Paediatrics (RCH) - Theses
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Item4.7 Tesla magnetic resonance imaging and spectroscopy of infants with neonatal encephalopathy(University of Melbourne, 2007)
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ItemThe relationship between the volume state of the lung, gas exchange and lung mechanics during high-frequency oscillatory ventilation( 2008)During mechanical ventilation, lung volume is determined by the applied transpulmonary pressure. Inappropriate application of this pressure increases the risk of ventilator-induced lung injury and, in the neonate, chronic lung disease. High-frequency oscillatory ventilation (HFOV) has been advocated as a lung protective mode of ventilation. But, even when HFOV is applied with a high lung volume strategy, the reductions in chronic lung disease are modest at best. In general, this is because standard high lung volume strategies do not account for the complex relationship between pressure and lung volume. In part, this is due to difficulties in determining lung volume at the bedside during HFOV.
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ItemSevere crouch gait in the sagittal gait patterns of spastic diplegic cerebral palsy: the impact of single event multilevel surgery( 2005)The purpose of this thesis was to study the outcome of Single Event Multilevel Surgery (SEMLS) on the gait pattern known as crouch gait in children with spastic diplegic cerebral palsy. The term “crouch gait” in the literature has been defined by many authors to mean a flexed knee coupled with many different combinations of posture at the ankle. Consequently it was necessary to provide a robust definition of crouch gait before the outcome study could proceed. Crouch gait was defined in the context of a classification of sagittal gait patterns in spastic diplegia. In the cross-sectional study on the classification of sagittal gait patterns, 187 children with spastic diplegia were categorised according to visual recognition of their gait pattern and sagittal plane kinematic data. Six gait patterns in spastic diplegia were identified, one of which was crouch gait. A pattern of increasing age, severity and biomechanical incompetency in maintaining an extended posture was seen across the gait patterns and crouch gait appeared to be the “end” gait pattern. A longitudinal study documented how the identified gait patterns evolved over time. Thirty-four children were followed for more than one year and the results indicated that the stability of the gait pattern was variable. The reliability of the classification was found to be acceptable. (For complete abstract open document)
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ItemHolding your breath: predictive genetic testing in young people( 2005-07)A clash in perception is taking place. Some perceive predictive genetic testing in young people to be too potentially harmful to allow. Others perceive it to be an opportunity for benefit, even an opportunity for the prevention of harm. In this thesis I consider the issue of potential harm to mature young people who seek predictive genetic tests. There are two parts to this thesis. In part one (chapters 1-4) I provide a background to the current debate. I describe the prohibitive stance purported within current guidelines, the arguments used to justify this stance and the opposition that has arisen in response. I discuss the psychological and social ways in which young people differ from adults, arguing that it is likely young people will react differently from adults in response to predictive genetic tests. However, I conclude that the lack of empirical evidence means we are unable to determine if these differences will confer a greater potential for harm or benefit when young people are tested. Finally, I present a discussion of two fundamental gaps in our knowledge about testing in young people: a lack of knowledge about current practice and a lack of first-hand evidence about the effects of testing. I argue that empirical research is required. In part two of this thesis (chapters 5-7) I present the findings of my own empirical research. Firstly, I describe the findings of an international survey of clinical geneticists. Secondly, I describe the outcomes of 18 in-depth interviews performed with young people who have experienced predictive genetic testing for either Familial Adenomatous Polyposis or Huntington Disease. These young people ranged in age from 14 to 25 years. The international survey uncovered 49 cases where predictive genetic tests had been provided to young people for non-medical reasons. When such tests are provided, the impacts are rarely followed-up as part of a formal research protocol. Clinicians’ reasons for providing and refusing tests are highly varied and are driven more by the nuances of individual cases than by any one ethical principle or set of guidelines. When young people talk about the predictive genetic tests they have experienced, they refer to the entire experience of being at risk of a genetic condition, not simply the time after receipt of their test result. Young people speak about a far more extensive range of harms and benefits associated with the testing process than have been previously researched. I argue that some young people growing up at risk of a genetic condition suffer several harms prior to their request for predictive genetic testing, because of their risk status. I argue that when we understand this, it becomes clear that for these mature young people who seek such testing, the provision of a test may not only serve to alleviate some of these harms, but may in fact create benefits for them, irrespective of their test result. In these cases, the provision of a predictive genetic test is appropriate, logical and ethical.
