Autologous blood cell transplantation (ABCT) has been successfully used to treat a variety of haematological cancers and some solid tumours. The number of patients who are long term survivors and free of disease following this treatment is growing rapidly. To enable nurses and health care workers to provide optimal supportive care for these patients, an understanding of how the transplant has affected their quality of life (QOL) is essential. In the last two decades numerous studies have focused on QOL issues in this patient group. However, the majority of these studies tend to approach QOL from a bio-physiological perspective, generating knowledge about the treatment and its side effects. Little is known about the patients' experiences and how they interpret their QOL in the years following their transplants. The purpose of this study was to explore QOL issues from the perspectives of 12 patients who had undergone an ABCT. Heideggerian phenomenology (interpretive phenomenology) was chosen as the theoretical framework for the study, as it allows for the transparent world of people's everyday lived experiences to be illuminated, and so reveal how they interpret their QOL. The aims of this study was to gain a deeper understanding of QOL issues through the participants interpretations of their experiences, and to uncover themes and different patterns of meaning which embody the participants' QOL. Data was collected through in-depth, unstructured interviews with each participant. Thematic analysis, exemplars and paradigm cases were utilised to present the participants' interpretations of their QOL. The findings showed that the participants' QOL was influenced by their interpretations of embodiment, being in time, being in society and re-appraisal of life. The findings also revealed that QOL following an ABCT is a highly individualised, dynamic experience that depends on the challenges the participants confront in their everyday lives. As the participants re-interpreted their lives following their transplants, their perspectives on their QOL changed. For some this was a positive experience, but for others their QOL diminished. The implication of this study is that nurses must be committed to providing individualised, patient focused care following an ABCT. The findings of this study offer a deeper understanding of patients' everyday lived experiences and their QOL following an ABCT, and will enable nurses and other health professionals to develop supportive care infrastructure to assist patients during their recoveries, thus improving their QOL.

Imatinib was successfully introduced into haematology-oncology practice in 2001 and rapidly endorsed as a first line treatment for chronic myeloid leukaemia (CML) in the chronic, accelerated, and blastic phases. The survival advantage demonstrated by this target kinase inhibitor has meant that patients are now treated with this agent on a long-term basis. There is a growing literature on the potential toxic effects of chronic imatinib use (Fruttiger et al., 1999; Grove et al., 2004). A safety sub-study undertaken by the Australasian Leukaemia and Lymphoma Group (ALLG) identified a range of subtle effects consistent with the inhibition of targeted kinases in the immunological, respiratory, endocrine, and reproductive systems (Seymour et al., 2004). To date, there has been no attempt to elucidate possible neuropsychological sequelae of chronic imatinib use. However concerns exist about the potential neurotoxic effects of this agent, given that the inhibition of protein kinase in animal studies has been associated with a range of deleterious consequences, such as impaired learning and memory, and reduced synaptic efficacy (Grove et al., 2004; Moresco et al., 2003). The purpose of the current study was to monitor the neuropsychological function of a group of adult CML patients’ newly prescribed imatinib.

