Consequences of intrauterine growth restriction for the kidney

Low birth weight due to intrauterine growth restriction is associated with various diseases in adulthood, such as hypertension, cardiovascular disease, insulin resistance and end-stage renal disease. The purpose of this review is to describe the effects of intrauterine growth restriction on the kidney. Nephrogenesis requires a fine balance of many factors that can be disturbed by intrauterine growth restriction, leading to a low nephron endowment. The compensatory hyperfiltration in the remaining nephrons results in glomerular and systemic hypertension. Hyperfiltration is attributed to several factors, including the renin-angiotensin system (RAS), insulin-like growth factor (IGF-I) and nitric oxide. Data from human and animal studies are presented, and suggest a faltering IGF-I and an inhibited RAS in intrauterine growth restriction. Hyperfiltration makes the kidney more vulnerable during additional kidney disease, and is associated with glomerular damage and kidney failure in the long run. Animal studies have provided a possible therapy with blockage of the RAS at an early stage in order to prevent the compensatory glomerular hyperfiltration, but this is far from being applicable to humans. Research is needed to further unravel the effect of intrauterine growth restriction on the kidney

The effect of urbanization on ant abundance and diversity

The aim of the study was to evaluate the effect of continuous and discontinuous growth hormone treatment in Noonan's syndrome (NS) on linear growth and bone maturation. Thirty-seven children with NS aged between 5.4 and 17.5 y were treated with growth hormone (GH) in a dose of 0.15 IU kg)(-1) per day; 23 of these children were randomly assigned to one of 2 groups in a 3 y partly controlled prospective multicentre study. Group A (n = 8) immediately started GH treatment and after 2 y discontinued GH treatment for 1 y; group B (n = 15) served as a control group during the first year and started GH treatment after 1 y. After the 3 y study period, 17 out of the 23 children continued GH treatment. An additional 14 children (group C) were treated according to the same protocol, but without discontinuation of GH treatment. The effect of GH treatment for up to 3 y was evaluated in terms of gain in height standard deviation score (H-SDS) for calendar age and for bone age. Gain in H-SDS over the first year was significantly higher in the GH treatment group (+0.5) than in the non-treated group (+0.0); mean bone maturation was significantly faster in the GH treatment group (1.2 vs 0.5 y/y). Discontinuation in group A in the third study year resulted in catch-down growth (mean deltaH-SDS -0.2). Over 3 y of GH treatment, mean AH-SDS for calendar age was not significantly different between discontinuous (A: +0.8) and continuous treatment (B: +0.8; C: +1.2). Mean gain in H-SDS for bone age in the 3 groups (+0.2, 0.0. +0.3) was minimal after 3 y of GH treatment. CONCLUSION: This study confirmed the gain in H-SDS CA in Noonan's syndrome during long-term GH treatment. However, the accelerating effect of GH on bone maturation seemed to compromise the final height prognosis

Body size in five-year-old twins: Heritability and comparison to singleton standards

The aim of this study is to examine causes of individual differences in height, weight and body mass index (BMI) in 5-year-old children registered with the Netherlands Twin Register. In addition, we examine whether the results of twin studies can be expanded to the singleton population by comparing the data from twins to Dutch reference growth data and by looking at the twins' target height, which was derived from parental height. For 2996 5-year-old twin pairs, information on height and weight and on parental height was available. Univariate and bivariate genetic analyses of height and weight and univariate analyses of BMI were conducted. In order to compare the twins to the singleton population, standard deviation scores (SDS) for height, BMI and target height were calculated based on Dutch reference growth charts for the general population from 1997. Genetic influences were an important source of variation in height, weight and BMI and the main source of covariation between height and weight. Additive genetic factors accounted for 69% and 66% of the individual differences in height in boys and girls, respectively. For weight, heritability estimates were 59% in boys and 78% in girls and for BMI 34% and 74%. The influence of common environment on height was 25% and 27%, on weight 24% and 10% and on BMI 44% and 12% in boys and girls. The bivariate model showed a large overlap between the genes influencing height and weight. Genes explain 78% (in boys) and 76% (in girls) of the covariance between weight and height. At the age of 5 years, female twins were as tall as singleton children, while male twins were shorter than singletons. For both boys and girls, however, mean height SDS was 0.6 standard deviation scores below the mean target height. All twins had lower BMI than singletons. Twins grow fairly well compared to singletons, but they grow below their target height. This may be due to the above average height of twin parents

The association between low birth weight and high levels of cholesterol is not due to increased cholesterol synthesis or absorption: analysis in twins

Low birth weight may be associated with high levels of cholesterol in later life through genetic factors that affect both birth weight and cholesterol metabolism. Alterations in cholesterol synthesis and absorption may play an important role in this association. We examined birth weight and plasma ratios of a precursor of cholesterol, lathosterol (an estimate of cholesterol synthesis), and plant sterols, campesterol and �-sitosterol (estimates of cholesterol absorption), to cholesterol in 53 dizygotic and 58 monozygotic adolescent twin pairs. After adjustment for current weight, birth weight was not associated with the ratios of lathosterol, campesterol, and �-sitosterol either in the overall sample [�0.07 �mol/mmol/kg (95 % confidence interval: �0.11 to 0.25), p � 0.5; �0.02 �mol/mmol/kg (�0.33 to 0.37), p � 0.9; and �0.04 �mol/mmol/kg (�0.23 to 0.15), p � 0.8, respec-Low birth weight is associated with an increased risk o

A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period. Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2-3; boys, G2-3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m(2). day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively. During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) 'yr'/yr vs. 1.15 (0.37) 'yr'/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment. Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m(2) seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children. We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment

Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density

Background: Recessive mutations in the leptin receptor (LEPR) are a rare cause of hyperphagia and severe early-onset obesity. To date, the phenotype has only been described in 25 obese children, some of whom also had altered immune function, hypogonadotropic hypogonadism, reduced growth hormone secretion, hypothalamic hypothyroidism or reduced adult height. We provide a detailed description of the phenotype of 2 affected girls to add to this knowledge. Methods: Whole-exome sequencing and targeted sequencing were used to detect the LEPR mutations. RNA analysis was performed to assess the effect of splice-site mutations. Results: In 2 unrelated girls with severe obesity, three novel LEPR mutations were detected. Longitudinal growth data show normal childhood growth, and in the older girl, a normal adult height despite hypogonadotropic hypogonadism and the lack of an obvious pubertal growth spurt. Bone age is remarkably advanced in the younger (prepubertal) girl, and bone mineral density (BMD) is high in both girls, which might be directly or indirectly related to leptin resistance. Conclusion: The spectrum of clinical features of LEPR deficiency may be expanded with increased BMD. Future observations in LEPR-deficient subjects should help further unravel the role of leptin in human bone biology

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes