Anaesthetic impairment of immune function is mediated via GABA(A) receptors.

BACKGROUND: GABA(A) receptors are members of the Cys-loop family of neurotransmitter receptors, proteins which are responsible for fast synaptic transmission, and are the site of action of wide range of drugs. Recent work has shown that Cys-loop receptors are present on immune cells, but their physiological roles and the effects of drugs that modify their function in the innate immune system are currently unclear. We are interested in how and why anaesthetics increase infections in intensive care patients; a serious problem as more than 50% of patients with severe sepsis will die. As many anaesthetics act via GABA(A) receptors, the aim of this study was to determine if these receptors are present on immune cells, and could play a role in immunocompromising patients. PRINCIPAL FINDINGS: We demonstrate, using RT-PCR, that monocytes express GABA(A) receptors constructed of α1, α4, β2, γ1 and/or δ subunits. Whole cell patch clamp electrophysiological studies show that GABA can activate these receptors, resulting in the opening of a chloride-selective channel; activation is inhibited by the GABA(A) receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABA(A) receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin. SIGNIFICANCE: Our results show that functional GABA(A) receptors are present on monocytes with properties similar to CNS GABA(A) receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABA(A) receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABA(A) receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be advantageous where infection is a life threatening problem.

ROBOT DYNAMIC CONTROL INSTABILITIES.

The authors demonstrate that a widely proposed method of robot dynamic control can be inherently unstable, due to an algebraic feedback loop condition causing an ill-posed feedback system. By focussing on the concept of ill-posedness a necessary and sufficient condition is derived for instability in robot manipulator systems which incorporate online acceleration cross-coupling control. Also demonstrated is a quasilinear multivariable control framework useful for assessing the robustness of this type of control when the instability condition is not obeyed.

Demodulation as probabilistic inference

Demodulation is an ill-posed problem whenever both carrier and envelope signals are broadband and unknown. Here, we approach this problem using the methods of probabilistic inference. The new approach, called Probabilistic Amplitude Demodulation (PAD), is computationally challenging but improves on existing methods in a number of ways. By contrast to previous approaches to demodulation, it satisfies five key desiderata: PAD has soft constraints because it is probabilistic; PAD is able to automatically adjust to the signal because it learns parameters; PAD is user-steerable because the solution can be shaped by user-specific prior information; PAD is robust to broad-band noise because this is modeled explicitly; and PAD's solution is self-consistent, empirically satisfying a Carrier Identity property. Furthermore, the probabilistic view naturally encompasses noise and uncertainty, allowing PAD to cope with missing data and return error bars on carrier and envelope estimates. Finally, we show that when PAD is applied to a bandpass-filtered signal, the stop-band energy of the inferred carrier is minimal, making PAD well-suited to sub-band demodulation. © 2006 IEEE.

Application of the fixed point method for solution in time stepping finite element analysis using the inverse vector Jiles-Atherton model

An implementation of the inverse vector Jiles-Atherton model for the solution of non-linear hysteretic finite element problems is presented. The implementation applies the fixed point method with differential reluctivity values obtained from the Jiles-Atherton model. Differential reluctivities are usually computed using numerical differentiation, which is ill-posed and amplifies small perturbations causing large sudden increases or decreases of differential reluctivity values, which may cause numerical problems. A rule based algorithm for conditioning differential reluctivity values is presented. Unwanted perturbations on the computed differential reluctivity values are eliminated or reduced with the aim to guarantee convergence. Details of the algorithm are presented together with an evaluation of the algorithm by a numerical example. The algorithm is shown to guarantee convergence, although the rate of convergence depends on the choice of algorithm parameters. © 2011 IEEE.

Towards the development of an integrated design framework using the Blackboard model

Current research into the process of engineering design is extending the use of computers towards the acquisition, representation and application of design process knowledge in addition to the existing storage and manipulation of product-based models of design objects. This is a difficult task because the design of mechanical systems is a complex, often unpredictable process involving ill-structured problem solving skills and large amounts of knowledge, some which may be of an incomplete and subjective nature. Design problems require the integration of a variety of modes of working such as numerical, graphical, algorithmic or heuristic and demand products through synthesis, analysis and evaluation activities.