An increasing number of people with chronic illness use complementary and alternative medicine (CAM) (Metz, 2000) and rarely disclose such use to treating biomedical physicians [B/M] (Adler & Fosket, 1999). Although the incidence of CAM use amongst people with chronic illness has been investigated (Nader et al., 2000; Sharon & Mark, 2006; Yang et al., 2002) research specifically examining that section of people who require ongoing biomedical treatment from a very early age until death has never before been conducted. This thesis examined the patterns of self-prescribed and CAM practitioner prescribed CAM use, reasons for CAM use and disclosure of CAM use to treating physicians, among people with a lifelong medical condition, thalassaemia major (TM). To examine the reasons for use and disclosure of CAM in this population, 21 people (eight males, 13 females) aged between 24 and 43 years volunteered for the three-phase study, which forms the thesis. The participants were English speakers whose physical and cognitive capacities did not prevent participation in the study. Interviews were conducted in the participants’ homes and followed standard consent procedures. All phases were conducted face-to-face. In Phase 1, using an in-depth unstructured questionnaire and two structured questions, participants were asked about their medical history, CAM use and whether they disclosed such use to their biomedical physician/s. In addition, the participants were asked to nominate any CAM practices they had heard of, that people might use. A written list was devised as the participants mentioned CAM therapies/treatments. The participants were then asked which of these CAM therapies/treatments they had used. In Phase 1, all of the participants reported having multiple co-morbidities and at least one major surgical procedure. Twelve of the participants reported using CAM when asked a dichotomous choice question. All participants were found to be CAM users when CAM was estimated according to the substances and therapies that participants reported using. Phase 1 showed that CAM estimates varied according to which CAM definition was applied to analyse the data. In Phase 1 there was only one participant out of 21 (4.76%) who reported CAM disclosure and disclosure was ongoing in that case. The reasons for CAM use and disclosure were elicited using in-depth conversational interviews, which constituted Phases 2 and 3 respectively. The operational definition of CAM devised for this thesis was based on the intent of CAM use and not prescribed by a biomedical physician. Based on the operational definition of CAM proposed for thesis there were 21 CAM users. Examination of the reasons the participants gave for CAM use confirmed there were 21 CAM users. Phase 2 showed the participants wanted safe and effective treatment to manage and cure the primary illness and co-morbidities. Phase 2 also indicated that CAM was used, at times in lieu of biomedicine, to prevent illnesses and to enhance quality of life (QoL) and to increase life expectancy. Phase 2 showed biomedical failure and adverse outcomes from biomedicine motivated CAM use. These reasons shaped perceptions of dissatisfaction with biomedical treatment and the prescribers of such treatment. Phase 3, addressed CAM disclosure, showed most of the participants considered they had disclosed their CAM use when they asked their treating biomedical physician about CAM. Phase 3 demonstrated most participants attempted to disclose CAM use and whilst they felt it was important for the treating physician to know about such use, they abandoned disclosure because of dissatisfaction with biomedical practitioners’ responses to their attempts to disclose. Other reasons for non-disclosure or aborted disclosure included a desire to maintain privacy and a belief that CAM was harmless. Phases 2 and 3 showed core reasons for CAM use and CAM non-disclosure were dissatisfaction and a loss of confidence in biomedicine. The one person who did disclose CAM use stated disclosure symbolised their dissatisfaction with biomedicine. This thesis showed people with a serious life-long illness used CAM because biomedicine was often ineffective, frequently palliative and sometimes considered deleterious to health. These aspects of biomedical care instigated dissatisfaction and a loss of confidence in biomedicine treatment and practitioners. The negative perceptions held by the participants of biomedical treatment and biomedical physicians were the primary motivators for CAM use and disclosure. All participants were found to be CAM users and this might have serious implications for their on-going biomedical treatment because some CAM products have a pharmacological effect that might interact with prescribed biomedicine medication. The findings suggest CAM was beneficial in an environment in which biomedicine could only offer palliative care, but this finding requires further research. This thesis showed that CAM use and disclosure are complex issues, deserving indepth examination in people with a range of medical conditions, as well as in the general population.

