Paediatrics (RCH) - Theses
Permanent URI for this collection
Search Results
1 - 7 of 7
-
ItemSurgical strategies for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries and pulmonary atresia with intact ventricular septum at the Royal Children's Hospital, Melbourne, Australia( 2013)Congenital heart disease affects approximately six to eight babies in every thousand live births. In Australia over two thousand babies are born with congenital heart disease each year, with about half requiring either surgery or catheter intervention. The other half has minor abnormalities that have little to no functional impact and rarely require intervention. Historically most patients with complex congenital heart disease died in childhood. However, the past three to four decades has seen considerable advances in the fields of cardiac surgery, cardiology, cardiac imaging and intensive care, to the extent where most congenital cardiac lesions are now considered repairable with minimal morbidity. There remain, however, specific cardiac lesions that have yet to achieve this level of safe correction. Pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals, and pulmonary atresia with intact ventricular septum are two such lesions. Pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals is a rare and complex lesion. There is considerable variability in the anatomy, morphology and geometry of the native pulmonary vessels and the collateral arteries. The ultimate goal of therapy is a biventricular repair with closure of intracardiac defects and establishment of right ventricle to pulmonary artery blood flow. Throughout the world, surgeons have tried many different techniques to achieve this goal. The Cardiac Surgery Unit at the Royal Children’s Hospital in Melbourne achieved excellent early success in the treatment of this malformation in the 1980s – 1990s. However, long-term follow-up has revealed limitations in the surgical strategy applied during that era. Whilst complete repair was achievable in 67% of patients, survival to thirty years of age was only 58% and after complete repair only 51% of patients were alive twelve years later. A new approach – “repair without unifocalisation” was devised and is explained in this thesis. The first twenty patients who then underwent this surgical technique are examined. Early survival is excellent with no deaths to date. Complete repair was achieved in 60% of patients, 30% are awaiting complete repair, and 10% of patients are deemed unlikely to achieve complete repair and my need to be assessed for heart/lung transplantation when their symptoms progress. Pulmonary Atresia with intact ventricular septum is another lesion in which it has been difficult to achieve low morbidity and mortality. In this malformation there is complete obstruction between the right ventricle and the pulmonary arteries, and newborn babies are typically dependent on ductal blood flow for pulmonary perfusion. With a lack of a ventricular septal defect there is no outflow from the right ventricle and this results in variable degrees of right ventricular and tricuspid valve hypoplasia, and sometimes extensive right ventricular hypertrophy with coronary artery anomalies. Surgical strategies aimed at achieving a biventricular repair with reconnection of the right ventricle to the pulmonary artery have always been the ideal, as this most closely reflects the natural physiological state. However, poor results emphasized by a 5-year survival of only 49%, have encouraged surgeons to explore different strategies in the treatment of this malformation. In this modern era it is quite clear that a single surgical strategy to this malformation is inappropriate. If a univentricular palliation pathway is used exclusively then many patients fail to attain a biventricular repair and the long-term benefit this provides. If a biventricular strategy is applied exclusively then early mortality increases to unacceptable levels. An approach utilising both biventricular and univentricular repairs appears to provide the best balance between decreasing early mortality and providing the best long-term prognosis. Unfortunately there are limited criteria to decide which patients should be directed towards a univentricular or biventricular repair. Using data from patients operated on over a period of sixteen years at the Royal Children’s Hospital I have tried to identify preoperative variables that may guide this decision making process. Multivariate analysis revealed two significant risk factors for mortality. These were the presence of right ventricle to coronary artery connections and a tricuspid valve size Z score of less than negative two. Surgical results revealed an 80% ten-year survival rate. Using a simple three tiered right ventricle size categorization one can stratify those with the smallest right ventricles to univentricular palliation and those with near normal right ventricles to biventricular repair. Those patients with moderate sized right ventricles can be directed towards biventricular repair except if they also possess the significant risk factors for mortality. This approach is hoped to improve survival.
