Medicine and Health Sciences Commons^™

The Rho Gtpases Rac1, Cdc42, And Rhoa Regulate App Transport To Lysosomes And Aβ Production, Justin K. Chiu .

Electronic Thesis and Dissertation Repository

Alzheimer’s Disease (AD) is characterized by Beta-Amyloid (Aβ) plaques within the brain. Aβ peptides are produced by the cleavage of Amyloid Precursor Protein (APP). Our lab has previously discovered a novel pathway for APP internalization mediated by ADP-ribosylation factor 6 (Arf6). This pathway resembles macropinocytosis, transporting cell surface APP directly to lysosomes, a possible site for Aβ production. We set out to characterize the effectors downstream of Arf6. In SN56 and N2A cells we co-transfected HA-tagged APP (to label cell-surface APP) with compartment markers, to visualize APP trafficking. We used dominant negative and constitutively active mutants, pharmacological inhibitors, and siRNA …

Phase Ii Clinical Trial Of Concurrent Neoadjuvant Chemotherapy With Radiotherapy In Locally Advanced Breast Cancer, Muriel Brackstone

Electronic Thesis and Dissertation Repository

Locally advanced breast cancer (LABC) represents 15% of all non-metastatic breast cancers, with an overall poor prognosis, despite current guidelines that recommend neoadjuvant chemotherapy followed by surgery and adjuvant radiation. Therefore, a novel treatment paradigm using concurrent neoadjuvant chemoradiotherapy was proposed. A clinical trial was designed, where 32 LABC patients were treated with q3 weekly 5-fluorouracil, epirubicin and cyclophosphamide for three cycles, followed by weekly docetaxel for 9 weeks with concurrent regional radiation (45+5.4Gy) for the first 6 weeks. Patients subsequently underwent modified radical mastectomies. Pathological complete responses (pCR) and 3 year overall survival rates were compared to a matched …

Evidence Reversal: When New Evidence Contradicts Established Practices, Desiree S. Sutton

Electronic Thesis and Dissertation Repository

Evidence reversal occurs when new evidence contradicts established practices. The first component of this thesis is an umbrella overview of investigations – reviews and collections of studies – into evidence reversal to gather concepts and methods that we identified as useful to lay a foundation for a standardized ‘theory of reversal.’ The foundation of this review enables the construction of a framework that will provide structure to this field, as no formal organization currently exists. The next component builds upon this foundation and proposes a framework for evidence reversal and its related concepts. The second review takes this framework …

Quality Of Life And Subjective Outcomes Following Maxillomandibular Advancement Surgery For The Treatment Of Obstructive Sleep Apnea, Andrew D. Emanuele

Electronic Thesis and Dissertation Repository

Objective: The aim of this study was to assess outcomes related to general quality of life, daytime sleepiness and functional sleep outcomes, functional outcomes of orthognathic surgery, and facial aesthetics in patients undergoing maxillomandibular advancement (MMA) surgery for the treatment of obstructive sleep apnea (OSA).

Materials and Methods: This was a cross-sectional self-report study. A questionnaire was constructed using questions drawn from previously validated questionnaires. The survey was distributed to 25 patients who underwent MMA surgery for the treatment of OSA at LHSC in London, Ontario by a single surgeon between 2002 and 2013.

Results: The survey results showed that …

The Role Of Bone Sialoprotein In Periodontal Tissue Development And Bone Repair, Yohannes Soenjaya

Electronic Thesis and Dissertation Repository

Bone development and repair involve complex processes that include interaction between cells and their surrounding matrix. In the body, bone sialoprotein (BSP) expression is up-regulated at the onset of mineralization. BSP is a multifunctional acidic phosphoprotein with collagen-binding, hydroxyapatite nucleating, and integrin recognition (RGD sequence, which is important for cell-attachment and signaling) regions. Mice lacking BSP expression (Bsp^-/-), exhibit a bone phenotype with reductions in bone mineral density, bone length, osteoclast activation, and impaired bone healing. This thesis examined the role of BSP in tooth development and also its potential use as a therapeutic reagent for bone …

