Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47

Recent studies suggest that exposure to endocrine-disrupting compounds (EDCs) may play a role in the development of obesity. EDCs such as the flame retardant 2,2′,4,4′-tetrabrominated diphenyl ether (BDE-47) have been shown to enhance adipocyte differentiation in the murine 3T3-L1 model. The mechanisms by which EDCs direct preadipocytes to form adipocytes are poorly understood. Here, we examined transcriptional and epigenetic mechanisms underlying the induction of in vitro adipocyte differentiation by BDE-47. Quantitative high content microscopy revealed concentration-dependent enhanced adipocyte differentiation following exposure to BDE-47 or the antidiabetic drug troglitazone (TROG). BDE-47 modestly activated the key adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) in COS7 cells, transiently transfected with a GAL4 reporter construct. Increased gene expression was observed for Pparγ2, leptin (Lep), and glucose-6-phophatase catalytic subunit (G6pc) in differentiated 3T3-L1 cells after BDE-47 exposure compared to TROG. Methylation-sensitive high resolution melting (MS-HRM) revealed significant demethylation of three CpG sites in the Pparγ2 promoter after exposure to both BDE-47 and TROG in differentiated 3T3-L1 cells. This study shows the potential of BDE-47 to induce adipocyte differentiation through various mechanisms that include Pparγ2 gene induction and promoter demethylation accompanied by activation of PPARγ, and possible disruption of glucose homeostasis and IGF1 signaling

Capgras delusion in posterior cortical atrophy: A quantitative multimodal imaging single case study

Although Alzheimer's disease presents homogeneous histopathology, it causes several clinical phenotypes depending on brain regions involved. Beside the most abundant memory variant, several atypical variants exist. Among them posterior cortical atrophy (PCA) is associated with severe visuospatial/visuoperceptual deficits in the absence of significant primary ocular disease. Here, we report for the first time a case of Capgras delusion-a delusional misidentification syndrome, where patients think that familiar persons are replaced by identical "doubles" or an impostor-in a patient with PCA. The 57-year-old female patient was diagnosed with PCA and developed Capgras delusion 8 years after first symptoms. The patient did not recognize her husband, misidentified him as a stranger, and perceived him as a threat. Such misidentifications did not happen for other persons. Events could be interrupted by reassuring the husband's identity by the patient's female friend or children. We applied in-depth multimodal neuroimaging phenotyping and used single-subject voxel-based morphometry to identify atrophy changes specifically related to the development of the Capgras delusion. The latter, based on structural T1 magnetic resonance imaging, revealed progressive gray matter volume decline in occipital and temporoparietal areas, involving more the right than the left hemisphere, especially at the beginning. Correspondingly, the right fusiform gyrus was already affected by atrophy at baseline, whereas the left fusiform gyrus became involved in the further disease course. At baseline, glucose hypometabolism as measured by positron emission tomography (PET) with F18-fluorodesoxyglucose (FDG-PET) was evident in the parietooccipital cortex, more pronounced right-sided, and in the right frontotemporal cortex. Amyloid accumulation as assessed by PET with F18-florbetaben was found in the gray matter of the neocortex indicating underlying Alzheimer's disease. Appearance of the Capgras delusion was related to atrophy in the right posterior cingulate gyrus/precuneus, as well as right middle frontal gyrus/frontal eye field, supporting right frontal areas as particularly relevant for Capgras delusion. Atrophy in these regions respectively might affect the default mode and dorsal attention networks as shown by meta-analytical co-activation and resting state functional connectivity analyses. This case elucidates the brain-behavior relationship in PCA and Capgras delusion

Der ökonomische Fußabdruck der Privaten Krankenversicherung in Deutschland. Quantifizierung der volkswirtschaftlichen Bedeutung der PKV im Kontext der Gesundheitswirtschaftlichen Gesamtrechnung (GGR) des Bundesministeriums für Wirtschaft und Energie (BMWi)

The health economy today plays a central role in many areas of society. This development is evidenced, not least, by the increased perception of the health economy as a key economic factor in Germany. On this basis, many sub-sectors of the industry, such as the industrial health economy, are experiencing mounting social and political attention from an economic perspective. In this connection, health insurance, an important segment of the health economy, has so far been the subject of only a small number of academic studies. This study therefore aims to examine the importance, in economic and employment policy terms, of private health insurance as a key player in the health economy in the context of the German economy at large. Its importance will be quantified on the basis of the economic contribution that private health insurance makes to economic growth and the labour market. The answer to this question augments the current (academic) debate about the health economy generally as well as its individual players. The analysis places particular emphasis on the significance of these economic activities to German society and ultimately also to German gross domestic product (GDP). The design of this study builds on numerous research projects conducted by the Federal Ministry for Economic Affairs and Energy. These studies demonstrate that the health economy is one of the largest industries in Germany, accounting for roughly 12 percent of GDP in 2015. At the same time, just under one in six employed persons in Germany were employed in this industry, which also generates over 7 percent of Germany’s total exports. Taking as its basis the aforementioned research projects of the Federal Ministry for Economic Affairs and Energy, this study entitled “The economic footprint of private health insurance in Germany” is the first of its kind to depict private health insurance as an economic player with-in the health economy and, building on this, to quantify the direct, indirect and induced contribution private health insurance makes to growth and employment in Germany. This macroeconomic perspective constitutes an important step towards a comprehensive analysis of health economy players within a value chain of care. The recording of the individual contributions and, in particular, the interconnections between players such as the private health insurers and other industries allows quantitative arguments to be put forward in order to overcome the prevailing silo mentality of the individual actors in the health economy

