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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Avaliação do modelo de hamster para detecção das alterações lipídicas e cardiotoxicidade associadas à terapia contra o vírus da imunodeficiência humana / Evaluation of the hamster model for the detection of lipidic and cardiotoxicity alterations associated to therapy against human immunodeficiency virus

Sanchez, Eduardo Milton Ramos 04 February 2010 (has links)
Com a introdução de uma nova classe de antiretrovirais integrantes da terapia anti-retroviral altamente ativa (HAART) para o tratamento das infecções pelo vírus da imunodeficiência humana, começaram a ser descritos inúmeros efeitos secundários.Na tentativa de se estabelecer um modelo animal para o estudo destes efeitos buscou-se uma espécie com similaridade no perfil e metabolismo lipídico. Iniciou-se estudo em Mesocricetus auratus. Foram avaliados o perfil lipídico e glicêmico,função hepática e renal, níveis de auto-anticorpos anti ox-LDL, perfil eletrocardiográfico, alterações histopatológicas renais e cardíacas nos animais sob dieta hiperlipídica e normal,tratados com Indinavir, inibidor de protease utilizado na HAART. Observou-se uma diminuição da sobrevida nos animais tratados com indinavir, aumento do nível sérico de triglicérides e glicose, redução de auto-anticorpos anti ox-LDL,aumento do segmento QRS no eletrocardiograma, presença de fibrose renal e cardíaca, hipercelularidade glomerular nos animais tratados com a droga com ou sem dieta hiperlipídica quando comparados com os controles. Concluimos que Mesocricetus auratus se apresenta como um bom modelo para o desvendamento dos mecanismos patológicos observados na HAART. / With the introduction of a new antiretroviral class use, integrants of highly active anti-retroviral therapy (HAART) for the treatment of infections by human immunodeficiency virus, several side effects started to be described.To establish an animal model for the study of these side effects, was chosen specie that have similarities in the lipidic profile and metabolism. A study in Mesocricetus auratus was started. It was evaluated the lipidic and glicemic profile ,hepatic and renal function, the levels of auto-antibodies against ox-LDL, electrocardiographic profile and renal and cardiac histopathological alterations in these animals under hyperlipidic and normal diets,treated with Indinavir, a protease inhibitor used in HAART.It was observed a decrease in the survival rate in the animals treated with Indinavir; an increase of the triglycerides and glucose serum level; reduction of anti ox-LDL auto-antibodies; increased QRS segment in the electrocardiogram; presence of renal and cardiac fibrosis; glomerular hypercellularity in the animals treated with the drug, with or without hyperlipidic diet when compared with the controls. We conclude that the Mesocricetus auratus is a good model for disclosure of the pathological mechanisms generated by HAART.
2

Avaliação do modelo de hamster para detecção das alterações lipídicas e cardiotoxicidade associadas à terapia contra o vírus da imunodeficiência humana / Evaluation of the hamster model for the detection of lipidic and cardiotoxicity alterations associated to therapy against human immunodeficiency virus

