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      Increase of circulating endocan over sepsis follow-up is associated with progression into organ dysfunction

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          Abstract

          How circulating inflammatory mediators change upon sepsis progression has not been studied. We studied the follow-up changes of circulating vasoactive peptides and cytokines until the improvement or the worsening of a patient and progression into specific organ dysfunctions. In a prospective study, concentrations of tumor necrosis factor-alpha (TNFα), interleukin (IL)-6, IL-8, IL-10, interferon-gamma (IFNγ), endocan and angiopoietin-2 (Ang-2) were measured in serum by an enzyme immunoassay in 175 patients at baseline; this was repeated within 24 h upon progression into new organ dysfunction ( n = 141) or improvement ( n = 34). Endocan and Ang-2 were the only parameters that were significantly increased among patients who worsened. Any increase of endocan was associated with worsening with odds ratio 16.65 ( p < 0.0001). This increase was independently associated with progression into acute respiratory distress syndrome (ARDS) as shown after logistic regression analysis (odds ratio 2.91, p: 0.002). Changes of circulating cytokines do not mediate worsening of the critically ill patients. Instead endocan and Ang2 are increased and this may be interpreted as a key-playing role in the pathogenesis of ARDS and septic shock. Any increase of endocan is a surrogate of worsening of the clinical course.

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          Most cited references12

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          The international sepsis forum consensus conference on definitions of infection in the intensive care unit.

          To develop definitions of infection that can be used in clinical trials in patients with sepsis. Infection is a key component of the definition of sepsis, yet there is currently no agreement on the definitions that should be used to identify specific infections in patients with sepsis. Agreeing on a set of valid definitions that can be easily implemented as part of a clinical trial protocol would facilitate patient selection, help classify patients into prospectively defined infection categories, and therefore greatly reduce variability between treatment groups. Experts in infectious diseases, clinical microbiology, and critical care medicine were recruited and allocated specific infection sites. They carried out a systematic literature review and used this, and their own experience, to prepare a draft definition. At a subsequent consensus conference, rapporteurs presented the draft definitions, and these were then refined and improved during discussion. Modifications were circulated electronically and subsequently agreed upon as part of an iterative process until consensus was reached. Consensus definitions of infection were developed for the six most frequent causes of infections in septic patients: pneumonia, bloodstream infections (including infective endocarditis), intravascular catheter-related sepsis, intra-abdominal infections, urosepsis, and surgical wound infections. We have described standardized definitions of the common sites of infection associated with sepsis in critically ill patients. Use of these definitions in clinical trials should help improve the quality of clinical research in this field.
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            Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study.

            Reversal of sepsis-induced immunoparalysis may reduce the incidence of secondary infections and improve outcome. Although IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) restore immune competence of ex vivo stimulated leukocytes of patients with sepsis, effects on immunoparalysis in vivo are not known. To investigate the effects of IFN-γ and GM-CSF on immunoparalysis in vivo in humans. We performed a double-blind, placebo-controlled, randomized study in 18 healthy male volunteers that received Escherichia coli endotoxin (LPS; 2 ng/kg, intravenously) on days 1 and 7 (visits 1 and 2). On days 2, 4, and 6, subjects received subcutaneous injections of IFN-γ (100 μg/day; n = 6), GM-CSF (4 μg/kg/day; n = 6), or placebo (NaCl 0.9%; n = 6). In the placebo group, immunoparalysis was illustrated by a 60% (48-71%) reduction of LPS-induced tumor necrosis factor (TNF)-α plasma concentrations during visit 2 (P = 0.03), whereas the antiinflammatory IL-10 response was not significantly attenuated (39% [2-65%]; P = 0.15). In contrast, in the IFN-γ group, TNF-α concentrations during visit 2 were not significantly attenuated (28% [1-47%]; P = 0.09), whereas the IL-10 response was significantly lower (reduction of 54% [47-66%]; P = 0.03). Compared with the placebo group, the reduction in the LPS-induced TNF-α response during visit 2 was significantly less pronounced in the IFN-γ group (P = 0.01). Moreover, compared with placebo, treatment with IFN-γ increased monocyte HLA-DR expression (P = 0.02). The effects of GM-CSF tended in the same direction as IFN-γ, but were not statistically significant compared with placebo. IFN-γ partially reverses immunoparalysis in vivo in humans. These results suggest that IFN-γ is a promising treatment option to reverse sepsis-induced immunoparalysis.
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              Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity.

