The development of calibration and adaptive filtering procedures for neuromagnetic studies of human visual function

This thesis first considers the calibration and signal processing requirements of a neuromagnetometer for the measurement of human visual function. Gradiometer calibration using straight wire grids is examined and optimal grid configurations determined, given realistic constructional tolerances. Simulations show that for gradiometer balance of 1:104 and wire spacing error of 0.25mm the achievable calibration accuracy of gain is 0.3%, of position is 0.3mm and of orientation is 0.6°. Practical results with a 19-channel 2nd-order gradiometer based system exceed this performance. The real-time application of adaptive reference noise cancellation filtering to running-average evoked response data is examined. In the steady state, the filter can be assumed to be driven by a non-stationary step input arising at epoch boundaries. Based on empirical measures of this driving step an optimal progression for the filter time constant is proposed which improves upon fixed time constant filter performance. The incorporation of the time-derivatives of the reference channels was found to improve the performance of the adaptive filtering algorithm by 15-20% for unaveraged data, falling to 5% with averaging. The thesis concludes with a neuromagnetic investigation of evoked cortical responses to chromatic and luminance grating stimuli. The global magnetic field power of evoked responses to the onset of sinusoidal gratings was shown to have distinct chromatic and luminance sensitive components. Analysis of the results, using a single equivalent current dipole model, shows that these components arise from activity within two distinct cortical locations. Co-registration of the resulting current source localisations with MRI shows a chromatically responsive area lying along the midline within the calcarine fissure, possibly extending onto the lingual and cuneal gyri. It is postulated that this area is the human homologue of the primate cortical area V4.

Scintillation proximity assays for the real-time detection and quantification of the progress of reactions upon solid supports

A scintillation proximity assay (SPA) has been used successfully to detect and quantify, in real-time, the kinetic progress of hydrolysis of [ H]acetate esters from scintillant-containing styrenic and poly(ethylene glycol) (PEG)-based polymer supports in both organic and aqueous media.

Respiratory function monitoring using a real-time three-dimensional fiber-optic shaping sensing scheme based upon fiber Bragg gratings

An array of in-line curvature sensors on a garment is used to monitor the thoracic and abdominal movements of a human during respiration. The results are used to obtain volumetric changes of the human torso in agreement with a spirometer used simultaneously at the mouth. The array of 40 in-line fiber Bragg gratings is used to produce 20 curvature sensors at different locations, each sensor consisting of two fiber Bragg gratings. The 20 curvature sensors and adjoining fiber are encapsulated into a low-temperature-cured synthetic silicone. The sensors are wavelength interrogated by a commercially available system from Moog Insensys, and the wavelength changes are calibrated to recover curvature. A three-dimensional algorithm is used to generate shape changes during respiration that allow the measurement of absolute volume changes at various sections of the torso. It is shown that the sensing scheme yields a volumetric error of 6%. Comparing the volume data obtained from the spirometer with the volume estimated with the synchronous data from the shape-sensing array yielded a correlation value 0.86 with a Pearson's correlation coefficient p <0.01.

Real-time 3D shape sensing and reconstruction scheme based upon fibre optic bragg gratings

An array of FBG curvature sensors are wavelength-interrogated and the recovered data combined with a three-dimensional algorithm to reconstruct in real time the enveloped object with a 1% to 9% volumetric error. © 2012 OSA.

Respiratory function monitoring using a real-time three-dimensional fiber-optic shaping sensing scheme based upon fiber Bragg gratings

An array of in-line curvature sensors on a garment is used to monitor the thoracic and abdominal movements of a human during respiration. The results are used to obtain volumetric changes of the human torso in agreement with a spirometer used simultaneously at the mouth. The array of 40 in-line fiber Bragg gratings is used to produce 20 curvature sensors at different locations, each sensor consisting of two fiber Bragg gratings. The 20 curvature sensors and adjoining fiber are encapsulated into a low-temperature-cured synthetic silicone. The sensors are wavelength interrogated by a commercially available system from Moog Insensys, and the wavelength changes are calibrated to recover curvature. A three-dimensional algorithm is used to generate shape changes during respiration that allow the measurement of absolute volume changes at various sections of the torso. It is shown that the sensing scheme yields a volumetric error of 6%. Comparing the volume data obtained from the spirometer with the volume estimated with the synchronous data from the shape-sensing array yielded a correlation value 0.86 with a Pearson's correlation coefficient p <0.01.

