao solo. Num Argissolo
Vermelho distrófico arênico e utilizando o delineamento experimental inteiramente casualizado, com quatro repetições, foram avaliados os seguintes tratamentos: T1- Solo; T2-
Solo + palha em superfície; T3- Solo + palha incorporada; T4- Solo + dejetos em superfície; T5- Solo + dejetos incorporados; T6- Solo + dejetos incorporados + palha em superfície; T7- Solo + dejetos incorporados + palha incorporada; T8- Solo + palha em superfície + dejetos em
superfície. A umidade do solo foi ajustada para 100% da capacidade de campo e a incubação foi conduzida durante 95 dias a uma temperatura de 25ºC. Foram avaliados, continuamente, a liberação de C-CO2 e o seu excesso isotópico em 13C e, periodicamente, as quantidades remanescentes de matéria seca e de C da palha e de C no solo, com seus respectivos excessos isotópicos em 13C. A mineralização aparente do C dos dejetos não aumentou pela sua incorporação ao solo, a qual favoreceu apenas a mineralização do C da palha. Nos tratamentos com palha de trigo, com e sem dejetos, a mineralização aparente do C da palha (C-CO2) aos 95 dias foi, em média, de 58,4%, enquanto a mineralização real (13C-CO2) foi de 45,8%, evidenciando a ocorrência de efeito priming positivo. Apesar da elevada relação C/N (65,2) da palha de trigo, a sua mineralização aumentou apenas quando ela foi mantida na superfície do solo e os dejetos suínos foram aplicados sobre a mesma. Nessa condição, em que o contato da palha com o solo é deficiente, a presença do N mineral dos dejetos favoreceu a população
microbiana heterotrófica, responsável pela decomposição da palha. Com o maior contato da palha com o solo, pela sua incorporação, os microrganismos atenderam sua demanda em N
para a biossíntese a partir da mineralização da palha e da matéria orgânica do solo, independentemente do N aplicado com os dejetos. Ao final do experimento, o balanço de 13C
(13C-palha + 13C-solo + 13C-CO2), indicou que, na média de todos os tratamentos, aproximadamente 24% do 13C aplicado com a palha não foram recuperados, provavelmente pela captura incompleta do 13C-CO2 liberado e pela dificuldade em recuperar completamente a palha nos tratamentos em que ela foi incorporada ao solo
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Prevalência e fatores associados ao anticorpo contra o vírus da hepatite “C” em pacientes com diabetes mellitus tipo 2 atendidos no Hospital Universitário Dr. Miguel Riet Corrêa Jr. – Rio Grande, RS / Prevalence and associated factors to the anti-VHC in patients with type 2 diabetes mellitus attending Hospital Universitário Miguel Riet Corrêa Jr. - Rio Grande, RS / Prevalencia y factores asociados al anticuerpo contra el virus de la hepatitis C en pacientes com diabetes mellitus tipo 2 atendidos en Hospital Universitario Dr. Miguel Riet Correa Jr. – Rio Grande, RSSparvoli, Jucéli Márcia Hendges January 2004 (has links)
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Previous issue date: 2004 / A hepatite C e o diabetes mellitus tipo 2 apresentam substancial morbidade, complicações devastadoras e mortalidade significativa. A prevalência do diabetes mellitus tipo 2 está aumentando exponencialmente, adquirindo características epidêmicas. A prevalência global da hepatite C crônica é estimada em 3%. No Brasil, a prevalência da infecção varia de 0,9 a 2,8%. O vírus da hepatite C pode ser transmitido parenteralmente e, raramente, por relação sexual. O anti-VHC é o marcador utilizado para seu rastreamento. Esta infecção causa primariamente doença hepática. A epidemia da hepatite C ampliou sua dimensão quando foram constatadas diversas manifestações extra-hepáticas. Recentemente, a possibilidade da associação da hepatite C com o diabetes mellitus tipo 2 tem despertado muito interesse. Contudo, a existência desta associação ainda desperta polêmica. Disso surgiu a necessidade de estudos experimentais, epidemiológicos e clínicos. Realizamos um estudo prospectivo observacional em 454 pacientes com diabetes mellitus tipo 2, atendidos no Centro Integrado de Diabetes do Hospital Universitário Dr. Miguel Riet Corrêa Jr., em Rio Grande, RS. Nesta amostra avaliamos a prevalência do anti-VHC, assim como numa subamostra que preenchia