Srf1 Is a Novel Regulator of Phospholipase D Activity and Is Essential to Buffer the Toxic Effects of C16:0 Platelet Activating Factor

During Alzheimer's Disease, sustained exposure to amyloid-β42 oligomers perturbs metabolism of ether-linked glycerophospholipids defined by a saturated 16 carbon chain at the sn-1 position. The intraneuronal accumulation of 1-O-hexadecyl-2-acetyl-sn-glycerophosphocholine (C16:0 PAF), but not its immediate precursor 1-O-hexadecyl-sn-glycerophosphocholine (C16:0 lyso-PAF), participates in signaling tau hyperphosphorylation and compromises neuronal viability. As C16:0 PAF is a naturally occurring lipid involved in cellular signaling, it is likely that mechanisms exist to protect cells against its toxic effects. Here, we utilized a chemical genomic approach to identify key processes specific for regulating the sensitivity of Saccharomyces cerevisiae to alkyacylglycerophosphocholines elevated in Alzheimer's Disease. We identified ten deletion mutants that were hypersensitive to C16:0 PAF and five deletion mutants that were hypersensitive to C16:0 lyso-PAF. Deletion of YDL133w, a previously uncharacterized gene which we have renamed SRF1 (Spo14 Regulatory Factor 1), resulted in the greatest differential sensitivity to C16:0 PAF over C16:0 lyso-PAF. We demonstrate that Srf1 physically interacts with Spo14, yeast phospholipase D (PLD), and is essential for PLD catalytic activity in mitotic cells. Though C16:0 PAF treatment does not impact hydrolysis of phosphatidylcholine in yeast, C16:0 PAF does promote delocalization of GFP-Spo14 and phosphatidic acid from the cell periphery. Furthermore, we demonstrate that, similar to yeast cells, PLD activity is required to protect mammalian neural cells from C16:0 PAF. Together, these findings implicate PLD as a potential neuroprotective target capable of ameliorating disruptions in lipid metabolism in response to accumulating oligomeric amyloid-β42

81. Upper body arterio-central venous PCO2 gap (UBCO2G) in monitoring sick children with cardiac disease

To determine the validity of using UBCO2G for monitoring sick children with cardiac disease. Design: A prospective, observational non interventional cohort study. Setting: King Abdul Aziz Medical City, Pediatric Cardiac ICU (PCICU), Riyadh. Patients: Between April 2011 and May 2013, 257 patients admitted to our PCICU were recruited in the study. Intervention: Arterial and central venous blood samples were collected as needed per patients’ conditions. Patients’ clinical and laboratory data were collected simultaneously. Results: A total of 421 data sets with arterial, upper (SVC) and lower (FV) body central venous PCO2 were collected spontaneously from 257 patients age 17.0 ± 25.8 months, weight 7.45 ± 5.53 kg. UBPCO2G was higher than lower (art-FV) body PCO2 (LBPCO2G) gap 7.80 ± 3.28 vs. 5.95 ± 3.65 mmHg (p = 0.001. In 75% of our data sets UBPCO2G was ⩽9.65 and LBPCO2 gap was ⩽7.8 mmHg. Patients with UBPCO2G ⩾9.65 vs. <9.65 mmHg had higher lactic acid (LA) 2.0 ± 1.4 vs. 1.6 ± 1.3 mmol/L (p = 0.014), BUN 6.1 ± 5.2 vs. 4.8 ± 2.1 mmol/L (p = 0.013), creatinine 48 ± 17 vs. 43 ± 13 μmol/L (p = 0.004), glucose 8.7 ± 4.1 vs. 7.1 ± 3.7 mmol/L (p = 0.001) and PRISM score 9 ± 6 vs. 7 ± 6 (p = 0.038) and lower urine output 5.2 ± 2.8 vs. 6.1 ± 4.3 ml/kg/3 h. However patients with UBPCO2G ⩾6 vs. <6 mmHg were different in LA only 1.8 ± 1.5 vs. 1.5 ± 1.0 mmol/L, respectively (p = 0.018). Conclusion: Upper is higher than lower body PCO2gap. UBPCO2G ⩾9.65 was associated with higher LA, BUN, creatinine, serum glucose and PRISM and lower urine output. Patients with UBPCO2G ⩾9.65 were sicker. UBPCO2G can be used as a biomarker in monitoring children with cardiac disease

Does Kidney Transplant Increase the Risk of Ipsilateral Lower Extremity Deep Venous Thrombosis?

Introduction: There is limited information on the development and laterality of symptomatic deep vein thrombosis (DVT) following kidney transplantation. In this study, we want to define the incidence of DVT in this population and determine if the side of DVT corresponds to the side of the transplanted kidney. Methods: We performed a retrospective review of all kidney transplant recipients from January, 2004 to August, 2014 at our institution and who subsequently developed symptomatic DVT. Kidney transplant recipients and confirmed DVT patients were obtained as two separate data files and were matched to obtain our cohort. Patients with concomitant pancreatic transplants, repeat, and bilateral kidney transplants were excluded. We used Cohen’s kappa statistic to test the agreement between the surgical incision site of the kidney transplant to the side at which the DVT occurred. Results: A total of 1827 kidney transplant recipients were performed between January 2004 to August 2014. A total of 877 kidney transplant recipients met the inclusion criteria as our total cohort. From our total cohort, 217 recipients underwent ultrasounds to rule out DVT. A total of 41 kidney transplant patients received a positive duplex ultrasound. The incidence of DVT in our kidney transplant cohort was 4.7%. The most common period of DVT diagnosis was in the perioperative period within the first 4 weeks. A Cohen kappa statistic of -0.02 occurred between the surgical incision site of the kidney transplant and the side of DVT occurrence. Large positive kappa statistic values indicate agreement, whereas large negative values indicate disagreement. Approximately 64.6% of transplant patients with a positive duplex ultrasound had a 1:1 correlation to the side of DVT, although this did not reach statistical significance. There was no statistically significant difference in patient sex, race, or age between the two groups. Conclusion: The incidence of symptomatic DVT in this cohort was 4.7%, which is lower than that reported in the literature. DVT was highest during the first four weeks postoperatively. There was an increased rate of ipsilateral DVTs to the kidney transplant, although this did not reach statistical significance.https://scholarlycommons.henryford.com/merf2019clinres/1056/thumbnail.jp

Physicians&apos; guideline adherence is associated with long-term heart failure mortality in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry

Background: Physicians&apos; adherence to guideline-recommended therapy is associated with short-term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer-term outcomes is poorly documented. Here, we present results from the 18-month follow-up of the QUALIFY registry. Methods and results: Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed for five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF-related (191/394) and the same was true for unplanned hospitalizations (1175 CV and 861 HF-related hospitalizations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87–0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalization or CV death (SHR 0.97, 95% CI 0.94–0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all-cause, CV or HF hospitalizations were not (all-cause: SHR 0.99, 95% CI 0.9–1.02; CV: SHR 0.98, 95% CI 0.96–1.01; and HF: SHR 0.99, 95% CI 0.96–1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively). Conclusion: These results suggest that physicians&apos; adherence to guideline-recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians&apos; adherence to guidelines. © 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiolog