PPARγ agonists negatively regulate αIIbβ3 integrin outside-in signalling and platelet function through upregulation of protein kinase A activity

BACKGROUND: Agonists for the peroxisome proliferator activated receptor PPARγ, have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. OBJECTIVES: Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbβ3 mediated signalling. Both GPVI and GPCR signalling pathways lead to αIIbβ3 activation, and signalling through αIIbβ3 plays a critical role in platelet function and normal haemostasis. METHODS: The effects of PPARγ agonists on the regulation of αIIbβ3 outside-in signalling was determined by monitoring the ability of platelets to adhere and spread on fibrinogen and undergo clot retraction. Effects on signalling components downstream of αIIbβ3 activation were also determined following adhesion to fibrinogen by western blotting. RESULTS: Treatment of platelets with PPARγ agonists inhibited platelet adhesion and spreading on fibrinogen and diminished clot retraction. A reduction in phosphorylation of several components of αIIbβ3 signalling, including the integrin β3 subunit, Syk, PLCγ2, FAK and Akt was also observed as a result of reduced interaction of the integrin β3 subunit with Gα13. Studies of VASP phosphorylation revealed that this was a due to an increase in PKA activity following treatment with PPARγ receptor agonists. CONCLUSIONS: This study provides further evidence for anti-platelet actions of PPARγ agonists, identifies a negative regulatory role for PPARγ agonists in the control of integrin αIIbβ3 outside-in signalling, and provides a molecular basis by which the PPARγ agonists negatively regulate platelet activation and thrombus formation

Supercruiser Arrow HS-8

Technology in aeronautics has advanced dramatically since the last design of a production High Speed Civil Transport (HSCT) aircraft. Newly projected requirements call for a new High Speed Civil Transport aircraft with a range of approximately 550 nm and at least 275 passenger capacity. The aircraft must be affordable and marketable. The new HSCT must be able to sustain long-duration flights and to absorb the abuse of daily operation. The new aircraft must be safe and simple to fly and require a minimum amount of maintenance. This aircraft must meet FAA certification criteria of FAR Part 25 and environmental constraints. Several design configurations were examined and two designs were selected for further investigation. The first design employs the delta planform wings and conventional empennage layout. The other design uses a swing wing layout and conventional empennage. Other engineering challenges, including materials and propulsion are also discussed. At a cruise flight speed between Mach 2.2 and Mach 3.0, no current generation of materials can endure the thermal loading of supersonic flight and satisfy the stringent weight requirements. A new generation of lightweight composite materials must be developed for the HSCT. With the enforcement of stage 3 noise restrictions, these new engines must be able to propel the aircraft and satisfy the noise limit. The engine with the most promise is the variable cycle engine. At low subsonic speeds the engine operates like a turbofan engine, providing the most efficient performance. At higher speeds the variable cycle engine operates as a turbojet power plant. The two large engine manufacturers, General Electric and Pratt & Whitney in the United States, are combining forces to make the variable cycle engine a reality

Relationship of metabolic syndrome and its components with -844 G/A and HindIII C/G PAI-1 gene polymorphisms in Mexican children

<p>Abstract</p> <p>Background</p> <p>Several association studies have shown that -844 G/A and <it>HindIII </it>C/G <it>PAI-1 </it>polymorphisms are related with increase of PAI-1 levels, obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia, which are components of metabolic syndrome. The aim of this study was to analyze the allele and genotype frequencies of these polymorphisms in <it>PAI-1 </it>gene and its association with metabolic syndrome and its components in a sample of Mexican mestizo children.</p> <p>Methods</p> <p>This study included 100 children with an age range between 6-11 years divided in two groups: a) 48 children diagnosed with metabolic syndrome and b) 52 children metabolically healthy without any clinical and biochemical alteration. Metabolic syndrome was defined as the presence of three or more of the following criteria: fasting glucose levels ≥ 100 mg/dL, triglycerides ≥ 150 mg/dL, HDL-cholesterol < 40 mg/dL, obesity BMI ≥ 95^thpercentile, systolic blood pressure (SBP) and diastolic blood pressure (DBP) ≥ 95^thpercentile and insulin resistance HOMA-IR ≥ 2.4. The -844 G/A and <it>HindIII </it>C/G <it>PAI-1 </it>polymorphisms were analyzed by PCR-RFLP.</p> <p>Results</p> <p>For the -844 G/A polymorphism, the G/A genotype (OR = 2.79; 95% CI, 1.11-7.08; <it>p </it>= 0.015) and the A allele (OR = 2.2; 95% CI, 1.10-4.43; <it>p </it>= 0.015) were associated with metabolic syndrome. The -844 G/A and A/A genotypes were associated with increase in plasma triglycerides levels (OR = 2.6; 95% CI, 1.16 to 6.04; <it>p </it>= 0.02), decrease in plasma HDL-cholesterol levels (OR = 2.4; 95% CI, 1.06 to 5.42; <it>p </it>= 0.03) and obesity (OR = 2.6; 95% CI, 1.17-5.92; <it>p </it>= 0.01). The C/G and G/G genotypes of the <it>HindIII </it>C/G polymorphism contributed to a significant increase in plasma total cholesterol levels (179 vs. 165 mg/dL; <it>p </it>= 0.02) in comparison with C/C genotype.</p> <p>Conclusions</p> <p>The -844 G/A <it>PAI-1 </it>polymorphism is related with the risk of developing metabolic syndrome, obesity and atherogenic dyslipidemia, and the <it>HindIII </it>C/G <it>PAI-1 </it>polymorphism was associated with the increase of total cholesterol levels in Mexican children.</p