Semantic Integration In Adults With Nonverbal Learning Disabilities And Autism Spectrum Disorder: Influence Of Word Knowledge And Gestalt Perception, Margot E. Stothers

Electronic Thesis and Dissertation Repository

Language in individuals with nonverbal learning disabilities (NLD) and autism spectrum disorder (ASD) has been described as semantically empty and impoverished, despite apparently average word knowledge. Here, inter-related studies explored semantic representations in adults with these disorders of social perception. Studies highlighted semantic integration, a form of gestalt perception in which new concepts are developed by connecting familiar terms in novel ways. Semantic integration was compared to vocabulary breadth, and to nonverbal gestalt perception, comparing clinical groups to each other and to adults without a diagnosis. Because weaknesses in gestalt perception have been seen in NLD and ASD, it was …

Serotonergic System And Gait: Dorsal Raphe Nucleus As A Control System For Gait, Nahal Farhani

Electronic Thesis and Dissertation Repository

In advanced stages of Parkinson Disease (PD), gait and postural abnormalities emerge. These symptoms are not prominent at early stages of PD despite significant dopaminergic neuronal loss. Gait abnormalities are largely not responsive to levodopa. Therefore, other types of neurons might be responsible for gait abnormalities of the PD.

Since the reticulospinal tract (RET) is mainly implicated in the control of axial muscles, the degeneration of this pathway or populations of neurons controlling this pathway might be responsible for axial symptoms. However, there is limited data about the neurons controlling the RET. Our aim in this study is to delineate …

Exercise Identity: Origins, Applications, And Future Utility, Vincent L. Liardi

Electronic Thesis and Dissertation Repository

It has been determined that exercise identity (EI) is a key component of the self-concept and is a strong determinant of exercise behaviours. The primary purpose of study 1 was to examine EI’s relationship with three key self-presentational variables: self-presentational efficacy (SPE), social physique anxiety (SPA), and impression motivation (IM). Specifically, we looked at how EI contributed uniquely to predicting exercise behaviour over and above these self-presentational concerns. The analyses demonstrated that EI is positively correlated with SPE and unrelated to SPA in both genders. Further analyses revealed that EI contributes a significant amount of variance towards exercise behaviour over …

Intracellular Acidification In Brain Tumors Induced By Topiramate : In-Vivo Detection Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging, Kamini Y. Marathe

Electronic Thesis and Dissertation Repository

Glioblastoma Multiforme (GBM) is the most aggressive and malignant form of primary brain tumor. In many tumors, increased intracellular pH (pH_i) is a hallmark of aggressiveness. This increased pH_i has been shown to be related to cell proliferation and evasion of apoptosis as well as resistance to chemotherapy. As such, monitoring pH_i and the tumor pH_i response to pharmacologic challenge, may aid in treatment planning and patient management for this deadly cancer. A magnetic resonance imaging (MRI) method called Chemical Exchange Saturation Transfer (CEST) has been used to detect changes in pH_i. Our group …

Smoking And Exercise: Mechanisms And Effects During Simulated And Genuine Quit Attempts, Stefanie De Jesus

Electronic Thesis and Dissertation Repository

Cigarette smoking is a leading agent for premature morbidity and mortality among the global community. Most individuals surrender to tobacco use disorder due to the inability to cope with cravings and withdrawal symptoms. Exercise appears to provide acute relief. Currently, it is unclear how exercise attenuates these reductions. Furthermore, the available evidence has focused on acute outcomes besides smoking behaviour and is limited to simulated quit attempts. Three experimental studies were designed to address these outstanding issues. Not surprisingly, a bout of moderate intensity exercise was found in study 1 (chapter 2) to reduce cravings associated with a temporary period …

Mothers Experiencing Homelessness: Social Exclusion, Resistance, And Health, Sarah Benbow

Electronic Thesis and Dissertation Repository

Background and Purpose: Mothers experiencing homelessness in Canada are faced with unique challenges in achieving health. The purpose of this two-phase study was to critically examine the socio-political context, health needs, exclusionary and inclusionary forces, and strategies of resistance demonstrated by mothers experiencing homelessness.

