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The development of atherosclerotic lesions and endothelial cell damage can originate during early childhood. Endothelial cells produce and release vasodilatory chemicals, which dictate the artery’s ability to vasodilate or vasoconstrict. Brachial artery FMD is a non-invasive, reproducible and a sensitive technique used to detect changes in arterial diameter and is correlated with coronary artery endothelial function. Cross-sectional studies have indicated increases in arterial diameter in children between the ages of 6-18 years however, a longitudinal, observational design study has not been conducted to understand how arterial diameters and FMD change over time in children, with considerations for the influences of physical activity and sex. The purpose of this study was to understand the impact of age and sex on arterial diameter and FMD and investigate the effects of habitual moderate-to-vigorous physical activity (MVPA) during both the school-age and preschool years on endothelial function trajectories during the school-age years. Over three years, 418 children between 3-5 years old participated in the HOPP study annually, and 279 of these children attended the lab when they were between 6-12 years old for an additional 3 annual visits in the SKIP study. Habitual MVPA was measured for 7 days in both the HOPP and SKIP studies each year, and FMD was measured each year during SKIP. Linear mixed-effects modeling was implemented to study the trend in FMD and the influence of chronological and biological age, sex and MVPA on arterial function; effects are reported as unstandardized estimates (Est). Boys had larger baseline and peak brachial artery diameters compared to girls (p<0.001). Girls had larger brachial artery FMD compared to boys (6.82±3.39 vs. 6.23±3.50 %, p<0.001). There was an effect of MVPA in the SKIP study on allometrically scaled FMD (Est. -0.017, p=0.03), but not on relative FMD (Est. -0.01, p=0.17). MVPA in the preschool years did not predict school-aged scaled FMD (Est. 0.11, p=0.24) or FMD (Est. -0.003, p=0.64). The observed trends in brachial artery diameter and FMD are in-line with expected changes in growth and maturation in children. Children who engaged in more habitual MVPA during the childhood years, but not the preschool years, demonstrated changes endothelial function during the school-age years. / Thesis / Master of Science (MSc) / It is clear that preliminary signs of atherosclerosis begin during the early years of childhood, and typically precede the development of future cardiovascular disease. Engaging in habitual physical activity at higher intensities, has been shown to positively influence cardiovascular health, specifically in central and peripheral arteries. This study sought to investigate the trends in vascular heath over time in children and examine the effect of moderate-to-vigorous physical activity engagement during the preschool years on vascular health during the school-age years. Our results suggest that as children age, their arteries get bigger in size and that school-aged girls have elevated vascular function when compared to boys. Children who engage in greater amounts of moderate-to-vigorous physical activity during their school-age years does not influence measures of vascular health. Additionally, engagement in habitual moderate to vigorous physical activity during the preschool years does not impact these vascular health relationships during the school-age years.

In this thesis, we present variants of Shor and Zhurbenko's r-algorithm, motivated by the memoryless and limited memory updates for differentiable quasi-Newton methods. This well known r-algorithm, which employs a space dilation strategy in the direction of the difference between two successive subgradients, is recognized as being one of the most effective procedures for solving nondifferentiable optimization problems. However, the method needs to store the space dilation matrix and update it at every iteration, resulting in a substantial computational burden for large-sized problems. To circumvent this difficulty, we first develop a memoryless update scheme. In the space transformation sense, the new update scheme can be viewed as a combination of space dilation and reduction operations. We prove convergence of this new algorithm, and demonstrate how it can be used in conjunction with a variable target value method that allows a practical, convergent implementation of the method. For performance comparisons we examine other memoryless and limited memory variants, and also prove a modification of a related algorithm due to Polyak that