Benefits of cooperation among large-scale cohort studies and human biomonitoring projects in environmental health research: An exercise in blood lead analysis of the Environment and Child Health International Birth Cohort Group

A number of prospective cohort studies are ongoing worldwide to investigate the impact of foetal and neonatal exposures to chemical substances on child health. To assess multiple exposure (mixture) effects and low prevalence health outcomes it is useful to pool data from several studies and conduct mega-data-analysis. To discuss a path towards data harmonization, representatives from several large-scale birth cohort studies and a biomonitoring programme formed a collaborative group, the Environment and Child Health International Birth Cohort Group (ECHIBCG). In this study, an intra-laboratory trial was performed to harmonize existing blood lead measurements within the groups' studies. Then, decentralized analyses were conducted in individual countries' laboratories to evaluate blood lead levels (BLL) in each study. The measurements of pooled BLL samples in French, German and three Japanese laboratories resulted in an overall mean blood lead concentration of 8.66 μg l^?1 (95% confidence interval: 8.59–8.72 μg l^?1) with 3.0% relative standard deviation. Except for China's samples, BLL from each study were comparable with mean concentrations below or close to 10 μg l^?1. The decentralized multivariate analyses revealed that all models had coefficients of determination below 0.1. Determinants of BLL were current smoking, age >35 years and overweight or obese status. The three variables were associated with an increase in BLL in each of the five studies, most strongly in France by almost 80% and the weakest effect being in Norway with only 15%; for Japan, with the far largest sample (~18,000), the difference was 36%. This study successfully demonstrated that the laboratory analytical methods were sufficiently similar to allow direct comparison of data and showed that it is possible to harmonize the epidemiological data for joint analysis. This exercise showed the challenges in decentralized data analyses and reinforces the need for data harmonization among studies.     

Effect of vitamin C and iron chelation on diesel exhaust particle and carbon black induced oxidative damage and cell adhesion molecule expression in human endothelial cells

Exposure to particulate matter is associated with oxidative stress and risk of cardiovascular diseases. We investigated if vitamin C and desferrioxamine (iron chelator) altered the levels of oxidative stress and expression of cell adhesion molecules upon exposure to diesel exhaust particles (DEP) and carbon black in cultured human umbilical vein endothelial cells (HUVECs). We found that the particles were only slightly cytotoxic in the high concentration ranges. Particle-induced intracellular reactive oxygen species (ROS) production was attenuated by vitamin C administration or iron chelation and particularly when combined (p < 0.001). Only desferrioxamine protected the DNA from oxidative damage in terms of strand breaks and formamidopyrimidine DNA glycosylase sensitive sites induced by carbon black (p < 0.01). Carbon black and small sized DEP generated from an Euro4 engine increased the surface expression of VCAM-1 and ICAM-1, whereas DEP from an engine representing an old combustion type engine (SRM2975) with larger particles did not affect the expression of cell adhesion molecules. These effects were also attenuated by desferrioxamine but not vitamin C. The study shows that exposure to carbon black and DEP in HUVECs can generate both oxidative stress and expression of cell surface adhesion molecules and that these effects can in part be attenuated by vitamin C and desferrioxamine.     

α7 Nicotinic Acetylcholine Receptor Regulates Airway Epithelium Differentiation by Controlling Basal Cell Proliferation