This report presents the results of a feasibility study into the blackboard approach and discusses the development of an initial prototype system that will enable an alphanumeric design dialogue between a designer and an expert to be analysed in a formal way, thus providing real-life protocol data on which to base the blackboard message structures.

Imaging the femoral cortex: thickness, density and mass from clinical CT.

There is growing evidence that focal thinning of cortical bone in the proximal femur may predispose a hip to fracture. Detecting such defects in clinical CT is challenging, since cortices may be significantly thinner than the imaging system's point spread function. We recently proposed a model-fitting technique to measure sub-millimetre cortices, an ill-posed problem which was regularized by assuming a specific, fixed value for the cortical density. In this paper, we develop the work further by proposing and evaluating a more rigorous method for estimating the constant cortical density, and extend the paradigm to encompass the mapping of cortical mass (mineral mg/cm(2)) in addition to thickness. Density, thickness and mass estimates are evaluated on sixteen cadaveric femurs, with high resolution measurements from a micro-CT scanner providing the gold standard. The results demonstrate robust, accurate measurement of peak cortical density and cortical mass. Cortical thickness errors are confined to regions of thin cortex and are bounded by the extent to which the local density deviates from the peak, averaging 20% for 0.5mm cortex.

Probabilistic amplitude and frequency demodulation

A number of recent scientific and engineering problems require signals to be decomposed into a product of a slowly varying positive envelope and a quickly varying carrier whose instantaneous frequency also varies slowly over time. Although signal processing provides algorithms for so-called amplitude-and frequency-demodulation (AFD), there are well known problems with all of the existing methods. Motivated by the fact that AFD is ill-posed, we approach the problem using probabilistic inference. The new approach, called probabilistic amplitude and frequency demodulation (PAFD), models instantaneous frequency using an auto-regressive generalization of the von Mises distribution, and the envelopes using Gaussian auto-regressive dynamics with a positivity constraint. A novel form of expectation propagation is used for inference. We demonstrate that although PAFD is computationally demanding, it outperforms previous approaches on synthetic and real signals in clean, noisy and missing data settings.

Imaging the femoral cortex: Thickness, density and mass from clinical CT

There is growing evidence that focal thinning of cortical bone in the proximal femur may predispose a hip to fracture. Detecting such defects in clinical CT is challenging, since cortices may be significantly thinner than the imaging system's point spread function. We recently proposed a model-fitting technique to measure sub-millimetre cortices, an ill-posed problem which was regularized by assuming a specific, fixed value for the cortical density. In this paper, we develop the work further by proposing and evaluating a more rigorous method for estimating the constant cortical density, and extend the paradigm to encompass the mapping of cortical mass (mineral mg/cm 2) in addition to thickness. Density, thickness and mass estimates are evaluated on sixteen cadaveric femurs, with high resolution measurements from a micro-CT scanner providing the gold standard. The results demonstrate robust, accurate measurement of peak cortical density and cortical mass. Cortical thickness errors are confined to regions of thin cortex and are bounded by the extent to which the local density deviates from the peak, averaging 20% for 0.5mm cortex. © 2012 Elsevier B.V.

Decomposing signals into a sum of amplitude and frequency modulated sinusoids using probabilistic inference

There are many methods for decomposing signals into a sum of amplitude and frequency modulated sinusoids. In this paper we take a new estimation based approach. Identifying the problem as ill-posed, we show how to regularize the solution by imposing soft constraints on the amplitude and phase variables of the sinusoids. Estimation proceeds using a version of Kalman smoothing. We evaluate the method on synthetic and natural, clean and noisy signals, showing that it outperforms previous decompositions, but at a higher computational cost. © 2012 IEEE.

Statistical inference for single- and multi-band probabilistic amplitude demodulation.

Amplitude demodulation is an ill-posed problem and so it is natural to treat it from a Bayesian viewpoint, inferring the most likely carrier and envelope under probabilistic constraints. One such treatment is Probabilistic Amplitude Demodulation (PAD), which, whilst computationally more intensive than traditional approaches, offers several advantages. Here we provide methods for estimating the uncertainty in the PAD-derived envelopes and carriers, and for learning free-parameters like the time-scale of the envelope. We show how the probabilistic approach can naturally handle noisy and missing data. Finally, we indicate how to extend the model to signals which contain multiple modulators and carriers.

