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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]

Why you should read this article: • To recognise the importance of speaking up in emergency care settings to enhance patient safety • To be aware of the barriers that can prevent nurses from speaking up • To enhance your knowledge of structured assessment and communication frameworks that can support nurses to speak up. Nurses’ competence and confidence in raising concerns with senior clinicians is integral to patient safety and the quality of patient care. If nurses do not speak up when needed it can contribute to incidences of failure to rescue. There are many barriers to nurses speaking up in busy emergency departments and complex major trauma patient cases. Assessment and communication tools such as the SBAR (situation, background, assessment, recommendation) approach and communication techniques such as graded assertiveness can help to overcome some of these barriers. This article uses a case study to discuss how nurses can respectfully but efficiently escalate their concerns to the trauma team leader. It describes barriers to nurses speaking up and tools that can support nurses to speak up, with a focus on graded assertiveness. [ABSTRACT FROM AUTHOR]

Most currently available wearable devices to noninvasively detect hypoxia use the spatially resolved spectroscopy (SRS) method to calculate cerebral tissue oxygen saturation (StO2). This study applies the single source—detector separation (SSDS) algorithm to calculate StO2. Near-infrared spectroscopy (NIRS) data were collected from 26 healthy adult volunteers during a breath-holding task using a wearable NIRS device, which included two source—detector separations (SDSs). These data were used to derive oxyhemoglobin (HbO) change and StO2. In the group analysis, both HbO change and StO2 exhibited significant change during a breath-holding task. Specifically, they initially decreased to minimums at around 10 s and then steadily increased to maximums, which were significantly greater than baseline levels, at 25–30 s (p-HbO < 0.001 and p-StO2 < 0.05). However, at an individual level, the SRS method failed to detect changes in cerebral StO2 in response to a short breath-holding task. Furthermore, the SSDS algorithm is more robust than the SRS method in quantifying change in cerebral StO2 in response to a breath-holding task. In conclusion, these findings have demonstrated the potential use of the SSDS algorithm in developing a miniaturized wearable biosensor to monitor cerebral StO2 and detect cerebral hypoxia. [ABSTRACT FROM AUTHOR]

The levels and potential role of prolactin (PRL) in the brain under conditions of acute systemic hypoxia were examined, focusing on the accumulation of PRL in cerebrospinal fluid (CSF) and its effects on neuronal activity and injury. The amount of PRL in the brain was investigated using brain tissues from forensic autopsy cases. We counted the number of neurites that formed in human primary neurons (HNs) after the addition of PRL. Furthermore, HNs supplemented with PRL or triiodothyronine (T3) were exposed to hypoxic conditions, and the dead cells were counted. The results showed correlations between brain PRL and CSF PRL levels. Additionally, PRL accumulation in the brain was observed in cases of asphyxia. In vitro experimental findings indicated increased neurite formation in the HNs treated with PRL. Moreover, both PRL and T3 demonstrated neuroprotective effects against hypoxia-induced neuronal cell death, with PRL showing stronger neuroprotective potential than T3. These results suggest that PRL accumulates in the brain during hypoxia, potentially influences neuronal activity, and exhibits neuroprotective properties against hypoxia-induced neuronal injury. [ABSTRACT FROM AUTHOR]

Background: While severe hypoxia is known to contribute to neurotoxicity and lead to abnormal behavior, mild hypoxia may have beneficial effects mediated through endogenous adaptive responses. Objectives: The present study aimed to investigate the effects of mild hypoxia postconditioning and long-term neurobehavioral ability rehabilitation after hypoxic-ischemic brain damage (HIBD). Methods: Seven-day-old rats underwent left carotid ligation followed by 2 hours of hypoxia stress. Rats received different protocols of mild hypoxia postconditioning for 5 days and underwent neurobehavioral testing during the last week of the study. Hypoxia-inducible factor1 alpha (HIF-1a) expression was assessed, and neurobehavioral ability assays were performed. Results: Compared with the HIBD group, rats postconditioning with mild hypoxia showed increased HIF-1a expression, and their brain functions were better in neurobehavioral analyses. The rehabilitation of brain functions may be associated with high HIF-1a expression and better behavioral performance. Conclusions: Our findings indicate that mild hypoxia postconditioning improves neurobehavioral ability, and HIF-1a may be a potential mediator of the observed effects. Our findings suggest that there may be clinical implications for treating infants with HIBD. [ABSTRACT FROM AUTHOR]

Several sleep-related breathing disorders provoke repeated hypoxia stresses, which potentially lead to neurological diseases, such as cognitive impairment. Nevertheless, consequences of repeated intermittent hypoxia on the blood-brain barrier (BBB) are less recognized. This study compared two methods of intermittent hypoxia induction on the cerebral endothelium of the BBB: one using hydralazine and the other using a hypoxia chamber. These cycles were performed on an endothelial cell and astrocyte coculture model. Na-Fl permeability, tight junction protein, and ABC transporters (P-gp and MRP-1) content were evaluated with or without HIF-1 inhibitors YC-1. Our results demonstrated that hydralazine as well as intermittent physical hypoxia progressively altered BBB integrity, as shown by an increase in Na-Fl permeability. This alteration was accompanied by a decrease in concentration of tight junction proteins ZO-1 and claudin-5. In turn, microvascular endothelial cells up-regulated the expression of P-gp and MRP-1. An alteration was also found under hydralazine after the third cycle. On the other hand, the third intermittent hypoxia exposure showed a preservation of BBB characteristics. Furthermore, inhibition of HIF-1α with YC-1 prevented BBB dysfunction after hydralazine treatment. In the case of physical intermittent hypoxia, we observed an incomplete reversion suggesting that other biological mechanisms may be involved in BBB dysfunction. In conclusion, intermittent hypoxia led to an alteration of the BBB model with an adaptation observed after the third cycle. [ABSTRACT FROM AUTHOR]

Background: Bradycardia frequently occurs in heart-transplanted patients, mainly as a temporally restricted manifestation early after transplantation and often without symptoms. A high-degree atrioventricular block is mostly symptomatic through cerebral hypoxia induced through cerebral hypoperfusion. Only a few published cases show this specific electroencephalography result in this context. The purpose of this case is to bring attention to atypical manifestations of typical cardiac complications after heart transplantation and the importance of perseverance in the diagnostic. Case presentation: A Central European man in his 50s with history of heart transplantation 31 years previously was admitted to the internal medicine ward for short-lived recurrent episodes of generalized weakness with multiple falls but without loss of consciousness. During routine electroencephalography, the patient perceived this recurrent sensation. This episode coincided with a transient third-degree atrioventricular block followed 8–10 seconds later by a generalized slowing of the electroencephalography, reflecting cerebral hypoxia due to cerebral hypoperfusion. Holter monitoring confirmed the diagnosis. A pacemaker was implanted, consequently resolving the episodes. Conclusion: This case report illustrates the pathophysiological central hypoxemic origin of episodes of generalized weakness caused by a high-degree atrioventricular block in a patient surviving 29 years after heart transplant. It highlights the benefit of electroencephalography as a diagnostic tool in well-selected patients. [ABSTRACT FROM AUTHOR]

Trauma brain injury is a heterogeneous and dynamic entity characterized, whatever its etiology, by a decrease in cerebral perfusion the first hours after the impact. Brain injury due to hypoxia can occur after trauma, so monitoring brain hypoxia, metabolic dysfunction, intracranial hypertension and seizure activity must be detected early to prevent brain sequelae. Neuromonitoring will detect those anomalies that could compromise the adequate oxygen supply and substrates of cerebral metabolism. Despite cerebral oximetry monitoring has increased in recent years, unfortunately very limited in our country, neuromonitoring is often based on intracranial pressure and cerebral perfusion pressure, insufficient to measure cerebral oxygenation. The objective of this review is to integrate the pathophysiology of trauma brain injury with the different neuromonitoring techniques to provide an updated and more individualized management that improves the prognosis of neurocritical patients. [ABSTRACT FROM AUTHOR]

Background: Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, cannabinoid CB2 and serotonin 5HT1A receptors included. These two receptors may interact to form heteromers (CB2–5HT1A-Hets) that are also a target of CBD. Aims: We aimed to assess whether the expression and function of CB2–5HT1A-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen-deprived neurons. Methods: We developed a quantitation of signal transduction events in a heterologous system and in glucose/oxygen-deprived neurons. The expression of receptors was assessed by immuno-cyto and -histochemistry and, also, by using the only existing technique to visualize CB2–5HT1A-Hets fixed cultured cells and tissue sections (in situ proximity ligation PLA assay). Results: CBD and cannabigerol, which were used for comparative purposes, affected the structure of the heteromer, but in a qualitatively different way; CBD but not CBG increased the affinity of the CB2 and 5HT1A receptor–receptor interaction. Both cannabinoids regulated the effects of CB2 and 5HT1A receptor agonists. CBD was able to revert the upregulation of heteromers occurring when neurons were deprived of oxygen and glucose. CBD significantly reduced the increased expression of the CB2–5HT1A-Het in glucose/oxygen-deprived neurons. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of CB2–5HT1A-Hets. Conclusions: Benefits of CBD in the hypoxia of the neonate are mediated by acting on CB2–5HT1A-Hets and by reducing the aberrant expression of the receptor–receptor complex in hypoxic-ischemic conditions. These results reinforce the potential of CBD for the therapy of the hypoxia of the neonate. [ABSTRACT FROM AUTHOR]