Airway epithelial basal cells are known to be critical for regenerating injured epithelium and maintaining tissue homeostasis. Recent evidence suggests that the α7 nicotinic acetylcholine receptor (nAChR), which is highly permeable to Ca²⁺, is involved in lung morphogenesis. Here, we have investigated the potential role of the α7 nAChR in the regulation of airway epithelial basal cell proliferation and the differentiation of the human airway epithelium. In vivo during fetal development and in vitro during the regeneration of the human airway epithelium, α7 nAChR expression coincides with epithelium differentiation. Inactivating α7 nAChR function in vitro increases cell proliferation during the initial steps of the epithelium regeneration, leading to epithelial alterations such as basal cell hyperplasia and squamous metaplasia, remodeling observed in many bronchopulmonary diseases. The regeneration of the airway epithelium after injury in α7^−/− mice is delayed and characterized by a transient hyperplasia of basal cells. Moreover, 1-year-old α7^−/− mice more frequently present basal cells hyperplasia. Modulating nAChR function or expression shows that only α7 nAChR, as opposed to heteropentameric α_xβ_y nAChRs, controls the proliferation of human airway epithelial basal cells. These findings suggest that α7 nAChR is a key regulator of the plasticity of the human airway epithelium by controlling basal cell proliferation and differentiation pathway and is involved in airway remodeling during bronchopulmonary diseases.The respiratory epithelium, which is constantly exposed to airborne pollutants, is frequently injured, which results in altered epithelial functions. To restore these functions, the respiratory epithelium must undergo rapid repair via epithelial cell spreading and migration and regenerate its structure via basal cell proliferation and differentiation.¹ These processes are tightly controlled to restore the pseudostratified architecture of the normal mucociliary epithelium. However, in most respiratory diseases, alterations of the regeneration processes induce epithelial remodeling such as hyperplasia, metaplasia, and fibrosis. Understanding the sequence of processes involved in cell proliferation and differentiation is therefore of crucial importance. Both in vivo and in vitro, human airway basal cells are able to proliferate and reconstitute a fully differentiated and functional epithelium.² These cells are such considered as progenitors of the human airway epithelium and important actors of the airway epithelium regeneration.The nonneuronal cholinergic system is thought to be involved in the regulation of cell functions such as cell-cell interaction, apoptosis, and proliferation.³ It is now established that human bronchial epithelial cells contain all of the machinery for the production, storage, secretion, and degradation of acetylcholine, which acts as an autocrine or paracrine hormone.^4,5 Acetylcholine exerts its effects through muscarinic and nicotinic acetylcholine receptors. Nicotinic acetylcholine receptors (nAChRs) are composed of five subunits, arranged as α/β heteromeric or α homomeric nAChRs, and assembled around a central ion channel, mediating the influx of Ca²⁺.⁶ The airway epithelium expresses α3, α4, α5, α7, α9, β2, and β4 subunits for nAChRs.^7,8,9α7 nAChR is characterized by an elevated Ca²⁺ permeability¹⁰ and has been involved in several important biological processes such as cell proliferation, apoptosis, and angiogenesis in cancer.^11,12 Prenatal nicotine exposure significantly increases pulmonary α7 nAChR expression and alters fetal lung development¹³ and subsequently pulmonary function in newborn.¹⁴ In particular, alteration of lung branching morphogenesis induced by nicotine is mediated by α7 nAChR.¹⁵ Altogether, these observations led us to investigate whether the α7 nAChR could be involved in the differentiation of the respiratory epithelium. In the human airway epithelium, we observed α7 nAChR expression in basal cells, which play a critical role in the epithelial regeneration. Both in vivo and in vitro, the α7 nAChR expression is associated with the airway epithelium differentiation. Moreover, in vitro inactivating α7 nAChR or in vivo disrupting genetic α7 nAChR expression induces airway epithelium remodeling by modulating basal cell proliferation. This study thus provides several lines of evidence that α7 nAChR is significant for airway epithelial differentiation and suggests that α7 nAChR is a key regulator of the plasticity of the airway epithelium.     

Running enhances spatial pattern separation in mice

Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of newly born neurons may bolster dentate gyrus-mediated encoding of fine spatial distinctions.     

Effect of the new antiepileptic drug retigabine in a rodent model of mania

Bipolar spectrum disorders are severe chronic mood disorders that are characterized by episodes of mania or hypomania and depression. Because patients with manic symptoms often experience clinical benefit from treatment with anticonvulsant drugs, it was hypothesized that retigabine, a novel compound with anticonvulsant efficacy, may also possess antimanic activity. The amphetamine (AMPH)+chlordiazepoxide (CDP)-induced hyperactivity model has been proposed as a suitable model for studying antimanic-like activity of novel compounds in mice and rats. The aims of the present study in rats were therefore (1) to confirm previous findings with lithium and lamotrigine, and (2) to evaluate the effect of the novel compound retigabine on AMPH+CDP-induced hyperactivity in rats. In all experiments, co-administration of AMPH and CDP induced a significant increase (191-295%) in locomotor activity. Lithium chloride (0.9 mg/kg) and lamotrigine (20 mg/kg), which are known to effectively stabilize mood in humans, both significantly decreased AMPH+CDP-induced locomotor activity without affecting basal locomotor activity. The results furthermore indicate that retigabine, like lithium and lamotrigine, significantly and dose-dependently attenuates the induced hyperactivity at a lowest effective dose of 1.0 mg/kg, whereas basal locomotor activity is reduced only at doses 4.0 mg/kg. In conclusion, retigabine was found to have an antimanic-like effect in the AMPH+CDP-induced hyperactivity model, suggesting a potential role for retigabine in the treatment of mania and possibly in the management of bipolar disorder.     

Etiology and VTE risk factor distribution in patients with inferior vena cava thrombosis

Introduction

Inferior vena cava (IVC) thrombosis is a rare event and data detailing the underlying etiology are scarce.

Materials and methods

Therefore, we reviewed all available cases of IVC thrombosis consecutively registered in the MAISTHRO (MAin-ISar-THROmbosis) database and described the prevalence of VTE risk factors and other conditions contributing to IVC thrombosis development.

Results

53 patients (35 F, 18 M) with IVC thrombosis aged 12 to 79 years were identified. 40 patients (75.5%) developed thrombosis under the age of 45. Local problems, such as IVC anomalies or external venous compression, contributed to the development of thrombosis in 12 cases (22.6%). Lupus anticoagulants (10.9 vs. 2.3%, p = 0.013) and malignoma (17.0 vs. 6.4%, p = 0.023) were more prevalent in IVC thrombosis patients compared to 265 age and sex matched controls with isolated lower extremity DVT. No difference was identified with regard to inherited thrombophilia or other known VTE risk factors. Symptomatic pulmonary embolism (PE) occurred in 32.1% of IVC thrombosis patients compared to 15.2% of controls (p = 0.005).

