The Eph receptor tyrosine kinases and their ephrin ligands are cell surface molecules with a wide range of biological functions. Specifically, the Eph/ephrin receptor-ligand family influences cell behaviour during both embryogenesis and adult life, principally through modification of cytoskeletal organisation and cell adhesion. EphA1 (previously referred to as eph) was isolated during a search for novel tyrosine kinases with oncogenic potential. The murine homologue of hEphA1, formerly Esk and now mEphA1, was cloned by reverse transcriptase PCR using degenerate oligonucleotide primers and RNA prepared from embryonic stem cells in culture. Northern blot analysis revealed expression in day 12 mouse embryo, and adult mouse thymus, liver, kidney, lung and placenta. The work in this thesis investigates the expression and function of EphA1 in mutant mouse and other animal models. This has been achieved by a number of different techniques including:- (1) the classical techniques of molecular biology; (2) a search for the zebrafish homologue of mEphA1; (3) generation and phenotypic analysis of the hPLAP EphA1 reporter knockout mouse and (4) generation of the EphA1 conditional knockout mouse. The chromosomal localisation and Southern blotting of genomic digests confirmed that Esk (mEphA1) is the murine homologue of eph (hEphA1). The binding of soluble mEphA1 to a panel of ephrin ligands analysed by surface plasmon resonance (BIACore), and the binding of various ephrin-Fc molecules to cell surface expressed EphA1, confirmed that EphA1 is the cognate receptor for the ephrin-A1 ligand. The mEphA1 genomic sequence was isolated, sequenced and the exon-intron boundaries mapped. Interestingly, Exon 3, which includes the ligand binding domain, is split into two smaller exons (Exon 3a and Exon 3b). This pattern was also found in hEphA1; however, it is a novel finding compared with the other Ephs, and the reason underlying this difference remains speculative. In situ hybridisation analysis confirmed epithelial expression of mEphA1 in the basal layer of the epidermis, developing hair follicles, thymic epithelial cells and adult kidney. At the commencement of the zebrafish (ZF) library screening project in 1997, it seemed likely that there was an ZF orthologue of EphA1. However, over 50 clones were isolated by degenerate PCR of zebrafish cDNA and genomic libraries, and although some of the sequences had homology to known Ephs, none matched EphA1. The ZF genome has now been sequenced completely [http://wwwmap.tuebingen.mpg.de/ ; http://zfin.org/] and has confirmed that there is indeed no zebrafish orthologue of EphA1. The hPLAP EphA1 reporter knockout mouse was generated with the technical assistance of Dr Graham Kay (Queensland Transgenic Laboratory). The homozygous null mice have a kinky tail in two separate embryonic stem cell lines with a high degree of penetrance. A proportion of female null mice display the imperforate vagina phenotype. The null mice are otherwise grossly normal, with equal sex ratios and normal growth, health and life expectancy. The microscopic examination of haematoxylin and eosin stained sections of all the major organs revealed no histological abnormalities. The expression of hPLAP, (hence mEphA1), analysed in frozen sections confirmed the previous work which defined the epithelial expression of mEphA1 to the basal epidermis and hair follicle. There was also previously undescribed hPLAP (mEphA1) expression in the uterus, vagina and small intestine. The EphA1 conditional knockout mouse was also generated with the assistance of the Queensland Transgenic Facility. The homozygous null mice were grossly normal with equal sex ratio and normal health and life expectancy. The kinky tail phenotype was observed infrequently and has not yet been fully characterised in these mice. Similarly the imperforate vagina phenotype has not been observed in this strain of mice. This strain of genetically modified EphA1 knockout mice can be mated with various strains of Cre-deleter mice to achieve tissue specific silencing of EphA1 and consequently allow more precise analysis of EphA1 function. In summary, the studies described in this thesis have confirmed the importance of the Eph/ephrin receptor-ligands in both embryonic development and the maintenance of adult tissues, and have generated several new findings which add to our knowledge of the biology of EphA1. The generation of the hPLAP EphA1 reporter mice and EphA1 conditional knockout mice has provided us with very useful tools. These knockout mice will allow further analysis of the role of EphA1 in mouse models of human diseases, including skin and colon cancer, severe sepsis and post-traumatic injury.

