Invertebrate Cells as Targets for Hazardous Substances

Electron microscopy is an established diagnostic method in pathology of man as well as of vertebrate animals. During the last decade, ultrastructural studies have also been performed in invertebrates to elucidate cellular injuries caused by hazardous substances (BAYNE et al. 1985, MOORE 1985, STORCH 1988, HOPKIN 1989). The interest in invertebrates has increased due to their suitability to monitor environmental pollution. For example field and laboratory studies have been performed using the bivalve Mytilus edulis or the gastropod Littorina littorea as indicator of chemical contamination (AUFFRET 1988, CAJARAVILLE et al. 1989, CAJARAVILLE et al. 1990, MOORE 1988). Additionally, many invertebrates, such as aphids, grasshoppers, caterpillars or slugs are of significance as pest organisms in agriculture. Others, in most cases insects like the Ichneumonidae or Planipennia, are of increasing importance in biological or integrated pest control. In a series of laboratory tests we examined cellular reactions in a variety of invertebrates after exposure to environmentally relevant toxicants, like metals or pesticides. The following animals were selected for their environmental or commercial significance: -the shrimp, Penaeus monodon (Crustacea, Decapoda), as a commercially important aquaculture species which is impaired by environmental toxicants, -the flatworm, Polycelis felina (Turbellaria, Tricladida), a common inhabitant of central European brooks, which is menaced by acid rain and subsequently released aluminium, -the millipede, Cylindroiulus punctatus (Diplopoda, Julida), as an important animal of the soil macrofauna, involved in the decomposition of organic material, -the moss mite, Nothrus silvestris (Acari, Oribatida), as a representative of saprophagous soil animals occurring in high population densities, -the slug, Deroceras reticulatum (Gastropoda, Pulmonata), which is an important pest organism in European agriculture, -and Chrysoperla carnea (Insecta, Planipennia), as a beneficial species used in the biological control of aphids. It was the aim of this study to demonstrate the suitability of electron microscopy for evaluating the effects of hazardous substances on cells of invertebrate tissues

Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.This work was supported by grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014 and SysInflame, grant 01ZX1306A), and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). Further grants were received from the DFG as part of the Sonderforschungsbereich CRC 1123 (B2). T.K. was supported by a DZHK Rotation Grant. I.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001 - Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Proceedings of the 13th annual conference of INEBRIA

CITATION: Watson, R., et al. 2016. Proceedings of the 13th annual conference of INEBRIA. Addiction Science & Clinical Practice, 11:13, doi:10.1186/s13722-016-0062-9.The original publication is available at https://ascpjournal.biomedcentral.comENGLISH SUMMARY : Meeting abstracts.https://ascpjournal.biomedcentral.com/articles/10.1186/s13722-016-0062-9Publisher's versio

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Effects of conventional insecticides and insect growth regulators on fecundity and other life-table parameters of Micromus tasmaniae (Neuroptera: Hemerobiidae)

Effects of 3 conventional insecticides (methyl parathion, azinphos-methyl, cypermethrin) and 3 insect growth regulators (fenoxycarb, diflubenzuron, and tebufenozide) on life-table parameters of Micromus tasmaniae Walker were determined in adults derived from insecticide-treated larvae. The following parameters were compared with the control: sex ratio, longevity, sterility, and fecundity. Power analysis was used to increase the efficiency and the predictability of the life-table test. Diflubenzuron resulted in a higher proportion female lacewings. Longevity was reduced for females emerging from fenoxycarb- and diflubenzurontreated larvae. Total number of eggs was reduced for diflubenzuron- and fenoxycarb-treated lacewings, as well as the following generation oftebufenozide-exposed lacewings. Daily number of eggs was reduced for the diflubenzuron treatment. Peak egg production was increased for lacewings exposed to azinphos-methyl and was decreased for the following generation of tebufenozide-exposed lacewings. Diflubenzuron treatment resulted in an extended preoviposition period. Oviposition periods were reduced for lacewings treated with fenoxycarb, diflubenzuron or azinphos-methyl as well as for the following generation of the tebufenozide treatment. The time to peak egg production was similar for all treatments. Methyl parathion, cypermethrin, and tebufenozide treatments showed no differences in any of the tested life-table parameters in the 1st generation. In summary, the insect growth regulators fenoxycarb and diflubenzuron had a more severe impact on life-table parameters than the 2 organophosphates and the pyrethroid. In future research, increased attention should be paid to long-term (e.g., the following generation) effects on life-table parameters

Protective mental health factors in children of parents with alcohol and drug use disorders: A systematic review

<div><p>Children of parents with drug and alcohol use disorders often grow up under severe stress and are at greater risk of developing psychological and social problems. However, a substantial proportion of affected children adapt to their distressing life conditions and show positive development in terms of their mental health. These children are described as resilient. One difference between resilient and maladapted children is the presence of protective factors. The aim of this systematic review is to provide an overview of the current state of the research concerning protective mental health factors in children of parents with alcohol or drug use disorders (COPAD). For that purpose, the PsychInfo, PubMed, CINAHL and ISI Web of Science databases were searched through January 2017. All the identified publications were screened using previously developed inclusion criteria. The search yielded 3,402 articles. Eleven of these publications (2003–2013) met the criteria for inclusion in the present review. Information on the studies was extracted using an extraction form. A narrative analysis was performed, and the methodological quality was examined using a checklist based on the Mixed Methods Appraisal Tool. The research identified familial, parental, child-related and biological factors that influenced mental health outcomes in affected children (N = 1,376, age range = 1–20 years). Overall, protective mental health factors are understudied in this target group. Most of the included studies were conducted in the United States and employed a cross-sectional design. A comparison of the included cross-sectional and longitudinal studies indicated consistent results related to a secure parent-child attachment. Based on the current state of the research, no causal conclusions with regard to the effectiveness of protective factors can be drawn. To develop effective prevention programs, further longitudinal studies and studies assessing the interactions between risk and protective factors are needed.</p></div

Propiverine-induced accumulation of nuclear and cytosolic protein in F344 rat kidneys : Isolation and identification of the accumulating protein

Male and female F344 rats but not B6C3F1 mice exposed for 104 weeks to propiverine hydrochloride (1-methylpiperid-4-yl 2,2-diphenyl-2-(1-propoxy)acetate hydrochloride), used for treatment of patients with neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), presented with an accumulation of proteins in the cytosol and nuclei of renal proximal tubule epithelial cells, yet despite this, no increased renal tumor incidence was observed. In order to provide an improved interpretation of these findings and a better basis for human health risk assessment, male and female F344 rats were exposed for 16 weeks to 1000 ppm propiverine in the diet, the accumulating protein was isolated from the kidneys via cytosolic and nuclear preparations or laser capture microdissection and analyzed using molecular weight determination and mass spectrometry. The accumulating proteinwas found to be D-amino acid oxidase (DAAO), an enzyme involved in amino and fatty acid metabolism. Subsequent reanalysis of kidney homogenate and nuclear samples as well as tissue sections using western blot and DAAO-immunohistochemistry, confirmed the presence and localization of DAAO in propiverine-treated male and female F344 rats. The accumulation of DAAO only in rats, and the limited similarity of rat DAAO with other species, including humans, suggests a rat-specific mechanism underlying the drug-induced renal DAAO accumulation with little relevance for patients chronically treated with propiverine

Flow of information through the different phases of the systematic review.

<p>Flow of information through the different phases of the systematic review.</p

Assessment of the methodological quality of the included studies.

<p>Assessment of the methodological quality of the included studies.</p