Hemoglobin J-Auckland: a clinically silent low oxygen affinity variant presenting with persistent asymptomatic hypoxemia at high altitude.

BACKGROUND: Inherited hemoglobin disorders are common in clinical practice. While qualitative (i.e. sickle cell disease) and quantitative (thalassemia) hemoglobinopathies are usually diagnosed clinically and confirmed through simple laboratory assessments, hemoglobin variants with altered oxygen affinity often go undetected due to their typically silent clinical presentation. Hemoglobin (Hb) J-Auckland, a low oxygen affinity hemoglobin variant first described in 1987 in Auckland, New Zealand, is one such silent disorder. CASE PRESENTATION: We report for the first time a clinically evident case of previously undiagnosed Hb J-Auckland in an 8-year-old girl who presented with unexplained hypoxemia at high altitude. Her oxygen level was corrected with supplemental oxygen and when assessed at low altitude. A brief discussion of the diagnostic approach and clinical implications is provided. CONCLUSION: Standard hemoglobin analysis is essential for the evaluation of suspected altered affinity hemoglobinopathy, and genetic testing is often required for definitive diagnosis. Early recognition and diagnosis of these variants can prevent mismanagement and improve patient outcomes.

[Training under normoxia and normobaric hypoxia in patients with type 1 diabetes]. / Wysilek fizyczny w warunkach normoksji i hipoksji normobarycznej u pacjentów z cukrzyca typu 1.

Apart from insulin, physical exercise is a crucial component of therapy in patients with type 1 diabetes mellitus (T1DM). The benefits of physical activity in such patients include improved insulin sensitivity, lowered blood glucose, reduced body fat and improved cardiovascular function and physical performance. Hypoglycemia is a crucial issue in the peri-training period in insulin-treated patients. Proper preparation for exercise is the key to reducing the risk of hypoglycemia. The selection of the training type and the patient's knowledge of the effect of such training on glycemia are also significant. Physical exercise under normobaric hypoxia in the training rooms is also available commercially and is becoming increasingly popular. Under such conditions, the air consists of 15.4% oxygen and 84.5% nitrogen, which corresponds to the conditions at an altitude of approximately 2,500 meters above sea level. Hypoxia induces the production of the hypoxia-inducible factor (HIF-1), which regulates the expression of over 100 genes. It modulates key metabolic pathways to optimize glucose utilization by increasing cell sensitivity to insulin, more efficient glucose uptake from the blood and activating effect on glycolytic enzymes. Additionally, HIF-1 shows beneficial effects on the lipid profile, vascular endothelium and performance as measured by the maximal oxygen uptake (VO2max). The aim of this paper was to review and summarize the most recent studies on the effects of exercise on glycemic control and physical performance under normoxia and normobaric hypoxia in patients with T1DM.

Radiographic scores as a predictor of oxygenation index in very low-birthweight infants.

BACKGROUND: Very low birthweight infants (VLBWIs) often undergo chest radiographic examinations without standardization or objectivity. This study aimed to assess the association of two radiographic scores, the Brixia and radiographic assessment of lung edema (RALE), with oxygenation index (OI) in ventilated VLBWIs and to determine the optimal cutoff values to predict hypoxic respiratory severity. METHODS: VLBWIs who received invasive respiratory support with arterial lines between January 2010 and October 2023 were enrolled in this study (n = 144). The correlation between the Brixia or RALE scores and OI was investigated. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff points of the two radiographic scores for predicting OI values (OI ≥5, ≥10, and ≥15). RESULTS: The enrolled infants had a median gestational age of 27 weeks (interquartile range [IQR], 25-28 weeks) and a median birthweight of 855 g (IQR, 684-1003 g). Radiographic scoring methods correlated with the OI (Brixia score: r = 0.79, p < 0.001; RALE score: r = 0.72, p < 0.001). The optimal cutoff points for predicting OI values were as follows: Brixia score: OI ≥5, 10; OI ≥10, 13; OI ≥15, 15; RALE score: OI ≥5, 22; OI ≥10, 31; and OI ≥15, 40. CONCLUSIONS: Brixia and RALE scores are useful predictive markers of the oxygenation status in intubated VLBWIs with stable hemodynamics. These scores are easy to use and promising tools for clinicians to identify patients with a higher risk of hypoxic respiratory failure.

