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Despite the absence of responsiveness during anesthesia, conscious experience may persist. However, reliable, easily acquirable and interpretable neurophysiological markers of the presence of consciousness in unresponsive states are still missing. A promising marker is based on the decay-rate of the power spectral density (PSD) of the resting EEG. We acquired resting electroencephalogram (EEG) in three groups of healthy participants (n = 5 each), before and during anesthesia induced by either xenon, propofol or ketamine. Dosage of each anesthetic agent was tailored to yield unresponsiveness (Ramsay score = 6). Delayed subjective reports assessed whether conscious experience was present (‘Conscious report’) or absent/inaccessible to recall (‘No Report’). We estimated the decay of the PSD of the resting EEG—after removing oscillatory peaks—via the spectral exponent β, for a broad band (1–40 Hz) and narrower sub-bands (1–20 Hz, 20–40 Hz). Within-subject anesthetic changes in β were assessed. Furthermore, based on β, ‘Conscious report’ states were discriminated against ‘no report’ states. Finally, we evaluated the correlation of the resting spectral exponent with a recently proposed index of consciousness, the Perturbational Complexity Index (PCI), derived from a previous TMS-EEG study. The spectral exponent of the resting EEG discriminated states in which consciousness was present (wakefulness, ketamine) from states where consciousness was reduced or abolished (xenon, propofol). Loss of consciousness substantially decreased the (negative) broad-band spectral exponent in each subject undergoing xenon or propofol anesthesia—indexing an overall steeper PSD decay. Conversely, ketamine displayed an overall PSD decay similar to that of wakefulness—consistent with the preservation of consciousness—yet it showed a flattening of the decay in the high-frequencies (20–40 Hz)—consistent with its specific mechanism of action. The spectral exponent was highly correlated to PCI, corroborating its interpretation as a marker of the presence of consciousness. A steeper PSD of the resting EEG reliably indexed unconsciousness in anesthesia, beyond sheer unresponsiveness. •Unconsciousness does not imply unresponsiveness.•Consciousness is abolished during xenon and propofol, yet preserved during ketamine.•EEG Spectral exponent indexes the 1/f-like decay of non-oscillatory PSD background.•Xenon and propofol steepen broad-band decay; ketamine flattens high-frequency decay.•Spectral exponent separates un/consciousness in anesthesia-induced unresponsiveness.

Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement. Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36–43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155. The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference −0·01, 95% CI −0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded. Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia. UK Medical Research Council.

In hyperpolarized xenon magnetic resonance imaging (HP (129)Xe MRI), the inhaled spin-1/2 isotope of xenon gas is used to generate the MR signal. Because hyperpolarized xenon is an MR signal source with properties very different from those generated from water-protons, HP (129)Xe MRI may yield structural and functional information not detectable by conventional proton-based MRI methods. Here we demonstrate the differential distribution of HP (129)Xe in the cerebral cortex of the rat following a pain stimulus evoked in the animal's forepaw. Areas of higher HP (129)Xe signal corresponded to those areas previously demonstrated by conventional functional MRI (fMRI) methods as being activated by a forepaw pain stimulus. The percent increase in HP (129)Xe signal over baseline was 13-28%, and was detectable with a single set of pre and post stimulus images. Recent innovations in the production of highly polarized (129)Xe should make feasible the emergence of HP (129)Xe MRI as a viable adjunct method to conventional MRI for the study of brain function and disease.

Background Traumatic brain injury (TBI) is a major cause of morbidity and mortality, but there are no clinically proven treatments that specifically target neuronal loss and secondary injury development following TBI. In this study, we evaluate the effect of xenon treatment on functional outcome, lesion volume, neuronal loss and neuroinflammation after severe TBI in rats. Methods Young adult male Sprague Dawley rats were subjected to controlled cortical impact (CCI) brain trauma or sham surgery followed by treatment with either 50% xenon:25% oxygen balance nitrogen, or control gas 75% nitrogen:25% oxygen. Locomotor function was assessed using Catwalk-XT automated gait analysis at baseline and 24 h after injury. Histological outcomes were assessed following perfusion fixation at 15 min or 24 h after injury or sham procedure. Results Xenon treatment reduced lesion volume, reduced early locomotor deficits, and attenuated neuronal loss in clinically relevant cortical and subcortical areas. Xenon treatment resulted in significant increases in Iba1-positive microglia and GFAP-positive reactive astrocytes that was associated with neuronal preservation. Conclusions Our findings demonstrate that xenon improves functional outcome and reduces neuronal loss after brain trauma in rats. Neuronal preservation was associated with a xenon-induced enhancement of microglial cell numbers and astrocyte activation, consistent with a role for early beneficial neuroinflammation in xenon’s neuroprotective effect. These findings suggest that xenon may be a first-line clinical treatment for brain trauma.

Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable “biological gas” (CO, H2, H2S, NO, O2, O3, and N2O) or “noble gas” (He, Ar, and Xe) treatment may preserve cells against common pathologies by regulating oxidative, inflammatory, apoptotic, survival, and/or repair processes. Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO‐CO, HIF‐1α/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF‐1α/ERK activation. Primary findings also reveal that the need to utilize cutting‐edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad‐spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma. This systematic review is focused on tissue protections, mechanisms, data qualities, and translational challenges of experimental gas therapies. The outcome suggests that biological/noble gases in safe dosages preserve cells by modulating oxidative, inflammatory, apoptotic, survival, and/or repair processes; it remains urgent to validate therapeutic targets via cutting‐edge molecular/genetic technologies. Gas agents may be developed to treat organ failure and neurotrauma.

We show that the general anesthetics xenon, sulfur hexafluoride, nitrous oxide, and chloroform cause rapid increases of different magnitude and time course in the electron spin content of Drosophila . With the exception of CHCl ₃, these changes are reversible. Anesthetic-resistant mutant strains of Drosophila exhibit a different pattern of spin responses to anesthetic. In two such mutants, the spin response to CHCl ₃ is absent. We propose that these spin changes are caused by perturbation of the electronic structure of proteins by general anesthetics. Using density functional theory, we show that general anesthetics perturb and extend the highest occupied molecular orbital of a nine-residue α-helix. The calculated perturbations are qualitatively in accord with the Meyer–Overton relationship and some of its exceptions. We conclude that there may be a connection between spin, electron currents in cells, and the functioning of the nervous system.

Research has indicated that general anesthetics may potentially induce neuroapoptosis, resulting in long-term neurological deficits in the developing brain. Fortunately, xenon, a noble gas, emerges as a promising candidate for an ideal anesthetic due to its favorable properties, offering neuroprotection and mitigating the neurotoxic effects of other general anesthetics during early life stages. Nevertheless, it is important to highlight that xenon has also been observed to cause neuroapoptosis in the neonatal brain, suggesting that xenon possesses both neuroprotective qualities (as evidenced by pre-clinical and clinical studies) and neurotoxic potential (based mainly on pre-clinical evidence) during brain development. To gain a comprehensive understanding the effects xenon, this review will explore the anesthetic properties of xenon, examine its effects on anesthesia, and elucidate its mechanisms of potential neuroprotection and neurotoxicity in the developing brain. The primary emphasis will be on xenon’s application in the context of anesthetic-induced developmental neurotoxicity (AIDN), hypoxic-ischemic encephalopathy (HIE), and teratogenicity, aiming to provide valuable insights for pediatricians, pediatric anesthesiologists, and other healthcare professionals involved in the use and study of xenon anesthesia.

