Stroke is the 3rd leading cause of death and the leading cause of major disability worldwide. Currently, there are no neuroprotective drugs approved for the acute treatment of ischaemic stroke. The vast majority of stroke therapeutics failed in clinical trials due to toxic side effects and/or a clinically irrelevant therapeutic window. This thesis is focused on exploiting the delayed neurodegeneration that occurs in the compromised penumbra, as these cells may be capable of being saved by therapeutic intervention in a clinically obtainable window. In order to investigate the ischaemic cascade and be able to draw conclusions that are applicable to humans, the international gold standard animal model for cerebral ischaemia, the filament insertion middle cerebral artery occlusion (MCAO) model, was established at the University of Otago. This model was validated under new laboratory conditions and employed adult male Sprague Dawley rats. After testing multiple occlusion lengths, it was concluded that a 2hr ischaemic period was sufficient to produce a consistent infarct of optimal size. It has been well documented that neuroinflammation contributes to much of the delayed progression of neural injury post-stroke. Therefore, the catechin (-)-epigallocatechin gallate (EGCG), which is an anti-inflammatory, anti-oxidant and free-radical scavenging agent was investigated in the MCAO model of stroke. 50mg/kg i.p. of EGCG or saline was administered immediately post-MCAO and animals were sacrificed at 72hr post-filament insertion. The results confirmed that treatment with EGCG was neuroprotective and non-toxic. However, EGCG also induced an over 50% increase in the risk of haemorrhagic conversions. The anti-platelet effects of EGCG and lack of toxicity suggests that the catechin may prove to be an efficacious prophylactic for stroke. The contrary findings for EGCG treatment led to the re-evaluation of the neuroinflammatory pathway for alternate mechanisms to target therapeutic interventions. The temporal profile of the primary inducible enzymes nitric oxide synthase (NOS), cyclooxygenase (COX) and arginase (and their isoforms) were quantified 0, 3 and 7 days post-stroke. In both hemispheres, total NOS activity exhibited a significant and sustained up-regulation to 7 days post-occlusion. In the ipsilateral hemisphere at least half of the total increase was accounted for by inducible NOS (iNOS) expression. Arginase, which competes with NOS for L-arginine, demonstrated a delayed but significant increase in activity by day 7 in the infarcted hemisphere, thereby correlating well with the downward slope of NOS activity (illustrating the switch in the conversion pathway). COX activity was observably increased in the ipsilateral hemisphere, but the up-regulation did not reach significance by day 7. Alternately, the contralateral hemisphere displayed a significant decrease in activity by day 3. These results give conclusive evidence that the contralateral hemisphere is NOT an appropriate internal control and imply that NOS and COX inhibitors may prove to be efficacious for a much longer therapeutic window than current treatments. However, the delayed induction of COX activity may also indicate that this enzyme has a finite therapeutic window, as it may also stimulate remodelling of surviving neural networks. The prolonged up-regulation of inflammatory mediators implies that there may be an induction of an autoimmune component to the response. Therefore, the thymus (T) lymphocyte activation was quantified up to 14 days post-stroke. Cluster of differentiation (CD) 3⁺ T lymphocytes (equally contributed to by CD4⁺ and CD8⁺ T cells) exhibited a significant and sustained up-regulation in the infarcted region from day 3 up to at least day 14 post-ischaemia. Quantitative analysis of all cells present post-stroke determined that immune cells make up an average of 73% of all cells present in the 'peak' ischaemic areas. The CD4⁺ T helper cell response was delineated by double immunohistochemical labelling. Interferon-γ positively labelled with CD4⁺ T cells at days 3, 7 and 14 post-insult detailing a Th1-driven pro-inflammatory response. This evidence indicates that the autoimmune response is critical post-ischaemia and that it may be highly susceptible to modification by anti-inflammatory therapeutic intervention. The primary downstream effect of the pro-inflammatory/immune cascade is apoptosis. The main organelle responsible for the 'go, no go' response to apoptotic factors is the mitochondria. In order to distinguish whether mitochondrial dysfunction was initiated shortly after ischaemia induction or if it was delayed, like the inflammatory/immune response, to a clinically relevant window, the temporal profile of mitochondrial complex inactivation was studied. It was found that mitochondrial membrane viability was impaired by day 3, followed by a significant decrease in respiratory complex activation and an increase in tissue injury by oxidative stress by 7 days post-ischaemia. These results indicate that targeting the early decrease in membrane viability or mitochondrial permeability transition pore opening combined with anti-apoptotic therapeutics, may attenuate the proceeding mitochondrial impairment in oxidative phosphorylation, reactive oxygen species generation and subsequent cell death cascades. The current investigations into the temporal profile and quantitative contributions of the inflammatory, immune and apoptotic mechanisms post-stroke highlight potential strategies for modulation by acute stroke therapeutics. Furthermore, the general knowledge amassed from these studies dictates the necessity of a new approach to therapeutic intervention. The acknowledgement of so many contributing systems suggests that in addition to a thrombolytic, a combination therapy involving multiple neuroprotectants should be employed to account for the multifaceted nature of the sequelae of ischaemic stroke.

