Medicine and Health Sciences Commons^™

The Effects Of Maternal Delta-9-Tetrahydrocannabinol And Cannabidiol Exposure On Fetal Heart Development In Mice, Gregory Robinson

Electronic Thesis and Dissertation Repository

Up to 22.6% of pregnant women consume cannabis during pregnancy despite the uncertainty of teratogenicity of the main ingredients in cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). This study tested the hypothesis that gestational THC and CBD exposure leads to heart abnormalities. Daily, oral THC exposure induced heart abnormalities in 68% of offspring with three main phenotypes including thickened semilunar valves, ventricular myocardial hypertrophy and hypoplastic coronary arteries in fetuses, and postnatal cardiac dysfunction. Altered gene expression of key cardiogenic regulators, increased proliferation, and reduced epicardial epithelial-to-mesenchymal-transition were demonstrated implicating potential mechanisms responsible for these abnormalities. Also, maternal CBD exposure resulted …

The Effect Of Mtor Inhibitor Rapamycin On A Dietary Drosophila Melanogaster Model Of Calcium Oxalate Nephrolithiasis, Michael T. Pignanelli

Electronic Thesis and Dissertation Repository

Impaired cellular tolerance of reactive oxygen species (ROS) has been suggested as a common mechanistic link associated with aging in both metabolic syndrome and nephrolithiasis. The mechanistic (mammalian) target of rapamycin (mTOR) activity is characteristic of metabolic syndrome. When nutrients are abundant, mTOR is active. Conversely, fasting inhibits mTOR. Metabolic syndrome is correlated with an increased risk of self-reported or imaging findings of nephrolithiasis. At the individual level, patients with a higher BMI have an increased prevalence of recurrent symptomatic nephrolithiasis, 24-hour urinary excretion of oxalate, sodium, uric acid, calcium, and phosphorous as well as lower pH. Calcium oxalate crystals …

Cardiovascular Effects Of Exercise And Use Of Abdominal Binder In Patients Of Parkinson’S Disease With Orthostatic Hypotension, Faizan Ahmed

Electronic Thesis and Dissertation Repository

Orthostatic hypotension (OH) is a common manifestation of autonomic dysfunction in Parkinson’s Disease. It can adversely affect a patient’s functional capacity, exercise tolerance and quality of life, while increasing the risk of falls, cerebrovascular disease and overall mortality. Use of an abdominal binder (AB) can help counter OH; however, this has not been sufficiently studied in patients with Parkinson’s Disease (PwPD). Moreover, the hemodynamic effects of upper and lower extremity exercise are unclear in PwPD with OH. Although OH can impair the cerebral circulation, the consequences on the cerebral hemodynamics of wearing an AB or performing exercise are unknown in …

Ultrasound-Guided Resuscitation In Open Aortic Surgery - The Aortus Trial, John H. Landau

Electronic Thesis and Dissertation Repository

Introduction: Major abdominal aortic surgery requires significant fluid resuscitation in the post-operative phase. Patients are at significant risk of perioperative morbidity and mortality which can be affected by the approach to post-operative fluid resuscitation. Point of care ultrasonography (POCUS) has evolved as a tool to perform whole-body assessments at the bedside to augment the physical exam and guide the resuscitation of the critically ill. This study will aim to explore the value of rigorous goal-directed resuscitation in aortic surgery using point of care ultrasonography (POCUS).

Methods: In an open-label, randomized, feasibility trial we enrolled 17 patients to receive resuscitation guided …

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 …

Developing A Model To Assess The Contribution Of Cytokeratin 19-Expressing Cells During Multipotent Stromal Cell-Induced Islet Regeneration, Brianna Ananthan

Electronic Thesis and Dissertation Repository

Previously, pharmacological activation of Wnt-signaling in human bone marrow-derived multipotent stromal cells (hMSC) generated conditioned media (CM) that promoted β-cell regeneration in streptozotocin-treated mice. Ductal-derived endocrine progenitors, which have been shown to generate β-cells following pancreatic injury, represent a candidate for the ‘signal-receiving cell’. Ductal (CK19+) cells from mice pancreata obtained by purification of live Dolichos Biflorus Agglutinin lectin+ cells and cultured in minimal media supplemented with Untreated, Wnt-activated, or Wnt-inhibited CM demonstrated a significantly increased proportion of EdU+/CK19+ cells following 48-hours of supplementation but no endocrine phenotype acquisition. Lineage-tracing CK19-CreERT;Ai9(RCL-tdT) mice treated with tamoxifen (single dose) demonstrated specific labeling …

The Impact Of Ethnicity And Immigration On Prostate Cancer Mortality In Canada, Noah Stern

