Metabolomic Biomarkers For Hypertensive Disease Of Pregnancy, Akasham Rajagopaul

Electronic Thesis and Dissertation Repository

Hypertensive disease of pregnancy (HDP) is a serious cardiometabolic pregnancy complication. Early onset HDP (EO-HDP) is more severe but rare, whereas late onset HDP (LO-HDP) is milder but common. Current disease markers, including placental growth factor (PlGF), are reasonable predictors of EO-HDP but poor predictors of LO-HDP. We sought to assess the performance of metabolomic biomarkers in HDP through a scoping review and primary analysis of plasma from symptomatic patients. Review of 31 studies indicated better prediction of all HDP and EO-HDP than LO-HDP using metabolomic biomarkers. Due to substantial heterogeneity in reported metabolites, no set of reliable biomarkers have …

Noninvasive Quantification Of Tissue Sodium Concentration In The Kidney Disease Spectrum Using 23na Magnetic Resonance Imaging, Fabio R. Salerno

Electronic Thesis and Dissertation Repository

Chronic kidney disease (CKD), especially when requiring kidney replacement therapy (hemodialysis (HD) and peritoneal dialysis (PD)), is associated with extracellular water expansion with increased total body sodium. Sodium can also be accumulated in tissues independently of extracellular water. Sodium-23 magnetic resonance imaging (²³Na MRI) can quantify the concentration of sodium nuclei in tissues. Applied to the human leg, quantification of tissue sodium concentrations mainly at the skin and muscle level is possible. We hypothesized that increased tissue sodium concentrations exert toxic effects in CKD and dialysis. We aimed to (1) compare tissue sodium concentrations in adults, children and …

The Effects Of Autophagy And Proteasomes On Tgfβ Signalling And Emt, Charles Brandon Trelford

Electronic Thesis and Dissertation Repository

Transforming growth factor-β (TGFβ) signalling regulates growth, proliferation, immunity, and development. Although TGFβ typically antagonizes tumour formation, tumour cells often acquire mutations within the TGFβ signalling pathway that activate epithelial-mesenchymal transition (EMT). During EMT, epithelial tumour cells lose epithelial-like properties and acquire mesenchymal-like characteristics, which allows tumour cells to detach from the primary tumour and establish metastatic colonies. In addition to EMT, TGFβ augments tumourigenesis by increasing the degradation of damaged macromolecules and organelles via autophagy. Autophagy contributes to radiotherapy and chemotherapy resistance by mitigating the damages inflicted on tumour cells. Currently, there is a growing interest in the relationship …

Differential Effects Of Kim-1 In Subcutaneous And Orthotopic Renca Models Of Kidney Cancer, Demitra M. Yotis Dy

Electronic Thesis and Dissertation Repository

Renal Cell Carcinoma (RCC) is the most common and fatal type of kidney cancer. Over 30% of patients that are diagnosed with RCC exhibit metastases. Almost 88% of patients with distant metastases succumb to the disease within 5 years of diagnosis. Kidney Injury Molecule-1 (KIM-1) is a cell surface glycoprotein that is not expressed in a healthy kidney but becomes highly expressed on proximal tubular epithelial cells (PTECs) following injury. Data from the Cancer Genome Atlas (TCGA) reveals that >90% of RCC tumours express KIM-1 mRNA and that higher expression levels correlate with increased overall survival rates of patients. The …

Investigating Pathways Associated With Intervertebral Disc Degeneration And Back Pain., Geoffrey J. Kerr

Electronic Thesis and Dissertation Repository

Lower back pain (LBP) is one of the most common conditions worldwide, yet, current therapeutics are limited to symptomatic relief and do not directly treat the underlying cause of pain. This is largely due to an incomplete understanding of the biological pathways and tissues involved in LBP. While many tissues appear to be involved, intervertebral disc (IVD) degeneration is believed to be a major contributor.