-
ItemTelomerase and its role in calcitriol-induced cell death in human colon adenocarcinoma HT29 cells( 2013)Since its discovery in 1984, the role of telomerase in maintaining cellular longevity has been well-studied, raising hopes for cancer therapeutics that selectively target the telomerase pathway. Similarly, various investigations have looked into the impacts of Calcitriol (Vitamin D) in cancer cell death on different cancer cell lines. The role of Calcitriol in mediating telomerase in relation to cancer cell death, however, has not yet been clearly established. To this end, this work is focused on examining the potential role of telomerase in mediating Calcitriol-treated cancer cells. We found that even though Calcitriol alone is sufficient in inducing cell death in colon cancer (HT29) and breast cancer (MCF7) cell lines, it is inadequate in terms of inhibiting telomerase expression or activity levels in colon (HT29), breast (PMC42, MD231) and prostate (PC3) cancer cell lines. Inhibition of telomerase expression and activity was only evident with the combinatorial treatment of Calcitriol along with Retinoic Acid (Vitamin A). Furthermore, we were able to observe in Calcitriol-treated HT29 cells intracellular vacuoles consistent with a catabolic process of autophagocytosis as reported elsewhere in literature. Another interesting observation was that while telomerase activity levels in HT29 cells treated with both Calcitriol and Retinoic Acid were reduced maximally at 48 hours (consistent with Calcitriol having a half-life of about 20 hours in vivo), these activity levels appear to “rebound” beyond the baseline levels of untreated cells at 72 and 96 hours although cell death were maximum at these stages. This strongly suggests that an alternative pathway may be involved. We postulate that this increased in telomerase activity may be attributed to the level of cellular stress imposed as a consequence of Calcitriol treatment rather than Calcitriol itself acting through telomerase to cause cancer cell death. However, further work is needed to characterize this phenomenon. Collectively, we conclude that while Calcitriol alone is sufficient in inducing cell death in cancer cell lines, this outcome is likely mediated via programmed cell death pathway rather than a telomerase-mediated pathway.
-
ItemFamily function and congenital heart disease( 2013)Introduction: Congenital heart disease (CHD) is one of the most common birth defects, and the most complex defects often require cardiac surgery in early infancy. Cardiac surgery typically requires intensive care unit admission. The ongoing effect on the family from having a baby with CHD that requires surgery in early infancy has been incompletely defined. Aim: To describe family function and the burden of having an infant with operated CHD, in the families of two year-olds who underwent surgery for CHD in early infancy. Method: The primary caregivers (n = 99) of young infants (less than 8 weeks of age) that required cardiac surgery in Melbourne, Australia and Auckland, New Zealand completed a series of psychosocial questionnaires assessing family function, family burden, significant life stress, and coping style when their child with CHD was 2 years old. Initial surgery complexity (RACHS-1), need for reoperation, maternal education, timing of diagnosis, and intensive care length of stay was also collected. Results: Healthy family function was found in the majority (79%), Unhealthy family function related to significant life stress (p < 0.02) and avoidance coping style (p < 0.02). Unhealthy family function did not relate to complexity of surgery, diagnostic class, need for reoperation, intensive care length of stay, or maternal education. There was a greater family burden for those with more complex lesions (single ventricle physiology with initial palliation) compared to less complex lesions (biventricular physiology requiring corrective surgery) (p < .02). Conclusion: The majority of families of two year-olds with operated CHD had healthy family function. Unhealthy family function was not related to surgical complexity, reoperation, or diagnostic class, but was related to significant life stress and coping style. Families that indicated a higher level of maternal education were more likely to utilise an adaptive style of coping. However those with a lower level of maternal education were more likely to utilise a less adaptive style of coping. Maternal education per se did not influence family function or family burden however coping style did. Family burden was greater for those that required reoperation and had a greater surgical complexity and significant life stress.
-
ItemQuality of life assessment in children requiring oral anticoagulant therapy( 2011)The absence of robust evidence regarding the management and clinical outcomes of anticoagulant therapy in children challenges interpretation of the risks and benefits of long-term anticoagulation therapy for children. Decisions about treatment increase in complexity in light of the potential burden of treatment on children and families. Quality of life (QoL) is a recognised and validated measure of the burden of treatments for children; yet, there is a lack of data about the impact of long-term warfarin therapy on QoL for children and families. This thesis describes the first study to evaluate the impact of a home international normalised ratio (INR) self-testing (home ST) program on the QoL of children and their families. The aim of the study was to determine if participation in a home ST program improves QoL for children requiring long-term warfarin therapy and their families. Parents of children requiring long-term warfarin therapy and children aged eight to 18 years participated in the QoL study. Three validated QoL questionnaires, the Pediatric Quality of life Inventory Generic Core Scale™, the Pediatric Quality of Life Family Impact Module™ and the KIDCLOT Pediatric Anticoagulation Quality of Life © inventory were employed to measure QoL. Questionnaires were completed before commencing home ST and six to 12 months later. Participants answered four open-ended questions when completing the questionnaires for the second time. Fifty-six families entered the home ST program during the study period. The children were aged between 2 and 17 years. Fifty-five parents and 35 children completed QoL questionnaires. Results of INRs tested at home were collected. The percentage of time the children’s INRs were in their target therapeutic range was 71.3%, which is comparable to many published paediatric studies of home ST. Parents reported statistically significant improvements in QoL for themselves, their family and their child, across all questionnaires following the commencement of home ST (mean difference in score p ≤ 0.003 on all questionnaires). The children’s scores of their own QoL also improved; however, this improvement was not significant. Parents’ report of their children’s QoL was significantly lower than the children’s report of QoL on all questionnaires at both time points. As well as being the first validated baseline QoL data in an Australian population of children requiring oral anticoagulant therapy, this study reports QoL for the largest cohort of children requiring warfarin therapy worldwide. The employment of both quantitative and qualitative methods to assess QoL enhanced understanding about the impact of home ST on QoL. This study has demonstrated that home ST in a population of children requiring long-term warfarin therapy is safe, efficacious and improves the QoL of children and parents. This study confirms home ST successfully reduced the burden of therapy and maintained excellent clinical outcomes. The results of this study not only identify the impact of warfarin therapy upon QoL in children, but offer an alternative evaluation strategy to sensitively measure the impact of interventions in this population. Accurate QoL assessments ensure children’s and families’ values are integrated with the current evidence for best clinical practice.
