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Hypoxia is a pivotal factor in the pathophysiology of various clinical conditions, including obstructive sleep apnea, which has a strong association with cardiovascular diseases like hypertension, posing significant health risks. Although the precise mechanisms linking hypoxemia-associated clinical conditions with hypertension remains incompletely understood, compelling evidence suggests that hypoxia induces plasticity of the neurocirculatory control system. Despite variations in experimental designs and the severity, frequency, and duration of hypoxia exposure, evidence from animal and human models consistently demonstrates the robust effects of hypoxemia in triggering reflex-mediated sympathetic activation. Both acute and chronic hypoxia alters neurocirculatory regulation and, in some circumstances, leads to sympathetic outflow and elevated blood pressures that persist beyond the hypoxic stimulus. Dysregulation of autonomic control could lead to adverse cardiovascular outcomes and increase the risk of developing hypertension. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze signal loss (SL) resulting from low signal quality of pulse oximetry-derived hemoglobin oxygen saturation (SpO2) measurements during prolonged hypoxemic episodes (pHE) in very preterm infants receiving automatic oxygen control (AOC). We did a post hoc analysis of a randomized crossover study of AOC, programmed to set FiO2 to "back-up FiO2" during SL. In 24 preterm infants (median (interquartile range)) gestational age 25.3 (24.6 to 25.6) weeks, recording time 12.7 h (12.2 to 13.6 h) per infant, we identified 76 pHEs (median duration 119 s (86 to 180 s)). In 50 (66%) pHEs, SL occurred for a median duration of 51 s (33 to 85 s) and at a median frequency of 2 (1 to 2) SL-periods per pHE. SpO2 before and after SL was similar (82% (76 to 88%) vs 82% (76 to 87%), p = 0.3)). Conclusion: SL is common during pHE and must hence be considered in AOC-algorithm designs. Administering a "backup FiO2" (which reflects FiO2-requirements during normoxemia) during SL may prolong pHE with SL. Trial registration: The study was registered at www.clinicaltrials.gov under the registration no. NCT03785899. What is Known: • Previous studies examined SpO2 signal loss (SL) during routine manual oxygen control being rare, but pronounced in lower SpO2 states. • Oxygen titration during SL is unlikely to be beneficial as SpO2 may recover to a normoxic range. What is New: • Periods of low signal quality of SpO2 are common during pHEs and while supported with automated oxygen control (SPOC), FiO2 is set to a back-up value reflecting FiO2 requirements during normoxemia in response to SL, although SpO2 remained below target until signal recovery. • FiO2 overshoots following pHEs were rare during AOC and occurred with a delayed onset; therefore, increased FiO2 during SL does not necessarily lead to overshoots. [ABSTRACT FROM AUTHOR]

Simple Summary: The atavistic theory of cancer suggests that cancer development proceeds through cells reverting to ancient survival mechanisms. The Serial Atavism Model (SAM) expands on this, proposing that cancer progresses through multiple stages of reversion to earlier evolutionary forms with cells losing modern traits and regaining primitive ones. One example is the Warburg effect, where cancer cells prefer a type of energy production used by ancient cells before Earth's atmosphere had oxygen. However, this review argues that cancer metabolism is too complex to be fully explained by this theory. Cancer cells exhibit a wide range of metabolic behaviors that do not fit neatly into a pattern of reverting to an ancient state, indicating that the SAM may not provide a complete understanding of cancer. The atavistic theory of cancer posits that cancer emerges and progresses through the reversion of cellular phenotypes to more ancestral types with genomic and epigenetic changes deactivating recently evolved genetic modules and activating ancient survival mechanisms. This theory aims at explaining the known cancer hallmarks and the paradox of cancer's predictable progression despite the randomness of genetic mutations. Lineweaver and colleagues recently proposed the Serial Atavism Model (SAM), an enhanced version of the atavistic theory, which suggests that cancer progression involves multiple atavistic reversions where cells regress through evolutionary stages, losing recently evolved traits first and reactivating primitive ones later. The Warburg effect, where cancer cells upregulate glycolysis and lactate production in the presence of oxygen instead of using oxidative phosphorylation, is one of the key feature of the SAM. It is associated with the metabolism of ancient cells living on Earth before the oxygenation of the atmosphere. This review addresses the question of whether cancer metabolism can be considered as an atavistic reversion. By analyzing several known characteristics of cancer metabolism, we reach the conclusion that this version of the atavistic theory does not provide an adequate conceptual frame for cancer research. Cancer metabolism spans a whole spectrum of metabolic states which cannot be fully explained by a sequential reversion to an ancient state. Moreover, we interrogate the nature of cancer metabolism and discuss its characteristics within the framework of the SAM. [ABSTRACT FROM AUTHOR]

Simple Summary: Dendritic cells are important mediators in the activation of the innate and adoptive immune response. The generation of DC/DCleu was comparable under physiological hypoxic and normoxic culture conditions, with no significant differences in frequencies of generated DC/DCleu from leukemic cell lines, peripheral blood mononuclear as well as whole blood cells from patients with acute myeloid leukemia. Moreover, the composition of immune cells and anti-leukemic immune activity after T cell enriched mixed lymphocyte culture with patients' blood pretreated vs not pretreated with defined response modifiers (Kits) was improved, particularly under hypoxic conditions. These data show that the generation of DC/DCleu as well as the induction of anti-leukemic immune activating functionality is possible under standard normoxic as well as physiological hypoxic culture conditions ex vivo. Hypoxia can modulate the immune system by affecting the function and activity of immune cells, potentially leading to altered immune responses. This study investigated the generation of leukemia-derived dendritic cells (DCleu) from leukemic blasts and their impact on immune cell activation under hypoxic (5–10% O2) compared to normoxic (21% O2) conditions using various immunomodulatory Kits. The results revealed that DC/DCleu-generation was similar under hypoxic and normoxic conditions, with no significant differences observed in frequencies of generated DC/DCleu. Furthermore, the study showed that the activation of immune cells and their anti-leukemic activity improved when T cell-enriched immunoreactive cells were co-cultured with DC/DCleu which were generated with Kit I and M compared to the control after mixed lymphocyte cultures. The anti-leukemic activity was improved under hypoxic compared to normoxic conditions after MLCWB-DC Kit M. These findings suggest that DC/DCleu-cultures of leukemic whole blood with Kits under hypoxic conditions yield comparable frequencies of DC/DCleu and can even increase the anti-leukemic activity compared to normoxic conditions. Overall, this research highlights the potential of utilizing DC/DCleu (potentially induced in vivo with Kits) as a promising approach to enhance immune response in patients with acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Simple Summary: This research explores the role of selenoprotein P, a protein crucial for transporting selenium in the body, in liver cancer. The study aims to understand how selenoprotein P levels relate to the severity of hepatocellular carcinoma and its impact on patient outcomes. Findings indicate that selenoprotein P expression varies significantly with cancer stage and patient demographics like race and gender. It also correlates strongly with hormone and lipid metabolism markers. Importantly, selenoprotein P shows potential as a predictor of patient survival and as a biomarker for hypoxia, a condition affecting cancer progression. These insights may lead to better diagnostic tools and personalized treatments for liver cancer, emphasizing the need for further studies to validate selenoprotein P's clinical utility in real-world settings. Selenoprotein P (SELENOP) acts as a crucial mediator, distributing selenium from the liver to other tissues within the body. Despite its established role in selenium metabolism, the specific functions of SELENOP in the development of liver cancer remain enigmatic. This study aims to unravel SELENOP's associations in hepatocellular carcinoma (HCC) by scrutinizing its expression in correlation with disease characteristics and investigating links to hormonal and lipid/triglyceride metabolism biomarkers as well as its potential as a prognosticator for overall survival and predictor of hypoxia. SELENOP mRNA expression was analyzed in 372 HCC patients sourced from The Cancer Genome Atlas (TCGA), utilizing statistical methodologies in R programming and machine learning techniques in Python. SELENOP expression significantly varied across HCC grades (p < 0.000001) and among racial groups (p = 0.0246), with lower levels in higher grades and Asian individuals, respectively. Gender significantly influenced SELENOP expression (p < 0.000001), with females showing lower altered expression compared to males. Notably, the Spearman correlation revealed strong positive connections of SELENOP with hormonal markers (AR, ESR1, THRB) and key lipid/triglyceride metabolism markers (PPARA, APOC3, APOA5). Regarding prognosis, SELENOP showed a significant association with overall survival (p = 0.0142) but explained only a limited proportion of variability (~10%). Machine learning suggested its potential as a predictive biomarker for hypoxia, explaining approximately 18.89% of the variance in hypoxia scores. Future directions include validating SELENOP's prognostic and diagnostic value in serum for personalized HCC treatment. Large-scale prospective studies correlating serum SELENOP levels with patient outcomes are essential, along with integrating them with clinical parameters for enhanced prognostic accuracy and tailored therapeutic strategies. [ABSTRACT FROM AUTHOR]

A retrospective analysis was performed from May 2003 to October 2021 at our hospital. One hundred and eleven neonates diagnosed with gastric perforation were categorized into non-survivor and survivor groups based on prognosis. The mortality rate was 23.42%. Logistic regression was used to analyze the factors influencing the early neonatal death. The non-survivor groups showed more abdominal distension, vomiting, hypoxia, acidosis, hyperkalemia, and coagulation abnormalities. Serum potassium concentration (odds ratio [OR] 2.148, P =.043) was an independent risk factor; however, arterial partial pressure of oxygen (OR 0.977, P =.024), bicarbonate (OR 0.779, P =.023), and platelet count (OR 0.986, P =.014) had protective effects on neonatal death. Based on this, a visualized nomogram prediction model was constructed, patients who had a nomogram score of more than 163.787 was considered to have high risks of mortality, the area under the curve of this was up to 0.828 (95% confidence interval [0.733, 0.923]), the sensitivity was 80.0%, and the specificity was 76.9%. [ABSTRACT FROM AUTHOR]

