Gina Morgan

Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin

The action of insulin in the central nervous system produces sympathetic nervous system activation (also called sympathoactivation), although the neuronal intracellular mechanisms that mediate this are unclear. We hypothesized that PI3K and MAPK, the major pathways involved in insulin receptor signaling, mediate sympathetic nerve responses to insulin. Intracerebroventricular administration of insulin in rat increased multifiber sympathetic nerve activity to the hindlimb, brown adipose tissue (BAT), adrenal gland, and kidney. Ex vivo biochemical studies of mediobasal hypothalamic tissue revealed that insulin stimulated the association of insulin receptor substrate-1 with the p85alpha subunit of PI3K and also tyrosine phosphorylation of p42 and p44 subunits of MAPK in the hypothalamus. In order to determine whether PI3K and/or MAPK were involved in insulin-mediated sympathoactivation, we tested the effect of specific inhibitors of PI3K (LY294002 and wortmannin) and MAPK (PD98059 and U0126) on regional sympathetic responses to insulin. Interestingly, regional sympathoactivation to insulin was differentially affected by blockade of PI3K and MAPK. Inhibition of PI3K specifically blocked insulin-induced sympathoactivation to the hindlimb, while inhibition of MAPK specifically blocked insulin-induced sympathoactivation to BAT. Sympathoactivation to corticotrophin-releasing factor, however, was not affected by inhibition of PI3K and MAPK. These data demonstrate that PI3K and MAPK are specific and regionally selective mediators of the action of insulin on the sympathetic nervous system.

Periprostatic adipose tissue from obese prostate cancer patients promotes tumor and endothelial cell proliferation: A functional and MR imaging pilot study

Obesity, particularly visceral adiposity, confers a worse prognosis for prostate cancer (PCa) patients, and increasing periprostatic adipose (PPA) tissue thickness or density is positively associated with more aggressive disease. However, the cellular mechanism of this activity remains unclear. Therefore, in this pilot study, we assessed the functional activity of PPA tissue secretions and established a biochemical profile of PPA as compared to subcutaneous adipose (SQA) tissues from lean, overweight and obese PCa patients.

Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel

The voltage-gated cardiac Na+ channel (Nav1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na+ current (INa) and is vital for normal cardiac electrical activity. Inherited loss-of-function mutations in SCN5A lead to defects in the generation and conduction of the cardiac electrical impulse and are associated with various arrhythmia phenotypes. Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Nav1.5 at lysine 1479 (K1479) and stimulates INa via lysine-deacetylation-mediated trafficking of Nav1.5 to the plasma membrane. Cardiac Sirt1 deficiency in mice induces hyperacetylation of K1479 in Nav1.5, decreases expression of Nav1.5 on the cardiomyocyte membrane, reduces INa and leads to cardiac conduction abnormalities and premature death owing to arrhythmia. The arrhythmic phenotype of cardiac-Sirt1-deficient mice recapitulated human cardiac arrhythmias resulting from loss of function of Nav1.5. Increased Sirt1 activity or expression results in decreased lysine acetylation of Nav1.5, which promotes the trafficking of Nav1.5 to the plasma membrane and stimulation of INa. As compared to wild-type Nav1.5, Nav1.5 with K1479 mutated to a nonacetylatable residue increases peak INa and is not regulated by Sirt1, whereas Nav1.5 with K1479 mutated to mimic acetylation decreases INa. Nav1.5 is hyperacetylated on K1479 in the hearts of patients with cardiomyopathy and clinical conduction disease. Thus, Sirt1, by deacetylating Nav1.5, plays an essential part in the regulation of INa and cardiac electrical activity.

