The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study

-1 SD) were included in the study. A final group of 13 patients (9 males and 4 females), mean age 23.7 ± 2.9 years (range 20 – 29.7) completed a 2-year treatment with GH. IQ and neuropsychological performance were assessed at pre-treatment (T1) and after one (T2) and two (T3) years. ANOVA was performed with assessment at T1, T2 and T3 as repeated measurements factor. Relations between test score changes and changes of IGF-I levels were determined by calculating the Pearson correlation coefficient. Results Scores on the cognitive tests were in the normal range. Verbal short- and long-term memory performance decreased between T1 and T2, and increased between T2 and T3. Performance at T3 was not significantly different from that at T1. Performance for sustained attention improved from T1 to T2 and from T1 to T3. Visual-spatial memory was improved after one year of GH treatment. A significant positive correlation was found for Δ IGF-I (T2-T1) with difference scores of visual-spatial memory (T2-T1 and T3-T1), indicating that IGF-I increase after one year of GH treatment is associated with increase in cognitive-perceptual performance at month 12 and 24. Conclusion Since the level of intellectual functioning of our patient cohort was in the normal range the present finding that GH treatment has negative effects on verbal memory and positive on attention and visual-spatial memory warrants similar studies in other groups of ALL survivors. Also, a lower dose of GH should be determined inducing as much IGF as needed to improve verbal as well as visual cognitive functions. The present findings indicate that more knowledge is needed before GH treatment may be recommended to enhance cognitive functions in ALL survivors

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

Global and Regional Differences in Brain Anatomy of Young Children Born Small for Gestational Age

In children who are born small for gestational age (SGA), an adverse intrauterine environment has led to underdevelopment of both the body and the brain. The delay in body growth is (partially) restored during the first two years in a majority of these children. In addition to a negative influence on these physical parameters, decreased levels of intelligence and cognitive impairments have been described in children born SGA. In this study, we used magnetic resonance imaging to examine brain anatomy in 4- to 7-year-old SGA children with and without complete bodily catch-up growth and compared them to healthy children born appropriate for gestational age. Our findings demonstrate that these children strongly differ on brain organisation when compared with healthy controls relating to both global and regional anatomical differences. Children born SGA displayed reduced cerebral and cerebellar grey and white matter volumes, smaller volumes of subcortical structures and reduced cortical surface area. Regional differences in prefrontal cortical thickness suggest a different development of the cerebral cortex. SGA children with bodily catch-up growth constitute an intermediate between those children without catch-up growth and healthy controls. Therefore, bodily catch-up growth in children born SGA does not implicate full catch-up growth of the brain

HP1 Recruits Activity-Dependent Neuroprotective Protein to H3K9me3 Marked Pericentromeric Heterochromatin for Silencing of Major Satellite Repeats

H3 lysine 9 trimethylation (H3K9me3) is a histone posttranslational modification (PTM) that has emerged as hallmark of pericentromeric heterochromatin. This constitutive chromatin domain is composed of repetitive DNA elements, whose transcription is differentially regulated. Mammalian cells contain three HP1 proteins, HP1α, HP1β and HP1γ These have been shown to bind to H3K9me3 and are thought to mediate the effects of this histone PTM. However, the mechanisms of HP1 chromatin regulation and the exact functional role at pericentromeric heterochromatin are still unclear. Here, we identify activity-dependent neuroprotective protein (ADNP) as an H3K9me3 associated factor. We show that ADNP does not bind H3K9me3 directly, but that interaction is mediated by all three HP1 isoforms in vitro. However, in cells ADNP localization to areas of pericentromeric heterochromatin is only dependent on HP1α and HP1β. Besides a PGVLL sequence patch we uncovered an ARKS motif within the ADNP homeodomain involved in HP1 dependent H3K9me3 association and localization to pericentromeric heterochromatin. While knockdown of ADNP had no effect on HP1 distribution and heterochromatic histone and DNA modifications, we found ADNP silencing major satellite repeats. Our results identify a novel factor in the translation of H3K9me3 at pericentromeric heterochromatin that regulates transcription

Susceptibility to chronic mucus hypersecretion, a genome wide association study

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations.Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and metaanalysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (&gt;= 20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP).Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25610(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3610 29) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture.Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.</p

The association between medically unexplained physical symptoms and health care use over two years and the influence of depressive and anxiety disorders and personality traits: a longitudinal study

Background Medically unexplained physical symptoms (MUPS) are highly prevalent and are associated with frequent health care use (HCU). MUPS frequently co-occur with psychiatric disorders. With this study we examined the longitudinal association between MUPS and HCU over 2 years and the influence of depressive and anxiety disorders and personality traits on this association. Methods We analysed follow-up data from 2045 to 2981 participants from the Netherlands Study of Depression and Anxiety (NESDA), a multisite cohort study. The study population included participants with a current depressive and/or anxiety disorder, participants with a lifetime risk and/or subthreshold symptoms for depressive and/or anxiety disorders and healthy controls. HCU, measured with the Trimbos and iMTA questionnaire on Costs associated with Psychiatric illness (TIC-P), was operationalized as the number of used medical services and the number of associated contacts. MUPS were measured with the Four Dimensional Symptoms Questionnaire, depressive and anxiety disorders with the Composite International Diagnostic Interview and personality traits with the NEO Five-Factory Inventory. Measurements were taken at baseline, 1 and 2 years follow-up. We used generalized estimating equations (GEE), using HCU at all three measurements as (multivariate) outcome. GEE also takes into account the dependency of observations within participants. Results MUPS were positively associated with HCU over 2 years (medical services: RR 1.020, 95 % CI 1.017–1.022; contacts: RR 1.037, 95 % CI 1.030–1.044). Neuroticism and depression had the strongest influence on the associations. After adjustment for these factors, the associations between MUPS and HCU weakened, but remained significant (services: RR 1.011, 95 % CI 1.008–1.014; contacts: RR 1.023, 95 % CI 1.015–1.032). Conclusions Our results show that MUPS were positively associated with HCU over 2 years, even after adjusting for depressive and anxiety disorders and personality traits