Effects of novel muscarinic M3 receptor ligand C1213 in pulmonary arterial hypertension models.

Pulmonary hypertension (PH) is a complex disease comprising a pathologic remodeling and thickening of the pulmonary vessels causing an after load on the right heart ventricle that can result in ventricular failure. Triggered by oxidative stress, episodes of hypoxia, and other undetermined causes, PH is associated with poor outcomes and a high rate of morbidity. In the neonate, this disease has a similar etiology but is further complicated by the transition to breathing after birth, which requires a reduction in vascular resistance. Persistent pulmonary hypertension of the newborn (PPHN) is one form of PH that is frequently unresponsive to current therapies including inhaled nitric oxide (due to lack of proper absorption and diffusion), and other therapeutics targeting signaling mediators in vascular endothelium and smooth muscle. The need for novel agents, which target distinct pathways in pulmonary hypertension, remains. Herein, we investigated the therapeutic effects of novel muscarinic receptor ligand C1213 in models of PH We demonstrated that via M3 muscarinic receptors, C1213 induced activating- eNOS phosphorylation (serine-1177), which is known to lead to nitric oxide (NO) production in endothelial cells. Using signaling pathway inhibitors, we discovered that AKT and calcium signaling contributed to eNOS phosphorylation induced by C1213. As expected for an eNOS-stimulating agent, in ex vivo and in vivo models, C1213 triggered pulmonary vasodilation and induced both pulmonary artery and systemic blood pressure reductions demonstrating its potential value in PH and PPHN In brief, this proof-of-concept study provides evidence that an M3 muscarinic receptor functionally selective ligand stimulates downstream pathways leading to antihypertensive effects using in vitro, ex vivo, and in vivo models of PH

The impact of corporate social responsibility disclosure on financial performance of industrial companies in New Zealand

Corporate Social Responsibility (CSR) maintains the balance between internal and external factors of the organisations. The study aims to explore the relationship between the CSR disclosure and the Financial Performance (FP) of industrial organisations operating in New Zealand. Six industrial companies of New Zealand were selected randomly, and secondary data of their annual reports as well as CSR reports and online reports were prepared for a regression analysis. Average Share Price and CSR activities disclosed are the variables of the regression analysis. Findings revealed that there is a positive relationship between CSR disclosure and the FP of the industrial companies operating in New Zealand

Acute abdomen caused by bladder rupture attributable to neurogenic bladder dysfunction following a stroke: a case report.

INTRODUCTION: Spontaneous bladder rupture is a rare and serious event with high mortality. It is not often considered in the patient presenting with peritonitis. This often leads to delays in diagnosis. There are very few case reports of true spontaneous rupture in the literature. This is the first such reported case in which bladder rupture was attributable to neurogenic bladder dysfunction following a stroke. CASE PRESENTATION: We report the case of a 67-year-old Caucasian man who presented with lower abdominal pain and a peritonitic abdomen. He had a long-term urethral catheter because of urinary retention following a previous stroke. He was treated conservatively with antibiotics before a surgical opinion was sought. Exploratory laparotomy confirmed the diagnosis of spontaneous bladder rupture. After repair of the defect, he eventually made a full recovery. CONCLUSION: In this unusual case report, we describe an example of a serious event in which delays in diagnosis may lead to increased morbidity and mortality. To date, no unifying theory explaining why rupture occurs has been postulated. We conducted a thorough literature search to examine the etiological factors in other published cases. These etiological factors either increase intra-vesical pressure or decrease the strength of the bladder wall. We hope that by increasing awareness of these etiological factors, spontaneous bladder rupture may be diagnosed earlier and appropriate therapy started

Response and resilience of soil microbial communities inhabiting in edible oil stress/contamination from industrial estates

Metagenomic DNA extracted from polluted as well as control soil sample and electrophoresed on 0.8 % agarosa gel. Lane M is of marker, Lane 1, is for polluted sample (representing pooled metagenomic DNA for P1 + P2 + P3 = P) and Lane 2 is for control soil sample (representing pooled metagenomic DNA for C1 + C2 + C3 = C). Figure S2. Distribution of taxa among bacteria at rank phylum classified according to 16S rDNA using RDP classifier for both polluted as well as control sample. Figure S3. Distribution of taxa among bacteria at rank phylum classified according to lowest common ancestor (LCA) for both polluted as well as control sample. Figure S4. Comparative distribution of taxa among bacteria at rank class classified according to WebCARMA and M5NR datasets for both polluted as well as control sample. Table S1. Enzymes mapped for lipid metabolism pathways in KEEG database. (DOC 300 kb

