Thesis (M.D. 1972) from the Dept. of Child Health, University of Adelaide.

The increasing demand for recombinant therapeutic proteins coupled with advances in technologies allow research to develop approaches to improve the efficiency, yield, and quality of biopharmaceutical products from CHO cells. CHO DG44 cells used in this study were engineered to express erythropoeitin (EPO) as the model recombinant protein in a DHFR-based selection system. From a series of CHO-DG44 cell lines derived from a polyclonal population, one cell line expressed a notable change in growth phenotype during prolonged culture (10 weeks). This cell line (IJ4) exhibited prolonged growth, reached a greater density, and delayed cell death. The change in growth was reflected in an increased total yield of EPO, whilst the specific productivity of cell line IJ4 remained similar. The increased total yield of EPO presents a desirable goal for production and hence detailed ‘omics studies were performed to identify factors associated with better cell growth and survivability. Two different ‘omics analyses were performed (microarray transcriptomic and GC-MS metabolic profiling) to identify potential target genes and key metabolites associated with changes in growth profile. The -omics analyses identified a subset of genes (MMP20, PLA1A, POSTN, SLC46A3, and TOP2A), and a metabolic marker (farnesal) strongly associated with changes in cell growth and nutrient uptake. The use of complementary ‘omics approaches to identify molecular markers has allowed an integrated model to be built, which explains how CHO cell phenotype can adapt to long-term culture, and this defines molecular approaches for cell line screening and engineering.

Background: Currently, if traveling the posted speed limit, the typical commuter driver in the Toronto Metropolitan area will travel round trip upwards of 60 minutes a day to work (Heisz and LaRochelle-Cote, 2005). As urban congestion continues to rise, commuting distances and times will progressively increase, placing commuter drivers at increased risk of developing musculoskeletal disorders (Porter and Gyi, 2002; Walsh et al., 1989; Chen et al., 2005; Sakakibara et al., 2006). As urban areas continue to expand, it is believed that a greater percentage of our urban populations will be defined as overweight or obese (Puska et al., 2003). To date the influence of body mass on driver posture, pressure distribution and discomfort during a prolonged driving situation has been left relatively untested. The purpose of this investigation is to determine the influence body mass has on driver posture, pressure distribution and discomfort during a prolonged driving situation. Methodology: Twelve male and 12 female participants, between 167 and 172 cm in stature were used in this investigation. Even numbers of males were assigned to either a light (51.3-57.7 kg), moderate (63.7-69.4 kg), or heavy (82.7-92.0 kg) body mass group. Participants were than placed in a 2 hour in lab driving simulation. During the simulation, lumbar flexion, pelvic angle, joint/segment angles, pressure distribution and discomfort were recorded. A three way mixed general linear model was used to determine if significant (α = 0.05) differences in discomfort, posture and/or interface pressure measurements existed over time. Results: Heavy drivers displayed increased total IT pressures and total seat pan/back pressures during driving. When normalizing these total pressures to area, differences in total IT pressure recorded from the seat pan, and total pressure recorded from the seat back were not significantly different (α = 0.05) across body mass groups. Due to the lack of seat pan accommodation with respect to surface area, the heavy body mass group’s total pressures per unit area for the seat pan was elevated relative to the lighter body mass groups. No differences in two-dimensional joint or segment kinematics and ratings of perceived discomfort were observed between body mass groups or between genders. Gender specific lumbo-pelvic postures and pressure distribution profiles were observed. Conclusion: With appropriate design of the seat pan to accommodate heavy body mass populations with respect to seat pan area, the influence of body mass as a potential risk factor in the development of discomfort would be reduced. With stature and body mass controlled between gender groups, biomechanical differences in both pressure distribution and lumbo-sacral postures were observed between males and females, verifying gender as a risk factor in the development of discomfort during prolonged driving. Recommendations to car seat manufacturers to recognize gender and body mass as important variables in the design of a car seat should be made.

