This thesis explores aspects pertinent to the phenotypic classification of paediatric patients with inflammatory bowel disease (IBD). In the current era it has never been more important to have rigourous phenotypic classification to facilitate genotype-phenotype correlation studies as well as to optimize design of clinical trials of emerging therapies, where frequently response may differ according to phenotype of disease. The first study examined the reliability of the Montreal Classification for classifying paediatric IBD patients. This is the first study exploring the reliability of phenotypic classification in a paediatric population. The reliability of assigning an overall diagnosis of type of IBD was good, but not excellent. Amongst Crohn’s disease patients, reliability of assigning disease behaviour was excellent, while the reliability of assigning disease location categories varied from fair to good. The percentage agreement when describing disease extent for ulcerative colitis was high. The second study described the evolution of disease phenotype in a cohort of paediatric IBD patients. Similar to observations in adult-onset IBD, disease location was found to be relatively stable, while Crohn’s disease behaviour evolves from an inflammatory to a stricturing and/or penetrating phenotype in 20% of patients by 5 years of follow-up. The final study explored the association between 2 polymorphisms in the NOD2 gene with the requirement for intestinal resection (a surrogate marker of complicated disease) in models that included and excluded disease duration. Although no difference was found, this may have been influenced by data quality, which was suboptimal. In conclusion, this thesis has demonstrated that imprecision exists in the phenotyping of paediatric IBD patients, in whom phenotypic characteristics evolve over time. It is pertinent that disease duration be considered in any study attempting to make phenotypic correlations.

No description available.

Doctor of Philosophy(PhD) / The vast majority of children undergoing surgical repair of cardiac lesions do spectacularly well. However a significant proportion, ~ 25%, struggle to progress in the early postoperative period and require additional pharmacological and occasionally mechanical circulatory support. All children typically have some degree of postoperative myocardial dysfunction, with the severe spectrum termed the low cardiac output state (LCOS). LCOS is clinically defined as the requirement for new or escalated inotrope therapy, a widened arteriovenous oxygen difference, cardiac arrest or the need for reinstitution of mechanical circulatory support. LCOS is largely responsible for the morbidity and mortality involved in paediatric cardiac surgery. Despite the predictability of LCOS in the initial postoperative hours, the underlying pathophysiology remains unclear. The period of decline in cardiac function that typifies LCOS is temporally associated with the development of oedema in the tissues of the body, including the heart. This relationship between oedema and dysfunction has increasingly become blurred, with a tendency to elevate the temporal association to a causal link. We sought to explore the causes and contributions to myocardial dysfunction in this setting, including the roles of oedema and ischaemia within the heart. In focusing on oedema and ischaemia we also examined the effects of these insults on relevant myocardial membrane proteins, including those that permit rapid water transport – aquaporins (AQPs), and those involved in membrane mechanics – dystrophin, and membrane repair – dysferlin. Experimental settings which enabled the in vitro dissection of these insults and proteins of interest were combined with a clinically accurate in vivo model. This thesis describes a series of thematically linked experiments that examined LCOS, myocardial oedema and the role of various membrane proteins. We performed isolated cardiomyocyte studies, isolated heart studies as well as a clinically relevant large animal (lamb) cardiopulmonary bypass (CPB) model. Across these models we also explored the role of therapeutically protecting myocardial membranes with Poloxamer 188 (P188) and assessed any influence on myocardial function, oedema and membrane proteins. vi The results from these three models suggest that the clinically accepted dogma of a causative link between myocardial oedema and dysfunction overstates the contribution of myocardial oedema to LCOS. We found that ischaemia/reperfusion was of primary importance in causing myocardial dysfunction. Myocardial oedema without ischaemia had a mild and reversible contribution to myocardial dysfunction, but this was minor in comparison to the gross dysfunction attributable to ischaemia. Isolated cardiomyocytes, with induced oedema, functioned well. Whilst ischaemic cardiomyocytes, with less swelling still had severe contractile dysfunction. Isolated hearts, perfused with an oedema inducing crystalloid perfusate developed myocardial oedema and had minimal reversible systolic and diastolic dysfunction. Isolated hearts which experienced global ischaemia had comparable degrees of myocardial oedema, and significantly greater degrees of myocardial dysfunction that increased in severity with increasing duration of ischaemia. In the lamb CPB model, only those lambs which underwent aortic cross clamping and had a period of ischaemia had poor myocardial function. These lambs also had swollen hearts, raised myocardial AQP1 mRNA and reduced membrane dysferlin protein expression. Membrane dystrophin protein expression was not altered, somewhat unexpectedly with CPB with or without ischaemia. Lambs placed on CPB without ischaemia had good myocardial function, minimal oedema and unchanged membrane protein expression during the survival period. In a blinded lamb CPB trial of P188 there were improved haemodynamics and indicies of myocardial function associated with its use. This was also associated with preservation of dysferlin expression and reduced membrane injury. In parallel isolated heart trials of this therapy, there was a reduction in myocardial oedema associated with its use in non-ischaemic experiments. There was also a suggestion of improved diastolic function in ischaemic experiments, but no change in myocardial water content. In conclusion, we have highlighted the primacy of ischaemia/reperfusion over oedema in contributing to LCOS. We have refuted the accepted dogma that myocardial oedema causes significant dysfunction in itself, with important oedema likely to result from ischaemia. We have shown that AQP1 may be involved in the pathogenesis of the capillary leak syndrome. Finally we have hinted at a role for prophylactic P188 in the vii setting of LCOS, possibly highlighting the role of membrane repair in recovery after surgery. Isolated heart trials of P188 further support a non-rheological mechanism of action and also lend support to the causal separation of myocardial oedema and dysfunction. The integral membrane protein dysferlin, rather than dystrophin, is relevant in the setting of LCOS in the current era.