Electronic Thesis and Dissertation Repository

Despite the prevalence of prostate cancer its pathogenesis remains unclear. Marked differences in mortality rates have been observed between countries, however, it is unclear whether the source of the observed differences is driven by underlying genetics, geographic, or social factors. This thesis investigated the impact of ethnicity and immigration on prostate cancer mortality in Canada using the Canadian Census Health and Environment Cohort. South Asian and East Asian men were seen to be at decreased risk of prostate cancer mortality, while no increased risk was observed in black men. These results affirm studies showing lower risks in Asian men; however, …

Prematurity, Socioeconomic Status, And Childhood Asthma: A Canadian Cohort Study, Crystal P. Mcleod

Electronic Thesis and Dissertation Repository

Introduction: Preterm birth (PTB) and socioeconomic status (SES) have both been associated previously with the onset of childhood asthma in high income countries. Yet, these factors have been studied minimally outside of an exposure or confounded relationship, and amongst the Canadian population.

Materials and Methods: Merging household interview data from Cycles 2 to 5 of the Canadian Health Measures Survey, this study analyzed data from weighted respondents in early (3-5 years, n = 1,096,609) and middle (6-11 years, n = 2,112,059) childhood. Bivariate, stepwise logistic regression, and logit decomposition were performed using STATA software. Intersectionality guided the study’s methodology.

Results: …

The Role Of Regulator Of G Protein Signaling 2 In Inflammatory Cytokine Release In Endotoxemia In Mice, Xin Tong Ma

Electronic Thesis and Dissertation Repository

In sepsis, lipopolysaccharide (LPS) activates toll-like receptor 4 to stimulate the release of inflammatory cytokines (e.g. tumor necrosis factor-alpha, TNF-α), leading to cardiac dysfunction. Regulator of G protein signaling 2 (RGS2) limits G protein-coupled receptor signaling by increasing the rate of G protein deactivation or inhibiting G protein-effector interactions. We hypothesized that RGS2 deficiency would enhance proinflammatory responses in endotoxemia. Adult wild-type and RGS2^-/- C57BL/6 mice and neonatal cardiomyocytes were treated with LPS and assessed for inflammatory responses and cardiac function. Myocardial TNF-α expression was higher in RGS2^-/- mice during endotoxemia. Additionally, cardiac function was impaired in …

Boosting Cellular Nad+ Concentration With Nicotinamide Mononucleotide Prevents Doxorubicin-Induced Cardiotoxicity, Rebecca Dang

Electronic Thesis and Dissertation Repository

Doxorubicin (DOX) is a powerful chemotherapy that functions by interfering with cancer cells’ growth. However, the use of DOX is limited due to its detrimental side effects that can lead to serious cardiovascular complications. Our goal is to determine if nicotinamide mononucleotide (NMN) and histone acetyltransferase (HAT) inhibitors can protect against DOX-induced cardiotoxicity. Our findings revealed that DOX reduced NAD⁺ concentration and induced damage to H9c2 cells as evidenced by higher caspase-3 activity and lactate dehydrogenase release. Pre-incubation with NMN increased NAD⁺ concentration and attenuated DOX-induced damage. There was higher cell viability in the NMN pre-incubated group compared …

Multi-Scale Evolution Of Virulence Of Hiv-1, David W. Dick

Electronic Thesis and Dissertation Repository

HIV-1 is a rapidly replicating retrovirus that faces two distinct fitness landscapes: within-host HIV-1 faces viral competition for host cells and for escape from the immune system, and between hosts HIV-1 faces a transmission bottleneck in which the majority of new infections are started by a single virus strain. Possibly as a result of these conflicting selective pressures, the rate of evolution of HIV-1 tends to be greater within-host than between hosts.

A current hypothesis for this difference in evolutionary rates is that the HIV-1 latent reservoir acts to archive virus for later transmission. We offer a related but complimentary …

In-Hospital Outcomes Following Left Atrial Appendage Closure, Shubrandu S. Sanjoy

Electronic Thesis and Dissertation Repository

Left atrial appendage closure (LAAC) is a non-pharmacologic approach for stroke prevention in patients with atrial fibrillation. The impact of comorbidity burden on adverse outcomes following LAAC is very important for clinical decision making. Cohort-based observational study was conducted to evaluate the association of comorbidity burden with in-hospital complications. Of 3294 participants (mean age was 75.7±8.2 years), 60% were male and 86% whites. The majority of participants undergoing LAAC presented with a significant number of comorbid conditions. The occurrence of in-hospital major adverse events (MAE) was 4.6%. Women and patients exhibiting higher Charlson Comorbidity Index (adjusted odds ratio [aOR]: 1.14, …

Characterizing T Cell Phenotype In Patients With Hypersensitivity Reactions To Sulfamethoxazole And Beta-Lactam Antibiotics, Christine Caron

Electronic Thesis and Dissertation Repository

Delayed drug hypersensitivity reactions (DHRs) are idiosyncratic, T-cell mediated, and can present days after exposure to the culprit drug, resulting in varying degrees of skin rashes. We hypothesize that differences in activated peripheral T cell subsets and types of mediators released produce different clinical phenotypes of drug hypersensitivity reactions to sulphnamides and beta-lactam antibiotics.

