A function for tyrosine phosphorylation of type 1 inositol 1,4,5-trisphosphate receptor in lymphocyte activation

Sustained elevation of intracellular calcium by Ca2+ release–activated Ca2+ channels is required for lymphocyte activation. Sustained Ca2+ entry requires endoplasmic reticulum (ER) Ca2+ depletion and prolonged activation of inositol 1,4,5-trisphosphate receptor (IP3R)/Ca2+ release channels. However, a major isoform in lymphocyte ER, IP3R1, is inhibited by elevated levels of cytosolic Ca2+, and the mechanism that enables the prolonged activation of IP3R1 required for lymphocyte activation is unclear. We show that IP3R1 binds to the scaffolding protein linker of activated T cells and colocalizes with the T cell receptor during activation, resulting in persistent phosphorylation of IP3R1 at Tyr353. This phosphorylation increases the sensitivity of the channel to activation by IP3 and renders the channel less sensitive to Ca2+-induced inactivation. Expression of a mutant IP3R1-Y353F channel in lymphocytes causes defective Ca2+ signaling and decreased nuclear factor of activated T cells activation. Thus, tyrosine phosphorylation of IP3R1-Y353 may have an important function in maintaining elevated cytosolic Ca2+ levels during lymphocyte activation

Vitamin D deficiency is associated with increased mortality in critically ill patients especially in those requiring ventilatory support

Introduction: Vitamin D (VitD) classically recognized for its role in the musculoskeletal system, has been implicated in myriad of conditions such as diabetes, immune dysfunction, cancers, heart disease, metabolic syndrome, etc. We studied the role of VitD in acute care setting and its correlation with mortality. Materials and Methods: A total of 85 consecutive consenting patients admitted in medical intensive care unit of tertiary care hospital who fulfilled the inclusion criteria were included. All patients were evaluated clinically, and blood samples were collected for hemogram, biochemical investigations including serum calcium, phosphorus, alkaline phosphatase, magnesium, along with 25(OH) VitD, 1,25(OH) VitD and intact parathormone levels. Simplified acute physiology score (SAPS II) was calculated for all patients. Results: VitD was deficient (<30 ng/ml) in 27 patients (32%). The overall mortality was more in VitD deficient group as compared to VitD sufficient group (74 vs. 41%; P < 0.05). The actual mortality in VitD deficient group was higher than the mortality predicted by SAPS II score (50 vs. 74%; P < 0.0507). VitD deficiency was also associated with more mortality among those requiring ventilator support (95% vs. 40%; P < 0.05) as well as with higher blood glucose (124.5 ± 29.7 vs. 94.8 ± 19.8: P < 0.01) levels. Conclusion: VitD deficiency was associated with increased mortality, poor ventilator outcomes, and increased blood glucose in critically ill patients

Association between the first-hour intravenous fluid volume and mortality in pediatric septic shock

Study objective: To determine whether the receipt of more than or equal to 30 mL/kg of intravenous fluid in the first hour after emergency department (ED) arrival is associated with sepsis-attributable mortality among children with hypotensive septic shock. Methods: This is a retrospective cohort study set in 57 EDs in the Improving Pediatric Sepsis Outcomes quality improvement collaborative. Patients less than 18 years of age with hypotensive septic shock who received their first intravenous fluid bolus within 1 hour of arrival at the ED were propensity-score matched for probability of receiving more than or equal to 30 mL/kg in the first hour. Sepsis-attributable mortality was compared. We secondarily evaluated the association between the first-hour fluid volume and sepsis-attributable mortality in all children with suspected sepsis in the first hour after arrival at the ED, regardless of blood pressure. Results: Of the 1,982 subjects who had hypotensive septic shock and received a first fluid bolus within 1 hour of arrival at the ED, 1,204 subjects were propensity matched. In the matched patients receiving more than or equal to 30 mL/kg of fluid, 26 (4.3%) of 602 subjects had 30-day sepsis-attributable mortality compared with 25 (4.2%) of 602 receiving less than 30 mL/kg (odds ratio 1.04, 95% confidence interval 0.59 to 1.83). Among the patients with suspected sepsis regardless of blood pressure, 30-day sepsis-attributable mortality was 3.0% in those receiving more than or equal to 30 mL/kg versus 2.0% in those receiving less than 30 ml/kg (odds ratio 1.52, 95% confidence interval 0.95 to 2.44.) CONCLUSION: In children with hypotensive septic shock receiving a timely first fluid bolus within the first hour of ED care, receiving more than or equal to 30 mL/kg of bolus intravenous fluids in the first hour after arrival at the ED was not associated with mortality compared with receiving less than 30 mL/kg

The Scottish Bladder Cancer Quality performance indicators influencing Outcomes, Prognosis, and Surveillance (Scot BC Quality OPS) clinical project

No abstract available