Doctor of Philosophy(PhD) / The vast majority of children undergoing surgical repair of cardiac lesions do spectacularly well. However a significant proportion, ~ 25%, struggle to progress in the early postoperative period and require additional pharmacological and occasionally mechanical circulatory support. All children typically have some degree of postoperative myocardial dysfunction, with the severe spectrum termed the low cardiac output state (LCOS). LCOS is clinically defined as the requirement for new or escalated inotrope therapy, a widened arteriovenous oxygen difference, cardiac arrest or the need for reinstitution of mechanical circulatory support. LCOS is largely responsible for the morbidity and mortality involved in paediatric cardiac surgery. Despite the predictability of LCOS in the initial postoperative hours, the underlying pathophysiology remains unclear. The period of decline in cardiac function that typifies LCOS is temporally associated with the development of oedema in the tissues of the body, including the heart. This relationship between oedema and dysfunction has increasingly become blurred, with a tendency to elevate the temporal association to a causal link. We sought to explore the causes and contributions to myocardial dysfunction in this setting, including the roles of oedema and ischaemia within the heart. In focusing on oedema and ischaemia we also examined the effects of these insults on relevant myocardial membrane proteins, including those that permit rapid water transport – aquaporins (AQPs), and those involved in membrane mechanics – dystrophin, and membrane repair – dysferlin. Experimental settings which enabled the in vitro dissection of these insults and proteins of interest were combined with a clinically accurate in vivo model. This thesis describes a series of thematically linked experiments that examined LCOS, myocardial oedema and the role of various membrane proteins. We performed isolated cardiomyocyte studies, isolated heart studies as well as a clinically relevant large animal (lamb) cardiopulmonary bypass (CPB) model. Across these models we also explored the role of therapeutically protecting myocardial membranes with Poloxamer 188 (P188) and assessed any influence on myocardial function, oedema and membrane proteins. vi The results from these three models suggest that the clinically accepted dogma of a causative link between myocardial oedema and dysfunction overstates the contribution of myocardial oedema to LCOS. We found that ischaemia/reperfusion was of primary importance in causing myocardial dysfunction. Myocardial oedema without ischaemia had a mild and reversible contribution to myocardial dysfunction, but this was minor in comparison to the gross dysfunction attributable to ischaemia. Isolated cardiomyocytes, with induced oedema, functioned well. Whilst ischaemic cardiomyocytes, with less swelling still had severe contractile dysfunction. Isolated hearts, perfused with an oedema inducing crystalloid perfusate developed myocardial oedema and had minimal reversible systolic and diastolic dysfunction. Isolated hearts which experienced global ischaemia had comparable degrees of myocardial oedema, and significantly greater degrees of myocardial dysfunction that increased in severity with increasing duration of ischaemia. In the lamb CPB model, only those lambs which underwent aortic cross clamping and had a period of ischaemia had poor myocardial function. These lambs also had swollen hearts, raised myocardial AQP1 mRNA and reduced membrane dysferlin protein expression. Membrane dystrophin protein expression was not altered, somewhat unexpectedly with CPB with or without ischaemia. Lambs placed on CPB without ischaemia had good myocardial function, minimal oedema and unchanged membrane protein expression during the survival period. In a blinded lamb CPB trial of P188 there were improved haemodynamics and indicies of myocardial function associated with its use. This was also associated with preservation of dysferlin expression and reduced membrane injury. In parallel isolated heart trials of this therapy, there was a reduction in myocardial oedema associated with its use in non-ischaemic experiments. There was also a suggestion of improved diastolic function in ischaemic experiments, but no change in myocardial water content. In conclusion, we have highlighted the primacy of ischaemia/reperfusion over oedema in contributing to LCOS. We have refuted the accepted dogma that myocardial oedema causes significant dysfunction in itself, with important oedema likely to result from ischaemia. We have shown that AQP1 may be involved in the pathogenesis of the capillary leak syndrome. Finally we have hinted at a role for prophylactic P188 in the vii setting of LCOS, possibly highlighting the role of membrane repair in recovery after surgery. Isolated heart trials of P188 further support a non-rheological mechanism of action and also lend support to the causal separation of myocardial oedema and dysfunction. The integral membrane protein dysferlin, rather than dystrophin, is relevant in the setting of LCOS in the current era.

