Background: Women are more likely to develop age-related cognitive impairment compared with men of the same age. Pregnancy complications, such as preeclampsia (PE), and menopause may contribute to an elevated risk of cognitive decline with aging in women potentially through an adverse impact on vascular function. PE is associated with a heightened risk of hypertension and large elastic artery stiffness (i.e., aortic and carotid arteries) for several years postpartum. Persistent large artery stiffness may be further amplified in women with a history of PE during the menopause transition, which is marked by an accelerated rate of vascular aging. However, large artery stiffness has not been studied extensively in postmenopausal women with a history of PE. Age-related elevations in large artery stiffness are associated with cognitive decline in middle-aged and older adults however, this relation has not been investigated in young women with a history of PE. Moreover, the degree to which elevated large artery stiffness is amplified and associated with reduced cognitive function among postmenopausal women with a history of PE remains unknown. The purpose of this study was to examine the extent to which large elastic artery stiffness is associated with reductions in cognitive function in premenopausal and postmenopausal women with a history of PE. Methods: Large elastic artery stiffness and domains of cognitive function were assessed in young women one year postpartum (n=18, ages 24-41 yrs.) and postmenopausal women (n=19, ages 52-77 yrs.) thirty-five years postpartum. Aortic stiffness was measured via non-invasive applanation tonometry at the carotid and femoral pulse sites and expressed as carotid-femoral pulse wave velocity (cfPWV). Carotid artery stiffness was quantified as beta-stiffness index (β-stiffness) was measured via ultrasonography and carotid tonometry. Cognitive tests were administered to assess cognitive function in immediate and delayed recall, working memory, processing speed, and executive function. Results: Premenopausal women with a history of PE had higher systolic blood pressure (121 ± 4 vs. 101 ± 3 mmHg, p =0.01) one year postpartum but did not differ significantly from controls in cfPWV (6.2 ± 0.4 vs. 5.1 ± 0.2 m/s, p =0.08), β-stiffness (6.1 ± 0.5 vs. 6.1 ± 0.7 U, p =0.97), or cognitive domains of memory, executive function, or processing speed (all p>0.05). Higher systolic blood pressure was associated with lower executive function (r = -0.53, p = 0.05) in young women one year postpartum. Postmenopausal women with a history of PE did not differ from controls in blood pressure, large artery stiffness, or age-adjusted cognitive domains of memory, executive function, or processing speed (all p>0.05). Large artery stiffness was not associated with cognitive function in premenopausal or postmenopausal women. Conclusions: Young women with a history of PE had elevated systolic pressure one year postpartum, which was associated with reductions in executive function. Large artery stiffness was not elevated or related to cognitive function in postmenopausal women with a history of PE. These preliminary findings suggest that young women with a history of PE are susceptible to reductions in selective cognitive domains related to higher blood pressure, but this effect does not appear to extend into the postmenopausal period.

Physical activity (PA) provides many benefits to adolescents with Type 1 Diabetes (T1D); however, adolescents with T1D tend to have lower fitness and PA levels. One reason adolescents with T1D engage in less PA is due to a fear of hypoglycemia. Most studies examining PA in relation to glycemic control measure PA through self-report, thus introducing bias. The purpose of this study was to objectively monitor PA and glucose in adolescents with T1D to examine the temporal associations between moderate and vigorous intensity physical activity (MVPA) and hypoglycemia. Twenty participants (14 to 19 yr, n=10 females and 10 males) with a T1D diagnosis for at least 1 year were recruited. Participant fitness was evaluated via indirect calorimetry during a maximal treadmill exercise test, and body composition was measured using air displacement plethysmography. An accelerometer (GENEActiv, Activinsights Ltd, Kimbolton, UK) was worn on the wrist continuously for 7 days and the waveform data used to estimate MVPA in min/d. Blood glucose values were simultaneously tracked using continuous glucose monitoring (DexCom SEVEN PLUS, San Diego, CA). After controlling for gender, % body fat (%BF), and fitness, the likelihood of hypoglycemia (¡Ü 70 mg/dl) at nighttime or the next day due to MVPA was examined using logistic regression. Participants were of avg fitness (females: 43.9 ml/kg/min; males: 49.8 ml/kg/min) and fatness (females: 26.2%; males: 19.2%), and 63.2% of participants met the US federal guidelines of accumulating 60 min/d of MVPA. Hypoglycemia was 22% more likely in those who had 30 min/d more MVPA than those with less (95% CI: 1.03, 1.45; p =0.022). The results indicate that participating in MVPA increases the risk of hypoglycemia during the night time and the following day. The relationship is independent of gender, %BF and fitness. While promoting PA as a healthy behavior, it is important to educate adolescents with T1D on prevention of hypoglycemia following PA.

