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Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, and Jian Huang. Nitric oxide ameliorates the effects of hypoxia in mice by regulating oxygen transport by hemoglobin. High Alt Med Biol. 25:174–185, 2024.—Hypoxia is a common pathological and physiological phenomenon in ischemia, cancer, and strenuous exercise. Nitric oxide (NO) acts as an endothelium-derived relaxing factor in hypoxic vasodilation and serves as an allosteric regulator of hemoglobin (Hb). However, the ultimate effects of NO on the hematological system in vivo remain unknown, especially in extreme environmental hypoxia. Whether NO regulation of the structure of Hb improves oxygen transport remains unclear. Hence, we examined whether NO altered the oxygen affinity of Hb (Hb-O2 affinity) to protect extremely hypoxic mice. Mice were exposed to severe hypoxia with various concentrations of NO, and the survival time, exercise capacity, and other physical indexes were recorded. The survival time was prolonged in the 5 ppm NO (6.09 ± 1.29 minutes) and 10 ppm NO (6.39 ± 1.58 minutes) groups compared with the 0 ppm group (4.98 ± 1.23 minutes). Hypoxia of the brain was relieved, and the exercise exhaustion time was prolonged when mice inhaled 20 ppm NO (24.70 ± 6.87 minutes vs. 20.23 ± 6.51 minutes). In addition, the differences in arterial oxygen saturation (SO2%) (49.64 ± 7.29% vs. 42.90 ± 4.30%) and arteriovenous SO2% difference (25.14 ± 8.95% vs. 18.10 ± 6.90%) obviously increased. In ex vivo experiments, the oxygen equilibrium curve (OEC) left shifted as P50 decreased from 43.77 ± 2.49 mmHg (0 ppm NO) to 40.97 ± 1.40 mmHg (100 ppm NO) and 38.36 ± 2.78 mmHg (200 ppm NO). Furthermore, the Bohr effect of Hb was enhanced by the introduction of 200 ppm NO (−0.72 ± 0.062 vs.−0.65 ± 0.051), possibly allowing Hb to more easily offload oxygen in tissue at lower pH. The crystal structure reveals a greater distance between Asp94β-His146β in nitrosyl -Hb(NO-Hb), NO-HbβCSO93, and S-NitrosoHb(SNO-Hb) compared to tense Hb(T-Hb, 3.7 Å, 4.3 Å, and 5.8 Å respectively, versus 3.5 Å for T-Hb). Moreover, hydrogen bonds were less likely to form, representing a key limitation of relaxed Hb (R-Hb). Upon NO interaction with Hb, hydrogen bonds and salt bridges were less favored, facilitating relaxation. We speculated that NO ameliorated the effects of hypoxia in mice by promoting erythrocyte oxygen loading in the lung and offloading in tissues. [ABSTRACT FROM AUTHOR]

Chronic vascular encephalopathy (CVE) is a frequent cause of vascular mild cognitive impairment and dementia, which significantly worsens the quality of life, especially in the elderly population. CVE is a result of chronic cerebral hypoperfusion, characterized by prolonged limited blood flow to the brain. This causes insufficient oxygenation of the brain leading to hypoxia. The latter can trigger a series of events associated with the development of oxidative/reductive stresses and neuroinflammation. Addressing the gap in knowledge regarding oxidative and reductive stresses in the development of vascular disorders and neuroinflammation can give a start to new directions of research in the context of CVE. In this review, we consider the hypoxiainduced molecular challenges involved in the pathophysiology of CVE, focusing on oxidative stress and neuroinflammation, which are combined in a vicious cycle of neurodegeneration. We also briefly describe therapeutic approaches to the treatment of CVE and outline the prospects for the use of sulforaphane, an isothiocyanate common in cruciferous plants, and vitamin D to break the vicious cycle and alleviate the cognitive impairments characteristic of patients with CVE. [ABSTRACT FROM AUTHOR]

Recently, the role of high-concentration oxygen therapy in cerebral hemorrhage has been extensively discussed. This review describes the research progress in high-concentration oxygen therapy after cerebral hemorrhage. High-concentration oxygen therapy can be classified into two treatment methods: hyperbaric and normobaric high-concentration oxygen therapy. Several studies have reported that high-concentration oxygen therapy uses the pathological mechanisms of secondary ischemia and hypoxia after cerebral hemorrhage as an entry point to improve cerebral oxygenation, metabolic rate, cerebral edema, intracranial pressure, and oxidative stress. We also elucidate the mechanisms by which molecules such as Hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor, and erythropoietin (EPO) may play a role in oxygen therapy. Although people are concerned about the toxicity of hyperoxia, combined with relevant literature, the evidence discussed in this article suggests that as long as the duration, concentration, pressure, and treatment interval of patients with cerebral hemorrhage are properly understood and oxygen is administered within the treatment window, it can be effective to avoid hyperoxic oxygen toxicity. Combined with the latest research, we believe that high-concentration oxygen therapy plays an important positive role in injuries and outcomes after cerebral hemorrhage, and we recommend expanding the use of normal-pressure high-concentration oxygen therapy for cerebral hemorrhage. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved in autophagy to modulate this process under pathological conditions. This study aimed to analyze the role of autophagy in cell death induced by an in vitro ischemia–reperfusion (IR) model and to determine whether nitrones, known for their neuroprotective and antioxidant effects, could modulate this process. We focused on key proteins involved in different phases of autophagy: HIF-1α, BNIP3, and BECN1 for induction and nucleation, LC3 for elongation, and p62 for degradation. Our findings confirmed that the IR model promotes autophagy, initially via HIF-1α activation. Additionally, the neuroprotective effect of three of the selected synthetic nitrones (quinolylnitrones QN6 and QN23, and homo-bis-nitrone HBN6) partially derives from their antiautophagic properties, demonstrated by a downregulation of the expression of molecular markers involved in various phases of autophagy. In contrast, the neuroprotective power of cholesteronitrone ChN2 seems to derive from its promoting effects on the initial phases of autophagy, which could potentially help inhibit other forms of cell death. These results underscore the importance of autophagy modulation in neuroprotection, highlighting the potential of inhibiting prodeath autophagy and promoting prosurvival autophagy as promising therapeutic approaches in treating ischemic stroke clinically. [ABSTRACT FROM AUTHOR]

Background: Sex differences in oxidative stress-associated cognitive decline are influenced by sex hormone levels. Notably, oxidative stress-associated neuronal cell death can be exacerbated through testosterone signaling via membrane androgen receptor AR45, which is complexed with G protein Gaq within plasma membrane-associated lipid rafts. The objective of this study was to elucidate the impact of sex on the expression of AR45 and Gaq in brain regions associated with cognitive function, specifically hippocampus subregions and entorhinal cortex. Additionally, we investigated whether chronic intermittent hypoxia (CIH), an oxidative stressor with sex-specific effects, would modulate AR45 and Gaq expression in these brain regions. Methods: Adult male and female Sprague-Dawley rats were exposed to CIH or normoxia (room air) during their sleep phase for 14 days. We quantified AR45 and Gaq protein expression in various cognition-associated brain regions [dorsal hippocampal CA1, CA3, dentate gyrus (DG), and entorhinal cortex (ETC)] via western blotting. For comparisons, AR45 and Gaq protein expression were also assessed in brain regions outside the hippocampal-ETC circuit [thalamus (TH) and striatum (STR)]. Results: The highest AR45 levels were expressed in the hippocampal CA1 and DG while the lowest expression was observed in the extrahippocampal STR. The highest Gaq levels were expressed in the hippocampal-associated ETC while the lowest expression was observed in the extrahippocampal TH. Females expressed higher levels of AR45 in the hippocampal DG compared to males, while no sex differences in Gaq expression were observed regardless of brain region assessed. Moreover, there was no effect of CIH on AR45 or Gaq expression in any of the brain regions examined. AR45 expression was positively correlated with Gaq expression in the CA1, DG, ETC, TH, and STR in a sex-dependent manner. Conclusion: Our findings reveal enrichment of AR45 and Gaq protein expression within the hippocampal-ETC circuit, which is vulnerable to oxidative stress and neurodegeneration during cognitive decline. Nonetheless, CIH does not modulate the expression of AR45 or Gaq. Importantly, there are sex differences in AR45 expression and its association with Gaq expression in various brain regions, which may underlie sex-specific differences in cognitive and motor functionassociated declines with aging. [ABSTRACT FROM AUTHOR]

