Exploring the parameter space of a rabbit ventricular action potential model to investigate the effect of variation on action potential and calcium transients

Computational models for cardiomyocyte action potentials (AP) often make use of a large parameter set. This parameter set can contain some elements that are fitted to experimental data independently of any other element, some elements that are derived concurrently with other elements to match experimental data, and some elements that are derived purely from phenomenological fitting to produce the desired AP output. Furthermore, models can make use of several different data sets, not always derived for the same conditions or even the same species. It is consequently uncertain whether the parameter set for a given model is physiologically accurate. Furthermore, it is only recently that the possibility of degeneracy in parameter values in producing a given simulation output has started to be addressed. In this study, we examine the effects of varying two parameters (the L-type calcium current (I(CaL)) and the delayed rectifier potassium current (I(Ks))) in a computational model of a rabbit ventricular cardiomyocyte AP on both the membrane potential (V(m)) and calcium (Ca(2+)) transient. It will subsequently be determined if there is degeneracy in this model to these parameter values, which will have important implications on the stability of these models to cell-to-cell parameter variation, and also whether the current methodology for generating parameter values is flawed. The accuracy of AP duration (APD) as an indicator of AP shape will also be assessed.

Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker.

BACKGROUND: Although we know much about the molecular makeup of the sinus node (SN) in small mammals, little is known about it in humans. The aims of the present study were to investigate the expression of ion channels in the human SN and to use the data to predict electrical activity. METHODS AND RESULTS: Quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence were used to analyze 6 human tissue samples. Messenger RNA (mRNA) for 120 ion channels (and some related proteins) was measured in the SN, a novel paranodal area, and the right atrium (RA). The results showed, for example, that in the SN compared with the RA, there was a lower expression of Na(v)1.5, K(v)4.3, K(v)1.5, ERG, K(ir)2.1, K(ir)6.2, RyR2, SERCA2a, Cx40, and Cx43 mRNAs but a higher expression of Ca(v)1.3, Ca(v)3.1, HCN1, and HCN4 mRNAs. The expression pattern of many ion channels in the paranodal area was intermediate between that of the SN and RA; however, compared with the SN and RA, the paranodal area showed greater expression of K(v)4.2, K(ir)6.1, TASK1, SK2, and MiRP2. Expression of ion channel proteins was in agreement with expression of the corresponding mRNAs. The levels of mRNA in the SN, as a percentage of those in the RA, were used to estimate conductances of key ionic currents as a percentage of those in a mathematical model of human atrial action potential. The resulting SN model successfully produced pacemaking. CONCLUSIONS: Ion channels show a complex and heterogeneous pattern of expression in the SN, paranodal area, and RA in humans, and the expression pattern is appropriate to explain pacemaking.

Bayesian mixtures for modelling complex medical data : a case study in Parkinson’s disease

Mixture models are a flexible tool for unsupervised clustering that have found popularity in a vast array of research areas. In studies of medicine, the use of mixtures holds the potential to greatly enhance our understanding of patient responses through the identification of clinically meaningful clusters that, given the complexity of many data sources, may otherwise by intangible. Furthermore, when developed in the Bayesian framework, mixture models provide a natural means for capturing and propagating uncertainty in different aspects of a clustering solution, arguably resulting in richer analyses of the population under study. This thesis aims to investigate the use of Bayesian mixture models in analysing varied and detailed sources of patient information collected in the study of complex disease. The first aim of this thesis is to showcase the flexibility of mixture models in modelling markedly different types of data. In particular, we examine three common variants on the mixture model, namely, finite mixtures, Dirichlet Process mixtures and hidden Markov models. Beyond the development and application of these models to different sources of data, this thesis also focuses on modelling different aspects relating to uncertainty in clustering. Examples of clustering uncertainty considered are uncertainty in a patient’s true cluster membership and accounting for uncertainty in the true number of clusters present. Finally, this thesis aims to address and propose solutions to the task of comparing clustering solutions, whether this be comparing patients or observations assigned to different subgroups or comparing clustering solutions over multiple datasets. To address these aims, we consider a case study in Parkinson’s disease (PD), a complex and commonly diagnosed neurodegenerative disorder. In particular, two commonly collected sources of patient information are considered. The first source of data are on symptoms associated with PD, recorded using the Unified Parkinson’s Disease Rating Scale (UPDRS) and constitutes the first half of this thesis. The second half of this thesis is dedicated to the analysis of microelectrode recordings collected during Deep Brain Stimulation (DBS), a popular palliative treatment for advanced PD. Analysis of this second source of data centers on the problems of unsupervised detection and sorting of action potentials or "spikes" in recordings of multiple cell activity, providing valuable information on real time neural activity in the brain.

