Familial Dilated Cardiomyopathy of Young Portuguese Water Dogs

A novel dilated cardiomyopathy (DCM) in 12 related Portuguese Water Dogs was identified by retrospective analysis of postmortem and biopsy case records. Male and female puppies born to clinically healthy parents typically died at 13 (± 7.3) weeks of age (range, 2–32 weeks) because of congestive heart failure. Puppies died suddenly without previous signs or with mild depression followed by clinical signs of congestive heart failure 1–5 days before death. There was no sex predilection. The hearts were enlarged and rounded, with marked left ventricular and atrial dilation. No other significant structural cardiac defects were noted. The histologic changes in the myocardium were diffuse and characterized by myofibers of irregular sizes separated by an edematous interstitium. The myofibers had multifocal swollen, cleared segments often involving perinuclear areas that contained granular, phosphotungstic-acid-hematoxylin-positive material consistent with mitochondria. There was loss of the cross-striation pattern, and intercalated discs were difficult to identify. There was no evidence of concurrent myocardial fibrosis; rare chronic inflammatory infiltrates were noted in one dog. Noncardiac skeletal muscles were not affected. The underlying cause is unknown. From the pedigree analysis, an autosomal recessive pattern of inheritance is suspected. Based on the histologic findings, this DCM is most likely due to an underlying molecular (biochemical or structural) defect. The early onset and rapid progression of the disease makes this a clinically distinctive form of canine DCM

Patterns and predictors of fast food consumption with acute myocardial infarction

Computational Infrastructure & Informatics Poster SessionBackground: Fast food is affordable and convenient, yet high in calories, saturated fat and sodium. The prevalence of fast food intake at the time of acute myocardial infarction (AMI) and patterns of fast food intake in recovery are unknown. Moreover, the association between dietary counseling at hospital discharge and fast food intake after MI has not been described. Methods: We assessed baseline, 1 and 6-month fast food intake in 2494 patients in TRIUMPH, a 26-center, prospective registry of AMI patients. Fast food intake was divided into frequent (≥ weekly) vs. infrequent (< weekly) consumption. Multivariable regression was used to identify predictors of frequent fast food intake at 6-months, adjusted for baseline fast food consumption, sociodemographics and clinical factors. Results: Frequent fast food intake was common at the time of AMI (36%), but decreased substantially after AMI to 17% at 1-month and 20% at 6-months (p-value <0.0001). Patient characteristics independently associated with frequent fast food intake at 6-months included white race, male gender, health literacy, financial difficulty, dyslipidemia and diabetes. College education, heart failure and coronary revascularization during AMI admission were inversely associated with 6-month fast food consumption. Importantly, dietary counseling at discharge was not associated with lower 6-month fast food intake. Conclusion: Fast food consumption declined substantially after AMI. Certain populations, including patients with financial difficulty and lower health literacy continued to eat fast food frequently after their event. Although several patient groups are at risk for persistent high fast food intake, current dietary counseling efforts appear ineffective at altering behavior and new counseling strategies are needed

Amygdala Nuclei Volumes Are Selectively Associated With Social Network Size in Homeless and Precariously Housed Persons

Objective: The amygdala is a brain region comprised of a group of functionally distinct nuclei that play a central role in social behavior. In homeless and precariously housed individuals, high rates of multimorbidity, and structural aspects of the environment may dysregulate social functioning. This study examined the neurobiological substrates of social connection in homeless and precariously housed persons by examining associations between amygdala nuclei volumes and social network size. Methods: Sixty participants (mean age 43.6 years; 73.3% male) were enrolled from an ongoing study of homeless and precariously housed adults in Vancouver, Canada. Social network size was assessed using the Arizona Social Support Interview Schedule. Amygdala nuclei volumes were extracted from anatomic T1-weighted MRI data. The central and basolateral amygdala nuclei were selected as they are implicated in anxiety-related and social behaviors. The hippocampus was included as a control brain region. Multivariable regression analysis investigated the relationship between amygdala nuclei volumes and social network size. Results: After controlling for age, sex, and total brain volume, individuals with the larger amygdala and central nucleus volumes had a larger network size. This association was not observed for the basolateral amygdala complex, though subsequent analysis found the basal and accessory basal nuclei of the basolateral amygdala were significantly associated with social network size. No association was found for the lateral amygdala nucleus or hippocampus. Conclusions: These findings suggest that select amygdala nuclei may be differentially involved in the social connections of persons with multimorbid illness and social marginalization