Improvements in fatigue and quality of life observed in primary and secondary progressive multiple sclerosis (MS) patients adhering to a modified Paleolithic dietary intervention (MPDI), nutritional supplementation, exercise, and neuromuscular electrical stimulation regime are hypothesized to be due primarily to the effect of diet. However, no research has been conducted evaluating effects of the dietary intervention alone thus, the purpose of this research was to evaluate a MPDI in the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS). We tested effects of the MPDI in seventeen men and women (mean age: 36.3 ±4.7 years) with neurologist-verified RRMS. Nine subjects (one male) were randomized to a "usual care" (control) group and eight subjects (one male) were taught the MPDI. Both groups adhered to their assigned protocol for three months. Significant improvement was seen in Fatigue Severity Scale (FSS, p=0.03), Multiple Sclerosis Quality of Life-54 Physical Health (MSQOL-P, p=0.03), and Mental Health (MSQOL-M, p=0.02) scores from baseline in MPDI subjects compared to controls. Increased vitamin K serum levels (p=0.02) were also observed in MPDI subjects at three months compared to controls. Significantly reduced time to complete 9-Hole Peg Test (9-HPT) with the dominant hand (p=0.02) was also observed. Our results indicate trends for improved non-dominant 9-HPT (p=0.05), Metabolic Equivalent Tasks (METs, p=0.08), and 25-Foot Walk (25-FW, p=0.09) scores from baseline in MPDI subjects compared to controls. A Paleolithic diet may be useful in the treatment and management of MS, by reducing perceived fatigue, increasing mental and physical quality of life, increasing exercise capacity, and improving hand and leg function. The MPDI may also reduce inflammation as evidenced by increased vitamin K serum levels.

Training is associated with specific neural adaptations. Skill training has been associated with increases in corticospinal tract excitability, leading to long term adaptations within motor cortex. Neural adaptations associated with strength training are less well established. It is not known how they are affected by volume, intensity, rate of muscle activation, or rest period. We evaluated the acute neural adaptations to a single session of strength training with the goal of evaluating the influence of rate of muscle activation on neural adaptations at the cortical and spinal levels. Thirty subjects participated in a single session of maximal, isometric knee extensions with the right leg. The training consisted of 4 sets of 5 contractions, with sets separated by approximately 5 minutes. Subjects were randomized into a high rate of muscle-activation group (Ballistic), a low rate of muscle-activation group (Ramp), and a Control group that did all testing but no training. Cortical spinal tract excitability was assessed using transcranial magnetic stimulation, spinal excitability was assessed using peripheral nerve stimulation, and inhibition of motor cortex was assessed using short-interval intracortical inhibition. In addition, we measured changes in motor performance. These same measures were assessed 24 hours later. Results showed that an acute strength training session is associated with a depression in resting cortical spinal tract excitability, but no change in active excitability. This change was immediate, taking place after just 2 contractions. Training was also associated with an increase in the excitability of the monosynaptic reflex circuit within the spinal cord during muscle activation, but not at rest. After 24 hours, cortical motor tract excitability had returned to normal, but intracortical inhibition was decreased from the original measure. Subjects from all groups increased maximum rate of torque development from Day 1 to Day 2. These results indicate that strength-training is associated with neural adaptations, though the adaptations were different than those for skill training. Understanding these adaptations will allow coaches and clinicians to better design programs to optimize the strength potential of the nervous system along with that of the muscles.