os principais critérios para doação de sangue, denominada “diabéticos-doadores”. Foram submetidos a questionário-padrão sobre dados demográficos, epidemiológicos e clínicos com relação à hepatite C e diabetes mellitus tipo 2. Comparamos dados epidemiológicos, clínicos e da terapêutica entre pacientes diabéticos tipo 2 anti-VHC positivo e negativo. Características da amostra global: média de idade 57,37 anos; sexo masculino 35,24% e brancos 88,33%. Os dados demográficos não foram significativamente diferentes entre os diabéticos anti-VHC positivo e negativo. A prevalência global de anti-VHC em pacientes com diabetes mellitus tipo 2 foi de 7,27%. Nos “diabéticos-doadores” a prevalência foi de 6,31%. Foram transfundidos 23,34% dos pacientes; 0,44% foram usuários de drogas endovenosas e 1,76% relataram hepatite após os 10 anos de idade. A história de transfusão e de hepatite após os 10 anos foi significativamente associada com maior prevalência do anti-VHC nos diabéticos. Nos transfundidos, a prevalência do anti-VHC foi elevada: 16,04%. Naqueles com história de hepatite, a prevalência foi de 6,06%, ao passo que nos que não apresentaram esse dado foi de somente 1,42%. Em relação ao número de hospitalizações e cirurgias, não houve associação com a prevalência do anti-VHC mesmo com o aumento progressivo desses procedimentos. Em relação à terapia empregada, estratificou-se em: 1) somente dieta; 2) antidiabéticos orais; 3) somente insulina e 4) antidiabéticos orais e insulina. Nos diabéticos mais graves, naqueles que usavam somente insulina, encontrou-se uma prevalência elevada do anti-VHC: 17,30%. Se o paciente relatava simultaneamente transfusão e usava insulina, verificou-se a elevada positividade de 25%. Assim, nosso estudo verificou uma elevada prevalência do anti-VHC em pacientes diabéticos. Em particular, em pacientes transfundidos e usuários de insulina como tratamento exclusivo, a prevalência alcançou valores extremamente significativos. A coexistência de duas doenças com graves perspectivas, que numa eventual associação podem se potencializar mutuamente, exigirá uma progressiva atenção e um trabalho multidisciplinar para enfrentar esse grande problema de saúde pública. / Hepatitis C virus infection and type 2 diabetes mellitus are important public health issues. They are leading causes of morbidity and mortality. Worldwide, type 2 diabetes mellitus is increasing substantially. Hepatitis C affects up to 3% of the world population. Hepatitis C affects 0,9% to 2,8% at the Brazilian population. Hepatitis C virus is transmitted primarily through percutaneous routes and, rarely, by sexual contact. Serological tests for anti-HCV are made for routine screening. Besides hepatic disease, recent evidence links C virus with a number of diverse diseases, including type 2 diabetes mellitus. However, a genuine link between these two conditions is polemic. To assess the relationship between type 2 diabetes mellitus and hepatitis C virus we studied 454 type 2 diabetic patients attending the outpatient diabetic unit in the “Centro Integrado de Diabetes” from “Hospital Universitário Dr. Miguel Riet Corrêa Jr.”, in Rio Grande, RS, Brazil. We divided the diabetic patients in two groups according to their HCV antibody status; and we also analyzed patients for the following variables: age, sex, race, treatment of diabetes (e. g. diet; oral agents; only insulin; oral agents and insulin), previous blood transfusions, intravenous drug addiction, hospital admissions, major surgery procedures and hepatitis history after the age of 10. We did not observe any
difference for age, sex and race between diabetics according to their HCV antibody status. Previous blood transfusion (23,34%), intravenous drug addiction (0,44%) and hepatitis history after the age of 10 (1,76%) were found in these patients. Anti-HCV was detected in 33 diabetic patients (7,27%). When we excluded patients with previous blood transfusion in the previous year, hepatitis history after the age of 10 and intravenous drug addiction, anti-HCV was detected in 27 diabetic patients (6,31%). Previous blood transfusion and hepatitis history after the age of 10 were related to high anti-HCV (16,04% and 6,06%). We did not observe any difference on hospital admissions and major surgery procedures. We observed differences