GPR54 (KISS1R) Transactivates EGFR to Promote Breast Cancer Cell Invasiveness

Kisspeptins (Kp), peptide products of the Kisspeptin-1 (KISS1) gene are endogenous ligands for a G protein-coupled receptor 54 (GPR54). Previous findings have shown that KISS1 acts as a metastasis suppressor in numerous cancers in humans. However, recent studies have demonstrated that an increase in KISS1 and GPR54 expression in human breast tumors correlates with higher tumor grade and metastatic potential. At present, whether or not Kp signaling promotes breast cancer cell invasiveness, required for metastasis and the underlying mechanisms, is unknown. We have found that kisspeptin-10 (Kp-10), the most potent Kp, stimulates the invasion of human breast cancer MDA-MB-231 and Hs578T cells using Matrigel-coated Transwell chamber assays and induces the formation of invasive stellate structures in three-dimensional invasion assays. Furthermore, Kp-10 stimulated an increase in matrix metalloprotease (MMP)-9 activity. We also found that Kp-10 induced the transactivation of epidermal growth factor receptor (EGFR). Knockdown of the GPCR scaffolding protein, β-arrestin 2, inhibited Kp-10-induced EGFR transactivation as well as Kp-10 induced invasion of breast cancer cells via modulation of MMP-9 secretion and activity. Finally, we found that the two receptors associate with each other under basal conditions, and FRET analysis revealed that GPR54 interacts directly with EGFR. The stability of the receptor complex formation was increased upon treatment of cells by Kp-10. Taken together, our findings suggest a novel mechanism by which Kp signaling via GPR54 stimulates breast cancer cell invasiveness

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA).</p> <p>Methods</p> <p>We systematically assessed gene expression changes induced by clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction.</p> <p>Results</p> <p>The expression of 156 genes was significantly increased by clorgyline at all time points over the time course of 6 – 96 hr identified by Significance Analysis of Microarrays (SAM). The list is enriched with genes repressed in 7 of 12 oncogenic pathway signatures compiled from the literature. In addition, genes downregulated ≥ 2-fold by clorgyline were significantly enriched with those upregulated by key oncogenes including beta-catenin and ERBB2, indicating an anti-oncogenic effect of clorgyline. Another striking effect of clorgyline was the induction of androgen receptor (AR) and classic AR target genes such as prostate-specific antigen together with other secretory epithelial cell-specific genes, suggesting that clorgyline promotes differentiation of cancer cells. Moreover, clorgyline downregulated EZH2, a critical component of the Polycomb Group (PcG) complex that represses the expression of differentiation-related genes. Indeed, many genes in the PcG repression signature that predicts PCa outcome were upregulated by clorgyline, suggesting that the differentiation-promoting effect of clorgyline may be mediated by its downregulation of EZH2.</p> <p>Conclusion</p> <p>Our results suggest that inhibitors of MAO-A, already in clinical use to treat depression, may have potential application as therapeutic PCa drugs by inhibiting oncogenic pathway activity and promoting differentiation.</p

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Traumatic Brain Injury in Precariously Housed Persons: Incidence and Risks