Vibratory communication has evolved in numerous animal groups, including insects, spiders, fishes, mammals, and was recently discovered in veiled chameleons (Chamaeleo calyptratus). I examined the mechanism by which C. calyptratus produce these biotremors. Muscle activity data were gathered during simulated anti-predator responses via electromyography (EMG) with simultaneous recordings of biotremor production using an accelerometer. I correlated EMG data with the accelerometer data to implicate the muscles responsible for the production of the biotremors. Mixed-effect linear regression models described the mechanism, and a model selection framework determined which model fit the data best. I then used an analysis of variance to partition the variance to each variable to determine which muscles were most important in the biotremor producing mechanism. The Mm. sternohyoideus superficialis et profundus, Mm. mandibulohyoideus, and M. levator scapulae were active during the production of biotremors. Mean latency calculations revealed that the M. levator scapulae and Mm. mandibulohyoideus activated prior to the vibration onset, and the Mm. sternohyoideus superficialis et profundus activated after the vibration onset. The M. sternohyoideus superficialis then ceased activity prior to vibration cessation, and the M. sternohyoideus profundus, Mm. mandibulohyoideus, and M. levator scapulae ceased activity after the vibration had ended. The description of the biotremor producing mechanism further supports that C. calyptratus can produce biotremors, possibly for communication.

In spite of significant progress in our knowledge of mechanisms that control blood pressure, our understanding of the pathogenesis of hypertension, its genetics, and population efforts to control blood pressure, hypertension remains the leading risk factor for mortality worldwide. It’s estimated that 1 out of every 3 adults has hypertension. Hypertension is a major risk factor for cardiovascular disease and stroke, and is considered a primary or contributing cause of death to more than 2.4 million US deaths each year. Although spontaneous hypertension has been the subject of substantial research, many critical questions remain unanswered. To investigate mechanisms underlying spontaneous hypertension, a unique rodent breeding approach was used to isolate nuclear and mitochondrial genes contributing to the disease. By diluting the nuclear genome of the Spontaneously Hypertensive Rat on a normotensive Brown Norway background while maintaining the SHR mitochondrial genome, I investigated both intrinsic and extrinsic mechanisms of the kidney and its relationship to hypertension. Chapter 2 documents the dominance of the hypertensive phenotype in our rodent colony, despite the dilution of the nuclear genome of the SHR. Chapter 3 presents data indicating that the renin-angiotensin system, particularly the location and abundance of the AT1 receptor may play an important role in the manifestation of spontaneous hypertension. Chapter 4 presents that rats in our rodent colony exhibited normal pressure-natriuresis and kidney function; however, hypertensive rats had a reduced ability to sense orally ingested sodium chloride, thus necessitating chronic elevations of arterial pressure in order to maintain sodium balance. This chronic pressure-natriuresis relationship shifts the renal function curve to the right, thus sustaining elevated blood pressure. Chapter 5 presents data that genes important for oxidative phosphorylation may play a critical role in the development of hypertension. Both nuclear and mitochondrial oxidative phosphorylation genes were downregulated in hypertensive rats compared with normotensive rats. Data presented in every chapter highlights the importance of the kidney in the pathogenesis of hypertension. Humoral, genetic and genomic mechanisms of the kidney appear to play a dominant role in the development and maintenance of the disease.

