Prolonged treatment of genetically obese mice with conjugated linoleic acid improves glucose tolerance and lowers plasma insulin concentration: possible involvement of PPAR activation

Background

Studies in rodents and some studies in humans have shown that conjugated linoleic acid (CLA), especially its trans -10, cis -12 isomer, reduces body fat content. However, some but not all studies in mice and humans (though none in rats) have found that CLA promotes insulin resistance. The molecular mechanisms responsible for these effects are unclear, and there are conflicting reports on the effects of CLA on peroxisomal proliferator-activated receptor-γ (PPARγ) activation and expression. We have conducted three experiments with CLA in obese mice over three weeks, and one over eleven weeks. We have also investigated the effects of CLA isomers in PPARγ and PPARα reporter gene assays.

Results

Inclusion of CLA or CLA enriched with its trans -10, cis -12 isomer in the diet of female genetically obese (lep ^ob /lep ^ob ) mice for up to eleven weeks reduced body weight gain and white fat pad weight. After two weeks, in contrast to beneficial effects obtained with the PPARγ agonist rosiglitazone, CLA or CLA enriched with its trans -10, cis -12 isomer raised fasting blood glucose and plasma insulin concentrations, and exacerbated glucose tolerance. After 10 weeks, however, CLA had beneficial effects on glucose and insulin concentrations. At this time, CLA had no effect on the plasma TNFα concentration, but it markedly reduced the plasma adiponectin concentration. CLA and CLA enriched with either isomer raised the plasma triglyceride concentration during the first three weeks, but not subsequently. CLA enriched with its trans -10, cis -12 isomer, but not with its cis -9, trans -11 isomer, stimulated PPARγ-mediated reporter gene activity; both isomers stimulated PPARα-mediated reporter gene activity.

Conclusions

CLA initially decreased but subsequently increased insulin sensitivity in lep ^ob /lep ^ob mice. Activation of both PPARγ and PPARα may contribute to the improvement in insulin sensitivity. In the short term, however, another mechanism, activated primarily by trans -10, cis -12-CLA, which probably leads to reduced adipocyte number and consequently reduced plasma adiponectin concentration, may decrease insulin sensitivity.     

Integrating visual cues for motor control: a matter of time

The visual system continuously integrates multiple sensory cues to help plan and control everyday motor tasks. We quantified how subjects integrated monocular cues (contour and texture) and binocular cues (disparity and vergence) about 3D surface orientation throughout an object placement task and found that binocular cues contributed more to online control than planning. A temporal analysis of corrective responses to stimulus perturbations revealed that the visuomotor system processes binocular cues faster than monocular cues. This suggests that binocular cues dominated online control because they were available sooner, thus affecting a larger proportion of the movement. This was consistent with our finding that the relative influence of binocular information was higher for short-duration movements than long-duration movements. A motor control model that optimally integrates cues with different delays accounts for our findings and shows that cue integration for motor control depends in part on the time course of cue processing.     

Infectious keratitis after overnight orthokeratology in Canada

PURPOSE: To report 3 cases of infectious keratitis related to overnight orthokeratology use. METHODS: Retrospective case observation. RESULTS: All 3 patients were using overnight orthokeratology lenses when they presented with unilateral corneal ulcers. The organisms isolated were Acanthamoeba, Pseudomonas aeruginosa, and Serratia marcescens. The clinical presentation and treatment of each case is presented. CONCLUSIONS: Overnight orthokeratology use may be associated with infectious keratitis despite the use of more oxygen-permeable materials and improved lens design. Patient education with informed consent, appropriate lens care, and meticulous follow-up is important. Because this complication is potentially sight threatening, orthokeratology requires further analysis and evaluation to establish its safety. The cases here are the first few reported cases in North America.     

Mechanisms of improved survival from intensive followup in colorectal cancer: a hypothesis

A meta-analysis of six randomised trials demonstrated that intensive followup in colorectal cancer was associated with an absolute reduction in all-cause 5-year mortality of 10% (95% confidence interval (CI): 4-16)--however, only two percent (95% CI: 0-5) was attributable to cure from salvage re-operations. We postulate that other factors, such as increased psychological well-being and/or altered lifestyle, and/or improved treatment of coincidental disease may contribute to the remaining lives saved, and form important future research questions.     