Statistics show that Australia has an ageing population which will experience radical changes over the next 50 years due to the progression into retirement of generations born in the ‘baby boom’ years (1945-1965). Statistics also show that the proportion of Australian people over 65 is increasing and, as the majority of deaths occur in this age group the demand for palliative care, or care of the dying, is also likely to increase. Many retiring baby boomers looking for a sea change, gravitate towards coastal and rural areas may well be contributing to Foskey’s (1998) notion of ‘Aged Care Ghettos’ where these areas may not have the desired infrastructure to deal with an increased demand for health services including palliative care services. An increasing focus on, and public interest in palliative care research will likely emerge in keeping with the changing needs of an ageing population. It will become particularly important that relevant research undertakings are initiated to establish a clearer understanding of the issues and problems surrounding palliative care. At the present time there exists a limited research base in relation to palliative care and related services in Australia. While there has been a concentration of palliative support services in urban settings this has not been the case in rural based settings. Palliative Care Australia (2000) reported that half of the people receiving palliative care in Victoria in 1997 died in rural and regional areas, which may be attributed to harsher living environments, poor access to health services, specialists, and health professionals, lower socio-economic status and employment levels, and exposure to occupational hazards. This thesis is concerned with examining palliative care services and related needs in a selected rural area within the Australian state of Victoria. The overall aim of this research was to investigate the availability of palliative care services, trends in ageing and to examine the relationship between the two. Methodology used in this research incorporated a sequential mixed methods approach of quantitative and then qualitative methodology to determine the relationship between the needs of an ageing population and rural palliative care service delivery in Australia. The data collection included demographic statistics from the Australian Bureau of Census and Statistics and Palliative Care Australia, and were used for descriptive purposes to inform and support this research. Other ordinal data were obtained using a questionnaire. These data were analysed in the context of the research. Qualitative data were obtained through interviews with focus groups. The Gippsland area provided an excellent area for this research and the findings of this research would appear to be consistent with the literature relating to access and equity issues faced in rural areas. Other rural areas may replicate the data gathering used in this research. A number of conclusions are able to be drawn from this research based on the review of literature and examination of the emerging issues, results and findings. Statistical projections into ageing indicate that the health of all Australians will have significant consequences for our society as we generally live longer and healthier lives. Health and ageing predictions and projections should prompt key stakeholders including baby boomers, the aged cohorts of the future, to plan and prepare, perhaps redefining ageing in the attempt. Findings further show that planning should include preparations for the expected rise of dementia related diseases and the implications of gender on health which will have ramifications for an ageing population, and in particular for women as carers in our society. As a result of this research recommendations are made for a model for the delivery of palliative care services in rural areas, which is specific to the needs of an ageing population. These recommendations are made in acknowledgement and with respect and consideration for the concerns of the rural community where feedback from focus group participants suggests that rather than another ‘model’, a hospice is what is needed to meet the current and future needs of rural communities. “Another ‘Model’ is the last thing we need, it’s not the how we are doing things, it’s the where – we desperately need a hospice down here” and, “It’s bricks and mortar we want down here, not more theories”. Evidence collected from this research also suggests that a ‘rural attitude’ to death and dying may prevail. In its simplest form, this attitude emerges in statements such as: ‘it’s the country you expect to get less’ and ‘we just look after our own when we can’. It is also apparent that while people in rural areas have the same medical and palliative care needs as those in metropolitan areas, this research shows that they are differentially disadvantaged when it comes to accessing palliative care services. This research has found that a negative relationship exists between ageing trends in a selected rural area of Australia chosen for this study and the availability of palliative care services.

One of the major yeast stressors during fermentation is ethanol accumulation. Ethanol stress is associated with reduced cell growth and viability, consequently lowering yeast productivity. Although the underlying causes of ethanol inhibition of cells are yet to be identified, it has been discovered that yeast acclimatise more quickly to ethanol stress in the presence of low acetaldehyde concentrations; however, the biochemical processes underpinning this effect are unknown. The objective of this project was to identify the mechanisms associated with the acetaldehyde-mediated adaptation of yeast to ethanol stress, which may facilitate the development of yeast strains with improved ethanol tolerance and/or strategies for improving ethanol tolerance in yeast. Gene array analysis was used to study gene expression in Saccharomyces cerevisiae during acclimatisation to non-lethal ethanol stress, in the presence and absence of acetaldehyde. Acetaldehyde caused significant changes in gene expression in ethanol-stressed yeast. For example, many genes associated with protein biosynthesis were more highly expressed, as were pyruvate decarboxylase genes. Interestingly, however, there was no significant increase in the expression of trehalose synthesis genes or genes encoding HSPs; genes which, in previous studies, appeared to be associated with acclimatisation to ethanol-stress. In addition, acetaldehyde did not have a major impact on gene expression in non-stressed cultures. The results of this project are consistent with the speculation that the addition of acetaldehyde to ethanol-stressed S. cerevisiae primes glycolytic flux in ethanol-stressed cells by regenerating NAD+ from accumulated NADH. This, in turn, stimulates glyceraldehyde-3- phosphate dehydrogenase activity and might account for the acetaldehyde-mediated increased expression levels of pyruvate decarboxylase genes; elevated levels of pyruvate would potentially increase the need for PDC activity. Overall, these speculated effects of acetaldehyde on ethanol-stressed yeast would increase glycolytic rate and energy production.