Introduction: Acute high‐altitude hypoxia exposure causes multiple adverse neurological consequences. However, the exact mechanisms are still unclear, and there is no targeted treatment with few side effects. Excessive cerebral formaldehyde (FA) impairs numerous functions, and can be eliminated by nano‐packed coenzyme Q10 (CoQ10). Aims: In this study, we aimed to investigate whether cerebral FA was accumulated after hypobaric hypoxia exposure, and further explored the preventative effect of CoQ10 through FA elimination. Results: Accumulated cerebral FA was found in C57BL/6 mice after acute high‐altitude hypoxia exposure, which resulted in FA metabolic disturbance with the elevation of semicarbazide‐sensitive amine oxidase, and declination of aldehyde dehydrogenase‐2. Excessive FA was also found to induce neuronal ferroptosis in vivo. Excitingly, administration with CoQ10 for 3 days before acute hypobaric hypoxia reduced cerebral FA accumulation, alleviated subsequent neuronal ferroptosis, and preserved neurological functions. Conclusion: Cerebral FA accumulation mediates neurological deficits under acute hypobaric hypoxia, and CoQ10 supplementation may be a promising preventative strategy for visitors and sojourners at plateau. [ABSTRACT FROM AUTHOR]

Previous reports have indicated that natural muscone has neuroprotective effects against cerebral hypoxia injury; however, little is known in regards to its pharmacological mechanism. In this study, we tried to evaluate the neuroprotective effects and mechanisms of muscone against cerebral hypoxia injury using an in vitro model. The cerebral hypoxia injury cell model was produced by hypoxia/reoxygenation (H/R). The cell viability and apoptosis were measured using the cell counting Kit-8 and the Annexin V-FITC/PI Apoptosis Detection kit, respectively. To screen microRNAs regulated by muscone, we analyzed the gene expression datasets of GSE84216 retrieved from gene expression omnibus (GEO). Here, it was demonstrated that muscone treatment significantly alleviated the cell apoptosis, oxidative stress and inflammation in H/R-exposed neurons. Subsequently, through analyzing GSE84216 from the GEO database, miR-142-5p was markedly upregulated by treatment of muscone in this cell model of cerebral hypoxia injury. Further experiments revealed that downregulation of miR-142-5p eliminated the neuroprotective effects of muscone against H/R induced neuronal injury. Additionally, high mobility group box 1 (HMGB1), an important inflammatory factor, was identified as a direct target of miR-142-5p in neurons. Meanwhile, we further demonstrated that muscone could reduce the expression of HMGB1 by upregulating miR-142-5p expression, which subsequently resulted in the inactivation of TLR4/NF-B pathway, finally leading to the improvement of cell injury in H/Rexposed neurons. Overall, we demonstrate for the first time that muscone treatment alleviates cerebral hypoxia injury in in vitro experiments through blocking activation of the TLR4/NF-B signaling pathway by targeting HMGB1, suggesting that muscone may serve as a potential therapeutic drug for treating cerebral hypoxia injury. [ABSTRACT FROM AUTHOR]

KAT Gcn5 and DUB Ubp8 are required for respiration and mitochondria functions in budding yeast, and in this study we show that loss of respiratory activity is acquired over time. Interestingly, we show that absence of Ubp8 allows cells to grow in hypoxic conditions with altered mitophagy. Comparatively, the aggressive glioblastoma (GBM) multiforme tumor shows survival mechanisms able to overcome hypoxia in the brain. Starting from yeast and our findings on the role of Ubp8 in hypoxia, we extended our analysis to the human ortholog and signature cancer gene Usp22 in glioblastoma tumor specimens. Here we demonstrate that Usp22 is localized and overexpressed in the pseudo-palisade tissue around the necrotic area of the tumor. In addition, Usp22 colocalizes with the mitophagy marker Parkin, indicating a link with mitochondria function in GBM. Collectively, this evidence suggests that altered expression of Usp22 might provide a way for tumor cells to survive in hypoxic conditions, allowing the escape of cells from the necrotic area toward vascularized tissues. Collectively, our experimental data suggest a model for a possible mechanism of uncontrolled proliferation and invasion in glioblastoma. [ABSTRACT FROM AUTHOR]

Cistanche deserticola is a kind of parasitic plant living in the roots of desert trees. It is a rare Chinese medicine, which has the effect of tonifying kidney Yang, benefiting essence and blood and moistening the intestinal tract. Cistache deserticola phenylethanoid glycoside (PGS), an active component found in Cistanche deserticola Ma, have potential kidney tonifying, intellectual enhancing, and neuroprotective effects. Cistanche total glycoside capsule has been marketed to treat vascular dementia disease. To identify the potential renal, intellectual enhancing and neuroprotective effects of PGS and explore the exact targets and mechanisms of PGS. This study systematically investigated the four types of pathways leading to ferroptosis through transcriptome, metabolome, ultrastructure and molecular biology techniques and explored the molecular mechanism by which multiple PGS targets and pathways synergistically exert neuroprotective effects on hypoxia. PGS alleviated learning and memory dysfunction and pathological injury in mice exposed to hypobaric hypoxia by attenuating hypobaric hypoxia-induced hippocampal histopathological damage, impairing blood‒brain barrier integrity, increasing oxidative stress levels, and increasing the expression of cognitive proteins. PGS reduced the formation of lipid peroxides and improved ferroptosis by upregulating the GPX-4/SCL7A311 axis and downregulating the ACSL4/LPCAT3/LOX axis. PGS also reduced ferroptosis by facilitating cellular Fe2+ efflux and regulating mitochondrial Fe2+ transport and effectively antagonized cell ferroptosis induced by erastin (a ferroptosis inducer). This study demonstrated the mechanism by which PGS prevents hypobaric hypoxic nerve injury through four types of ferroptosis pathways, achieved neuroprotective effects and alleviated learning and memory dysfunction in hypobaric hypoxia mice. This study provides a theoretical basis for the development and application of PGS. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Moderate hypobaric hypoxia induces cerebral ischemic tolerance. We investigated the optimal method for applying hypobaric hypoxia preconditioning at 5,000 m to ischemic brain tissue and combined it with proteomics to determine the mechanisms underlying this effect. Methods: Male SD rats were randomly grouped as S (sham, n = 20), M (middle cerebral artery occlusion [MCAO], n = 28), H2M (intermittent hypobaric hypoxia preconditioned MCAO group, 2 h/day, 10 days, n = 20), H6M (intermittent hypobaric hypoxia preconditioned MCAO group, 6 h/day, 10 days, n = 28), and HpM (persistent hypobaric hypoxia preconditioned MCAO group, 10 days, n = 28). The permanent MCAO model was established based on the Zea Longa method. Infarction was assessed with the modified neurological severity score (mNSS) and 2,3,5-triphenyl tetrazolium chloride staining. The total protein expression of the neuron-specific nuclear protein (NeuN), cysteinyl aspartate specific proteinase 3 (caspase-3), cleaved-caspase-3, and interleukin 6 (IL-6) was determined using western blotting. We assessed the peri-infarct cortex's ultrastructural changes. A label-free proteomic study and western blot verification were performed on the most effective preconditioned group. Results: The H6M group showed a lower infarct volume (p = 0.0005), lower mNSS score (p = 0.0009) than the M group. The H2M showed a lower level of IL-6 (p = 0.0213) than the M group. The caspase-3 level decreased in the H2M (p = 0.0002), H6M (p = 0.0025), and HpM groups (p = 0.0054) compared with that in the M group. Cleaved-caspase-3 expression decreased in the H2M (p = 0.0011), H6M (p < 0.0001), and HpM groups (p < 0.0001) compared with that in the M group. The neurons' ultrastructure and the blood-brain barrier in the peri-infarct tissue improved in the H2M and H6M groups. Immunofluorescence revealed increased NeuN-positive cells in the peri-infarct tissue in the H6M group (p = 0.0003, H6M vs. M). Protein expression of Chmp1a, Arpc5, and Hspa2 factors related to endocytosis were upregulated in the H6M compared with those of the M group (p < 0.05 for all) on western blot verification of label-free proteomics. Conclusions: Intermittent hypobaric hypoxia preconditioning exerts a neuroprotective effect in a rat stroke model. Persistent hypobaric hypoxia stimulation exhibited no significant neuroprotective effect. Intermittent hypoxic preconditioning for 6 h/day for 10 days upregulates key proteins in clathrin-dependent endocytosis of neurons in the cortex. [ABSTRACT FROM AUTHOR]

