Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyGln) tract in the human androgen receptor (hAR). One mechanism by which polyGln-expanded proteins are believed to cause neuronotoxicity is through aberrant interaction(s) with, and possible sequestration of, critical cellular protein(s). / Our goal was to confirm and further characterize the interaction between hAR and cytochrome c oxidase subunit Vb (COXVb), a nuclear-encoded mitochondrial protein. We had previously isolated COXVb as an AR-interacting protein in a yeast two-hybrid search to identify candidates that interact with normal and polyGln-expanded AR. Using the mammalian two-hybrid system, we confirm that COXVb interacts with normal and mutant AR and demonstrate that the COXVb-normal AR interaction is stimulated by heat shock protein 70 (Hsp70). Also, BFP-tagged AR specifically co-localizes with cytoplasmic aggregates formed by GFP-labelled polyGln-expanded AR in androgen-treated cells. / Mitochondrial dysfunction may precede neuropathological findings in polyGln-expanded disorders and may thus represent an early event in neuronotoxicity. Interaction of COXVb and hAR, with subsequent sequestration of COXVb, may provide a mechanism for putative mitochondrial dysfunction in SBMA.

Wheelchair propulsion is an important part of daily living for many people with spinal cord injuries (SCI's). The aim of this project was to establish the validity of using a new approach for measuring wheelchair propulsion ability. The variation in methods observed by subject's hands in contacting and propelling their wheelchair, namely, using the push rims only; wedging the hands between push rims and tyre and grasping both push rims and tyres, highlighted that earlier studies using instrumented push rims (including the SMART ) for people with tetraplegia would not provide a true indication of propulsion ability for the participants in this study. As a result, a new inertia dynamometer was built and calibrated for measuring wheelchair propulsion ability. Kinetic and kinematic models were developed to calculate wheelchair propulsion parameters such as power output, wheelchair velocity and arm motion patterns. After testing 22 subjects with different SCI levels, the results indicated that arm function was a more important factor in wheelchair propulsion, in terms of power output, than trunk stability and strength. More importantly, people with C5/C6 tetraplegia had a significantly reduced capability in terms of wheelchair propulsion compared with other subjects with a lower lesion (T1-T8, T9-T12 and L1-S5). A further study for quantifying the contribution of triceps function on improving wheelchair propulsion for people with tetraplegia was performed by comparing kinetic and kinematics parameters in C5/C6 tetraplegia subjects. Depending on the control of elbow extension, the subjects were divided into groups with: no active elbow extension, deltoid to triceps transfer surgery (TROIDS) to provide elbow extension, and incomplete C5/C6 tetraplegia with retained active triceps function providing elbow extension. The results demonstrated that the restoration of triceps following TROIDS surgery not only allows active elbow extension, but also increased the amplitude and strength as well as the speed of arm movement. Finally, the results also point to TROIDS allowing a more pronounced and natural push phase and an improved arm movement pattern during both propulsion and recovery phase under normal and extreme conditions.

It was hypothesized that superparamagnetic nanoparticles encapsulated in a silica shell with a fluorescent dye could be functionalized with axonal tracers and could be used for serial, non-invasive imaging with magnetic resonance imaging (MRI) for axon tract tracing. Nanoparticles functionalized with amine, octadecyl, silica, and biotinylated dextran amine were manufactured and characterized with MRI, scanning electron microscopy, and UV-visible, infrared, and fluorescence spectroscopy. Nanoparticle concentrations of 10 mM were not toxic to adult rat neural progenitor cells (NPCs) and labeled approximately 90% of cells. Nanoparticles were assessed for anterograde and retrograde tract tracing in adult rat models. With MRI and microscopy, the nanoparticles did not appear to trace axons but did provide an MRI signal for up to 3 weeks post implantation. While functionalized nanoparticles did not appear to trace axons, they are not toxic to NPCs and may be used as a MRI contrast agent in the neural axis.

At the author’s request, the abstract has been removed due to the confidential nature of the thesis. It will be added once the embargo period has passed.

