Skeletal muscle weakness is a problem for people living with Multiple Sclerosis (MS). Alterations in the central nervous system may be the primary source of muscle weakness because of the pathophysiology of MS. However, changes in peripheral mediators of force production may also contribute to muscle weakness in persons with MS. The main objective of the dissertation was to systematically identify key neural (motor unit discharge rates, spasticity) and muscular (muscle size, contractile function) mechanisms of force production that may explain lower isometric strength and dynamic power in persons with MS compared with age-matched controls. The knee extensor muscles of the weaker leg were studied, because this muscle group is commonly affected by MS. We showed that persons with MS had lower peak isometric torque and dynamic power compared with controls. Persons with MS had lower motor unit discharge rates, smaller muscle size, and lower specific power compared with controls. There was no difference in passive torque (spasticity), specific strength, or maximal rate of force development between groups. Because differences in isometric strength between persons with MS and controls were abolished when torque was normalized to muscle size, smaller muscle size may explain a large portion of lower isometric strength in persons with MS. Differences in dynamic power were reduced when peak power was normalized to muscle size, but remained lower in persons with MS compared with controls, suggesting that changes in neural factors (e.g., lower motor unit discharge rates) may explain lower dynamic power in persons with MS. These results suggest that different mechanisms may contribute to muscle weakness in MS, depending on the mode of contraction. Lower motor unit discharge rates and smaller muscle size were identified as key mechanisms of muscle weakness in persons with MS. Each of these mechanisms has been shown to improve with resistance training in controls. Thus, this dissertation provides an evidence-based rationale for resistance training interventions in persons with MS, to improve isometric strength and power production by increasing motor unit discharge rates and muscle size.

The purpose of this thesis is to examine how rehabilitation interventions, specifically physiotherapy (PT), occupational therapy (OT), and speech and language pathology (SLP) or a combination of these interventions affect quality of life (QoL) in people with amyotrophic lateral sclerosis (ALS). The purpose of the first study (Chapter 2) was to synthesize qualitative research through a qualitative meta-synthesis on the potential of rehabilitation interventions to maintain and/or improve QoL from the perspective of people with ALS. The literature search for this study was conducted using the SPIDER strategy and five articles were included. Four themes emerged: 1) the concept of control; 2) adapting interventions to disease stage; 3) struggles with interventions; and 4) barriers between healthcare providers and patients. The evidence suggests that from the perspective of people with ALS, PT, OT, and SLP interventions, or a combination of these interventions have the potential to be beneficial in the management of people with ALS and to optimize QoL. The systematic review (Chapter 3) aimed to determine the effectiveness of rehabilitation interventions, in particular PT, OT and SLP interventions or a combination of these interventions, on QoL in people with ALS. The PICO search strategy was used and six studies were included: three RCTs, two cohort studies, and one cross-sectional study. A narrative synthesis of interventions was conducted as the included studies were not sufficiently similar thus data extracted were not adequate for conducting meta-analyses. Need to briefly discuss interventions, which outcomes you included and inconsistency in results across studies. Due to the limited evidence, it was difficult to determine the exact effects of the interventions from each rehabilitation field to affect QoL for people with ALS. The evidence suggests that more research is required; currently therapists need to rely on their clinical expertise, expert opinions, and theoretical models to select the most effective interventions to sustain or improve QoL in people with ALS. Future research needs to take into consideration the needs of people with ALS to evaluate the impact of rehabilitation interventions on QoL. / Thesis / Master of Science (MSc)

Rapidly progressive diffuse systemic sclerosis (dSSc) is a life-threatening condition characterized by increased mortality with few effective therapies, typically only helpful in stabilizing disease. Autologous hematopoietic stem cell transplantation (AHSCT) is the only treatment that has demonstrated improved survival. Despite promising results from three randomized controlled trials (RCTs), best practice use of AHSCT in the real-world setting is not well established. The primary objective of this thesis was to summarize the clinical efficacy, limitations and utilization of AHSCT in the management of rapidly progressive dSSc. Specifically, we conducted (1) a systematic review to describe the efficacy of AHSCT in dSSc as well as practice variation in patient selection and treatment regimens; and (2) a multicenter retrospective cohort study to compare outcomes for subjects who received AHSCT in France compared to those who received conventional care in Canada. There was important variability in the criteria for patient selection and treatment protocols. While AHSCT is associated with improved overall survival, skin fibrosis and lung function, further studies are needed to understand its potential for expanded eligibility and effects on other disease manifestations.

