Thesis (Ph. D.)--University of Queensland, 2002. / Includes bibliographical references.

Acute Lymphoblastic Leukemia (ALL) is the most commonly diagnosed malignancy in children (Pui, 2000; Steen & Mirro, 2000; American Cancer Society, 2009; Westlake & Bertolone, 2002). Modern advances in cancer treatment, such as combination chemotherapy (Ettinger, Bond, & Sievers, 2002; Rodman & Reed, 2009), have increased survivorship of ALL to nearly 85% (Westlake & Bertolone, 2002). This new population of ALL survivors is displaying a unique profile of cognitive late effects that are a result of the treatment (e.g. chemotherapy) which while effective in eradicating the disease, has neurotoxic properties (American Cancer Society, 2009). Late effects have been discovered in a variety of cognitive skills, including academic achievement, visual-spatial skills, and processing speed, but the most commonly seen late effects are in the areas of attention and memory (e.g. Askins & Moore, 2008; Cullen, Derrickson, & Potter, 2002; Leigh, 2000). While working memory is a skill that depends on both attention and memory (Baddeley 2000) and is important in both academic performance and life skills (Dark & Benbow, 1991; Geary, Hoard, & Hamson, 1999), it is relatively unstudied in this population. The purpose of this study was to investigate working memory abilities in survivors of pediatric ALL. Working memory skills in this population were compared to both sample and population IQ. Comparisons of verbal and nonverbal working memory and male and female working memory skills were compared as well. First, working memory, as measured by a composite, was not found to be significantly impaired when compared to sample and population mean IQ. However, a single subtest, Digit Span Backward from the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV; Wechsler, 2003), when compared to IQ outside the composite, was found to be significantly below IQ for both the sample and population mean. Second, no gender differences were found for working memory abilities. Finally, there was no difference between nonverbal and verbal working memory performance. While the results were nonsignificant, verbal working memory was worse than nonverbal working memory, which was the opposite of the hypothesized pattern. Implications, recommendations, and limitations of this study are discussed in detail. / text

It is recognised that research in paediatric palliative and complex care is in the early stages. Chapter One examines the available literature of fathering a child with a chronic, life threatening or life limiting illness. The research reviewed supports the notion that fathers are under-represented in paediatric palliative and complex care. The findings highlight that men express their vulnerability in gender specific ways, which has implications for support and service provision. Particular gaps in the research on fathers are highlighted, in relation to the long term impact of fathering a child with life limiting, life threatening, or chronic condition, fathers’ needs in the marital dyad, and studies on the efficacy of father focused interventions. Chapter Two explores health professionals’ experiences of managing boundaries, in the context of paediatric complex and palliative care in the community. The findings indicate that there are a number of issues relating to boundaries that require balancing and which have an impact on service provision and professional wellbeing. Chapter Three is a reflection on the research journey, particularly developing the boundary discussion with regard to ethics. This includes reflections on research in paediatric palliative care, the boundaries of this research, overlaps with clinical practice, and personal and professional learning.

Children with disruptive behaviour disorders include a complex pattern of causation and comorbidity. As such, it is important to identify problems at early stages of development so that intervention can target relevant areas. Computerised assessments and interventions for children with disruptive behaviour disorders offer several advantages over traditional approaches. These include speed, accuracy, engagement, agreeability, and cost. The first chapter of this thesis discusses the utility of five computerised packages that could be used to screen populations for the disorders. It examines issues relating to test administration, reliability, agreeability, cost, and validity and makes appropriate recommendations. The second chapter describes an empirical study, which examined the effectiveness of a computerised token economy system to encourage learning in children with emotional and behavioural difficulties. This study also investigated the role of self-esteem in relation to learning problems and the disruptive behaviour disorders. The final chapter involves a discussion of new frontiers of mental health technology based on personal practice and reflection.

