Common Variations in Endocrine Genes in Relation to Growth and Body Composition: Studies in childhood and adolescence

Growth and changes in body composition during childhood and adolescence are regulated and influenced by multiple factors. Among the well-known important hormonal systems are the growth hormone – insulin-like growth factor I (IGF-1) axis, sex steroids and glucocorticoids. Environmental factors like a safe environment, the absence of disease and sufficient nutritional intake are equally important. Another important factor associated with postnatal growth and body composition is size at birth. The non-environmental factors are more or less inheritable. Variation in genetic background among individuals determines to a large extent phenotypic outcome. Genetic polymorphisms are assumed to play an important role in gene expression and explaining heritability. This thesis describes common variations, polymorphisms, in several endocrine genes in relation to growth and body composition. The studies focus on polymorphisms in the IGF-1 gene, the glucocorticoid receptor (GR) gene, the estrogen receptor ï¡ (ERï¡ or ESR1) gene and the androgen receptor (AR) gene. Most studies were performed in two large cohorts of healthy children and adolescents, who grew up in the same area of the Netherlands, but were born with an interval of approximately 20 years. One study also describes the results of a study in a group of children born small for gestational age (SGA) without catch up growth

An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36

OBJECTIVE: To investigate whether IGF-I promoter polymorphism was associated with birth weight and risk factors for cardiovascular disease (CVD) and type 2 diabetes (T2DM), and whether the birth weight – risk factor relationship was the same for each genotype. DESIGN AND PARTICIPANTS: 264 subjects (mean age 36 years) had data available on birth weight, IGF-I promoter polymorphism genotype, CVD and T2DM risk factors. Student's t-test and regression analyses were applied to analyse differences in birth weight and differences in the birth weight – risk factors relationship between the genotypes. RESULTS: Male variant carriers (VCs) of the IGF-I promoter polymorphism had a 0.2 kg lower birth weight than men with the wild type allele (p = 0.009). Of the risk factors for CVD and T2DM, solely LDL concentration was associated with the genotype for the polymorphism. Most birth weight – risk factor relationships were stronger in the VC subjects; among others the birth weight – systolic blood pressure relationship: 1 kg lower birth weight was related to an 8.0 mmHg higher systolic blood pressure CONCLUSION: The polymorphism in the promoter region of the IGF-I gene is related to birth weight in men only, and to LDL concentration only. Furthermore, the genotype for this polymorphism modified the relationships between birth weight and the risk factors, especially for systolic and diastolic blood pressure

Analysis of miRNA and mRNA Expression Profiles Highlights Alterations in Ionizing Radiation Response of Human Lymphocytes under Modeled Microgravity

BACKGROUND: Ionizing radiation (IR) can be extremely harmful for human cells since an improper DNA-damage response (DDR) to IR can contribute to carcinogenesis initiation. Perturbations in DDR pathway can originate from alteration in the functionality of the microRNA-mediated gene regulation, being microRNAs (miRNAs) small noncoding RNA that act as post-transcriptional regulators of gene expression. In this study we gained insight into the role of miRNAs in the regulation of DDR to IR under microgravity, a condition of weightlessness experienced by astronauts during space missions, which could have a synergistic action on cells, increasing the risk of radiation exposure. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed miRNA expression profile of human peripheral blood lymphocytes (PBL) incubated for 4 and 24 h in normal gravity (1 g) and in modeled microgravity (MMG) during the repair time after irradiation with 0.2 and 2Gy of \u3b3-rays. Our results show that MMG alters miRNA expression signature of irradiated PBL by decreasing the number of radio-responsive miRNAs. Moreover, let-7i*, miR-7, miR-7-1*, miR-27a, miR-144, miR-200a, miR-598, miR-650 are deregulated by the combined action of radiation and MMG. Integrated analyses of miRNA and mRNA expression profiles, carried out on PBL of the same donors, identified significant miRNA-mRNA anti-correlations of DDR pathway. Gene Ontology analysis reports that the biological category of "Response to DNA damage" is enriched when PBL are incubated in 1 g but not in MMG. Moreover, some anti-correlated genes of p53-pathway show a different expression level between 1 g and MMG. Functional validation assays using luciferase reporter constructs confirmed miRNA-mRNA interactions derived from target prediction analyses. CONCLUSIONS/SIGNIFICANCE: On the whole, by integrating the transcriptome and microRNome, we provide evidence that modeled microgravity can affects the DNA-damage response to IR in human PBL