Bibliography: leaves 350-389 / xii, 389 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Psychiatry, 1987

Long-term potentiation (LTP) is an activity-dependent increase in the efficacy of synaptic transmission. In concert with long-term depression (LTD), this synaptic plasticity likely underlies some types of learning and memory. It has been suggested that for LTP/LTD to act as effective memory storage mechanisms, homeostatic regulation is required. This need for plasticity regulation is incorporated into the Bienenstock, Cooper and Munro (BCM) theory by a threshold determining LTD/LTP induction, which is altered by the previous history of activity (Bienenstock et al., 1982). The present work aimed to test key predictions of the BCM model. This was done using field and intracellular recordings in area CA1 of hippocampal slices from young, adult male Sprague-Dawley rats. The first prediction tested was that following a strong, high-frequency priming stimulation all synapses on primed cells will show inhibition of subsequent LTP and facilitation of LTD induction (heterosynaptic metaplasticity). This was confirmed using two independent Schaffer collateral pathways to the same CA1 pyramidal cells. Following priming stimulation to one pathway, LTP induction was heterosynaptically inhibited and LTD facilitated. To more fully investigate whether all synapses show metaplastic changes, the priming stimulation was given in a different dendritic compartment, in stratum oriens, prior to LTP induction in stratum radiatum. This experiment supported the conclusion that all synapses show inhibited LTP following priming. A second prediction of the BCM model is that metaplasticity induction is determined by the history of cell firing. To investigate this, cells were hyperpolarized during priming to completely prevent somatic action potentials. Under these conditions inhibitory priming of LTP was still observed, and thus somatic action potentials are not critical for the induction of the effect. The next aim was to determine the mechanism underlying heterosynaptic metaplasticity. One way in which plasticity induction can be altered is through changes in gamma-aminobutyric acid (GABA)-mediated inhibition of pyramidal cells. For this reason, it was tested whether blocking all GABAergic inhibition, for the duration of the experiment, would prevent priming of LTP. However, priming inhibited subsequent LTP and it was concluded that GABAergic changes do not underlie either the induction, or expression, of the metaplastic state. Proposed revisions to the BCM model predict that postsynaptic elevations in intracellular Ca�⁺ determine the induction of metaplasticity. There are many potential sources for postsynaptic Ca�⁺ elevations, including entry through N-methyl-D-asparate receptors (NMDARs) or voltage-dependent calcium channels (VDCCs), or release from intracellular stores. Results of the present work demonstrate that the inhibition of LTP is dependent on the release of Ca�⁺ from intracellular stores during priming; however this release is not triggered by Ca�⁺ entry through NMDARs or VDCCs, or via activation of metabotropic glutamate receptors. Overall, the present results show that, in accordance with the BCM model, a high level of prior activity induces a cell-wide metaplastic state, such that LTD is facilitated and LTP is inhibited. In contrast to predictions of the BCM model, this is not mediated by cell-firing during priming. Instead the release of Ca�⁺ from intracellular stores is critical for induction of the metaplastic state.

This study explores the intrapersonal and interpersonal ecological factors that influence adolescent females' perceptions of sex and the extent to which their perceptions of sex impact onset of sexual intercourse as they mature. Particular attention is given to how depression influences individual, personal and social factors in an adolescent female's life, to shape her attitudes towards sex, and determine her engagement in sex as she reaches young adulthood. Ecological Systems Theory is used to examine the extent to which individual, family, and social factors impact adolescent females' perceptions of sex and onset of sexual intercourse. Data are from the National Longitudinal Study of Adolescent Health. Multinomial logistic regression reveals that the factors associated with less positive perceptions of sex are age, self-esteem, sexual intercourse, religiosity and connection to mother and peers, as well as, depression in combination with religiosity and connection to one's peers. More positive perceptions of sex are linked with depression, connection to one's school, as well as, depression in conjunction with aging and sexual intercourse. Results from the logistic regression analysis determines that less positive perceptions of sex delay onset of sexual intercourse among adolescent females; however, adolescent females' attitudes towards sex vary greatly in determining onset of sexual intercourse as they mature. Furthermore, there is no association between depression and adolescent females' perceptions of sex in predicting onset of sexual intercourse as they progress into young adulthood. The findings from this study suggest that programs focused on shaping attitudes toward sex should assist young women in forming a definite opinion about their decision to have sexual intercourse or abstain from engagement in sexual intercourse. A female's age, sense of self-worth, emotional state, and religiosity as well as the strength of her relationships with parents, peers and school must be considered when addressing her sexual health. This investigation supports the use of Ecological Systems Theory as a useful theoretical framework for examining the factors that influence adolescent females' perceptions of sex and engagement in sexual intercourse. A more cognitive investigation of the relationship between depression and the factors in an adolescent female's life that influence her attitudes towards sex and how depression affects an adolescent female's perception of sex and her decision to engage in sexual intercourse is warranted as this study finds only minor support for the use of Ecological Systems Theory when exploring the association between depression and adolescent female sexual health. / Graduation date: 2006