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ItemDNA methylation at the neocentromere( 2006-01)The Centromere is a vital chromosomal structure that ensures faithful segregation of replicated chromosomes to their respective daughter cells. With such an important structure, one would expect the underlying centromeric DNA sequence would be highly conserved across all species. It turns out that the underlying centromeric DNA sequences between species ranging from the yeast, fly, mouse to humans are in fact highly diverged suggesting a DNA sequence independent or an epigenetic mechanism of centromere formation. Neocentromeres are centromeres that form de-novo at genomic locations that are devoid of highly repetitive a-satellite DNA sequences of which normal centromeres are usually comprised from. To date, the 10q25 neocentromere is the most well-characterised, fully functional human centromere that has been used previously to characterise the extent of a number of centromeric protein binding domains and characterise the properties of the underlying DNA sequence. Along with other factors, the existence of neocentromeres has given rise to a hypothesis where centromeres are defined by epigenetic or DNA sequence independent mechanisms. The putative 10q25 neocentromere domain was recently redefined by high resolution mapping of Centromeric protein A (CENP-A) binding through a chromatin immunoprecipitation and array (CIA) analysis. The underlying DNA sequence was investigated to determine and confirm that the formation of the 10q25 neocentromere was through an epigenetic mechanism. Through a high-density restriction fragment length polymorphism (RFLP) analysis using overlapping PCR amplified DNA derived from genomic DNA representing the 10q25 region before and after neocentromere activation. No sequence polymorphisms, large insertions or deletions were detected and confirmed the epigenetic hypothesis of centromere formation. DNA methylation is one of many epigenetic factors that are important for cellular differentiation, gene regulation and genomic imprinting. As the mechanisms and functions of DNA methylation have been well characterised, its role at the 10q25 neocentromere was investigated to try and identify the candidate epigenetic mechanism involved in the formation of centromeres. DNA methylation across the neocentromere was assessed using sodium bisulfite PCR and sequencing of selected CpG islands located across the 10q25 neocentromere. Overall, the methylation level of the selected CpG islands demonstrated no difference in DNA methylation before and after neocentromere activation. However, significant hypomethylation upon neocentromere formation was detected close to the protein-binding domain boundaries mapped previously suggesting that this may have a role in demarcating protein binding domains at the neocentromere. Further analysis of DNA methylation investigated non-CpG island methylation at sites defined as CpG islets and CpG orphans. Interestingly, the DNA methylation level measured at selected CpG islets and CpG orphans across the 10q25 neocentromere were not completely hypermethylated as previously thought, but demonstrated variable methylation that became fully hypermethylated upon neocentromere activation in most sites investigated. These results suggested that a role for DNA methylation existed at the 10q25 neocentromere and that it occurred at sites devoid of CpG islands. This study has found that DNA methylation at non-CpG island sites was variable contrary to popular belief and, was linked with neocentromere formation through the observation of increased DNA methylation at the 10q25 neocentromere. Inhibition of DNA methylation demonstrated increased neocentromere instability and a decrease in methylation of these CpG islets and CpG orphans confirming the importance of DNA methylation at neocentromeres. This study has characterised a new class of sequences that are involved in the maintenance of chromatin structure through DNA methylation at the 10q25 neocentromere.
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ItemRespiratory function tracking in survivors of prematurity and low birth weight( 2009)INTRODUCTION: To investigate longitudinal ‘tracking’ in lung growth, decline or stability of adult preterm/very low birth weight survivors over the study period. To investigate whether those who have clinically abnormal lung function fall further behind their contemporaries or demonstrate evidence of ‘catch-up’ growth. METHODS: 210 babies born ≤34 weeks’ gestation and with birth weights ≤ 1500g in 1977-1982 were followed up at 8, 11, 14, 18 and 25 years of age. Respiratory outcome was evaluated using Spirometry. Spirometry was performed at each of the follow-up periods. Mixed model regression was used to assess longitudinal lung function trajectories and the influence of Bronchopulmonary dysplasia, being small for gestational age and abnormal lung function. Restricted maximum likelihood modelling was used for longitudinal FEV1 z-score as it allows for analysis of data from different time points that are not necessarily evenly spaced, without being affected by missing data. RESULTS: 137 VLBW children completed lung function testing at 8 years of age. Twenty VLBW children (14.6%) had abnormal FEV1 z-scores and 26 (21.0%) [Defined as >2 standard deviation’s below the mean]. VLBW survivors showed minimal ‘catch-up’ in FEV1 z-score over the 13 years of the study; those without BPD (Bronchopulmonary dysplasia) FEV1 improved 0.034 (p=0.014) z-scores, those with BPD FEV1 improved 0.033 (p=0.039) z-scores. VLBW with BPD survivors did not return to within normal limits; those with abnormal FEF25-75 z-scores did not show significant ‘catch-up’ growth (p=0.41) and remained abnormal. CONCLUSIONS: Mixed models do not reveal any significant effects from being born with VLBW and its interaction with age; it does lead to a reduction in FEV1/FVC mean z-score. Although those VLBW individuals who were small for gestational age had significantly reduced FEV1, FVC and FEV1/FVC mean z-scores and these small for gestational age individuals show evidence of ‘catch-up’ growth in terms of lung function, with the exception of FEV1/FVC z-score which falls further from their contemporaries. This effect on FEV1 and FVC z-scores may suggest some protective element or compensatory mechanism of being born small for gestational age. Reassuringly, Bronchopulmonary dysplasia as a neonate did not significantly affect lung function variables as these individuals as they age. Those with clinically abnormal lung function show a progressive failure to achieve optimal lung function whether or not they had Bronchopulmonary dysplasia.