This document provides a comprehensive examination of the use of nitrogen anoxia as a method of execution in Alabama. The authors argue that this method is inherently inhumane and flawed from a physiological perspective. They discuss the respiratory physiology of nitrogen anoxia and its impact on the body until death, highlighting the vulnerability of the brain to oxygen deprivation. The article also addresses misinformation surrounding nitrogen-induced hypoxia as a form of capital punishment, emphasizing the importance of understanding the physiological effects of nitrogen inhalation. The authors express their opposition to the death penalty and advocate for challenging authority in matters of human health and life. [Extracted from the article]

Research into oxygen sensing and response has been impactful in physiology and pathology. New functions for hypoxia-inducible factor (HIF) transcription factors are emerging. The 2-oxoglutarate-dependent dioxygenase (2-OGDD) family is vast, but knowledge regarding its family members is still emerging. New tools and methods need to be developed to quantify and visualize O 2 levels in cells, organs, and organisms. Investigating how cells and organisms sense and respond to O 2 levels is essential to our understanding of physiology and pathology. This field has advanced considerably since the discovery of the major transcription factor family, hypoxia-inducible factor (HIF), and the enzymes that control its levels: prolyl hydroxylases (PHDs). However, with its expansion, new complexities have emerged. Herein we highlight three main areas where, in our opinion, the research community could direct some of their attention. These include non-transcriptional roles of HIFs, specificity and O 2 sensitivity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), and new tools and methods to detect O 2 concentrations in cells and organs. A greater understanding of these areas would answer big questions and help drive our knowledge of cellular responses to hypoxia forward. [ABSTRACT FROM AUTHOR]

Activation of the vagus nerve mediates cardioprotection and attenuates myocardial ischemia/reperfusion (I/R) injury. In response to vagal activation, acetylcholine (ACh) is released from the intracardiac nervous system (ICNS) and activates intracellular cardioprotective signaling cascades. Recently, however, a nonneuronal cholinergic cardiac system (NNCCS) in cardiomyocytes has been described as an additional source of ACh. To investigate whether the NNCCS mediates cardioprotection in the absence of vagal and ICNS activation, we used a reductionist approach of isolated adult rat ventricular cardiomyocytes without neuronal cells, using hypoxic preconditioning (HPC) as a protective stimulus. Adult rat ventricular cardiomyocytes were isolated, the absence of neuronal cells was confirmed, and HPC was induced by 10/20 min hypoxia/reoxygenation (H/R) before subjection to 30/5 min H/R to simulate I/R injury. Cardiomyocyte viability was assessed by trypan blue staining at baseline and after HPC+H/R or H/R. Intra- and extracellular ACh was quantified using liquid chromatography-coupled mass spectrometry at baseline, after HPC, after hypoxia, and after reoxygenation, respectively. In a subset of experiments, muscarinic and nicotinic ACh receptor (m- and nAChR) antagonists were added during HPC or during H/R. Cardiomyocyte viability at baseline (69 ± 4%) was reduced by H/R (10 ± 3%). With HPC, cardiomyocyte viability was preserved after H/R (25 ± 6%). Intra- and extracellular ACh increased during hypoxia; HPC further increased both intra- and extracellular ACh (from 0.9 ± 0.7 to 1.5 ± 1.0 nmol/mg; from 0.7 ± 0.6 to 1.1 ± 0.7 nmol/mg, respectively). The addition of mAChR and nAChR antagonists during HPC had no impact on HPC's protection; however, protection was abrogated when antagonists were added during H/R (cardiomyocyte viability after H/R: 23 ± 5%; 13 ± 4%). In conclusion, activation of the NNCCS is involved in cardiomyocyte protection; HPC increases intra- and extracellular ACh during H/R, and m- and nAChRs are causally involved in HPC's cardiomyocyte protection during H/R. The interplay between upstream ICNS activation and NNCCS activation in myocardial cholinergic metabolism and cardioprotection needs to be investigated in future studies. NEW & NOTEWORTHY: The intracardiac nervous system is considered to be involved in ischemic conditioning's cardioprotection through the release of acetylcholine (ACh). However, we demonstrate that hypoxic preconditioning (HPC) protects from hypoxia/reoxygenation injury and increases intra- and extracellular ACh during hypoxia in isolated adult ventricular rat cardiomyocytes. HPC's protection involves cardiomyocyte muscarinic and nicotinic ACh receptor activation. Thus, besides the intracardiac nervous system, a nonneuronal cholinergic cardiac system may also be causally involved in cardiomyocyte protection by ischemic conditioning. [ABSTRACT FROM AUTHOR]

Cardiorespiratory control is immature in infants born preterm compared to those born at term. Animal studies have shown that repetitive hypoxia associated with periodic breathing can alter autonomic control. We aimed to elucidate if the amount of time spent with apnoea and periodic breathing in the neonatal unit was associated with longitudinal changes in autonomic control assessed using heart rate variability. Twenty-nine very preterm infants (10 M 19F) were studied during supine daytime sleep on 4 occasions. Study 1: 32–36 weeks post menstrual age (PMA) (n = 29), Study 2: 36–40 weeks PMA (n = 27), Study 3: 3-months corrected age (CA) (n = 20) and Study 4: 6-months CA (n = 26). The percentage total sleep time (%TST) spent having apnoeas in active (AS) and quiet sleep (QS) at each study was calculated. Total power, low frequency (LF, sympathetic + parasympathetic activity) high frequency (HF, parasympathetic activity), and LF/HF (sympathovagal balance) were calculated. Infants were divided into two groups based on the %TST spent with apnoeas above and below the median in AS and QS at Study 1. Data were normalised and compared with two-way ANOVA with Bonferroni post-hoc tests. When apnoeas were included in the analysis, in QS Total power and HF power were higher, and when apnoeas were excluded HF power was higher in QS but lower in AS in the above median group at Study 4. This study provides new evidence that short apnoeas, particularly periodic breathing, which is currently not detected or treated in the neonatal unit can affect autonomic cardiovascular control. • Cardiorespiratory control is immature in infants born preterm. • Animal studies have shown that repetitive hypoxia can alter autonomic control. • The sleep time spent with short apnoeas decreased with increasing postnatal age. • Short apnoeas in the neonatal period can affect autonomic cardiovascular control. [ABSTRACT FROM AUTHOR]

The transcriptional response to hypoxia is largely regulated by the hypoxia-inducible factors (HIFs), which induce the expression of genes involved in glycolysis, angiogenesis, proliferation, and migration. Virtually all cell culture-based hypoxia experiments have used near-atmospheric (18% O2) oxygen levels as the baseline for comparison with hypoxia. However, this is hyperoxic compared with mammalian tissue microenvironments, where oxygen levels range from 2% to 9% O2 (physioxia). Thus, these experiments actually compare hyperoxia to hypoxia. To determine how the baseline O2 level affects the subsequent response to hypoxia, we cultured PC-3 prostate cancer cells in either 18% or 5% O2 for 2 wk before exposing them to hypoxia (∼1.1% pericellular O2) for 12–48 h. RNA-seq revealed that the transcriptional response to hypoxia was dependent on the baseline O2 level. Cells grown in 18% O2 before hypoxia exposure showed an enhanced induction of HIF targets, particularly genes involved in glucose metabolism, compared with cells grown in physioxia before hypoxia. Consistent with this, hypoxia significantly increased glucose consumption and metabolic activity only in cells previously cultured in 18% O2, but not in cells preadapted to 5% O2. Transcriptomic analyses also indicated effects on cell proliferation and motility, which were followed up by functional assays. Although unaffected by hypoxia, both proliferation and migration rates were greater in cells cultured in 5% O2 versus 18% O2. We conclude that an inappropriately hyperoxic starting condition affects the transcriptional and metabolic responses of PC-3 cells to hypoxia, which may compromise experiments on cancer metabolism in vitro. NEW & NOTEWORTHY: Although human cell culture models have been instrumental to our understanding of the mechanisms involved in the cellular response to hypoxia, in virtually all experiments, cells are routinely cultured in near-atmospheric (∼18% O2) oxygen levels, which are hyperoxic relative to physiological conditions in vivo. Here, we show for the first time that cells cultured in physiological O2 levels (5% O2) respond differently to subsequent hypoxia than cells grown at 18%. [ABSTRACT FROM AUTHOR]

Angiogenesis is critical for the repair of damaged or diseased tissues. Hypoxia is a major factor promoting angiogenesis in physiological conditions. Baicalein, a flavone derived from the Chinese skullcap or Huangqin, Scutellaria baicalensis Georgi which is known to exhibit hypoxia mimetic activity. Here, we investigated the pro-angiogenic and wound healing potential of baicalein in vitro, in ovo, and in silico with a view to develop green wound dressings. The human keratinocyte cell line, HaCaT, was subjected to baicalein at varied concentrations in vitro and assessed for cell viability, cell cycle, and apoptosis induction. The study showed that lower concentrations of baicalein (below 10 µM) promoted HaCaT proliferation, while higher concentrations induced apoptosis. Baicalein at low concentrations also promoted angiogenesis, as evidenced by the CAM (Chorioallantoic membrane) assay performed on chicken eggs. Gene expression analysis of Keratin 10 also suggested the activation of keratinocytes, leading to augmented wound healing after baicalein treatment. The in silico docking experiments reflect the potential of baicalein to promote angiogenesis via a HIF-independent pathway involving the agonistic transcriptional activation of the ERRα-PGC1α complex. The results highlight the capability of baicalein to promote angiogenesis and wound healing and thus hold potential for the development of angiogenesis-promoting scaffolds and wound dressings. [ABSTRACT FROM AUTHOR]

