Administration of memantine, an antagonist of the N-methyl- d-aspartate receptor, prevents Ca2+ overload and dehydration of red blood cells (RBCs) in patients with sickle cell disease (SCD). The objectives of the 1-year dose-escalation Phase IIa/IIb Memantine trial (MeMAGEN - NCT03247218) with 17 SCD patients who were under stable hydroxycarbamide therapy were to test the drug's safety and tolerability. Daily memantine doses ranged from 5 to 15 mg for children/adolescents and from 5 to 20 mg for adults. Clinical and laboratory analysis showed that memantine was well tolerated. In children, a decrease in days spent in the hospital was observed. Safety was confirmed by laboratory tests, which were not, or were only minimally, altered during memantine therapy. In a subgroup of six patients whose RBCs presented with elevated K+ leakage before treatment, memantine therapy at its lowest dosage reduced this K+ loss and increased hemoglobin concentration. This study shows that memantine is safe and well tolerated by SCD patients, including children. Memantine has the potential to become a supportive and low-cost therapy in conjunction with hydroxycarbamide.

Iron deficiency aggravates hypoxic pulmonary vasoconstriction, exacerbating the increase of pulmonary arterial pressure at high altitude (HA). This may be especially relevant for patients with pulmonary hypertension (PH) travelling to HA, who moreover have a high prevalence of iron deficiency. Currently, no data is available on iron parameters and their influence on HA adaptation in PH-patients. In a randomized cross-over trial, 27 patients (44% female, mean age 61.7 ± 13.6 y) with pulmonary arterial hypertension (67%) or chronic thromboembolic PH (33%) were assessed at baseline (Zurich, 470 m) and during a stay at 2500 m. Blood samples were taken at baseline and after 20 h at 2500 m. A significant increase in ferritin (131 ± 68 to 140 ± 75, p = 0.002), transferrin (28.0 ± 4.7 to 30.3 ± 4.4, p = 0.012) and soluble transferrin receptor (sTfR) levels (2.7 ± 0.7 to 2.9 ± 0.6, p = 0.014) was observed at HA, all of which correlated with decreasing hepcidin levels. Arterial partial pressure of carbon dioxide (PaCO2) was inversely correlated with transferrin levels (Pearson's r = -0.57, p < 0.001), and baseline transferrin concentration was an independent predictor of PaCO2 at baseline and HA (p = 0.037). Furthermore, transferrin levels < 30 µmol/L were an independent predictor of mean nocturnal oxygen saturation (SpO2) at baseline and HA. The need for oxygen supplementation at HA could be predicted using a model including baseline transferrin, achieving a positive predictive value of 84%, suggesting that transferrin may serve as a useful clinical marker to identify PH patients at risk of oxygen desaturation at HA.

High altitude inhabitants are exposed to chronic hypobaric hypoxia environments that cause low arterial oxygen saturation. To compensate hypoxia by increasing erythropoiesis, signals derived from oxygen sensing, iron availability and inflammation need to be tightly coordinated. To understand the evolutionary adaptations of high-altitude natives we analyzed molecular and physiological biomarkers in 211 adult Aymara (3,600 m) and Quechua (5,000 m) individuals from the Bolivian Andes. We observed that Quechua males living at higher altitudes than Aymara males only marginally increase their hemoglobin (Hb) concentrations, which may be explained by hypoferremia and iron-restricted erythropoiesis. Erythropoietin (EPO) and erythroferrone (ERFE) levels showed the expected increase, and although C-reactive protein reflecting increased inflammation was elevated in Quechua males, hepcidin remained suppressed, likely via ERFE-mediated control. Analysis of seven gene variants involved in high-altitude adaptation revealed that the NFKB1 rs230511 (T/T genotype) is associated with altered hepcidin and ferritin regulation in Quechua males, suggesting that inflammation-related pathways in high altitude residents affect their ability to adapt to high-altitude. Our findings highlight a dominant influence of inflammation on erythropoiesis, especially in Quechua men, offering new insights into high-altitude adaptation.

