Diseases Commons^™

The Regulation Of Pannexin1 And Pannexin2 In The Skin In Health And Disease, Rafael E. Sanchez Pupo

Electronic Thesis and Dissertation Repository

Pannexins (PANX1, 2, 3) are a family of channel-forming glycoproteins that mediate intracellular and paracrine signaling. In contrast to PANX2, PANX1 has been extensively investigated in the skin, modulating cell differentiation, wound healing, and melanoma development. PANX1 and PANX2 can co-exist in the same cell and form mixed channels where their glycosylation seems to regulate their intermixing. N-glycosylation and caspase cleavage have been proposed as modulators of the function of PANX1, but their effects on PANX2 are unknown. We explored the PANX2 expression in mouse skin and showed that a Panx2 splice variant (PANX2-202) is continuously expressed throughout aging skin. …

Health Concerns Of Adolescents And Adults With Spina Bifida, Jessica A. Starowicz

Electronic Thesis and Dissertation Repository

The Transitional and Lifelong Care (TLC) program is a multidisciplinary clinical service providing comprehensive, coordinated care to adolescents and adults with spina bifida (SB). This study sought to identify the most common health concerns among this population at initial consultation and identify patient factors related to these concerns to ultimately improve health care delivery. A retrospective chart review was performed. Descriptive analyses were completed and associations between concerns and patient factors were determined using Spearman’s rho correlation coefficients. A multiple linear regression was performed to estimate the relationship between patient factors and total number of concerns reported. Ninety-four patient charts …

Incidence Of Cancer And Stage At Diagnosis Among People With Recent-Onset Psychotic Disorders, Jared C. Wootten

Electronic Thesis and Dissertation Repository

Evidence on cancer incidence in people with psychotic disorders, compared to the general population, is equivocal, although those with psychotic disorders so have more advanced stage of cancer at the time of diagnosis. The objective of this thesis was to compare cancer incidence and stage at diagnosis for people with psychotic disorders, relative to the general population. Our systematic review did not observe a significant difference in overall cancer incidence among people diagnosed with psychotic disorders (RR = 1.08, 95% CI: 1.00 to 1.16), however people with psychotic disorders were more likely to be present with advanced stage cancer at …

Genetic Approaches For The Study Of Complex Human Diseases, Julieta Lazarte

Electronic Thesis and Dissertation Repository

The field of human genetics has evolved from its initial narrow focus on single-gene Mendelian disorders, which largely affect children, to our current understanding that for most diseases there is continuum of rare to common variants which can exert a range of phenotypic effects. Despite advances in sequencing capabilities and our overall understanding of diseases, there remains a large proportion of heritability unexplained. Through the use of next-generation sequencing technologies and DNA microarray, I have explored a spectrum of genetic variations from rare, single and structural variants to common variants in individuals with i) “lone” atrial fibrillation; ii) familial hypercholesterolemia; …

Characterizing The Cellular, Molecular, And Behavioural Pathology Of Repetitive Mtbi In A Human Tau Transgenic Mouse, Morgan A. Walker

Electronic Thesis and Dissertation Repository

After an episode of repetitive mild traumatic brain injury (rmTBI), many cellular and molecular cascades are initiated that result in the disruption of the structural and chemical integrity of the components in the brain, leading to the development of various cognitive deficits. The goal of this thesis was to evaluate a mouse model of concussion in order to study the relationship between rmTBI, GSK3β and tau phosphorylation, and behavioural outcomes in a transgenic mouse line expressing solely human tau. We found that there was increased phosphorylation of the two main regulatory sites on GSK3β, Tyr216 and Ser9, in the C57BL/6 …

Addressing Bias In Non-Experimental Studies Assessing Treatment Outcomes In Prostate Cancer, David E. Guy

Electronic Thesis and Dissertation Repository

We evaluated the ability of matching techniques to balance baseline characteristics between treatment groups using non-experimental data. We identified a set of balance diagnostics that assessed key differences in baseline covariates with potential for confounding. These diagnostics were used in a novel systematic approach to developing and evaluating models for use in propensity score matching that optimized balance and data retention. We then compared the performance of propensity score and coarsened exact matching strategies in optimizing balance and data retention, using non-experimental data from a pan-Canadian prostate cancer database. Both matching techniques balanced baseline covariates adequately and retained approximately 70% …

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 …

Measuring The Impact Of Atrial Fibrillation On Patients, Justine Chang

Electronic Thesis and Dissertation Repository

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Patients experience the effects of AF from early symptom onset to treatment and beyond. A previous qualitative study found AF to substantially affect patients’ emotional wellbeing, social relationships, employment, and finances. Existing quality of life questionnaires do not adequately assess the AF impact. In this thesis, a new patient-reported questionnaire was developed to measure the impact of AF as experienced by patients. An exploratory factor analysis was conducted on the new questionnaire, revealing five domains: “Affect”, “Social Support”, “Major Life Events”, “Financial Impact”, and “Diagnostic Experience”. Age, marital status, educational …

