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BACKGROUND The use of veno-venous extracorporeal membrane oxygenation (V-V ECMO) has rapidly increased in recent years. Today, applications of V-V ECMO include a variety of clinical conditions such as acute respiratory distress syndrome (ARDS), bridge to lung transplantation and primary graft dysfunction after lung transplantation. The purpose of the present study was to investigate in-hospital mortality of adult patients undergoing V-V ECMO therapy and to determine independent predictors associated with mortality. METHODS This retrospective study was conducted at the University Hospital Zurich, a designated ECMO center in Switzerland. Data was analyzed of all adult V-V ECMO cases from 2007 to 2019. RESULTS In total, 221 patients required V-V ECMO support (median age 50 years, 38.9% female). In-hospital mortality was 37.6% and did not statistically vary significantly between indications (P=0.61): 25.0% (1/4) for primary graft dysfunction after lung transplantation, 29.4% (5/17) for bridge to lung transplantation, 36.2% (50/138) for ARDS and 43.5% (27/62) for other pulmonary disease indications. Cubic spline interpolation showed no effect of time on mortality over the study period of 13 years. Multiple logistic regression modelling identified significant predictor variables associated with mortality: age [odds ratio (OR), 1.05; 95% confidence interval (CI): 1.02-1.07; P=0.001], newly detected liver failure (OR, 4.83; 95% CI: 1.27-20.3; P=0.02), red blood cell transfusion (OR, 1.91; 95% CI: 1.39-2.74; P<0.001) and platelet concentrate transfusion (OR, 1.93; 95% CI: 1.28-3.15; P=0.004). CONCLUSIONS In-hospital mortality of patients receiving V-V ECMO therapy remains relatively high. Patients' outcomes have not improved significantly in the observed period. We identified age, newly detected liver failure, red blood cell transfusion and platelet concentrate transfusion as independent predictors associated with in-hospital mortality. Incorporating such mortality predictor

Rheumatoid arthritis (RA) is associated with systemic osteoporosis, which leads to severe disability and low quality of life. Current therapies target osteoclasts to reduce bone degradation, but more treatment options would be required to promote bone protection by acting directly on osteoblasts (OB). Recently, the local production of dopamine in inflamed joints of RA has been observed. Thus, in this project, we aimed to determine the implication of the neurotransmitter dopamine in the bone formation process in RA. Dopamine receptors (DR) in the human bone tissue of RA or osteoarthritis (OA) patients were examined by immunohistochemistry. DR in isolated human osteoblasts (OB) was analyzed by flow cytometry, and dopamine content was evaluated by ELISA. Osteoclasts (OC) were differentiated from the PBMCs of healthy controls (HC) and RA patients. Isolated cells were treated with specific dopamine agonists. The effect of dopamine on mineralization was evaluated by Alizarin red staining. Cytokine release in supernatants was measured by ELISA. Osteoclastogenesis was evaluated with TRAP staining. OC markers were analyzed via real-time PCR and bone resorption via staining of resorption pits with toluidine blue. All DR were observed in bone tissue, especially in the bone remodeling area. Isolated OB maintained DR expression, which allowed their study in vitro. Isolated OB expressed tyrosine hydroxylase, the rate-limiting enzyme for dopamine production, and contained dopamine. The activation of D2-like DR significantly increased bone mineralization in RA osteoblasts and increased osteoclastogenesis but did not alter the expression of OC markers nor bone resorption. DR were found in the bone remodeling area of human bone tissue and dopamine can be produced by osteoblasts themselves, thus suggesting a local autocrine/paracrine pathway of dopamine in the bone. D2-like DRs are responsible for bone mineralization in osteoblasts from RA patients without an increase in bone

GABAB receptors control neuronal excitability via slow and prolonged inhibition in the central nervous system. One important function of GABAB receptors under physiological condition is to prevent neurons from shifting into an overexcitation state which can lead to excitotoxic death. However, under ischemic conditions, GABAB receptors are downregulated, fostering over-excitation and excitotoxicity. One mechanism downregulating GABAB receptors is mediated via the interaction with the endoplasmic reticulum (ER) stress-induced transcription factor CHOP. In this study, we investigated the hypothesis that preventing the interaction of CHOP with GABAB receptors after an ischemic insult restores normal expression of GABAB receptors and reduces neuronal death. For this, we designed an interfering peptide (R2-Pep) that restored the CHOP-induced downregulation of cell surface GABAB receptors in cultured cortical neurons subjected to oxygen and glucose deprivation (OGD). Administration of R2-Pep after OGD restored normal cell surface expression of GABAB receptors as well as GABAB receptor-mediated inhibition. As a result, R2-Pep reduced enhanced neuronal activity and inhibited progressive neuronal death in OGD stressed cultures. Thus, targeting diseases relevant protein-protein interactions might be a promising strategy for developing highly specific novel therapeutics. Keywords: CHOP; GABAB receptor; cerebral ischemia; interfering peptide; neuroprotection; oxygen and glucose deprivation (OGD)