Metformin has been associated with a reduction in breast cancer incidence, however its effect on mortality following cancer has not been adequately examined. The purpose of this study was to evaluate the impact of metformin therapy on mortality in women with breast cancer. Using Ontario health databases, this retrospective cohort examined the impact of metformin on mortality among women aged 66 years or older with diabetes and breast cancer. After a mean follow-up of 4.5 years, there was no association between cumulative metformin use and either all-cause or breast cancer-specific mortality (HR 0.97, 95% CI 0.92-1.07; HR 0.91, 95% CI 0.81-1.03 respectively per additional year of cumulative metformin use). Though metformin was not associated with a reduction in mortality in our study of older women with breast cancer, there is still a need to examine whether metformin has an effect on mortality in other breast cancer populations.

Metformin has been associated with a reduction in breast cancer incidence, however its effect on mortality following cancer has not been adequately examined. The purpose of this study was to evaluate the impact of metformin therapy on mortality in women with breast cancer. Using Ontario health databases, this retrospective cohort examined the impact of metformin on mortality among women aged 66 years or older with diabetes and breast cancer. After a mean follow-up of 4.5 years, there was no association between cumulative metformin use and either all-cause or breast cancer-specific mortality (HR 0.97, 95% CI 0.92-1.07; HR 0.91, 95% CI 0.81-1.03 respectively per additional year of cumulative metformin use). Though metformin was not associated with a reduction in mortality in our study of older women with breast cancer, there is still a need to examine whether metformin has an effect on mortality in other breast cancer populations.

Master of Science / Department of Kinesiology / Craig A. Harms / High-intensity interval training (HIT) has been utilized as a time-efficient strategy to induce numerous physiological adaptations and improve performance usually associated with “traditional” endurance training (ET). It is not known however, if HIT might lead to improvements in pulmonary function. Therefore we hypothesized that HIT would increase respiratory muscle strength and expiratory flow rates. Fifteen healthy subjects were randomly assigned to an ET group (n = 7) and a HIT group (n = 8). All subjects performed an incremental test to exhaustion (VO2 max) on a cycle ergometer prior to and after training. Standard pulmonary function tests, maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax), and maximal flow volume loops, were performed pre training and after each week of training. HIT subjects performed a four week training program on a cycle ergometer at 90% of their VO2 max final workload while the ET subjects performed exercise at 60-70% of their VO2 max final workload. All subjects trained three days/ week. The HIT group performed five one-minute bouts with three minute recovery periods and the ET group cycled for 45 minutes continuously at a constant workload. A five-mile time trial was performed prior to training, after two weeks of training, and after four weeks of training. Both groups showed similar (p<0.05) increases in VO2 max (~8-10%) and improvements in time trials following training (HIT 6.5 ± 1.3%, ET 4.4 ± 1.8%) with no difference (p>0.05) between groups. Both groups increased (p<0.05) PImax post training (ET ~25%, HIT ~43%) with values significantly higher for HIT than ET. There was no change (p>0.05) in expiratory flow rates with training in either group. These data suggest that whole body exercise training is effective in increasing inspiratory muscle strength with HIT leading to greater improvements than ET. Also, HIT offers a time-efficient alternative to ET in improving aerobic capacity and performance.

This research considers the treatment of malignant melanoma. Data were collected from patient records for 78 individuals treated within the Yale Cancer Center Melanoma Unit. The patients were diagnosed with malignant melanoma prior to 1994 and progressed to stage I11 or N disease before their deaths.Due to the rapid progression of malignant melanoma, treatments are initiated at the time of diagnosis. Results of experimental Extreme Drug Resistance (EDR) tests subsequently become available. Physicians are warned the test results are not intended to guide therapy; however, assay directed therapies arguably result in better outcomes with other cancers. Thus, the question arises of whether the use of these tests might benefit patients in this context.This study evaluates the treatment decisions made using a multi-disciplinary approach within the Yale Cancer Center Melanoma Unit regarding patients with malignant melanoma relative to information contained in EDR tests conducted by Oncotech Inc. Within this comparison, three specific outcomes consistent with hypotheses of the study were assessed: the utilization of test results, drug toxicity and cost effectiveness and survival.Results were found to suggest that the initial treatment decisions of the Yale Cancer Center Melanoma Unit were in accord with tests results that were received henceforth for 74 of 78 patients. Two of those patients were in terminal stages of the disease thus treatments were unchanged; however two patients received a change in therapy.It is suggested that physicians made use of the tests as they became available. However, only two patients with therapies altered by the test results were shown to face reduced costs, drug toxicity, or have the benefit of improved survival. From the patient data collected, four patients receiving drugs to which their tumors exhibited EDR were found to exhibit shorter survival times. Literature review studies conducted to evaluate physician treatment approach and patient preference rate favorably the consideration of quality of life issues. The principle finding of this observational study which focuses upon the development of the Yale Cancer Center Melanoma Unit, suggest that a multidisciplinary approach to the treatment of malignant melanoma may offer quality of life benefits to the patient.

In Ontario, the organs of deceased donors are usually allocated to those recipients who are ranked highest on the province’s waiting list for transplant surgery. However, on rare occasion, a donor, or the donor’s family, will request that an organ be given to a designated recipient or designated group of recipients. The ethical acceptability of these so-called “directed donations” of organs from deceased donors is debated in the transplant literature. The purpose of this study was to elicit the views of a group of transplant professionals in Ontario on the question, “Under what circumstances, if any, should a donor or the donor’s family be allowed to choose the recipient of the organ?” Qualitative in-depth interviews were conducted with 14 Ontario transplant professionals from a range of clinical disciplines. An analysis of these interviews revealed several practical and ethical considerations that the transplant professionals believed to be important in assessing the acceptability of directed donations.

In Ontario, the organs of deceased donors are usually allocated to those recipients who are ranked highest on the province’s waiting list for transplant surgery. However, on rare occasion, a donor, or the donor’s family, will request that an organ be given to a designated recipient or designated group of recipients. The ethical acceptability of these so-called “directed donations” of organs from deceased donors is debated in the transplant literature. The purpose of this study was to elicit the views of a group of transplant professionals in Ontario on the question, “Under what circumstances, if any, should a donor or the donor’s family be allowed to choose the recipient of the organ?” Qualitative in-depth interviews were conducted with 14 Ontario transplant professionals from a range of clinical disciplines. An analysis of these interviews revealed several practical and ethical considerations that the transplant professionals believed to be important in assessing the acceptability of directed donations.

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.