Metformin monotherapy versus predominantly older non-metformin antidiabetic medications for cerebrovascular risk in early type 2 diabetes management.

AIM: Choosing the initial treatment for type 2 diabetes (T2D) is pivotal, requiring consideration of solid clinical evidence and patient characteristics. Despite metformin's historical preference, its efficacy in preventing cerebrovascular events lacked empirical validation. This study aimed to evaluate the associations between first-line monotherapy (metformin or non-metformin antidiabetic medications) and cerebrovascular complications in patients with T2D without diabetic complications. METHODS: We analysed 9090 patients with T2D without complications who were prescribed either metformin or non-metformin medications as initial therapy. Propensity score matching ensured group comparability. Cox regression analyses, stratified by initial metformin use, assessed cerebrovascular disease risk, adjusting for multiple covariates and using competing risk analysis. Metformin exposure was measured using cumulative defined daily doses. RESULTS: Metformin users had a significantly lower crude incidence of cerebrovascular diseases compared with non-users (p < .0001). Adjusted hazard ratios (aHRs) consistently showed an association between metformin use and a lower risk of overall cerebrovascular diseases (aHRs: 0.67-0.69) and severe events (aHRs: 0.67-0.69). The association with reduced risk of mild cerebrovascular diseases was significant across all models (aHRs: 0.73-0.74). Higher cumulative defined daily doses of metformin correlated with reduced cerebrovascular risk (incidence rate ratio: 0.62-0.94, p < .0001), indicating a dose-dependent effect. CONCLUSION: Metformin monotherapy is associated with a reduced risk of cerebrovascular diseases in early-stage T2D, highlighting its dose-dependent efficacy. However, the observed benefits might also be influenced by baseline differences and the increased risks associated with other medications, such as sulphonylureas. These findings emphasize the need for personalized diabetes management, particularly in mitigating cerebrovascular risk in early T2D stages.

Adverse postoperative outcomes in elderly patients with sarcopenia.

PURPOSE: No study has compared 30-day and 90-day adverse postoperative outcomes between old-age patients with and those without sarcopenia. PATIENTS AND METHODS: We categorize elderly patients receiving major surgery into two groups according to the presence or absence of preoperative sarcopenia that were matched at a 1:4 ratio through propensity score matching (PSM). We analyzed 30-day or 90-day adverse postoperative outcomes and mortality in patients with and without sarcopenia receiving major surgery. RESULTS: Multivariate logistic regression analyses revealed that the patients with preoperative sarcopenia were at significantly higher risk of 30-day postoperative mortality (adjusted odds ratio [aOR]. = 1.25; 95% confidence interval [CI]. = 1.03-1.52) and 30-day major complications such as postoperative pneumonia (aOR = 1.15; 95% CI = 1.00-1.40), postoperative bleeding (aOR = 2.18; 95% CI = 1.04-4.57), septicemia (aOR = 1.31; 95% CI = 1.03-1.66), and overall complications (aOR = 1.13; 95% CI = 1.00-1.46). In addition, surgical patients with sarcopenia were at significantly higher risk of 90-day postoperative mortality (aOR = 1.50; 95% CI = 1.29-1.74) and 90-day major complications such as pneumonia (aOR = 1.27; 95% CI = 1.10-1.47), postoperative bleeding (aOR = 1.90; 95% CI = 1.04-3.48), septicemia (aOR = 1.52; 95% CI = 1.28-1.82), and overall complications (aOR = 1.24; 95% CI = 1.08-1.42). CONCLUSIONS: Sarcopenia is an independent risk factor for 30-day and 90-day adverse postoperative outcomes such as pneumonia, postoperative bleeding, and septicemia and increases 30-day and 90-day postoperative mortality among patients receiving major surgery. No study has compared 30-day and 90-day adverse postoperative outcomes between patients with and those without sarcopenia. We conducted a propensity score?matched (PSM) population-based cohort study to investigate the adverse postoperative outcomes and mortality in patients undergoing major elective surgery with preoperative sarcopenia versus those without preoperative sarcopenia. We demonstrated that sarcopenia is an independent risk factor for 30-day and 90-day adverse postoperative outcomes, such as postoperative pneumonia, bleeding, septicemia, and mortality after major surgery. Therefore, surgeons and anesthesiologists should attempt to correct preoperative sarcopenia, swallowing function, and respiratory muscle training before elective surgery to reduce postoperative complications that contribute to the decrease in surgical mortality.

