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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]

Monitoring of brain tissue oxygenation (PbtO2) is an important component of multimodal monitoring in traumatic brain injury. Over recent years, use of PbtO2 monitoring has also increased in patients with poor-grade subarachnoid hemorrhage (SAH), particularly in those with delayed cerebral ischemia. The aim of this scoping review was to summarize the current state of the art regarding the use of this invasive neuromonitoring tool in patients with SAH. Our results showed that PbtO2 monitoring is a safe and reliable method to assess regional cerebral tissue oxygenation and that PbtO2 represents the oxygen available in the brain interstitial space for aerobic energy production (i.e., the product of cerebral blood flow and the arterio-venous oxygen tension difference). The PbtO2 probe should be placed in the area at risk of ischemia (i.e., in the vascular territory in which cerebral vasospasm is expected to occur). The most widely used PbtO2 threshold to define brain tissue hypoxia and initiate specific treatment is between 15 and 20 mm Hg. PbtO2 values can help identify the need for or the effects of various therapies, such as hyperventilation, hyperoxia, induced hypothermia, induced hypertension, red blood cell transfusion, osmotic therapy, and decompressive craniectomy. Finally, a low PbtO2 value is associated with a worse prognosis, and an increase of the PbtO2 value in response to treatment is a marker of good outcome. [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]

Stroke and perinatal asphyxia have detrimental effects on neuronal cells, causing millions of deaths worldwide each year. Since currently available therapies are insufficient, there is an urgent need for novel neuroprotective strategies to address the effects of cerebrovascular accidents. One such recent approach is based on the neuroprotective properties of estrogen receptors (ERs). However, activation of ERs by estrogens may contribute to the development of endometriosis or hormone-dependent cancers. Therefore, in this study, we utilized ospemifene, a novel selective estrogen receptor modulator (SERM) already used in dyspareunia treatment. Here, we demonstrated that posttreatment with ospemifene in primary neocortical cell cultures subjected to 18 h of hypoxia and/or ischemia followed by 6 h of reoxygenation has robust neuroprotective potential. Ospemifene partially reverses hypoxia- and ischemia-induced changes in LDH release, the degree of neurodegeneration, and metabolic activity. The mechanism of the neuroprotective actions of ospemifene involves the inhibition of apoptosis since the compound decreases caspase-3 overactivity during hypoxia and enhances mitochondrial membrane potential during ischemia. Moreover, in both models, ospemifene decreased the levels of the proapoptotic proteins BAX, FAS, FASL, and GSK3β while increasing the level of the antiapoptotic protein BCL2. Silencing of specific ERs showed that the neuroprotective actions of ospemifene are mediated mainly via ESR1 (during hypoxia and ischemia) and GPER1 (during hypoxia), which is supported by ospemifene-evoked increases in ESR1 protein levels in hypoxic and ischemic neurons. The results identify ospemifene as a promising neuroprotectant, which in the future may be used to treat injuries due to brain hypoxia/ischemia. [ABSTRACT FROM AUTHOR]

Syntaxin binding protein 1 (STXBP1), commonly known as MUNC18–1, is a member of SEC1 family membrane trafficking proteins; their function consists in controlling the soluble N-ethylmaleimide-sensitive factor attachment protein receptors complex assembly, making them essentials regulators of vesicle fusion. The precise function and molecular mechanism through which Munc18–1 contributes to neurotransmitter releasing is not entirely understood, but several evidences suggest its probable role in exocytosis. In 2008, heterozygous de novo mutations in neuronal protein Munc18–1 were first referred as a cause of Ohtahara syndrome development. Currently, a wide examination of the published data proved that 3.1% of patients with severe epilepsy carry a pathogenic de novo mutation including STXBP1 and approximately 10.2% of early onset epileptic encephalopathy is due to an aberrant STXBP1 form codified by the mutated gene. STXBP1 mutations can be associated to a wide clinical heterogeneity. All affected individuals show developmental delay and approximately the 95% of cases have seizures and early onset epileptic encephalopathy, characterized by infantile spasms as the main consistent feature. Burst suppression pattern and hypsarrhythmia are the most frequent EEG anomalies. Other neuronal disorders include Rett syndrome and behavioral and movement disorders. Mild dysmorphic features have been detected in a small number of cases. No genotype–phenotype correlation has been reported. Management of STXBP1 encephalopathy requires a multidisciplinary approach, including epilepsy control and neurological rehabilitation. About 25% of patients are refractory to standard therapy. A single or combined antiepileptic drugs may be required. Several studies described vigabatrin, valproic acid, levetiracetam, topiramate, clobazam, and oxcarbazepine as effective in seizure control. Lamotrigine, zonisamide, and phenobarbital are also commonly used. To date, it remains unclear which therapy is the most effective. Severe morbidity and high mortality are inevitable consequences in some of these patients. [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]