High-velocity, low-amplitude (HVLA) manipulation is commonly advocated by manual therapists to relieve spinal pain and dysfunction. The aim of this controlled, single blinded study was to investigate whether HVLA manipulation of the occipito-atlantal (OA) joint had any lasting effect on pressure pain thresholds (PPT) in the suboccipital musculature in an asymptomatic population. HVLA manipulation of the OA joint did not significantly change the PPT of the suboccipital muscles in asymptomatic participants. HVLA produced a greater mean increase in PPT and effect size compared to the control group over both time intervals, and therefore investigation of the effect of this technique with a symptomatic population is warranted. This minor thesis was written by a post-graduate student as part of the requirements of the Master of Health Science (Osteopathy) program.

Mobilisation is a common technique used by manual therapists in the treatment of spinal pain, but there has been little investigation into its effect on pain in the lumbar region. The aim of this study is to determine the immediate effects of mobilisation on pressure pain thresholds (PPT) in the lumbar spine in an asymptomatic population. Analysis of pre and post intervention PPT values showed that there was only minimal increase in PPT in the mobilisation group and a decrease in the sham group. Paired t-tests indicated that there was no significant change following mobilisation and the effect size was small. When the different scores of the 2 groups were analyzed with an independent t-test, a significant difference between groups was found. Extension mobilisation of the lumbar spine did not produce any significant improvement in PPT in an asymptomatic population. Further research on the effectiveness of mobilisation, as well as other manual interventions, for low back pain is recommended. This minor thesis was written by a post-graduate student as part of the requirements of the Master of Health Science (Osteopathy) program.

Occupational stress is an important, but under-explored issue in osteopathic practice. In related professions, such as general medical practice, occupational stress is a key factor compromising job satisfaction, and potentially compromising patient care. This study was developed to explore the job satisfaction and sources of occupational stress, in osteopaths with less than 5 years clinical practice experience. A concurrent study was conducted to explore the same issues in more experienced practitioners. Sources of occupational stress and job satisfaction were explored via a questionnaire mailed to osteopaths at their practicing addresses. Participants returned the questionnaire to the researchers using reply-paid envelopes. Participation in this study was voluntary. Personal indentifiers have been kept confidential. The Osteopaths' Stress Survey (OSS) was mailed to 936 Australian osteopaths with an invitation to participate in this study and provide data on their occupational stress and job satisfaction. The returned surveys were divided between the two lead researchers on the basis of the respondents years in practice. Surveys returned from practitioners of less than 5 years clinical practice were analysed in this study. Most new graduate osteopaths (93%) reported being very satisfied, or somewhat satisfied, with their chosen career. The most frequent sources of occupational stress among new graduate osteopaths included, managing patients who were "difficult", managing time pressures to see patients and dealing with paperwork. The most severe stressors included, earning enough money, excessive clinical responsibility and managing difficult patients. The severity of stressor is somewhat tempered by the frequency of that stressor. Although largely satisfied with osteopathic practice, new graduate osteopaths find paperwork, time pressures, and difficult patients frequently stressful in their work. This minor thesis was written by a post-graduate student as part of the requirements of the Master of Health Science (Osteopathy) program.

Weight transfer in the golf swing is considered important in the coaching literature. However, scientific studies on weight transfer have been conflicting due to a number of limitations. This thesis examined weight transfer in the golf swing using more trials per golfer, Club Velocity at ball contact rather than handicap to indicate performance and more swing events at which weight position was quantified. Also, cluster analysis was used to identify if different swing styles exist. In study 1, 62 golfers performed ten simulated drives, hitting a golf ball into a net, while standing on two force plates. CP position relative to the feet (CPy%) was quantified at eight swing events identified from 200 Hz video. Cluster analysis identified two CPy% styles: ‘Front Foot’ style and ‘Reverse’ style. Both styles began with CPy% positioned evenly between the feet, moved to the back foot during backswing and then forward during early downswing. Beyond early downswing, the Front Foot group continued to move CPy% towards the front foot to ball contact, while the Reverse group moved CPy% towards the back foot to ball contact. Both styles occurred across skill levels from professional to high handicap golfers, indicating that neither style was a technical error. In study 2, group based relationships between CP parameters and Club Velocity for each swing style was examined. For the Front Foot group, a larger CP range and a more rapid CP movement in downswing were associated with a larger Club Velocity at ball contact. For the Reverse group, positioning CP further from the back foot at late backswing and a more rapid CP transfer towards the back foot at ball contact was associated with a larger Club Velocity at ball contact. In study 3, individual-based analysis was conducted on five golfers performing 50 swings under the same test conditions. All golfers returned significant relationships between CP parameters and Club Velocity but these were individual specific. The most consistently related parameter was CP range, which was significantly related to Club Velocity for all golfers. Nonlinear techniques also were explored, with Poincare plots returning useful results for some golfers. In conclusion, analysis of weight transfer in the golf swing requires styles to be identified prior to any performance analysis. Individual-based analysis as well as group-based analysis is required to extract the most relevant information. Further, the use of more trials per golfer and more swing events should be employed in future studies.

