Estrogen is known to play an important role in longitudinal bone growth and growth plate maturation, but the mechanism by which estrogens exert their effect is not fully understood. In this thesis... Show moreEstrogen is known to play an important role in longitudinal bone growth and growth plate maturation, but the mechanism by which estrogens exert their effect is not fully understood. In this thesis this role is further explored. Chapter 1 contains a general introduction to longitudinal bone growth and the regulation of the growth plate in respect to relevant topics further studied in this thesis. Estrogen can act through a genomic or a nongenomic pathway. Both pathways are explored in rats at the onset of maturation in chapter 2. Estrogen stimulates VEGF expression in uterus and bone, which is an important growth factor for chondrocyte differentiation and chondrocytes survival in the growth plate. In chapter 3 the effect of estrogen on VEGF expression in the growth plate was studied in the rat and human growth plate. Another effect of estrogen is that it accelerates growth plate senescence. Senescence is one of the postulated intrinsic mechanisms by which the growth plate matures and finally fuses. In chapter 4 we investigated senescence in relation to proliferation, by investigating a cell cycle inhibitor p27Kip1. In animal models, catch-up growth is suggested to be caused by delayed growth plate senescence. In chapter 5 this hypothesis was further tested in humans. With puberty estrogen levels increase, the growth plate matures and at the end growth ceases with epiphyseal fusion through mechanisms not yet completely understood. In order to further explore growth plate maturation we subjected two growth plate tissues of the same patient, but with one year and one pubertal Tanner stage in between, to microarray analyses. Gene expression patterns and transcription factor binding sides in relation to pubertal maturation were studied in a longitudinal study within this single patient in chapter 6. In addition, we collected extra prepubertal and pubertal growth plate tissues and studied these samples with microarray techniques as well in chapter 7. In chapter 8 the process of epiphyseal fusion and apoptosis was studied in human growth plates. Animal models are frequently used but not fully representative for the human growth plate. Therefore we investigated a promising human in vitro model with multipotent mesenchymal stem cells (MSCs) that can differentiate into chondrocytes. MSCs can be isolated from various tissues. In chapter 9 we investigated the chondrogenic potential of MSCs from different origins and in chapter 10 we compared this model with the epiphyseal growth plate by analyzing gene expression patterns and pathways with micro-array analyses. Chapter 11 contains general conclusions and a discussion regarding the results. Show less
The content of this thesis is of two sorts: in one part, three topics about the early origins of adult disease are addressed, preceded by three related methodological studies which form the other... Show moreThe content of this thesis is of two sorts: in one part, three topics about the early origins of adult disease are addressed, preceded by three related methodological studies which form the other part. The thesis starts with a systematic review of the literature about the growth of infants born preterm. Next, three specific methodological issues related to early origins of adult disease studies are addressed. A: the most favorable regression model for analyzing and interpreting the effect of both prenatal and subsequent postnatal growth on adult health outcomes. B: the efficiency of reliability studies in the context of a multi-centre study. And C: the correct and clear assessment of reliability in case of log transformed outcomes. These methods are used ind the second part, in which three topics about the effects of prenatal and early postnatal growth on adult health outcomes are addressed, namely: A the association between birth weight and adult renal function in non-premature subjects. B: The association between birth weight and the adult metabolic syndrome, and its separate components in the same population. And finally, C: the association between early growth and adult body composition in subjects born very preterm. 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
Children born small-for-gestational-age (SGA) are at risk for short stature, and cardiovascular disease and type 2 diabetes in later life. There is some preliminary evidence for a similar phenotype... Show moreChildren born small-for-gestational-age (SGA) are at risk for short stature, and cardiovascular disease and type 2 diabetes in later life. There is some preliminary evidence for a similar phenotype in survivors of preterm birth. In contrast to children born SGA, preterm infants born appropriate-for-gestational-age who experienced neonatal growth retardation, resulting in a small size at term, are excluded from growth hormone therapy if they fail to catch up in height subsequently. We tested in 19-year-olds born before 32 gestational weeks from the Project On Preterm and Small-for-gestational-age infants cohort the effect of early growth on the growth pattern and adult metabolic health. Childhood growth and adult height were similar in preterm infants born SGA and those with neonatal growth retardation (weight and/or length at 3 months <-2 SD score). Young adults born preterm had a waist circumference and a waist-to-hip ratio much greater than the population reference mean, especially women. In addition, they showed a tendency towards insulin resistance and a high prevalence of hypertension. These findings were not explained by antenatal glucocorticoid treatment. Carriers of the 23K variant of the R23K polymorphism in the glucocorticoid receptor, associated with a mild glucocorticoid resistance, were less insulin-resistant and showed complete catch-up growth early in infancy and attained height was similar to the population reference mean, whereas stature in non-carriers was on average 0.5 SD below this mean Show less
This thesis describes the results of the Leiden Follow-Up Project on Prematurity (LFUPP): a prospective study in three health regions in the Netherlands, which included all live born infants with... Show moreThis thesis describes the results of the Leiden Follow-Up Project on Prematurity (LFUPP): a prospective study in three health regions in the Netherlands, which included all live born infants with gestational age (GA) <32 weeks, born in 1996/1997. Mortality, neonatal morbidity and the neurological examination as well as mental and psychomotor development according to the BSID I are described until the corrected age of 2 years. Special attention is paid to the infants with GA <27 weeks and the ethics of maintaining these extremely preterm infants. Growth (length, weight and head circumference) until 2 years of age is compared with the Dutch reference group. The influence of preterm growth restraint is compared with the influence of intrauterine growth restriction. The development and respiratory status at 2 years of age in infants with bronchopulmonary dysplasia are described. Finally, a comparison was made between the outcome of 2 cohorts, POPS (1983) and LFUPP (1996/1997) at time of hospital discharge and at 2 years of age. Show less
Growth is a complex process, regulated by multiple external and internal factors. Deviation from the normal growth pattern can be one of the first manifestations of an underlying disorder,... Show moreGrowth is a complex process, regulated by multiple external and internal factors. Deviation from the normal growth pattern can be one of the first manifestations of an underlying disorder, disrupting the normal growth process. The growth hormone __ IGF-I axis plays a key role in regulating this growth process. This thesis focuses on growth disorders as a result of genetic defects in the GH-IGF-I axis. The aim of the thesis is to study the genotype-fenotype relationship in patients with a documented genetic defect in one of the components of the GH-IGF-I axis and to unravel the role of the GH-IGF-I axis in the complex process of growth and development throughout life. Two patients with a mutation in the GH releasing hormone receptor gene demonstrate that combined treatment of GH and gonadotropin-releasing hormone antagonists is very effective in increasing final height. The characteristics of the first male patient with a STAT5b mutation are described in detail. The fenotype of the first patient with an inactivating mutation of the IGF-I gene is described, as well as functional characteristics of the mutation. Finally the consequences of a genetic defect of the IGF-I receptor gene are discussed. Show less
