Neuropathic pain is a complex clinical syndrome characterized by increased sensitivity to thermal and/or mechanical stimuli that may or may not be accompanied by the phenomenon of spontaneous or aberrant pain sensations. <p>Over the past decade, the mechanisms underlying the behavioral manifestations of inflammatory neuropathic pain have become more clearly elucidated. These include the involvement of: 1) transient receptor potential vanilloid receptor 1 (TRPV1) in the generation of thermal hyperalgesia; 2) acid sensing ion channel 3 (ASIC3) in some aspects of the development/maintenance of mechanical hypersensitivity; 3) the tetrodotoxin resistant sodium channels Nav1.8 and Nav1.9 in both hyperalgesia and spontaneous pain; and 4) activation of the MAP Kinases p38 and ERK1/2 in the regulation of expression of the aforementioned molecules.<p>Interestingly, it is the pro-inflammatory neurotrophin nerve growth factor (NGF) that is the common link between all of these mediators of neuropathic pain. Increased availability of NGF under conditions of inflammation has been shown to drive increased expression/upregulation of TRPV1, ASIC3, Nav1.8 and Nav1.9, as well as phospho-p38 and phospho-ERK1/2.<p>Evidence presented here continues to support a role for neurotrophin-3 (NT-3) in antagonizing the effects of increased NGF on trkA signaling, neuropathic pain behaviors and some of the molecules associated with the generation of such behaviors.<p>More specifically, the work culminating in this thesis demonstrates a novel role for NT-3 in negative modulation of TRPV1, ASIC3, Nav1.8 and Nav1.9, as well as phospho-p38 expression in response to the chronic constriction injury model of neuropathic pain. Finally, initial insights into how this negative regulation of these nociceptive markers might occur is elucidated in studies demonstrating that NT-3 differentially affects levels of the key signaling molecule phospho-ERK in trkA-positive versus trkC-positive neurons in naïve dorsal root ganglia (DRG).

Mutations of the α1A subunit of CaV 2.1 voltage gated calcium (VGCC) channels are responsible for several inherited disorders affecting humans, including familial hemiplegic migraine, episodic ataxia type and spinocerebellar ataxia type. The leaner mouse also carries an autosomal recessive mutation in the α1A subunit of CaV 2.1 VGCCs, which, in the homozygous condition, results in a severe cerebellar atrophy and ataxia. The leaner mutation results in reduced calcium influx through CaV 2.1 VGCCs. To better understand cerebellar neurodegeneration and cerebellar dysfunction we focused our research on elucidating the relationship between mitochondrial function/dysfunction and calcium channel mutations. The aims of this dissertation were: 1) to estimate the extent of neuronal cell death, basal intracellular calcium and mitochondrial (dys)function in cerebellar granule cells (CGC) of adult leaner mice; 2) to analyze the role of the leaner calcium channel mutation on postnatal development of CGCs; and 3) to test whether inducing increased calcium influx by exposing cultured granule cells to potassium chloride can eliminate or reduce the CGC death. By using mechanism independent Fluoro-Jade staining and apoptosis specific TUNEL staining, we demonstrated that leaner CGC death continues into adulthood and the spatial pattern of granule cell death observed during postnatal development also continues into adulthood. The present investigation showed a reduced resting intracellular calcium in CGC from leaner mice as compared to age matched wild type mice, and tottering mice. The tottering mouse is another mutant mouse that carries a mutation in the α1A subunit of CaV 2.1 VGCCs like leaner mouse. However, these mice do not show any neurodegeneration and therefore they were used as a second control. Our results also showed that even though CGC of leaner mice have dysfunctional CaV2.1 channels, there is no change in depolarization induced Ca2+ influx, which suggests a functional compensation for CaV2.1 calcium channels by other VGCCs. Our results showed reduced mitochondrial membrane potential at the time of peak CGC death in leaner mice as compared to wild type CGCs and tottering CGCs. The results of this investigation suggest mitochondrial mediated but reactive oxygen species independent cell death in CGCs of leaner mice.

Thesis (M.A.)--University of Oregon, 2000. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 354-373). Also available for download via the World Wide Web; free to University of Oregon users.

Thesis (Ph. D.)--University of Virginia, 2001. / Includes bibliographical references (leaves 144-167). Also available online through Digital Dissertations.

Thesis (doctoral)--Reale Accademia di Scienze e Belle Lettere di Mantova, 1784. / Attributed to Antonio Ludeña. Signatures: a-c⁸ d³.