Abnormal tissue texture and tenderness detected in the paravertebral gutter (PVG) region by manual palpation has been proposed to be an important diagnostic finding in osteopathic medicine. The pathophysiology of tissues at sites detected as abnormal by palpation and reported as tender by the subject (AbPT) is speculative, because evidence of objective characteristics that distinguish abnormal sites from non-tender, normal to palpation (NT) sites is lacking. The first study of this thesis examined the pressure sensitivity of AbPT sites in 32 subjects using a novel pressure algometer. The AbPT regions had a lower mean pressure pain threshold than the three NT regions, and a one-way ANOVA determined these differences to be significant (P < 0.01). This study demonstrated that these sites were significantly more sensitive to manual pressure than adjacent NT sites, above, below, and on the opposite side of the spine, and established that these sites had characteristics different from adjacent NT sites, and were therefore not merely a result of practitioner imagination. Authors in the field of osteopathy have suggested that abnormal tissue texture in the PVG region may be due to either atrophy or hypertrophy of the underlying paraspinal muscle mass. The second study in this thesis compared the thickness of deep paraspinal muscles underlying AbPT and NT sites in the thoracic PVG regions of 40 subjects. The anteroposterior dimension of the deep muscle mass was measured using diagnostic ultrasound by an ultrasonographer who was blinded to the designation of the sites, and found that there was no significant difference (P = 0.61) in the thickness of paraspinal muscles underlying AbPT and NT sites. Early researchers in the field of osteopathy have claimed to provide evidence of paraspinal muscle hyperactivity at sites designated as abnormal using palpation, which has been used to promote the ‘facilitated segment’ aetiology for intervertebral somatic dysfunction. The final study in this thesis examined the electromyographic (EMG) activity of deep paraspinal muscles underlying AbPT and NT sites in the thoracic PVG using fine-wire, intramuscular electrodes in 12 subjects. The normalised EMG activity of muscles underlying AbPT sites was higher than the mean activity at NT sites under all experimental conditions, and analysis with SPANOVA revealed a significant difference between the sites (P = 0.03). The EMG recordings during the prone resting were found to have been contaminated with electromagnetic noise, but, when these were excluded from the analysis, there remained a statistically significant difference between the sites (P = 0.02). Post-hoc analysis revealed the significant difference between sites to occur under the condition of resting seated. The trend for higher EMG activity under other experimental conditions were not significant, most likely due to the large variation between subjects and small sample size, but large and medium effect sizes were calculated for differences between the sites under most conditions. Non-significant trends of decreased EMG responsiveness from baseline resting to more demanding tasks were seen at the AbPT sites relative to the NT sites. Caution must be exercised when interpreting the results of this study because the validity of the method of EMG normalisation requires further investigation. This thesis established that AbPT sites detected by palpation in the thoracic PVG region are more sensitive to pressure, and have differing EMG characteristics from NT sites. This research suggests that increased EMG activity may be a contributing factor to the altered tissue texture detected with palpation.

Premenstrual syndrome is a common disorder troubling many women during their reproductive years. The Chinese have been using herbal medicines to treat menstrual cycle related symptoms for centuries. Traditional Chinese medicine provides the aetiology and pathogenesis of the symptoms of this disorder by applying Pattern Identification to diagnose the signs and symptoms of individual patients and to design individualised treatments which seek to address the entire pattern/s of disharmony. It follows that PMS, which has many symptoms and an idiosyncratic nature, is precisely an area for which Chinese medicine is most suitable. The aim of this study is to scientifically evaluate the effectiveness of Chinese herbal medicine on Australian women for the treatment of PMS within the theoretical frame-work of TCM. A double-blind randomized placebo-controlled crossover clinical trial was conducted by a qualified Chinese herbal practitioner and pharmacist. Following two months confirmatory assessment, sixty-one subjects were assigned randomly into two groups within different TCM patterns of Liver Qi Stagnation, Liver and Kidney Yin Deficiency, Liver and Spleen Disharmony and Heart and Spleen Deficiency. Herbal medicine (n=31) and placebo (n=30) were provided sequentially for a period of three months. There were significant differences (p < .01) in scores after three months of treatment between Chinese herbal medicine and placebo in premenstrual physical and psychological symptoms, depression, anxiety and anger, but with no difference in perceived stress (p > .05). There were highly significant reductions (p < .001) in all assessments in both groups except that a significant result (p < .05) was recorded on perceived stress only in the treatment-first group between baseline and the end of the third herbal treatment month. Also, there was no significant difference on treatment effects shown between TCM patterns. No adverse effects were reported by any participant. The results support the hypothesis that the symptoms occurrence and severity of PMS can be effectively reduced by the use of Chinese herbal medicine. On this basis, it is considered that Chinese herbal medicine may offer an alternative treatment method to western drugs for PMS sufferers who either do not accept the current treatment options or are having unwanted side-effects with their current treatment.

