Paediatrics (RCH) - Theses
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ItemThe implementation of new technologies in prenatal testing: implications for service delivery and genetic counselling( 2012)Background: For the last 35 years, women who wanted to have prenatal diagnosis had no choice but to have an invasive procedure with associated miscarriage risks. Most women who chose to have diagnosis did so because of an increased risk of a Down syndrome pregnancy. The test however, called a karyotype, involves searching for any type of chromosome abnormality, not just Down syndrome. New technologies such as chromosome microarray and non-invasive prenatal testing (NIPT), are being introduced that could change the focus of prenatal testing from increased risk of Down syndrome, to increased risks of outcomes for an even wider range of chromosomally abnormal conditions. Aims: 1. To determine the decisions women who had screening for Down syndrome in their current pregnancy would make, if offered safe diagnostic tests for chromosome abnormalities with different types of clinical outcomes. 2. To determine if the underlying beliefs used to make these decisions varied depending on the clinical outcome of the chromosome abnormality. Method: Questionnaires were administered to pregnant women who had a screening test for Down syndrome in their current pregnancy. The methodology and the analysis were based on the Theory of Planned Behaviour. Measurements included their intentions, attitudes, subjective norm (social pressure) and perceived behavioural control (ability to undertake the test) to having a prenatal diagnostic test for one of four conditions: Down syndrome, Klinefelter syndrome, triple X, or mosaic trisomy 20. Results: 381 women completed the main questionnaires. The percentage intending to test varied by condition: 98% for Down syndrome; 78.4% for Klinefelter syndrome; 74.1% for triple X; 87.6% for mosaic trisomy 20. Women’s overall attitude to the test and their perception of social pressure on their decisions, predicted an intention to test, regardless of the condition. There was a difference between the conditions, for the specific beliefs (e.g. having the test provided an opportunity to terminate an affected pregnancy) and specific people that predicted their intention to test. Conclusion: Not all women who have screening tests for Down syndrome want diagnostic testing for conditions with different types of outcome. They make decisions about testing based on different sets of beliefs which depend on the type of outcome. The introduction of new technologies provides the possibility of offering women a choice as to the type of conditions they want diagnosed and this may result in more informed decisions and less anxiety.
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ItemInvestigation of the genetic mechanisms regulating embryonic skeletal development( 2012)Endochondral ossification is the process by which the majority of the bones of the body are formed. It occurs via the differentiation of mesenchymal cells into chondrocytes to produce a cartilage template of the skeleton (chondrogenesis), followed by replacement of cartilage with bone (osteogenesis). This complex process is not completely understood, particularly given the large number of genes of unknown function differentially regulated during chondrogenesis (Cameron, Belluoccio et al. 2009). This project investigated several of these genes, demonstrating the utility of the avian retroviral system for testing the function of candidate skeletal regulator genes in vivo. Kruppel-like factor 2 (Klf2) is a zinc finger transcription factor upregulated 30-fold during chondrogenesis. With known roles in regulating development of the lungs, blood vessels, T-cells and adipocytes, it had not previously been linked to skeletal development. Presented here is the first demonstration of a skeletal regulatory activity for Klf2. Ubiquitous overexpression of Klf2 in chick embryos was able to transform digit identity, alter pelvic girdle morphology, and reduce the length of skeletal elements in the chick limb. Conversely, cartilage-specific Klf2 overexpression elongated skeletal elements, suggesting differential regulation of development by Klf2 when expressed in different tissues. Constitutive activation and repression variants of the gene were also used to explore Klf2 activity in vivo, and indicated that Klf2 functions as a repressor in skeletal development. None of the known patterning and skeletal regulator genes investigated were shown to be altered by Klf2 overexpression. Finally, the expression of two other Kruppel-like family members dynamically expressed during chondrogenesis were examined. Of particular interest, a complementary expression pattern was demonstrated for Klf2 and Klf7 in skeletal tissues, suggesting an importance for Klf7 in regulating skeletal development. A comprehensive understanding of individual gene function in skeletal development is important for understanding normal development, provides possible links to genetic diseases of bone development, and enhances our ability to treat skeletal disease and injury.
