Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion.

AIM: To study the effects of preconditioning on inducible nitric oxide synthase (iNOS) and interleukin 1 (IL-1) receptor transcription in rat liver ischemia/reperfusion injury (IRI). METHODS: Seventy-two male rats were randomized into 3 groups: the one-hour segmental ischemia (IRI, n = 24) group, the ischemic preconditioning (IPC, n = 24) group or the remote ischemic preconditioning (R-IPC, n = 24) group. The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion. The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR. The total Nitrite and Nitrate (NOx) in continuously sampled microdialysate (MD) from the liver was analyzed. In addition, the NOx levels in the serum were analyzed. RESULTS: After 4 h of reperfusion, the iNOS mRNA was significantly higher in the R-IPC (ΔCt: 3.44 ± 0.57) group than in the IPC (ΔCt: 5.86 ± 0.82) group (P = 0.025). The IL-1 receptor transcription activity was reduced in the IPC group (ΔCt: 1.88 ± 0.53 to 4.81 ± 0.21), but not in the R-IPC group, during reperfusion (P = 0.027). In the MD, a significant drop in the NOx levels was noted in the R-IPC group (12.3 ± 2.2 to 4.7 ± 1.2 µmol/L) at the end of ischemia compared with the levels in early ischemia (P = 0.008). A similar trend was observed in the IPC group (11.8 ± 2.1 to 6.4 ± 1.5 µmol/L), although this difference was not statistically significant. The levels of NOx rose quickly during reperfusion in both groups. CONCLUSION: IPC, but not R-IPC, reduces iNOS and IL-1 receptor transcription during early reperfusion, indicating a lower inflammatory reaction. NOx is consumed in the ischemic liver lobe.

N-acetyl cysteine improves glycogenesis after segmental liver ischemia and reperfusion injury in pigs.

OBJECTIVE: N-acetylcysteine (NAC) is an antioxidative molecule known to protect liver tissue from oxygen radical species generated during ischemia and reperfusion (IR). Nutritional and toxicology studies have shown that NAC also improves glucose metabolism and glycogen stores. We hypothesized that NAC improves glycogenesis and that impaired glycogenesis is a key element in IR injury. MATERIAL AND METHODS: In an experimental model, 80 min of segmental liver ischemia was induced in 16 pigs and the reperfusion was followed for 360 min. Eight animals received NAC 150 mg/kg as a bolus injection followed by an infusion of NAC 50 mg/kg/h intravenously. RESULTS: AST and leukocyte density were lower in the NAC-treated animals, unrelated to the glutathione levels or apoptosis. Glycogen stores returned to a higher degree in the NAC-treated animals and microdialysis revealed lower levels of lactate during the reperfusion phase. Nitrite/Nitrate levels in the NAC group were lower in both serum and microdialysates, indicating that NAC scavenges radical nitrosative species. CONCLUSIONS: NAC treatment improves glycogenesis after liver IR injury and reduces the level of intraparenchymal lactate during reperfusion, possibly due to the scavenging of radical nitrosative species.

Remote or conventional ischemic preconditioning--local liver metabolism in rats studied with microdialysis.

BACKGROUND: Ischemic preconditioning (IPC) of the liver decreases liver injury secondary to ischemia and reperfusion. An attractive alternative to IPC is remote ischemic preconditioning (R-IPC), but these two methods have not previously been compared. MATERIAL AND METHODS: Eighty-seven rats were randomized into four groups: sham operated (n = 15), 1 h segmental ischemia (IRI, n = 24), preceded by IPC (n = 24), or R-IPC (n = 24) (to the left hindleg). IPC and R-IPC were performed with 10 min ischemia and 10 min of reperfusion. Analyses of liver microdialysate (MD), serum transaminase levels, and liver histology were made. RESULTS: Rats treated with IPC and R-IPC had significantly lower AST, 71.5 (19.6) IU/L respective 96.6 (12.4) at 4 h reperfusion than those subjected to IRI alone, 155 (20.9), P = 0.0004 and P = 0.04 respectively. IPC also had lower ALT levels, 41.6 (11.3) IU/L than had IRI 107.4 (15.5), P = 0.003. The MD glycerol was significantly higher during ischemia in the R-IPC [759 (84) µM] and the IRI [732 (67)] groups than in the IPC 514 (70) group, P = 0.022 and P = 0.046 respectively. The MD glucose after ischemia was lower in the IPC group 7.1 (1.2) than in the IRI group 12.7 (1.6), P = 0.005. Preconditioning to the liver caused an direct increase in lactate, glucose and glycerol in the ischemic segment compared with the control segment an effect not seen in the R-IPC and IRI groups. CONCLUSIONS: IPC affects glucose metabolism in the rat liver, observed with MD. IPC reduces liver cell injury during ischemic and reperfusion in rats. R-IPC performed over the same length of time as IPC does not have the same effect as the latter on ALT levels and MD glycerol; this may suggest that R-IPC does not offer the same protection as IPC in this setting of rat liver IRI.

