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Endothelin-1 (ET-1) and its receptors are linked to increases in sensitivity of the chemoreceptors to hypoxic stress and the development of hypertension in preclinical models. We hypothesized ET receptor antagonism would lower resting blood pressure (BP) as well as the acute BP response to chemoreflex stress. Twenty-four men (31 ± 5 years, 26 ± 3 kg/m 2 ) completed two study visits (control, bosentan). On each visit, BP was assessed under three conditions: (1) normoxia (F i O 2 0.21), (2) chemoreflex excitation via hypoxia (F i O 2 0.05-0.21), (3) chemoreflex inhibition via hyperoxia (F i O 2 1.00). Bosentan increased plasma ET-1 (0.94 ± 0.90 to 1.27 ± 0.62 pg/mL, p = 0.004), supporting receptor blockade. Resting diastolic (73 ± 5 to 69 ± 7 mmHg, p = 0.007) and mean (93 ± 7 to 88 ± 7 mmHg, p = 0.005) BP were reduced following bosentan compared to control with no change in systolic BP (p = 0.507). The mean BP response to both acute hypoxia (-0.48 ± 0.38 to -0.25 ± 0.31 mmHg/%, p = 0.004) and hyperoxia (area under the curve -93 ± 108 to -27 ± 66 AU, p = 0.018) were attenuated following bosentan. Acute ET receptor inhibition attenuates the rise in BP during chemoreflex excitation as well as the fall in BP during chemoreflex inhibition in healthy young men. These data support a role for ET-1 in control of resting BP, possibly through a chemoreceptor-mediated mechanism., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Our group previously showed that genetic or pharmacological inhibition of the cystine/glutamate antiporter, system x c - , mitigates excitotoxicity after anoxia by increasing latency to anoxic depolarization, thus attenuating the ischaemic core. Hypoxia, however, which prevails in the ischaemic penumbra, is a condition where neurotransmission is altered, but excitotoxicity is not triggered. The present study employed mild hypoxia to further probe ischaemia-induced changes in neuronal responsiveness from wild-type and xCT KO (xCT -/- ) mice. Synaptic transmission was monitored in hippocampal slices from both genotypes before, during and after a hypoxic episode. Although wild-type and xCT -/- slices showed equal suppression of synaptic transmission during hypoxia, mutant slices exhibited a persistent potentiation upon re-oxygenation, an effect we termed 'post-hypoxic long-term potentiation (LTP)'. Blocking synaptic suppression during hypoxia by antagonizing adenosine A 1 receptors did not preclude post-hypoxic LTP. Further examination of the induction and expression mechanisms of this plasticity revealed that post-hypoxic LTP was driven by NMDA receptor activation, as well as increased calcium influx, with no change in paired-pulse facilitation. Hence, the observed phenomenon engaged similar mechanisms as classical LTP. This was a remarkable finding as theta-burst stimulation-induced LTP was equivalent between genotypes. Importantly, post-hypoxic LTP was generated in wild-type slices pretreated with system x c - inhibitor, S-4-carboxyphenylglycine, thereby confirming the antiporter's role in this phenomenon. Collectively, these data indicate that system x c - interference enables neuroplasticity in response to mild hypoxia, and, together with its regulation of cellular damage in the ischaemic core, suggest a role for the antiporter in post-ischaemic recovery of the penumbra., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Occupational pulmonary diseases (OPDs) pose a significant global health challenge, contributing to high mortality rates. This review delves into the pathophysiology of hypoxia and the safety of intermittent hypoxic conditioning (IHC) in OPD patients. By examining sources such as PubMed, Relemed, NLM, Scopus, and Google Scholar, the review evaluates the efficacy of IHC in clinical outcomes for OPD patients. It highlights the complexities of cardiovascular and respiratory regulation dysfunctions in OPDs, focusing on respiratory control abnormalities and the impact of intermittent hypoxic exposures. Key areas include the physiological effects of hypoxia, the role of hypoxia-inducible factor-1 alpha (HIF-1α) in occupational lung diseases, and the links between brain ischemia, stroke, and OPDs. The review also explores the interaction between intermittent hypoxic exposures, mitochondrial energetics, and lung physiology. The potential of IHE to improve clinical manifestations and underlying pathophysiology in OPD patients is thoroughly examined. This comprehensive analysis aims to benefit molecular pathologists, pulmonologists, clinicians, and physicians by enhancing understanding of IHE's clinical benefits, from research to patient care, and improving clinical outcomes for OPD patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose of Review: 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., Recent Findings: 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., Summary: 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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Failure to recover from repeated hypercapnia and hypoxemia (HH) challenges caused by severe GCS and postictal apneas may contribute to sudden unexpected death in epilepsy (SUDEP). Our previous studies found orexinergic dysfunction contributes to respiratory abnormalities in a preclinical model of SUDEP, Kcna1 - / - mice. Here, we developed two gas challenges consisting of repeated HH exposures and used whole body plethysmography to determine whether Kcna1 - / - mice have detrimental ventilatory responses. Kcna1 - / - mice exhibited an elevated ventilatory response to a mild repeated hypercapnia-hypoxia (HH) challenge compared to WT. Moreover, 71% of Kcna1 - / - mice failed to survive a severe repeated HH challenge, whereas all WT mice recovered. We next determined whether orexin was involved in these differences. Pretreating Kcna1 - / - mice with a dual orexin receptor antagonist rescued the ventilatory response during the mild challenge and all subjects survived the severe challenge. In ex vivo extracellular recordings in the lateral hypothalamus of coronal brain slices, we found reducing pH either inhibits or stimulates putative orexin neurons similar to other chemosensitive neurons; however, a significantly greater percentage of putative orexin neurons from Kcna1 - / - mice were stimulated and the magnitude of stimulation was increased resulting in augmentation of the calculated chemosensitivity index relative to WT. Collectively, our data suggest that increased chemosensitive activity of orexin neurons may be pathologic in the Kcna1 - / - mouse model of SUDEP, and contribute to elevated ventilatory responses. Our preclinical data suggest that those at high risk for SUDEP may be more sensitive to HH challenges, whether induced by seizures or other means; and the depth and length of the HH exposure could dictate the probability of survival., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To provide timely and relevant insights into the complex relationship between pulmonary vascular disease (PVD) and chronic lung disease (CLD), focusing on the causative and consequential dynamics between these conditions., Recent Findings: There are shared pathogenic mechanisms between pulmonary arterial hypertension (PAH) and group 3 pulmonary hypertension, including altered expression of mediators and growth factors implicated in both conditions. Factors such as hypoxia, hypoxemia, and hypercapnia also contribute to pulmonary vascular remodelling and endothelial dysfunction. However, the role of hypoxia as the sole driver of pulmonary hypertension in CLD is being reconsidered, particularly in chronic obstructive pulmonary disease (COPD), with evidence suggesting a potential role for cigarette smoke products in initiating pulmonary vascular impairment. On the other hand, interstitial lung disease (ILD) encompasses a group of heterogeneous lung disorders characterized by inflammation and fibrosis of the interstitium, leading to impaired gas exchange and progressive respiratory decline, which could also play a role as a cause of pulmonary hypertension., Summary: Understanding the intricate interplay between the pulmonary vascular compartment and the parenchymal and airway compartments in respiratory disease is crucial for developing effective diagnostic and therapeutic strategies for patients with PVD and CLD, with implications for both clinical practice and research., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Exposure to hypoxia immediately challenges a variety of physiologic systems that limit exercise capacity. Under normoxia, caffeine (CAFF) increases ventilation and subsequent oxygenation of hemoglobin (SpO2) and skeletal muscle (SmO2). CAFF improves exercise performance at altitude. However, little attention has been given to submaximal exercise in hypoxia, particularly regarding low CAFF consumers and female participants. The aim of this study was to determine the effect of CAFF on pulmonary, metabolic, and perceptual variables in response to submaximal running in hypoxia in low CAFF consuming males and females., Methods: In a double blinded, counterbalanced design, 14 (6 females) individuals (24.1±5.1 years; VO2max: 40.6±5.6 mL × kg -1 × min -1 ; 20.8±8.0% body fat), who habitually consumed ≤150 mg/day of CAFF performed treadmill running at workloads of 25%, 40%, 60%, and 75% of sea level VO2max in normobaric hypoxia (FIO2=0.15) on two separate occasions: 1) 60 minutes after 6 mg/kg of CAFF; or 2) placebo., Results: CAFF had no effect on any variable measured. Specifically, VE (condition: P=0.12; interaction: P=0.19), VT (condition: P=0.16; interaction: P=0.57), and Ve:VO2 (condition: P=0.07; interaction: P=0.69) were similar between groups. Further, CAFF had no effect on relative VO2 (condition: P=0.84; interaction: P=0.95), HR (condition: P=0.28; interaction: P=0.35), SmO2 (condition: P=0.66; interaction: P=0.82), or SpO2 (condition: P=0.16; interaction: P=0.97). Finally, rating of perceived exertion (RPE; P=0.92) and acute mountain sickness scores (P=0.29) were similar across conditions., Conclusions: These data demonstrate that CAFF provides no physiologic advantage to submaximal exercise in acute, normobaric hypoxia with low CAFF consuming males and females.

