Yield of chest computed tomography angiogram in cystic fibrosis patients with suspected pulmonary embolism

IntroductionIndividuals with cystic fibrosis (CF) may be at increased risk of pulmonary embolism (PE). Symptoms of PE overlap substantially with those of CF respiratory exacerbations. CF patients commonly undergo chest computed tomography (CT) angiograms (CTPA) to evaluate for PE, but little is known about the clinical presentation and diagnosis of PE in this population.ObjectivesThe objectives of this study are to determine the diagnostic yield of CTPA for PE in adult patients with CF and assess the utility of the Revised Geneva Score (RGS) in this population.MethodsRetrospective review of all CTPA results was performed on CF patients with suspected PE at a large CF center from 1 January 2011 through 31 March 2017. Patient demographics, medical history, and presenting signs and symptoms were abstracted by chart review.ResultsA total of 103 unique CTPA studies were performed in 68 patients. Most were hospitalized at the time of CTPA, predominantly for respiratory manifestations of CF. CTPA identified four patients with PE. The small number of positive studies precluded analysis of predictors of PE. Fewer PE were diagnosed than predicted by the Revised Geneva Score, which was intermediate probability in 77/103 (75%) patients.ConclusionThe prevalence of PE in CF patients undergoing CTPA for suspected PE was 4%, which is lower than predicted by the Revised Geneva Score. This may be due to a large overlap in the signs and symptoms of PE and exacerbations of CF lung disease.     

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.     

Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene

Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier (Mvwf2). Mvwf2 accounts for approximately 16% of the 8-fold plasma VWF variation (or approximately 25% of the genetic variation) observed between the A/J and CASA/RkJ strains and maps to the murine Vwf gene itself. Twenty SNPs were identified within the coding regions of the A/J and CASA/RkJ Vwf alleles, and in vitro analysis of recombinant VWF demonstrated that a single SNP (+7970G>A) and the associated nonsynonymous amino acid change (R2657Q) confers a significant increase in VWF biosynthesis from the CASA/RkJ Vwf allele. This change appears to represent a unique gain of function that likely explains the mechanism of Mvwf2 in vivo. The identification of a natural Vwf gene variant among inbred mice affecting biosynthesis suggests that similar genetic variation may contribute to the wide range of VWF levels observed in humans.     

Evaluation of the Heart Truth Professional Education Campaign on Provider Knowledge of Women and Heart Disease

BackgroundThe Heart Truth Professional Education Campaign was developed to facilitate education of health care providers in evidence-based strategies to prevent cardiovascular disease (CVD) in women.MethodsAs part of the 3-year campaign, lectures based on the American Heart Association's evidence-based guidelines for CVD prevention in women were presented by local speakers to healthcare providers and students in three high-risk states: Delaware, Ohio, and New York. Participants' responses to pretest and posttest questions about CVD in women are presented. We performed t-test and multivariable linear regression to assess the influence of provider characteristics on baseline knowledge and knowledge change after the lecture.ResultsBetween 2008 and 2011, 2,995 healthcare providers, students, and other participants completed the baseline assessment. Knowledge scores at baseline were highest for physicians, with obstetrician/gynecologists scoring lowest (63%) and cardiologists highest (76%). Nurses had intermediate total knowledge (56%) and students had the lowest total knowledge (49%) at baseline. Pre- and post-lecture assessments were completed by 1,893 (63%) of attendees. Scores were significantly higher after the educational lecture (p ≤ .001), with greater increase for those with lower baseline scores. Baseline knowledge of the use of statins, hormone therapy, and antioxidants, as well as approaches to smoking cessation and treatment of hypertension, differed by provider type.ConclusionTailoring of lectures for non-physician audiences may be beneficial given differences in baseline knowledge. More emphasis is needed on statin use for all providers and on smoking cessation and treatment of hypertension for nurses, students, and other healthcare professionals.