Prolonged disorder of consciousness (DoC) is a rising challenge. Pediatric data on diagnosis and prognosis of prolonged DoC were too limited and heterogeneous, making it difficult to define the natural course and evaluate the prognosis. The present study explored the emergence from the Minimally Conscious State (eMCS) incidence at different months postinjury drawing the natural course, and detected the predictors of the incidence in children with prolonged DoC. A hospital-based prospective cohort study was conducted. Kaplan–Meier curves, as well as univariate and multivariate COX regression analysis, were performed. The study enrolled 383 pediatric DoC individuals, including 220 males (57.4%), with an average age of 3.9 (1.9–7.3) years. The median duration between onset and rehabilitation is 30.0 (21.0–46.0) days. At enrollment, the ratio of vegetative state/unresponsive wakefulness syndrome (VS/WUS) to MCS is 78.9%–21.1%. Traumatic brain injury and infection are the major etiologies (36.8% and 37.1%, respectively), followed by hypoxia cerebral injury (12.3%). For children with prolonged DoC, the cumulative incidence of eMCS at months 3, 6, 12, and 24 was 0.510, 0.652, 0.731, 0.784 VS 0.290, 0.418, 0.539, 0.603 in the traumatic VS non-traumatic subgroup, respectively. For children in a persistent vegetative state (PVS), the cumulative incidence of emergence at months in 3, 6, 12, 24, 36 and 48 was testified as 0.439, 0.591, 0.683, 0.724, 0.743 and 0.743 in the traumatic subgroup, and 0.204, 0.349, 0.469, 0.534, 0.589 and 0.620 in the non-traumatic subgroup. Participants who exhibit any of the following four demographical and/or clinical characteristics—namely, older than 4 years at onset, accepted rehabilitation within 28 days of onset, remained MCS at enrollment, or with etiology of traumatic brain injuries—had a significantly positive outcome of consciousness recovery (eMCS). Moreover, both prolongation of the central somatosensory conductive time (CCT) (level 2) and absence of N20 (level 3) independently predict a negative outcome. In children with prolonged DoC, we found that 12 months postinjury was critical to eMCS, and a preferred timepoint to define chronic vegetative state (VS). The characteristics including age, etiology, time before rehabilitation, consciousness state, and SEP results were useful predictors of conscious recovery. Trial registration Registered 06/11/2018, the registration number is chiCTR1800019330 (chictr.org.cn). Registered prospectively. [ABSTRACT FROM AUTHOR]

Background: Acute hypobaric hypoxia-induced brain injury has been a challenge in the health management of mountaineers; therefore, new neuroprotective agents are urgently required. Meldonium, a well-known cardioprotective drug, has been reported to have neuroprotective effects. However, the relevant mechanisms have not been elucidated. We hypothesized that meldonium may play a potentially novel role in hypobaric hypoxia cerebral injury. Methods: We initially evaluated the neuroprotection efficacy of meldonium against acute hypoxia in mice and primary hippocampal neurons. The potential molecular targets of meldonium were screened using drug-target binding Huprot™ microarray chip and mass spectrometry analyses after which they were validated with surface plasmon resonance (SPR), molecular docking, and pull-down assay. The functional effects of such binding were explored through gene knockdown and overexpression. Results: The study clearly shows that pretreatment with meldonium rapidly attenuates neuronal pathological damage, cerebral blood flow changes, and mitochondrial damage and its cascade response to oxidative stress injury, thereby improving survival rates in mice brain and primary hippocampal neurons, revealing the remarkable pharmacological efficacy of meldonium in acute high-altitude brain injury. On the one hand, we confirmed that meldonium directly interacts with phosphoglycerate kinase 1 (PGK1) to promote its activity, which improved glycolysis and pyruvate metabolism to promote ATP production. On the other hand, meldonium also ameliorates mitochondrial damage by PGK1 translocating to mitochondria under acute hypoxia to regulate the activity of TNF receptor-associated protein 1 (TRAP1) molecular chaperones. Conclusion: These results further explain the mechanism of meldonium as an energy optimizer and provide a strategy for preventing acute hypobaric hypoxia brain injury at high altitudes. [ABSTRACT FROM AUTHOR]

Purpose: Applied Behavior Analysis (ABA) tact-training was provided to an adult with post-stroke anomic aphasia, with the main purposes to improve naming of pictures, with a possible generalization to another different setting, through telehealth sessions. Method: The Multiple probe experimental design across behaviors was used. Two sets of stimuli were used (SET 1 and SET 2), including 60 laminated photos, belonging to three different categories for each set. Procedure included the baseline, the intervention phases (face-to-face and telehealth sessions), and the follow-up (1 month after the end of a tact training). Results: For both, SET 1 and SET 2, the mastery criterion (80% correct stimulus tacts, for three consecutive times, simultaneously for all categories) was achieved. No increased percentage of correct picture tacts was found for untrained items. At follow-up, the patient provided 70 to 100% correct responses. For both SET 1 and SET 2, telehealth did not modify the correct response trends. Conclusion: The results of our study seem to suggest that specific tact-training procedures might be successfully carried out in adult and elderly people with post-stroke aphasia. It also appears necessary to arrange protocols providing telehealth sessions, with benefits for both families and the health system. [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]

Brain hypoxia is associated with a wide range of physiological and clinical conditions. Although oxygen is an essential constituent of maintaining brain functions, our understanding of how specific brain cell types globally respond and adapt to decreasing oxygen conditions is incomplete. In this study, we exposed mouse primary neurons, astrocytes, and microglia to normoxia and two hypoxic conditions and obtained genome-wide transcriptional profiles of the treated cells. Analysis of differentially expressed genes under conditions of reduced oxygen revealed a canonical hypoxic response shared among different brain cell types. In addition, we observed a higher sensitivity of neurons to oxygen decline, and dissected cell type-specific biological processes affected by hypoxia. Importantly, this study establishes novel gene modules associated with brain cells responding to oxygen deprivation and reveals a state of profound stress incurred by hypoxia. [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]

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose‐dependent impact of opioids on respiratory depression in children, the leading cause of opioid‐associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age‐dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen‐related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric‐specific factors may need to be considered. [ABSTRACT FROM AUTHOR]

Choroid plexus (CP) can be seen as a watchtower of the central nervous system (CNS) that actively regulates CNS homeostasis. A growing body of literature suggests that CP alterations are involved in the pathogenesis of multiple sclerosis (MS) but the underlying mechanisms remain elusive. CPs are enlarged and inflamed in relapsing-remitting (RRMS) but also in clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) stages, far beyond MS diagnosis. Increases in the choroid plexus/total intracranial volume (CP/TIV) ratio have been robustly associated with increased lesion load, higher translocator protein (TSPO) uptake in normal-appearing white matter (NAWM) and thalami, as well as with higher annual relapse rate and disability progression in highly active RRMS individuals, but not in progressive MS. The CP/TIV ratio has only slightly been correlated with magnetic resonance imaging (MRI) findings (cortical or whole brain atrophy) and clinical outcomes (EDSS score) in progressive MS. Therefore, we suggest that plexus volumetric assessments should be mainly applied to the early disease stages of MS, whereas it should be taken into consideration with caution in progressive MS. In this review, we attempt to clarify the pathological significance of the temporal CP volume (CPV) changes in MS and highlight the pitfalls and limitations of CP volumetric analysis. [ABSTRACT FROM AUTHOR]