Purpose: We hypothesised that during a rest-to-exercise transient in hypoxia (H), compared to normoxia (N), (i) the initial baroreflex sensitivity (BRS) decrease would be slower and (ii) the fast heart rate (HR) and cardiac output (CO) response would have smaller amplitude (A 1 ) due to lower vagal activity in H than N., Methods: Ten participants performed three rest-to-50 W exercise transients on a cycle-ergometer in N (ambient air) and three in H (inspired fraction of O 2  = 0.11). R-to-R interval (RRi, by electrocardiography) and blood pressure profile (by photo-plethysmography) were recorded non-invasively. Analysis of the latter provided mean arterial pressure (MAP) and stroke volume (SV). CO = HR·SV. BRS was calculated by modified sequence method., Results: Upon exercise onset in N, MAP fell to a minimum (MAPmin) then recovered. BRS decreased immediately from 14.7 ± 3.6 at rest to 7.0 ± 3.0 ms mmHg -1 at 50 W (p < 0.01). The first BRS sequence detected at 50 W was 8.9 ± 4.8 ms mmHg -1 (p < 0.05 vs. rest). In H, MAP showed several oscillations until reaching a new steady state. BRS decreased rapidly from 10.6 ± 2.8 at rest to 2.9 ± 1.5 ms mmHg -1 at 50 W (p < 0.01), as the first BRS sequence at 50 W was 5.8 ± 2.6 ms mmHg -1 (p < 0.01 vs. rest). CO-A 1 was 2.96 ± 1.51 and 2.31 ± 0.94 l min -1 in N and H, respectively (p = 0.06). HR-A 1 was 7.7 ± 4.6 and 7.1 ± 5.9 min -1 in N and H, respectively (p = 0.81)., Conclusion: The immediate BRS decrease in H, coupled with similar rapid HR and CO responses, is compatible with a withdrawal of residual vagal activity in H associated with increased sympathetic drive., (© 2024. The Author(s).)

Li, Xiaoxu, Zhijun Pu, Gang Xu, Yidong Yang, Yu Cui, Xiaoying Zhou, Chenyuan Wang, Zhifeng Zhong, Simin Zhou, Jun Yin, Fabo Shan, Chengzhong Yang, Li Jiao, Dewei Chen, and Jian Huang. Hypoxia-induced myocardial hypertrophy companies with apoptosis enhancement and p38-MAPK pathway activation. High Alt Med Biol. 25:186-196, 2024. Background: Right ventricular function and remodeling are closely associated with symptom severity and patient survival in hypoxic pulmonary hypertension. However, the detailed molecular mechanisms underlying hypoxia-induced myocardial hypertrophy remain unclear. Methods: In Sprague-Dawley rats, hemodynamics were assessed under both normoxia and hypobaric hypoxia at intervals of 7 (H7), 14 (H14), and 28 (H28) days. Morphological changes in myocardial tissue were examined using hematoxylin and eosin (HE) staining, while myocardial hypertrophy was evaluated with wheat germ agglutinin (WGA) staining. Apoptosis was determined through TUNEL assays. To further understand the mechanism of myocardial hypertrophy, RNA sequencing was conducted, with findings validated via Western blot analysis. Results: The study demonstrated increased hypoxic pulmonary hypertension and improved right ventricular diastolic and systolic function in the rat models. Significant elevations in pulmonary arterial systolic pressure (PASP), mean pulmonary arterial pressure (mPAP), right ventricular mean pressure (RVMP), and the absolute value of +dp/dt max were observed in the H14 and H28 groups compared with controls. In addition, right ventricular systolic pressure (RVSP), -dp/dt max , and the mean dp/dt during isovolumetric relaxation period were notably higher in the H28 group. Heart rate increased in the H14 group, whereas the time constant of right ventricular isovolumic relaxation (tau) was reduced in both H14 and H28 groups. Both the right heart hypertrophy index and the heart weight/body weight ratio (HW/BW) were elevated in the H14 and H28 groups. Myocardial cell cross-sectional area also increased, as shown by HE and WGA staining. Western blot results revealed upregulated HIF-1α levels and enhanced HIF-2α expression in the H7 group. In addition, phosphorylation of p38 and c-fos was augmented in the H28 group. The H28 group showed elevated levels of Cytochrome C (Cyto C), whereas the H14 and H28 groups exhibited increased levels of Cleaved Caspase-3 and the Bax/Bcl-2 ratio. TUNEL analysis revealed a rise in apoptosis with the extension of hypoxia duration in the right ventricle. Conclusions: The study established a link between apoptosis and p38-MAPK pathway activation in hypoxia-induced myocardial hypertrophy, suggesting their significant roles in this pathological process.

Intermittent hypoxia (IH) and intermittent transcutaneous electrical stimulation (ITES) might benefit patients with obstructive sleep apnea (OSA). However, the therapeutic value of combined IH and ITES in OSA is unknown. In this prospective, randomized, controlled crossover study, normoxia (air exposure for 50 min before sleep and sham stimulation for 6 h during sleep), IH (5 repeats of 5 min 10-12 % O 2 alternating with 5 min air for 50 min, and sham stimulation for 6 h), ITES (air exposure for 50 min and 6 repeats of 30 min transcutaneous electrical stimulation alternating with 30 min of sham stimulation for 6 h), and IH&ITES (10-12 % O 2 alternating with air for 50 min and transcutaneous electrical stimulation alternating with sham stimulation for 6 h) were administered to patients with OSA over four single-night sessions. The primary endpoint was difference in OSA severity between the interventions according to apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). The efficacy was response to IH, ITES, IH&ITES defined as a ≥50 % reduction in AHI compared with normoxia. Twenty participants (17 male, 3 female) completed the trial. The median (IQR) AHI decreased from 14.5 (10.8, 17.5) events/h with normoxia to 6.9 (3.9, 14.8) events/h with IH (p=0.020), 5.7 (3.4, 9.1) events/h with ITES (p=0.001), and 3.5 (1.8, 6.4) events/h with IH&ITES (p=0.001). AHI was significantly different between IH and IH&ITES (p=0.042) but not between ITES and IH&ITES (p=0.850). For mild-moderate OSA (n=17), IH, ITES, and IH&ITES had a significant effect on AHI (p=0.013, p=0.001, p=0.001, respectively) compared with normoxia, but there were no differences in post hoc pairwise comparisons between intervention groups. No serious adverse events were observed. In conclusion, IH, ITES, and IH&ITES significantly reduced OSA severity. IH&ITES showed better efficacy in mild-moderate OSA than IH and was comparable to ITES. Our data do not support recommending IH&ITES over ITES for OSA., Competing Interests: Declaration of Competing Interest The authors have no relevant disclosures., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objective: The apnoea-hypopnoea index (AHI) and oxygen desaturation index (ODI) encounter challenges in capturing the intricate relationship between obstructive sleep apnoea (OSA) and cardiovascular disease (CVD) risks. Although novel hypoxic indices have been proposed to tackle these limitations, there remains a gap in comprehensive validation and comparisons across a unified dataset., Methods: Samples were derived from the Sleep Heart Health Study (SHHS), involving 4485 participants aged over 40 years after data quality screening. The study compared several key indices, including AHI, ODI, the reconstructed hypoxic burden (rHB), the percentage of sleep time with the duration of respiratory events causing desaturation (pRED&#95;3p) and the sleep breathing impairment index (SBII), in relation to CVD mortality and morbidity risks. Adjusted Cox proportional models were employed to calculate hazard ratios (HRs) for each index, and comparisons were performed., Results: SBII and pRED&#95;3p exhibited significant correlations with both CVD mortality and morbidity, with SBII showing the highest adjusted HR (95% confidence interval) for mortality (2.04 [1.25, 3.34]) and pRED&#95;3p for morbidity (1.43 [1.09-1.88]). In contrast, rHB was only significant in predicting CVD mortality (1.63 [1.05-2.53]), while AHI and ODI did not show significant correlations with CVD outcomes. The adjusted models based on SBII and pRED&#95;3p exhibited optimal performance in the CVD mortality and morbidity datasets, respectively., Conclusion: This study identified the optimal indices for OSA-related CVD risks prediction, SBII for mortality and pRED&#95;3p for morbidity. The open-source online platform provides the computation of the indices., (© 2024 Asian Pacific Society of Respirology.)

Hermand, Eric, Léo Lesaint, Laura Denis, Jean-Paul Richalet, and François J. Lhuissier. A step test to evaluate the susceptibility to severe high-altitude illness in field conditions. High Alt Med Biol. 25:158-163, 2024.-A laboratory-based hypoxic exercise test, performed on a cycle ergometer, can be used to predict susceptibility to severe high-altitude illness (SHAI) through the calculation of a clinicophysiological SHAI score. Our objective was to design a field-condition test and compare its derived SHAI score and various physiological parameters, such as peripheral oxygen saturation (SpO 2 ), and cardiac and ventilatory responses to hypoxia during exercise (HCRe and HVRe, respectively), to the laboratory test. A group of 43 healthy subjects (15 females and 28 males), with no prior experience at high altitude, performed a hypoxic cycle ergometer test (simulated altitude of 4,800 m) and step tests (20 cm high step) at 3,000, 4,000, and 4,800 m simulated altitudes. According to tested altitudes, differences were observed in O 2 desaturation, heart rate, and minute ventilation ( p < 0.001), whereas the computed HCRe and HVRe were not different ( p = 0.075 and p = 0.203, respectively). From the linear relationships between the step test and SHAI scores, we defined a risk zone, allowing us to evaluate the risk of developing SHAI and take adequate preventive measures in field conditions, from the calculated step test score for the given altitude. The predictive value of this new field test remains to be validated in real high-altitude conditions.