The purpose of this evaluative case study was to evaluate the effectiveness of a 48 hour Medical Unit in relation to Patient Satisfaction, Patient Care, Nursing Staff Job satisfaction and the Average Length of Stay for patients' Pre and Post a Rapid Assessment Medical Unit's (RAMU) inception. The study used a combination of Patient Satisfaction Survey's, Interviews, and data of the average length of stay of patients pre and post RAMU. This report aims to provide a comprehensive description of the research process and the results obtained from the collection of data throughout this research project. An evaluative case study using Yin (2003), as a framework of this study was deemed appropriate, as no research to date had been conducted on 48 hours Medical Wards, because of their uniqueness. A case study allowed for "multiple sources of evidence gathering", thus ensuring that the findings to this study are more likely to be accurate if based on several different sources of information. Despite the study's limitations, the results to this study were surprisingly supportive and positive of those patients who had participated in this research project. Nursing Staff on both wards that participate in the interviews had a positive attitude in relation to how well RAMU is functioning. The findings indicate there are a few minor changes that are required and further research is recommended, however the hospital and staff have managed to find a formula that works extremely well in providing patient satisfaction, patient care and job satisfaction in a short period of time.

Perinatal associations of low birth weight and its long term sequelae were surveyed and the resulting hypotheses examined in a study of 240 children classified by birth weight, gestational age and sex. Subjects were placed in small for gestational age, pre-term appropriate for gestational age, control, pre-term small for gestational age, low birth weight with gastroenteritis and very low birth weight groups. Assessment was blind and, where necessary, groups were randomly selected. Data were gathered from four stages of the subjects’ development; the pregnancy, the newborn period, pre-school and school age. Analysis of pregnancy data showed that some aspects of the intrauterine environment provided by a number of mothers was less than optimal. In the neonatal period, the low birth weight groups were at some disadvantage and, further, there were aspects where there was some evidence that either the treatment or the condition for which it was required could possiblY influence subsequent development. The pre-school period was marked by sex differences, particularly in cognitive functioning. Disadvantage in all instances was confined to the low birth weight male groups. Some events in the prenatal, perinatal and neonatal periods appeared to be associated with poorer performance on intelligence tests more than four years later. Among these influences were mothers' smoking habits, temperature, duration of tube feeding and gastroenteritis while in hospital. Assessment at school revealed the same pattern of cognitive development among the subgroups that had been apparent at the pre-school stage. The pre-term males found adjustment to school difficult and made slow progress in reading in comparison with the females belonging to the same group. At this age the term - small for gestational age group was still lagging behind in physical development. It was concluded that the low birth weight males constituted a group who were ‘at risk’ because of slower cognitive development. This was particularly evident in so far as the pre-term males were concerned.