Methodology: This study falls under the critical paradigm informed by the theoretical perspective of intersectionality. Methodologies employed included critical narrative and critical discourse analysis. Data were collected at various homeless shelters and programs that provide services for women and mothers who are homeless in Southern Ontario. A purposive sample of women experiencing homelessness, and service …

Towards The Development Of A Wearable Tremor Suppression Glove, Yue Zhou

Electronic Thesis and Dissertation Repository

Patients diagnosed with Parkinson’s disease (PD) often associate with tremor. Among other symptoms of PD, tremor is the most aggressive symptom and it is difficult to control with traditional treatments. This thesis presents the assessment of Parkinsonian hand tremor in both the time domain and the frequency domain, the performance of a tremor estimator using different tremor models, and the development of a novel mechatronic transmission system for a wearable tremor suppression device. This transmission system functions as a mechatronic splitter that allows a single power source to support multiple independent applications. Unique features of this transmission system include low …

The Use Of Exercise Self-Talk By Female Adolescents, Sadie Puddister

Electronic Thesis and Dissertation Repository

Already below recommended levels, physical activity participation in female youth is known to decline throughout adolescence. Self-talk, a form of self-regulation has been demonstrated to influence behaviour in both sport and exercise settings. The purpose of the present research was to explore the exercise related self-talk of teen girls (aged 14-18) with the intent of uncovering reoccurring themes and attributes in the self-talk of both low frequency exercisers (LFEs) and high frequency exercisers (HFEs). Participants were teen girls (N=28, M_age=15.56, SD_age=1.47) recruited from A. B. Lucas Secondary School in London, Ontario. Physical activity …

Evidence For Using Immunosuppressive Treatments When Treating Idiopathic Non-Infectious Uveitis: A Systematic Review And Meta-Analysis, Hargurinder Singh

Electronic Thesis and Dissertation Repository

Idiopathic non-infectious uveitis is the spontaneous inflammation of the eye, which can lead to blindness if not treated correctly. Due to long-term side effects of corticosteroids, 4 classes of off-label immunosuppressive treatments are sometimes used (alkylating agents, inhibitors of T-lymphocyte signalling, antimetabolites and biological modifiers). We conducted a systematic review and meta-analysis to assess the effectiveness of different treatment classes on uveitis patients with similar characteristics. Results of the systematic review concurred with the conclusions from the meta-analysis, which found that all immunosuppressive treatments improved patient vision, with a statistically significant change in logMAR of -0.11 (95% CI of -0.152 …

Physical Exertion As A Risk Factor For Ventricular Arrhythmia: A Prospective Cohort Study, Harpreet S. Chahal

Electronic Thesis and Dissertation Repository

Episodes of physical exertion are associated with an immediately higher risk of cardiovascular events while physical activity over the long-term is cardioprotective. To assess the transient and long-term risk of ventricular arrhythmia (VA), we conducted a nested case-crossover study within a prospective cohort of 97 patients with implantable cardioverter-defibrillators (ICD). Within an hour of episodes of exertion, the risk of VA was 5.3 (95% CI 2.7 – 10.6) times greater compared to periods of rest. The association was higher among patients with aerobic fitness below the median (RR[relative risk]=17.5, 95% 5.2 – 58.5) than for patients with aerobic fitness above …

Overcoming Innate And Acquired Therapy Resistance By Targeting Dna Repair In Human Cancer Cells, Mateusz Rytelewski

