Nicholas M. Szary

Angiotensin II-induced NADPH Oxidase Activation Impairs Insulin Signaling in Skeletal Muscle Cells

The renin-angiotensin system (RAS) and reactive oxygen species (ROS) have been implicated in the development of insulin resistance and its related complications. There is also evidence that angiotensin II (Ang II)-induced generation of ROS contributes to the development of insulin resistance in skeletal muscle, although the precise mechanisms remain unknown. In the present study, we found that Ang II markedly enhanced NADPH oxidase activity and consequent ROS generation in L6 myotubes. These effects were blocked by the angiotensin II type 1 receptor blocker losartan, and by the NADPH oxidase inhibitor apocynin. Ang II also promoted the translocation of NADPH oxidase cytosolic subunits p47phox and p67phox to the plasma membrane within 15 min. Furthermore, Ang II abolished insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), activation of protein kinase B (Akt), and glucose transporter-4 (GLUT4) translocation to the plasma membrane, which was reversed by pretreating myotubes with losartan or apocynin. Finally, small interfering RNA (siRNA)-specific gene silencing targeted specifically against p47phox (p47siRNA), in both L6 and primary myotubes, reduced the cognate protein expression, decreased NADPH oxidase activity, restored Ang II-impaired IRS1 and Akt activation as well as GLUT4 translocation by insulin. These results suggest a pivotal role for NADPH oxidase activation and ROS generation in Ang II-induced inhibition of insulin signaling in skeletal muscle cells.

Bowel preparation with split-dose polyethylene glycol before colonoscopy: a meta-analysis of randomized controlled trials

BACKGROUND Polyethylene glycol (PEG) is a commonly used bowel preparation for colonoscopy. Unfortunately, the standard large-volume solution may reduce patient compliance. Split-dosing of PEG has been studied in various randomized, controlled trials (RCTs). However, results have been conflicting. OBJECTIVE We conducted a meta-analysis to assess the role of split-dose PEG versus full-dose PEG for bowel preparation before colonoscopy. DESIGN Multiple databases were searched (January 2011). RCTs on adults comparing full-dose and split-dose of PEG for bowel preparation before colonoscopy were included and analyzed by calculating pooled estimates of quality of bowel preparation, preparation compliance, willingness to repeat the same preparation, and side effects by using odds ratio (OR) by fixed and random-effects models. SETTING Literature search. PATIENTS Per RCTs. MAIN OUTCOME MEASUREMENTS Satisfactory bowel preparation, willingness to repeat same bowel preparation, patient compliance, and side effects. RESULTS Five trials met inclusion criteria (N = 1232). Split-dose PEG significantly increased the number of satisfactory bowel preparations (OR 3.70; 95% CI, 2.79-4.91; P < .01) and willingness to repeat the same preparation (OR 1.76; 95% CI, 1.06-2.91; P = .03) compared with full-dose PEG. Split-dose PEG also significantly decreased the number of preparation discontinuations (OR 0.53; 95% CI, 0.28-0.98; P = .04) and nausea (OR 0.55; 95% CI, 0.38-0.79; P < .01) compared with full-dose PEG. LIMITATIONS Limited number of studies. CONCLUSIONS The use of a split-dose PEG for bowel preparation before colonoscopy significantly improved the number of satisfactory bowel preparations, increased patient compliance, and decreased nausea compared with the full-dose PEG.

Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review

BACKGROUND Acute pancreatitis is a common complication of ERCP. Several randomized, controlled trials (RCTs) have evaluated the use of pancreatic stents in the prevention of post-ERCP pancreatitis with varying results. OBJECTIVE We conducted a meta-analysis and systematic review to assess the role of prophylactic pancreatic stents for prevention of post-ERCP pancreatitis. DESIGN MEDLINE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, PubMed, and recent abstracts from major conference proceedings were searched. RCTs and retrospective or prospective, nonrandomized studies comparing prophylactic stent with placebo or no stent for post-ERCP pancreatitis were included for the meta-analysis and systematic review. Standard forms were used to extract data by 2 independent reviewers. The effect of stents (for RCTs) was analyzed by calculating pooled estimates of post-ERCP pancreatitis, hyperamylasemia, and grade of pancreatitis. Separate analyses were performed for each outcome by using the odds ratio (OR) or weighted mean difference. Random- or fixed-effects models were used. Publication bias was assessed by funnel plots. Heterogeneity among studies was assessed by calculating I(2) measure of inconsistency. SETTING Systematic review and meta-analysis of patients undergoing pancreatic stent placement for prophylaxis against post-ERCP pancreatitis. PATIENTS Adult patients undergoing ERCP. INTERVENTIONS Pancreatic stent placement for the prevention of post-ERCP pancreatitis. MAIN OUTCOME MEASUREMENTS Post-ERCP pancreatitis, hyperamylasemia, and complications after pancreatic stent placement. RESULTS Eight RCTs (656 subjects) and 10 nonrandomized studies met the inclusion criteria (4904 subjects). Meta-analysis of the RCTs showed that prophylactic pancreatic stents decreased the odds of post-ERCP pancreatitis (odds ratio, 0.22; 95% CI, 0.12-0.38; P<.01). The absolute risk difference was 13.3% (95% CI, 8.8%-17.8%). The number needed to treat was 8 (95% CI, 6-11). Stents also decreased the level of hyperamylasemia (WMD, -309.22; 95% CI, -350.95 to -267.49; P≤.01). Similar findings were also noted from the nonrandomized studies. LIMITATIONS Small sample size of some trials, different types of stents used, inclusion of low-risk patients in some studies, and lack of adequate study of long-term complications of pancreatic stent placement. CONCLUSIONS Pancreatic stent placement decreases the risk of post-ERCP pancreatitis and hyperamylasemia in high-risk patients.

Erythromycin prior to endoscopy in acute upper gastrointestinal bleeding: A meta-analysis

Abstract Objective. Upper gastrointestinal bleeding (UGIB) is a medical emergency requiring urgent endoscopy and diagnosis. However, adequate visualization is a necessity. Studies have been performed evaluating the efficacy of erythromycin infusion prior to endoscopy to improve visibility and therapeutic potential of esophagogastroduodenoscopy (EGD) with varied results. Therefore, a meta-analysis was performed comparing the efficacy of erythromycin infusion prior to endoscopy in acute UGIB. Materials and methods. Multiple databases were searched. Meta-analysis for the effect of erythromycin prior to endoscopy in UGIB was analyzed by calculating pooled estimates of visualization of gastric mucosa, need for second endoscopy, and units of blood transfused using odds ratio (OR) and weighted mean difference (WMD). Results. Four studies (N = 269) met the inclusion criteria. Erythromycin prior to endoscopy in UGIB demonstrated a statistically significant improvement in visualization of the gastric mucosa (OR 4.89; 95% CI 2.85–8.38, p < 0.01), a decrease in the need for a second endoscopy (OR 0.42; 95% CI 0.24–0.74, p < 0.01), and a trend for less units of blood transfused (WMD −0.48; 95% CI −0.97 to 0.01, p = 0.05) with erythromycin as compared with no erythromycin. Conclusions. Erythromycin infusion prior to endoscopy in acute UGIB significantly improves visualization of gastric mucosa while decreasing the need for a second endoscopy. Based upon these results, erythromycin should be strongly considered prior to endoscopy in patients with UGIB.

Enteral feeding within three hours after percutaneous endoscopic gastrostomy placement: a meta-analysis.

Background Traditionally, tube feedings have been delayed after gastrostomy placement to the next day and up to 24 hours postprocedure. However, results from various randomized clinical trials (RCTs) indicate earlier feeding may be an option. Therefore, we conducted a meta-analysis to analyze the effect of earlier feedings (⩽3 h) after percutaneous endoscopic gastrostomy (PEG) placement. Methods Various medical databases and recent abstracts from major conference proceedings were searched (8/09). Only RCTs on adult subjects that compared early (⩽3 h) versus delayed or next-day feedings after PEG placement were included. Meta-analysis was performed using pooled estimates of complications, death ⩽72 hours, and significant increases in the number of postprocedural gastric residual volume during day 1 using odds ratio (OR) with the fixed and random effects models. Heterogeneity was assessed by calculating the I2 measure of inconsistency. RevMan 5.0 was utilized for statistical analysis. Results Five studies (N=355) met the inclusion criteria. No significant differences were noted between early (⩽3 h) and delayed or next day feedings for patient complications [OR 0.78; 95% confidence interval (CI), 0.39-1.53; P=0.47], death in ⩽72 hours (OR 0.60; 95% CI, 0.18-1.99; P=0.40), and number of significant gastric residual volume during day 1 (OR 1.46; 95% CI, 0.75-2.84; P=0.27). No publication bias and no significant heterogeneity were noted. Conclusions Early tube feeding ⩽3 hours after PEG placement has no significant differences to delayed or next-day feeding in respect to complications, death in ⩽72 hours, or number of significant gastric residual volumes at day 1.

High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model

Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide “metabolic protection” from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and β-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model.