Association between the rs6950982 polymorphism near the SERPINE1 gene and blood pressure and lipid parameters in a high-cardiovascular-risk population: interaction with Mediterranean diet

The SERPINE1 (serpin peptidase inhibitor, clade E, member 1) gene, better known by its previous symbol PAI-1 (plasminogen activator inhibitor 1), has been associated with cardiovascular phenotypes with differing results. Our aim was to examine the association between the rs6950982 (G > A) near the SERPINE1 gene, blood pressure (BP) and plasma lipid concentrations as well as the modulation of the polymorphism effects by adherence to Mediterranean diet (AMD). We studied 945 high-cardiovascular-risk subjects. Biochemical, clinical, dietary and genetic data (rs6950982) were obtained. We also determined the common rs1799768 (4G/5G), for checking independent effects. AMD was measured by a validated questionnaire, and four groups were considered. rs6950982 (A > G) and rs1799768 (4G/5G) were only in moderate–low linkage disequilibrium (D′ = 0.719; r2 = 0.167). The most significant associations we obtained were with rs6950982 (A > G). In males, the G allele was nominally associated with higher diastolic BP (AA: 81.5 ± 10.9, AG: 82.1 ± 11.4, GG: 85.7 ± 10.5 mmHg; Padditive = 0.030) and systolic BP (AA + AG: 141.4 ± 6.9 mmHg vs. GG: 149.8 ± 8.0 mmHg; Precessive = 0.036). In the whole population, the rs6950982 was also associated with plasma lipids. Subject with the G allele presented higher total cholesterol (Padditive = 0.016, Precessive = 0.011), low-density lipoprotein cholesterol (Padditive = 0.032, Precessive = 0.031) and triglycerides (Padditive = 0.040, Precessive = 0.029). AMD modulated the effect of rs6950982 on triglyceride concentrations (P for interaction = 0.036). Greater AMD reduced the higher triglyceride concentrations in GG subjects. No significant interactions were found for the other parameters. The rs6950982 was associated with higher BP in men and higher triglycerides in the whole population, this association being modulated by AMD

Activation of SK2 channels preserves ER Ca(2+) homeostasis and protects against ER stress-induced cell death

Alteration of endoplasmic reticulum (ER) Ca(2+) homeostasis leads to excessive cytosolic Ca(2+) accumulation and delayed neuronal cell death in acute and chronic neurodegenerative disorders. While our recent studies established a protective role for SK channels against excessive intracellular Ca(2+) accumulation, their functional role in the ER has not been elucidated yet. We show here that SK2 channels are present in ER membranes of neuronal HT-22 cells, and that positive pharmacological modulation of SK2 channels with CyPPA protects against cell death induced by the ER stressors brefeldin A and tunicamycin. Calcium imaging of HT-22 neurons revealed that elevated cytosolic Ca(2+) levels and decreased ER Ca(2+) load during sustained ER stress could be largely prevented by SK2 channel activation. Interestingly, SK2 channel activation reduced the amount of the unfolded protein response transcription factor ATF4, but further enhanced the induction of CHOP. Using siRNA approaches we confirmed a detrimental role for ATF4 in ER stress, whereas CHOP regulation was dispensable for both, brefeldin A toxicity and CyPPA-mediated protection. Cell death induced by blocking Ca(2+) influx into the ER with the SERCA inhibitor thapsigargin was not prevented by CyPPA. Blocking the K(+) efflux via K(+)/H(+) exchangers with quinine inhibited CyPPA-mediated neuroprotection, suggesting an essential role of proton uptake and K(+) release in the SK channel-mediated neuroprotection. Our data demonstrate that ER SK2 channel activation preserves ER Ca(2+) uptake and retention which determines cell survival in conditions where sustained ER stress contributes to progressive neuronal death.Cell Death and Differentiation advance online publication, 20 November 2015; doi:10.1038/cdd.2015.146.</p

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

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

The music of lipids: how lipid composition orchestrates cellular behaviour

Background. Lipids are best known for their fundamental role in forming biological membranes and as intracellular signalling molecules. Interactions between proteins and lipids are central to nearly every cellular process yet these crucial relationships often go overlooked. Changes or switches in the lipid profile of a cell drastically affects cellular metabolism and signal transduction. In relationship to cancer, upregulation of lipid metabolism is often observed during the early stages of neoplasia and is a recognised hallmark of many types of cancer. Methods. We performed a comprehensive review of the literature using PubMed regarding lipid metabolism in cancer and the importance of protein-lipid interactions in the function of mitochondria. Results. An increase in the basal rate of de novo lipogenesis generates a substantial rise in the saturated fatty acid content of cellular membranes. The ensuing alteration in the acyl chain profile of phospholipids has severe consequences on the function of organelles and membrane-bound proteins, and result in a host of pathologies including the cardiac disorder Barth Syndrome. Conclusions. Although increased lipogenesis is specifically selected for during cellular transformation it remains unclear if it confers an advantage for survival or is a byproduct of more global changes in cellular metabolism. We discuss the current data regarding the potential of targeting the lipogenic switch as a cancer therapy. In addition, we describe the importance of mitochondrial phospholipid composition during a number mitochondria-driven events observed to have roles in cancer. We specifically highlight the function of cardiolipin in maintaining mitochondrial structure, regulating mitochondrial dynamics and bioenergetics as well as its contributions to mitophagy/autophagy and apoptosis