The World Health Organization (WHO) states that iron deficiency (ID) is the preeminent global micronutrient deficiency. Maternal ID is linked to cardiovascular disease and hypertension in offspring, and yet the impact of ID on the kidney is not known. We characterized the impact of ID on circulating and tissue levels of iron and renal function. Seven and ten week old male and female Wistar rats were fed either control (270ppm) or low iron (3ppm) diet for ten weeks. Total, non-heme and heme iron levels in liver, kidney cortex and kidney medulla were measured following the dietary period. Hematocrit decreased most in males regardless of age (Male 7-17wk: 47%→ 31%; 10-20wk: 47%→ 33.5%; Female 7-17wk: 47%→ 34%; 10-20wk: 47%→ 39%). Dietary ID markedly decreased liver and kidney cortex non-heme iron in both males and females (Female: liver-178±25 to 21±7 ppm; kidney cortex-51±9 ppm to 10±1 ppm; Male: liver-102±18 ppm to 11±1 ppm; kidney cortex 36±14 to 15±8 ppm). In contrast, non-heme iron in the kidney medulla was not significantly decreased Secondly, in order to determine the impact of ID on renal function, blood pressure was monitored using radio-telemetry starting at six weeks of age (~175g body weight). Dietary salt challenge (5 days Low5 days HighNormal) was administered to all animals (n=16) starting at eight weeks of age. At ten weeks rats were assigned to either control (225pm) or low (3ppm) iron diet. Dietary salt challenge was repeated at 13 and 18 weeks of age respectively. Despite significant lowering of hematocrit (Control 45%  Low iron 38.6%) hemodynamic changes were minimal, in that, although blood pressure was lowered following ten weeks of dietary iron restriction, blood pressure did not change in response to dietary salt (Control MAP:105.0 ± 2.5mmHg; ID MAP:100.6 ± 3.2mmHg ). Collectively the tissue and functional analyses demonstrate that the body adapts to lowering of tissue iron supply with ID. The relative sparing of non-heme iron in the kidney medulla suggests that iron in this region of the kidney may be spared because of its importance in the systems responsible for regulating fluid and sodium balance. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2007-07-18 12:00:09.853

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Individuals with abdominal obesity are at higher risk for developing type 2 diabetes, predisposing cardiovascular events and insulin resistance. Low glycemic index (GI) diets may be beneficial in the management of insulin resistance. Insulin resistance is associated with increased intramyocellular lipid (IMCL) content as measured by proton nuclear magnetic resonance spectroscopy (1H-MRS). The primary objective of this thesis was to determine whether a low GI diet can improve insulin sensitivity by reducing IMCL of skeletal muscle. One hundred and twenty-one male and female participants aged 30 to 70 years (mean+SD, 53+10)) with abdominal obesity, entered a 4 to 6 week weight-maintaining, low-fat dietary advice run-in phase. Of the 121 eligible participants, 95 completed the run-in phase and were randomly assigned to either a low-GI (LGID, n=48) or high-GI diet (HGID, n=47) for 24 weeks. Participants underwent a 75g oral glucose tolerance test (OGTT) and had soleus-muscle IMCL measured by 1H-MRS at the beginning and end of the intervention period. Insulin sensitivity was assessed by the homeostatic model assessment index (HOMA) and the insulinogenic index (ISI) was calculated for insulin secretion. At the end of the run-in phase, there were significant reductions in serum total-, LDL-, and HDL-cholesterol (all, p<0.0001) and an increase in fasting plasma glucose (p<0.05). In 57 participants who wore a continuous glucose monitoring system for 24 hours during the run-in period, a total of 30% (p<0.001) of the variation in the incremental area under the blood glucose curve after self-selected breakfast meals was explained by GI. After 24 weeks, diet GI was significantly lower in the LGID than HGID group (55.5+3.1 vs 63.9+3.1, p<0.0001). Plasma glucose 60 minutes after the OGTT was significantly lower on the LGID than at baseline (p<0.05) and there was a non-significant trend towards an increase in ISI (p=0.07). On the HGID, ISI increased significantly from baseline (p<0.01). It is concluded that the LGID reduced 60 minute plasma glucose but did not significantly affect IMCL or insulin sensitivity in individuals with abdominal obesity.