employs a projection on a pair of Kelley's cutting planes. These variants are tested along with Shor's r-algorithm on a set of standard test problems from the literature as well as on randomly generated dual transportation and assignment problems. Our computational experiments reveal that the proposed memoryless space dilation and reduction algorithm (VT-MSDR) and the proposed modification of the Polyak-Kelly cutting plane method (VT-PKC) provide an overall competitive performance relative to the other methods tested with respect to solution quality and computational effort. The r-Algorithm becomes increasingly more expensive with an increase in problem size, while not providing any gain in solution quality. The fixed dilation (with no reduction) strategy (VT-MSD) provides a comparable, though second-choice, alternative to VT-MSDR. Employing a two-step limited memory extension over VT-MSD sometimes helps in improving the solution quality, although it adds to computational effort, and is not as robust a procedure. / Master of Science

In systemic sclerosis (SSc), interstitial lung disease (ILD) and engagement of the vascular system lead to increased morbidity and mortality. The aim of this thesis was to elucidate, in a consecutively included cohort of SSc (limited and diffuse) patients (n = 33), the T cell cytokine profile driving the disease in ILD and to explore the role of matrix metalloproteinase 9 (MMP-9) and its inhibitor: tissue inhibitor of metalloproteinase 1 (TIMP-1) in the extracellular matrix (ECM) degrading process leading to fibrous scarring and honey combing. Moreover, to characterize the role of nitric oxide (NO) in vascular engagement. Peripheral arterial changes cause Raynaud’s phenomenon and digital ulcers. Nitric oxide (NO) a main inducer of vasodilation is produced by endothelial nitric oxide synthase (eNOS) in response to changes in blood flow or by inflammatory cytokine inducible (i) NOS. In the vascular smooth muscle cell (VSMC) NO activates guanylate cyclase to produce cGMP, causing relaxation. We showed elevated plasma nitrate, a degradation product of NO, and increased urinary excretion of nitrate and cGMP. Plasma nitrate correlated with elevated levels of endothelial adhesion molecules: endothelial (E) selectin and vascular adhesion molecule 1, indicating that the activated endothelium is the site of NO synthesis by iNOS. Endothelial staining for E-selectin and the finding of iNOS and eNOS in SSc skin biopsies supported this notion. In SSc increased vascular stiffness may limit the NO vasodilatory effects. We found normal endothelium-dependent (i.e. flow mediated (FMD%)) and endothelium-independent (i.e. nitroglycerin-induced (NTG%)) vasodilation in the brachial artery. Radial arterial wall stiffness measured as maximum increase in pulse pressure (dP/dtmax) was increased. FMD% and especially NTG% correlated negatively and dP/dtmax positively to measures of endothelial inflammation: plasma- nitrate and adhesion molecule levels. Thus inflammatory vascular wall changes may interfere with dilation as may the presence of nitrate tolerance. We found elevated alveolar MMP-9 in both its pro- and active form in ILD. The levels correlated to decline in lung capacity, pointing at a causal relation. We suggest that neutrophils secrete MMP-9, which may degrade collagen IV, (the main constituent of basal membranes), collagen V, gelatins, proteoglycans and elastin. MMP-9 activity is partly regulated by the binding of pro- and active form to TIMP-1. Alveolar TIMP-1, which even stimulates fibroblast ECM synthesis, was increased independent of ILD. The inflammatory process in ILD is orchestrated by activated T helper (h) lymphocytes. We found a mixed Th1/Th2 reaction in SSc alveolar T cells expressing messenger for interferon gamma (Th1), IL-6 and IL-10 (both Th2). No particular cytokine mRNA profile distinguished alveolar T cells in ILD. Neutrophils invaded the bronchial epithelium, which seemed otherwise inert as levels of inflammatory cytokine sensitive transcription factors and their nuclear translocation tended to be low. The neutrophil recruitment pathway is uncertain as chemoattractants and endothelial adhesion molecules were normally expressed. In conclusion, MMP-9 probably causes degradation of lung tissue in ILD and may represent a future therapeutic target. Alveolar T cells show a mixed Th1/Th2 cytokine profile independent of ILD. Neutrophils invade the bronchial epithelium. Activated endothelium produces increased amounts of NO and adhesion molecules and the level of activation influences brachial arterial FMD% and NTG% and radial arterial compliance. Nitrate tolerance may be present.