Improvement of the Staggered Fermion Operators

We present a complete and detailed derivation of the finite lattice spacing corrections to staggered fermion matrix elements. Expanding upon arguments of Sharpe, we explicitly implement the Symanzik improvement program demonstrating the absence of order $a$ terms in the Symanzik improved action. We propose a general program to improve fermion operators to remove $O(a)$ corrections from their matrix elements, and demonstrate this program for the examples of matrix elements of fermion bilinears and $B_K$. We find the former does have $O(a)$ corrections while the latter does not.Comment: 16 pages, latex, 1 figur

Scanning the visual world: a study of patients with homonymous hemianopia.

Published versio

The association between sleep patterns and obesity in older adults.

BackgroundReduced sleep duration has been increasingly reported to predict obesity. However, timing and regularity of sleep may also be important. In this study, the cross-sectional association between objectively measured sleep patterns and obesity was assessed in two large cohorts of older individuals.MethodsWrist actigraphy was performed in 3053 men (mean age: 76.4 years) participating in the Osteoporotic Fractures in Men Study and 2985 women (mean age: 83.5 years) participating in the Study of Osteoporotic Fractures. Timing and regularity of sleep patterns were assessed across nights, as well as daytime napping.ResultsGreater night-to-night variability in sleep duration and daytime napping were associated with obesity independent of mean nocturnal sleep duration in both men and women. Each 1 h increase in the standard deviation of nocturnal sleep duration increased the odds of obesity 1.63-fold (95% confidence interval: 1.31-2.02) among men and 1.22-fold (95% confidence interval: 1.01-1.47) among women. Each 1 h increase in napping increased the odds of obesity 1.23-fold (95% confidence interval: 1.12-1.37) in men and 1.29-fold (95% confidence interval: 1.17-1.41) in women. In contrast, associations between later sleep timing and night-to-night variability in sleep timing with obesity were less consistent.ConclusionsIn both older men and women, variability in nightly sleep duration and daytime napping were associated with obesity, independent of mean sleep duration. These findings suggest that characteristics of sleep beyond mean sleep duration may have a role in weight homeostasis, highlighting the complex relationship between sleep and metabolism

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors.

PurposeImmune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).Patients and methodsWe performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.ResultsThirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.ConclusionsIpilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease

Increased circulating ANG II and TNF-α represents important risk factors in obese Saudi adults with hypertension irrespective of diabetic status and BMI

Central adiposity is a significant determinant of obesity-related hypertension risk, which may arise due to the pathogenic inflammatory nature of the abdominal fat depot. However, the influence of pro-inflammatory adipokines on blood pressure in the obese hypertensive phenotype has not been well established in Saudi subjects. As such, our study investigated whether inflammatory factors may represent useful biomarkers to delineate hypertension risk in a Saudi cohort with and without hypertension and/or diabetes mellitus type 2 (DMT2). Subjects were subdivided into four groups: healthy lean controls (age: 47.9±5.1 yr; BMI: 22.9±2.1 Kg/m2), non-hypertensive obese (age: 46.1±5.0 yr; BMI: 33.7±4.2 Kg/m2), hypertensive obese (age: 48.6±6.1 yr; BMI: 36.5±7.7 Kg/m2) and hypertensive obese with DMT2 (age: 50.8±6.0 yr; BMI: 35.3±6.7 Kg/m2). Anthropometric data were collected from all subjects and fasting blood samples were utilized for biochemical analysis. Serum angiotensin II (ANG II) levels were elevated in hypertensive obese (p<0.05) and hypertensive obese with DMT2 (p<0.001) compared with normotensive controls. Systolic blood pressure was positively associated with BMI (p<0.001), glucose (p<0.001), insulin (p<0.05), HOMA-IR (p<0.001), leptin (p<0.01), TNF-α (p<0.001) and ANG II (p<0.05). Associations between ANG II and TNF-α with systolic blood pressure remained significant after controlling for BMI. Additionally CRP (p<0.05), leptin (p<0.001) and leptin/adiponectin ratio (p<0.001) were also significantly associated with the hypertension phenotype. In conclusion our data suggests that circulating pro-inflammatory adipokines, particularly ANG II and, TNF-α, represent important factors associated with a hypertension phenotype and may directly contribute to predicting and exacerbating hypertension risk