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Sudden cardiac death is an important cause of cardiovascular mortality with the majority of cases occurring in low-risk groups. HMG-CoA reductase inhibitors (statins) have recently been shown to reduce the incidence of ventricular tachycardia (VT)/fibrillation (VF) and sudden cardiac death, and this has been attributed to their pleiotropic effects. However, it is unclear whether this occurs through an 'indirect' anti-ischemic or 'direct' antiarrhythmic effect. We systematically reviewed articles published on MEDLINE between January 1996 and December 2009 focusing on the reduction of VT/VF and sudden cardiac death by statins and the potential mechanisms. Studies reporting sudden cardiac death or VT/VF outcomes with statin use (n = 23) or the pathophysiology of sudden cardiac death reduction by statins (n = 19) were included. We found that statins have been shown to reduce VT/VF and sudden cardiac death only in subjects with underlying coronary artery disease or ischemic cardiomyopathy. No definite benefits were seen with statins in sudden cardiac death and VT/VF in patients with non-ischemic cardiomyopathy. There is insufficient evidence to point toward a benefit in populations at low risk for VT/VF. In conclusion, an anti-ischemic rather than a primary antiarrhythmic effect emerges as the likely mechanism of sudden cardiac death reduction with statins.

Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. We present a strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d x 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, we demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. Our results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.

Ischemia/reperfusion (I/R)-induced injury of the vital organs is a well-known pathology that can lead to increased morbidity and mortality. Several pharmacological therapeutic options have been explored for the prevention and attenuation of I/R-induced injury. The TRPV1 (transient receptor potential vanilloid 1) channel, which is primarily expressed in the sensory nerves, represents a new target molecule. Studies have demonstrated that modulation of sensory nerve activity can attenuate local inflammatory responses, and may function in the maintenance of tissue integrity. The activation of the TRPV1 receptor by its agonists reduces inflammation during I/R-induced injury through several pathways. TRPV1 agonists have demonstrated beneficial effects in the prevention of renal I/R-induced injury. This review focuses on recent developments in investigational drugs that target TRPV1 and/or the downstream pathways activated by TRPV1 for the prevention or treatment of I/R-induced injury of the kidneys.

Osteopontin (OPN) is both a matrix protein in mineralized tissues and a cytokine, and it has a pivotal role in osteoclast-mediated bone resorption. Here, using a proprietary hydroxyapatite substitute for bone mineral (Osteologic discs), we investigated the requirement for OPN in mineral resorption. Resorption pits formed in the Osteologic discs, revealed by staining with silver nitrite (Von Kossa stain), were analyzed using the NIH Image J program, which can determine the number of pits formed per unit area, their average size, and the fractional area resorbed. After a preincubation of bone marrow cells from OPN -/- and OPN +/+ mice with M-CSF to allow the multiplication of osteoclast precursors on cell culture plastic, osteoclast formation on both Osteologic discs and standard cell culture plates was induced with soluble receptor activator of NFkappaB ligand, sRANKL. We did not detect a dramatic difference in osteoclast formation between OPN +/+ and OPN -/- cells, as judged by staining for tartrate-resistant acid phosphatase in osteoclasts formed on cell culture plastic, nor was there a significant difference in the ability of the osteoclasts to form resorption pits in the Osteologic discs. Additionally, none of six different anti-OPN monoclonal antibodies had a significant and reproducible effect on the formation or subsequent functioning of the OPN+/+ osteoclasts. These studies suggest that, in contrast to what has been found for normal bone, the efficiency of dissolution of a ceramic, protein-free (excepting protein adsorbed from the culture medium) hydroxyapatite/tri-calcium phosphate substrate by osteoclasts is not substantially enhanced by endogenous or exogenous OPN.

We conducted a prospective study to determine the most reliable indicator of common bile duct stones before laparoscopic cholecystectomy. One hundred thirty-seven patients were referred for endoscopic retrograde cholangiography before laparoscopic cholecystectomy for suspected choledocholithiasis due to one or more of the following abnormalities: (a) altered liver function tests, (b) increased serum amylase levels, or (c) a dilated common bile duct (> 7 mm) with or without evidence of stones on sonography. Sensitivity, specificity, positive and negative predictive values, and the likelihood of the presence or absence of morbidity were calculated for 25 different variables. Common bile duct stones were detected in 63 (46%) patients. Abnormal result of sonography of the common bile duct was the best predictor of choledocholithiasis (p < 0.0001). Abnormalities of the combined liver function tests were statistically significant predictors only when combined with abnormal sonographic results. Improving liver function tests before endoscopy had a significant negative predictive value (p = 0.01). Stepwise logistic regression analysis showed that abnormal ultrasound and the presence of common bile duct stones on ultrasound were significant (p = 0.009 and p = 0.049, respectively). Abnormal result of sonography of the common bile duct is the best predictor of choledocholithiasis before laparoscopic cholecystectomy.