Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Bochum, Universiẗat, Diss., 2004.

Existen cada vez más evidencias de que el virus de la hepatitis C favorece el desarrollo de diabetes. Objetivos: 1.- Analizar la prevalencia de las alteraciones del metabolismo hidrocarbonado (diabetes y glucemia anómala en ayunas) en los pacientes con infección crónica por el VHC (n=498) y compararla con la que presentan los pacientes con otras enfermedades hepáticas (n=144), considerando el grado de lesión hepática (hepatitis crónica o cirrosis) y los genotipos del VHC en el análisis de los resultados. 2.- Evaluar los mecanismos etiopatogénicos por los que el VHC puede favorecer el desarrollo de diabetes (citocinas proinflamatorias, resistencia a la insulina, disfunción célula beta) mediante un estudio caso control en pacientes con hepatitis crónica no diabéticos (14 VHC (-) y 28 (+)) estrictamente equiparados por los factores relacionados con la aparición de diabetes.3.- Analizar si el aumento de ferritina que existe en los pacientes infectados por el VHC es debido a la propia infección o, si por el contrario, puede atribuirse a la mayor prevalencia de diabetes (enfermedad que también cursa con ferritina elevada) en estos pacientes.4.- Complementando al último objetivo, determinar mediante el análisis de los receptores solubles de la transferrina (sTfR), si la concentración de ferritina en los pacientes diabéticos tipo 2 es un buen indicador de los depósitos de hierro.Conclusiones:1.- Los pacientes con infección por el VHC presentan una elevada prevalencia tanto de glucemia anómala en ayunas como de diabetes en comparación con los pacientes con otras enfermedades hepáticas no atribuibles al VHC (17% vs. 7% y 15% vs. 5%, respectivamente). Este aumento de prevalencia se produce fundamentalmente en los pacientes con hepatitis crónica e incluso se objetiva en sujetos con transaminasas normales.2.- El análisis del genotipo no parece útil para identificar una población de pacientes infectados por el VHC con mayor riesgo para desarrollar alteraciones hidrocarbonadas.3.- La infección por el VHC debe consideradarse un factor de riesgo para el desarrollo de diabetes. Por tanto, es recomendable realizar un cribado sistemático de las alteraciones hidrocarbonadas en los pacientes infectados por el VHC.4.- En los pacientes infectados por el VHC la prueba de la sobrecarga oral de glucosa es el método de elección para realizar el diagnóstico de la diabetes.5.- En los pacientes infectados por el VHC que aún no han desarrollado una diabetes existe un hiperinsulinismo, tanto en situación basal como tras la estimulación con glucagón endovenoso o la ingesta de una comida estándar, lo que traduce un estado de insulinresistencia. 6.- El aumento de resistencia a la insulina en los pacientes infectados por el VHC se asocia a un incremento de citocinas proinflamatorias.7.- Los pacientes infectados por el VHC no diabéticos presentan concentraciones similares de ferritina que la población general. De ello puede deducirse que el aumento de los depósitos de hierro, evaluados mediante los niveles séricos de ferritina, no parece un elemento fundamental en la etiopatogenia de la diabetes asociada al VHC.8.- La diabetes mellitus es el principal factor relacionado con el aumento de las concentraciones séricas de ferritina observado en los pacientes con infección crónica por el VHC. Por tanto, la diabetes mellitus debe ser tenida en cuenta al evaluar el metabolismo del hierro en los pacientes infectados por el VHC.9.- El aumento de la ferritina en los pacientes diabéticos no se acompaña de un descenso recíproco de los niveles de sTfR, lo que sugiere que es un reflejo del estado inflamatorio crónico de baja intensidad característico de la DM tipo 2.10.- La determinación de la concentración sérica de ferritina no es un marcador útil de los depósitos de hierro en los pacientes con DM tipo 2. / There is growing evidence to suggest an association between hepatitis C virus infection and type 2 diabetes mellitus. Objetives: 1.- To compare the prevalence of both diabetes and impaired fasting glucose between hepatitis C virus (HCV)-infected patients (n=498) and patients with other liver diseases but not HCV (n=144), taking into account the degree of liver damage (chronic hepatitis and cirrhosis) and the different HCV genotypes. 2.- To explore the specific mechanisms responsible for the development of diabetes in HCV infected patients (proinflammatory cytokines, insulin resistance and beta-cell function) in a case-control study with nondiabetic noncirrhotic patients (14 anti-HCV negative and 28 anti-HCV positive) carefully matched for the main items related with diabetes development.3.- To investigate if the high ferritin levels observed in HCV-infected patients are related with HCV infection itself or could be associated with the higher prevalence of diabetes (also related with hyperferritinemia) in HCV infected patients.4.- To determine circulating transferrin receptor levels (sTfR) to evaluate if serum ferritin reflects iron body stores in type 2 diabetic patients.Conclusions:1.- Both impaired fasting glucose and diabetes were more prevalent among patients with HCV infection than among anti-HCV negative patients. This finding was mainly due to the group of patients with chronic hepatitis, and it was also present among patients with normal transaminases.2.- No differences in the prevalence of either impaired fasting glucose or diabetes among HCV genotypes were observed.3.- HCV infected patients must be considered as a high risk group for type 2 diabetes development, and testing for glucose abnormalities should be mandatory in these patients.4.- The high percentage of new cases of diabetes detected using postload hyperglycemia in the subset of patients with chronic hepatitis suggests that the oral glucose tolerance test (OGTT) should be recommended as the primary screening test for diabetes in these patients.5.- In HCV nondiabetic noncirrhotic patients an hyperinsulinemia is detected, both basal and after stimulation tests (intravenous administration of 1 mg of glucagon and the standard food intake test), suggesting an insulin resistance state. 6.- This state of insulin resistance, before the development of glucose abnormalities, is accompanied with a marked increase of proinflammatory cytokines.7.- Serum ferritin levels in anti-HCV positive nondiabetic patients were similar to those in the control group, suggesting that iron deposition is not one of the main mechanisms linking HCV infection and diabetes. 8.- The increase in ferritin levels detected in HCV patients was closely related to the presence of diabetes. So, diabetes should be taken into consideration when evaluating iron metabolism in HCV-infected patients.9.- Serum ferritin levels are increased in Type 2 diabetic patients in the absence of a reciprocal decrease of sTfR. This finding suggest that elevated ferritin levels in Type 2 diabetic patients are mainly as a result of inflammatory mechanisms rather than iron overload.10.- Serum ferritin levels may not be a reliable tool for evaluating iron deficiency anaemia in Type 2 diabetes.

