HCV Induces Oxidative and ER Stress, and Sensitizes Infected Cells to Apoptosis in SCID/Alb-uPA Mice

Hepatitis C virus (HCV) is a blood-borne pathogen and a major cause of liver disease worldwide. Gene expression profiling was used to characterize the transcriptional response to HCV H77c infection. Evidence is presented for activation of innate antiviral signaling pathways as well as induction of lipid metabolism genes, which may contribute to oxidative stress. We also found that infection of chimeric SCID/Alb-uPA mice by HCV led to signs of hepatocyte damage and apoptosis, which in patients plays a role in activation of stellate cells, recruitment of macrophages, and the subsequent development of fibrosis. Infection of chimeric mice with HCV H77c also led an inflammatory response characterized by infiltration of monocytes and macrophages. There was increased apoptosis in HCV-infected human hepatocytes in H77c-infected mice but not in mice inoculated with a replication incompetent H77c mutant. Moreover, TUNEL reactivity was restricted to HCV-infected hepatocytes, but an increase in FAS expression was not. To gain insight into the factors contributing specific apoptosis of HCV infected cells, immunohistological and confocal microscopy using antibodies for key apoptotic mediators was done. We found that the ER chaperone BiP/GRP78 was increased in HCV-infected cells as was activated BAX, but the activator of ER stress–mediated apoptosis CHOP was not. We found that overall levels of NF-κB and BCL-xL were increased by infection; however, within an infected liver, comparison of infected cells to uninfected cells indicated both NF-κB and BCL-xL were decreased in HCV-infected cells. We conclude that HCV contributes to hepatocyte damage and apoptosis by inducing stress and pro-apoptotic BAX while preventing the induction of anti-apoptotic NF-κB and BCL-xL, thus sensitizing hepatocytes to apoptosis

Health-related Quality of Life in Urban African Americans with Type 2 Diabetes

OBJECTIVE: To examine the association of socioeconomic barriers, familial barriers, and clinical variables with health-related quality of life (HRQL). METHODS: A cross-sectional study was conducted of 186 African Americans with type 2 diabetes recruited from 2 primary care clinics in East Baltimore, Maryland. Physical functioning, social functioning, mental health, and general health were measured using the Medical Outcomes Study 36-item short form. Socioeconomic (money, housing, street crime) and familial (family problems, caretaker responsibilities) barriers were assessed by standardized interview. Insulin use, comorbid disease, and measured abnormalities in body mass index, hemoglobin A(1c) (HbA(1c)), blood pressure, lipids, and renal function were investigated. RESULTS: Mean HRQL scores were: physical functioning, 61 ± 29; social functioning, 76 ± 26; mental health, 69 ± 21; and general health, 48 ± 21. Linear regression analyses revealed that each barrier to care was significantly associated with lower scores in 1 or more HRQL domain. As number of socioeconomic and familial barriers increased from 0 to 5, HRQL scores decreased by 18 for social functioning, 21 for general health, 23 for physical functioning, and 28 for mental health (all P for trend <.01). Clinical variables significantly associated with reduced HRQL were obesity, impaired renal function, insulin use, and comorbid disease. Blood pressure, lipids, and HbA(1c) were not significantly associated with HRQL. CONCLUSIONS: An independent, graded relationship was found between socioeconomic and familial barriers to care and HRQL. This relationship was at least as strong as the association between HRQL and the clinical variables more likely to be perceived by participants as causing symptomatic distress or impacting lifestyle