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ItemRisk factors for early-onset cervical carcinoma and high grade cervical dysplasia: are there high risk groups that require earlier papanicolau cytology screening and human papillomavirus vaccination?( 2012)International recommendations suggest delayed onset of cervical cytology screening. This may raise concern for perceived high risk women, including sexual abuse victims. However risk for early development of cervical carcinoma (CC) is unknown. This thesis will shed light on virological or environmental risk factors for early onset cervical disease (EOCD: CC, cervical intraepithelial neoplasia 3, adenocarcinoma in situ), in women ≤ 25 years. This could inform cervical screening and human papillomavirus (HPV) vaccination strategies. In Section 1, morphology, survival, HPV genotypes and HPV 16 variants (in E6, E2, L1 genes) in women ≤ 25 years with CC (cases), was compared to women diagnosed >25 years (controls), between 1983-2007. Median age of CC diagnosis in cases was 24 years, with 39% diagnosed at 25 years. Squamous cell carcinoma (SCC) accounted for 61% of cases and adenocarcinoma (AC) 23%, and was not significantly different from controls. Microinvasive cancers were more common in cases. Cases had significantly better survival, however survival advantage was lost for AC or less common morphological types, advanced stage and high grade disease. There was heterogeneity of disease in young women. In cases diagnosed at 25 years, 82% had SCC (representing the beginning of the age-incidence curve for SCC with good prognosis) and 5% had AC; whereas for cases diagnosed ≤ 24 years, 34% had AC with equivalent survival to controls. HPV 18 was more common in cases than controls. In cases with early stage disease, HPV 18 conferred poorer prognosis, compared to non-HPV 18 genotypes. HPV 16 or 18 was found in 88% of cases, suggesting the currently licensed vaccines should, with widespread coverage, be highly efficacious for young people, provided administration prior to infection. The proportion of HPV 16 variants did not differ between groups. European variants accounted for 88% of HPV 16 positive CC in the study population. There was no significant difference in genomic variability between cases and controls for E6, E7, or L1 genes. L1 variants were highly conserved and unlikely to affect HPV vaccine immunogenicity. Controls had a higher proportion of amino acid changes compared to cases, but it is unclear if this confers any protection from rapid-onset disease. In Section 2 a self-administered postal survey was sent to women with EOCD diagnosed from 1983-2007, and matched control groups (including women attending a Well Women’s Clinic [WW]), to estimate risk of EOCD associated with childhood sexual abuse (CSA), unwanted adolescent sexual activity (UASE), sexual, reproductive and lifestyle factors. Cases had higher-risk sexual-reproductive profiles than controls. CSA was experienced in 23% of all participants and associated with known risk factors for CC. Cases with CC (but not insitu disease) had a higher proportion of severe forms of CSA or UASE compared to WW. Median age of penile-genital abuse was 10 years. Findings support vaccination within forensic protocols, identification and earlier vaccination of high-risk youth (wards of the state, institutionalised youth), and continued cervical screening from 18 years in sexual violence victims. This is the first study investigating the effect of sexual violence on EOCD.
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ItemExploration of antenatal β-thalassaemia carrier screening in Victoria, Australia( 2012)Currently there is no coordinated β-thalassaemia carrier screening program carried out in Australia. Unlike other genetic screening programs, this screening has been incorporated into routine healthcare practice. This is attributable to most women undergoing a full blood examination (FBE) at their initial prenatal visit, with a low mean corpuscular volume (MCV) or mean corpuscular haemoglobin (MCH) indicating that they may be a carrier, therefore triggering further β-thalassaemia diagnostic testing. Little is known about the processes currently applied across the different hospitals and practices within Australia to screen women for β-thalassaemia, as well as both women’s and healthcare professionals’ attitudes towards this screening process. To further understand the β-thalassaemia carrier screening process(es) undertaken within Victoria as well as the acceptability of this different approach to carrier screening, a qualitative study was carried out. This aimed to explore carriers’ and health professionals’ experiences of and attitudes towards the β-thalassaemia carrier screening process in Victoria. Semi-structured interviews were carried out with 26 female carriers of β-thalassaemia who had been pregnant within 12 months prior to being interviewed, 10 carrier couples of β-thalassaemia, as well as 23 healthcare professionals who attend to women during the antenatal β-thalassaemia screening process. Data were analysed using inductive content analysis and process mapping. Findings revealed that women had undergone variable experiences while being identified as a carrier, with surprisingly more than half of the participants being made aware of their carrier status prior to pregnancy, at various ages. This was due to women having undergone FBEs for numerous reasons, other than thalassaemia screening specifically. Pre-pregnancy screening was seen to be preferable due to both women and healthcare professionals believing this to be the most suitable time for testing. Other women had only become aware of their carrier status during pregnancy. Variation was also seen amongst the screening processes carried out by the different healthcare professionals, with often little use of guidelines and lack of knowledge, which was often not believed to be ideal by healthcare professionals. This highlights a need for further education of healthcare professionals. Most of the women did not recall being informed about β-thalassemia before notification of their carrier status and therefore did not make a decision about being screened. They were generally satisfied, however, for doctors to make the decisions regarding tests conducted. The women however would have preferred to have been informed about the screening test before it was carried out. Insufficient information was also reported being provided to women after they were notified of their carrier status, leading to misconceptions and confusion. Even though most women did not provide informed consent, this variable thalassaemia carrier screening process incorporated into routine care was seen to be acceptable amongst this community who overall had positive attitudes. A greater emphasis, however, should be placed on information provision, both pre and post testing, as well as further education for healthcare professionals.