between anti-HCV positive and anti-HCV negative in terms of mode of treatment: diabetics using only insulin have the highest prevalence: 17,30%. Amongst the diabetics who use insulin and simultaneously had previous blood transfusions, the anti-HCV positive prevalence was 25%. Thus, we observed a high prevalence of anti-HCV positive in our type 2 diabetic population. Due to the high prevalence and the worldwide distribution of HCV infection and type 2 diabetes mellitus, this association may have an important impact on the public health and preparing a complete team of health care workers must be of paramount importance. / La hepatitis C (VHC) y la diabetes mellitus tipo 2 (DMII) son grandes problemas de salud
pública. Presentan una morbilidad substancial, complicaciones devastadoras y mortalidad
significativa. La prevalencia de la DMII está aumentado exponencialmente, adquiriendo
características epidémicas. La prevalencia global de VHC crónica está estimada en 3%. En el Brasil, la prevalencia de infección varía entre 0,9 y 2,8%. El virus de la hepatitis C puede ser transmitido por vía parenteral y raramente, por contacto sexual. El anti-VHC es un marcador utilizado para su rastreamiento. Esta infección causa primariamente enfermedad hepática, La epidemia de VHC amplió su dimensión cuando se constataron diversas manifestaciones extrahepáticas. Recientemente, la posibilidad de asociación entre el VHC con la DMII ha despertado mucho interés. Con todo, la existencia o no de esta asociación es aún polémica. De esto surgió la necesidad de realizar estudios experimentales, epidemiológicos y clínicos. Realizamos un estudio prospectivo observacional con 454 pacientes con DMII, atendidos en el Centro Integrado de Diabetes del Hospital Universitario Dr. Miguel Riet Corrêa Jr., en Rio Grande, RS, Brasil. En esta muestra evaluamos la prevalencia del anti-VHC, así como una submuestra que cumplía los principales criterios para donar sangre, denominada “diabéticos donadores”. Fueron sometidos a un cuestionario padrón con datos demográficos, epidemiológicos, clínicos con relación a la VHC y la DMII. Comparamos datos demográficos, epidemiológicos, clínicos y terapéuticos entre pacientes diabéticos tipo 2 anti VHC positivos y negativos. Características de la muestra global: edad media 57,37 años; sexo masculino 35,24% y blancos 88,33%. Los datos demográficos no fueron significativamente diferentes entre los diabéticos anti-VHC positivo y negativo. La prevalencia global de anti-VHC en
pacientes con DMII fue de 7,27%. En los “diabéticos donadores” la prevalencia fue 6,31%. Fueron transfundidos 23,34% de los pacientes; 0,44% eran usuarios de drogas inyectables y 1,76% relataron hepatitis después de los 10 años de edad, La historia transfusional y de hapatitis después de los 10 años se asoció significativamente con una mayor prevalencia de anti-VHC. En los transfundidos, la prevalencia de anti-VHC foi alta:16,04%. En aquellos con historia de hepatitis la prevalencia fue de 6,06%, mientras que en los que no presentaban esta
característica fue de apenas 1,42%. Con relación al número de hospitalizaciones y cirugías, no hubo asociación con la prevalencia del anti-VHC, mismo con el aumento progresivo de estos procedimientos. En relación con la terapéutica instituida, se estratificó en: 1) solo dieta; 2) antidiabéticos orales; 3) solo insulina y 4) antidiabéticos orales e insulina. En los diabéticos más graves, aquellos que usaban solo insulina, se encontró una prevalencia elevada de antiVHC: 17,30%. Si el paciente relataba simultáneamente transfusión sanguínea y usaba insulina, la prevalencia se elevaba a 25%. Nuestro estudio verificó una alta prevalencia del anti-VHC en pacientes diabéticos. En particular, en pacientes transfundidos y usuarios de insulina como tratamiento exclusivo, la prevalencia alcanzó valores extremadamente altos. La coexistencia de dos enfermedades con graves perspectivas, que en una eventual asociación pueden mutuamente potencializarse, exigirá una progresiva atención y un trabajo multidisciplinar para enfrentar este gran problema de salud pública.
