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  1. Article ; Online: Cellular immunophenotype of major spine surgery in adults.

    Turnbull, Isaiah R / Hess, Annie / Fuchs, Anja / Frazier, Elfaridah P / Ghosh, Sarbani / Hughes, Shin-Wen / Kelly, Michael P

    Spine deformity

    2022  Volume 10, Issue 6, Page(s) 1375–1384

    Abstract: Purpose: ASD reconstructions are a major, sterile traumatic insult, likely causing perturbations to the immune systems. The immune response to surgery is associated with outcomes. The purpose of this study was to examine for a detectable immune ... ...

    Abstract Purpose: ASD reconstructions are a major, sterile traumatic insult, likely causing perturbations to the immune systems. The immune response to surgery is associated with outcomes. The purpose of this study was to examine for a detectable immune signature associated with ASD surgery.
    Methods: Consecutive patients undergoing ASD surgery were approached and enrolled. Peripheral blood was drawn before incision, 4 h after, and 24 h after incision. Blood was stabilized and comprehensive flow cytometric immunophenotyping performed. Leukocyte population frequency, absolute number and activation marker expression were defined. Immunologic features were defined and analyzed by hierarchical clustering and principal component analysis (PCA). Changes over time were evaluated by repeated measures ANOVA (RMANOVA) and were corrected for a 1% false discovery rate. Post hoc testing was by Dunn's test. p values of <  = 0.05 were considered significant.
    Results: Thirteen patients were enrolled; 11(85%) F, 65.4 years (± 7.5), surgical duration 418 ± 83 min, EBL 1928 ± 1253 mL. Hierarchical clustering and PCA found consistent time from incision-dependent changes. HLA-DR and activating co-stimulatory molecule CD86 were depressed at 4 h and furthermore at 24 h on monocyte surfaces. CD4 + HLA-DR + T cells, but not CD8 +, increased over time with increased expression of PD-1 at 4 and 24 h.
    Conclusions: Despite surgery and patient heterogeneity, we identified an immune signature associated with the sterile trauma of ASD surgery. Circulating leukocyte populations change in composition and signaling protein expression after incision and persisting to 24 h after incision, suggesting an immunocompromised state. Further work may determine relationships between this state and poor outcomes after surgery.
    MeSH term(s) Adult ; Humans ; Immunophenotyping ; Programmed Cell Death 1 Receptor ; HLA-DR Antigens/metabolism ; Flow Cytometry
    Chemical Substances Programmed Cell Death 1 Receptor ; HLA-DR Antigens
    Language English
    Publishing date 2022-06-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2717704-X
    ISSN 2212-1358 ; 2212-134X ; 2212-1358
    ISSN (online) 2212-1358 ; 2212-134X
    ISSN 2212-1358
    DOI 10.1007/s43390-022-00524-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Defects in vein valve PROX1/FOXC2 antithrombotic pathway in endothelial cells drive the hypercoagulable state induced by trauma and critical illness.

    Hoofnagle, Mark H / Hess, Annie / Nalugo, Margaret / Ghosh, Sarbani / Hughes, Shin-Wen / Fuchs, Anja / Welsh, John D / Kahn, Mark L / Bochicchio, Grant V / Randolph, Gwendalyn J / Leonard, Jennifer M / Turnbull, Isaiah R

    The journal of trauma and acute care surgery

    2023  Volume 95, Issue 2, Page(s) 197–204

    Abstract: Objectives: Deep venous thrombosis (DVT) causes significant morbidity and mortality after trauma. Recently, we have shown that blood flow patterns at vein valves induce oscillatory stress genes, which maintain an anticoagulant endothelial phenotype that ...

