Nebulized heparin in burn patients with inhalation trauma : safety and feasibility

Background: Pulmonary hypercoagulopathy is intrinsic to inhalation trauma. Nebulized heparin could theoretically be beneficial in patients with inhalation injury, but current data are conflicting. We aimed to investigate the safety, feasibility, and effectiveness of nebulized heparin. Methods: International multicenter, double-blind, placebo-controlled randomized clinical trial in specialized burn care centers. Adult patients with inhalation trauma received nebulizations of unfractionated heparin (25,000 international unit (IU), 5 mL) or placebo (0.9% NaCl, 5 mL) every four hours for 14 days or until extubation. The primary outcome was the number of ventilator-free days at day 28 post-admission. Here, we report on the secondary outcomes related to safety and feasibility. Results: The study was prematurely stopped after inclusion of 13 patients (heparin N = 7, placebo N = 6) due to low recruitment and high costs associated with the trial medication. Therefore, no analyses on effectiveness were performed. In the heparin group, serious respiratory problems occurred due to saturation of the expiratory filter following nebulizations. In total, 129 out of 427 scheduled nebulizations were withheld in the heparin group (in 3 patients) and 45 out of 299 scheduled nebulizations were withheld in the placebo group (in 2 patients). Blood-stained sputum or expected increased bleeding risks were the most frequent reasons to withhold nebulizations. Conclusion: In this prematurely stopped trial, we encountered important safety and feasibility issues related to frequent heparin nebulizations in burn patients with inhalation trauma. This should be taken into account when heparin nebulizations are considered in these patients

Exploring a link between the Middle Eocene Climatic Optimum and Neotethys continental arc flare-up

© Author(s) 2021.The Middle Eocene Climatic Optimum (MECO), a ~ 500 kyr episode of global warming that initiated at ~40.5 Ma, is postulated to be driven by a net increase in volcanic carbon input, but a direct source has not been identified. Here we show, based on new and previously published radiometric ages of volcanic rocks, that the interval spanning the MECO corresponds to a massive increase in continental arc volcanism in Iran and Azerbaijan. Ages of Eocene igneous rocks in all volcanic provinces of Iran cluster around 40 Ma, very close to the peak warming phase of the MECO. Based on the spatial extent and volume of the volcanic rocks as well as the carbonaceous lithology in which they are emplaced, we estimate the total amount of CO2 that could have been released at this time corresponds to between 1052 and 12 565 Pg carbon. This is compatible with the estimated carbon release during the MECO. Although the uncertainty in both individual ages, and the spread in the compilation of ages, is larger than the duration of the MECO, a flare-up in Neotethys subduction zone volcanism represents a plausible excess carbon source responsible for MECO warming

Rhinovirus infection induces procoagulant changes in parallel with eosinophilic airway inflammation

Background: Asthma exacerbations are frequently triggered by rhinovirus infections. Asthma itself is associated with activated coagulation and increased risk of venous thromboembolism1 and also respiratory viruses may activate hemostasis. Vice versa, a prothrombotic state in the lung can also induce or aggravate pulmonary inflammation. Aim: To determine whether rhinovirus infection and asthmatic airway inflammation act on the local and systemic hemostatic balance in patients in vivo. Methods: In a two-groups parallel study design 28 volunteers (14 patients with mild asthma (seven females, 19-26 years) and 14 healthy controls (13 females, 19-31 years)) were experimentalliy infected with low-dose rhinovirus serotype 16 (RV16). Patients with mild asthma were stable after discontinuation of their asthma medication 2 weeks prior to RV16 inoculation. Venous plasma and bronchoalveolar lavage fluid (BAL fluid) were obtained 1 day before and 6 days after rhinovirus challange to evaluate several key markers of coagulation activation in plasma and BAL fluid, as well as the coagulant features of microparticles in BAL fluid. Thrombin-antithrombin complexes (TATc), von Willebrand factor (vWF), Plasmin-antiplasmin complexes (PAP), Plasminogen activator inhibitor type-1 (PAI-1), and eosinophil cationic protein (ECP) in plasma and BAL fluid were measured by immunoassay. Endogenous thrombin potential (ETP) was analysed using the Calibrated Automated Thrombogram® and tissue factor bearing microparticles, measured by fibrin generation test (FGT). Eosinophils were counted on cytospin preparations. Comparisons and correlations were performed by non-parametric testing. Results: In plasma, RV16 challange resulted in increased PAI-1 levels in patients with asthma after viral infection (26.5 ng/mL in patients with astma vs. 10.0 ng/mL in healthy controls, P = 0.01) and decreased PAP levels (318 vs. 534 ng/mL resp., P = 0.04). Changes in PAI-1 levels were significantly elevated in asthma than in control subjects (3.0 vs. -3.5 ng/L respectively, P = 0.024), while changes in TATc, D-dimer, vWF and ETP did not differ between both groups. In BAL fluid, the FGT shortened after viral infection in asthma (t = -1 day: 689s vs. t = 6 days: 516 s; P = 0.011), but not in healthy controls (t = -1 day: 695s vs. t = 6 days: 672 s; P = 0.79). The changes in TATc and PAP did not differ between both groups and vWF, D-dimer and PAI-1 were below the detection limit. Both FGT and TATc in BAL fluid correlated (Spearman) with eosinophil counts and ECP (r = -0.583 and -0.682 resp. for FGT and r = 0.535 and 0.619 resp. for TATc, all P <0.01) Conclusion: Experimental rhinovirus infection induces procoagulant changes in patients with asthma systemically through PAI-1 and in the airways by TF-bearing microparticles. This did not lead to changes in global assays of hemostasis, probably due to the relatively mild infection in patients with mild to intermittent asthma. In the airways, microparticle-associated procoagulant changes are associated with eosinophilic inflammation, suggesting that virus infection and eosinophilic inflammation both act on the hemostatic (dis)balance during asthma exacerbations

