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Aspirin exerts its unique pharmacological effects by irreversibly acetylating a serine residue in the cyclooxygenase site of prostaglandin-H 2 -synthases (PGHSs). Despite the irreversibility of the inhibition, the potency of aspirin varies remarkably between cell types, suggesting that molecular determinants could contribute to cellular selectivity. Using purified enzymes, we found no evidence that aspirin is selective for either of the two PGHS isoforms, and we showed that hydroperoxide substrates of the PGHS peroxidase inhibited the rate of acetylation of PGHS-1 by 68%. Using PGHS-1 reconstituted with cobalt protoporphyrin, a heme devoid of peroxidase activity, we demonstrated that reversal by hydroperoxides of the aspirin-mediated acetylation depends upon the catalytic activity of the PGHS peroxidase. We demonstrated that inhibition of PGHS-2 by aspirin in cells in culture is reversed by 12-hydroperoxyeicosatetraenoic acid dose-dependently (ED 50 = 0.58 ± 0.15 μM) and that in cells with high levels of hydroperoxy-fatty acids (RAW264.7) the efficacy of aspirin is markedly decreased as compared to cells with low levels of hydroperoxides (A549; IC 50 s = 256 ± 22 μM and 11.0 ± 0.9 μM, respectively). Together, these findings indicate that acetylation of the PGHSs by aspirin is regulated by the catalytic activity of the peroxidase which yields a higher oxidative state of the enzyme.

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ObjectivesType I diabetes mellitus (T1DM) is one of the most common chronic diseases of childhood. Diabetic ketoacidosis (DKA) in this population contributes to significant healthcare utilization, including emergency room visits, hospitalizations, and ICU care. Comorbid psychiatric illnesses (CPI) are additional risks for increased healthcare utilization. While CPI increased risk for DKA hospitalization and readmission, there are no data evaluating the relationship between CPI and hospital outcomes. We hypothesized that adolescents with T1DM and CPI admitted for DKA have increased length of stay (LOS) and higher charges compared to those without CPI.MethodsRetrospective review of 2000–2012 Healthcare Cost and Utilization Project’s (HCUP) Kids’ Inpatient Databases (KID). Patients 10–21 years old admitted with ICD-9 codes for DKA or severe diabetes (250.1–250.33) with and without ICD-9 codes for depression (296–296.99, 311) and anxiety (300–300.9). Comparisons of LOS, mortality, and charges between groups (No CPI, Depression and Anxiety) were made with one way ANOVA with Bonferroni correction, independent samples Kruskal-Wallis test with Bonferroni correction and χ2.ResultsThere were 79,673 admissions during the study period: 68,573 (86%) No CPI, 8,590 (10.7%) Depression and 12,510 (15.7%) Anxiety. Female patients comprised 58.2% (n=46,343) of total admissions, 66% of the Depression group, and 71% of the Anxiety group. Patients with depression or anxiety were older and had longer LOS and higher mean charges (p<0.001 for both).ConclusionComorbid depression or anxiety are associated with significantly longer LOS and higher charges in adolescents with T1DM hospitalized for DKA. This study adds to the prior findings of worse outcomes for patients with both T1DM and CPI, emphasizing the importance of identifying and treating these comorbid conditions.