    Abstract Objectives: Deep venous thrombosis (DVT) causes significant morbidity and mortality after trauma. Recently, we have shown that blood flow patterns at vein valves induce oscillatory stress genes, which maintain an anticoagulant endothelial phenotype that inhibits spontaneous clotting at vein valves and sinuses, is lost in the presence of DVT in human pathological samples, and is dependent on expression of the transcription factor FOXC2. We describe an assay, modifying our mouse multiple injury system, which shows evidence of clinically relevant microthrombosis and hypercoagulability applicable to the study of spontaneous DVT in trauma without requiring direct vascular injury or ligation. Finally, we investigated whether these model findings are relevant to a human model of critical illness by examining gene expression changes by quantitative polymerase chain reaction and immunofluorescence in veins collected from critically ill.
    Methods: C57/Bl6 mice were subjected to a modified mouse multiple injury model with liver crush injury, crush and pseudofracture of a single lower extremity, and 15% total blood volume hemorrhage. Serum was assayed for d-dimer at 2, 6, 24, and 48 hours after injury by enzyme-linked immunosorbent assay. For the thrombin clotting assay, veins of the leg were exposed, 100 μL of 1 mM rhodamine (6 g) was injected retro-orbitally, and 450 μg/mL thrombin was then applied to the surface of the vein with examination of real-time clot formation via in vivo immunofluorescence microscopy. Images were then examined for percentage area of clot coverage of visible mouse saphenous and common femoral vein. Vein valve specific knockout of FOXC2 was induced with tamoxifen treatment in PROX1 Ert2Cre FOXC2 fl/fl mice as previously described. Animals were then subjected to a modified mouse multiple injury model with liver crush injury, crush and pseudofracture of a single lower extremity, and 15% total blood volume hemorrhage. Twenty-four hours after injury, we examined the valve phenotype in naive versus multiple injury animals, with and without loss of the FOXC2 gene from the vein valve (FOXC2 del ) via the thrombin assay. Images were then examined for proximity of clot formation to the valve present at the junction of the mouse saphenous, tibial, and superficial femoral vein and presence of spontaneous microthrombi present in the veins before exposure to thrombin. Human vein samples were obtained from excess tissue preserved after harvest for elective cardiac surgery and from organ donors after organ procurement. Sections were submitted for paraffin embedding and then assayed by immunofluorescence for PROX1, FOXC2, thrombomodulin, endothelial protein C receptor, and von Willebrand's factor. All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee, and all human studies reviewed and approved by the institutional review board.
    Results: After mouse multiple injuries, enzyme-linked immunosorbent assay for d-dimer showed evidence of products of fibrin breakdown consistent with formation of clot related to injury, fibrinolysis, and/or microthrombosis. The thrombin clotting assay demonstrated higher percentage area of vein covered with clot when exposed to thrombin in the multiple injury animals compared with uninjured (45% vs. 27% p = 0.0002) consistent with a phenotype of hypercoagulable state after trauma in our model system. Unmanipulated FoxC2 knockout mice manifest increased clotting at the vein valve as compared with unmanipulated wild type animals. After multiple injuries, wild type mice manifest increase clotting at the vein after thrombin exposure ( p = 0.0033), and equivalent to that of valvular knockout of FoxC2 (FoxC2del), recapitulating the phenotype seen in FoxC2 knockout animals. The combination of multiple injuries and FoxC2 knockout resulted in spontaneous microthrombi in 50% of the animals, a phenotype not observed with either multiple injuries or FoxC2 deficiency alone (χ 2 , p = 0.017). Finally, human vein samples demonstrated the protective vein valve phenotype of increased FOXC2 and PROX1 and showed decreased expression in the critically ill organ donor population by immunofluorescence imaging in organ donor samples.
    Conclusion: We have established a novel model of posttrauma hypercoagulation that does not require direct restriction of venous flow or direct injury to the vessel endothelium to assay for hypercoagulability and can generate spontaneous microthrombosis when combined with valve-specific FOXC2 knockout. We find that multiple injuries induce a procoagulant phenotype that recapitulates the valvular hypercoagulability seen in FOXC2 knockout and, in critically ill human specimens, find evidence for loss of oscillatory shear stress-induced gene expression of FOXC2 and PROX1 in the valvular endothelium consistent with potential loss of DVT-protective valvular phenotype.
    MeSH term(s) Animals ; Humans ; Mice ; Critical Illness ; Crush Injuries ; Endothelial Cells ; Femoral Vein ; Fibrinolytic Agents ; Multiple Trauma ; Thrombin/pharmacology ; Thrombophilia/etiology ; Thrombosis/etiology ; Transcription Factors
    Chemical Substances Fibrinolytic Agents ; Thrombin (EC 3.4.21.5) ; Transcription Factors ; mesenchyme fork head 1 protein ; prospero-related homeobox 1 protein
    Language English
    Publishing date 2023-04-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2651070-4
    ISSN 2163-0763 ; 2163-0755
    ISSN (online) 2163-0763
    ISSN 2163-0755
    DOI 10.1097/TA.0000000000003945
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 127: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Extrathoracic multiple trauma dysregulates neutrophil function and exacerbates pneumonia-induced lung injury.