Background: In patients with idiopathic pulmonary fibrosis (IPF) with isolated exertional desaturation, there are limited data regarding the effectiveness of oxygen supplementation during exercise training; the underlying mechanisms that contribute to these responses are unknown. Objectives: To examine in these IPF patients the effects of oxygen supplementation during submaximal exercise (vs. medical air) on cerebral/skeletal muscle oxygenation and systemic hemodynamics. Methods: In this randomized, cross-over, placebo-controlled trial, IPF patients (n = 13; 63.4 ± 9.6 years) without resting hypoxemia but a significant desaturation during maximal cardiopulmonary exercise testing underwent 2 steady-state exercise trials (65% peak-work-load), breathing either oxygen-enriched or medical air. Cerebral/skeletal muscle oxygenation (near-infrared spectroscopy) and beat-by-beat hemodynamics (photoplethysmography) were monitored. Results: In the air protocol, from the initial minutes of submaximal exercise, patients exhibited a marked decline in cerebral oxygenated hemoglobin (O2Hb) and an abrupt rise in deoxygenated hemoglobin (HHb). Oxygen supplementation alleviated desaturation, lessened dyspnea, and prolonged exercise duration (p < 0.01). Oxygen supplementation during exercise (i) attenuated cerebral deoxygenation (cerebral-HHb: 0.7 ± 1.9 vs. 2.5 ± 1.5 μmol/L, O2 and air protocol; p = 0.009) and prevented cerebral-Hbdifference decline (2.1 ± 2.7 vs. −1.7 ± 2.0 μmol/L; p = 0.001), (ii) lessened the decline in muscle O2-saturation index, and (iii) at isotime exercise, it resulted in lower muscle-HHb (p = 0.05) and less leg fatigue (p < 0.05). No differences between protocols were observed in exercise cardiac output and vascular resistance. Conclusions: IPF patients with isolated exertional hypoxemia exhibit an inability to increase/maintain cerebral oxygenation during submaximal exercise. Correcting desaturation with O2 supplementation prevented the decline in brain oxygenation, improved muscle oxygenation, and lessened dyspnea, suggesting an efficacy of acute oxygen supplementation during exercise training in protecting brain hypoxia in these IPF patients. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Does the ventilatory response to moderate acute hypoxia increase cerebral perfusion independently of changes in arterial oxygen tension in humans?What is the main finding and its importance?The ventilatory response does not increase middle cerebral artery mean blood velocity during moderate isocapnic acute hypoxia beyond that elicited by reduced oxygen saturation. Hypoxia induces ventilatory, cardiovascular and cerebrovascular adjustments to defend against reductions in systemic oxygen delivery. We aimed to determine whether the ventilatory response to moderate acute hypoxia increases cerebral perfusion independently of changes in arterial oxygenation. Eleven young healthy individuals were exposed to four 15 min experimental conditions: (1) normoxia (partial pressure of end‐tidal oxygen, PETO2 = 100 mmHg), (2) hypoxia (PETO2 = 50 mmHg), (3) normoxia with breathing volitionally matched to levels observed during hypoxia (hyperpnoea; PETO2 = 100 mmHg) and (4) hypoxia (PETO2 = 50 mmHg) with respiratory frequency and tidal volume volitionally matched to levels observed during normoxia (i.e., restricted breathing (RB)). Isocapnia was maintained in all conditions. Middle cerebral artery mean blood velocity (MCA Vmean), assessed by transcranial Doppler ultrasound, was increased during hypoxia (58 ± 12 cm/s, P = 0.04) and hypoxia + RB (61 ± 14 cm/s, P < 0.001) compared to normoxia (55 ± 11 cm/s), while it was unchanged during hyperpnoea (52 ± 13 cm/s, P = 0.08). MCA Vmean was not different between hypoxia and hypoxia + RB (P > 0.05). These findings suggest that the hypoxic ventilatory response does not increase cerebral perfusion, indexed using MCA Vmean, during moderate isocapnic acute hypoxia beyond that elicited by reduced oxygen saturation. [ABSTRACT FROM AUTHOR]

Introduction: Brain hypoxia has important role to the onset and progression of sporadic form of Alzheimer disease via expression of hypoxia‐inducible factor‐1 (HIF‐1). Crocin by anti‐amyloidogenic property inhibits β‐amyloid formation. However, the molecular mechanism associated with anti‐amyloidogenic activity of crocin is unknown. So, the present study was designed to investigate the effect of crocin on cognitive behavior and expression of HIF‐1α and β‐secretase (BACE1) genes in the brain of neonate rats following different intensities of hypoxia during pregnancy. Material and methods: Pregnant female rats were divided into six groups including sham, control crocin treated (CC), hypoxia with three different intensities (H1–H3), and most intense of hypoxic group treated with crocin (H3C) (30 mg/kg; i.p) at P14. Hypoxia induced on the 20th day of pregnancy. Animals in sham and CC were put in hypoxia chamber at the same time of hypoxia group without any hypoxia induction. Morris water maze (MWM) and qRT‐PCR were used to evaluate the cognitive behavior and mRNA levels of BACE1 and HIF‐1α genes in the brain tissues. Results: Animal under 7% O2 + 93% N2 condition for 3 hr showed the highest cognitive behavior impairment and upregulated HIF‐1α and BACE1 mRNA in brains of offspring (p <.001). Crocin treatment improved memory impairment and attenuated the gene expression of HIF‐1α and BACE1 in the brains of neonate rat. Conclusions: It was concluded that crocin has beneficial effects on the brain of neonate rats under gestational hypoxia by improvement of memory impairment and molecular alteration related to hypoxia. [ABSTRACT FROM AUTHOR]

Brain tissue oxygen tension (PbtO2)-guided care, a therapeutic strategy to treat or prevent cerebral hypoxia through modifying determinants of cerebral oxygen delivery, including arterial oxygen tension (PaO2), end-tidal carbon dioxide (ETCO2), and mean arterial pressure (MAP), has recently been introduced. Studies have reported that cerebral hypoxia occurs after cardiac arrest in the absence of hypoxemia or hypotension. To obtain preliminary information on the degree to which PbtO2 is responsive to changes in the common target variables for PbtO2-guided care in conditions without hypoxemia or hypotension, we investigated the relationships between the common target variables for PbtO2-guided care and PbtO2 using data from an experimental study in which the animals did not experience hypoxemia or hypotension after resuscitation. We retrospectively analyzed 170 sets of MAP, ETCO2, PaO2, PbtO2, and cerebral microcirculation parameters obtained during the 60-min post-resuscitation period in 10 pigs resuscitated from ventricular fibrillation cardiac arrest. PbtO2 and cerebral microcirculation parameters were measured on parietal cortices exposed through burr holes. Multiple linear mixed effect models were used to test the independent effects of each variable on PbtO2. Despite the absence of arterial hypoxemia or hypotension, seven (70%) animals experienced cerebral hypoxia (defined as PbtO2 <20 mmHg). Linear mixed effect models revealed that neither MAP nor ETCO2 were related to PbtO2. PaO2 had a significant linear relationship with PbtO2 after adjusting for significant covariates (P = 0.030), but it could explain only 17.5% of the total PbtO2 variance (semi-partial R2 = 0.175; 95% confidence interval, 0.086–0.282). In conclusion, MAP and ETCO2 were not significantly related to PbtO2 in animals without hypoxemia or hypotension during the early post-resuscitation period. PaO2 had a significant linear association with PbtO2, but its ability to explain PbtO2 variance was small. [ABSTRACT FROM AUTHOR]

The article focuses on the research conducted by the University Hospital Bonn (UKB) and DZNE to address brain damage caused by oxygen deficiency during birth, which has been a significant cause of newborn mortality globally. It is reported that the researchers employed a small animal model to test 25 different active agents as potential treatments. It is further noted that seven of these substances were found to be more effective than the standard therapy of artificial cooling.

