UNASSIGNED: High altitude retinopathy (HAR) is a retinal functional disorder caused by inadequate adaptation after exposure to high altitude. However, the cellular and molecular mechanisms underlying retinal dysfunction remain elusive. Retinal ganglion cell (RGC) injury is the most important pathological basis for most retinal and optic nerve diseases. Studies focusing on RGC injury after high-altitude exposure (HAE) are scanty. Therefore, the present study sought to explore both functional and morphological alterations of RGCs after HAE.
UNASSIGNED: A mouse model of acute hypobaric hypoxia was established by mimicking the conditions of a high altitude of 5000 m. After HAE for 2, 4, 6, 10, 24, and 72 hours, the functional and morphological alterations of RGCs were assessed using retinal hematoxylin and eosin (H&E) sections, retinal whole mounts, transmission electron microscopy (TEM), and the photopic negative response (PhNR) of the electroretinogram.
UNASSIGNED: Compared with the control group, the thickness of the ganglion cell layer and retinal nerve fiber layer increased significantly, RGC loss remained significant, and the amplitudes of a-wave, b-wave, and PhNR were significantly reduced after HAE. In addition, RGCs and their axons exhibited an abnormal ultrastructure after HAE, including nuclear membrane abnormalities, uneven distribution of chromatin in the nucleus, decreased cytoplasmic electron density, widening and vacuolization of the gap between axons, loosening and disorder of myelin sheath structure, widening of the gap between myelin sheath and axon membrane, decreased axoplasmic density, unclear microtubule and nerve fiber structure, and abnormal mitochondrial structure (mostly swollen, with widened membrane gaps and reduced cristae and vacuolization).
UNASSIGNED: The study findings confirm that the morphology and function of RGCs are damaged after HAE. These findings lay the foundation for further study of the specific molecular mechanisms of HAR and promote the effective prevention.

Permanent residence at high-altitude and chronic mountain sickness (CMS) may alter the cerebrovascular homeostasis and orthostatic responses. Healthy male participants living at sea-level (LL; n = 15), 3800 m (HL3800m; n = 13) and 5100 m (HL5100m; n = 17), respectively, and CMS highlanders living at 5100 m (n = 31) were recruited. Middle cerebral artery mean blood flow velocity (MCAv), cerebral oxygen delivery (CDO2), mean blood pressure (MAP), heart rate variability and spontaneuous cardiac baroreflex sensitivity (cBRS) were assessed while sitting, initial 30 s and after 3 min of standing. Cerebral autoregulation index (ARI) was estimated (ΔMCAv%baseline)/ΔMAP%baseline) in response to the orthostatic challenge. Altitude and CMS were associated with hypoxemia and elevated hemoglobin concentration. While sitting, MCAv and LFpower negatively correlated with altitude but were not affected by CMS. CDO2 remained preserved. BRS was comparable across all altitudes, but lower with CMS. Within initial 30 s of standing, altitude and CMS correlated with a lesser ΔMAP while ARI remained unaffected. After 3 min standing, MCAv, CDO2 and cBRS remained preserved across altitudes. The LF/HF ratio increased in HL5100m compared to LL and HL3800m from sitting to standing. In contrary, CMS showed blunted autonomic nervous activation in responses to standing. Despite altitude- and CMS-associated hypoxemia, erythrocytosis and impaired blood pressure regulation (CMS only), cerebral homeostasis remained overall preserved.

