Open Access

Disruption of the blood-air barrier, which is formed by lung microvascular endothelial and alveolar epithelial cells, is a hallmark of acute lung injury. It was shown that alveolar epithelial cells release an unidentified soluble factor that enhances the barrier function of lung microvascular endothelial cells. In this study we reveal that primarily prostaglandin (PG) E2 accounts for this endothelial barrier-promoting activity. Conditioned media from alveolar epithelial cells (primary ATI-like cells) collected from BALB/c mice and A549 cells increased the electrical resistance of pulmonary human microvascular endothelial cells, respectively. This effect was reversed by pretreating alveolar epithelial cells with a cyclooxygenase-2 inhibitor or by blockade of EP4 receptors on endothelial cells, and in A549 cells also by blocking the sphingosine-1-phosphate1 receptor. Cyclooxygenase-2 was constitutively expressed in A549 cells and in primary ATI-like cells, and was upregulated by lipopolysaccharide treatment. This was accompanied by enhanced PGE2 secretion into conditioned media. Therefore, we conclude that epithelium-derived PGE2 is a key regulator of endothelial barrier integrity via EP4 receptors under physiologic and inflammatory conditions. Given that pharmacologic treatment options are still unavailable for diseases with compromised air-blood barrier, like acute lung injury, our data thus support the therapeutic potential of selective EP4 receptor agonists.

We have investigated and interpreted the production cross sections and isotopic distributions of projectile-like residues in the reactions 124Sn + 124Sn and 112Sn + 112Sn at an incident beam energy of 1 GeV/nucleon measured with the FRS fragment separator at the GSI laboratory. For the interpretation of the data, calculations within the statistical multifragmentation model (SMM) for an ensemble of excited sources were performed with ensemble parameters. The possible modification of symmetry energy parameter, in the multifragmentation region at the low density and hot freeze-out environment, is studied. It is reconfirmed that a significant reduction of the symmetry energy term is found necessary to reproduce experimental results at these conditions. We have also found a decreasing trend of the symmetry energy for large neutron-rich fragments of low excitation energy which is interpreted as a nuclear-structure effect.

We investigate the onset of multifragmentation employing an improved version of the N-body ‘‘quantum’’ molecular-dynamics approach. We study in detail the reaction 18O+197Au at 84 MeV/nucleon and find good agreement between the calculated results and the data for the double-differential proton cross section, the mass yield, the multiplicity, the kinetic energy of the fragments, and even for the kinematic correlations between intermediate mass fragments (IMF’s), which have been measured in this experiment for the first time. We observe a strong correlation between the impact parameter and both the size of the target remnant as well as the average proton multiplicity. Hence both observables can be used to determine the impact parameter experimentally. The IMF’s come from the most central collisions. The calculations confirm the experimental result that they are not emitted from an equilibrated system. Although the inclusive energy spectra look thermal, we cannot identify an impact parameter-independent isotropically emitting source. Even in central collisions global equilibrium is not observed. We find that multifragment emission at this bombarding energy is caused by a process very similar to that proposed in the macroscopic cold multifragmentation model. Thus it has a different origin than at beam energies around 1 GeV/nucleon, although the mass yield has an almost identical slope.

Background: Recombinant porcine factor VIII (rpFVIII; susoctocog alfa) is indicated for the treatment of bleeding events (BEs) in adults with acquired hemophilia A (AHA). Objectives: To assess the safety, utilization, and effectiveness of rpFVIII in clinical practice. Design: EU post-authorization safety study (PASS) (NCT03199794) was a multicenter, noninterventional, post-authorization safety study conducted in adults with AHA. Methods: Data were collected retrospectively or prospectively for up to 180 days after the last rpFVIII dose. The primary objective was safety, as assessed by adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs) (e.g. immunogenicity, hypersensitivity reactions, thromboembolic events). Secondary endpoints included immunogenicity, rpFVIII hemostatic effectiveness, and rpFVIII utilization. Results: Fifty patients were enrolled; 31 completed the study. The median (range) follow-up for patients who completed or discontinued the study was 178 (26–371) days. The median (range) first dose of rpFVIII was 54.0 (11–200) U/kg. Thirty patients reported 46 SAEs; 5 SAEs were considered probably related to rpFVIII, of which 1 was lack of rpFVIII efficacy, and 4 were AESIs: drug resistance due to FVIII inhibition (one patient), antibody test positive for anti-pFVIII inhibitors (one patient), and de novo anti-pFVIII inhibitors (two patients). No hypersensitivity reactions or thromboembolic events were reported. Of the 50 initial BEs, 37 resolved [in a median (interquartile range) of 8.0 (4.0–16.0) days]. Conclusion: Results from this real-world study support the use of rpFVIII for AHA, aligning with findings from the clinical trial of rpFVIII (NCT01178294) in the treatment of BEs in adults with AHA. Trial registration: EUPAS16055; NCT03199794.