Summary Purpose Epilepsy is a complex disease characterized by a predisposition toward seizures. There are numerous barriers to the successful treatment of epilepsy. For instance, current anti-epileptic drugs have adverse side effects and variable efficacies. Further, the pathophysiological basis of epilepsy remains largely elusive. Therefore, investigating novel genes and biological processes underlying epilepsy may provide valuable insight and enable the development of new therapeutic agents. We previously identified methylglyoxal (MG) as an endogenous GABAA receptor agonist. Here, we investigated the role of MG and its catabolic enzyme, glyoxalase 1 (GLO1), in seizures. Methods We pre-treated mice with MG before seizure induction with picrotoxin or pilocarpine and then assessed seizures behaviorally or by electroencephalography (EEG). We then investigated the role of GLO1 in seizures by treating mice with a pharmacological inhibitor of GLO1 before seizure induction with pilocarpine and measured subsequent seizure phenotypes. Next, we explored the genetic relationship between Glo1 expression and seizures. We analyzed seizure phenotypes among BXD recombinant inbred (RI) mice with differential Glo1 expression. Lastly, we investigated a causal role for Glo1 in seizures by administering pilocarpine to transgenic (Tg) mice that overexpress Glo1. Key Findings Pre-treatment with MG attenuated pharmacologically-induced seizures at both the behavioral and EEG levels. GLO1 inhibition, which increases MG concentration in vivo, also attenuated seizures. Among BXD RI mice, high Glo1 expression was correlated with increased seizure susceptibility. Tg mice overexpressing Glo1 displayed reduced MG concentration in the brain and increased seizure severity. Significance These data identify MG as an endogenous regulator of seizures. Similarly, inhibition of GLO1 attenuates seizures, suggesting that this may be a novel therapeutic approach for epilepsy. Furthermore, this system may represent an endogenous negative feedback loop whereby high metabolic activity increases inhibitory tone via local accumulation of MG. Finally, Glo1 may contribute to the genetic architecture of epilepsy, as Glo1 expression regulates both MG concentration and seizure severity.
Introduction: This student-driven curriculum intervention, implemented with first-year medical students,
BackgroundThe aim of this study was to identify factors associated with variability in Cesarean delivery (CD) rates amongst providers at a single institution.MethodsA retrospective cohort analysis was carried out on all births at NYU Langone Medical Center from 2005–2013. Data was collected for subjects and linked to diagnosis codes for singleton and twin deliveries. Descriptive characteristics were generated for all deliveries, and inferential analysis was performed including multiple covariates for singleton deliveries in the 2010–2013 cohort, including both univariate and multivariate regression analyses to identify factors associated with higher CD rates.Results37,692 deliveries were identified at our institution during the study period, performed by 88 unique providers. The mean CD rate was 29.6%, with a range for individual physicians from 9.9% to 75.6%. In multivariate regression analysis, CD rate was directly correlated with average patient age, physician male gender, proportion of high-risk deliveries, and Maternal-Fetal Medicine specialty, and it was inversely correlated with total number of deliveries by physician and forceps delivery rate. There was no significant difference in CD rates between group and solo practices. Within the same group practice, each member’s CD rate was strongly correlated with the average CD rate of the group.ConclusionOur study demonstrates the wide range of CD rates for providers practicing within the same institution and reiterates the association of CD rates with patient age, high-risk pregnancy, and provider volume. Among operative vaginal deliveries, forceps delivery rate was associated with lower CD rates whereas vacuum delivery rate was not. Despite these findings, practice patterns within individual practices appear to contribute significantly to the wide range of CD rates.
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