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Synthèse et caractérisation de nanocatalyseurs à base de palladium pour l'oxydation du glucose et la réduction de l'oxygène moléculaire en milieu alcalin / Synthesis and characterization of Pd based nanocatalysts for glucose oxidation and dioxygen reduction in alkaline mediumDiabaté, Donourou 18 December 2012 (has links)
L'objet de cette étude était le développement de nanocatalyseurs pour une application dans unepile glucose/oxygène en milieu alcalin. Avec la demande de plus en plus croissante d'énergiepropre et moins chère, il paraît judicieux de s'orienter vers des dispositifs moins toxiques de pile àcombustible qui peuvent utiliser le glucose comme combustible. Ce travail de thèse s’est doncattaché à synthétiser et caractériser de nouveaux matériaux catalytiques à base de palladium(Pd/C, PdAg/C et PdNi/C) et à analyser leur activité vis-à-vis des réactions de réduction del'oxygène et de l'électrooxydation du glucose. Les nanocatalyseurs utilisés lors de ces travaux ontété synthétisés par microémulsion «water-in-oil» et sont supportés sur du carbone Vulcan XC-72R.Les caractérisations physiques montrent des nanoparticules assez uniformes et la taille moyennedes particules reste inférieure à 5 nm. La réaction de réduction de l'oxygène commence tôt à lasurface de ces catalyseurs (environ 0,92 V vs. ERH) et le nombre d'électrons échangés est prochede 4. Le couplage voltammétrie / spectroscopie IR a permis de montrer que le glucose s’oxyde àbas potentiel à la surface de ces électrodes. Le produit primaire de cette déshydrogénation est lagluconolactone qui s’hydrolyse en solution en gluconate. Le dioxyde de carbone est aussi unproduit d’oxydation. Sa présence à des potentiels élevés montre que le squelette de la moléculeinitiale du glucose subit une adsorption dissociative notamment sur Pd70Ag30. / This work concerns the development of nanocatalysts for a glucose/oxygen fuel in alkalinemedium. Therefore, carbon supported based palladium nanomaterials (Pd/C, PdAg/C and PdNi/C)were synthesized and characterized. Their electrocatalytic activity towards both the glucoseoxidation and oxygen reduction reaction (ORR) was studied. The electrode materials have beensynthesized by “water-in-oil microemulsion” and the physic-chemical characterizations providedinformation on their shape, morphology. Their average particle size remained less than 5 nm. Theoxygen reduction reaction performed with Rotation Ring Disk Electrode (RRDE) on these catalystsled to a four electrons process i.e. without hydrogen peroxide as intermediate (at ca. 0.85 V vs.RHE). Cycling voltammetry combined with Single Potential Alteration Infrared ReflectanceSpectroscopy (SPAIRS) was helpful to show that the primary product of the glucosedehydrogenation is the d-gluconolactone. The latter oxidation product undergoes hydrolysis togluconate in electrolytic solution. At high potential, the dissociative adsorption of glucose onPd70Ag30 gave carbon dioxide as another oxidation product.
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Palladium-catalysed C-C bond construction in virtue of C-H functionalisation : direct arylation of heteroaromatics tolerant to reactive functional groups / Construction de liaisons C-C via fonctionnalisation de liaisons C-H par des catalyseurs du palladium : arylation directe d’hétéroaromatiques tolérant des groupes fonctionnels réactifsChen, Lu 29 January 2013 (has links)
Durant ma thèse, j'ai recherché les conditions pour l'activation / fonctionnalisation de liaisons C-H pour la construction de bi(hétéro)aryles tolérant des groupement fonctionnels réactifs tels que des silyles, des alcènes, des esters ou encore des amides. Par rapport aux protocoles de couplage classiques tels que les réactions de Suzuki, Stille ou Negishi, la fonctionalisation de liaisons C-H fournit des procédures moins coûteuses et plus écologiques si elle tolère des groupements utiles en synthèse. D'abord, nous avons observé que les thiophènes substitués par des silyles en C2 peuvent être arylés avec des bromures d'aryle sans désilylation en présence du précatalyseur Pd(OAc)2/dppb. Les produits de couplage sont obtenus avec de bons rendements et avec inhibition de la réaction de désilylation. Ensuite, nous avons démontré que le système Pd(OAc)2/KOAc sans ligand phosphine, favorise l'arylation directe des hétéroaromatiques et inhibe la réaction de type Heck avec des thiophenes substitués par des alcènes substituées sur les carbones 2 ou 3. Ensuite, nous