This report delineates the intricate diagnostic journey and therapeutic conundrum presented by a 61-year-old male who exhibited atypical neurological deterioration shortly after lumbar fusion surgery, manifesting clinical and radiological features suggestive of pseudohypoxic encephalopathy, an entity characterized by symptoms mimicking cerebral hypoxia in the absence of a discernible hypoxic insult. Following an initially unremarkable recovery from an elaborate spinal surgery, the patient's postoperative condition was confounded by a perplexing decline in consciousness, unresponsive to conventional therapeutic interventions and devoid of clear etiological indicators on standard neuroimaging. The subsequent diagnostic odyssey unraveled a cerebrospinal fluid leak as the putative reason, positing a nuanced clinical paradigm wherein the cerebrospinal fluid leak engendered a state mimicking pseudohypoxic brain swelling. This report underscores the clinical challenges and emphasizes the need for an astute diagnostic approach in postoperative patients with unexplained neurological symptoms advocating for a comprehensive evaluation to identify underlying cerebrospinal fluid leaks and mitigate potential morbidity. [ABSTRACT FROM AUTHOR]

Purpose. Glioblastoma is the most aggressive primary brain tumor, characterized by its distinctive intratumoral hypoxia. Sequential preoperative examinations using fluorine-18-fluoromisonidazole (18F-FMISO) and fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) could depict the degree of glucose metabolism with hypoxic condition. However, molecular mechanism of glucose metabolism under hypoxia in glioblastoma has been unclear. The aim of this study was to identify the key molecules of hypoxic glucose metabolism. Methods. Using surgically obtained specimens, gene expressions associated with glucose metabolism were analyzed in patients with glioblastoma (n = 33) who underwent preoperative 18F-FMISO and 18F-FDG PET to identify affected molecules according to hypoxic condition. Tumor in vivo metabolic activities were semiquantitatively evaluated by lesion-normal tissue ratio (LNR). Protein expression was confirmed by immunofluorescence staining. To evaluate prognostic value, relationship between gene expression and overall survival was explored in another independent nonoverlapping clinical cohort (n = 17) and validated by The Cancer Genome Atlas (TCGA) database (n = 167). Results. Among the genes involving glucose metabolic pathway, mRNA expression of glucose-6-phosphatase 3 (G6PC3) correlated with 18F-FDG LNR (P = 0.03). In addition, G6PC3 mRNA expression in 18F-FMISO high-accumulated glioblastomas was significantly higher than that in 18F-FMISO low-accumulated glioblastomas (P < 0.01). Protein expression of G6PC3 was consistent with mRNA expression, which was confirmed by immunofluorescence analysis. These findings indicated that the G6PC3 expression might be facilitated by hypoxic condition in glioblastomas. Next, we investigated the clinical relevance of G6PC3 in terms of prognosis. Among the glioblastoma patients who received gross total resection, mRNA expressions of G6PC3 in the patients with poor prognosis (less than 1-year survival) were significantly higher than that in the patients who survive more than 3 years. Moreover, high mRNA expression of G6PC3 was associated with poor overall survival in glioblastoma, as validated by TCGA database. Conclusion. G6PC3 was affluently expressed in glioblastoma tissues with coincidentally high 18F-FDG and 18F-FMISO accumulation. Further, it might work as a prognostic biomarker of glioblastoma. Therefore, G6PC3 is a potential key molecule of glucose metabolism under hypoxia in glioblastoma. [ABSTRACT FROM AUTHOR]

Introduction: Severe acute global cerebral hypoxia can lead to significant disability in humans. Although different animal models have been described to study hypoxia, there is no endogenous model that considers hypoxia and its effect on the brain as an independent factor. Thus, we developed a minimally invasive rat model, which is based on the non-depolarizing muscle blocking agent rocuronium in anesthetized animals. This drug causes respiratory insufficiency by paralysis of the striated muscles. Methods: In this study, 14 rats underwent 12 min of hypoxemia with an oxygen saturation of approximately 60% measured by pulse oximetry; thereafter, animals obtained sugammadex to antagonize rocuronium immediately. Results: Compared to controls (14 rats, anesthesia only), hypoxic animals demonstrated significant morphological alterations in the hippocampus (cell decrease in the CA 1 region) and the cerebellum (Purkinje cell decrease), as well as significant changes in hypoxia markers in blood (Hif2α, Il1β, Tgf1β, Tnfα, S100b, cspg2, neuron-specific enolase), hippocampus (Il1β, Tnfα, S100b, cspg2, NSE), and cerebellum (Hif1α, Tnfα, S100b, cspg2, NSE). Effects were more pronounced in females than in males. Discussion: Consequently, this model is suitable to induce hypoxemia with consecutive global cerebral hypoxia. As significant morphological and biochemical changes were proven, it can be used to investigate therapeutic and preventive drugs for global cerebral hypoxia. [ABSTRACT FROM AUTHOR]

Background: Cerebral ischemia–hypoxia leads to excitotoxicity‐mediated neuronal damage and cognitive dysfunction, especially in the elderly. Excessive intracellular [Cl−]i accumulation weakens γ‐aminobutyric acid (GABA) compensatory effects. Sub‐anesthetic dose of propofol protected the brain against ischemia–hypoxia, which was abolished by blocking Cl− efflux transporter K+/Cl− cotransporter 2 (KCC2). We aimed to determine whether low‐dose anesthetic combined with [Cl−]i regulators could restore the compensatory GABAergic system and improve cognitive function. Methods: Chronic cerebral hypoxia (CCH) model was established by bilateral carotid artery ligation in aged rats. Sub‐dose of anesthetics (propofol and sevoflurane) with or without KCC2 agonist N‐ethylmaleimide (NEM) or Na+/K+/Cl− cotransporter 1 (NKCC1) antagonist bumetanide (BTN) was administered systemically 30 days post‐surgery. Primary rat hippocampal neuronal cultures were subjected to hypoxic injury with or without drug treatment. Memory function, hippocampal neuronal survival, GABAergic system functioning, and brain‐derived neurotrophic factor (BDNF) expressions were evaluated. Results: Sub‐anesthetic dose of combined propofol (1.2 μg mL−1) and sevoflurane [0.7 MAC (minimum alveolar concentration)] did not aggravate the hypoxic brain injury in rats or cell damage in neuronal cultures. Adding either BTN or NEM protected against hypoxic injury, associated with improved cognitive function in vivo, less intracellular accumulation of [Cl−]i, reduced cell death, restored GABAergic compensation, and increased BDNF expression both in vivo and in vitro. Conclusion: Sub‐anesthetic dose of propofol and sevoflurane is a recommended anesthesia regimen in at‐risk patients. Restoration of [Cl−]i homeostasis and GABAergic could further reduce the brain damage caused by ischemia–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]

Objectives: Literature on invasive neuromonitoring and bilateral decompressive craniectomies (BDC) in patients with refractory status epilepticus (RSE)-mediated hypoxic-ischemic brain injury (HIBI) is limited. Neuromonitoring can guide decision making and treatment escalation. Methods and results: We report a case of a 17  years-old male who was admitted to our hospital’s intensive care unit for RSE. HIBI was detected on neuroimaging on this patient’s second day of admission after he developed central diabetes insipidus (DI). Invasive neuromonitoring revealed raised intracranial pressure (ICP) and brain hypoxia as measured by reduced brain tissue oxygen tension (PbtO2). Treatments were escalated in a tiered fashion, including administration of hyperosmolar agents, analgesics, sedatives, and a neuromuscular blocking drug. Eventually, BDC was performed as a salvage therapy as a means of controlling refractory ICP crisis in the setting of diffuse cerebral edema (DCE) following HIBI. Discussion: SE-mediated HIBI can result in refractory ICP crisis. Neuromonitoring can help identify secondary brain injury (SBI), guide treatment strategies, including surgical interventions, and may lead to better outcomes. [ABSTRACT FROM AUTHOR]