Hypoxic–ischemic encephalopathy (HIE) is a leading cause of long‐term neurological disability in neonates and adults. Despite emerging advances in supportive care, like the most effective approach, hypothermia, poor prognosis has still been present in current clinical treatment for HIE. Stem cell therapy has been adopted for treating cerebral ischemia in preclinical and clinical trials, displaying its promising therapeutic value. At present, reported treatments for stroke employed stem cells to replace the lost neurons and integrate them into the existing host circuitry, promoting the release of growth factors to support and stimulate endogenous repair processes and so on. In this review, a meaningful overview to numerous studies published up to now was presented by introducing the preclinical and clinical research status of stem cell therapy for cerebral ischemia and hypoxia, discussing potential therapeutic mechanisms of stem cell transplantation for curing HI‐induced brain injury, summarizing a series of approaches for marking transplanted cells and existing imaging systems for stem cell labelling and in vivo tracking and expounding the endogenous regeneration capability of stem cells in the newborn brain when subjected to an HI insult. Additionally, it is promising to combine stem therapy with neuromodulation through specific regulation of neural circuits. The crucial neural circuits across different brain areas related to functional recovery are of great significance for the application of neuromodulation strategies after the occurrence of neonatal hypoxic–ischemic encephalopathy (NHIE). [ABSTRACT FROM AUTHOR]

Diffuse cortical diffusion changes on magnetic resonance imaging (MRI) are characteristically ascribed to global cerebral anoxia, typically after cardiac arrest. Far from being pathognomonic, however, this neuroimaging finding is relatively nonspecific, and can manifest in a myriad of disease states including hypoxia, metabolic derangements, infections, seizure, toxic exposures, and neuroinflammation. While these various conditions can all produce a neuroimaging pattern of widespread cortical diffusion restriction, many of these underlying causes do have subtly unique imaging features that are appreciable on MRI and can be of clinical and diagnostic utility. Specific populations of neurons are variably sensitive to certain types of injury, whether due to differences in perfusion, receptor type density, or the unique tropisms of infectious organisms. In this narrative review, we discuss a number of distinct etiologies of diffuse cortical diffusion restriction on MRI, the unique pathophysiologies responsible for tissue injury, and the resulting neuroimaging characteristics that can be of assistance in differentiating them. As widespread cortical injury from any cause often presents with altered mental status or coma, the differential diagnosis can be enhanced with rapid acquisition of MRI when clinical history or detailed physical examination is limited. In such settings, the distinct imaging features discussed in this article are of interest to both the clinician and the radiologist. [ABSTRACT FROM AUTHOR]

Objective: Systemic hypoxia occurs in COVID-19 infection; however, it is unknown if cerebral hypoxia occurs in convalescent individuals. We have evidence from other conditions associated with central nervous system inflammation that hypoxia may occur in the brain. If so, hypoxia could reduce the quality of life and brain function. This study was undertaken to assess if brain hypoxia occurs in individuals after recovery from acute COVID-19 infection and if this hypoxia is associated with neurocognitive impairment and reduced quality of life. Methods: Using frequency-domain near-infrared spectroscopy (fdNIRS), we measured cerebral tissue oxygen saturation (StO2) (a measure of hypoxia) in participants who had contracted COVID-19 at least 8 weeks prior to the study visit and healthy controls. We also conducted neuropsychological assessments and health-related quality of life assessments, fatigue, and depression. Results: Fifty-six percent of the post-COVID-19 participants self-reported having persistent symptoms (from a list of 18), with the most reported symptom being fatigue and brain fog. There was a gradation in the decrease of oxyhemoglobin between controls, and normoxic and hypoxic post-COVID-19 groups (31.7 ± 8.3 μM, 27.8 ± 7.0 μM and 21.1 ± 7.2 μM, respectively, p = 0.028, p = 0.005, and p = 0.081). We detected that 24% of convalescent individuals' post-COVID-19 infection had reduced StO2 in the brain and that this relates to reduced neurological function and quality of life. Interpretation: We believe that the hypoxia reported here will have health consequences for these individuals, and this is reflected in the correlation of hypoxia with greater symptomology. With the fdNIRS technology, combined with neuropsychological assessment, we may be able to identify individuals at risk of hypoxia-related symptomology and target individuals that are likely to respond to treatments aimed at improving cerebral oxygenation. [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]

A 30-year-old woman developed symptoms, signs and neurophysiology consistent with Guillain-Barré syndrome and was admitted to the neurosciences intensive care unit owing to respiratory compromise. Here, she received a clonidine infusion for agitation, complicated by a minor hypotensive episode, following which she became unconscious. MR scan of the brain showed changes compatible with hypoxic brain injury. Urinary amino acids showed increased urinary α-ketoglutarate. Genetic testing using whole-exome sequencing identified pathogenic variants in the SLC13A3 gene known to be associated with an acute reversible leukoencephalopathy with increased urinary α-ketoglutarate. The case highlights the importance of considering inborn errors of metabolism in cases of unexplained encephalopathy. [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]

Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease (CLD) and has a complex pathogenesis. Several preclinical and clinical studies have reported the presence of both peripheral and brain inflammation in CLD and their potential impact in the development of HE. Altered brain vascular density and tone, as well as compromised cerebral and systemic blood flow contributing to the development of brain hypoxia, have also been reported in animal models of HE, while a decrease in cerebral metabolic rate of oxygen and cerebral blood flow has consistently been observed in patients with HE. Whilst significant strides in our understanding have been made over the years, evaluating all these mechanistic elements in vivo and showing causal association with development of HE, have been limited through the practical constraints of experimentation. Nonetheless, improvements in non-invasive assessments of different neurophysiological parameters, coupled with techniques to assess changes in inflammatory and metabolic pathways, will help provide more granular insights on these mechanisms. In this special issue we discuss some of the emerging evidence supporting the hypothesis that brain inflammation and abnormal oxygen homeostasis occur interdependently during CLD and comprise important contributors to the development of HE. This review aims at furnishing evidence for further research in brain inflammation and oxygen homeostasis as additional therapeutic targets and potentially diagnostic markers for HE. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cerebral ischemia and hypoxia can trigger a series of complex cascade reactions. Due to its complex pathogenesis, there is no ideal drug for the treatment of cerebral ischemia and hypoxia. OBJECTIVE: To investigate the effects of heat shock proteins on heme oxygenase-1 protein expression and neurological function in rats with cerebral ischemia and hypoxia. METHODS: Thirty rats were randomly divided into sham-operated group, model group, heat shock protein 70 group, with 10 rats in each group. Animal models of cerebral ischemia and hypoxia were made in the latter two groups. Rats in the sham-operated group were given no ligation. After modeling, the heat shock protein 70 group was given tail injection of recombinant adenovirus vAd-HSP70 suspension (0.5 mL), once a day for 3 days. The neurological function, oxidation index, water content and infarct area of the three groups were compared. Hematoxylin-eosin staining was used to observe the morphology of the rat brain. Western blot was used to detect the expression of heme oxygenase-1 protein in the rat brain. RESULTS AND CONCLUSION: Compared with the sham-operated group, the neurological function scores in the model group were significantly decreased, while those in the heat shock protein 70 group were significantly increased (P < 0.05). The brain water content and infarct area of rats in the model group were significantly higher than those in the sham-operated group (P < 0.05), and the brain tissue of rats in the model group had significant changes, with scattered cell distribution, significant loss of cells and increased number of necrotic cells. Compared with the model group, the brain water content and infarct area were significantly decreased in the heat shock protein 70 group (P < 0.05) and the morphology of brain tissue was significantly improved (P < 0.05). The expression of heme oxygenase-1 protein in the brain tissue was significantly lower in the model group than the sham-operated group, but was significantly higher in the heat shock protein 70 group than the model group (P < 0.05). To conclude, heat shock proteins can effectively reduce oxidative stress damage, improve neurological function, and decrease cerebral infarct area and brain water content in the rat model of cerebral ischemia and hypoxia. Its mechanism of action may be related to the increase of heme oxygenase-1 protein expression. [ABSTRACT FROM AUTHOR]

Advancements in cardiac arrest and post-cardiac arrest care have led to improved survival to hospital discharge. While survival to hospital discharge is an important clinical outcome, neurologic recovery is also a priority. With the advancement of targeted temperature management (TTM), the American Heart Association guidelines for post-cardiac arrest care recommend TTM in patients who remain comatose after return of spontaneous circulation (ROSC). Recently, the TTM2 randomized controlled trial found no significant difference in neurologic function and mortality at 6-months between traditional hypothermia to 33°C versus 37.5°C. While TTM has been evaluated for decades, current literature suggests that the use of TTM to 33° when compared to a protocol of targeted normothermia does not result in improved outcomes. Instead, perhaps active avoidance of fever may be most beneficial. Extracorporeal cardiopulmonary resuscitation and membrane oxygenation can provide a means of both hemodynamic support and TTM after ROSC. This review aims to describe the pathophysiology, physiologic aspects, clinical trial evidence, changes in post-cardiac arrest care, potential risks, as well as controversies of TTM. [ABSTRACT FROM AUTHOR]

Cerebral stroke is a serious clinical condition in which oxidative stress, inflammation, necrosis, apoptosis, and autophagy play important roles in its pathogenesis. This study investigated the neuroprotective and healing effects of calcium dobesilate (CD) on cerebral hypoxia/reperfusion injury in rats. Forty Wistar albino male rats, each weighing 300–350 g, were separated into the Control group (no surgery and no pharmacological agent was administered); Sham-A group (only surgery was performed); DBL-A group (surgery was performed and CD 100 mg/kg/day was administered intraperitoneally for 3 days); Sham-C group (only surgery was performed); and DBL-C group (surgery was performed and 100 mg/kg/day CD was administered intraperitoneally for 10 days). Under sedation anesthesia, the bilateral common carotid arteries of all rats except the Control group were clipped for 30 min. After 4 h, the CD was given to the relevant groups, and then, all subjects were euthanized at scheduled times. The brain of each animal was removed for histopathological (hematoxylin and eosin staining), immunohistochemical (beclin-1, anti-MHC class II and anti-CD-68 staining), and biochemical (TNF, IL-1β, IL-6, caspase-3, GSH/GSSG, malondialdehyde, protein carbonyl, LC3II/LC3I, and beclin-1 levels) evaluations. It was observed that CD could reduce necrosis and mitigate polarization of microglia to the M1 phenotype, autophagy, free oxygen radicals, protein carbonylation, lipid peroxidation, IL-1β, IL6, TNF, caspase-3, beclin-1, and LC3II/LC3I levels in acute and chronic periods of hypoxia/reperfusion injury. From these results, it was observed that CD treatment could reduce neuronal necrosis and create anti-inflammatory, anti-edema, anti-oxidant, anti-apoptotic, and anti-autophagic effects in hypoxia/reperfusion injury in rats. [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]