Direct inhibitory effects of an antisense oligodeoxynucleotide upon the volume-sensitive chloride current in rat osteoblast-like (ROS 17/2.8) cells

The effects of a 15-mer antisense c-myc phosphorothioate modified oligodeoxynucleotide (OdN) upon the volume-sensitive Cl- current in ROS 17/2.8 cells were investigated using the whole-cell configuration of the patch clamp technique. At 5 microM, the OdN reversibly inhibited the current in a voltage- and time-dependent fashion. This was evident from the reduction in the peak current as assessed at the termination of each voltage pulse and an acceleration of the time-dependent inactivation present at strongly depolarised potentials. The kinetic modifications induced by the OdN suggest it may act by blocking the pore of open channels when the cell membrane potential is depolarised.

Effects of arachidonic acid upon the volume-sensitive chloride current in rat osteoblast-like (ROS 17/2.8) cells.

1. The effects of arachidonic acid upon the volume-sensitive Cl- current present in cultured osteoblastic cells (ROS 17/2.8) was studied using the whole-cell patch-clamp technique. 2. Arachidonate produced two distinct phases of inhibition, a rapid phase occurring within 10-15 s of application preceding a slower phase that occurred 2 min after onset of arachidonate superfusion. Accompanying the slower inhibitory phase was an acceleration of the time-dependent inactivation exhibited by the current at strongly depolarized potentials (> + 50 mV). The half-maximal inhibitory concentrations (IC50) were 177 +/- 31 and 10 +/- 4 microM for the two phases respectively. 3. Arachidonate was still effective in the presence of inhibitors of cyclo-oxygenase (indomethacin, 10 microM), lipoxygenase (nordihydroguaretic acid, 10-100 microM) and cytochrome P450 (SKF525A, 100 microM; ethoxyresorufin, 10 microM; metyrapone, 500 microM; piperonyl butoxide, 500 microM; cimetidine, 1 mM). The effects of arachidonate could not be produced by another cis unsaturated fatty acid, oleic acid. 4. Measurements of cell volume showed that arachidonate effectively inhibited the regulatory volume decrease elicited by ROS 17/2.8 cells in response to a reduction in extracellular osmolarity. 5. It is concluded that the volume-sensitive Cl- conductance in ROS 17/2.8 cells is directly modulated by arachidonate and may represent a physiological mechanism by which volume regulation can be controlled in these cells.

Novel repair action of vitamin C upon in vivo oxidative DNA damage

There appears to be a paucity of data examining the effect of dietary antioxidants on levels of oxidative DNA damage in vivo, limiting evidence-based assessment of antioxidant efficacy, mechanisms and recommendation for optimal intake. We have examined levels of 8-oxo-2'-deoxyguanosine (8-oxodG) in mononuclear cell DNA, serum and urine from subjects undergoing supplementation with 500 mg/day vitamin C. Significant decreases in DNA levels of 8-oxodG were seen, correlating strongly with increases in plasma vitamin C concentration. Furthermore we established a timecourse for sequential, significant increases in serum and urinary 8-oxodG levels. These results illustrate, for the first time in humans, the kinetics of 8-oxodG removal and processing in vivo, suggesting a role for vitamin C in the regulation of DNA repair enzymes and thereby demonstrating a non-scavenging antioxidant effect.

The anti-inflammatory actions of methotrexate are critically dependent upon the production of reactive oxygen species

1. The mechanism of action by which methotrexate (MTX) exerts its anti-inflammatory and immunosuppressive effects remains unclear. The aim of this study is to investigate the hypothesis that MTX exerts these effects via the production of reactive oxygen species (ROS). 2. Addition of MTX (100 nM-10 μM) to U937 monocytes induced a time and dose dependent increase in cytosolic peroxide [peroxide] cyt from 6-16 h. MTX also caused corresponding monocyte growth arrest, which was inhibited (P<0.05) by pre-treatment with N-acetylcysteine (NAC; 10 mM) or glutathione (GSH; 10 mM). In contrast, MTX induction of [peroxide] cyt in Jurkat T cells was more rapid (4 h; P<0.05), but was associated with significant apoptosis at 16 h at all doses tested (P<0.05) and was significantly inhibited by NAC or GSH (P<0.05). 3. MTX treatment of monocytes (10 nM-10 μM) for 16 h significantly reduced total GSH levels (P<0.05) independently of dose (P>0.05). However in T-cells, GSH levels were significantly elevated following 30 nM MTX treatment (P<0.05) but reduced by doses exceeding 1 μM compared to controls (P<0.05). 4. MTX treatment significantly reduced monocyte adhesion to 5 h and 24 h LPS (1 μg ml -1) activated human umbilical vein endothelial cells (HUVEC; P<0.05) but not to resting HUVEC. Pre-treatment with GSH prevented MTX-induced reduction in adhesion. 5. In conclusion, ROS generation by MTX is important for cytostasis in monocytes and cytotoxicity T-cells. Furthermore, MTX caused a reduction in monocyte adhesion to endothelial cells, where the mechanism of MTX action requires the production of ROS. Therefore its clinical efficacy can be attributed to multiple targets.

