The signaling pathways that mediate neurodegeneration are complex and involve a balance between phosphorylation and dephosphorylation of signaling and structural proteins. We have shown previously that 17-estradiol and its analogs are potent neuroprotectants. The purpose of this study was to delineate the role of protein phosphatases (PPs) in estrogen neuroprotection against oxidative stress and excitotoxicity. HT-22 cells, C6-glioma cells, and primary rat cortical neurons were exposed to the nonspecific serine/threonine protein phosphatase inhibitors okadaic acid and calyculin A at various concentrations in the presence or absence of 17-estradiol and/or glutamate. Okadaic acid and calyculin A caused a dose-dependent decrease in cell viability in HT-22, C6-glioma, and primary rat cortical neurons. 17-Estradiol did not show protection against neurotoxic concentrations of either okadaic acid or calyculin A in these cells. In the absence of these serine/threonine protein phosphatase inhibitors, 17-estradiol attenuated glutamate toxicity. However, in the presence of effective concentrations of these protein phosphatase inhibitors, 17-estradiol protection against glutamate toxicity was lost. Furthermore, glutamate treatment in HT-22 cells and primary rat cortical neurons caused a 50% decrease in levels of PP1, PP2A, and PP2B protein, whereas coadministration of 17-estradiol with glutamate prevented the decrease in PP1, PP2A, and PP2B levels. These results suggest that 17-estradiol may protect cells against glutamate-induced oxidative stress and excitotoxicity by activating a combination of protein phosphatases.
Aim: We critically evaluated empiric antibiotic practice in the surgical and trauma intensive care unit (STICU) with three specific objectives: (1) To characterize empiric antibiotics practice prospectively; (2) to determine how frequently STICU patients started on empiric antibiotics subsequently have a confirmed infection; and (3) to elucidate the complications associated with unnecessary empiric antibiotic therapy. Methods: We collected data prospectively using the Surgical Intensive Care-Infection Registry (SIC-IR) including all 1,185 patients admitted to the STICU for >2 days from March 2007 through May 2008. Empiric antibiotics were defined as those initiated because of suspected infections. Results: The mean patient age was 56 years and 62% were male. The mean STICU length of stay was eight days, and the mortality rate was 4.6%. Empiric antibiotics were started for 26.3% of the patients. The average length of antibiotic use was three days. Of the 312 patients started on empiric antibiotics, only 25.6% were found to have an infection. Factors associated with correctly starting empiric antibiotics were a longer STICU stay (5 vs. 3 days), prior antibiotics (29% vs. 17%), and mechanical ventilation (93% vs. 79%). Patients who were started on antibiotics without a subsequent confirmed infection were compared with patients not given empiric antibiotics. Incorrect use of empiric antibiotics was associated with younger age (p < 0.001), more STICU days (10.6 vs. 5.9 days; p < 0.001), more ventilator days (p < 0.001), more development of acute renal failure (24.1% vs. 12.1%; p < 0.001), and a significant difference in mortality rate (8.6% vs. 3.2%; p < 0.001). Conclusions: After admission to the STICU, 26% of patients received at least one course of empiric antibiotics. Only 25.6% of these patients were confirmed to have an infection. These results provide key benchmark data for the critical care community to improve antibiotic stewardship.
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