Neurologic dysfunctions such as Guillain-Barre' syndrome, encephalitis, meningitis and transverse myelitis occur frequently in patients with hepatitis E virus (HEV) infection, and this study was conducted to better characterize the role of HEV in the pathogenesis of neurologic disorders. Genotype 4 strain of swine HEV was used to inoculate Mongolian gerbils. Reverse transcription-nested polymerase chain reaction (RT-nPCR), ELISA, histopathology, ultrastructural pathology and enzyme immunohistochemistry method were conducted to investigate the replication and localization of HEV in the central nervous system (CNS) and the consequent pathological changes. Both positive- and negative-strand HEV RNA was detectable in brain and spinal cord from 7 to 28 dpi (days postinoculation) via RT-nPCR. Various pathological changes such as perineural invasion, neuron necrosis, microglia nodule, lymphocyte infiltration, perivascular cuff and myelin degeneration were observed in HEV-positive brains and spinal cords. Immunohistochemical (IHC) staining targeting on HEV ORF2 protein revealed positive signals concentrated mainly in the cytoplasm of neuron, ependymal epithelium and choroid plexus area. Positive area density of ZO-1 (zonula occludens-1) in brain of HEV-positive gerbils decreased, while the GFAP (glial fibrillary acidic protein) expression was upregulated compared with control groups. These results provide strong evidence that HEV is able to damage the blood-brain barrier (BBB), replicate in brain and spinal cord, and hammer the causative role of HEV in the pathogenesis of neurologic disorders.
Chronic inflammation has been implicated in the pathogenesis of colorectal cancer. The objective of this study was to evaluate the association of prediagnostic circulating levels of C-reactive protein (CRP), a biomarker of systemic inflammation, with subsequent development of colorectal cancer. Prediagnostic plasma CRP levels were examined among 288 colorectal cancer cases and 576 individually-matched controls nested within the Shanghai Men's Health Study (2002-06), a population-based cohort study of 61 482 Chinese men. The association between CRP levels and colorectal cancer risk was investigated. Baseline plasma CRP levels were 53% higher among men who subsequently developed colorectal cancer than among those who remained free of the disease (1.15 versus 0.75 μg/ml; P < 0.001). Multivariate analyses showed a dose-dependent relationship between CRP and colorectal cancer risk (P trend = 0.003); men in the highest tertile (CRP > 1.19 μg/ml) had 1.88-fold (95% confidence interval (CI): 1.24-2.86) increased odds of developing colorectal cancer compared with men in the lowest tertile (CRP < 0.45 μg/ml). The association was only significant for colon cancer, when cancer site was considered, and was predominantly seen for cases diagnosed within 4 years of blood collection; adjusted odds ratios for the highest versus the lowest tertiles were 3.28 (95% CI: 1.28-8.37), 3.68 (95% CI: 1.62-8.38) and 1.05 (95% CI: 0.56-1.97), respectively, for cases diagnosed <2, 2-4 and >4 years after blood collection. The findings from our study suggest that circulating CRP level is positively associated with colorectal cancer risk in Chinese men, and this association, at least in part, is explained by inflammation-related cancerous or precancerous processes.
gp96 or its N-terminal fragment greatly improved humoral immune response induced by HBsAg, but failed to enhance the CTL response, which demonstrated the potential of using gp96 or its N-terminal fragment as a possible adjuvant to augment humoral immune response against HBV infection.
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