Summary of the 10th International workshop on Models@run.time

The 10th anniversary of the workshop Models@run.time was held at the 18th International Conference on Model Driven Engineering Languages and Systems. The workshop took place in the city of Ottawa, Canada, on the 29th of September 2015. The workshop was organized by Sebastian Gtz, Nelly Bencomo, Gordon Blair and Hui Song. Here, we present a summary of the discussions at the workshop and a synopsis of the topics discussed and highlighted during the workshop. The workshop received the award for the best workshop at the MODELS 2015 conference out of 18 workshops in total. The award was based upon the organization, program, web site timing and the feedback provided by the workshop participants.

The Once and future pioneers? : the role of voluntary organizations in innovation in the personal social services

This thesis explores the innovative capacity of voluntary organizations in the field of the personal social services. It commences with a full literature review, which concludes that the wealth of research upon innovation in the organization studies field has not addressed this topic, whilst the specialist literatures upon voluntary organizations and upon the personal social services have neglected the study of innovation. The research contained in this thesis is intended to right this neglect and to integrate lessons from both fields. It combines a survey of the innovative activity of voluntary organizations in three localities with cross-sectional case studies of innovative, developmental and traditional organizations. The research concludes that innovation is an important, but not integral, characteristic of voluntary organizations. It develops a contingent model of this innovative capacity of voluntary organizations, which stresses the role of external environmental and institutional forces in shaping and releasing this capacity. It concludes by considering the contribution of this model both to organization studies and to the study of voluntary organizations.

The effects of varying forms and degrees of government intervention upon the effective competitiveness of UK small businesses

This doctoral thesis responds to the need for greater understanding of small businesses and their inherent unique problem-types. Integral to the investigation is the theme that for governments to effectively influence small business, a sound understanding of the factors they are seeking to influence is essential. Moreover, the study, in its recognition of the many shortcomings in management research and, in particular that the research methods and approaches adopted often fail to give adequate understanding of issues under study, attempts to develop an innovative and creative research approach. The aim thus being to produce, not only advances in small business management knowledge from the standpoints of government policy makers and `lq recipient small business, but also insights into future potential research method for the continued development of that knowledge. The origins of the methodology lay in the non-acceptance of traditional philosophical positions in epistemology and ontology, with a philosophical standpoint of internal realism underpinning the research. Internal realism presents the basis for the potential co-existence of qualitative and quantitative research strategy and underlines the crucial contributory role of research method in provision of ultimate factual status of the assertions of research findings. The concept of epistemological bootstrapping is thus used to develop a `lq partial research framework to foothold case study research, thereby avoiding limitations of objectivism and brute inductivism. The major insights and issues highlighted by the `lq bootstrap, guide the researcher around the participant case studies. A novel attempt at contextualist (linked multi-level and processual) analysis was attempted in the major in-depth case study, with two further cases playing a support role and contributing to a balanced emphasis of empirical research within the context of time constraints inherent within part-time research.

The influence of cutting tool geometry upon aspects of chip flow and tool wear:a theoretical, three dimensional examination of the cutting geometry and the shape of the twist drill

