Negative regulation of the interferon response by an interferon-induced long non-coding RNA.

Long non-coding RNAs (lncRNAs) play critical roles in diverse cellular processes; however, their involvement in many critical aspects of the immune response including the interferon (IFN) response remains poorly understood. To address this gap, we compared the global gene expression pattern of primary human hepatocytes before and at three time points after treatment with IFN-α. Among ∼ 200 IFN-induced lncRNAs, one transcript showed ∼ 100-fold induction. This RNA, which we named lncRNA-CMPK2, was a spliced, polyadenylated nuclear transcript that was induced by IFN in diverse cell types from human and mouse. Similar to protein-coding IFN-stimulated genes (ISGs), its induction was dependent on JAK-STAT signaling. Intriguingly, knockdown of lncRNA-CMPK2 resulted in a marked reduction in HCV replication in IFN-stimulated hepatocytes, suggesting that it could affect the antiviral role of IFN. We could show that lncRNA-CMPK2 knockdown resulted in upregulation of several protein-coding antiviral ISGs. The observed upregulation was caused by an increase in both basal and IFN-stimulated transcription, consistent with loss of transcriptional inhibition in knockdown cells. These results indicate that the IFN response involves a lncRNA-mediated negative regulatory mechanism. lncRNA-CMPK2 was strongly upregulated in a subset of HCV-infected human livers, suggesting a role in modulation of the IFN response in vivo.

Impact of aberrant arterial anatomy and location of anastomosis on technical outcomes after liver transplantation.

Variations in donor and recipient arterial anatomy frequently present challenges for surgeons when attempting to establish proper arterial inflow during liver transplantation. We reviewed our data on 233 adult primary liver transplants, conducted from January 1996 through December 2001, to determine the impact of these variations on the outcomes after liver transplantation. Twenty-four (10.3%) arterial complications were encountered at a mean of 2.27 months after transplant. Carrel patches for the anastomoses were not used in 33 patients (14%), which had no relation to arterial complications (P = 0.7). Sixty-one donors (26.2%) had at least one aberrant artery, which had no relation to arterial complications. However, use of donor celiac artery for anastomosis was significantly associated with higher arterial complications (16% versus other choices, P = 0.03). Furthermore, use of common hepatic recipient artery was associated with higher arterial complications (16%, P = 0.03). There were 58 total biliary complications (24.8%). Biliary complications were associated with the presence of arterial complications (P = 0.01). In conclusion, aberrant donor arterial anatomy was not associated with an increased rate of arterial complications; however, choice of location of arterial anastomosis may be a significant factor. Biliary complications were associated with arterial complications.

Bioelectrical impedance analysis for the evaluation of hepatic fibrosis in patients with chronic hepatitis C infection.

Bioelectrical impedance analysis (BIA) is a non-invasive technique that measures electrical resistance (R) and reactance (Xc), which are then used to calculate phase angle (PA). The aim of this pilot study was to assess whether BIA can differentiate between minimal and advanced hepatic fibrosis in patients with chronic hepatitis C (HCV) infection. Twenty patients with HCV participated in this study, and were divided into minimal (Metavir 1) and advanced (Metavir 3 or 4) fibrosis groups. We obtained BIA measurements (R and Xc) in several axes and calculated PA from each pair of measurements. We found no statistically significant differences between the two groups with respect to PA, R, or Xc for the whole body, the trunk or the right upper quadrant measurements in any axis. Mean whole body PA was 7.0 and 7.1 (P = 0.9) in the minimal and advanced fibrosis groups, respectively. Bioelectrical impedance analysis did not demonstrate the ability to distinguish between minimal and advanced degrees of hepatic fibrosis in patients with chronic HCV infection.

The efficacy and limitations of sirolimus conversion in liver transplant patients who develop renal dysfunction on calcineurin inhibitors.

This study evaluates sirolimus in preserving renal function in 28 patients who developed renal insufficiency after liver transplantation. Patients with a creatinine level higher than 1.8 mg/ml were eligible for conversion. Of the 28 patients, 7 (25%) did not tolerate sirolimus, 6 (21%) progressed to end-stage renal disease (ESRD), and 14 (50%) have been maintained on sirolimus with stable renal function. The 28 patients overall had a decline in creatinine of 0.38 mg/dl (P = 0.029) at week 4, with a small increase by week 24. However, the subset of 14 patients who did not develop ESRD had a decline in creatinine that persisted to week 48. While the differences between those who developed ESRD and those with stable renal function were not statistically significant, the patients who developed ESRD had a higher creatinine at conversion (2.8 vs 2.3) and a lower creatinine clearance (36 vs 53 ml/min). Patients receiving sirolimus had a persistent rise in cholesterol (P < 0.05). The use of sirolimus to preserve renal function was limited by patients unable to tolerate drug- (25%) and patients who developed ESRD (21%). A subgroup of patients (50%) had an improvement in creatinine that persisted for 48 weeks.