In this thesis, four studies on children and adolescents with Down syndrome are described. The first study showed that the number of live births of children with Down syndrome in the Netherlands... Show moreIn this thesis, four studies on children and adolescents with Down syndrome are described. The first study showed that the number of live births of children with Down syndrome in the Netherlands remained stable over the period 1997-2007 on 14.6 per 10,000 births. Of these, 85% were live born. In the second study is observed that growth retardation in children with Down syndrome meanly occurs in three critical periods of growth, resulting in shorter final stature and smaller head circumference than the general Dutch population shows. Furthermore, Dutch children with Down syndrome have alarmingly high prevalence rates of overweight and obesity during childhood and adolescence. The third study showed that eight-year-old children with Down syndrome have an average developmental delay of four years, more often have emotional and behavioral problems, and have a less favorable health-related quality of life (HRQoL) compared with children from the general population. Children with Down syndrome and recurrent respiratory tract infections showed relatively more delayed development. In the fourth study, results showed that adolescents with Down syndrome remain dependent to a large degree and have serious difficulties in functioning socially. Additionally, results showed that serious problem behavior is highly prevalent in adolescents with Down syndrome. Show less
This thesis provides a comparison of mostly perceptual development during vocal learning in songbirds (zebra finches) and human infants. The aim is to disentangle experience dependent and... Show moreThis thesis provides a comparison of mostly perceptual development during vocal learning in songbirds (zebra finches) and human infants. The aim is to disentangle experience dependent and independent processes during vocal learning. In both human infants and juvenile songbirds, a perceptual preference for __universal__ sounds was found, independent of adult auditory input. Later in development, both infants and juvenile songbirds show a change is preference. The juvenile songbirds clearly change their preference towards sounds they have been auditorily exposed to (chapter 3). In human infants in the influence of experience is less clear in this thesis. In combination with previous literature the most likely scenario is a combination of experience dependent and independent processes (chapter 2). To further compare human and birdsong phonology, a __typology__ of zebra finch song elements was performed (chapter 4). The results of this study indicate commonality as well as variation between populations in terms of phonology. In the order of elements within a sequence however, there is little evidence for common patterns across populations and there is variation within and between populations. In summary, this thesis shows similarities in developmental mechanisms in two vocally learning species. There might be a link between development and typology. Show less
In this thesis the evolutionary background, function and localization of the domesticated transposase DAYSLEEPER are described. We found that DAYSLEEPER-like genes can be found in angiosperms, but... Show moreIn this thesis the evolutionary background, function and localization of the domesticated transposase DAYSLEEPER are described. We found that DAYSLEEPER-like genes can be found in angiosperms, but not in lower plants. We also found that DAYSLEEPER interacts with several proteins and is probably involved in regulating protein degradation through involvement in ubiquitin-mediated protein degradation. Show less
Synthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and... Show moreSynthetic glucocorticoids such as dexamethasone are frequently used to enhance pulmonary development in preterm ventilator-dependent infants. In contrast to the short-term benefit on survival and lung maturation, early glucocorticoid exposure has been shown to adversely affect neurodevelopmental processes. Both human and animal studies have reported acute and long-lasting impairments, including shortening of the lifespan in rodents. Therefore, the objective of the studies described in this thesis was to investigate, using an animal model: 1) the short- and long-term consequences of neonatal dexamethasone treatment and 2) the possibility to prevent these effects using pharmacological and behavioural intervention strategies. We reported that systemic dexamethasone treatment acutely affects brain development by suppressing cell proliferation and glial activity. These acute effects on the brain can be partially prevented by central glucocorticoid receptor antagonist pre-treatment, which might serve as a protective strategy against the adverse effects of dexamethasone treatment on the developing brain. Although neonatal dexamethasone exposure clearly affects the developmental trajectory, we did not observe the frequently described detrimental long-lasting consequences of this treatment. We showed that daily handling of the neonate, which was an inevitable component of our experimental design and leads to enhanced levels of maternal care towards the offspring, may compensate for some of the adverse effects of dexamethasone treatment. We conclude that the impact of neonatal glucocorticoid exposure highly depends on interactions with other components of the early environment and is therefore susceptible to pharmacological and behavioural intervention strategies. Show less