Hypoxia, a common environmental condition, can affect cell survival and physiological function by triggering oxidative stress. Akt/FoxO pathway has been proven to play a non-negligible role in the regulation of autophagy. However, the role of Akt/FoxO pathway in hypoxia-induced autophagy is unclear in fish. Therefore, in this study, grass carp hepatocyte cells (L8824) were treated by CoCl2 to simulate hypoxia, and the results showed that CoCl2 can increase the expression of Hif-1a protein at different concentrations or different treatment time. Further study found that hypoxia increased intracellular reactive oxygen species (ROS) level, and the expression of autophagy-related genes (LC3-II, pink1, beclin-1 and p62) and foxO1a/1b. The mitochondrial membrane potential (ΔΨm) was also depolarized, and autophagosomes were intriguingly detected by transmission electron microscope (TEM) after the treatment of hypoxia. Moreover, hypoxia inhibited Akt phosphorylation, while PI3K/Akt pathway inhibitor, LY294002 significantly up-regulated the expression of foxO1a/1b and autophagy-related genes. Additionally, silencing foxo1b also resulted in down-regulation of autophagy-related genes. It was demonstrated that hypoxia induced autophagy via Akt/FoxO1 pathway. These results will provide a new light on further understanding the role of Akt/FoxO pathway in the response to hypoxia in fish. [ABSTRACT FROM AUTHOR]

Purpose: Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 < 80 mmHg is a life-threatening condition. The optimal management strategy is unclear. The aim of this meta-analysis was to compare the effects of low tidal volumes (Vt), moderate Vt, prone ventilation, and venovenous extracorporeal membrane oxygenation (VV-ECMO) on mortality in severe ARDS. Methods: We performed a frequentist network meta-analysis of randomised controlled trials (RCTs) with participants who had severe ARDS and met eligibility criteria for VV-ECMO or had PaO2/FiO2 < 80 mmHg. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to discern the relative effect of interventions on mortality and the certainty of the evidence. Results: Ten RCTs including 812 participants with severe ARDS were eligible. VV-ECMO reduces mortality compared to low Vt (risk ratio [RR] 0.77, 95% confidence interval [CI] 0.59–0.99, moderate certainty) and compared to moderate Vt (RR 0.75, 95% CI 0.57–0.98, low certainty). Prone ventilation reduces mortality compared to moderate Vt (RR 0.78, 95% CI 0.66–0.93, high certainty) and compared to low Vt (RR 0.81, 95% CI 0.63–1.02, moderate certainty). We found no difference in the network comparison of VV-ECMO compared to prone ventilation (RR 0.95, 95% CI 0.72–1.26), but inferences were based solely on indirect comparisons with very low certainty due to very wide confidence intervals. Conclusions: In adults with ARDS and severe hypoxia, both VV-ECMO (low to moderate certainty evidence) and prone ventilation (moderate to high certainty evidence) improve mortality relative to low and moderate Vt strategies. The impact of VV-ECMO versus prone ventilation remains uncertain. [ABSTRACT FROM AUTHOR]

Drowning is the process of respiratory impairment from immersion or submersion in a liquid. Worldwide, approximately 360,000 deaths annually can be attributed to drowning. Morbidity and mortality are a result of hypoxia, so the focus during resuscitation should be on airway management and optimizing oxygenation. This article describes several drowning scenarios and discusses appropriate response and treatment algorithms. [ABSTRACT FROM AUTHOR]

[Display omitted] • ALKBH5 plays an important protective role during the post-MI repair phase. • The loss of ALKBH5 in fibroblasts leads to cardiac rupture and deteriorated cardiac function. • This study identities the ALKBH5 as hypoxia-related role in cardiac fibroblasts. • ALKBH5 regulates fibroblast activation via ErbB4 mRNA demethylation. • ALKBH5/ErbB4 are possible therapeutic targets to reduce the occurrence of cardiac rupture. N6-methyladenosine (m6A) methylation produces a marked effect on cardiovascular diseases. The m6A demethylase AlkB homolog 5 (ALKBH5), as an m6A "eraser", is responsible for decreased m6A modification. However, its role in cardiac fibroblasts during the post-myocardial infarction (MI) healing process remains elusive. To investigate the effect of ALKBH5 in cardiac fibroblasts during infarct repair. MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets. Dramatic alterations in ALKBH5 expression were observed during the early stages post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and ameliorated cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both in vivo and in vitro ALKBH5 loss resulted in impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-β1 or Ang II, upregulated ALKBH5 expression in myofibroblasts by HIF-1α-dependent transcriptional regulation. Mechanistically, ALKBH5 promoted the stability of ErbB4 mRNA and the degradation of ST14 mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout. Fibroblast ALKBH5 positively regulates post-MI healing by stabilization of ErbB4 mRNA in an m6A-dependent manner. ALKBH5/ErbB4 might be potential therapeutic targets for post-MI cardiac rupture. [ABSTRACT FROM AUTHOR]

We have reported previously that during hypoxia exposure, the expression of mature miR-17~92 was first upregulated and then downregulated in pulmonary artery smooth muscle cells (PASMC) and in mouse lungs in vitro and in vivo. Here, we investigated the mechanisms regulating this biphasic expression of miR-17~92 in PASMC in hypoxia. We measured the level of primary miR17~92 in PASMC during hypoxia exposure and found that short-term hypoxia exposure (3% O2, 6 h) induced the level of primary miR-17~92, whereas long-term hypoxia exposure (3% O2, 24 h) decreased its level, suggesting a biphasic regulation of miR17~92 expression at the transcriptional level. We found that short-term hypoxia-induced upregulation of miR-17~92 was hypoxiainducible factor 1α (HIF1α) and E2F1 dependent. Two HIF1α binding sites on miR-17~92 promoter were identified. We also found that long-term hypoxia-induced suppression of miR-17~92 expression could be restored by silencing of p53. Mutation of the p53-binding sites in the miR-17~92 promoter increased miR-17~92 promoter activity in both normoxia and hypoxia. Our findings suggest that the biphasic transcriptional regulation of miR-17~92 during hypoxia is controlled by HIF1/E2F1 and p53 in PASMC: during short-term hypoxia exposure, stabilization of HIF1 and induction of E2F1 induce the transcription of miR-17~92, whereas during long-term hypoxia exposure, hyperphosphorylation of p53 suppresses the expression of miR-17~92. NEW & NOTEWORTHY We showed that the biphasic transcriptional regulation of miR-17~92 during hypoxia is controlled by two distinct mechanisms: during short-term hypoxia exposure, induction of HIF1 and E2F1 upregulates miR-17~92. Longer hypoxia exposure induces hyperphosphorylation of p53 at ser15, which leads to its binding to miR-17~92 promoter and inhibition of its expression. Our findings provide novel insights into the spatiotemporal regulation of miR-17~92 that may play a role in the development of human lung diseases including pulmonary hypertension (PH). [ABSTRACT FROM AUTHOR]

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This research is concentrated on investigating the role and mechanism of miR-652-3p in the protective effects of isoflurane (ISO) against myocardial ischemia–reperfusion (I/R) injury. H9c2 cells underwent pretreatment with varying concentrations of ISO, and subsequently, a hypoxia/reoxygenation (H/R) model was constructed. The levels of miR-652-3p, ISL LIM homeobox 1 (ISL1), and inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were evaluated through reverse transcription polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent assay was employed to investigate concentrations of myocardial injury markers, such as creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI). Cell counting kit-8 was used to evaluate cell viability, while flow cytometry was utilized to measure apoptosis. Additionally, a dual luciferase reporter assay was conducted to validate the targeting relationship between ISL1 and miR-652-3p. Herein, we confirmed that the level of miR-652-3p was gradually increased with prolonged hypoxia; nevertheless, this increase was suppressed by ISO pretreatment (P < 0.05). Additionally, ISO pretreatment prevented the decrease in cell viability, increase in apoptosis, and overproduction of IL-6, TNF-α, CK-MB, and cTnI induced by H/R (P < 0.05). However, the inhibitory effects of ISO were counteracted by the increased levels of miR-652-3p (P < 0.05). ISL1 is a potential target of miR-652-3p. H/R induction suppressed ISL1 levels compared to the control, but ISO treatment increased its expression (P < 0.05). Overexpression of ISL1 inhibited the elimination of the protective effect of ISO on myocardial damage induced by the elevation of miR-652-3p (P < 0.05). The findings of this research confirm that miR-652-3p attenuated the protective effect of ISO on cardiomyocytes in myocardial ischemia by targeting ISL1. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Cabin decompression presents a threat in high-altitude-capable aircraft. A chamber study was performed to compare effects of rapid (RD) vs. gradual decompression and gauge impairment at altitude with and without hypoxia, as well as to assess recovery. METHODS: There were 12 participants who completed RD (1 s) and Gradual (3 min 12 s) ascents from 2743-7620 m (9000-25000 ft) altitude pressures while breathing air or 100% O2. Physiological indices included oxygen saturation (SPO2), heart rate (HR), respiration, end tidal O2 and CO2 partial pressures, and electroencephalography (EEG). Cognition was evaluated using SYNWIN, which combines memory, arithmetic, visual, and auditory tasks. The study incorporated ascent rate (RD, gradual), breathing gas (air, 100% O2) and epoch (ground-level, pre-breathe, ascent-altitude, recovery) as factors. RESULTS: Physiological effects in hypoxic "air" ascents included decreased SPO2 and end tidal O2 and CO2 partial pressures (hypocapnia), with elevated HR and minute ventilation (V̇ E); SPO2 and HR effects were greater after RD (-7.3% lower and +10.0 bpm higher, respectively). HR and V̇ E decreased during recovery. SYNWIN performance declined during ascent in air, with key metrics, including composite score, falling further (-75% vs. -50%) after RD. Broad cognitive impairment was not recorded on 100% O2, nor in recovery. EEG signals showed increased slow-wave activity during hypoxia. DISCUSSION: In hypoxic exposures, RD impaired performance more than gradual ascent. Hypobaria did not comprehensively impair performance without hypoxia. Lingering impairment was not observed during recovery, but HR and V̇ E metrics suggested compensatory slowing following altitude stress. Participants' cognitive strategy shifted as hypoxia progressed, with efficiency giving way to "satisficing," redistributing effort to easier tasks. [ABSTRACT FROM AUTHOR]