Microstructure and Properties of Pressureless-Sintered Zirconium Carbide Ceramics with MoSi2 Addition.

Zirconium carbide (ZrC) ceramics have a high melting point, low neutron absorption cross section, and excellent resistance to the impact of fission products and are considered to be one of the best candidate materials for fourth-generation nuclear energy systems. ZrC ceramics with a high relative density of 99.1% were successfully prepared via pressureless sintering using a small amount of MoSi2 as an additive. The influence of the MoSi2 content on the densification behavior, microstructure, mechanical properties, and thermal properties of ZrC ceramics was systematically investigated. The results show that the densification of ZrC was significantly enhanced by the introduction of MoSi2 due to the formation of a liquid phase during sintering. In addition, the ZrC grains were refined due to the pinning effect of the generated silicon carbide. The flexural strength and Vickers hardness of ZrC ceramics with 2.5 vol% MoSi2 sintered at 1850 °C were 408 ± 12 MPa and 17.1 GPa, respectively, which were approximately 30% and 10% higher compared to the samples without the addition of MoSi2. The improved mechanical properties were mainly attributed to the high relative density (99.1%) and refined microstructure.

Effect of Ti Doping on the Microstructure and Properties of SiCp/Al Composites by Pressureless Infiltration.

The effects of Ti doping on the microstructure and properties of SiCp/Al composites fabricated by pressureless infiltration were comprehensively investigated using first-principles calculations and experimental analyses. First-principles calculations revealed that the interface wetting and bonding strength in an Al/SiC system could be significantly enhanced by Ti doping. Subsequently, the Ti element was incorporated into SiC preforms in the form of TiO2 and TiC to verify the influence of Ti doping on the pressureless infiltration performance of SiCp/Al composites. The experimental results demonstrated that the pressureless infiltration of molten Al into SiC preforms was promoted by adding TiC or TiO2 due to the improved wettability. However, incorporating TiO2 leads to the growth of AlN whiskers under a N2 atmosphere, thereby hindering the complete densification of the composites. On the other hand, TiC doping can improve wettability and interface strength without deleterious reactions. As a consequence, the TiC-doped SiCp/Al composites exhibited excellent properties, including a high relative density of 99.4%, a bending strength of 287 ± 18 MPa, and a thermal conductivity of 142 W·m-1·K-1.

Persistence of analgesic usage and opioid consumption in sarcopenic patients undergoing neuraxial anesthesia: a nationwide retrospective cohort study.

Introduction: This study investigates the association between chronic postsurgical pain (CPSP) and long-term postsurgical analgesic usage in patients undergoing neuraxial anesthesia, with a specific focus on the presence or absence of sarcopenia. Objectives: To assess the rate of analgesic prescription, including opioids, at 3 and 6 months postsurgery for patients with and without preoperative sarcopenia, and to determine the impact of sarcopenia on analgesic use after neuraxial anesthesia surgery. Methods: Patients undergoing surgery under neuraxial anesthesia were categorized into sarcopenic and nonsarcopenic groups based on preoperative diagnosis using the ICD-10-CM code M62.84. Propensity score matching in a 1:4 ratio was applied for group matching. Analgesic prescription rates were evaluated at 3 and 6 months postsurgery, and multivariable logistic regression was used to analyze analgesic use, comparing patients with and without preoperative sarcopenia. Results: Among 3805 surgical patients, 761 had sarcopenia, while 3044 did not. At 3 months postsurgery, 62.3% of sarcopenic patients received analgesics, with 2.9% receiving opioids, compared to 57.1% of nonsarcopenic patients receiving analgesics and 0.8% receiving opioids. At 6 months postsurgery, 30.8% of sarcopenic patients received analgesics (1.7% opioids), while 26.3% of non-sarcopenic patients received analgesics (0.3% opioids). Multivariable logistic regression analysis revealed that preoperative sarcopenia was significantly associated with higher analgesic prescription rates at both 3 months (adjusted odds ratio [aOR], 1.27; 95% confidence interval [CI], 1.05-1.53) and 6 months (aOR, 1.17; 95% CI, 1.07-1.42) postsurgery. Furthermore, sarcopenic patients exhibited significantly higher opioid prescription rates at 3 months (aOR, 1.11; 95% CI, 1.05-2.45) and 6 months (aOR, 1.89; 95% CI, 1.12-4.96) postsurgery. Conclusion: Sarcopenia emerges as an independent risk factor for prolonged analgesic use after neuraxial anesthesia surgery and significantly elevates the risk of developing CPSP.

Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders.

In recent years, sevoflurane and isoflurane are the most popular anesthetics in general anesthesia for their safe, rapid onset, and well tolerant. Nevertheless, many studies reported their neurotoxicity among pediatric and aged populations. This effect is usually manifested as cognitive impairment such as perioperative neurocognitive disorders. The wide application of sevoflurane and isoflurane during general anesthesia makes their safety a major health concern. Evidence indicates that iron dyshomeostasis and ferroptosis may establish a role in neurotoxicity of sevoflurane and isoflurane. However, the mechanisms of sevoflurane- and isoflurane-induced neuronal injury were not fully understood, which poses a barrier to the treatment of its neurotoxicity. We, therefore, reviewed the current knowledge on mechanisms of iron dyshomeostasis and ferroptosis and aimed to promote a better understanding of their roles in sevoflurane- and isoflurane-induced neurotoxicity.

Application of Butorphanol versus Sufentanil in Multimode Analgesia via Patient Controlled Intravenous Analgesia After Hepatobiliary Surgery: A Retrospective Cohort Study.

Purpose: We investigate the efficacy and safety of butorphanol in multimodal analgesia combined with dexmedetomidine and ketorolac via patient-controlled intravenous analgesia (PCIA) after hepatobiliary surgery, as compared with sufentanil. Patients and Methods: Postoperative follow-up data of hepatobiliary surgery patients in Henan Provincial People's Hospital from March 2018 to June 2021 were collected retrospectively and divided into butorphanol group (group B) or sufentanil group (group S) according to the postoperative intravenous controlled analgesia scheme. The baseline characteristics and surgical information of the two groups were matched through propensity score matching (PSM). Results: A total of 3437 patients were screened, and PSM yielded 1816 patients after matching, including 908 in the butorphanol group and 908 in the sufentanil group. Compared with group S, the incidence of moderate-to-severe pain on the first postoperative day and the second postoperative day was lower in group B during rest (3.2% vs 10.9%, P<0.001; 1.2% vs 4.6%, P<0.001), and during movement (7.0% vs 18.9%, P<0.001; 2.6% vs 8.7%, P<0.001). Patients receiving butorphanol had a lower morphine consumption (50mg vs 120mg, P<0.001). The bolus attempts of an analgesic pump in group B were significantly lower than in group S (1 vs 2, P<0.001). Postoperative hospital length of stay was shortened in group B (11d vs 12d, P=0.017). The occurrence of postoperative vomiting was lower in group B (1.4% vs 3.0%, P=0.025) than in group S. However, more patients in group B experienced dizziness (0.9% vs 0.1%, P=0.019). Conclusion: Compared with sufentanil, the application of butorphanol in multimodal analgesia combined with dexmedetomidine and ketorolac via PCIA ameliorated postoperative pain after hepatobiliary surgery, with reduced opioid consumption and shorter postoperative hospital length of stay.

Berberine Protects against High-Energy and Low-Protein Diet-Induced Hepatic Steatosis: Modulation of Gut Microbiota and Bile Acid Metabolism in Laying Hens.

Berberine (BBR) is a natural alkaloid with multiple biotical effects that has potential as a treatment for fatty liver hemorrhagic syndrome (FLHS). However, the mechanism underlying the protective effect of BBR against FLHS remains unclear. The present study aimed to investigate the effect of BBR on FLHS induced by a high-energy, low-protein (HELP) diet and explore the involvement of the gut microbiota and bile acid metabolism in the protective effects. A total of 90 healthy 140-day-old Hy-line laying hens were randomly divided into three groups, including a control group (fed a basic diet), a HELP group (fed a HELP diet), and a HELP+BBR group (high-energy, high-protein diet supplemented with BBR instead of maize). Our results show that BBR supplementation alleviated liver injury and hepatic steatosis in laying hens. Moreover, BBR supplementation could significantly regulate the gut's microbial composition, increasing the abundance of Actinobacteria and Romboutsia. In addition, the BBR supplement altered the profile of bile acid. Furthermore, the gut microbiota participates in bile acid metabolism, especially taurochenodeoxycholic acid and α-muricholic acid. BBR supplementation could regulate the expression of genes and proteins related to glucose metabolism, lipid synthesis (FAS, SREBP-1c), and bile acid synthesis (FXR, CYP27a1). Collectively, our findings demonstrate that BBR might be a potential feed additive for preventing FLHS by regulating the gut microbiota and bile acid metabolism.

