Cd36 and molecular mechanisms of insulin resistance in the stroke-prone spontaneously hypertensive rat

Insulin resistance is of pathogenic importance in several common human disorders including type 2 diabetes, hypertension, obesity and hyperlipidemia, but the underlying mechanisms are unknown. The spontaneously hypertensive rat (SHR) is a model of these human insulin resistance syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridemia, and hypertension map to a single region on rat chromosome 4. Genetic analysis of an SHR derived from a National Institutes of Health colony led to the identification of a causative mutation in the SHR Cd36. We have investigated glucose and fatty acid metabolism in the stroke-prone SHR (SHRSP). We demonstrate defects in insulin action on 2-deoxy-D-glucose transport (SHRSP 3.3 +/- 1.5 vs. 21.0 +/- 7.4 pmol x min(-1) x [20 microl packed cells](-1), SHRSP vs. WKY, respectively, P = 0.01) and inhibition of catecholamine-stimulated lipolysis (P < 0.05 at all concentrations of insulin) in adipocytes isolated from SHRSP. In contrast, basal levels of catecholamine-stimulated nonesterified free fatty acid (NEFA) release and plasma levels of NEFA are similar in SHRSP and WKY. These results are in agreement with the data on the SHR.4 congenic strain, which suggested that the QTL containing Cd36 mutations accounted for the entire defect in basal catecholamine action but only for approximately 40% of the SHR defect in insulin action. In the SHR, both abnormalities appear consequent of defective Cd36 expression. Because Cd36 sequence and expression are apparently normal in SHRSP, it is likely that the molecular mechanism for defective insulin action in this strain is caused by a gene(s) different than Cd36.     

Chloramphenicol resistance in vancomycin-resistant enterococcal bacteremia: impact of prior fluoroquinolone use?

OBJECTIVE: The prevalence of vancomycin-resistant enterococci (VRE) has increased markedly during the past decade. Few data exist regarding the epidemiology of resistance of VRE to chloramphenicol, one of the few therapeutic options. DESIGN: Survey and case-control study. SETTING: A 725-bed, tertiary-care academic medical center and a 344-bed urban community hospital. PATIENTS: Hospitalized patients with blood cultures demonstrating VRE. METHODS: We examined the trends in the prevalence of chloramphenicol resistance in VRE blood isolates at our institution from 1991 through 2002 and conducted a case-control study to identify risk factors for chloramphenicol resistance among these isolates. RESULTS: From 1991 through 2002, the annual prevalence of chloramphenicol-resistant VRE increased from 0% to 12% (P < .001, chi-square test for trend). Twenty-two case-patients with chloramphenicol-resistant VRE bloodstream isolates were compared with 79 randomly selected control-patients with chloramphenicol-susceptible VRE. Independent risk factors for chloramphenicol-resistant VRE were prior chloramphenicol use (odds ratio [OR], 10.9; 95% confidence interval [CI95], 1.72-68.91; P = .01) and prior fluoroquinolone use (OR, 4.74; CI95, 1.15-19.42; P = .03). Chloramphenicol-resistant VRE isolates were more likely to be susceptible to beta-lactams and resistant to tetracycline than were chloramphenicol-susceptible VRE isolates. CONCLUSIONS: Significant increases in the prevalence of chloramphenicol-resistant VRE may limit the future utility of chloramphenicol in the treatment of VRE infections, and close monitoring of susceptibility trends should continue. The association between fluoroquinolone use and chloramphenicol-resistant VRE, reflecting possible co-selection of resistance, suggests that recent dramatic increases in fluoroquinolone use may have broader implications than previously recognized.     

Disrupted local innervation results in less VIP expression in CF mice tissues

Vasoactive Intestinal Peptide (VIP) is the major physiological agonist of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride channel activity. VIP functions as a neuromodulator and neurotransmitter secreted by neurons innervating all exocrine glands. VIP is also a potent vasodilator and bronchodilator that regulates exocrine gland secretions, contributing to local innate defense by stimulating the movement of water and chloride transport across intestinal and tracheobronchial epithelia. Previous human studies have shown that the rich intrinsic neuronal networks for VIP secretion around exocrine glands could be lost in tissues from patients with cystic fibrosis. Our research has since confirmed, in vitro and in vivo, the need for chronic VIP exposure to maintain functional CFTR chloride channels at the cell surface of airways and intestinal epithelium, as well as normal exocrine tissues morphology [1]. The goal of the present study was to examine changes in VIP in the lung, duodenum and sweat glands of 8- and 17-weeks old F508del/F508del mice and to investigate VIPergic innervation in the small intestine of CF mice, before important signs of the disease development. Our data show that a low amount of VIP is found in CF tissues prior to tissue damage. Moreover, we found a specific reduction in VIPergic and cholinergic innervation of the small intestine. The general innervation of the primary and secondary myenteric plexus was lost in CF tissues, with the presence of enlarged ganglionic cells in the tertiary layer. We propose that low amount of VIP in CF tissues is due to a reduction in VIPergic and cholinergic innervation and represents an early defect that constitutes an aggravating factor for CF disease progression.     

Association between cognitive impairments and anxiety disorders following traumatic brain injury

This study examined the association between cognitive impairment and anxiety disorders following traumatic brain injury (TBI). Sixty-six participants recruited from a rehabilitation hospital completed the Structured Clinical Interview for the DSM–IV (Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition) and cognitive tests at one year post injury. Prevalence of anxiety disorder was 27.3%. Logistic regression analyses revealed that the attention/working memory, information processing, and executive functions models were significantly associated with anxiety disorder. The memory model was not significant. Processing speed emerged as the strongest model associated with anxiety disorder. The role of cognitive impairment in the etiology of anxiety disorders after TBI is discussed, and treatment implications are explored.