African Linguistics in Central and Eastern Europe, and in the Nordic Countries

Non peer reviewe

Beyond the merchant and the clergyman: assessing moral claims about development cooperation

This article proposes to move beyond the categories of altruism and self-interest in the analyses of the motives for development cooperation. This opposition ignores the inherently moral nature of development policy. The article illustrates the shortcomings of such a perspective by tracing the metaphor of the merchant and the clergyman as archetypical figures shaping Dutch development policy. Through these images the suggestion of an opposition between moral and amoral motives in the history of development has gained a strong foothold within the interplay of scholars, policy makers and public opinion. We go on to assess claims about economy, security, solidarity, prestige and guilt, and ecology, which have been brought forward to legitimise Dutch foreign aid. This analysis calls for research on the dynamics of the transnational exchanges of ideas, interests and expectations, especially during episodes when the moral validity of policy has been explicitly contested

Gender injustice in compensating injury to autonomy in English and Singaporean negligence law

The extent to which English law remedies injury to autonomy (ITA) as a stand-alone actionable damage in negligence is disputed. In this article I argue that the remedy available is not only partial and inconsistent (Keren-Paz in Med Law Rev, 2018) but also gendered and discriminatory against women. I first situate the argument within the broader feminist critique of tort law as failing to appropriately remedy gendered harms, and of law more broadly as undervaluing women’s interest in reproductive autonomy. I then show by reference to English remedies law’s first principles how imposed motherhood cases—Rees v Darlington and its predecessor McFarlane v Tayside Health Board—result in gender injustice when compared with other autonomy cases such as Chester v Afshar and Yearworth v North Bristol NHS Trust: A minor gender-neutral ITA is better remedied than the significant gendered harm of imposing motherhood on the claimant; men’s reproductive autonomy is protected to a greater extent than women’s; women’s reproductive autonomy is protected by an exceptional, derisory award. Worst of all, courts refuse to recognise imposed motherhood as detriment; and the deemed, mansplained, nonpecuniary joys of motherhood are used to offset pecuniary upkeep costs, forcing the claimant into a position she sought to avoid and thus further undermining her autonomy. The recent Singaporean case ACB v Thomson Medical Pte Ltd, awarding compensation for undermining the claimant’s genetic affinity in an IVF wrong-sperm-mix-up demonstrates some improvement in comparison to English law, and some shared gender injustices in the context of reproductive autonomy. ACB’s analysis is oblivious to the nature of reproductive autonomy harm as gendered; and prioritises the father’s interest in having genetic affinity with the baby over a woman’s interest in not having motherhood imposed upon her

High serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) during high-dose GH treatment in short children born small for gestational age.

Contains fulltext : 50261.pdf (publisher's version ) (Open Access)CONTEXT: Epidemiological studies have indicated that high serum levels of GH and IGF-I are associated with long-term risks. OBJECTIVE: The objective of the study was to evaluate the changes in serum levels of GH during overnight profiles, IGF-I, and IGF binding protein 3 (IGFBP-3) in short small for gestational age (SGA) children during GH treatment with two doses. PATIENTS: Thirty-six prepubertal short SGA children were the subjects of this study. Intervention: Subjects received 1 (group A) or 2 (group B) mg GH/m(2).d. MAIN OUTCOME MEASURES: At baseline and after 6 months of GH treatment, overnight GH profiles were performed, and serum IGF-I and IGFBP-3 levels were measured. RESULTS: After 6 months, group B had significantly higher GH levels during the profile (mean, maximum, and area under the curve above zero line) than group A (P < 0.009). In group B, maximum GH levels increased from 43.9-161 mU/liter (P < 0.0002), and in group A, from 57.2-104 mU/liter (P = 0.002). During the profile (i.e. 12 h per day), children of group B had mean GH levels of 64.4 vs. 34.8 mU/liter in group A (P = 0.001). The IGF-I and IGF-I to IGFBP-3 ratio sd scores increased significantly in both groups, but were higher in group B than A [1.5 vs. 0.2 (P = 0.002) and 1.4 vs. 0.3 (P = 0.007), respectively]. In group B, 74% of the children had IGF-I levels in the highest quintile during GH treatment compared with 19% in group A. CONCLUSION: Our study shows that high-dose GH treatment in short SGA children results in high serum GH and IGF-I levels in most children. We recommend monitoring IGF-I levels during GH therapy to ensure that these remain within the normal range

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirt