Mestrado em Medicina e Oncologia Molecular / Master Degree Course in Molecular and Oncology Medicine / Chronic hepatitis C (HC) is a major public health problem because of the number of infected persons (3% of the world population and about 150000 Portuguese individuals) and the potencial to cause cirrhosis, end-stage liver disease, and hepatocelular carcinoma in many of those infected. The most effective treatment (pegylated interferon and ribavirin) has variable response rates, between 45 e 80%, and major side effects. Treatment duration depends on viral genotype and virological response after the first 12 weeks on therapy. Genotype and viral load are independent factors of response. However, the question is why hosts infected with same genotype and similar viral loads have different treatment response rates. Genotype 1, high viral load, higher quasispecies diversity, NS5A interferon determining sensitivity domain variations was associated with lower responses. Others identified host factors for therapy response such as race, gene expression, HLA-DRB and class I alleles and cytokine gene polymorphisms as interferon- , TNF- , interferon response genes. Gene expression analysis by microarrays found 8 genes as response discriminants. Pre-treatment cytokine and supressors of cytokine levels may also correlate with treatment response. Our aim was to analyse if host genetic polymorphisms related to Th1 immune response polarization, hepatic lesion mechanisms and signaling after TCR activation or IFN signaling - OPN, TNF- , ACP1 respectivelly could explain different treatment responses. We also analysed healthy individuals and correlated OPN plasma levels and OPN genotypes. Patients with HCV genotype 1 and 4 were included. Matherial: 95 patients treated with pegylated interferon and ribavirin were selected. Control group included healthy blood donors. HC group was classified according to treatment response type: non responders (NR); end of treatment response and relapse (RR); Sustained response (SR). Absence of SR (NSR) = NR+RR. Methods: Blood was collected for DNA and plasma extraction. Genetic polymorphisms were performed by PCR-RFLP: 8090 OPN (C/T), -308 TNF- (A/G), ACP1 (A/B/C). Plasma OPN concentrations measured by ELISA commercial Kit. Statistical analysis: SPSS vs13. Results: OPN and ACP1 genotype distribution was signifficantly different in subjects with HC in comparison with those of control group. OPN TT genotype, TNF- GG, ACP1 AA and AB are more frequent in HC group. OR for HC was : 2,22 if OPN TT genotype, 1,57 if TNF- AA or AG, and 9,99 if ACP1 with lower phosphatasic activity. 87 CHC patients were infected by genotype 1 virus and 8 by genotype 4. According to treatment response HC subgroups are: 43 NR, 16 RR, 36 SR and 59 NSR. No significant differences were observed between those groups concerning age, sex, viral load, histological activity and fibrosis stages. OPN TT allele carriers predominate in NSR and CC predominate in SR. OR for SR versus NSR is 3,32 if one T allele is present and 0,29 if one C allele is present. TNF- and ACP1 genotypes were not significantly different is those treatment response subgroups. NSR has lower median plasma OPN levels. Also TT genotypes had lower levels. RR patients had the lowest levels plasma OPN levels. Conclusions: our results suggest that both OPN and ACP1 genotypes are related to HC susceptibility. OPN genotype is a host factor related to treatment response and that there is a trend toward higher median plasma OPN levels in responders.

Mestrado Integrado em Medicina / Master Degree in Medicine

Mestrado em Medicina e Oncologia Molecular / Master Degree Course in Molecular and Oncology Medicine

Mestrado em Medicina e Oncologia Molecular / Master Degree Course in Molecular and Oncology Medicine

Mestrado em Medicina e Oncologia Molecular / Master Degree Course in Molecular and Oncology Medicine / Introdução: A activação do sistema dos peptídeos natriuréticos (PN s) desempenha um papel importante nos mecanismos de adaptação renal à expansão de volume. Apesar de estar descrito um aumento da actividade do sistema dos PN s nas situações de redução da massa renal como a uninefrectomia e a insuficiência renal crónica (IRC), o papel deste sistema na progressão da doença renal e no aumento da pressão arterial permanece ainda por esclarecer. O objectivo do presente trabalho foi o de avaliar a modulação renal do sistema dos PN s em modelos experimentais de uninefrectomia e de insuficiência renal crónica. Material e Métodos: Ratos wistar machos (n=66) foram submetidos a uninefrectomia (Unx) ou nefrectomia de ( nx). Duas, 10 e 26 semanas após a cirurgia procedeu-se à avaliação da hemodinâmica cardíaca, dos níveis plasmáticos de BNP, da resposta natriurética à expansão de volume e da expressão renal do receptor efector (RPNA) e do receptor de clearance (RPN-C) dos PN s. Resultados: Os animais Unx e nx apresentaram ao longo do estudo um aumento progressivo da pressão arterial sistólica e diastólica e um aumento sustentado dos níveis plasmáticos de BNP. Verificou-se uma diminuição precoce e sustentada na expressão do RPN-A na medula renal dos animais nx enquanto que os níveis de ARNm do RPN-C aumentaram no córtex renal às 10 e 26 semanas após a cirurgia. Nos animais Unx os níveis de ARNm do RPN-A na medula renal apresentaram-se diminuídos às 10 semanas, mas aumentaram de forma marcada às 26 semanas após a cirurgia. No córtex renal dos animais Unx observou-se também um aumento da expressão do RPN-A às 26 semanas. Conclusões: No rim remanescente dos animais Unx e nx verifica-se uma modulação dependente do tempo do RPN-A e do RPN-C, que é distinta no córtex e na medula renal. A alteração da expressão renal dos receptores dos PN s depende do grau de ablação da massa renal e ocorre independentemente da activação sistémica do sistema dos PN s. Estes resultados poderão contribuir para o esclarecimento do papel desempenhado pelo sistema dos PN s nos mecanismos de adaptação à perda de massa renal.

Medicina / Doctoral Programme in Medicine

Ciências Cardiovasculares / Doctoral Programm in Cardiovascular Sciences

Medicina / Doctoral Programme in Medicine

Ciências Cardiovasculares / Doctoral Programm in Cardiovascular Sciences

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