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ItemNovel approaches to the immunodiagnosis of childhood tuberculosis( 2012)Approximately one-third of the global population is infected with Mycobacterium tuberculosis (MTB). Despite a number of advances, tuberculosis (TB) remains one of the diagnostically most challenging diseases. For almost a century, the tuberculin skin test (TST) was the only method available to identify latent TB infection (LTBI). However, the TST has variable sensitivity and limited specificity. In 2002, a new generation of immune-based tests, interferon-γ release assays (IGRA), were licensed for clinical use. IGRA rely on the detection of interferon-γ produced by sensitised T cells in response to stimulation with relatively MTB-specific antigens. Since these are absent from all BCG vaccine strains and most non-tuberculous mycobacteria, it is assumed that IGRA have greater specificity than the TST. However, increasing data cast doubt on the performance of IGRA, especially in the paediatric setting. Two constellations are particularly common in children: (a) discordance between TST and IGRA results (ie TST+/IGRA- or-TST-/IGRA+), and (b) indeterminate IGRA results. The underlying basis for discordance remains unknown and it is uncertain which of the test results accurately reflects the true TB infection status. Both indeterminate and discordant IGRA results present a considerable management dilemma in clinical practice. The principle hypothesis of this thesis was that a detailed analysis of mycobacteria-specific cellular immune responses would provide insights into the origins of discordance, and provide important information to enable the development of improved immunoassays for the diagnosis of TB. This thesis begins with a systematic review of the literature on the performance of IGRA in children, highlighting the lack of evidence supporting the hypothesis that prior BCG vaccination and exposure to non-tuberculous mycobacteria are the primary cause of common discordance (TST+/IGRA-). The next chapter describes the development of whole blood assays that enable detailed analyses of mycobacteria-specific immune responses. It also describes the development of a complex multi-colour flow cytometric procedure for simultaneous analysis of major T cell surface markers (CD3, CD4, CD8), T cell memory markers (CD45RA, CCR7) and intracellular cytokines (IFN-γ, IL-2, TNF-α, IL-17), as well as the optimisation of Luminex bead-based cytokine assays used to determine mycobacteria-specific cytokine responses in supernatants. The subsequent chapters describe the results of a clinical study in children at risk of TB infection that used these methods. The data show that individuals with common discordance are a heterogeneous group, comprising both TB-uninfected and TB-infected cases. A number of mycobacteria-specific cytokine responses that have the potential to improve diagnostic assays for TB were identified. Importantly, the results indicate that certain cytokine responses can identify TB infection, and also discriminate between LTBI and active TB. Furthermore, the results show that the proportion of mycobacteria-specific single-positive TNF-α+ CD4+ T cells differs significantly between uninfected children, those with LTBI and those with active TB. The discovery of biomarkers that can simultaneously identify TB infection and determine disease stage is an important breakthrough, as existing immune-based TB tests are unable to distinguish between disease stages. This represents a significant advance in TB diagnostics, with the potential to be developed for use in low-resource settings where better TB tests are needed most.
