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Alcohol is a neuroactive molecule that is able to exert variable and often detrimental effects on the developing brain, resulting in a broad range of physiological, behavioural, and cognitive phenotypes that characterize ‘fetal alcohol spectrum disorders’ (FASD). Factors affecting the manifestation of these phenotypes include alcohol dosage, timing of exposure, and pattern of maternal alcohol consumption; however, the biological processes that are vulnerable to ethanol at any given neurodevelopmental stage are unclear, as is how their disruption results in the emergence of specific pathological phenotypes later in life. The research included in this thesis utilizes a C57BL/6J (B6) mouse model to examine the changes to gene expression and behaviour following a binge-like exposure to ethanol during synaptogenesis, a period of neurodevelopment characterized by the rapid formation and pruning of synaptic connectivity that correlates to brain development during the human third trimester. B6 pups were treated with a high dose (5 g/kg over 2 hours) of ethanol at postnatal day 4 (P4), P7, or on both days (P4+7). Mice were evaluated using a battery of behavioural tests designed to assess FASD-relevant phenotypes, and showed delayed achievement of neuromuscular coordination, hyperactivity, increased anxiety-related traits, and impaired spatial learning and memory. Gene expression analysis identified 315 transcripts that were altered acutely (4 hours) following ethanol exposure. Up-regulated transcripts were associated with cellular stress response, including both pro- and anti-apoptotic molecules, as well as maintenance of cell structural integrity. Down-regulated transcripts were associated with energetically costly processes such as ribosome biogenesis and cell cycle progression. Genes critical to synapse formation were also affected, as well as genes important for the appropriate development of the hypothalamic-pituitary-adrenal axis. Additionally, gene expression changes within the adult brain of mice treated with ...

CYP2D6 metabolizes a range of centrally acting drugs, neurotoxins, and endogenous neurochemicals. Higher levels of brain, but not liver, CYP2D6 have been identified in alcoholics and smokers, suggesting exposure to ethanol and/or nicotine may induce brain CYP2D6. We investigated the independent and combined effects of chronic ethanol self-administration and nicotine treatment on CYP2D expression. METHODS: Monkeys were randomized into 4 groups of 10/group consisting of a control group, ethanol-only group, nicotine-only group, and a combined ethanol and nicotine group; treatments occurred for 64 days. RESULTS: Exposure to chronic ethanol and nicotine induced CYP2D across various brain regions and cell types, particularly when both drugs were given in combination. No changes in protein levels were observed in liver or in CYP2D mRNA levels in liver and brain. CONCLUSIONS: Ethanol and nicotine increase brain CYP2D levels, which may affect CNS drug response, neurodegeneration and personality among those exposed to alcohol and/or nicotine. ; MAST

High performance gradient and shim coils are highly interested for high-field magnetic resonance imaging and spectroscopy to correct for large B0 inhomogeneities created by the magnetic susceptibility differences between tissues, bone, and air. In chapter two, complete sets of high-performance gradient and shim coils are designed using two different methods: the minimum inductance and the minimum power target field methods. A quantitative comparison of shim performance in terms of merit of inductance, ML, and merit of resistance, MR, is made for shim coils designed using the minimum inductance and the minimum power design algorithms. The coils designed using the target field method are not controlled over the length of the coil. In order to produce realistic coils for use in human or small-animal studies, direct control over the length of the coils is necessary. Therefore in chapter three, an extended Fourier series method for the design of shim coils with predetermined length is presented. This simple method is based on a truncated Fourier series expansion of the current density to allow for explicit control over the coil length. This method is mathematically simple, easy to implement and computationally fast. Also a quantitative comparison of figures of merit for inductance and resistance is made as a function of shim coil length. Coils of 40 cm diameter are designed with lengths of 50 cm, 60 cm, 80 cm, and 100 cm. Pushing the boundaries of shim design in MRI, we designed a region specific, custom shim coil to correct for large field inhomogeneities that are consistent among subjects. In chapter four, we have designed a custom shim coil for the medial temporal lobe of the human head to correct for the significant field inhomogeneities caused by magnetic susceptibility differences at air/tissue interfaces. The custom coil was designed using the boundary element method. This method is capable of designing coils wound on arbitrarily shaped surfaces so as to produce specific field shapes. We propose that, the ...