Fossati, Alexandre, and Aleid C. J. Ruijs. Changes in fingertip cold-induced vasodilatation (hunting reaction) on acute exposure to altitude. High Alt Med Biol . 25:212-217, 2024. Objective: Cold-induced vasodilation (CIVD) of the extremities is an interesting part of human physiology. Although the physiology of the CIVD reaction remains unknown, there are indications that hypoxia influences our CIVD reaction. The objective of this study is to measure the influence of acute hypoxia on the CIVD reaction of the fingertips. Methods: The CIVD reaction was measured using immersion of one hand in a water bath of 0°C in 12 healthy volunteers at low (1,235 m) and high (3,800 m) altitude during 35 minutes. High altitude was reached by a 20-minute cable car ride. Testing was performed indoors (room temperature, 22-25°C) at both altitudes. Data analysis was performed measuring the parameters of the CIVD reaction. Differences were found using the paired Student's t-test . Results: There was no significant difference in baseline finger temperature, onset time, peak time, and frequency of the CIVD reaction. However, at high altitude, maximum temperature and amplitude were significantly higher, slope was steeper, and minimum temperature was lower. Conclusion: We did not find evidence for a diminished CIVD reaction at high altitude due to hypoxia.

The present study aimed to investigate the occurrence of ferroptosis in mouse hippocampal tissue and changes in related pathways after exposure to high-altitude hypoxia. A low-pressure hypoxia model was established using a high-altitude environment at 4 010 m. HE staining was used to observe morphological changes in mouse hippocampal tissue, immunohistochemical staining was used to observe lipid peroxidation levels in hippocampal tissue, and corresponding kits were used to measure malondialdehyde (MDA), reduced glutathione (GSH), and Fe 2+ levels in hippocampal tissue. Western blot was used to detect glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthase long chain family member 4 (ACSL4). The results showed that, compared with the plain control group, the mice exposed to high-altitude hypoxia for 1, 3, 7, and 14 d exhibited significant pathological damage, disordered arrangement, and obvious nuclear condensation in the dentate gyrus of the hippocampus. Compared with the plain control group, high-altitude hypoxia exposure increased 4-hydroxynonenal (4-HNE) content in the dentate gyrus and hippocampal MDA content, whereas significantly decreased hippocampal GSH content. Compared with the plain control group, the Fe 2+ content in the hippocampus of mice exposed to high-altitude hypoxia for 14 d significantly increased. Compared with the plain control group, the protein expression levels of GPX4, FTH1, FPN1, TfR1, and FSP1 in the hippocampus of mice exposed to high-altitude hypoxia were significantly down-regulated (SLC7A11 was significantly down-regulated only in the 7-d high-altitude hypoxia exposure group), while the protein expression level of ACSL4 was only significantly up-regulated in the 14-d high-altitude hypoxia exposure group. These results suggest that exposure to high-altitude hypoxia for 14 d can reduce GSH synthesis in mouse hippocampus, down-regulate GPX4 expression, lead to GSH metabolism disorders, inhibit iron storage and efflux, promote lipid peroxidation reaction, and inhibit CoQ10H2's anti-lipid peroxidation effect, ultimately leading to ferroptosis.

Introduction: Achieving simultaneous cerebral blood flow (CBF) and oxygenation measures, specifically for point-of-care injury monitoring in prolonged field care, requires the implementation of appropriate methodologies and advanced medical device design, development, and evaluation. The near-infrared spectroscopy (NIRS) method measures the absorbance of light whose attenuation is related to cerebral blood volume and oxygenation. By contrast, diffuse correlation spectroscopy (DCS) allows continuous noninvasive monitoring of microvascular blood flow by directly measuring the degree of light scattering because of red blood cell (RBC) movement in tissue capillaries. Hence, this study utilizes these two optical approaches (DCS-NIRS) to obtain a more complete hemodynamic monitoring by providing cerebral microvascular blood flow, hemoglobin oxygenation and deoxygenation in hemorrhage, and hypoxia-induced injuries., Materials and Methods: Piglet models of hemorrhage and hypoxia-induced brain injury were used with DCS and NIRS sensors placed over the preorbital to temporal skull regions. To induce hemorrhagic shock, up to 70% of the animal's total blood volume was withdrawn through graded hemorrhage serially via a syringe from a femoral artery cannula in 10 mL/kg aliquots over 1 minute every 10 minutes. A second group of animals was subjected to hypoxia for ∼1 hour through graded hypoxia by serial titration from normoxic fraction inspired oxygen of 21% to hypoxic fraction inspired oxygen of 6%. A subset of animals served as sham-controls undergoing anesthesia, instrumentation, and ventilation as the injury groups, yet experiencing no blood loss or hypoxia., Results: We first investigated the relationship between hemorrhagic shock and no shock by using measured biomarkers, including blood flow index from DCS associated with CBF and oxygenated (HbO) and de-oxygenated hemoglobin from NIRS. The statistical analysis revealed a significant difference between no shock and hemorrhagic shock (P < .01). The HbO decreased with each blood loss as expected, yet the de-oxygenated hemoglobin was slightly changed. During hypoxia-induced global hypoxic-ischemic injury tests, the CBF results from graded hypoxia were consistent with the response previously measured during hemorrhagic shock. Moreover, HbO decreased when the animal was hypoxic, as expected. A statistical analysis was also conducted to compare the results with those of the sham controls., Conclusions: There is a consistency in blood flow measures in both injury mechanisms (hemorrhagic shock and hypoxia), which is significant as the new prototype system provides similar measures and trends for each brain injury type, suggesting that the optical system can be used in response to different injury mechanisms. Notably, the results support the idea that this optical system can probe the hemodynamic status of local cerebral cortical tissue and provide insight into the underlying changes of cerebral tissue perfusion at the microvascular level. These measurement capabilities can improve shock identification and monitoring of medical management of injuries, particularly hemorrhagic shock, in prolonged field care., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Hypoxic hypoxia arises from an inadequate oxygen supply to the blood, resulting in reduced arterial oxygen partial pressure and a consequent decline in oxygen diffusion into tissue cells for utilization. This condition is characterized by diminished oxygen content in the blood, while the supply of other nutrients within the blood remains normal. The brain is particularly sensitive to oxygen deficiency, with varying degrees of hypoxic hypoxia resulting in different levels of neural functional disorder. Since the brain has a specific threshold range for the perception of hypoxic hypoxia, mild hypoxic hypoxia can trigger compensatory protective responses in the brain without affecting neural function. These hypoxic compensatory responses enable the maintenance of an adequate oxygen supply and energy substrates for neurons, thereby ensuring normal physiological functions. To further understand the hypoxic compensatory mechanisms of the central nervous system (CNS), this article explores the structural features of the brain's neurovascular unit model, hypoxic signal transduction, and compensatory mechanisms., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Respiratory plasticity is a beneficial response to chronic hypoxia in fish. Red drum, a teleost that commonly experiences hypoxia in the Gulf of Mexico, have shown respiratory plasticity following sublethal hypoxia exposure as juveniles, but implications of hypoxia exposure during development are unknown. We exposed red drum embryos to hypoxia (40% air saturation) or normoxia (100% air saturation) for 3 days post fertilization (dpf). This time frame encompasses hatch and exogenous feeding. At 3 dpf, there was no difference in survival or changes in size. After the 3-day hypoxia exposure, all larvae were moved and reared in common normoxic conditions. Fish were reared for ∼3 months and effects of the developmental hypoxia exposure on swim performance and whole-animal aerobic metabolism were measured. We used a cross design wherein fish from normoxia (N=24) were exercised in swim tunnels in both hypoxia (40%, n=12) and normoxia (100%, n=12) conditions, and likewise for hypoxia-exposed fish (n=10 in each group). Oxygen consumption, critical swim speed (Ucrit), critical oxygen threshold (Pcrit) and mitochondrial respiration were measured. Hypoxia-exposed fish had higher aerobic scope, maximum metabolic rate, and higher liver mitochondrial efficiency relative to control fish in normoxia. Interestingly, hypoxia-exposed fish showed increased hypoxia sensitivity (higher Pcrit) and recruited burst swimming at lower swim speeds relative to control fish. These data provide evidence that early hypoxia exposure leads to a complex response in later life., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Small (SGA) and large (LGA) for gestational age infants have higher risks of infant morbidity when compared to those who are appropriate for gestational age (AGA). Increasing pre-pregnancy maternal BMI and gestational weight gain (GWG) are associated with higher risks of LGA and lower risks of SGA infants; however, their direct effects on infant morbidity are unknown. Therefore, we intended to 1) assess how maternal pre-pregnancy BMI, GWG, and birthweight (categorized as SGA, AGA or LGA) affect infant morbidity and 2) estimate at entry of care the risk of infant morbidity according to pre-pregnancy BMI and possible GWG., Methods: we used Consortium on Safe Labor data, a retrospective observational cohort study collecting pregnancy and birth data from 2002 to 2008 in 12 US centers. The association between maternal BMI, GWG and infant morbidity was estimated in singleton gestations delivering ≥ 37 weeks using binomial logistic regression. Hypoxic composite neonatal morbidity was defined as any the following: stillbirth, neonatal death, resuscitation at birth, NICU admission, intracranial hemorrhage, PVH grade III and IV, neonatal seizures, NEC, meconium aspiration, CPAP or mechanical ventilation, RDS, and sepsis. Traumatic composite neonatal morbidity included shoulder dystocia or birth injuries., Results: In this study of 110,594 mother-infant dyads, a total of 8,369 (7.6%) infants experienced hypoxic, while 2,134 (1.9%) developed traumatic morbidity. The risk of hypoxic morbidity among SGA, AGA and LGA infants increased when mothers were overweight (aOR 1.26 [95%CI 1.18-1.34]) or obese (class 1: aOR 1.3 [1.2-1.4]; class 2: aOR 1.7 [1.5-1.9]; class 3: aOR 1.8 [1.6-2]) as opposed to normal weight, and when GWG exceeded (aOR 1.08 [1.02-1.014]) rather than remained within recommendations. The risk of traumatic morbidity increased with maternal obesity (class 1: aOR 1.3 [1.1-1.5]), whilst it dropped with GWG below recommendations (aOR 0.7 [0.6-0.8]). The risk of hypoxic events estimated at entry of care increased with maternal overweight (aOR 1.27 [1.19-1.35]) or obesity (class 1: aOR 1.4 [1.2-1.5]; class 2: aOR 1.7 [1.5-1.9]; class 3: aOR 1.8 [1.6-2.1]), and with possible GWG above (aOR 1.09 [1.03-1.015]) recommendations. The risk of traumatic morbidity increased with overweight (aOR 1.1 [1-1.3]) or obesity (class 1: aOR 1.4 [1.2-1.6]; class 2: aOR 1.3 [1-1.6]), with possible GWG above (aOR 1.2 [1-1.3]), as opposed to below recommendations (aOR 0.7 [0.6-0.8])., Conclusions: While maternal pre-pregnancy BMI and GWG equally affected traumatic morbidity, the former had a greater impact on hypoxic complications. Therefore, weight control prior to pregnancy is at least as effective as avoiding excessive gestational weight gain to prevent neonatal morbidity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chiossi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O 2 ) and normoxia. HIIT included 10 3-min bouts alternating between treadmill speeds of 50 cm·s -1 and 15 cm·s -1 . In the hippocampus, IH and HIIT significantly downregulated Acan and NgR2 mRNA that are involved in the inhibition of neuroplasticity. However, IH and IH + HIIT significantly upregulated Lingo-1 and NgR3 in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity-inhibiting pathways. These results provide a fundamental step toward elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity that will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation. NEW & NOTEWORTHY Intermittent hypoxia (IH) and high-intensity interval training (HIIT) enhance neuroplasticity and upregulate neurotrophic factors in the central nervous system (CNS). We provide evidence that IH and IH + HIIT also have the capacity to regulate genes involved in the RhoA/ROCK signaling pathway that is known to restrict structural plasticity in the CNS. This provides a new mechanistic insight into how these interventions may enhance hippocampal-related plasticity and facilitate learning, memory, and neuroregeneration.

Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H 2 S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H 2 S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H 2 S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H 2 S production and enhanced third-order femoral artery dilator responses to the H 2 S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H 2 S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H 2 S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H 2 S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H 2 S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Athletes use hypoxic living and training to increase hemoglobin mass (Hb mass ), but Hb mass declines rapidly upon return to sea level. We investigated whether intermittent hypoxic exposure (IHE) + continuous hypoxic training (CHT) after return to sea level maintained elevated Hb mass , and if changes in Hb mass were transferred to changes in maximal oxygen uptake (V̇o 2max ) and exercise performance. Hb mass was measured in 58 endurance athletes before (PRE), after (POST1), and 30 days after (POST2) a 27 ± 4-day training camp in hypoxia ( n = 44, HYP) or at sea level ( n = 14, SL). After returning to sea level, 22 athletes included IHE (2 h rest) + CHT (1 h training) in their training every third day for 1 mo (HYP IHE + CHT ), whereas the other 22 HYP athletes were not exposed to IHE or CHT (HYP SL ). Hb mass increased from PRE to POST1 in both HYP IHE + CHT (4.4 ± 0.7%, means ± SE) and HYP SL (4.1 ± 0.6%) (both P < 0.001). Compared with PRE, Hb mass at POST2 remained 4.2 ± 0.8% higher in HYP IHE + CHT ( P < 0.001) and 1.9 ± 0.5% higher in HYP SL ( P = 0.023), indicating a significant difference between the groups ( P = 0.002). In SL, no significant changes were observed in Hb mass with mean alterations between -0.5% and 0.4%. V̇o 2max and time to exhaustion during an incremental treadmill test ( n = 35) were elevated from PRE to POST2 only in HYP IHE + CHT (5.8 ± 1.2% and 5.4 ± 1.4%, respectively, both P < 0.001). IHE + CHT possesses the potential to mitigate the typical decline in Hb mass commonly observed during the initial weeks after return to sea level. NEW & NOTEWORTHY Sets of 2-h intermittent hypoxic exposure + 1-h continuous hypoxic training, every third day, possess the potential to mitigate the typical decline in Hb mass that is commonly observed during the initial weeks after return to sea level from an altitude camp. Inclusion of IHE + CHT in the training regimen was also accompanied by improvements in V̇o 2max and exercise performance in most but not all Tier 3-Tier 5 level endurance athletes during the training season.

Aging is associated with vascular endothelial dysfunction observed through a progressive loss of flow-mediated dilation caused partly by a decreased nitric oxide bioavailability. Intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and normoxic air, was reported to either maintain or improve vascular function in young adults. The aim of this study was to determine the impact of age on the vascular response to intermittent hypoxia. Twelve young adults and 11 older adults visited the laboratory on two occasions. Plasma nitrate concentrations and brachial artery flow-mediated dilation were assessed before and after exposure to either intermittent hypoxia or a sham protocol. Intermittent hypoxia consisted of eight 4-min hypoxic cycles at a targeted oxygen saturation of 80% interspersed with breathing room air to resaturation, and the sham protocol consisted of eight 4-min normoxic cycles interspersed with breathing room air. Vascular responses were assessed during intermittent hypoxia and the sham protocol. Intermittent hypoxia elicited a brachial artery vasodilation but did not change brachial artery shear rate in both young and older adults. Plasma nitrate concentrations were not significantly affected by intermittent hypoxia compared with the sham protocol in both groups. Brachial artery flow-mediated dilation was not acutely affected by intermittent hypoxia or the sham protocol in either young or older adults. In conclusion, the brachial artery vasodilatory response to intermittent hypoxia was not influenced by age. Intermittent hypoxia increased brachial artery diameter but did not acutely affect endothelium-dependent vasodilation in young or older adults. NEW & NOTEWORTHY The objective of this study was to determine the impact of age on the vascular response to intermittent hypoxia. Eight 4-min bouts of hypoxia at a targeted oxygen saturation of 80% induced a brachial artery vasodilation in both young and older adults, indicating that age does not influence the vasodilatory response to intermittent hypoxia. Intermittent hypoxia did not acutely affect brachial artery flow-mediated dilation in young or older adults.

Purpose: Both maximal-intensity exercise and altitude exposure challenge the pulmonary system that may reach its maximal capacities. Expiratory flow limitation (EFL) and exercise-induced hypoxemia (EIH) are common in endurance-trained athletes. Furthermore, because of their smaller airways and lung size, women, independently of their fitness level, may be more prone to pulmonary limitations during maximal-intensity exercise, particularly when performed in hypoxic conditions. The objective of this study was to investigate the impact of sex and fitness level on pulmonary limitations during maximal exercise in normoxia and their consequences in acute hypoxia., Methods: Fifty-one participants were distributed across four different groups according to sex and fitness level. Participants visited the laboratory on three occasions to perform maximal incremental cycling tests in normoxia and hypoxia (inspired oxygen fraction = 0.14) and two hypoxic chemosensitivity tests. Pulmonary function and ventilatory capacities were evaluated at each visit., Results: EIH was more prevalent (62.5% vs 22.2%, P = 0.004) and EFL less common (37.5% vs 70.4%, P = 0.019) in women than men. EIH prevalence was different ( P = 0.004) between groups of trained men (41.7%), control men (6.7%), trained women (50.0%), and control women (75.0%). All EIH men but only 40% of EIH women exhibited EFL. EFL individuals had higher slope ratio ( P = 0.029), higher ventilation (V̇ E ) ( P < 0.001), larger ΔVO 2max ( P = 0.019), and lower hypoxia-related V̇ E increase ( P < 0.001)., Conclusions: Women reported a higher EIH prevalence than men, regardless of their fitness level, despite a lower EFL prevalence. EFL seems mainly due to the imbalance between ventilatory demands and capacities. It restricts ventilation, leading to a larger performance impairment during maximal exercise in hypoxic conditions., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

