Apoptosis is a prominent feature of acute anterior uveitis in the Fischer 344 rat

AIMS: To examine the hypothesis that apoptosis of infiltrating cells contributes to spontaneous resolution of uveitis in clinically relevant rodent models. METHODS: Experimental melanin induced uveitis (EMIU) was induced in Fischer 344 rats by immunisation with 250 microg bovine ocular melanin. Endotoxin induced uveitis (EIU) was induced by injection of 200 microg Escherichia coli lipopolysaccharide. Formalin fixed, paraffin embedded ocular cross sections were stained by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate biotin nick end labelling (TUNEL) to identify apoptotic cells. Indirect immunoperoxidase staining of paraformaldehyde lysine periodate fixed tissue cross sections was used to demonstrate expression of inducible nitric oxide synthase (iNOS). RESULTS: TUNEL positive mononuclear cells were observed in the anterior uvea during both EMIU and EIU at all selected time points. However, whereas the majority of mononuclear cells appeared apoptotic from the outset of disease, neutrophils were notably TUNEL negative at all time points examined. Many infiltrating neutrophils expressed iNOS. CONCLUSION: Apoptosis occurs early in the course of rat EMIU and EIU, and may contribute to resolution of these diseases. In general, infiltrating mononuclear cells die rapidly, while neutrophils survive, producing inducible nitric oxide synthase which may contribute to disease pathogenesis

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Effects of taurocholic acid on glycemic, glucagon-like peptide-1, and insulin responses to small intestinal glucose infusion in healthy humans

CONTEXT: In vitro and animal studies suggest that bile acids have the capacity to reduce blood glucose by stimulating glucagon-like peptide-1 (GLP-1) and, thereby, insulin. OBJECTIVE: This study evaluated the effects of intrajejunal taurocholic acid (TCA) on blood glucose, GLP-1, and insulin responses to jejunal glucose infusion in healthy men. PARTICIPANTS AND DESIGN: Ten healthy men were each studied on 2 days in a double-blind, randomized order. After the subjects fasted overnight, a jejunal catheter was positioned and a balloon inflated 30 cm beyond the pylorus with aspiration of endogenous bile. Two grams TCA in saline, or saline control, was infused beyond the balloon over 30 minutes, followed by 2 g TCA or control, together with 60 g glucose, over the next 120 minutes. Blood was sampled frequently for the measurements of blood glucose, total GLP-1, insulin, C-peptide, and glucagon. RESULTS: Intrajejunal infusion of TCA alone (t = −30 to 0 minutes) had no effect on blood glucose, GLP-1, insulin, C-peptide, or glucagon concentrations. During intrajejunal glucose infusion (t = 0 to 120 minutes), blood glucose concentrations were lower (P < .001), and plasma GLP-1 (P < .001) and the C-peptide/glucose ratio (P = .008) were both greater, whereas plasma insulin, C-peptide, and glucagon levels were not significantly different after TCA than after control. CONCLUSIONS: In healthy humans, small intestinal infusion of TCA potently reduces the glycemic response to small intestinal glucose, associated with an increase in GLP-1 and C-peptide/glucose ratio. These observations indicate the potential for bile acid-based therapy in type 2 diabetes.Tongzhi Wu, Michelle J. Bound, Scott D. Standfield, Karen L. Jones, Michael Horowitz, and Christopher K. Rayne

Effects of intraduodenal lipid and protein on gut motility and hormone release, glycemia, appetite, and energy intake in lean men

BACKGROUND: Intraduodenal lipid modulates gastrointestinal motility and hormone release and suppresses energy intake (EI) more than does intraduodenal glucose. Oral protein is the most satiating macronutrient and modulates postprandial glycemia; the comparative effects of intraduodenal protein and lipid and their combined effects are unclear. OBJECTIVE: We investigated the effects of intraduodenal protein and lipid, alone or in combination, on antropyloroduodenal motility, gastrointestinal hormone release, glycemia, and EI. DESIGN: Twenty lean men were studied on 5 randomized, double-blind occasions. Antropyloroduodenal motility, cholecystokinin, glucagon-like peptide-1 (GLP-1), insulin, glucagon, blood glucose, appetite, and nausea were measured during 90-min isocaloric (3 kcal/min) intraduodenal infusions of lipid [pure lipid condition (L3)], protein [pure protein condition (P3)], a 2:1 combination of lipid and protein [2:1 lipid:protein condition (L2P1)], a 1:2 combination of lipid and protein [1:2 lipid:protein condition (L1P2)], or a control. Immediately after the infusion, EI from a buffet lunch was quantified. RESULTS: In comparison with the control, all nutrient infusions suppressed antral and duodenal and stimulated pyloric pressures (P < 0.05). Cholecystokinin and GLP-1 release and pyloric stimulation were lipid-load dependent (r ≥ 0.39, P < 0.01), insulin and glucagon releases were protein-load dependent (r = 0.83, P < 0.001), and normoglycemia was maintained. L3 but not P3 increased nausea (P < 0.05). Compared with the control, L3 and P3 but not L2P1 or L1P2 suppressed EI (P < 0.05) without major effects on appetite. CONCLUSIONS: In lean men, despite differing effects on gut function, intraduodenal lipid and protein produce comparable reductions in energy intake. The effects of lipid may be a result of nausea. Protein also regulates blood glucose by stimulating insulin and glucagon. In contrast, at the loads selected, lipid:protein combinations did not suppress energy intake, suggesting that a threshold load is required to elicit effects. This trial was registered at Australia and New Zealand Clinical Trial Registry (http://www.anzctr.org.au) as 12609000949280.Amy T Ryan, Natalie D Luscombe-Marsh, Alexander A Saies, Tanya J Little, Scott Standfield, Michael Horowitz, and Christine Feinle-Bisse