Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice

Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN?) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [¹⁴C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [¹⁴C]-diclofenac was incubated with HRN? mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN? mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN? mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN? mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN? mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN? mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment.     

Symptoms During or Shortly After Isolated Carpal Tunnel Release and Problems Within 24?hours After Surgery

This study used the National Survey of Ambulatory Surgery (NSAS) database to measure the incidence of and risk factors for symptoms in the ambulatory surgery center and problems within 24 h after isolated carpal tunnel release (CTR). The NSAS contained records on 400,000 adult patients with carpal tunnel syndrome who were treated with CTR in 2006, based on ICD-9 codes. The type of anesthesia used and factors associated with symptoms and problems were sought in bivariate and multivariable statistical analyses. The mean duration of the procedure was 16 ± 8.8 min. Only 5 % were performed under local anesthesia without sedation, 45 % with IV sedation, 28 % regional anesthesia, and 19 % general anesthesia. Symptoms in the ambulatory surgery center or a problem within 24 h after discharge were recorded in 10 % of patients, all of them minor and transient, including difficulties with pain and its treatment. The strongest risk factors were male sex, age of 45 years and older, and participation of an anesthesiologist. Local anesthesia and regional anesthesia were associated with more perioperative symptoms and postoperative problems. Most CTR are performed with some sedation in the United States. CTR is a safe procedure: one in 10 patients will experience a minor issue in the perioperative or immediate postoperative period.     

Elevated glycohemoglobin HbA1c is associated with low back pain in nonoverweight diabetics

Background Context

Low back pain (LBP) is a common complaint in clinical practice of multifactorial origin. Although obesity has been thought to contribute to LBP primarily by altering the distribution of mechanical loads on the spine, the additional contribution of obesity-related conditions such as diabetes mellitus (DM) to LBP has not been thoroughly examined.