The following review considers current concepts concerning the characteristics of DRP1-related mitochondrial division in brain cells during hypoxic-ischemic pathology. The functional role of DRP1 in neurons and astroglia in cerebral ischemia conditions was analyzed. We discuss the potential for regulating DRP1 activity through the selective inhibitor of mitochondrial fission, mdivi-1. The article also presents data on DRP1 involvement in astro- and microglia-mediated intercellular mitochondrial transport. Understanding of the molecular mechanisms responsible for mitochondrial fission during hypoxic-ischemic exposure will allow us to consider DRP1 as an effective therapeutic target for treating conditions with a hypoxic component. [ABSTRACT FROM AUTHOR]

The primary afferent system in the rat's spinal cord starts to develop in the third last week of gestation. First, the pseudounipolar DRG neurons extend their centripetal long primary axons, targeting rostral supra-segmental nuclei in the spinal cord. Meanwhile, the subsequent innervation of the juxta- and intra-segmental spinal levels enables the three subdivisions to commence integrating a complex network with the body periphery. This process may continue to refine and adapt the system life-long. The experimental data elucidated the steps involved in developing the cytoarchitecture by separating the axons of the long and intermediate subdivisions from the short subdivision. Here, we present a blueprint of the features of the long primary afferent axons developing in sequential waves. The pioneering long afferent axons targeted the dorsal gracile nuclei at spring tide and Clarke's nuclei at neap tide in ventrally bent trajectories. The paradigm's myelotomy blocked these pioneering fibers from stepping down the developmental cascade, rendering an unknown phenotype. This reflected a hypothetical transition hub stationed on the assembly line, delineating a critical period. The paradigm also affected the neuropil's ripening independently from the long primary afferent system. The data disclosed that fetal hyposaturation yielded an in vivo genomic engineering capability. Fetal tissue was susceptible to hyposaturation, showing remarkable versatility early in fetal life. The translational impact may favor research into the elusive etiology of clinical syndromes concerning the afferent system relating to fetal hyposaturation. [ABSTRACT FROM AUTHOR]

Cerebral hypoxia is an important cause of secondary brain injury. Improving systemic oxygenation may increase brain tissue oxygenation (PbtO2). The effects of increased positive end-expiratory pressure (PEEP) on PbtO2 and intracranial pressure (ICP) needs to be further elucidated. This is a single center retrospective cohort study (2016–2021) conducted in a 34-bed Department of Intensive Care unit. All patients with acute brain injury under mechanical ventilation who were monitored with intracranial pressure and brain tissue oxygenation (PbtO2) catheters and underwent at least one PEEP increment were included in the study. Primary outcome was the rate of PbtO2 responders (increase in PbtO2 > 20% of baseline) after PEEP increase. ΔPEEP was defined as the difference between PEEP at 1 h and PEEP at baseline; similarly ΔPbtO2 was defined as the difference between PbtO2 at 1 h after PEEP incrementation and PbtO2 at baseline. We included 112 patients who underwent 295 episodes of PEEP increase. Overall, the median PEEP increased form 6 (IQR 5–8) to 10 (IQR 8–12) cmH2O (p = 0.001), the median PbtO2 increased from 21 (IQR 16–29) mmHg to 23 (IQR 18–30) mmHg (p = 0.001), while ICP remained unchanged [from 12 (7–18) mmHg to 12 (7–17) mmHg; p = 0.42]. Of 163 episode of PEEP increments with concomitant PbtO2 monitoring, 34 (21%) were PbtO2 responders. A lower baseline PbtO2 (OR 0.83 [0.73–0.96)]) was associated with the probability of being responder. ICP increased in 142/295 episodes of PEEP increments (58%); no baseline variable was able to identify this response. In PbtO2 responders there was a moderate positive correlation between ΔPbtO2 and ΔPEEP (r = 0.459 [95% CI 0.133–0.696]. The response in PbtO2 and ICP to PEEP elevations in brain injury patients is highly variable. Lower PbtO2 values at baseline could predict a significant increase in brain oxygenation after PEEP increase. [ABSTRACT FROM AUTHOR]

Background/Aim. Several serious complications can accompany both spontaneous and post-traumatic subarachnoid hemorrhage (SAH) such as the development of intracranial hypertension, hydrocephalus, re-bleeding, cerebral hypoxia, cerebral vasospasm, impaired pituitary function, electrolyte imbalance, and electrocardiographic (ECG) abnormalities. Although there is a declining trend in mortality, the treatment of SAH and its complications represents a challenge even in imposing neurosurgical centers. The aim of the study was to compare some clinical characteristics and complications between spontaneous and post-traumatic SAH. Methods. The retrospective study included 138 patients treated at the Department of Neurosurgery from January 2018 to January 2023. There were 71 patients with spontaneous and 67 patients with post-traumatic SAH. Results. A predominance of spontaneous SAH in female and post-traumatic SAH in male patients (p < 0.001) was found. There was a statistically significant difference in the frequency of hydrocephalus between groups of spontaneous and post-traumatic SAH patients (p = 0.013). Cerebral vasospasm was significantly more prevalent in patients with spontaneous SAH (p < 0.001). A statistically significant association was also obtained between the thickness of the coagu-lum in these two groups (p < 0.001). Patients with spontaneous SAH were significantly more likely to have a negative T wave in ECG findings (p < 0.001). Furthermore, there was no statistically significant difference regarding electrolyte imbalance in these two groups of patients with SAH. Conclusion. There were statistically significant differences between gender distribution, the frequency of abnormal ECG findings in the form of a negative T wave, greater coagulum thickness, vasospasm occurrence, and a higher rate of hydrocephalus in patients with spontaneous SAH compared to patients with post-traumatic SAH. [ABSTRACT FROM AUTHOR]

Introduction: Adequate sedation and analgesia are two crucial factors affecting recovery of intensive care patients. Improper use of sedation and analgesia in intensive care patients may adversely lead to brain oxygen desaturation. This study aims to determine cerebral oxygenation as measured by near-infrared spectroscopy (NIRS) and inotropic interventions received among mechanically ventilated children in the pediatric intensive care unit (PICU). Methods: This study is a nested case − control study in the PICU of Indonesian tertiary hospital. Children aged 1 month to 17 years on mechanical ventilation and were given sedation and analgesia were included in the study. Subjects were divided into two groups according to the protocol of the main study (Clinical Trial ID NCT04788589). Cerebral oxygenation was measured by NIRS at five time points (before sedation, 5-min, 1, 6, and 12 h after sedation). Results: Thirty-nine of the 69 subjects were categorized into the protocol group and the rest were in the control group. A decrease of >20% NIRS values was found among subjects in the protocol group at 5-min (6.7%), 1-h (11.1%), 6-h (26.3%), and 12-h (23.8%) time-point. The mean NIRS value was lower and the inotropic intervention was more common in the control group (without protocol), although not statistically significant. Conclusion: This study found that mechanically ventilated children who received sedation and analgesia based on the protocol had a greater decrease of >20% NIRS values compared to the other group. The use of sedation and analgesia protocols must be applied in selected patients after careful consideration. [ABSTRACT FROM AUTHOR]

COVID-19 is a pandemic disease in which most patients have pulmonary symptoms. However, several cases of CNS involvement associated with COVID-19 have been reported. Acute necrotizing encephalopathy of childhood (ANEC) is a rare CNS complication of viral infections such as influenza, herpes virus, and COVID-19, leading to high mortality and morbidity rates. Several cases of COVID-19-associated acute necrotizing encephalopathy (ANE) have been reported since March 2020 in adults, with just a few cases in pediatrics. This article reports a 5-month-old child who presented with seizures, with the final diagnosis of ANE as a complication of COVID-19. MRI findings of ANEC, as reported in most COVID-19-associated ANEC case reports, involve bilateral, symmetric, multifocal lesions in the central thalami. Moreover, the brainstem, cerebral white matter, and cerebellum could be affected. The prognosis of COVID-19-associated ANE is poor, leading to neurologic dysfunction or mortality. COVID-19-associated ANE cases must be reported, especially in pediatrics, with detailed clinical history, laboratory data, and radiologic findings to introduce diagnostic criteria, prognosis, and a management protocol. [ABSTRACT FROM AUTHOR]

