Whole-body vibration (WBV) was recently introduced as a potential modality for strengthening bones, and this thesis was set out to investigate whether it plays a role in the prevention of postmenopausal bone loss. First, effects of WBV on bone mineral density (BMD) were systematically evaluated in previous randomized controlled trials (RCTs) in postmenopausal women. Second, a RCT of 202 postmenopausal women with primary osteopenia not on bone medications was conducted to investigate the effects of WBV at 0.3g and 90 Hz versus 0.3g and 30 Hz versus controls on various bone outcomes, as measured by dual-energy x-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and quantitative ultrasound (QUS). In the systematic evaluation of previous RCTs, statistically significant increase in areal BMD (aBMD) at the hip was found in postmenopausal women receiving WBV versus controls, but the effect was small and may have been due to study bias. Also, WBV was not found to influence aBMD at the lumbar spine or volumetric BMD (vBMD) at the distal tibia in the systematic evaluation. In the RCT conducted in this thesis, no statistically significant effects of WBV were found on aBMD at the femoral neck, total hip or lumbar spine, as measured by DXA, or on vBMD or bone structure parameters at the distal tibia or distal radius, as measured by HR-pQCT. Further in this RCT, a statistically significant decrease was observed in QUS attenuation at the calcaneus in women receiving 90 Hz or 30 Hz WBV compared to controls. This may have been due to heel bone or soft tissue damage, although the effect was small and may not be clinically important. In conclusion, this investigation of postmenopausal women did not find clinically relevant benefits of WBV on osteoporotic-prone skeletal sites, including the hip, spine, tibia or radius, while potentially harmful effects on heel bone and/or soft tissue was observed in response to WBV. Thus based on this thesis, WBV is currently not recommended for the prevention of bone loss in community-dwelling postmenopausal women with primary osteopenia.

Master of Science / Department of Kinesiology / Mary A. McElroy / Arthritis is one of the most prevalent and debilitating chronic health conditions for Americans. As no cure exists for arthritis, one emphasis of treatment focuses on the self-management of the disease through regular physical activity. Despite the well known health benefits, low physical activity rates exist among people with arthritis, particularly women. Research needs to focus on what influences decisions to participate in physical activity, one such influence is barriers. The purpose of the study was to examine the relationships among perceived barrier presence and perceived barrier limitation of 25 general and 16 arthritis-specific barriers and moderate physical activity. Participants were 279 women (M = 48.57years) with arthritis who completed a web-based survey. A hierarchical multiple regression to predict moderate physical activity was significant (p < .001). General barrier limitation contributed the most to predicting total moderate physical activity participation. Education, body mass index, general barrier presence, arthritis-specific barrier presence, and arthritis-specific barrier limitations were also significant independent predictors. Findings suggest that the more general and arthritis-specific barriers identified (barrier presence) and higher extent of limitation (barrier limitation) was associated with lower levels of participation in physical activity. Future research would benefit from including a measurement of frequency of perceived barriers to better understand the impact of barriers to physical activity. A greater understanding of general and arthritis-specific barriers to physical activity may be used as a basis for targeted interventions to help women with arthritis participate in physical activity.

Master of Science / Department of Kinesiology / Thomas J. Barstow / Near infrared spectroscopy is currently routinely used to assess tissue (muscle) oxygenation at rest and during exercise. While most investigators assume that hemoglobin ([Hb]) is the major contributor to the responses seen during exercise, the relative contribution of myoglobin ([Mb]) to the NIRS signals remains controversial. PURPOSE: a) To calculate the range of light absorbing potential (LAP) of hemoglobin and myoglobin in mammalian skeletal muscle at rest based on analysis of published chemical and morphometric data in humans and other mammals (Part 1), and b) use the information in a) to interpret changes in total [Hb+Mb] from NIRS during exercise (Part 2). METHODS: Part 1: Information was retrieved from five published studies with regard to capillary density (#caps/mm2) and [Mb] in skeletal muscle of human, horse and rat. Preference was given to studies in which both measurements were provided for the same muscles. [Hb] in skeletal muscle was estimated as a function of capillary density, [Hb] in systemic blood, and the ratio of capillary-to-systemic hematocrit at rest and during exercise. Part 2: Changes in total [Hb] + [Mb] (as t[Hb+Mb]) from published NIRS data obtained from human subjects performing cycling or knee extension exercise were interpreted in the context of the results of Part 1. RESULTS: Part 1: Individual group mean values for skeletal muscle [Mb] in the literature ranged from 0.25-0.67 mM in human samples, with a similar range for muscles of the rat hindlimb; horse limb muscles tended to be higher (up to 1.0 mM). Capillary densities ranged from ~200 to 600 caps/mm2 in human and rat muscles, and up to 800 caps/mm2 in horse muscle. Assuming a resting capillary hematocrit of 22% and 4 fold greater LAP for each mole [Hb] vs [Mb], the resulting estimation of capillary [Hb] ranged from ~0.03 to 0.09 mM in human and rat muscles, and up to ~0.13 mM in horse muscles. The results suggest that [Mb] could contribute ~50-70% of the total LAP at rest in human skeletal muscle. Part 2: With exercise, total heme by NIRS can increase ≥ 30% in individual human subjects. Assuming this increase reflects only increased [Hb], this fits well with the observed increase in capillary hematocrit with exercise. CONCLUSIONS: 1) In skeletal muscle at rest, [Mb] is likely to be at least as significant a light absorbing heme as is [Hb] in most mammalian muscles, including the human leg. 2) Observed increases in t[Hb+Mb] with NIRS during exercise can be explained by an increase in capillary hematocrit, even in the presence of significant [Mb].