Drugs for cardiac arrhythmmias, antithrombotic drugs and lipid modulating drugs

13.1 Drugs for cardiac arrhythmias 13.1.1 Introduction to cardiac arrhythmias 13.1.2 Cardiac action potentials 13.1.3 Mechanisms of cardiac arrhythmias 13.1.3 Class I 13.1.4 Class II 13.1.5 Class III 12.1.6 Class IV 13.1.7 Amiodarone 13.1.8 Adenosine 13.2 Antithrombotic drugs 13.2.1 Thrombus formation 13.2.2 Platelet aggregation and anti-platelet drugs 13.2.3 Coagulation 13.2.4 Anticoagulants 13.2.5 Fibrinolysis and fibrinolytics 13.3. Lipid modulating drugs 13.3.1 Cholesterol 13.3.2 Statins 13.3.3 Fibric acid derivatives 13.3.4 Ezetimibe

Rodent Scope: A User-Configurable Digital Wireless Telemetry System for Freely Behaving Animals

This paper describes the design and implementation of a wireless neural telemetry system that enables new experimental paradigms, such as neural recordings during rodent navigation in large outdoor environments. RoSco, short for Rodent Scope, is a small lightweight user-configurable module suitable for digital wireless recording from freely behaving small animals. Due to the digital transmission technology, RoSco has advantages over most other wireless modules of noise immunity and online user-configurable settings. RoSco digitally transmits entire neural waveforms for 14 of 16 channels at 20 kHz with 8-bit encoding which are streamed to the PC as standard USB audio packets. Up to 31 RoSco wireless modules can coexist in the same environment on non-overlapping independent channels. The design has spatial diversity reception via two antennas, which makes wireless communication resilient to fading and obstacles. In comparison with most existing wireless systems, this system has online user-selectable independent gain control of each channel in 8 factors from 500 to 32,000 times, two selectable ground references from a subset of channels, selectable channel grounding to disable noisy electrodes, and selectable bandwidth suitable for action potentials (300 Hz–3 kHz) and low frequency field potentials (4 Hz–3 kHz). Indoor and outdoor recordings taken from freely behaving rodents are shown to be comparable to a commercial wired system in sorting for neural populations. The module has low input referred noise, battery life of 1.5 hours and transmission losses of 0.1% up to a range of 10 m.

Learning, evaluation, action and reflection for new technologies, empowerment and rural sustainability (The LEARNERS project)

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Developing a participatory impact assessment approach and action research culture within a communication for social change organisation in Nepal

Developing an effective impact evaluation framework, managing and conducting rigorous impact evaluations, and developing a strong research and evaluation culture within development communication organisations presents many challenges. This is especially so when both the community and organisational context is continually changing and the outcomes of programs are complex and difficult to clearly identify.----- This paper presents a case study from a research project being conducted from 2007-2010 that aims to address these challenges and issues, entitled Assessing Communication for Social Change: A New Agenda in Impact Assessment. Building on previous development communication projects which used ethnographic action research, this project is developing, trailing and rigorously evaluating a participatory impact assessment methodology for assessing the social change impacts of community radio programs in Nepal. This project is a collaboration between Equal Access – Nepal (EAN), Equal Access – International, local stakeholders and listeners, a network of trained community researchers, and a research team from two Australian universities. A key element of the project is the establishment of an organisational culture within EAN that values and supports the impact assessment process being developed, which is based on continuous action learning and improvement. The paper describes the situation related to monitoring and evaluation (M&E) and impact assessment before the project began, in which EAN was often reliant on time-bound studies and ‘success stories’ derived from listener letters and feedback. We then outline the various strategies used in an effort to develop stronger and more effective impact assessment and M&E systems, and the gradual changes that have occurred to date. These changes include a greater understanding of the value of adopting a participatory, holistic, evidence-based approach to impact assessment. We also critically review the many challenges experienced in this process, including:----- • Tension between the pressure from donors to ‘prove’ impacts and the adoption of a bottom-up, participatory approach based on ‘improving’ programs in ways that meet community needs and aspirations.----- • Resistance from the content teams to changing their existing M&E practices and to the perceived complexity of the approach.----- • Lack of meaningful connection between the M&E and content teams.----- • Human resource problems and lack of capacity in analysing qualitative data and reporting results.----- • The contextual challenges, including extreme poverty, wide cultural and linguistic diversity, poor transport and communications infrastructure, and political instability.----- • A general lack of acceptance of the importance of evaluation within Nepal due to accepting everything as fate or ‘natural’ rather than requiring investigation into a problem.

