A general introduction to glucocorticoid biology

Glucocorticoids (GCs) are steroid hormones widely used for the treatment of inflammation, autoimmune diseases, and cancer. To exert their broad physiological and therapeutic effects, GCs bind to the GC receptor (GR) which belongs to the nuclear receptor superfamily of transcription factors. Despite their success, GCs are hindered by the occurrence of side effects and glucocorticoid resistance (GCR). Increased knowledge on GC and GR biology together with a better understanding of the molecular mechanisms underlying the GC side effects and GCR are necessary for improved GC therapy development. We here provide a general overview on the current insights in GC biology with a focus on GC synthesis, regulation and physiology, role in inflammation inhibition, and on GR function and plasticity. Furthermore, novel and selective therapeutic strategies are proposed based on recently recognized distinct molecular mechanisms of the GR. We will explain the SEDIGRAM concept, which was launched based on our research results

Learning lessons in sepsis from the children

Sepsis research has had relatively limited therapeutic success so far. In their recent study, Kobzik and colleagues (Joachim etal, ) identify novel drug-sensitive pathways in sepsis, derived exclusively from patient data. Their strategy is based on the analysis of a naturally sepsis-resistant population (pre-puberty children) and on the implementation of a novel-rich Pathway Drug Network, constructed from human gene expression data enriched in drug-pathway-gene clusters

The International Academy for Research in Learning Disabilities

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68863/2/10.1177_002221948301600718.pd

The Arctic Ocean spices up

Author Posting. © American Meteorological Society, 2016. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 46 (2016): 1277-1284, doi:10.1175/JPO-D-16-0027.1.The contemporary Arctic Ocean differs markedly from midlatitude, ice-free, and relatively warm oceans in the context of density-compensating temperature and salinity variations. These variations are invaluable tracers in the midlatitudes, revealing essential fundamental physical processes of the oceans, on scales from millimeters to thousands of kilometers. However, in the cold Arctic Ocean, temperature variations have little effect on density, and a measure of density-compensating variations in temperature and salinity (i.e., spiciness) is not appropriate. In general, temperature is simply a passive tracer, which implies that most of the heat transported in the Arctic Ocean relies entirely on the ocean dynamics determined by the salinity field. It is shown, however, that as the Arctic Ocean warms up, temperature will take on a new role in setting dynamical balances. Under continued warming, there exists the possibility for a regime shift in the mechanisms by which heat is transported in the Arctic Ocean. This may result in a cap on the storage of deep-ocean heat, having profound implications for future predictions of Arctic sea ice.Support was provided by the National Science Foundation Division of Polar Programs Award 1350046 and Office of Naval Research Grant Number N00014-12-1-0110.2016-10-0

The nature of the GRE influences the screening for GR-activity enhancing modulators

Glucocorticoid resistance (GCR), i.e. unresponsiveness to the beneficial anti-inflammatory activities of the glucocorticoid receptor (GR), poses a serious problem in the treatment of inflammatory diseases. One possible solution to try and overcome GCR, is to identify molecules that prevent or revert GCR by hyper-stimulating the biological activity of the GR. To this purpose, we screened for compounds that potentiate the dexamethasone (Dex)induced transcriptional activity of GR. To monitor GR transcriptional activity, the screen was performed using the lung epithelial cell line A549 in which a glucocorticoid responsive element (GRE) coupled to a luciferase reporter gene construct was stably integrated. Histone deacetylase inhibitors (HDACi) such as Vorinostat and Belinostat are two broad-spectrum HDACi that strongly increased the Dex-induced luciferase expression in our screening system. In sharp contrast herewith, results from a genome-wide transcriptome analysis of Dexinduced transcripts using RNAseq, revealed that Belinostat impairs the ability of GR to transactivate target genes. The stimulatory effect of Belinostat in the luciferase screen further depends on the nature of the reporter construct. In conclusion, a profound discrepancy was observed between HDACi effects on two different synthetic promoter-luciferase reporter systems. The favorable effect of HDACi on gene expression should be evaluated with care, when considering them as potential therapeutic agents. GEO accession number GSE96649

Markerless motion capture systems as training device in neurological rehabilitation: a systematic review of their use, application, target population and efficacy