Objectives: Hypoxia, or abnormally low blood‐oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. Methods: We analyzed high‐resolution T1‐weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic‐clonic seizures (GTCS) recorded during long‐term video‐electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age‐ and sex‐matched healthy controls (n = 43). Subjects were sub‐divided into those with mild/moderate (GTCS‐hypox‐mild/moderate, n = 12) and severe (GTCS‐hypox‐severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2) during VEEG. Whole‐brain voxel‐based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. Results: Morphometric and volumetric alterations appeared in association with peri‐GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. Significance: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures. [ABSTRACT FROM AUTHOR]

Introduction: Hypoxia via expression of Hypoxia-Inducible Factor-1 (HIF-1) is an important and effective factor in the onset and progression of memory disorders, such as Alzheimer Disease (AD). The activity of ß-secretase (BACE1) is increased in hypoxia conditions. BACE1 triggers a cascade of pathological events resulting in AD. Crocin acts as a memoryimproving agent but its molecular mechanism is not well-known. Therefore, in this study, the effect of crocin on spatial memory, HIF-1a, and BACE1 gene expression was investigated in rat offspring under maternal hypoxia. Methods: Female pregnant rats on the 20th day of pregnancy were divided into 4 groups, including sham, crocin-treated, hypoxia, and hypoxia group treated with crocin. In the hypoxia groups, pregnant rats were exposed to 7% oxygen and 93% nitrogen intensity for 3 h. In the crocin-treated group, crocin (30 mg/kg) was injected at P14-28 (i.p). At the end, Morris water maze was used to assess spatial memory and real-time polymerase chain reaction was performed to measure the expression of BACE1 and HIF-1a genes in the brain of offspring. Results: Maternal hypoxia impaired memory compared with the sham group. However, crocin treatment improved cognitive behavior. HIF-1a and BACE1 expressions were upregulated in the brain of offspring in the hypoxia group. Crocin treatment could attenuate the expression of both genes. Conclusion: According to our results, down-regulation of HIF-1a and BACE1 gene expressions in the brain of rat offspring after crocin treatment can be suggested as a molecular mechanism for crocin to improve spatial memory. [ABSTRACT FROM AUTHOR]

Introduction: Research in traumatic brain injury suggests better patient outcomes when invasive oxygen monitoring is used to detect and correct episodes of brain hypoxia. Invasive brain oxygen monitoring is, however, not routinely used due to the risks, costs and technical challengers. We are developing a non-invasive brain oximeter to address these limitations. The monitor uses the principles of pulse oximetry to record a brain photoplethysmographic waveform and oxygen saturations. We undertook a study in volunteers to assess the new monitor. Patients and Methods: We compared the temporal changes in the brain and skin oxygen saturations in six volunteers undergoing progressive hypoxia to reach arterial saturations of 70%. This approach provides a method to discriminate potential contamination of the brain signal by skin oxygen levels, as the responses in brain and skin oxygen saturations are distinct due to the auto-regulation of cerebral blood flow to compensate for hypoxia. Conventional pulse oximetry was used to assess skin oxygen levels. Blood was also collected from the internal jugular vein and correlated with the brain oximeter oxygen levels. Results: At baseline, a photoplethysmographic waveform consistent with that expected from the brain was obtained in five subjects. The signal was adequate to assess oxygen saturations in three subjects. During hypoxia, the brain's oximeter oxygen saturation fell to 74%, while skin saturation fell to 50% (P< 0.0001). The brain photoplethysmographic waveform developed a high-frequency oscillation of ∼ 7 Hz, which was not present in the skin during hypoxia. A weak correlation between the brain oximeter and proximal internal jugular vein oxygen levels was demonstrated, R2=0.24, P=0.01. Conclusion: Brain oximeter oxygen saturations were relatively well preserved compared to the skin during hypoxia. These findings are consistent with the expected physiological responses and suggest skin oxygen levels did not markedly contaminate the brain oximeter signal. [ABSTRACT FROM AUTHOR]

Real-time reverse transcription PCR (qPCR) normalized to an internal reference gene (RG), is a frequently used method for quantifying gene expression changes in neuroscience. Although RG expression is assumed to be constant independent of physiological or experimental conditions, several studies have shown that commonly used RGs are not expressed stably. The use of unstable RGs has a profound effect on the conclusions drawn from studies on gene expression, and almost universally results in spurious estimation of target gene expression. Approaches aimed at selecting and validating RGs often make use of different statistical methods, which may lead to conflicting results. Based on published RG validation studies involving hypoxia the present study evaluates the expression of 5 candidate RGs (Actb, Pgk1, Sdha, Gapdh, Rnu6b) as a function of hypoxia exposure and hypothermic treatment in the neonatal rat cerebral cortex–in order to identify RGs that are stably expressed under these experimental conditions–using several statistical approaches that have been proposed to validate RGs. In doing so, we first analyzed RG ranking stability proposed by several widely used statistical methods and related tools, i.e. the Coefficient of Variation (CV) analysis, GeNorm, NormFinder, BestKeeper, and the ΔCt method. Using the Geometric mean rank, Pgk1 was identified as the most stable gene. Subsequently, we compared RG expression patterns between the various experimental groups. We found that these statistical methods, next to producing different rankings per se, all ranked RGs displaying significant differences in expression levels between groups as the most stable RG. As a consequence, when assessing the impact of RG selection on target gene expression quantification, substantial differences in target gene expression profiles were observed. Altogether, by assessing mRNA expression profiles within the neonatal rat brain cortex in hypoxia and hypothermia as a showcase, this study underlines the importance of further validating RGs for each individual experimental paradigm, considering the limitations of the statistical methods used for this aim. [ABSTRACT FROM AUTHOR]

Objective: Thresholds of cerebral hypoxia through monitoring of near-infrared spectroscopy tissue oxygenation index (TOI) were used to investigate the relationship between intraventricular haemorrhage (IVH) and indices of hypoxia.Design: Prospective observational study.Setting: A single-centre neonatal intensive care unit.Patients: Infants <28 weeks' gestation with an umbilical artery catheter.Methods: Thresholds of hypoxia were determined from mean values of TOI using sequential Χ2 tests and used alongside thresholds from existing literature to calculate percentage of time in hypoxia and burden of hypoxia below each threshold. These indices were then compared between IVH groups.Results: 44 infants were studied for a median of 18.5 (range 6-21) hours in the first 24 hours of life. Sequential Χ2 analysis yielded a TOI threshold of 71% to differentiate between IVH (16 infants) and no IVH (28 infants). Percentage of time in hypoxia was significantly higher in infants with IVH than those without, using thresholds of 60%-67%. Burden of hypoxia was significantly higher in infants with IVH than without, using thresholds of 62%-80%. With the threshold of 71%, percentage of time in hypoxia was lower by 12.2% with a 95% CI of (-25.7 to 1.2) (p=0.073), and the burden of hypoxia was lower by 29.2% hour (%h) (95% CI -55.2 to -3.1)%h (p=0.012) in infants without IVH than those with IVH.Conclusions: Using defined TOI thresholds, infants with IVH spent higher percentage of time in hypoxia with higher burden of cerebral hypoxia than those without, in the first 24 hours of life. [ABSTRACT FROM AUTHOR]

BACKGROUND: 8-Hydroxy-2-(di-n-propylamino)tetralin (8-0H-DPAT} can decrease brain temperature, which is the potential mechanism of its neuroprotection. OBJECTIVE: To investigate the effect of 8-0H-DPAT on hypoxia inducible factor 1a in the brain tissue of rats with diffuse axonal injury, and to explore the underlying mechanism of 8-0H-DPAT exerting neuroprotection in rats of diffuse axonal injury. METHODS: The study was approved by the Laboratory Animal Ethical Committee of General Hospital of Northern Theater Command. Wistar rats were randomly assigned into four groups: model group (n=35), constant temperature group (n=35), 8-0H-DPAT group (n=35} and normal group (n=7). Excepting the nonnal group, rat models of diffuse axonal injury were established according to Marmarou method. Rat models in the constant temperature and 8-0H-DPAT were intraperitoneally injected with 8-0H-DPAT, but those in the model and normal groups were intraperitoneally injected with physiological saline. The body temperature of rats in the constant temperature group was maintained at (37.0±0.5)0C using the blanket. The body temperature of rats was measured every 1 hour. Then, brain injury and hypoxia inducible factor 1a expression level were observed at 6, 12, 24, 72, and 168 hours after diffuse axonal injury in rats. RESULTS AND CONCLUSION: (1) Compared with the constant temperature and model groups, brain temperature was significantly lower in the 8-0H-DPAT group at 1 hour following modeling (P < 0.05), became lowest at 2 hours (P < 0.05), and then gradually increased. (2) Hematoxylin-eosin staining results revealed that brain injury was more serious in the model group, followed by constant temperature group, and lightest in the 8-0H-DPAT group. (3) Results of immunohistochemistry and ELISA showed that the expression level of hypoxia inducible factor 1α in the serum and brain tissue was lowest in the nonnal group. In the 8-0H-DPAT group, the expression level of hypoxia inducible factor 1α was increased at 6 hours after diffuse axonal injury, and peaked at 24 hours. Compared with the model group, the expression level of hypoxia inducible factor 1 a in serum and brain tissue in the constant temperature and 8-0H-DPAT groups was significantly decreased (P < 0.05 or P < 0.01), especially the 8-0H-DPAT group (P < 0.01 ). {4) These results imply that 8-0H-DPAT decreases hypoxia inducible factor 1a expression in brain tissue of diffuse axonal injury rats by reducing brain temperature, alleviates the degree of nerve injury, and exerts a neuroprotective effect. [ABSTRACT FROM AUTHOR]