This dissertation is a response to an academic and popular discussion that painted a bleak picture of the African state and by extension the endeavour of development cooperation. It focuses on the... Show moreThis dissertation is a response to an academic and popular discussion that painted a bleak picture of the African state and by extension the endeavour of development cooperation. It focuses on the Zambian health sector and the people who create it through their words and deeds. For health workers and their families the sector appears to be an avenue for upward mobility. For politicians it is a platform to further their political careers, while providing access to the resources needed to expand the presence of the state and ensure regime survival. The formal goals of providing quality health care to ordinary citizens appear to be of secondary importance. This insight into the Zambian health sector presents an African state as a dynamic human system undergoing its own historical development. It is different from what policy makers had promised or planned, or how other countries have evolved, but it is not necessarily a story of state failure or collapse. Show less
Schizophrenia is a devastating mental disorder characterized by a hyperactive dopamine system and deregulated stress system. Human studies have suggested that the schizophrenia symptoms precipitate... Show moreSchizophrenia is a devastating mental disorder characterized by a hyperactive dopamine system and deregulated stress system. Human studies have suggested that the schizophrenia symptoms precipitate if a hyperactive dopaminergic genotype interacts with adverse life experiences that activate the stress system. To examine this gene-by-environment interaction, we exposed rats genetically-selected for enhanced apomorphine susceptibility to two stress-provoking life events, poor maternal care early-in-life, and isolation rearing later-in-life. This promoted the development of schizophrenia endophenotypes. Our experiments involved two complementary steps: First, we focused on the immediate endocrine adaptations to maternal separation in common rats. It is known that a single episode of prolonged maternal separation slowly increases corticosterone levels in the neonate rat. We discovered that if the pups had been previously exposed to maternal separation, this rise in corticosterone was abolished, suggesting that the pups had learned to predict the return of the dam. While readily adapting to repeated maternal absence, the pups, surprisingly, stayed alert and displayed a rapid response to an acute stressor. We then investigated whether pup__s stress responsiveness was influenced by the context of maternal separation. It appeared that the experience of being kept in isolation in a novel environment during repeated maternal separation, rather than the maternal absence per se, caused priming of the amygdala fear pathway, with lasting consequences for the responsiveness of the neuroendocrine and behavioral stress system. These endocrine and behavioral alterations, caused by early-life stress experience, consisted of schizophrenia-like phenotypes. Second, we sought to investigate the interplay of such early-life stress experience with schizophrenia genetic predisposition and/or later-life social stress experience. Thus, we were able to test the three-hit (cumulative stress) and the developmental mismatch hypotheses. The former states that exposure to earlylife adversity and later-life psychosocial stressors, superimposed on genetic susceptibility, result in a severe schizophrenia-like phenotype. The latter proposes that experiences early-in-life program the developing brain in preparation for the future. In the case of genetically-predisposed apomorphine susceptible rats (schizophrenia-susceptible), we provide strong evidence for the three-hit hypothesis. In the case of the nongenetically selected Wistar rats, the mismatch hypothesis is supported since the outcome of early-life stress often negatively interacted with the pre-puberty social context. In agreement with the three-hit hypothesis of schizophrenia, we conclude from the current experiments that early-life stress experience in interaction with highly reactive dopaminergic alleles, leads to amygdala priming that, together with additional stressors, precipitate schizophrenia. Show less
The book The United Nations, the Evolution of Global Values and International Law by Otto Spijkers describes how moral values have determined the founding of the United Nations Organization in 1945... Show moreThe book The United Nations, the Evolution of Global Values and International Law by Otto Spijkers describes how moral values have determined the founding of the United Nations Organization in 1945 and the evolution of its purposes, principles and policies since then. A detailed examination of the proceedings of the United Nations Conference on International Organization in San Francisco demonstrates that the drafting of the United Nations Charter was significantly influenced by global moral values, i.e. globally shared beliefs distinguishing right from wrong, good from bad, and the current from a preferable state-of-the-world. A common desire to eradicate war, poverty, inhuman treatment, and to halt the exploitation of peoples, has led to an affirmation of the values of peace and security, social progress and development, human dignity and the self-determination of all peoples. All these values ended up in the UN Charter. The book further analyzes how the United Nations, and especially its General Assembly, has continued to influence the maturing of global morality through contributions to the values-debate, and to the translation of these values into the language of international law, including the law on the use of force, sustainable development, human rights and the right to self-determination. Show less
