Medical Sciences Commons^™

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 …

Functional Role Of Dream And Dyrk1a In High-Grade Serous Ovarian Cancer Cell Dormancy, Pirunthan Perampalam

Electronic Thesis and Dissertation Repository

High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer. The majority of women are disproportionately diagnosed at an advanced stage (stage III-IV) of the disease when tumours have progressed beyond the ovaries or fallopian tubes and into the peritoneal cavity. Survival rates at late-stage are as low as 25% and chemoresistant disease recurrence is common, affecting up to 90% of patients. Multicellular clusters called spheroids contribute to dormancy, chemoresistance, and metastases and are a major challenge to treatment of HGSOC. Spheroid cells undergo reversible quiescence to evade chemotherapy in a process mediated by the mammalian DREAM …

Evaluating Anesthetic Protocols For Non-Human Primate Functional Neuroimaging, Megha Verma

Electronic Thesis and Dissertation Repository

Functional magnetic resonance imaging (fMRI) is a non-invasive technique that can be used to measure a proxy of neural activity in vivo with high spatial specificity. One subject can be followed for a long period of time to assess changes in functional brain organization. However, fMRI is extremely sensitive to motion. The challenges of training non-human primates to reduce motion in an MRI scanner motivate the study of anesthesia which is commonly used to substitute for this training. In this thesis, I compare three different commonly used anesthetic protocols: isoflurane, propofol-fentanyl in combination, and fentanyl alone, to test which of …

Pathway‐Extended Gene Expression Signatures Integrate Novel Biomarkers That Improve Predictions Of Patient Responses To Kinase Inhibitors, Ashis Bagchee‐Clark, Eliseos J. Mucaki, Tyson Whitehead, Peter Rogan

Biochemistry Publications

Cancer chemotherapy responses have been related to multiple pharmacogenetic biomarkers, often for the same drug. This study utilizes machine learning to derive multi‐gene expression signatures that predict individual patient responses to specific tyrosine kinase inhibitors, including erlotinib, gefitinib, sorafenib, sunitinib, lapatinib and imatinib. Support vector machine (SVM) learning was used to train mathematical models that distinguished sensitivity from resistance to these drugs using a novel systems biology‐based approach. This began with expression of genes previously implicated in specific drug responses, then expanded to evaluate genes whose products were related through biochemical pathways and interactions. Optimal pathway‐extended SVMs predicted responses in …

Impact Of Graded Passive Cycling On Hemodynamics, Cerebral Blood Flow, And Heart Function In Healthy Adults And Septic Icu Patients, Jennifer Chen

Electronic Thesis and Dissertation Repository

Sepsis is a life-threatening dysregulation of host response to an infectious insult, which often leads to multi-organ failure. Sepsis survivors suffer from post-intensive care syndrome in part due to their prolonged bed rest and lack of mobility. Although early mobilization has been championed as a mechanism to counter the adverse effects associated with ICU immobility, due to sedation and mechanical ventilation, active early mobilization is not often administered in septic patients due to worries of hemodynamic instability and potential for inducing adverse events. Passive exercise is a mobilization modality that circumvents the need for patients to be conscious and participatory …

A Clinically Representative Rat Model Of Hip Hemiarthroplasty, Adam Dm Paish

Electronic Thesis and Dissertation Repository

Joint replacement is an increasingly common surgery with over 130,000 procedures performed annually in Canada. Although joint replacement surgery is highly successful, implants do not last a lifetime, and often have to be replaced via costly revision surgeries. Before innovations aimed at extending the life of implants are applied to the clinic, testing must be performed in animal models. Clinically representative small-animal models of joint replacement would be ideal in the initial stages of research and development, due to ease of handling and low costs, but few such models have been established in the literature. Thus, we describe the development …

Epilepsy Risk Among Survivors Of Intensive Care Unit Hospitalization For Sepsis, Tresah C. Antaya, Britney N. Allen, Lucie Richard, Salimah Z. Shariff, Gustavo Saposnik, Jorge Burneo

Neuroepidemiology Research Unit Project Summaries

Research Summary: Key Findings

• 407 (0.28%) patients developed epilepsy within 2 years of their ICU discharge, 103 (25.3%) of whom were exposed to sepsis.
• Sepsis survivors were significantly more likely to develop epilepsy, relative to non-septic ICU survivors.
• Among sepsis survivors, epilepsy risk increased with age and was higher among those with chronic kidney disease.

