Interleukin (IL)-17/IL-22-producing T cells enriched within the liver of patients with chronic hepatitis C viral (HCV) infection.

BACKGROUND: Effector CD4+ helper T cells have historically been classified into T helper 1 (Th1) and Th2 based on the production of signature cytokines. The recently identified interleukin (IL)-17 cytokine family plays important roles in host immunity against intracellular pathogens and in chronic inflammatory conditions; data have implicated IL-17 in autoimmune and viral liver disease. METHODS: This study used three patient groups with HCV infection: acute HCV who either cleared spontaneously or became chronically infected (n = 12), endstage liver disease from whom both peripheral and intrahepatic lymphocytes were studied directly ex vivo (n = 11), and 134 patients with different stages of HCV-related fibrosis from whom serum was collected concurrently with liver biopsy. Normal healthy subjects (n = 41) served as controls. RESULTS: Acute HCV was not associated with expansion of either CD4+ or CD8+ T cells producing IL-17 (Th17, Tc17) or IL-22, and frequencies did not differ in the blood of patients who cleared versus became persistently infected. The hepatic compartment of chronic HCV patients demonstrated statistically more CD4+ and CD8+ that produced IL-17, IL-22 or both as compared to peripheral blood. These T cells displayed a distinct phenotypic profile, high expression of the homing receptor CD161 and low levels of inhibitory receptors, mucin-domain-containing-molecule-3 (Tim-3) and programmed-death 1. Using a sensitive ELISA, we found no significant differences in serum levels of IL-17 according to HCV-related fibrosis. CONCLUSIONS: In chronic HCV, T cells producing IL-17/IL-22 may home to the liver; however, circulating levels of IL-17 do not correlate with fibrosis.

Hepatitis C virus-infected women have a higher risk of advanced fibrosis and graft loss after liver transplantation than men.

UNLABELLED: In natural history studies of hepatitis C virus (HCV) infection, women have a lower risk of disease progression to cirrhosis. Whether female sex influences outcomes of HCV in the posttransplantation setting is unknown. All patients transplanted for HCV-related liver disease from 2002-2007 at five United States transplantation centers were included. The primary outcome was development of advanced disease, defined as biopsy-proven bridging fibrosis or cirrhosis. Secondary outcomes included death, graft loss, and graft loss with advanced recurrent disease. A total of 1,264 patients were followed for a median of 3 years (interquartile range, 1.8-4.7), 304 (24%) of whom were women. The cumulative rate of advanced disease at 3 years was 38% for women and 33% for men (P=0.31), but after adjustment for recipient age, donor age, donor anti-HCV positivity, posttransplantation HCV treatment, cytomegalovirus infection and center, female sex was an independent predictor of advanced recurrent disease (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.02-1.70; P=0.04). Among women, older donor age and treated acute rejection were the primary predictors of advanced disease. The unadjusted cumulative 3-year rates of patient and graft survival were numerically lower in women (75% and 74%, respectively) than men (80% and 78%, respectively), and in multivariable analyses, female sex was an independent predictor for death (HR, 1.30; 95% CI, 1.01-1.67; P=0.04) and graft loss (HR, 1.31; 95% CI, 1.02-1.67; P=0.03). CONCLUSION: Female sex represents an underrecognized risk factor for advanced recurrent HCV disease and graft loss. Further studies are needed to determine whether modification of donor factors, immunosuppression, and posttransplantation therapeutics can equalize HCV-specific outcomes in women and men.

Percutaneous computed tomography-guided gastric remnant access after laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: The bypassed portion of the stomach is difficult to access and evaluate after Roux-en-Y gastric bypass. Access to the excluded stomach may be needed for nutritional support or decompression owing to acute distension and obstruction. We report our experience with percutaneous, computed tomography (CT)-guided gastrostomy tube placement into the gastric remnant after laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS: Of 569 consecutive LRYGB procedures performed, 9 patients underwent successful percutaneous, CT-guided gastrostomy placement. One additional patient was referred from another facility. We reviewed the indications, interval from surgery to the intervention, interval to removal, complications, and success or outcome of the procedure in our patient population. RESULTS: Ten patients underwent percutaneous, CT-guided gastric remnant gastrostomy tube placement. The indications included distended gastric remnant in 6, nutritional access in 4, and remnant drainage after leak in 1. Of the 10 patients, 2 had undergone previous gastric operations. The attempt at percutaneous gastrostomy was unsuccessful in 1 additional patient, who subsequently required laparoscopic gastrostomy (success rate 91%). CONCLUSION: In selected patients after LRYGB, CT-guided gastrostomy tube placement is safe and efficient. It may be used to manage complications of LRYGB, serve as a bridge to definitive surgery, or offer a convenient route for enteral nutritional support.

The antiapoptosis protein survivin is associated with cell cycle entry of normal cord blood CD34(+) cells and modulates cell cycle and proliferation of mouse hematopoietic progenitor cells.

The inhibitor of the apoptosis protein (IAP) survivin is expressed in proliferating cells such as fetal tissues and cancers. We previously reported that survivin is expressed and growth factor regulated in normal adult CD34(+) cells. Herein, we examined survivin expression in CD34(+) cells before and after cell cycle entry and demonstrate a role for survivin in cell cycle regulation and proliferation. Analysis of known human IAPs revealed that only survivin is cytokine regulated in CD34(+) cells. Survivin expression is coincident with cell cycle progression. Up-regulation of survivin by thrombopoietin (Tpo), Flt3 ligand (FL), and stem cell factor (SCF) occurred in underphosphorylated-retinoblastoma protein (Rb)(positive), Ki-67(negative), and cyclin D(negative) CD34(+) cells. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) and multivariate flow cytometry demonstrated that Tpo, SCF, and FL increase survivin mRNA and protein in quiescent G(0) CD34(+) cells without increasing Ki-67 expression, indicating that cytokine-stimulated up-regulation of survivin in CD34(+) cells occurs during G(0), before cells enter G(1). Selective inhibition of the PI3-kinase/AKT and mitogen-activated protein kinase (MAPK(p42/44)) pathways blocked survivin up-regulation by growth factors before arresting cell cycle. Retrovirus transduction of survivin-internal ribosome entry site-enhanced green fluorescent protein (survivin-IRES-EGFP) in primary mouse marrow cells increased granulocyte macrophage-colony-forming units (CFU-GM) by 1.7- to 6.2-fold and the proportion of CFU-GM in S phase, compared to vector control. An antisense survivin construct decreased total and S-phase CFU-GM. These studies provide further evidence that survivin up-regulation by growth factors is not a consequence of cell cycle progression and strongly suggest that survivin is an important early event for cell cycle entry by CD34(+) cells.