Studies in young women show that rowing exercise is osteogenic at the spine. However, little is known regarding rowing exercise and spine bone mineral density in older women. The aim of this study was to examine differences in spine bone mineral density (BMD) and back strength between premenopausal and postmenopausal competitive female masters rowers (n=28, 45.5 ± 4.7 yrs, n=28, 56.1 ± 5.7 years, respectively) and age-matched non-rowers (n=30, 43.3 ± 4.2 yrs; n=26, 56.8 ± 4.8 years). Competitive rowers were recruited from nine rowing clubs in the local area and compared to controls recruited from the same region who were normally active but not participating in rowing activity. Participating rowers had been engaged in competitive rowing for a minimum of one year. The average years spent rowing for the premenopausal and postmenopausal groups was 7.5 ± 6.6 yrs and 5.9 ± 6.9 yrs, respectively. BMD (g/cm²) of the third lumbar vertebrae (L3) was measured by dual-energy x-ray absorptiometry (DXA) in both the anterior-posterior and lateral views. Back strength was assessed using a standing cable tensiometer. Subjects also completed questionnaires to assess diet, physical activity, medical history and rowing history. Differences in BMD and back strength between groups were determined by analysis of covariance, controlling for lean mass. Compared to controls, postmenopausal rowers had 3.2% higher BMD at the anterior-posterior spine (p=.02) and 4.4% higher lateral spine BMD (p=.04). Furthermore, isometric back strength was 22.6% greater in these rowers than controls (p=.01). In contrast, controls had higher lateral BMD than rowers, with no differences in AP spine BMD or back strength between the premenopausal rowers and controls. Back strength was a significant predictor of AP spine BMD in premenopasual rowers and controls (R²=0.137, p=0.004) and of lateral spine BMD in postmenopausal rowers only (R²=0.153, p=0.04). There were no differences in calcium intake, age, menopausal status, weight, or lean mass between rowers and controls in either the premenopausal or postmenopausal samples. Since both increased BMD and back strength are associated with reductions in vertebral fracture risk, our results suggest that rowing exercise may be an important strategy to promote bone health and reduce vertebral fracture risk in postmenopausal women. However, the forces applied in rowing may not be great enough to alter bone mass before the onset of menopause. Therefore more research is needed examining rowing exercise in these older populations. / Graduation date: 2005

Discordance in bone mass between young adult swimmers and soccer players may be a direct result of differences in bone loading patterns that influence bone mineralization during growth. Our aim was to evaluate whether sports participation (soccer and swimming) had an independent effect on bone mass accrual at the hip and lumbar spine in adolescent female athletes. We recruited boys and girls 10 to 14-years of age from Corvallis, Albany, Sweet Home, Salem, Eugene, and the greater Portland area. Bone mineral content (BMC, g) and bone mineral density (BMD, g/cm²) of the proximal left hip, spine, and whole body were assessed by dual energy x-ray absorptiometry (Hologic QDR 4500A; Hologic Inc., Waltham, MA, USA). We used ANCOVA and report that baseline BMC and BMD values of girl soccer players at the greater trochanter were significantly higher compared to controls and the swim group, and femoral neck BMC was significantly greater than the swimmers. At baseline, all boy groups were similar at the hip and spine. After 12-months, ANCOVA was also used to assess absolute change for BMC and BMD at the hip and spine. The girl soccer players had significantly more BMC and BMD at the greater trochanter as well as total hip BMD and lumbar spine BMC compared to the swimmers, but not the controls. The girl control group showed a significantly greater 12-month change for femoral neck and greater trochanter BMC than swimmers. Overall, the girl swimmers demonstrated a lower accumulation of bone mass during the 12-month study period. As for the boys, soccer players had a significantly higher 12-month change for femoral neck BMC than swimmers, but were similar at the spine. There were no differences between the boy control subjects and the swimmers for 12-month change values at the hip and spine. While preliminary and limited by the small sample size, our results indicate that after controlling for growth, soccer players gained significantly more BMC at the femoral neck than swimmers. Furthermore, exposing the young skeleton to impact loading exercise has site-specific benefits at the hip whereas prolonged training in a non-weight bearing environment may compromise skeletal acquisition. / Graduation date: 2004