Electronic Thesis and Dissertation Repository

Genomic instability and a high mutation rate lead to heterogeneity in human tumors. Mathematical modelling predicts that these characteristics promote acquired resistance to cytotoxic and targeted therapies, by increasing the likelihood that resistant subpopulations exist at the start of treatment (and promoting the accumulation of de novo resistance mutations during treatment). As a result, genome plasticity promotes increased fitness on the population level, but individual tumor cells must nonetheless maintain a level of DNA integrity that allows for continued survival, particularly in the context of DNA-damaging therapy (which DNA repair counteracts). Thus, DNA repair proteins are a source of innate …

Intracellular Trafficking Governs The Processing Of The Amyloid Precursor Protein And The Secretion Of Beta-Amyloid, Joshua Hoi Ki Tam

Electronic Thesis and Dissertation Repository

One of the hallmarks of Alzheimer’s disease (AD) is the pathological accumulation of β-amyloid (Aβ) in the brains of AD patients. Oligomeric and fibrillar aggregates of Aβ have been shown to be neurotoxic to neurons and hippocampal slices. Therefore, limiting Aβ production is an important area of research in order to delay or stop AD progression. Aβ is produced by amyloidogenic cleavage of amyloid precursor protein (APP). Amyloidogenic cleavage requires ectodomain removal by β-secretase and intramembrane γ-cleavage by γ-secretase to release Aβ products ranging from 38-43 residues. Work from our lab has shown that APP and γ-secretase are resident proteins …

Complications Of Vaginal Synthetic Sling Surgeries In Women: Population Based Cohort Study, Hanaa Al-Hothi

Electronic Thesis and Dissertation Repository

Synthetic sling surgery is the procedure of choice for surgical correction of stress urinary incontinence (SUI) in females. However, complications are recognized, with surgical intervention to treat them in some instances. In a retrospective study we identified and analyzed those complication to determine their incidence and associated predictive factors. A total of 59,887 women who had synthetic sling procedure were included. Incidence of surgically treated complications was 2.2 % ((95% CI 2.07- 2.30) and on 10 years follow up cumulative incident rate was 3.3% (95% CI 3.0- 3.5). There was no significant difference in complication rate between urologists versus gynecologists. …

"A Family Doctor Can Do That!" Is There A Role For A Formalized Referral Network For Office Procedures In Family Practices Of Newfoundland And Labrador?, Annabeth J. Loveys

Electronic Thesis and Dissertation Repository

Office procedures are an important part of the comprehensive care package provided by family physicians. Every family physician cannot feasibly perform every office procedure. A cadre of family physicians drawing upon each other’s procedural skills has the potential to improve patient care and enhance physician satisfaction. A mixed methods approach was used to explore potential clinical and educational roles of a formalized referral networkfor office procedures in Newfoundland and Labrador, Canada. In a quantitative study, using a self-administered survey, family physicians identified that while there are procedures being performed in family practice, there is a discrepancy between the demand for, …

Pathophysiologic Mechanisms Of Immune-Mediated Drug Hypersensitivity Reactions To Sulfonamides, Elham A. Sultan

Electronic Thesis and Dissertation Repository

As sulfonamide hypersensitivity reactions are serious clinical problem, it is necessary to determine which patients tolerate therapy and which patients are at risk. Although the exact pathogenesis of these reactions remains unclear, the imbalance in the production and detoxification of reactive sulfamethoxazole (SMX) metabolites appears to be important in the propagation of these reactions. It is known that these reactive metabolites can cause lymphocytes toxicity and produce reactive oxygen species (ROS) which can damage proteins, lipids, and DNA. The hypothesis of this research is that there are differences in cytotoxicity and expression of oxidative stress to reactive SMX metabolites in …

Cd4+ T-Cell Mediated Microvascular Endothelial Cell Death And Chronic Cardiac Allograft Rejection Involves Necroptosis, Cecilia Yt Kwok