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Study of consumer benefit functions for demand response algorithm

P. Bala Sai Kiran and Naran M. Pindoriy

Day-ahead energy management of a microgrid with battery energy storage integration

by Dhanapala Prudhviraj, P. B. S. Kiran and Naran M. Pindoriy

A retrospective cohort study of risk factors and outcomes in older patients admitted to an inner-city geriatric unit in London during first peak of COVID-19 pandemic.

PURPOSE: Compared to younger patients, coronavirus disease 2019 (COVID-19) clinical presentation in older people can be more heterogeneous and fatal. We aim to describe a cohort of older adults admitted in an inner-city London hospital during the first peak of the pandemic. METHODS: A retrospective observational study that enrolled older adults consecutively admitted into two geriatric wards with suspected or confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We collected socio-demographic data, comorbidities, symptoms at presentation and/or during admission, biochemical and radiological data and outcomes at 28 days. RESULTS: One hundred twenty-four patients were included, and 75% were > 80 years old. 19.5% of COVID-19 cases were judged to be hospital-acquired. More than half presented or developed typical symptoms, respiratory failure or fatigue. 46.8% were diagnosed with delirium, 24.2% with falls and dysphagia was present in 13.7%. The mortality rate was 29.8% and was higher among males, those > 80 years, patients with a higher grade of frailty, a history of dementia or chronic kidney disease, as well as those diagnosed with respiratory failure, acute kidney injury or hypernatremia. Independent predictors of mortality were male sex, age > 80 years, respiratory failure and hypernatremia. CONCLUSION: We have described a cohort of patients with SARS-CoV-2 infection in the first UK peak of the global pandemic. We found that these patients had significant frailty with multiple comorbidities. There was a high mortality and increased dependency and greater social care need in survivors

Balancing Distraction Forces in the Mandible: Newton’s Third Law of Distraction

Summary:. Vertical mandibular distraction results in translation of both proximal and distal segments. The force exerted on the condylar segment not only places unwanted force on the joint but also rotates the coronoid process into the cranial base. To prevent these sequelae, we investigate the use of a "check plate" on the condylar segment in an attempt to decrease force at the Temporomandibular joint (TMJ) and prevent unwanted rotation of the coronoid. Patients with hemifacial microsomia, seen at our Children's Hospital from 2012 to 2016 having undergone unilateral vertical mandibular distraction with placement of check plate were compared with a sample of those similarly having undergone distraction without use of the plate. Preoperative and postoperative cephalometric measures and 3-dimensional computed tomography imaging were analyzed. Three subjects were identified in each group. Age and Pruzansky-Kaban classification did not differ between groups. Vertical distance from the coronoid process perpendicular to the Frankfort Horizontal did not differ between groups (P < 0.07); however, postoperative distance significantly differed with the coronoid process rotating upward into the cranial base in subjects without a check plate (P < 0.005). Preoperative angle of the coronoid process based on the Frankfort Horizontal did not differ (P < 0.06); however, postoperative angle significantly changed, confirming upward rotation into the cranial base (P < 0.01). Total regenerate did not differ (P < 0.08). Vertical mandibular distraction results in undesirable upward rotation of the proximal segment into the cranial base and superior displacement of regenerate. This can be prevented with the use of a check plate