Eduardo Milton Ramos Sanchez 04 February 2010 (has links)
Com a introdução de uma nova classe de antiretrovirais integrantes da terapia anti-retroviral altamente ativa (HAART) para o tratamento das infecções pelo vírus da imunodeficiência humana, começaram a ser descritos inúmeros efeitos secundários.Na tentativa de se estabelecer um modelo animal para o estudo destes efeitos buscou-se uma espécie com similaridade no perfil e metabolismo lipídico. Iniciou-se estudo em Mesocricetus auratus. Foram avaliados o perfil lipídico e glicêmico,função hepática e renal, níveis de auto-anticorpos anti ox-LDL, perfil eletrocardiográfico, alterações histopatológicas renais e cardíacas nos animais sob dieta hiperlipídica e normal,tratados com Indinavir, inibidor de protease utilizado na HAART. Observou-se uma diminuição da sobrevida nos animais tratados com indinavir, aumento do nível sérico de triglicérides e glicose, redução de auto-anticorpos anti ox-LDL,aumento do segmento QRS no eletrocardiograma, presença de fibrose renal e cardíaca, hipercelularidade glomerular nos animais tratados com a droga com ou sem dieta hiperlipídica quando comparados com os controles. Concluimos que Mesocricetus auratus se apresenta como um bom modelo para o desvendamento dos mecanismos patológicos observados na HAART. / With the introduction of a new antiretroviral class use, integrants of highly active anti-retroviral therapy (HAART) for the treatment of infections by human immunodeficiency virus, several side effects started to be described.To establish an animal model for the study of these side effects, was chosen specie that have similarities in the lipidic profile and metabolism. A study in Mesocricetus auratus was started. It was evaluated the lipidic and glicemic profile ,hepatic and renal function, the levels of auto-antibodies against ox-LDL, electrocardiographic profile and renal and cardiac histopathological alterations in these animals under hyperlipidic and normal diets,treated with Indinavir, a protease inhibitor used in HAART.It was observed a decrease in the survival rate in the animals treated with Indinavir; an increase of the triglycerides and glucose serum level; reduction of anti ox-LDL auto-antibodies; increased QRS segment in the electrocardiogram; presence of renal and cardiac fibrosis; glomerular hypercellularity in the animals treated with the drug, with or without hyperlipidic diet when compared with the controls. We conclude that the Mesocricetus auratus is a good model for disclosure of the pathological mechanisms generated by HAART.
3

Bases moleculares de las alteraciones del tejido adiposo y cambios metabólicos asociados al síndrome lipodistrófico en pacientes infectados por HIV-1

