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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ItemAssessment of pulmonary function in childhood neuromuscular weakness( 2004)Children with neuromuscular weakness may have severe or progressive weakness that results in pulmonary restriction. Weakness can also result in spinal deformity that worsens the pulmonary restriction. Corrective spinal surgery carries significant respiratory risk. Accurate respiratory assessment is important for pre-operative risk assessment. Aims: 1) to evaluate the current clinical practice of pulmonary function testing and their role in respiratory assessment in children with neuromuscular weakness undergoing corrective spinal surgery and 2) to develop a precise method of predicting pulmonary function tests in children with neuromuscular weakness.
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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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ItemHuman centromeric and neocentromeric chromatin( 2000-09)Human centromeres contain large arrays of α-satellite DNA that are thought to provide centromere function. These arrays show size and sequence variations. However, the lower limit of the sizes of these DNA arrays in normal centromeres is unknown. Using a set of chromosome-specific α-satellite probes for each of the human chromosomes, interphase Fluorescence In Situ Hybridisation (FISH) was performed in a population screening study. This study demonstrated that extreme reduction of chromosome-specific α-satellite is unusually common in chromosome 21 (screened with the αRI probe), with a prevalence of 3.70%, compared to <=.12 % for each of chromosomes 13 and 17, and 0 % for the other chromosomes. No analphoid centromere was identified in over 17,000 morphologically normal chromosomes studied. All the low-alphoid centromeres are fully functional as indicated by their mitotic stability and binding to centromere proteins including CENtromere Protein-A (CENP-A), CENtromere Protein-B (CENP-B), CENtromere Protein-C (CENP-C), and CENtromere Protein-E (CENP-E). Sensitive metaphase FISH analysis of the low-alphoid chromosome 21 centromeres established the presence of residual αRI as well as other non-αRI α-satellite DNA suggesting that centromere function may be provided by (i) the residual αRI DNA, (ii) other non-αRI a-satellite sequences, (iii) a combination of i and ii, or (iv) an activated neocentromere DNA. (For complete abstract open document)
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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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ItemThe genetic control of neural crest development in early craniofacial morphogenesis( 2004-11)Craniofacial development requires orchestrated and complex interactions between multiple tissues of different origins. Cranial neural crest stem cells migrate from the dorsal neural tube into the frontonasal process and branchial arches where they ultimately form most of the skeletal structures and connective tissue of the craniofacial complex, as well as contributing neurons and glia to cranial ganglia. The timing and mechanism by which cranial neural crest cells progressively differentiate from multipotent stem cells into lineage restricted and terminally differentiating cell types has previously not been investigated. In addition, there are many deficits in our knowledge of the molecular controls regulating early development of neural crest cells within the branchial arches. Spatial and temporal changes in migratory and lineage potential in neural crest populations contributing to the developing first branchial arch and trigeminal ganglia were examined by back-transplanting cells from quail into chick embryos. Neural crest cells that had barely entered the first branchial arch had largely lost both the ability to localise to the trigeminal ganglia and neurogenic differentiation capacity but were still capable of long-distance migration. However, after a further 12 hours residence in the branchial arch, neural crest cells had lost long-distance migratory ability.
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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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ItemInhalation pneumonitis in children with severe cerebral palsy( 1999)Aspiration occurs frequently in children with severe cerebral palsy. Our study demonstrated at least one positive test for aspiration in 68% of children. The salivagram was positive in 56%, the barium video-fluoroscopy in 39%, and the milk scan in only 6%. The study demonstrates poor agreement between radiological tests of aspiration. This suggests that the tests measure different aspects of swallowing, that the intermittent nature of aspiration results in poor agreement, or that the tests are poor measures of aspiration. Positive radiological tests of aspiration are associated with a history from parents that the child has asthma and with poorer motor skills. A history of cough or wheeze, of cough with feed, of regurgitation and of recent asthma are associated with positive tests. Poorer overall adaptive ability, smaller head circumference centile, higher resting respiratory rate and abnormal measures of gastro-oesophageal reflux are associated with positive tests of aspiration. Chronic respiratory acidosis occurred in some children. Our study of this abnormality was hampered by the problem of defining normal values, and the appropriate reference range for our methodology. Using the Arbus nomogram definition of chronic respiratory acidosis we found an association between chronic respiratory acidosis and larger angle of scoliosis, poorer clearance of aspiration from the lung on salivagram, poorer clearance of acid from the oesophagus on pH probe, a history of pneumonia, and better weight for height Z score. Gastro-oesophageal reflux is associated with aspiration as mentioned. Both younger age and decreasing levels of ability are associated with greater frequency of gastro-oesophageal reflux. A history of asthma, regurgitation, a parental impression that the child aspirates but not a history of vomiting, were more frequent in children with gastro-oesophageal reflux. Altered voice following liquid feeding was associated with gastro-oesophageal reflux. We found less gastro-oesophageal reflux amongst children with more severe scoliosis, though this may have been the result of inadequate probe placement. There is poor agreement between the pH probe and milk scan in the diagnosis of gastro-oesophageal reflux.