This work is undertaken in the attempt to understand the processes at work at the cutting edge of the twist drill. Extensive drill life testing performed by the University has reinforced a survey of previously published information. This work demonstrated that there are two specific aspects of drilling which have not previously been explained comprehensively. The first concerns the interrelating of process data between differing drilling situations, There is no method currently available which allows the cutting geometry of drilling to be defined numerically so that such comparisons, where made, are purely subjective. Section one examines this problem by taking as an example a 4.5mm drill suitable for use with aluminium. This drill is examined using a prototype solid modelling program to explore how the required numerical information may be generated. The second aspect is the analysis of drill stiffness. What aspects of drill stiffness provide the very great difference in performance between short flute length, medium flute length and long flute length drills? These differences exist between drills of identical point geometry and the practical superiority of short drills has been known to shop floor drilling operatives since drilling was first introduced. This problem has been dismissed repeatedly as over complicated but section two provides a first approximation and shows that at least for smaller drills of 4. 5mm the effects are highly significant. Once the cutting action of the twist drill is defined geometrically there is a huge body of machinability data that becomes applicable to the drilling process. Work remains to interpret the very high inclination angles of the drill cutting process in terms of cutting forces and tool wear but aspects of drill design may already be looked at in new ways with the prospect of a more analytical approach rather than the present mix of experience and trial and error. Other problems are specific to the twist drill, such as the behaviour of the chips in the flute. It is now possible to predict the initial direction of chip flow leaving the drill cutting edge. For the future the parameters of further chip behaviour may also be explored within this geometric model.

An advanced real-time predictive maintenance framework for large scale machine systems

This thesis introduces and develops a novel real-time predictive maintenance system to estimate the machine system parameters using the motion current signature. Recently, motion current signature analysis has been addressed as an alternative to the use of sensors for monitoring internal faults of a motor. A maintenance system based upon the analysis of motion current signature avoids the need for the implementation and maintenance of expensive motion sensing technology. By developing nonlinear dynamical analysis for motion current signature, the research described in this thesis implements a novel real-time predictive maintenance system for current and future manufacturing machine systems. A crucial concept underpinning this project is that the motion current signature contains infor­mation relating to the machine system parameters and that this information can be extracted using nonlinear mapping techniques, such as neural networks. Towards this end, a proof of con­cept procedure is performed, which substantiates this concept. A simulation model, TuneLearn, is developed to simulate the large amount of training data required by the neural network ap­proach. Statistical validation and verification of the model is performed to ascertain confidence in the simulated motion current signature. Validation experiment concludes that, although, the simulation model generates a good macro-dynamical mapping of the motion current signature, it fails to accurately map the micro-dynamical structure due to the lack of knowledge regarding performance of higher order and nonlinear factors, such as backlash and compliance. Failure of the simulation model to determine the micro-dynamical structure suggests the pres­ence of nonlinearity in the motion current signature. This motivated us to perform surrogate data testing for nonlinearity in the motion current signature. Results confirm the presence of nonlinearity in the motion current signature, thereby, motivating the use of nonlinear tech­niques for further analysis. Outcomes of the experiment show that nonlinear noise reduction combined with the linear reverse algorithm offers precise machine system parameter estimation using the motion current signature for the implementation of the real-time predictive maintenance system. Finally, a linear reverse algorithm, BJEST, is developed and applied to the motion current signature to estimate the machine system parameters.

The stability and formulation of topical analgesics

High-performance liquid chromatographic methods are developed for the simultaneous determination of various salicylates, their p-hydroxy isomers and nicotinic acid esters. The method is sensitive enough to detect trace amounts (~µM/L)of the product generated from cross reactivity between the drugs and the vehicle. The developed method also allows analysis of various topical products containing salicylate and nicotinate esters in their formulations. Applying this method, the degradation profiles of salicylates, nicotinates, p-hydroxy benzoate, o-methoxy benzoate and aspirin prodrugs in alkaline media are determined. The profile for alkyl salicylate degradation is found to be first order (A---? B) When the alcoholic radical is similar to that of the ester. In alcohol having a radical different from that of the ester function, the degradation is found to proceed through competitive transesterification and hydrolysis. The intermediates are identified following synthesis and isolation. The rate and extent of transesterification depends on the proportion of alcohol present in the system. Equations are presented to model the time profiles of reactant and product concentration. The reactions are base catalysed and the predominant pathway involves a concerted solvent attack upon the salicylate anion. Competitive hydrolysis of both ester components also follows this mechanism at moderate pH values but rates increase under strongly alkaline conditions as direct hydroxide attack becomes significant. In contrast, transesterification is independent of base concentration once full ionization is accomplished. The competitive hydrolysis is modelled using equations involving the dielectric constant of the medium. A range of other esters are also shown to undergo base-catalysed transesterification. In non-alcoholic solution phenyl salicylate undergoes a concentration-dependent oligomerisation which yields salsalate among the products. Competitive transesterification and hydrolysis also occur in products for topical use which have vehicles based upon alcohol, glycol or glycol polymers. Such reactions may compromise stability assessments, pharmaceutical integrity and delivery profiles.