OBJECTIVE: Emergency medical services (EMS) providers transiently ascend to high altitude for primary missions and secondary transports in mountainous areas in helicopters that are unpressurised and do not have facilities for oxygen supplementation. The decrease in cerebral oxygen saturation can lead to impairment in attention and reaction time as well as in quality of care during acute exposure to altitude.
OBJECTIVE: The primary aim of the current study was to investigate the effect of oxygen supplementation on cognitive performance in Helicopter EMS (HEMS) providers during acute exposure to altitude.
METHODS: This interventional, randomized, controlled, double-blind, cross-over clinical trial was conducted in October 2021. Each trial used a simulated altitude scenario equivalent to 4000 m, in which volunteers were exposed to hypobaric hypoxia with a constant rate of ascent of 4 m/s in an environmental chamber under controlled, replicable, and safe conditions. Trials could be voluntarily terminated at any time. Inclusion criteria were being members of emergency medical services and search and rescue services with an age between 18 and 60 years and an American Society of Anesthesiologists physical status class I.
METHODS: Each participant conducted 2 trials, one in which they were exposed to altitude with oxygen supplementation (intervention trial) and the other in which they were exposed to altitude with ambient air supplementation (control trial).
METHODS: Measurements included peripheral oxygen saturation (SpO2), cerebral oxygenation (ScO2), breathing and heart rates, Psychomotor Vigilance Test (PVT), Digit-Symbol Substitution Test (DSST), n-Back test (2-BACK), the Grooved Pegboard test, and questionnaires on subjective performance, stress, workload, and positive and negative affect. Paired t-tests were used to compare conditions (intervention vs. control). Data were further analyzed using generalized estimating equations (GEE).
RESULTS: A total of 36 volunteers (30 men; mean [SD] age, 36 [9] years; mean [SD] education, 17 [4] years) were exposed to the intervention and control trials. The intervention trials, compared with the control trials, had higher values of SpO2 (mean [SD], 97.9 [1.6] % vs. 86 [2.3] %, t-test, p = 0.004) and ScO2 (mean [SD], 69.9 [5.8] % vs. 62.1 [5.2] %, paired t-test, p = 0.004). The intervention trials compared with the control trials had a shorter reaction time (RT) on the PVT after 5 min (mean [SD], 277.8 [16.7] ms vs. 282.5 [15.3] ms, paired t-test, p = 0.006) and after 30 min (mean [SD], 276.9 [17.7] ms vs. 280.7 [15.0] ms, paired t-test, p = 0.054) at altitude. While controlling for other variables, there was a RT increase of 0.37 ms for each % of SpO2 decrease. The intervention trials showed significantly higher values for DSST number of correct responses (with a difference of mean [SD], 1.2 [3.2], paired t-test, p = 0.035). Variables in the intervention trials were otherwise similar to those in the control trials for DSST number of incorrect responses, 2-BACK, and the Grooved Pegboard test.
CONCLUSIONS: This randomized clinical trial found that oxygen supplementation improves cognitive performance among HEMS providers during acute exposure to 4000 m altitude. The use of oxygen supplementation may allow to maintain attention and timely reaction in HEMS providers. The impact of repeated altitude ascents on the same day, sleep-deprivation, and additional stressors should be investigated. Trial registration NCT05073406, ClinicalTrials.gov trial registration.

BACKGROUND: High-altitude cerebral edema (HACE) is considered an end-stage acute mountain sickness (AMS) that typically occurs in people after rapid ascent to 2500 m or more. While hypoxia is a fundamental feature of the pathophysiological mechanism of HACE, emerging evidence suggests that inflammation serves as a key risk factor in the occurrence and development of this disease. However, little is known about the molecular mechanism underlying their crosstalk.
METHODS: A mouse HACE model was established by combination treatment with hypobaric hypoxia exposure and lipopolysaccharides (LPS) stimulation. Lactylated-proteomic analysis of microglia was performed to reveal the global profile of protein lactylation. Molecular modeling was applied to evaluate the 3-D modeling structures. A combination of experimental approaches, including western blotting, quantitative real-time reverse transcriptionpolymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and RNA interference, were used to explore the underlying molecular mechanisms.
RESULTS: We found that hypoxia exposure increased the lactate concentration and lactylation in mouse HACE model. Moreover, hypoxia aggravated the microglial neuroinflammatory response in a lactate-dependent manner. Global profiling of protein lactylation has shown that a large quantity of lysine-lactylated proteins are induced by hypoxia and preferentially occur in protein complexes, such as the NuRD complex, ribosome biogenesis complex, spliceosome complex, and DNA replication complex. The molecular modeling data indicated that lactylation could affect the 3-D theoretical structure and increase the solvent accessible surface area of HDAC1, MTA1 and Gatad2b, the core members of the NuRD complex. Further analysis by knockdown or selectively inhibition indicated that the NuRD complex is involved in hypoxia-mediated aggravation of inflammation.
CONCLUSIONS: These results revealed a comprehensive profile of protein lactylation in microglia and suggested that protein lysine lactylation plays an important role in the regulation of protein function and subsequently contributes to the neuroinflammatory response under hypoxic conditions.