This thesis examined neuropsychological and psychological outcomes following paediatric traumatic brain injury (TBI). The introductory chapter provides an overview of the paediatric TBI literature, giving definitions of key terms and concepts and providing a description of the epidemiology of childhood head injury. Key models relevant to paediatric TBI are introduced, including developmental neurological, cognitive and psychological perspectives. This is followed by a discussion of factors pertinent to outcome after TBI, followed by a description of outcomes relating to cognitive, behavioural, psychological, adaptive and family functioning domains. Existing research demonstrates that poor outcomes are frequently observed in paediatric TBI populations across these domains and difficulties are persistent over time, particularly where children have sustained severe head injury. Thus, research has turned its focus to the prediction of outcomes which can assist clinicians in the identification of those individuals who will require rehabilitation in order to promote their long-term recovery. Whilst the literature has identified injury and demographic factors that can assist in this process, little attention has been given to the potential utility of psychological screening assessment. Given the prevalence of neuropsychological and psychosocial problems after paediatric TBI and lack of empirical data considering factors predictive of difficulty at the post-acute phase, this research aimed to consider the clinical utility of completing a pre-discharge screening assessment in children and adolescents with TBI. Specific areas of consideration included the potential impact of injury severity on neuropsychological functioning, psychosocial impairment and return to full-time schooling. The study design comprised a prospective case series of 11 children and adolescents with TBI (aged 7-15 years), who were assessed both pre- and post-discharge (3-6 month follow-up). Domains of intellectual, emotional, behavioural, and adaptive functioning, health-related quality of life and parenting stress were assessed at both time-points. Clinically significant findings were demonstrated in domains of neuropsychological and psychosocial functioning, particularly for those with a severe TBI. Specifically, ratings of self-reported emotional distress, and parental perceptions of child health-related quality of life were found to be within clinical ranges at pre- and post-discharge for more than half of the participants. The majority of participants with severe injury required further neuropsychological assessment and interventions relating to emotional and/or behavioural management. The post-discharge functioning of this cohort provided preliminary evidence for the clinical utility of cognitive and psychosocial screening after paediatric TBI. The observed level of clinical need, particularly in the severely-injured group indicated that screening was a useful tool for early identification of difficulties, and provided an opportunity for timely intervention. Without screening, children and adolescents with TBI may be discharged to the community without appropriate support in place; raising long-term concerns for the child, family, and the wider social and economic systems. Despite this, further research which explicates these findings within larger samples is required. The discussion chapter reviews these findings in relation to the wider literature, followed by consideration of this study's limitations. The thesis concludes with a description of the clinical implications of the findings and suggested future directions.