Gallego Escuredo, José Miguel 21 November 2012 (has links)
El uso de la terapia HAART (Highly-Active-Antiretroviral-Therapy), puede dar lugar a múltiples efectos secundarios. El más frecuente de ellos es el denominado HALS (“HIV-infection, HAARTtreatment- associated-lipodystrophy-syndrome”) que comprende alteraciones como la lipoatrofia periferica; un aumento de tejido adiposo visceral o la lipomatosis del tejido adiposo. Además, estas alteraciones fisiológicas pueden ir acompañadas de alteraciones metabólicas. Para saber la aportación individual de algunos fármacos al desarrollo del síndrome lipodistrófico HALS se realizó un estudio de los efectos de Efavirenz, Nevirapina (NNRTIs) y Kaletra (PI) sobre adipocitos primarios de linaje blanco en cultivo. Efavirenz, que no era considerado un fármaco asociado al síndrome lipodistrófico, es capaz de inhibir la adipogénesis con mayor potencia que Kaletra y Nevirapina. Ninguno de estos fármacos provoca toxicidad mitocondrial por lo que sus efectos ocurren en ausencia de toxicidad mitocondrial. Tanto efavirenz como kaletra reducen la secreción de adipoquinas y aumentan la expresión y secreción de citoquinas relacionadas con la inflamación, pero estos efectos siempre son mayores con el EFV mientras la Nevirapina parece no afectar a este tipo de secreciónes. Para estudiar las características moleculares de los diferentes depósitos de tejido adiposo con comportamiento opuesto como el tejido adiposo subcutáneo lipoatrófico y el tejido adiposo visceral lipohipertrófico o el tejido adiposo lipomatoso de las “buffalo-hump” de los pacientes se han comparado características moleculares de ellas con tejido adiposo de individuos control. En la comparación entre el tejido adiposo subcutáneo lipoatrófico y el visceral se ha observado que en ambos casos el tejido adiposo presenta alteraciones similares en la función mitocondrial. En cambio el descenso de marcadores de adipogénesis observado en el tejido subcutáneo de pacientes no se reproduce en el tejido visceral. Este hecho, acompañado de diferencias en el perfil de expresión de marcadores de inflamación (que parece más leve en el tejido visceral), podría explicar el comportamiento opuesto de ambos depósitos en pacientes. El estudio en el que se compararon el tejido adiposo lipomatosos de las “buffalo-hump” y el tejido adiposo subcutáneo lipoatrófico de pacientes infectados por el HIV- indica que el tejido adiposo de las “buffalo-hump” presenta alteraciones especificas en la expresión génica respecto al tejido lipoatrófico en las que destaca una expresión normal de genes adipogénicos. Así mismo, el tejido lipomatoso es capaz de expresar UCP1, un gen característico del tejido adiposo marrón, y su capacidad proliferativa concuerda más con un fenotipo del tipo marrón, por lo que se puede decir que estos adipocitos tienen un fenotipo intermedio entre blanco y marrón que se mantiene cuando este tejido lipomatoso es utilizado para trasplante autólogo a la zona facial lipoatrófica en la que mantiene la proliferación desarrollándose el síndrome hámster. No se observan diferencias en las alteraciones mitocondriales observadas en ambos tejidos. Por otra parte la ausencia de un estado de inflamación local en BH podría explicar en parte este comportamiento diferente de ambos tejidos. Además se ha observado que los pacientes muestran niveles elevados de FGF21 y disminuidos de FGF19 (dos agentes homeostaticos) respecto a los controles. Estas diferencias con los controles se acentúan a medida que los pacientes infectados por el virus HIV-1 pasan de ser no tratados a tratados y aun más al desarrollar la lipodistrofia. Los niveles de FGF21 en suero se correlacionaban con indicadores de sensibilidad a insulina o marcadores de síndrome metabólico así como con marcadores de daño hepático que podrían estar relacionados con esteatosis hepática. Los niveles disminuidos en suero de FGF19 se correlacionan negativamente con parámetros indicativos de resistencia a insulina. Además se ha descrito en esta tesis que los receptores de estos agentes endocrinos FGFR1 y β-Klotho aparecen disminuidos en el tejido adiposo de los pacientes infectados por el virus HIV-1. / Molecular basis of adipose tissue alterations and metabolic disturbances associated to HIV-1-infected lipodystrophic patients Disturbances in adipose tissue in HIV-1-infected patients undergoing HAART involve a complex set of alterations known as HAART-associated-lipodystrophy-syndrome (HALS). In most cases, lipoatrophy occur in the face, arms and legs. An enlargement of visceral adipose tissue, reminiscent of visceral obesity, is present often in combination with peripheral lipoatrophy. Lipomatosis is also commonly found in HALS, usually as an enlargement in the dorso-cervical area (buffalo-hump), although the development of lipomas in distinct anatomical sites has also been reported. This adipose tissue redistribution is associated with systemic metabolic alterations such as insulin resistance or dyslipidemia. To determine the individual contribution to HALS of some HAART-prescriptioned drugs, we performed an assessment of the effects of efavirenz, nevirapine and Kaletra on human cultured adipocytes. Our results support the fact that efavirenz and Kaletra impair adipogenesis, reduce the release of adipokines and increase the expression and release of inflammation-related cytokines, while nevirapine does not. Overall, those effects are greater in the case of efavirenz. We compared as well the molecular signature of subcutaneous lipoatrophic, visceral lipohipertrophic and dorso-cervical lipomatous adipose tissues from patients in order to determine the molecular basis causing these fat depots to behave in an opposite way. All fat biopsies from patients exhibited alterations in mitochondrial function marker genes. Visceral and “buffalo hump” fat didn’t show any alterations in the expression of adipogenesis marker genes when compared to healthy controls, while subcutaneous fat showed lower levels. The inflammatory profile was normal in “buffalo hump”, whereas visceral and subcutaneous adipose tissue depots exhibited a distinct, more exacerbated, pro-inflammatory profile. These differences could be part of the explanation of the mentioned different behavior. The serum levels of novel homeostatic agents FGF19 and FGF21 was also assessed in samples from lipodystrophic patients. FGF21 levels were significantly higher in patients and correlated positively with markers of insulin resistance, metabolic syndrome and hepatic damage. On the other hand, FGF19 levels were significantly lower in patients and correlated negatively with markers of insulin resistance. We studied the transcription level of FGF receptors in adipose tissue as well, resulting in a lower expression in biopsies from HALS patients.

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