Background Homeless and precarious housed persons are particularly prone to traumatic brain injuries (TBIs), but existent incidence rates are hampered by poor case acquisition. We rigorously documented TBIs in precariously housed persons transitioning in and out of homelessness. Methods Between December 2016 and May 2018, 326 precariously housed participants enrolled in a longitudinal study in Vancouver, Canada were assessed monthly for TBI occurrences after education on sequelae. Over one participant-year, 2433 TBI screenings were acquired for 326 person-years and variables associated with odds of incident TBI were evaluated. Findings One hundred participants acquired 175 TBIs, yielding an observed incidence proportion of 30¢7% and event proportion of 53¢7%. Of the injured, 61% reported one TBI and 39% reported multiple injuries. Acute intoxication was present for more than half of the TBI events assessed. Additionally, 9¢7% of TBI events occurred in the context of a drug overdose. Common injury mechanisms were falls (45¢1%), assaults (25¢1%), and hitting one’s head on an object (13¢1%). In this community-based but non-randomly recruited sample, exploratory analyses identified factors associated with odds of an incident TBI over one year of follow-up, including: schizophrenia disorders (odds ratio (OR) = 0¢43, 95% confidence interval (CI) 0¢19, 0¢94), role functioning (OR = 0¢69, 95% CI 0¢52, 0¢91), opioid dependence (OR = 2¢17, 95% CI 1¢27, 3¢72) and those reporting past TBIs (OR = 1¢99, 95% CI 1¢13, 3¢52). Interpretation Given the ubiquity of TBIs revealed in this precariously housed sample, we identify an underappreciated and urgent healthcare priority. Several factors modified the odds of incident TBI, which can facilitate investigations into targeted prevention efforts

Inhibition of Serine Palmitoyl Transferase I Reduces Cardiac Ceramide Levels and Increases Glycolysis Rates following Diet-Induced Insulin Resistance

Objective: Diet-induced obesity (DIO) leads to an accumulation of intra-myocardial lipid metabolites implicated in causing cardiac insulin resistance and contractile dysfunction. One such metabolite is ceramide, and our aim was to determine the effects of inhibiting de novo ceramide synthesis on cardiac function and insulin stimulated glucose utilization in mice subjected to DIO. Materials and Methods: C57BL/6 mice were fed a low fat diet or subjected to DIO for 12 weeks, and then treated for 4 weeks with either vehicle control or the serine palmitoyl transferase I (SPT I) inhibitor, myriocin. In vivo cardiac function was assessed via ultrasound echocardiography, while glucose metabolism was assessed in isolated working hearts. Results: DIO was not associated with an accumulation of intra-myocardial ceramide, but rather, an accumulation of intra-myocardial DAG (2.63±0.41 vs. 4.80±0.97 nmol/g dry weight). Nonetheless, treatment of DIO mice with myriocin decreased intra-myocardial ceramide levels (50.3±7.7 vs. 26.9±2.7 nmol/g dry weight) and prevented the DIO-associated increase in intra-myocardial DAG levels. Interestingly, although DIO impaired myocardial glycolysis rates (7789±1267 vs. 2671±326 nmol/min/g dry weight), hearts from myriocin treated DIO mice exhibited an increase in glycolysis rates. Conclusions: Our data reveal that although intra-myocardial ceramide does not accumulate following DIO, inhibition of de novo ceramide synthesis nonetheless reduces intra-myocardial ceramide levels and prevents the accumulation of intra-myocardial DAG. These effects improved the DIO-associated impairment of cardiac glycolysis rates, suggesting that SPT I inhibition increases cardiac glucose utilization. © 2012 Ussher et al.published_or_final_versio

Component Processes of Decision Making in a Community Sample of Precariously Housed Persons: Associations With Learning and Memory, and Health-Risk Behaviors

The Iowa Gambling Task (IGT) is a widely used measure of decision making, but its value in signifying behaviors associated with adverse, “real-world” consequences has not been consistently demonstrated in persons who are precariously housed or homeless. Studies evaluating the ecological validity of the IGT have primarily relied on traditional IGT scores. However, computational modeling derives underlying component processes of the IGT, which capture specific facets of decision making that may be more closely related to engagement in behaviors associated with negative consequences. This study employed the Prospect Valence Learning (PVL) model to decompose IGT performance into component processes in 294 precariously housed community residents with substance use disorders. Results revealed a predominant focus on gains and a lack of sensitivity to losses in these vulnerable community residents. Hypothesized associations were not detected between component processes and self-reported health-risk behaviors. These findings provide insight into the processes underlying decision making in a vulnerable substance-using population and highlight the challenge of linking specific decision making processes to “real-world” behaviors