Carta al editor

This collection of studies begins by exploring the development of recognition memory in a group of healthy children and adolescents using experimental memory tests developed as part of this thesis. Various versions of these recognition memory tests were trialled in order to establish age appropriate tests for children aged 6-14 years. In keeping with previous literature in this area, these tests showed relatively stable familiarity memory throughout childhood compared to a steep developmental course for recollection memory. Paediatric brain tumour survivors are known to suffer from significant memory deficits following treatment. However, a clear description of this clinical group’s deficits, in terms of recognition and recall (and therefore also familiarity and recollection), has not previously been established. Using standard clinical memory assessments, the current body of work contributes to this area by characterising this population’s memory deficits as primarily recall-based, particularly when recalling information presented as prose. A sex difference is also noted; with female brain tumour survivors being significantly more impaired than their age-matched male counterparts. This finding is discussed with respect to the differing neural development of males and females. The experimental memory tests developed with normal children were also administered to a group of paediatric brain tumour patients. They were found to have a varied pattern of performance, including auditory recognition impairments but intact visual recognition, even when the test format incorporated similar foils. Associative memory tests revealed impairments in recollection-based recognition; this effect was dependant on the type of information being associated and the length of the encoding-test delay. A learning intervention was developed (and trialled with healthy children), using a method known as the ‘testing effect’, in an attempt to enhance recall of prose at long delays in a group of paediatric brain tumour survivors. Structured repeated retrieval was compared to repeated study for prose passages. This was found, with some patients, to be a successful method of improving recall after a delay of one week. Taken together, the work described in this thesis provides further understanding of recognition memory development in healthy children, novel insights into the residual memory function of paediatric brain tumour survivors and an exciting foundation on which to build a rehabilitation programme for this vulnerable group.

Advancements in the medical field with regard to the development of new techniques, reassessment and analyses of the old and unsatisfactory techniques and the expansion and improvement of acceptable techniques have led to an increase in the use of regional anaesthetic nerve blocks in paediatric patients. However, several regional anaesthetic procedures are currently not being performed by anaesthetists due to the high number of complications and difficulties experienced. Some medical practitioners are under the impression that they lack the knowledge and confidence to perform these regional nerve blocks, especially on neonatal and infant patients. In order to assist these doctors in refining their anatomical knowledge and increasing their confidence in performing these nerve blocks, the procedures which are experienced as problematic need to be identified and evaluated. The aim of this study was therefore: (1) to establish the most efficient method of blocking the maxillary nerve within the pterygopalatine fossa; (2) to investigate which head and neck regional nerve blocks are performed most frequently on paediatric patients and identify problem procedures that are performed by practicing anaesthesiologist in South Africa; (3) to develop a clinical anatomy information base for the selected procedures. Three methods / techniques for maxillary nerve blocks were simulated and compared on 24 dry paediatric skulls and 30 dissected paediatric cadavers. The depth and angles at which the needle travels to block the maxillary nerve in the pterygopalatine fossa, after existing the skull through the foramen rotundum, was measured and compared. The method using the supra-zygomatic approach (method B), from the frontozygomatic angle towards the pterygopalatine fossa, exhibited no statistical significance (p > 0.05) when comparing the measurements in the skulls and cadavers. Method A, a supra-zygomatic approach from the midpoint on the lateral border of the orbit, as well as method C, an infra-zygomatic approach with an entry at the site of a vertical line extending along the lateral orbit wall, showed statistical significance when comparing measurements in the skulls and cadavers. It can therefore be concluded that method B produces the most consistent data and should be tested in a clinical setting. Seventeen commonly performed paediatric regional nerve blocks were identified. A detailed questionnaire was completed by 111 respondents, either electronically or from others attending either the Pain Interventions and Regional Anaesthesia Conference or the South African Society of Anaesthesiologists Conference. Difficulties in performing the regional anaesthetic nerve blocks, and complications encountered, were the main areas of focus, when selecting the four problem procedures. The problem procedures selected are the following: supra-orbital and supra-trochlear nerve blocks, infra-orbital nerve block (Extra-oral approach), superior laryngeal and recurrent laryngeal nerve blocks. A detailed anatomical information base was developed through an extensive literature review. This will aid in educating and facilitating doctors in performing paediatric regional nerve blocks, thereby enabling them to successfully practice medicine. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Anatomy / unrestricted

No description available.

