Childhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In... Show moreChildhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In children with obesity and respiratory symptoms the diagnosis of asthma was studied and in children with ADHD dosing regimens. Overtreatment as a consequence of overdiagnosis was frequently observed in children with obesity and asthma and undertreatment due to relative underdosing in the ADHD population with obesity. This highlights the necessity for accurate diagnostic processes alongside dosing regimens based on pharmacokinetic changes caused by obesity. The focus in the second part of this thesis was on screening for complications of obesity namely insulin resistance and cardiovascular diseases. Given the high prevalence of insulin resistance and the observed changes of cardiovascular parameters, screening on cardiometabolic complications is warranted in all children with obesity. Pharmacological treatment with metformin in addition to lifestyle intervention was studied in the last part of this thesis. Given the favorable effect on BMI in children and adults and the maintenance of weight loss and reduction in progression towards T2DM in adults, metformin can be considered in children with obesity and insulin resistance in addition to lifestyle intervention. Show less
When trying to understand texts, readers engage in various cognitive processes. If all goes well, the engagement in these cognitive processes during reading results in the construction of a... Show moreWhen trying to understand texts, readers engage in various cognitive processes. If all goes well, the engagement in these cognitive processes during reading results in the construction of a coherent mental representation of the text, the essence of successful reading comprehension. To construct such a representation, readers need to monitor the coherence of the text and of their emerging mental representation of what the text is about. The central aim of the empirical studies described is to examine coherence-monitoring processes across development by measuring reader’s ability to detect coherence breaks during reading of narratives. The first part of this dissertation consists of three empirical studies (chapter 2-4). The first study examined whether good and poor comprehenders at age 8-9 and 10-11 detected coherence-breaks during and/or after reading. The second study builds on the first study by examining the protracted development of coherence monitoring in an adolescent population (ages 10-22) using the same task under more challenging circumstances. The third study explored the neural correlates of coherence-break detection in young adults in an fMRI study. The second part of this dissertation consists of two conceptual chapters in which the results are summarized and discussed in a broader theoretical perspective (chapter 5-6). Show less
Special populations are groups of patients that may respond differently to drug treatment due to a variety of factors, such as age or disease. Therefore, in drug development dedicated clinical... Show moreSpecial populations are groups of patients that may respond differently to drug treatment due to a variety of factors, such as age or disease. Therefore, in drug development dedicated clinical studies are often required to determine the optimal dose for these (vulnerable) patient groups. Such studies are complicated by ethical and practical barriers that can hinder the objective of the study when not well designed. To optimise the design of such studies, the application of model-based approaches is essential. In this thesis, we aimed to develop a semi-physiological framework that constitutes a scientific basis for optimisation of study designs in special populations. First, we examined the accuracy of existing approaches in paediatric patients. For the "allometric scaling plus maturation function" approach, the accuracy was shown low especially in young children. An alternative approach was found in the physiological well-stirred-model of hepatic clearance. On this basis, the semi-physiological PK models were developed by interfacing descriptive compartmental pharmacokinetic models with the well-stirred-model of hepatic clearance, and a mechanistic description of plasma-protein binding. The performance of these models was evaluated using two paradigm-drugs (solifenacin and tamsulosin) and was shown successful for the prediction of the pharmacokinetics in paediatric, hepatic-impaired and renal-impaired patients. Show less
Improving survival rates in children and adolescents with malignant bone tumours, paved the way to the application of new surgical extremity-salvage techniques. For the surgical treatment of... Show moreImproving survival rates in children and adolescents with malignant bone tumours, paved the way to the application of new surgical extremity-salvage techniques. For the surgical treatment of malignant bone tumours of the lower extremity, there are a number of resection options (amputation, limb sparing, and rotationplasty) available. Each option has its own indication and after the surgery different advantages and disadvantages. The debate is whether limb-salvage or ablative surgery is advantageous for the individual patient. Purpose of the studies presented in this thesis are evaluate and compare QoL, functional ability and physical activity levels among children and young adults in the first years after bone cancer surgery of the leg. A cross sectional and a prospective study were conducted in the Dutch university bone cancer centres. The results of the cross-sectional study show that outcomes are equivalent for those undergoing limb salvage or ablative surgery. The results of the prospective study showed that; survivors improve in the two years following resection of the bone tumour and the resulting limb-sparing or ablative surgery at all domains evaluated, with the exception of the mental QoL domains. These improvements were most pronounced over the first year after surgery. Show less
This thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis... Show moreThis thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis of potential improvements in risk stratification and possible treatment adaptation, in order to decrease relapse frequency and disease-related death. Firstly, to study the role of chemokine receptor/ligand interactions in the context of extramedullary leukaemia, we analyzed the homing receptor expression on leukemic blast cells in skin or intestine, peripheral blood and bone marrow of patients with T-ALL en AML, respectively. Secondly, the treatment results of 132 children, who received an allogeneic HLA-identical SCT for acute leukaemia was evaluated, showing the effect of biologically effective TBI dose on relapse risk. Thirdly, to optimize the use of Cyclosporin A(CsA) for adequate Graft-versus-host disease(GVHD) prophylaxis and to avoid drug toxicity, we investigated the pharmacokinetics of CsA in children after SCT, and showed that monitoring CsA exposure early after SCT may provide a tool to influence outcome. Finally, to gain a better understanding of the mechanism of chimerism induction of endothelial and epithelial cells following allogeneic SCT, the occurrence of chimerism in relation to the conditioning regimen, time interval after SCT and development of GVHD was studied. Show less
This thesis addressed the physiological impact of fear in 4- and 7-year-old children, induced by media and social fear-inducing tasks (the Trier Social Stress Test for Children). The main question... Show moreThis thesis addressed the physiological impact of fear in 4- and 7-year-old children, induced by media and social fear-inducing tasks (the Trier Social Stress Test for Children). The main question pertained to individual differences in physiological reactivity to fear-inducing stimuli. The possibly relevant factors of attachment security, the child’s temperamental fearfulness, and variations in the serotonin transporter gene (5-HTTLPR; long vs. short allele) were taken into account. Results showed that temperament, attachment, and genetic influences play significant and interactive roles in the expression of fear reactivity. A secure relationship affected the reactivity to media-induced fear stimuli in temperamentally more fearful children but not in less fearful children irrespective of children’s ages. This finding adds to the growing literature showing that children high in negative emotion are more susceptible to positive as well as negative rearing influences. Furthermore, we found evidence that reactivity to the social fear-inducing task was explained by a combination of variations in the serotonin transporter gene and attachment security. Children with a secure attachment representation and two long 5-HTT alleles showed the lowest levels of fear reactivity, indicating that physiological reactivity to a social fear-inducing task is a product of the child’s biology and environment. Show less