Neurodevelopmental Outcomes Of Infantile Hydrocephalus: An Fmri Case Study, Ikhlas Ahmed Hashi

Electronic Thesis and Dissertation Repository

Ventricle dilatation caused by infantile hydrocephalus may result in extensive damage of the posterior cortex (parietal and occipital lobes). We hypothesize that pathological changes in the development of the posterior cortex can be linked to non-verbal learning disabilities in children with previous infantile hydrocephalus. This case study will investigate the neurodevelopmental outcomes of 3 treated hydrocephalus patients, when compared to a group of healthy control children (n = 12). Within the hydrocephalus group, patients displayed differences in non-verbal test performance as well as parietal brain activation during an fMRI number comparison task. We associated these differences with clinical variables such …

Modulation Of Inflammation Driven Wound Healing After Glaucoma Surgery, James J. Armstrong

Electronic Thesis and Dissertation Repository

Dysregulated wound healing contributes to most currently unanswered ophthalmological morbidity. Opacification and structure altering contractures compromise the delicate ocular anatomy upon which ocular function and healthy vision are reliant. Glaucoma filtration surgery, corneal stromal injury, proliferative vitreoretinopathy and age-related macular degeneration are major contributors to ocular morbidity – all with myofibroblast transdifferentiation and pathognomonic scarring activity at their core.

This thesis aims to revaluate the means by which dysregulated ocular wound healing is combated with evidence describing a novel strategy to mitigate its effects. A translational approach was used. An initial retrospective analysis of over ten thousand glaucoma surgeries found …

Phylogenetic Estimates Of Hiv-1 Gp120 Indel Rates Across The Group M Subtypes, John Palmer, Art Poon

Western Research Forum

Insertions and deletions (indels) in the HIV-1 envelope glycoprotein gp120 play a significant role in the evolution of HIV pathogenesis and transmission fitness. While substitution rates in HIV-1 are well characterized by phylogenetic models, there is a lack of quantitative measures of indel rates in HIV-1. Here we use a dated-tip phylogenetic analysis of gp120 sequences to estimate indel rates for 7 subtypes and CRFs of HIV-1 group M.

We obtained and processed 26,359 HIV-1 gp120 sequences from the Los Alamos National Laboratory HIV Sequence database. After filtering these sequences, we extracted the conserved and variable regions from the remaining …

The Effect Of Sepsis On Cerebral Microvascular Blood Flow, Laura Mawdsley, Mamadou Diop, Chris G. Ellis

Western Research Forum

Background: Sepsis is a dysregulated host response to infection that affects 18 000 000 people worldwide, and over 325 000 000 dollars are spent treating sepsis in Canada every year. One of the symptoms of severe sepsis is an altered mental state, which is accompanied with a measured decrease in oxygen levels in the skeletal muscle microvasculature. It is hypothesized that his altered mental state is due to a lack of oxygenated blood reaching the brain.

Hypothesis: After the onset of sepsis, microvascular cerebral blood flow and oxygen levels in the blood will decrease. Onset of decreased blood flow in …

Translational Control Of Stress Induced Breast Cancer Plasticity, Michael Jewer

Electronic Thesis and Dissertation Repository

Cancer cell plasticity, whereby stem-cell-like properties are acquired in response to stress, represents a major challenge in cancer treatment. Using cell line and patient-derived xenograft (PDX) models, we demonstrate that translational reprogramming occurs in response to stresses such as hypoxia and chemotherapy which elicits stem cell properties in breast cancer. Other stresses like chemotherapy demonstrate the translational inhibition that has been well characterized as an integral hypoxic cellular response. The inhibition of translation is primarily regulated at initiation by mTOR/4E-BP1 and PERK/eIF2α signalling. We identify previously undescribed 5’ untranslated regions (5’UTRs) of plasticity-associated genes like NANOG, SNAIL and NODAL. …

The Risk Of New-Onset Epilepsy And Refractory Epilepsy In Older Adult Stroke Survivors, Jorge G. Burneo, Tresah C. Antaya, Britney N. Allen, Andrea Belisle, Salimah Z. Shariff, Gustavo Saposnik

Neuroepidemiology Research Unit Project Summaries

Research Summary: Key Findings

• Stroke is a common cause of epilepsy in older adults, but little is known about stroke-related epilepsy or its outcomes in this population.
• 1.1% of older adult stroke survivors developed epilepsy in this study, of whom 12.9% developed refractory epilepsy, indicating that this population is particularly responsive to treatment.
• Over 85% of deaths in this population are not due to stroke or epilepsy.