Practical joint dietetic/medical guidelines are required for children with differing levels of severity of chronic renal insufficiency (CRI). This thesis describes the current dietetic/medical package of care provided within a specialised paediatric renal unit, and provides an insight into considerations for future clinical guidelines. Children were grouped at baseline following [51Cr]-labelled EDTA glomerular filtration rate (GFR, m1/min/1.73m2) estimations, into 'normal' kidney function [GFR > 75, mean 106 (SD 19.5), n=58], providing baseline data only, mild (GFR 51-75, n=27), moderate (GFR 25-50, n=21) and severe (GFR < 25, n=19) CRI. Those with CRI were followed for two years and 51 children completed the study (19 mild, 19 moderate, 13 severe CRI). Baseline and 6 monthly measurements of anthropometry, blood pressure, laboratory investigations and yearly dietary intakes (3-day semi-quantitative diaries) were obtained. EDTA GFR's were compared to estimations of GFR using serum cystatin C and plasma creatinine/height concentrations. Amongst the findings, mean standard deviation scores (SDS) for all anthropometric markers deteriorated with worsening renal function at baseline, from mean SDS for weight, height, body mass index and mid upper arm circumference in 'normal' children of O.28 (SD 1.0), 0.19 (SD 1.0),0.21 (SD 1.1) and 0.39 (SD 1.0) respectively, to values of -1.32 (SD 1.0), -1.55 (SD 1.1), -0.44 (SD 1.1) and -0.58 (SD 0.9) in severe CRI. Over two years, mean height SDS significantly increased in children with severe CRI (p=0.003) and was maintained in mild and moderate CRI, despite deterioration in renal function. Correlation between changes in energy intake and height SDS was observed in severe CRI (r2=0.5, p=0.001). From individual observations and correlation, higher phosphate and sodium intakes appeared to be associated with greater deterioration in estimated GFR in children with mild CRI. An inverse correlation between calcium intake and plasma parathyroid hormone was observed in severe CRI (r2=0.27, p=0.065). Disturbances in nutritional intakes, bone biochemistry and growth occurred early in the course of CRI and deterioration in renal function, as determined by estimated GPR, was greatest in those with mild CRI. Regular joint dietetic/medical intervention is likely to be beneficial in children with mild and moderate CRI, in addition to those with more severe CRI, to both correct initial disturbances and reduce the chances of progression.

Unintentional injuries in childhood are a major cause of mortality and morbidity. Numerous risk factors for unintentional injury have been identified over recent years, and there have been several suggestions that injury prevention programmes should be targeted at children identified as high risk, based on these risk factors. There has also been increasing interest in, and emphasis on, the role of members of the primary health care team in preventing unintentional injuries to children, including within recent government policy. There is some evidence, so far, that primary care interventions can be effective in reducing hazards, increasing knowledge and changing behaviour. There is however, less evidence that they can be effective in reducing injury frequency or severity, with very few studies of high quality addressing this issue. The objectives of the research presented in this thesis are: 1.) to examine the relationship between accident and emergency department attendance and future hospital admission following unintentional injury, and to consider the transmission of injury data between secondary and primary care and the uses of such data within primary care; 2.) to examine the associations between risk factors for childhood injury and a variety of injury outcomes and to calculate the sensitivity, specificity and positive predictive value for risk factors in identifying children who will subsequently suffer an unintentional injury, and to consider high risk group and whole population strategies for injury prevention in the light of the findings; 3.) to assess knowledge, attitudes and current practices in childhood injury prevention amongst members of the primary health care team and to consider the implications of the findings for injury prevention in primary care. The first objective has been achieved by a matched case-control study. The main findings were that children who had been admitted to hospital following an unintentional injury were twice as likely to have previously attended the accident and emergency (A&E) department than community controls. However, only one third of hospital admissions had a history of previous A&E department attendance, hence most of the children admitted to hospital would not have been identified using A&E attendance. Current practice in many A&E departments is that a paediatric liaison health visitor notifies the community health visitor of children attending A&E following injury. Most authors in the field discuss post injury follow up visits as an appropriate response to receipt of such notifications, but there is little evidence for their effectiveness, and several studies show such visits are perceived to be difficult for both parents and health visitors. There is little evidence that, at present, injury data transmitted from secondary care is collated in a systematic way, to be used in primary care for needs assessment or injury surveillance. It is therefore recommended that the role of the paediatric liaison health visitor in the collection and transmission of injury data is in need of further consideration, and that post injury follow up visits require further study to demonstrate their effectiveness. The second objective has been achieved by a cross sectional survey followed by a cohort study. The main findings from this study are that only previous injury and male sex were associated with A&E department attendance and only previous injury with primary health care team attendance, despite sufficient power to demonstrate associations for several other risk factors. Consequently the sensitivity and positive predictive value of the risk factors in identifying children who will suffer previous injury was found to be low. The specificity was high for most risk factors, suggesting they will miss most children who will have injuries but will correctly identify most children who will not suffer future injury. The number of children needing to be targeted with an intervention to prevent one injury was similar for most risk factors, and similar to that if the whole population received an intervention. The results could not be adequately explained by bias, confounding or insufficient power Further work examining associations between risk fectors and unintentional injury in childhood is needed with larger sample sizes and in a population with a wide cross section of socioeconomic status to confirm these findings. At present, it is recommended that injury prevention programmes in primary care use a population approach. The third objective was achieved by a cross sectional survey of general practitioners, practice nurses and health visitors in Nottinghamshire. The main findings from this survey were that health visitors had a significantly higher score for knowledge of childhood unintentional injury epidemiology than general practitioners or practice nurses. They held significantly more positive attitudes to, and were undertaking significantly more injury prevention than, both general practitioners and practice nurses. Despite this both general practitioners and practice nurses held positive attitudes to at least some injury prevention activities. The activities most commonly undertaken were those using a preventive model of health education, for all professional groups. Activities involving empowerment or radical or political models of health education were used less often. There was little evidence of a systematic approach to injury prevention, with prevention occurring most often opportunistically. For all activities, and across all professional groups, a greater proportion of respondents agreed that an activity should be undertaken than actually undertook that activity, suggesting there may be barriers to undertaking injury prevention in primary care. The difference between the proportion agreeing an activity should be undertaken and doing so, was greatest for lobbying or campaigning and for collecting injury data. The conclusions from this study are that current injury prevention practice, which often uses a preventive model of health education, often as an isolated approach, and most often opportunistically, may not be the most effective strategy for reducing unintentional injuries in primary care. Further studies are needed to assess the effectiveness of primary health care team interventions offered systematically, using a combination of health education models and approaches. Such studies must address the barriers to injury prevention in primary care. The findings from this study suggest there is already some knowledge, and positive attitudes towards injury prevention, amongst at least some primary health care team members, on which to build interest in such future research. NB. This ethesis has been created by scanning the typescript original and contains some inaccuracies. In case of difficulty, please refer to the original text.