Master of Science / Department of Kinesiology / Craig A. Harms / In comparison to adults and adolescents, relatively little is known about ventilatory responses of prepubescent children to exercise. Children have smaller airways relative to lung size than adults and ventilate "out of proportion" to metabolic demands of exercise which may render them more susceptible to ventilatory limitations during exercise. It is also not known if there are any sex differences in ventilatory limitations during incremental exercise in children. Therefore, the purpose of this study was to determine the prevalence of ventilatory constraints (expiratory flow limitation, EFL) during incremental exercise to exhaustion in prepubescent (Tanner stage 1) boys and girls. Forty healthy, prepubescent boys (n = 20) and girls (n = 20) with no history of asthma completed baseline pulmonary function and lung volume tests. Subjects then completed an incremental cycle VO[subscript]2max test where workload was increased 10W every 90 sec until exhaustion. RPE, dyspnea ratings, and % EFL were recorded at the end of each exercise stage. EFL was determined by placing the exercising tidal volume loop inside a post-exercise maximal flow volume envelope. Ventilatory and metabolic data were recorded on a breath by breath basis throughout exercise via a metabolic cart. Arterial oxygen saturation was determined via pulse oximetry. Body composition was determined using dual-energy x-ray absorptiometry. Following 15 minutes of recovery, subjects exercised at 105% of their VO[subscript]2max workload until exhaustion to provide confident in the VO[subscript]2max measurement. There were no differences (p>0.05) in anthropometric measures (height, weight) or body composition (lean body mass, percent body fat) measures between boys and girls. At rest, boys had significantly higher lung volumes (TLC, boys = 2.6 + 0.5 L, girls = 2.1 + 0.5 L; FRC, boys = 0.9 + 0.3 L, girls = 0.7 + 0.3 L) and maximal flows (FVC, boys = 2.2 + 0.3 L, girls = 1.9 + 0.4 L; PEF, boys = 3.6 + 0.7 L/sec, girls = 2.9 + 0.6 L/sec; FEV1, boys = 1.9 + 0.2 L/sec, girls = 1.6 + 0.3 L/sec). At maximal exercise, boys had significantly higher VO[subscript]2max (boys = 35.4 + 7.5 ml/kg/min, girls = 29.5 + 6.6 ml/kg/min; boys = 1.2 + 0.2 L/min, girls = 1.0 + 0.2 L/min), VE (boys = 49.8 + 8.8 L/min, girls = 41.2 U+U 8.3 L/min), and VCO[subscript]2 (boys = 1.2 + 0.2 L/min, girls = 0.9 + 0.2 L/min) compared to girls. There were no differences (p>0.05) in VE/VCO2 (boys = 41.1 + 3.9, girls = 43.4 + 5.5), PETCO2 (boys = 35.5 + 2.5 mmHg, girls = 35.7 + 3.2 mmHg) maximal HR (boys = 174.4 + 23.1 bpm; girls = 183.4 + 16.6 bpm), RER (boys = 1.04 + 0.05, 1.03 + 0.08), or SaO2 (boys = 96.7 + 3.4%, girls = 97.7 + 1.3%) which was maintained within 3% of baseline throughout exercise for all subjects. EFL during exercise was present in 19 of 20 boys and 18 of 20 girls. Severity of EFL at VO2max, as judged by % overlap of tidal volume with maximal flow volume envelope, was not different between genders at any time during exercise (at VO[subscript]2max: boys = 58 + 7%, girls = 43 + 8%). There was no significant association between % EFL at VO[subscript]2max and aerobic capacity or total lung volume. A significant relationship existed between % EFL at VO[subscript]2max and the change in end-expiratory lung volume from rest to maximal exercise in boys (r = 0.77) and girls (r = 0.75). In summary, our data suggests that ventilatory constraints in the form of expiratory flow limitation are highly and equally prevalent in prepubescent boys and girls from moderate to maximal exercise which likely leads to an increased work of breathing, but not to decreases in arterial oxygen saturation.

