Enhancement of fibrinogen-triggered pro-coagulant activation of monocytes in vitro by matrix metalloproteinase-9

<p>Abstract</p> <p>Background</p> <p>Interaction of fibrinogen with specific leukocyte integrins of monocytes may link coagulation and inflammation, however, the precise mechanism of fibrinogen leading to the pro-inflammatory and pro-coagulatory response on monocytes is yet unknown.</p> <p>Results</p> <p>Fibrinogen and its digestion fragment D induced pro-coagulant activation of monocytes as assessed in a cellular coagulation assay by reductions in clotting times. Pro-coagulant activation was reversed by blocking antibodies against Mac-1 or LFA-1. Pre-exposure of monocytes to the p38 MAPK inhibitor SB 202190 and the MEK1.2 inhibitor U0126 led to significant increasees in coagulation times whereas blocking JNKII with its inhibitor had no such effect. Blocking NFκB with MG-132 also inhibited pro-coagulant activation of monocytes by fibrinogen. A selective inhibitor of matrix metalloproteinase-9 increased times to clot formation whereas other matrix metalloproteinase inhibitors did not significantly interfere with fibrinogen-augmented clot formation in this assay. Treatment of monocytes with fibrinogen increased concentrations of matrix metalloproteinase-9 immunoreactivity in their supernatants.</p> <p>Conclusions</p> <p>Fibrinogen induces monocyte pro-coagulant activation in an integrin-, nuclear factor κB-, p38 MAPK-, and MEK1.2-dependent manner. Activation of monocytes by fibrinogen increases metalloproteinase-9 secretion, metalloproteinase-9 itself enhances monocyte coagulation by an autocrine mechanism. Results provide further evidence that mediators of hemostasis have a profound impact on cells of the immune system and are closely related to inflammatory pathways.</p

Impact of Morphine Treatment on Infarct Size and Reperfusion Injury in Acute Reperfused ST-Elevation Myocardial Infarction

Current evidence regarding the effect of intravenous morphine administration on reperfusion injury and/or cardioprotection in patients with myocardial infarction is conflicting. The aim of this study was to evaluate the impact of morphine administration, on infarct size and reperfusion injury assessed by cardiac magnetic resonance imaging (CMR) in a large multicenter ST-elevation myocardial infarction (STEMI) population. In total, 734 STEMI patients reperfused by primary percutaneous coronary intervention <12 h after symptom onset underwent CMR imaging at eight centers for assessment of myocardial damage. Intravenous morphine administration was recorded in all patients. CMR was completed within one week after infarction using a standardized protocol. The clinical endpoint of the study was the occurrence of major adverse cardiac events (MACE) within 12 months after infarction. Intravenous morphine was administered in 61.8% (n = 454) of all patients. There were no differences in infarct size (17%LV, interquartile range [IQR] 8–25%LV versus 16%LV, IQR 8–26%LV, p = 0.67) and microvascular obstruction (p = 0.92) in patients with versus without morphine administration. In the subgroup of patients with early reperfusion within 120 min and reduced flow of the infarcted vessel (TIMI-flow ≤2 before PCI) morphine administration resulted in significantly smaller infarcts (12%LV, IQR 12–19 versus 19%LV, IQR 10–29, p = 0.035) and reduced microvascular obstruction (p = 0.003). Morphine administration had no effect on hard clinical endpoints (log-rank test p = 0.74) and was not an independent predictor of clinical outcome in Cox regression analysis. In our large multicenter CMR study, morphine administration did not have a negative effect on myocardial damage or clinical prognosis in acute reperfused STEMI. In patients, presenting early ( ≤120 min) morphine may have a cardioprotective effect as reflected by smaller infarcts; but this finding has to be assessed in further well-designed clinical studie

The Transmogrification of Teacher Education

The version of this article archived here is the author's post-print.Ye

Prognostic Impact of Active Mechanical Circulatory Support in Cardiogenic Shock Complicating Acute Myocardial Infarction, Results from the Culprit-Shock Trial

