Dexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there... Show moreDexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there is growing concern about the long-term outcome of this treatment, since follow-up studies of prematurely born infants have shown lasting adverse neurodevelopmental effects. Since the mechanism underlying these neurodevelopmental impairments is largely unknown, the aim of the present study was (i) to investigate the acute effects of neonatal DEX treatment on the developing brain; and (ii) to block specifically the effects of DEX on the brain by central administration of the glucocorticoid receptor (GR) antagonist mifepristone. Long Evans rat pups were injected subcutaneously with tapering doses of DEX or saline (SAL) on postnatal days (pnd) 1, 2 and 3. Separate groups received intracerebroventricular injections with mifepristone prior to DEX treatment. On pnd 4 and 10, pups were sacrificed and brains collected for analysis of cell proliferation (Ki-67) and astrogliosis (GFAP). We report that neonatal DEX treatment reduced hippocampal cell proliferation on pnd 4, an effect that was normalized by pnd 10. Although on pnd 4, GFAP expression was not affected, DEX treatment caused a significant reduction in the number and density of astrocytes in hippocampus and corpus callosum on pnd 10, which was normalized by mifepristone pre-treatment. These acute alterations in the neonate brain might underlie later functional impairments reported in DEX-treated animals and humans and further illustrate the impact of early GR activation on brain development. (C) 2012 Elsevier B.V. All rights reserved. Show less
Claessens, S.E.F.; Daskalakis, N.P.; Oitzl, M.S.; Kloet, E.R. de 2012
Synthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous... Show moreSynthetic glucocorticoids such as dexamethasone (DEX) are used to prevent or treat respiratory disorders in prematurely born infants. Besides the short-term benefit on lung development, numerous human and animal studies have reported adverse neurodevelopmental side effects. In contrast, maternal care is known to exert a positive influence on neurodevelopmental outcome in rodents. The aim of the current study was therefore to investigate whether neonatal handling (days 1-21), known to induce maternal care, might serve as an intervention strategy modulating the adverse effects of DEX treatment (days 1-3). For this purpose we have measured the outcome of these early-life manipulations on development as well as adult endocrine and behavioral phenotype of male rats. Maternal care was observed during the first week of life and indeed enhanced in response to handling. Eye opening was accelerated and body weight reduced in DEX-treated animals. In adulthood, we report that handling ameliorated impaired spatial learning observed in DEX treated non-handled animals in the T-maze. Additionally, handling reduced susceptibility to the impact of DEX treatment in the water maze. Although DEX treatment and handling both resulted in enhanced negative feedback of the stress-induced corticosterone response and both reduced startle reactivity, the acquisition of fear was only reduced by handling, without effect of DEX. Interestingly, handling had a beneficial effect on pre-pulse inhibition, which was diminished after DEX treatment. In conclusion, these findings indicate that handling of the neonate enhances maternal care and attenuates specific DEX-induced alterations in the adult behavioral phenotype. (C) 2012 Elsevier Inc. All rights reserved. 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
Jolles, D.D.; Buchem, M.A. van; Rombouts, S.A.R.B.; Crone, E.A. 2012
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
Human epidemiology and animal studies have convincingly shown the long-lasting impact of early life experiences on the development of individual differences in stress responsiveness in later life.... Show moreHuman epidemiology and animal studies have convincingly shown the long-lasting impact of early life experiences on the development of individual differences in stress responsiveness in later life. The interplay between genes and environment underlies this phenomenon.We provide an overview of studies investigating the impact of early life experiences on the development of individual differences in neuroendocrine stress responsiveness in adulthood and address (1) impact of environment on later stress phenotypes, (2) role of genetic factors in modulating the outcome of environment, and (3) role of nonshared environmental experience in the outcome of gene x environment interplays. We present original findings where we investigated the influence of nonshared experiences in terms of individual differences in maternal care received, on the development of stress phenotype in later life in rats.Environmental influences in early life exert powerful effects on later stress phenotypes, but they do not always lead to expression of diseases. Heterogeneity in response is explained by the role of particular genetic factors in modulating the influence of environment. Nonshared experiences are important in the outcome of gene x environment interplays in humans. We show that nonshared experiences acquired through within-litter variation in maternal care in rats predict the stress phenotype of the offspring.The outcome of early experience is not deterministic and depends on several environmental and genetic factors interacting in an intricate manner to support stress adaptation. The degree of "match" and "mismatch" between early and later life environments predicts resilience and vulnerability to stress-related diseases, respectively. Show less
Al jaren zijn we op zoek naar een hervorming van het kennisbeleid waar de ontwikkelingssector echt iets aan heeft. Hoogleraar Ton Dietz, directeur van het Afrika-Studiecentrum, schreef een manifest... Show moreAl jaren zijn we op zoek naar een hervorming van het kennisbeleid waar de ontwikkelingssector echt iets aan heeft. Hoogleraar Ton Dietz, directeur van het Afrika-Studiecentrum, schreef een manifest met vijf concrete verbeterpunten. Een noodkreet in historisch perspectief. 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
