Neuronale alpha-adrenerge Stimulation von IFN-gamma, IL-6 und CXCL1 in murinen Milzen im Tiermodell der Arthritisspätphase

Es war vorbekannt, dass sympathische Nervenfasern mit Zytokin-produzierenden Zellen in der Milz von Mäusen in der Frühphase (Tag 32) des CIA-Modells kommunizieren (STRAUB). Diese Daten zeigten jeweils ausschließlich eine neuronale sympathische Regulation von IFN-y, CXCL1, IL-6 und TGF-ß. Allerdings könnte sich diese Schnittstelle in der Spätphase der CIA durch den Verlust sympathischer Nervenfasern und das Neuauftreten von NT-produzierenden Zellen ändern. Daher betrachten wir in dieser Arbeit die NT-abhängige Regulation von IFN-y, CXCL1, IL-6 und TGF-ß in der Milz von Mäusen, die sich in der Spätphase (Tag 58) der CIA befinden. Methodisch wurden hierfür Mäusemilzen am Tag 58 (46-68) nach Immunisierung in ca. 0,35mm dicke Scheibchen geteilt. Diese wurden in einem Superfusionsaufbau elektrischer Stimulation ausgesetzt, um so NT aus den sympathischen Nervenfasern freizusetzen. Durch den Einsatz von NT-Antagonisten und Kontrollbedingungen ohne ES konnte so der Einfluss der NT auf die Zytokinausschüttung untersucht werden. Es zeigte sich eine Hemmung von IFN-c, CXCL1, und IL-6, sowie eine Stimulation von TGF-b durch die ES. Diese Effekte waren deutlich schwächer ausgeprägt als in der Frühphase des CIA-Modells. Weiterhin zeigte sich eine ß-adrenerge Hemmung von IFN-y, IL-6 und TGF-ß, sowie eine Stimulation von CXCL1. Diese Effekte waren allesamt unabhängig von der ES und müssen daher als nicht-neuronal interpretiert werden. Neuronal vermittelt konnten wir eine α1/2 adrenerge Stimulation von IFN-y, CXCL1 und IL-6, sowie eine A1-adenosinerge Stimulation von TGF-ß beobachten. Daraus lässt sich ableiten, dass in der Spätphase des CIA-Modells der Einfluss nicht-neuronaler Zytokinregulation zunimmt, während der neuronale Einfluss abnimmt. Hierbei werden ß-adrenerge Effekte nicht-neuronal vermittelt, während α1/2 adrenerge Effekte offensichtlich neuronal vermittelt werden. Daraus lässt sich ableiten, dass zeitgleich mit der Veränderung der sympathischen Innervation der Milz sich auch die neuroimmunologische Wechselwirkung zwischen SNS und dem Immunsystem deutlich verändert

The SYSTERS Protein Family Database in 2005

The SYSTERS project aims to provide a meaningful partitioning of the whole protein sequence space by a fully automatic procedure. A refined two-step algorithm assigns each protein to a family and a superfamily. The sequence data underlying SYSTERS release 4 now comprise several protein sequence databases derived from completely sequenced genomes (ENSEMBL, TAIR, SGD and GeneDB), in addition to the comprehensive Swiss-Prot/TrEMBL databases. The SYSTERS web server (http://systers.molgen.mpg.de) provides access to 158 153 SYSTERS protein families. To augment the automatically derived results, information from external databases like Pfam and Gene Ontology are added to the web server. Furthermore, users can retrieve pre-processed analyses of families like multiple alignments and phylogenetic trees. New query options comprise a batch retrieval tool for functional inference about families based on automatic keyword extraction from sequence annotations. A new access point, PhyloMatrix, allows the retrieval of phylogenetic profiles of SYSTERS families across organisms with completely sequenced genomes

Pearls & Oy-sters: Bilateral Mononeuropathic Neuralgic Amyotrophy Triggered by Bartonella henselae Infection Responsive to Immunoglobulin.

We present a case of a cat owner with a scar on his right thenar eminence, followed by lymphadenopathy in the right axilla, general malaise and fever, and subsequent onset of bilateral neuralgic amyotrophy within one week. After a comprehensive workup, cat scratch disease caused by Bartonella henselae was confirmed serologically and adequately treated. Despite antibiotic treatment, the patient presented clinically with persistent bilateral, asymmetric neuropathy of the median nerve, predominantly the interosseous anterior nerve, which was confirmed by multifocal swelling and hyperintense signal of the nerves on T2-weighted MR neurography. Electrophysiological examination confirmed axonal median neuropathies bilaterally. After an unsuccessful steroid treatment trial, the patient showed an excellent and sustained response to intravenous immunoglobulin despite a delay from symptom onset to treatment of 10 months

Non-Invasive Time-Lapsed Monitoring and Quantification of Engineered Bone-Like Tissue

