Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Class IIa HDAC Inhibitors for Huntington’s Disease

Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC₅₀, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease.     

Establishing biennial paramedic experience benchmarks

Objective. Since stroke symptoms are often vague, and acute therapies for stroke are more recently available, it has been hypothesized that stroke patients may not be treated with the same urgency as myocardial infarction (MI) patients by emergency medical services (EMS). To examine this hypothesis, EMS transport times were examined for both stroke and MI patients who used a paramedic-level, county-based EMS system for transportation to a single hospital during 1999. Methods. Patients were first identified by their hospital discharge diagnosis as stroke (ICD-9 430–436, n = 50) or MI (ICD-9 410, n = 55). Trip sheets with corresponding transport times were retrospectively obtained from the 911 center. A separate analysis was performed on patients identified by dispatchers with a chief complaint of stroke (n = 85) or MI (n = 372). Results. Comparing stroke and MI patients identified by ICD-9 codes, mean EMS transport times in minutes did not meaningfully differ with respect to dispatch to scene arrival time (8.3 vs 8.9, p = 0.61), scene time (19.5 vs 21.4, p = 0.23), and transport time (13.7 vs 16.2, p = 0.10). Mean total call times in minutes from dispatch to hospital arrival were similar between stroke and MI patients (41.5 vs 46.4, p = 0.22). Results were similar when comparing patients identified by dispatchers with a chief complaint indicative of stroke or MI. Conclusion. In this single county, EMS response times were not different between stroke and MI patients. Replication in other EMS settings is needed to confirm these findings.     

What Can I Do With a Doctoral Degree in Gerontology? Expanding Your Options

An endless number of career trajectories are possible for gerontologists. With a growing aging population, our skills and areas of expertise are of high value to numerous industries. The purpose of this study is to describe the professional development and career trajectories of alumni of U.S. doctoral gerontology programs obtained through the Gerontology Education Longitudinal Study (GELS). Specifically, the authors examine how professional identification, doctoral program career preparation, and perception of job prospects affect alumni decisions to pursue “traditional” (i.e., academic) versus “nontraditional” (i.e., non-academic) careers. Results from the GELS revealed a fairly even split in the alumni sample of careers in traditional and nontraditional settings. The decision to pursue a traditional versus nontraditional career was not significantly associated with personal identification, doctoral program career preparation, or perception of employment options. These results suggest that the skill set obtained in doctoral gerontology programs is useful and is in demand in a variety of careers; therefore, doctoral programs may want to consider tailoring training to meet students’ future career goals in both academic and non-academic settings.     

Introduction to the Special Section on Consensual Non-Monogamy

Archives of Sexual Behavior -     

Barriers to Help-Seeking Behavior Among Women With Postpartum Depression

Postpartum depression affects approximately 900,000 women annually, but only approximately 6% of these women seek psychological help (Postpartum, Progress, 2016). This lack of help-seeking behavior must be addressed to decrease the negative effects of postpartum depression on maternal and infant outcomes. The purpose of this article is to describe the barriers that prevent women from seeking psychological help and provide suggestions to address these barriers.     

Endothelial lipase promotes the catabolism of ApoB-containing lipoproteins

Endothelial lipase (EL) has been found to be a key enzyme in high-density lipoprotein (HDL) metabolism in mice, leading to the concept that inhibition of EL could be a novel strategy for raising HDL cholesterol levels. However, mice are "HDL animals" and the effect of EL on atherogenic apoB-containing lipoproteins has not been elucidated. We previously found that EL is capable of hydrolyzing very low-density lipoprotein (VLDL) and LDL lipids ex vivo. To investigate the role of EL in the metabolism of apoB-containing lipoproteins in vivo, we expressed human EL in three mouse models of elevated apoB-containing lipoproteins: apoE-deficient, LDL receptor-deficient, and human apoB transgenic mice. Unexpectedly, hepatic expression of EL resulted in markedly decreased levels of VLDL/LDL cholesterol, phospholipid, and apoB accompanied by significantly increased LDL apolipoprotein and phospholipid catabolism. To determine whether lipolytic activity is required for this effect, we also expressed a catalytically inactive form of human EL (ELS149A); unexpectedly, expression of ELS149A did not lower and in fact increased plasma lipids. Coexpression and coimmunoprecipitation studies suggested that catalytically inactive ELS149A inhibits endogenous mouse EL, accounting for the increased lipid levels. We conclude that (1) in addition to its known effects on HDL metabolism, EL influences the metabolism of apoB-containing particles; (2) catalytic activity of EL is required for its effects on apoB-containing lipoproteins; and (3) overexpressed catalytically inactive EL inhibits endogenous mouse EL, resulting in increased levels of plasma lipids. In light of these results, inhibition of EL has the potential to raise levels of atherogenic lipoproteins in addition to HDL-C levels.