Distortion to hemodynamic, ischemic and metabolic stimuli during low load resistance exercise with blood flow restriction (BFR) may influence regional vascular adaptation. This thesis investigated the acute response and chronic adaptations of the peripheral vasculature to low load resistance exercise with BFR. The methodology utilised Doppler ultrasound, strain gauge plethysmography and muscle biopsy for insightful measures of the vasculature at different regions of the arterial tree. Short term (4-6 weeks) localised low load (30-40% 1RM) resistance exercise with BFR increased brachial (3.1%) and popliteal (3.3%) artery maximal diameter (in response to ischemic exercise), forearm (29%) and calf (24%) post-occlusive blood flow, and calf filtration capacity (14%). These findings indicate potential vascular remodelling at the conduit (chapters 3, 4) resistance (chapter 4) and capillary (chapter 4) level of the vascular tree. Regional, rather than systemic, factors are responsible for these adaptations as evidenced by an absent response in the contralateral control limb. Transient improvements in popliteal artery FMD% occurred at week 2 before increased maximal diameter at week 6, suggesting functional changes precede structural remodelling (chapter 4). Maximal brachial artery diameter and forearm post-occlusive blood flow returned to baseline values after a 2 week detraining period, signifying rapid structural normalisation after stimulus removal (chapter 3). Enhanced capillarity, despite low training loads, could be explained by augmentation of VEGF (~7 fold), PGC-1α (~6 fold) and eNOS (~5 fold) mRNA, and upregulation VEGFR-2 (~5 fold) and HIF-1α (~2.5 fold) mRNA with BFR (chapter 5). This indicates a targeted angiogenic response potentially mediated through enhanced metabolic, ischemic and shear stress stimuli. Large between subject variability in the level of BFR was observed during upper and lower limb cuff inflation protocols. Adipose tissue thickness and mean arterial pressure were the largest independent determinants of upper and lower limb BFR, respectively (Chapter 6). In conclusion, this thesis demonstrates that low load resistance exercise with BFR induces adaptation in the conduit, resistance and capillary vessels. The mediators of this response are likely to be the hemodynamic and chemical signals elicited by repeated bouts of BFR resistance exercise, although confirmation of these mechanisms is required. The functional significance of these adaptations is unknown and warrants further investigation.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / To analyze the roles of CCTA, MPI, and CC to formulate a sequential clinical algorithm to use in patients with chest pain, risk factors for CAD, and an abnormal EKG. The goals of the study are to streamline and refine workup, to decrease radiation exposure to patients, and to contain costs. 39 patients underwent CCTA, MPI, and CC within 30 months of each other. CCTA was used to categorize mild, moderate, or severe CAD. MPI used SSS, SDS, TID, and formal reading to define mild, moderate, or severe physiologic ischemia. CC and coronary intervention cine films were analyzed to define and treat anatomical CAD medically or by intervention. Results: There was strong correlation between CCTA, CC, and treatment type (p<0.0001). CCTA was able to stratify all patients with mild or severe ischemia to appropriate treatment groups, and to reduce the need for MPI. With moderate ischemia from CCTA, the additional use of MPI could have reduced the need for 16/18 (89%) patients who underwent CC to undergo further testing. No patients with mild or moderate CAD by CCTA, followed by mild to moderate physiologic ischemia by MPI, needed CC or intervention. 37/39 patients (95%) could have avoided one or more tests using our algorithm. CCTA followed by MPI may be used in symptomatic patients with risk factors for CAD and an abnormal EKG to stratify mild and moderate CAD, and to thereby avoid cardiac catheterization. Our algorithm could lead to savings in healthcare expenditures, save patients from unnecessary invasive procedures, decrease radiation exposure, and total cost.

The cell population is used to determine the effect of a drug to understand the disease mechanisms. Thus the analysis of the population behavior provides new insights in medicine development. This project focuses on developing a simple method for cell images which have low resolution and high complexity. The various techniques such as image thresholding, watershed segmentation, opening, dilation, contrast stretching are applied in segmentation and analysis of the image. The estimate of the cell boundary is done using the nucleus image which is assumed as the central part of the considered cells. The cancer cell images of Scott and White(SW) cel line of Beta Catenin(BC) and Krupel Like Factor(KLF) genes have been analyzed and the corresponding average intensity data of the population and a comparison of the Otsu and Huang thresholding methods has been produced. The softwares used in the project are MATLAB 2014 and ImageJ.