Ischemic preconditioning prior to intermittent Pringle maneuver in liver resections.

BACKGROUND/PURPOSE: Continuous inflow vascular occlusion during liver resections causes less severe ischemia and reperfusion injury (IRI) if it is preceded by ischemic preconditioning (IP) or if intermittent inflow occlusion is used during the resection. No previous clinical trial has studied the effects of adding IP to intermittent inflow occlusion. METHODS: Consecutive patients (n = 32) with suspicion of malignant liver disease had liver resections (minimum 2 segments) performed with inflow occlusion (intermittent clamping in a manner of 15 min of ischemia and 5 min of reperfusion repetitively; 15/5). Half of the patients were randomized to receive IP (10 min of ischemia and 10 min of reperfusion before parenchymal transection; 10/10). The patients were stratified according to volume of resection and none had chronic liver disease. The patients were followed for 5 days with microdialysis (µD). RESULTS: All patients completed the study and there were no deaths. No differences were seen between the groups regarding demographics or perioperative parameters (bleeding, duration of ischemia, resection volume, complications, and serum laboratory tests). There were no differences in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, or prothrombin time (PT)-INR levels, but µD revealed lower levels of lactate, pyruvate, and glucose in the IP group having major liver resections (analysis of variance; ANOVA). Nitrite and nitrate levels in µD decreased postoperatively, but no differences were seen between the groups. In one patient an elevated µD-glycerol curve was seen before the diagnosis of a stroke was made. CONCLUSIONS: IP before intermittent vascular occlusion does not reduce the serum parameters used to assess IRI. IP seems to improve aerobic glucose metabolism, as the levels of glucose, pyruvate, and lactate locally in the liver were reduced, compared to controls, in patients having >3 segments resected. µD may be used to monitor metabolism locally.

Novel gene hBiot2 is an independent prognostic factor in colorectal cancer patients.

The present study investigated the expression of the novel gene hBiot2 in colorectal cancer (CRC) and its relationships with clinicopathological variables in CRC patients. The expression of hBiot2 in 163 primary CRCs together with the corresponding normal mucosa, 36 liver metastases and 5 colon cancer cell lines was examined using real-time PCR. In situ hybridization (ISH) was performed to evaluate the localization of hBiot2 expression in CRC and normal mucosa. hBiot2 expression at the RNA level was localized in the nucleus of tumor cells and normal epithelial cells. The mean expression of hBiot2 in the CRCs (243.571±564.569) was higher compared to the normal mucosa (107.252±413.635, P<0.0001) and liver metastasis samples (42.002±40.809, P=0.0002). hBiot2 expression was increased from stages I+II to III (P=0.047), and no difference in the expression was found in stages III and IV (P=0.452). A high value of hBiot2 was associated with a poorer prognosis compared with a low value independently of gender, age, tumor site, stage and differentiation (P=0.007, RR 7.519, 95% CI 1.729-32.704). Liver metastasis, smaller tumors, non-local recurrence and primary liver surgery alone were associated with a higher value of hBiot2 compared to larger tumors, local recurrence and repeated liver surgery (P=0.003, 0.044 and 0.026, respectively). An inverse relationship was found between hBiot2 expression and the metastatic potential of the colon cancer cell lines. Thus, increased expression of hBiot2 may be an early and interim event in the development of CRC. A higher expression of hBiot2 in primary CRC patients independently indicates a poorer prognosis.

Systematic review of cholecystostomy as a treatment option in acute cholecystitis.

OBJECTIVES: Percutaneous cholecystostomy (PC) is an established low-mortality treatment option for elderly and critically ill patients with acute cholecystitis. The primary aim of this review is to find out if there is any evidence in the literature to recommend PC rather than cholecystectomy for acute cholecystitis in the elderly population. METHODS: In April 2007, a systematic electronic database search was performed on the subject of PC and cholecystectomy in the elderly population. After exclusions, 53 studies remained, comprising 1918 patients. Three papers described randomized controlled trials (RCTs), but none compared the outcomes of PC and cholecystectomy. A total of 19 papers on mortality after cholecystectomy in patients aged >65 years were identified. RESULTS: Successful intervention was seen in 85.6% of patients with acute cholecystitis. A total of 40% of patients treated with PC were later cholecystectomized, with a mortality rate of 1.96%. Procedure mortality was 0.36%, but 30-day mortality rates were 15.4 % in patients treated with PC and 4.5% in those treated with acute cholecystectomy (P < 0.001). CONCLUSIONS: There are no controlled studies evaluating the outcome of PC vs. cholecystectomy and the papers reviewed are of evidence grade C. It is not possible to make definitive recommendations regarding treatment by PC or cholecystectomy in elderly or critically ill patients with acute cholecystitis. Low mortality rates after cholecystectomy in elderly patients with acute cholecystitis have been reported in recent years and therefore we believe it is time to launch an RCT to address this issue.