Key points: The control of cerebral blood flow in hypoxia, anaemia and hypocapnia is reviewed with an emphasis on the links between cerebral blood flow and possible stimuli.A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia.The model demonstrates that hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, an effect exacerbated when blood flow regulation is impaired.The suitability of brain hypoxia as a common regulator of cerebral blood flow in hypoxia and anaemia was explored, although we failed to find support for this hypothesis. Rather, cerebral blood flow appears to be related to arterial oxygen concentration in both anaemia and hypoxia. A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia. The model simulation assesses the physiological plausibility of some currently hypothesized cerebral blood flow control mechanisms in hypoxia and anaemia, and also examines the impact of anaemia and hypoxia on brain hypoxia. In addition, carbon dioxide is examined for its impact on brain hypoxia in the context of concomitant changes associated with anaemia and hypoxia. The model calculations are based on a single compartment of brain tissue with constant metabolism and perfusion pressure, as well as previously developed equations describing oxygen and carbon dioxide carriage in blood. Experimental data are used to develop the control equations for cerebral blood flow regulation. The interactive model illustrates that there are clear interactions of anaemia, hypoxia and carbon dioxide in the determination of cerebral blood flow and brain tissue oxygen tension. In both anaemia and hypoxia, cerebral blood flow increases to maintain oxygen delivery, with brain hypoxia increasing when cerebral blood flow control mechanisms are impaired. Hypocapnia superimposes its effects, increasing brain hypoxia. Hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, and this effect is exacerbated when blood flow regulation is degraded by conditions that negatively impact cerebrovascular control. Differences in brain hypoxia in anaemia and hypoxia suggest that brain oxygen tension is not a plausible sensor for cerebral blood flow control. Key points: The control of cerebral blood flow in hypoxia, anaemia and hypocapnia is reviewed with an emphasis on the links between cerebral blood flow and possible stimuli.A mathematical model is developed to examine the changes in the partial pressure of oxygen in brain tissue associated with changes in cerebral blood flow regulation produced by carbon dioxide, anaemia and hypoxia.The model demonstrates that hypoxia, anaemia and hypocapnia, alone or in combination, produce varying degrees of cerebral hypoxia, an effect exacerbated when blood flow regulation is impaired.The suitability of brain hypoxia as a common regulator of cerebral blood flow in hypoxia and anaemia was explored, although we failed to find support for this hypothesis. Rather, cerebral blood flow appears to be related to arterial oxygen concentration in both anaemia and hypoxia. [ABSTRACT FROM AUTHOR]

Using the rat hypoxia model, the imbalanced work of antiradical defense enzymes with insufficient dismutase activity in blood leading to the development of oxidative stress, which was more pronounced in animals receiving a natural drinking diet, has been confirmed on the basis of the comparative analysis of the antiradical defense enzyme functioning index. It has been observed that acute hypoxia in the brain tissues is characterized by the development of catalase deficiency and the risk of excessive hydrogen peroxide production. It has been demonstrated that a decrease in the D/H (deuterium/protium) ratio in the blood and brain reduces the severity of the impairment of antioxidant enzyme work in hypoxia. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?What are the independent effects of hypoxia and hypocapnia on cerebral haemodynamics and cognitive function?What is the main finding and its importance?Exposure to hyperventilation‐induced hypocapnia causes cognitive impairment in both normoxia and hypoxia. In addition, supplementation of carbon dioxide during hypoxia alleviates the cognitive impairment and reverses hypocapnia‐induced vasoconstriction of the cerebrovasculature. These data provide new evidence for the independent effect of hypocapnia on the cognitive impairment associated with hypoxia. Hypoxia, which is accompanied by hypocapnia at altitude, is associated with cognitive impairment. This study examined the independent effects of hypoxia and hypocapnia on cognitive function and assessed how changes in cerebral haemodynamics may underpin cognitive performance outcomes. Single reaction time (SRT), five‐choice reaction time (CRT) and spatial working memory (SWM) tasks were completed in 20 participants at rest and after 1 h of isocapnic hypoxia (IH, end‐tidal oxygen partial pressure (P ET O2) = 45 mmHg, end‐tidal carbon dioxide partial pressure (P ETC O2) clamped at normal) and poikilocapnic hypoxia (PH, P ET O2 = 45 mmHg, P ETC O2 not clamped). A subgroup of 10 participants were also exposed to euoxic hypocapnia (EH, P ET O2 = 100 mmHg, P ETC O2 clamped 8 mmHg below normal). Middle cerebral artery velocity (MCAv) and prefrontal cerebral haemodynamics were measured with transcranial Doppler and near infrared spectroscopy, respectively. IH did not affect SRT and CRT performance from rest (566 ± 50 and 594 ± 70 ms), whereas PH (721 ± 51 and 765 ± 48 ms) and EH (718 ± 55 and 755 ± 34 ms) slowed response times (P < 0.001 vs. IH). Performance on the SWM task was not altered by condition. MCAv increased during IH compared to PH (P < 0.05), which was unchanged from rest. EH caused a significant fall in MCAv and prefrontal cerebral oxygenation (P < 0.05 vs. baseline). MCAv was moderately correlated to cognitive performance (R2 = 0.266–0.289), whereas prefrontal cerebral tissue perfusion and saturation were not (P > 0.05). These findings reveal a role of hyperventilation‐induced hypocapnia per se on the development of cognitive impairment during normoxic and hypoxic exposures. [ABSTRACT FROM AUTHOR]

Microglia are resident immune cells that act as the first active defence in the central nervous system. These cells constantly monitor the tissue microenvironment and rapidly react in response to hypoxia, infection and injuries. Hypoxia in the brain has been detected in several neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. Hypoxic conditions activate microglia cells towards M1 phenotype resulting in oxidative stress and the release of pro-inflammatory cytokines. Recently, we have demonstrated that oxidative stress induces S-glutathionylation of the STAT1 and hyper-activates its signaling in microglia BV2 cells pointing out the importance of this transcription factor in neuroinflammation. In this paper we analyse the cellular mechanisms that drive M1 microglia activation in BV2 cells in response to hypoxia correlating it to STAT1 activation. The analysis of the molecular mechanism of STAT1 signaling reveals that hypoxia generates oxidative stress and induces both phosphorylation and S-glutathionylation of STAT1 that are responsible of its aberrant activation. The silencing of STAT1 protein expression counteracts hypoxia-M1 microglia phenotype suggesting the strong link between hypoxia-STAT1 and STAT1-microglia activation. STAT1 activation in neuroinflammation: Microglia respond to hypoxia and switch from resting ramified to amoeboid cells (M1-phenotype) resulting in the release of ROS/RNS and pro-inflammatory cytokines. The oxidative stress induces S-glutathionylation of the transcription factor STAT1 and hyper-activates its signaling pointing out the importance of this protein in neuroinflammation. The silencing of STAT1 counteracts hypoxia- M1 phenotype suggesting the link between hypoxia-STAT1 and STAT1-microglia activation. Image 1 [ABSTRACT FROM AUTHOR]

>bold<>italic/italic<>/bold< Hypoxic but viable neural tissue is seen on 1-(2–>sup<18>/supsup<18>/supbold<>italic/italic<>/bold< We used brain perfusion single-photon emission computed tomography (SPECT) and >sup<18>/supbold<>italic/italic<>/bold< Eighteen patients with abnormally reduced cerebral blood flow (CBF) in the affected cerebral hemispheres on preoperative brain perfusion SPECT -underwent CEA. They underwent >sup<18>/supbold<>italic/italic<>/bold< The CBF ratio (>italic/italic< = 0.0006) and >sup<18>/supitalic/italic< = 0.0084) were significantly increased and reduced, respectively, after surgery compared to the corresponding ratios before surgery. The difference in the >sup<18>/supitalic<ρ>/italic< = –0.695; >italic/italic< = 0.0009). The difference in the >sup<18>/supitalic/italic< = 0.0007). The area under the receiver operating characteristics curve for the difference in the >sup<18>/supitalic/italic< = 0.0248). >bold<>italic/italic<>/bold< Hypoxic tissue is reduced following the restoration of cerebral perfusion with revascularization surgery in patients with severe atherosclerotic stenosis of the cervical ICA. The reduction in hypoxic tissue is associated with cognitive improvement in such patients. [ABSTRACT FROM AUTHOR]