OBJECTIVE: This review addresses the concern of the health effects associated with high-altitude living and chronic hypoxia with a focus on pulmonary hypertension. With an increasing global population residing at high altitudes, understanding these effects is crucial for public health interventions and clinical management.
RESULTS: Recent literature on the long-term effects of high-altitude residence and chronic hypoxia is comprehensively summarized. Key themes include the mechanisms of hypoxic pulmonary vasoconstriction, the development of pulmonary hypertension, and challenges in distinguishing altitude-related pulmonary hypertension and classical pulmonary vascular diseases, as found at a low altitude.
CONCLUSIONS: The findings emphasize the need for research in high-altitude communities to unravel the risks of pulmonary hypertension and pulmonary vascular diseases. Clinically, early and tailored management for symptomatic individuals residing at high altitudes are crucial, as well as access to advanced therapies as proposed by guidelines for pulmonary vascular disease. Moreover, identifying gaps in knowledge underscores the necessity for continued research to improve understanding and clinical outcomes in high-altitude pulmonary vascular diseases.

BACKGROUND: Acute mountain sickness (AMS) is the most prevalent condition resulting from hypobaric hypoxia (HH) at high altitudes. Although evidence suggests the involvement of inflammatory cytokines in AMS development, there is currently a lack of reports on variations in cytokine levels between individuals susceptible to AMS and those resistant to AMS prior to ascending to high altitude. Thus our current study aims to assess the predictive capability for AMS occurrence by evaluating differences in cytokine levels at low altitudes.
METHODS: The present study recruited 48 participants, who ascended from low altitude to middle high-altitude (3700 m) and further to extreme high-altitude (5000 m). Based on Lake Louise Score (LLS) at the two high altitudes, participants were categorized into severe AMS-susceptible (sAMS), moderate AMS-susceptible (mAMS), and non-AMS groups. The Bio-Plex MAGPIX System was employed to measure plasma levels of 11 inflammatory cytokines. Cytokines at low altitude and middle high-altitude were analyzed through receiver operating characteristic (ROC) analysis to obtain area under the ROC curve (AUROC), sensitivity, and specificity.
RESULTS: Based on LLS at 3700 m, we initially categorized the study subjects into the sAMS group (n = 8) and the Non-AMS group (n = 40). Among individuals in the non-AMS group (n = 40) at the altitude of 3700 m, those who developed AMS at the altitude of 5000 m were assigned to the mAMS group (n = 17), whereas those who did not experience AMS were included into the non-AMS group (n = 23). The concentration of TNF-α at low altitude exhibited robust predictive performance for predicting AMS occurrence at the altitude of 3700 m. Among the non-AMS group at the altitude of 3700 m, we identified that the concentration of IL-2 and IL-17A demonstrated high efficacy in predicting the onset of AMS following ascent to 5000 m. In addition, differentially expressed cytokines including IL-17A, TNF-α and IL-2 at low altitude possessed discriminatory potential among the three groups at 5000 m..
CONCLUSIONS: We posited that the levels of TNF-α, IL-2, IL-17A in serum of low altitude could be considered as potential biomarkers to predict the occurrence of AMS at high altitude.
UNASSIGNED: Through the two comparisons at different two altitudes (baseline level and 3700 m), we provided a model to progressively screen individuals who are susceptible and resistant to different high altitudes (3700 m and 5000 m). TNF-α could firstly screen out the AMS susceptible individuals at the altitude of 3700 m. And through its combination with IL-2 and IL-17A, we could further screen out AMS susceptible individuals at the altitude of 5000 m.

UNASSIGNED: To investigate the short-term changes in chest CT images of low-altitude populations after entering a high-altitude environment.
UNASSIGNED: Chest CT images of 3,587 people from low-altitude areas were obtained within one month of entering a high-altitude environment. Abnormal CT features and clinical symptoms were analyzed.
UNASSIGNED: Besides acute high-altitude pulmonary edema, the incidence of soft tissue space pneumatosis was significantly higher than that in low-altitude areas. Pneumatosis was observed in the mediastinum, cervical muscle space, abdominal cavity, and spinal cord epidural space, especially the mediastinum.
UNASSIGNED: In addition to acute high-altitude pulmonary edema, spontaneous mediastinal emphysema often occurs when individuals in low-altitude areas adapt to the high-altitude environment of cold, low-pressure, and hypoxia. When the gas escapes to the abdominal cavity, it is easy to be misdiagnosed as gastrointestinal perforation. It is also not uncommon for gas accumulation to escape into the epidural space of the spinal cord. The phenomenon of gas diffusion into distant tissue space and the mechanism of gas escape needs to be further studied.