Hypoxic/ischemic brain injuries are a major medical challenge. One of the approaches to the development of therapeutic interventions is elucidating the neuronal survival pathways in O2 deficiency-tolerant vertebrates, which could suggest the ways to mitigate a hypoxia-induced catastrophe in individual nerve cells under conditions of oxygen starvation. Metabolic depression is considered a universal survival strategy for hypoxia-tolerant animals; however, the ins and outs of the mechanism that imposes limitations on brain metabolism when PO2 decreases are still unknown. Under oxygen starvation, an increase in the extracellular concentration of inhibitory neurotransmitters can be one of the significant links in the apparatus for electrical activity suppression, which makes it possible to reduce energy consumption. GABA (γ-aminobutyric acid) serves as a universal inhibitory neurotransmitter in the CNS of higher and lower vertebrates, whose functioning is attributed to metabolic suppression and leveling of energy failure consequences. GABA is found in various vertebrate taxa. This review addresses the strategies of GABA involvement in the mechanisms that ensure brain tolerance to oxygen starvation in members of various taxonomic groups of lower vertebrates (cyclostomes, cartilaginous and bony fish, amphibians, reptiles) distinguished by a most prominent ability to survive under acute and chronic hypoxia-anoxia. [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: Interstitial lung diseases (ILD) are a group of diffuse parenchymal lung disorders associated with cough, dyspnea, hypoxemia and restrictive pulmonary function. Vertigo and dizziness are early symptoms of cerebral hypoxia. The aim of this study was to assess the effect of hypoxia and chronic cough in patients with ILD on central and peripheral vestibular functions. Method: A cross sectional study was conducted in Audio-vestibular unit, ENT Department and Chest Department, Zagazig University Hospitals. Sixty two patients diagnosed to have ILD were included. Full VNG test battery was done. Results: There was statistical significance decrease in mean of optokinetic speed and smooth pursuit gain at high frequency (0.6) in both Rt & LT sides among cases who had moderate hypoxia compared to cases who had mild hypoxia). No difference was found between mild and moderate cases in other oculomotor tests parameters. Also, there was statistical significance increase in frequency of BPPV among cases who had moderate hypoxia compared to cases who had mild hypoxia. Conclusions: Degree of hypoxia was correlated with both central and peripheral vestibular functions. [ABSTRACT FROM AUTHOR]

Background: Cardiac arrest with subsequent cardiopulmonary resuscitation is common in emergency medicine and is often associated with an unfavorable neurologic outcome. Lactate level corresponds to the severity of tissue hypoxia and damage and thus could be useful in predicting neurologic outcome. Objectives: To investigate whether lactate and its clearance can serve as early prognostic biomarkers of neurologic outcome after cardiopulmonary resuscitation. Methods: This study was a retrospective analysis of 249 patients of the Kliniken Maria Hilf hospital who survived at least 12 hours after cardiac arrest and cardiopulmonary resuscitation between 2012 and 2020. Multivariable logistic regressions were performed to correlate the neurologic outcome with lactate level, lactate clearance, and treatment-related patient data to identify factors that are predictors of neurologic outcome. Results: A lactate level greater than 4.2 mmol/L at admission was significantly associated with an unfavorable neurologic outcome. Among patients with a lactate level greater than 4.2 mmol/L at admission, lactate clearance at 24 hours after admission that was greater than 80.9% was associated with a significant decrease in the probability of an unfavorable neurologic outcome. Conclusions: These results suggest that lactate and its clearance have an impact on neurologic outcome and can be used as prognostic biomarkers and in treatment decision-making in patients with cardiac arrest and successful resuscitation. [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]

This prospective study investigated and analyzed the clinical characteristics and prognosis of paroxysmal sympathetic hyperactivity (PSH) in patients with severe nontraumatic brain injury. Patients presenting with severe nontraumatic brain injury with PSH from July 2018 to June 2019 were enrolled. A PSH assessment measure ≥ 8 points was used as the criterion for PSH. Clinical data, indicators related to PSH, treatment effects and the prognosis were prospectively collected and analyzed. A total of 220 patients with severe nontraumatic brain injury were analyzed, and PSH occurred in 8 patients (3.6%). The primary neurological diseases included acute cerebral infarction, anti-N-methyl-D-aspartate receptor encephalitis, hypoxic encephalopathy and acute disseminated encephalitis. The Glasgow Coma Scale score was lower than 8 in the 8 patients with PSH. Seven of these eight patients had a Glasgow outcome scale (GOS) score of 3 or less than 3, and one patient had a GOS of 5 after 6 months. The medicines that effectively controlled PSH included dexmedetomidine, clonazepam, midazolam and diazepam. Although the incidence was lower for nontraumatic brain injury complicated with PSH than for traumatic brain injury, patients with PSH had a more severe disease state and poorer prognoses. Dexmedetomidine might effectively control PSH. [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]