Depression has been one of the most prevalent psychological disorders. Its relationship with life events is reviewed in light of factors influencing the relationship such as self-esteem, attributional styles, and cognitive complexity. The mechanism of depression and its links with personality disorders are looked at in relation to anxiety. The role of self-awareness in therapy is discussed along with the dynamic of change and the emotion component in psychoanalytic, Adlerian, existential, gestalt, person-centered, and cognitive psychotherapies. In addition, self-awareness is also highlighted in terms of hardiness, openness to experience, and a sense of salvation. A survey was conducted focused on the relationship between stress and well-being. Self-esteem, self-efficacy, rumination, reflection, and religion were examined as possible moderators or mediators of the relation between life events and well-being in predominantly white female college students. Life events were analyzed in terms of perceived stressfulness, objective severity of events, and controllability of events. Well-being was measured as depression, total symptoms, and life satisfaction. Self-esteem was found to buffer the negative impact of life events. Self-efficacy, on the other hand, created a susceptibility to their negative impact. Reflection buffered the negative effect of rumination on life satisfaction. Religion was also found to moderate the relationship between events and well-being. Self-esteem and rumination mediated this relationship. Limitations of the present study and suggestions for future research are discussed. / Graduation date: 2004

The ulnar collateral ligament (UCL) is the primary restraint against valgus forces at the elbow. This structure cannot support the entire load placed upon the medial elbow during overhand throwing motions such as pitching a baseball. In this study we measured the contributions that different muscle groups make to the stability of the medial elbow, under conditions intended to reproduce the loads during pitching by varying the forearm position and loading conditions. We also evaluated the strength of the elbow musculature for the possibility of a training effect in the dominant arm of 11 male high school baseball pitchers. We collected surface EMG data in the two forearm positions to determine if the different positions used in various pitches have an effect on muscular action. We also tested an isometric and dissipative loading condition to determine if the muscles activity was load reactive. The four muscle groups tested were the flexor-pronator group (FP), the extensor-supinator group (ES), the tricep brachii (TB), and the pectoralis major (PM). We found significantly (p-value=0.001) higher peak activity levels of the flexor-pronator group in the neutral forearm position (79.4% MVIC �� 27.0% MVIC full trial peak, 30.8% MVIC �� 20.8% MVIC initial l50ms peak following activation) when compared to the supinated position (55.5% MVIC �� 29.6% MVIC full trial peak, 16.9% MVIC �� 14.8% MVIC initial l50ms peak following activation), which may explain the link between breaking pitches and medial elbow injury. We found an increase (p-value=0.001) in force output of the dominant arm (49.3 N/kg �� 12.5 N/kg) over the non-dominant arm (38.1 N/kg �� 11.0 N/kg). This finding is attributed to a training effect, which assists in protecting the elbow. These findings help provide baseline muscle activity information on protection of the medial soft tissue structures of the elbow. / Graduation date: 2004

Graduation date: 1997

The purpose of this study was to compare the levels of bone mineral density (BMD) of the whole body (WB) and proximal femurs of physically active men with spinal cord injuries (SCI) to nonactive men with spinal cord injuries. Also, the lean muscle mass (LMM) of active men with SCI was compared to the LMM of nonactive men with SCI. In addition, BMD values of the radii of physically active men with SCI were compared to that of able bodied men of the same age. The subjects N. 46 were between the age of 20-55 (��=37.83 �� 6.63 years), and were at least 2 years post spinal cord injury. Subjects with SCI were matched on similar level of lesion of the spinal cord, age, height, weight, and years post injury for the purpose of analyzing data. There were 14 active men with paraplegia and 14 nonactive men with paraplegia, 9 active men with quadriplegia and 9 nonactive men with quadriplegia. All BMD data was obtained utilizing a Hologic QDR 1000W dual energy x-ray absorptiometer. A two-factor (level by group) analysis of variance revealed no significant difference for all sites (Whole body, Total hip, radii, LMM) comparing the active and nonactive men with SCI. T-scores and z-scores generated from the Ho logic QDR 1000/W were analyzed using two-factor ANOVA (level by group). The active men with paraplegia had significantly higher BMD levels for all sites when compared to the other groups. These values may be explained by the number of incomplete injuries in the experimental group. Subjects in the physically active group did not clearly show a statistically significant difference on any of the dependent measures. However, values for the dependent measures were higher for the physically active group compared to the values of the nonactive group. / Graduation date: 1995