This thesis shows the final results of a longitudinal project where the same participants (12 to 15 yrs.) were followed for three consecutive years. The first objective of this study was to... Show moreThis thesis shows the final results of a longitudinal project where the same participants (12 to 15 yrs.) were followed for three consecutive years. The first objective of this study was to investigate the development of both quantity and quality of metacognitive skills. The second objective was to establish whether the development of metacognitive skills is intelligence-related or relatively intelligence-independent. Finally, the generality vs. domain-specificity of developing metacognitive skills was investigated. While thinking aloud, participants performed two different tasks representing two different domains: A text-studying task and a problem-solving task. Participants__ intellectual ability was assessed, as well as their metacognitive skills and learning performance for both domains separately. In summary, this thesis has shown that (1) Metacognitive skills do increase spontaneously in frequency and quality during young adolescence, albeit not continuously. The various subscales of metacognitive skillfulness do not develop at the same pace; (2) Metacognitive skills have their own contribution to the prediction of learning performance, on top of intellectual ability. The relation between intellectual ability and metacognitive skills as predictors of learning performance is not affected by development between 12 and 15 yrs.; (3) Around the age of 15 yrs. metacognitive skills become fully general. Show less
It is well known that complex mental abilities develop at least until late adolescence. Yet, there are also skills that children master perfectly, sometimes even better than adults. The goal of... Show moreIt is well known that complex mental abilities develop at least until late adolescence. Yet, there are also skills that children master perfectly, sometimes even better than adults. The goal of this thesis was to learn more about the possibilities of cognitive functioning in children and young adults, and the constraints set by the developing brain. An fMRI training approach was used to examine age- and experience-related effects in the development of working memory and resting-state functional connectivity. More specifically, we studied age differences on task performance and brain activation during a working memory task with various demands and difficulty levels, both before and after 6 weeks of practice with the task. In addition, to learn more about the interaction between different brain regions, we also examined age differences and practice effects on functional connectivity during resting-state. Show less
In this thesis we describe normal and abnormal pulmonary vein development in human and mouse hearts, and focus on the histo(patho)logy of the pulmonary venous and left atrial dorsal wall, in order... Show moreIn this thesis we describe normal and abnormal pulmonary vein development in human and mouse hearts, and focus on the histo(patho)logy of the pulmonary venous and left atrial dorsal wall, in order to elucidate the role of the posterior heart field in the formation and differentiation of the pulmonary venous vessel wall and its possible consequences for the onset of arrhythmias and susceptibility for pulmonary vein stenosis. Another aim of this thesis is that the understanding of normal pulmonary vein development will contribute to the understanding of the development of abnormal pulmonary venous connections and its clinical consequences. Show less
This is the first time developmental outcome following hearing screening in children with permanent childhood hearing impairment was studied in a unique, pseudo-randomized design. We found that... Show moreThis is the first time developmental outcome following hearing screening in children with permanent childhood hearing impairment was studied in a unique, pseudo-randomized design. We found that early detection of hearing loss by newborn hearing screening (and subsequent early intervention) is beneficial for the development of children with permanent childhood hearing impairment, although their development at 3-5 years is not yet comparable to that of children with normal hearing. We showed that the yield of the current hearing screening program is large, but that there is ample room for improvement in the timing following early detection of hearing loss. We would like to emphasize that the aetiology of permanent childhood hearing impairment should be investigated and the cause taken into account when evaluating the development of the child. Show less
School refusal is an attendance problem characterized by a young person’s difficulty in going to school, accompanied by emotional distress on the part of the young person and parental attempts to... Show moreSchool refusal is an attendance problem characterized by a young person’s difficulty in going to school, accompanied by emotional distress on the part of the young person and parental attempts to return the young person to regular school attendance. Prolonged absence from school has serious short- and long-term consequences for young people, their families, and schools. Therefore, effective treatment of school refusal is essential. Numerous treatment outcome studies provide evidence for the efficacy of cognitive-behavioural therapy (CBT) for school refusal. Previous research has however indicated that adolescent school refusers may be particularly disturbed and harder to treat. An existing treatment for school-refusing children and adolescents was modified to better account for the impact of developmental variables on engagement in treatment. The studies presented in this dissertation describe the preparation, implementation, and evaluation of the resulting developmentally-appropriate CBT for adolescent school refusal. The treatment was associated with increased school attendance, reduced emotional symptoms, and increased adolescent and parental self-efficacy. Exploratory analyses revealed that several developmental factors were related to treatment outcomes, namely clinician developmental appropriateness, insight, and autonomy. Recommendations for research and clinical practice are made on the basis of these findings, and on the methodological strengths and limitations of the current research. Show less