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ItemThe role of filaggrin in food allergy and eczema in the first year of life( 2012)Eczema and IgE-mediated food allergy often develop early in life and have a substantial impact on the quality of life of a child for many years. Family history is a strong risk factor for the development of allergic disease and the strongest genetic association with eczema to date is the filaggrin gene (FLG), which produces a key structural protein in the epidermis. Eczema, food sensitisation and food allergy commonly co-associate in early childhood. Although many studies have now identified the link between FLG and eczema, to date only one study has looked at the association between FLG and peanut allergy. No other study has investigated whether the presence of FLG mutations increases the risk of developing food allergy in early life. The recent rise in the prevalence of eczema and food allergy has occurred too rapidly to be explained by genetic factors alone, suggesting that environmental factors play a role. However, the rise might only be occurring amongst those genetically at risk. This warrants the investigation of the role of gene-environment interactions, in particular epigenetic regulation, which remains largely unexplored. Within this thesis, I investigated the association of FLG mutations with infantile eczema, food sensitisation and food allergy in one-year-old infants, using samples from the HealthNuts study. HealthNuts is a large population-based cohort study of 5276 infants recruited at 12 months of age in Melbourne, Australia. During recruitment, all infants were examined for eczema and underwent a skin prick test to four common food allergens. Those with a wheal size ≥ 1mm underwent a hospital-based oral food challenge (the gold standard for food allergy diagnosis) and bloods were taken. Non-sensitised infants were randomly invited to clinic to act as negative biological controls. I also investigated the role of DNA methylation in regulating FLG expression and the outcome of allergic disease using a small pilot study and the HealthNuts study. The association of FLG mutations with infantile eczema was replicated in this study, with an odds ratio [OR] of 4.2 (95% CI, 2.0-8.8; P <0.001) for broad definition of eczema; an OR of 2.4 (95% CI, 1.5-4.1; P=0.001) for diagnosed eczema; and OR of 2.0 (95% CI, 1.3-3.3; P=0.003) for current eczema. FLG mutations were associated with atopic eczema (eczema with IgE-mediated food sensitisation) with an OR of 4.4 (95% CI, 2.1-9.6; P< 0.001), but not non-atopic eczema (p=0.984). FLG mutations increased the risk of IgE-mediated food sensitisation in the first year of life, after adjusting for the presence of eczema (adjusted OR [aOR], 3.0; 95% CI, 1.0-8.7; p= 0.043). However, there was no significant difference in FLG mutations when comparing food-tolerant infants with those with food allergy (OR, 0.7; 95% CI, 0.3-1.7; P= 0.478). This indicates that FLG mutations do not further increase the risk of IgE-mediated food allergy over and above that of IgE-mediated food sensitisation. Together these results support the biologically plausible hypothesis that decreased skin barrier function increases the risk of food sensitisation in early life, but other as yet undetermined factors must be important in the conversion from food sensitisation to allergy. FLG was found to be expressed in adult buccal epithelia, ~19% relative to FLG expression in adult skin tissue. FLG expression in infant buccal epithelia was found to be twice as high as those of adult buccal epithelia. Methylation was measured at three CpG sites upstream of FLG transcription start site. However, there was no clear correlation between methylation and FLG expression. Therefore, although associations between FLG methylation and various allergic outcomes were identified, the clinical relevance of these findings is unclear. Nevertheless, this epigenetic study has contributed novel data to add to our understanding of the role of gene-environment interaction involving FLG in allergic disease. In summary, this study has generated evidence for an important role for FLG in the establishment of food sensitisation and food allergy in infants.