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]

The brain is the most sensitive organ to hypoxia in the human body. Hypoxia in the brain will lead to damage to local brain tissue. When the blood supply of ischemic brain tissue is restored, the damage will worsen, that is, cerebral ischemia–reperfusion injury. Hydrogen sulfide (H2S) is a gaseous signal molecule and a novel endogenous neuroregulator. Indeed, different concentrations of H2S have different effects on neurons. Low concentration of H2S can play an important protective role in cerebral ischemia–reperfusion injury by inducing anti-oxidative stress injury, inhibition of inflammatory response, inhibition of cell apoptosis, reduction of cerebrovascular endothelial cell injury, regulation of autophagy, and other ways, which provides a new idea for clinical diagnosis and treatment of related diseases. This review aims to report the recent research progress on the dual effect of H2S on brain tissue during cerebral ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has been associated with mild cerebral dysfunction and cognitive decline, although the exact pathophysiological mechanism remains ambiguous. Using a diet-induced model of NAFLD and monocarboxylate transporter-1 (Mct1 +/−) haploinsufficient mice, which resist high-fat diet-induced hepatic steatosis, we investigated the hypothesis that NAFLD leads to an encephalopathy by altering cognition, behaviour, and cerebral physiology. We also proposed that global MCT1 downregulation offers cerebral protection. Behavioural tests were performed in mice following 16 weeks of control diet (normal chow) or high-fat diet with high fructose/glucose in water. Tissue oxygenation, cerebrovascular reactivity, and cerebral blood volume were monitored under anaesthesia by multispectral optoacoustic tomography and optical fluorescence. Cortical mitochondrial oxygen consumption and respiratory capacities were measured using ex vivo high-resolution respirometry. Microglial and astrocytic changes were evaluated by immunofluorescence and 3D reconstructions. Body composition was assessed using EchoMRI, and liver steatosis was confirmed by histology. NAFLD concomitant with obesity is associated with anxiety- and depression-related behaviour. Low-grade brain tissue hypoxia was observed, likely attributed to the low-grade brain inflammation and decreased cerebral blood volume. It is also accompanied by microglial and astrocytic morphological and metabolic alterations (higher oxygen consumption), suggesting the early stages of an obesogenic diet-induced encephalopathy. Mct1 haploinsufficient mice, despite fat accumulation in adipose tissue, were protected from NAFLD and associated cerebral alterations. This study provides evidence of compromised brain health in obesity and NAFLD, emphasising the importance of the liver–brain axis. The protective effect of Mct1 haploinsufficiency points to this protein as a novel therapeutic target for preventing and/or treating NAFLD and the associated brain dysfunction. This study is focused on unravelling the pathophysiological mechanism by which cerebral dysfunction and cognitive decline occurs during NAFLD and exploring the potential of monocarboxylate transporter-1 (MCT1) as a novel preventive or therapeutic target. Our findings point to NAFLD as a serious health risk and its adverse impact on the brain as a potential global health system and economic burden. These results highlight the utility of Mct1 transgenic mice as a model for NAFLD and associated brain dysfunction and call for systematic screening by physicians for early signs of psychological symptoms, and an awareness by individuals at risk of these potential neurological effects. This study is expected to bring attention to the need for early diagnosis and treatment of NAFLD, while having a direct impact on policies worldwide regarding the health risk associated with NAFLD, and its prevention and treatment. [Display omitted] • Diet-induced NAFLD and associated systemic alterations result in behavioural changes and low-grade brain tissue hypoxia. • Brain hypoxia is likely linked to the induced low-grade brain inflammation, as well as cerebrovascular, glial, and metabolic alterations. • Mct1 haploinsufficient mice are protected from NAFLD and detrimental cerebral alterations. • MCT1 is a potential novel therapeutic target for preventing and/or treating NAFLD and the associated multifactorial encephalopathy. [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]

Background: Citrobacter freundii is a common cause of neonatal intensive care unit (NICU) outbreaks, causing high morbidity and mortality as a hospital-acquired pathogen. This is the first study from our geographic region, which makes it of utmost importance for spreading awareness about this unusual pathogen amongst healthcare settings. Aim: Investigating an outbreak caused by C. freundii in the NICU of a tertiary care hospital. Settings and Design: During the month of May 2023, an outbreak of C. freundii causing neonatal septicaemia was suspected in the NICU of a tertiary care hospital in Western Uttar Pradesh. The outbreak was investigated and surveillance conducted by the hospital infection control (HIC) team, to find a source of the infection by root cause analysis (RCA), to study clinical profiles and outcomes, to determine their antimicrobial susceptibility pattern, to take corrective action preventive action (CAPA). Materials and Methods: A total of 132 blood samples were tested for blood culture and sensitivity using the BD FX40 system. Positive flagged bottles were processed for Gram stain and sub-cultured on 5% sheep blood agar and MacConkey's agar media plates. Final bacterial identification and antibiotic susceptibility were done with an automated BD-Phoenix M-50 system. Results: C. freundii with similar antimicrobial susceptibility was identified in seven neonates, contributing to a major percentage of neonatal blood culture positivity of 13.7%, out of a total positivity rate of 38.63%. The mortality rate of this outbreak was 28.57%. The HIC team investigates this outbreak for CAPA and RCA. On environmental surveillance, C. freundii was isolated from infant incubators, dressing trolleys, and laryngoscope blades of the NICU. Discussion: C. freundii association in Blood culture from critical areas patients is life-threatening 'Consociatio Vita Minabatur Procursus'. Direct access to the bloodstream causing neonatal septicaemia in a short time is a concern for its potential severity, making it as 'Periculosus Pathogen'. Laboratory automation and implementation of strict infection control strategies in critical areas can improve clinical outcomes and prevent future outbreaks. [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]