Acute intermittent hypoxia (AIH) can induce sustained facilitation of motor output in people with spinal cord injury (SCI). Most studies of corticospinal tract excitability in humans have used 9% fraction inspired oxygen (F I O 2 ) AIH (AIH-9%), with inconsistent outcomes. We investigated the effect of single sessions of 9% F I O 2 and 12% F I O 2 AIH (AIH-12%) on corticospinal excitability of a hand and leg muscle in able-bodied adults. Ten naïve participants completed three sessions on separate days comprising 15 epochs of 1 min of AIH-9%, AIH-12%, or sham (SHAM-21%) followed by 1 min of room air (21% F I O 2 ) in a randomized crossover design. Motor-evoked potentials (MEPs; n = 30, ∼1 mV) elicited at rest by transcranial magnetic stimulation and maximal M-waves (Mmax) evoked by peripheral nerve stimulation were measured from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles at baseline and at ∼0, 20, 40, and 60 min post intervention. AIH-9% induced the greatest reduction in peripheral oxygen saturation (to 85% vs. 93% and 100% in AIH-12% and SHAM-21%, respectively; P < 0.001) and the greatest increase in ventilation [by 22% vs. 12% and −3% in AIH-9%, AIH-12%, and SHAM-21%, respectively (P < 0.001)]. There was no difference in MEP amplitudes (%Mmax) after any of the three conditions (AIH-9%, AIH-12%, SHAM-21%) for both the FDI (P = 0.399) and TA (P = 0.582). Despite greater cardiorespiratory changes during AIH-9%, there was no evidence of corticospinal facilitation (tested with MEPs) in this study. Further studies could explore variability in response to AIH between individuals and other methods to measure motor facilitation in people with and without spinal cord injuries. NEW & NOTEWORTHY: This is the first study that tests whether acute intermittent hypoxia (AIH) induces motor output facilitation in humans after two different doses of AIH (9% and 12% F I O 2 ) and the reproducibility of participant responses after a repeat AIH intervention at 9% AIH. There was no motor output facilitation in response to either dose of AIH. The results question the effectiveness of a single 30-min session of AIH in inducing motor output facilitation, tested in this way. [ABSTRACT FROM AUTHOR]

Rationale: Nocturnal hypoxemia is common in sleep-disordered breathing (SDB) and is associated with increased morbidity and mortality. Although impaired diffusing capacity of the lung for carbon monoxide (DlCO) is associated with daytime hypoxemia, its influence on SDB-related nocturnal hypoxemia is not known. Objectives: To characterize the effects of DlCO impairment on SDB-related nocturnal hypoxemia and associated health outcomes. Methods: Data from a multicenter cohort of men with and without human immunodeficiency virus (HIV) infection, with concomitant measures of DlCO and home-based polysomnography (n = 544), were analyzed. Multivariable quantile regression models characterized associations between DlCO and several measures of SDB-related hypoxemia (e.g., total sleep time with oxygen saturation as measured by pulse oximetry [SpO2] < 90% [T90]). Structural equation models were used to assess associations of impaired DlCO and SDB-related hypoxemia measures with prevalent hypertension and type 2 diabetes. Results: DlCO impairment (<80% predicted) was associated with sleep-related hypoxemia. Participants with severe SDB (apnea–hypopnea index ⩾ 30 events/h) and impaired DlCO had higher T90 (median difference, 15.0% [95% confidence interval (CI), 10.3% to 19.7%]) and average SDB-related desaturation (median difference, 1.0 [95% CI, 0.5 to 1.5]) and lower nadir SpO2 (median difference, −8.2% [95% CI, −11.4% to −4.9%]) and average SpO2 during sleep (median difference, −1.1% [95% CI, −2.1% to −0.01%]) than those with severe SDB and preserved DlCO. Higher T90 was associated with higher adjusted odds of prevalent hypertension (odds ratio, 1.39 [95% CI, 1.14 to 1.70]) and type 2 diabetes (odds ratio, 1.25 [95% CI, 1.07 to 1.46]). Conclusions: DlCO impairment in severe SDB was associated with sleep-related hypoxemia, prevalent hypertension, and type 2 diabetes. Assessment of SDB should be considered in those with impaired DlCO to guide testing and risk stratification strategies. [ABSTRACT FROM AUTHOR]

Background/Aim: Patients with hypoxic bladder cancer benefit from hypoxia modification added to radiotherapy, but no biomarkers exist to identify patients with hypoxic tumours. We, herein, aimed to implement oxygenenhanced MRI (OE-MRI) in xenografts derived from muscleinvasive bladder cancer (MIBC) for future hypoxia biomarker discovery work; and generate gene expression data for future biomarker discovery. Materials and Methods: The flanks of female CD-1 nude mice inoculated with HT1376 MIBC cells. Mice with small (300 mm³) or large (700 mm3) tumours were imaged, breathing air then 100% O2, 1 h post injection with pimonidazole in an Agilant 7T 16cm bore magnet interfaced to a Bruker Avance III console with a T2-TurboRARE sequence using a dynamic MPRAGE acquisition. Dynamic Spoiled Gradient Recalled Echo images were acquired for 5 min, with 0.1mmol/kg Gd-DOTA (Dotarem, Guerbet, UK) injected after 60 s (1 ml/min). Voxel size and field of view of dynamic contrast enhanced (DCE)-MRI and OE-MRI scans were matched. The voxels considered as perfused with significant post-contrast enhancement (p<0.05) in DCE-MRI scans and tissue were further split into pOxyE (normoxic) and pOxyR (hypoxic) regions. Tumours harvested in liquid N2, sectioned, RNA was extracted and transcriptomes analysed using Clariom S microarrays. Results: Imaged hypoxic regions were greater in the larger versus smaller tumour. Expression of known hypoxia-inducible genes and a 24 gene bladder cancer hypoxia score were higher in pimonidazole-high versus -low regions: CA9 (p=0.012) and SLC2A1 (p=0.012) demonstrating expected transcriptomic behaviour. Conclusion: OE-MRI was successfully implemented in MIBC-derived xenografts. Transcriptomic data derived from hypoxic and non-hypoxic xenograft regions will be useful for future studies. [ABSTRACT FROM AUTHOR]

The association between preoperative pain catastrophizing and postoperative patient-reported outcome measures of patients with pre-arthritic hip disease was evaluated. All patients scheduled for joint-preserving surgeries of the hip (JPSH) at our institution were approached. Patient demographics (age, sex, body mass index (BMI)), pain intensity (Numeric Pain Scale (NPS)) and pain catastrophizing (Pain Catastrophizing Scale (PCS)) were collected preoperatively. Patient function (12-Item International Hip Outcome Tool (iHot-12)) and physical and mental health (Patient-Reported Outcomes Measurement Information System (PROMIS-10) mental/physical) were collected preoperatively, three-month and one-year postoperatively. The analysis consisted of multivariate linear regression models fitted for continuous scores of outcome measures at three-month and one-year. Correlation between preoperative PCS and iHot-12 was assessed using the Pearson correlation coefficient. A total of 274 patients completed the PCS and were included in the multivariate linear regression models. Most patients were females (66.8%), mean age was 33 (SD 9), mean BMI was 26.5 (SD 5.8) and most were diagnosed with femoro-acetabular impingement (46.0%) and underwent arthroscopy (77.0%). There were statistically significant correlations between PCS and iHot-12 (preoperatively −0.615, P  < 0.001; three-month −0.242, P  = 0.002). Statistically significant associations were found for function (three-month PCS P  = 0.046, age P  = 0.014, NPS P  = 0.043; one-year BMI P  = 0.005, NPS P  = 0.014), physical health (three-month BMI, P  = 0.002, NPS P  = 0.008; one-year BMI P  = 0.002, NPS P  = 0.013) and mental health (three-month BMI P  = 0.047; one-year BMI P  = 0.030). There is an association between function and preoperative pain catastrophizing in patients with pre-arthritic hip disease undergoing JPSH. When considering confounding variables, preoperative pain catastrophizing is associated with short-term recovery. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 pandemic has significantly affected people worldwide. Herein, we present a case of massive heterotopic ossification (HO) of the right hip following severe SARS-CoV-2 infection. The exact origin of HO development is still unknown, but a critical illness, chronic immobilization and hypoxia are important risk factors. Considering the location and size of the HOs in this case, modified Ludloff's medial approach of the hip was used. This approach allows for good exposure and access to the medial and inferior part of the hip joint and the successful extirpation of the pathologic tissue. [ABSTRACT FROM AUTHOR]

