Differences in BMI z-Scores between Offspring of Smoking and Nonsmoking Mothers: A Longitudinal Study of German Children from Birth through 14 Years of Age

BACKGROUND: Children of mothers who smoked during pregnancy have a lower birth weight but have a higher chance to become overweight during childhood. OBJECTIVES: We followed children longitudinally to assess the age when higher body mass index (BMI) z-scores became evident in the children of mothers who smoked during pregnancy, and to evaluate the trajectory of changes until adolescence. METHODS: We pooled data from two German cohort studies that included repeated anthropometric measurements until 14 years of age and information on smoking during pregnancy and other risk factors for overweight. We used longitudinal quantile regression to estimate age-and sex-specific associations between maternal smoking and the 10th, 25th, 50th, 75th, and 90th quantiles of the BMI z-score distribution in study participants from birth through 14 years of age, adjusted for potential confounders. We used additive mixed models to estimate associations with mean BMI z-scores. Results: Mean and median (50th quantile) BMI z-scores at birth were smaller in the children of mothers who smoked during pregnancy compared with children of nonsmoking mothers, but BMI z-scores were significantly associated with maternal smoking beginning at the age of 4-5 years, and differences increased over time. For example, the difference in the median BMI z-score between the daughters of smokers versus nonsmokers was 0.12 (95% CI: 0.01, 0.21) at 5 years, and 0.30 (95% CI: 0.08, 0.39) at 14 years of age. For lower BMI z-score quantiles, the association with smoking was more pronounced in girls, whereas in boys the association was more pronounced for higher BMI z-score quantiles. CONCLUSIONS: A clear difference in BMI z-score (mean and median) between children of smoking and nonsmoking mothers emerged at 4-5 years of age. The shape and size of age-specific effect estimates for maternal smoking during pregnancy varied by age and sex across the BMI z-score distribution

Identification of a novel benzimidazole pyrazolone scaffold that inhibits KDM4 lysine demethylases and reduces proliferation of prostate cancer cells

Human lysine demethylase (KDM) enzymes (KDM1-7) constitute an emerging class of therapeutic targets, with activities that support growth and development of metastatic disease. By interacting with and co-activating the androgen receptor, the KDM4 subfamily (KDM4A-E) promotes aggressive phenotypes of prostate cancer (PCa). Knockdown of KDM4 expression or inhibition of KDM4 enzyme activity reduces the proliferation of PCa cell lines and highlights inhibition of lysine demethylation as a possible therapeutic method for PCa treatment. To address this possibility, we screened the ChemBioNet small molecule library for inhibitors of the human KDM4E isoform and identified several compounds with IC50 values in the low micromolar range. Two hits, validated as active by an orthogonal enzyme-linked immunosorbent assay, displayed moderate selectivity toward the KDM4 subfamily and exhibited antiproliferative effects in cellular models of PCa. These compounds were further characterized by their ability to maintain the transcriptionally silent histone H3 tri-methyl K9 epigenetic mark at subcytotoxic concentrations. Taken together, these efforts identify and validate a hydroxyquinoline scaffold and a novel benzimidazole pyrazolone scaffold as tractable for entry into hit-to-lead chemical optimization campaigns

Overweight in Adolescence Can Be Predicted at Age 6 Years: A CART Analysis in German Cohorts

Objective: To examine, whether overweight in adolescents can be predicted from the body mass index (BMI) category, at the age of 6, the mother's education level and mother's obesity and to quantify the proportion of overweight at the age of 14 that can be explained by these predictors. Method: Pooled data from three German cohorts providing anthropometric and other relevant data to a total of 1 287 children. We used a classification and regression tree (CART) approach to identify the contribution of BMI category at the age of 6 (obese: BMI>97th percentile (P97);overweight: P90P90) at the age of 14. Results: While 4.8% [95% CI: 3.2;7.0] of 651 boys and 4.1% [95% CI: 2.6;6.2] of 636 girls with a BMI= P75. The lowest prevalence was 1.9% [95% CI: 0.8;3.8] in boys with a BMI P97 (similar results for girls). BMI >= P75 at the age of 6 explained 63.5% [95% CI: 51.1;74.5]) and 72.0% [95% CI: 60.4;81.8] of overweight/obesity at the age of 14 in boys and girls, respectively. Conclusions: Overweight/obesity in adolescence can be predicted by BMI category at the age of 6 allowing for parent counselling or risk guided interventions in children with BMI >= P75, who accounted for >2/3 of overweight/obesity in adolescents

Discrimination, labour markets and the Labour Market Prospects of Older Workers: What Can a Legal Case Teach us?

As governments become increasingly concerned about the fiscal implications of the ageing population, labour market policies have sought to encourage mature workers to remain in the labour force. The ‘human capital’ discourses motivating these policies rest on the assumption that older workers armed with motivation and vocational skills will be able to return to fulfilling work. This paper uses the post-redundancy recruitment experiences of former Ansett Airlines flight attendants to develop a critique of these expectations. It suggests that policies to increase older workers’ labour market participation will not succeed while persistent socially constructed age- and gender- typing shape labour demand. The conclusion argues for policies sensitive to the institutional structures that shape employer preferences, the competitive rationality of discriminatory practices, and the irresolvable tension between workers’ human rights and employers’ property rights

Incidence and classification of pediatric diffuse parenchymal lung diseases in Germany

<p>Abstract</p> <p>Background</p> <p>Diffuse parenchymal lung diseases (DPLD) in children represent a rare and heterogeneous group of chronic pulmonary disorders. Despite substantial advances in genetics and pathomechanisms, these often lethal diseases are still under-diagnosed. This is due to the fact that (i) the incidence is low, and (ii) clinical presentation, (iii) disease classification and (iv) specific treatment options are largely unknown.</p> <p>Methods</p> <p>Here we systematically assessed the incidence, the presentation, the diagnostic yield and treatments of pediatric DPLD in Germany, using the Surveillance Unit for Rare Paediatric Disorders (ESPED).</p> <p>Results</p> <p>The incidence of DPLD was 1.32 new cases per 1 million of children per year. The majority of these children were diagnosed within the first year of life. Overall survival was 87%. Using centralized data entry and stratification tools, the patients were categorized into an advanced classification system based on diagnostic algorithms, including clinical presentations, genetics and/or histology. Combining molecular and clinical information, this survey provides an etiological overview and specific diagnostic recommendations for children with DPLD.</p> <p>Conclusions</p> <p>Standardized surveys and systematic classifications are valuable tools for the clinical handling of children with DPLD and aim to improve the disease understanding and the prognosis of these rare detrimental lung diseases.</p

Discovery of Mycobacterium Tuberculosis Protein Tyrosine Phosphatase A (MptpA) Inhibitors Based on Natural Products and a Fragment-Based Approach

Naturally inspired or fragment based. Mcyobacterium tuberculosis has two functional phosphatases, protein tyrosine phosphates A and B (MptpA and B), which are thought to mediate mycobacterial survival in the host. Here we describe the first inhibitors of MptpA (see scheme). Initial hits were identified in screening collections that were inspired by natural products and composed by fragment-based approach

Cyclin-dependent kinase 18 controls trafficking of aquaporin-2 and its abundance through ubiquitin ligase STUB1, which functions as an AKAP

Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure