Melbourne Medical School Collected Works - Research Publications
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ItemNo Preview AvailableHuman immune responses to infective stage larval-specific chitinase of filarial parasite, Onchocerca volvulus, Ov-CHI-1.(Springer Science and Business Media LLC, 2003-03-14)BACKGROUND: Ov-CHI-1 is a chitinase specifically expressed in the infective stage larvae of the human filarial parasite Onchocerca volvulus. Evidence has show that it could be a vaccine candidate, however, there is no data available regarding the immunological status of people naturally exposed to infective stage larvae and thus provoked by this antigen. METHOD: We analysed the Ov-CHI-1-specific immune response present in four endemic foci of human onchocerciasis (Ecuador, Nigeria, Togo and Cameroon) by enzyme-linked immunosorbent assays and T-cell proliferation assays. RESULTS: In these foci of infection, antibodies to Ov-CHI-1 were found to be present in only 22% of individuals from Ecuador, but were detected in 42-62% of infected individuals in the three foci from West Africa (Nigeria, Togo and Cameroon). There was found to be no relationship between antibody level and age, gender, or infection intensity as indicated by microfilarial density and numbers of skin nodules. The isotype response to Ov-CHI-1 was dominated by the presence of IgG3, IgG1 was present to a lesser extent. Our results show a positive correlation between N- and C-termini of Ov-CHI-1 in their ability to provoke humoral and cellular immune responses in the human. Peripheral blood mononuclear cell (PBMC) proliferative responses to Ov-CHI-1 when assayed, were found to be significantly higher in the individuals from endemic areas and there was a statistically elevated response to Ov-CHI-1 in the infected individuals when compared to putative immune individuals. CONCLUSION: Ov-CHI-1 is an antigen that we have found strongly induces both humoral and cellular immune responses in humans.
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ItemNo Preview AvailableCan physical activity improve the mental health of older adults?(Springer Science and Business Media LLC, 2004-06-29)The world population is aging rapidly. Whilst this dramatic demographic change is a desirable and welcome phenomenon, particularly in view of people's increasing longevity, it's social, financial and health consequences can not be ignored. In addition to an increase of many age related physical illnesses, this demographic change will also lead to an increase of a number of mental health problems in older adults and in particular of dementia and depression. Therefore, any health promotion approach that could facilitate introduction of effective primary, secondary and even tertiary prevention strategies in old age psychiatry would be of significant importance. This paper explores physical activity as one of possible health promotion strategies and evaluates the existing evidence that supports its positive effect on cognitive impairment and depression in later life.
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ItemCombination of contrast with stress echocardiography: a practical guide to methods and interpretation.(Springer Science and Business Media LLC, 2004-08-26)Contrast echocardiography has an established role for enhancement of the right heart Doppler signals, the detection of intra-cardiac shunts, and most recently for left ventricular cavity opacification (LVO). The use of intravenously administered micro-bubbles to traverse the myocardial microcirculation in order to outline myocardial viability and perfusion has been the source of research studies for a number of years. Despite the enthusiasm of investigators, myocardial contrast echocardiography (MCE) has not attained routine clinical use and LV opacification during stress has been less widely adopted than the data would support. The purpose of this review is to facilitate an understanding of the involved imaging technologies that have made this technique more feasible for clinical practice, and to guide its introduction into the practice of the non-expert user.