Spontaneous and Stimulated Production of Cytokines by Blood Cells Ex Vivo as a Biomarker of Initially High or Low Hypoxia Resistance in Rats.

Spontaneous and stimulated production of cytokines by peripheral blood cells obtained from the caudal vein of male Wistar rats was assessed before testing their resistance to oxygen deficiency in a decompression chamber. To study the spontaneous production of cytokines, heparinized blood cells were incubated in a culture medium (24 h, 5% CO2, 37°C) and the content of proinflammatory cytokines IL-6 and TNFα and anti-inflammatory IL-10 in the culture medium was assessed by ELISA. To stimulate cytokine production, blood cells were incubated for 24 h with LPS, phytohemagglutinin, and concanavalin A at final concentrations of 2, 4, and 4 µg, respectively. Two weeks after blood sampling, individual resistance of the animals to hypoxia in a decompression chamber was determined. In animals with low resistance to hypoxia, the levels of spontaneous production of all three cytokines were significantly higher, while after stimulation, the level of IL-1ß increased by more than 2 times. The animals with spontaneous production of IL-10>50 pg/ml, IL-6>10 pg/ml, and TNFα>10 pg/ml, as well as with the increase in IL-1ß production by more than 2 times upon stimulation were classified as low-resistant. At IL-10<15 pg/ml, IL-6<9 pg/ml, and TNFα<7 pg/ml, as well as the absence of the increase in IL-1ß production upon stimulation, they were classified as high-resistant. The identified features of spontaneous and stimulated production of cytokines can be used as non-invasive biomarkers to determine the resistance to hypoxia without exposure to sublethal hypoxia in a decompression chamber.

A larval zebrafish model of cardiac physiological recovery following cardiac arrest and myocardial hypoxic damage.

Contemporary cardiac injury models in zebrafish larvae include cryoinjury, laser ablation, pharmacological treatment and cardiac dysfunction mutations. Although effective in damaging cardiomyocytes, these models lack the important element of myocardial hypoxia, which induces critical molecular cascades within cardiac muscle. We have developed a novel, tractable, high throughput in vivo model of hypoxia-induced cardiac damage that can subsequently be used in screening cardioactive drugs and testing recovery therapies. Our potentially more realistic model for studying cardiac arrest and recovery involves larval zebrafish (Danio rerio) acutely exposed to severe hypoxia (PO2=5-7 mmHg). Such exposure induces loss of mobility quickly followed by cardiac arrest occurring within 120 min in 5 days post fertilization (dpf) and within 40 min at 10 dpf. Approximately 90% of 5 dpf larvae survive acute hypoxic exposure, but survival fell to 30% by 10 dpf. Upon return to air-saturated water, only a subset of larvae resumed heartbeat, occurring within 4 min (5 dpf) and 6-8 min (8-10 dpf). Heart rate, stroke volume and cardiac output in control larvae before hypoxic exposure were 188±5 bpm, 0.20±0.001 nL and 35.5±2.2 nL/min (n=35), respectively. After briefly falling to zero upon severe hypoxic exposure, heart rate returned to control values by 24 h of recovery. However, reflecting the severe cardiac damage induced by the hypoxic episode, stroke volume and cardiac output remained depressed by ∼50% from control values at 24 h of recovery, and full restoration of cardiac function ultimately required 72 h post-cardiac arrest. Immunohistological staining showed co-localization of Troponin C (identifying cardiomyocytes) and Capase-3 (identifying cellular apoptosis). As an alternative to models employing mechanical or pharmacological damage to the developing myocardium, the highly reproducible cardiac effects of acute hypoxia-induced cardiac arrest in the larval zebrafish represent an alternative, potentially more realistic model that mimics the cellular and molecular consequences of an infarction for studying cardiac tissue hypoxia injury and recovery of function.

Exosomes derived from hypoxic alveolar epithelial cells promote the phenotypic transformation of pulmonary artery smooth muscle cells via the Rap1 pathway.