Exercise training promotes a beneficial endothelial cell (EC) phenotype and results in conduit vessel adaptation. The specific underlying mechanisms have been proposed (shear stress, circumferential stress, hypoxia, metabolic) but are yet to be fully elucidated. This thesis investigated the predominant stimuli responsible for conduit vessel adaptation with training. Further, it developed a method of in situ EC extraction to allow for determination of the cellular and molecular mechanisms underpinning these adaptations. The methodology utilised two-dimensional (2D) Doppler ultrasound, strain gauge plethysmography, immunocytochemistry and RT-qPCR to provide insight in to vascular characteristics, predominantly of the brachial artery and peripheral EC. Long-term repeated isometric forearm muscle contractions as performed by well-trained rock climbers promoted greater resting, peak (in response to 5 min ischaemia) and maximal (in response to ischaemic exercise) brachial artery diameters compared with controls. This structural response is dependent upon confounders associated with exercise additional to shear stress as evidenced by the lack of brachial artery remodelling in response to 8 weeks of ischaemic preconditioning (IPC). A transient increase in flow-mediated dilation (FMD)% was observed following 6 weeks exposure to IPC, which became significant when controlled for baseline artery diameter, despite an absence of augmentation following long-term (≥ 8 weeks) exposure to a shear stimulus. This is in line with the suggested timeline of conduit vessel adaptation to exercise training of a transient increase in function at 2-4 weeks. Underpinning molecular mechanisms responsible were not determined but may be further investigated given that the endovascular biopsy technique was developed and improved in this thesis. The endovascular biopsy successfully yields approximately 2100 ± 1700 EC per sample, providing sufficient material for determination of expression of both mRNA (RT-qPCR) and protein (immunocytochemistry). Specifically, type 2 diabetics (T2DM) with symptomatic cardiac abnormalities exhibited augmented eNOS mRNA and protein in brachial artery EC as compared with non-diabetic controls with symptomatic cardiac abnormalities. In conclusion, this thesis demonstrates that although shear stress promotes a transient trend for enhancement in function of the peripheral conduit arteries, additional factors are required for long-term structural adaptations. Further, the endovascular biopsy technique offers a novel method of extracting and analysing EC for genes and proteins of interest to vascular health. The use of this technique to decipher the underlying cellular and molecular mechanisms involved in vascular adaptations with exercise requires further investigation.

Introdução: O hábito de fumar causa inúmeros prejuízos à saúde, entre os quais aumenta o risco de disfunção endotelial. Atualmente, o método mais utilizado para a avaliação não invasiva da função vascular, é a dilatação mediada por fluxo da artéria braquial: através da ultrassonografia. Objetivos: Avaliar em que tempo ocorre à máxima dilatação, e se existe diferença na avaliação da função endotelial avaliada pela ultrassonografia ao comparar quatro grupos de mulheres (gestantes ou não e fumantes ou não). Métodos Estudo transversal no qual foi realizada a mensuração do diâmetro da artéria braquial em repouso e em quatro tempos após estímulo (30, 60, 90 e 120 segundos) em quatro grupos de mulheres entre 20 e 30 anos de idade, incluindo gestantes entre 24 e 28 semanas de idade gestacional: gestantes não fumantes (N=47), gestantes fumantes (N=33), mulheres não fumantes (N=34) e mulheres fumantes (N=19), resultando em 133 avaliações. Resultados: Dados antropométricos, idade, paridade e idade gestacional não houve diferença significativa nos grupos estudados, bem como, os níveis de pressão arterial diastólica (PAD) (mmHg) e índice de massa corporal. Uma diferença significativa foi observada entre o número de cigarros consumidos por semana entre gestantes e não gestantes (p=0,04). A DMF foi maior entre as gestantes não fumantes em comparação às fumantes (11,50 ± 5,77 vs. 8,74 ± 4,83; p=0,03) como também no grupo de não gestantes não fumantes em comparação as fumantes (10,52 ± 4,76 vs. 7,21 ± 5,57; p=0,03). Ambas com diferença significativa em relação ao grupo controle. Em relação à avaliação da dilatação nos diferentes tempos, esta foi máxima para todos os grupos no tempo 60 segundos após a desinsuflação. Uma diferença significante foi observada em todos os tempos e entre todos os grupos. Conclusões: A máxima dilatação mediada por fluxo foi observada 60 segundos, após o estímulo em todos os grupos. O hábito de fumar parece levar a disfunção endotelial, tanto em mulheres gestantes quanto em não gestantes, o que foi demonstrado por uma menor dilatação mediada por fluxo nas fumantes. / There is innumerous health problems associated with smoking habits, among them an increased risk of endothelial dysfunction. Currently, the most used method for noninvasive evaluation of vascular function is flow-mediated dilatation (FMD) of the brachial artery determined by ultrasonography. Objectives: To determine at what time the maximum dilatation occurs and whether there is a difference in the evaluation of endothelial function determined by ultrasonography when comparing four groups of women (pregnant smokers and pregnant no smokers, and non-pregnant smokers and non-pregnant no-smokers). Methods This cross sectional study included a total of 133 women. The women were divided into 4 groups non-smoking pregnant women (N=47), smoking pregnant women (N=33), non-smoking women (N=34), and smoking pregnant women (N=19). The diameter of the brachial artery was measured at five times (rest, after a stimulus (30, 60, 90 and 120 seconds). Results: Anthropometric data, age, parity, gestational age, diastolic blood pressure (DBP) and body mass index did not differ significantly between groups. A significant difference was observed in the number of cigarettes smoked per week between pregnant women and non-pregnant women (p=0.04). The FMD was greater among non-smoking pregnant women compared to smoking pregnant women (11.50 ± 5.77 vs. 8.74 ± 4.83; p=0.03) and also among non-smoking non-pregnant women compared to smoking non-pregnant women (10.52 ± 4.76 vs. 7.21 ± 5.57; p=0.03). The difference was significant in both cases. Regarding the evaluation of dilation at the different time points, the maximum value was obtained for all groups at the 60 second time point after disinsufflation. A significant difference was observed at all times and between all groups. Conclusions: Maximum FMD was observed 60 seconds after the stimulus in all groups. The smoking habit seems to lead to endothelial dysfunction both in pregnant and non-pregnant women, as demonstrated by the lower FMD among smokers.