              Proteoglycans that modulate the activities of growth factors, chemokines, and coagulation factors regulate in turn the vascular endothelium with respect to processes such as inflammation, hemostasis, and angiogenesis. Endothelial cell-specific molecule-1 is mainly expressed by endothelial cells and regulated by pro-inflammatory cytokines (Lassalle, P., Molet, S., Janin, A., Heyden, J. V., Tavernier, J., Fiers, W., Devos, R., and Tonnel, A. B. (1996) J. Biol. Chem. 271, 20458-20464). We demonstrate that this molecule is secreted as a soluble dermatan sulfate (DS) proteoglycan. This proteoglycan represents the major form either secreted by cell lines or circulating in the human bloodstream. Because this proteoglycan is specifically secreted by endothelial cells, we propose to name it endocan. The glycosaminoglycan component of endocan consists of a single DS chain covalently attached to serine 137. Endocan dose-dependently increased the hepatocyte growth factor/scatter factor (HGF/SF)-mediated proliferation of human embryonic kidney cells, whereas the nonglycanated form of endocan did not. Moreover, DS chains purified from endocan mimicked the endocan-mediated increase of cell proliferation in the presence of HGF/SF. Overall, our results demonstrate that endocan is a novel soluble dermatan sulfate proteoglycan produced by endothelial cells. Endocan regulates HGF/SF-mediated mitogenic activity and may support the function of HGF/SF not only in embryogenesis and tissue repair after injury but also in tumor progression.
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                Author and article information

                Contributors
                +30-210-5831994 , egiamarel@med.uoa.gr
                Journal
                Eur J Clin Microbiol Infect Dis
                Eur. J. Clin. Microbiol. Infect. Dis
                European Journal of Clinical Microbiology & Infectious Diseases
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0934-9723
                1435-4373
                28 April 2017
                2017
                : 36
                : 10
                : 1749-1756
                Affiliations
                [1 ]Intensive Care Unit, Korinthos General Hospital, Korinthos, Greece
                [2 ]GRID grid.414012.2, Intensive Care Unit, , Korgialeneion Benakeion General Hospital, ; Athens, Greece
                [3 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, 2nd Department of Critical Care Medicine, , National and Kapodistrian University of Athens, Medical School, ; Athens, Greece
                [4 ]GRID grid.414012.2, Intensive Care Unit, , “G. Gennimatas” General Hospital, ; Thessaloniki, Greece
                [5 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, 3rd Department of Internal Medicine, , National and Kapodistrian University of Athens, Medical School, ; Athens, Greece
                [6 ]GRID grid.414012.2, Intensive Care Unit, , “Aghios Pavlos” General Hospital, ; Thessaloniki, Greece
                [7 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, 4th Department of Internal Medicine, , National and Kapodistrian University of Athens, Medical School, ; Athens, Greece
                [8 ]ISNI 0000 0004 0622 4662, GRID grid.411449.d, 4th Department of Internal Medicine, , ATTIKON University General Hospital, ; 124 62 Athens, Greece
                [9 ]GRID grid.417374.2, Intensive Care Unit, , Tzaneion General Hospital, ; Piraeus, Greece
                [10 ]ISNI 0000 0001 2159 9858, GRID grid.8970.6, INSERM U1019E13, Pasteur Institute of Lille, ; Lille, France
                [11 ]ISNI 0000 0004 0576 5395, GRID grid.11047.33, Department of Internal Medicine, , University of Patras, Medical School, ; Patras, Greece
                Author information
                http://orcid.org/0000-0003-4713-3911
                Article
                2988
                10.1007/s10096-017-2988-6
                7101577
                28455780
                60b4a05a-def3-4f08-ba59-4841ce37debf
                © Springer-Verlag Berlin Heidelberg 2017

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 23 January 2017
                : 13 April 2017
                Funding
                Funded by: Hellenic Institute for the Study of Sepsis
                Funded by: Lunginnov s.a.s Campus de l’Institut Pasteur de Lille
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany 2017

                Infectious disease & Microbiology
                septic shock,acute lung injury,organ dysfunction,acute kidney injury,systemic inflammatory response syndrome

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