Total mortality and hospitalization for congestive heart failure are significantly reduced by ACE inhibitors with consistent effects in a broad range of patients.

The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.

IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn's disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.inflammatory bowel disease | anti-TNF therapy | SAMP1/YitFc mouse model

Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure.

Our study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia or low HDL-C levels. JAMA. 2000;284:1263-1270

The SAMP1/YitFc mouse strain represents a model of Crohn's disease (CD)-like ileitis that is ideal for investigating the pathogenesis of chronic intestinal inflammation. Differently from the vast majority of animal models of colitis, the ileal-specific phenotype characteristic of SAMP1/ YitFc mice occurs spontaneously, without genetic, chemical or immunological manipulation. In addition, SAMP1/YitFc mice possess remarkable similarities to the human condition in regard to disease location, histologic features, incidence of extra-intestinal manifestations, and response to conventional therapies. SAMP1/YitFc mice also display a well-defined time course of a predisease state, and phases of acute and chronic ileitis. As such, the SAMP1/YitFc model is particularly suitable for elucidating pathways that precede the clinical phenotype that may lead to preventive, and therefore more efficacious, intervention with the natural course of disease, or alternatively, for the development of therapeutic strategies directed against chronic, established ileitis. In the following review, we summarize important contributions made by our group and others that uncover potential mechanisms in the pathogenesis of CD using this unique murine model of chronic intestinal inflammation.

Background: The high cardiovascular morbidity and mortality in patients with end-stage kidney disease could be partially caused by extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. Methods: This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization. Results: The mean change in coronary artery calcium volume score was 11% (95% CI, 7–15) for the combined SNF472 dose group and 20% (95% CI, 14–26) for the placebo group ( P =0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5–24] versus 98% [95% CI, 77–123]; P <0.001) but not in the thoracic aorta (23% [95% CI, 16–30] versus 28% [95% CI, 19–38]; P =0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least 1 treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively. Conclusions: Compared with placebo, SNF472 significantly attenuated the progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02966028.

Objective-To determine long-term survival for subjects with severe sepsis enrolled in the previous multicenter trial (PROWESS) of drotrecogin alfa (activated) [DrotAA] versus placebo.Address for correspondence: Derek C. Angus, MB, ChB, MPH, 604 Scaife Hall, Critical Care Medicine, University of Pittsburgh, 3550 Terrace, Pittsburgh, PA 15261, Tel: (412) 647 8110, Fax: (412) 647 3791, angusdc@ccm.upmc.edu. AUTHORSHIP ROLES Dr Angus, a lead investigator for the long-term follow-up study, was involved in all phases of the study and wrote the manuscript. Dr Laterre, a lead investigator for the long-term follow-up study, participated in the design and conduct of the study, provided review and interpretation of the results, and provided critical review of drafts of the manuscript. Dr Helterbrand participated in the design and conduct of the study, performed the statistical analysis, provided interpretation of the results, contributed to the writing of the manuscript, and provided critical review of drafts of the manuscript. Dr Ely participated in the review and interpretation of the results, and provided critical review of drafts of the manuscript. Mr. Ball participated in the design and conduct of the study, provided review and interpretation of the results, contributed to the writing of the manuscript, and provided critical review of drafts of the manuscript. Dr Garg participated in the design and conduct of the study, provided review and interpretation of the results, contributed to the writing of the manuscript, and provided critical review of drafts of the manuscript. Dr Weissfeld participated in the statistical review and interpretation of the results, and provided critical review of drafts of the manuscript. Dr Bernard was the principal investigator of the PROWESS trial that enrolled and treated all of the subjects studied additionally here. Dr Bernard also participated in the review and interpretation of the long-term follow-up results, and provided critical review of drafts of the manuscript. FINANCIAL SUPPORT AND POTENTIAL CONFLICT OF INTEREST Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptDesign-Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled trial.Setting-164 tertiary care institutions in 11 countries.Interventions-DrotAA (n=850), 24 μg/kg/h for 96 hours, or placebo (n=840).Participants-The 1690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1220 were alive at 28 days (the end of the original PROWESS follow-up). Measurements and MainResults-Long-term survival data were collected. We had followup information on 100% of subjects at 28 days, 98% at hospital discharge, 94% at 3 months, and 93% at 1 year. The longest follow-up was 3.6 years. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptDrotAA for the treatment of adults with severe sepsis. Notably, these agencies generally suggested restricting use to sicker patients. For example, the US FDA recommended use ...