Short-term outcomes of five heroin detoxification methods in the Australian NEPOD Project

This study included 380 participants in five heroin detoxification trials whose data were pooled to enable direct comparison of five detoxification methods in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD). Rapid detoxification achieved similar initial abstinence rates with either anaesthesia or sedation (average 59%), which were higher than was achieved by inpatient detoxification using clonidine plus other symptomatic medications (24%), which in turn was higher than outpatient detoxification using either buprenorphine (12%) or clonidine plus other symptomatic medications (4%). Older participants and those using more illicit drugs were more likely to achieve abstinence. Entry rates into ongoing postdetoxification treatment were as follows: buprenorphine outpatient (65%), sedation (63%), anaesthesia (42%), symptomatic outpatient (27%), and symptomatic inpatient (12%). Postdetoxification treatment with buprenorphine or methadone was preferred over naltrexone. Participants with more previous detoxification attempts were more likely to enter postdetoxification treatment. Given that outpatient detoxification was more effective with buprenorphine than with symptomatic medications and that rapid detoxification was more effective than the symptomatic inpatient method, the roles of the symptomatic methods should be reconsidered.     

Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1

High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.     

Potent, orally active corticotropin-releasing factor receptor-1 antagonists containing a tricyclic pyrrolopyridine or pyrazolopyridine core

Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.     

Systematic review: acute colonic pseudo-obstruction

Acute colonic pseudo-obstruction is the clinical syndrome of acute large bowel dilatation without mechanical obstruction that is an important cause of morbidity and mortality. Acute colonic pseudo-obstruction occurs in hospitalized or institutionalized patients with serious underlying medical and surgical conditions. The pathogenesis of acute colonic pseudo-obstruction is not completely understood but likely results from an imbalance in the autonomic regulation of colonic motor function. Metabolic or pharmacological factors, as well as spinal or retroperitoneal trauma, may alter the autonomic regulation of colonic function, leading to excessive parasympathetic suppression or sympathetic stimulation. This imbalance results in colonic atony and dilatation. Early recognition and appropriate management are critical to minimizing morbidity and mortality. The mortality rate is estimated at 40% when ischaemia or perforation occurs. The best-studied treatment of acute colonic pseudo-obstruction is intravenous neostigmine, which leads to prompt colon decompression in the majority of patients after a single infusion. In patients failing or having contraindications to neostigmine, colonoscopic decompression is the active intervention of choice. Surgery is reserved for those with peritonitis or perforation.     

The management of strabismus in adults--II. Patient and provider perspectives on the severity of adult strabismus and on outcome contributors.

PURPOSE: As part of a larger study intended to evaluate the management of strabismus in adults, we documented and compared patient and provider perspectives on the various factors that may contribute to treatment outcome and value of strabismus care. METHODS: By completing a questionnaire, 170 patients with strabismus (ages 19 to 87 years) and 11 strabismus specialists who performed surgery on these patients each indicated the relative weight of several disease- and treatment-related contributors to the outcome and value of care. In addition, each respondent rated the severity of the strabismus before and after surgery. RESULTS: Overall severity ratings improved as a result of surgery. The improvement perceived by the physicians was 5.1 +/- 1.7 on a 10-point scale and was larger than the 2.6 +/- 3.6 points improvement perceived by the patients ( P < 0.001). Patients and physicians expressed different views on the relative contributions to outcome and value (overall P < 0.001). Both groups indicated "the condition," "the physician," and "the procedures" as the largest contributors, but "condition" was perceived as more important by the physicians than by the patients ( P < 0.001), and "physician" was more important to the patients than to the physicians ( P < 0.001). CONCLUSION: Although in approximate agreement on the main contributors to outcome and value, discrepancies exist between perspectives of patients and physicians on the relative weights of those contributors. Public information, education, and counseling may bring these perspectives better in line and ultimately improve both quality and patient satisfaction.