With ascent to high altitude (HA), compensatory increases in cerebral blood flow and oxygen delivery must occur to preserve cerebral metabolism and consciousness. We hypothesized that this compensation in cerebral blood flow and oxygen delivery preserves tolerance to simulated hemorrhage (via lower body negative pressure, LBNP), such that tolerance is similar during sustained exposure to HA vs. low altitude (LA). Healthy humans (4F/4 M) participated in LBNP protocols to presyncope at LA (1130 m) and 5-7 days following ascent to HA (3800 m). Internal carotid artery (ICA) blood flow, cerebral delivery of oxygen (CDO 2 ) through the ICA, and cerebral tissue oxygen saturation (ScO 2 ) were determined. LBNP tolerance was similar between conditions (LA: 1276 ± 304 s vs. HA: 1208 ± 306 s; P = 0.58). Overall, ICA blood flow and CDO 2 were elevated at HA vs. LA (P ≤ 0.01) and decreased with LBNP under both conditions (P < 0.0001), but there was no effect of altitude on ScO 2 responses (P = 0.59). Thus, sustained exposure to hypobaric hypoxia did not negatively impact tolerance to simulated hemorrhage. These data demonstrate the robustness of compensatory physiological mechanisms that preserve human cerebral blood flow and oxygen delivery during sustained hypoxia, ensuring cerebral tissue metabolism and neuronal function is maintained., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Patients with early onset scoliosis are at high risk of sleep disordered breathing, sleep disruption, and adverse consequences of poor sleep. In this study, we aim to assess the prevalence of periodic limb movements of sleep in a cohort of children with early onset scoliosis and identify factors that correlate with the presence of periodic limb movements., Methods: This is a retrospective chart review of 40 patients with EOS (ages 1-17 years) who underwent a PSG from 2003 through 2019. Data collected included age, sex, and polysomnography parameters. Descriptive statistics were used: independent T test and Pearson correlation., Results: The average age was 9.6 years (SD 5.2); 22 were female. Eleven patients (27.5%) had elevated periodic limb movement index (PLMI) (≥ 5). Those with PLMI ≥ 5 had arousal index of 15.4 (SD 7.2) and those with normal PLMI having an arousal index of 9.4 (SD 4.9); this reached statistical significance (p < 0.05). Those with elevated PLMI spent 4.9 (SD 8.3) minutes with saturations below 88%, while those with normal PLMI spent 1.0 (SD 1.8); this was statistically significant. There was a moderate positive correlation between arousal index, hypoxemia, and PLMI., Conclusion: The study suggests that children with early onset scoliosis have higher frequency of periodic limb movements during sleep, and these may be correlated with increased arousal and with hypoxemia., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Ventilatory responses to hypoxia and hypercapnia play a vital role in maintaining gas exchange homeostasis and in adaptation to high-altitude environments. This study investigates the mechanisms underlying sensitization of hypoxic and hypercapnic ventilatory response (HVR and HCVR, respectively) in individuals acclimatized to moderate high altitude (3,800 m). Thirty-one participants underwent chemoreflex testing using the Duffin-modified rebreathing technique. Measures were taken at sea level and after 2 days of acclimatization to high altitude. Ventilatory recruitment threshold (VRT), HCVR-Hyperoxia, HCVR-Hypoxia, and HVR were quantified. Acclimatization to high altitude resulted in increased HVR ( P < 0.001) and HCVR-Hyperoxia ( P < 0.001), as expected. We also observed that the decrease in VRT under hypoxic test conditions significantly contributed to the elevated HVR at high altitude since the change in VRT across hyperoxic and hypoxic test conditions was greater at high altitudes compared to baseline sea-level tests ( P = 0.043). Pre-VRT, or basal, ventilation also increased at high altitudes ( P < 0.001), but the change did not differ between oxygen conditions. Taken together, these data suggest that the increase in HVR at high altitude is at least partially driven by a larger decrease in the VRT in hypoxia versus hyperoxia at high altitude compared to sea level. This study highlights the intricacies of respiratory adaptations during acclimatization to moderate high altitude, shedding light on the roles of the VRT, baseline respiratory drive, and two-slope HCVR in this process. These findings contribute to our understanding of how human respiratory control responds to hypoxic and hypercapnic challenges at high altitude. NEW & NOTEWORTHY We report the first measurements of the hypoxic ventilatory response (HVR) after 2 days at high altitude using a CO 2 rebreathing technique. We evaluated mechanisms by which the HVR becomes elevated with acclimatization (increased hypercapnic ventilatory response sensitivity in hypoxia, increased baseline respiratory drive in hypoxia, or lower ventilatory recruitment thresholds in hypoxia). For the first time, we report that decreases in the ventilatory recruitment threshold in hypoxia contribute to elevated HVR at high altitude.

Silent hypoxemia, or "happy hypoxia," is a puzzling phenomenon in which patients who have contracted COVID-19 exhibit very low oxygen saturation ( SaO 2 < 80%) but do not experience discomfort in breathing. The mechanism by which this blunted response to hypoxia occurs is unknown. We have previously shown that a computational model of the respiratory neural network (Diekman et al. in J Neurophysiol 118(4):2194-2215, 2017) can be used to test hypotheses focused on changes in chemosensory inputs to the central pattern generator (CPG). We hypothesize that altered chemosensory function at the level of the carotid bodies and/or the nucleus tractus solitarii are responsible for the blunted response to hypoxia. Here, we use our model to explore this hypothesis by altering the properties of the gain function representing oxygen sensing inputs to the CPG. We then vary other parameters in the model and show that oxygen carrying capacity is the most salient factor for producing silent hypoxemia. We call for clinicians to measure hematocrit as a clinical index of altered physiology in response to COVID-19 infection., (© 2024. The Author(s).)

We sought to determine the effects of acute simulated altitude on the maximal lactate steady state (MLSS) and physiological responses to cycling at and 10 W above the MLSS-associated power output (PO) (MLSS p and MLSS p+10 , respectively). Eleven (4 females) participants (means [SD]; 28 [4] yr; V̇o 2max : 54.3 [6.9] mL·kg -1 ·min -1 ) acclimatized to ∼1,100 m performed 30-min constant PO trials in simulated altitudes of 0 m sea level (SL), 1,111 m mild altitude (MILD), and 2,222 m moderate altitude (MOD). MLSS p , defined as the highest PO with stable (<1 mM change) blood lactate concentration ([BLa]) between 10 and 30 min, was significantly lower in MOD (209 [54] W) compared with SL (230 [56] W; P < 0.001) and MILD (225 [58] W; P = 0.001), but MILD and SL were not different ( P = 0.12). V̇o 2 and V̇co 2 decreased at higher simulated altitudes due to lower POs ( P < 0.05), but other end-exercise physiological responses (e.g., [BLa], ventilation [V̇e], heart rate [HR]) were not different between conditions at MLSS p or MLSS p + 10 ( P > 0.05). At the same absolute intensity (MLSS p for MILD), [BLa], HR, and V̇ E and all perceptual variables were exacerbated in MOD compared with SL and MILD ( P < 0.05). Maximum voluntary contraction, voluntary activation, and potentiated twitch forces were exacerbated at MLSS p + 10 relative to MLSS p within conditions ( P < 0.05); however, condition did not affect performance fatiguability at the same relative or absolute intensity ( P > 0.05). As MLSS p decreased in hypoxia, adjustments in PO are needed to ensure the same relative intensity across altitudes, but common indices of exercise intensity may facilitate exercise prescription and monitoring in hypoxia. NEW & NOTEWORTHY This study demonstrates the power output and metabolic rate associated with the maximal lactate steady-state (MLSS) decline in response to simulated altitude; however, common indices of exercise intensity remained unchanged when cycling was performed at the work rate associated with MLSS at each simulated altitude. These results support previous studies that investigated the effects of hypoxia on alternative measures of the critical intensity of exercise and will inform exercise prescription/monitoring across altitudes.

This study investigated the effect of a resistance training (R T ) period at terrestrial (HH) and normobaric hypoxia (NH) on both muscle hypertrophy and maximal strength development with respect to the same training in normoxia (N). Thirty-three strength-trained males were assigned to N (FiO 2  = 20.9%), HH (2,320 m asl) or NH (FiO 2  = 15.9%). The participants completed an 8-week R T program (3 sessions/week) of a full body routine. Muscle thickness of the lower limb and 1RM in back squat were assessed before and after the training program. Blood markers of stress, inflammation (IL-6) and muscle growth (% active mTOR, myostatin and miRNA-206) were measured before and after the first and last session of the program. Findings revealed all groups improved 1RM, though this was most enhanced by R T in NH (p = 0.026). According to the moderate to large excess of the exercise-induced stress response (lactate and Ca 2+ ) in HH and N, results only displayed increases in muscle thickness in these two conditions over NH (ES > 1.22). Compared with the rest of the environmental conditions, small to large increments in % active mTOR were only found in HH, and IL-6, myostatin and miR-206 in NH throughout the training period. In conclusion, the results do not support the expected additional benefit of R T under hypoxia compared to N on muscle growth, although it seems to favour gains in strength. The greater muscle growth achieved in HH over NH confirms the impact of the type of hypoxia on the outcomes., (© 2024. The Author(s).)

