Substantial data implicate the commensal flora as triggers for the initiation of enteric inflammation or inflammatory disease relapse. We have shown that enteric epithelia under metabolic stress respond to nonpathogenic bacteria by increases in epithelial paracellular permeability and bacterial translocation. Here we assessed the structural basis of these findings. Confluent filter-grown monolayers of the human colonic T84 epithelial cell line were treated with 0.1 mM dinitrophenol (which uncouples oxidative phosphorylation) and noninvasive, nonpathogenic Escherichia coli (strain HB101, 10 6 CFU) with or without pretreatment with various pharmacological agents. At 24 h later, apoptosis, tight-junction protein expression, transepithelial resistance (TER; a marker of paracellular permeability), and bacterial internalization and translocation were assessed. Treatment with stabilizers of microtubules (i.e., colchicine), microfilaments (i.e., jasplakinolide) and clathrin-coated pit endocytosis (i.e., phenylarsine oxide) all failed to block DNP؉E. coli HB101-induced reductions in TER but effectively prevented bacterial internalization and translocation. Neither the TER defect nor the enhanced bacterial translocations were a consequence of increased apoptosis. These data show that epithelial paracellular and transcellular (i.e., bacterial internalization) permeation pathways are controlled by different mechanisms. Thus, epithelia under metabolic stress increase their endocytotic activity that can result in a microtubule-, microfilament-dependent internalization and transcytosis of bacteria. We speculate that similar events in vivo would allow excess unprocessed antigen and bacteria into the mucosa and could evoke an inflammatory response by, for example, the activation of resident or recruited immune cells.In many respects the human interaction with bacteria is one of conflict. A voluminous literature illustrates how the pathogen affects host target cells and the host response to destroy or eradicate the pathogen (23). In contrast, the human colon is home to an immense and complex microflora of commensal bacteria. Indeed, the presence of a normal microbiota is a requirement for mucosal immune cell education and normal gut physiology, such as short-chain fatty acid synthesis as an energy source for the colonocyte (33, 35). However, evidence now indicates that commensal bacteria and their products may trigger or exacerbate chronic idiopathic intestinal inflammatory diseases, such as Crohn's disease (28). For instance, virtually every rodent model of colitis, whether spontaneous or chemically induced, is significantly less severe if the animals are raised in germfree conditions (16,38). Similarly, bowel rest via surgically diverting the fecal stream and antibiotic treatment can lead to symptomatic relief in some patients with Crohn's disease (26,37).A common feature of gut inflammation is increased epithelial permeability, both paracellular (i.e., the pathway between adjacent cells) and transcellular (i.e., material cross...

Guidelines increasingly highlight the importance of multifactorial management in type 2 diabetes, in contrast to the more traditional focus on glycemic control. Semaglutide, a recently approved glucagon-like peptide-1 receptor agonist, is indicated in Canada for adults with type 2 diabetes to improve glycemic control as monotherapy with diet and exercise when metformin is inappropriate or as an add-on to either metformin alone or metformin plus a sulfonylurea or basal insulin. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial program for semaglutide comprises 6 pivotal global phase 3a trials (SUSTAIN 1 through 6) and 2 Japanese phase 3a trials. Phase 3b trials include SUSTAIN 7, and SUSTAIN 8 and 9 (both ongoing). Results from the completed trials support the superiority of semaglutide for reduction of glycated hemoglobin levels and weight loss vs. placebo as well as active comparators, including sitagliptin, exenatide extended-release, dulaglutide and insulin glargine. SUSTAIN 6 trial data confirmed cardiovascular safety and demonstrated significant reductions in major cardiovascular events with semaglutide vs. placebo, an outcome that confirmed the noninferiority of semaglutide. The robust and sustained effects of semaglutide on glycated hemoglobin levels and weight loss vs. comparators, as well as its safety and possible cardiovascular benefit, address an unmet need in the treatment of type 2 diabetes. This article overviews data from across the semaglutide clinical trial program, including efficacy and safety results and findings from post hoc analyses. The potential place of semaglutide in clinical practice is discussed.

Objective: Physical restraint is controversial, but still frequently used in psychiatric units. We describe two cases of thromboembolic phenomena, one with a fatal outcome, in association with physical restraint. Method: The world literature on physical restraint and thrombosis was reviewed by undertaking a search of electronic databases. Results: To our knowledge, we are the first to report thrombosis associated with physical restraint. Conclusion: Immobilization and trauma to the legs while restraining a patient are adequate explanations for the occurrence of thrombosis. Special attention should be paid to thrombosis when employing restraints in psychiatric wards. Further systematic research into physical restraints in psychiatry is clearly needed.

Immobilization and trauma to the legs while restraining a patient are adequate explanations for the occurrence of thrombosis. Special attention should be paid to thrombosis when employing restraints in psychiatric wards. Further systematic research into physical restraints in psychiatry is clearly needed.

Background: Adjusting total calcium for serum albumin is a common practice among medical practitioners.