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Detailed information on C1INH-concentrate: Cetor® consists of dried C1INH prepared from human plasma. The product is known to be >90% pure. After being dissolved in the prescribed volume of water for injections the product contains 100U of C1INH/ ml. Analysis of the batch, used in the current study, demonstrated a protein amount of 13.7g/l and a specific activity of 5.9 U/ml. Detailed information on the measurements of the hemodynamic and clinical response: After admission to our research intensive care unit, the radial artery was cannulated with a 20 gauge arterial catheter (Angiomat, Deseret Medical, Becton Dickinson, Sandy, UT) under local anaesthesia (lidocaine HCL 20 mg/ml). This catheter was connected to an arterial pressure monitoring set (Edwards Lifesciences LLC, Irvine, CA) and a Philips IntelliVue MP70 monitor (Philips Medical Systems, Eindhoven, The Netherlands). The mean arterial pressure (MAP) was determined using the electronically integrated area under the arterial pulse wave curve. Heart rate and respiratory rate monitoring were performed during the entire experiment using a 5-lead ECG. A cannula was placed in an antecubital vein to permit infusion of prehydration fluid (1.5 L 2.5% glucose/0.45% saline in 1 hr), endotoxin, C1INH or placebo and a continuous infusion of 150 ml/hr 2.5% glucose/0.45% saline during the rest of the experiment until discharge. Detailed information on the assays performed: All blood samples (anticoagulated with EDTA) were drawn from the arterial line, except for samples obtained at t=24 h when blood was sampled using regular vena puncture. For cytokine measurements, plasma was obtained immediately after blood sampling by centrifugation at 2000xg for 15 minutes at a temperature of 4°C. Hereafter, plasma was stored at -80°C until analysis. The concentrations of circulating cytokines TNF-α, IL-10, IL-6, Monocyte Chemotactic Protein (MCP)-1, IL1-β and IL-1RA, as well as concentrations of soluble vascular cell and inter-cellular adhesion molecules (VCAM-1 and ICAM-1), von Willebrand Factor (VWF) and platelet (P)-selectin were determined in EDTA plasma obtained immediately before endotoxin administration and serially thereafter. Measurements of all cytokines and of the soluble adhesion molecules VCAM-1 and ICAM-1 were performed by a multiplex assay according to the manufacturer’s instructions (Bio-plex cytokine assay, BioRad, Hercules, CA, USA at Luminex 100, Luminex Corporation, Oosterhout, The Netherlands). Coefficients of variation were less than 10% for all cytokines and for VCAM-1 and ICAM- analysis. The lower limits of detection in this assay amounted 6 pg/ml for IL-6 and IL-10, 7 pg/ml for MCP-1, 10 pg/ml for IL-1β, 20 pg/ml for TNF-α, 72 pg/ml for IL1-RA, 581 pg/ml for VCAM-1 and 3633 pg/ml for ICAM-1. VWF and P-selectin were determined by ELISA (Progen biotechnik, Heidelberg, Germany and R&D systems, Minneapolis, MN). Activity of C1INH, C1INH antigen and complement factor 4 were determined just before and serially after endotoxin administration on plasma obtained immediately after sampling by centrifugation at 2000xg for 15 minutes at 20°C. The determination of C1INH activity was performed using the Berichrom C1INH kit (Siemens healthcare diagnostics, Deerfield, IL, USA, previously Dade Behring) and a Tecan Freedom EVO 150 robot (Tecan Group, Männedorf, Switzerland). The quantitative determination of C1INH antigen and complement factor 4 was achieved using a Behring Nefelometer (BNII) (Siemens healthcare diagnostics, Deerfield, IL, previously Dade Behring). C-reactive protein (CRP) levels were measured just before and at 8 and 24 hrs after endotoxin administration in lithium heparin plasma using immunologic detection according to the instructions of the manufacturer (Aeroset, Abbott Laboratories, Abbott Park, IL, U.S.A.). Hematologic values were determined in EDTA anti-coagulated blood using flow-cytometry (Sysmex XE-2100, Goffin Meyvis, Etten- Leur, The Netherlands) just before and serially after endotoxin infusion.