Background: Hypoxic pulmonary hypertension (HPH) is one of the important pathophysiological changes in chronic pulmonary heart disease. Hypoxia promotes the phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs). Extracellular exosomes regulate vascular smooth muscle cell (VSMC) phenotypic switch. Aim: Given the importance of exosomes and alveolar epithelial cells (AECs) in HPH, the present study aimed to address the issue of whether AEC-derived exosomes promote HPH by triggering PASMC phenotypic switch. Methods: Cell Counting Kit-8 (CCK-8), TRITC-phalloidin staining, and Western blotting were used to examine the effects of AEC-derived exosomes on cell proliferation, intracellular actin backbone distribution, and expression of phenotypic marker proteins in PASMCs. Transcriptomics sequencing was used to analyze differentially expressed genes (DEGs) between groups. Results: Hypoxia-induced exosomes (H-exos) could promote the proliferation of PASMCs, cause the reduction of cellular actin microfilaments, promote the expression of synthetic marker proteins (ELN and OPN), reduce the expression of contractile phenotypic marker proteins (SM22-α and α-SMA), and induce the phenotypic transformation of PASMCs. Transcriptomics sequencing analysis showed that the Rap1 signaling pathway was involved in the phenotypic transformation of PASMCs induced by H-exos. Conclusion: The present study identified that hypoxia-induced AEC-derived exosomes promote the phenotypic transformation of PASMCs and its mechanism is related to the Rap1 signaling pathway.

Adipose Tissue Hypoxia in Obesity: Clinical Reappraisal of Hypoxia Hypothesis.

Obese subjects exhibit lower adipose tissue oxygen consumption in accordance with the lower adipose tissue blood flow. Thereby, compared to lean subjects, obese individuals have almost half lower capillary density and more than half lower vascular endothelial growth factor (VEGF). The VEGF expression together with hypoxia-inducible transcription factor-1 alpha (HIF-1α) activity also requires phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR)-mediated signaling. Especially HIF-1α is an important signaling molecule for hypoxia to induce the inflammatory responses. Hypoxia contributes to several biological functions, such as angiogenesis, cell proliferation, apoptosis, inflammation, and insulin resistance (IR). Pathogenesis of obesity-related comorbidities is attributed to intermittent hypoxia (IH), which is mostly observed in visceral obesity. Proinflammatory phenotype of the adipose tissue is a crucial link between IH and the development of IR. Inhibition of adaptive unfolded protein response (UPR) in hypoxia increases ß cell death. Moreover, deletion of HIF-1α worsens ß cell function. Oxidative stress, as well as the release of proinflammatory cytokines/adipokines in obesity, is proportional to the severity of IH. Reactive oxygen species (ROS) generation at mitochondria is responsible for propagation of the hypoxic signal; however, mitochondrial ROS production is required for hypoxic HIF-1α protein stabilization. Alterations in oxygen availability of adipose tissue directly affect the macrophage polarization and are responsible for the dysregulated adipocytokines production in obesity. Hypoxia both inhibits adipocyte differentiation from preadipocytes and macrophage migration from the hypoxic adipose tissue. Upon reaching a hypertrophic threshold beyond the adipocyte fat loading capacity, excess extracellular matrix (ECM) components are deposited, causing fibrosis. HIF-1α initiates the whole pathological process of fibrosis and inflammation in the obese adipose tissue. In addition to stressed adipocytes, hypoxia contributes to immune cell migration and activation which further aggravates adipose tissue fibrosis. Therefore, targeting HIF-1α might be an efficient way to suppress hypoxia-induced pathological changes in the ECM. The fibrosis score of adipose tissue correlates negatively with the body mass index and metabolic parameters. Inducers of browning/beiging adipocytes and adipokines, as well as modulations of matrix remodeling enzyme inhibitors, and associated gene regulators, are potential pharmacological targets for treating obesity.

Effect of endothelin-1 on the blood pressure response to acute hypoxia and hyperoxia in healthy young men.