Thesis (M.B.A.)--University of Hong Kong, 1989.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

This study had three primary aims. Firstly, to establish the flow resistance characteristics of meandering channels in flood with different inner channel sinuosities and morphology. Secondly, to gain a better understanding of the coherent flow structures and energy loss mechanisms present within such flows. Third, to establish a link between the identified energy loss mechanisms and the flow resistance behaviour of channels with different geometry. The study begins with a review of current literature appertaining to three flow systems. These were; Inbank flow through meandering channels, overbank flow through channels comprising a straight channel with straight parallel floodplains, and meandering channels with floodplain flow. The available literature with regards to flooded meandering channels was limited to a handful of studies. It was clear there existed a deficiency in stage-discharge data over a range of inner channel sinuosities, and the flow descriptions given were limited to inner channels of relatively low sinuosity i.e. 1.25 - 1.3, rectangular or trapezoidal cross-section and unrealistically low width to depth (aspect) ratio. In addition, the influence of roughened floodplains also required further study. To address these needs, a small-scale laboratory investigation was undertaken at Aberdeen, together with a large-scale collaborative experimental study centred at the SERC Flood Channel Facility. These two experimental studies, in which two inner channels of sinuosity 1.4 and 2 were investigated in detail, are described. The experimental techniques and data collection procedures used are also described. The data types collected include: stage- discharge data, flow visualisation, flow velocity measurement, water surface profiles and bed shear stress analysis using an erodible bed. The stage-discharge data were used for the following; to establish the relationship between inner channel sinuosity and overall channel flow resistance; to establish the effect of inner channel morphology on overall channel resistance: and to assess the implications of roughened floodplains on resistance behaviour. The analysis of these data, together with existing related overbank data, yielded a number of conclusions; i). Overall flow resistance increases as inner channel sinuosity increases, ii). At deep floodplain flows, a floodplain comprising a trapezoidal inner channel was less efficient than one comprising a smaller natural inner channel, iii). Roughening the floodplains has a significant effect on channel resistance characteristics. The flow description data, of overbank flow, revealed the presence of coherent flow structures in flows over inner channels of sinuosity 1.4 and 2, and at a number of flow depths. It is suggested these coherent flow structures are a source of additional energy loss, and a link is proposed between the vigour and frequency of these structures for several flow conditions and channel geometries, and the overall resistance behaviour. Contour maps of water surface elevation are presented for several flow conditions and channel geometries. An increase in surface relief was observed as floodplain depth, and therefore velocity, increased. These maps and earlier related work were then discussed. Plots of near bed velocities, secondary circulation patterns and erodible bed observations strongly indicated a change in sediment erosion and deposition patterns, and thus a change in inner channel morphology during overbank flow. Implications of this change are proposed and discussed. Finally, suggestions for future work are presented. with particular emphasis on a 3-dimensional numerical model presently under development at the University of Aberdeen.

Graduate

Multiple-Input Multiple-Output (MIMO) systems have gained an enormous amount of attention as one of the most promising research areas in wireless communications. However, while MIMO systems have been extensively explored over the past decade, few schemes acknowledge the nonlinearity caused by the use of high power amplifiers (HPAs) in the communication chain. When HPAs operate near their saturation points, nonlinear distortions are introduced in the transmitted signals, and the resulting MIMO channel will be nonlinear. The nonlinear distortion is further exacerbated by the fading caused by the propagation channel. The goal of this thesis is: 1) to use neural networks (NNs) to model and identify nonlinear MIMO channels; and 2) to employ the proposed NN model in designing efficient detection techniques for these types of MIMO channels. In the first part of the thesis, we follow a previous work on modeling and identification of nonlinear MIMO channels, where it has been shown that a proposed block-oriented NN scheme allows not only good identification of the overall MIMO input-output transfer function but also good characterization of each component of the system. The proposed scheme employs an ordinary gradient descent based algorithm to update the NN weights during the learning process and it assumes only real-valued inputs. In this thesis, natural gradient (NG) descent is used for training the NN. Moreover, we derive an improved variation of the previously proposed NN scheme to avoid the input type restriction and allow for complex modulated inputs as well. We also investigate the scheme tracking capabilities of time-varying nonlinear MIMO channels. Simulation results show that NG descent learning significantly outperforms the ordinary gradient descent in terms of convergence speed, mean squared error (MSE) performance, and nonlinearity approximation. Moreover, the NG descent based NN provides better tracking capabilities than the previously proposed NN. The second part of the thesis focuses on signal detection. We propose a receiver that employs the neural network channel estimator (NNCE) proposed in part one, and uses the Zero-Forcing Vertical Bell Laboratories Layered Space-Time (ZF V-BLAST) detection algorithm to retrieve the transmitted signals. Computer simulations show that in slow time-varying environments the performance of our receiver is close to the ideal V-BLAST receiver in which the channel is perfectly known. We also present a NN based linearization technique for HPAs, which takes advantage of the channel information provided by the NNCE. Such linearization technique can be used for adaptive data predistortion at the transmitter side or adaptive nonlinear equalization at the receiver side. Simulation results show that, when higher modulation schemes (>16-QAM) are used, the nonlinear distortion caused by the use of HPAs is greatly minimized by our proposed NN predistorter and the performance of the communication system is significantly improved. / Thesis (Master, Electrical & Computer Engineering) -- Queen's University, 2007-08-08 14:55:50.489