Both hypoxia and the complement lectin pathway (CLP) are involved in atherosclerosis and atherosclerosis-related stroke and acute myocardial infarction (AMI). We have previously shown that mannose-binding lectin-associated serine protease-1 (MASP-1), the most abundant enzyme of CLP, induces an inflammatory phenotype of endothelial cells (ECs) by cleaving protease activated receptors (PARs). In the absence of data, we aimed to investigate whether hypoxia and MASP-1 interact at the level of ECs, to better understand their role in atherosclerosis-related diseases. Hypoxia attenuated the wound healing ability of ECs, increased ICAM-1 and decreased ICAM-2 expression and upregulated PAR2 gene expression. Hypoxia and MASP-1 increased GROα and IL-8 production, and endothelial permeability without potentiating each other's effects, whereas they cooperatively disrupted vascular network integrity, activated the Ca2+, CREB and NFκB signaling pathways, and upregulated the expression of E-selectin, a crucial adhesion molecule in neutrophil homing. VCAM-1 expression was not influenced either by hypoxia, or by MASP-1. In summary, hypoxia potentiates the effect of MASP-1 on ECs, at least partially by increasing PAR expression, resulting in interaction at several levels, which may altogether exacerbate stroke and AMI progression. Our findings suggest that MASP-1 is a potential drug target in the acute phase of atherosclerosis-related diseases. [ABSTRACT FROM AUTHOR]

Introduction: Hypoxemia is a common complication of childhood respiratory tract infections and non-respiratory infections. Hypoxemic children have a five-fold increased risk of death compared to children without hypoxemia. In addition, there is limited evidence about hypoxemia and clinical predictors in Ethiopia. Therefore, this study was conducted to assess the prevalence and clinical predictors of hypoxemia among children with respiratory distress admitted to the University of Gondar Comprehensive Specialized Hospital. Methods: An institutional-based cross-sectional study was conducted from December 2020 to May 2021 in northwest Ethiopia. A total of 399 study participants were selected using systematic random sampling. The oxygen saturation of the child was measured using Masimo rad-5 pulse oximetry. SPSS version 21 software was used for statistical analysis. Result: In this study, the prevalence of hypoxemia among children with respiratory distress was 63.5%. The clinical signs and symptoms significantly associated with hypoxemia were: head-nodding (AOR: 4.1, 95% CI: 1.81–9.28) and chest indrawing (AOR: 3.08, 95% CI: 1.32–7.16) which were considered statistically the risk factors for hypoxemia while inability to feed (AOR: 0.13, 95% CI: 0.02–0.77) was the protective factor for hypoxemia. The most sensitive predictors of hypoxemia were fast breathing with sensitivity (98.4%), nasal flaring (100.0%), chest indrawing (83.6%), and intercostal retraction (93.1%). The best specific predictors of hypoxemia were breathing difficulty with specificity (79.4%), inability to feed (100.0%), wheezing (83.0%), cyanosis (98.6%), impaired consciousness (94.2%), head-nodding (88.7%), and supra-sternal retraction (96.5%). Conclusion and recommendation: The prevalence of hypoxemia among children was high. The predictors of hypoxemia were the inability to feed, head nodding, and chest indrawing. It is recommended that the health care settings provide immediate care for the children with an inability to feed, head nodding, and chest indrawing. The policymakers better to focus on preventive strategies, particularly those with the most specific clinical predictors. [ABSTRACT FROM AUTHOR]

Purpose: Vibrio parahaemolyticus is a leading seafood borne pathogen worldwide. The aim of this study was to decipher the response mechanism of V. parahaemolyticus isolates of clinical and aquatic animal origins to the hypoxic condition, which challenges the bacterial survival in the host and in the environment. Methods: Growth profiles of V. parahaemolyticus isolates (n = 5) of clinical and aquatic animal origins were examined at different stress conditions (osmolality, acid, temperature, and O2 concentrations). Draft genomes of the V. parahaemolyticus isolates were determined using the Illumina sequencing technique. Comparative genomic analysis were performed to identify and validate the hypoxic tolerance-related genes. Results: The V. parahaemolyticus isolates had an oxygen concentration-dependent growth mode, and the 10% O2 condition strongly inhibited the bacterial growth, when incubated in TSB medium (pH 8.5, 3% NaCl) at 37 °C. Unexpectedly, in marked contrast to the normal 21% O2 condition, the 10% O2 treatment for 24 h significantly increased biofilm formation of V. parahaemolyticus isolates (p < 0.05). Draft genome sequences of four V. parahaemolyticus isolates of aquatic animal origins were determined (4.914–5.3530 Mb), which carried mobile genetic elements (n = 12–29). Genome-wide gene expression changes triggered by the hypoxic condition were further examined. Comparative transcriptomic analyses unveiled multiple molecular strategies employed by the bacterium to mitigate the cell damage caused by the hypoxia. Of note, the pathogenic V. parahaemolyticus ATCC17802 down-regulated and/or shut down ten metabolic pathways to reduce cell viability and maintain cell structure under the hypoxic stress. Conclusions: The results of this study fill prior gaps in the response mechanism of V. parahaemolyticus to the hypoxic condition. Different tolerance to hypoxia contributes to the persistence of pathogenic V. parahaemolyticus in the niches. [ABSTRACT FROM AUTHOR]

Objective: Oral lichen planus carries a risk for malignancy. The pathogenesis of the disease is mediated by various inflammatory mediators. Several mediators could be responsible for the oncogenic behavior in certain cases. Hypoxia-inducible factor-1a (HIF-1), and its possible correlation to Galactin-3 (Gal-3) and matrix metalloproteinase-9 (MMP-9) over expression represents an important indicator for malignant transformation. The investigation of these factors may present evidence-based information on malignant transformation of the disease. Subjects and methods: The study investigated the expression of HIF-1, Gla-3 and MMP-9 in tissue samples of OLP compared to control subjects of un-inflamed gingival overgrowth. 20 biospecimen were allocated in each group. Results: Immunohistochemical findings of OLP showed immunoreactivity for Galectin 3, HIF1a and MMP-9 by most of the epithelial cells. There was a positive correlation between HIF1α and MMP-9, r = 0.9301 (P-value < 0.00001). A positive correlation was detected between Galectin 3 and MMP-9, r = 0.7292 (P-value = 0.000264) between Galectin 3 and HIF1α, r = 0.5893 (P-value = 0.006252). Conclusion: These findings confirm the hypothesis that the adaptive pathways to hypoxia as Gal 3 and MMP-9 expressions and their HIF-1 may play a crucial role in carcinogenesis of OLP. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is characterized by cyclic normoxic and hypoxic conditions (intermittent hypoxia, IH) induced by the repeated closure of the upper-airway respiratory tract. As a pathomechanism of OSA, IH results in various comorbidities via chronic inflammation and related pathways. However, the role of other inflammatory cells, such as lymphocytes, has not been well-explored. This study aimed to examine the effects of IH on the distribution and balance of T cell subsets and other related cytokines, and mechanisms in the immune system. We modified OSA mouse model (male C57BL/6N male) using our customized chamber that controls specific sleep and oxygenic cycles. To induce hypoxia, the IH group was repeatedly exposed to 5% O2 and 21% O2 lasting for 120 s each for 7 h daily for 4 weeks. Mice were then subjected to a recovery period of 4 weeks, in which IH stimulation was ceased. T cells and related cytokines were analyzed using flow cytometry and immunohistochemistry. Compared with the control group, the IH group had significantly lower levels of CD4+CD25+Foxp3+ regulatory T cells but higher levels of Th 17, IL-4, HIF-1, and inflammatory cytokines. After the recovery period, these altered changes in the immune cells were recovered, and we found no significant difference in their levels between the control and recovery groups. This study revealed that the Th17/Treg ratio is increased by intermittent hypoxia, and this imbalance can explain immune-related diseases, including recently reported allergies, autoimmune, and even cancer diseases, arising from OSA. [ABSTRACT FROM AUTHOR]

