Patients with sepsis have ongoing mortality beyond short-term end points, and survivors consistently demonstrate impaired quality of life. The use of 28-day mortality as an end point for clinical studies may lead to inaccurate inferences. Both observational and interventional future studies should include longer-term end points to better-understand the natural history of sepsis and the effect of interventions on patient morbidities.

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1 It was supposed that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase (statins) might inhibit the expression of the ®brosis-related factor CTGF (connective tissue growth factor) by interfering with the isoprenylation of Rho proteins. 2 The human renal ®broblast cell line TK173 was used as an in vitro model system to study the statin-mediated modulation of the structure of the actin cytoskeleton and of the expression of CTGF mRNA. 3 Incubation of the cells with simvastatin or lovastatin time-dependently and reversibly changed cell morphology and the actin cytoskeleton with maximal e ects observed after about 18 h. 4 Within the same time period, statins reduced the basal expression of CTGF and interfered with CTGF induction by lysophosphatidic acid (LPA) or transforming growth factor beta. Simvastatin and lovastatin proved to be much more potent than pravastatin (IC 50 1 ± 3 mM compared to 500 mM). 5 The inhibition of CTGF expression was prevented when the cells were incubated with mevalonate or geranylgeranylpyrophosphate (GGPP) but not by farnesylpyrophosphate (FPP). Speci®c inhibition of geranylgeranyltransferase-I by GTI-286 inhibited LPA-mediated CTGF expression whereas an inhibitor of farnesyltransferases FTI-276 was ine ective. 6 Simvastatin reduced the binding of the small GTPase RhoA to cellular membranes. The e ect was prevented by mevalonate and GGPP, but not FPP. 7 These data are in agreement with the hypothesis that interference of statins with the expression of CTGF mRNA is primarily due to interference with the isoprenylation of RhoA, in line with previous studies, which have shown that RhoA is an essential mediator of CTGF induction. 8 The direct interference of statins with the synthesis of CTGF, a protein functionally related to the development of ®brosis, may thus be a novel mechanism underlying the bene®cial e ects of statins observed in renal diseases.

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Background: Fragmented hyaluronan (a major extracellular matrix component) and eicosanoids (potent lipid mediators) are associated with chronic inflammatory diseases and cancer. Results: Fragmented hyaluronan stimulates lipid mediator production in human monocytes and macrophages and influences macrophage differentiation toward a distinct activation pattern. Conclusion: These findings reveal a novel link between hyaluronan-mediated inflammation and lipid metabolism. Significance: This link may provide new targets for disease therapeutics.

Objective This study evaluated whether worsened outcomes in sex mismatch are related to mismatch of organ size in heart transplantation. Background Sizing for organ allocation in heart transplantation currently incorporates only body weight differences between the donor and recipient. Weight correlates poorly to cardiac size, and donor–recipient weight differences are not associated with differential survival. Heart size correlates with sex, and donor–recipient sex mismatch conveys worse-than-expected outcomes. Methods We performed a retrospective cohort study of 31,634 donor–recipient adult heart transplant pairings from the United Network for Organ Sharing transplantation registry. We used predictive models to calculate the predicted total heart mass (pHM) for recipient and donor pairs. We assessed organ size mismatch by calculating the percent difference between the donor and recipient pHM as [(pHMrecipient − pHMdonor)/(pHMrecipient)]*100. Results The most-undersized pHM septile demonstrated higher mortality during the first year post-transplantation (hazard ratio [HR]: 1.27; p < 0.001), which remained robust in adjusted models (HR: 1.25; p = 0.03). Survival did not vary across septiles of weight differences. On univariate analysis, sex mismatch was associated with higher mortality in male patients, but not in female patients. Controlling for differences in pHM reversed these associations. Adjusted models demonstrated worse survival associated with sex mismatch in female patients (1-year HR: 1.28; p = 0.02) but no difference in male patients (1-year HR, 1.00; p = 1.0). Conclusions Differences in donor–recipient pHM modulated the survival associated with donor–recipient sex mismatch and identified donor heart undersizing as an otherwise occult and potentially preventable cause of mortality following orthotopic heart transplantation.

SummaryDocosahexaenoic acid (DHA) is one of the major ingredients of fish oil and has been reported to have anti-inflammatory properties mediated through the GPR120 receptor. Whether cytosolic phospholipase A 2 (cPLA 2 ) and lipid mediators produced from cPLA 2 activation are involved in the anti-inflammatory role of DHA in macrophages has not been reported. We report here that DHA and the GPR120 agonist, GW9508, activate cPLA 2 and cyclooxygenase 2 (COX-2), and cause prostaglandin E 2 (PGE 2 ) release in a murine macrophage cell line RAW264.7 and in human primary monocyte-derived macrophages. DHA and GW9508 activate cPLA 2 via GPR120 receptor, G protein Gaq and scaffold protein b-arrestin 2. Extracellular signal-regulated kinase 1/2 activation is involved in DHAand GW9508-induced cPLA 2 activation, but not p38 mitogen-activated protein kinase. The anti-inflammatory role of DHA and GW9508 is in part via activation of cPLA 2 , COX-2 and production of PGE 2 as a cPLA 2 inhibitor or a COX-2 inhibitor partially reverses the DHA-and GW9508-induced inhibition of lipopolysaccharide-induced interleukin-6 secretion. The cPLA 2 product arachidonic acid and PGE 2 also play an anti-inflammatory role. This effect of PGE 2 is partially through inhibition of the nuclear factor-jB signalling pathway and through the EP4 receptor of PGE 2 because an EP4 inhibitor or knock-down of EP4 partially reverses DHA inhibition of lipopolysaccharide-induced interleukin-6 secretion. Hence, DHA has an anti-inflammatory effect partially through induction of PGE 2 .