Master of Science / Department of Kinesiology / Thomas J. Barstow / The accumulation of reactive oxygen species (ROS) has been linked to the development of muscular fatigue. Antioxidant administration has the potential to counteract the increased levels of ROS, leading to improvements in performance. N-acetylcysteine (NAC), a nonspecific antioxidant, is especially promising due to its ability to support the biosynthesis of glutathione, one of the primary endogenous antioxidants. Despite this, the effects of NAC on time to fatigue appear to be dependent upon the exercise intensity, with the more pronounced effects evident at submaximal exercise intensities. The purpose of this study was to determine the effects of an acute dose of NAC on whole body fatigue, critical power (CP) and W’ during high-intensity exercise. It was hypothesized that pretreatment with NAC would result in (1) an increase in time to fatigue (TTF), CP and W’, (2) NAC administration would attenuate changes in the EMG responses indicative of fatigue, and (3) speeding of the kinetics of the primary phase of VO2 and a reduction in the slow component. Seven healthy, active males (age: 21.4 ± 1.6 years, weight: 89.1 ± 11.0 kg, height: 183 ± 5 cm) completed an incremental ramp test until exhaustion for the determination of peak VO2 and power. Four tests were subsequently performed at power outputs corresponding to 80, 90, 100, and 110% Pmax under NAC and placebo (PLA) conditions. NAC resulted in a significant increase in [tGSH] in red blood cells compared to baseline and PLA condition. TTF was significantly increased only in the 80% Pmax trial (p = 0.033). CP was also significantly higher with NAC (NAC: 232 ± 28 W vs PLA: 226 ± 31 W; p = 0.032), but W’ showed a tendency to decrease (NAC: 15.5 ± 3.8 kJ vs W’: 16.4 ± 4.5 kJ). The change in W’ was negatively related to CP (r = -0.96), indicating that the increase in CP was associated with a decrease in W’. EMG analysis revealed a tendency for MdPF and RMS to demonstrate less of a change with NAC. There were no significant differences in VO2 kinetics, but an inverse relationship was observed between the change in τp and the magnitude of the slow component expressed both in absolute terms (r = -0.632, p = 0.007) and as a gain (r = -0.751, p = 0.0005). We conclude that NAC was effective in delaying fatigue and improving exercise performance at 80% peak power, although the exact mechanisms are still unclear.

Master of Science / Department of Family Studies and Human Services / Jared R. Anderson / An individual’s desire to marry and ideal age of marriage, two elements of the marital horizon theory, are examined in relation to dating violence perpetration, both physical assault and psychological aggression, in the present study using a sample of 611 college students from a large Midwestern university. Looking at the possible predictive power that the marital horizon variables might have on dating violence perpetration, above and beyond other known predictors of dating violence, could reveal an important area of investigation in both the emerging adulthood literature and the dating violence literature. Results indicate that victimization of dating violence accounted for the vast majority of the variance in perpetration of dating violence. Desire to marry emerged as a significant predictor of women’s perpetration of psychological aggression only when the victimization variables were excluded from the regression equation.

The family of human kallikrein-related peptidases (KLKs) numbers 15 serine proteinases implicated in tumour progression. Despite the wide tissue distribution of KLKs and the numerous reports of their differential expression in pathological settings, the signalling mechanism(s) whereby these enzymes regulate tissue function are not yet known. Further, knowledge of the levels of their activity, as well as of their potential endogenous targets, has only been extracted from in vitro studies and cell culture systems. We hypothesized that KLKs can trigger tumour signalling via proteinase-activated receptors (PARs), a family of G-protein-coupled receptors. To test our hypothesis, we evaluated the ability of KLKs 5, 6, and 14: to activate or prevent signalling via PARs 1, 2, and 4 in cells and tissues expressing these receptors. Further, we used a novel activity-based probe approach, coupled with conventional immunoassay (ELISA), to determine the abundance of active KLK6 relative to total immunoreactive KLK6 in cancer-related biological fluids. We concluded that KLKs can regulate multiple signalling pathways triggered by PARs 1, 2, and 4, resulting in calcium release, platelet aggregation and vascular relaxation, and they can cause murine inflammation. Further, our activity-based ELISA demonstrated the presence of active KLK6 in ovarian cancer ascites fluids and cancer cell supernatants. We, therefore, suggest that tumours can produce active KLKs, which can potentially control tumour behaviour by regulating PAR activity.