Background: Obesity and metabolic syndrome are highly complex disease states and still needs effective treatment and prevention strategies. Growing evidence suggests that dietary milk proteins and prebiotics plays a role in preventing metabolic disorders; however, the underlying mechanisms are unknown. Objective: This dissertation examines how dietary milk proteins and prebiotics (inulin fiber) affect energy balance, host physiology, and gut microbiota to affect metabolic health. The overall objectives of this thesis include: 1) assess the effects of milk protein components on energy balance and stroke onset in stroke-prone rats; 2) determine the role of prebiotics and gut microbiota in regulation of energy balance in obesity-prone and obesity-resistant rats; 3) assess the combined effects of milk protein components and prebiotic on energy balance in obese rats. Methods: Animal studies were conducted using male wistar-kyoto, spontaneously hypertensive stroke-prone, sprague-dawley (SD), obesity-prone (OP) and obesity-resistant(OR) rats. Energy intake, meal patterns, respiratory quotient, and energy expenditure were measured using CLAMS metabolic chambers. Body composition was measured with magnetic resonance imaging. Intraperitoneal glucose and meal tolerance tests were conducted to measure glucose and plasma hormone concentrations. Gut microbiota was assessed using qPCR and 16S rRNA gene sequencing. Gene mRNA abundance was measured using real-time RT-PCR. Results: The primary findings from our study objectives were: 1) supplementation of dietary casein, whey, or its components lactalbumin and lactoferrin, improved energy balance, prevented neurological deficits, morbidity and renal damage and delayed the onset of stroke in stroke-prone rats; 2) gut microbiota play an indispensable role in mediating prebiotic fiber-induced satiety via its effects on cholecystokinin-A and peptide YY Y-2 receptor signaling in high-fat-fed SD, OP, and OR rats; 3) combination of lactoferrin and inulin additively improved energy balance and decreased body weight and adiposity in diet-induced obese rats. Conclusion: Our results provide evidence for the role of milk protein components and prebiotics in improving metabolic dysfunctions in obesity and metabolic syndrome. The findings from our preclinical studies provide a rationale for clinical trials assessing the effects of milk protein components and prebiotics in the prevention and treatment of obesity and its related metabolic abnormalities.

Arthroscopic surgery is a type of Minimally Invasive Surgery (MIS) performed in human joints, which can be used for diagnostic or treatment purposes. The nature of this type of surgery makes it such that surgeons require extensive training to become experts at performing surgical tasks in tight environments and with reduced force feedback. MIS increases the possibility of erroneous actions, which could result in injury to the patient. Many of these injuries can be prevented by implementing appropriate training and skills assessment methods. Various performance methods, including Global Rating Scales and technical measures, have been proposed in the literature. However, there is still a need to further improve the accuracy of surgical skills assessment and improve its ability to distinguish fine variations in surgical proficiency. The main goal of this thesis is to enhance surgical, and specifically, arthroscopic skills assessment. The optimal assessment method should be objective, distinguish between subjects with different levels of expertise, and be computationally efficient. This thesis proposes a new method of investigating surgical skills by introducing energy expenditure metrics. To this end, two main approaches are pursued: 1) evaluating the kinematics of instrument motion, and 2) exploring the muscle activity of trainees. Mechanical energy expenditure and work are investigated for a variety of laparoscopic and arthroscopic tasks. The results obtained in this thesis demonstrate that expert surgeons expend less energy than novice trainees. The different forms of mechanical energy expenditure were combined through optimization methods and machine learning algorithms. An optimum two-step optimization method for classifying trainees into detailed levels of expertise is proposed that demonstrates an enhanced ability to determine the level of expertise of trainees compared to other published methods. Furthermore, performance metrics are proposed based on electromyography signals of the forearm muscles, which ...