Background The licensed anesthetic xenon, which exerts organ protective properties, was recently added by the World Anti-Doping Agency to the list of prohibited substances. Xenon is supposed to trigger the production of hypoxia-inducible factor 1α (HIF-1α) and subsequently erythropoietin, but data are limited to in vivo experimental work. Therefore we evaluated the effect of xenon on erythropoietin levels in healthy persons. Methods Twenty-four healthy volunteers were randomly assigned either to a group spontaneously breathing xenon 30 % (Xe/O 2 30 %/60 %) or a group breathing control gas (N 2 /O 2 40 %/60 %) for 45 min. Primary outcome parameters were erythropoietin levels at several time-points after exposure. Secondary outcome parameters were serum levels of testosterone, cytokines, and growth factors as well as concentrations of xenon in blood and exhalation samples measured at several time-points after exposure. In addition, hemodynamic safety parameters were monitored during exposure. Results The administration of xenon significantly increased erythropoietin levels 8 h after exposure (1.34 [±0.368]; p  = 0.008), peaking at 24 h compared to the baseline values (1.45 [±0.498]; p  = 0.01) and remained traceable in blood and exhalation probes until 24 h after exposure. In contrast, no significant change was observed in the control group. Measurement of stromal cell-derived factor 1 (SDF-1) revealed a significant increase of SDF-1 levels ( p  = 0.005), whereas no differences were observed with respect to growth factors, cytokines, or androgens. In an in vitro chemotaxis assay, endothelial progenitor cells (EPCs) showed a trend towards increased migration in serum samples received from participants after xenon exposure ( p  = 0.080). Conclusion The present study presents first evidence about a xenon-induced effect on increased erythropoietin levels in healthy volunteers. The study was registered at the European Medicines Agency (EudraCT-number: 2014-000973-38) and at ClinicalTrials.gov (NCT number: 02129400).

Previous studies have shown that xenon reduces hyperpolarization-activated cyclic nucleotide-gated channels type-2 (HCN2) channel-mediated current (Ih) amplitude and shifts the half-maximal activation voltage (V1/2) in thalamocortical circuits of acute brain slices to more hyperpolarized potentials. HCN2 channels are dually gated by the membrane voltage and via cyclic nucleotides binding to the cyclic nucleotide-binding domain (CNBD) on the channel. In this study, we hypothesize that xenon interferes with the HCN2 CNBD to mediate its effect. Using the transgenic mice model HCN2EA, in which the binding of cAMP to HCN2 was abolished by two amino acid mutations (R591E, T592A), we performed ex-vivo patch-clamp recordings and in-vivo open-field test to prove this hypothesis. Our data showed that xenon (1.9 mM) application to brain slices shifts the V1/2 of Ih to more hyperpolarized potentials in wild-type thalamocortical neurons (TC) (V1/2: −97.09 [−99.56–−95.04] mV compared to control −85.67 [−94.47–−82.10] mV; p = 0.0005). These effects were abolished in HCN2EA neurons (TC), whereby the V1/2 reached only −92.56 [−93.16– −89.68] mV with xenon compared to −90.03 [−98.99–−84.59] mV in the control (p = 0.84). After application of a xenon mixture (70% xenon, 30% O2), wild-type mice activity in the open-field test decreased to 5 [2–10] while in HCN2EA mice it remained at 30 [15–42]%, (p = 0.0006). In conclusion, we show that xenon impairs HCN2 channel function by interfering with the HCN2 CNBD site and provide in-vivo evidence that this mechanism contributes to xenon-mediated hypnotic properties.

The aim of this study was to evaluate the neuroprotective efficacy of the inert gas xenon as a treatment for patients with blast-induced traumatic brain injury in an in vitro laboratory model. We developed a novel blast traumatic brain injury model using C57BL/6N mouse organotypic hippocampal brain-slice cultures exposed to a single shockwave, with the resulting injury quantified using propidium iodide fluorescence. A shock tube blast generator was used to simulate open field explosive blast shockwaves, modeled by the Friedlander waveform. Exposure to blast shockwave resulted in significant (p < 0.01) injury that increased with peak-overpressure and impulse of the shockwave, and which exhibited a secondary injury development up to 72 h after trauma. Blast-induced propidium iodide fluorescence overlapped with cleaved caspase-3 immunofluorescence, indicating that shock-wave–induced cell death involves apoptosis. Xenon (50% atm) applied 1 h after blast exposure reduced injury 24 h (p < 0.01), 48 h (p < 0.05), and 72 h (p < 0.001) later, compared with untreated control injury. Xenon-treated injured slices were not significantly different from uninjured sham slices at 24 h and 72 h. We demonstrate for the first time that xenon treatment after blast traumatic brain injury reduces initial injury and prevents subsequent injury development in vitro. Our findings support the idea that xenon may be a potential first-line treatment for those with blast-induced traumatic brain injury.