Introdução. A prática regular do exercício de força (EF) está associada a adaptações metabólicas, neuromusculares e cardiovasculares que repercutem de maneira positiva sobre a saúde e qualidade de vida de seus praticantes. No entanto, Indivíduos sedentários apresentam comprometimentos agudos na função endotelial após EF de alta intensidade. Objetivo. Avaliar a função endotelial de indivíduos sedentários de meia idade em resposta a diferentes intensidades do EF. Métodos. 11 indivíduos sedentários (40,1±3,9 anos; 27,3±1,4 kg/m2) realizaram EF em três condições experimentais: extensão de joelhos a 50% de 1RM (MI), 80% de 1RM (AI) e repouso na condição controle (CON). Foi realizada avaliação da vasodilatação mediada pelo fluxo (FMD) antes, 30 minutos após e 60 minutos após os protocolos. A quantificação das concentrações de NO2 e NO3 (NOx), endotelina-1 (ET-1) e TBARS foram realizadas antes, imediatamente após e 60 minutos após os protocolos. A pressão arterial foi mensurada antes e após os protocolos Resultados. A FMD aumentou significativamente 30 minutos após o exercício na condição MI (12,5± 4,10 para 17,2±3,9 %; p=0,01) bem como os níveis de NOx (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). A concentração de ET-1 aumentou imediatamente após na condição AI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). A elevação da pressão arterial não diferiu entre as condições MI e AI. As concentrações de TBARS não se alteraram ao longo dos protocolos. Conclusão. O EF de moderada intensidade aumenta a FMD e os níveis NOx após uma sessão aguda de exercício em indivíduos sedentários de meia idade, estes resultados sugerem que menores intensidades do EF são mais seguras ao iniciar um programa de exercícios. / Regular resistance exercise (RE) is associated with metabolic, neuromuscular and cardiovascular adaptation that results in improvement of quality of life and health. However, sedentary subjects have been showing an acute impairment on endothelial function after high intensity resistance exercise. The aim of this study was to evaluate the endothelial function in sedentary middle age men after RE in different intensities. Methods. Eleven middle age sedentary men (40,1±3,9 years; 27,3±1,4 kg/m2) performed RE in three different conditions: knee extension at 50% of one 1RM (MI), at 80% of 1RM (HI) and rest in the control group (CON). Flow mediated dilation (FMD) was assessed before, 30 and 60 minutes of exercise. Venus plasma concentration of ET-1 NOx and TBARS were measured before, immediately after and 60 minutes after exercise. Blood pressure was evaluated before and after exercise. Results. There was a significant improvement in FMD 30 minutes after exercise in the MI condition (12,5± 4,10 vs 17,2±3,9%; p= 0,016; p=0,01). The plasma NOx concentration was significant higher immediately after MI (6,8± 3,3 vs. 12,6± 4,2μM; p= 0,007). There was a significant improvement in the plasma ET-1 concentration immediately after HI (20,02±2,2 vs. 25,4± 2,1pg/ml; p= 0,004). There was no significant difference in the BP between the experimental conditions (MI vs HI) and TBARS throughout the experimental conditions. Conclusions. Resistance exercise performed in moderate intensity improve endothelial function in sedentary middle aged men, there results suggest that lower intensities of RE could be safe for this population in the beginning of the exercise programs.