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/m2) completed two study visits (control, bosentan). On each visit, BP was assessed under three conditions: (1) normoxia (FiO2 0.21), (2) chemoreflex excitation via hypoxia (FiO2 0.05-0.21), (3) chemoreflex inhibition via hyperoxia (FiO2 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.

Long-Term Oxygen Therapy for 24 or 15 Hours per Day in Severe Hypoxemia.

BACKGROUND: Long-term oxygen supplementation for at least 15 hours per day prolongs survival among patients with severe hypoxemia. On the basis of a nonrandomized comparison, long-term oxygen therapy has been recommended to be used for 24 hours per day, a more burdensome regimen. METHODS: To test the hypothesis that long-term oxygen therapy used for 24 hours per day does not result in a lower risk of hospitalization or death at 1 year than therapy for 15 hours per day, we conducted a multicenter, registry-based, randomized, controlled trial involving patients who were starting oxygen therapy for chronic, severe hypoxemia at rest. The patients were randomly assigned to receive long-term oxygen therapy for 24 or 15 hours per day. The primary outcome, assessed in a time-to-event analysis, was a composite of hospitalization or death from any cause within 1 year. Secondary outcomes included the individual components of the primary outcome assessed at 3 and 12 months. RESULTS: Between May 18, 2018, and April 4, 2022, a total of 241 patients were randomly assigned to receive long-term oxygen therapy for 24 hours per day (117 patients) or 15 hours per day (124 patients). No patient was lost to follow-up. At 12 months, the median patient-reported daily duration of oxygen therapy was 24.0 hours (interquartile range, 21.0 to 24.0) in the 24-hour group and 15.0 hours (interquartile range, 15.0 to 16.0) in the 15-hour group. The risk of hospitalization or death within 1 year in the 24-hour group was not lower than that in the 15-hour group (mean rate, 124.7 and 124.5 events per 100 person-years, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.72 to 1.36; 90% CI, 0.76 to 1.29; P = 0.007 for nonsuperiority). The groups did not differ substantially in the incidence of hospitalization for any cause, death from any cause, or adverse events. CONCLUSIONS: Among patients with severe hypoxemia, long-term oxygen therapy used for 24 hours per day did not result in a lower risk of hospitalization or death within 1 year than therapy for 15 hours per day. (Funded by the Crafoord Foundation and others; REDOX ClinicalTrials.gov number, NCT03441204.).

Peri-Tumoural Lipid Composition and Hypoxia for Early Immune Response to Neoadjuvant Chemotherapy in Breast Cancer.

The deregulation of monounsaturated, polyunsaturated, and saturated fatty acids (MUFAs, PUFAs, SFAs) from de novo synthesis and hypoxia are central metabolic features of breast tumour. Early response markers for neoadjuvant chemotherapy (NACT) are critical for stratified treatment for patients with breast cancer, and restoration of lipid metabolism and normoxia might precede observable structural change. In this study, we hypothesised that peri-tumoural lipid composition and hypoxia might be predictive and early response markers in patients with breast cancer undergoing NACT. Female patients with breast cancer were scanned on a 3T clinical MRI scanner at baseline and Cycle1, with acquisition of lipid composition maps of MUFAs, PUFAs, and SFAs, and hypoxia maps of effective transverse relaxation rate R2*. The percentage change in lipid composition and hypoxia at Cycle1 was calculated with reference to baseline. Tumour-associated macrophages were analysed based on immunostaining of CD163 from biopsy and resection, with the percentage change in the resected tumour calculated across the entire NACT. We found no significant difference in lipid composition and R2* between good and poor responders at baseline and Cycle1; however, the correlation between the percentage change in MUFAs and PUFAs against CD163 suggested the modulation in lipids with altered immune response might support the development of targeted therapies.

Cartilage Homeostasis under Physioxia.

