SUMMARYBackground: Studies have shown that past alcohol consumption reduces response rates in patients with chronic hepatitis C treated with interferon monotherapy. Aim: To clarify the importance of alcohol consumption on response rates in patients undergoing treatment with pegylated interferon and ribavirin. Methods: In a single centre, prospective study, median daily alcohol consumption (determined by previously validated method) and quartiles of alcohol consumption were calculated. Univariate and binary logistic regression analyses were performed using treatment response status as the dependent variable.

The plasminogen activator system has been implicated in the modulation of the response to vascular injury. Although urokinase-type plasminogen activator (uPA) and its receptor (uPAR) may enhance matrix degradation as well as migration and invasion by smooth muscle cells (SMCs), their roles in cell adhesion are uncertain. Therefore, we examined the ability of uPA and uPAR to modulate adhesion of cultured human vascular SMCs to various matrices. We demonstrated a dose-dependent stimulation of adhesion by single-chain uPA (scuPA) to vitronectin (maximum 1.55-fold [+/-0. 04-fold] increase, 10 nmol/L, P<0.002) but not to laminin, collagen I, or collagen IV. Baseline adhesion to vitronectin was completely inhibited by both EDTA and RGD peptide but was restored to >40% of control in the presence of scuPA (P=0.001 and 0.046, respectively). Adhesion to vitronectin was also significantly enhanced by the amino-terminal fragment of uPA (P=0.007) and two-chain, high-molecular-weight uPA (P<0.01) but not by the low-molecular-weight fragment of uPA, which lacks the receptor-binding domain. Aprotinin, a plasmin inhibitor, had no effect on baseline or scuPA-stimulated adhesion, suggesting a plasmin-independent process. Preincubation of scuPA with soluble uPAR inhibited scuPA stimulation of adhesion by 88+/-14% (P=0.01), as did pretreatment of SMCs with phosphatidylinositol-specific phospholipase C, which removes glycophosphatidylinositol-anchored proteins, including uPAR. Antibodies to both alphavbeta3 and alphavbeta5 integrin inhibited baseline adhesion but not scuPA stimulation. Finally, coating plates with scuPA alone enabled cell adhesion, which could be inhibited by both soluble uPAR and anti-uPAR antibodies. These data suggest that uPA stimulates adhesion of SMCs specifically to vitronectin and that it is mediated by an interaction with uPAR. Upregulation of both proteins after vascular injury may facilitate migration through stimulation of both matrix degradation and cell adhesion.

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Background: During treatment of hepatitis C, ribavirin-induced anemia (RIA) requires reduction of the ribavirin dose or initiation of erythropoietin in up to 20% of patients. RIA usually occurs in the first 8 weeks of treatment, and a decrease >3 g/dL or a nadir <10 g/dL is considered significant. Objective: To prospectively examine factors associated with RIA in a population of patients with hepatitis C. Methods: Consecutive patients with hepatitis C (hepatitis B virus and HIV negative) underwent treatment with pegylated interferon and weight-based ribavirin. Prospectively gathered data included demographics, alcohol consumption, and hepatitis C virus risk factors. Patients underwent laboratory studies at baseline and at intervals of 4–8 weeks after starting treatment. Results: One hundred eight patients were enrolled. Of these, 30 (27.8%) experienced a >3 g/dL fall in hemoglobin levels in the first 8 weeks; in 10 (33%) patients, the change occurred by week 4. The initial hemoglobin level was higher in those with a decrease compared with those without a fall (15.3 vs 14.1 g/dL; p < 0.001). In addition, for patients with a decrease, the iron saturation was higher (44.6% vs 30.1%; p = 0.002). Finally, those with fibrosis stage 6/6 (cirrhosis) had a greater percent fall in hemoglobin (27.0% vs 14.0%; p = 0.009) than those with less severe fibrosis. By logistic regression analysis, only iron saturation was associated with RIA (p = 0.002). Conclusions: In our patients, initial hemoglobin, serum iron, and fibrosis were associated with a potentially clinically important decrease in hemoglobin. In approximately one-third of the population, RIA occurred in the first 4 weeks of treatment. No patient had a severe complication.