Diseases Commons^™

Pannexin3 In Exercise, Obesity, And Osteoarthritis, Brent Wakefield

Electronic Thesis and Dissertation Repository

Pannexin 3 (PANX3), is a glycoprotein that oligomerizes to form mechano-sensitive channels expressed in musculoskeletal tissues, and has been identified as a potential target for the treatment of obesity and osteoarthritis (OA). Obesity and OA are two of the most prevalent diseases worldwide, leading to disability and even death. These conditions are thought to originate from a complex interaction between genetics, aging, sex, and modifiable lifestyle factors, such as exercise. Investigating the interactions between genetic and exercise may provide a more comprehensive, context-specific understanding of gene function. This thesis aimed to understand the interactions between PANX3 and exercise interventions on …

Assessing Inflammation In The Pathology Of Knee Osteoarthritis, Zachary J. Koudys

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is a joint disease that causes pain, stiffness, and loss of function. Inflammation of the synovium plays a role in the pathology of OA. Macrophages are the dominant immune cells in synovial tissue. Activated macrophages over-express the translocator protein (TSPO). [¹⁸F]FEPPA is a 2^nd generation positron emission tomography (PET) tracer that can target TSPO with high specificity. Hybrid [¹⁸F]FEPPA PET/MRI may enable accurate quantification of macrophage activity in vivo. In this work, [¹⁸F]FEPPA tracer uptake in knee synovial tissue was measured ex vivo using autoradiography and was validated to correlate to …

Rna Isolation In Duchenne Muscular Dystrophy (Dmd) Mice Models, Salem Abu Al-Burak

Undergraduate Student Research Internships Conference

Fibrosis is a progressive and typically irreversible disease process characterized by the excessive deposition of collagen in organs and in tissues of the musculoskeletal (MSK) system^1,2. This process, which causes loss of organ and tissue function, can be initiated by micro-traumas³, an excessive and/or prolonged immune response¹, the activation and proliferation of fibrosis-inducing progenitor cells⁴, and a pro-fibrotic extra-cellular microenvironment⁵. In parallel with the events that initiate fibrosis, genetic or environmental influences may cause cells and tissues to become predisposed to fibrosis development prior to initiation. This suggests that these …

Characterization Of The Ang/Tie2 Signaling Pathway In The Skeletal Muscle Of Dmd, Yiming Lin

Electronic Thesis and Dissertation Repository

In Duchenne muscular dystrophy (DMD), angiogenesis appears to be attenuated. Local administration of angiopoietin 1 (Ang1) has been shown to reduce inflammation, ischemia, and fibrosis in DMD mice. Ang1 is a vital vascular stabilizing factor that activates the endothelial cell receptor Tie2, leading to downstream pro-survival PI3K/Akt pathway activation and eNOS phosphorylation. In this study, we aim to characterize the Ang/Tie2 signaling pathway within the skeletal muscle of mouse models of DMD. Utilizing immunoblots and RT-qPCR, we show that Ang1 is downregulated, while the antagonist angiopoietin 2 (Ang2) is upregulated, leading to a decreased Ang1/Ang2 ratio. This correlates with a …

Three-Dimensional Ultrasound Imaging For Quantifying Knee Cartilage Volume, Samuel Papernick

Electronic Thesis and Dissertation Repository

Arthritis is the most common chronic health condition in Canada, with the most common form being osteoarthritis (OA). There is a great clinical need for an objective imaging-based point-of-care tool to assess OA status, progression, and response to treatment. This thesis aims to validate a handheld mechanical three-dimensional (3D) ultrasound (US) device against the current clinical standard of magnetic resonance imaging (MRI) for quantifying femoral articular cartilage (FAC) volume. Knee images of 25 healthy volunteers were acquired using 3D US and 3.0 Tesla MRI scans. Two raters manually segmented the trochlear FAC during separate sessions to assess intra- and inter-rater …

