Thesis (Ph. D.)--University of Rhode Island, 2005. / Typescript. Includes bibliographical references (leaves 130-142).

Thesis (D.P.H.)--University of Hawaii at Manoa, 2000. / Heading on electronic reproduction: Morrow, James Walter. Includes bibliographical references (leaves 172-196). Also available on microfiche.

Dexamethasone, a glucocorticoid, is used extensively in clinical medicine in the treatment of respiratory diseases, notably asthma. This medical effect is probably due in part to a down-regulation of many cytokines, e.g. IL-8. However, the side effects of steroids often may outweigh the beneficial effects, especially if the disease in question is of a chronic nature. This combined with steroid resistance has led to an increase in the use of non-steroidal anti-inflammatory drugs. These tend to be aspirin derivatives, and many have side-effects. I have investigated a factor that is naturally produced by the body which may alleviate the symptoms of inflammation without many of the side- effects, with an aim to providing a viable alternative. A novel steroid induced monocyte derived factor was described twenty years ago by Stevenson as part of an MD thesis submitted to this university. This remains an unusual phenomenon, as most of the effects of steroids are due to a down-regulation of release; here is one of the few examples of the reverse. Although it raised many interesting points about dispersive motility of populations of polymorphonuclear leukocytes (PMN) it did not look at individual cells, nor at many of the interesting properties of neutrophils. One of the known effects of some steroids (though not Dexamethasone), and many NSAIDs, is a reduction of adhesion of PMN to venous endothelium. Human umbilical vein endothelial cells (and bovine aorta endothelium) were used as an ex vivo model for this, and my results show there is a marked decrease in this adhesion. This effect was observed not only on resting endothelium, but also when the endothelial cells had been pre-treated with ILip or thrombin. This decreased adhesion was due to an interaction with the PMN and the factor, as shown by adhesion being reduced when protein coated coverslips were used as the substrate for adhesion. It is suspected that the reasons for this may be due to an inactivation of integrins such as Mac-1, although a role for selectins cannot be ruled out. Recent work by Diaz-Gonzalez suggests that some NSAIDs act by inducing PMN to shed L-selectin. Other effects of this steroid induced monocyte derived factor on human PMN were determined using biological and biochemical techniques. Previous work has shown a novel dispersive effect of this factor on PMN when used in a uniform concentration, and so I decided to look at the moiphology of treated PMN. Using scanning electron microscopy I observed a polarisation of the PMN, but without any raffling of the membrane, a feature that is normally observed with polarisation. This morphology was not observed with control supernatants taken from monocytes cultured in the absence of Dexamethasone. This moiphology was conserved using cells in suspension and adhered to bovine aorta endothelium. The underlying actin cytoskeleton was examined using confocal microscopy, and the microfilamentous airay was noted as being devoid of spikes, observed with activation, for example with fMLP. Late cytoskeletal controlled effects, the release of granule contents, were also investigated, and it was noted that the release of primary granule contents could be inhibited by this factor in a dose dependent manner. This fusion of granules with the plasma membrane is controlled by the activation of numerous tyrosine kinases, and follows a strict order. Secondary granule release was shown to be inhibited also, as assayed by the cleavage of type I collagen, and analysis of SDS gels. The effects on the metabolic burst showed conflicting results with inhibition being present, again in a dose dependent manner, but much of this activity was removed with increasing purification, leaving only very slight inhibition.