White Matter Inflammation And Executive Dysfunction: Implications For Alzheimer Disease And Vascular Cognitive Impairment, Alexander Levit

Electronic Thesis and Dissertation Repository

White matter integrity is crucial to healthy executive function, the cognitive domain that enables functional independence. However, in the ageing brain, white matter is highly vulnerable. White matter inflammation increases with age and Alzheimer disease (AD), which disrupts the normal function of white matter. This may contribute to executive dysfunction, but the relationship between white matter inflammation and executive function has not been directly evaluated in ageing nor AD. White matter is also particularly vulnerable to cerebrovascular disease, corresponding with the common presentation of executive dysfunction in vascular cognitive impairment (VCI). Thus, white matter may be an important substrate by …

Wearable Sensors And Total Knee Arthroplasty: Assessing Quantitative Function To Improve The Patient Experience, Megan Fennema

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is a chronic degenerative disease for which the only long-term solution is total knee arthroplasty (TKA), though many patients are not satisfied with their TKA. Satisfaction in TKA patients is not well understood. Subjective questionnaires and objective functional tests have been previously used to assess TKA outcomes, but both have disadvantages. Wearable sensors have facilitated affordable biomechanical measurement in OA and TKA populations. The objective of this work was to use wearable sensors alongside functional tests with TKA patients to identify quantitative function that related to subjective function and satisfaction. A wearable sensor-setup was validated before implementation in …

Effects Of Maternal Protein Restriction On The Pulmonary Surfactant System During The Early Life And Adulthood, Reza Khazaee

Electronic Thesis and Dissertation Repository

Fetal growth restriction (FGR) is defined by low birth weight and contributes to a variety of adult-onset diseases with different severities between males and females. However, the effects of FGR on the pulmonary surfactant are not fully elucidated. In this thesis, first, we investigated the FGR effects on the lung function and the surfactant system at the early postnatal life. It was hypothesized that FGR contributes to alterations of lung mechanics and the surfactant system during the neonatal period. Second, we assessed the FGR effects on the surfactant system in response to sepsis in adulthood. It was hypothesized that FGR …

The Epidemiology Of Infective Endocarditis Among People Who Inject Drugs In London, Ontario., Brian Hallam

Electronic Thesis and Dissertation Repository

Infective endocarditis is an infectious disease that affects the valves of the heart. Injection drug use is currently a leading risk factor among patients with endocarditis. We conducted a prospective study using data from hospital chart records among patients with endocarditis in London, Ontario, which has a relatively high prevalence of people who inject drugs to assess the severity of the issue and the major risk factors of mortality pertaining to this population. This study had a sample size of 353 and included a review of the incidence of admissions of endocarditis, as well as a survival analysis, using both …

Drug Response And Metabolism In Crohn's Disease, Aze Wilson

Electronic Thesis and Dissertation Repository

Inflammatory bowel disease (IBD) is an illness of chronic intestinal inflammation comprised of Crohn's disease (CD) and ulcerative colitis (UC). Specialists rely heavily on drugs that target a dysregulated immune system. There is a staggering degree of variation in drug response in CD. Our understanding of drug metabolism and response in IBD is limited. Gaining new insights into IBD-specific modifications of drug metabolism may allow for improved drug efficacy and reduced toxicity. Cytochrome P450 (CYP) 3A4 is the most relevant determinant of drug metabolism and exposure for medications prescribed today. CYP3A4 is highly expressed in the liver, but is also …

Head Injury Risk And Car Seat Use For Children In Collisions, Peyton A. Schroeder, M.J. Skhurm, D. Fraser, K. Mcclafferty

Western Research Forum

Background: Motor vehicle collisions (MVCs) are the leading cause of death for people under the age of 17 years. Almost 80% of rear seat motor vehicle passengers are children. Previous studies have shown that a large fraction of injuries to children in MVCs involved the head and chest. In this study, the hypothesis that children under the age of eight using a forward-facing child restraint system (FFCRS) will have more severe head injuries than children using any other type of restraints in an MVC was tested.

