Soluble ST2 Levels Are Associated with Bleeding in Patients with Severe Leptospirosis 英文参考文献.docVIP

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Soluble ST2 Levels Are Associated with Bleeding in Patients with Severe Leptospirosis 英文参考文献.doc

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SolubleST2LevelsAreAssociatedwithBleedingin PatientswithSevereLeptospirosis JiriF.P.Wagenaar1*,M.HusseinGasem2,MargaG.A.Goris3,MariskaLeeflang3,RudyA.Hartskeerl3, TomvanderPoll4,Cornelisvan’tVeer4,EricC.M.vanGorp1 1Department ofInternalMedicine,SlotervaartHospital,Amsterdam,TheNetherlands, 2Department ofInternal Medicine,Dr.KariadiHospital–DiponegoroUniversity, Semarang, Indonesia, 3Royal Tropical Institute (KIT), KIT Biomedical Research, Amsterdam, The Netherlands, 4Center for Experimental and Molecular Medicine, Amsterdam,TheNetherlands Abstract Background: Severe leptospirosis features bleeding and multi-organ failure, leading to shock and death. Currently it is assumedthatbothexaggeratedinflammationandimmunesuppressioncontributetomortalityinsepsis.Indeed,several proinflammatorycytokinesarereportedtobeinducedduringleptospirosis.Toll-likereceptors,whichplayanimportantrole intheinitiationofaninnateimmuneresponse,areinhibitedbynegativeregulatorsincludingthemembrane-boundST2 (mST2)receptor.SolubleST2(sST2)hasbeenimplicatedtoinhibitsignalingthroughmST2.Theaimofthisstudywasto determinetheextentofsST2and(pro-)inflammatorycytokinereleaseinpatientswithsevereleptospirosis. MethodologyandPrincipalFindings:Inanobservationalstudy,68consecutivecasesofsevereleptospirosiswereincluded. SolubleST2andcytokines(TNF-a,IL-1b,IL-6,IL-8,andIL-10)wererepeatedlymeasured.Todeterminewhetherbloodcells are a source of sST2 during infection, we undertook an in vitro experiment: human whole blood and peripheral blood mononuclearcells(PBMC)werestimulatedwithviablepathogenicLeptospira.AllpatientsshowedelevatedsST2,IL-6,IL-8, andIL-10levelsonadmission.AdmissionsST2levelscorrelatedwithIL-6,IL-8,andIL-10.Thirty-fourpatients(50%)showed clinicalbleeding.SolubleST2levelsweresignificantlyassociatedwithbleedingoverall(OR2.0;95%CI:1.2–3.6)andsevere bleeding (OR 5.1; 95%CI: 1.1–23.8). This association was unique, since none of the cytokines showed this correlation. Moreover,sST2wasassociatedwithmorta