Electronic Thesis and Dissertation Repository

Heart transplantation is the only viable option for patients with end-stage heart failure. Despite advances in immunosuppressive therapies, the rate of transplanted graft loss remains substantial. Graft loss is primarily due to tissue damage mediated by immune responses. Cell death and organ rejection can occur as an active molecular process through apoptotic and necrotic pathways. We now recognize that cell death may also ensue through a newly described form of programmed necrotic cell death, termed necroptosis that involves receptor-interacting protein kinase (RIPK) 1/3. In this study, I aim to establish the role of RIPK3 in T cell-mediated chronic cardiac allograft …

Pulmonary Imaging To Better Understand Asthma, Sarah Svenningsen

Electronic Thesis and Dissertation Repository

Asthma is characterized using the spirometry measurement of the forced expiratory volume in one second (FEV₁). Simple and inexpensive, FEV₁ provides a global estimate of lung function but this metric cannot regionally identify airways responsible for airflow limitation, asthma symptoms or control. Work that brought about an understanding that airway abnormalities are heterogeneously distributed within the lung in asthma patients has motivated the development of pulmonary imaging approaches, such as hyperpolarized helium-3 (³He) and xenon-129 (¹²⁹Xe) magnetic resonance imaging (MRI). These methods provide a way to visualize and quantify lung regions accessed by …

Eating And Swallowing, Oral Health, And Saliva Production, Rebecca H. Affoo

Electronic Thesis and Dissertation Repository

Eating and maintaining optimal nutrition are essential to health and quality of life. In both health and disease, eating is influenced by multiple factors including swallowing, oral health, and saliva production. Perturbations to any, or all, of these inter-related factors may result in consequences that negatively affect the health and wellness of an individual. Eating and swallowing impairment are common symptoms of neurodegenerative diseases such as dementia, and these symptoms are associated with a host of negative sequelae such as malnutrition, dehydration, aspiration pneumonia, and reduced quality of life. The studies reported in this dissertation explored elements of eating and …

Dexamethasone Regulates Gene Expression Induced By The Mechanosensitive P2x7 Receptor In Osteoblasts, Meena Na

Electronic Thesis and Dissertation Repository

Orthodontic tooth movement involves activation of osteoblasts and osteoclasts in response to mechanical forces. Extracellular nucleotides, released in response to mechanical stimuli, signal through P2 receptors in osteoblasts. P2X7 receptors are ATP-gated cation channels implicated in mechanotransduction in bone. Corticosteroids such as dexamethasone exhibit anti-inflammatory effects and their chronic use has been linked to serious side-effects such as osteoporosis. We investigated gene expression following P2X7 receptor activation with benzoylbenzoyl-ATP (P2X7 receptor agonist) in osteoblast precursor cells in the presence or absence of dexamethasone. We hypothesized that dexamethasone inhibits the ability of ATP to stimulate the expression of anabolic (bone forming) …

Treatment Of Ischemia Reperfusion Injury With Rna Interference, Terry M. Zwiep

Electronic Thesis and Dissertation Repository

Ischemia reperfusion injury (IRI) occurs during transplantation and causes apoptosis and inflammation. The purpose of this research was to determine the effect of caspase-3, complement 3, and RelB gene silencing in the reduction of IRI using an in vitro model.

LLC-PK1 cells were used along with antimycin A for the in vitro IRI model. Prior to exposure to antimycin A, cells were transfected with caspase-3, C3, and RelB small interfering RNA (siRNA) alone or in combination and then analyzed.