Objectives: Most weight loss medications target reductions in energy intake while neglecting energy expenditure, a critical predictor of weight loss/regain. This pilot study examined the effect of short-acting methylphenidate (MPH) on resting energy expenditure (REE), thermic effect of food (TEF), physical activity energy expenditure (PAEE), and how changes in energy expenditure relate to changes in body composition in youth and adults living with obesity. Methods: This study was a randomized, double-blind, placebo-controlled two-parallel arm study. In total, 19 participants were screened, of which 14 participants were randomized into the study, but complete data was only collected for 12, and only analyzed for 10 participants. Those 10 participants aged 28.8 ± 6.9 yrs. (5 Male, 5 Female) were randomized to receive either MPH (0.5 mg/kg) (n = 5) or placebo (n =5) twice daily for 60 days. Participants’ REE and TEF (indirect calorimetry), were measured at baseline (no drug/placebo), and day 60 post-treatment (drug/placebo). Participants’ PAEE (Actical) was measured between screening and baseline for a 1-week period (no drug/placebo), and on day 53 for a 1-week period (drug/placebo). Participants’ anthropometrics were measured using DEXA at baseline, and day 60 post-treatment. Results: From baseline to day 60, MPH showed a relative difference to placebo in relative REE (Relative REE: F(1, 8) = 4.235, p = 0.074, d = 0.83, 2 = 0.346) of 10%, evidenced by a 6% increase in relative REE kcal/kg (18.53 ± 1.97 Kcal/day/kg at baseline, 19.71 ± 2.52 Kcal/day/kg at final) for the MPH group, and a 4% decrease (19.08 2.36 Kcal/day/kg at baseline, 18.26 ± 2.04 Kcal/day/kg at final) in placebo, translating to moderate-effect size (Cohen’s d=0.63) favouring MPH. From baseline to day 60, there were no significant differences between groups on changes in TEF (TEF AUC: F(1, 8) = 0.079, p = 0.785, d = 0.15, 2 = 0.010) or any PAEE variables such as sedentary behavior (SB: F (1, 8) = 0.455, p = 0.52, d = 0.02, 2 = 0.054), light physical activity (LPA: F (1, 8) = 0.504, p = 0.50, d = 0.16, 2 = 0.059), moderate physical activity (MPA: F (1, 8) = 0.281, p = 0.61, d = 0.19, 2 = 0.034), moderate-to-vigorous physical activity (MVPA: F (1, 8) = 0.120, p = 0.74, d = 0.15, 2 = 0.015), or vigorous physical activity (VPA: F (1, 8) = 3.495, p = 0.098, d = 0.91, 2 = 0.304) . Mean change in body weight (kg) resulted in a weight loss of roughly -2.66 ± 2.00 kg in the MPH group and -1.64 ± 1.41 kg in the placebo group, differences that were not statistically significant. Mean change in both groups for body fat% of -0.33 ± 2.08 %, mean change in fat mass of -1.05 ± 2.59 kg, and finally a mean change in fat-free mass of -0.06 ± 1.19 kg was reported. Changes in relative REE were inversely correlated with changes in body weight (r = -0.599, p = 0.067), body fat (r = -0.524, p = 0.12) and fat mass (r = -0.599, p = 0.096). These associations were stronger in the MPH group. Conclusions: Our data suggests that MPH administration may lead to a meaningful increase in relative REE, and these suggested changes were associated with reductions in adiposity among individuals with obesity. These preliminary findings suggest that MPH should be further examined using a larger sample size and study duration to determine its effectiveness in promoting weight loss and maintenance of weight loss in individuals with obesity, a population at high risk of morbidity and premature mortality.