Introduction: Lactate concentration in umbilical cord blood is an important measure of intrapartum anaerobic metabolism. The aim of the study was to compare lactate production of large-for-gestational-age (LGA) fetuses against appropriate-for-gestational-age (AGA) fetuses during hypoxia, in diabetic and non-diabetic mothers.Material and Methods: A total of 17 358 validated paired arterial and venous umbilical cord blood samples taken at birth with a full panel of pH, glucose, and lactate were analyzed relative to LGA (n = 2789) and AGA (n = 14 569). Umbilical cord blood acidemia (pH < mean minus 2 SD) was identified in 518 cases.Results: Diabetes, but not acidemia, was more common among LGA (5.4%) than AGA cases (2.9%) (respectively P < .0001 and P < .69). At normal pH, glucose was lower in non-diabetes LGA cases, but not in diabetes LGA compared with corresponding AGA cases (respectively P < .0001 and P < .067). Glucose levels were higher in all groups during acidemia (P ≤ .0005), with lower values in non-diabetes LGA but not in diabetes LGA compared with corresponding AGA cases (respectively P = .005 and P < .58). At normal pH, lactate was lower in non-diabetes LGA but not in diabetes LGA compared with corresponding AGA cases (respectively P < .0001 and P < .98); during acidemia, lactate levels were higher in all groups (P < .0001), resulting in no significant difference between LGA and AGA in diabetes as well as in non-diabetes cases (respectively P = .29 and P < .084).Conclusions: Considering cord acidemia a proxy for intrapartum hypoxia, LGA fetuses showed no impaired ability to produce lactate during hypoxia. Maternal diabetes did not hamper the ability of LGA fetuses to produce lactate during hypoxia. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction, especially in terms of mitochondrial dynamics, has been reported to be closely associated with neuronal outcomes and neurological impairment in cerebral ischemia/hypoxia injury. Dynamin-related protein 1 (Drp1) is a cytoplasmic GTPase that mediates mitochondrial fission and participates in neuronal cell death, calcium signaling, and oxidative stress. The neuroprotective role of Drp1 inhibition has been confirmed in several central nervous system disease models, demonstrating that targeting Drp1 may shed light on novel approaches for the treatment of cerebral ischemia/hypoxia injury. In this review, we aimed to highlight the roles of Drp1 in programmed cell death, oxidative stress, mitophagy, and mitochondrial function to provide a better understanding of mitochondrial disturbances in cerebral ischemia/hypoxia injury, and we also summarize the advances in novel chemical compounds targeting Drp1 to provide new insights into potential therapies for cerebral ischemia/hypoxia injury. [Display omitted] • Dynamin-related protein 1 (Drp1) is a cytoplasmic GTPase that mediates mitochondrial fission. • The function of Drp1 depends on its post-translational modifications, particularly phosphorylation. • Drp1 is associated with programmed cell death, oxidative stress, mitochondrial function, calcium signaling and synapses in cerebral hypoxia/ischemia. • Drp1 inhibition may shed light on novel approaches for the treatment of cerebral ischemia/hypoxia injury. [ABSTRACT FROM AUTHOR]

Hemodialysis patients have multiple risk factors for small vessel cerebrovascular disease and cognitive dysfunction. Hemodialysis itself may cause clinically significant neurological injury through repetitive cerebral ischemia. However, supporting evidence to date consists of epidemiological associations, expert opinion, and small, single-centre studies of variable methodological quality. Isolating the impact of intra-dialytic hemodynamic instability from underlying renal and vascular disease on clinically relevant functional outcomes would require very large, controlled studies, given the heterogeneity and confounding comorbidities of the population, and the complex relationship between blood pressure and cerebral oxygen delivery. There has been an increase in complementary physiological studies looking directly at intra-dialytic cerebral oxygen balance, which have provided supporting evidence for the occurrence of cerebral ischemia, often independently of hemodynamics. Data suggesting a relationship between these measures of oxygen balance and functional outcomes is only hypothesis-generating at this stage. We advocate the testing of interventions that aim to reduce intra-dialytic cerebral hypoxia (rather than hypotension) in sufficiently powered studies, followed by correlation with validated, longitudinal assessment of clinically relevant neurological damage. [ABSTRACT FROM AUTHOR]

Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia. We report a case of an adult patient who developed the rare condition DPHL and made a nearly complete recovery in the setting of treatment with clemastine, a widely available antihistamine that in preclinical models promotes oligodendrocyte precursor cell differentiation. This suggested possible therapeutic benefit in the more clinically prevalent hypoxic injury of newborns, and we demonstrate in murine neonatal hypoxic injury that clemastine dramatically promotes oligodendrocyte precursor cell differentiation, myelination, and improves functional recovery. We show that its effect in hypoxia is oligodendroglial specific via an effect on the M1 muscarinic receptor on oligodendrocyte precursor cells. We propose clemastine as a potential therapy for hypoxic brain injuries associated with white matter injury and oligodendrocyte precursor cell maturation arrest. [ABSTRACT FROM AUTHOR]

Perinatal hypoxia leads to behavioral abnormalities, cognitive disabilities, and epilepsy resulting from alterations in neurodevelopment, maturation and construction of the network. Considering a particular role of γ-aminobutyric acid (GABA) for an immature brain, we analysed transporter-mediated [ 3 H]GABA uptake in the cortical, hippocampal and thalamic nerve terminals isolated from rats of different age in the control and after perinatal hypoxia. The state of hypoxia was induced by exposure of rats at the age of 10 postnatal days (pd) (that corresponds approximately to the time of birth in humans) to a respiratory medium with low O 2 content (4% O 2 and 96%N 2 ) for 12 min (up to the initiation of clonico-tonic seizures). Here, we found that the initial rate of [ 3 Н]GABA uptake was higher in the young rats (pd 17–19) as compared to the older ones (pd 24–26, 38–40 and 66–73) in both control and hypoxia groups. It decreased abruptly by 50% in the thalamus and by 25% in the cortex for the period from pd 17–19 to pd 66–73. In the hippocampus, a decrease in the rate during the same time interval was 25%. Exposure to hypoxia had no effect on the intensity of [ 3 Н]GABA uptake by the cortical and thalamic nerve terminals, but caused a significant age-dependent attenuation (by 35%) of the uptake intensity in the hippocampal ones. Significant age-dependent hypoxia-independent decrease in [ 3 Н]GABA uptake with step-like dynamics of changes was shown in the thalamus and cortex. Gradual age-dependent hypoxia-dependent decrease in [ 3 Н]GABA uptake was revealed in the hippocampus, and so a particular vulnerability of the latest structure to hypoxia as compared to the cortex and thalamus was revealed. [ABSTRACT FROM AUTHOR]

Background: Mapping the hypoxic brain in acute ischemic stroke has considerable potential for both diagnosis and treatment monitoring. PET using 18F-fluoro-misonidazole (FMISO) is the reference method; however, it lacks clinical accessibility and involves radiation exposure. MR-based T2' mapping may identify tissue hypoxia and holds clinical potential. However, its validation against FMISO imaging is lacking. Here we implemented back-to-back FMISO-PET and T2' MR in rodents subjected to acute middle cerebral artery occlusion. For direct clinical relevance, regions of interest delineating reduced T2' signal areas were manually drawn. Methods: Wistar rats were subjected to filament middle cerebral artery occlusion, immediately followed by intravenous FMISO injection. Multi-echo T2 and T2* sequences were acquired twice during FMISO brain uptake, interleaved with diffusion-weighted imaging. Perfusion-weighted MR was also acquired whenever feasible. Immediately following MR, PET data reflecting the history of FMISO brain uptake during MR acquisition were acquired. T2' maps were generated voxelwise from T2 and T2*. Two raters independently drew T2' lesion regions of interest. FMISO uptake and perfusion data were obtained within T2' consensus regions of interest, and their overlap with the automatically generated FMISO lesion and apparent diffusion coefficient lesion regions of interest was computed. Results: As predicted, consensus T2' lesion regions of interest exhibited high FMISO uptake as well as substantial overlap with the FMISO lesion and significant hypoperfusion, but only small overlap with the apparent diffusion coefficient lesion. Overlap of the T2' lesion regions of interest between the two raters was ~50%. Conclusions: This study provides formal validation of T2' to map non-core hypoxic tissue in acute stroke. T2' lesion delineation reproducibility was suboptimal, reflecting unclear lesion borders. [ABSTRACT FROM AUTHOR]

