Clinical studies implicate the perioperative period in cognitive complications, and increasing experimental evidence shows that the anesthetic agents can affect neuronal processes that underpin ...learning and memory. Calcineurin, a Ca-dependent phosphatase critically involved in synaptic plasticity, is activated after isoflurane exposure, but its role in the neurological response to anesthesia is unclear.
We investigated the effect of chronic calcineurin inhibition on postanesthetic cognitive function. Mice were treated with 30 minutes of isoflurane anesthesia during a chronic cyclosporine A regimen. Behavioral end points during the perianesthesia period were quantified. Visuospatial learning was assessed with the water radial arm maze. Total and biotinylated surface protein expression of the α5β3γ2 γ-aminobutyric acid (GABA) type A receptors was measured. Expression of the GABA synthesis enzyme glutamate decarboxylase (GAD)-67 was also measured.
Mice treated with cyclosporine A before anesthesia showed significant deficits in visuospatial learning compared to sham and cyclosporine A-treated mice (n = 10 per group, P = .0152, Tukey post hoc test). Induction and emergence were unaltered by cyclosporine A. Analysis of hippocampal protein expression revealed an increased surface expression of the α5 GABA type A receptor subunit after isoflurane treatment (P = .019, Dunnett post hoc testing), as well as a decrease in GAD-67 expression. Cyclosporine A did not rescue either effect.
Our results confirm the work of others that isoflurane induces changes to inhibitory network function and exclude calcineurin inhibition via cyclosporine A as an intervention. Further, our studies suggest that calcineurin mediates a protective role in the neurological response to anesthesia, and patients receiving cyclosporine A may be an at-risk group for memory problems related to anesthesia.
Telemetric electroencephalography (EEG) recording, using subdermal needle electrodes, is a minimally-invasive method to investigate mammalian neurophysiology during anesthesia. These inexpensive ...systems may streamline experiments examining global brain phenomena during surgical anesthesia or disease. We utilized the OpenBCI™ Cyton board with subdermal needle electrodes to extract EEG features in six C57BL/6J mice undergoing isoflurane anesthesia. Burst suppression ratio (BSR) and spectral features were compared for a verification of our method. Following an increase from 1.5% to 2.0% isoflurane, the BSR increased (Wilcoxon-signed-rank statistic; p = 0.0313). Furthermore, although the absolute EEG spectral power decreased, the relative spectral power remained comparable (Wilcoxon-Mann-Whitney U-Statistic; 95% CI exclusive AUC=0.5; p < 0.05). Compared to tethered systems, this method confers several improvements for anesthesia specific protocols: 1-Avoiding electrode implant surgical procedures, 2-Anatomical non-specificity for needle electrode placement to monitor global cortical activity representative of anesthetic state, 3-Facility to repeat recordings in the same animal, 4-User-friendly for non-experts, 5-Rapid set-up time, and 6-Lower costs.•Minimally-invasive telemetric EEG recording systems ergonomically improve tethered systems for anesthesia protocols.•Using this method, we verified that higher isoflurane concentrations resulted in an increased EEG burst suppression ratio and decreased EEG absolute spectral power, with no change in frequency distribution.
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This study examined the short- and long-term neuroprotective and analgesic activity of honokiol (a naturally occurring lignan isolated from Magnolia) on developing brains in neonates exposed to ...inflammatory pain, known to cause neuronal cell death. Postnatal day 4 (P4) neonatal rat pups were subjected to intraplantar formalin injection to four paws as a model of severe neonatal pain. Intraperitoneal honokiol (10 mg/kg) or corn oil vehicle control was administered 1 h prior to formalin insult, and animals were maintained on honokiol through postnatal day 21 (P21). Behavioral tests for stress and pain were performed after the painful insult, followed by morphological examinations of the brain sections at P7 and P21. Honokiol significantly attenuated acute pain responses 30 min following formalin insult and decreased chronic thermal hyperalgesia later in life. Honokiol-treated rats performed better on tests of exploratory behavior and performed significantly better in tests of memory. Honokiol treatment normalized hippocampal and thalamic c-Fos and hippocampal alveus substance P receptor expression relative to controls at P21. Together, these findings support that (1) neonatal pain experiences predispose rats to the development of chronic behavioral changes and (2) honokiol prevents and reduces both acute and chronic pathological pain-induced deteriorations in neonatal rats.