This study was conducted in two parts, a survey study and a comparative balance and mobility pilot study. Firstly, a series of self-administered questionnaires were mailed to people in Queensland with chronic fatigue syndrome (CFS). The main purpose of the survey study was to 1) develop a demographic and health profile of the population of people who suffer from CFS in Queensland; 2) to establish the reliability and validity of an alternate measure of fatigue, the Multidimensional Assessment of Fatigue (MAF) and 3) to document functional mobility, history of falls and degree of fear of falling experienced by those with CFS. The average age of CFS subjects who participated in the survey study was 52 years, and 69 percent were between the ages of 40 and 70 years. Seventy-seven percent of the subjects were women. CFS subjects reported a mean duration of CFS symptoms of 16.95 years. Sixty-three percent of CFS subjects suffered from a concomitant diagnosis of fibromyalgia. Fatigue severity was measured by the Fatigue Severity Scale (FSS) and the MAF. The mean fatigue score obtained from the FSS and the MAF was 6.3 (SD+/-0.7) and 37.81 (SD+/-6.96) respectively. The FSS (Intraclass Coefficient=0.9, p<0.001) and the MAF (Intraclass Coefficient=0.84, p<0.001) were highly reliable when measuring fatigue in CFS over two occasions within a one-month period. There was a weak, but significant correlation between the MAF and the FSS (Spearman’s Rank Order Coefficient=0.476, p<0.001), indicating that the MAF is a reliable and valid measure of fatigue in the CFS population. Fifty-one percent of the CFS cohort reported a history of a fall occurring in the past six months, while thirty-nine percent of the total CFS cohort were identified as recurrent fallers. A fear of falling was reported by fifty-two percent of CFS subjects. The mean modified falls efficacy score for the CFS cohort was 7.7 (SD. +/-2.24). Falls and fear of falling appeared to be related to a concurrent diagnosis of fibromyalgia. The high incidence of falls and fear of falling in the CFS population prompted a pilot comparative study of balance and mobility function in women with CFS. The main aims of this study were to 1) identify the type of balance and mobility deficits experienced by a cohort of younger women with CFS; 2) to compare balance and mobility function of women with CFS to an age matched control group and 3) to identify the test conditions that are best able to differentiate the balance and mobility performance of the CFS cohort and controls. The grip strength, gaze stability and balance and mobility function of 14 females with a current diagnosis of CFS and 20 age matched control females was tested. Upper limb strength (p<0.003) and dynamic visual acuity (p<0.003) were significantly reduced in CFS subjects when compared to control subjects. There were no significant differences between CFS and control subjects for postural stability measures of bilateral stance on the Clinical Test of Sensory Integration of Balance. There was a strong trending increase in velocity of postural sway demonstrated when CFS females stood on a firm surface with eyes closed (p=0.018). No significant difference between the CFS cohort and the controls was demonstrated for all single leg stance (SLS) time and sway measures. However there was a strong trend for increased postural sway and less time measured for left and right SLS with eyes open. Slower reaction times when weight shifting in a mediolateral direction ((R) p=0.004, (L) p=0.007) were demonstrated in CFS subjects. CFS subjects performed the Timed Up and Go (TUG) test, manual TUG and the combined TUG significantly slower than control subjects (p=0.001). Gait parameters were significantly different between the two groups on all 10m walk tests. CFS subjects exhibited a slower gait velocity, shorter step length, less cadence and longer duration of gait cycle. Dual tasking did not appear to effect the gait pattern of CFS subjects more than controls, however, more complex multitask conditions may have identified greater differences between the two groups. This study has demonstrated that a community based cohort of the CFS population in Queensland experience significant levels of impairment and disability associated with fatigue and other CFS symptoms, falls and perceived fear of falling. Preliminary findings suggest that people with CFS exhibit mild balance and mobility deficits and impaired upper limb strength and gaze stability. Recommendations are made regarding the future delivery of intervention programmes for people with CFS in Queensland.

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