An Approach For The In-Vivo Characterization Of Brain And Heart Inflammation In Duchenne Muscular Dystrophy, Joanne Tang

Electronic Thesis and Dissertation Repository

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss—notably within muscles and CNS neurons. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies improved life expectancy, but this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, there is an increasing need to both better understand and track disease pathophysiology in the dystrophic heart and brain prior to onset of severe degenerative symptoms. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration, however chronic neuroinflammation’s role is largely unknown in …

Assessment Of Intrinsic Hand Neuromuscular Physiology, Philemon Tsang

Electronic Thesis and Dissertation Repository

Alterations to the peripheral nervous system and neuromuscular physiology may impact hand function in a typical or clinical population, such as individuals with ulnar neuropathy. The mechanisms that influence these positive and negative changes are still not well understood. The three studies within my thesis aim to validate the reliability of decomposition-based quantitative electromyography (DQEMG) measurements and explore the changes in intrinsic hand neuromuscular physiology in a typical aging population and individuals recovering from a surgical intervention for severe ulnar neuropathy.

The purpose of the first study was to determine the test-retest reliability of near-fibre (NF) jiggle, a measure of …

The Role Of Synovium And Synovial Macrophages In Experimental Post-Traumatic Knee Osteoarthritis, Yue Lai-Zhao

Electronic Thesis and Dissertation Repository

In osteoarthritis (OA), synovitis is associated with symptom severity. As synovium secretes both catabolic and anabolic factors into the joint, the impact of synovitis in OA remains unclear. We developed a novel co-culture system using tissues from an established rat model of post-traumatic knee OA (PTOA) to study signaling between synovium and chondrocytes. We found that synovium from early stage but not later stage PTOA joints caused an overall protective effect in chondrocytes. We then selectively treated synovial macrophages with liposomal drugs causing depletion, STAT1 inhibition, or STAT6 inhibition in early PTOA joints. We found cartilage damage in vivo was …

Investigating The Role Of Nuclear Receptor Peroxisome Proliferator-Activated Receptor Δ In Obesity-Associated Osteoarthritis, Bethia C. To

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is a heterogeneous disease, differentiated based by risk factors that drive joint damage. Peroxisome proliferator-activated receptor delta (PPARd) is a nuclear receptor previously implicated in cartilage damage in OA. Given its deleterious role in post-traumatic OA and in regulating metabolism, we hypothesized that PPARd inhibition will protect against obesity-associated OA. Diet-induced obesity was used to induce OA in mice. Mice fed the western diet for 40 weeks exhibited mild OA, with subchondral bone remodelling occurring alongside cartilage damage. Cartilage-specific Ppard knockout (KO) mice were generated to study its role in metabolic OA. Both wildtype and PPARd KO mice …

Tomographic And Histological Analyses Of Ectopic Calcification Associated With Diffuse Idiopathic Skeletal Hyperostosis (Dish), Dale Edward Fournier

Electronic Thesis and Dissertation Repository

Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory spondyloarthropathy characterised by the formation of ectopic calcifications of the ligaments/enthuses along the anterolateral aspect of the vertebral column. Despite affecting 15-25% of North Americans over the age of 50, the aetiology of DISH is poorly understood and there are no disease modifying treatments. Our discovery-based approach implemented a transdisciplinary research team to study the basic biology, imaging science, clinical anatomy and significance of DISH in humans. Our novel characterisation defined distinct morphological presentations of ectopic calcifications associated with DISH in cadaveric specimens using micro-computed tomography imaging. Subsequent histopathological analyses demonstrated that …

The Development Of A Temporomandibular Force Simulator To Study Craniofacial Strain In-Vitro, Kenneth Kc Ip