The research described in this thesis mainly focussed on making and refining a model that describes axial patterning during gastrulation in the frog Xenopus laevis. Chapter 2 and 3 describe that... Show moreThe research described in this thesis mainly focussed on making and refining a model that describes axial patterning during gastrulation in the frog Xenopus laevis. Chapter 2 and 3 describe that axial information arises in the mesoderm and subsequently in the neurectoderm. Also is shown that this information, under influence of the Spemann organiser and cellular movements, is translated from a time sequence into a space sequence. The function of the Spemann organiser, important for AP patterning is neural induction. In chapter 4 is described that retinoids, important for axial patterning and formed in the mesoderm, have a patterning effect on neurectoderm. An important conclusion in this chapter is that retinoids are candidates for transfer of axial information from mesoderm to neurectoderm and can, in this way, coordinate the expression of axial information between mesoderm and neurectoderm. In chapter 5 a study is described where the transcriptional targets of Hoxc6 or Antennapedia in the frog Xenopus laevis and the fruitfly Drosophila melanogaster are compared. From this comparison conclusions can be drawn about the processes that are important for the function of Hoxc6/Antp. From this study could be concluded that celldivision, cellmigration, and suppresion of head formation are processes that are important for the function of Hoxc6/Antp. Show less
This thesis examines the effect of developmental care in a tertiary NICU in 2 locations in the Netherlands on preterm infants born < 32 weeks gestational age. Following a pilot study with 22... Show moreThis thesis examines the effect of developmental care in a tertiary NICU in 2 locations in the Netherlands on preterm infants born < 32 weeks gestational age. Following a pilot study with 22 preterm infants and their parents, two consecutive randomized controlled trials (n=179, n=164) in which first basic developmental care (use of incubator covers and positioning aids), and then the comprehensive Newborn Individualized Developmental Care and Assessment Program (NIDCAP), an individual approach in which caregiving is based on the behavior of the infant, was studied in preterm infants born < 32 weeks GA. Basic developmental care had no effect on short-term physical and neurological outcomes; a positive effect on psychomotor development at 1 CA, but no effect on neurological and mental development or growth at 1 and 2 years. NIDCAP showed no effect on short-term physical and neurological outcomes as well as no effect on growth, neurological, mental and psychomotor development at 1 and 2 years CA in infants born < 32 weeks, as compared to basic developmental care. Future research should include not only the effect of developmental care in the neonatal centers but also the effect of continuing the intervention once infants are transferred to regional hospitals. Show less
Caecilians, or Gymnophiona, constitute one of the three extant orders of the Recent Amphibia and are the least known, major living tetrapod clade. Compared to frogs and salamanders, caecilians have... Show moreCaecilians, or Gymnophiona, constitute one of the three extant orders of the Recent Amphibia and are the least known, major living tetrapod clade. Compared to frogs and salamanders, caecilians have an unusual skull morphology. Earlier reports of an unusually high number of individual skull ossifications in Hypogeophis rostratus are addressed and found to be erroneous. Changes in skull morphology and myology at metamorphoses are investigated in representatives of all taxa possessing free-living larvae. It is argued that caecilians are derived from gymno- or zygokrotaphic ancestors and that stegokrotaphy evolved within Recent caecilians. The influence of different life-histories on postembryonic skull development was studied in two direct-developing species. The direct-developing Boulengerula taitanus is characterized by very immature hatchlings, which is correlated with an extended period of post-hatching parental care in this species, during which juveniles feed on the modified skin of their mothers. Direct development in caecilians is characterized by ontogenetic repatterning and heterochronic shifts in certain developmental events. The ontogeny of Scolecomorphus kirkii was studied as a representative of a viviparous form. The emerging picture of available published information, together with observations presented here, suggest a previously unsuspected degree of developmental diversity among caecilians. It is further argued that caecilians are lissamphibians with temnospondyl affinities rather than closely related to lepospondyl microsaurs. Show less