Articular cartilage receives nutrients and oxygen from the synovial fluid to maintain homeostasis. However, compared to tissues with abundant blood flow, articular cartilage is exposed to a hypoxic environment (i.e., physioxia) and has an enhanced hypoxic stress response. Hypoxia-inducible factors (HIFs) play a pivotal role in this physioxic environment. In normoxic conditions, HIFs are downregulated, whereas in physioxic conditions, they are upregulated. The HIF-α family comprises three members: HIF-1α, HIF-2α, and HIF-3α. Each member has a distinct function in articular cartilage. In osteoarthritis, which is primarily caused by degeneration of articular cartilage, HIF-1α is upregulated in chondrocytes and is believed to protect articular cartilage by acting anabolically on it. Conversely, in contrast to HIF-1α, HIF-2α exerts a catabolic influence on articular cartilage. It may therefore be possible to develop a new treatment for OA by controlling the expression of HIF-1α and HIF-2α with drugs or by altering the oxygen environment in the joints.

Hypoxia Abrogates Tumor-Suppressive Activities of C/EBPδ in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a low 5-year survival rate of only 13%. Despite intense research efforts, PDAC remains insufficiently understood. In part, this is attributed to opposing effects of key players being unraveled, including the stroma but also molecules that act in a context-dependent manner. One such molecule is the transcription factor C/EBPδ, where we recently showed that C/EBPδ exerts tumor-suppressive effects in PDAC cells in vitro. To better understand the role of C/EBPδ in different contexts and the development of PDAC, we here build on these findings and assess the effect of C/EBPδ in a PDAC model in mice. We establish that the lack of oxygen in vivo-hypoxia-counteracts the tumor-suppressive effects of C/EBPδ, and identify a reciprocal feedback loop between C/EBPδ and HIF-1α. RNA sequencing of C/EBPδ-induced cells under hypoxia also suggests that the growth-limiting effects of C/EBPδ decrease with oxygen tension. Consequently, in vitro proliferation assays reveal that the tumor-suppressive activities of C/EBPδ are abrogated due to hypoxia. This study demonstrates the importance of considering major physiological parameters in preclinical approaches.

A Hypoxia-Decidual Macrophage Regulatory Axis in Normal Pregnancy and Spontaneous Miscarriage.

The significance of hypoxia at the maternal-fetal interface is proven to be self-explanatory in the context of pregnancy. During the first trimester, low oxygen conditions play a crucial role in processes such as angiogenesis, trophoblast invasion and differentiation, and immune regulation. Recently, there has been increasing research on decidual macrophages, which contribute to the maintenance of immune tolerance, placental and fetal vascular development, and spiral artery remodeling, to investigate the effects of hypoxia on their biological behaviors. On these grounds, this review describes the dynamic changes in oxygen levels at the maternal-fetal interface throughout gestation, summarizing current knowledge on how the hypoxic environment sustains a successful pregnancy by regulating retention, differentiation and efferocytosis of decidual macrophages. Additionally, we explore the relationship between spontaneous miscarriages and an abnormal hypoxia-macrophage axis, shedding light on the underlying mechanisms. However, further studies are essential to elucidate these pathways in greater detail and to develop targeted interventions that could improve pregnancy outcomes.

PX-478 Alleviated the Autism Spectrum Disorder Progression of Offspring Rats Induced by Prenatal Hypoxia.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction, communication, repetitive behaviors, and narrow interests. This study aimed to investigate the impact of the Hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor (PX-478) on ASD-like behaviors in rat offspring exposed to prenatal hypoxia (PH). METHODS: Pregnant rats were randomly assigned to control or PH groups, with the latter experiencing six hours of hypoxia on the 17th day of gestation. Offspring were further treated with PX-478 treatment initiated at one week (+1 w) or three weeks (+3 w) after birth. Hippocampal histology was assessed using hematoxylin and eosin (HE) staining, while protein levels of HIF-1α and phosphatase and tensin homolog (PTEN) were analyzed via western blotting. The concentration of vascular endothelial growth factor (VEGF) was measured using an Enzyme-Linked Immunosorbent Assay (ELISA) kit. RESULTS: PX-478 treatment significantly improved spatial memory, learning, and social ability, while reducing anxiety-like behavior in PH-exposed offspring rats. HE staining revealed that PX-478 treatment decreased the number of hippocampal neurons necrosis in offspring. However, PX-478 treatment at one week post-birth led to decreased body weight and elevated levels of alkaline phosphatase (ALP) and Alanine aminotransferase (ALT) in offspring rats, whereas no significant effect was observed after three weeks of treatment. Additionally, PX-478 treatment resulted in reduced HIF-1α protein levels in the hippocampus and VEGF concentration in the serum of PH-exposed offspring rats, along with elevated PTEN protein levels. CONCLUSIONS: The findings suggest that PX-478 treatment attenuated autism-like behavior in offspring. HIF-1α might play an important role in autism-like behavior induced by prenatal hypoxia, which may be realized by inhibiting PTEN activity.