Type I diabetes effects over 16,500 children in the UK. For these young people, care is needed to maintain 'near normal' blood glucose levels in order to relieve the unpleasant symptoms of high and low blood glucose. Although good metabolic control may decrease the risk of severe long term complications, adolescents often have difficulty juggling all the aspects of a complex and demanding treatment regimen, and poor adherence is commonplace. The literature review proposes a theoretical framework for understanding the role of responsibility in the management of type 1 diabetes during adolescence. The pattern of responsibility is explored in relation to the individual and their interpersonal context. In terms of health outcome, the effects of individual and shared responsibility are considered, necessitating a balance between the adolescent's assumption of responsibility and their level of parental involvement. Suggestions for clinical practice are discussed, methodological limitations raised, and future research opportunities identified. The role of dietary self efficacy in predicting self care during adolescence is established. Using data for two distinct phases of adolescence, paper 1 examines whether social support from family and friends makes any additional contribution to the prediction of dietary self care, over and above that of self efficacy. For the younger group (aged 12-13), the prediction of self care is improved by better perceived support from friends. An interactive effect of shared family responsibility is also reported, confirming the importance of shared responsibility, between parent and child, to facilitate good self management as highlighted in the literature review. None of the variables are significant predictors of self care in the older group (14-18 year olds).

Juvenile GM2 gangliosidosis (jGM2) is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase A (Hex A) resulting in GM2 ganglioside accumulation in brain. Like many other lysosomal storage diseases (LSDs), no specific treatment currently exists. In order to establish clinical outcomes for the investigation of potential therapies for jGM2, I collected comprehensive information on the natural history of the condition by studying retrospective and prospectively a cohort of 21 patients with the disease, and reviewing previously published reports of 134 patients. Several symptoms at disease onset, symptom latencies, and the survival curve were described. Genotype-phenotype correlations and neuroradiological findings were also studied. Based on pre-clinical results in animal models, we studied substrate reduction therapy (SRT), with miglustat, in a phase I/II clinical trial to assess its pharmacokinetics (PK), safety, tolerability in infantile and jGM2. Miglustat showed a PK profile similar to the one found in adult patients. The drug was found to be safe and well-tolerated in patients with jGM2, with diarrhea and weight loss being the most common drug-related adverse events. The analysis of efficacy showed that SRT was unable to arrest the full neurological progression of the condition; however, relative stabilization of cognitive function was noted, which was consistent with brain MRI findings. Because of the limited efficacy obtained with SRT, enzyme-enhancement therapy was considered to be an attractive alternative therapy for the late onset forms of GM2 gangliosidosis. Screening of a FDA-approved library of approved therapeutic compounds resulted in the identification of pyrimethamine, as a potential pharmacological chaperone for mutant forms of Hex A. Relative enhancements of enzyme activity and protein levels were observed in patient cells treated with therapeutic concentrations of drug. Applying the same principles, ambroxol was identified as a potential PC for mutant glucocerebrosidase (GCC), the lysosomal enzyme that when deficient causes Gaucher disease (GD). Significant increases of residual mutant GCC were observed in cultured patients cells with type 1 GD. In conclusion, principles developed in the course of studies on jGM2 were shown to be useful for the investigation of novel small-molecule therapies for LSDs, associated with significant neurodegeneration.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Sydney, 2002. / Title from title screen (viewed April 6, 2009). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Veterinary Science. Degree awarded 2002; thesis submitted 2001. Includes bibliographical references. Also available in print form.