We recruited participants with previous DHRs to sulfamethoxazole or beta-lactams . Peripheral blood mononuclear cells were isolated from participants. T-cell subset proliferation and activation was assessed by T-cell specific surface markers using 3H- thymidine incorporation and flow cytometry, and secreted cytokines were measured using bead-based detection. …

Implications Of Long Non-Coding Rnas In The Pathogenesis Of Diabetic Retinopathy: A Novel Epigenetic Paradigm., Saumik Biswas

Electronic Thesis and Dissertation Repository

With the rising incidence of diabetic retinopathy (DR), there is an urgent need for novel therapies. Presently, several altered metabolic pathways have been implicated in the pathogenesis of DR. Recent advances in genomic technologies have identified considerable epigenetic alterations that also contribute to DR progression. Long non-coding RNAs (lncRNAs; >200 nucleotides), critical regulators of gene expression, are aberrantly expressed in DR and have not been comprehensively characterized. Our microarray analyses using human retinal endothelial cells (HRECs) revealed thousands of differentially expressed lncRNAs following high glucose (HG) exposure, with profound increases in the lncRNAs MALAT1 and HOTAIR. Using multiple techniques, …

Nutrient Sensing Pathways Mediating Igfbp1 Phosphorylation In Fgr, Shapnil Bhuiyan

Electronic Thesis and Dissertation Repository

Impairment of fetal oxygen levels and nutrient delivery contributes to fetal growth restriction (FGR), which affects 20% of pregnancies. Such cellular stress induces hepatic Insulin-like Growth Factor Binding Protein 1 (IGFBP1) phosphorylation, which sequesters Insulin-like Growth Factor 1 (IGF-I) and markedly reduces fetal growth signaling. IGFBP1 hyperphosphoryaltion in hypoxia is mediated through the mTOR signaling pathway and through the Amino Acid Response (AAR) pathway during amino acid deprivation. Hypoxia stimulates upstream mTORC1 regulators, AMPK and REDD1 which are well-established upstream regulators of one of the two mTOR complexes, mTORC1. The molecular mechanisms by which upstream mTORC1-driven processes regulate IGFBP1 phosphorylation …

Regulation Of Glucagon Secretion And Trafficking By Proteins In The Glucagon Interactome, Farzad Asadi Jomnani

Electronic Thesis and Dissertation Repository

Patients with diabetes exhibit hyperglucagonemia, or excess glucagon secretion. The glucagonocentric hypothesis of diabetes states that hyperglucagonemia, rather than hypoinsulinemia, may be the underlying mechanism of hyperglycemia of diabetes. Thus, uncovering mechanisms that regulate glucagon secretion from pancreatic α-cells is crucial for developing treatments for hyperglycemia. One clue to the regulation of glucagon secretion may lie in the proteins that interact with glucagon in α-cell’s secretory pathway, primarily within the secretory granule. The purpose of my work was to identify proteins that interact with glucagon within the secretory granule and characterize a candidate protein within this network that regulates the …

Atypical Structural Connectivity And Integrity In Children With Hydrocephalus And Its Relation To Executive Function, Daamoon Ghahari

Electronic Thesis and Dissertation Repository

Infants with hydrocephalus are a high-risk group for adverse neurodevelopmental outcomes, including impairments in executive functions such as goal-directed behaviour, focusing, and shifting attention. The current pilot study aimed to profile white matter and executive dysfunction in school-aged children with ventriculoperitoneal (VP) shunted hydrocephalus and age-matched healthy controls using the Behaviour Rating Inventory for Executive Functions and diffusion tensor imaging. To assess the degree of similarity between patient structural networks and controls, probabilistic streamlines between striatal and cortical regions and their respective diffusivity metrics were assessed. For a number of patients with hydrocephalus, white matter in the striatal-executive network showed …

Development And Evaluation Of A Heterogenous Virus-Like Particle (Vlp) Formulation To Achieve Hiv-1 Latency Reversal And Cure., Joshua P. Pankrac

Electronic Thesis and Dissertation Repository

HIV-1 is the etiological agent behind acquired immune deficiency syndrome (AIDS) – a chronic, life-threatening condition that compromises host immune function. After nearly four decades and despite ongoing global efforts, HIV-1 persists in nearly 38 million individuals worldwide. Of this population, only 60% have access to life-saving combination antiretroviral therapy (cART), clearly emphasizing the need to realize a cure. Unfortunately, the establishment of replication-competent provirus in resting CD4+ T lymphocytes represents a significant barrier to HIV-1 curative research. The viral reservoir is highly stable and has a half-life of ~44 months. Therefore, it is unlikely that infection will naturally exhaust …