New information technologies bring with them new possibilities for defining and simulating complex physical systems. A huge amount of progress was made in this field with the Modelica language standard, developed by the worldwide nonprofit Modelica Association. Using the Modelica language specification, new chemical, hydraulic, thermal and population components for human physiology were designed for the implementation of the physiological principles in this thesis. The presented free Modelica libraries was named PHYSIOLIBRARY and CHEMICAL. Similarly to the electrical circuits already implemented in the Modelica Standard Library, it is also possible to connect the components of these libraries to the diagrams and, in this way, define more complex components of physiological systems. Using this kind of implementation, this thesis presents an extension and improvement of the HumMod version 1.6 model, developed at the University of Mississippi Medical Center (Jackson, MS), which has more than 5,000 variables. As a result of the use of graphical diagrams, our implementation is more expandable and more modifiable at each point. The precise rules of connections lead to fewer implementation errors. In addition, the visual verification of the model is achieved, because the physiological connections of...

Older age is a primary risk factor for the development of cardiovascular disease in part through the stiffening of the large cardiothoracic elastic arteries (e.g., aorta, carotid arteries). Aging is also associated with reduced cognitive function, cerebrovascular reactivity and brain white matter integrity, but whether these changes in brain structure and function are associated with age-related large artery stiffness remains unclear. In contrast, older adults who have high aerobic fitness demonstrate attenuated large artery stiffness and better cognitive performance compared to their sedentary counterparts, but the effects of aerobic fitness on white matter integrity and cerebrovascular reactivity with aging are conflicting and limited. Moreover, whether high aerobic fitness-associated lower large artery stiffness in older adults is associated with, and perhaps mediates, the beneficial changes in cognitive function and white matter structure remains unknown. The purpose of this study was to investigate the extent to which high aerobic fitness is associated with preserved white matter structure, cerebrovascular reactivity, and cognitive performance in aged individuals, and if these changes in brain structure and function are associated with attenuated large artery stiffness. In young (n=19, 23.6 ± 2.5 years) and old (n=22, 64.4 ± 4.2 years) healthy adults, large elastic artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV, aortic stiffness) via non-invasive applanation tonometry of carotid and femoral pulse waveforms and carotid artery beta-stiffness index (β-stiffness index) and compliance using high-resolution ultrasound and carotid blood pressure via applanation tonometry. Aerobic fitness was measured as maximal exercise oxygen uptake (VO2max) using respiratory gas analysis on an upright cycle ergometer. Older subjects were stratified as high or low fit based on gender and age VO2max classification. Letter, pattern and N-Back cognitive tests were used to assess processing speed and working memory respectively. Fractional anisotropy (FA) from diffusion tensor images and Blood Oxygenation Level Dependent (BOLD) imaging was used to assess cerebrovascular reactivity (CVR) response to a breath hold and brain activation during a working memory task. The association between large artery stiffness and FA was then assessed using a voxel-wise general linear model approach and a region-of-interest analysis. Our results confirmed age-related increases in cfPWV, carotid β-stiffness index and central (carotid) but not brachial systolic blood pressure, and expected reductions in carotid compliance, VO2max, working memory and processing speed, and in white matter integrity in select brain regions (bilateral cingulate, frontal, occipital, temporal). In contrast, we found no age-associated differences in CVR to breath hold stimulus or change in BOLD response to the N-Back. In our cohort of health adults, we found that the age-related changes in large artery stiffness were not attenuated by high compared with low VO2max. Among older adults, large elastic artery stiffness was not associated with regional white matter integrity or cerebrovascular reactivity in any regions-of-interest. Greater carotid artery compliance and lower β-stiffness index was associated with higher processing speed, while compliance was related to higher d'Prime scores and lower reaction time on the 2-Back task among the older adults. CVR to a breath hold stimulus was not related to any measure of cognitive performance. VO2max was not associated with any measures of vascular function, brain structure, function or cognition, indicating relations between large artery stiffness and cognition were independent of aerobic fitness capacity. Taken together, these data suggest that select measures of cognitive performance, but not white matter structure or CVR, may be susceptible to age-related changes in carotid stiffness/compliance and that are unaffected by aerobic fitness. More work is needed to understand the mechanisms by which age-related declines in carotid artery compliance and increased carotid stiffness are associated with reductions in cognitive function in older adults.

