Molecular danger signals attract neutrophilic granulocytes (polymorphonuclear leukocytes (PMNs)) to sites of infection. The G protein-coupled receptor (GPR) 43 recognizes propionate and butyrate and is abundantly expressed on PMNs. The functional role of GPR43 activation for in vivo orchestration of immune response is unclear. We examined dextrane sodium sulfate (DSS)-induced acute and chronic intestinal inflammatory response in wild-type and Gpr43-deficient mice. The severity of colonic inflammation was assessed by clinical signs, histological scoring, and cytokine production. Chemotaxis of wild-type and Gpr43-deficient PMNs was assessed through transwell cell chemotactic assay. A reduced invasion of PMNs and increased mortality due to septic complications were observed in acute DSS colitis. In chronic DSS colitis, Gpr43−/− animals showed diminished PMN intestinal migration, but protection against inflammatory tissue destruction. No significant difference in PMN migration and cytokine secretion was detected in a sterile inflammatory model. Ex vivo experiments show that GPR43-induced migration is dependent on activation of the protein kinase p38α, and that this signal acts in cooperation with the chemotactic cytokine keratinocyte chemoattractant. Interestingly, shedding of L-selectin in response to propionate and butyrate was compromised in Gpr43−/− mice. These results indicate a critical role for GPR43-mediated recruitment of PMNs in containing intestinal bacterial translocation, yet also emphasize the bipotential role of PMNs in mediating tissue destruction in chronic intestinal inflammation.

Aims.To evaluate the prognostic value of the QT interval and QT interval dispersion in total and in cardiovascular mortality, as well as in cardiac morbidity, in a general population.Methods and results. The QT interval was measured in all leads from a standard 12-lead ECG in a random sample of 1658 women and 1797 men aged 30-60 years. QT interval dispersion was calculated from the maximal difference between QT intervals in any two leads. All cause mortality over 13 years, and cardiovascular mortality as well as cardiac morbidity over 11 years, were the main outcome parameters. Subjects with a prolonged QT interval (430 ms or more) or prolonged QT interval dispersion (80 ms or more) were at higher risk of cardiovascular death and cardiac morbidity than subjects whose QT interval was less than 360 ms, or whose QT interval dispersion was less than 30 ms. Cardiovascular death relative risk ratios, adjusted for age, gender, myocardial infarct, angina pectoris, diabetes mellitus, arterial hypertension, smoking habits, serum cholesterol level, and heart rate were 2·9 for the QT interval (95% confidence interval 1·1-7·8) and 4·4 for QT interval dispersion (95% confidence interval 1·0-19·1). Fatal and non-fatal cardiac morbidity relative risk ratios were similar, at 2·7 (95% confidence interval 1·4-5·5) for the QT interval and 2·2 (95% confidence interval 1·1-4·0) for QT interval dispersion. Conclusion.Prolongation of the QT interval and QT interval dispersion independently affected the prognosis of cardiovascular mortality and cardiac fatal and non-fatal morbidity in a general population over 11 years.

A long-standing challenge in optical neuroimaging has been the assessment of hemodynamics and oxygen metabolism in the awake rodent brain at the microscopic level. Here, we report first-of-a-kind head-restrained photoacoustic microscopy (PAM), which enables simultaneous imaging of the cerebrovascular anatomy, total concentration and oxygen saturation of hemoglobin, and blood flow in awake mice. Combining these hemodynamic measurements allows us to derive two key metabolic parameters—oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2). This enabling technology offers the first opportunity to comprehensively and quantitatively characterize the hemodynamic and oxygen-metabolic responses of the mouse brain to isoflurane, a general anesthetic widely used in preclinical research and clinical practice. Side-by-side comparison of the awake and anesthetized brains reveals that isoflurane induces diameter-dependent arterial dilation, elevated blood flow, and reduced OEF in a dose-dependent manner. As a result of the combined effects, CMRO2 is significantly reduced in the anesthetized brain under both normoxia and hypoxia, which suggests a mechanism for anesthetic neuroprotection. The head-restrained functional and metabolic PAM opens a new avenue for basic and translational research on neurovascular coupling without the strong influence of anesthesia and on the neuroprotective effects of various interventions, including but not limited to volatile anesthetics, against cerebral hypoxia and ischemia.

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In adults undergoing hip fracture surgery, regional anesthesia may reduce postoperative delirium, but there is uncertainty about its effectiveness.OBJECTIVE To investigate, in older adults undergoing surgical repair for hip fracture, the effects of regional anesthesia on the incidence of postoperative delirium compared with general anesthesia. DESIGN, SETTING, AND PARTICIPANTSA randomized, allocation-concealed, open-label, multicenter clinical trial of 950 patients, aged 65 years and older, with or without preexisting dementia, and a fragility hip fracture requiring surgical repair from 9 university teaching hospitals in Southeastern China. Participants were enrolled between October 2014 and September 2018; 30-day follow-up ended November 2018.INTERVENTIONS Patients were randomized to receive either regional anesthesia (spinal, epidural, or both techniques combined with no sedation; n = 476) or general anesthesia (intravenous, inhalational, or combined anesthetic agents; n = 474).MAIN OUTCOMES AND MEASURES Primary outcome was incidence of delirium during the first 7 postoperative days. Secondary outcomes analyzed in this article include delirium severity, duration, and subtype; postoperative pain score; length of hospitalization; 30-day all-cause mortality; and complications. RESULTS Among 950 randomized patients (mean age, 76.5 years; 247 [26.8%] male), 941 were evaluable for the primary outcome (6 canceled surgery and 3 withdrew consent). Postoperative delirium occurred in 29 (6.2%) in the regional anesthesia group vs 24 (5.1%) in the general anesthesia group (unadjusted risk difference [RD], 1.1%; 95% CI, -1.7% to 3.8%; P = .48; unadjusted relative risk [RR], 1.2 [95% CI, 0.7 to 2.0]; P = .57]). Mean severity score of delirium was 23.0 vs 24.1, respectively (unadjusted difference, -1.1; 95% CI, -4.6 to 3.1). A single delirium episode occurred in 16 (3.4%) vs 10 (2.1%) (unadjusted RD, 1.1%; 95% CI, -1.7% to 3.9%; RR, 1.6 [95% CI, 0.7 to 3.5]). Hypoactive subtype in 11 (37.9%) vs 5 (20.8%) (RD, 11.5; 95% CI, -11.0% to 35.7%; RR, 2.2 [95% CI, 0.8 to 6.3]). Median worst pain score was 0 (IQR, 0 to 20) vs 0 (IQR, 0 to 10) (difference 0; 95% CI, 0 to 0). Median length of hospitalization was 7 days (IQR, 5 to 10) vs 7 days (IQR, 6 to 10) (difference 0; 95% CI, 0 to 0). Death occurred in 8 (1.7%) vs 4 (0.9%) (unadjusted RD, -0.8%; 95% CI, -2.2% to 0.7%; RR, 2.0 [95% CI, 0.6 to 6.5]). Adverse events were reported in 106 episodes in the regional anesthesia group and 102 in the general anesthesia group; the most frequently reported adverse events were nausea and vomiting (47 [44.3%] vs 34 [33.3%]) and postoperative hypotension (13 [12.3%] vs 10 [9.8%]). CONCLUSIONS AND RELEVANCEIn patients aged 65 years and older undergoing hip fracture surgery, regional anesthesia without sedation did not significantly reduce the incidence of postoperative delirium compared with general anesthesia.