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ItemEarly stuttering, temperament and anxiety( 2012)Many stuttering adults and adolescents experience speech-related anxiety. This relationship has not been examined in the preschool population. Given this, it is unknown whether stuttering preschool children also exhibit anxiety traits. Particular temperament traits have been identified as precursors of anxiety. Temperament refers to the way an individual reacts to or interacts with their environment. While the expression of temperament traits is largely genetically determined, it is also influenced by environmental factors. Variations in the expression of temperament traits between individuals are observed as personality traits. Two hypotheses regarding the relationship between temperament and early stuttering have been discussed in the literature. The first is that temperament is associated with the development of stuttering. Certain temperament traits are theorised to influence the onset, development and maintenance of the disorder. The second hypothesis is that temperament differences arise as an effect of stuttering. Stuttering preschool children can experience negative communication interactions. It is therefore possible that those negative interactions may influence the expression of temperament traits, particularly the precursors of anxiety. Further exploration of the relationship between temperament and early stuttering is crucial in order to ascertain which of the above hypotheses is true. Knowledge about the expression of temperament traits is required in order to determine whether stuttering children express temperament traits differently from non-stuttering children as well as to determine whether they have a heightened risk of developing anxiety. This doctoral study was embedded within the Early Language in Victoria Study (ELVS). ELVS has a prospective, longitudinal design. The overall aim of ELVS was to examine the epidemiology and evolution of communication impairments, including stuttering, from infancy through to 7 years. The aim of the present study was to investigate the expression of temperament traits, including the precursors of anxiety, among stuttering children in ELVS. Data were collected with a prospective, longitudinal cohort design. In total, 1444 children were recruited into this study. By 4 years, 173 children had been confirmed as stuttering and 1271 children were assigned to the non-stuttering group. Temperament data were collected using a parent-report scale which was included in annual parent completed questionnaires from 2-4 years. During this time, parents of stuttering participants also completed a stuttering questionnaire at 12 consecutive, monthly home visits, immediately post stuttering onset. At 6 and 7 years, temperament and stuttering behaviour data were collected from stuttering participants in annual parent completed questionnaires. The results from this study revealed little evidence of differences between stuttering and non-stuttering preschool children’s expression of temperament traits, including the precursors of anxiety, up to 4 years. There was little evidence of associations between various stuttering behaviours and the expression of temperament traits amongst stuttering participants. These findings suggest that within this study’s cohort, stuttering children were not at greater risk of developing anxiety compared to non-stuttering children and the range of stuttering characteristics exhibited by stuttering children did not influence the expression of their temperament traits, including the precursors of anxiety.
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ItemCharacterisation of the centromere protein FAM44A in human and mouse cells( 2012)The centromere is responsible for ensuring correct segregation of newly replicated sister chromatids into daughter cells. This structure is found in all eukaryotes ranging from single cell to complex multicellular organisms. Any errors in chromosome segregation, including mutations in proteins that have a role in the assembly of the spindle microtubule attachment site, known as the kinetochore, can result in daughter cells with an abnormal chromosomal number, or aneuploidy. In humans, changes in chromosome number significantly contribute to medical conditions such as spontaneous abortions, infertility and birth disorders (Hassold and Hunt, 2001), and is commonly linked with cancer via changes in copy numbers of oncogenes and tumour-suppressor genes. A novel centromere protein, FAM44A, was identified by the screening of a panel of patient sera with autoimmune antibodies that localise to the centromere. These sera were chosen for their presence of uncommon fragment sizes as visualised by Western blot. One such serum sample was subsequently used to probe a HeLa cDNA phage expression library. The 330 kDa FAM44A protein was identified, and contains the following chromatin domains; AT-hook motif, Cps15 domain, histone deacetylase interaction domain, and proline rich domain. The main aim of this study was to localise and functionally characterise the cell cycle roles of the FAM44A protein in mammalian cells. The cellular localisation of FAM44A using a FAM44A-specific antibody demonstrated that this protein is a centromeric and is present during all the mitotic stages. The functional study used RNAi-mediated down-regulation of FAM44A transcripts, which demonstrated a clear mitotic progression defect where accumulation of the cells at different mitotic stages was observed at 48 and 72 hours post siRNA knockdown. Further, several mitotic defects were observed to include, poor chromosome alignment during metaphase, lagging anaphases and chromatin bridges and an increase in the number of cells with micronuclei. These mitotic defects indicate that this protein plays an important role in the correct segregation of chromosomes during mitosis. Interestingly, further analysis showed most of these aberrant chromosomes and micronuclei were acentric, which suggest that FAM44A could be involved DNA repair, chromatin modification or remodelling processes. The identification and characterisation of FAM44A in this study contributes to the growing list of novel centromere proteins discovered in recent years. From the interesting mitotic phenotype observed, we can anticipate that further in-depth characterisation will fully define FAM44A as an important component of the centromere and chromatin that has multiple functions in the regulation of the cell cycle and chromosome segregation.