The main aim of this thesis was to characterize the role of two environmental risk factors, mechanical loading and obesity, in the initiation of IVD degeneration and associated pain using the mouse as a preclinical …

Neuronal Correlates For Neuroendocrine Habituation To Repeated Stress, Sara Matovic

Electronic Thesis and Dissertation Repository

One way that the body actively responds to an impending stressor is by increasing systemic glucocorticoids through the activation of the hypothalamic-pituitary-adrenal (HPA) axis. While it is essential for short-term adaptation to stress, the sustained activation of the HPA axis during chronic stress can be detrimental and is linked to stress-related psychiatric conditions such as anxiety and depression. Therefore, it is important that the HPA axis adapts, or habituates, during chronic stress to minimize the negative consequences. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) function to assimilate incoming information from the stress circuitry and …

Atrial Fibrillation Promotion By Intermittent Hypoxia In The Rat, Sara Bober

Electronic Thesis and Dissertation Repository

Obstructive sleep apnea (OSA) is a significant risk factor for developing atrial fibrillation (AF) in clinical populations, but the underlying mechanisms are unknown. Intermittent hypoxia (IH), as elicited by nocturnal airway obstructive events in OSA patients, has been implicated as the mediator of OSA-related cardiovascular outcomes. However, the role of IH in OSA-related atrial arrhythmogenesis has not been reported. For the first time, this thesis demonstrates AF promotion in a rodent model of OSA using IH to mimic hypoxic events, and investigates the underlying vulnerable substrates of induced AF. Rats exposed to IH for 7 days had significantly enhanced AF …

The Effect Of Aerobic Exercise Training On Hepatic Glycogen Metabolism In Type 1 Diabetic Rats, Michael Murray

Electronic Thesis and Dissertation Repository

The purpose of this investigation was to determine if ten weeks of aerobic exercise training could increase hepatic glycogen storage in rats with Type 1 Diabetes Mellitus (T1DM) and whether elevated hepatic glycogen content is associated with alterations in glycogenic proteins and insulin signaling. Rats were divided into control-sedentary, control-exercised, T1DM-sedentary and T1DM-exercised groups. Animals from each group underwent a euglycemic-hyperinsulinemic clamp at the conclusion of the study. Exercise training consisted of treadmill running at 27m/min, 6% incline for 1hr, five days/week for ten weeks. T1DM rats had lower liver glycogen concentrations than control rats and glycogen was not increased …

Nerve Blood Flow Control In Health & Disease:The Effects Of Type 1 Diabetes And Exercise Training, Terry D. Olver

Electronic Thesis and Dissertation Repository

Peripheral nerve blood flow (NBF) is critical to nerve health. Impaired NBF control may contribute to the progression of diabetes peripheral neuropathy. The purposes of this dissertation were: i) to investigate the acute and chronic effects of hyperglycemia on basal sciatic NBF (measured via Doppler ultrasound), ii) to examine the potential vasodilatory effects of insulin (euglycemic hyperinsulinemic clamp; 10 mµ•kg^-1•min^-1) on NBF control in healthy rats and rats with insulin-treated type 1 diabetes (DS) and iii) to determine if exercise training (~75% VO₂max, 60 min/day, 5 days/wk for 10 wk) improves vasa nervorum reactivity …

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] …

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 …

Investigating Adenosine’S Role In Controlling The Cerebral Metabolic Rate Of Oxygen Following Hypoxia-Ischemia, Mustafa Ridha

Electronic Thesis and Dissertation Repository

The cerebral metabolic rate of oxygen (CMRO2) has been shown to be an early indicator of hypoxia-ischemia (HI); however, the mechanisms controlling post-HI CMRO2 are not clear. One potential mechanism is the activation of the adenosine A1 receptor due to increased adenosine concentrations during the insult. The present study investigated if the specific adenosine A1 antagonist, DPCPX, would reduce the typical reduction in CMRO2 and electrical cortical activity following HI. Measurements of CMRO2 and electrical cortical activity were obtained on piglets by near-infrared spectroscopy (NIRS) and amplitude-integrated electroencephalography (aEEG), respectively. The post-HI measurements of CMRO2 and mean aEEG background voltage …

