Levosimendan: current data, clinical use and future development.

Levosimendan is an inodilator indicated for the short-term treatment of acutely decompensated severe chronic heart failure, and in situations where conventional therapy is not considered adequate. The principal pharmacological effects of levosimendan are (a) increased cardiac contractility by calcium sensitisation of troponin C, (b) vasodilation, and (c) cardioprotection. These last two effects are related to the opening of sarcolemmal and mitochondrial potassium-ATP channels, respectively. Data from clinical trials indicate that levosimendan improves haemodynamics with no attendant significant increase in cardiac oxygen consumption and relieves symptoms of acute heart failure; these effects are not impaired or attenuated by the concomitant use of beta-blockers. Levosimendan also has favourable effects on neurohormone levels in heart failure patients. Levosimendan is generally well tolerated in acute heart failure patients: the most common adverse events encountered in this setting are hypotension, headache, atrial fibrillation, hypokalaemia and tachycardia. Levosimendan has also been studied in other therapeutic applications, particularly cardiac surgery - in which it has shown a range of beneficial haemodynamic and cardioprotective effects, and a favourable influence on clinical outcomes - and has been evaluated in repetitive dosing protocols in patients with advanced chronic heart failure. Levosimendan has shown preliminary positive effects in a range of conditions requiring inotropic support, including right ventricular failure, cardiogenic shock, septic shock, and Takotsubo cardiomyopathy

Snoring in primary school children and domestic environment: A Perth school based study

BACKGROUND: The home is the predominant environment for exposure to many environmental irritants such as air pollutants and allergens. Exposure to common indoor irritants including volatile organic compounds, formaldehyde and nitrogen dioxide, may increase the risk of snoring for children. The aim of this study was to investigate domestic environmental factors associated with snoring in children. METHODS: A school-based respiratory survey was administered during March and April of 2002. Nine hundred and ninety six children from four primary schools within the Perth metropolitan area were recruited for the study. A sub-group of 88 children aged 4–6 years were further selected from this sample for domestic air pollutant assessment. RESULTS: The prevalences of infrequent snoring and habitual snoring in primary school children were 24.9% and 15.2% respectively. Passive smoking was found to be a significant risk factor for habitual snoring (odds ratio (OR) = 1.77; 95% confidence interval (CI): 1.20–2.61), while having pets at home appeared to be protective against habitual snoring (OR = 0.58; 95% CI: 0.37–0.92). Domestic pollutant assessments showed that the prevalence of snoring was significantly associated with exposure to nitrogen dioxide during winter. Relative to the low exposure category (<30 μg/m(3)), the adjusted ORs of snoring by children with medium (30 – 60 μg/m(3)) and high exposures (> 60 μg/m(3)) to NO(2 )were 2.5 (95% CI: 0.7–8.7) and 4.5 (95% CI: 1.4–14.3) respectively. The corresponding linear dose-response trend was also significant (P = 0.011). CONCLUSION: Snoring is common in primary school children. Domestic environments may play a significant role in the increased prevalence of snoring. Exposure to nitrogen dioxide in domestic environment is associated with snoring in children

Outcomes of patients hospitalized for acute decompensated heart failure: does nesiritide make a difference?

<p>Abstract</p> <p>Background</p> <p>Nesiritide is indicated in the treatment of acute decompensated heart failure. However, a recent meta-analysis reported that nesiritide may be associated with an increased risk of death. Our goal was to evaluate the impact of nesiritide treatment on four outcomes among adults hospitalized for congestive heart failure (CHF) during a three-year period.</p> <p>Methods</p> <p>CHF patients discharged between 1/1/2002 and 12/31/2004 from the Adventist Health System, a national, not-for-profit hospital system, were identified. 25,330 records were included in this retrospective study. Nesiritide odds ratios (OR) were adjusted for various factors including nine medications and/or an APR-DRG severity score.</p> <p>Results</p> <p>Initially, treatment with nesiritide was found to be associated with a 59% higher odds of hospital mortality (Unadjusted OR = 1.59, 95% confidence interval [CI]: 1.31–1.93). Adjusting for race, low economic status, APR-DRG severity of illness score, and the receipt of nine medications yielded a nonsignificant nesiritide OR of 1.07 for hospital death (95% CI: 0.85–1.35). Nesiritide was positively associated with the odds of prolonged length of stay (all adjusted ORs = 1.66) and elevated pharmacy cost (all adjusted ORs > 5).</p> <p>Conclusion</p> <p>In this observational study, nesiritide therapy was associated with increased length of stay and pharmacy cost, but not hospital mortality. Randomized trials are urgently needed to better define the efficacy, if any, of nesiritide in the treatment of decompensated heart failure.</p

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz

Treponema denticola chymotrypsin-like protease as associated with HPV-negative oropharyngeal squamous cell carcinoma

BACKGROUND: An opportunistic oral pathogen, Treponema denticola (Td), has been linked to orodigestive carcinogenesis, but its role in oropharyngeal squamous cell carcinoma (OPSCC) has remained open. We evaluated the presence of Td chymotrypsin-like protease (Td-CTLP) in a series of 201 unselected consecutive OPSCC patients, and the relation of the Td-CTLP to human papillomavirus (HPV) status, to expression of toll-like receptors (TLR) 5, 7, and 9, and to clinical parameters and patient outcome. METHODS: Clinicopathological data came from hospital registries. The expression of cell surface-bound Td-CTLP was evaluated by immunohistochemistry. Immunoexpression of TLRs 5, 7, and 9, and HPV status we studied earlier in this patient series. RESULTS: We detected Td-CTLP in 81% of the OPSCC, and especially in HPV-negative tumours (48% of all OPSCCs). Among the HPV-positive tumours (52% of all OPSCCs), low Td-CTLP expression associated with low TLR 5 and high TLR 7 expression. Among those HPV-negative, higher TLR 5 and lower TLR 7 expression associated with high Td-CTLP expression. Strong Td-CTLP expression associated with poor disease-specific survival, but no similar association among HPV-positive and HPV-negative subgroups emerged. CONCLUSIONS: Td-CTLP was highly expressed in OPSCC and was associated with the HPV status of tumour tissue.Peer reviewe