Background: Hypoxia-activated prodrugs present new opportunities for safe and effective tumor drug resistance therapy due to their high selectivity for hypoxic cells. However, the uneven distribution of oxygen in solid tumor and insufficient hypoxia in the tumor microenvironment greatly limit its therapeutic efficacy. Results: In this paper, a novel AQ4N-Mn(II)@PDA coordination nanoplatform was designed and functionalized with GMBP1 to target drug-resistant tumor cells. Its excellent photothermal conversion efficiency could achieve local high-temperature photothermal therapy in tumors, which could not only effectively exacerbate tumor hypoxia and thus improve the efficacy of hypoxia-activated chemotherapy of AQ4N but also significantly accelerate Mn2+-mediated Fenton-like activity to enhance chemodynamic therapy. Moreover, real-time monitoring of blood oxygen saturation through photoacoustic imaging could reflect the hypoxic status of tumors during treatment. Furthermore, synergistic treatment effectively inhibited tumor growth and improved the survival rate of mice bearing orthotopic drug-resistant tumors. Conclusions: This study not only provided a new idea for PTT combined with hypoxia-activated chemotherapy and CDT for drug-resistant tumors but also explored a vital theory for real-time monitoring of hypoxia during treatment. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) and chemodynamic therapy (CDT) are promising tumor treatments mediated by reactive oxygen species (ROS), which have the advantages of being minimally invasive. However, the hypoxia of tumor microenvironment and poor target ability often reduce the therapeutic effect. Here we propose a tumor targeted nanoplatform PCN‐224@Co3O4‐HA for enhanced PDT and synergistic CDT, constructed by hyaluronate‐modified Co3O4 nanoparticles decorated metal‐organic framework PCN‐224. Co3O4 can catalyze the decomposition of highly expressed H2O2 in tumor cells to produce oxygen and alleviate the problem of hypoxia. It can also produce hydroxyl radicals according to the Fenton‐like reaction for chemical dynamic therapy, significantly improving the therapeutic effect. The cell survival experiment showed that after in vitro treatment, 4T1 and MCF‐7 cancer cells died in a large area under the anaerobic state, while the survival ability of normal cell L02 was nearly unchanged. This result effectively indicated that PCN‐224@Co3O4‐HA could effectively relieve tumor hypoxia and improve the effect of PDT and synergistic CDT. Cell uptake experiments showed that PCN‐224@Co3O4‐HA had good targeting properties and could effectively aggregate in tumor cells. In vivo experiments on mice, PCN‐224@Co3O4‐HA presented reliable biosafety performance, and can cooperate with PDT and CDT therapy to prevent the growth of tumor. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of TRPC5 on intermittent hypoxia-induced myocardial pyroptosis. Methods TRPC5 knock out (TRPC5-/-) and SD rats were each randomly divided into chronic intermittent hypoxia group (CIH group) and normoxia group (Control group) (n = 6 for each group). The myocardial fibrosis in rats was visualized by Masson staining, the levels of serum inflammatory factors were measured by ELISA and the relative expression levels of TRPC 5 and pyroptosis-related proteins were determined by Western blotting. Results Masson staining showed that the collagen volume fraction in the TRPC5-/--CIH group was higher than that in the TRPC5-/--Control group and lower than that in the WT-CIH group. The ELISA results showed that the serum levels of IL-1, IL-6, and TGF- β in the TRPC5-/--CIH group were higher than those in the TRPC5-/--Control group and lower in the WT-CIH group. Western blotting results showed that the relative expression levels of pyroptosis related proteins caspase-1, NLRP3, GSDMD, and GSDMD-N in the TRPC5-/--CIH group were higher than those in the TRPC5-/--Control group and lower than those in the WT-CIH group. Conclusion TRPC5 deficiency alleviates myocardial pyroptosis and myocardial fibrosis induced by hypoxia. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a neurodegenerative disease for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that repeated exposure to intermittent hypoxia might have short- and long-term benefits in PD. In a previous exploratory phase I trial, we demonstrated that in-clinic intermittent hypoxia exposure is safe and feasible with short-term symptomatic effects on PD symptoms. The current study aims to explore the safety, tolerability, feasibility, and net symptomatic effects of a four-week intermittent hypoxia protocol, administered at home, in individuals with PD. Methods/Design: : This is a two-armed double-blinded randomized controlled trial involving 40 individuals with mild to moderate PD. Participants will receive 45 min of normobaric intermittent hypoxia (fraction of inspired oxygen 0.16 for 5 min interspersed with 5 min normoxia), 3 times a week for 4 weeks. Co-primary endpoints include nature and total number of adverse events, and a feasibility-tolerability questionnaire. Secondary endpoints include Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II and III scores, gait tests and biomarkers indicative of hypoxic dose and neuroprotective pathway induction. Discussion: This trial builds on the previous phase I trial and aims to investigate the safety, tolerability, feasibility, and net symptomatic effects of intermittent hypoxia in individuals with PD. Additionally, the study aims to explore induction of relevant neuroprotective pathways as measured in plasma. The results of this trial could provide further insight into the potential of hypoxia-based therapy as a novel treatment approach for PD. Trial registration: ClinicalTrials.gov Identifier: NCT05948761 (registered June 20th, 2023). [ABSTRACT FROM AUTHOR]

Background: Cancer stem cells (CSCs) are a specific subpopulation of cancer cells with the ability of self‐renewal, infinite proliferation, multidifferentiation and tumorigenicity, and play critical roles in cancer progression and treatment resistance. CSCs are tightly regulated by the tumor microenvironment, such as hypoxia; however, how hypoxia regulates CSCs in non‐small cell lung cancer (NSCLC) remains unclear. Methods: The proportion of ALDHhi cells was examined using the Aldefluor assay. Tankyrase inhibitor XAV939 and siRNA were used to inhibit β‐catenin while pcDNA3‐β‐catenin (S33Y) plasmid enhanced the expression of β‐catenin. Western blot was administered for protein detection. The mRNA expression was measured by quantitative real‐time PCR. Results: We found that hypoxia led to an increase in the proportion of ALDHhi cells in lung squamous carcinoma (LUSC) H520 cells, while causing a decrease in the ALDHhi cell proportion in lung adenocarcinoma (LUAD) A549 cells. Similarly, β‐catenin expression was upregulated in H520 cells but downregulated in A549 cells upon exposure to hypoxia. Mechanically, the proportion of ALDHhi cells in both cell lines was decreased by β‐catenin inhibitor or siRNA knockdown, whereas increased after β‐catenin overexpression. Furthermore, hypoxia treatment suppressed E‐cadherin expression in H520 cells and enhanced N‐cadherin and β‐catenin expression, while this effect was completely opposite in A549 cells. Conclusion: The hypoxia‐EMT‐β‐catenin axis functions as an important regulator for the proportion of CSCs in NSCLC and could potentially be explored as therapeutic targets in the future. [ABSTRACT FROM AUTHOR]

The complex and dynamic interaction between cellular energy control and gene expression modulation is shown by the intersection between mitochondrial metabolism and epigenetics in hypoxic environments. Poor oxygen delivery to tissues, or hypoxia, is a basic physiological stressor that sets off a series of reactions in cells to adapt and endure oxygen-starved environments. Often called the "powerhouse of the cell," mitochondria are essential to cellular metabolism, especially regarding producing energy through oxidative phosphorylation. The cellular response to hypoxia entails a change in mitochondrial metabolism to improve survival, including epigenetic modifications that control gene expression without altering the underlying genome. By altering the expression of genes involved in angiogenesis, cell survival, and metabolism, these epigenetic modifications help cells adapt to hypoxia. The sophisticated interplay between mitochondrial metabolism and epigenetics in hypoxia is highlighted by several important points, which have been summarized in the current article. Deciphering the relationship between mitochondrial metabolism and epigenetics during hypoxia is essential to understanding the molecular processes that regulate cellular adaptation to reduced oxygen concentrations. [ABSTRACT FROM AUTHOR]

Background: Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment. Methods: Pregnant Sprague–Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence. Results: Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels. Conclusions: Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring. Highlights: Prenatal hypoxia increases thromboxane-mediated vasoconstrictor responses in both coronary and mesenteric arteries from the adult female and male offspring. This was more pronounced in females, and was prevented by maternal placental antioxidant treatment in pregnancy. The mechanisms for the increased thromboxane-mediated vasoconstrictor responses by prenatal hypoxia exposure were sex-specific, where females had reduced nitric oxide modulation of vasoconstriction, while males had increased thromboxane receptor expression. There are sex-specific differences on how prenatal hypoxia impairs vascular function in the adult offspring. Placenta-targeted therapies in pregnancy should be considered to improve cardiovascular outcomes in the offspring later life but should take the sex of the fetus into consideration. Plain language summary: Prenatal hypoxia, when the fetus does not receive enough oxygen, is a common problem during pregnancy that impacts the developing fetus. It is associated with an increased risk of cardiovascular disease in the offspring in adulthood. While the mechanisms are not fully understood, the blood vessel function in the offspring may be impacted by prenatal hypoxia. We hypothesize that prenatal hypoxia increases the constriction of the blood vessels in the offspring. The placenta, an essential organ for fetal development, supplies oxygen and nutrients to the fetus. In prenatal hypoxia pregnancies, the placenta does not work properly. We have been studying a placental treatment (called nMitoQ) to improve placenta function and thereby the blood vessel function of the offspring. We used a rat model of prenatal hypoxia, where pregnant rats (dams) were placed in a low oxygen environment (hypoxia) during the last trimester of pregnancy. Control rats were kept in normal oxygen conditions. The dams were treated with nMitoQ, or with saline (control). Next, we studied the blood vessels of the offspring in adulthood. We found that prenatal hypoxia increases the constriction of the blood vessels, which was prevented by treating the dams with nMitoQ. Interestingly, this impact was more severe in females compared to males, and the mechanisms were different between the sexes. This study helps in the understanding of how complicated pregnancies can impair cardiovascular health in the offspring, and in a potential development of targeted and sex-specific therapies for those offspring at high risk for future cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Evidence for the management of pregnant women with acute hypoxaemic respiratory failure (AHRF) is currently lacking. The likelihood of avoiding intubation and the risks of continuing the pregnancy under invasive ventilation remain undetermined. We report the management and outcome of pregnant women with pneumonia related to SARS-CoV-2 admitted to the ICU of tertiary maternity hospitals of the Paris area. Methods: We studied a retrospective cohort of pregnant women admitted to 15 ICUs with AHRF related to SARS-CoV-2 defined by the need for O2 ≥ 6 L/min, high-flow nasal oxygen (HFNO), non-invasive or invasive ventilation. Trajectories were assessed to determine the need for intubation and the possibility of continuing the pregnancy on invasive ventilation. Results: One hundred and seven pregnant women, 34 (IQR: 30–38) years old, at a gestational age of 27 (IQR: 25–30) weeks were included. Obesity was present in 37/107. Intubation was required in 47/107 (44%). Intubation rate according to respiratory support was 14/19 (74%) for standard O2, 17/36 (47%) for non-invasive ventilation and 16/52 (31%) for HFNO. Factors significantly associated with intubation were pulmonary co-infection: adjusted OR: 3.38 (95% CI 1.31–9.21), HFNO: 0.11 (0.02–0.41) and non-invasive ventilation: 0.20 (0.04–0.80). Forty-six (43%) women were delivered during ICU stay, 39/46 (85%) for maternal pulmonary worsening, 41/46 (89%) at a preterm stage. Fourteen non-intubated women were delivered under regional anaesthesia; 9/14 ultimately required emergency intubation. Four different trajectories were identified: 19 women were delivered within 2 days after ICU admission while not intubated (12 required prolonged intubation), 23 women were delivered within 2 days after intubation, in 11 intubated women pregnancy was continued allowing delivery after ICU discharge in 8/11, 54 women were never intubated (53 were delivered after discharge). Timing of delivery after intubation was mainly dictated by gestational age. One maternal death and one foetal death were recorded. Conclusion: In pregnant women with AHRF related to SARS-CoV-2, HFNO and non-invasive mechanical ventilation were associated with a reduced rate of intubation, while pulmonary co-infection was associated with an increased rate. Pregnancy was continued on invasive mechanical ventilation in one-third of intubated women. Study registration retrospectively registered in ClinicalTrials (NCT05193526). [ABSTRACT FROM AUTHOR]