Neuronal excitability is a critical feature of central nervous system development, playing a fundamental role in the functional maturation of brain regions, including the hippocampus, cerebellum, auditory and visual systems. The present study aimed to determine the mechanism by which hypoxia causes brain dysfunction through perturbation of neuronal excitability in a hypoxic neonatal mouse model. Functional brain development was assessed in humans using the Gesell Development Diagnosis Scale. In mice, gene transcription was evaluated via mRNA sequencing and quantitative PCR; furthermore, patch clamp recordings assessed potassium currents. Clinical observations revealed disrupted functional brain development in 6‐ and 18‐month‐old hypoxic neonates, and those born with normal hearing screening unexpectedly exhibited impaired central auditory function at 3 months. In model mice, CA1 pyramidal neurons exhibited reduced spontaneous activity, largely induced by excitatory synaptic input suppression, despite the elevated membrane excitability of hypoxic neurons compared to that of control neurons. In hypoxic neurons, Kcnd3 gene transcription was upregulated, confirming upregulated hippocampal Kv4.3 expression. A‐type potassium currents were enhanced, and Kv4.3 participated in blocking excitatory presynaptic inputs. Elevated Kv4.3 activity in pyramidal neurons under hypoxic conditions inhibited excitatory presynaptic inputs and further decreased neuronal excitability, disrupting functional brain development in hypoxic neonates. [ABSTRACT FROM AUTHOR]

Introduction: Neuronal cell death is an important factor in the pathogenesis of acute high-altitude cerebral hypoxia; however, the underlying molecular mechanism remains unclear. In this study, we tested if high-altitude hypoxia (HAH) causes neuronal death and mitochondrial dysfunction using various in vivo and in vitro approaches. Methods: Acute high-altitude cerebral hypoxia was induced by hypobaric hypoxia chamber in male mice. we explored the mechanisms of neuronal cell death using immunofluorescence, western blotting, transmission electron microscopy, and flow cytometry. Next, mitochondrial function and morphology were observed using Jc-1 staining, seahorse assay, western blotting, MitoTracker staining, and transmission electron microscopy. Moreover, open field test, elevated plus test, and Morris water maze were applied for animal behavior. Results: Results revealed that HAH disrupted mitochondrial function and promoted neuronal apoptosis and necroptosis both in HT-22 cells and in mouse hippocampal neurons. Moreover, the mitochondrial membrane potential and adenosine triphosphate production decreased in neurons after HAH, while oxidative stress and mitochondrial fission increased. Behavioral studies suggested that HAH induced anxiety-like behavior and impaired spatial memory, while it had no effect on athletic ability. Discussion: These findings demonstrated that HAH promotes mitochondrial dysfunction and apoptosis of mouse neurons, thus providing new insights into the role of mitochondrial function and neuronal cell death in acute high-altitude cerebral hypoxia. [ABSTRACT FROM AUTHOR]

Accurate identification and characterization of the severity, extent, and location of brain injury is essential to predict the neurodevelopmental outcome of newborns. The pattern of brain injury depends on the severity and duration of hypoxia and degree of brain maturation. Various neuroimaging modalities such as neurosonogram, CT, MRI are available which help in identification of severity of brain injury. Initial scans were obtained within 72 hrs of birth and subsequent follow up scans were done on 8-10th day and 30th day so as not to miss the relatively late developing intracranial changes. The infants were then followed up after 6-12 months for a detailed neurological assessment for correlation of clinical outcome with NSG findings using statistical analysis. In our study 66% newborns were term and 34% were preterm where as in a study by Sushmita et al., it was 76% term and 24% preterms. In our study 26% neonates had HIE I, 58% were HIE II, 16% were HIE III as compared to another study by Behere A et al., in which 11.3% were HIE I, 72.8% were HIE II and 15.95% were HIE III. In our study 90% of cases had abnormal neurosonogram findings and 10% cases had normal neurosonogram. [ABSTRACT FROM AUTHOR]

Background: A wide variety of movement disorders can be observed after cerebral hypoxia, including akineto-hypertonic syndrome and dystonia. Post-anoxic dystonia is a rare clinical syndrome that is not widely reported in the literatures. It is thought to be related to cerebral hypoxia leading to ischaemia of the basal ganglia. Case description: We report a case of an 11-year-old girl who represented with generalized dystonia following resuscitation from a cardiac arrest after open heart surgery. Brain MRI showed basal ganglia hypersignals in T2-FLAIR (fluid attenuated inversion recovery) weighted sequence and in the diffusion sequence without restriction of ACD in favour of subacute ischemic lesions. Treated with oral baclofen, the evolution was favourable with regression of the dystonia. Conclusion: It is often difficult to accurately predict the final neurological outcome of a patient who has survived cardiac arrest. Baclofen and anticholinergic can be used for the treatment for dystonia post-cerebral hypoxia. [ABSTRACT FROM AUTHOR]

Purpose: Recently, cerebral autoregulation indices based on moving correlation indices between mean arterial pressure (MAP) and cerebral oximetry (NIRS, ORx) or transcranial Doppler (TCD)-derived middle cerebral artery flow velocity (Mx) have been introduced to clinical practice. In a pilot study, we aimed to evaluate the validity of these indices using incremental lower body negative pressure (LBNP) until presyncope representing beginning cerebral hypoperfusion as well as lower body positive pressure (LBPP) with added mild hypoxia to induce cerebral hyperperfusion in healthy subjects. Methods: Five male subjects received continuous hemodynamic, TCD and NIRS monitoring. Decreasing levels of LBNP were applied in 5-minute steps until subjects reached presyncope. Increasing levels of LBPP were applied stepwise up to 20 or 25 mmHg. Normobaric hypoxia was added until an oxygen saturation of 84% was reached. This was continued for 10 minutes. ORx and Mx indices were calculated using previously described methods. Results: Both Indices showed an increase > 0.3 indicating impaired cerebral autoregulation during presyncope. However, there was no significant difference in Mx at presyncope compared to baseline (p = 0.168). Mean arterial pressure and cardiac output decreased only in presyncope, while stroke volume was decreased at the last pressure level. Neither Mx nor ORx showed significant changes during LBPP or hypoxia. Agreement between Mx and ORx was poor during the LBNP and LBPP experiments (R2 = 0.001, p = 0.3339). Conclusion: Mx and ORx represent impaired cerebral autoregulation, but in Mx this may not be distinguished sufficiently from baseline. LBPP and hypoxia are insufficient to reach the upper limit of cerebral autoregulation as indicated by Mx and ORx. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO), in conjunction with its life-saving benefits, carries a significant risk of acute brain injury (ABI). Hypoxic-ischemic brain injury (HIBI) is one of the most common types of ABI in ECMO patients. Various risk factors, such as history of hypertension, high day 1 lactate level, low pH, cannulation technique, large peri-cannulation PaCO2 drop (∆PaCO2), and early low pulse pressure, have been associated with the development of HIBI in ECMO patients. The pathogenic mechanisms of HIBI in ECMO are complex and multifactorial, attributing to the underlying pathology requiring initiation of ECMO and the risk of HIBI associated with ECMO itself. HIBI is likely to occur in the peri-cannulation or peri-decannulation time secondary to underlying refractory cardiopulmonary failure before or after ECMO. Current therapeutics target pathological mechanisms, cerebral hypoxia and ischemia, by employing targeted temperature management in the case of extracorporeal cardiopulmonary resuscitation (eCPR), and optimizing cerebral O2 saturations and cerebral perfusion. This review describes the pathophysiology, neuromonitoring, and therapeutic techniques to improve neurological outcomes in ECMO patients in order to prevent and minimize the morbidity of HIBI. Further studies aimed at standardizing the most relevant neuromonitoring techniques, optimizing cerebral perfusion, and minimizing the severity of HIBI once it occurs will improve long-term neurological outcomes in ECMO patients. [ABSTRACT FROM AUTHOR]