Background Client-centred task-oriented training is important in neurological rehabilitation but is time consuming and costly in clinical practice. The use of technology, especially motion capture systems (MCS) which are low cost and easy to apply in clinical practice, may be used to support this kind of training, but knowledge and evidence of their use for training is scarce. The present review aims to investigate 1) which motion capture systems are used as training devices in neurological rehabilitation, 2) how they are applied, 3) in which target population, 4) what the content of the training and 5) efficacy of training with MCS is. Methods A computerised systematic literature review was conducted in four databases (PubMed, Cinahl, Cochrane Database and IEEE). The following MeSH terms and key words were used: Motion, Movement, Detection, Capture, Kinect, Rehabilitation, Nervous System Diseases, Multiple Sclerosis, Stroke, Spinal Cord, Parkinson Disease, Cerebral Palsy and Traumatic Brain Injury. The Van Tulder’s Quality assessment was used to score the methodological quality of the selected studies. The descriptive analysis is reported by MCS, target population, training parameters and training efficacy. Results Eighteen studies were selected (mean Van Tulder score = 8.06 ± 3.67). Based on methodological quality, six studies were selected for analysis of training efficacy. Most commonly used MCS was Microsoft Kinect, training was mostly conducted in upper limb stroke rehabilitation. Training programs varied in intensity, frequency and content. None of the studies reported an individualised training program based on client-centred approach. Conclusion Motion capture systems are training devices with potential in neurological rehabilitation to increase the motivation during training and may assist improvement on one or more International Classification of Functioning, Disability and Health (ICF) levels. Although client-centred task-oriented training is important in neurological rehabilitation, the client-centred approach was not included. Future technological developments should take up the challenge to combine MCS with the principles of a client-centred task-oriented approach and prove efficacy using randomised controlled trials with long-term follow-up

Glucocorticoid-induced microRNA-511 protects against TNF by down-regulating TNFR1

TNF is a central actor during inflammation and a well-recognized drug target for inflammatory diseases. We found that the mouse strain SPRET/Ei, known for extreme and dominant resistance against TNF-induced shock, displays weak expression of TNF receptor 1 protein (TNFR1) but normal mRNA expression, a trait genetically linked to the major TNFR1 coding gene Tnfrsf1a and to a locus harbouring the predicted TNFR1-regulating miR-511. This miRNA is a genuine TNFR1 regulator in cells. In mice, overexpression of miR-511 down-regulates TNFR1 and protects against TNF, while anti-miR-511 up-regulates TNFR1 and sensitizes for TNF, breaking the resistance of SPRET/Ei. We found that miR-511 inhibits endotoxemia and experimental hepatitis and that this miR is strongly induced by glucocorticoids and is a true TNFR1 modulator and thus an anti-inflammatory miR. Since minimal reductions of TNFR1 have considerable effects on TNF sensitivity, we believe that at least part of the anti-inflammatory effects of glucocorti-coids are mediated by induction of this miR, resulting in reduced TNFR1 expression

Gesetzgebung im politischen System der Niederlande

Die Niederlande sind eine parlamentarische Monarchie, die verfassungsrechtlich im Grundgesetz (Grondwet) des Königreichs der Niederlande verankert ist. Diese Verfassung stammt ursprünglich aus dem Jahre 1815. In jenem Jahr erlangten die Niederlande ihre Unabhängigkeit von der napoleonischen Herrschaft in Frankreich. Die Rechtsgrundlage der heutigen Niederlande wurde bereits bei der Gründung der Republik der Vereinigten Niederlande, einem aus sieben Provinzen bestehenden Staatenbund, im Jahre 1579 geschaffen. In der ersten Hälfte des 17. Jahrhundert stand das Territorium der Niederlande unter spanischer Herrschaft, die mit dem Westfälischen Frieden im Jahre 1648 ihr Ende fand. Aus dieser Zeit stammt auch die Verbundenheit mit dem Haus von Oranje-Nassau, dem Geschlecht der Erbmonarchie, das bis auf den heutigen Tag die Regenten stellt. Nach der Abtrennung von Belgien im Jahre 1830 und von Luxemburg im Jahre 1890 erhielten die Niederlande ihre heutigen Staatsgrenzen