Development Of A Translational Animal Model Of Sepsis, Nathaniel E. Hayward

Electronic Thesis and Dissertation Repository

Sepsis is an excessive inflammatory response to infection that leads to multiple organ failure. The high mortality rates in the intensive care unit have remained stagnant, which can be attributed to the disconnect between the bench and the bedside. There is a global need for an animal model of sepsis that is more relevant to the clinical scenario. We developed an in vivo rat model of sepsis, with a high level of instrumentation, to monitor macrovascular and microvascular changes over the course of a feces-induced peritonitis (FIP) .

In addition, early fluid resuscitation of septic patients is associated with better …

Investigating The Effects Of Custom Made Orthotics On Brain Forms: A Pilot Study, Lindsay Carey

Electronic Thesis and Dissertation Repository

OBJECTIVES: To determine (1) the feasibility of this novel approach and technique of recording brain activity, wirelessly and continuously, during human gait, and (2) if custom made orthotics will alter the brain activity patterns recorded. METHODS: Gait trials were performed on 16 participants walking with and without orthotic devices in their shoes while simultaneously collecting EEG data through the Emotiv wireless neuroheadset. RESULTS: The Emotiv neuroheadset was capable of detecting changes in brain activity between the two gait trials. The differences in brain activity identified between conditions were not statistically significant. CONCLUSION: The findings suggest the Emotiv EEG device is …

Intermittent Hypoxia Alters Metabolic And Cardiovascular Neural Pathways, Jason Michael Moreau

Electronic Thesis and Dissertation Repository

Intermittent hypoxia (IH) is a major pathophysiological manifestation of obstructive sleep apnea (OSA). Previous studies have implicated IH in mediating many pathophysiological outcomes associated with OSA. Only few studies have examined IH-induced alterations to central signaling pathways important in cardiovascular and metabolic phenotypes associated with OSA. This thesis employed a rodent model of IH to examine changes to molecular neural pathways associated with metabolic and cardiovascular pathophysiological outcomes of OSA. Acute IH induces a specific negative body energy balance phenotype. This is concomitant to a reduction in body weight and food intake, with an elevation in food conversion efficiency. Increased …

Effects Of A Power-Line Frequency Magnetic Field On Human Cognitive Processing, Michael Corbacio

Electronic Thesis and Dissertation Repository

Extremely low frequency (ELF, < 300 Hz) magnetic fields (MFs) have been reported to modulate human cognitive performance. However, little research has investigated MF exposures comparable to the highest levels experienced in some occupations. This research evaluated the impact of a 60 Hz, 3 mT MF on human cognitive performance. Ninety-nine participants completed the double-blind protocol performing a selection of psychometric tests under two consecutive MF exposure conditions (exposure vs. no exposure). A significant interaction effect on a working memory test (digit span forward - F=5.21, p

The Effects Of Pre- And Postnatal Administration Of Propionic Acid And Lipopolysaccharide On The Behaviour Of Adolescent Male And Female Rats, Kelly A. Foley

Electronic Thesis and Dissertation Repository

The gut microbiome plays an important role in immune functioning and neurodevelopment. Altered microbiome composition, leading to short chain fatty acid, and/or immune system dysfunction has been observed in children with autism spectrum disorders (ASD). This thesis describes the developmental influence of prenatal exposure to propionic acid (PPA), a metabolic fermentation product of enteric bacteria, or prenatal exposure to lipopolysaccharide (LPS), a bacterial mimetic and product of enteric bacteria, on a range of behaviours in male and female neonatal, adolescent and adult rats. Study one evaluated the effects of prenatal PPA and LPS, and postnatal PPA, on developmental milestones in …

Cholesterol-Mediated Dysfunction Of Surfactant Effects Of Surfactant Protein-A And Diet-Induced Hypercholesterolemia, Joshua Qua Hiansen