Near-infrared spectroscopy (NIRS) is a non-invasive technique for measuring regional tissue haemoglobin (Hb) concentrations and oxygen saturation (rSO2). It may be used to monitor cerebral perfusion and oxygenation in patients at risk of cerebral ischemia or hypoxia, for example, during cardiothoracic or carotid surgery. However, extracerebral tissue (mainly scalp and skull tissue) influences NIRS measurements, and the extent of this influence is not clear. Thus, before more widespread use of NIRS as an intraoperative monitoring modality is warranted, this issue needs to be better understood. We therefore conducted a systematic review of published in vivo studies of the influence of extracerebral tissue on NIRS measurements in the adult population. Studies that used reference techniques for the perfusion of the intra- and extracerebral tissues or that selectively altered the intra- or extracerebral perfusion were included. Thirty-four articles met the inclusion criteria and were of sufficient quality. In 14 articles, Hb concentrations were compared directly with measurements from reference techniques, using correlation coefficients. When the intracerebral perfusion was altered, the correlations between Hb concentrations and intracerebral reference technique measurements ranged between |r| = 0.45–0.88. When the extracerebral perfusion was altered, correlations between Hb concentrations and extracerebral reference technique measurements ranged between |r| = 0.22–0.93. In studies without selective perfusion modification, correlations of Hb with intra- and extracerebral reference technique measurements were generally lower (|r| < 0.52). Five articles studied rSO2. There were varying correlations of rSO2 with both intra- and extracerebral reference technique measurements (intracerebral: |r| = 0.18–0.77, extracerebral: |r| = 0.13–0.81). Regarding study quality, details on the domains, participant selection and flow and timing were often unclear. We conclude that extracerebral tissue indeed influences NIRS measurements, although the evidence (i.e., correlation) for this influence varies considerably across the assessed studies. These results are strongly affected by the study protocols and analysis techniques used. Studies employing multiple protocols and reference techniques for both intra- and extracerebral tissues are therefore needed. To quantitatively compare NIRS with intra- and extracerebral reference techniques, we recommend applying a complete regression analysis. The current uncertainty regarding the influence of extracerebral tissue remains a hurdle in the clinical implementation of NIRS for intraoperative monitoring. The protocol was pre-registered in PROSPERO (CRD42020199053). [ABSTRACT FROM AUTHOR]

The brain needs sufficient oxygen in order to function normally. This is achieved by a large vascular capillary network ensuring that oxygen supply meets the changing demand of the brain tissue, especially in situations of hypoxia. Brain capillaries are formed by endothelial cells and perivascular pericytes, whereby pericytes in the brain have a particularly high 1:1 ratio to endothelial cells. Pericytes not only have a key location at the blood/brain interface, they also have multiple functions, for example, they maintain blood–brain barrier integrity, play an important role in angiogenesis and have large secretory abilities. This review is specifically focused on both the cellular and the molecular responses of brain pericytes to hypoxia. We discuss the immediate early molecular responses in pericytes, highlighting four transcription factors involved in regulating the majority of transcripts that change between hypoxic and normoxic pericytes and their potential functions. Whilst many hypoxic responses are controlled by hypoxia-inducible factors (HIF), we specifically focus on the role and functional implications of the regulator of G-protein signaling 5 (RGS5) in pericytes, a hypoxia-sensing protein that is regulated independently of HIF. Finally, we describe potential molecular targets of RGS5 in pericytes. These molecular events together contribute to the pericyte response to hypoxia, regulating survival, metabolism, inflammation and induction of angiogenesis. [ABSTRACT FROM AUTHOR]

Zinc is an indispensable trace element in the human body and plays an important role in regulating normal growth and development. Zinc homeostasis in the central nervous system is closely related to the development of neuroinflammation, and synaptic zinc homeostasis disorders affect zinc homeostasis in the brain. Under the condition of synaptic zinc homeostasis, proper zinc supplementation improves the body's immunity and inhibits neuroinflammation. Synaptic zinc homeostasis disorder in the brain promotes the occurrence and development of neuroinflammation. Cerebral ischemia and hypoxia cause a massive release of synaptic Zn2+ into the synaptic cleft, resulting in neurotoxicity and neuroinflammation. Synaptic zinc homeostasis disorder is a high-risk factor for neurodegenerative diseases. Maintaining cerebral zinc homeostasis suppresses the progression of neuroinflammation-mediated neurodegenerative diseases. This article reviews the relationship between brain zinc homeostasis and neuroinflammation and proposes that maintaining synaptic zinc homeostasis prevents neuroinflammation. [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]

Occlusion of cerebral blood vessels causes acute cerebral hypoxia—an important trigger of ischemic white matter injury and stroke in sickle cell disease (SCD). While chronic hypoxia triggers compensatory neuroprotection via insulin-like growth factor-1 (IGF-1) and hypoxia inducible factor-1α (HIF-1α), severe bouts of acute hypoxia and subsequent restoration of blood flow (hypoxia/reoxygenation, H/R) overwhelm compensatory mechanisms and cause neuroaxonal damage–identified as white matter lesions–in the brain. The neuroprotective role of IGF-1 in the pathogenesis of white matter injury in SCD has not been investigated; however, it is known that systemic IGF-1 is reduced in individuals with SCD. We hypothesized that IGF-1 supplementation may prevent H/R-induced white matter injury in SCD. Transgenic sickle mice homozygous for human hemoglobin S and exposed to H/R developed white matter injury identified by elevated expression of non-phosphorylated neurofilament H (SMI32) with a concomitant decrease in myelin basic protein (MBP) resulting in an increased SMI32/MBP ratio. H/R-challenge also lowered plasma and brain IGF-1 expression. Human recombinant IGF-1 prophylaxis significantly induced HIF-1α and averted H/R-induced white matter injury in the sickle mice compared to vehicle-treated mice. The expression of the IGF-1 binding proteins IGFBP-1 and IGFBP-3 was elevated in the IGF-1-treated brain tissue indicating their potential role in mediating neuroprotective HIF-1α signaling. This study provides proof-of-concept for IGF-1-mediated neuroprotection in SCD. [ABSTRACT FROM AUTHOR]

The modes of action of insecticides frequently involve a neurotoxic effect; therefore, the study of neurotoxic effects caused by long-term and low-dose insecticide exposure is of particular interest. This study looks at whether or not new studies conducted after 2009 and up to 2021 have provided new evidence for a better understanding of the actual neurobehavioral risk associated with long-term insecticide exposure. We selected and reviewed studies carried out on the neurobehavioral effects of neurotoxic insecticides (organophosphates and/or carbamates, pyrethroids, multiple or undefined insecticides, and organochlorines) considering occupational and non-occupational exposures. The articles were also scored and ranked based on seven parameters. Eighty-six studies were chosen for a final review process from among the 950 scientific papers identified. Twenty-six addressed occupational exposure and six environmental exposure. Among the latter group of studies, 17 focused on rural residents, to be assumed exposed because of living in rural areas, and 43 on the general population. Pending doubts have not been resolved in the last ten years due to the presence of contradictory and hardly comparable results and the fact that in most of the studies showing an evident neurobehavioral impairment the frequent presence of a previous episode of poisoning and hospitalization, with severe brain hypoxia, impaired the possibility of confirming the presence of a causal association with insecticide exposure. Interestingly, the most severely exposed groups, such as applicators who did not wear personal protective equipment, performed worse on neurobehavioral tests. As for residential exposure, there is sufficient evidence to suggest that prenatal OP exposure may increase the risk of ADHD in children. [ABSTRACT FROM AUTHOR]

