Doctor of Philosophy

dissertationOne in 26 people in America will develop epilepsy at some point in their life. Approximately one-third of patients with epilepsy do not have full control of their seizures on their current antiseizure drug (ASD) regimen. In the past 20 years, 16 new ASDs have been made available to the patient with epilepsy. However, the percentage of pharmacoresistant patients has remained relatively constant. Thus, it is necessary to explore alternative avenues to explain the lack of seizure control in these patients. It is unknown how the practice of nonadherence contributes to the percentage of refractory patients. An animal model of nonadherence would permit the study of nonadherence and its consequences on seizure control. To model nonadherence, a computer-automated system was created to dose animals with antiseizure drugs (ASDs) using a drug-in-food protocol. Two studies were conducted and serve as a first-pass characterization. In the first study, newly-diagnosed epileptic rats were administered carbamazepine (CBZ) at varying levels of adherence. Two groups, one adherent (100%), and one nonadherent (50%), were compared to placebo control (0%). The 50% group displayed similar seizure frequency and severity to the placebo controls, while the 100% adherent group were observed to have fewer seizures overall. This suggesting that taking medication 50% of the time had no measurable effect on seizure control. In the second study, a group of newly diagnosed epileptic rats was subjected to a two-week on (100%), two-week off (0%) and two-week on CBZ (100%) paradigm. Despite numerous seizures after discontinuation of CBZ treatment, animals regained the same level of seizure control when CBZ treatment was reinstituted. Finally, nonadherence can lead to status epilepticus (SE), a severe seizure lasting several minutes. In an effort to aid drug discovery, a new and simple method which results in an unbiased method to assess the duration and severity of the electrographic component of SE was created. This method has been used to quantify the response of electrographic SE to novel investigational compounds. Together, this dissertation aims to aid in the treatment of epilepsy by providing etiologically relevant models of nonadherence and analysis of electrographic SE

Attracting University-educated Job Seekers: Challenges and Recommendations for the Auto Sales Industry

While a strong demand for university-educated employees exists within the auto sales industry, few graduates give serious consideration to car dealerships as career opportunities. Lexus of Edmonton, a leading luxury car dealership, presented our team with this concern, prompting a three-month marketing research project. This report examines the factors which influence university-educated job seekers’ decisions when searching for employment, and how Lexus of Edmonton can tailor their recruitment strategies to target graduates. Our examination followed a three-phase research design involving a review of 25 academic articles, a qualitative analysis of five in-depth interviews, and a quantitative analysis of 101 questionnaire responses. In summary, we found that school involvement, internships, and online platforms were effective means of attracting university graduates. We identified business-majors as the audience most interested in a career with Lexus of Edmonton. We also found that corporate social responsibility and organizational culture were major concerns for graduates, with some metrics being considered as highly as salary and compensation. Based on these findings, our team recommends that Lexus of Edmonton expand their ongoing involvement with local universities, leverage their online presence to network with students, and tailor its communications to reflect their commitment to employee wellbeing. Drawing on this report as a case study in recruitment strategies, we hope that other employers and universities may optimize their own processes to better match graduates to career opportunities

Decoding spoken words using local field potentials recorded from the cortical surface

Pathological conditions such as amyotrophic lateral sclerosis or damage to the brainstem can leave patients severely paralyzed but fully aware, in a condition known as 'locked-in syndrome'. Communication in this state is often reduced to selecting individual letters or words by arduous residual movements. More intuitive and rapid communication may be restored by directly interfacing with language areas of the cerebral cortex. We used a grid of closely spaced, nonpenetrating micro-electrodes to record local field potentials (LFPs) from the surface of face motor cortex and Wernicke's area. From these LFPs we were successful in classifying a small set of words on a trial-by-trial basis at levels well above chance. We found that the pattern of electrodes with the highest accuracy changed for each word, which supports the idea that closely spaced micro-electrodes are capable of capturing neural signals from independent neural processing assemblies. These results further support using cortical surface potentials (electrocorticography) in brain–computer interfaces. These results also show that LFPs recorded from the cortical surface (micro-electrocorticography) of language areas can be used to classify speech-related cortical rhythms and potentially restore communication to locked-in patients

Classification of spoken words using surface local field potentials

Cortical surface potentials recorded by electrocorticography (ECoG) have enabled robust motor classification algorithms in large part because of the close proximity of the electrodes to the cortical surface. However, standard clinical ECoG electrodes are large in both diameter and spacing relative to the underlying cortical column architecture in which groups of neurons process similar types of stimuli. The potential for surface micro-electrodes closely spaced together to provide even higher fidelity in recording surface field potentials has been a topic of recent interest in the neural prosthetic community. This study describes the classification of spoken words from surface local field potentials (LFPs) recorded using grids of subdural, nonpenetrating high impedance micro-electrodes. Data recorded from these micro-ECoG electrodes supported accurate and rapid classification. Furthermore, electrodes spaced millimeters apart demonstrated varying classification characteristics, suggesting that cortical surface LFPs may be recorded with high temporal and spatial resolution to enable even more robust algorithms for motor classification

Classification of spoken words using surface local field potentials

Cortical surface potentials recorded by electrocorticography (ECoG) have enabled robust motor classification algorithms in large part because of the close proximity of the electrodes to the cortical surface. However, standard clinical ECoG electrodes are large in both diameter and spacing relative to the underlying cortical column architecture in which groups of neurons process similar types of stimuli. The potential for surface micro-electrodes closely spaced together to provide even higher fidelity in recording surface field potentials has been a topic of recent interest in the neural prosthetic community. This study describes the classification of spoken words from surface local field potentials (LFPs) recorded using grids of subdural, nonpenetrating high impedance micro-electrodes. Data recorded from these micro-ECoG electrodes supported accurate and rapid classification. Furthermore, electrodes spaced millimeters apart demonstrated varying classification characteristics, suggesting that cortical surface LFPs may be recorded with high temporal and spatial resolution to enable even more robust algorithms for motor classification