-
ItemWhole-genome expression profiling of cord blood mononuclear cells from monozygotic twin pairs( 2010)Substantial variation in gene expression levels exists between individuals, within specific tissues or cell types. With gene expression being the primary mechanism through which genetic information is translated into phenotype, the extent, nature and sources of this variation constitutes an important aspect of human biology. Variation in gene expression levels reflects a complex interplay of genetic and environmental factors. Certain environmental factors and exposures can modify gene expression through epigenetic modifications of DNA and chromatin, thus regulating transcription in a manner largely independent of genetic variation. The sensitivity of epigenetic mechanisms to these factors offers a means through which the environment can modulate expression of the genotype, with effects upon gene expression and ultimately, the phenotype. Studies of variation in gene expression in monozygotic (genetically identical) twins support a substantial environmental contribution to variation in gene expression levels. It is known that the epigenetic and gene expression profiles of monozygotic twins diverge throughout life. Mounting evidence suggests that the period of pre-natal development represents a particularly sensitive one for the occurrence of environmentally induced changes to epigenetic status and gene activity. The current study forms part of a larger research program investigating epigenetic variation in twins and its association with birth weight, maternal nutrition and foetal genotype. The Peri-/Post-natal Epigenetic Twins Study (PETS) builds upon the ‘developmental origins of adult disease’ hypothesis, based on the association between low birth weight and increased risk of cardiovascular and metabolic disease in later life, and focuses on epigenetic changes occurring in utero as the basis of the ‘foetal programming’ phenomenon. The current study is based on the hypothesis that divergence of epigenetic and gene expression profiles occurs from conception in monozygotic twins, in response to differing environments as experienced in utero. This study investigates the gene expression profiles of the cord blood mononuclear cells (CBMCs) of twelve newborn monozygotic twin pairs, including six pairs with birth weight discordance at greater than 15%. Genome-wide expression profiling was performed using the Illumina® Human-6 v2 BeadChip system. Gene expression discordance within twin pairs was assessed using three measures. Of these, the measure of Euclidean distance was considered to be the most systematic and useful. Expression discordance was found to vary substantially across pairs in our sample, with expression discordance being generally lower within twin pairs than between unrelated individuals. A significant correlation was identified between expression discordance and chorionicity, with greater expression discordance in dichorionic pairs compared to monochorionic pairs. The measure of Euclidean distance was also applied to publicly available datasets from genome-wide expression profiling of comparable tissues from adult twin pairs, revealing higher levels of expression discordance within the adult pairs relative to the newborn pairs. All genes surveyed by the microarray analysis were ranked according to the degree of within-pair variation shown across twin pairs. This ranked gene list was subjected to gene ontology analysis to identify gene ontology (GO) terms for which the corresponding ranks were higher than expected. Of the 27 GO terms ranked significantly higher than expected, one third related to immune response or response to other external signals. This data supports our hypothesis that divergence of gene expression profiles occurs from conception in monozygotic twins, and is reflected in differential expression phenotypes detectable at birth. Taken together, these results highlight the role of environment in determining gene expression profiles, and the contribution of environmentally induced changes in gene expression to expression discordance within monozygotic twin pairs. The increased variation observed within dichorionic twin pairs, coupled with the prominence of genes involved in immune/external signal response amongst those showing increased variation across pairs, implies that this variation may arise in response to subtly differing environments experienced by co-twins in utero. Birth weight is a phenotype of particular interest in the Peri-/Post-natal Epigenetic Twins Study (PETS), due to the association of low birth weight with an elevated risk of cardiovascular and metabolic disease in later life. In this study, linear modelling identified 342 genes whose expression levels showed a significant association with birth weight in dichorionic twin pairs. Gene ontology analysis of these genes revealed significant over-representation of GO terms relating to protein dephosphorylation, a process intrinsic to many forms of signal transduction. These data imply a link between the environmental modulation of gene activity via signal response/transduction and the phenotype of birth weight. Due to the myriad number of signal transduction pathways and physiological processes regulated by protein phosphorylation and dephosphorylation, it is not possible to pinpoint with certainty those that may be linked to birth weight or implicated in the association between low birth weight and elevated disease risk from our data. However, these results do provide a basis for further investigation of the specific environmental factors involved in the determination of gene expression variants associated with birth weight. It is to be hoped that future analyses will assist in the identification of the mechanisms underlying the correlation between low birth weight and an elevated risk of cardiovascular and metabolic disease in later life.