Background: Currently, if traveling the posted speed limit, the typical commuter driver in the Toronto Metropolitan area will travel round trip upwards of 60 minutes a day to work (Heisz and LaRochelle-Cote, 2005). As urban congestion continues to rise, commuting distances and times will progressively increase, placing commuter drivers at increased risk of developing musculoskeletal disorders (Porter and Gyi, 2002; Walsh et al., 1989; Chen et al., 2005; Sakakibara et al., 2006). As urban areas continue to expand, it is believed that a greater percentage of our urban populations will be defined as overweight or obese (Puska et al., 2003). To date the influence of body mass on driver posture, pressure distribution and discomfort during a prolonged driving situation has been left relatively untested. The purpose of this investigation is to determine the influence body mass has on driver posture, pressure distribution and discomfort during a prolonged driving situation. Methodology: Twelve male and 12 female participants, between 167 and 172 cm in stature were used in this investigation. Even numbers of males were assigned to either a light (51.3-57.7 kg), moderate (63.7-69.4 kg), or heavy (82.7-92.0 kg) body mass group. Participants were than placed in a 2 hour in lab driving simulation. During the simulation, lumbar flexion, pelvic angle, joint/segment angles, pressure distribution and discomfort were recorded. A three way mixed general linear model was used to determine if significant (α = 0.05) differences in discomfort, posture and/or interface pressure measurements existed over time. Results: Heavy drivers displayed increased total IT pressures and total seat pan/back pressures during driving. When normalizing these total pressures to area, differences in total IT pressure recorded from the seat pan, and total pressure recorded from the seat back were not significantly different (α = 0.05) across body mass groups. Due to the lack of seat pan accommodation with respect to surface area, the heavy body mass group’s total pressures per unit area for the seat pan was elevated relative to the lighter body mass groups. No differences in two-dimensional joint or segment kinematics and ratings of perceived discomfort were observed between body mass groups or between genders. Gender specific lumbo-pelvic postures and pressure distribution profiles were observed. Conclusion: With appropriate design of the seat pan to accommodate heavy body mass populations with respect to seat pan area, the influence of body mass as a potential risk factor in the development of discomfort would be reduced. With stature and body mass controlled between gender groups, biomechanical differences in both pressure distribution and lumbo-sacral postures were observed between males and females, verifying gender as a risk factor in the development of discomfort during prolonged driving. Recommendations to car seat manufacturers to recognize gender and body mass as important variables in the design of a car seat should be made.

These studies investigated the effect of physical inactivity (prolonged sitting) and physical activity (walking, standing, and moderate intensity exercise) on postprandial plasma triglyceride concentration (PPTG). In the first study, we evaluated the effect of low intensity intermittent walking at ~25% VO₂max (WALK) and energy-matched moderate intensity running at ~65% VO₂max (RUN) on PPTG, compared to a sitting control (SIT). RUN reduced incremental area under the curves for plasma triglyceride concentration (TG AUC[subscript I]), compared to WALK by 17.3% (p = 0.04) and SIT by 27% (p [less than] 0.001). The reduced TG AUC[subscript I] in RUN was accompanied by enhanced whole body insulin sensitivity, compared to WALK and SIT (for both, p [less than] 0.05). Whole body postprandial fat oxidation at rest following a high fat test meal intake was enhanced in RUN by 31% (P [less than] 0.001) and to a lesser extent in WALK by 8.4% (p [less than] 0.005), compared to SIT. In the second study, we evaluated 1) the effect of 2 days of prolonged sitting on PPTG, and 2) the effect of 4 days of SIT on the ability of an acute bout of exercise to reduce PPTG, compared to the same days of active walking and standing with calorically balanced diet (WALK+B). To distinguish the effect of prolonged sitting from the excess calorie effect, we had a sitting condition with calorically balanced diet (SIT+B) in addition to a sitting condition with hypercaloric diet (SIT+H). Following 2 days of respective food and activity control, WALK+B was lower in TG AUC[subscript T] by 21.3% and AUC[subscript I] by 17.4%, compared to SIT+H (for both, p [less than] 0.005). WALK+B was lower than SIT+B for TG AUC[subscript T] by 17.7% (p = 0.165) and AUC[subscript I] by 23.5% (p = 0.145) although statistical significance was not achieved. Remarkably, an acute exercise following 4 days of either SIT+H or SIT+B failed to reduce both TG AUC[subscript T] and AUC[subscript I], compared to SIT+B in HFTT1. The same exercise following 4 days of WALK+B, however, reduced both TG AUC[subscript T] by 29% and TG AUC[subscript I] by 32% in HFTT2, compared to SIT+B in HFTT1 (for both, p [less than] 0.02). Further, both SIT conditions reduced relative whole body fat oxidation in favor of increases in carbohydrate oxidation, compared to WALK+B by more than 40% in both HFTT1 and HFTT2. Taken together, our data suggest that 1) exercise intensity plays an independent role with higher intensity being more effective than lower intensity exercise in reducing PPTG, and 2) prolonged sitting with excess energy intake amplifies PPTG and prolonged sitting impairs the ability of an acute bout of moderate intensity exercise to reduce PPTG. This emphasizes the importance of regular participation in moderate-to-vigorous intensity exercise and reducing sitting time by increasing non-exercise physical activities (i.e., walking and standing) for the favorable postprandial metabolic health from the individual and public health perspectives. / text

