The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology

β-Adrenoceptor blocking agents (β-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant β-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (β1HAR), but cause cardiostimulation mainly through a low-affinity site (β1LAR) of the myocardial β1-adrenoceptor. The experimental non-conventional partial agonist (−)-CGP12177 increases cardiac L-type Ca2+ current density and Ca2+ transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca2+ transients and arrhythmic cardiocyte contractions. Other β-blockers, which do not cause cardiostimulation, consistently have lower affinity for β1LAR than β1HAR. These sites were verified and the cardiac pharmacology of non-conventional partial agonists confirmed on recombinant β1-adrenoceptors and on β1-adrenoceptors overexpressed into the heart. A targeted mutation of Asp138 to Glu138 virtually abolished the pharmacology of β1HAR but left intact the pharmacology of β1LAR. Non-conventional partial agonists may be beneficial for the treatment of peripheral autonomic neuropathy but probably due to their arrhythmic propensities, may be harmful for the treatment of chronic heart failure.

Waist circumference cut-off values for the prediction of cardiovascular risk factors clustering in Chinese school-aged children : a cross-sectional study

Background: Waist circumference has been identified as a valuable predictor of cardiovascular risk in children. The development of waist circumference percentiles and cut-offs for various ethnic groups are necessary because of differences in body composition. The purpose of this study was to develop waist circumference percentiles for Chinese children and to explore optimal waist circumference cut-off values for predicting cardiovascular risk factors clustering in this population.----- ----- Methods: Height, weight, and waist circumference were measured in 5529 children (2830 boys and 2699 girls) aged 6-12 years randomly selected from southern and northern China. Blood pressure, fasting triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and glucose were obtained in a subsample (n = 1845). Smoothed percentile curves were produced using the LMS method. Receiver-operating characteristic analysis was used to derive the optimal age- and gender-specific waist circumference thresholds for predicting the clustering of cardiovascular risk factors.----- ----- Results: Gender-specific waist circumference percentiles were constructed. The waist circumference thresholds were at the 90th and 84th percentiles for Chinese boys and girls respectively, with sensitivity and specificity ranging from 67% to 83%. The odds ratio of a clustering of cardiovascular risk factors among boys and girls with a higher value than cut-off points was 10.349 (95% confidence interval 4.466 to 23.979) and 8.084 (95% confidence interval 3.147 to 20.767) compared with their counterparts.----- ----- Conclusions: Percentile curves for waist circumference of Chinese children are provided. The cut-off point for waist circumference to predict cardiovascular risk factors clustering is at the 90th and 84th percentiles for Chinese boys and girls, respectively.

Time course of temperature effects on cardiovascular mortality in Brisbane, Australia

Objective To quantify the lagged effects of mean temperature on deaths from cardiovascular diseases in Brisbane, Australia. Design Polynomial distributed lag models were used to assess the percentage increase in mortality up to 30 days associated with an increase (or decrease) of 1°C above (or below) the threshold temperature. Setting Brisbane, Australia. Patients 22 805 cardiovascular deaths registered between 1996 and 2004. Main outcome measures Deaths from cardiovascular diseases. Results The results show a longer lagged effect in cold days and a shorter lagged effect in hot days. For the hot effect, a statistically significant association was observed only for lag 0–1 days. The percentage increase in mortality was found to be 3.7% (95% CI 0.4% to 7.1%) for people aged ≥65 years and 3.5% (95% CI 0.4% to 6.7%) for all ages associated with an increase of 1°C above the threshold temperature of 24°C. For the cold effect, a significant effect of temperature was found for 10–15 lag days. The percentage estimates for older people and all ages were 3.1% (95% CI 0.7% to 5.7%) and 2.8% (95% CI 0.5% to 5.1%), respectively, with a decrease of 1°C below the threshold temperature of 24°C. Conclusions The lagged effects lasted longer for cold temperatures but were apparently shorter for hot temperatures. There was no substantial difference in the lag effect of temperature on mortality between all ages and those aged ≥65 years in Brisbane, Australia.

Edaravone containing isoindoline nitroxides for the potential treatment of cardiovascular ischaemia

A novel antioxidant for the potential treatment of ischaemia was designed by incorporating an isoindoline nitroxide into the framework of the free radical scavenger edaravone. 5-(3-Methyl-pyrazol-5-ol-1-yl)-1,1,3,3-tetramethylisoindolin-2-yloxyl 7 was prepared by N-arylation of 3-methyl-5-pyrazolone with 5-iodo-1,1,3,3-tetramethylisoindoline-2-yloxyl 8 in the presence of catalytic copper(I)iodide. Evaluation of 7, its methoxyamine derivative 10 and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) against edaravone 1 in ischaemic rat atrial cardiomyocytes revealed significant decreases in cell death after prolonged ischaemia for each agent; however the protective effect of the novel antioxidant 7 (showing greater than 85% reduction in cell death at 100 μM) was significantly enhanced over that of edaravone 1 alone. Furthermore, the activity for 7 was found to be equal to or greater than the potent cardioprotective agent N6-cyclopentyladenosine (CPA). The methoxyamine adduct 10 and edaravone 1 showed no difference between the extent of reduction in cell death whilst CTMIO had only a modest protective effect.