Electronic Thesis and Dissertation Repository

This thesis explored the effects of cholesterol and SP-A on surfactant function in vitro, and lung function in vivo. In the first experiment, we determined whether SP-A could mitigate cholesterol-mediated surfactant dysfunction. We hypothesized that SP-A can mitigate the surfactant inhibition caused by high cholesterol. In the second experiment, we tested the contribution of diet-induced serum hypercholesterolemia to surfactant composition and the development of lung injury in rats. We hypothesized that serum hypercholesterolemia would increase the amount of cholesterol in surfactant and would cause rats to develop more severe lung injury. Our results indicate that SP-A mitigates cholesterol-mediated surfactant …

Effect Of Fluid Loss Following Hemodialysis On Tibialis Anterior Muscle Strength In People With End-Stage Renal Disease, Anuradha Sawant

Electronic Thesis and Dissertation Repository

ABSTRACT

PURPOSE: The purpose of this study was to evaluate the effect of fluid loss following hemodialysis (HD) on tibialis anterior (TA) strength in participants with end-stage renal disease. Issues concerning measures of skeletal muscle hydration and efficacy of exercise as an anabolic intervention were also addressed.

METHODS: Data from published literature were combined in a meta-analysis to establish efficacy of exercise in participants on HD. Three clinical studies were undertaken using data acquired from healthy volunteers and participants on HD. Hydration of the calf muscles was estimated using bioelectrical impedance spectroscopy (BIS) [extracellular (ECF) and intracellular (ICF) fluid] …

Structure-Function Analysis Of Udp-Sugar: Polyisoprenyl Phosphate Sugar-1-Phosphate Transferases, Sarah E. Furlong

Electronic Thesis and Dissertation Repository

The synthesis of lipid-linked glycans is a conserved process in eukaryotes and prokaryotes that is initiated by two major enzyme families: the polyisoprenyl-phosphate hexose-1-phosphate transferases (PHPTs) and the polyisoprenyl-phosphate N-acetylaminosugar-1-phosphate transferases (PNPTs). These enzymes contain multiple membrane domains and transfer a sugar-1-phosphate from a nucleotide sugar precursor to a lipid carrier. The prototypic PNPT member used in this study is the E. coli WecA, which initiates the synthesis of O antigen and enterobacterial common antigen in Enterobacteriaceae by transferring N-acetylglucosamine-1-P to undecaprenyl phosphate (Und-P). We investigated the topology and function of the highly conserved VFMGD motif. Our results revealed that …

Er Stress Coupled Pannexin Channel Activation Via Stim Proteins, Ankur Bodalia

Electronic Thesis and Dissertation Repository

Many neurodegenerative diseases, including Alzheimer’s Disease, are associated with ER stress. It is suggested that plasma membrane channels contribute to the increased ionic influx and subsequent cell death in response to ER stress. Pannexin channels, which have been implicated in various pathophysiological conditions, are a suitable candidate for facilitating this response. However, mechanisms of pannexin channel activation are poorly defined. I investigated the potential regulation of pannexin activity by the ER stress sensor, STIM. It was hypothesized that pannexin channel activation during ER stress is contingent on the recruitment of STIM proteins. In neurons, pannexin activation was observed in response …

The Effects Of Acute High- And Low-Intensity Exercise On Hsp70 And Hsp90 Accumulation In Rat Skeletal Myofibres And Vasculature, Hana Kowalchuk

Electronic Thesis and Dissertation Repository

Exercise induces cytoprotective stress proteins in blood vessels (BV) and skeletal myofibres. The localization and extent of induction with different exercise intensities is unclear. Rats (n=10 per group) were run at high (HIEX; 30m/min) versus low-intensity exercise (LOEX; 15m/min) for 1hr, sacrificed 24hr later. Sections of the white portion of the vastus were immunofluorescently stained for Hsp70 and Hsp90. It was hypothesized that: 1) a greater abundance of Hsp70 and Hsp90 would be observed in BVs following HIEX, 2) due to earlier recruitment, larger BVs would have a more robust response than small BVs, 3) more myofibres surrounding BVs expressing …