Sociologists have only recently paid attention to how men experience physical disability. However, current research continues to ignore how different racial groups experience it. The goal of this study was to examine how black and white men experience life with a physical disability. Using qualitative research techniques involving in-depth, face-to-face interviews with 10 black and 10 white men, I focus on how meanings of disability and masculinity shift after a traumatic injury. Using symbolic interactionism and social construction as theoretical frameworks, I examine how these men formed and modified meanings for disability and masculinity through social interactions. I also analyze the strategies they use to manage a stigmatized identity. Finally, I explore how they negotiate a masculine identity within larger social contexts. My findings suggest that black and white men’s constructions of masculinity and disability are more similar than different on all levels. Furthermore, these men used three strategies to negotiate their new social identities: reinforcing idealized masculinity, modified masculinity, and lost masculinity.

Spinal cord injury (SCI) is a devastating condition that causes its victims to experience functional deficits. Inflammation plays a complex role in the progression of SCI. While some inflammatory cells attenuate further damage to the spinal cord tissue, other inflammatory mediators exacerbate the damage. Attenuating the detrimental aspects of inflammation after SCI is an attractive neuroprotective strategy that could potentially lead to significant functional improvement. In this regard, intravenous immunoglobulin G (IgG), which has many proposed immuno-modulatory mechanisms, is a potential treatment candidate. In this study, we investigated the neuroprotective properties of IgG by examining its effects after SCI at the molecular, cellular, and neurobehavioral levels. We observed that IgG treatment after SCI is associated with significant reduction in pro-inflammatory mediators and significant improvement in neurobehavioral recovery compared to the control. The results of the study suggest that IgG could potentially be used as an immuno-modulatory therapy for SCI.

Spinal cord injury (SCI) is a debilitating condition accompanied by motor and sensory deficits and a reduced quality of life. Current treatment options are limited and are associated with variable efficacy and a risk of adverse effects. The pathophysiology of SCI is initiated by a primary mechanical insult to the spinal cord, followed by a complex series of deleterious events known as secondary injury. Secondary injury processes include free radical formation, glutamate excitotoxicity, inflammation and cell death. Apoptotic cell death in particular plays a key role in the secondary injury processes and exacerbates tissue degradation and loss of function. The role of Fas-mediated apoptosis in SCI pathophysiology is poorly defined in the literature to date. Correlative evidence suggests that this form of cell death is delayed and occurs in white matter adjacent to sites of primary damage. The cellular and temporal mechanisms of Fas-mediated apoptosis following experimental SCI were evaluated using a clinically relevant clip compression SCI model in the rat. Furthermore, therapeutic manipulation of Fas activation using a soluble form of the Fas receptor (sFasR) was carried out to establish the efficacy and clinical relevance of targeting this aspect of secondary injury. This work shows that Fas-mediated apoptosis is an important contributor to secondary SCI pathology. Oligodendrocytes are targeted by this form of cell death in a delayed fashion post-injury, providing an opportunity for therapeutic intervention. Intrathecal administration of sFasR following SCI reduced post-traumatic apoptosis, improved cell survival, enhanced tissue preservation and resulted in an improved motor recovery. Administration of sFasR was effectively delayed by up to 24 hours post-injury, however a shorter delay of 8 hours post-injury was most efficacious. A surprising result emerged from this work. Delayed intrathecal administration of IgG following SCI showed significant efficacy in both cellular and tissue level outcomes, as well as at the functional level. Fas-mediated apoptosis is an important aspect of secondary SCI pathophysiology and is an attractive therapeutic target. The beneficial outcomes of manipulating Fas activation using sFasR provide further evidence for this. Future work will refine this treatment strategy, bringing it into the SCI patient population.