SN 28049 is a novel DNA intercalating anti-cancer drug developed at the Auckland Cancer Society Research Centre as part of ongoing research into topoisomerase II poisons with high activity against solid tumours. SN 28049 was curative against murine Colon 38 tumours, a model of colorectal adenocarcinoma which is generally unresponsive to topoisomerase II poisons (1), while two clinically used topoisomerase II poisons, doxorubicin and etoposide, were respectively moderately active and inactive against this tumour. The aim of this thesis was to use human tumour cell lines in order to develop an understanding of the mechanism of anti-tumour activity of SN 28049. Topoisomerase II poisons induce DNA double strand breaks which signal through multiple pathways, and two of these, the γ-phosphorylation of histone H2AX (γ-H2AX) and the induction of p53 protein were investigated in HCT 116 colorectal carcinoma cells and in NZM3, NZM6 and NZM52 melanoma cells. SN 28049 induced only a small increase in γ- H2AX phosphorylation, comparable to that mediated by doxorubicin and etoposide. However, a low concentration of SN 28049 (25 nM) stimulated p53 protein expression in HCT 116 cells to levels in excess of those observed in response to doxorubicin or etoposide. The activation of p53 by SN 28049 cells was investigated using the HCT 116 line and an isogenic line lacking p53 expression. As assessed by expression of the representative p53 transcriptional targets FAS, p21WAF1 and survivin, SN 28049 was considerably more active than doxorubicin or etoposide in stimulating the p53 pathway. However, there was little evidence of SN 28049 inducing either G1 arrest or apoptosis in these cells. SN 28049 instead induced p53-dependent G1 tetraploid arrest following mitotic failure in the absence of cell division. In response to a five-hour drug exposure and further growth in the absence of drug, HCT 116 p53 +/+ cells arrested with a ‘4N’ DNA content, expressing high levels of G1-phase cyclin E. At later times, senescence associated β-galactosidase (SA-β-Gal) activity increased, indicative of senescence. Under similar conditions, HCT 116 p53 -/- cells continued cycling with a DNA content of >4N. In contrast, doxorubicin added under similar conditions to HCT 116 p53 +/+ cells caused cycle arrest with an ‘8N’ DNA content and signs of senescence, while etoposide induced only signs of senescence. The activity of SN 28049 and a series of its analogues was also compared to that of doxorubicin and etoposide in both the HCT 116 p53 +/+ and p53 -/- lines using growth inhibition assays. When cells were cultured at a density that allows exponential growth, SN 28049 selectively inhibited HCT 116 cells expressing wild-type p53, and the selectivity was related to potency. However, responses to SN28049 were not distinguished qualitatively from doxorubicin and etoposide. In contrast, under conditions of high cell density, SN28049 and several active analogues maintained selectivity for HCT 116 p53 +/+ over p53 -/- cells while doxorubicin and etoposide lost their selectivity. The ability of SN 28049 to activate p53 was retained at high cell density. It is concluded that SN28049 has two cellular actions. The first, shared with doxorubicin and etoposide, is mediated by topoisomerase II-induced DNA damage, is cell cycle non-specific and leads to cell cycle arrest. The second, which is unique to SN28049 and is most easily observed in a cell line (HCT 116) growing at high cell density to ensure minimal expression of active topoisomerase II, involves bypass of mitosis and entry into a G1 tetraploid phase and is characterised by high expression of p53 and its downstream products. It is hypothesised that this second cellular action could explain the high in vivo activity of SN 28049.