Conclusions

Local problems such as IVC anomalies and external venous compression, malignancy and the presence of lupus anticoagulants contribute to the risk of IVC thrombosis. The risk of symptomatic pulmonary embolism in the acute setting is high.     

Risk factors and predictors of Torsade de pointes ventricular tachycardia in patients with left ventricular systolic dysfunction receiving Dofetilide

The purpose of this study was to identify risk factors of Torsade de pointes (TdP) ventricular tachycardia in patients medicated with a class III antiarrhythmic drug (dofetilide) and left ventricular systolic dysfunction with heart failure (HF) or recent myocardial infarction (MI). The 2 Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) studies enrolled patients with HF (DIAMOND-HF) or MI (DIAMOND-MI) and left ventricular systolic dysfunction. The present analysis includes only patients treated solely with dofetilide. The incidence of TdP was 2.1% (32 of 1,511). Twenty-five of the incidences occurred in the DIAMOND-HF study and 7 cases in the DIAMOND-MI study (p = 0.0015). TdP was more frequent in women than in men (47% vs 28%, p = 0.02). Risk factors for developing TdP were female gender (odds ratio 2.2, 95% confidence interval [CI] 1.0 to 5.0), MI within 8 weeks (odds ratio 0.3, 95% CI 0.1 to 0.7), being in New York Heart Association class III or IV (odds ratio 3.2, 95% CI 1.2 to 8.6), and baseline QTc duration (odds ratio 1.14, 95% CI 1.00 to 1.30) per 10 ms. Women with chronic HF, QTc duration >400 ms. and New York Heart Association class III or IV had a risk of TdP of 10%, whereas no TdP episodes were observed in patients with QTc duration <400 ms. In conclusion, severity of HF, female gender, and QTc duration make it possible to identify patients with a high risk of early TdP when treated with dofetilide. Patients with recent MI less often had TdP compared with patients with chronic HF.     

Intrauterine growth and infant temperamental difficulties: the Generation R Study

OBJECTIVE: To determine whether intrauterine growth trajectories are associated with temperamental difficulties in infancy. METHOD: The Generation R Study is a population-based cohort study from fetal life onward. Size at different time points during gestation and growth trajectories, calculated on the basis of repeatedly measured fetal growth characteristics, were related to temperamental dimensions, assessed with the Infant Behavior Questionnaire-Revised, in 3,792 infants age 6 months. RESULTS: Birth weight, adjusted for gestational age, was negatively associated with activity level and duration of orienting. These associations disappeared after additional adjustment for maternal height, age, educational level, and national origin. Similarly, the negative associations between intrauterine total body weight gain and falling reactivity and activity level diminished after correction for maternal and child characteristics. After full adjustment, reduced fetal weight gain was only related to prolonged duration of orienting. Children scored 0.38 (95% confidence interval 0.09-0.68) points higher on duration of orienting per SD decrease in total body weight gain from mid-pregnancy to birth. CONCLUSIONS: After controlling for several genetic and socioeconomic status related factors, we found little indication of an association between intrauterine growth trajectories and temperamental difficulties in infants.     

The epsin 4 gene is associated with psychotic disorders in families of Latin American origin

This study attempted to replicate evidence for association of the Epsin 4 gene (which encodes enthoprotin, a protein involved in vesicular transport) to schizophrenia in a new sample of families segregating schizophrenia drawn from the Latin American population. 1,423 subjects (767 with a history of psychosis) from 337 Latino families were genotyped using three single nucleotide polymorphisms (SNPs) spanning the Epsin 4 gene. A family based association test was utilized to test for association of these SNPs to the phenotypes of psychosis and schizophrenia. Haplotypes defined by these three SNPs showed significant association to the phenotype of psychosis in this sample (global p value=0.014, bi-allelic p value=0.047). Variation in the Epsin 4 gene is significantly associated with psychotic disorder in this Latino population. This provides additional support for the involvement of enthoprotin in the pathogenesis of schizophrenia and other psychotic disorders.     

Hodgkin-lymphoma-derived cells show high sensitivity to dactinomycin and paclitaxel

Depending on stage and risk factors, up to 30% of patients with advanced Hodgkin lymphoma (HL) progress or relapse. Patients with pleural effusions have a particularly poor prognosis and this stage of HL is regularly resistant to chemotherapy. All currently available HL cell lines are derived from late stage HL patients. In the present study we measured the sensitivity of these HL lines against the 26 most frequently used cytostatic drugs. We used a novel fluorescent short-term survival assay where the cell was incubated with the drugs for 4 days. The precise number of differentially stained live and dead cells was determined using a custom-built automated laser confocal fluorescent microscope. We found that HL cells, independently of their origin, showed very similar sensitivity patterns for several of the drugs. All HL cell lines were highly sensitive to dactinomycin, paclitaxel and etoposide. Our data suggest that the inclusion of dactinomycin and paclitaxel into chemotherapy protocols against late stage Hodgkin lymphoma with pleural effusion may be justified.