Background: Obstructive sleep apnea (OSA) is associated with multiple comorbidities, including diabetes. Its development is preceded by alterations in the initial phase of carbohydrate metabolism characterized by insulin resistance. This study aims to evaluate the role of intermittent hypoxia and sleep fragmentation characteristic of OSA on the risk of insulin resistance among apneic patients without diabetes., Methodology: 92 consecutive patients with OSA without evidence of diabetes were recruited. Overnight video polysomnography was performed and, the following morning, fasting blood glucose, insulin and glycosylated hemoglobin were determined. Insulin resistance was measured using the HOMA-IR index., Results: Insulin resistance was present in 52.2% of OSA patients. In these subjects, insulin resistance was independently associated to the apnea index during REM sleep (adjusted odds ratio [aOR] 1.09; 95% CI, 1.03 to 1.16; p = 0.004), desaturation index (aOR 1.08; 95% CI: 1.04 to 1.13; p = 0.027), and sleep time with oxygen saturation below 90% (aOR 1.04; 95% CI 1.00 to 1.08; p = 0.049). Furthermore, the HOMA-IR level was also directly related to the desaturation index (standardized regression coefficient [B] = 0.514, p < 0.001) and to the apnea index during REM sleep (B = 0.344, p = 0.002)., Conclusions: Intermittent hypoxia and disturbances in REM sleep emerge as main contributors to insulin resistance in OSA patients yet to experience diabetes onset., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Obstructive sleep apnea (OSA) is a sleep disorder that has been associated with the incidence of other pathologies. Diagnosis is mainly based on the apnea-hypopnea index (AHI) obviating other repercussions such as intermittent hypoxemia, which has been found to be associated to cardiovascular complications. Blood-based samples and urine have been the most utilised biofluids in metabolomics studies related to OSA, while sweat could be an alternative due to its non-invasive and accessible sampling, its reduced complexity, and comparability with other biofluids. Therefore, this research aimed to evaluate metabolic overnight changes in sweat collected from patients with OSA classified according to the AHI and oxygen desaturation index (ODI), looking for potential cardiovascular repercussions. Pre- and post-sleeping sweat samples from all individuals (n = 61) were analysed by gas chromatography coupled to high-resolution mass spectrometry after appropriate sample preparation to detect as many metabolites as possible. Permanent significant alterations in the sweat were reported for pyruvate, serine, lactose, and hydroxybutyrate. The most relevant overnight metabolic alterations in sweat were reported for lactose, succinate, urea, and oxoproline, which presented significantly different effects on factors such as the AHI and ODI for OSA severity classification. Overall metabolic alterations mainly affected energy production-related processes, nitrogen metabolism, and oxidative stress. In conclusion, this research demonstrated the applicability of sweat for evaluation of OSA diagnosis and severity supported by the detected metabolic changes during sleep., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Purpose: To investigate the influence of acute normobaric hypoxia on standing balance under single and dual-task conditions, both with and without visual input., Methods: 20 participants (7 female, 20-31 years old) stood on a force plate for 16, 90-s trials across four balance conditions: single-task (quiet stance) or dual-task (auditory Stroop test), with eyes open or closed. Trials were divided into four oxygen conditions where the fraction of inspired oxygen (F I O 2 ) was manipulated (normoxia: 0.21 and normobaric hypoxia: 0.16, 0.145 and 0.13 F I O 2 ) to simulate altitudes of 1100, 3,400, 4300, and 5200 m. Participants breathed each F I O 2 for ~ 3 min before testing, which lasted an additional 7-8 min per oxygen condition. Cardiorespiratory measures included heart rate, peripheral blood oxygen saturation, and pressure of end tidal (P ET ) CO 2 and O 2 . Center of pressure measures included total path length, 95% ellipse area, and anteroposterior and mediolateral velocity. Auditory Stroop test performance was measured as response accuracy and latency., Results: Significant decreases in oxygen saturation and P ET O 2 , and increased heart rate were observed between normoxia and normobaric hypoxia (P < 0.0001). Total path length was higher at 0.13 compared to 0.21 F I O 2 for the eyes closed no Stoop test condition (P = 0.0197). No other significant differences were observed., Conclusion: These findings suggest that acute normobaric hypoxia has a minimal impact on standing balance and does not influence auditory Stroop test or dual-task performance. Further investigation with longer exposure is required to understand the impact and time course of normobaric hypoxia on standing balance., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: This study examined the effects of acute normoxic and hypoxic exposure on neuromuscular and hemodynamic physiological responses performed during dynamic step muscle actions., Methods: Thirteen recreationally active men (mean ± SD age: 21.2 ± 2.9 yrs) performed dynamic leg extensions unilaterally under Normoxic (FiO 2  = 21 %) and Hypoxic (FiO 2  = 13 %) conditions in a randomized order at 20 %, 40 %, 60 %, 80 %, and 100 % of their maximal strength. Electromyographic (EMG) amplitude, EMG frequency, (Oxygenated and Deoxygenated hemoglobin; Oxy Hb , Deoxy Hb) , Total hemoglobin (Total Hb ), and skeletal muscle tissue oxygenation status (StO 2 ) were measured from the vastus lateralis during all contractions., Results: There were no detectable differences in the neuromuscular responses between normoxia and hypoxia for EMG amplitude (p = 0.37-0.74) and frequency (p = 0.17-0.83). For EMG amplitude there were general increases with intensity (p < 0.01-0.03). EMG frequency remained similar from 20% to 80% and then increased at 100 % effort (p = 0.02). There was no significant difference in patterns of responses for Oxy Hb (p = 0.870) and Total Hb (p = 0.200) between normoxia and hypoxia. StO 2 (p = 0.028) decreased and Deoxy Hb (p = 0.006) increased under hypoxia compared to normoxia during dynamic step muscle actions performed in a randomized order., Conclusion: Unlike fatigue, acute hypoxemia in an unfatigued state does not impact the localized neuromuscular responses, but minimally impacts the hemodynamic responses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We examine the impact of the acute manipulation of oxygen availability during discrete phases (active and passive) of a repeated-sprint cycling protocol on performance, physiological, and perceptual responses. On separate days, twelve trained males completed four sets of five 5-s 'all out' cycle sprints (25-s inter-sprint recovery and 5-min interset rest) in four randomized conditions: normobaric hypoxia (inspired oxygen fraction of 12.9%) applied continuously (C-HYP), intermittently during only the sets of sprints (I-HYP SPRINT ) or between-sets recovery periods (I-HYP RECOVERY ), or not at all (C-NOR). Peak and mean power output, peripheral oxygen saturation, heart rate, blood lactate concentration, exercise-related sensations, and vastus lateralis muscle oxygenation using near-infrared spectroscopy were assessed. Peak and mean power output was ∼4%-5% lower for C-HYP compared to C-NOR (P ≤ 0.050) and I-HYP RECOVERY (P ≤ 0.027). Peripheral oxygen saturation was lower during C-HYP and I-HYP SPRINT compared with C-NOR and I-HYP RECOVERY during sets of sprints (∼83-85 vs. ∼95%-97%; P < 0.001), while lower values were obtained for C-HYP and I-HYP RECOVERY than C-NOR and I-HYP SPRINT during between-sets rest period (∼84-85 vs. ∼96%; P < 0.001). Difficulty in breathing was ∼21% higher for C-HYP than C-NOR (P = 0.050). Ratings of perceived exertion (P = 0.435), limb discomfort (P = 0.416), heart rate (P = 0.605), blood lactate concentration (P = 0.976), and muscle oxygenation-derived variables (P = 0.056 to 0.605) did not differ between conditions. In conclusion, the method of hypoxic exposure application (continuous vs. intermittent) affects mechanical performance, while internal demands remained essentially comparable during repeated cycle sprints., (© 2024 The Author(s). European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.)

Microglia are described as the immune cells of the brain, their immune properties have been extensively studied since first described, however, their neural functions have only been explored over the last decade. Microglia have an important role in maintaining homeostasis in the central nervous system by surveying their surroundings to detect pathogens or damage cells. While these are the classical functions described for microglia, more recently their neural functions have been defined; they are critical to the maturation of neurons during embryonic and postnatal development, phagocytic microglia remove excess synapses during development, a process called synaptic pruning, which is important to overall neural maturation. Furthermore, microglia can respond to neuronal activity and, together with astrocytes, can regulate neural activity, contributing to the equilibrium between excitation and inhibition through a feedback loop. Hypoxia at birth is a serious neurological condition that disrupts normal brain function resulting in seizures and epilepsy later in life. Evidence has shown that microglia may contribute to this hyperexcitability after neonatal hypoxia. This review will summarize the existing data on the role of microglia in the pathogenesis of neonatal hypoxia and the plausible mechanisms that contribute to the development of hyperexcitability after hypoxia in neonates. This article is part of the Special Issue on "Microglia"., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To compare external and internal training load markers during resistance training (R T ) in normoxia (N), intermittent hypobaric hypoxia (HH), and intermittent normobaric hypoxia (NH)., Methods: Thirty-three volunteers were assigned an 8-week R T program in either N (690 m, n = 10), HH (2320 m, n = 10), or NH (inspired fraction of oxygen = 15.9%; ~ 2320 m, n = 13). The R T program (3x/week) consisted of six exercises, with three sets of six to 12 repetitions at ~ 70% of one repetition maximum (1RM) with the first session of each week used for analysis. 1RM in back squat and bench press was used to evaluate muscle strength before and after the program. External load was assessed by the volume load relative to body mass (RVL, kg·kg -1 ). Internal load was assessed by the ratings of perceived exertion (RPE) and heart rate (HR)., Results: Smaller relative improvements were found for the back squat in the N group (11.5 ± 8.8%) when compared to the NH group (22.2 ± 8.2%, P = 0.01) and the HH group (22 ± 8.1%, P = 0.02). All groups showed similar RVL, HR responses and RPE across the program (P˃0.05). However, reduced HR recovery values, calculated as the difference between the highest HR value (HR peak ) and the resting heart rate after a two min rest, were seen in the N and NH groups across the program (P < 0.05)., Conclusion: It seems that 8 weeks of intermittent R T in hypoxic environments could maximize time-efficiency when aiming to improve strength levels in back squat without evoking higher levels of physiological stress. Performing R T at hypobaric hypoxia may improve the cardiorespiratory response, which in turn could speed recovery., (© 2024. The Author(s).)