Electronic Thesis and Dissertation Repository

An in-vitro musculoskeletal loading simulator was developed to replicate the internal forces of mastication, and then employed in a comparison of clinically relevant facial fracture repairs. Muscle forces are simulated by pneumatic pistons via 3D printed mounts that are reverse-engineered from CT scan to match muscle attachment sites, which are adhered to bone in order to simulate native stress distributions. Bite force and bone strain pattern of the craniofacial structure under load were measured using a force sensor and strain gauges respectively. In a series of five fresh-frozen cadaveric heads, it was found that strain patterns of the craniofacial structure …

Analysis Of Subchondral Bone And Microvessels Using A Novel Vascular Perfusion Contrast Agent And Optimized Dual-Energy Computed Tomography, Justin J. Tse

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA), is a chronic debilitating disease that affects millions of individuals and is characterized by the degeneration of joint subchondral bone and cartilage. These tissue degenerations manifest as joint pain, limited range of joint motion, and overall diminished quality of life. Currently, the exact mechanism(s) and cause(s) by which OA initiates and progresses remain unknown. The multi-factorial complex nature of OA (i.e. age, diabetes, obesity, and prior injuries have all been shown to play a role in OA) contributes to the current lack of a cure or effective long-term treatment for OA.

One re-emerging and interesting hypothesis …

Liver X Receptor And Retinoid X Receptor In Cartilage Development And Homeostasis, Man-Ger Sun

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is a heterogeneous and multifactorial degenerative disease characterized by cartilage degradation in the joint. Available treatment options target symptoms but do not address the underlying issue of joint tissue degeneration. A better understanding of the molecular mechanisms maintaining cartilage health is essential for developing novel therapeutic strategies. Previous studies have shown the nuclear receptor Liver X Receptor (LXR) to possess protective roles against cartilage breakdown in OA, however the underlying mechanisms behind this process remain unknown. Since LXR regulates transcription by forming obligate heterodimers with another nuclear receptor, the Retinoid X Receptor (RXR), I hypothesized that LXR and …

The Feasibility Of Square-Stepping Exercise As A Universal Intervention For Older Adults With Chronic Disease To Improve Cognitive And Physical Function, Erin M. Shellington

Electronic Thesis and Dissertation Repository

Square-stepping exercise (SSE) is a cognitive training program with a physical component. An instructor demonstrates a stepping pattern across a gridded mat and participants are required to memorize and repeat the patterns on their own. In community-dwelling older adults, SSE has demonstrated some benefits on global cognitive functioning (GCF), balance, functional fitness, and social interaction.

Aims: to investigate the feasibility and efficacy of SSE in varied populations and settings to improve mobility and cognition. Populations included older adults with: knee osteoarthritis (OA), type 2 diabetes mellitus (T2DM) and self-reported cognitive complaints (sCC), and those living in long-term care (LTC) …

Mechanical Properties Of Retrieved Highly Cross-Linked Polyethylene Acetabular Liners In Total Hip Arthroplasty, Gurpreet Singh

Electronic Thesis and Dissertation Repository

Highly cross-linked polyethylene (HXLPE) has replaced the conventional ultra-high-molecular-weight-polyethylene (UHMWPE) as the gold standard bearing surface in total hip arthroplasty (THA) due to superior wear characteristics and survivorship. However, HXLPE has demonstrated poorer mechanical properties, in vivo oxidation, and concerns of rim fractures. The purpose of this project was to study the mechanical properties at the rim of retrieved HXLPE acetabular liners.

We developed a simple technique for measurement of hardness at the rim of irradiated, remelted, HXLPE liners of a specific design. The effect of shelf time on mechanical properties of retrieved liners was determined and showed no correlation …

Fatigue In Children And Adolescents With Duchenne Muscular Dystrophy, Basmah El-Aloul

Electronic Thesis and Dissertation Repository

Fatigue was recently reported to be the largest predictor of poor health-related quality of life (HRQOL) in children and adolescents with Duchenne muscular dystrophy (DMD). The objectives of this thesis were to describe fatigue from patients’ and parents’ perspectives and to explore associations of patient characteristics with fatigue in children and adolescents with DMD using a multicentre cross-sectional study design. Eligible patients and their parents were identified via the Canadian Neuromuscular Disease Registry and received mailed paper questionnaires. Children and adolescents with DMD experienced greater fatigue compared to healthy controls from published data. Fatigue was a significant issue in children …

