Background and Purpose-Cellular response to hypoxia is mainly controlled by hypoxia-inducible factor 1 (HIF-1). The HIF-1 target gene erythropoietin (EPO) has been described as neuroprotective. Thus, we hypothesize EPO to be an essential mediator of protection in hypoxic preconditioning. Methods-We randomized Sv129 mice into groups for different pretreatments, different hypoxia-ischemia intervals, or different durations of ischemia. For hypoxic preconditioning, the animals were exposed to a hypoxic gas mixture (8% O 2 and 92% N 2 ) for 30, 60, 180, 300, or 360 minutes. At 0, 24, 48, 72, or 144 hours later, we performed middle cerebral artery occlusion and allowed reperfusion after 30, 45, 60, or 120 minutes, or occlusion was left to be permanent. We studied EPO gene expression in brain tissue with a real-time reverse transcriptase-polymerase chain reaction and measured HIF-1 DNA-binding activity with an electrophoretic mobility shift assay. To block endogenously produced EPO, we instilled soluble EPO receptor into the cerebral ventricle. Results-Hypoxic preconditioning for 180 or 300 minutes induced relative tolerance to transient focal cerebral ischemia, as evidenced by a reduction of infarct volumes to 75% or 54% of the control, respectively. Hypoxic pretreatment was effective only when applied 48 or 72 hours before middle cerebral artery occlusion. Sixty minutes after hypoxia, we found a marked activation of HIF-1 DNA-binding activity and a 7-fold induction of EPO transcription. Infusion of soluble EPO receptor significantly reduced the protective effect of hypoxic pretreatment by 40%. Key Words: erythropoietin Ⅲ ischemic preconditioning Ⅲ stroke Ⅲ transcription factors Ⅲ mice I t has long been known that the brain is very sensitive to hypoxia and ischemia. 1 However, more recently it has been discovered that the brain, like other organs, is capable of inducing protective mechanisms when challenged by stressors or substrate deprivation. 2 These mechanisms, collectively labeled as ischemic tolerance or ischemic preconditioning, are of putative importance for limiting the damage during substrate deprivation. Protection may occur within minutes, 3 but this early tolerant state is lost within hours. However, tolerance can be seen in a second time window after 24 to 48 hours and then lasts for 2 to 3 days. Evidence for the existence of ischemic preconditioning in humans has been reported. 4 The major goal of ischemic preconditioning research at present is to identify the underlying endogenous protective signaling cascades, with the long-term goal to allow therapeutic augmentation of the endogenous protective mechanisms in cerebral ischemia and possibly to induce a protected state of the brain in conditions in which brain ischemia can be anticipated, for example, during surgery of the heart or brain. Conclusions-EndogenouslyTo study the mechanisms of ischemic preconditioning, robust and clinically relevant models are needed. Short and nondamaging periods of focal cerebral ischemia were reported to induce ischemic p...

Background The COVID-19 pandemic has disrupted healthcare systems worldwide. In addition to the direct impact of the virus on patient morbidity and mortality, the effect of lockdown strategies on health and healthcare utilization have become apparent. Little is known on the effect of the pandemic on pediatric and adolescent medicine. We examined the impact of the pandemic on pediatric emergency healthcare utilization. Methods We conducted a monocentric, retrospective analysis of n = 5,424 pediatric emergency department visits between January 1st and April 19th of 2019 and 2020, and compared healthcare utilization during the pandemic in 2020 to the same period in 2019. Results In the four weeks after lockdown in Germany began, we observed a massive drop of 63.8% in pediatric emergency healthcare utilization (mean daily visits 26.8 ± SEM 1.5 in 2019 vs. 9.7 ± SEM 1 in 2020, p < 0.005). This drop in cases occurred for both communicable and non-communicable diseases. A larger proportion of patients under one year old (daily mean of 16.6% ±SEM 1.4 in 2019 vs. 23.1% ±SEM 1.7 in 2020, p < 0.01) and of cases requiring hospitalisation (mean of 13.9% ±SEM 1.6 in 2019 vs. 26.6% ±SEM 3.3 in 2020, p < 0.001) occurred during the pandemic. During the analysed time periods, few intensive care admissions and no fatalities occurred. Conclusions Our data illustrate a significant decrease in pediatric emergency department visits during the COVID-19 pandemic. Public outreach is needed to encourage parents and guardians to seek medical attention for pediatric emergencies in spite of the pandemic.

The widely prescribed drug desferrioxamine is a known activator of the hypoxia-inducible transcription factor 1 (HIF-1) and the subsequent transcription of erythropoietin. In the brain, HIF-1 is a master switch of the transcriptional response to hypoxia, whereas erythropoietin is a potent neuroprotectant. The authors show that desferrioxamine dose-dependently and time-dependently induces tolerance against focal cerebral ischemia in rats and mice, and against oxygen-glucose deprivation in purified cortical neurons. Desferrioxamine induced HIF-1 DNA binding and transcription of erythropoietin in vivo, the temporal kinetics of which were congruent with tolerance induction. Desferrioxamine is a promising drug for the induction of tolerance in humans when ischemia can be anticipated.