This critique evaluates a letter to the editor discussing the role of brain tissue oxygen partial pressure (PbtO2) monitoring in the prognosis of patients with traumatic brain injury (TBI). The meta-analysis aims to synthesize existing evidence, highlighting the potential of PbtO2 monitoring as an early indicator of cerebral hypoxia and its correlation with improved patient outcomes. Despite these promising findings, the analysis is constrained by significant methodological variability among the included studies, potential publication bias, and the practical challenges of implementing PbtO2 monitoring widely. The letter emphasizes the need for standardized protocols and further research to solidify the clinical utility of PbtO2 monitoring and integrate it with other monitoring strategies for comprehensive TBI management. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major public health burden, causing death and disability worldwide. Intracranial hypertension and brain hypoxia are the main mechanisms of secondary brain injury. As such, management strategies guided by intracranial pressure (ICP) and brain oxygen (PbtO2) monitoring could improve the prognosis of these patients. Our objective was to summarize the current evidence regarding the impact of PbtO2-guided therapy on the outcome of patients with TBI. We performed a systematic search of PubMed, Scopus, and the Cochrane library databases, following the protocol registered in PROSPERO. Only studies comparing PbtO2/ICP–guided therapy with ICP-guided therapy were selected. Primary outcome was neurological outcome at 3 and 6 months assessed by using the Glasgow Outcome Scale; secondary outcomes included hospital and long-term mortality, burden of intracranial hypertension, and brain tissue hypoxia. Out of 6254 retrieved studies, 15 studies (n = 37,245 patients, of who 2184 received PbtO2-guided therapy) were included in the final analysis. When compared with ICP-guided therapy, the use of combined PbO2/ICP–guided therapy was associated with a higher probability of favorable neurological outcome (odds ratio 2.21 [95% confidence interval 1.72–2.84]) and of hospital survival (odds ratio 1.15 [95% confidence interval 1.04–1.28]). The heterogeneity (I2) of the studies in each analysis was below 40%. However, the quality of evidence was overall low to moderate. In this meta-analysis, PbtO2-guided therapy was associated with reduced mortality and more favorable neurological outcome in patients with TBI. The low-quality evidence underlines the need for the results from ongoing phase III randomized trials. [ABSTRACT FROM AUTHOR]

Introduction: Neurodevelopmental impairment is a growing concern for preterm infants who received surgical ligation of patent ductus arteriosus (PDA). We aimed to explore the cerebral hemodynamics during the critical period of PDA ligation. Methods: Very-low-birth-weight (VLBW) preterm infants who underwent PDA ligation were prospectively enrolled. Patients were monitored preoperatively and until 72 h post-ligation. Middle cerebral artery (MCA) flow, regional cerebral oxygen saturation (rcSO2), and cardiac output were measured through Doppler ultrasound, near-infrared spectroscopy, and electrical cardiometry, respectively. Using rcSO2 <55% indicating cerebral hypoxia, the duration (% of time) and burden (cumulative negative quantity of rsSO2 <55% × the period [minutes]) were estimated. An abnormal MCA was defined as an MCA flow of <10th percentile of flow velocity or >90th percentile of pulsatility or resistance index. Poor outcomes were defined as in-hospital death or neurologic disorders, either neuroimaging or functional abnormalities, upon discharge. Results: Thirty-two VLBW infants were examined, and 15 (46.9%) had poor outcomes. Infants with poor outcomes had significantly longer duration of cerebral hypoxia (5.4 [2.2–32.3] vs. 1.8 [0.4–5.6] %, p = 0.033) and worse hypoxic burden (2,118 [684–13,549] vs. 622 [88–1,669] %minutes, p = 0.027). In a linear mixed model, rcSO2 was positively correlated with arterial saturation (β 0.860, 95% CI: 0.649–1.070) and negatively correlated with abnormal MCA flow (β −5.287, 95% CI: −8.238 to −2.335). Conclusion: Longer duration of cerebral hypoxia and worse hypoxic burden post-ligation was associated with an increased risk of in-hospital mortality or neurologic disorders upon discharge in VLBW preterm infants. [ABSTRACT FROM AUTHOR]

