No abstract

Mitochondrial protein kinase C isozymes have been reported to mediate both cardiac ischemic preconditioning and ischemia/reperfusion injury. In addition, cardiac preconditioning improves the recovery of ATP levels after ischemia/reperfusion injury. We have, therefore, evaluated protein kinase C modulation of the

The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults, including trauma, stroke, tumors, infections, and long seizures [status epilepticus (SE)], create a neuronal state of increased metabolic demand or decreased energy supply. Neurons express molecules that monitor their metabolic state, including sirtuins (Sirts). Sirtuins deacetylate cytoplasmic proteins and nuclear histones, and their epigenetic modulation of the chromatin governs the expression of many genes, influencing neuronal properties. Thus, sirtuins are poised to enduringly modulate neuronal properties following SE, potentially contributing to epileptogenesis, a hypothesis supported by the epilepsy-attenuating effects of blocking a downstream target of Sirt1, Neuron-Restrictive Silencer Factor (NRSF) also know as REST (RE1-Silencing Transcription factor). Here we used an adult male rat model of epileptogenesis provoked by kainic acid–induced SE (KA-SE). We assessed KA-SE-provoked Sirt1 activity, infused a Sirt1 inhibitor (EX-527) after KA-SE, and examined for epileptogenesis using continuous digital video–EEG. Sirt1 activity, measured using chromatin immunoprecipitation for Sirt1 binding at a target gene, increased rapidly after SE. Post hoc infusion of the Sirt1 inhibitor prevented Sirt1-mediated repression of a target gene. Blocking Sirt1 activity transiently after KA-SE did not significantly influence the time- course and all of the parameters of epilepsy development. Specifically, latency to first seizure and seizure number, duration, and severity (using the Racine scale and EEG measures) as well as the frequency and duration of interictal spike series, were all unchanged. KA-SE provoked a robust inflammatory response and modest cell loss, yet neither was altered by blocking Sirt1. In conclusion, blocking Sirt1 activity after KA-SE does not abrogate epilepsy development, suggesting that the mechanisms of such acquired epileptogenesis are independent of Sirt1 function.

Electronic health records (EHR) are widely used sources of real-world data in pharmacoepidemiologic research. As there is no end-to-end guidance for generating medication safety evidence with EHR, this study conducted a systematic review to determine the current and recommended practices in the literature. PubMed, Scopus, and CINAHL were searched for English articles published between 1 January 2010 and 11 June 2020. Selected articles were published in peer-reviewed journals, conducted in the United States, analyzed structured EHR data, and defined drug exposure and adverse drug events (ADEs). The study evaluated methodological quality with a modified Newcastle-Ottawa Scale (NOS) score ranging from 0 to 9 points. Data synthesis was performed with thematic analysis. Twenty-six from 3885 articles were selected. The majority were cohort studies (85%). The studies were well designed, with a median NOS score of 9. Drug exposure was defined with dispensing (58%) and prescribing (31%) records. ADEs were defined across five categories: diagnosis codes (77%), validated outcome algorithms (35%), objective measures (35%), treatment procedures (19%), and antidotes (2%). Common covariates were age (89%), gender (85%), comorbidities (81%), and medication-co-medication use (73%).Four studies (15%) empirically defined covariates in a data-driven manner. Twentytwo (85%) analyzed covariates as confounders or effect modifiers in their analyses.Results were analyzed with either intention-to-treat (73%) or as-treated (39%) approaches. Key recommendations include selecting dispensing rather than prescribing records, considering a proxy date of dispensation where applicable, selecting new instead of prevalent drug users, improving adoption of validated outcome algorithms, and not utilizing objective measures as the primary indicator of ADEs.