Review article : ecological approach in studying the relation of perception-action : review of the theoretical and empirical data

In daily activities people are using a number of available means for the achievement of balance, such as the use of hands and the co-ordination of balance. One of the approaches that explains this relationship between perception and action is the ecological theory that is based on the work of a) Bernstein (1967), who imposed the problem of ‘the degrees of freedom’, b) Gibson (1979), who referred to the theory of perception and the way which the information is received from the environment in order for a certain movement to be achieved, c) Newell (1986), who proposed that movement can derive from the interaction of the constraints that imposed from the environment and the organism and d) Kugler, Kelso and Turvey (1982), who showed the way which “the degrees of freedom” are connected and interact. According to the above mentioned theories, the development of movement co-ordination can result from the different constraints that imposed into the organism-environment system. The close relation between the environmental and organismic constraints, as well as their interaction is responsible for the movement system that will be activated. These constraints apart from shaping the co-ordination of specific movements can be a rate limiting factor, to a certain degree, in the acquisition and mastering of a new skill. This frame of work can be an essential tool for the study of catching an object (e.g., a ball). The importance of this study becomes obvious due to the fact that movements that involved in catching an object are representative of every day actions and characteristic of the interaction between perception and action.

Consumers' emotional appraisals and action tendencies arising from mobile viral marketing

This study examines consumers' emotional responses to receiving viral mobile marketing communications in comparison to receiving mobile marketing communications where permission has not been given. The study also examines the relationship between these experienced emotions and what action tendencies consumers might consider as a result of these emotions, as well as how they attribute causality for their emotions. Using scenarios in an experimental design, the findings show that there are differences in consumer emotions as a result of the two marketing approaches. The findings also identify relationships between consumers' causal attributions and action tendencies in relation to themselves, the friend sending the viral m-marketing communication and the company involved.

Kids, counsellors and troubles-telling : morality-in-action in talk on an Australian children’s helpline

This chapter investigates one instance of ‘morality-in-action’, which transpires when children describe their troubles to the adult counsellors at Kids Help Line, an Australian national helpline that deals specifically with callers aged approximately 5-18 years. We focus, in particular, on how a young female caller who has forged a medical certificate in relation to a problem with school attendance, determines both what to report, and how this should be disclosed. Throughout the call, the moral implications of the troubles talk are delicately managed by both caller and counsellor. The call takes the form of an extended story (Labov & Waletzky, 1997) that includes a preface (‘I have some problems at school’), an orientation (“I was sick, went to the doctor, stayed home”), a complicating action (“I went back to school and photocopied my certificate from last time”), result (“I got caught”) and evaluation (“I don’t know why it happened”). As the account unfolds, we observe how both the student and counsellor seek to make sense of these actions. While this account is partly about deception, both the caller and counsellor delicately sidestep naming this action, precluding this implication. For example, the counsellor lets stand the caller’s main assessment of the trouble. He simply asks, “so what happened then,” when the caller reports that her forgery was discovered. The caller, from the very beginning of the call, seeks to find out why she could have done this, “you see I don’t know why it happened”. As the call unfolds, the counsellor follows the opening provided by the caller and they put forward motives for consideration. By agreeing that the motives are to be explored, the act takes on a character other than deception.

Facilities management action agenda : the Australian government and industry working together for improvement

This paper provides an overview of the Australian Government’s Facilities Management (FM) Action Agenda as announced in 2004 as a key policy plank designed to facilitate growth of the FM industry. The resulting consultation with industry leaders has seen the criterion and release in April 2005 of the FM Action Agenda’s strategic plan entitled ‘Managing the Built Environment’. This framework, representing a collaboration between the Australian Government, public and private sector stakeholders and Facility Management Association of Australia (FMA Australia) and other allied bodies, sets out to achieve the vision of a more “…productive and sustainable built environment…” through improved innovation, education and standards. The 36 month implementation phase is now underway and will take a multi-pronged approach to enhancing the recognition of the FM industry and removing impediments to its growth with a 20 point action plan across the following platforms: • Innovation – Improved appreciation of facility life cycles, and greater understanding of the key drivers of workplace productivity, and the improved application of information technology. • Education and Training – Improved access to dedicated FM education and training opportunities and creation clear career pathways into the profession. • Regulatory Reform – Explore opportunities to harmonise cross jurisdictional regulatory compliance requirements that have an efficiency impact on FM. • Sustainability – Improved utilization of existing knowledge and the development of tools and opportunities to improve the environmental performance of facilities. Additional information is available at www.fma.com.au