Evaluating The Co-Commensal Lifestyles Of Staphylococcus Aureus And Staphylococcus Epidermidis, Piraveina Gnanasuntharam

Electronic Thesis and Dissertation Repository

Staphylococcus epidermidis is a ubiquitous skin commensal, and produces a serine protease Esp that can eradicate nasal carriage of the opportunistic pathogen, Staphylococcus aureus. We evaluated the ability of S. epidermidis and S. aureus to express serine protease and compete with one another in response to acidic pH and unsaturated free fatty acids; conditions encountered on human skin. The hypervirulent USA300 strain of S. aureus was more competitive in co-culture conditions of acidic pH or 25 µM palmitoleic acid alone, but could not compete with S. epidermidis when these conditions were combined. Conversely, in pure culture, these conditions promoted …

Adjustment Of Pulmonary O2 Uptake, Muscle Deoxygenation And Metabolism During Moderate-Intensity Exercise Transitions Initiated From Low And Elevated Baseline Metabolic Rates, Joshua P. Nederveen

Electronic Thesis and Dissertation Repository

When instantaneous step-wise transitions within the moderate intensity domain are initiated from elevated metabolic rates, the rate of pulmonary oxygen uptake (V̇O_2p) adjustment is slowed, and the V̇O_2p gain (ΔV̇O_2p /ΔWR) is greater. This study sought to determine the relationship between V̇O_2p kinetics and metabolic activity and energy status during step transitions from low and elevated metabolic rates within the moderate intensity domain. Ten young men completed six double-step constant load cycling bouts, consisting of step-wise transitions from 20 W to 45% θ_L and 45% θ_L [lower step (LS)] to 90% θ_{L …}

The Impact Of Lateral Electron Disequilibrium On Stereotactic Body Radiation Therapy Of Lung Cancer, Brandon Disher

Electronic Thesis and Dissertation Repository

Stereotactic Body Radiation Therapy (SBRT) is an effective treatment option for patients with inoperable early-stage lung cancer. SBRT uses online image-guidance technology [e.g. cone-beam CT (CBCT)] to focus small-fields of high energy x-rays onto a tumour to deliver ablative levels of radiation dose (e.g. 54 Gy) in a few treatment fractions (e.g. 3). For the combination of these treatment parameters and a low density lung, lateral electron disequilibrium (LED) can potentially occur, reducing lung and tumour doses. The goal of this thesis was to determine the impact of LED on stereotactic body radiation therapy for lung cancer.

The effect of …

The Role Of Il-22 Produced By Th17 Cells In Type 1 Diabetes, Stacey M. Bellemore

Electronic Thesis and Dissertation Repository

Interleukin-22 (IL-22) is produced by T helper 17 (Th17) cells. Th17 cells have been shown to be pathogenic in autoimmune diseases, however their role in type 1 diabetes (T1D) remains controversial. We have shown that Th17-differentiation of naïve T cells can be driven by IL-23 + IL-6 to produce large amounts of IL-22 and induce T1D. Conversely, polarizing T cells using TGF-β + IL-6 led to nonpathogenic Th17 cells that produced lower IL-22 levels. We have shown that neutralizing IFN-γ during polarization leads to a drastic increase in IL-22. We have also found IL-22-producing cells in the pancreas of diabetic …

Vascular Stem Cells In Diabetic Complications, Emily C. Keats

Electronic Thesis and Dissertation Repository

Diabetes leads to a variety of secondary complications. At the heart of these complications lies endothelial cells (ECs) – cells that take up unregulated plasma glucose, experience various biochemical alterations, and provide the basis for whole organ vascular dysfunctions. With the purpose of generating new vascular networks for the treatment of these chronic complications, my initial work focused on vascular stem cells (VSCs). VSCs have the ability to differentiate into both endothelial (EPC) and mesenchymal (MPC) progenitor cells, both of which are necessary for the creation of stable and functional blood vessels. To establish whether these progenitor populations retain their …