Nitrous oxide (N2O), a potent greenhouse gas, can be generated by multiple biological and abiotic processes in diverse contexts. Accurately tracking the dominant sources of N2O has the potential to improve our understanding of N2O fluxes from soils as well as inform the diagnosis of human infections. Isotopic "Site Preference" (SP) values have been used toward this end, as bacterial and fungal nitric oxide reductases (NORs) produce N2O with different isotopic fingerprints, spanning a large range. Here, we show that flavohemoglobin (Fhp), a hitherto biogeochemically neglected yet widely distributed detoxifying bacterial NO reductase, imparts a distinct SP value onto N2O under anoxic conditions (~+10%o) that correlates with typical environmental N2O SP measurements. Using Pseudomonas aeruginosa as a model organism, we generated strains that only contained Fhp or the dissimilatory NOR, finding that in vivo N2O SP values imparted by these enzymes differ by over 10%o. Depending on the cellular physiological state, the ratio of Fhp:NOR varies significantly in wild-type cells and controls the net N2O SP biosignature: When cells grow anaerobically under denitrifying conditions, NOR dominates; when cells experience rapid, increased nitric oxide concentrations under anoxic conditions but are not growing, Fhp dominates. Other bacteria that only make Fhp generate similar N2O SP biosignatures to those measured from our P. aeruginosa Fhp-only strain. Fhp homologs in sequenced bacterial genomes currently exceed NOR homologs by nearly a factor of four. Accordingly, we suggest a different framework to guide the attribution of N2O biological sources in nature and disease. [ABSTRACT FROM AUTHOR]

Introduction: Sleep-disordered breathing (SDB) is a major comorbidity in idiopathic pulmonary fibrosis (IPF) and is associated with a poor outcome. There is a lack of knowledge regarding the impact of SDB treatment on IPF. We assessed at one year: (1) the effect of CPAP and/or nocturnal oxygen therapy on IPF regarding lung function, blood mediators, and quality of life; (2) adherence to SDB treatment and SDB changes. Methodology: This is a prospective study of consecutive newly diagnosed IPF patients initiating anti-fibrotic treatment. Lung function, polysomnography, blood tests and quality of life questionnaires were performed at inclusion and after one year. Patients were classified as obstructive sleep apnoea (OSA), central sleep apnoea (CSA), and sleep-sustained hypoxemia (SSH). SDB therapy (CPAP and/or nocturnal oxygen therapy) was initiated if needed. Results: Fifty patients were enrolled (36% had OSA, 22% CSA, and 12% SSH). CPAP was started in 54% of patients and nocturnal oxygen therapy in 16%. At one-year, polysomnography found improved parameters, though 17% of patients had to add nocturnal oxygen therapy or CPAP, while 33% presented SDB onset at this second polysomnography. CPAP compliance at one year was 6.74 h/night (SD 0.74). After one year, matrix metalloproteinase-1 decreased in OSA and CSA (p = 0.029; p = 0.027), C-reactive protein in OSA (p = 0.045), and surfactant protein D in CSA group (p = 0.074). There was no significant change in lung function. Conclusions: Treatment of SBD with CPAP and NOT can be well tolerated with a high compliance. IPF patients may exhibit SDB progression and require periodic re-assessment. Further studies to evaluate the impact of SDB treatment on lung function and serological mediators are needed. [ABSTRACT FROM AUTHOR]

Introduction: This study was undertaken to explore the potential therapeutic effects of Tongyang Huoxue Granules (TYHX) on sinoatrial node (SAN) dysfunction, a cardiac disorder characterized by impaired impulse generation or conduction. The research question addressed whether TYHX could positively influence SAN ion channel function, specifically targeting the sodium-calcium exchanger (INCX) and L-type calcium channel (ICaL) of the SAN. Methods: Sinoatrial node cells (SANCs) were isolated and cultured from neonatal Japanese big-eared white rabbits within 24 h of birth. The study encompassed five groups: Control, H/R (hypoxia/reoxygenation), H/R+100 μg/mL TYHX, H/R+200 μg/mL TYHX, and H/R+400 μg/mL TYHX. The H/R model, simulating hypoxia/reoxygenation stress, was induced within 5 days of culture. Whole-cell patch clamp technique was employed to record currents following a 3-min perfusion and stabilization period with TYHX. Results: TYHX administration demonstrated improvements in the ignition phase of impaired SANCs. The half-maximal effective dose of TYHX, as determined by SANC beating frequency, was found to be 323.63 μg/mL. Inward current density of INCX increased in response to TYHX (200 and 400 μg/mL), while TYHX enhanced ICaL current density in H/R SANCs, with 400 μg/mL exhibiting greater efficacy. Additionally, TYHX regulated the gating mechanisms of ICaL by right-shifting the steady-state inactivation curve and accelerating recovery from inactivation. Notably, TYHX increased the activation time constant under 200 and 400 μg/mL, prolonged the fast inactivation time constant t1 with 400 μg/mL, and extended the slow inactivation time constant t2 with 100 and 400 μg/mL. Discussion and conclusion: The findings suggest that TYHX may hold promise as a therapeutic intervention for sinus node dysfunction, offering potential avenues for drug development aimed at safeguarding SAN function. [ABSTRACT FROM AUTHOR]

During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α plays dual roles in airway epithelial cells during Mucorales infection. We observed an increase in HIF1α protein accumulation and increased expression of many known HIF1α-responsive genes during in vitro infection, indicating that HIF1α signaling is activated by Mucorales infection. Inhibition of HIF1α signaling led to a substantial decrease in the ability of R. delemar to invade cultured airway epithelial cells. Transcriptome analysis revealed that R. delemar infection induces the expression of many pro-inflammatory genes whose expression was significantly reduced by HIF1α inhibition. Importantly, pharmacological inhibition of HIF1α increased survival in a mouse model of pulmonary mucormycosis without reducing fungal burden. These results suggest that HIF1α plays two opposing roles during mucormycosis: one that facilitates the ability of Mucorales to invade the host cells and one that facilitates the ability of the host to mount an innate immune response. Mucorales fungi are the cause of deadly pulmonary infections. Here, Kavaliauskas et al show that fungal spores activate hypoxia-inducible factor 1-alpha signalling to promote invasion into airway epithelial cells. [ABSTRACT FROM AUTHOR]

Hypoxia can cause a variety of diseases, including ischemic stroke and neurodegenerative diseases. Within a certain range of partial pressure of oxygen, cells can respond to changes in oxygen. Changes in oxygen concentration beyond a threshold will cause damage or even necrosis of tissues and organs, especially for the central nervous system. Therefore, it is very important to find appropriate measures to alleviate damage. MiRNAs can participate in the regulation of hypoxic responses in various types of cells. MiRNAs are involved in regulating hypoxic responses in many types of tissues by activating the hypoxia-inducible factor (HIF) to affect angiogenesis, glycolysis and other biological processes. By analyzing differentially expressed miRNAs in hypoxia and hypoxia-related studies, as well as the HT22 neuronal cell line under hypoxic stress, we found that the expression of miR-18a was changed in these models. MiR-18a could regulate glucose metabolism in HT22 cells under hypoxic stress by directly regulating the 3'UTR of the Hif1a gene. As a small molecule, miRNAs are easy to be designed into small nucleic acid drugs, so this study can provide a theoretical basis for the research and treatment of nervous system diseases caused by hypoxia. [ABSTRACT FROM AUTHOR]