Facets of prior experience and the effectiveness of inclusive design

Research in inclusive design has shown the importance of prior experience for the usability of interactive products. Prior experience, however, is an ill-defined and inconsistently used construct. A number of different definitions and operationalisations of experience exist, but the differing power of these operationalisations to predict the usability of products for older users has rarely been investigated systematically. This study seeks to fill that gap. It is argued that the construct of experience has at least three components. It is proposed that two of these components, exposure and competence, are directly relevant for the current discussion about prior experience in inclusive design and that they can predict to different degrees the usability of a product for older users. In an empirical study, these facets of expertise are each operationalised on three levels of specificity and their impact on usability is assessed. The results show that measures of competence predict usability variables more strongly than measures of exposure and that levels of medium and high specificity are the best predictors. The application of inclusive design principles to a redesigned version of a ticket vending machine-although not resulting in a difference of overall usability-changed the impact of prior experience on usability measures implying an enhanced inclusiveness of the redesign with regard to prior experience. The implications of these findings for the effectiveness of inclusive design for older users are discussed. © 2013 Springer-Verlag Berlin Heidelberg.

Reinforcement learning using a continuous time actor-critic framework with spiking neurons.

Animals repeat rewarded behaviors, but the physiological basis of reward-based learning has only been partially elucidated. On one hand, experimental evidence shows that the neuromodulator dopamine carries information about rewards and affects synaptic plasticity. On the other hand, the theory of reinforcement learning provides a framework for reward-based learning. Recent models of reward-modulated spike-timing-dependent plasticity have made first steps towards bridging the gap between the two approaches, but faced two problems. First, reinforcement learning is typically formulated in a discrete framework, ill-adapted to the description of natural situations. Second, biologically plausible models of reward-modulated spike-timing-dependent plasticity require precise calculation of the reward prediction error, yet it remains to be shown how this can be computed by neurons. Here we propose a solution to these problems by extending the continuous temporal difference (TD) learning of Doya (2000) to the case of spiking neurons in an actor-critic network operating in continuous time, and with continuous state and action representations. In our model, the critic learns to predict expected future rewards in real time. Its activity, together with actual rewards, conditions the delivery of a neuromodulatory TD signal to itself and to the actor, which is responsible for action choice. In simulations, we show that such an architecture can solve a Morris water-maze-like navigation task, in a number of trials consistent with reported animal performance. We also use our model to solve the acrobot and the cartpole problems, two complex motor control tasks. Our model provides a plausible way of computing reward prediction error in the brain. Moreover, the analytically derived learning rule is consistent with experimental evidence for dopamine-modulated spike-timing-dependent plasticity.

A PDE viewpoint on basic properties of coordination algorithms with symmetries

Several recent control applications consider the coordination of subsystems through local interaction. Often the interaction has a symmetry in state space, e.g. invariance with respect to a uniform translation of all subsystem values. The present paper shows that in presence of such symmetry, fundamental properties can be highlighted by viewing the distributed system as the discrete approximation of a partial differential equation. An important fact is that the symmetry on the state space differs from the popular spatial invariance property, which is not necessary for the present results. The relevance of the viewpoint is illustrated on two examples: (i) ill-conditioning of interaction matrices in coordination/consensus problems and (ii) the string instability issue. ©2009 IEEE.

Differential geometry and design coupling in MDO

The notion of coupling within a design, particularly within the context of Multidisciplinary Design Optimization (MDO), is much used but ill-defined. There are many different ways of measuring design coupling, but these measures vary in both their conceptions of what design coupling is and how such coupling may be calculated. Within the differential geometry framework which we have previously developed for MDO systems, we put forth our own design coupling metric for consideration. Our metric is not commensurate with similar types of coupling metrics, but we show that it both provides a helpful geo- metric interpretation of coupling (and uncoupledness in particular) and exhibits greater generality and potential for analysis than those similar metrics. Furthermore, we discuss how the metric might be profitably extended to time-varying problems and show how the metric's measure of coupling can be applied to multi-objective optimization problems (in unconstrained optimization and in MDO). © 2013 by the American Institute of Aeronautics and Astronautics, Inc. All rights reserved.