Data on sleep and respiratory patterns among adolescents residing at very high altitude (> 3500 m) remain scarce, and altitude-related physiological differences may influence these parameters. Studying adolescents at different very high altitudes is crucial, as subtle environmental variations could affect sleep-related oxygenation and respiratory function. This study aimed to characterise sleep-related oxygenation and respiratory parameters in healthy adolescents native to two distinct very high-altitude environments. Overnight sleep polygraphy was performed in 163 healthy adolescents aged 13.5 to < 18 years living in La Paz (3620 m) and El Alto (4060 m), Bolivia. Mean nocturnal oxygen saturation, oxygen desaturation index, and apnea-hypopnea index were assessed alongside subjective sleep quality, morning blood pressure, heart rate, haemoglobin concentration, and Epworth Sleepiness Scale scores. Adolescents at 4060 m had significantly lower mean nocturnal oxygen saturation (84.8% ± 2.2%) compared with those at 3620 m (87.8% ± 1.8%), and a higher oxygen desaturation index (21.2 ± 8.5/h vs. 17.1 ± 9.0/h). The apnea-hypopnea index did not differ significantly between altitudes (6.2 ± 4.8/h vs. 5.6 ± 4.6/h). At 3620 m, females showed lower oxygen desaturation and apnea-hypopnea indices compared with males. Despite the more pronounced nocturnal hypoxemia at 4060 m, haemoglobin concentration did not increase, suggesting limited haematological compensation. Subjective sleep quality, blood pressure, and heart rate were similar between both altitude groups. Healthy adolescents living chronically at very high altitude exhibit altitude-dependent reductions in nocturnal oxygenation and increased desaturation frequency, without evidence of sleep-disordered breathing. These findings underscore the need for altitude-specific normative values to support accurate interpretation of sleep studies in high-altitude populations.

Hypobaric hypoxia, a defining feature of high-altitude environments, poses a considerable physiological challenge to both humans and rodents. To withstand hypoxic stress, mammals have developed cellular and systemic adaptations that not only safeguard against acute and future episodes of oxygen deprivation but may also enhance overall resilience and functional capacity. A central aim of current research is to harness these health-promoting effects of hypoxic exposure as a therapeutic strategy for a range of medical conditions. To date, much of the evidence regarding the safety and efficacy of such interventions derives from rodent studies. In this review, we summarize current knowledge on hypoxia tolerance, oxygen transport, and oxygen consumption in humans, rats, and mice, and evaluate the extent to which findings from rodent models can be extrapolated to humans. While the anatomical, physiological, and molecular foundations of oxygen transport and utilization are broadly conserved across species, there are important quantitative differences-largely linked to body-mass variation-as well as qualitative distinctions. Mice that evolved in high-altitude environments, display remarkable hypoxia tolerance. Their physiological repertoire includes highly efficient pulmonary gas exchange, metabolic downregulation, and substantial plasticity of the mitochondrial electron transport system under hypoxic conditions. In contrast, rats exhibit heightened vulnerability in hypoxia, manifesting as right ventricular hypertrophy, excessive erythropoiesis, and myocardial injury. These interspecies differences highlight that the robust hypoxia tolerance of mice-and the potentially comparatively greater susceptibility of rats than humans-must be carefully considered when translating findings from rodent hypoxia research into human contexts.

It is a common misconception that cognitive function is impaired in a linear fashion by declining oxygen availability (e.g. at altitude). While this may apply for prolonged exposures to high altitudes (>2500 m), moderate altitude (1500–2500 m) or short intermittent hypoxic episodes can even be beneficial for the brain.