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ItemMODULATION OF CELL-ADHESION BY CHANGES IN ALPHA(L)BETA(2) (LFA-1, CD11A/CD18) CYTOPLASMIC DOMAIN/CYTOSKELETON INTERACTION(ROCKEFELLER UNIV PRESS, 1995-01-01)The integrin alpha L beta 2 (leukocyte function-associated molecule 1, CD11a/CD18) mediates activation-dependent adhesion of leukocytes. The cytoplasmic domains of alpha L beta 2 have been demonstrated to modulate adhesiveness of alpha L beta 2. Affinity changes of alpha L beta 2 for its ligand or postreceptor events can be responsible for this modulation of adhesiveness. To investigate the possible role of the alpha L beta 2 cytoplasmic domains in postreceptor events we constructed cDNA encoding chimeric proteins with intracellular alpha L beta 2 domains, which are responsible for alpha L beta 2 specific intracellular interactions, and extracellular alpha IIIb beta 3 (GP IIb/IIIa) domains, which allow the assessment of the receptor affinity state. The cDNA was stably transfected in Chinese hamster ovary cells and chimeric heterodimer formation proven by immunoprecipitations and flow cytometry. The chimeric receptors mediate adhesion to immobilized fibrinogen, and this adhesion is increased by phorbol myristate acetate and abolished by cytochalasin D. However, neither treatment affects the affinity state of the chimeric receptor, suggesting involvement of the cytoskeleton in the regulation of alpha L beta 2 mediated cell adhesion. To exclude the possibility of postoccupancy affinity changes of the chimeric receptors, we locked the receptors into a high affinity state by creating a deletion variant. The region deleted (VGFFK) is highly conserved in integrin alpha subunit cytoplasmic domains. Cotransfection of this deletion variant with a beta subunit truncation (beta 3 delta 724) and a triple mutation at 758-760 (TTT to AAA) of beta 2 abolishes adhesion without changing the affinity state. A single mutation (TTT to TAT) reduces adhesion by half without affinity change. Scanning electron microscopy reveals impaired spreading of these truncated/mutated chimeras. Immunofluorescence microscopy demonstrates a correlation between impaired adhesion and a decrease in the ability to form focal adhesions and to organize the cytoskeleton into stress fibers. These results describe the integrin/cytoskeleton interaction, the organization of the cytoskeleton, and cell spreading as postreceptor events modulating alpha L beta 2 cytoplasmic domain mediated cell adhesion. Furthermore, we demonstrate that the cytoplasmic domain of the beta 2 subunit, and within it the TTT region, are required for these postreceptor events. Additionally, we present a new approach, using deletion variants to lock integrins in a high affinity state without interfering with the investigated integrin/cytoskeleton interaction. This approach may be generally useful to investigate the role of postreceptor events in integrin-mediated cell adhesion and migration.
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ItemINTEGRIN CYTOPLASMIC DOMAINS MEDIATE INSIDE-OUT SIGNAL-TRANSDUCTION(ROCKEFELLER UNIV PRESS, 1994-03)We analyzed the binding of fibronectin to integrin alpha 5 beta 1 in various cells; in some cells fibronectin bound with low affinity (e.g., K562 cells) whereas in others (e.g., CHO), it bound with high affinity (Kd approximately 100 nM) in an energy-dependent manner. We constructed chimeras of the extracellular and transmembrane domains of alpha IIb beta 3 joined to the cytoplasmic domains of alpha 5 beta 1. The affinity state of these chimeras was assessed by binding of fibrinogen or the monoclonal antibody, PAC1. The cytoplasmic domains of alpha 5 beta 1 conferred an energy-dependent high affinity state on alpha IIb beta 3 in CHO but not K562 cells. Three additional alpha cytoplasmic domains (alpha 2, alpha 6A, alpha 6B) conferred PAC1 binding in CHO cells, while three others (alpha M, alpha L, alpha v) did not. In the high affinity alpha chimeras, cotransfection with a truncated (beta 3 delta 724) or mutated (beta 3(S752-->P)) beta 3 subunit abolished high affinity binding. Thus, both cytoplasmic domains are required for energy-dependent, cell type-specific affinity modulation. In addition, mutations that disrupted a highly conserved alpha subunit GFFKR motif, resulted in high affinity binding of ligands to alpha IIb beta 3. In contrast to the chimeras, the high affinity state of these mutants was independent of cellular metabolism, cell type, and the bulk of the beta subunit cytoplasmic domain. Thus, integrin cytoplasmic domains mediate inside-out signaling. Furthermore, the highly conserved GFFKR motif of the alpha subunit cytoplasmic domain maintains the default low affinity state.
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ItemNo Preview AvailablePrevention and Mental Health Promotion in Adolescents: the evidence(McGraw Hill Australia, 2002)
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ItemAdolescent chronic illness: A qualitative study of psychosocial adjustment(ACAD MEDICINE SINGAPORE, 2003-01)INTRODUCTION: The purpose of this study was to investigate the psychosocial issues facing young people living with a chronic medical condition. MATERIALS AND METHODS: Subjects were young people with a range of medical conditions who were on a waiting list to participate in the Chronic Illness Peer Support programme at the Centre for Adolescent Health, Royal Children's Hospital, Melbourne, Australia. Young people agreed to in-depth interviews which were taped and transcribed. Thematic analysis was undertaken by two researchers working independently. RESULTS: Thirty-five young people were interviewed. Thematic analysis revealed five broad themes: control (in control, under control, out of control); emotional reactions (happiness, frustration, anger, sadness, anxiety); acceptance (of illness, of others, of self); coping strategies, and; a search for meaning. The importance of social connections was emphasised. While illustrating the difficulties of managing a chronic medical condition during adolescence, a generally positive message emerges about these young people. CONCLUSIONS: Many young people with chronic illness appear relatively resilient in the face of the adjustment challenges presented by their illness. Interventions that allow a young person to explore meaning, build self-esteem, and acceptance through positive social connections are likely to improve adjustment outcomes in this group.