Disability And Return To Work Following Musculoskeletal Injury, Qiyun Shi

Electronic Thesis and Dissertation Repository

Musculoskeletal disorders (MSDs) are injuries, damage or disorders affecting the musculoskeletal system including muscles, ligaments, nerves, tendons, bones or cartilage etc. MSDs are highly prevalent and associated with sickness absence, reduced work efficiency, job changes and earlier retirement.. They also affect daily activity and social functioning. Although many MSDs are accompanied by minor symptoms and settled spontaneously, approximately 10% of the workforce with MSDs have difficulty resuming their original work or exit the workforce permanently. Return to work after MSDs is complex, and is influenced by many factors including physical, psychological, economic and social factors.

Although there are extensive studies …

Inpatient Versus Outpatient Total Hip Arthroplasty, Michael Pollock

Electronic Thesis and Dissertation Repository

We conducted a randomized controlled trial to evaluate patients undergoing a total hip arthroplasty (THA) who were discharged from the hospital either on the day of surgery (outpatient) or were admitted overnight following surgery (inpatient). Our primary outcome was the rate of serious adverse events during the first three months postoperatively. Secondary outcome measures included cost, patient satisfaction, functional outcomes, quality of life and pain. We found no statistically significant difference between the two groups in serious adverse events. We found that outpatient THA was less expensive from the perspectives of the hospital and ministry of health; but the difference …

Peroxisome Proliferator Activated Receptor Delta In Osteoarthritis, Anusha Ratneswaran

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) affects 1 in 10 Canadians and is a leading cause of mobility disability worldwide. This condition is characterized by cartilage degeneration, subchondral bone damage and inflammation of the synovium, resulting in pain and joint failure. No treatments exist to stop the progression of this disease, and its underlying molecular mechanisms remain largely unknown. We previously identified the peroxisome proliferator activated receptor (PPAR) nuclear receptor pathway as altered in OA cartilage. In-vitro studies identified PPARd as a promoter of catabolic activity in chondrocytes, providing the foundation for my overarching hypothesis that PPARd inhibition is protective in OA.

I commenced …

Epidermal Growth Factor Receptor In Joint Health And Osteoarthritis, Michael A. Pest

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases in the world. Our laboratory has shown that epidermal growth factor receptor (EGFR) signalling is involved in the process of cartilage degeneration in OA. Regulation of EGFR signalling by mitogen-inducible gene 6 (Mig-6) and dual specificity phosphatase 1 (DUSP-1) allows for signal modulation, and mouse models have linked these proteins to joint pathologies. Failure to control EGFR signalling may be involved in OA progression leading to my overarching hypothesis: regulation of EGFR signalling is essential for maintenance of joint health.

I initially tested the role of Mig-6 in cartilage health …

Investigating The Mechanism Of Ectopic Mineralization In A Mouse Model Of Diffuse Idiopathic Skeletal Hyperostosis (Dish), Neil A. Tenn

Electronic Thesis and Dissertation Repository

Equilibrative nucleoside transporter 1 (ENT1) transfers adenosine across plasma membranes. Mice lacking ENT1 (ENT1^-/-) develop pathological calcification of spinal tissues resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans. Our goal was to investigate the mechanism underlying ectopic mineralization in ENT1^-/- mice. We detected aberrant alkaline phosphatase (ALP, promoter of mineralization) activity in the annulus fibrosus (AF) of ENT1^-/- mice. In vitro, AF cells from ENT1^-/- mice exhibited greater ALP activity than cells from wild-type (WT) mice. Inhibition of ENT1 in the presence of extracellular adenosine modeled in WT cells the phenotype of ENT1 …