Strunz, Patrick-Pascal, Raphael N. Vuille-dit-Bille, Heiko Fruehauf, Mark Fox, Andreas Geier, Marco Maggiorini, Max Gassmann, Thomas A. Lutz, and Oliver Goetze. Acute high-altitude exposure increases transcription of tricarboxylic acid cycle enzymes in human duodenal biopsies. High Alt Med Biol. 27:184-188, 2026. BACKGROUND:A recent study of our group quantifying 13C-octanoate metabolism in HA (Capanna Margherita [MG]/4,559 m) showed that acute HA exposure might lead to an increase of the lipolytic and CO2-producing pathways. OBJECTIVE:To further test this hypothesis, we investigated intestinal biopsies from the same participants from simultaneously performed endoscopy studies for changes of mRNA-expression levels of the beta-oxidation enzymes and the decarboxylating tricarboxylic acid cycle (TCA) enzymes. METHODS:Duodenal biopsies of 16 subjects exposed to HA were sampled via gastro-duodenoscopy at Zurich (baseline ZH, 490 m), on day 2 (MG2) and on day 4 at HA (MG4). After mRNA extraction, quantitative real-time polymerase chain reaction was performed to assess mRNAs expression of TCA cycle enzymes as well as beta-oxidation enzymes. RESULTS:Aconitase mRNA levels increased early (MG2 vs. ZH, p < 0.05) and were still higher at day 4 compared with ZH (MG4 vs. ZH, p < 0.05). Isocitrate dehydrogenase (DH) levels increased with time spent at 4,559 m (MG4 vs. ZH, p < 0.01). The remaining TCA cycle and beta-oxidation enzymes investigated tended to higher values at HA but without reaching significance. CONCLUSION:We conclude that acute exposure to HA leads to increased transcription of aconitase and isocitrate DH in the duodenal mucosa due to hypobaric hypoxia exposure.

ABSTRACT Iron deficiency (ID) is prevalent in pulmonary hypertension(PH), but there is no consensus on ID definition and its possible correlation to prognostic markers. Hence, in this study, PH‐patients were recruited at the University Hospital Zurich from May 2019 to April 2021. Clinical and hemodynamic characteristics were recorded at inclusion and venous blood samples were taken. ID was defined as: (i) ferritin‐ID: ferritin< 100 µg/L or 100–299 µg/L plus a transferrin saturation (TSAT) < 20%; (ii) TSAT‐ID: a TSAT < 20% (males)/< 15% (females) and (iii) TFRI‐ID: a transferrin receptor index (TFRI) > 3.2/ > 2.0 depending on CRP < / > 5 mg/L. 94 patients (52% female, mean age 62.9 ± 14.6 years) with pulmonary arterial hypertension(48%), PH associated with lung disease (20%) or chronic thromboembolic PH (32%) were included. Sixty‐seven percent fulfilled criteria for ferritin‐ID, 35% for TSAT‐ID, and 13% for TFRI‐ID. Mean pulmonary arterial pressure (mPAP) was elevated in TFRI‐ID patients compared to non‐ID (50 ± 12.2 mmHg vs. 35.9 ± 11.7 mmHg); however, after correction for age, sex, PH‐type, and anticoagulation, the difference was nonsignificant ( p = 0.085). NT‐proBNP was significantly higher in TFRI‐ID‐positive (1237 ± 1166 pg/mL vs. 334 ± 417 pg/mL, p = 0.004). No significant differences were found for ferritin‐ID and TSAT‐ID ( p > 0.05). Six‐minute walk distance (6MWD) was reduced for both TSAT‐ID (402 ± 133 m vs. 469 ± 152 m, p = 0.006) and TFRI‐ID (370 ± 112 m vs. 459 ± 151 m, p = 0.052), but not for ferritin‐ID ( p > 0.05). In conclusion, TFRI‐ID is seemingly associated with clinical markers of right heart parameters and disease severity. This could not be seen with the currently recommended ferritin‐ID‐definition or TSAT‐ID. More data is needed to assess the use of the TFRI‐ID instead of the ferritin‐ID‐definition as a method to identify PH‐patients at risk and as a threshold for iron substitution.

INTRODUCTION:Retrospective data suggest association of high-altitude exposure and inflammatory bowel disease flares. Knowledge about underlying pathogenesis remains limited. METHODS:This prospective interventional trial evaluated the effect of 3 hours hypobaric low-pressure chamber exposure on 11 patients with Crohn's disease (CD), 9 with ulcerative colitis (UC), and 10 controls. RESULTS:Proportion of patients with clinical and endoscopic activity did not increase. However, 33.3% of patients with UC experienced a flare. More patients had calprotectin-based activity (>100 μg/g) after the intervention (26.7 vs 63.3%, P = 0.013). Transient changes in certain bacterial strains were seen in controls and patients with UC. DISCUSSION:Low-pressure chamber exposure, although the primary outcome was not met, led to a flare in a third of patients with UC, with changes in calprotectin levels and specific bacterial strains ( Clinicaltrials.gov number, NCT02849821).