Background and purposes: There has been both great interest in and skepticism about the strategies for headache inhibition in patients with patent foramen ovale and migraines (PFO-migraine). Furthermore, many questions remain about the fundamental pathophysiology of PFO-migraines. Herein, the inhibiting effect of normobaric oxygenation (NBO) on PFO-migraine was analyzed. Methods: This real-world self-control study consecutively enrolled patients during the ictal phase of migraines who had patent foramen ovale (PFO) confirmed by Trans esophageal Ultrasound(TEE). After comparing the baseline arterial oxygen partial pressure (PaO2) in their blood gas with that of healthy volunteers, all the patients with PFO-migraine underwent treatment with NBO (8 L/min. for 1 h/q8h) inhalation through a mask. Their clinical symptoms, blood gas, and electroencephalograph (EEG) prior to and post-NBO were compared. Results: A total of 39 cases with PFO-migraine (in which 36% of participants only had a small-aperture of PFO) and 20 non-PFO volunteers entered the final analysis. Baseline blood gas analysis results showed that the PaO2 in patients with PFO-migraine were noticeably lower than PaO2 levels in non-PFO volunteers. After all patients with PFO-migraines underwent NBO treatment, 29(74.4%) of them demonstrated dramatic headache attenuation and a remarkable increase in their arterial PaO2 levels after one time treatment of NBO inhalation (p < 0.01). The arterial PaO2 levels in these patients gradually went down during the following 4 h after treatment. 5 patients finished their EEG scans prior to and post-NBO, and 4(80%) were found to have more abnormal slow waves in their baseline EEG maps. In the follow up EEG maps post-NBO treatment for these same 4 patients, the abnormal slow waves disappeared remarkably. Conclusions: Patients with PFO–migraine may derive benefit from NBO treatment. PFOs result in arterial hypoxemia due to mixing of venous blood, which ultimately results in brain hypoxia and migraines. This series of events may be the key pathologic link explaining how PFOs lead to migraines. NBO use may attenuate the headaches from migraines by correcting the hypoxemia. Highlights: Brain hypoxia may be the key point of pathological link between PFO and migraine. NBO may be a feasible promising method on PFO–migraine control. The size of PFO aperture may be not very matched with the severity and the incidence of migraine. [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]

Background: Although blood transfusions can be lifesaving in severe hemorrhage, they can also have potential complications. As anemia has also been associated with poor outcomes in critically ill patients, determining an optimal transfusion trigger is a real challenge for clinicians. This is even more important in patients with acute brain injury who were not specifically evaluated in previous large randomized clinical trials. Neurological patients may be particularly sensitive to anemic brain hypoxia because of the exhausted cerebrovascular reserve, which adjusts cerebral blood flow to tissue oxygen demand. Methods: We described herein the methodology of a prospective, multicenter, randomized, pragmatic trial comparing two different strategies for red blood cell transfusion in patients with acute brain injury: a "liberal" strategy in which the aim is to maintain hemoglobin (Hb) concentrations greater than 9 g/dL and a "restrictive" approach in which the aim is to maintain Hb concentrations greater than 7 g/dL. The target population is patients suffering from traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), or intracerebral hemorrhage (ICH). The primary outcome is the unfavorable neurological outcome, evaluated using the extended Glasgow Outcome Scale (eGOS) of 1–5 at 180 days after the initial injury. Secondary outcomes include, among others, 28-day survival, intensive care unit (ICU) and hospital lengths of stay, the occurrence of extra-cerebral organ dysfunction/failure, and the development of any infection or thromboembolic events. The estimated sample size is 794 patients to demonstrate a reduction in the primary outcome from 50 to 39% between groups (397 patients in each arm). The study was initiated in 2016 in several ICUs and will be completed in December 2022. Discussion: This trial will assess the impact of a liberal versus conservative strategy of blood transfusion in a large cohort of critically ill patients with a primary acute brain injury. The results of this trial will help to improve blood product and transfusion use in this specific patient population and will provide additional data in some subgroups of patients at high risk of brain ischemia, such as those with intracranial hypertension or cerebral vasospasm. Trial registration: ClinicalTrials.gov NCT02968654. [ABSTRACT FROM AUTHOR]

Toll-like receptor 9 (TLR9) is an intracellular innate immunity receptor that plays a vital role in chronic inflammation and in recognizing pathogenic and self-DNA in immune complexes. This activation of intracellular signaling leads to the transcription of either immune-related or malignancy genes through specific transcription factors. Thus, it has been hypothesized that TLR9 may cause glioma. This article reviews the roles of TLR9 in the pathogenesis of glioma and its related signaling molecules in either defending or promoting glioma. TLR9 mediates the invasion-induced hypoxia of brain cancer cells by the activation of matrix metalloproteinases (2, 9, and 13) in brain tissues. In contrast, the combination of the TLR9 agonist CpG ODN to radiotherapy boosts the role of T cells in antitumor effects. The TLR9 agonist CpG ODN 107 also enhances the radiosensitivity of human glioma U87 cells by blocking tumor angiogenesis. CpG enhances apoptosis in vitro and in vivo. Furthermore, it can enhance the antigen-presenting capacity of microglia, switch immune response toward CD8 T cells, and reduce the number of CD4CD25 Treg cells. CpG ODN shows promise as a potent immunotherapeutic drug against cancer, but specific cautions should be taken when activating TLR9, especially in the case of glioblastoma. [ABSTRACT FROM AUTHOR]

Introduction. As a main consumer of energy, the brain is particularly susceptible to the effects of hypoxia. However, during long-term evolution, the brain of the plateau yak developed adaptive mechanisms enabling it to maintain normal physiological conditions. Material and methods. A total of 20 male yaks belonging to two age groups [newborns (1–6 days old; n = 10) and adults (3–5 years old; n = 10)] were obtained, and the brain tissue was fixed and processed by standard methods. RT-qPCR, ELISA and IHC assays were used to investigate the expression and localization of HIF1α, BNIP3 and beclin-1 in the hippocampus, cerebral cortex, thalamus, medulla oblongata and cerebellum of newborn and adult yak brains and to explore their potential neuroprotective role. Results. We found that the expression levels of HIF1α, BNIP3 and beclin-1 at the mRNA and protein levels varied in the different regions of yak brain, with the highest expression observed in the hippocampus, followed by the cerebral cortex, thalamus, medulla oblongata and the cerebellum. Moreover, the HIF1α, BNIP3 and beclin-1 expression were significantly higher in the newborn yaks’ brains than in the adult yak. The IHC results showed that HIF1α, BNIP3 and beclin-1 were mainly distributed in the neurons of the cerebral cortex, hippocampus, thalamus, medulla oblongata and cerebellum. In particular, HIF1α accumulated in the nucleus and cytoplasm. Furthermore, the immunoreactivity of BNIP3 and beclin-1 was concentrated in the cytoplasm. Conclusions. The results indicate that the yak hippocampus and cerebral cortex may be more resistant to hypoxia than thalamus, medulla oblongata and cerebellum, and the expression of BNIP3 and beclin-1 may be regulated by HIF1α to serve a neuroprotective role in the yak’s brain to adaptation to hypoxia. Additionally, the brain of adult yaks may have a higher tolerance to hypoxia than the brain of newborn yaks. [ABSTRACT FROM AUTHOR]

Endotracheal intubation (ETI) is a common intervention performed in a pediatric emergency. The pediatric laryngeal anatomy creates a challenge and requires an expertise for this procedure. Tracheal injury is a rare but serious complication that can occur during ETI. The stylet, if used improperly, can lead to this life-threatening complication. Here, we present a case of tracheal injury in an infant that happened during ETI with stylet use. [ABSTRACT FROM AUTHOR]