Methotrexate And Cardiovascular Events, Alpesh Shah

Electronic Thesis and Dissertation Repository

We conducted a systematic review and meta-analysis to assess the association of MTX with cardiovascular morbidity, cardiovascular mortality and all-cause mortality in patients with autoimmune disease. Our primary outcome was incident cardiovascular events. After screening 13,479 citations, we identified a total of 30 eligible studies. We synthesized adjusted risk estimates using a random effects model. MTX was significantly associated with a 25% reduction in cardiovascular events (pooled RR: 0.75, 95% CI: 0.65, 0.86, I²: 11%), a 55% reduction in cardiovascular mortality (0.45, 95% CI: 0.26, 0.80, I²: 33%) and a 40% reduction in all-cause mortality (0.60, …

A Health Promotion Perspective On Transitioning Into Retirement, Catherine P. Gelinas

Electronic Thesis and Dissertation Repository

The transitional stages towards retirement of those with chronic disorder(s) often present a diversity of additional challenges and people look at the measurement of their anticipated quality of life as a meaningful way of determining this successful adjustment. The overall objective of this research study was to understand transition into retirement considering the impact of comorbidity and associated socio-demographic factors have on the (physical and mental) health status. Quantitative data analysis of people (aged 50-65) with chronic upper extremity musculoskeletal disorders was used to inform health impacts in the group transitioning towards retirement; or who have selected or required early …

Gender Does Not Influence The Relationship Between Posterior Cruciate Ligament Design And Patient-Reported Outcomes In Patients Receiving Primary Unilateral Total Knee Arthroplasty, Ryan Milan

Electronic Thesis and Dissertation Repository

The effect of the interaction between gender and posterior cruciate ligament (PCL) prosthesis design on patient-reported outcomes is an understudied area of research. We evaluated 1613 patients, from the Ontario Joint Replacement Registry (2001-2006), who underwent primary total knee replacement. This study investigated the impact of the gender-PCL design interaction on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) change scores and patient satisfaction, by performing linear regression analysis, using full-adjusted models that also included the gender-PCL prosthesis design interaction variable. PCL prosthesis design did not affect WOMAC change scores or satisfaction (p>0.05). Moreover, Gender did not influence either …

Characterization Of Cardiomyopathy In A Mouse Model Of Duchenne Muscular Dystrophy (Dmd) Using Echocardiography, Dce-Ct, And Pet-Fdg, Seyed Hamed Moazami

Electronic Thesis and Dissertation Repository

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disease that is the result of a loss of functional dystrophin, which causes cardiomyocyte fibrosis and death, leading to cardiomyopathy. In this thesis, I have utilized dynamic contrast-enhanced computed tomography (DCE-CT), positron emission tomography-fluorodeoxyglucose (PET-FDG), echocardiography, and traditional histology to longitudinally assess disease progression and degree of cardiomyopathy in a murine model of DMD (mdx:utrn-/-). No significant changes were observed in the blood flow, blood volume, or cardiac volume measured via DCE-CT, nor in standard uptake value (SUV) of glucose as measured by PET-FDG in the left myocardium between and within …

Characterization Of Quadriceps Neuromuscular Function In Knee Osteoarthritis, Michael James Berger

Electronic Thesis and Dissertation Repository

PURPOSE: The purpose of this thesis was to characterize quadriceps neuromuscular dysfunction in patients with knee osteoarthritis (OA). Concerns pertaining to study design in this patient population (e.g. disease severity criteria and muscle imaging outcome measures) were also addressed.

METHODS: Five studies were undertaken using data acquired from volunteers recruited at the local institution and from participants in the public source dataset of the Osteoarthritis Initiative (http://oai.epi-ucsf.org/datarelease/). Clinical disease severity was evaluated with the Western Ontario and McMaster Osteoarthritis Index (WOMAC). Radiographic severity was evaluated with Kellgren-Lawrence Grading (KLG). Quadriceps muscle isometric strength and isotonic power were measured …