Interventions to Improve Emergency Department-Related Transitions in Care for Adult Patients With Atrial Fibrillation and Flutter.

BACKGROUND: Patients presenting to emergency departments (EDs) with acute atrial fibrillation or flutter undergo numerous transitions in care (TiC), including changes in their provider, level of care, and location. During transitions, gaps in communications and care may lead to poor outcomes. OBJECTIVE: We sought to examine the effectiveness of ED-based interventions to improve length of stay, return to normal sinus rhythm, and hospitalization, among other critical patient TiC outcomes. METHODS: Comprehensive searches of electronic databases and the gray literature were conducted. Two independent reviewers completed study selection, quality, and data extraction. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model, where appropriate. RESULTS: From 823 citations, 11 studies were included. Interventions consisted of within-ED clinical pathways (n = 6) and specialized observation units (n = 2) and post-ED structured patient education and referrals (n = 3). Three of five studies assessing hospital length of stay reported a significant decrease associated with TiC interventions. Patients undergoing within-ED interventions were also more likely to receive electrical cardioversion. Two of 3 clinical pathways reporting hospitalization proportions showed significant decreases associated with TiC interventions (RR = 0.63 [95% CI 0.42-0.92] and RR = 0.20 [95% CI 0.12-0.32]), as did 1 observation unit (RR = 0.54 [95% CI 0.36-0.80]). No significant differences in mortality, complications, or relapse were found between groupings among the studies. CONCLUSIONS: There is low to moderate quality evidence suggesting that within-ED TiC interventions may reduce hospital length of stay and decrease hospitalizations. Additional high-quality comparative effectiveness studies, however, are warranted.

Treatment of obesity and diabetes in mice by transplant of gut cells engineered to produce leptin.

Leptin injections evoke weight loss by causing a reduction in food consumption and an increase in energy expenditure. Also, the administration of leptin lowers blood glucose levels in some rodent models of diabetes and in humans with lipodystrophy. We explored the therapeutic potential of delivering leptin to obese, diabetic ob/ob mice and to mice fed on a high-fat diet (HFD), by transplanting gut-derived cells engineered to produce leptin, under the regulation of an inducing agent, mifepristone. These cells expressed and released leptin in a mifepristone dose-dependent and time-dependent manner. The engineered cells were either transplanted into the mice under the kidney capsule or were encapsulated in alginate and injected into the intraperitoneal cavity, while mifepristone was delivered by implanting 14-day release pellets. In ob/ob mice, leptin delivery by this method caused a significant reduction in food intake and profound weight loss, which was controllable by adjusting the dose of mifepristone. These transplants also achieved rapid and persistent amelioration of diabetes. However, mice fed on a HFD were resistant to the leptin therapy. These results indicate that gut cells can be modified to express leptin in an inducible manner and that the transplantation of these cells has a therapeutic effect in leptin-deficient mice, but not in mice fed on a HFD.

Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic beta-cells.

Leptin inhibits insulin secretion and preproinsulin gene expression in pancreatic beta-cells, but signal transduction pathways and molecular mechanisms underlying this effect are poorly characterized. In this study, we analyzed leptin-mediated signal transduction and preproinsulin gene regulation at the molecular level in pancreatic beta-cells. Leptin stimulation led to janus kinase (JAK)2-dependent phosphorylation and nuclear translocation of the transcription factors signal transducer and activator of transcription (STAT)3 and STAT5b in INS-1 beta-cells. Leptin also induced mRNA expression of the JAK-STAT inhibitor suppressor of cytokine signaling (SOCS)3 in INS-1 beta-cells and human pancreatic islets in vitro and in pancreatic islets of ob/ob mice in vivo. Transcriptional activation of the rat SOCS3 promoter by leptin was observed with concomitant leptin-induced STAT3 and STAT5b DNA binding to specific promoter regions. Unexpectedly, SOCS3 inhibited both basal and STAT3/5b-dependent rat preproinsulin 1 gene promoter activity in INS-1 cells. These results suggest that SOCS3 represents a transcriptional inhibitor of preproinsulin gene expression, which is induced by leptin through JAK-STAT3/5b signaling in pancreatic beta-cells. In conclusion, although SOCS3 is believed to be a negative feedback regulator of JAK-STAT signaling, our findings suggest involvement of SOCS3 in a direct gene regulatory pathway downstream of leptin-activated JAK-STAT signaling in pancreatic beta-cells.

Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase 1B expression.

Leptin has been shown to improve insulin sensitivity and glucose metabolism in obese diabetic ob/ob mice, yet the mechanisms remain poorly defined. We found that 2 d of leptin treatment improved fasting but not postprandial glucose homeostasis, suggesting enhanced hepatic insulin sensitivity. Consistent with this hypothesis, leptin improved in vivo insulin receptor (IR) activation in liver, but not in skeletal muscle or fat. To explore the cellular mechanism by which leptin up-regulates hepatic IR activation, we examined the expression of the protein tyrosine phosphatase PTP1B, recently implicated as an important negative regulator of insulin signaling. Unexpectedly, liver PTP1B protein abundance was increased by leptin to levels similar to lean controls, whereas levels in muscle and fat remained unchanged. The ability of leptin to augment liver IR activation and PTP1B expression was also observed in vitro in human hepatoma cells (HepG2). However, overexpression of PTP1B in HepG2 cells led to diminished insulin-induced IR phosphorylation, supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes. Collectively, our results suggest that leptin acutely improves hepatic insulin sensitivity in vivo with concomitant increases in PTP1B expression possibly serving to counterregulate insulin action and to maintain insulin signaling in proper balance.