Methods: Several datasets obtained from Transport Canada and Level 1 Pediatric Trauma Centre emergency …

Kallikrein-Related Peptidases Are Dysregulated In Pleomorphic Adenoma, Matthew D. Morrison

Electronic Thesis and Dissertation Repository

Objectives: Pleomorphic adenoma (PA) is the most common benign salivary gland tumor. Kallikrein-related peptidases (KLKs) have been identified as biomarkers in many human tumors and may influence tumor behavior. We investigated KLK1-15 messenger ribonucleic acid (mRNA) and proteins in PA specimens to determine a KLK expression profile for this tumor.

Methods: Fresh frozen PA tissue specimens (n = 26) and matched controls were subjected to RT-qPCR to detect KLK1-15 mRNA. Expression of KLK1, KLK12, KLK13 and KLK8 proteins were then evaluated via immunostaining techniques. Statistical analyses were performed with the level of significance set at P < .05.

Results: We observed downregulation …

Acute Pharmacologic Modulation Of Glioblastoma Ph Monitored By Chemical Exchange Saturation Transfer Magnetic Resonance Imaging, Mohammed Albatany

Electronic Thesis and Dissertation Repository

The response of tumor intracellular pH (pH_i) to a pharmacological challenge could help identify aggressive cancer. In addition, tumor pH_i may influence cell proliferation, apoptosis, chemotherapy resistance, and thermosensitivity. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is sensitive to cellular pH. More specifically, a CEST method called amine and amide concentration-independent detection (AACID) produces images weighted by intracellular pH (pH_i) and can be used to study pharmacologic pH modulation in tumours.

The overall goal of this thesis was to maximize the magnitude of intracellular tumour acidification using pharmacologic agents. Several …

Characterization Of Urinary Microbiome And Their Association With Health And Disease, Yige Bao

Electronic Thesis and Dissertation Repository

There has been a growing interest in human microbiome studies in the past decade, with the development of high-throughput sequencing techniques. These microorganisms interact and respond to the host as an entity, and are involved in various homeostatic functions including nutrition digestion, immune response, metabolism and endocrine regulation. The urinary microbiome, however, remains relatively under-investigated.

One of the technical challenges of urinary microbiome studies is the samples usually contain a large number of host cells and low microbial biomass. These samples with the high host, low microbial abundance (“high-low” samples) are associated with increased risk of compromised quality of …

Prostate Cancer Microparticles In Men Undergoing Radical Prostatectomy, Malcolm James Dewar

Electronic Thesis and Dissertation Repository

Objectives: To determine changes in prostate microparticle (PMP) concentrations in men with prostate cancer (PCa) after digital rectal examination (DRE), after radical prostatectomy (RP), and at follow-up.

Materials and Methods: 22 men were recruited before RP. Four blood specimens were collected – baseline (specimen 1), post-DRE (specimen 2), immediately post-RP (specimen 3), and follow-up (specimen 4). Pre- and post-DRE urine was collected (Specimen A and B respectively). Flow cytometric analysis of biofluids was performed with fluorescent-labeled antibodies against prostate-specific membrane antigen (PSMA) and polysialic acid. Total MP (TMP) and dual positive (PMP) events per µl of plasma or urine were …

Disruption Of Hippocampal Multisynaptic Networks By General Anesthetics., Min-Ching Kuo, L Stan Leung

Physiology and Pharmacology Publications

BACKGROUND: Previous studies showed that synaptic transmission is affected by general anesthetics, but an anesthetic dose response in freely moving animals has not been done. The hippocampus provides a neural network for the evaluation of isoflurane and pentobarbital on multisynaptic transmission that is relevant to memory function.

METHODS: Male Long-Evans rats were implanted with multichannel and single electrodes in the hippocampus. Spontaneous local field potentials and evoked field potentials were recorded in freely behaving rats before (baseline) and after various doses of isoflurane (0.25 to 1.5%) and sodium pentobarbital (10 mg/kg intraperitoneal).

