5 research outputs found

    Src kinase participates in LPS-induced activation of NADPH oxidase

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    The production of superoxide from NADPH oxidase by macrophages in response to endotoxin (LPS) is an important innate immune response, yet it is not clear how LPS signals the activation of NADPH oxidase. The hypothesis is that LPS-induced src kinase and PI3 kinase (PI3K) facilitates the activation of p47phox, the regulatory subunit of NADPH oxidase. In mouse macrophage RAW264.7 cells, inhibition of src tyrosine family kinases inhibited LPS-induced activation of NADPH oxidase, phosphorylation of p47phox, activation of PI3K and phosphorylation of the TLR4. Moreover, inhibition of LPS-induced increases in intracellular calcium blunted src kinase activation, PI3K association with TLR4, as well as PI3 kinase activation. These data suggest that both src kinase and PI3 kinase are involved in LPS-induced NADPH oxidase activation. Importantly, these data suggest that LPS-induced src kinase activation is critical for PI3 kinase activation as well as TLR4 phosphorylation and is dependent upon LPS-induced increase in intracellular calcium. These signaling events fill critical gaps in our understanding of LPS-induced free radical production as well as may potentially responsible for the mechanism of innate immune tolerance or desensitization caused by steroids or ethanol

    Spinal Anesthesia or General Anesthesia for Hip Surgery in Older Adults

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    Background: The effects of spinal anesthesia as compared with general anesthesia on the ability to walk in older adults undergoing surgery for hip fracture have not been well studied. Methods: We conducted a pragmatic, randomized superiority trial to evaluate spinal anesthesia as compared with general anesthesia in previously ambulatory patients 50 years of age or older who were undergoing surgery for hip fracture at 46 U.S. and Canadian hospitals. Patients were randomly assigned in a 1:1 ratio to receive spinal or general anesthesia. The primary outcome was a composite of death or an inability to walk approximately 10 ft (3 m) independently or with a walker or cane at 60 days after randomization. Secondary outcomes included death within 60 days, delirium, time to discharge, and ambulation at 60 days. Results: A total of 1600 patients were enrolled; 795 were assigned to receive spinal anesthesia and 805 to receive general anesthesia. The mean age was 78 years, and 67.0% of the patients were women. A total of 666 patients (83.8%) assigned to spinal anesthesia and 769 patients (95.5%) assigned to general anesthesia received their assigned anesthesia. Among patients in the modified intention-to-treat population for whom data were available, the composite primary outcome occurred in 132 of 712 patients (18.5%) in the spinal anesthesia group and 132 of 733 (18.0%) in the general anesthesia group (relative risk, 1.03; 95% confidence interval [CI], 0.84 to 1.27; P = 0.83). An inability to walk independently at 60 days was reported in 104 of 684 patients (15.2%) and 101 of 702 patients (14.4%), respectively (relative risk, 1.06; 95% CI, 0.82 to 1.36), and death within 60 days occurred in 30 of 768 (3.9%) and 32 of 784 (4.1%), respectively (relative risk, 0.97; 95% CI, 0.59 to 1.57). Delirium occurred in 130 of 633 patients (20.5%) in the spinal anesthesia group and in 124 of 629 (19.7%) in the general anesthesia group (relative risk, 1.04; 95% CI, 0.84 to 1.30). Conclusions: Spinal anesthesia for hip-fracture surgery in older adults was not superior to general anesthesia with respect to survival and recovery of ambulation at 60 days. The incidence of postoperative delirium was similar with the two types of anesthesia. (Funded by the Patient-Centered Outcomes Research Institute; REGAIN ClinicalTrials.gov number, NCT02507505.)
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