Human Cerebrovascular Endothelial Cell Responses In Severe Sepsis, Christopher J. Blom

Electronic Thesis and Dissertation Repository

Sepsis-associated encephalopathy (SAE) is an independent predictor of mortality in severe sepsis patients. Mechanisms of SAE are poorly characterized. Pro-inflammatory mediators are up-regulated in blood plasma of severe sepsis patients and may lead to activation/dysfunction of cerebrovascular endothelial cells (CMEC) of the blood-brain barrier (BBB) – potentially contributing to brain dysfunction. The objective of the present study was to determine the effects/mechanisms of both human severe sepsis blood plasma (hSSP; 20% v/v) and a mixture of 8 cytokines/chemokines that mimicked physiological concentrations of cytokines/chemokines in hSSP (cytomix; SSCM) on human-derived CMEC (hCMEC/D3) activation/dysfunction

in vitro. hSSP-stimulation up-regulated hCMEC/D3 pro-adhesive …

The Vascular Link Between Intrauterine Hypoxia And Postnatal Cardiovascular Pathology, Jennifer A. Thompson

Electronic Thesis and Dissertation Repository

The effect of intrauterine hypoxia on arterial development was evaluated with use of large and small animal models. Analyses included expression and deposition of extracellular matrix (ECM) proteins, differentiation and proliferation of vascular smooth muscle cells (VSMCs), intima formation and wall thickening. A comprehensive investigation of possible molecular, mechanical and hormonal mediators of altered arterial development was afforded by a sheep model with both acute and chronic hypoxemia studies, whereas a guinea pig model allowed for long-term study. Our findings show that chronically hypoxic fetal sheep and intrauterine growth restricted (IUGR) guinea pigs exhibit a reduction in elastic fibre content …

Representation Of Somatosensory Afferents In The Cortical Autonomic Network, Ruma Goswami

Electronic Thesis and Dissertation Repository

The relationship between somatosensory stimulation and the autonomic nervous system has been established with effects on heart rate (HR) and sympathetic tone. However, the involvement of the cortical autonomic network (CAN) during muscle sensory afferent stimulation has not been identified. The main objective of the research in this dissertation was to determine the representation of somatosensory afferents in the CAN and their physiologic impact on cardiovascular control. Somatosensory afferent activation was elicited by electrical stimulation of type I and II afferents (sub-motor threshold) and type III and IV afferents (motor threshold), and CAN patterns were assessed using blood-oxygenation level-dependent functional …

The Effects Of Low Protein During Gestation On Mouse Pancreas Development And Beta Cell Regeneration, Aaron R. Cox

Electronic Thesis and Dissertation Repository

Effects of a low protein (LP) diet during gestation on the metabolism of rat offspring have been well characterized and leads to glucose intolerance in adulthood. It is unknown how LP impacts endocrine pancreas development in the mouse, or whether this affects future β-cell plasticity. Streptozotocin (STZ) – induced β-cell injury has been demonstrated to be followed by β-cell regeneration in young animals, but the mechanism(s) of regeneration are not clear. Our objective was to characterize a mouse model of maternal LP, in addition to identifying factors that contribute to the long term development of glucose intolerance and the mechanism …

Mechanisms Of Atrial Arrhythmia: Investigations Of The Neuro-Myogenic Interface In The Mouse, Jari Michael Tuomi

Electronic Thesis and Dissertation Repository

Arrhythmia mechanisms rely on multiple factors including structural (myogenic), nervous (neurogenic), and interrelated (the neuro-myogenic interface) factors. I hypothesized that due to this neuro-myogenic interface, the intrinsic cardiac autonomic nervous system (ICANS) is involved in most atrial arrhythmias. This thesis also provides a "Threshold Model" as a tool to assess the role of different physiological factors influencing arrhythmia. This model allows relative comparison and interpretation of the role of various factors influencing arrhythmogenesis. The mouse allows relatively simple manipulation of genes to determine their role in arrhythmia. This thesis determined what atrial arrhythmias are inducible in the mouse (in vivo) …