The prevalence of neurodegenerative disease in India is rising. Regenerative medicine (RM) is being developed to treat these conditions. However, despite advances in RM application for neurological disorders (NeuroRM), there is a lack of research on clinical translation of NeuroRM technologies in developing countries. Given that India is one of the first nations to translate in this field, much can be learned on challenges and solutions arising during translation. This study identifies stakeholders involved in such translation and outlines roles of each; it describes India’s regulatory environment concerning NeuroRM translation; and discusses the impact of collaboration in clinical translation. Twenty-three face-to-face interviews with clinicians, researchers and policy-makers within India were undertaken and transcripts subjected to thematic analysis. The study demonstrates that clinical translation of NeuroRM within India is taking place robustly, it identifies barriers and good practices being adopted, and provides recommendations based on participants’ experiences.

Doctor of Philosophy / Department of Anatomy and Physiology / David C. Poole / The overall aim of this dissertation is to better understand the mechanisms determining skeletal muscle oxygen delivery-utilization matching in health and disease. Emphasis is directed toward the role of nitric oxide (NO) bioavailability in modulating muscle microvascular oxygenation (PO2mv; the sole driving force for blood-myocyte oxygen flux) during transitions in metabolic demand. The first investigation of this dissertation (Chapter 2) demonstrates that alterations in NO bioavailability have a major impact on skeletal muscle PO2mv kinetics following both the onset and cessation of contractions. Specifically, increased NO levels (via the NO donor sodium nitroprusside; SNP) elevates whereas reduced NO levels (non-specific NOS inhibition with NG-nitro-L-arginine methyl ester; L-NAME) diminishes muscle PO2mv at the onset and during recovery from contractions in the spinotrapezius muscle of healthy young rats. Consistent with these results, inhibition of the neuronal NO synthase isoform (S-methyl-L-thiocitrulline; SMTC; Chapter 3) reveals alterations in NO-mediated regulation of skeletal muscle PO2mv with advanced age that likely contribute to exercise intolerance in this population. In Chapter 4 we observed that pronounced oxidative stress is implicated in these pathological responses seen in aged and diseased states. Transient elevations in the oxidant hydrogen peroxide to levels seen in the early stages of senescence and cardiovascular diseases promote detrimental effects on skeletal muscle contractile function (i.e., augmented oxygen cost of force production). Chapter 5 demonstrates that endurance exercise training improves skeletal muscle microvascular oxygenation (i.e., greater PO2mv and slower PO2mv kinetics) across the metabolic transient partly via enhanced NO-mediated function in healthy young individuals. These data carry important clinical implications given that exercise training may ameliorate NO-mediated function, muscle microvascular oxygenation deficits and consequently exercise intolerance in aged and diseased populations. In conclusion, alterations in NO bioavailability have a major impact on the dynamic balance between skeletal muscle oxygen delivery and utilization (i.e., PO2mv kinetics) in health and disease. While advanced age or the predations of disease impair considerably skeletal muscle microvascular oxygenation, exercise training-induced adaptations on the oxygen transport system constitute a non-pharmacological therapeutic intervention potentially capable of mitigating these microcirculatory deficits.

Master of Public Health / Department of Diagnostic Medicine and Pathobiology / M. M. Chengappa / Rabies is the most deadly disease on earth and has a 99.9% human fatality rate. Rabies kills 61,000 humans annually and results in an economic burden of $124 billion USD annually. Each day 3.3 million people live with the risk of rabies. It is estimated that 95% of human rabies cases are a result of coming in contact with an infected canine, majority of these cases being children 15 years and younger. It is estimated that 1 person every 8 minutes dies of rabies. Rabies is a highly neurotropic disease which attacks the brain and central nervous system. Once clinical symptoms are presented, death is invariably the outcome as no cure exists for rabies. Rabies is 100% preventable in humans by proper wound management and proper administration of prophylaxis. Rabies can be adequately controlled in animal populations by contraception and animal rabies vaccine efforts. Whilst it is known that rabies can be prevented in humans and controlled in animal populations, further scientific efforts are still warranted to fully understand this deadly virus so that a cure can one day be discovered. As human and animal populations continue to grow, so does the cost and burden of this horrific disease. As a result, the importance of prophylaxis and passive immunity are critical in the event of medically managing an exposure, and preventing exposures. The World Health Organization has defined global recommendations for individuals and animals who have received prophylaxis to be adequately protected. Measuring this protection is performed using a variety of approved testing methodologies, virus-neutralizing assays and antigen-binding assays. Whilst the WHO recommendations were defined from clinical studies performed with virus-neutralizing assays, the assumption that these recommendations are suitable for the antigen-binding assays is inaccurate. The testing methodologies, virus-neutralization and antigen-binding, share similarities, as they are measuring an immune response to the rabies virus. However; enough differing characteristics are presented such that exact comparisons cannot be made. Establishing the same standards and recommendations for both testing methodologies will never be sufficient.