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ItemChronic constipation in children and the roles of nuclear transit scintigraphy (NTS) and transcutaneous electrical stimulation (TES) therapy( 2012)Chronic constipation in children is a challenging and difficult problem to manage for clinicians. It has huge psycho-socio-economic impact on the child, parents and the health care system. If left untreated, 1/3 of children will have their symptoms persisting into adulthood, contributing to poor quality of life. There is no standard therapy for the treatment of chronic constipation despite the numerous laxatives available in the market. Various conservative strategies like behavioural therapy, dietary modifications and biofeedback therapy have reported short-term success. Surgery is reserved as the last option for patients with intractable symptoms. Since the introduction of antegrade continence enema (ACE) by Malone in the 1990s, it was considered a less invasive surgical option to treat children with intractable constipation with faecal soiling. Various investigations have been used to characterize the underlying colonic dysmotility in patients suffering from intractable chronic constipation, with the hope of identifying a treatable cause. Ultrasound has a limited role for faecal matter and volume assessment in the rectum. Colonic transit study using scintigraphy (radioisotopes with gamma camera images) has replaced radio-opaque sitz markers (with x-rays) in our hospital, providing better characterization of segmental colonic transit. Wireless capsule motility studies and colonic manometry provide useful information on the underlying colonic dysmotility but are only available at certain centres with research interests. Electrical stimulation is available in two forms: the invasive form involving surgical implantation of electrodes, as in sacral nerve stimulation (SNS), and the noninvasive form involving the use of adhesive electrodes applied over the skin of the abdomen and paraspinal region, as in transcutaneous electrical stimulation (TES). Slow-transit constipation (STC) is a well-recognized cause of chronic constipation in women. The diagnosis of slow-transit constipation [by nuclear transit scintigraphy (NTS)] in children, by contrast, is a new diagnosis and the use of TES to treat STC in children is a novel therapy. However, little was known about 1) the various colonic dysmotility patterns contributing to chronic constipation in childhood, 2) an optimal diagnostic algorithm in children with intractable constipation, 3) targeted therapy for children with chronic constipation if underlying colonic dysmotility is revealed, 4) whether TES is effective in the treatment of childhood STC and its long-term effects, 5) whether TES at home is possible when a clinician is supervising the treatment, and finally 6) whether home TES is effective in the treatment of the commonest form of chronic constipation in children – anorectal retention/functional faecal retention. The aims of this thesis were: (1) to address these questions using clinical information from a database in a tertiary institution, and (2) perform prospective clinical studies using TES to treat children with chronic constipation, and (3) to perform a follow-up study of children treated with TES in a previous randomised controlled trial. In Chapter 1, I provide an overview of the literature on the diagnosis and various medical and surgical treatments of children suffering from chronic constipation. Chapters 2-8 are the clinical studies comprising the thesis. In Chapter 2, there is a detailed description on the use of nuclear transit scintigraphy (NTS) to diagnose colonic dysmotility in children with chronic constipation at a tertiary institution. A database of children with chronic constipation investigated by NTS has led to the development of a standardised protocol. The identification of different types of colonic dysmotlity as the potential underlying pathological cause of chronic constipation has changed the management algorithm in these children. This has enabled the treatment to target the likely cause of the chronic constipation in children. I aimed to provide the diagnostic criteria of different colonic transit patterns using the standardised gastro-intestinal transit protocol. Interestingly, in Chapter 3a, the potential use of NTS to identify a new subgroup of children with rapid proximal colonic transit has led to a new treatment strategy in a subgroup of children with chronic constipation. In addition, Chapter 3b illustrates how we can gather useful anatomical information from a physiological study like NTS as it provides information on colonic length. In Chapter 4, I show that NTS has potential monitoring values in children with chronic constipation with NTS produces no change in gastrointestinal transit if the patient symptoms did not improve after treatment. Therefore, any physiological changes identify at the repeat study will indicate the effects of treatment. It has great potential to monitor progression of disease and also to monitor response to treatments. Chapter 5a described the key elements for a successful administration of TES at home. Close regular contacts and appropriate supervision are essential elements for positive outcome of TES. Chapter 5b is a prospective study of home STC to treat children with STC. This study shows that home TES is effective to overcome symptoms