Detection, Prioritization And Analysis Of Variants Of Unknown Significance In Familial Breast Cancer Genes, Eddie A. Dovigi

Electronic Thesis and Dissertation Repository

Currently, Molecular Diagnostics Laboratories in Ontario sequence coding and adjacent intronic regions in BRCA1 and BRCA2 in patients with a family history of breast cancer. At LHSC it is estimated that ~15% of patients have BRCA1 or BRCA2 variants of clinical significance, and ~15-20% patients have variants of unknown clinical significance (VUS), while the remaining patients have variants of no clinical significance, making patient prognosis difficult to ascertain. To elucidate VUS and improve deleterious variant detection, my study has three aims, 1) assess the effects of VUS on splicing using bioinformatics and transfection assays; 2) investigate the limitations of BRCA1 …

Identification Of The Salivary Proteome In Children Throughout The Course Of Dental Eruption, Nada Tabbara

Electronic Thesis and Dissertation Repository

The salivary proteome is recognized as a valuable source of potential oral and systemic disease biomarkers. Major efforts in salivary research have been dedicated to identify and characterize salivary proteins present in saliva using both classical biochemical methods and proteomics approaches in adults. Despite considerable research on the salivary proteome, little attention has been given to the changes in the salivary proteome occurring in children, specifically from 0-3 years of age. Through the use of anionic PAGE, SDS PAGE, HPLC and MS/MS, salivary protein profiles in children before, during and after dental eruption were compared with edentulous adult controls. We …

Secular Trends In Ischemic Stroke Subtypes, Chrysi Bogiatzi

Electronic Thesis and Dissertation Repository

Background: With an aging population and an increasing prevalence of therapy for atherosclerosis, it might be expected that stroke subtypes would be changing over time. Limited information exists on the ischemic stroke subtypes in adults in Canada.

Methods: Patients referred to the Urgent TIA Clinic, in London, Ontario, between 2002-2012 were included. Secular trends were analyzed using Poisson regression with spline trend function. Ischemic stroke subtype classification was validated.

Results: 3,445 consecutive patients (mean age + SD 64.8 + 14.9) were included. Cardioembolic strokes/TIAs increased from 21% in 2002 to 56% in 2012, whereas all other ischemic stroke subtypes …

The Role Of Kisspeptin And Kndy Cells In The Reproductive Neuroendocrine System, Christina M. Merkley

Electronic Thesis and Dissertation Repository

The gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus represent the final common output in the central control of reproduction. GnRH secretion is modulated indirectly by steroid feedback action of gonadal steroids on afferent interneurons. In recent years, the neuropeptide, kisspeptin, has emerged as a key mediator of steroid feedback onto GnRH neurons and the reproductive system. Kisspeptin neurons located in the preoptic area (POA) mediate estradiol (E2) positive feedback leading to the preovulatory surge, and kisspeptin cells in the arcuate nucleus (ARC) have been shown to mediate the negative feedback actions of E2 on pulsatile GnRH secretion. ARC kisspeptin neurons …

Pharmacogenetics Of Oral Anticoagulants And Antiplatelets, Inna Gong

Electronic Thesis and Dissertation Repository

Thromboembolic disorders are a major cause of morbidity and mortality. Therapeutic intervention with anticoagulants and antiplatelets greatly reduces the risk of arterial and venous thrombosis. However, the observed large interindividual variation in responsiveness to these drugs indicates that subsets of patients are not attaining optimal therapy, resulting in either lack of antithrombotic effect or elevated bleeding risk. Recently, single nucleotide polymorphisms (SNPs) have been linked to the variation observed in efficacy and toxicity for many cardiovascular drugs.