Allium chinense G. Don is a popular medicinal and aromatic plant, known as "Ganoderma of vegetables" in history for treating blood stasis syndrome that reduces red blood cell oxygen-carrying capacity and often causes severe brain damage. However, the effect of A. chinense on cerebral anoxia remains obscure. Here, the anti-hypoxic effect of A. chinense was investigated for the first time through the cerebral anoxia model of mice. Subsequent a bio-guided investigation brought about the isolation of 16 compounds, including 9 phenolic derivatives (2 new compounds (compound 1, 8) and one new natural product (compound 2), 4 steroidal saponins and 3 fatty acid monoglycerides, among which, 6 compounds (1–4 , 7 , 16) exhibited significant anoxia-tolerant activity in vitro. Moreover, the release of reactive oxygen species (ROS) was decreased significantly, and glutathione (GSH) and lactate dehydrogenase (LDH) were regulated by the 6 bioactive compounds in oxygen‑glucose deprivation/ reoxygenation (OGD/R)-induced BV-2 cells damage. Besides that, protein expressions of HIF-1 α , NLRP3, COX-2, NF- κ B p65 and IL-18 were suppressed effectively. The investigation provided a new nutritional strategy for A. chinense against cerebral anoxia and altitude illness, which might be partially mediated by downregulating NLRP3/NF- κ B. [Display omitted] • The anoxia-tolerant activity of A. chinense was studied for the first time. • Bio-guided investigation led to the isolation of 16 compounds, including three new compounds. • Bioactive compounds improved anoxia-tolerant ability may be associated to regulating NLRP3/NF- κ B. • It may be a source for sustainable foods, dietary supplements and pharmaceutical use. [ABSTRACT FROM AUTHOR]

The tumor microenvironment has been widely exploited as an active participant in tumor progression. Extensive reports have defined the dual role of tumor-associated macrophages (TAMs) in tumor development. The protumoral effect exerted by the M2 phenotype has been correlated with a negative outcome in most solid tumors. The high infiltration of immune cells in the hypoxic cores of advanced solid tumors leads to a chain reaction of stimuli that enhances the expression of protumoral genes, thrives tumor malignancy, and leads to the emergence of drug resistance. Many studies have shown therapeutic targeting systems, solely to TAMs or tumor hypoxia, however, novel therapeutics that target both features are still warranted. In the present review, we discuss the role of hypoxia in tumor development and the clinical outcome of hypoxia-targeted therapeutics, such as hypoxia-inducible factor (HIF-1) inhibitors and hypoxia-activated prodrugs. Furthermore, we review the state-of-the-art of macrophage-based cancer therapy. We thoroughly discuss the development of novel therapeutics that simultaneously target TAMs and tumor hypoxia. Nano-based systems have been highlighted as interesting strategies for dual modality treatments, with somewhat improved tissue extravasation. Such approach could be seen as a promising strategy to overcome drug resistance and enhance the efficacy of chemotherapy in advanced solid and metastatic tumors, especially when exploiting cell-based nanotherapies. Finally, we provide an in-depth opinion on the importance of exploiting the tumor microenvironment in cancer therapy, and how this could be translated to clinical practice. [ABSTRACT FROM AUTHOR]

Background and Purpose: The role of apparent diffusion coefficient (ADC) for preoperative grading and treatment planning of high-grade gliomas (HGG) is still debated since the assumption of inverse correlation between ADC and cellularity is not completely coherent with the results of some studies. It has been recently hypothesized that restricted diffusivity in HGG may be related to hypoxic/ischemic changes inside the tumor. We therefore investigated the differences of ADC values between areas with magnetic resonance spectroscopy (MRS) markers of hypoxia and necrosis (lactate and lipid compounds) and regions with lack of both metabolites.Methods: The MRS datasets and the corresponding ADC maps of 28 patients with HGG were retrospectively reviewed. Circular regions of interest (ROIs) were placed on ADC maps by means of spectral characteristics, considering the solid portions of gliomas. One-way ANOVA or Welch test were performed for multiple comparison of the Mean ADC, minimum ADC (minADC), and standard deviation of pixel-by-pixel ADC measurements (ADC SD) values among the groups of ROIs with lactate, lipids, and lack of both metabolites (LAC, LIP, and NEG group, respectively).Results: The minADC values in LAC group (908 ± 161 × 10-6 mm2 s-1 ) were found to be significantly (P = .03) higher than in NEG group (792 ± 122 × 10-6 mm2 s-1 ). We did not find other significant differences by the multiple comparison tests.Conclusions: HGG areas with MRS markers of hypoxia and necrosis are not associated with restricted diffusivity. To explain the trend to diffusion facilitation in HGG lactate-expressing regions, we hypothesize a possible hypoxia-induced volume reduction of glioma cells with extracellular shift of cytoplasmic water. [ABSTRACT FROM AUTHOR]

Objectives Electroencephalography (EEG) is one of the methods used in predicting the outcome after cerebral hypoxia. In this study we aim to evaluate the significance of generalized periodic discharges (GPD) as a prognostic marker. Methods We retrospectively analyzed the medical histories of patients, who underwent an EEG after cardiac arrest during the time period from 2005 to 2013 at the University Hospital Zurich. All EEGs were re-interpreted using the 2012 American Clinical Neurophysiology Society (ACNS) classification for intensive care unit (ICU) EEGs. Results Out of 131 patients, in which an EEG was recorded after cardiopulmonary resuscitation, 119 were included in our study. The average interval between cardiac arrest and EEG-recording was 3.8 ± 3.0 days (range: 0–14 days). Persistent GPDs (i.e. GPDs more than 24 h after the event) were found in thirty-two (26.9%) of the patients initial EEGs. The appearance of persistent GPDs preceded fatal outcome in 100% of all cases (vs. 69.0% in the non-GPD-group, p < 0.0001). Conclusion Among other encephalopathic markers in EEG persistent GPDs are a highly specific prognostic marker of fatal outcome in patients with hypoxic encephalopathy. Significance Using standardized EEG interpretation, this study identified persistent GPDs as a specific prognostic marker in post cardiac arrest syndrome. [ABSTRACT FROM AUTHOR]

Hypoxia poses a significant energetic challenge and most species exhibit metabolic remodelling when exposed to prolonged hypoxia. One component of this remodelling is mitochondrial biogenesis/mitophagy, which alter mitochondrial abundance and helps to adjust metabolic throughput to match changes in energy demands in hypoxia. However, how acute hypoxia impacts mitochondrial abundance in hypoxia-tolerant species is poorly understood. To help address this gap, we exposed hypoxia-tolerant naked mole-rats to 3 h of normoxia or acute hypoxia (5% O 2) and measured changes in mitochondrial abundance using two well-established markers: citrate synthase (CS) enzyme activity and mitochondrial DNA (mtDNA) abundance. We found that neither marker changed with hypoxia in brain, liver, or kidney, suggesting that mitochondrial biogenesis is not initiated during acute hypoxia in these tissues. Conversely in skeletal muscle, the ratio of CS activity to total protein decreased 50% with hypoxia. However, this change was likely driven by an increase in soluble protein density in hypoxia because CS activity was unchanged relative to wet tissue weight and the mtDNA copy number was unchanged. To confirm this, we examined skeletal muscle mitochondria using transmission electron microscopy and found no change in mitochondrial volume density. Taken together with previous studies of mitochondrial respiratory function, our present findings suggest that naked mole-rats primarily rely on tissue-specific functional remodelling of metabolic pathways and mitochondrial respiratory throughput, and not physical changes in mitochondrial number or volume, to adjust to short-term hypoxic exposure. • Hypoxia tolerant species adjust their metabolic rate in acute hypoxia. • Changes in mitochondrial function play central roles in this metabolic rate depression. • It is not known if mitochondrial abundance changes in the tissues of hypoxia-tolerant species during acute hypoxia. • We found that naked mole-rats do not alter mitochondrial abundance in acute hypoxia. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide (NO) appears to play a key role in the hypoxic injury to the brain. We have previously reported that hypoxia/reoxygenation downregulated NO synthases (NOS) in the adult striatum. Until now, no data were available concerning the influence of aging in conjunction with hypoxia/reoxygenation on the NO system in the striatum.Objective: The aim of this study was to assess the role of the NO pathway in the hypoxic aged striatum.Methods: Wistar rats 24-25 months old were submitted to hypobaric hypoxia (20 min)/reoxygenation (0 h, 24 h, 5 days). Expression (PCR, immunohistochemistry/image analysis) and activity (NADPH-diaphorase/image analysis) of NOS isoforms (neuronal NOS or nNOS, endothelial NOS or eNOS, inducible NOS or iNOS) were analyzed together with nitrated protein expression (immunohistochemistry/image analysis). NO levels were indirectly quantified as nitrates/nitrites (NOx).Results: The mRNA levels of NOS isoforms were undetectable at 0 h after hypoxia in the striatum compared to the control. At later reoxygenation times, nNOS mRNA decreased, while eNOS mRNA augmented. Protein levels of nNOS and eNOS rose at 24 h after hypoxia, and iNOS protein increased at 5 days. NOx levels remained unchanged, whereas in situ NOS activity and protein nitration diminished during reoxygenation in the aged striatum.Conclusion: The aged striatum may overexpress NOS isoforms as a neuroprotective-adaptive mechanism to hypoxia. However, this mechanism may not work properly in the aged striatum, since no changes in NO levels were detected after hypoxia. This may be related to the low activity of NOS isoforms in the hypoxic striatum. [ABSTRACT FROM AUTHOR]