In fish, thermal and hypoxia tolerances may be functionally related, as suggested by the oxygen- and capacity-limited thermal tolerance (OCLTT) concept, which explains performance failure at high temperatures due to limitations in oxygen delivery. In this study the interrelatedness of hyperthermia and hypoxia tolerances in the Nile tilapia (Oreochromis niloticus), and their links to cardiorespiratory traits were examined. Different groups of O. niloticus (n = 51) were subjected to hypoxia and hyperthermia challenges and the O 2 tension for aquatic surface respiration (ASR pO 2 ) and critical thermal maximum (CTmax) were assessed as measurement endpoints. Gill filament length, total filament number, ventricle mass, length and width were also measured. Tolerance to hypoxia, as evidenced by ASR pO 2 thresholds of the individual fish, was highly variable and varied between 0.26 and 3.39 kPa. ASR events increased more profoundly as O 2 tensions decreased below 2 kPa. The CTmax values recorded for the O. niloticus individuals ranged from 43.1 to 44.8 °C (Mean: 44.2 ± 0.4 °C). Remarkably, there was a highly significant correlation between ASR pO 2 and CTmax in O. niloticus (r = -0.76, p < 0.0001) with ASR pO 2 increasing linearly with decreasing CTmax. There were, however, no discernible relationships between the measured cardiorespiratory properties and hypoxia or hyperthermia tolerances. The strong relationship between hypoxia and hyperthermia tolerances in this study may be related to the ability of the cardiorespiratory system to provide oxygen to respiring tissues under thermal stress, and thus provides some support for the OCLTT concept in this species, at least at the level of the entire organism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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 (HL 3800m ; n = 13) and 5100 m (HL 5100m ; 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 (CDO 2 ), 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 LF power negatively correlated with altitude but were not affected by CMS. CDO 2 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, CDO 2 and cBRS remained preserved across altitudes. The LF/HF ratio increased in HL 5100m compared to LL and HL 3800m 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., (© 2024. The Author(s).)

Purpose: We examined changes in stride temporal parameters and spring-mass model characteristics during repeated sprints following a 3-week period of "live high-train low and high" (LHTLH) altitude training in team-sport players., Methods: While residing under normobaric hypoxia (≥14 h/d; inspired oxygen fraction [FiO2] 14.5%-14.2%) for 14 days, elite field hockey players performed, in addition to their regular field hockey practice in normoxia, 6 sessions (4 × 5 × 5-s maximal sprints; 25-s passive recovery; 5-min rest) under either normobaric hypoxia (LHTLH; FiO2 ∼14.5%, n = 11) or normoxia (live high-train low; FiO2 20.9%, n = 12). A control group (live low-train low; FiO2 ∼20.9%, n = 9) residing in normoxia without additional repeated-sprint training was included. Before (Pre) and a few days (Post-1) and 3 weeks (Post-2) after the intervention, stride mechanics were assessed during an overground repeated-sprint test (8 × 20 m, 20-s recovery). Two-way repeated-measures analysis of variance (time [Pre, Post-1, and Post-2] × condition [LHTLH, live high-train low, and live low-train low]) were conducted., Results: Peak sprinting speed increased in LHTLH from Pre to Post-1 (+2.2% [2.0%]; P = .002) and Post-2 (+2.0% [2.4%]; P = .025), with no significant changes in live high-train low and live low-train low. There was no main effect of time (all P ≥ .062), condition (all P ≥ .771), or a significant time × condition interaction (all P ≥ .230) for any stride temporal variable (contact time, flight time, stride frequency, and stride length) or spring-mass model characteristics (vertical and leg stiffness)., Conclusions: Peak sprinting speed improved in elite field hockey players following LHTLH altitude training, while stride mechanical adjustments to repeated overground sprints remained unchanged for at least 3 weeks postintervention.

Background: An increasing number of hypertensive persons travel to high altitude (HA) while using antihypertensive medications such as beta-blockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In animals, beta-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans, propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC)., Methods: In seven healthy male lowlanders, Ppa was invasively measured without medication, with PROP and PROP + GLYC, both at sea level (SL, 488 m) and after a 3-week sojourn at 3454 m altitude (HA). Bilateral thigh-cuff release manoeuvres were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility., Results: At SL, PROP increased Ppa and PVR from (mean ± SEM) 14 ± 1 to 17 ± 1 mmHg and from 69 ± 8 to 108 ± 11 dyn s cm-5 (21% and 57% increase, P = 0.01 and P < 0.0001). The PVR response to PROP was amplified at HA to 76% (P < 0.0001, P[interaction] = 0.05). At both altitudes, PROP + GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9 ± 0.5 to 1.7 ± 0.2 at HA (P < 0.0001) and to 1.2 ± 0.2 with PROP, and further decreased to 0.9 ± 0.2% mmHg-1 with PROP + GLYC (P = 0.01)., Conclusions: Our data show that beta-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that beta-adrenergic blockade exaggerates HPV for the management of mountaineers using beta-blockers for prevention or treatment of cardiovascular conditions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima-media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO 2 , 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.

The study investigated the protective effect and mechanism of 2-phenylethyl-beta-glucopyranoside(Phe) from Huaizhong No.1 Rehmannia glutinosa on hypoxic pulmonary hypertension(PH), aiming to provide a theoretical basis for clinical treatment of PAH. Male C57BL/6N mice were randomly divided into normal group, model group, positive drug(bosentan, 100 mg·kg~(-1)) group, and low-and high-dose Phe groups(20 and 40 mg·kg~(-1)). Except for the normal group, all other groups were continuously subjected to model induction in a 10% hypoxic environment for 5 weeks, with oral administration for 14 days starting from the 3rd week. The cardiopulmonary function, right ventricular pressure, cough and asthma index, lung injury, cell apoptosis, oxidative stress-related indicators, immune cells, and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxic inducible factor 1α(HIF-1α) pathway-related proteins or mRNA levels were examined. Furthermore, hypoxia-induced pulmonary arterial smooth muscle cell(PASMC) were used to further explore the mechanism of Phe intervention in PH combined with PI3K ago-nist(740Y-P). The results showed that Phe significantly improved the cardiopulmonary function of mice with PH, decreased right ventricular pressure, cough and asthma index, and lung injury, reduced cell apoptosis, oxidative stress-related indicators, and nuclear levels of phosphorylated Akt(p-Akt) and phosphorylated mTOR(p-mTOR), inhibited the expression levels of HIF-1α and PI3K mRNA and proteins, and maintained the immune cell homeostasis in mice. Further mechanistic studies revealed that Phe significantly reduced the viability and migration ability of hypoxia-induced PASMC, decreased the expression of HIF-1α and PI3K proteins and nuc-lear levels of p-Akt and p-mTOR, and this effect was blocked by 740Y-P. Therefore, it is inferred that Phe may exert anti-PH effects by alleviating the imbalance of oxidative stress and apoptosis in lung tissues and regulating immune levels, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR/HIF-1α pathway. This study is expected to provide drug references and research ideas for the treatment of PH.