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ItemThe influence of BCG vaccine strain on the immune response and protection against tuberculosis( 2009)More than 100 million doses of Bacille-Calmette-Guérin (BCG) vaccine are given each year to protect infants against tuberculosis (TB). BCG is a live attenuated strain derived from Mycobacterium bovis. Subsequent to its development and first use in 1921, BCG was distributed to laboratories worldwide. Culture under dissimilar conditions led to the evolution of more than 20 BCG vaccine strains in different countries. Phenotypic differences between these BCG vaccine strains were first recognised in the 1920s and, more recently, molecular studies have defined their genomic differences. Although several animal and human studies suggest that the particular BCG vaccine strain used for immunisation influences the mycobacterial-specific immune response, there is currently insufficient data to favour or recommend one BCG vaccine strain. The principal aim of this thesis was to investigate the influence of BCG vaccine strain on the mycobacterial-specific cellular immune response in infants. Related to this, three additional studies addressed questions that provided critical information for the design and interpretation of the main study. These studies investigated: (i) the BCG vaccine strains used in each country worldwide, (ii) the susceptibility of different BCG vaccine strains to antimycobacterial drugs; and (iii) the difference in the immune response induced by BCG immunisation in children and adults. For the main study in this thesis, newborns were randomly allocated to be immunised soon after birth with one of the three BCG vaccine strains currently most commonly used worldwide (BCG-Denmark, BCG-Japan or BCG-Russia). Ten weeks after BCG immunisation, the mycobacterial-specific cellular immune response was investigated using a comprehensive panel of immunological assays. This comprised flow cytometric analysis of intracellular cytokines and cytotoxicity in T cells, as well as the measurement of cytokines and chemokines in supernatants, from in vitro whole blood stimulation assays. Data from 167 BCG-immunised infants was included in the final analysis. Infants immunised with BCG-Denmark or BCG-Japan had significantly higher proportions of multifunctional CD4 T cells than infants immunised with BCG-Russia. Similarly, infants immunised with BCG-Japan had significantly higher levels of Th1 cytokines in supernatants than infants immunised with BCG-Denmark or BCG-Russia. These findings are particularly important in the light of recent evidence from animal studies that the frequency of multifunctional CD4 T cells induced by immunisation correlates with protection against intracellular pathogens such as Mycobacterium tuberculosis. This suggests that immunisation with BCG-Denmark or BCG-Japan is associated with better protection against TB than immunisation with BCG-Russia. Until correlates of protection against TB are determined in humans, cautious interpretation of these findings is warranted. Nonetheless, the findings from this thesis have important implications. The use of a BCG vaccine strain with even a moderately higher protective efficacy would have a large effect on TB morbidity and mortality in infants on a global scale. This thesis may therefore inform future BCG immunisation policy worldwide.