Canada is a global leader in flax production, but flax acreage in Canada remains limited since flax is not well adapted to the northern Prairies. Therefore, breeding early-flowering and early maturing flax cultivars that are adapted to the climate of the northern Prairies is one of the major strategies to expand flax acreage in Canada. The objective of this project is to understand flowering time in flax and generate early flowering genotypes that are adapted to the continental climate of the Canadian Prairies. This project examined photoperiod sensitivity in five Canadian flax cultivars (CDC Sorrel, CDC Bethune, Flanders, Prairie Thunder and Royal) and three M9 genotypes derived from 5-azacytidine (5-azaC) treatment (RE1, RE2 and RE3). To investigate how each cultivar or genotype responds to photoperiod changes, a reciprocal transfer experiment between long day and short day conditions was conducted. All cultivars and genotypes were photoperiod sensitive. However, the level of sensitivity and length of the sensitive phase varied among cultivars and genotypes. The five cultivars were more sensitive to photoperiod changes compared with the three mutant genotypes, while RE2, which was the earliest flowering genotype, was the least sensitive genotype. This project, in addition, examined the expression pattern of ELF4 (EARLY FLOWERING 4), a specific flowering-related gene. This experiment was conducted with three Canadian flax cultivars (CDC Sorrel, CDC Bethune and Royal) and one 5-azaC mutant genotype (RE2). GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) was used as a reference gene in RT-qPCR. Results of RT-qPCR demonstrated that CDC Sorrel and CDC Bethune had a similar expression pattern, while Royal and RE2 had a similar expression pattern. This project also sought to generate early-flowering genotypes by treating CDC Sorrel with 5-azaC as well as to introgress the early-flowering trait from RE genotypes into CDC Sorrel via hybridization. Mutant populations (M2, M3, bulk M3) and hybrid populations (F2, F3, and bulk F3) were grown and evaluated for time to flowering, maturity and height under latitude (53° N) field conditions in 2012 and 2013. 5-azaC treatment did not induce significant differences in flowering or maturity in the CDC Sorrel background. However, the early flowering trait was successfully introgressed into CDC Sorrel background since selected progeny lines flowered significantly earlier than the later flowering CDC Sorrel parental line.

Laser forming is an innovative technique that uses a defocused laser beam to form sheet metal by thermal stresses rather than external forces. Promising potential applications of laser forming include rapid prototyping, straightening, aligning and adjusting of macro/micro-metallic components. Research to-date on laser forming has been largely focused, theoretically and experimentally, on the problem of characterization of process parameters on the forming results, and computational simulations of laser forming remain limited only providing the insight into the process. This study investigates the laser forming processes using the finite element analysis with respect to material responses during the processes, including complex processes, process optimization, process reliability and the effects of thermal and mechanical material properties. The first part of this thesis describes a nonlinear transient three-dimensional heat transfer finite element model and a rate dependent three-dimensional deformation model, which are developed for the laser forming simulations. Simulations are performed using an indirect coupled thermal-structural method for the processes of a straight-line heating, a circle-line heating, and a laser micro-adjustment. The thermo-mechanical behaviours during the straight-line heating process are presented in terms of temperature, stress and strain, and displacement distributions. The emphasis in the circle-line heating simulations is placed on the characterization of the quality of the deformed geometry by obtaining the radial and circumferential waviness. The micron size movements induced by laser point heating are focused the simulations of the micro-adjustment process. Simulation results are validated by comparison with published data or correlation to engineering point of view. The second part of this thesis presents the development of an effective method to determine optimum process parameters in laser forming. For the process optimization, design optimisation techniques are introduced into the finite element analysis of the laser forming process. The optimum parameter values to produce a predefined bend angle of 3° in the straight-line heating process are sought by two optimization procedures - one is the procedure involving the non-gradient method and the other is the gradient-based method. Optimum values of laser power, feed rate, beam diameter and number of passes are determined to produce a predefined bend angle in a multiple straight-line heating process using the two optimization procedures. A more suitable optimisation method for laser forming is chosen, which is used for a new optimisation problem to generate a maximum bend angle in a single pass of laser forming. In the third part of this thesis, a strategy to assess the reliability of the laser forming process is established by employing a well-known reliability analysis method, the Monte Carlo simulation. Robustness of the straight-line heating process of producing 3° with the optimum parameters determined by process optimization is evaluated with regard to the uncertain input variables of laser power, feed rate, plate thickness and coefficient of thermal expansion via the Monte Carlo simulations based on the finite element simulations of the process. The final part of this thesis identifies the effects of material properties on the bend angle resulting from laser forming. Process sensitivity to the properties of coefficient of thermal expansion, thermal conductivity, specific heat capacity and elastic modulus is investigated by measuring the Pearson product-moment correlation coefficient between the properties and the bend angle, which are based on the Monte Carlo simulations of laser forming. The conclusion is that the developed finite element models contribute to a better understanding of the laser forming process, and the optimization procedure is able to be used for straightening, aligning and adjusting of components.