Spinal Excitability Changes Following Sensory Electrical Stimulation Of The Forearm, Devin K. Box

Electronic Thesis and Dissertation Repository

Sensory electrical stimulation can be used to suppress tremor in Parkinson’s disease. This study investigated the central mechanism underlying this suppression in healthy participants. Reciprocal inhibition (RI) of the wrist flexors before and after a session of sensory electrical stimulation (SES) applied to the antagonistic extensor muscles was assessed using electromyography. It was hypothesized that a 15-minute session of SES, rated by participants as a 3 on a 0-10 pain scale, would produce an increase in RI. Seven of the 18 participants experienced an increase in RI at 0-5 minutes post stimulation, which returned to baseline at 10-15 minutes. The …

Testing A Novel Peptide-Infused Cream For Treatment Of Rheumatoid Arthritis In Dr4tg Mice, Alisha J. Moynahan

Electronic Thesis and Dissertation Repository

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes joint pain and damage. Studies have shown that inducing immune tolerance towards RA-specific proteins/peptides in RA mouse models can reduce arthritis severity and pro-inflammatory responses. The objectives of this study were to determine if a novel peptide cream treatment could modify RA-specific immune responses and reduce joint swelling in a humanized mouse model expressing the HLA-DRB1*0401 allele (known as DR4tg mice), the strongest genetic risk-factor for RA. Hyaluronan-Phosphatidylethanolamine cream infused with synthetic peptides HomoCitJED and CitJED was applied to HomoCitJED-immunized DR4tg mice before or after arthritis induction. Knee joint …

Exploring The Burden Experiences Of Care Partners For People With Parkinson's Disease Living In Southwestern Ontario, Lisa A. Moszczynski

Electronic Thesis and Dissertation Repository

This thesis quantitatively explored the burden experiences of care partners of people with Parkinson’s Disease in Southwestern Ontario. Thirty-five complete responses (27 females, 8 males) and three partial responses to an online survey were obtained. The survey included a demographic section (41 items), two measures of burden and a quality of life measure. Care partner data were stratified based on Zarit Burden Inventory scores for analysis. Of the Little to No Burden (n=4), Mild Burden (n=15), Moderate Burden (n=8), and Severe Burden (n=4) groups, weekly hours spent on care duties and years in the care partner role were similar. The …

Hiv-1 Drug Resistance To Integrase Strand Transfer Inhibitors In Hiv-1 Non-B Subtypes, Emmanuel Ndashimye

Electronic Thesis and Dissertation Repository

Human immunodeficiency syndrome (HIV-1) has infected over 75 million people and over 35 million have succumbed to virus related illnesses. Despite access to a variety of antiretroviral therapy (ART) options, ART programs have been disproportionally spread in the world with low-and middle-income countries (LMICs) facing challenges to access the most potent ART options. With less potent ART remaining in use in LMICs, HIV-1 drug resistance (HIVDR) presents a growing challenge in LMICs. Since approval of the first-generation integrase strand transfer inhibitor (INSTIs), Raltegravir (RAL) in 2007, INSTIs remain the best choice as a backbone of ART. Access to second generation …

Trna Regulation In Humans: The Cellular Effect Of A Pathological Hars Y454s Mutation, Rosan Kenana

Electronic Thesis and Dissertation Repository

tRNAs are the adapter molecules involved in translating the genetic code into functional protein in a living cell. tRNAs are charged with their cognate amino acids - by aminoacyl-tRNA synthetases (aaRS or ARS) - which are then transferred to a growing peptide in a process called mRNA translation. The efficiency of translation is dependent on the ratio of ARS enzymes to their cognate tRNAs and the availability of correctly amino acylated tRNAs. Disruptions of this process, caused by mutations in ARS genes, in particular, have been linked to complex inherited diseases. USH3B syndrome, a recessively inherited disorder among consanguineous families …

Novel Imaging Tools Reveal The Dynamics Of The Myocardial Growth Hormone Secretagogue Receptor In Heart Disease And Heart Failure, Rebecca Sullivan

Electronic Thesis and Dissertation Repository

Heart disease (HD) is the leading cause of mortality worldwide. Currently, diagnosis is based on clinical features, imaging, and circulating cardiac biomarkers. Cardiac imaging technologies, such as echocardiography and cardiac magnetic resonance imaging (cMRI), enable the non-invasive detection of changes in heart function. Although these modalities can detect changes in structure and anatomy, it is usually at later stages, where prevention may not be possible. In conjunction with imaging, circulating biomarkers of heart failure (HF), notably B-type natriuretic peptide (BNP) and cardiac troponin I and T, can be detected with increased levels in the blood. These biomarkers are associated with …

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 …