RESULTS: Monosynaptic population excitatory postsynaptic potentials at the …

A Clinico-Pathological Study Of The Structural And Functional Changes In The Retina And Optic Nerve Following Diabetic Retinopathy Treatments, Richard Filek

Electronic Thesis and Dissertation Repository

Diabetic retinopathy (DR) is the result of microvascular changes in the retina due to hyperglycemia which alter the blood-retinal barrier (BRB). The increased permeability of BRB results in the accumulation of extracellular fluid, the development of diabetic macular edema (DME) and capillary occlusion. Capillary occlusion results in retinal ischemia which increases vascular endothelial growth factor (VEGF) levels, increases vascular permeability and results in neovascularization in proliferative diabetic retinopathy (PDR) patients. The treatments clinically used for DR are panretinal photocoagulation (PRP) for PDR and injectable vascular endothelial growth factor inhibitors (anti-VEGFs) for DME.

The safety of PRP and anti-VEGF therapy on …

3d Ultrasound In The Management Of Post Hemorrhagic Ventricle Dilatation, Jessica Kishimoto

Electronic Thesis and Dissertation Repository

Enlargement of the cerebral ventricles is relatively common among extremely preterm neonates born before 28 weeks gestational age. One common cause of ventricle dilatation is post hemorrhagic ventricle dilatation following a bleed in the cerebral ventricles. While many neonates with PHVD will have spontaneous resolution of the condition, severe, persistent PHVD is associated with a greater risk of brain injury and morbidity later in life and left untreated can cause death. The current clinical management strategy consists of daily measurements of head circumference and qualitative interpretation of two-dimensional US images to detect ventricular enlargement and monitoring vital signs for indications …

A National Perspective On Childhood Obesity Medical Education: Do Medical Students In Canada Perceive That They Are Prepared To Treat Children With Obesity?, Dr. Dalia Hasan

Electronic Thesis and Dissertation Repository

The purposes of this survey-based, mixed-methods study were to investigate medical students’ perceptions of: (1) the overall level of medical school training acquired in relation to childhood obesity treatment; (2) the medical school training acquired in relation to specific competencies associated with the treatment of children with obesity and their caregiver(s); and (3) additional training needed. Results showed that of the 507 students who provided complete data, approximately 60% (n = 303) disagreed or strongly disagreed that their medical training related to childhood obesity was adequate. With regard to specific competencies and additional training needed, quantitative and qualitative data revealed …

Therapeutic Application Of Carbon Monoxide In Acute Limb Compartment Syndrome, Aurelia Bihari

Electronic Thesis and Dissertation Repository

Acute limb compartment syndrome (CS), a devastating complication of musculoskeletal trauma, develops in response to elevation of the pressure within a closed osseofascial compartment, producing muscle- and limb-threatening ischemia. Full decompression of all involved compartments by fasciotomy is the current gold-standard therapy, but it must be performed within a surgical window of 6-8 hours, before tissue damage becomes permanent.

Carbon monoxide (CO), a byproduct of heme metabolism, has been shown protective in ischemia. While inhalation of CO leads to elevation of carboxyhemoglobin (COHb), recent development of transitional metal carbonyls, CO-releasing molecules (CO-RMs), particularly the water-soluble CORM-3, delivers CO in a …

Developments In Pet-Mri For Radiotherapy Planning Applications, John Christian Patrick

Electronic Thesis and Dissertation Repository

The hybridization of magnetic resonance imaging (MRI) and positron emission tomography (PET) provides the benefit of soft-tissue contrast and specific molecular information in a simultaneous acquisition. The applications of PET-MRI in radiotherapy are only starting to be realised. However, quantitative accuracy of PET relies on accurate attenuation correction (AC) of, not only the patient anatomy but also MRI hardware and current methods, which are prone to artefacts caused by dense materials. Quantitative accuracy of PET also relies on full characterization of patient motion during the scan. The simultaneity of PET-MRI makes it especially suited for motion correction. However, quality assurance …

Pulmonary Surfactant Fortified With Cath-2 As A Novel Therapy For Bacterial Pneumonia, Brandon J. Baer

Western Research Forum

Background: Bacterial pneumonia is a leading cause of death worldwide, with high mortality rates persisting even after antibiotic treatment. Current treatments for pneumonia involve administration of antibiotics, however after the bacteria are killed they release toxic substances that induce inflammation and lung dysfunction. Host defense peptides represent a potential solution to this problem through their ability to down regulate inflammation. However, effective delivery to the lung is difficult because of the complex branching structure of the airways. My study addresses this delivery problem by using exogenous surfactant, a pulmonary delivery vehicle capable of improving spreading of these peptides throughout the …