Warfarin has been the gold standard anticoagulant for prevention of stroke and thromboembolism in atrial fibrillation (AF) and venous thromboembolism (VTE) patients. SNPs …

Fetal And Neonatal Exposure To Nicotine Augments Hepatic Fatty Acid Synthesis In Rat Offspring Long-Term, Noelle L. Ma

Electronic Thesis and Dissertation Repository

While nicotine replacement therapy (NRT) is presumed to be a safer alternative to smoking in pregnancy, the long-term consequences in offspring are still largely unknown. Animal studies now suggest that maternal nicotine exposure during pregnancy and lactation (MNE-PL) leads to a wide variety of adverse outcomes for the offspring, including increased adiposity. The focus of this study was to investigate how MNE-PL in rats may lead to liver dysfunction long-term in offspring through alterations in gene expression and epigenetic modifications. Postnatal day 180 (PND180) offspring exposed to nicotine during pregnancy and lactation (1mg/kg/day) exhibited increased circulating and hepatic triglycerides concomitant …

The Effects Of A Single Acute And Repeated Intracerebroventricular Infusions Of Propionic Acid On Locomotor Activity And Neuroinflammation In Rats, Stacey Holbrook

Electronic Thesis and Dissertation Repository

Dietary and gastrointestinal factors may contribute to the etiology of autism spectrum disorders (ASD). Propionic acid (PPA) is a short chain fatty acid that is an intermediary of fatty acid metabolism and a fermentation by-product of enteric bacteria. Using a single infusion (Chapter 2) and repeated infusions (Chapter 3), the temporal relationship between PPA-induced locomotor activity and astrocyte/microglial changes was demonstrated. Adult Long-Evans rats were centrally infused with 4µl of 0.26M PPA or 0.1M PBS vehicle once or once a week for four weeks. Locomotor activity was evaluated for 20 minutes following infusion and again several days later to assess …

Genetic Approaches To Studying Complex Human Disease, Joseph B. Dube

Electronic Thesis and Dissertation Repository

Common, complex diseases such as cardiovascular disease (CVD) represent an intricate interaction between environmental and genetic factors and now account for the leading causes of mortality in western society. By investigating the genetic component of complex disease etiology, we have gained a better understanding of the biological pathways underlying complex disease and the heterogeneity of complex disease risk. However, the development of high throughput genomic technologies and large well-phenotyped multi-ethnic cohorts has opened the door towards more in-depth and trans-disciplinary approaches to studying the genetics of complex disease pathogenesis. Accordingly, we sought to investigate select complex traits and diseases using …

Improving Acute Stroke Management With Ct Perfusion Imaging: Approaches To Treatment Guidance And Brain Tissue Salvage, Christopher D. D'Esterre

Electronic Thesis and Dissertation Repository

CT Perfusion (CTP) provides measurement of perfusion at the capillary level which can be used to characterize tissue viability, and blood-brain-barrier (BBB) compromise. Using CTP, the goals of this research are to: 1) select patients that will benefit from acute stroke treatment, and 2) determine if pre-stroke neuroprotection reduces stroke severity.

Chapter two investigates the cerebral blood volume (CBV) parameter in a small acute ischemic stroke (AIS) patient set. Overestimation of the acute CBV defect is caused by incomplete wash-out of the CT contrast due to a shortened CTP acquisition time (“truncation artifact”).

In chapter three we examine the prognostic …

Characterizing Stomatin-Like Protein 2 And Its Role In Neuron Survival, Lisa A. Foris

Electronic Thesis and Dissertation Repository

Stomatin-like Protein 2 (SLP-2) has been identified as a stress-inducible transcript and has been shown to interact with and stabilize mitochondrial proteins. Since mitochondria are critical for neuronal function, we hypothesized that SLP-2 regulates neuron survival in response to stressful stimuli. A conditional SLP-2 knockout mouse (deletion) and the SN56 cell line (upregulation) were employed to study the role of SLP-2 in mitochondrial dynamics and neuron survival. SLP-2 deficient primary cortical neurons displayed significantly decreased levels of various mitochondrial respiratory chain proteins, indicating SLP-2 contributes to maintenance of mitochondrial membrane integrity. SLP-2 was up-regulated in response to oxidative stress and …

Improving Cardiac Repair By Stem Cell Factor Post-Myocardial Infarction, Fuli Xiang