in STC children and to improve their quality of life with a small but demonstrable increase in colonic transit measured objectively by NTS. Chapter 6a is a prospective study conducted to establish the long-term effects of TES in STC children previously treated in a separate randomised, controlled trial. This study showed variable responses with long-term effect lasting as long as 3 years in some children. In contrast, Chapter 6b is a retrospective study to assess how the use of TES at a single tertiary institution has affected the role of surgery as a treatment in children with slow-transit constipation. Chapter 7 is a pilot study to examine the role of home TES to treat the commonest form of chronic constipation in children – anorectal retention (AR) or functional faecal retention (FFR). Chapter 8a is a study to examine the effect of upper gastrointestinal dysmotility in children with slow-transit constipation and whether this will affect their response to TES. Excitingly, chapter 8b describes the effect of TES on gastric motility and its possible implications as a non-invasive treatment for delayed gastric emptying or gastroparesis. In chapter 9, I discuss the major conclusions from this study and the implications of this work. The studies comprising this thesis provide the first detailed description of the use of a standardised NTS protocol to diagnose colonic dysmotility in children, changing the algorithm of investigation and management of children with chronic constipation at a tertiary institute. The use of home TES to overcome chronic constipation in children offers a promising and non-invasive treatment option without surgery in treatment-resistant cases. Moreover, the exciting finding of TES affecting gastric motility will form the ground for future studies in investigating its role as a non-invasive treatment option for patients with intractable upper gastrointestinal tract symptoms.
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ItemCerebral palsy in Victoria: a population-based study( 2012)BACKGROUND AND AIMS: This thesis reports an exploration of the epidemiology of cerebral palsy in Victoria and a comparison of Victorian data with data from other populations. Each of six broad aims related to a particular area of investigation and thesis chapter. The aims were to describe 1) the frequency of cerebral palsy in Victoria, 2) overall temporal trends and by gestational age group, 3) clinical characteristics, including motor type, topographical pattern, and motor severity, 4) accompanying disorders and impairments, 5) neuroimaging patterns and their relationship to perinatal variables and clinical characteristics, and 6) survival. METHODS: The Victorian Cerebral Palsy Register was used to extract data on individuals born in Victoria with non-postneonatally acquired cerebral palsy based on specific criteria for each chapter. A systematic review of the literature was also undertaken to enable comparison of classification, definitions, and epidemiological data with the Victorian data. RESULTS: The decade-specific prevalence of cerebral palsy in Victoria was 1.6 per 1000 live births for the 1980s, 1.8 for the 1990s and 1.7 for 2000-2004. In comparison, the range of prevalence estimates from 33 surveillance systems was 1.8-4.0 per 1000 for 1990s birth cohorts and 1.2-3.0 per 1000 for 1980s cohorts; no methodological or population factors explained the wide variability. The rate of cerebral palsy in Victoria increased during the 1980s and early 1990s, particularly for extremely preterm infants, but also for infants born at term. The data suggest a reversal of this trend from the mid-1990s for both term and extremely preterm infants, a finding observed in other populations. In general, the proportion of cerebral palsy cases with each motor type, topographical pattern, motor severity level, and associated impairment varied widely between surveillance systems, and there was a lack of consensus on definitions and classifications. Victorian data showed a relative increase in mild motor impairment between 1970 and 2003 and an increase in the proportion of cerebral palsy cases with spastic hemiplegia and diplegia relative to spastic quadriplegia; however, no improvement in survival was seen, even for the most severely affected. The most common imaging finding was periventricular white matter injury (PWMI), a pattern associated with spastic diplegia and hemiplegia, and mild-moderate motor impairment. While PWMI was the primary pattern in children born preterm, it was also common in children born at term. Grey matter injuries and malformations were predominantly associated with term birth, and bilateral brain injuries were associated with poor gross motor function. The majority of focal vascular insults and unilateral malformations resulted in spastic hemiplegia. CONCLUSIONS: Through a series of systematic reviews, this thesis has contributed to a better understanding of issues relating to the definition and classification of cerebral palsy and, in particular, emphasised the potential for these to affect estimates of prevalence and distribution of clinical subtypes. In addition, it has resulted in a deeper understanding of clinical, temporal and neuropathological patterns in cerebral palsy and exemplifies the potential benefits of inclusion of MRI data in epidemiological research into a condition with diverse causal networks and clinical manifestations.