Currently, there is a new surge of interest in the problem of hypoxia, almost lost in recent decades. Due to the fact that the circle of competent specialists in this field has significantly narrowed, it is necessary to carry out an intensive exchange of knowledge. In order to inform a wide range of interested researchers and doctors, this review summarizes the current understanding of hypoxia, its pathogenic and adaptogenic consequences, as well as key physiological and molecular mechanisms that implement the response to hypoxia at various levels—from cellular to organismic. The review presents a modern classification of forms of hypoxia, the understanding of which is necessary for the formation of a scientifically based approach to experimental modeling of hypoxic states. An analysis of the literature covering the history and current level of hypoxia modeling in mammals and human experiments, including methods for creating moderate hypoxia used to increase the resistance of the nervous system to severe forms of hypoxia and other extreme factors, is carried out. Special attention is paid to the discussion of the features and limitations of various approaches to the creation of hypoxia, as well as the disclosure of the potential for the practical application of moderate hypoxic effects in medicine. [ABSTRACT FROM AUTHOR]

Behavioral changes in newborn 3-day-old rats (n=44) with modeled hypoxic-ischemic brain injury (HIBI) were observed, and the expression of CDK8 in brain tissues was detected to clarify the significance of CDK8. In 30 min, 3 h, and 3 days after HIBI, the left (ischemic) hemisphere was taken for examination. In 3 days after HIBI, the rat pups were examined in the behavioral tests. In rat pups with HIBI, changes of CDK8 expression were detected by Western blotting and real-time PCR and changes in the righting reflex and forelimb grip strength test (p<0.05) were revealed in comparison with sham-operated animals. The expression of CDK8 increased 30 min after HIBI and decreased in 3 h and 3 days. Hypoxia and ischemia of the left brain may affect locomotion, but not sensation. Since CDK8 is involved in the immune response after cerebral hypoxia and ischemia, this kinase can be used as an early diagnostic index. [ABSTRACT FROM AUTHOR]