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ItemGeneral anaesthesia or conscious sedation for painful procedures in childhood cancer: the family's perspective(BRITISH MED JOURNAL PUBL GROUP, 2003-03)BACKGROUND: Until recently, midazolam sedation was routinely used in our institution for bone marrow aspirates and lumbar punctures in children with cancer. It has been perceived by many doctors and nurses as being well tolerated by children and their families. AIM: To compare the efficacy of inhalational general anaesthesia and midazolam sedation for these procedures. METHODS: A total of 96 children with neoplastic disorders, who received either inhalational general anaesthesia with sevoflurane, nitrous oxide, and oxygen (GA) or sedation with oral or nasal midazolam (SED) as part of their routine preparation for procedures were studied. The experiences of these children were examined during their current procedure and during their first ever procedure. Main outcome measures were the degree of physical restraint used on the child, and the levels of distress and pain experienced by the child during the current procedure and during the first procedure. The family's preference for future procedures was also determined. RESULTS: During 102 procedures under GA, restraint was needed on four occasions (4%) when the anaesthetic mask was first applied, minimal pain was reported, and children were reported as distressed about 25% of the time. During 80 SED procedures, restraint was required in 94%, firm restraint was required in 66%, the child could not be restrained in 14%, median pain score was 6 (scale 0 (no pain) to 6 (maximum pain)), and 90% of the parents reported distress in their child. Ninety per cent of families wanted GA for future procedures. Many families reported dissatisfaction with the sedation regime and raised concerns about the restraint used on their child. CONCLUSIONS: This general anaesthetic regime minimised the need for restraint and was associated with low levels of pain and distress. The sedation regime, by contrast, was much less effective. There was a significant disparity between the perceptions of health professionals and those of families with respect to how children coped with painful procedures.
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ItemFamily risk factors for cannabis use: a population-based survey of Australian secondary school students(CARFAX PUBLISHING, 2003-06)The objective of this study was to investigate relationships between adolescent cannabis use and indices of parent - child attachment, family functioning and parent attitudes to drugs and delinquency. A total of 2848 year 9 and 2363 year 11 students participated in the Victorian Adolescent Health and Well-Being Survey (1999). The study was a school-based random sample of 535 metropolitan and rural, government and non-government secondary schools throughout Victoria, Australia. Cannabis use was defined as 'any' and 'weekly' use in the last 30 days. Multivariate logistic regression was used to identify independent associations between cannabis use and parent - child attachment, family functioning and parent attitudes to drugs and delinquency. Cannabis use in year 9 was associated with permissive parent attitudes to drugs and delinquency (any use: adjusted odds ratio (OR) = 8.1; weekly use: adjusted OR = 7.6), and was particularly sensitive to small changes in the quality of the parent - child relationship with risk increasing threefold for those describing their attachment as 'good' compared with 'very good' (any use: adjusted OR = 2.8, weekly use adjusted OR = 2.9). A similar, but more moderate pattern association was evident in year 11. After adjusting for other family and background factors, poor family functioning showed minimal association with level of cannabis use at both year levels. Results suggest that intervention efforts might sensibly target strengthening parent - children relationships and promoting less permissive parent attitudes to drug use.
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ItemAdolescent resilience: a concept analysis(ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2003-02)There is need for greater clarity around the concept of resilience as it relates to the period of adolescence. Literature on resilience published between 1990 and 2000 and relevant to adolescents aged between 12- and 18-years of age was reviewed with the aim of examining the various uses of the term, and commenting on how specific ways of conceptualizing of resilience may help develop new research agendas in the field. By bringing together ideas on resilience from a variety of research and clinical perspectives, the purpose of the review is to explicate core elements of resilience in more precise ways, in the hope that greater conceptual clarity will lead to a range of tailored interventions that benefit young people.