The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis

Introduction: Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficacy of a novel polyethylene glycol (PEG)-clustered Tie2 agonist peptide, vasculotide (VT), to protect against vascular leakage and mortality in a murine model of polymicrobial abdominal sepsis. Methods: Polymicrobial abdominal sepsis in C57BL6 mice was induced by cecal-ligation-and-puncture (CLP). Mice were treated with different dosages of VT or equal volume of phosphate-buffered saline (PBS). Sham-operated animals served as time-matched controls. Results: Systemic administration of VT induced long-lasting Tie2 activation in vivo. VT protected against sepsis-induced endothelial barrier dysfunction, as evidenced by attenuation of vascular leakage and leukocyte transmigration into the peritoneal cavity. Histological analysis revealed that VT treatment ameliorated leukocyte infiltration in kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression. VT-driven effects were associated with significantly improved organ function and reduced circulating cytokine levels. The endothelial-specific action of VT was supported by additional in vitro studies showing no effect of VT on either cytokine release from isolated peritoneal macrophages, or migratory capacity of isolated neutrophils. Finally, administration of VT pre-CLP (hazard ratio 0.39 [95% confidence interval 0.19-0.81] P < 0.001) and post-CLP reduced mortality in septic mice (HR 0.22 [95% CI 0.06-0.83] P < 0.05). Conclusions: We provide proof of principle in support of the efficacious use of PEGylated VT, a drug-like Tie2 receptor agonist, to counteract microvascular endothelial barrier dysfunction and reduce mortality in a clinically relevant murine sepsis model. Further studies are needed to pave the road for clinical application of this therapeutic concept

Shared characteristics underpinning C 4 leaf maturation derived from analysis of multiple C 3 and C 4 species of Flaveria

Most terrestrial plants use C3 photosynthesis to fix carbon. In multiple plant lineages a modified system known as C4 photosynthesis has evolved. To better understand the molecular patterns associated with induction of C4 photosynthesis, the genus Flaveria that contains C3 and C4 species was used. A base to tip maturation gradient of leaf anatomy was defined, and RNA sequencing was undertaken along this gradient for two C3 and two C4Flaveria species. Key C4 traits including vein density, mesophyll and bundle sheath cross-sectional area, chloroplast ultrastructure, and abundance of transcripts encoding proteins of C4 photosynthesis were quantified. Candidate genes underlying each of these C4 characteristics were identified. Principal components analysis indicated that leaf maturation and the photosynthetic pathway were responsible for the greatest amount of variation in transcript abundance. Photosynthesis genes were over-represented for a prolonged period in the C4 species. Through comparison with publicly available data sets, we identify a small number of transcriptional regulators that have been up-regulated in diverse C4 species. The analysis identifies similar patterns of expression in independent C4 lineages and so indicates that the complex C4 pathway is associated with parallel as well as convergent evolution

Indoleamine-2,3-dioxygenase activity in experimental human endotoxemia

Background: Excessive tryptophan metabolism to kynurenine by the rate-limiting enzyme endothelial indoleamine 2,3-dioxygenase 1 (IDO) controls arterial vessel relaxation and causes hypotension in murine endotoxemia. However, its relevance in human endotoxemia has not been investigated so far. We thus aimed to study changes in blood pressure in parallel with tryptophan and kynurenine levels during experimental endotoxemia in humans. Findings: Six healthy male volunteers were given E. coli lipopolysaccharide (LPS; 4 ng/kg) as a 1-min intravenous infusion. They had levels of soluble E-Selectin and soluble vascular cell adhesion molecule-1 as well as IDO activity assessed as the kynurenine-to-tryptophan plasma ratio by liquid chromatography-tandem mass spectrometry at various time points during a 24 h time course. During endotoxemia, IDO activity significantly increased, reaching peak levels at 8 h after LPS infusion (44.0 ± 15.2 vs. 29.4 ± 6.8 at baseline, P<0.0001). IDO activity correlated inversely with the development of hypotension as shown by random effects linear regression models. Finally, IDO activity exhibited a kinetic profile similar to that of soluble endothelial-specific adhesion molecules. Conclusions: LPS is a triggering factor for the induction of IDO in men. Our findings strongly support the concept that the induction of IDO in the vascular endothelium contributes to hypotension in human sepsis

Universitäre Notaufnahmen in der Coronapandemie – Ergebnisse des ReCovERRegisters / University emergency departments in the corona pandemic—Results from the ReCovER registry

Background: The current COVID-19 pandemic, despite the availability of rapid tests and the start of the vaccination campaign, continues to pose major challenges to emergency departments (ED). Structured collection of demographic, clinical, as well as treatment-related data provides the basis for establishing evidence-based processes and treatment concepts. Aim of the work: To present the systematic collection of clinical parameters in patients with suspected COVID-19 in the Registry for COVID-19 in the Emergency Room (ReCovER) and descriptive presentation of the first 1000 patients. Materials and methods: Data from patients with suspected COVID-19, regardless of evidence of SARS-CoV‑2 infection, are continuously entered into a web-based, anonymized registry in ED at six university hospitals. Results: Between 19 May 2020 and 13 January 2021, 1000 patients were entered into the registry, of whom 594 patients (59.4%) were in the SARS-CoV‑2 positive group (PG) and 406 patients (40.6%) were in the negative group (NG). Patients of the PG had significantly fewer pre-existing conditions and a significantly longer latency between symptom onset and presentation to the ED (median 5 vs. 3 days), were more likely to suffer from cough, myalgia, fatigue, and loss of smell/taste and had significantly higher oxygen requirements than NG patients. The rate of severe disease progression was significantly higher in the PG, and persistent symptoms were more common after discharge (11.1 vs. 4.6%). Conclusions: The multicenter collection of comprehensive clinical data on COVID-19 suspected cases in the ED allows analysis of aspects specific to the situation in Germany in particular. This is essential for a targeted review and adaptation of internationally published strategies

Isolationsmaßnahmen, Diagnostik und Organisation in deutschen Notaufnahmen während der COVID-19-Pandemie 2020

Background!#!Since the beginning of the coronavirus disease 19 (COVID-19) pandemic, German emergency departments (ED) have been working in the area of conflict between high case load and demanding hygienic and organizational challenges. The aim of this study was to gain an overview of the current status of isolation measures, diagnostics and patient allocation of suspected COVID-19 cases.!##!Methods!#!Supported by the German Society for Interdisciplinary Emergency and Acute Medicine (DGINA) we invited leading ED physicians to answer an anonymous online survey regarding isolation measures, diagnostics and organization in emergency rooms during the COVID-19 pandemic.!##!Results!#!A total of 139 responders from all federal states and all levels of care took part in the survey. Standard operating procedures on COVID-19 exist in almost all participating EDs, although concrete measures to end isolation are often missing. Most EDs screen patients for the 'classic' COVID-19 symptoms such as fever, respiratory symptoms or contact to positive subjects in a standardized fashion, although the threshold for prophylactic isolation varies greatly. The individual swab-testing and allocation strategies vary relatively strongly. Less than half of all EDs have a separate procedure for uninterrogatable patients (e.g. major trauma). In about 8% of suspected cases, COVID-19-specific thoracic computed tomography is performed in the ED.!##!Conclusion!#!The current survey shows that the German EDs are well positioned for the moment, even though the isolation threshold is too high at some locations. In view of a possible increase in the number of cases during the winter season, a more precise differentiation of the previous recommendations of the Robert Koch Institute, especially for emergency admission patients, would be desirable. In this context, we propose a universal algorithm for the (de-)isolation of suspect cases in the ED