The influence of the human genome on chronic viral hepatitis outcome A influência do genoma humano no curso das hepatites virais crônicas

The mechanisms that determine viral clearance or viral persistence in chronic viral hepatitis have yet to be identified. Recent advances in molecular genetics have permitted the detection of variations in immune response, often associated with polymorphism in the human genome. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virulence of microbial agents. Several recent advances concerning the influence of human genes in chronic viral hepatitis B and C are discussed in this article: a) the associations between human leukocyte antigen polymorphism and viral hepatic disease susceptibility or resistance; b) protective alleles influencing hepatitis B virus (HBV) and hepatitis C virus (HCV) evolution; c) prejudicial alleles influencing HBV and HCV; d) candidate genes associated with HBV and HCV evolution; d) other genetic factors that may contribute to chronic hepatitis C evolution (genes influencing hepatic stellate cells, TGF-beta1 and TNF-alpha production, hepatic iron deposits and angiotensin II production, among others). Recent discoveries regarding genetic associations with chronic viral hepatitis may provide clues to understanding the development of end-stage complications such as cirrhosis or hepatocellular carcinoma. In the near future, analysis of the human genome will allow the elucidation of both the natural course of viral hepatitis and its response to therapy.<br>Os mecanismos que determinam o clearance ou a persistência da infecção viral nas hepatites virais crônicas não estão ainda bem identificados. O progresso no conhecimento sobre as ferramentas genéticas moleculares tem permitido detectar variações na resposta imune, que freqüentemente são associadas com polimorfismos do genoma humano. As diferenças na susceptibilidade do hospedeiro para as doenças infecciosas e a intensidade das doenças não podem ser atribuídas apenas à virulência do agente microbiano. Neste artigo são discutidos vários avanços recentes no conhecimento sobre a influência dos genes humanos nas hepatites crônicas B e C, a saber: a) As associações entre os polimorfismos HLA e a susceptibilidade ou resistência às doenças hepáticas virais; b) Alelos protetores influenciando as hepatites virais B (HVB) e C (HVC); c) Alelos prejudiciais influenciando HVB e HVC; d) Genes candidatos associados com a evolução clínica de HVB e HVC (genes que influenciam as células estreladas do fígado, a produção de TGF-beta1 e TNF-alfa, os depósitos de ferro hepáticos, a produção de angiotensina II, entre outros). O conhecimento das associações genéticas com as hepatites virais crônicas pode fornecer indícios para o pleno entendimento de como se desenvolvem as suas complicações terminais, como a cirrose e o carcinoma hepatocelular. Em futuro próximo, a análise do genoma humano será capaz de elucidar o curso natural de uma hepatite viral, bem como a sua resposta à terapêutica

Explaining the encoding/retrieval flip: Memory-related deactivations and activations in the posteromedial cortex

Item does not contain fulltextThe posteromedial cortex (PMC) is strongly linked to episodic memory and age-related memory deficits. The PMC shows deactivations during a variety of demanding cognitive tasks as compared to passive baseline conditions and has been associated with the default-mode of the brain. Interestingly, the PMC exhibits opposite levels of functional MRI activity during encoding (learning) and retrieval (remembering), a pattern dubbed the encoding/retrieval flip (E/R-flip). Yet, the exact role of the PMC in memory function has remained unclear. This review discusses the possible neurofunctional and clinical significance of the E/R-flip pattern. Regarding neurofunctional relevance, we will review four hypotheses on PMC function: (1) the internal orienting account, (2) the self-referential processing account, (3) the reallocation account, and (4) the bottom-up attention account. None of these accounts seem to provide a complete explanation for the E/R-flip pattern in PMC. Regarding clinical relevance, we review work on aging and Alzheimer's disease, indicating that amyloid deposits within PMC, years before clinical memory deficits become apparent. High amyloid burden within PMC is associated with detrimental influences on memory encoding, in particular, the attenuation of beneficial PMC deactivations. Finally, we discuss functional subdivisions within PMC that help to provide a more precise picture of the variety of signals observed within PMC. Collective data from anatomical, task-related fMRI and resting-state studies all indicate that the PMC is composed of three main regions, the precuneus, retrosplenial, and posterior cingulate cortex, each with a distinct function. We will conclude with a summary of the findings and provide directions for future research