Spinal cord injury (SCI) is a devastating condition that causes its victims to experience functional deficits. Inflammation plays a complex role in the progression of SCI. While some inflammatory cells attenuate further damage to the spinal cord tissue, other inflammatory mediators exacerbate the damage. Attenuating the detrimental aspects of inflammation after SCI is an attractive neuroprotective strategy that could potentially lead to significant functional improvement. In this regard, intravenous immunoglobulin G (IgG), which has many proposed immuno-modulatory mechanisms, is a potential treatment candidate. In this study, we investigated the neuroprotective properties of IgG by examining its effects after SCI at the molecular, cellular, and neurobehavioral levels. We observed that IgG treatment after SCI is associated with significant reduction in pro-inflammatory mediators and significant improvement in neurobehavioral recovery compared to the control. The results of the study suggest that IgG could potentially be used as an immuno-modulatory therapy for SCI.

More than one million people are living with spinal cord injury (SCI) in North America alone. Restoring lost motor function can alleviate SCI-related health problems, as well as markedly increase the quality of life enjoyed by individuals with SCI. Functional electrical stimulation (FES) can replace motor function in individuals with SCI by using short electrical pulses to generate contractions in paralyzed muscles. A wide range of FES applications have been proposed, but few application are actually available for community use by SCI consumers. A major factor contributing to this shortage of real-world FES applications is the lack of a feasible closed-loop control algorithm. The purpose of this thesis is to develop a closed-loop control algorithm that is suitable for use in practical FES applications. This thesis consists of three separate studies. The first study examined existing closed-loop control algorithms for FES applications, and showed that a method of testing FES control algorithms under realistic conditions is needed to evaluate their likely real-world performance. The second study provided such a testing method by developing a non-idealities block that can be used to modify the nominal response of electrically stimulated muscle in simulations of FES applications. Fatigue, muscle spasm, and tremor non-idealities are included in the block, which allows the user to specify the severity level for each type of non-ideal behaviour. This nonidealities block was tested in a simulation of electrically induced knee extension against gravity, and showed that the nominal performance of the controllers was substantially better than their performance in the realistic case that included the non-idealities model. The third study concerned the development and testing of a novel observer-based sliding mode control (SMC) algorithm that is suitable for use in real-world FES applications. This algorithm incorporated a fatigue minimization objective as well as co-contraction of the antagonist muscle group to cause the joint stiffness to track a desired value. The SMC algorithm was tested in a simulation of FES-based quiet standing, and the non-idealities block was used to determine the probable performance of the controller in the real world. This novel controller performed very well in simulation, and would be suitable for use in selected practical FES applications. The work contained in this thesis can easily be extended to a wide range of FES applications. This work represents a significant step forward in closed-loop control for FES applications, and will facilitate the development of sophisticated new electrical stimulation systems for use by consumers in their homes and communities.

Neuropathic pain (NP) after spinal cord injury (SCI) can significantly and negatively affect a person’s quality of life and is often refractory to currently available treatments. In order to advance the field and find effective therapeutic avenues; signs, symptoms, and biomarkers in humans should be identified and related to specific pain-generating mechanisms. The present work utilizes quantitative sensory testing (QST) and magnetic resonance spectroscopy (MRS) to evaluate the relationship between the functional integrity of the dorsal column-medial lemniscus pathway (DCML), the spinothalamic tract (STT), and metabolic markers of neuronal loss and glial activation in the thalamus of persons with/without NP after SCI. This work was based on the hypothesis that the presence/severity of NP after SCI is dependent both on function of ascending somatosensory pathways and changes in neuronal and glial markers in the thalamus. The results indicate that NP is associated with a decreased afferent DCML input to the thalamus resulting in a loss of inhibitory neurons and that residual function from STT afferents may contribute to thalamic glial activation and NP. Based on this work, in combination with previous studies in animals and humans, it can be proposed that NP after SCI partly results from the combination of residual STT function and loss of neuronal inhibition leading to neuronal hyperexcitability in the spinal cord and the thalamus. Thus, the presence of NP in chronic SCI is dependent on several underlying mechanisms which may be measured in human subjects with methods such as QST and MRS. Clinical implications and recommendations for further research are enclosed.