Through evolution the social amoebas have developed mechanisms to adapt to environmental changes and ensure survival. This thesis explores the evolutionary origins of cAMP signalling and regulation... Show moreThrough evolution the social amoebas have developed mechanisms to adapt to environmental changes and ensure survival. This thesis explores the evolutionary origins of cAMP signalling and regulation of developmental decisions in the model organism Dictyostelium discoideum. It also shows the first molecular-based phylogeny of the Dictyostelids. Development in Dictyostelium is characterized by the formation of a multicellular structure, the fruiting body, with a well-defined temporal and spatial pattern. cAMP, normally used as intracellular second messenger, in Dictyostelium is used also as an extracellular signal (chemoattractant) to mediate cell movement and cell differentiation. The study of the different components that control the formation of a multicellular fruiting body at a molecular level and from an evolutionary perspective shows that extracellular cAMP signalling was originally developed to control fruiting body morphogenesis. Furthermore it reinforces the idea that Dictyostelium is a simple but yet robust model to study the origins of multicellularity. Do to cAMP being so prevalent in Dictyostelium development I have studied the regulation of cAMP production during particular developmental stages showing in this thesis novel roles for the adenylyl cyclases that produce cAMP and their specific patters of expression during development. A thorough pharmacological analysis of these enzymes is also present in this work. Show less
An adverse early life event is considered a risk factor for stress-related psychiatric disorders in genetically predisposed individuals, probably because of its lasting effect on susceptibility to... Show moreAn adverse early life event is considered a risk factor for stress-related psychiatric disorders in genetically predisposed individuals, probably because of its lasting effect on susceptibility to stress. The objective of this thesis research was to examine in the mouse CD1 strain the immediate and permanent effects of an adverse early experience on the neuroendocrine stress system. For this purpose the hypothalamic-pituitary-adrenal (HPA) axis was examined of mouse pups that were refrained from maternal care, a laboratory model for neglect mimicking aspects of abuse. The data show that the infants__ stress response system readily adapts to daily repeated 8 hours of maternal separation, but that it continues to respond to a novelty stressor. The rapid adaptation to repeated maternal absence seems rather due to the ability to predict return of the mother than to adjust metabolism to episodic food deprivation. If maternal separation was extended to a single episode of 24 hours the immediate outcome was more profound but transient, although subtle effects on stress reactions and cognitive performance did persist. The findings demonstrate the amazing plasticity of the newborn brain and provide a basis to study the mechanistic underpinning of vulnerability or resilience to psychopathology. Show less
Multiple processes are influenced by a protein family named the function of Mitogen Activated Protein Kinases (MAPK), where among tissue morphogenesis, cell-proliferation, cell-differentiation,... Show moreMultiple processes are influenced by a protein family named the function of Mitogen Activated Protein Kinases (MAPK), where among tissue morphogenesis, cell-proliferation, cell-differentiation, cell-survival and immune reactions. A consequence of this broad role of these proteins is that disturbed MAPK signaling possibly leads to severe affects, and could even lead to the development of a disease or disturb embryogenesis. The human genome encodes for 14 mapk genes. One of the best characterized MAPK signaling transductions pathways is the Extracellular signal Regulated Kinase 1 and 2 (ERK1/ERK2). The zebrafish is a relatively new, genetic accessible model organism, which is because of their transparency of the embryos, very suitable to study the role of the MAPKs in embryonic development. The study described in this thesis shows that the zebrafish genome encodes for the same mapk genes, which makes it possible to study the functions of these proteins, using the zebrafish. Further investigations to the roles of ERK1 and ERK2 during embryonic development led to the new insight that ERK1 and ERK2 have distinct roles during crucial developmental cell migration processes and the differentiation of tissues and cell types. In addition, it was found that ERK1 and ERK2 affect the expression of common as well as distinct target genes. Show less
Family businesses are experiencing a revival in the German economy. In the face of the challenges of globalization and the ongoing relocation of production facilities, home base oriented... Show moreFamily businesses are experiencing a revival in the German economy. In the face of the challenges of globalization and the ongoing relocation of production facilities, home base oriented enterprises meet with increasing attention and gain in importance. Family-owned enterprises have indeed been neglected in the past, a fact which shows clearly also in business economics research. But this was also due to the family businesses, or the owner families, respectively, failing to open up. In the present paper, the author succeeded in winning high-ranking representatives of producing family businesses as interview partners. The discussions and the subsequent analyses both of the topics discussed and of the theoretical context serve to provide a new and intriguing picture of family-owned enterprises on their international growth path to world market leaders. Show less
