Parkinson’s disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.

The product of the concentrations of urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 (urinary [TIMP-2] × [IGFBP-7]) has been suggested as biomarker for early detection of acute kidney injury (AKI) in various clinical settings. However, the performance of urinary [TIMP-2] × [IGFBP-7] to predict AKI has never been assessed in patients undergoing orthotopic liver transplantation (OLT). Thus, the aim of this study was to assess the early predictive value of urinary [TIMP-2] × [IGFBP-7] for the development of AKI after OLT. In this observational study, urinary [TIMP-2] × [IGFBP-7] was measured in samples from adult OLT patients. AKI was diagnosed and classified according to KDIGO criteria. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of urinary [TIMP-2] × [IGFBP-7] for the development of AKI. Forty patients (mean age 55 ± 8 years) were included. Twenty-eight patients (70%) developed AKI stage 1, 2, or 3 within 48 h after OLT. Urinary [TIMP-2] × [IGFBP-7] was not predictive for AKI at the end of OLT (AUC: 0.54, CI [0.32–0.75], P = 0.72), at day 1 (AUC: 0.60, CI [0.41–0.79], P = 0.31), or day 2 after OLT (AUC: 0.63, CI [0.46–0.8], P = 0.18). Based on our results, routine clinical use of urinary [TIMP-2] × [IGFBP-7] cannot be recommended for risk assessment of AKI in patients undergoing OLT.

Background: Associations between intraoperative hypotension (IOH) and various postoperative outcomes were shown in retrospective trials using a variety of different definitions of IOH. This complicates the comparability of these trials and makes clinical application difficult. Information about the best performing definitions of IOH regarding 30-day mortality, hospital length of stay (hLOS), and postanesthesia care unit length of stay (PACU-LOS) is missing. Methods: A retrospective cohort trial was conducted using data from patients undergoing noncardiothoracic surgery. We split the obtained dataset into two subsets. First, we used one subset to choose the best fitting definitions of IOH for the outcomes 30-day mortality, hLOS, and PACU-LOS. The other subset was used to independently assess the performance of the chosen definitions of IOH. Results: The final cohort consisted of 65,454 patients. In the shaping subset, nearly all tested definitions of IOH showed associations with the three outcomes, where the risk of adverse outcomes often increased continuously with decreasing MAP. The best fitting definitions were relative time with a MAP (mean arterial pressure) of <80 mmHg for 30-day mortality, lowest MAP for one minute for hLOS, and lowest MAP for one cumulative minute for PACU-LOS. Testing these three definitions of IOH in the independent second subset confirmed the associations of IOH with 30-day mortality, hLOS, and PACU-LOS. Conclusions: Using a data-driven approach, we identified the best fitting definitions of IOH for 30-day mortality, hLOS, and PACU-LOS. Our results demonstrate the need for careful selection of IOH definitions. Clinical trial number: n/a, EC #2245/2020

Background: In children born at high altitude, lung development is affected by hypoxia, which can lead to pulmonary hypertension and right ventricular failure. Animal models of postnatal, transient, hypoxia failed to reproduce these conditions seen in children living at high altitude. The aim of this study was to establish a mouse model of pediatric pulmonary hypertension associated with abnormal lung development. Methods: C57bl/6J mice were exposed to normobaric hypoxia at 11% inspired fraction of oxygen starting on postnatal‐days 1 to 4 (“11%‐birth”). At age 8 weeks, pulmonary arterial pressure and right ventricular function were assessed using echocardiography and invasive hemodynamics. The physiology and the structure of lung parenchyma and vasculature were assessed through evaluations of gas exchange, respiratory mechanics, and histopathology. Results were compared with control mice breathing 21% inspired fraction of oxygen for 8 weeks (21%‐birth), and to adult mice breathing 11% inspired fraction of oxygen for 8 weeks (11%‐adult). Results: Seventy percent of 11%‐birth mice survived until age 8 weeks; the mice subsequently experienced a steady decline in survival, with a median lifespan of 150 days. Mice that survived for 8 weeks had evidence of impaired lung development, such as alveolar and vascular simplification with muscularization of small pulmonary vessels, impaired gas exchange, and altered respiratory mechanics. These changes were associated with reduced exercise capacity, severe pulmonary hypertension, and right ventricular failure. Adult mice subjected to chronic hypoxia had mild changes in the pulmonary vasculature resulting in mild pulmonary hypertension without right ventricular dysfunction. Conclusions: This mouse model of prolonged hypoxia beginning early after birth offers a novel approach to explore treatments for pediatric pulmonary hypertension linked to abnormalities in lung development.

Background/Objectives: In the present study, we hypothesized that cardiac surgery in pediatric patients with congenital heart disease (CHD) leads to profound endothelial glycocalyx degradation, measured as the increase in plasma syndecan-1 concentration, and that this endothelial damage is more pronounced in patients with cyanotic CHD. Methods: A total of 40 infants (24 with acyanotic and 16 with cyanotic CHD) were enrolled in this prospective study. A total of 39 cardiac surgeries were performed with cardiopulmonary bypass (CPB), 38 with CPB and aortic clamping, and 3 with CPB, aortic clamping, and deep hypothermic circulatory arrest. Results: Syndecan-1 concentrations increased significantly post-surgery compared to the baseline in both groups (cyanotic: 24.4 to 48.0 ng/mL, p < 0.0001; acyanotic: 28.8 to 59.8 ng/mL, p < 0.0001). However, there was no significant difference in syndecan-1 concentrations at any timepoint between children with cyanotic and those with acyanotic CHD. Baseline syndecan-1 showed no correlation with preoperative arterial oxygen saturation (r = 0.26, p = 0.102), hemoglobin (r = −0.3, p = 0.06), age (r = 0.15, p = 0.36), and weight (r = 0.13, p = 0.42). Of note, CPB time (r = 0.08, p = 0.63) and AC time (r = 0.03, p = 0.86) were not related to syndecan-1 concentrations at the end of surgery. Conclusions: Cardiac surgery leads to profound glycocalyx degradation in children with CHD detected by increased plasma syndecan-1 concentrations. Regardless of major pathophysiological differences, children with cyanotic and acyanotic CHD presented similar plasma syndecan-1 values throughout the study.