Selective expansion of influenza A virus-specific T cells in symptomatic human carotid artery atherosclerotic plaques

BACKGROUND AND PURPOSE - Evidence is accumulating that infection with influenza A virus contributes to atherothrombotic disease. Vaccination against influenza decreases the risk of atherosclerotic syndromes, indicating that inflammatory mechanisms may be involved. We tested the hypothesis that influenza A virus-specific T cells contribute to atherosclerotic plaque inflammation, which mediates the onset of plaque rupture. METHODS - T-cell cultures were generated from atherosclerotic segments and peripheral blood of 30 patients with symptomatic carotid artery disease. The response of plaque and peripheral blood T cells to influenza A virus was analyzed and expressed as a stimulation index (SI). Selective outgrowth of intraplaque influenza A-specific T cells was calculated by the ratio of plaque T cell SI and peripheral blood T cell SI for each patient. Accordingly, the patients were categorized as high- (SI ratio ≥5), intermediate- (5 <SI ratio ≤2), and non- (SI ratio <2) responders. The presence of influenza A virus in the vessel fragments was evaluated by reverse transcription-polymerase chain reaction. RESULTS - High proliferative responses of plaque-derived T cells to influenza A virus were frequently observed. Among the 30 patients, 5 were categorized as high responders, 10 were intermediate responders, and 15 were nonresponders. Live influenza A viru

Bispecific antibody generated with sortase and click chemistry has broad anti-influenza virus activity

Bispecific antibodies have therapeutic potential by expanding the functions of conventional antibodies. Many different formats of bispecific antibodies have meanwhile been developed. Most are genetic modifications of the antibody backbone to facilitate incorporation of two different variable domains into a single molecule. Here, we present a bispecific format where we have fused two full-sized IgG antibodies via their C termini using sortase transpeptidation and click chemistry to create a covalently linked IgG antibody heterodimer. By linking two potent anti-influenza A antibodies together, we have generated a full antibody dimer with bispecific activity that retains the activity and stability of the two fusion partners

Bispecific antibody generated with sortase and click chemistry has broad anti-influenza virus activity

Bispecific antibodies have therapeutic potential by expanding the functions of conventional antibodies. Many different formats of bispecific antibodies have meanwhile been developed. Most are genetic modifications of the antibody backbone to facilitate incorporation of two different variable domains into a single molecule. Here, we present a bispecific format where we have fused two full-sized IgG antibodies via their C termini using sortase transpeptidation and click chemistry to create a covalently linked IgG antibody heterodimer. By linking two potent anti-influenza A antibodies together, we have generated a full antibody dimer with bispecific activity that retains the activity and stability of the two fusion partners

Phosphatidylinositol 4-Kinaseβ Is Critical for Functional Association of rab11 with the Golgi Complex

Phosphatidylinositol 4-kinaseβ (PI4Kβ) plays an essential role in maintaining the structural integrity of the Golgi complex. In a search for PI4Kβ-interacting proteins, we found that PI4Kβ specifically interacts with the GTP-bound form of the small GTPase rab11. The PI4Kβ-rab11 interaction is of functional significance because inhibition of rab11 binding to PI4Kβ abolished the localization of rab11 to the Golgi complex and significantly inhibited transport of vesicular stomatitis virus G protein from the Golgi complex to the plasma membrane. We propose that a novel function of PI4Kβ is to act as a docking protein for rab11 in the Golgi complex, which is important for biosynthetic membrane transport from the Golgi complex to the plasma membrane