Electronic Thesis and Dissertation Repository

Myocardial infarction (MI) occurs due to the complete occlusion of a coronary artery and is a leading cause of death, and a huge social and economic burden worldwide. Despite advances in treatment, patients still have a poor prognosis and there is a pressing need for strategies to improve cardiac repair post-MI. Stem cell factor (SCF), expressed by many cells and tissues including the myocardium, binds to its receptor, c-kit, and regulates the activity of c-kit-expressing cells. SCF has two isoforms: a soluble (S-SCF), and a membrane-associated isoform (M-SCF). M-SCF is more potent in supporting cell adhesion and survival. …

The Role Of Pu.1 And Spi-B In B Cell Acute Lymphoblastic Leukemia, Shereen Turkistany

Electronic Thesis and Dissertation Repository

ETV6-RUNX1 is the most common chromosomal alteration in pediatric B cell acute lymphoblastic leukemia. ETV6-RUNX1 represses RUNX1 target genes. However, little is known about the target genes of ETV6-RUNX1 that are involved in promoting leukemogenesis. A recent study with two human leukemia cell lines AT-2 and REH, which express ETV6-RUNX1, suggested that SPIB was one of the top of the genes that were up regulated after knocking down the ETV6-RUNX1 fusion protein. In addition, our lab showed that deletion of PU.1 and Spi-B in B cells in mice resulted in the development of B cell acute lymphoblastic leukemia with 100% …

Delta Relaxation Enhanced Magnetic Resonance - Development And Application Of A Field-Cycling Contrast Mechanism, Yonathan Araya

Electronic Thesis and Dissertation Repository

Delta relaxation enhanced magnetic resonance (dreMR) is a novel imaging method capable of producing contrast proportional only to the concentration of the bound form of the targetable contrast agent using a dynamic field-cycling technique. The characteristic high relaxivity magnetic field dependence of bound paramagnetic contrast agents enables suppression of tissue contrast from unbound agents and unenhanced tissue, thereby increasing probe specificity. The dreMR technique requires an auxiliary actively shielded field-shifting insert electromagnet to modulate the strength of the main clinical magnetic field as a function of time during the relaxation and evolution periods of a pulse sequence.

Ablavar (approved for …

Magnetic Resonance Imaging Of Brain Tissue Abnormalities: Transverse Relaxation Time In Autism And Tourette Syndrome And Development Of A Novel Whole-Brain Myelin Mapping Technique, Yann Gagnon

Electronic Thesis and Dissertation Repository

The transverse relaxation time (T2) is a fundamental parameter of magnetic resonance imaging sensitive to tissue microstructure and water content, thus offering a non-invasive approach to evaluate abnormalities of brain tissue in-vivo. Prevailing hypotheses of two childhood psychiatric disorders were tested using quantitative T2 imaging and automated region of interest (ROI) analyses. In autism, the under-connectivity theory, which proposes aberrant connectivity within white matter (WM) was assessed, finding T2 to be eleveted in the frontal and parietal lobes, while dividing whole brain data into neurodevelopmentally relevant WM ROIs found increased T2 in bridging and radiate WM. In Tourette syndrome, tissue …

Systematic Assessment Of The Contribution Of Superantigens To Nasopharyngeal Colonization In A Mouse Model Of Streptococcal Infection, Katherine J. Kasper

Electronic Thesis and Dissertation Repository

Streptococcus pyogenes is adapted for persistence in humans. It typically colonizes the tonsils and skin, and humans are the only known reservoir. S. pyogenes can cause a wide range of mild to serious infections. Most streptococci-related deaths are due to complications of rheumatic fever and invasive infections. S. pyogenes produces virulence factors that contribute to the pathogen’s ability to colonize and cause disease, including streptococcal superantigens (SAgs), also known as streptococcal pyrogenic exotoxins (Spes). SAgs function by cross-linking T cells and antigen presenting cells (APC) which may cause a massive inflammatory response, and as such have been found to contribute …