Development of the State Optimism Measure

Background Optimism, or positive expectations about the future, is associated with better health. It is commonly assessed as a trait, but it may change over time and circumstance. Accordingly, we developed a measure of state optimism. Methods An initial 29-item pool was generated based on literature reviews and expert consultations. It was administered to three samples: sample 1 was a general healthy population (n = 136), sample 2 was people with cardiac disease (n = 96), and sample 3 was persons recovering from problematic substance use (n = 265). Exploratory factor analysis and item-level descriptive statistics were used to select items to form a unidimensional State Optimism Measure (SOM). Confirmatory factor analysis (CFA) was performed to test fit. Results The selected seven SOM items demonstrated acceptable to high factor loadings on a single dominant factor (loadings: 0.64–0.93). There was high internal reliability across samples (Cronbach\u27s alphas: 0.92–0.96), and strong convergent validity correlations in hypothesized directions. The SOM\u27s correlations with other optimism measures indicate preliminary construct validity. CFA statistics indicated acceptable fit of the SOM model. Conclusions We developed a psychometrically-sound measure of state optimism that can be used in various settings. Predictive and criterion validity will be tested in future studies

IL-4 receptor engagement in human neutrophils impairs their migration and extracellular trap formation

Background Type 2 immunity serves to resist parasitic helminths, venoms, and toxins, but the role and regulation of neutrophils during type 2 immune responses are controversial. Helminth models suggested a contribution of neutrophils to type 2 immunity, whereas neutrophils are associated with increased disease severity during type 2 inflammatory disorders, such as asthma. Objective We sought to evaluate the effect of the prototypic type 2 cytokines IL-4 and IL-13 on human neutrophils. Methods Human neutrophils from peripheral blood were assessed without or with IL-4 or IL-13 for (1) expression of IL-4 receptor subunits, (2) neutrophil extracellular trap (NET) formation, (3) migration toward CXCL8 in vitro and in humanized mice, and (4) CXCR1, CXCR2, and CXCR4 expression, as well as (5) in nonallergic versus allergic subjects. Results Human neutrophils expressed both types of IL-4 receptors, and their stimulation through IL-4 or IL-13 diminished their ability to form NETs and migrate toward CXCL8 in vitro. Likewise, in vivo chemotaxis in NOD-scid-Il2rg−/− mice was reduced in IL-4–stimulated human neutrophils compared with control values. These effects were accompanied by downregulation of the CXCL8-binding chemokine receptors CXCR1 and CXCR2 on human neutrophils on IL-4 or IL-13 stimulation in vitro. Ex vivo analysis of neutrophils from allergic patients or exposure of neutrophils from nonallergic subjects to allergic donor serum in vitro impaired their NET formation and migration toward CXCL8, thereby mirroring IL-4/IL-13–stimulated neutrophils. Conclusion IL-4 receptor signaling in human neutrophils affects several neutrophil effector functions, which bears important implications for immunity in type 2 inflammatory disorders

Der ökonomische Fußabdruck der Privaten Krankenversicherung in Deutschland. Untersuchung der PKV als Finanzier von Gesundheitsleistungen

There is now much evidence for the vital importance of the health economy, and it is receiving more attention from social and political spheres. This development is evidenced, not least, by the increased perception of the health economy as a key economic factor in Germany. Private health insurance (PKV) plays an important role in the health economy in three respects: as an economic actor, as a financer of healthcare services, and as a provider of capital. In a first step, an earlier study determined the economic footprint of the private health insurance sector as an economic actor. In doing so, the economic significance of private health insurance was measured on the basis of official national accounts categories for the first time. The starting point for this earlier study was a change of perspective so as to view the health economy – including private health insurance – not just as a cost factor, but also from the angle of economic growth and employment. From this basis, the second step presented here measures the economic importance of private health insurance in its role as a financer of healthcare services. Unlike in the first step, the private health insurance sector’s expenditure on benefits for its members forms the subject of the study, instead of the economic activity of the sector. This expenditure finances medication and services rendered to private patients by licensed doctors and hospitals, for example. The aim of this study is to calculate the resultant gross value added and employment. The comprehensive economic footprint approach is unique in that it incorporates the economic significance of intermediate inputs (indirect effects) and the spending of employee compensation (induced effects). This study augments this approach by examining the economic effects of the additional revenue raised from private patients. Additional revenue is the sum that the entire health system would lose if private patients were insured under the statutory scheme instead of privately. This issue is relevant seeing as there is currently some debate about introducing a universal system