    Leonard, Jennifer M / Zhang, Christina X / Lu, Liang / Hoofnagle, Mark H / Fuchs, Anja / Clemens, Regina A / Ghosh, Sarbani / Hughes, Shin-Wen / Bochicchio, Grant V / Hotchkiss, Richard / Turnbull, Isaiah R

    The journal of trauma and acute care surgery

    2021  Volume 90, Issue 6, Page(s) 924–934

    Abstract: Background: Forty percent of critically ill trauma patients will develop an infectious complication. Pneumonia is the most common cause of death of trauma patients surviving their initial insult. We previously demonstrated that polytrauma (PT), defined ... ...

    Abstract Background: Forty percent of critically ill trauma patients will develop an infectious complication. Pneumonia is the most common cause of death of trauma patients surviving their initial insult. We previously demonstrated that polytrauma (PT), defined as two or more severe injuries in at least two areas of the body, induces emergency hematopoiesis characterized by accelerated myelopoiesis in the bone marrow and increased myeloid cell frequency in the peripheral tissues. We hypothesized that PT alone induces priming of neutrophils, resulting in hyperactivation upon secondary exposure to bacteria and causing acute lung injury and increased susceptibility to secondary exposure to Pseudomonas aeruginosa pneumonia.
    Methods: C57BL/6 mice were subjected to PT consisting of a lower extremity pseudofracture, liver crush injury, and 15% blood-volume hemorrhage. Pneumonia was induced by intratracheal injection of 5 × 106 CFU live P. aeruginosa or 1 × 107 of heat-killed P. aeruginosa (HKPA). For reactive oxygen species (ROS), studies polymorphonuclear neutrophils (PMNs) were isolated by immunomagnetic bead negative selection and stimulated ex-vivo with HKPA. Reactive oxygen species production was measured by immunofluorescence. For histology, lung sections were stained by hematoxylin-eosin and analyzed by a blinded grader.
    Results: Polytrauma induced persistent changes in immune function at baseline and to secondary infection. Pneumonia after injury resulted in increased mortality (60% vs. 5% p < 0.01). Blood neutrophils from PT mice had higher resting (unstimulated) ROS production than in naive animals (p < 0.02) demonstrating priming of the neutrophils following PT. After intratracheal HKPA injection, bronchoalveolar lavage PMNs from injured mice had higher ROS production compared with naive mice (p < 0.01), demonstrating an overexuberant immunopathologic response of neutrophils following PT.
    Conclusion: Polytrauma primes neutrophils and causes immunopathologic PMN ROS production, increased lung injury and susceptibility to secondary bacterial pneumonia. These results suggest that trauma-induced immune dysfunction can cause immunopathologic response to secondary infection and suggests neutrophil-mediated pulmonary damage as a therapeutic target for posttrauma pneumonia.
    MeSH term(s) Acute Lung Injury/blood ; Acute Lung Injury/immunology ; Acute Lung Injury/microbiology ; Acute Lung Injury/pathology ; Animals ; Disease Models, Animal ; Humans ; Lung/immunology ; Lung/microbiology ; Lung/pathology ; Male ; Mice ; Multiple Trauma/blood ; Multiple Trauma/complications ; Multiple Trauma/diagnosis ; Multiple Trauma/immunology ; Neutrophils/immunology ; Neutrophils/metabolism ; Pneumonia, Bacterial/blood ; Pneumonia, Bacterial/immunology ; Pneumonia, Bacterial/microbiology ; Pneumonia, Bacterial/pathology ; Pseudomonas Infections/blood ; Pseudomonas Infections/immunology ; Pseudomonas Infections/microbiology ; Pseudomonas Infections/pathology ; Pseudomonas aeruginosa/immunology ; Reactive Oxygen Species/metabolism ; Trauma Severity Indices
    Chemical Substances Reactive Oxygen Species
    Language English
    Publishing date 2021-03-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2651070-4
    ISSN 2163-0763 ; 2163-0755
    ISSN (online) 2163-0763
    ISSN 2163-0755
    DOI 10.1097/TA.0000000000003147
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 127: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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