Simple Summary: The extent of tumour oxygenation is crucial for glioblastoma progression and the effectiveness of radio- and chemotherapy. Patient-derived in vitro cell cultures are the mainstay of molecular biology research, the discovery of new therapeutic targets, and drug testing. Therefore, mirroring as many aspects of in vivo settings as possible, including oxygen concentration, is desired. Here we analyse the effect of oxygen tension on the transcriptome of numerous patient-derived GBM cells and demonstrate that cells cultured in lowered oxygen tension express more genes indicative of higher levels of hypoxia, metabolic adaptation, stemness and tumour progression than cells growing in standard, atmospheric oxygen concentration. The same transcriptomic pattern was also found in primary GBM samples. Its specificity for GBMs was confirmed using the public TCGA dataset. Our data strongly argue for the benefit of lower oxygen tension during culturing of patient-derived GBM cells to preserve oxygen-sensitive pathways in GBM. The proposed approach better mimics certain aspects of GBM pathophysiology than traditional cultures and may advance GBM research in finding a cure. Despite numerous efforts aiming to characterise glioblastoma pathology (GBM) and discover new therapeutic strategies, GBM remains one of the most challenging tumours to treat. Here we propose the optimisation of in vitro culturing of GBM patient-derived cells, namely the establishment of GBM-derived cultures and their maintenance at oxygen tension mimicking oxygenation conditions occurring within the tumour. To globally analyse cell states, we performed the transcriptome analysis of GBM patient-derived cells kept as spheroids in serum-free conditions at the reduced oxygen tension (5% O2), cells cultured at atmospheric oxygen (20% O2), and parental tumour. Immune cells present in the tumour were depleted, resulting in the decreased expression of the immune system and inflammation-related genes. The expression of genes promoting cell proliferation and DNA repair was higher in GBM cell cultures when compared to the relevant tumour sample. However, lowering oxygen tension to 5% did not affect the proliferation rate and expression of cell cycle and DNA repair genes in GBM cell cultures. Culturing GBM cells at 5% oxygen was sufficient to increase the expression of specific stemness markers, particularly the PROM1 gene, without affecting neural cell differentiation markers. GBM spheroids cultured at 5% oxygen expressed higher levels of hypoxia-inducible genes, including those encoding glycolytic enzymes and pro-angiogenic factors. The genes up-regulated in cells cultured at 5% oxygen had higher expression in parental GBMs compared to that observed in 20% cell cultures, suggesting the preservation of the hypoxic component of GBM transcriptome at 5% oxygen and its loss in standard culture conditions. Evaluation of expression of those genes in The Cancer Genome Atlas dataset comprising samples of normal brain tissue, lower-grade gliomas and GBMs indicated the expression pattern of the indicated genes was specific for GBM. Moreover, GBM cells cultured at 5% oxygen were more resistant to temozolomide, the chemotherapeutic used in GBM therapy. The presented comparison of GBM cultures maintained at high and low oxygen tension together with analysis of tumour transcriptome indicates that lowering oxygen tension during cell culture may more allegedly reproduce tumour cell behaviour within GBM than standard culture conditions (e.g., atmospheric oxygen tension). Low oxygen culture conditions should be considered as a more appropriate model for further studies on glioblastoma pathology and therapy. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) is a type of hemoglobinopathy characterized by abnormal hemoglobin molecules, which includes numerous acute and chronic complications. Ischemic stroke, silent cerebral infarction, headache, and neurocognitive impairment are the most common neurological complications associated with SCD. Summary: Acute anemia because of SCD can cause cognitive impairments because of cerebral hypoxia. Cognitive abnormalities in SCD manifest in various aspects such as working memory, verbal learning, executive functions, and attention. These neurocognitive impairments have been associated with poor functional results, such as transitioning from juvenile to adult care, adherence to medications, and unemployment. Key message: In this review, we focus on neurocognitive aspects of SCD patients based on different imaging techniques, psychological batteries, associated neuromarkers, and interventions for managing of cognitive deficiencies.. [ABSTRACT FROM AUTHOR]

Background: The hyperventilation test is used in clinical practice for diagnosis and therapeutic purposes; however, in the absence of a standardized protocol, the procedure varies significantly, predisposing tested subjects to risks such as cerebral hypoxia and ischemia. Near-infrared spectroscopy (NIRS), a noninvasive technique performed for cerebral oximetry monitoring, was used in the present study to identify the minimum decrease in the end-tidal CO2 (ETCO2) during hyperventilation necessary to induce changes on NIRS. Materials and Methods: We recruited 46 volunteers with no preexisting medical conditions. Each subject was asked to breathe at a baseline rate (8–14 breaths/min) for 2 min and then to hyperventilate at a double respiratory rate for the next 4 min. The parameters recorded during the procedure were the regional cerebral oxyhemoglobin and deoxyhemoglobin concentrations via NIRS, ETCO2, and the respiratory rate. Results: During hyperventilation, ETCO2 values dropped (31.4 ± 12.2%) vs. baseline in all subjects. Changes in cerebral oximetry were observed only in those subjects (n = 30) who registered a decrease (%) in ETCO2 of 37.58 ± 10.34%, but not in the subjects (n = 16) for which the decrease in ETCO2 was 20.31 ± 5.6%. According to AUC-ROC analysis, a cutoff value of ETCO2 decrease >26% was found to predict changes in oximetry (AUC-ROC = 0.93, p < 0.0001). Seven subjects reported symptoms, such as dizziness, vertigo, and numbness, throughout the procedure. Conclusions: The rise in the respiratory rate alone cannot effectively predict the occurrence of a cerebral vasoconstrictor response induced by hyperventilation, and synchronous ETCO2 and cerebral oximetry monitoring could be used to validate this clinical test. NIRS seems to be a useful tool in predicting vasoconstriction following hyperventilation. [ABSTRACT FROM AUTHOR]

Background: Transcranial color-coded duplex sonography (TCCD) can be used as an ancillary test for determining irreversible loss of brain function (ILBF) when demonstration of cerebral circulatory arrest (CCA) is required. However, visualization of the intracranial vessels by TCCD is often difficult, or even impossible, in this patient cohort due to elevated intracranial pressure, an insufficient transtemporal bone window, or warped anatomical conditions. Since extracranial color-coded duplex sonography (ECCD) can be performed without restriction in the aforementioned situations, we investigated the feasibility of omitting TCCD altogether, such that the ILBF examination would be simplified, without compromising on its reliability. Methods: A total of 122 patients were prospectively examined by two experienced neurointensivists for the presence of ILBF from01/2019-12/2021. Inclusion criteria were (i) the presence of a severe cerebral lesion on cranial CT or MRI, and (ii) brainstem areflexia. Upon standardized clinical examination, 9 patients were excluded due to incomplete brainstem areflexia, and a further 22 due to the presence of factors with a potentially confounding influence on apnea testing, EEG or sonography. A total of 91 patients were enrolled and underwent needle-EEG recording for >30min (= gold standard), as well as ECCD and TCCD. The sonographer was blinded to the EEG result. Results: All patients whose ECCD result was consistent with ILBF had this diagnosis confirmed by EEG (n = 77; specificity: 1). Both ECCD and EEG were not consistent with ILBF in a further 12 patients. In the remaining two patients, ECCD detected reperfusion due to long-lasting cerebral hypoxia; however, ILBF was ultimately confirmed by EEG (sensitivity: 0.975). This yielded a positive predictive value (PPV) of one and a negative predictive value of 0.857 for the validity of ECCD in ILBF confirmation. TCCD was not possible/inconclusive in 31 patients (34%). Conclusions: The use of ECCD for the confirmation of ILBF is associated with high levels of specificity and a high positive predictive value when compared to needle-electrode EEG. Thismakes ECCD a potential alternative to the ancillary tests currently used in this setting, but confirmation in a multi-center trial is warranted. [ABSTRACT FROM AUTHOR]

Currently, studies are being conducted on the possible role of the cytoprotective effect of biologically active substances in conditions of cerebral hypoxia or cardiomyopathies. At the same time, oxidative stress is considered one of the important mechanisms of cellular cytotoxicity and a target for the action of cytoprotectors. The aim of this study is to search for derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones. The probability of cytoprotective action was assessed by measuring cell viability using two tests (with neutral red dye and MTT test). It was found that some derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones under the conditions of our experiment had a pronounced cytoprotective activity, providing better cell survival in vitro, including the MTT test and conditions of blood hyperviscosity. To correlate the obtained results in vitro, molecular docking of the synthesized derivatives was also carried out. The standard drug omeprazole (co-crystallized with the enzyme) was used as a standard. It was shown that all synthesized derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones had higher affinity for the selected protein than the standard gastro-cytoprotector omeprazole. The studied derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones also fully satisfy Lipinski's rule of five (RO5), which increases their chances for possible use as orally active drugs with good absorption ability and moderate lipophilicity. Thus, the results obtained make it possible to evaluate derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones as having a relatively high cytoprotective potential. [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]