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Microglial erythrophagocytosis is crucial in injury response to hemorrhagic stroke. We hypothesized that regulation of microglial erythrophagocytosis via HO-1/CO depends on a pathway involving reactive oxygen species (ROS) and CD36 surface-expression. The microglial BV-2 cell line and primary microglia (PMG) were incubated +/−blood and +/−CO-exposure. PMG isolated from tissue-specific HO-1-deficient (LyzM-Cre-Hmox1 fl/fl) and CD36 −/− mice or siRNA against AMPK (AMP-activated protein kinase) were used to test our hypothesis. In a murine subarachnoid hemorrhage (SAH) model, we compared neuronal injury in wild-type and CD36 −/− mice. Readouts included vasospasm, microglia activation, neuronal apoptosis, and spatial memory. We observed increased microglial HO-1-expression after blood-exposure. A burst in ROS-production was seen after CO-exposure, which led to increased amounts of phosphorylated AMPK with subsequently enhanced CD36 surface-expression. Naïve PMG from LyzM-Cre-Hmox1 fl/fl mice showed reduced ROS-production and CD36 surface-expression and failed to respond to CO with increased CD36 surface-expression. Lack of HO-1 and CD36 resulted in reduced erythrophagocytosis that could not be rescued with CO. Erythrophagocytosis was enhanced in BV-2 cells in the presence of exogenous CO, which was abolished in cells treated with siRNA to AMPK. CD36 −/− mice subjected to SAH showed enhanced neuronal cell death, which resulted in impaired spatial memory function. We demonstrate that microglial phagocytic function partly depends on a pathway involving HO-1 with changes in ROS-production, phosphorylated AMPK, and surface expression of CD36. CD36 was identified as a crucial component in blood clearance after hemorrhage that ultimately determines neuronal outcome. These results demand further investigations studying the potential neuroprotective properties of CO. 相似文献
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Akbil Bengisu Meyer Tim Stubbemann Paula Thibeault Charlotte Staudacher Olga Niemeyer Daniela Jansen Jenny Mühlemann Barbara Doehn Jan Tabeling Christoph Nusshag Christian Hirzel Cédric Sanchez David Sökler Nieters Alexandra Lother Achim Duerschmied Daniel Schallner Nils Lieberum Jan Nikolaus August Dietrich Rieg Siegbert Falcone Valeria Hengel Hartmut Kölsch Uwe Unterwalder Nadine Hübner Ralf-Harto Jones Terry C. Suttorp Norbert Drosten Christian Warnatz Klaus Spinetti Thibaud Schefold Joerg C. Dörner Thomas Sander Leif Erik Corman Victor M. Merle Uta Kurth Florian von Bernuth Horst Meisel Christian Goffinet Christine 《Journal of clinical immunology》2022,42(6):1111-1129
Journal of Clinical Immunology - Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable... 相似文献
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Generation of activation-specific human anti-alphaMbeta2 single-chain antibodies as potential diagnostic tools and therapeutic agents 下载免费PDF全文
Eisenhardt SU Schwarz M Schallner N Soosairajah J Bassler N Huang D Bode C Peter K 《Blood》2007,109(8):3521-3528
The leukocyte integrin Mac-1 (alpha(M)beta(2)) plays a pivotal role in inflammation and host defense. Upon leukocyte activation, Mac-1 undergoes a conformational change exposing interaction sites for multiple ligands. We aimed to generate single-chain antibodies (scFv's) directed against activation-specific Mac-1 ligand-binding sites. Using human scFv phage libraries, we developed subtractive strategies with depletion of phages binding to nonactivated Mac-1 and selection of phages binding to activated Mac-1, using monocytes as well as CHO cells transfected with native or mutated, activated Mac-1. Three scFv clones demonstrated exclusive binding to activated Mac-1. Mac-1 binding of the ligands fibrinogen, heparin, and ICAM-1, but not C3bi, was inhibited. Using alanine substitutions, the paratope was identified within the heavy chain HCDR3s of the scFv's. The epitope was localized to Lys(245)-Arg(261) of the alpha(M) I-domain. In a pilot study with septicemic patients, we provide initial support for the use of these scFv's as markers of monocyte activation and as potential diagnostic tools. Potential therapeutic use was tested in adhesion assays under static and flow conditions demonstrating the selective blockade of activated monocytes only. Furthermore, scFv HCDR3-derived peptides retain selectivity for the activated integrin, providing a unique template for the potential development of inhibitors that are specific for the activated Mac-1. 相似文献