avons démontré que les fonctions esters sur les hétéroaromatiques peuvent être avantageusement utilisées comme groupements protecteurs, permettant l'arylation directe d'hétéroaromatiques sur le carbone C5. Enfin, l'heteroarylation directe de 2- ou 4-bromobenzamides avec des hétéroarènes catalysée au palladium a été étudiée. En présence de KOAc comme base, aucune formation de liaisons C-C ou C-N par couplage de deux bromobenzamides n'a été observée. / During my thesis, I focused on condition for the activation / functionalisation of C-H bonds for the construction of biaryl derivatives tolerant to the reactive functional groups such as silyl, alkenes, esters or amides. Compared to classic cross-coupling protocols (Suzuki, Stille or Negishi), C-H bond functionalisation provides a costly effective and environmentally attractive procedures. At first, we observed that the silyl-substituted thiophenes can be directly arylated with aryl bromides without desilylation, using the simple Pd(OAc)2/dppb precatalyst for both conversion and desilylation inhibition. Then, we have demonstrated that the Pd(OAc)2/KOAc catalyst system without phosphine ligand, even using as few as 0.1 mol% of Pd catalyst, promotes the direct arylation of heteroaromatics and inhibits the Heck type reaction with 1,2-disubstituted alkenes. In addition, we demonstrated that easily accessible esters on heteroaromatics can be advantageously employed as blocking groups in the course of the direct arylation of several heteroaromatic derivatives. Finally, the palladium-catalyzed direct heteroarylation of 2- or 4-bromobenzamide with heteroarenes was studied. In the presence of KOAc as the base, no formation of C-N or C-C bonds by coupling of two bromobenzamide was observed.
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Développement de nouvelles réactions métallo-catalysées pour la création de liaisons C-C et C-hétéroatomes : Application à la synthèse d’inhibiteurs de la Hsp90 et aux ligands de la lectine A. / New metal-catalyzed methodologies for C-C and C-heteroatom bond-forming reactions : Application to the synthesis of Hsp90 inhibitors and Lectine A ligands.Bruneau, Alexandre 11 December 2015 (has links)
Les travaux rapportés dans ce mémoire concernent le développement de nouvelles réactions métallo-catalysées pour la création de liaison carbone-hétéroatome et carbone-carbone ainsi que leurs applications à la synthèse de produits biologiquement actifs. La première partie de ce manuscrit est consacrée à l'étude de la réactivité des sucres dans les couplages organométalliques. Des conditions ont été développées pour la création de la liaison C-S entre glycosyl thiols et partenaires arylés. De plus, la création de la liaison carbone azote de glycosyl amines avec des acides boroniques a été étudiée. Les produits synthétisés dans cette première partie ont été évalués pour leur potentiel d'inhibition de la Lectine A chez Pseudomonas aeruginosa, impliquée dans de sévères infections pulmonaires.La seconde partie de ce travail est dédiée à la création d'une série inédite d'analogues du 6BrCaQ, inhibiteurs de la Hsp90 ainsi que leur évaluation biologique. Cette nouvelle série est obtenue grâce à une nouvelle méthodologie de synthèse basée sur l'activation C-H entre un hétérocycle halogéné et son partenaire C-H activable. L'activité antiproliférative et l'inhibition de la Hsp90 ont été évaluées et seront présentées dans ce manuscrit. / The work reported in this dissertation concerns the development of new metal-catalyzed reactions for the creation of carbon-heteroatom and carbon-carbon bonds as well as their applications to the synthesis of biologically active products.The first part of this manuscript is devoted to the study of the reactivity of sugars as nucleophiles in organometallic couplings. Conditions were developed for the creation of the C-S bond between glycosyl thiols and aryl partners. Moreover, the creation of the nitrogen carbon bond of glycosyl amine with boronic acids was studied. The products synthesized in this first part have been evaluated for their potential to inhibit the lectin A, in Pseudomonas aeruginosa related lung infections.The second part of this work is dedicated to the creation of a new series of 6BrCaQ analogues as Hsp90 inhibitors and their biological evaluation. This new series was synthetized through a new CH activation methodology. The antitumoral potential was evaluated and will be presented in this manuscript.
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