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      Low Serum Angiopoietin-1, High Serum Angiopoietin-2, and High Ang-2/Ang-1 Protein Ratio are Associated with Early Onset Sepsis in Surinamese Newborns

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          ABSTRACT

          Purpose:

          Vascular inflammation and leakage in sepsis is mediated by Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) and their phosphorylation of the endothelial Tie-2 receptor. This study investigates levels of Ang-1 and Ang-2 in newborns to gain insight in the vascular pathophysiology of early onset sepsis (EOS) within 72 h after birth.

          Methods:

          A prospective cohort study was performed among 71 Surinamese newborns treated with antibiotics for suspected EOS and 20 control newborns. Newborns with suspected EOS were divided in two groups: blood culture negative and positive EOS. Ang-1 and Ang-2 levels were measured in serum obtained at the start of antibiotic treatment and at re-evaluation after 48 to 72 h.

          Results:

          In this cohort 8.5% of newborns had a positive blood culture. At the start of antibiotic treatment Ang-1 serum levels were lower ( P < 0.01), and Ang-2 and Ang-2/Ang-1 serum protein ratios were higher ( P < 0.01 and P < 0.01, respectively) in newborns with blood culture positive EOS than in controls. These levels were not dependent on timing of first blood draw after birth. After 48 to 72 h levels of Ang-1 further decreased in blood culture positive EOS, while in the other groups no change was observed.

          Conclusions:

          Our findings support the hypothesis that a disbalance in the Angiopoietins plays a role in the vascular pathophysiology of EOS.

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          Most cited references28

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          Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

          The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.
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            Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium.

            Angiopoietin 2 (Ang2) was originally shown to be a competitive antagonist for Ang1 of the receptor tyrosine kinase Tie2 in endothelial cells (ECs). Since then, reports have conflicted on whether Ang2 is an agonist or antagonist of Tie2. Here we show that Ang2 functions as an agonist when Ang1 is absent but as a dose-dependent antagonist when Ang1 is present. Exogenous Ang2 activates Tie2 and the promigratory, prosurvival PI3K/Akt pathway in ECs but with less potency and lower affinity than exogenous Ang1. ECs produce Ang2 but not Ang1. This endogenous Ang2 maintains Tie2, phosphatidylinositol 3-kinase, and Akt activities, and it promotes EC survival, migration, and tube formation. However, when ECs are stimulated with Ang1 and Ang2, Ang2 dose-dependently inhibits Ang1-induced Tie2 phosphorylation, Akt activation, and EC survival. We conclude that Ang2 is both an agonist and an antagonist of Tie2. Although Ang2 is a weaker agonist than Ang1, endogenous Ang2 maintains a level of Tie2 activation that is critical to a spectrum of EC functions. These findings may reconcile disparate reports of Ang2's effect on Tie2, impact our understanding of endogenous receptor tyrosine kinase signal transduction mechanisms, and affect how Ang2 and Tie2 are targeted under conditions such as sepsis and cancer.
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              An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks.

              C-reactive protein (CRP) is one of the most studied and most used laboratory tests for neonatal sepsis. As part of the acute-phase reaction to infection, it plays a central role in the humoral response to bacterial invasion. The delayed synthesis during the inflammatory response accounts for its low sensitivity during the early phases of the disease. Diagnostic accuracy clearly improves by the performance of serial determinations and by the combination with earlier markers such as interleukins or procalcitonin. CRP is as well particularly useful for monitoring the response to treatment and guiding antibiotic therapy, though nothing replaces the clinical impression and the gold standard (i.e. culture results). In spite of the large amount of research done on CRP in neonates, some topics are still not fully understood, such as the influence of noninfectious factors on CRP levels in healthy as well as in symptomatic neonates and the role of gestational age and birthweight on CRP kinetics. In this review, we aim to give an update on the current evidence on the use of CRP in neonates. Copyright © 2012 S. Karger AG, Basel.
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                Author and article information

                Journal
                Shock
                Shock
                SHK
                Shock (Augusta, Ga.)
                Lippincott Williams & Wilkins
                1073-2322
                1540-0514
                December 2017
                13 November 2017
                : 48
                : 6
                : 638-643
                Affiliations
                []Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
                []Academic Pediatric Center Suriname, Paramaribo, Suriname
                []Scientific Research Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname
                [§ ]Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
                [|| ]Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
                []Department of Pediatrics, Diakonessen Hospital, Paramaribo, Suriname
                [# ]Department of Pediatrics, Tergooi Hospitals, Blaricum, The Netherlands
                Author notes
                Address reprint requests to Rens Zonneveld, MD, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: rens.zonneveld@ 123456gmail.com
                Article
                SHOCK-D-17-00176
                10.1097/SHK.0000000000000903
                5647105
                28538018
                cd601cdc-80bb-42c9-8947-a8657e73988e
                Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                : 29 March 2017
                : 13 April 2017
                : 20 May 2017
                Categories
                Clinical Science Aspects
                Custom metadata
                TRUE

                angiopoietins,early onset sepsis,newborn,suriname,ang-1,angiopoietin-1,ang-2,angiopoietin-2,eos,tie-2,tek tyrosine kinase endothelial-2 receptor

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