The relative risk reduction of apoptosis in antimycin A treated cells with caspase-3 siRNA was 46.6% (p=0.019), RelB siRNA 42.8% (p=0.038), …

Cytochrome P450 3a4 Expression And Regulation In Non-Alcoholic Fatty Liver Disease, Sarah J. Woolsey

Electronic Thesis and Dissertation Repository

Non-alcoholic fatty liver disease (NAFLD) is defined as lipid accumulation within hepatocytes (steatosis) in the absence of excess alcohol consumption. It is the most common liver disease in the western world, affecting one third of the general adult population with particularly high prevalence in obesity and type 2 diabetes. NAFLD is a disease continuum originating with simple hepatic steatosis that can progress to non-alcoholic steatohepatitis (NASH) with fibrosis and potentially cirrhosis, which places patients at risk for hepatocellular carcinoma. Unfortunately, there are not yet specific pharmacologic agents to treat NAFLD and so its management involves treatment of comorbidities, but there …

An Evaluation Of The Constructed Frankfort Mandibular Plane Angle Bisector (Cfmab) Wits' Appraisal In The Assessment Of Anteroposterior Jaw Relationships, Derek R. Tomson

Electronic Thesis and Dissertation Repository

For proper orthodontic diagnosis and treatment planning, an accurate measurement of the relationship of the maxilla to the mandible in the sagittal plane is required. The ANB measurement has long been the gold standard for explaining this association. The purpose of this longitudinal study was to evaluate three linear measurements of the maxillomandibular anteroposterior relationship and determine which one best correlates with ANB. The constructed Frankfort horizontal-mandibular plane angle bisector (cFMAB-Wits), maxillomandibular bisector (MMB-Wits), and Frankfort-mandibular plane angle bisector (FMAB-Wits) were measured using a Wits’-type analysis and compared to ANB.

Pre-treatment (TO), immediate post-treatment (T1), and two years post-retention (T2) …

Identification Of Participation-Related Activities To Be Used As Part Of The Development Of A Self-Efficacy Questionnaire For Adolescents With Hearing Loss, Sahar S. Zimmo

Electronic Thesis and Dissertation Repository

Investigating self-efficacy beliefs among adolescents with hearing loss is imperative as these perceptions affect a broad range of age-related functioning. Validated self-efficacy questionnaires for use with persons with hearing loss are currently limited to four adult measures. Development of an adolescent-relevant questionnaire aims to quantify self-efficacy for participation in daily activities and to individualize treatment interventions for adolescents with hearing loss.

Developing the self-efficacy questionnaire was based on a scoping literature review to develop a list of activities performed by typically developing adolescents. The questionnaire was piloted on a sample of youth with hearing loss.

The Adolescent Self-Efficacy Questionnaire for …

Survival Outcomes And Treatment Utilization Among Patients With Known And Unknown Primary Tumours In Ontario., Chong Sung Kim

Electronic Thesis and Dissertation Repository

I identify two cohorts of cancer patients with known and unknown primary tumours. Cancer of unknown primary (CUP) is defined by the presence of pathologically identified metastatic disease without clinical or radiological evidence of a primary tumour. Using the Ontario Cancer Registry, Same Day Surgery/Discharge Abstract Database and Ontario Health Insurance Plan, a novel linkage strategy was developed to cross-validate diagnoses. I found CUP patients represent a significant portion of all metastatic cancers. CUP patients with histological confirmed disease, squamous cell histology, or metastases localized to nodal regions had significantly better survival than other CUP patients. Knowledge of the primary …

How Family Physicians In Saskatchewan Make Lung Cancer Screening Decisions, Nusrat Jamil

Electronic Thesis and Dissertation Repository

Aims: This study explored family physicians’ (FPs) stated practices and decision-making for lung cancer screening.

Methods: Cross-sectional survey of a stratified random sample of Saskatchewan FPs using single item questions and simulated clinical scenarios.

Findings: Wide variations in FPs’ lung cancer screening practices exist in their decision to screen and choice of screening test. Certain physician, patient and non-medical factors influence FPs’ decision-making contrary to their perception of guidelines.

Conclusions: The high self-reported prevalence and measured inclination to screen in clinical scenarios contrary to prevailing guidelines adds unnecessary health care costs and has potential to cause harm.

Significance: First and …