No description available.

For both influenza viruses and hepatitis C viruses, T cell responses to conserved antigens are one strategy for the human host to control the spread of infection. Such T cell responses can be generated with the use of viral vectored vaccines. Initially I show that the viral vectored vaccine MVA-NP+M1 can boost memory T cell responses to influenza A virus in adults aged over 50 years old. However within this group, MVA-NP+M1 had reduced immunogenicity in adults who were aged over 70 years old. The influenza virus-specific T cell responses comprised both CD4 and CD8 T cells, and were capable of secreting multiple Th1 cytokines. I then show that MVA-NP+M1 can be safely co-administered alongside seasonal influenza vaccine. The combination does not interfere with the peak T cell response that normally occurs 1 week following MVA-NP+M1. There was a statistically significant increase in antibodies to the H3N2 strain when the vaccines were co-administered, suggesting that the MVA-NP+M1 can act as an adjuvant. The efficacy of MVA-NP+M1 in humans had been previously evaluated in an influenza virus challenge study. I used a whole blood transcriptome approach to improve the classification of outcomes following influenza virus challenge. For subjects with laboratory-confirmed influenza, individuals with moderate/severe symptoms were found to have a distinct transcriptional signature comprising over 2,000 genes. I used a machine learning algorithm to reduce this variation down to just six genes (CCL2, SEPT4, LAMP3, RTP4, MT1G and OAS3). I validated this finding using expression data from an independently conducted challenge experiment. Data from these six genes was successfully able to predict symptomatic and asymptomatic cases with 89% and 100% accuracy respectively. To induce T cell responses to hepatitis C virus, I used the vaccines ChAd3-NSmut and MVA-NSmut in a prime-boost regimen. While the combination was highly immunogenic in healthy young adults, MVA-NSmut alone was unable to prime immune responses. The magnitude of T cell responses to the vaccine immunogen was correlated with the breadth of the T cell responses to different epitopes. Re-administration of the same two vaccines after a short time interval (8 weeks) did not improve upon previous peaks in T cell response. However with a longer time interval (> 34 weeks), some individuals were able to achieve higher frequencies of virus-specific T cells compared to the first round of vaccines. A whole blood transcriptome approach was used to study gene expression in volunteers vaccinated with ChAd3-NSmut and MVA-NSmut. Vaccination with MVA-NSmut results in a very strong, but relatively short-lived host gene expression signature. In contrast, the transcriptional response seen following ChAd3-NSmut was much less pronounced. A comparison of the functional analysis of gene lists from both vaccines showed that similar pathways were being activated and repressed.