Thrombin’s role in the nervous system is not well understood. Under conditions of blood–brain barrier compromise (e.g., neurosurgery or stroke), thrombin can result in neuroapoptosis and the ...formation of glial scars. Despite this, preconditioning with thrombin has been found to be neuroprotective in models of cerebral ischemia and intracerebral hemorrhage. We investigated the effects of physiologically relevant concentrations of thrombin on cortical neurons using two culture-based assays. We examined thrombin’s effect on neurites by quantitative analysis of fluorescently labeled neurons. To characterize thrombin’s effects on neuron survival, we spectrophotometrically measured changes in enzymatic activity. Using receptor agonists and thrombin inhibitors, we separately examined the role of thrombin and its receptor in neuroprotection. We found that low concentrations of thrombin (1 nM) enhances neurite growth and branching, neuron viability, and protects against excitotoxic damage. In contrast, higher concentrations of thrombin (100 nM) are potentially detrimental to neuronal health as evidenced by inhibition of neurite growth. Lower concentrations of thrombin resulted in equivalent neuroprotection as the antifibrinolytic, aprotinin, and the direct thrombin inhibitor, argatroban. Interestingly, exogenous application of the species-specific thrombin inhibitor, antithrombin III, was detrimental to neuronal health; suggesting that some endogenous thrombin is necessary for optimal neuron health in our culture system. Activation of the thrombin receptor, protease-activated receptor-1 (PAR-1), via micromolar concentrations of the thrombin receptor agonist peptide, TRAP, did not adversely affect neuronal viability. An optimal concentration of thrombin exists to enhance neuronal health. Neurotoxic effects of thrombin do not involve activation of PAR receptors and thus separate pharmacologic manipulation of thrombin’s receptor in the setting of direct thrombin inhibitors could be a potential neuroprotective strategy.
We have determined Li abundances for eleven metal-poor turnoff stars, among which eight have Fe/H <-3, based on LTE analyses of high-resolution spectra obtained with the High Dispersion Spectrograph ...on the Subaru Telescope. The Li abundances for four of these eight stars are determined for the first time by this study. Effective temperatures are determined by a profile analysis of H alpha and H beta . While seven stars have Li abundances as high as the Spite Plateau value, the remaining four objects with Fe/H <-3 have A(Li) =log (Li/H)+ 12 2.0, confirming the existence of extremely metal-poor (EMP) turnoff stars having low Li abundances, as reported by previous work. The average of the Li abundances for stars with Fe/H<-3 is lower by 0.2 dex than that of the stars with higher metallicity. No clear constraint on the metallicity dependence or scatter of the Li abundances is derived from our measurements for the stars with Fe/H<-3. Correlations of the Li abundance with effective temperatures, with abundances of Na, Mg, and Sr, and with the kinematical properties are investigated, but no clear correlation is seen in the EMP star sample.
Excess death estimates quantify the full impact of the coronavirus disease 2019 (COVID-19) pandemic. Widely reported U.S. excess death estimates have not accounted for recent population changes, ...especially increases in the population older than 65 years.
To estimate excess deaths in the United States in 2020, after accounting for population changes.
Surveillance study.
United States, March to August 2020.
All decedents.
Age-specific excess deaths in the United States from 1 March to 31 August 2020 compared with 2015 to 2019 were estimated, after changes in population size and age were taken into account, by using Centers for Disease Control and Prevention provisional death data and U.S. Census Bureau population estimates. Cause-specific excess deaths were estimated by month and age.
From March through August 2020, 1 671 400 deaths were registered in the United States, including 173 300 COVID-19 deaths. An average of 1 370 000 deaths were reported over the same months during 2015 to 2019, for a crude excess of 301 400 deaths (128 100 non-COVID-19 deaths). However, the 2020 U.S. population includes 5.04 million more persons aged 65 years and older than the average population in 2015 to 2019 (a 10% increase). After population changes were taken into account, an estimated 217 900 excess deaths occurred from March through August 2020 (173 300 COVID-19 and 44 600 non-COVID-19 deaths). Most excess non-COVID-19 deaths occurred in April, July, and August, and 34 900 (78%) were in persons aged 25 to 64 years. Diabetes, Alzheimer disease, and heart disease caused the most non-COVID-19 excess deaths.
Provisional death data are underestimated because of reporting delays.
The COVID-19 pandemic resulted in an estimated 218 000 excess deaths in the United States between March and August 2020, and 80% of those deaths had COVID-19 as the underlying cause. Accounting for population changes substantially reduced the excess non-COVID-19 death estimates, providing important information for guiding future clinical and public health interventions.
National Cancer Institute.
The electroencephalogram (EEG) during the re-establishment of consciousness after general anesthesia and surgery varies starkly between patients. Can the EEG during this emergence period provide a ...means of estimating the underlying biological processes underpinning the return of consciousness? Can we use a model to infer these biological processes from the EEG patterns? A frontal EEG was recorded from 84 patients. Ten patients were chosen for state-space analysis. Five showed archetypal emergences; which consisted of a progressive decrease in alpha power and increase peak alpha frequency before return of responsiveness. The five non-archetypal emergences showed almost no spectral EEG changes (even as the volatile general anesthetic decreased) and then an abrupt return of responsiveness. We used Bayesian methods to estimate the likelihood of an EEG pattern corresponding to the position of the patient on a 2-dimensional manifold in a state space of excitatory connection strength vs. change in intrinsic resting neuronal membrane conductivity. We could thus visualize the trajectory of each patient in the state-space during their emergence period. The patients who followed an archetypal emergence displayed a very consistent pattern; consisting of progressive increase in conductivity, and a temporary period of increased connection strength before return of responsiveness. The non-archetypal emergence trajectories remained fixed in a region of phase space characterized by a relatively high conductivity and low connection strength throughout emergence. This unexpected progressive increase in conductivity during archetypal emergence may be due to an abating of the surgical stimulus during this period. Periods of high connection strength could represent forays into dissociated consciousness, but the model suggests all patients reposition near the fold in the state space to take advantage of bi-stable cortical dynamics before transitioning to consciousness.