The potential of the filamentous fungus Aspergillus fumigatus to act as an opportunistic pathogen may be related to its ability to resist the host defence network. Whilst phagocytic cells are clearly important in host defences against invading microorganisms their precise role in the killing of A. fumigatus remains undefined. The purpose of this study was to examine the basic interactions between phagocytic cells, from humans and rodents, with spores of A. fumigatus. In particular the mechanisms whereby phagocytic cells bind and kill spores of A. fumigatus, when compared with the relatively non-pathogenic fungus Penicillium ochrochloron were investigated. In order to investigate why people with asthma may develop some hypersensitivity reactions to A. fumigatus, in particular, rather than to the many other fungi in the atmosphere, the possibility that there may be a defect in the handling of the fungus by such patients has been tested. A comparison of the fungal handling by phagocytes from asthmatic patients, both sensitised and unsensitised to A. fumigatus with phagocytes from non-asthmatic subjects has been made. The principal findings from this study are that spores of A. fumigatus bind to the surface of the phagocytic cell yet are relatively resistant to phagocytosis. The spores also fail to trigger the phagocytic cells into releasing the potentially microbicidal reactive oxygen intermediates. These results may be related to a further finding which is that spores of A. fumigatus release a low molecular weight substance (diffusate) which interferes with various aspects of phagocytic cell activation. Spore diffusates were shown to inhibit the phagocytosis of radiolabelled antibody-coated sheep red blood cells and to suppress the spontaneous release of reactive oxygen intermediates by Corynebacterium parvum stimulated mouse peritoneal exudate cells. In addition spores diffusates inhibited the ability of phagocytic cells to spread on glass and reduce the number of phagocytic cells migrating towards a known chemoattractant. Studies on spore killing showed that spores of A. fumigatus opsonised in autologous serum were more resistant to killing by phagocytic cells from humans and rodents than similarly opsonised spores of P. ochrochloron. However, the ability of the phagocytic cells to kill spores of A. fumigatus was substantially increased when the spores were opsonised in sera which had been heat-treated for 30 minutes at 56?C. No increased killing was found with P. ochrochloron. People with asthma sensitised to A. fumigatus showed significant differences in their handling of A. fumigatus in vitro when compared with the control group. Monocytes from these sensitised patients killed significantly fewer spores of A. fumigatus (opsonised in auto? logous sera) whilst their polymorphonuclear leucocytes killed significantly more. No such differences were found for P. ochrochloron. The work reported in this Thesis has given us a clearer understanding of why Aspergillus fumigatus is an important cause of disease in man, and how the defence mechanisms that it has evolved in its natural environment the soil, enable it to act as a saprophyte or parasite in the lungs of humans and animals. The results also suggest a mechanism whereby heat-labile serum components may be an advantage to the survival of the fungus, thus perhaps explaining why it may be a particular problem in the airways of asthmatic patients.

Environmental problems, and human attempts to manage them, can be conceptualised as evolutionary complex systems, involving interlinked processes of physical, knowledge, technological, institutional, perceptual and behavioural change. Issues such as traffic pollution and asthma may be viewed as emergent systems, embedded within overlapping hierarchical systems. A distinction may be made beween changes in physical systems (“physical emergence”), changes in human knowledge about those systems (“knowledge emergence”) and changes in human perceptions (“perceptual emergence”). While processes of physical and knowledge emergence are important, it is through perceptual emergence that a phenomenon comes to be regarded as a “problem” or “issue”, potentially leading to changes in policy, institutional arrangements or behaviour. Physical changes may have impacts on human beings, which may be measurable and predictable in the mass. However, the outcome of such an impact, from the point of view of a particular individual, is mediated by that individual’s perception, which is dictated by his or her personal experience, understanding and interests (“appreciative system”). These perceptions in turn will determine the individual’s behaviour, which may feed back into the collective appreciative system, policy system, and the base physical system. The distinction between policy based on measurement and control of impacts and individual perceptions and behaviour dependent on outcomes leads to incongruity between the “institutional” and “individual” views of an issue. The thesis investigates this incongruity in the case of the “traffic pollution and asthma” emergent system. The perceptions of “institutional” and “individual” actors involved in the system were elicited by means of unstructured and semi-structured interviews, and analysed in terms of a number of key concepts (perceptions of measurement, risk and spatiality) across a number of dimensions (different actors in the same location, the same hierarchical position in different locations, and between a specific institution and individuals). The empirical investigation demonstrates differences between multiple institutions managing different aspects of the problem and a lack of understanding and communication between institutions and individuals, despite the fact that an expressed aim of policy in this area is directed at communicating with individuals with the intention of changing individual behaviour.

Class of 2015 Abstract / Objectives: The purpose of this study is to explore potential changes in cytokine and interferon expression during co-infection of rhinovirus and Alternaria. Methods: Alternaria filtrates were used to represent Alternaria spores in real-life. The responses were assessed by production of IL-6, IL-8 and interferon, which were measured by ELISA. mRNA expression was detected by quantitative real-time PCR. For data analysis, a two-sided t-test was performed to compare individual experimental groups. Results: Co-infection of Alternaria and rhinovirus enhanced IL-6 and IL-8 production significantly (p< 0.05). However, Alternaria significantly inhibited production of interferon which would otherwise be induced by rhinovirus. Average interferon-beta (IFN β) production was reduced by about 67%; interferon-lambda (IFN λ) was decrease by about 75%. The differences between treatment and control groups were also statistically significant (p < 0.05). Conclusions: These findings suggested that the Alternaria may cause an imbalanced mucosal antiviral response through inhibiting production of interferon while enhancing production of proinflammatory cytokines. These results indicated that Alternaria may lead to inhibit host innate immunity against virus infection, causing more inflammatory response.