Hyperglycemia is prevalent in critical care, as patients experience stress-induced hyperglycemia, even with no history of diabetes. Hyperglycemia has a significant impact on patient mortality, outcome and health care cost. Tight regulation can significantly reduce these negative outcomes, but achieving it remains clinically elusive, particularly with regard to what constitutes tight control and what protocols are optimal in terms of results and clinical effort. Hyperglycemia in critical care is not largely benign, as once thought, and has a deleterious effect on outcome. Recent studies have shown that tight glucose regulation to average levels from 6.1–7.75 mmol/L can reduce mortality 17–45%, while also significantly reducing other negative clinical outcomes. However, clinical results are highly variable and there is little agreement on what levels of performance can be achieved and how to achieve them. A typical clinical solution is to use ad-hoc protocols based primarily on experience, where large amounts of insulin, up to 50 U/hr, are titrated against glucose measurements variably taken every 1–4 hours. When combined with the unpredictable and sudden metabolic changes that characterise this aspect of critical illness and/or clinical changes in nutritional support, this approach results in highly variable blood glucose levels. The overall result is sustained periods of hyper- or hypo- glycemia, characterised by oscillations between these states, which can adversely affect clinical outcomes and mortality. The situation is exacerbated by exogenous nutritional support regimes with high dextrose content. Model-based predictive control can deliver patient specific and adaptive control, ideal for such a highly dynamic problem. A simple, effective physiological model is presented in this thesis, focusing strongly on clinical control feasibility. This model has three compartments for glucose utilisation, interstitial insulin and its transport, and insulin kinetics in blood plasma. There are two patient specific parameters, the endogenous glucose removal and insulin sensitivity. A novel integral-based parameter identification enables fast and accurate real-time model adaptation to individual patients and patient condition. Three stages of control algorithm developments were trialed clinically in the Christchurch Hospital Department of Intensive Care Medicine. These control protocols are adaptive and patient specific. It is found that glycemic control utilising both insulin and nutrition interventions is most effective. The third stage of protocol development, SPRINT, achieved 61% of patient blood glucose measurements within the 4–6.1 mmol/L desirable glycemic control range in 165 patients. In addition, 89% were within the 4–7.75 mmol/L clinical acceptable range. These values are percentages of the total number of measurements, of which 47% are two-hourly, and the rest are hourly. These results showed unprecedented tight glycemic control in the critical care, but still struggle with patient variability and dynamics. Two stochastic models of insulin sensitivity for the critically ill population are derived and presented in this thesis. These models reveal the highly dynamic variation in insulin sensitivity under critical illness. The stochastic models can deliver probability intervals to support clinical control interventions. Hypoglycemia can thus be further avoided with the probability interval guided intervention assessments. This stochastic approach brings glycemic control to a more knowledge and intelligible level. In “virtual patient” simulation studies, 72% of glycemic levels were within the 4–6.1 mmol/L desirable glycemic control range. The incidence level of hypoglycemia was reduced to practically zero. These results suggest the clinical advances the stochastic model can bring. In addition, the stochastic models reflect the critical patients’ insulin sensitivity driven dynamics. Consequently, the models can create virtual patients to simulated clinical conditions. Thus, protocol developments can be optimised with guaranteed patient safety. Finally, the work presented in this thesis can act as a starting point for many other glycemic control problems in other environments. These areas include the cardiac critical care and neonatal critical care that share the most similarities to the environment studied in this thesis, to general diabetes where the population is growing exponentially world wide. Furthermore, the same pharmacodynamic modelling and control concept can be applied to other human pharmacodynamic control problems. In particular, stochastic modelling can bring added knowledge to these control systems. Eventually, this added knowledge can lead clinical developments from protocol simulations to better clinical decision making.