High anxiety is associated with an increased risk of developing cardiovascular disease (CVD), in particular, atherosclerotic coronary artery disease. However, the mechanisms by which anxiety contributes to the development of CVD are unclear. Unlike other common psychiatric disorders such as depression, anxiety and its effects on CVD risk has not been studied extensively. Moreover, whether elevated anxiety is associated with arterial stiffness and vascular endothelial dysfunction, biomarkers of CVD risk, in healthy adults and whether a psychological intervention designed to lower anxiety levels in healthy adults with moderate to high baseline anxiety levels ameliorates vascular dysfunction remains unclear. The purpose of this study was twofold; first to determine the extent to which moderate to high anxiety levels are associated with vascular dysfunction including aortic stiffness as measured by carotid-femoral pulse wave velocity (cf-PWV), carotid artery stiffness via ultrasound-based β-stiffness index, and forearm resistance artery function measured as peak forearm blood flow using venous occlusion plethysmograph (VOP). Secondly, to determine whether the empirically validated Acceptance and Commitment Training (ACT) anxiety intervention improved vascular function after 12 weeks and if this was associated with reductions in anxiety in adults with moderate to high baseline anxiety levels. Our results indicated that there was no association between increased anxiety levels and any of the three vascular outcomes of interest. Conversely, there was an association between the ACT intervention participation and improvement in forearm resistance artery function independent of age, sex, education, race/ethnicity, BMI and STAI Trait anxiety. Taken together, these data suggest that although higher State and Trait anxiety was not associated with aortic stiffness, carotid stiffness or forearm resistance artery function, and the ACT intervention was associated with improved peripheral resistance artery function. Additional studies are needed to determine whether this effect occurs earlier than 12 weeks and sustained longer that 12 weeks, and whether it occurs in adults with CVD risk factors (i.e. atherosclerosis), non-white racial/ethnic backgrounds and in resistance vessel function in response to intra-arterial vasoactive agonists such as acetylcholine.

<p>Aging involves the progressive decline of physical performance and effective metabolic regulation. To date, dietary interventions to slow this deterioration have shown limited success. I tested the effectiveness of a complex dietary supplement (that targets five key mechanisms of aging) for ameliorating age-related declines in physical activity, metabolism and energetic efficiency in mice. Supplemented mice maintained youthful levels of daily physical activity in old age, compared with a progressive decline in untreated controls. The diet also influenced aspects of metabolic rate, as supplemented mice showed age-related increases in fasting oxygen consumption and respiratory quotient compared to declines in these biomarkers in untreated mice. Furthermore, oxygen consumption over 24-h was significantly lower in supplemented mice in spite of being more active than untreated mice. Taken in conjunction with higher resting respiratory exchange ratios across age, this suggests that supplemented mice may utilize more carbohydrate than lipid as an energy substrate and they may express increased metabolic efficiency. These results hold promise for augmenting youthful athleticism and extending geriatric functionality. I also assessed the impact of the supplement on age- related changes in biomarkers of oxidative stress in heart and kidney samples from normal (Nr) and transgenic (Tg) mice that over-express growth hormone. Measures of whole-tissue H2O2 in the heart showed no significant changes in Nr or Tg mice, but catalase activity was ~33% higher in supplemented Nr and Tg compared to untreated controls. Kidney tissue from Nr mice showed significant and opposite age-related trends of H2O2, increasing in supplemented mice and decreasing in untreated controls, however, no changes were observed in Tg mice. Catalase activity in kidney tissue remained unchanged in both genotypes regardless of diet. Furthermore, the ratio of reduced to oxidized glutathione was 43% higher in urine from older (>12 months-old) supplemented mice, indicative of substantially lower whole-body oxidative status. Lastly, older supplemented mice showed improved whole-body glucose tolerance compared with untreated counterparts. These results confirm that the supplement reduces aspects oxidative stress and improves insulin sensitivity, two of the key design criteria for formulating the supplement. This work represents proof of principle that complex dietary supplements can extend functional capacities associated with metabolism and energetic efficiency into older ages.</p> / Master of Science (MSc)