Synergistic Effects Of Non Contact Induction Heating & Antibiotics On Staphylococcus Aureus Biofilm, Rajeshwar Singh Sidhu

Electronic Thesis and Dissertation Repository

Staphylococcus aureus is a major cause of prosthetic joint infection (PJI) in which it forms adherent biofilms, thick aggregates of extracellular polymeric substances (EPS) produced by the bacteria. Biofilm associated infections are difficult to treat as they have increased resistance to various antimicrobial agents, which means infected implants often require multiple procedures and prolonged antibiotic therapy. However, a new and emerging method of treatment of PJI is non-contact induction heating (NCIH) of metal implants. We sought to investigate the feasibility and effectiveness of NCIH along with synergistic effects of antibiotics (Vancomycin) in reducing bacterial load within surface associated biofilms 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 …

Advanced Phenotyping Of Otosclerosis In An Ontario Population And Two Large Newfoundland Families, Matthew B. Lucas

Electronic Thesis and Dissertation Repository

Otosclerosis is a relatively common hearing loss disorder characterized by abnormal bone growth in the otic capsule leading to stapes fixation. In approximately half of cases, otosclerosis is inherited as an autosomal dominant trait. Typically, gene discovery efforts rely on surgical confirmation, audiometry and occasionally acoustic reflexes to identify affected cases of otosclerosis within families, requiring that the otosclerosis was at an advanced stage to be detected. This makes it difficult to identify individuals with early otosclerosis. The use of advanced phenotyping to identify cases of otosclerosis was tested in an Ontario otosclerotic population as well as in two large …

Effects Of Increased Sulfatide In Schwann And Mesenchymal Stromal Cells In Metachromatic Leukodystrophy, Srinitya Gannavarapu

Electronic Thesis and Dissertation Repository

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by deficient arylsulfatase A (ARSA) activity, resulting in intra-lysosomal accumulation of sulfatide. Sulfatide is integral for proper maintenance of myelin in the central and peripheral nervous systems. This study characterized mitochondrial morphology, cytokine secretion and phagocytic activity in Schwann and mesenchymal cells isolated from ARSA^-/- mice. Cells were treated with different, increasing concentrations of sulfatide for a period of 24 hours. ARSA^-/- cells presented with persistent, increased fragmented mitochondrial structures suggestive of prolonged mitochondrial fission. Sulfatide treatments increased secretion of pro-inflammatory cytokines TNF-α and IL-1β in ARSA^{-/- …}

Optimizing Fecal Microbiota Transplantations For Therapeutic Use Beyond Clostridioides Difficile Infection, Laura J. Craven

Electronic Thesis and Dissertation Repository

Fecal microbiota transplantation (FMT) is an emerging and effective therapy for the treatment of recurrent Clostridioides difficile infection. Members of the gut microbiome have been implicated in other diseases and FMT has been considered as a potential therapy. Two such conditions include non-alcoholic fatty liver disease (NAFLD) and multiple sclerosis (MS), both of which involve increased small intestinal permeability believed to contribute to the development and disease progression. One of the aims of this project was to determine if FMT could be safely used in patients with NAFLD and MS to improve health outcomes. Before starting the clinical studies, optimal …

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 …

Multimodality Imaging To Quantify The Pulmonary Vascular Tree In Copd, Andrea L. Barker Odhiambo

Electronic Thesis and Dissertation Repository

Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating disease resulting in chronic cough, shortness of breath, activity limitation and decreased pulmonary function. Developments in imaging technology have provided sensitive and reliable modalities for evaluating regional lung function and disease progression, and there is a growing interest in the role of imaging the vasculature in COPD. The ability to predict whether a patient is at risk of accelerated decline is important to disease management strategies. We hypothesize that CT blood vessel volume measurements are significantly different in ex-smokers without COPD than in those with this disease and will be …

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 …

Behavioural And Molecular Consequences Of Postnatal Stress In A Mouse Model Of Fetal Alcohol Spectrum Disorder, Bonnie Alberry

Electronic Thesis and Dissertation Repository

Fetal alcohol spectrum disorders (FASD) are caused by prenatal alcohol exposure (PAE) and affect 1‑5% of the North American population. Children born with FASD often face maternal separation throughout childhood. How this early life stress (ELS) affects the severity of FASD-related deficits is poorly understood. Using a mouse model, this dissertation establishes that behavioural deficits accumulate following prenatal alcohol exposure and early life stress, assessed using tests for activity, anxiety-like behaviour as well as learning and memory. Hippocampal gene expression was evaluated using RNA-seq followed by clustering of expression profiles through weighted gene co-expression network analysis (WGCNA). A set of …