The definition of frailty, as modeled by the Fried criteria, has been limited primarily to the physical domain. The purpose of this study was to assess the additive value of cognitive function with ...existing frailty criteria to predict poor postoperative outcomes in a large multidisciplinary cohort of patients undergoing major operations.
A 4-level composite frailty scoring system was created via the combination of the Fried frailty score and the Emory Clock Draw Test to assess preoperative frailty and cognitive impairment, respectively. Overall survival was defined as months from date of operation to date of death or last follow-up.
This study included 330 patients undergoing major operations; mean age was 58 years and a total of 53 patient deaths occurred during 4-year follow-up. Among the robust cohort, 20 of 168 patients died (11.9%), and among those who were both physically frail and cognitively impaired, 11 of 26 patients died (42.3%). Multivariable analysis demonstrated the physically frail and cognitively impaired cohort to have a 3.92 higher risk of death (95% CI 1.66 to 9.26) compared with the cohort of robust patients (p = 0.002). Kaplan-Meier survival curves reveal an overall difference in long-term survival (log-rank p < 0.0001), driven mainly by the high risk of mortality among patients with both physical frailty and cognitive impairment.
The use of a combined frailty and cognitive assessment score has a more powerful potential to predict adult patients at higher risk of overall survival than either measurement alone. The addition of cognitive assessment to physical frailty measure can lead to improved preoperative decision making and possibly early intervention, as well as more accurate patient counseling.
Rhinovirus (RV) infections in asthmatic patients are often associated with asthma exacerbation, characterized by worsened airways hyperreactivity and increased immune cell infiltration to the ...airways. The C-X-C chemokines, CXCL3 and CXCL5, regulate neutrophil trafficking to the lung via CXCR2, and their expression in the asthmatic lung is associated with steroid-insensitive type 2 inflammatory signatures. Currently, the role of CXCL3 and CXCL5 in regulating neutrophilic and type 2 responses in viral-induced asthma exacerbation is unknown. Inhibition of CXCL3 or CXCL5 with silencing RNAs in a mouse model of RV-induced exacerbation of asthma attenuated the accumulation of CXCR2
neutrophils, eosinophils, and innate lymphoid cells in the lung and decreased production of type 2 regulatory factors IL-25, IL-33, IL-5, IL-13, CCL11, and CCL24. Suppression of inflammation was associated with decreased airways hyperreactivity, mucus hypersecretion, and collagen deposition. Similar results were obtained by employing RC-3095, which has been shown to bind to CXCR2, or by depletion of neutrophils. Our data demonstrate that CXCL3 and CXCL5 may be critical in the perpetuation of RV-induced exacerbation of asthma through the recruitment of CXCR2-positive neutrophils and by promoting type 2 inflammation. Targeting the CXCL3/CXCL5/CXCR2 axis may provide a new therapeutic approach to attenuating RV-induced exacerbations of asthma.
Anesthetics produce unconsciousness by modulating ion channels that control neuronal excitability. Research has shown that specific GABA
A
receptor (GABA
A
R) subtypes in particular regions of the ...central nervous system contribute to different hyperpolarizing conductances, and behaviorally to distinct components of the anesthetized state. The expression of these receptors on the neuron cell surface, and thus the strength of inhibitory neurotransmission, is dynamically regulated by intracellular trafficking mechanisms. Pharmacologic or activity-based perturbations to these regulatory systems have been implicated in pathology of several neurological conditions, and can alter the individual response to anesthesia. Furthermore, studies are beginning to uncover how anesthetic exposure itself elicits enduring changes in subcellular physiology, including the processes that regulate ion channel trafficking. Here, we review the mechanisms that determine GABA
A
R surface expression, and elaborate on influences germane to anesthesia and emergence. We address known trafficking differences between the intrasynaptic receptors that mediate phasic current and the extra-synaptic receptors mediating tonic current. We also describe neurophysiologic consequences and network-level abnormalities in brain function that result from receptor trafficking aberrations. We hypothesize that the relationship between commonly used anesthetic agents and GABA
A
R surface expression has direct consequences on mature functioning neural networks and by extension ultimately influence the outcome of patients that undergo general anesthesia. Rational design of new anesthetics, anesthetic techniques, EEG-based monitoring strategies, or emergence treatments will need to take these effects into consideration.
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