Biomolecular Dynamics of Nitric Oxide Metabolites and HIF1α in HPV Infection.

INTRODUCTION: Viral infections cause oxygen deprivation, leading to hypoxia or anoxia in certain tissues. The limitation of mitochondrial respiration is one of the major events during hypoxia that induces alternative metabolic activities and increased levels of certain biomolecules such as nitric oxide (NO) metabolites. In this study, we aimed to investigate the role of NO metabolites and hypoxia in HPV infection. MATERIALS AND METHODS: We included 36 patients with palmoplantar warts and 36 healthy subjects and performed serum determinations of NO metabolites (direct nitrite, total nitrite, nitrate, and 3-nitrotyrosine) and HIF1α, a marker of hypoxia. RESULTS: We found elevated serum levels in NO metabolites and HIF1α, and decreased direct nitrite/nitrate ratios in patients with warts versus controls. Additionally, we identified statistically significant positive correlations between NO metabolites and HIF1α levels, except for 3-nitrotyrosine. CONCLUSIONS: Our findings show that HPV infection causes hypoxia and alterations in NO metabolism and suggest a link between wart development and cellular stress. Our research could provide new insights for a comprehensive understanding of the pathogenesis of cutaneous HPV infections.

Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

Recent Insights into Roles of Hypoxia-Inducible Factors in Retinal Diseases.

Hypoxia-inducible factors (HIFs) are transcriptional factors that function as strong regulators of oxygen homeostasis and cellular metabolisms. The maintenance of cellular oxygen levels is critical as either insufficient or excessive oxygen affects development and physiologic and pathologic conditions. In the eye, retinas have a high metabolic demand for oxygen. Retinal ischemia can cause visual impairment in various sight-threating disorders including age-related macular degeneration, diabetic retinopathy, and some types of glaucoma. Therefore, understanding the potential roles of HIFs in the retina is highly important for managing disease development and progression. This review focuses on the physiologic and pathologic roles of HIFs as regulators of oxygen homeostasis and cellular metabolism in the retina, drawing on recent evidence. Our summary will promote comprehensive approaches to targeting HIFs for therapeutic purposes in retinal diseases.

Performance in the Six-Minute Walking Test Does Not Discriminate Excessive Erythrocytosis Patients in a Severe Hypoxic Environment.

BACKGROUND: Chronic exposure to severe hypoxia causes an increase in hematocrit (Hct) and hemoglobin concentration ([Hb]), which can lead to excessive erythrocytosis (EE) and impact physical performance. This work aims to determine the differences in the six-minute walking test (6MWT) between EE and healthy subjects residing at more than 5000 m. METHODS: A prospective, cross-sectional study was performed on 71 men (36 healthy and 25 suffering from EE) living in La Rinconada, Peru (5100 m). Basal levels of [Hb] and Hct were obtained. All the subjects performed the 6MWT, and distance reached, vital signs, dyspnea, and fatigue (Borg scale) at the end of the test were recorded. RESULTS: The average [Hb] and Hct levels in the control group were 18.7 ± 1.2 g/dL and 60.4 ± 7.1%, respectively, contrasting with EE subjects, who showed 23.4 ± 1.6 g/dL and 73.6 ± 5.9% (p < 0.001). However, no statistically significant differences were observed in BMI or other anthropometric parameters. At the end of the 6MWT, the distance traveled and vital constants were similar between both groups, except for arterial oxygen saturation, which was consistently lower in subjects with EE throughout the test. CONCLUSION: EE does not significantly affect 6MWT performance at high altitudes, nor the hemodynamic control during moderate aerobic exercise of subjects who live permanently in a severely hypoxic environment.