Decoding spoken words using local field potentials recorded from the cortical surface

Pathological conditions such as amyotrophic lateral sclerosis or damage to the brainstem can leave patients severely paralyzed but fully aware, in a condition known as 'locked-in syndrome'. Communication in this state is often reduced to selecting individual letters or words by arduous residual movements. More intuitive and rapid communication may be restored by directly interfacing with language areas of the cerebral cortex. We used a grid of closely spaced, nonpenetrating micro-electrodes to record local field potentials (LFPs) from the surface of face motor cortex and Wernicke's area. From these LFPs we were successful in classifying a small set of words on a trial-by-trial basis at levels well above chance. We found that the pattern of electrodes with the highest accuracy changed for each word, which supports the idea that closely spaced micro-electrodes are capable of capturing neural signals from independent neural processing assemblies. These results further support using cortical surface potentials (electrocorticography) in brain–computer interfaces. These results also show that LFPs recorded from the cortical surface (micro-electrocorticography) of language areas can be used to classify speech-related cortical rhythms and potentially restore communication to locked-in patients

Looked After at Home, Not Home Alone : Partnership Working

A young person’s journey from their referral to Includem through to their exit, which illustrates how the established partnership between Glasgow Youth Justice, Social Work and Includem operates

The Chlamydia muridarum plasmid revisited : new insights into growth kinetics.

Background: Research in chlamydial genetics is challenging because of its obligate intracellular developmental cycle. In vivo systems exist that allow studies of different aspects of basic biology of chlamydiae, the murine Chlamydia muridarum model is one of great importance and thus an essential research tool. C. muridarum carries a plasmid that has a role in virulence.  Our aim was to compare and contrast the C. muridarum plasmid-free phenotype with that of a chromosomally isogenic plasmid-bearing strain, through the inclusion phase of the developmental cycle. Methods: We measured infectivity for plasmid bearing and plasmid-cured C. muridarum by inclusion forming assays in McCoy cells and in parallel bacterial chromosome replication by quantitative PCR, throughout the developmental cycle. In addition to these studies, we have carefully monitored chlamydial inclusion formation by confocal microscopy and transmission electron microscopy. A new E.coli/chlamydial shuttle vector (pNigg::GFP) was constructed using standard cloning technology and used to transform C. muridarum for further phenotypic studies. Results: We have advanced the definition of the chlamydial phenotype away from the simple static observation of mature inclusions and redefined the C. muridarum plasmid-based phenotype on growth profile and inclusion morphology. Our observations on the growth properties of plasmid-cured C. muridarum challenge the established interpretations, especially with regard to inclusion growth kinetics. Introduction of the shuttle plasmid pNigg::GFP into plasmid-cured C. muridarum restored the wild-type plasmid-bearing phenotype and confirmed that loss of the plasmid was the sole cause for the changes in growth and chromosomal replication. Conclusions: Accurate growth curves and sampling at multiple time points throughout the developmental cycle is necessary to define plasmid phenotypes.  There are subtle but important (previously unnoticed) differences in the overall growth profile of plasmid-bearing and plasmid-free C. muridarum.  We have proven that the differences described are solely due to the plasmid pNigg

Brief Amici Curiae of Prescription Policy Choices, Professors of Law, and Professors of Health Policy in Support of Petitioners on the Minimum Coverage Provision in Department of Health & Human Services v. State of Florida

One purpose of the individual mandate is to eliminate the market for self-insured healthcare transactions. It is well-established in this Court’s precedent that the elimination of an interstate commercial market is a constitutionally legitimate end for Congress to pursue under the Commerce Clause. Under the Necessary and Proper Clause, Congress may use any reasonably adapted means to accomplish constitutionally legitimate ends. The individual mandate is not only reasonably adapted but is quite elegant as a means of eliminating the market for self-insured healthcare transactions. The provision effectively encourages individuals to shift from the inefficient market for self-insured care to its more efficient substitute market for fully-insured care. The question presented is whether the minimum coverage provision is a valid exercise of Congress’s powers under Article I of the Constitution

A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity

Developing tissues contain motile populations of cells that can self-organize into spatially ordered tissues based on differences in their interfacial surface energies. However, it is unclear how self-organization by this mechanism remains robust when interfacial energies become heterogeneous in either time or space. The ducts and acini of the human mammary gland are prototypical heterogeneous and dynamic tissues comprising two concentrically arranged cell types. To investigate the consequences of cellular heterogeneity and plasticity on cell positioning in the mammary gland, we reconstituted its self-organization from aggregates of primary cells in vitro. We find that self-organization is dominated by the interfacial energy of the tissue–ECM boundary, rather than by differential homo- and heterotypic energies of cell–cell interaction. Surprisingly, interactions with the tissue–ECM boundary are binary, in that only one cell type interacts appreciably with the boundary. Using mathematical modeling and cell-type-specific knockdown of key regulators of cell–cell cohesion, we show that this strategy of self-organization is robust to severe perturbations affecting cell–cell contact formation. We also find that this mechanism of self-organization is conserved in the human prostate. Therefore, a binary interfacial interaction with the tissue boundary provides a flexible and generalizable strategy for forming and maintaining the structure of two-component tissues that exhibit abundant heterogeneity and plasticity. Our model also predicts that mutations affecting binary cell–ECM interactions are catastrophic and could contribute to loss of tissue architecture in diseases such as breast cancer