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ItemMeasurement of 'community readiness' for the prevention of adolescent substance abuse: a pilot study in four Australian regional communities( 2009)Health promotion and public health research increasingly recognise that a range of community organisation and attitudinal factors are important to a community’s level of readiness, or capacity, to undertake effective prevention activity required to reduce population rates of adolescent substance abuse. Although the importance of tailoring community capacity building to readiness levels is acknowledged, little research has been done to date, to develop a systematic framework for measuring readiness in Australia. Equally in Australia where national and state government drive public health drug policy and programme development, their interaction and support of community level interventions and efforts has not been widely examined. This methodological study of 100 telephone interviews with 60 community practitioners (15 in each community) was conducted to identify and assess the specific attitudinal, systemic and resource characteristics of four regional communities in order to extend their capacity or readiness to address adolescent substance abuse within their community. The study provided the opportunity to assess the feasibility, reliability and validity and utility of two North American questionnaires that had been developed to provide quantitative measurement of community readiness. Additional questions were included to try and gauge to what extent state government engaged with, and responded to, the four regional communities in the planning and initiation of prevention activity. Examination of this domain would also contribute to the understanding of state and community engagement with community empowerment. Each of the readiness questionnaires appeared comprehensible within the Australian context, requiring only minor modifications to wording and format to obtain reliable responses from community practitioners. Community readiness ratings for the four communities were consistent across the two instruments with each questionnaire assessing some overlapping and some distinct domains. The comparison of results from the two community readiness survey instruments suggested some advantages for the TECPR instrument in its slightly higher face validity to key informants and its ability to significantly discriminate the total readiness scores for the four communities. Analysis revealed some associations between the two readiness assessment methods; supporting the view that they were assessing some common underlying dimensions but also that they each provided some unique information. Analysis of the additional questions related to community empowerment suggested that the two assessment methods each contributed unique information in predicting local perceptions of community empowerment. It is concluded that each questionnaire has the potential to elicit detailed and reliable data concerning community-readiness, which can be quantitatively analysed; and is not unduly time-consuming or burdensome to the researcher or the respondents. One of the questionnaires holds particular merit for communities where research expertise in not available. Measurement of community readiness appears feasible in the Australian context opening opportunities for improved planning and evaluating of community development initiatives aimed at preventing adolescent substance abuse.
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ItemA profile of young adults aged 20-30 years with cerebral palsy in Victoria: health, function, pain, quality of life, social participation, and service utilisation( 2009)INTRODUCTION AND BACKGROUND: Cerebral palsy (CP) is the most common physical disability in childhood with a prevalence of approximately 2-2.5 per 100 live births. Improvements in paediatric care have increased the survival of individuals with CP. Overall 90% are expected to grow into adulthood yet little is known about the outcomes of young adults with this condition. In order to provide holistic services for this population, an understanding of various aspects of their lives is required. AIMS: To examine the outcome of young adults with CP from the perspective of perceived health status, functional ability, pain, quality of life (QOL), social participation, and healthcare service utilizations, compared with their able-bodied peers. To explore the determinants that contribute to the variation of these outcomes in the context of impairments, activity, participation, and personal and environmental factors. METHODS: This is a population based cross sectional study of young adults with CP based on the WHO International Classification of Functioning, Disability and Health (ICF) model. A cohort of 335 young adults with cerebral palsy born in Victoria, aged 20 to 30 years, was recruited from the Victorian Cerebral Palsy Register. Data of typically developed peers selected from the Household, Income and Labour Dynamics in Australia Survey 2004 were used for comparison for the outcomes of perceived health, pain, and social participation. Data from a population-based sample of 751 young adults in U.S. were used for comparative analyses of QOL. Participants were asked to complete a multidimensional questionnaire by self report, or proxy report by parents or carers for those with intellectual or severe physical impairments. The questionnaire was comprised of the Quality of Life Instrument for Young Adults, the Short Form-36 Health Survey Questionnaire version 2, the Gross Motor Function Classification System, the Barthel Index, and a demographic section. RESULTS: A total of 335 young adults with CP participated; 207 (62%) were able to self report and 128 (38%) were proxy reported. Compared with their able-bodied peers, self reported physical health in this population was lower but mental health was similar. Gross motor function, independence in self care, and limb distribution together explained 60% of the variance in the physical health data. They experienced more pain, impaired function, and reduced social participation, but despite this, their contact with medical and allied health professionals was low. Pain was linked with limb distribution and had a negative impact on functional ability, employment participation and QOL. Impaired functional ability, intellectual disability, and communication impairments had major effects in reducing social participation. Self reported QOL was similar to their peers in social relationship and environmental context domains, but was lower in the domains of physical health, psychological well-being, and role function. The impact of CP on the individuals’ QOL was on physical and functional aspects, and sometimes on social relationships, but not on psychological well-being. CONCLUSION: This study has demonstrated that greater efforts are needed to improve the health, function, QOL, and social participation in individuals with CP, accompanied by more research to monitor the effectiveness of interventions for them.