Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by beta cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in correlation with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600a) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, "emetine" is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nM. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas, and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted.

Blueprint for the development of resuscitation and emergency critical care fellowships.

The volume of critically ill patients presenting to the emergency department (ED) is increasing rapidly. Continued growth will likely further stress an already strained U.S. health care system. Numerous studies have demonstrated an association with worsened outcomes for critically ill patients boarding in the ED. To address the increasing volume and complexity of critically ill patients presenting to EDs nationwide, resuscitation and emergency critical care (RECC) fellowships were developed. RECC programs teach a general approach to the management of the undifferentiated critically ill patient, advanced management of critically ill patients by disease presentation, and ongoing supportive care of the critically ill patient boarding in the ED. The result is critical care training beyond that of a typical emergency medicine (EM) residency with a focus on the unique features and challenges of caring for critically ill patients in the ED not normally found in critical care fellowships. Graduates from RECC fellowships are well suited to practicing in any ED practice model and may be especially well prepared for EDs that distinguish acuity between zones (e.g., resuscitative care units, ED-based intensive care units). In addition to further developing clinical acumen, RECC fellowships provide graduates with a niche in EM education, research, and administration. In this article, we describe the philosophical principles and practical components necessary for the creation of future RECC fellowships.