OBJECTIVE: This study aimed to systematically review the effect of nitrate supplementation on blood oxygen saturation.
METHODS: We searched PubMed, Scopus, and Cochrane Library databases from their inception up to October 2022. Two reviewers independently conducted two stages of the screening process to include a randomized controlled trial with nitrate supplementation versus placebo intervention assessing oxygen saturation among lowlanders going to either real or simulated high altitude environments. We used the Cochrane Risk of Bias 2.0 tool to assess the risk of bias in the included studies. Fixed-effect model meta-analyses were conducted for laboratory-based studies. Random-effect meta-analyses were conducted for real-world studies.
RESULTS: We found 7 trials that met the eligibility criteria. A meta-analysis of studies with some bias concerns showed an increase of 1.26 % in the SpO2 with 44 % I2 during submaximal exercise at simulated high altitudes (GRADE: low). On the contrary, a meta-analysis of studies without heterogeneity showed that nitrate supplementation aggravated oxygen saturation decline (-2.64 %, p = 0.03, GRADE: high) during rest in real high-altitude environments. A meta-analysis also showed that nitrate supplementation did not affect Acute Mountain Sickness (AMS) symptoms (GRADE: high).
CONCLUSIONS: Our results suggest that nitrate supplementation did not provide benefits for AMS prevention during rest at high altitudes. The low-quality evidence showing small beneficial effects of nitrate supplementation during exercise calls for further studies.

Acute high altitude disease (AHAD) is a general term for a series of clinical reactions that occur when the body fails to adapt to the low-pressure hypoxic environment of high altitudes. Mild cases can cause symptoms such as headache, nausea and vomiting, while more severe cases can lead to life-threatening conditions such as pulmonary edema, cerebral edema and other critical conditions that can be fatal. With the increasing demand for high altitudes deployment, understanding the common preventive measures of AHAD can reduce its morbidity or mortality to a certain extent, which is of great benefit to those who reside temporarily at high altitudes. In recent years, as people\'s health awareness has improved, there has been a growing attention towards non-pharmacological methods of disease prevention. At the same time, non-pharmacological therapy has significant therapeutic effects in preventing and treating high-altitude diseases, which has attracted the attention of researchers in this field. This review summarizes the major non-pharmacological preventive components of modern medicine and outlines the current non-pharmacological approaches to AHAD from the perspective of traditional Chinese medicine, intending to serve clinical purposes and improve the onset and prognosis of AHAD.

About 140 million people worldwide live at an altitude above 2500 m. Studies have showed an increase of the incidence of hyperuricemia among plateau populations, but little is known about the possible mechanisms. This study aims to assess the effects of high altitude on hyperuricemia and explore the corresponding mechanisms at the histological, inflammatory and molecular levels. This study finds that intermittent hypobaric hypoxia (IHH) exposure results in an increase of serum uric acid level and a decrease of uric acid clearance rate. Compared with the control group, the IHH group shows significant increases in hemoglobin concentration (HGB) and red blood cell counts (RBC), indicating that high altitude hyperuricemia is associated with polycythemia. This study also shows that IHH exposure induces oxidative stress, which causes the injury of liver and renal structures and functions. Additionally, altered expressions of organic anion transporter 1 (OAT1) and organic cation transporter 1 (OCT1) of kidney have been detected in the IHH exposed rats. The adenosine deaminase (ADA) expression levels and the xanthione oxidase (XOD) and ADA activity of liver of the IHH exposure group have significantly increased compared with those of the control group. Furthermore, the spleen coefficients, IL-2, IL-1β and IL-8, have seen significant increases among the IHH exposure group. TLR/MyD88/NF-κB pathway is activated in the process of IHH induced inflammatory response in joints. Importantly, these results jointly show that IHH exposure causes hyperuricemia. IHH induced oxidative stress along with liver and kidney injury, unusual expression of the uric acid synthesis/excretion regulator and inflammatory response, thus suggesting a potential mechanism underlying IHH-induced hyperuricemia.