Objectives: To analyze the use and prognostic impact of active mechanical circulatory support (MCS) devices in a large prospective contemporary cohort of patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI). Background: Although increasingly used in clinical practice, data on the efficacy and safety of active MCS devices in patients with CS complicating AMI are limited. Methods: This is a predefined subanalysis of the CULPRIT-SHOCK randomized trial and prospective registry. Patients with CS, AMI and multivessel coronary artery disease were categorized in two groups: (1) use of at least one active MCS device vs. (2) no active MCS or use of intra-aortic balloon pump (IABP) only. The primary endpoint was a composite of all-cause death or renal replacement therapy at 30 days. Results: Two hundred of 1055 (19%) patients received at least one active MCS device (n = 112 Impella®; n = 95 extracorporeal membrane oxygenation (ECMO); n = 6 other devices). The primary endpoint occurred significantly more often in patients treated with active MCS devices compared with those without active MCS devices (142 of 197, 72% vs. 374 of 827, 45%; p < 0.001). All-cause mortality and bleeding rates were significantly higher in the active MCS group (all p < 0.001). After multivariable adjustment, the use of active MCS was significantly associated with the primary endpoint (odds ratio (OR) 4.0, 95% confidence interval (CI) 2.7–5.9; p < 0.001). Conclusions: In the CULPRIT-SHOCK trial, active MCS devices were used in approximately one fifth of patients. Patients treated with active MCS devices showed worse outcome at 30 days and 1 year

Dysregulation of macrophage polarization is associated with the metastatic process in osteosarcoma

Osteosarcoma (OS) is the most common bone sarcoma in adolescents, and has poor prognosis. A vicious cycle is established between OS cells and their microenvironment in order to facilitate the tumor growth and cell spreading. The present work aims to better characterize the tumor microenvironment in OS in order to identify new therapeutic targets relating to metastatic process. Tissue microarrays of pre-chemotherapy OS biopsies were used for characterizing the tumor niche by immunohistochemistry. Parameters studies included: immune cells (M1, Mβ-subtypes of tumor-associated macrophages (TAM); T, B lymphocytes; mast cells), vascularization (endothelial, perivascular cells), OPG, RANKL, and mitotic index. Two groups of patients were defined, ββ localized OS (OS Meta-) and β8 metastatic OS (OS Meta+). The OS Meta- group was characterized by a higher infiltration of INOS+ M1-polarized macrophages and upregulated OPG immunostaining. OS Meta+ tumors showed a significant increase in CD146+ cells. INOS+ M1-macrophages were correlated with OPG staining, and negatively with the presence of metastases. CD16γ+ Mβ-macrophages were positively correlated with CD146+ cells. In multivariate analysis, INOS and OPG were predictive factors for metastasis. An older age, non-metastatic tumor, good response to chemotherapy, and higher macrophage infiltration were significantly associated with better overall survival. TAMs are associated with better overall survival and a dysregulation of M1/Mβ polarized-macrophages in favor of M1 subtype was observed in non-metastatic OS

Biomarkers of Hemodynamic Stress and Aortic Stiffness after STEMI: A Cross-Sectional Analysis

Aim. Increased aortic stiffness might adversely affect cardiac structure, function, and perfusion. Release of biomarkers of hemodynamic stress is thought to be enhanced by these alterations. We aimed to evaluate the association between biomarkers of hemodynamic stress and aortic stiffness assessed at a chronic stage after ST-segment elevation myocardial infarction (STEMI). Methods. Fifty-four patients four months after STEMI were enrolled in this cross-sectional, single-center study. N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP), and mid-regional proadrenomedullin (MR-proADM) levels were measured by established assays. Aortic stiffness was assessed by the measurement of pulse wave velocity using phase-contrast cardiovascular magnetic resonance. Results. NT-proBNP, MR-proANP, and MR-proADM concentrations were all correlated with aortic stiffness in univariate analysis ( = 0.378, = 0.425, and = 0.532; all &lt; 0.005, resp.). In multiple linear regression analysis, NT-proBNP ( = 0.316, = 0.005) and MR-proADM ( = 0.284, &lt; 0.020) levels were associated with increased aortic stiffness independently of age, blood pressure, and renal function. NT-proBNP was the strongest predictor for high aortic stiffness (area under the curve: 0.82, 95% CI 0.67-0.96). Conclusion. At a chronic stage after STEMI, concentrations of biomarkers for hemodynamic stress, especially NT-proBNP, are positively correlated with aortic stiffness. These biomarkers might also be useful as predictors of high aortic stiffness after STEMI