Effect of the intracellular calcium concentration chelator BAPTA acetoxy-methylester on action potential duration in canine ventricular myocytes

Intracellular calcium concentration ([Ca(2+)]i) is often buffered by using the cell-permeant acetoxy-methylester form of the Ca(2+) chelator BAPTA (BAPTA-AM) under experimental conditions. This study was designed to investigate the time-dependent actions of extracellularly applied BAPTA-AM on action potential duration (APD) in cardiac cells. Action potentials were recorded from enzymatically isolated canine ventricular myocytes with conventional sharp microelectrodes. The effect of BAPTA-AM on the rapid delayed rectifier K(+) current (IKr) was studied using conventional voltage clamp and action potential voltage clamp techniques. APD was lengthened by 5 muM BAPTA-AM - but not by BAPTA - and shortened by the Ca(2+) ionophore A23187 in a time-dependent manner. The APD-lengthening effect of BAPTA-AM was strongly suppressed in the presence of nisoldipine, and enhanced in the presence of BAY K8644, suggesting that a shift in the [Ca(2+)]i-dependent inactivation of L-type Ca(2+) current may be an important underlying mechanism. However, in the presence of the IKr-blocker dofetilide or E-4031 APD was shortened rather than lengthened by BAPTA-AM. Similarly, the APD-lengthening effect of 100 nM dofetilide was halved by the pretreatment with BAPTA-AM. In line with these results, IKr was significantly reduced by extracellularly applied BAPTA-AM under both conventional voltage clamp and action potential voltage clamp conditions. This inhibition of IKr was partially reversible and was not related to the Ca(2+) chelator effect BAPTA-AM. The possible mechanisms involved in the APD-modifying effects of BAPTA-AM are discussed. It is concluded that BAPTA-AM has to be applied carefully to control [Ca(2+)]i in whole cell systems because of its direct inhibitory action on IKr

Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease

Mucopolysaccharidosis type II (MPS II) is a rare, life-limiting, X-linked recessive disease characterised by deficiency of the lysosomal enzyme iduronate-2-sulfatase. Consequent accumulation of glycosaminoglycans leads to pathological changes in multiple body systems. Age at onset, signs and symptoms, and disease progression are heterogeneous, and patients may present with many different manifestations to a wide range of specialists. Expertise in diagnosing and managing MPS II varies widely between countries, and substantial delays between disease onset and diagnosis can occur. In recent years, disease-specific treatments such as enzyme replacement therapy and stem cell transplantation have helped to address the underlying enzyme deficiency in patients with MPS II. However, the multisystem nature of this disorder and the irreversibility of some manifestations mean that most patients require substantial medical support from many different specialists, even if they are receiving treatment. This article presents an overview of how to recognise, diagnose, and care for patients with MPS II. Particular focus is given to the multidisciplinary nature of patient management, which requires input from paediatricians, specialist nurses, otorhinolaryngologists, orthopaedic surgeons, ophthalmologists, cardiologists, pneumologists, anaesthesiologists, neurologists, physiotherapists, occupational therapists, speech therapists, psychologists, social workers, homecare companies and patient societies. Take-home message. Expertise in recognising and treating patients with MPS II varies widely between countries. This article presents pan-European recommendations for the diagnosis and management of this life-limiting disease

GEO-6 assessment for the pan-European region

Through this assessment, the authors and the United Nations Environment Programme (UNEP) secretariat are providing an objective evaluation and analysis of the pan-European environment designed to support environmental decision-making at multiple scales. In this assessment, the judgement of experts is applied to existing knowledge to provide scientifically credible answers to policy-relevant questions. These questions include, but are not limited to the following:• What is happening to the environment in the pan-European region and why?• What are the consequences for the environment and the human population in the pan-European region?• What is being done and how effective is it?• What are the prospects for the environment in the future?• What actions could be taken to achieve a more sustainable future?<br/

The effect of K201 on the sarcoplasmic reticulum calcium release channel ryanodine receptor

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Exercise effects in a virtual type 1 diabetes patient: Using stochastic differential equations for model extension

Introduction: Individualized control therapies give better and better results in the artificial pancreas researches. However, due to neglected dynamics the robustness of the methodologies is still a challenge. The Hungarian Artificial Pancreas Working Group (MAP) investigates this problem from several years. On previous ATTD conferences a robust control algorithm based on the Sorensen-model and its validation results were presented.. Aim: The model-free property of the algorithm is investigated based on the Hovorka-model. Methods: The aforementioned two Type 1 diabetes model (T1DM) was used to generate the virtual patients. Their parameters were identified using data recorded of 203 weeks of 90 T1DM patients in clinical environment from the MAP’s insulin pump centers (aged 6-52 years). Results: Hypoglycaemia is efficiently avoided and hyperglycaemia is reduced more then 75% to the real datasets if parameter identification and the starting point of the algorithm is well determined. Hence, simulations were started 1-2 days before the start of the identification timeframe in order to minimize problems caused by initial states. However, this requires more apiori information from the patient side. Conclusions: Use of hard constraints proved their efficiency even in case of model-free investigations. However, a robust identification technique is required to support the proposed control algorithm. Despite the required improvements, preliminary results show that the methodology has the potential to globally handle patient groups and efficiently support individualized control (ex. MPC) protocols. Further steps: Fault detection analysis of different life situations (like stress, physical activity) is required together with a robust identification methodology