The current study evaluated whether NO synthase (NOS) contributes to cutaneous vasodilation and sweating during prolonged exercise in the heat. In addition, we determined if prolonged exercise-induced increases in reactive oxygen species (ROS) and activation of angiotensin II type 1 receptors (AT1R) impair heat loss responses. On two separate days, eleven young men completed 90-min of continuous cycling at ~600W of metabolic heat production followed by 40-min of recovery in the heat (40ºC). To evaluate the role of excess fluid loss via sweating, participants completed a second session of the same protocol while receiving fluid replacement (FR) determined during the first session (No-FR). Cutaneous vascular conductance (CVC) and local sweat rate (LSR) were measured at four intradermal microdialysis forearm sites perfused with either: (1) lactated Ringer (Control); (2) 10 mM NG-nitro-L-arginine methyl ester (L-NAME, NOS inhibition); (3) 10 mM ascorbate (non-selective anti-oxidant); or (4) 4.34 nM Losartan (AT1R inhibition). Ascorbate treatment increased CVC at 60- and 90-min of exercise versus Control during the FR (P < 0.02), but not the No-FR condition (P > 0.31). CVC was reduced at the L-NAME treated site (P < 0.02), but was not different relative to Control at the Losartan treated site (P > 0.19) irrespective of condition. LSR did not differ between sites or as a function of condition (all P > 0.10). We conclude that NO regulates cutaneous vasodilation but not sweating, irrespective of fluid replacement, and ascorbate sensitive ROS impair cutaneous vasodilation during prolonged exercise in the heat with FR.

No description available.

Among several work-related injuries, low back disorders (LBDs) are the leading cause of lost workdays, and with annual treatment costs in excess of $10 billion in the US. Epidemiological evidence has indicated that prolonged and/or repetitive non-neutral postures, such as trunk flexion, are commonly associated with an increased risk of LBDs. Trunk flexion can result in viscoelastic deformations of soft tissues and subsequent mechanical and neuromuscular alterations of the trunk, and may thereby increase LBD risk. While viscoelastic behaviors of isolated spinal motion segments and muscles have been extensively investigated, in vivo viscoelastic responses of the trunk have not, particularly in response to flexion exposures. Further, most biomechanical efforts at understanding occupational LBDS have not considered the influence of flexion exposures on spine loads. Four studies were completed to characterize viscoelastic deformation of the trunk in response several flexion exposures and to develop and evaluate a computational model of the human trunk that accounts for time-dependent characteristics of soft tissues. Participants were exposed to prolonged flexion at different trunk angles and external moments, and repetitive trunk flexion with different external moments and flexion rates. Viscoelastic properties were quantified using laboratory experiments and viscoelastic models. A multi-segment model of the upper body was developed and evaluated, and then used to estimate muscle forces and spine loads during simulated lifting tasks before and after prolonged trunk flexion at a constant angle and constant external moment. Material properties from the earlier experiments were used to evaluate/calibrate the model. Experimental results indicated important effects of flexion angle, external moment, and flexion rate on trunk viscoelastic behaviors. Material properties from fitted Kelvin-solid models differed with flexion angle and external moment. Nonlinear viscoelastic behavior of the trunk tissues was evident, and predictive performance was enhanced using Kelvin-solid models with ≥2 iii retardation/relaxation time constants. Predictions using the multi-segment model suggested increases in spine loads following prolonged flexion exposures, primarily as a consequence of additional muscle activity. As a whole, these results help to characterize the effects of trunk flexion exposures on trunk biomechanics, contribute to more effective estimates of load distribution among passive and active components, enhance our understanding of LBD etiology, and may facilitate future controls/interventions. / Ph. D.

No description available.

This study sought to explore the existence of a relationship between age and/or military affiliation (active, veteran, or family member) and awareness of local community mental health programs available for the treatment of post-traumatic stress disorder. The study separated age from military affiliation to better distinguish between influences on awareness level. Considerations that remain critical regarding post-traumatic stress disorder were described and used to guide a comprehensive review of the literature to find directions to fulfill the goal of this study. A survey was conducted and 586 active military, veterans, and their family members responded to an instrument that contained 40 items. This study was constrained to three items from the survey; age, military affiliation, self-rated awareness of treatment for PTSD. Multiple analysis techniques found no significant (p < .05) correlation between either age and awareness or military affiliation and awareness. Further analysis found a significant (p = .003) correlation between veterans and awareness, as well as between family members of veterans (p = .017) and awareness. Veterans and their family members indicated a greater awareness of local community mental health programs available for the treatment of post-traumatic stress disorder than did active troops and/or their family members. The significance of this finding presents new opportunities to study and improve both the marketing and the delivery of mental health treatment for PTSD to the active military population. Multiple opportunities for future research are discussed.