The review discusses the potential relationship between hypoxia resistance and longevity, the influence of carbon dioxide on the mechanisms of aging of the mammalian organism, and intermittent hypercapnic–hypoxic effects on the signaling pathways of aging mechanisms. In the article, we focused on the potential mechanisms of the gero-protective efficacy of carbon dioxide when combined with hypoxia. The review summarizes the possible influence of intermittent hypoxia and hypercapnia on aging processes in the nervous system. We considered the perspective variants of the application of hypercapnic–hypoxic influences for achieving active longevity and the prospects for the possibilities of developing hypercapnic–hypoxic training methods. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal/stem cells (MSCs) are a heterogeneous population of multipotent cells that can be obtained from various tissues, such as dental pulp, adipose tissue, bone marrow and placenta. MSCs have gained importance in the field of regenerative medicine because of their promising role in cell therapy and their regulatory abilities in tissue repair and regeneration. However, a better characterization of these cells and their products is necessary to further potentiate their clinical application. In this study, we used unbiased high-resolution mass spectrometry-based proteomic analysis to investigate the impact of distinct priming strategies, such as hypoxia and IFN-γ treatment, on the composition and therapeutic functionality of the secretome produced by MSCs derived from the amniotic membrane of the human placenta (hAMSCs). Our investigation revealed that both types of priming improved the therapeutic efficacy of hAMSCs, and these improvements were related to the secretion of functional factors present in the conditioned medium (CM) and exosomes (EXOs), which play crucial roles in mediating the paracrine effects of MSCs. In particular, hypoxia was able to induce a pro-angiogenic, innate immune responseactivating, and tissue-regenerative hAMSC phenotype, as highlighted by the elevated production of regulatory factors such as VEGFA, PDGFRB, ANGPTL4, ENG, GRO-γ, IL8, and GRO-α. IFN-γ priming, instead, led to an immunosuppressive profile in hAMSCs, as indicated by increased levels of TGFB1, ANXA1, THBS1, HOMER2, GRN, TOLLIP and MCP-1. Functional assays validated the increased angiogenic properties of hypoxic hAMSCs and the enhanced immunosuppressive activity of IFN-γ-treated hAMSCs. This study extends beyond the direct priming effects on hAMSCs, demonstrating that hypoxia and IFN-γ can influence the functional characteristics of hAMSC-derived secretomes, which, in turn, orchestrate the production of functional factors by peripheral blood cells. This research provides valuable insights into the optimization of MSC-based therapies by systematically assessing and comparing the priming type-specific functional features of hAMSCs. These findings highlight new strategies for enhancing the therapeutic efficacy of MSCs, particularly in the context of multifactorial diseases, paving the way for the use of hAMSC-derived products in clinical practice. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is characterized by acute inflammatory injury to the lungs, alterations in vascular permeability, loss of aerated tissue, bilateral infiltrates, and refractory hypoxemia. ARDS is considered a heterogeneous syndrome, which complicates the search for effective therapies. The goal of this review is to provide an update on the pharmacological management of ARDS. The difficulties in finding effective pharmacological therapies are mainly due to the challenges in designing clinical trials for this unique, varied population of critically ill patients. Recently, some trials have been retrospectively analyzed by dividing patients into hyper-inflammatory and hypo-inflammatory sub-phenotypes. This approach has led to significant outcome improvements with some pharmacological treatments that previously failed to demonstrate efficacy, which suggests that a more precise selection of ARDS patients for clinical trials could be the key to identifying effective pharmacotherapies. This review is provided after searching the main studies on this topics on the PubMed and clinicaltrials.gov databases. The future of ARDS therapy lies in precision medicine, innovative approaches to drug delivery, immunomodulation, cell-based therapies, and robust clinical trial designs. These should lead to more effective and personalized treatments for patients with ARDS. [ABSTRACT FROM AUTHOR]

Hypoxia poses a significant challenge to the effectiveness of radiotherapy in head and neck squamous cell carcinoma (HNSCC) patients, and it is imperative to discover novel approaches to overcome this. In this study, we investigated the underlying mechanisms contributing to x‐ray radioresistance in HPV‐negative HNSCC cells under mild hypoxic conditions (1% oxygen) and explored the potential for autophagy modulation as a promising therapeutic strategy. Our findings show that HNSCC cells exposed to mild hypoxic conditions exhibit increased radioresistance, which is largely mediated by the hypoxia‐inducible factor (HIF) pathway. We demonstrate that siRNA knockdown of HIF‐1α and HIF‐1β leads to increased radiosensitivity in HNSCC cells under hypoxia. Hypoxia‐induced radioresistance was not attributed to differences in DNA double strand break repair kinetics, as these remain largely unchanged under normoxic and hypoxic conditions. Rather, we identify autophagy as a critical protective mechanism in HNSCC cells following irradiation under mild hypoxia conditions. Targeting key autophagy genes, such as BECLIN1 and BNIP3/3L, using siRNA sensitizes these cells to irradiation. Whilst autophagy's role in hypoxic radioresistance remains controversial, this study highlights the importance of autophagy modulation as a potential therapeutic approach to enhance the effectiveness of radiotherapy in HNSCC. [ABSTRACT FROM AUTHOR]

Despite long-standing interest in the biogeochemistry of the Santa Barbara Basin (SBB), there are no direct rate measurements of different nitrogen transformation processes. We investigated benthic nitrogen cycling using in situ incubations with 15 NO 3- addition and quantified the rates of total nitrate (NO 3-) uptake, denitrification, anaerobic ammonia oxidation (anammox), N 2 O production, and dissimilatory nitrate reduction to ammonia (DNRA). Denitrification was the dominant NO 3- reduction process, while anammox contributed 0 %–27 % to total NO 3- reduction. DNRA accounted for less than half of NO 3- reduction except at the deepest station at the center of the SBB where NO 3- concentration was lowest. NO 3- availability and sediment total organic carbon content appeared to be two key controls on the relative importance of DNRA. The increasing importance of fixed N retention via DNRA relative to fixed N loss as NO 3- deficit intensifies suggests a negative feedback loop that potentially contributes to stabilizing the fixed N budget in the SBB. Nitrous oxide (N 2 O) production as a fraction of total NO 3- reduction ranged from 0.2 % to 1.5 %, which was higher than previous reports from nearby borderland basins. A large fraction of NO 3- uptake was unaccounted for by NO 3- reduction processes, suggesting that intracellular storage may play an important role. Our results indicate that the SBB acts as a strong sink for fixed nitrogen and potentially a net source of N 2 O to the water column. [ABSTRACT FROM AUTHOR]

The decision to intubate a patient with acute hypoxemic respiratory failure who is not in apparent respiratory distress is one of the most difficult clinical decisions faced by intensivists. A conservative approach exposes patients to the dangers of hypoxemia, while a liberal approach exposes them to the dangers of inserting an endotracheal tube and invasive mechanical ventilation. To assist intensivists in this decision, investigators have used various thresholds of peripheral or arterial oxygen saturation, partial pressure of oxygen, partial pressure of oxygen-to-fraction of inspired oxygen ratio, and arterial oxygen content. In this review we will discuss how each of these oxygenation indices provides inaccurate information about the volume of oxygen transported in the arterial blood (convective oxygen delivery) or the pressure gradient driving oxygen from the capillaries to the cells (diffusive oxygen delivery). The decision to intubate hypoxemic patients is further complicated by our nescience of the critical point below which global and cerebral oxygen supply become delivery-dependent in the individual patient. Accordingly, intubation requires a nuanced understanding of oxygenation indexes. In this review, we will also discuss our approach to intubation based on clinical observations and physiologic principles. Specifically, we consider intubation when hypoxemic patients, who are neither in apparent respiratory distress nor in shock, become cognitively impaired suggesting emergent cerebral hypoxia. When deciding to intubate, we also consider additional factors including estimates of cardiac function, peripheral perfusion, arterial oxygen content and its determinants. It is not possible, however, to pick an oxygenation breakpoint below which the benefits of mechanical ventilation decidedly outweigh its hazards. It is futile to imagine that decision making about instituting mechanical ventilation in an individual patient can be condensed into an algorithm with absolute numbers at each nodal point. In sum, an algorithm cannot replace the presence of a physician well skilled in the art of clinical evaluation who has a deep understanding of pathophysiologic principles. [ABSTRACT FROM AUTHOR]

We investigated the effect of tactile guided slow deep breathing compared with that of spontaneous breathing on blood oxygen saturation (SpO2), alertness, and hypoxia symptoms during acute hypobaric hypoxia. We also evaluated the usability of this tactile breathing guidance. Twelve male military pilots were exposed to a simulated altitude of 4,572 m (15,000 ft) in a repeated measures study while breathing spontaneously and during tactile guided slow deep breathing. Under both breathing conditions, measurements were performed at rest and during the performance of a cognitive task. The Stanford Sleepiness Scale was used to rate alertness, and hypoxia symptoms were reported using a list of general hypoxia symptoms. Usability was evaluated in a questionnaire. Tactile guidance of slow deep breathing significantly increased (p <.001) the SpO2 – 88% (95% confidence interval (CI) [84%, 91%]) at rest and 85% (95% CI [81%, 88%]) during the cognitive task – compared with spontaneous breathing – 78% (95% CI [75%, 81%]) at rest and 78% (95% CI [76%, 80%]) during the cognitive task. This increase in SpO2 had no effect on the level of alertness and number of hypoxia symptoms. Pilots were positive about the intensity and sensation of the vibration signal, but had difficulty following the vibration pattern during the cognitive task. Pre-training may improve slow deep breathing technique during performance of cognitive tasks. [ABSTRACT FROM AUTHOR]