This thesis assesses the effectiveness and cost-effectiveness of the 'Green Prescription' physical activity intervention amongst less-active adults in primary care, using the Auckland Heart Study (AHS) questionnaire to assess change in activity. The validity of two physical-activity questionnaires, the AHS and the GSS questionnaires, was assessed initially, comparing their performance with 7-day activity diaries and pedometers amongst less-active adults in primary care. A cluster randomised controlled trial was then conducted in the waikato region of New Zealand, with 42 general practices randomised to give the Green Prescription or 'usual care'. A systematic screening process identified less-active 40-79 year-old patients. Main outcome measures included change in physical activity, quality of life (SF-36), coronary risk, and blood pressure, over a twelve-month period. Costs of the programme and offset costs of primary and secondary health care utilisation, productivity, and exercising, were collected prospectively for cost-effectiveness analysis from a societal perspective. The AHS questionnaire was found to have adequate reliability and validity, and to be the most appropriate measurement tool for use in primary care research. In the Green Prescription trial, 74% of general practitioners (n=117) and 66% of screened eligible patients (n=878) participated. Follow-up rate, at one year, was 85% (n=750). Mean total energy expenditure increased by 9.4 kcal/kg/week (p=0.001) and leisure exercise by 2.7.kcal/kg/week (p=0.02) or 34 minutes/week more in the intervention group than the control group (p=0.04). The proportion of the intervention group undertaking 21/2 hours/week of leisure exercise increased by 9.72% (p=0.003) more than in the control group (NNT=10.3). SF-36 measures of 'general health', 'role-physical', 'vitality', and ‘bodily pain' improved significantly more in the intervention group (p<0.05), as a result of the Green Prescription intervention. There was a trend towards decreasing blood Pressure, no increase in adverse events, and no statistically significant difference in four-year risk of coronary heart disease. The cost of delivering the Green prescription was $170.45 per participant from a funder's perspective and $37.16 (95%CI:-$945.21,$1019.53) from a societal perspective. To increase leisure-time exercise by one hour per week cost $25.36 per month from a programme funder's perspective and $5.47 (95%CI:-$138.90,$149.84)per month from a societal perspective. The AHS questionnaire was considered reliable and valid. The Green Prescription intervention is effective in increasing physical activity and improving quality of life over 12 months without evidence of adverse effects. The intervention is more cost-effective than other physical activity interventions reported in the literature and may be cost-saving in terms of long-term health gains.

The Hyper Immunoglobulin M syndrome (HIM) is a rare primary immune deficiency disorder characterised by an inability to produce immunoglobulin isotypes other than IgM and IgD. The B cell-surface antigen CD40, and its conjugate T cell counter-structure, CD40 ligand (CD154), mediate immunoglobulin isotype switching to IgE and IgG4 in the presence of cytokines such as interleukin 4. Patients with the X-linked form of the hyper IgM syndrome (XHIM) have mutations in the CD40 ligand gene which is the molecular basis for impaired immunoglobulin isotype switching in XHIM. This thesis is a tale of two HIM patients, one with XHIM (patient H1) and the other (patient M1) with a novel immune defect which has yet to be fully characterised. Analysis of Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) products of the CD40 ligand gene from patient H1 revealed two mutant transcripts, one missing exon 4 and the other missing both exons 3 and 4. In addition, the cells of patient H1 also produce small quantities of wild type cD40 ligand transcripts. Molecular analysis has shown that this complex splicing defect is precipitated by a point mutation at the invariant 3’ splice acceptor site with a g→c substitution at position -1 (tcacGTA) of intron 3. RT-PCR studies have shown that the cells of the mother of patient H1 produce both wild type and deleted CD40 ligand transcripts, consistent with her carrier state. Genomic sequencing of intron 3 has shown that she is heterozygous for the point mutation (tcacgEGTA), confirming her carrier status. Analysis of other family members, including the sister and the maternal grandmother, has indicated that they have not inherited the mutation. Patients with XHIM are predisposed to Pneumocystis carinii pneumonitis and to Cryptosporidiosis. Studies of T cell function in patient H1 has identified a defect in antigenspecific proliferation which provides an explanation for the susceptibility of XHIM patients to opportunistic infections. In contrast to patient H1, the cells of patient M1 have wild type CD40 ligand sequence and express normal amounts of cell surface CD40 ligand indicating that he does not have XHIM. Flow cytometry and in vitro antibody synthesis studies have shown that the B cells of this patient are able to undergo immunoglobulin isotype switching both in vivo and in vitro. Unlike the mild T cell defect shown in XHIM patients, a severe T cell defect is present in this patient who also has impaired CD40-induced B cell function. The impaired CD40 function may be secondary to the T cell defect. The demonstration of wild type CD40 ligand transcripts in the patient with a splicing defect may explain the milder phenotype seen in some XHIM patients. The identification of the T cell defect should result in re-classification of XHIM as a combined immune deficiency disorder The characterisation of patient M1 extends the phenotypic spectrum of the hyper IgM syndrome to include a severe T cell defect in the context of normal CD40 ligand structure and function.