Targeted obstetric haemorrhage programme improves incoming resident confidence and knowledge

Postpartum haemorrhage is an infrequent but potentially life-threatening obstetrical emergency amenable to simulation. An educational programme consisting of a lecture and high-fidelity simulation exercise was given to incoming obstetrics and gynaecology (OB) and family medicine (FM) residents. Residents reported pre- and post-intervention confidence scores on a 1–5 Likert scale and a subset completed a postpartum haemorrhage knowledge assessment. Residents reported significant improvements in confidence in parameters involved in diagnosis and management of postpartum haemorrhage. The postpartum haemorrhage test mean scores significantly increased (57.4 ± 9.6% vs 77.1 ± 7.9%, p < 0.01) and were significantly correlated to confidence scores (Spearmans coefficient of 0.651, p < 0.001). In conclusion, an education programme that incorporates high-fidelity simulation of postpartum haemorrhage improves the confidence and knowledge of incoming residents and appears to be an effective educational approach.

Abstract 1499: Periprostatic fat from obese patients promotes prostate cancer growth

Background: Obesity, particularly visceral obesity, increases the risk of prostate cancer (PCa) progression. However, the mechanism of this remains unclear. Here, we hypothesized that the visceral periprostatic fat (PPF) from obese PCa patients stimulates progression as compared to subcutaneous fat (SQF) or PPF from lean patients. Methods: PPF and SQF were collected from PCa patients. MTT assays were performed on endothelial and PC-3 PCa cells to test proliferative activity in explant culture tissue conditioned media (CM). Angiogenesis was evaluated ex vivo using MR to generate T2 relaxation times from a series of T2-weighted spin-echo images (Bruker 14.1 T imager). Results: PPF CM from an obese patient increased endothelial cell proliferation ∼5 times that of PPF CM from a lean patient (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1499. doi:1538-7445.AM2012-1499

COMPOUND SCN5A MUTATION AND FGF12 VARIATION CAUSE BRUGADA SYNDROME

Background: Mutations in the voltage-gated sodium channel (SCN5A; Nav1.5) and its regulating genes, such as fibroblast growth factor 12 (FGF12), are linked to Brugada syndrome (BrS). The goal of this study is to identify additional FGF12 mutations and variants that may be linked to BrS. Methods:

0163 : ADRB2 Gln27Glu polymorphism is associated with early ventricular arrhythmias in primary myocardial infarct

The genetic variant rs1042714 (Gln27Glu) in ADBR2 gene coding for the β2 adrenergic receptor has been associated with sudden cardiac death and with ventricular arrhythmias in heart failure in previous population-based studies. We investigated whether the same polymorphism is associated with ventricular fibrillation (VF) in the context of myocardial Infarction (MI). Patients have been recruited between 2008 and 2013 during the MAP-IDM study. Subjects included 213 patients who experienced a VF during acute phase of primary myocardial infarct and 181 controls with MI but without VF. None of the patients had other cardiac history. Patients were genotyped for the ADRB2 Gln27Glu polymorphisms by RT-PCR. Cases and controls didn’t differ significantly in age (56.2±11.8 vs 57.4±11.4 years), in sex ratio (male 83.6% vs 83.4%), in smoker ratio (56.4% vs 58.0%) and in troponin peak value (64.2 +/-116.0 vs 70.0±78,7μg/L). Cases have a lower body mass index (BMI) (25.6±3.9 vs 26.7±4.1, p=0.01) and a lower left ventricular ejection fraction (LVEF) (45.8±11.9 vs 51.9±10.5%, p In the total cohort, the Gln27Glu is in Hardy Weinberg Equilibrium (157Gln27Gln, 181 Gln27Glu, 56 Glu27Glu). Genotypes were not associated with age, gender, BMI, troponin, EF or smoking in univariate analyses. The most interesting finding is that the delay of onset on VF in Gln27Glu cases is two times faster (73.1±105.6min) than cases carrying the Gln27Gln genotype (161.5±255.5min; p=0.004) or the Glu27Glu genotype (163.1± 314.9min; p=0.03). The Gln27Glu cases are more likely to have a VF in the 60 min after thoracic pain (OR=2.6, p=0.003). We also show that the delay of VF is twice as fast in summer/spring period than in autumn/winter period for Gln27Gln genotype (219.2vs86.7min; p=0.02) and for Glu27Glu genotype (205.4 vs 99.6min, no significative but few samples). However, we observed that this VF delay is almost the same for Gln27Glu genotype whatever the season (84.0vs64.8min).