Application of alpha1-antitrypsin in a rat model of veno-arterial extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients suffering from respiratory or cardiac failure. The ECMO-associated morbidity and mortality depends to a large extent on the underlying disease and is often related to systemic inflammation, consecutive immune paralysis and sepsis. Here we tested the hypothesis that human α1-antitrypsin (SERPINA1) due to its anti-protease and anti-inflammatory functions may attenuate ECMO-induced inflammation. We specifically aimed to test whether intravenous treatment with α1-antitrypsin reduces the release of cytokines in response to 2 h of experimental ECMO. Adult rats were intravenously infused with α1-antitrypsin immediately before starting veno-arterial ECMO. We measured selected pro- and anti-inflammatory cytokines and found, that systemic levels of tumor necrosis factor-α, interleukin-6 and interleukin-10 increase during experimental ECMO. As tachycardia and hypertension developed in response to α1-antitrypsin, a single additional bolus of fentanyl and midazolam was given. Treatment with α1-antitrypsin and higher sedative doses reduced all cytokine levels investigated. We suggest that α1-antitrypsin might have the potential to protect against both ECMO-induced systemic inflammation and immune paralysis. More studies are needed to corroborate our findings, to clarify the mechanisms by which α1-antitrypsin inhibits cytokine release in vivo and to explore the potential application of α1-antitrypsin in clinical ECMO.

Multiorgan Point-of-Care Ultrasound in a Patient With Coronavirus Disease 2019 Pneumonia Complicated by Subarachnoid Hemorrhage and Pulmonary Embolism.

Morbidity and mortality associated with the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (coronavirus disease 2019 [COVID-19]) are not only due to acute respiratory distress syndrome but also related to multiorgan involvement and dysfunction. In this report, we present a critically ill patient with severe COVID-19 pneumonia, during which he required extracorporeal membrane oxygenation and suffered from multiple complications. Bedside sonography became an important tool to manage the patient by adapting artificial ventilation parameters and played a key role in the diagnosis of thrombotic events and the monitoring of subarachnoid hemorrhage that unexpectedly complicated the case.

Platelet number and graft function predict intensive care survival in allogeneic stem cell transplantation patients.

Despite significant advances in the treatment of complications requiring intensive care unit (ICU) admission, ICU mortality remains high for patients after allogeneic stem cell transplantation. We evaluated the role of thrombocytopenia and poor graft function in allogeneic stem cell recipients receiving ICU treatments along with established prognostic ICU markers in order to identify patients at risk for severe complications. At ICU admission, clinical and laboratory data of 108 allogeneic stem cell transplanted ICU patients were collected and retrospectively analyzed. Platelet counts (≤ 50,000/µl, p < 0.0005), hemoglobin levels (≤ 8.5 mg/dl, p = 0.019), and leukocyte count (≤ 1500/µl, p = 0.025) along with sepsis (p = 0.002) and acute myeloid leukemia (p < 0.0005) correlated significantly with survival. Multivariate analysis confirmed thrombocytopenia (hazard ratio (HR) 2.79 (1.58-4.92, 95% confidence interval (CI)) and anemia (HR 1.82, 1.06-3.11, 95% CI) as independent mortality risk factors. Predominant ICU diagnoses were acute respiratory failure (75%), acute kidney injury (47%), and septic shock (30%). Acute graft versus host disease was diagnosed in 42% of patients, and 47% required vasopressors. Low platelet (≤ 50,000/µl) and poor graft function are independent prognostic factors for impaired survival in critically ill stem cell transplanted patients. The underlying pathophysiology of poor graft function is not fully understood and currently under investigation. High-risk patients may be identified and ICU treatments stratified according to allogeneic stem cell patients' individual risk profiles. In contrast to previous studies involving medical or surgical ICU patients, the fraction of thrombocytopenic patients was larger and low platelets were a better differentiating factor in multivariate analysis than any other parameter.

Correction to: Platelet number and graft function predict intensive care survival in allogeneic stem cell transplantation patients.

The author name Philipp Wohlfarth was incorrectly spelled as Philipp Wohlfahrth in the original version of this article.

Noisy predator-prey model explains oscillation patterns in sockeye salmon data.

A model of sockeye salmon population dynamics that incorporates predator-prey dynamics in the nursery lakes, salmon migration and stochastic effects is compared to Fraser River sockeye salmon spawner numbers with respect to cyclic dominance. For this comparison we use a method developed by White et al. (2014) to calculate measures for the consistency and strength of cyclic dominance in the time series using its wavelet transform. We find that the model can match the oscillation patterns found in nature, both for persistently oscillating populations and for intermittent oscillations. It matches persistently oscillating populations much better than a model that does not incorporate predator-prey interaction. Persistent oscillations are more likely to occur in the model if the growth conditions for the sockeye fry are good and the coupling to the predator is strong.

Effect of introducing a competitor on cyclic dominance of sockeye salmon.

We study the effects of introducing a competing species into a 3-species model for the population dynamics of sockeye salmon, thereby converting a food chain into a diamond module. We find that this often leads to the disappearance of the 4-year oscillation of sockeye salmon known as cyclic dominance when parameters are chosen such that all four species can coexist. Only when the population size of the competitor is small the phenomenon of cyclic dominance can persist. There is also a large region of parameter space where either the sockeye salmon or the competitor goes extinct. We discuss how these findings can be reconciled with the prevalence of cyclic dominance in many sockeye brood lakes.

The robustness of cyclic dominance under random fluctuations.

We investigate the influence of random perturbations on a recently introduced three-species model that reproduces the empirically observed pattern of cyclic dominance in Fraser River sockeye salmon. Since the sockeye populations are subject to various types of fluctuations affecting their growth and survival, we investigate the robustness of the model under several types of noise. In particular, we evaluate the variation of population sizes around their values in the deterministic model, the frequency of phase shifts in the 4-year oscillation, the extent of synchronization between different sockeye populations, and the response to strong one-time perturbations. Our main conclusion is that cyclic dominance is very stable even under strong noise in this model.

Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status.

Long-term exposure to ascorbate is known to enhance endothelial nitric oxide synthase (eNOS) activity by stabilizing the eNOS cofactor tetrahydrobiopterin (BH4). We investigated acute effects of ascorbate on eNOS function in primary (HUVEC) and immortalized human endothelial cells (EA.hy926), aiming to provide a molecular explanation for the rapid vasodilatation seen in vivo upon administration of ascorbate. Enzymatic activity of eNOS and intracellular BH4 levels were assessed by means of an arginine-citrulline conversion assay and HPLC analysis, respectively. Over a period of 4h, ascorbate steadily increased eNOS activity, although endothelial BH4 levels remained unchanged compared to untreated control cells. Immunoblot analyses revealed that as early as 5 min after treatment ascorbate dose-dependently increased phosphorylation at eNOS-Ser1177 and concomitantly decreased phosphorylation at eNOS-Thr495, a phosphorylation pattern indicative of increased eNOS activity. By employing pharmacological inhibitors, siRNA-mediated knockdown approaches, and overexpression of the catalytic subunit of protein phosphatase 2A (PP2A), we show that this effect was at least partly owing to reduction of PP2A activity and subsequent activation of AMP-activated kinase. In this report, we unravel a novel mechanism for how ascorbate rapidly activates eNOS independent of its effects on BH4 stabilization.