Der ökonomische Fußabdruck der Privaten Krankenversicherung in Deutschland. Untersuchung der PKV als Finanzier von Gesundheitsleistungen

There is now much evidence for the vital importance of the health economy, and it is receiving more attention from social and political spheres. This development is evidenced, not least, by the increased perception of the health economy as a key economic factor in Germany. Private health insurance (PKV) plays an important role in the health economy in three respects: as an economic actor, as a financer of healthcare services, and as a provider of capital. In a first step, an earlier study determined the economic footprint of the private health insurance sector as an economic actor. In doing so, the economic significance of private health insurance was measured on the basis of official national accounts categories for the first time. The starting point for this earlier study was a change of perspective so as to view the health economy – including private health insurance – not just as a cost factor, but also from the angle of economic growth and employment. From this basis, the second step presented here measures the economic importance of private health insurance in its role as a financer of healthcare services. Unlike in the first step, the private health insurance sector’s expenditure on benefits for its members forms the subject of the study, instead of the economic activity of the sector. This expenditure finances medication and services rendered to private patients by licensed doctors and hospitals, for example. The aim of this study is to calculate the resultant gross value added and employment. The comprehensive economic footprint approach is unique in that it incorporates the economic significance of intermediate inputs (indirect effects) and the spending of employee compensation (induced effects). This study augments this approach by examining the economic effects of the additional revenue raised from private patients. Additional revenue is the sum that the entire health system would lose if private patients were insured under the statutory scheme instead of privately. This issue is relevant seeing as there is currently some debate about introducing a universal system

Statistics of Atmospheric Correlations

For a large class of quantum systems the statistical properties of their spectrum show remarkable agreement with random matrix predictions. Recent advances show that the scope of random matrix theory is much wider. In this work, we show that the random matrix approach can be beneficially applied to a completely different classical domain, namely, to the empirical correlation matrices obtained from the analysis of the basic atmospheric parameters that characterise the state of atmosphere. We show that the spectrum of atmospheric correlation matrices satisfy the random matrix prescription. In particular, the eigenmodes of the atmospheric empirical correlation matrices that have physical significance are marked by deviations from the eigenvector distribution.Comment: 8 pages, 9 figs, revtex; To appear in Phys. Rev.

Identification of estrogenic compounds in fish bile using bioassay-directed fractionation

Conjugates of estrogenic chemicals, endogenous as well as xenobiotic, are mainly excreted via bile into the intestine. Therefore, measurement of estrogenic activity in bile yields useful information about an organism's internal exposure to (xeno-)estrogens. Although previous studies in The Netherlands have reported estrogenic activity in male fish bile, the contribution of natural hormones and xenobiotic substances to this activity is unknown. To identify compounds responsible for estrogenic activity in fish bile, we developed a bioassay-directed fractionation method for estrogenic chemicals. In this approach, the in vitro reporter gene assay ER-CALUX (Estrogen Responsive Chemical Activated Luciferase Gene Expression) was used to assess estrogenic activity in deconjugated bile samples and to direct RP-HPLC fractionation and chemical analysis (by GC-MS) of estrogenic compounds. The method was applied to bile from male breams (Abramis brama) collected at three locations in The Netherlands. At one of these locations, the River Dommel, extremely high levels of plasma vitellogenin and a high incidence of intersex gonads in these male breams have previously been observed, indicating the exposure to estrogens. In this study, the natural hormones 17β-estradiol, estrone, and estriol accounted for the majority of estrogenic activity in male bream bile. At the River Dommel, the synthetic contraceptive pill component ethynylestradiol was found in effective concentrations as well. The detected natural and synthetic hormones may be responsible for the estrogenic effects observed in wild bream from this location. Furthermore, a large number of xenobiotic chemicals was detected at relatively high levels in bile, including triclosan, chloroxylenol, and clorophene. Although chloroxylenol was shown for the first time to be weakly estrogenic, these compounds did not contribute significantly to the estrogenic activity observed

A 1-acetamido derivative of 6-epi-valienamine: an inhibitor of a diverse group of β-N-acetylglucosaminidases

The synthesis of an analogue of 6-epi-valienamine bearing an acetamido group and its characterisation as an inhibitor of β-N-acetylglucosaminidases are described. The compound is a good inhibitor of both human O-GlcNAcase and human β-hexosaminidase, as well as two bacterial β-N-acetylglucosaminidases. A 3-D structure of the complex of Bacteroides thetaiotaomicron BtGH84 with the inhibitor shows the unsaturated ring is surprisingly distorted away from its favoured solution phase conformation and reveals potential for improved inhibitor potency