Erythropoietin (EPO) plays a key role in energy metabolism, with EPO receptor (EpoR) expression in white adipose tissue (WAT) mediating its metabolic activity. Here, we show that male mice lacking EpoR in adipose tissue exhibit increased fat mass and susceptibility to diet-induced obesity. Our findings indicate that EpoR is present in WAT, brown adipose tissue, and skeletal muscle. Elevated EPO in male mice improves glucose tolerance and insulin sensitivity while reducing expression of lipogenic-associated genes in WAT, which is linked to an increase in transcription factor RUNX1 that directly inhibits lipogenic genes expression. EPO treatment in wild-type male mice decreases fat mass and lipogenic gene expression and increase in RUNX1 protein in adipose tissue which is not observed in adipose tissue EpoR ablation mice. EPO treatment decreases WAT ubiquitin ligase FBXW7 expression and increases RUNX1 stability, providing evidence that EPO regulates energy metabolism in male mice through the EPO-EpoR-RUNX1 axis. Erythropoietin (EPO) regulates energy metabolism via its receptor (EpoR) in adipose tissue. The authors demonstrate that EPO influences glucose tolerance, insulin sensitivity, and fat mass and that EPO treatment reduces lipogenic gene expression through the EPO-EpoR-RUNX1 axis.

Erythropoietin (EPO) plays an important role in promoting red blood cell production. In non-erythroid tissue, the EPO:EPO receptor (EPOR) interaction might affect fat synthesis and catabolism. Mice with deletion of EPOR in non-erythroid tissue become obese while transgenic mice overexpressing human EPO (Tg6) exhibit reduced body weight and fat mass compared with wild-type controls. How EPO:EPOR affects the synthesis and breakdown of dermal fat in skin, thereby affecting hair growth, is unknown. We verified EPOR expression in the dermal fat by fluorescent staining of skin tissue of EPOR-TdTomato-cre mice. We observed that EPOR knockout in HF stem cells did not affect skin hair growth nor showed significant differences in body weight and fat mass. In contrast, HF development in Tg6 mice was disrupted during the first catagen phase, resulting in formation of epithelium-lined HF cysts, filled with disorganized cysts. Transgenic human EPO in skin tissue was significantly higher than murine EPO during the first degenerative phase of HF development in Tg6 mice. The concomitant decrease in BODIPY positive cells suggested that high expression of transgenic EPO may affect hair growth during the first catagen phase by modulating lipogenesis and lipolysis of dermal fat. We assessed expression of transcription factors associated with EPO expression, HIF1aby Q-PCR. Indeed, increased EPO was accompanied by an increase in HIF1a. We found that EPO overexpression affected lipogenesis and lipolysis of dermal fat and HIF1a expression, disrupted hair growth during the first catagen phase and led to the formation of epithelial-lined HF cysts filled with disorganized keratin that ultimately manifest as truncal alopecia. In summary, we show here for the first time that EPO-HIF1a is essential in hair growth for the normal development and homeostasis of HFs. Disclosure W. Yin: None. H. Rogers: None. X. An: None. M. Gassmann: None. C.T. Noguchi: None.

Circular RNAs (circRNAs) are cardinal players in numerous physiological and pathological processes. CircRNAs play dual roles as tumor suppressors and oncogenes in different oncological contexts, including hepatocellular carcinoma (HCC). Their roles significantly impact the disease at all stages, including initiation, development, progression, invasion, and metastasis, in addition to the response to treatment. In this review, we discuss the biogenesis and regulatory functional roles of circRNAs, as well as circRNA–protein–mRNA ternary complex formation, elucidating the intricate pathways tuned by circRNAs to modulate gene expression and cellular processes through a comprehensive literature search, in silico search, and bioinformatics analysis. With a particular focus on the interplay between circRNAs, epigenetics, and HCC pathology, the article sets the stage for further exploration of circRNAs as novel investigational theranostic agents in the dynamic realm of HCC.