The formation of bone-like tissue from human mesenchymal stem cells (hMSC) cultured in osteogenic medium on silk fibroin scaffolds was monitored and quantified over 44days in culture using non-invasive time-lapsed micro-computed tomography (μCT). Each construct was imaged nine times insitu. From μCT imaging, detailed morphometrical data on bone volume density, surface-to-volume ratio, trabecular thickness, trabecular spacing, and the structure model index and tissue mineral density were obtained. μCT irradiation did not impact the osteogenic performance of hMSCs based on DNA content, alkaline phosphatase activity, and calcium deposition when compared to non-exposed control samples. Bone-like tissue formation initiated at day 10 of the culture with the deposition of small mineralized clusters. Tissue mineral density increased linearly over time. The surface-to-volume ratio of the bone-like tissues converged asymptotically to 26mm−1. Although in vitro formation of bone-like tissue started from clusters, the overall bone volume was not predictable from the time, number, and size of initially formed bone-like clusters. Based on microstructural analysis, the morphometry of the tissue-engineered constructs was found to be in the range of human trabecular bone. In future studies, non-invasive, time-lapsed monitoring may enable researchers to culture tissues in vitro, right until the development of a desired morphology is accomplished. Our data demonstrate the feasibility of qualitatively and quantitatively detailing the spatial and temporal mineralization of bone-like tissue formation in tissue engineerin

Aetiology, secondary prevention strategies and outcomes of ischaemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation

OBJECTIVE To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF). METHODS We analysed consecutive patients with AF with an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke. RESULTS Among 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy. CONCLUSIONS Stroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed. TRIAL REGISTRATION NUMBER ISRCTN48292829

CancerResource: a comprehensive database of cancer-relevant proteins and compound interactions supported by experimental knowledge

During the development of methods for cancer diagnosis and treatment, a vast amount of information is generated. Novel cancer target proteins have been identified and many compounds that activate or inhibit cancer-relevant target genes have been developed. This knowledge is based on an immense number of experimentally validated compound–target interactions in the literature, and excerpts from literature text mining are spread over numerous data sources. Our own analysis shows that the overlap between important existing repositories such as Comparative Toxicogenomics Database (CTD), Therapeutic Target Database (TTD), Pharmacogenomics Knowledge Base (PharmGKB) and DrugBank as well as between our own literature mining for cancer-annotated entries is surprisingly small. In order to provide an easy overview of interaction data, it is essential to integrate this information into a single, comprehensive data repository. Here, we present CancerResource, a database that integrates cancer-relevant relationships of compounds and targets from (i) our own literature mining and (ii) external resources complemented with (iii) essential experimental and supporting information on genes and cellular effects. In order to facilitate an overview of existing and supporting information, a series of novel information connections have been established. CancerResource addresses the spectrum of research on compound–target interactions in natural sciences as well as in individualized medicine; CancerResource is available at: http://bioinformatics.charite.de/cancerresource/

Outcome, efficacy and safety of endovascular thrombectomy in ischaemic stroke according to time to reperfusion: data from a multicentre registry

Endovascular; Mechanical thrombectomy; StrokeEndovascular; Trombectomia mecànica; Accident cerebrovascularEndovascular; Trombectomía mecánica; Accidente cerebrovascularBACKGROUND AND PURPOSE: In acute ischaemic stroke (AIS) of the anterior circulation (AC) treated with mechanical thrombectomy (MT), data point to a decline of treatment effect with increasing time from symptom onset to treatment. However, the magnitude of the decline will depend on the clinical setting and imaging selection used. The aims of this study were (1) to evaluate the clinical effect of time to reperfusion (TTR); and (2) to assess the safety and technical efficacy of MT according to strata of TTR. METHODS: Using the retrospective multicentre BEYOND-SWIFT registry data (ClinicalTrials.gov identifier: NCT03496064), we compared safety and efficacy of MT in 1461 patients between TTR strata of 0-180 min (n = 192), 180-360 min (n = 876) and >360 min (n = 393). Clinical effect of TTR was evaluated using multivariable logistic regression analyses adjusting for pre-specified confounders [adjusted odds ratios (aOR) and 95% confidence intervals (95% CI)]. Primary outcome was good functional outcome (modified Rankin Scale: mRS 0-2) at day 90. RESULTS: Every hour delay in TTR was a significant factor related to mRS 0-2 (aOR 0.933, 95% CI 0.887-0.981) with an estimated 1.5% decreased probability of good functional outcome per hour delay of reperfusion, and mRS 0-1 (aOR 0.929, 95% CI 0.877-0.985). Patients with late TTR had lower rates of successful and excellent reperfusion, higher complication rates and number of passes. CONCLUSIONS: TTR is an independent factor related to long-term functional outcome. With increasing TTR, interventional procedures become technically less effective. Efforts should be made to shorten TTR through optimized prehospital and in-hospital pathways

Scientific Developers v/s Static Analysis Tools: Vision and Position Paper

Usability and the use of automated static analysis tools in the software development process have been an evolving subject of research in the last decades. Several studies shed light on issues like high false positive rates and low comprehensibility, which hinder tool adoption for even software engineers. Yet, the tools' perceived usefulness and ease of use play a much larger role when it comes to untrained software developers, as is usually the case in scientific software development. In this paper, we outline a multi-stage interview study to learn more about how scientists come to accept and use static analysis tools