Effects of genetic loci associated with central obesity on adipocyte lipolysis

Objectives: Numerous genetic loci have been associated with measures of central fat accumulation, such as waist-to-hip ratio adjusted for body mass index (WHRadjBMI). However the mechanisms by which genetic variations influence obesity remain largely elusive. Lipolysis is a key process for regulation of lipid storage in adipocytes, thus is implicated in obesity and its metabolic complications. Here, genetic variants at 36 WHRadjBMI-associated loci were examined for their influence on abdominal subcutaneous adipocyte lipolysis. Subjects and Methods: Fasting subcutaneous adipose tissue biopsies were collected from 789 volunteers (587 women and 202 men, body mass index (BMI) range 17.7–62.3 kg/m2). We quantified subcutaneous adipocyte lipolysis, both spontaneous and stimulated by the catecholamine isoprenaline or a cyclic AMP analogue. DNA was extracted from peripheral blood mononuclear cells and genotyping of SNPs associated with WHRadjBMI conducted. The effects on adipocyte lipolysis measures were assessed for SNPs individually and combined in a SNP score. Results: The WHRadjBMI-associated loci CMIP, PLXND1, VEGFA and ZNRF3-KREMEN1 demonstrated nominal associations with spontaneous and/or stimulated lipolysis. Candidate genes in these loci have been reported to influence NFκB-signaling, fat cell size and Wnt signalling, all of which may influence lipolysis. Significance: This report provides evidence for specific WHRadjBMI-associated loci as candidates to modulate adipocyte lipolysis. Additionally, our data suggests that genetically increased central fat accumulation is unlikely to be a major cause of altered lipolysis in abdominal adipocytes

Denktank Overlijdensschade: nieuwe richting benadering en berekening overlijdensschade

De denktank overlijdensschade is ontstaan, omdat de rekenmethodiek voor overlijdensschade niet uit te leggen is aan nabestaanden en geen recht doet aan de maatschappelijke ontwikkelingen. Diverse professionals besloten niet langer slechts te ageren tegen de bestaande situatie, maar er werkelijk wat aan te doen. Dit heeft geresulteerd in een conceptnotitie ‘Nieuwe richting benadering en berekening overlijdensschade’. In dit artikel wordt deze notitie kort besproken

Notitie Denktank Overlijdensschade. Nieuwe richting benadering en berekening overlijdensschade

In 2009 is een werkgroep onder de naam Denktank Overlijdensschade gestart met het bestuderen van een ander, aan de huidige tijd aangepast model voor de berekening van overlijdensschade. Doelstelling was te komen tot een, ook voor nabestaanden, transparantie systematiek welke recht doet aan de vorderingsgerechtigdheid van de nabestaanden. In 2014 heeft de Denktank Overlijdensschade haar werkzaamheden voltooid met het opleveren van een nieuwe rekenmethodiek. In deze Notitie wordt beschreven hoe de Denktank tot deze nieuwe benadering van het berekenen van overlijdensschade is gekomen, welke onderzoeken daaraan ten grondslag liggen en wat de uiteindelijke rekenregel is, die nu voorgesteld wordt. Kern van de nieuwe methodiek is het uitgangspunt dat het gezin als economische eenheid wordt beschouwd, voor én na het overlijden

Migratory myiasis in a European traveller due to Hypoderma larvae

Immunogenetics and cellular immunology of bacterial infectious disease

Functional Characterization of Promoter Variants of the Adiponectin Gene Complemented by Epidemiological Data

# These authors contributed equally to the work. *Corresponding author

Contribution of Transcription Factor Binding Site Motif Variants to Condition-Specific Gene Expression Patterns in Budding Yeast

It is now experimentally well known that variant sequences of a cis transcription factor binding site motif can contribute to differential regulation of genes. We characterize the relationship between motif variants and gene expression by analyzing expression microarray data and binding site predictions. To accomplish this, we statistically detect motif variants with effects that differ among environments. Such environmental specificity may be due to either affinity differences between variants or, more likely, differential interactions of TFs bound to these variants with cofactors, and with differential presence of cofactors across environments. We examine conservation of functional variants across four Saccharomyces species, and find that about a third of transcription factors have target genes that are differentially expressed in a condition-specific manner that is correlated with the nucleotide at variant motif positions. We find good correspondence between our results and some cases in the experimental literature (Reb1, Sum1, Mcm1, and Rap1). These results and growing consensus in the literature indicates that motif variants may often be functionally distinct, that this may be observed in genomic data, and that variants play an important role in condition-specific gene regulation

Silencing and Nuclear Repositioning of the λ5 Gene Locus at the Pre-B Cell Stage Requires Aiolos and OBF-1

The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes λ5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the λ5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function

Effectiveness and safety of opicapone in Parkinson's disease patients with motor fluctuations: The OPTIPARK open-label study

BACKGROUND: The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. METHODS: OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). RESULTS: Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. CONCLUSIONS: Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. TRIAL REGISTRATION: Registered in July 2016 at clinicaltrials.gov (NCT02847442)