Since 2020, the COVID-19 pandemic, triggered by SARS-CoV-2, represents the major global issue affecting the lifestyle of people around the world. Wuhan, China was the first city to detect the SARS-CoV-2 virus, but the virus soon spread around the world, forcing the World Health Organization to declare a global epidemic on March 11, 2020 (1). Previous pathological conditions or comorbidities such as old age are one of the main causes of premature death and increased morbidity and mortality due to COVID-19 (4). Inactivity due to hospitalization and bed rest and reduced physical activity due to constant quarantine and social distancing can reduce the ability of organ systems to resist viral infection and the risk of damage to the immune, respiratory, and Increase cardiovascular systems, musculoskeletal and nervous system (4). On the other hand, the health benefits of physical activity, from cardiovascular health to mental health, have been well established (5). Decreased physical activity and increased sedentary behaviors were reported during quarantine in several populations, including children and patients with a variety of medical conditions (6). In general, COVID)19 lifestyle changes have led to a decrease in physical activity and consequently more inactivity in different parts of the community, which can pose a risk to general or mental health, especially for certain populations. In this study, we have tried to review the neurological and psychological effects of COVID-19 and the resulting lifestyle changes, and specifically the role of exercise in relation to these effects. Central nervous system (CNS) and peripheral nervous system (PNS) manifestations can occur during and after COVID-19, but the underlying mechanisms, symptomatology, and frequency of these complications are not well understood (7). Limited postmortem studies have shown signs of hypoxic brain damage and inflammatory neurological changes in the brainstem, while neuropathological data from the PNS are almost non-existent. Due to the cause, direct invasion of acute respiratory syndrome of COVID-19 virus to nerve tissue has been suggested in several cases, but autoimmune damage and neurological complications related to intensive care management can also be effective. The contribution of these mechanisms to the overall burden of CNS and PNS complications of COVID-19 is unknown (7). Follow-ups in Germany and the United Kingdom have shown that neuropsychological symptoms after COVID-19 in 20 to 70% of patients, even in young adults, last for months after the onset of respiratory symptoms, suggesting brain involvement persists (9). COVID-19, which enters through angiotensin)converting enzyme receptors, can damage endothelial cells, leading to inflammation, thrombosis, and brain damage. In addition, systemic inflammation leads to a decrease in monoamines and neurotrophic factors and activation of microglia, which leads to an increase in glutamate and N-methyl-d-aspartate-3 and excitatory toxicity, and these factors cause the onset or exacerbation of existing neuropsychiatric symptoms. They are already (9). However, the extent of damage caused by the COVID-19 pandemic strain is still speculated; it has recently been suggested that irregular neuro-endocrine-immune interactions may be behind psychiatric manifestations observed in quarantined individuals (12, 13). Persistent and increased stressful events can direct immune, endocrine, and nervous system responses primarily through hypothalamic-pituitary-adrenal (HPA) mediated dysfunction (12), and changes in the levels of systemic inflammatory mediators or the brain predispose individuals to pathological psychological conditions. It acts like anxiety and depression. In addition, stress can be a potential trigger for neuroinflammation, a term used to indicate an imbalance or intensification of immune signals in the brain that can lead to several disorders such as aggression, psychosis, depression, and anxiety disorders (12). Covid 19 has also been shown to alter nerve growth factors that may affect the neuropsychological effects of Covid-19 (16,17). The current situation of the epidemic as a stressful situation has led to a decrease in physical activity in the general population. Considering that exercise training has been shown to be useful in a number of pathologies with which post-COVID-19 syndrome bears similarities in terms of symptoms and possible pathogenic mechanisms; therefore, it is necessary to consider the potential optimal effect that this has on the improvement or prevention of COVID-19 neuropsychiatric complications. Despite the benefits of exercise, there are limitations to sports activities for different people, which can endanger the neurological and mental health of different people, especially people with underlying diseases or people with special conditions such as patients, children and the elderly. A review of a study that specifically looked at the effect of exercise training on nerve function in patients with COVID-19 were not found; However, based on trials, general recommendations for exercise training in patients have been identified that may be beneficial to the neurocognitive effects of COVID-19 in both healthy individuals and those with COVID-19 syndrome. There is ample evidence that appropriate, supervised exercise may be an effective multisystem therapy to reduce the neuropsychological effects of COVID-19 syndrome, which is commensurate with the variety of cases and symptoms. Further studies on the effects of exercise-based therapies on post-COVID-19 syndrome are needed to provide practical insights into what type of exercise training should preferably be prescribed, with an emphasis on weight management and adherence strategies. In addition, the effect of post-COVID-19 syndrome on neuropsychological complications of certain demographic groups such as children, adolescents or the elderly remains unknown; Even exercise training and rehabilitation programs for neuropsychiatric complications in these individuals are not known. Overall, a multidisciplinary and integrated approach, part of which is related to sports science, is essential to improve individuals' clinical conditions; nevertheless, neurological and psychological aspects must be integrated into the assessment, as well as the social impact that this pathology entails. Due to the limitations of studies, new proposals for long-term research into the disease in an effort to restore full function and return to previous life are recommended. [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: Prior studies have investigated the association between duration of resuscitation and short-term outcomes following in-hospital cardiac arrest (IHCA). However, it remains unknown whether there is an association between duration of resuscitation and long-term survival and functional outcomes.Method: We linked data from the Danish in-hospital cardiac arrest registry with nationwide registries and identified 8,727 patients between 2013 and 2019. Patients were stratified into four groups (A-D) according to quartiles of duration of resuscitation. Standardized average probability of outcomes was estimated using logistic regression.Results: Of 8,727 patients, 53.1% (n = 4,604) achieved return of spontaneous circulation. Median age was 74 (1st-3rd quartile [Q1-Q3] 65-81 years) and 63.1% were men. Among all IHCA patients the standardized 30-day survival was 62.0% (95% CI 59.8-64.2%) for group A (<5 minutes), 32.7% (30.8-34.6%) for group B (5-11 minutes), 14.4% (12.9-15.9%) for group C (12-20 minutes) and 8.1% (7.0-9.1%) for group D (21 minutes or more). Similarly, 1-year survival was also highest for group A (50.4%; 48.2-52.6%) gradually decreasing to 6.6% (5.6-7.6%) in group D. Among 30-day survivors, survival without anoxic brain damage or nursing home admission within one-year post-arrest was highest for group A (80.4%; 78.2-82.6%), decreasing to 73.3% (70.0-76.6%) in group B, 67.2% (61.7-72.6%) in group C and 73.3% (66.9-79.7%) in group D.Conclusion: Shorter duration of resuscitation attempt during an IHCA is associated with higher 30-day and 1-year survival. Furthermore, we found that the majority of 30-day survivors were still alive 1-year post-arrest without anoxic brain damage or nursing home admission despite prolonged resuscitation. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate electroencephalogram (EEG) parameters using computerized data processing methods to analyze the possible neurophysiological mechanisms underlying changes seen in patients in the somatogenic phase of acute poisoning with opioid receptor agonists. Materials and methods. The study included 31 patients in the somatogenic phase of acute poisoning with opioid receptor agonists with a level of consciousness of 3–15 points on the Glasgow Coma Scale. EEG recordings were made in accordance with the guidelines of the International Federation of Clinical Neurophysiologists. Indicators of brain electrical activity were analyzed and EEG data were processed by computer (spectral analysis, localization of equivalent dipole sources of pathological brain electrical activity, localization of equivalent current density maxima for EEG oscillations in the neocortex). Results and discussion. The EEG of most (65%, n = 20) patients was dominated by δ-range oscillations. Eight patients showed marked EEG changes, with a maximum amplitude of background oscillations of up to 45–55 μV in the absence of an α rhythm (four patients), though oscillations in the α frequency range could also be present in the EEG with an index of no more than 15–20% of the overall duration of the EEG recording (three patients) and, in one case, bilateral bursts of δ range oscillations (amplitude up to 145 μV) generalized in both hemispheres on this background. Gross EEG changes with diffuse slow-wave activity were detected in 12 patients, with dominance of δ-range index and power. The amplitude of the background δ oscillations was in the range 55–170 μV, reaching 200 μV during bilateral bursts. Conclusions. These results suggest that the EEG changes detected in these patients result from dysfunction of generator mechanisms of both the cortical and the arousal structures of the brain, while the slow-wave, predominantly δ activity, recorded here, taking into account the time the recordings were made (the somatogenic phase), may be due to the actions of secondary modifying factors (hypoxia and cerebral edema). [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]