Quantitative approaches to content analysis : identifying conceptual drift across publication outlets

Unstructured text data, such as emails, blogs, contracts, academic publications, organizational documents, transcribed interviews, and even tweets, are important sources of data in Information Systems research. Various forms of qualitative analysis of the content of these data exist and have revealed important insights. Yet, to date, these analyses have been hampered by limitations of human coding of large data sets, and by bias due to human interpretation. In this paper, we compare and combine two quantitative analysis techniques to demonstrate the capabilities of computational analysis for content analysis of unstructured text. Specifically, we seek to demonstrate how two quantitative analytic methods, viz., Latent Semantic Analysis and data mining, can aid researchers in revealing core content topic areas in large (or small) data sets, and in visualizing how these concepts evolve, migrate, converge or diverge over time. We exemplify the complementary application of these techniques through an examination of a 25-year sample of abstracts from selected journals in Information Systems, Management, and Accounting disciplines. Through this work, we explore the capabilities of two computational techniques, and show how these techniques can be used to gather insights from a large corpus of unstructured text.

Controlled drift: an investigation into the controllability of underwater vehicles with minimal actuation

This paper is directed towards providing an answer to the question, ”Can you control the trajectory of a Lagrangian float?” Being a float that has minimal actuation (only buoyancy control), their horizontal trajectory is dictated through drifting with ocean currents. However, with the appropriate vertical actuation and utilising spatio-temporal variations in water speed and direction, we show here that broad controllabilty results can be met such as waypoint following to keep a float inside of a bay or out of a designated region. This paper extends theory experimen- tally evaluted on horizontally actuated Autonomous Underwater Vehicles (AUVs) for trajectory control utilising ocean forecast models and presents an initial investi- gation into the controllability of these minimally actuated drifting AUVs. Simulated results for offshore coastal and within highly dynamic tidal bays illustrate two tech- niques with the promise for an affirmative answer to the posed question above.

Cardiac ARIA Index: Measuring Accessibility to Cardiovascular Services in Rural and Remote Australia via Applied Geographic Spatial Technology

Cardiovascular disease (CVD) continues to impose a heavy burden in terms of cost, disability and death in Australia. Evidence suggests that increasing remoteness, where cardiac services are scarce, is linked to an increased risk of dying from CVD. Fatal CVD events are reported to be between 20% and 50% higher in rural areas compared to major cities. The Cardiac ARIA project, with its extensive use of geographic Information Systems (GIS), ranks each of Australia’s 20,387 urban, rural and remote population centres by accessibility to essential services or resources for the management of a cardiac event. This unique, innovative and highly collaborative project delivers a powerful tool to highlight and combat the burden imposed by cardiovascular disease (CVD) in Australia. Cardiac ARIA is innovative. It is a model that could be applied internationally and to other acute and chronic conditions such as mental health, midwifery, cancer, respiratory, diabetes and burns services. Cardiac ARIA was designed to: 1. Determine by expert panel, what were the minimal services and resources required for the management of a cardiac event in any urban, rural or remote population locations in Australia using a single patient pathway to access care. 2. Derive a classification using GIS accessibility modelling for each of Australia’s 20,387 urban, rural and remote population locations. 3. Compare the Cardiac ARIA categories and population locations with census derived population characteristics. Key findings are as follows: • In the event of a cardiac emergency, the majority of Australians had very good access to cardiac services. Approximately 71% or 13.9 million people lived within one hour of a category one hospital. • 68% of older Australians lived within one hour of a category one hospital (Principal Referral Hospital with access to Cardiac Catheterisation). • Only 40% of indigenous people lived within one hour of the category one hospital. • 16% (74000) of indigenous people lived more than one hour from a hospital. • 3% (91,000) of people 65 years of age or older lived more than one hour from any hospital or clinic. • Approximately 96%, or 19 million, of people lived within one hour of the four key services to support cardiac rehabilitation and secondary prevention. • 75% of indigenous people lived within one hour of the four cardiac rehabilitation services to support cardiac rehabilitation and secondary prevention. Fourteen percent (64,000 persons) indigenous people had poor access to the four key services to support cardiac rehabilitation and secondary prevention. • 12% (56,000) of indigenous people were more than one hour from a hospital and only had access one the four key services (usually a medical service) to support cardiac rehabilitation and secondary prevention.