Type 2 diabetes has reached epidemic proportions worldwide. The resulting increase in chronic and costly diabetes related complications has potentially catastrophic implications for healthcare systems, and economies and societies as a whole. One of the key pathological factors leading to type 2 diabetes is insulin resistance (IR), which is the reduced or impaired ability of the body to make use of available insulin to maintain normal blood glucose levels. Diagnosis of developing IR is possible up to 10 years before the diagnosis of type 2 diabetes, providing an invaluable opportunity to intervene and prevent or delay the onset of the disease. However, an accurate, yet simple, test to provide a widespread clinically feasible early diagnosis of IR is not yet available. Current clinically practicable tests cannot yield more than a crude surrogate metric that allows only a threshold-based assessment of an underlying disorder, and thus delay its diagnosis. This thesis develops, analyses and pilots a model-based insulin sensitivity test that is simple, short, physiological and cost efficient. It is thus useful in a practical clinical setting for wider clinical screening. The method incorporates physiological knowledge and modelling of glucose, insulin and C-peptide kinetics and their pharmaco-dynamics. The clinical protocol is designed to produce data from a dynamic perturbation of the metabolic system that enables a unique physiologically valid assessment of metabolic status. A combination of a-priori information and a convex integral-based identification method guarantee a unique, robust and automated identification of model parameters. In addition to a high resolution insulin sensitivity metric, the test also yields a clinically valuable and accurate assessment of pancreatic function, which is also a good indicator of the progression of the metabolic defect. The combination of these two diagnostic metrics allow a clinical assessment of a more complete picture of the overall metabolic dysfunction. This outcome can assist the clinician in providing an earlier and much improved diagnosis of insulin resistance and metabolic status and thus more optimised treatment options. Test protocol accuracy is first evaluated in Monte Carlo simulations and subsequently in a clinical pilot study. Both validations yield comparable results in repeatability and robustness. Repeatability and resolution of the test metrics are very high, particularly when compared to current clinical standard surrogate fasting or oral glucose tolerance assessments. Additionally, the model based insulin sensitivity metric is shown to be highly correlated to the highly complex, research focused gold standard euglycaemic clamp test. Various reduced sample and shortened protocols are also proposed to enable effective application of the test in a wider range of clinical and laboratory settings. Overall, test time can be as short as 30 minutes with no compromise in diagnostic performance. A suite of tests is thus created and made available to match varying clinical and research requirements in terms of accuracy, intensity and cost. Comparison between metrics obtained from all protocols is possible, as they measure the same underlying effects with identical model-based assumptions. Finally, the proposed insulin sensitivity test in all its forms is well suited for clinical use. The diagnostic value of the test can assist clinical diagnosis, improve treatment, and provide for higher resolution and earlier diagnosis than currently existing clinical and research standards. High risk populations can therefore be diagnosed much earlier and the onset of complications delayed. The net result will thus improve overall healthcare, reduce costs and save lives.

Diamond and Carey (1986) identify sensitivity to second-order relational information (i.e., spatial relations among features such as the distance between eyes) as a vital part of achieving expertise with face processing. Previous research suggests that 5-month-olds are sensitive to second-order relational information when shown line drawings of faces in which this information has been manipulated to an exaggerated degree. The present series of experiments explored infants sensitivity to second-order relational information using photographs of real faces and with second-order manipulations that were within the normal range of human variability. A discrimination study conducted with adults provided additional evidence that the second-order manipulations were within the normal range. Five- and 7- month-olds exhibited sensitivity to changes in second-order relational information. Moreover, 5-months detected second-order changes in upright but not in inverted faces, thereby exhibiting an inversion effect that has been considered to be a hallmark of second-order relational processing in adulthood. These results suggest that infants as young as 5 months of age are sensitive to second-order relational changes that are within the normal range of human variability. They also indicate that at least rudimentary aspects of face-processing expertise are available early in life.

A novel surface plasmon resonance sensor is fabricated to evaluate its use in biochemical sensing. The sensor can differentiate between bulk refractive index changes and surface binding reactions of interest. There has been a great interest in developing sensors to differentiate biological or chemical agents from interfering effects, but they still remain in research phase. In this work, a prism coupler is used to simultaneously excite both long and short range surface plasmon modes of the sensor. The differing sensitivities of the long and short range modes allow one to distinguish surface binding reactions of interest from refractive index fluctuations. In this thesis, we have demonstrated the sensors self referencing capability by detecting the formation of an octadecanethiol self assembled monolayer while varying solution refractive index.

Equine pituitary pars intermedia dysfunction (PPID) typically occurs in horses older than 15 years of age and is characterized by hair coat abnormalities, muscle atrophy and decreased insulin sensitivity. The first objective of this research was to compare the rate of whole body protein metabolism and relative abundance of key factors in the signaling pathways associated with muscle protein synthesis and protein breakdown in response to feeding in Control and PPID horses. No differences (P > 0.05) were seen between the PPID and Control groups in whole-body protein metabolism or post-prandial activation of the muscle signaling pathways regulating skeletal muscle protein synthesis and breakdown. The second objective of this research was to determine if aged horses with PPID had reduced insulin sensitivity and alterations in the insulin-mediated signaling pathways in the skeletal muscle when compared to non-PPID, aged Control horses. Measures of insulin sensitivity and the activation of factors associated with protein synthesis and breakdown were similar between the PPID and Control groups (P > 0.05). Overall, insulin sensitivity and protein metabolism are similar between the PPID and Control groups. The studies suggest that abnormalities may exist as a function of advanced age rather than PPID status directly.