Chronic asthma is characterised by widespread inflammation and reversible narrowing of the bronchial airways. Inflammation of the bronchial mucous membrane renders it hyper-responsive to a variety of stimuli, resulting in wheezing, coughing, chest tightness and breathing difficulty. Asthma was first recognised by the Chinese, four thousand years ago and Hippocrates described it in the fourth century BC. Despite the amount of literature and information available on asthma, this disease is still on the increase world-wide. This research study was undertaken to establish the efficacy of homoeopathic simillimum remedies in the reduction of the frequency and severity of asthmatic symptoms, in adult individuals who suffered from chronic asthma. The research was carried out at the TWR health clinic at Doornfontein, from 1 June 2003 to 31 December 2003. Ten participants, eight males and two females, of all ethnic groups and between the ages of twenty-one and thirty-one, took part in this research. Each participant was interviewed during a homoeopathic consultation. Simillimum remedies were given and the participants were monitored over a period of fourteen weeks, at fortnightly follow-up consultations. Each participant received his/her own peak flow meter and a peak flow rate chart (Appendix E). Morning and evening PEFR were obtained by using the peak flow meter. These readings were recorded, along with any relevant symptoms experienced and/or bronchodilating medication used that day. Participants were required to record the above-mentioned data for two weeks before the homoeopathic treatment commenced and for the remaining twelve weeks of the study. The following results were obtained: • Most participants reported less frequent and less severe acute asthmatic attacks, as well as fewer nocturnal asthmatic symptoms. • Most participants reported an increased ability to participate in exercise without the need for bronchodilating medication during these activities. v • No statistically significant changes were found on the morning or evening peak expiratory flow rates recorded over fourteen weeks. • No statistically significant change was found on the frequency of bronchodilating medication used over fourteen weeks. The following conclusions may be drawn from the recorded results: • Homoeopathic simillimum remedies appear to have been effective in the treatment of chronic asthma in adults. • Homoeopathic simillimum remedies appear to have been effective in the reduction of acute asthmatic attacks and nocturnal asthmatic symptoms. • Homoeopathic simillimum remedies appear to have been effective in increasing the participants’ abilities to partake in physical exercise, as well as in decreasing their need for bronchodilating medicine during exercise. / Dr. S. C. van Es Dr. H. Niehaus

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This thesis follows the paper based format in that Papers One and Two are stand-alone papers prepared for submission for Clinical Child and Family Psychology Review and the Journal of Clinical Child and Adolescent Psychology respectively. The relevant submission guidelines are included in the appendix (Appendix 1). Asthma is the most common childhood chronic illness affecting an estimated 1.1 million children in the UK. A substantial body of research has shown that asthma prevalence and morbidity rates are associated not only with physiological factors but also with environmental and psychosocial factors. Identifying modifiable psychosocial variables involved in the expression and outcome of asthma in children enables identification of how and where interventions could be targeted. Two papers are presented in this thesis, which aims at contribute to research in this area followed by a critical evaluation of the research process, relevance and implications of the presented papers.Paper One is a review of the literature highlighting the biopsychosocial variables involved in the onset and development of childhood asthma. A model is proposed which aims at demonstrate the bidirectional influence of many variables thought to be involved in paediatric asthma expression. One significant area within the literature highlights the extent to which behaviour problems are elevated in asthmatic children. The prognosis for children who develop significant behaviour difficulties is poor.Research has shown that the quality of parenting a child receives has a significant impact on both the child's well-being and development. Literature included in Paper One highlights the relationship between asthma and parenting. Caregivers of asthmatic children have been shown to be more hostile and critical compared with caregivers of non-asthmatic children.Intervening early with families to promote warm, consistent and positive parenting is considered one of the most effective ways to treat behaviour difficulties. Parent training programmes have emerged as the most efficacious method of intervening with and treating child behaviour difficulties and enhancing parenting skills. In spite of their demonstrated effectiveness, engagement with programmes is often poor. As a result researchers have developed self-directed and web-based interventions. Despite their apparent benefits, uptake and continued engagement remains low.Paper Two aimed at examine whether providing asthma specific information enhanced engagement with a Triple P web-based intervention and identify any pre-treatment variables that predicted engagement. The final section, the Critical Evaluation, aimed at place the research in the wider context, consider the findings from both papers, highlight additional and unexpected outcomes and discuss the implications for future studies and limitations of the thesis.

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