BACKGROUND: Palliative chemotherapy is cancer-directed therapy, which aims at stopping or slowing down the progression of the malignancy even though it may not have any potential for remission or cure. In South Africa, delayed diagnosis of childhood cancer is a common problem for a variety of reasons including lack of health care facilities, transport, information about the disease and delayed presentation due to traditional healer visits or other cultural issues. In patients who present with advanced cancer, or in patients with relapsed cancer without realistic hope of cure, palliative chemotherapy can be offered in an attempt to manage symptoms, improve quality of life and prolong meaningful survival. OBJECTIVES: This research study evaluated South African paediatric oncologists' perspectives and practices regarding the use of chemotherapy in patients with cancer with no realistic hope of cure. The second part of the study described the use of palliative chemotherapy in patients who received treatment at the Steve Biko Academic Hospital Paediatric oncology unit. DESIGN & METHOD: An online survey was conducted among paediatric oncologists in South Africa. The main aims of the questionnaire were to assess paediatric oncologists' considerations around the use of palliative chemotherapy, and then focus on the most recent patients treated with palliative chemotherapy. For the second part of the study, a file review was done of deceased patients who died in the period from January 2012 to December 2018 and who had received palliative chemotherapy as part of their cancer management. We reviewed diagnoses, palliative chemotherapy regimens, timing of initiation and stopping palliative chemotherapy, and whether end of life decisions and discussions were documented. RESULTS: A total of 41 participants completed the survey, giving a response rate of 89%. The majority of the paediatric oncologists were either neutral or agreed that palliative chemotherapy should be considered. The most important treatment aim was to improve quality of life of the patient (92.7% of respondents). The most important considerations when prescribing palliative chemotherapy was to minimise toxicity of the chemotherapy regimen (4.56 mean, SD=0.5 utilising a 5 point scale where 1=not important to 5=very important), and the effectiveness of the chemotherapy (4.37; SD=0.48). Only 19.5% of patients received treatment primarily because parents requested it. According to the oncologists polled, the key considerations were largely achieved in the most recent patient treated with palliative chemotherapy. Individual opinions and preferences concerning recommending palliative chemotherapy differ between paediatric oncologists. Of the 305 patient deaths recorded in the study period, a total of 74 patients had received palliative chemotherapy and were included in the file review. The most common diagnoses were neuroblastoma (18.2%), retinoblastoma (15.6%) and osteosarcoma (14.3%). At the time of diagnosis, the median age of the patients was 6.0 years (range 0.3 to 17.6 years). In 47 patients (63.5%) the disease was deemed incurable at first diagnosis and palliative chemotherapy given from the onset of treatment, while 27 patients (36.5%) were given palliative chemotherapy at relapse. The median time from last palliative chemotherapy to death was 30 days (range 0-742 days). The main documented aim of palliative chemotherapy was to improve symptom control (97.3%) while parents' opinion played an important role in 32.9% of cases. About half of the patients (41 of 74, 55.4%) had documentation of symptomatic improvement. CONCLUSION: Although the overall attitude towards the use of palliative chemotherapy is positive, there is great inter-individual variation between oncologists in opinions and experience. The lack of empirical data to justify recommendations about palliative chemotherapy remains a problem, and the researcher hopes that this study will spark productive discussion and planning towards more structured use of palliative chemotherapy in children with cancer in South Africa. This study shows that many decisions around end of life care and decision-making could be better researched using a quantitative, prospective, interview-based approach. Repeated measurements of the child and family's quality of life and its associations with palliative chemotherapy should be a research priority in future.