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Systemic sclerosis (SSc) is a chronic autoimmune disease of the connective tissue. Immune system dysregulation, excessive deposition of collagen and microvascular damage in the skin and multiple internal organs are the main pathologic characteristics of the disease. Little is known about the mechanisms that are responsible for the pathogenesis of SSc. However, evidence has been accumulated demonstrating that T cells play a key role in the initiation and propagation of the disease. Previous studies in our laboratory have identified the presence of high proportions of identical β–chains TCR transcripts, demonstrating the presence of clonal expansion of T cells in skin biopsies from patients with SSc of recent onset. These T cells have undergone proliferation and clonal expansion in response to as yet unidentified antigen(s). The hypothesis that has been tested in this study is whether clonally expanded T cells in skin biopsies of patients with SSc of recent onset recognize self or non–self (possibly viral) putative SSc antigens, including DNA topoisomerase I, cytomegalovirus (CMV) and parvovirus. With the objective to identify the antigens recognized by clonally expanded T cells in skin biopsies of patients with SSc, we examined the presence of α– and β–chain TCR transcripts. Amplification of α–chain TCR transcripts by the non–palindromic adaptor PCR (NPA–PCR)/Vα specific PCR followed by cloning and sequencing revealed the presence of several clonally expanded α–chain TCR transcripts in skin biopsies from four patients with SSc and peripheral blood from one of these patients. Additionally, several clonally expanded β–chain TCR transcripts were identified in skin biopsies from all three of these patients with SSc examined, after NPA–PCR/Vβ specific amplification followed by cloning and sequencing. To identify the antigens recognized by these in vivo clonally expanded α– and β–chain TCR clones, full length α– and β– chain TCR transcripts containing the identified CDR3 regions from the clonally expanded TCR clones from the patients SSc–21 and SSc–22 were constructed. Pairs of clonally expanded, full length α– and β–chain TCR transcripts and appropriate controls were expressed in mutant TCR negative cells of the Jurkat T cell line (J.RT3–T3.5) by using a retroviral gene transfer and expression system. Each clonally expanded α–chain TCR transcript was combined with each clonally expanded β–chain TCR transcript from the same patient, generating T cells lines containing all pairing combinations of the clonally expanded TCR transcripts for each SSc patient. A total of 52 T cell lines were generated, including 10 control T cell lines. The surface expression of the TCR complex on these T cell lines was verified by flow cytometric analysis using antibodies against the α/β TCR and CD3epsilon. We employed an intracellular calcium mobilization assay to examine whether the Jurkat T cell lines transduced with the clonally expanded TCR transcripts from skin biopsies from patients with SSc (SSc–21 and SSc–22) recognize putative SSc antigens or their peptides presented by autologous EBV–transformed B cell lines. The putative SSc antigens that were tested are the self–antigen, DNA topoisomerase I and the viral antigens, cytomegalovirus and parvovirus which have been previously suggested to be involved in the pathogenesis of SSc. Significant intracellular calcium mobilization was observed in response to 3 DNA topoisomerase I and 2 CMV peptides by 5 T cell lines transduced with clonally expanded α– and β–chain TCR transcripts from patients SSc–21 and SSc–22. / Microbiology and Immunology

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No / Fatigue is common in people with multiple sclerosis (MS) and symptoms of fatigue are often reported as the most debilitating symptoms of the disease. However, there are few reports of interventions for fatigue in MS. A systematic review of published literature examining pharmacological and psychosocial/psychological interventions for fatigue in MS was conducted. The search and review strategy undertaken used the Centre for Reviews and Dissemination guidelines. Papers were reviewed by two independent reviewers. Of 81 studies short-listed for inclusion, 15 studies were included, of which 10 were studies of pharmacological therapy and five were studies of psychosocial/psychological interventions. Of the pharmacological studies, two were rated as of moderate-to-high quality, three of moderate quality, two of moderate-to-low quality and three of low quality. Of the psychosocial/psychological studies, three were rated as of moderate quality and two of moderate-to-low quality. None of the studies reviewed reached the highest level of quality according to pre-agreed criteria. Regardless of level of quality, effectiveness of both pharmacological and psychosocial/psychological interventions was modest at best and often absent. Accordingly, there is little evidence-based advice that can be offered to people with MS to help manage their fatigue.