To explore the mechanism of Liangfang Wenjing Decoction regulating coiled-coil-helix coiled-coil-helix domain containing 4(CHCHD4) in the treatment of hypoxia on endometriosis(EMs) with cold coagulation and blood stasis. The rat model of cold coagulation and blood stasis syndrome was prepared by the ice-water bath method, and then the EMs model was established by autologous intimal transplantation. The rats were randomly divided into model group, low, medium, and high(4.7, 9.4, and 18.8 g·kg~(-1)) dose groups of Liangfang Wenjing Decoction, Shaofu Zhuyu Decoction group, and sham group, with 10 rats in each group. The rats were given intragastric administration for four weeks. During the modeling, the general condition and vaginal smear of rats were observed, and the blood flow of ears and uterus were detected by laser speckle contrast imaging(LSCI) to judge the syndrome of cold coagulation and blood stasis. After the administration, the general condition of the rats was observed, and the area of ectopic lesions was measured by caliper. The localization and expression of CHCHD4 and hypoxia inducible factors-1α(HIF-1α) were detected by immunohistochemistry, and the mRNA and protein expressions of CHCHD4 and HIF-1α were detected by real-time quantitative polymerase chain reaction(RT-qPCR) and Western blot. The primary culture of ectopic endometrial stromal cells(ESCs) from EMs patients was performed, and the CHCHD4 overexpression plasmid was constructed and transfected to establish the ESCs model of CHCHD4 overexpression. The cells were divided into the control group, CHCHD4 overexpression group, CHCHD4 overexpression+control serum group, and CHCHD4 overexpression+Liangfang Wenjing Decoction serum group. The protein expression of CHCHD4 and HIF-1α was detected by Western blot, and the glucose consumption and lactic acid level were detected. The cell proliferation was detected by MTT assay. The experiment found that compared with normal rats, the modeling rats showed symptoms of cold coagulation and blood stasis, such as mental malaise, reduced diet and drinking water, disordered estrous cycle, and blocked blood circulation in ears and uterine microvessels. Compared with the sham group, the ectopic lesions in the model group were uplifted, and the mRNA and protein expressions of CHCHD4 and HIF-1α were significantly increased(P&lt;0.05). Compared with the model group, the symptoms of cold coagulation and blood stasis in each treatment group were improved, and the area of ectopic lesions was significantly reduced(P&lt;0.05 or P&lt;0.01). The mRNA and protein expression levels of CHCHD4 and HIF-1α were significantly decreased(P&lt;0.05 or P&lt;0.01). In the cell model, compared with the control group, the expression of CHCHD4, HIF-1α protein, glucose consumption, lactic acid level, and cell proliferation activity in the CHCHD4 overexpression group were significantly increased(P&lt;0.01). Compared with the CHCHD4 overexpression group, there was no significant change in each index in the control serum group, while the protein expression of CHCHD4 and HIF-1α in the Liangfang Wenjing Decoction serum group was decreased significantly(P&lt;0.05 or P&lt;0.01). The glucose consumption, lactic acid level, and cell proliferation activity decreased significantly(P&lt;0.01). It can be seen from the above that the therapeutic effect of Liangfang Wenjing Decoction on EMs with cold coagulation and blood stasis might be related to reducing the expression of CHCHD4 and then improving the hypoxia of ectopic lesions and ectopic ESCs.

Introduction: The co-existence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), or the overlap syndrome, is common and associated with a distinct pattern of nocturnal hypoxemia and worse clinical outcomes than either disease alone. Consequently, identifying who and how to treat these patients is essential., Areas Covered: Treatment is recommended in all patients with OSA and symptoms or systemic hypertension, but determining symptoms attributable to OSA can be challenging in patients with COPD. Treatment should be considered in asymptomatic patients with moderate to severe OSA and COPD with pulmonary hypertension and comorbid cardiovascular and cerebrovascular disease, especially if marked hypoxic burden. CPAP is effective, but in patients with the overlap syndrome and daytime hypercapnia, high-intensity noninvasive ventilation aiming to lower PaCO2 may have additional benefits. Additionally, in those with severe resting daytime hypoxemia, supplemental oxygen improves survival and should be added to positive airway pressure. The role of alternative non-positive airway pressure therapies in the overlap syndrome needs further study., Expert Opinion: Both COPD and OSA are heterogeneous disorders with a wide range of disease severity and further research is needed to better characterize and prognosticate patients with the overlap syndrome to personalize treatment.

Pediatric obstructive sleep apnea poses a significant health risk, with potential long-term consequences on cardiovascular health. This study explores the dichotomous nature of neonatal cardiac response to chronic intermittent hypoxia (CIH) between males and females, aiming to fill a critical knowledge gap in the understanding of sex-specific cardiovascular consequences of sleep apnea in early life. Neonates were exposed to CIH until p28 and underwent comprehensive in vivo physiological assessments, including whole-body plethysmography, treadmill stress-tests, and echocardiography. Results indicated that male CIH rats weighed 13.7% less than age-matched control males (p = 0.0365), while females exhibited a mild yet significant increased respiratory drive during sleep (93.94 ± 0.84 vs. 95.31 ± 0.81;p = 0.02). Transcriptomic analysis of left ventricular tissue revealed a substantial sex-based difference in the cardiac response to CIH, with males demonstrating a more pronounced alteration in gene expression compared to females (5986 vs. 3174 genes). The dysregulated miRNAs in males target metabolic genes, potentially predisposing the heart to altered metabolism and substrate utilization. Furthermore, CIH in males was associated with thinner left ventricular walls and dysregulation of genes involved in the cardiac action potential, possibly predisposing males to CIH-related arrhythmia. These findings emphasize the importance of considering sex-specific responses in understanding the cardiovascular implications of pediatric sleep apnea., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Early-life stress affects brain development, eventually resulting in adverse behavioral and physical health consequences in adulthood. The present study assessed the hypothesis that short-term early-life stress during infancy before weaning, a period for the maturation of mastication and sleep, poses long-lasting adverse effects on masticatory function and intraoral sensations later in life.Rat pups were exposed to either maternal separation (MS) or intermittent hypoxia (IH-Infancy) for 6 h/day in the light/sleep phase from postnatal day (P)17 to P20 to generate "neglect" and "pediatric obstructive sleep apnea" models, respectively. The remaining rats were exposed to IH during P45-P48 (IH-Adult). Masticatory ability was evaluated based on the rats' ability to chew pellets and bite pasta throughout the growth period (P21-P70). Intraoral chemical and mechanical sensitivities were assessed using two-bottle preference drinking tests, and hind paw pain thresholds were measured in adulthood (after P60).No differences were found in body weight, grip force, and hind paw sensitivity in MS, IH-Infancy, and IH-Adult rats compared with naïve rats. Masticatory ability was lower in MS and IH-Infancy rats from P28 to P70 than in naïve rats. MS and IH-Infancy rats exhibited intraoral hypersensitivity to capsaicin and mechanical stimulations in adulthood. The IH-Adult rats did not display inferior masticatory ability or intraoral hypersensitivity.In conclusion, short-term early-life stress during the suckling-mastication transition period potentially causes a persistent decrease in masticatory ability and intraoral hypersensitivity in adulthood. The period is a "critical window" for the maturation of oral motor and sensory functions., (© 2024. The Author(s).)

Aims: Patients with type 2 diabetes have a 20% lower total blood volume than age- and weight-matched healthy adults, suggesting a reduced capacity to transport oxygen in this population. Intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and normoxic air, increases erythropoietin levels, the hormone regulating red blood cell production, in young and older adults. The objective of this study was to determine the effect of a single session of intermittent hypoxia on erythropoietin levels and hemoglobin mass, the absolute mass of hemoglobin contained in red blood cells, in patients with type 2 diabetes., Methods: Ten patients with type 2 diabetes were exposed to an intermittent hypoxia protocol consisting of eight 4-min cycles at a targeted oxygen saturation of 80% interspersed with normoxic cycles to resaturation. Erythropoietin and hemoglobin mass responses to intermittent hypoxia in patients with type 2 diabetes were compared to previously published data from an identical intermittent hypoxia protocol performed in age-matched older adults., Results: Intermittent hypoxia increased erythropoietin levels in older adults but did not induce any change in erythropoietin levels in patients with type 2 diabetes (3.2 ± 2.2 vs. 0.2 ± 2.7 mU/ml, p = 0.01). Hemoglobin mass indexed to body weight was 21% lower in patients with type 2 diabetes than in older adults (8.1 ± 1.7 vs. 10.2 ± 2.1 g/kg, p < 0.01)., Conclusions: These findings suggest an impaired erythropoietin response to decreased oxygen levels in patients with type 2 diabetes, which may contribute to the reduced oxygen transport capacity observed in this population., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

One of the reasons of the development of pathologies causing death is hypoxia. The purposes of this study were (1) to study some physiological and biochemical mechanisms of α 2 -adrenoblockers, which ensure the tissue resistance increase to hypoxia; (2) to offer new drugs contributing to the increase of tissues' stability towards the hypoxic affection; and (3) to submit new medications to surpass by their anti-hypoxic activity of those already used in modern medicine and have some advantages. The reactivity of postsynaptic vascular α 2 -adrenoceptors was determined on the damaged spinal cord expressed by the blood pressure increase in response to intravenous administration of azepexole that selectively binds to α 2 -adrenoceptors. Determination of the systemic hemodynamic values and the vascular resistance to the blood flow was performed by the method with plastic microspheres of marked isotopes. pO 2 in the blood and the oxygen-transporting function were determined in a sample of 0.1 ml of blood in 30, 90, and 180 min after the α 2 -adrenoblockers' injections. It has been found that one of the major hemodynamic effects of mesedin and beditin was an improvement in cardiac output, as well as a prolonged increase in coronary blood flow and vasodilation of the heart vessels. Some anti-hypoxic mechanisms of the studied α 2 -adrenoblockers are an improvement of blood oxygen-transporting function followed by tissue oxygenation and the increased level of corticosterone and resistance to hypoxia. Revealing the mechanisms of action of the postsynaptic α 2 -adrenoceptors suggests that mesedin and beditin are potentially effective therapeutic means for many hypoxic conditions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)