This study evaluates the neurocognitive and electrophysiological effects of 1-year memantine treatment in 14 adolescents and young adults (mean age 24 years) with sickle cell disease (SCD, incluing sickle cell anaemia and sickle cell β-thalassemia), hypothesizing improvements in cognitive functions and neural processing. Participants underwent assessments using subtests from the Wechsler Intelligence Scale and a computerized task-switching paradigm with concurrent event-related potential (ERP) recordings, both before and after the treatment period. Assessments focused on processing speed, working memory, attention and executive function. ERP measurements targeted brain response changes during task switching. Memantine treatment enhanced cognitive test performance, especially in processing speed as shown by the Digit-Symbol Coding and Symbol-Search tests. Results indicated improved visuospatial and graphomotor speed, working memory and attention. The task-switching test revealed reduced error rates, suggesting decreased cognitive load and enhanced executive control. Electrophysiological changes in P1 and P3 amplitudes at frontal and parietal locations post-treatment pointed to more efficient neural processing in tasks requiring cognitive flexibility. These preliminary findings from a Phase II clinical study serve as a 'proof of concept', exploring the feasibility and potential effectiveness of memantine treatment in SCD-a previously uninvestigated context. They support the rationale for more extensive investigations to confirm these results and assess memantine's broader effectiveness.

Myoglobin (MB) is expressed in different cancer types and may act as a tumor suppressor in breast cancer. The mechanisms by which basal MB expression level impacts murine mammary tumorigenesis are unclear. We investigated how MB expression in breast cancer influences proliferation, metastasis, tumor hypoxia, and chemotherapy treatment in vivo. We crossed PyMT and WapCreTrp53flox mammary cancer mouse models that differed in tumor grade/type and onset of mammary carcinoma with MB knockout mice. The loss of MB in WapCre;Trp53flox mice did not affect tumor development and progression. On the other hand, loss of MB decreased tumor growth and increased tissue hypoxia as well as the number of lung metastases in PyMT mice. Furthermore, Doxorubicin therapy prevented the stronger metastatic propensity of MB-deficient tumors in PyMT mice. This suggests that, although MB expression predicts improved prognosis in breast cancer patients, MB-deficient tumors may still respond well to first-line therapies. We propose that determining the expression level of MB in malignant breast cancer biopsies will improve tumor stratification, outcome prediction, and personalized therapy in cancer patients.

Parabolic flights are one of the most important pillars for research, development, and applications in space. Accordingly, we developed the world’s first non-governmental parabolic flight program using Novespace’s Airbus A310 ZERO-G. Through the flexible combination of academic research with industrial experiments, as well as with the support of private persons and low administrative efforts, we achieved a highly cost-efficient small-scale campaign concept, which is located at the Air Base Dübendorf in Switzerland. The program was very successful, and it resulted in 31 experiments and tests conducted by Universities and organizations in the industry in microgravity, culminating in many scientific publications and in larger subsequent projects for all users. We describe here how we designed, developed, tested, and built up this program. We also discuss the difficulties, problems, and success factors of a project that—for the first time—was successfully built from the “bottom-up”, and which was a large-scale flight research platform by scientists for scientists on a voluntary, non-governmental, and non-commercial basis.

Extravehicular activities, the backbone of manned space exploration programs, set astronauts into mild hypoxia. Unfortunately, microgravity aggravates threatening symptoms of hypoxia such as vision impairment and brain edema. Hypoxia-inducible factors (HIFs) sense cellular hypoxia and, subsequently, change the cells’ expression profile instantaneously by rapidly translocating—most likely cytoskeleton-dependently—into the nucleus and subsequently forming transcription complexes with other proteins. We tested the hypothesis that this fundamental process could be altered by sudden changes in gravitational forces in parabolic flights using a newly developed pocket-size cell culture lab that deoxygenizes cells within 15 min. Sudden gravity changes (SGCs 1g–1.8g–0g–1.8g–1g) during hypoxic exposure suppressed expression of the HIF1α-dependent genes investigated as compared with hypoxia at constant 1g. Normoxic cells subjected to SGCs showed reduced nuclear but not cytoplasmatic HIF1α signal and appeared to have disturbed cytoskeleton architecture. Inhibition of the actin-dependent intracellular transport using a combination of myosin V and VI inhibitors during hypoxia mimicked the suppression of the HIF1α-dependent genes observed during hypoxic exposure during SGCs. Thus, SGCs seem to disrupt the cellular response to hypoxia by impairing the actin-dependent translocation of HIF1α into the nucleus.