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Johannes Kalbhenn Sven Maier Sebastian Heinrich Nils Schallner 《Journal of artificial organs》2017,20(3):285-288
We report a repositioning maneuver of a dislocated Avalon Elite dual lumen catheter during ongoing veno-venous ECMO support. The inferior tip of the catheter dislocated into a liver vein, which was accompanied by a dramatic decrease in pump flow. After standard repositioning maneuvers under transthoracic echocardiographic guidance had failed, a special guiding sheath was inserted into the main lumen through a Y-connector with a valve. Over this valve, a stiff wire could be placed into the inferior vena cava to help guiding the catheter back into the correct position. 相似文献
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Novel PRPS1 gain‐of‐function mutation in a patient with congenital hyperuricemia and facial anomalies 下载免费PDF全文
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6q22.33 microdeletion in a family with intellectual disability,variable major anomalies,and behavioral abnormalities 下载免费PDF全文
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Schädlich D Friebel D Schallner J Gehrisch S Siegert G Kuhlisch E Knöfler R 《Hamostaseologie》2010,30(Z1):S132-S137
Coagulation parameters were determined in children with valproic acid mono- and valproic acid-lamotrigin combination therapy. Patients, methods: Monotherapy group (n = 22; mean age: 10.5 years) was compared to combination therapy (n = 7; 12.9 years) and a control group (n = 22; 8.7 years). The following parameters were measured: aggregation and ATP-release in whole blood (ADP: 20 μmol/l, collagen: 1 μg/ml, thrombin: 0.5 U/ml), PFA-100? closure times (CT), blood cell counts, global tests, VWF:Ag, VWF:CBA, factors VIII and XIII as well as fibrinogen. Bleeding symptoms were evaluated by using a questionnaire. Results: For ADP- and collagen-induced aggregation as well as for ATP release no significant differences between the groups were detected. The combined therapy group showed significantly prolonged CT. Von Willebrand disease was not detected in any of the patients. The platelet count was significantly decreased in the monotherapy group. In six children a mild bleeding tendency was observed, mostly epistaxis. Conclusion: A clinically relevant influence of valproic acid on haemostasis was found only in few cases. However, before surgical procedures an extended coagulation diagnostics is recommended in patients with valproic acid therapy. 相似文献
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von der Hagen M Schallner J Kaindl AM Koehler K Mitzscherling P Abicht A Grieben U Korinthenberg R Kress W von Moers A Müller JS Schara U Vorgerd M Walter MC Müller-Reible C Hübner C Lochmüller H Huebner A 《Neuromuscular disorders : NMD》2006,16(1):4-13
The identification of an ever increasing number of gene defects in patients with neuromuscular disorders has disclosed both marked phenotype and genotype variability and considerable disease overlap. In order to offer an economic strategy to characterise the molecular defect in patients with unclassified neuromuscular disorders, we designed DNA marker sets for linkage analysis of 62 distinct neuromuscular disorders gene loci, including all known muscular dystrophies, congenital myopathies, congenital myasthenic syndromes and myotonias. Genotyping of marker loci of 140 clinically well-characterised families with unclassified neuromuscular disorders reduced the number of candidates to one or two genes in 49 % of the families. Subsequent mutation analysis and genome-wide scans enabled the determination of the genetic defect in 31 % of the families including the identification of a new gene and a new mutation in an unexpected candidate gene. This highlights the effective application of this approach both for diagnostic strategies as well as for the identification of new loci and genes. 相似文献