Objectives: To develop computer algorithms that can recognize physiologic patterns in traumatic brain injury patients that occur in advance of intracranial pressure and partial brain tissue oxygenation crises. The automated early detection of crisis precursors can provide clinicians with time to intervene in order to prevent or mitigate secondary brain injury.Design: A retrospective study was conducted from prospectively collected physiologic data. intracranial pressure, and partial brain tissue oxygenation crisis events were defined as intracranial pressure of greater than or equal to 20 mm Hg lasting at least 15 minutes and partial brain tissue oxygenation value of less than 10 mm Hg for at least 10 minutes, respectively. The physiologic data preceding each crisis event were used to identify precursors associated with crisis onset. Multivariate classification models were applied to recorded data in 30-minute epochs of time to predict crises between 15 and 360 minutes in the future.Setting: The neurosurgical unit of Ben Taub Hospital (Houston, TX).Subjects: Our cohort consisted of 817 subjects with severe traumatic brain injury.Measurements and Main Results: Our algorithm can predict the onset of intracranial pressure crises with 30-minute advance warning with an area under the receiver operating characteristic curve of 0.86 using only intracranial pressure measurements and time since last crisis. An analogous algorithm can predict the start of partial brain tissue oxygenation crises with 30-minute advanced warning with an area under the receiver operating characteristic curve of 0.91.Conclusions: Our algorithms provide accurate and timely predictions of intracranial hypertension and tissue hypoxia crises in patients with severe traumatic brain injury. Almost all of the information needed to predict the onset of these events is contained within the signal of interest and the time since last crisis. [ABSTRACT FROM AUTHOR]

Hypobaric hypoxic brain injury results in elevated peripheral S100B levels which may relate to blood-brain barrier (BBB) dysfunction. A period of acclimatisation or dexamethasone prevents altitude-related illnesses and this may involve attenuation of BBB compromise. We hypothesised that both treatments would diminish the S100B response (a measure of BBB dysfunction) on re-ascent to the hypobaric hypoxia of high altitude, in comparison to an identical ascent completed 48 h earlier by the same group. Twelve healthy volunteers, six of which were prescribed dexamethasone, ascended Mt Fuji (summit 3700 m) and serial plasma S100B levels measured. The S100B values reduced from a baseline 0.183 µg/l (95 % CI 0.083-0.283) to 0.145 µg/l (95 % CI 0.088-0.202) at high altitude for the dexamethasone group (n = 6) and from 0.147 µg/l (95 % CI 0.022-0.272) to 0.133 µg/l (95 % CI 0.085-0.182) for the non-treated group (n = 6) [not statistically significant (p = 0.43 and p = 0.82) for the treated and non-treated groups respectively]. [These results contrasted with the statistically significant increase during the first ascent, S100B increasing from 0.108 µg/l (95 % CI 0.092-0.125) to 0.216 µg/l (95 % CI 0.165-0.267) at high altitude]. In conclusion, an increase in plasma S100B was not observed in the second ascent and this may relate to the effect of acclimatisation (or hypoxic pre-conditioning) on the BBB. An exercise stimulated elevation of plasma S100B levels was also not observed during the second ascent. The small sample size and wide confidence intervals, however, precludes any statistically significant conclusions and a larger study would be required to confirm these findings. [ABSTRACT FROM AUTHOR]

The Src family kinases are a family of intracellular, non-receptor tyrosine kinases that are involved in a variety of cellular functions including the regulation of inflammation and apoptosis after brain hypoxia. Caspase-1 (C1) activates IL-1β through the formation of complex structures, the inflammasomes, while caspase-8 (C8) is part of the extrinsic apoptotic pathway. C8 has been found to directly activate the production of IL-1β. Previously, we observed that C1 and IL-1β are increased in the acute phase after hypoxia in the brain of piglets, but they follow a different pattern long term, with C1 remaining activated throughout the period of observation, while IL-1β returning to baseline at 15 days. Src kinase inhibition ameliorated the activation of C1 and IL-1β early, but did not appear to have any effect long term. Prompted by these findings, we assessed the changes that occur over time (1 h and 15 days) in C1 and C8 activities after brain hypoxia as well as the effect of pretreatment with a Src kinase inhibitor, PP2 on these biochemical markers. Enzymatic activities were determined by spectrophotometry with measurements of C1 and C8 in each cytosolic brain sample (N = 4 in each group). We found that C1 and C8 activities increase in the acute phase following hypoxia in the brain of newborn piglets, with C8 relatively more than C1 (C8/C1 ratio increased from 2:1 as baseline to 3:1 in hypoxia). Fifteen days after hypoxia C8/C1 ratio decreased to about 1:1. In piglets that were pretreated with a Src kinase selective inhibitor (PP2) and then subjected to hypoxia, the C8/C1 ratio early increase was not observed. Immediately after hypoxia C8 and C1 follow a similar pattern of increase while long term this appears to dissociate. We propose that following this experimental methodology, the previously observed IL-1β production after hypoxia might be associated with C8 rather than C1 and that Src kinase is involved in the above process. [ABSTRACT FROM AUTHOR]

Background: It is well documented that the nitric oxide (NO) might be directly involved in brain response to hypobaric hypoxia, and could contribute to memory deficiencies. Recent studies have shown that melatonin could attenuate hypoxia or ischemia-induced nerve injuries by decreasing the production of free radicals. The present study, using immunohistochemical and immunoblot methods, aimed to explore whether melatonin treatment may affect the expression of nitric oxide system and protein nitration, and provide neuroprotection in the rat hippocampus injured by hypobaric hypoxia. Prior to hypoxic treatment, adult rats were pretreated with melatonin (100 mg/kg, i.p.) before they were exposed to the altitude chamber with 48 Torr of the partial oxygen concentration (pO2) for 7 h to mimic the ambience of being at 9000 m in height. They were then sacrificed after 0 h, 1, and 3 days of reoxygenation.Results: The results obtained from the immunohistochemical and immunoblotting analyses showed that the expressions of neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), nitrotyrosine (Ntyr) and Caspase 3 in the hypoxic hippocampus were increased from 0 h to 3 days of reoxygenation. Interestingly, the hypoxia-induced increase of nNOS, eNOS, iNOS, Ntyr and Caspase 3 protein expression was significantly depressed in the hypoxic rats treated with melatonin.Conclusions: Activation of the nitric oxide system and protein nitration constitutes a hippocampal response to hypobaric hypoxia and administration of melatonin could provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaric hypoxia. [ABSTRACT FROM AUTHOR]

Cerebral ischemic stroke has long been recognized as a prevalent and serious neurological disease that was associated with high mortality and morbidity. However, the current therapeutic protocols remain suboptimal with major mechanisms underlying stroke urgently warranted. Inhibitor of DNA binding/differentiation 2 (Id2) is found to be up-regulated in neuronal cells following hypoxia/ischemia (H/I). This study was aimed to investigate whether knockdown of Id2 in neuronal cells could protect them from hypoxic and ischemic injury both in vitro and in vivo . Flow cytometric analysis was employed to assess neuronal apoptosis in CoCl 2 -treated neuroblastoma B35 cells engineered to overexpress or knockdown Id2 expression. In vivo knockdown of Id2 was performed in Sprague-Dawley rats by a single intracerebroventricular injection of Cy3-labeled and cholesterol-modified Id2-siRNA. We found that knockdown of Id2 attenuated H/I-induced neuronal apoptosis in vitro while overexpression of Id2 produced an opposite effect. In a rat model of middle cerebral artery occlusion (MCAO), in vivo knockdown of Id2 significantly improved neurological deficits, reduced the volume of ischemic infarction and diminished the neuronal apoptosis in the penumbra area. Double immunofluorescence staining showed less co-localization of retinoblastoma tumor suppressor protein (Rb)-Id2 but greater co-localization of Rb-E2F1 in the penumbra area. Cell cycle assay further demonstrated that Id2 knockdown induced G0/G1 cell cycle arrest in CoCl 2 -treated B35 cells. The present data support the implication of Id2 in the modulation of H/I-induced neuronal apoptosis and may provide a potential therapeutic option to protect brain tissues from ischemic injury by inhibition of its expression. [ABSTRACT FROM AUTHOR]