No abstract

HCV reoccurs after liver transplantation and increases mortality. Cyclosporine, but not tacrolimus, has potent antiviral effects against HCV replication in cell culture. To determine the conditions, if any, under which HCV is susceptible to cyclosporine in vivo, we selected for cyclosporine-resistant mutant HCV in vitro. The resulting mutations were mapped to x-ray crystallographic structures and sequence databases. Mutations selected by cyclosporine were clustered in the nonstructural (NS) proteins NS5A and NS5B. Different sets of mutations in NS5A, paired with the same 2 NS5B mutations, conferred different levels of cyclosporine resistance when engineered back into the HCV replicon. Mutations in NS5B are structurally consistent with a proposed model of regulation of RNA binding by cyclophilin B (CyPB). These mutations also highlight a natural polymorphism between different HCV genotypes that correlates with the variation in response to cyclosporine A (CsA) noted in some clinical trials. Replicons engineered to have mutations in only NS5A (P < 0.0001) or only NS5B (P ‫؍‬ 0.002) suggest that while both NS5A or NS5B variants alter cyclosporine susceptibility, NS5A has the largest effect. Conclusion: Preexisting sequence variation could alter the effect of cyclosporine on HCV in vivo. (HEPATOLOGY

Rationale and Hypothesis: Idiopathic pulmonary fibrosis is a fatal disease with a variable rate of progression. We hypothesized that changes in distance walked and quantity of desaturation during a six-minute-walk test (6MWT) would add prognostic information to changes in FVC or diffusing capacity for carbon monoxide. Methods: One hundred ninety-seven patients with idiopathic pulmonary fibrosis were evaluated. Desaturation during the 6MWT was associated with increased mortality even if a threshold of 88% was not reached. Baseline walk distance predicted subsequent walk distance but was not a reliable predictor of subsequent mortality in multivariate survival models. The predictive ability of serial changes in physiology varied when patients were stratified by the presence/absence of desaturation р 88% during a baseline 6MWT. For patients with a baseline saturation р 88% during a 6MWT, the strongest observed predictor of mortality was serial change in diffusing capacity for carbon monoxide. For patients with saturation Ͼ 88% during their baseline walk test, serial decreases in FVC and increases in desaturation area significantly predicted subsequent mortality, whereas decreases in walk distance and in diffusing capacity for carbon monoxide displayed less consistent statistical evidence of increasing mortality in our patients. Conclusion: These data highlight the importance of stratifying patients by degree of desaturation during a 6MWT before attributing prognostic value to serial changes in other physiologic variables.Keywords: idiopathic pulmonary fibrosis; six-minute-walk test; prognosis; pulmonary function; survival Idiopathic pulmonary fibrosis (IPF) is a uniformly fatal disease with a variable rate of progression. Identification of readily available baseline and short-term serial predictors of survival is critical for physicians and patients considering options such as lung transplantation and for the investigation of novel treatments. Recent studies have suggested several demographic (age, smoking), physiologic (diffusion capacity for carbon monoxide [Dl CO ], FVC, and desaturation), radiologic (high-resolution computed tomography [HRCT] fibrosis score), and histopathologic (fibroblastic foci) features are associated with survival (1-7). Serial change in FVC adds additional prognostic information to data obtained at baseline (8-11).(Received in original form April 6, 2006; accepted in final form June 30, 2006 ) Supported by National Institutes of Health NHLBI grants P50HL-56402, NHLBI, 2 K24 HL04212, 1 K23 HL68713, and 1K23 HL077719.Correspondence and requests for reprints should be addressed to Kevin R. A central feature in the pathophysiology of IPF is impaired gas exchange, which worsens with exercise (12, 13). This exerciseinduced widening of alveolar arterial O 2 gradient and fall in Pa O 2 is believed to be secondary to multiple abnormalities, including V /Q mismatch, decreased Pv O 2 and venous admixture (12-16). The six-min-walk test (6MWT) is a safe procedure for patients with IPF. Baseline des...