-
ItemA prospective study of the psychological impact, understanding and disclosure of gene test results for hypertrophic cardiomyopathy and long QT syndrome.( 2010)Hypertrophic cardiomyopathy (HCM) and Long QT syndrome (LQTS) are inherited cardiovascular conditions for which genetic testing has become more common in clinical practice. The most concerning feature of these conditions is sudden death which can be prevented if those at risk are identified. Research into the clinical and molecular aspects of these conditions has advanced rapidly but research on the psychosocial implications of genetic testing for these conditions has lagged behind. The present study aimed to add to the limited body of research about the impact of genetic testing for HCM and LQTS to guide genetic health professionals working with families who are considering genetic testing. A multi-centre prospective questionnaire-based study was conducted to examine the impact of diagnostic and predictive testing for HCM and LQTS. Understanding of test results, risk perception, motivations for and concerns about testing and psychological impact of result disclosure were examined as well as disclosure of gene test result to relatives. Participants were recruited from four Australian and one British site. Questionnaires were completed before testing and at two weeks and three months post-disclosure. Data from participants who underwent diagnostic testing (n=46, 15-76 years old, 40 (80%) tested positive) were analysed separately to those who had predictive testing (n=77, 14-67 years old, 29 (38%) tested positive). A high proportion of participants from both the diagnostic and predictive gene testing groups were pleased they had testing, recalled their result accurately and in the diagnostic group, understood the implications of their result for their own health and their relatives. In those who had predictive testing, perceptions of the likelihood of developing disease, level of worry, and the number of concerns about LQTS and HCM reported were consistent with gene test result. More than 90% of participants in both groups disclosed their gene test results to first‐degree relatives. Concerns about sudden death were evident in participants from both the diagnostic and predictive group, confirming anecdotal reports from clinical practice. Concerns about the possibility of at-risk relatives inheriting either LQTS or HCM and the unpredictable natural history of both conditions were also common concerns. For the predictive testing group, multivariable linear regression analysis adjusting for baseline psychological scores and potential confounders, and accounting for family clusters demonstrated a higher mean anxiety (p=0.005) and distress (p=0.003) score in gene positive compared to gene negative participants at 2 weeks, but these differences were less apparent at 3 months. There was no difference in depression scores at any time point in those who underwent predictive testing. The same analysis was performed in the diagnostic testing group and there were no statistically significant differences in adjusted mean anxiety, distress and depression scores when comparing participants with gene positive and gene negative results at any time point. Overall, high proportions of participants who underwent diagnostic and predictive testing were pleased to have undergone testing, understood the implications of their result and disclosed their result to relatives. There was no evidence for significant negative psychological sequelae three months after receipt of test result in participants who had either diagnostic or predictive testing. Implications for practice are presented.
-
ItemChildhood pneumonia and hypoxaemia in an urban diarrhoeal hospital, Dhaka, Bangladesh( 2010)The aim of this prospective cohort study was to evaluate clinical and socio-demographic predictors of pneumonia, deaths from pneumonia, and hypoxaemia in children. All under-five children who were admitted to the special care ward of ICDDR,B during September 2007-December 2007 were enrolled. Children sleeping in a bare bed and those having parents/caregivers with poor knowledge were at risk of pneumonia. Children with severe malnutrition, hypoxaemia, or severe sepsis were at higher risk of death. Chest wall-indrawing was the best predictor of hypoxaemia.