Developing a Short-Form Buss-Warren Aggression Questionnaire Based on Machine Learning.

For adolescents, high levels of aggression are often associated with suicide, physical injury, worsened academic performance, and crime. Therefore, there is a need for the early identification of and intervention for highly aggressive adolescents. The Buss-Warren Aggression Questionnaire (BWAQ) is one of the most widely used offensive measurement tools. It consists of 34 items, and the longer the scale, the more likely participants are to make an insufficient effort response (IER), which reduces the credibility of the results and increases the cost of implementation. This study aimed to develop a shorter BWAQ using machine learning (ML) techniques to reduce the frequency of IER and simultaneously decrease implementation costs. First, an initial version of the short-form questionnaire was created using stepwise regression and an ANOVA F-test. Then, a machine learning algorithm was used to create the optimal short-form questionnaire (BWAQ-ML). Finally, the reliability and validity of the optimal short-form questionnaire were tested using independent samples. The BWAQ-ML contains only four items, thirty items less than the BWAQ, and its AUC, accuracy, recall, precision, and F1 score are 0.85, 0.85, 0.89, 0.83, and 0.86, respectively. BWAQ-ML has a Cronbach's alpha of 0.84, a correlation with RPQ of 0.514, and a correlation with PTM of -0.042, suggesting good measurement performance. The BWAQ-ML can effectively measure individual aggression, and its smaller number of items improves the measurement efficiency for large samples and reduces the frequency of IER occurrence. It can be used as a convenient tool for early adolescent aggression identification and intervention.

Development and validation of a prediction model to predict major adverse cardiovascular events in elderly patients undergoing noncardiac surgery: A retrospective cohort study.

BACKGROUND AND AIMS: Current existing predictive tools have limitations in predicting major adverse cardiovascular events (MACEs) in elderly patients. We will build a new prediction model to predict MACEs in elderly patients undergoing noncardiac surgery by using traditional statistical methods and machine learning algorithms. METHODS: MACEs were defined as acute myocardial infarction (AMI), ischemic stroke, heart failure and death within 30 days after surgery. Clinical data from 45,102 elderly patients (≥65 years old), who underwent noncardiac surgery from two independent cohorts, were used to develop and validate the prediction models. A traditional logistic regression and five machine learning models (decision tree, random forest, LGBM, AdaBoost, and XGBoost) were compared by the area under the receiver operating characteristic curve (AUC). In the traditional prediction model, the calibration was assessed using the calibration curve and the patients' net benefit was measured by decision curve analysis (DCA). RESULTS: Among 45,102 elderly patients, 346 (0.76%) developed MACEs. The AUC of this traditional model was 0.800 (95% CI, 0.708-0.831) in the internal validation set, and 0.768 (95% CI, 0.702-0.835) in the external validation set. In the best machine learning prediction model-AdaBoost model, the AUC in the internal and external validation set was 0.778 and 0.732, respectively. Besides, for the traditional prediction model, the calibration curve of model performance accurately predicted the risk of MACEs (Hosmer and Lemeshow, p = 0.573), the DCA results showed that the nomogram had a high net benefit for predicting postoperative MACEs. CONCLUSIONS: This prediction model based on the traditional method could accurately predict the risk of MACEs after noncardiac surgery in elderly patients.

General anesthetic action profile on the human prefrontal cortex cells through comprehensive single-cell RNA-seq analysis.

The cellular and molecular actions of general anesthetics to induce anesthesia state and also cellular signaling changes for subsequent potential "long term" effects remain largely elusive. General anesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on the human fetal prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted "microgliosis" but only sevoflurane decreased microglia transcriptional similarity. Propofol and sevoflurane each extensively but transiently (<2 h) altered transcriptome profiling across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Utilizing scRNA-seq as a robust and high-through put tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anesthetics in clinically relevant settings.

Bicuculline and Bumetanide Attenuate Sevoflurane-Induced Impairment of Myelination and Cognition in Young Mice.

Sevoflurane (Sevo) is one of the most commonly used general anesthetics for infants and young children. We investigated whether Sevo impairs neurological functions, myelination, and cognition via the γ-aminobutyric acid A receptor (GABAAR) and Na+-K+-2Cl- cotransporter (NKCC1) in neonatal mice. On postnatal days 5-7, mice were exposed to 3% Sevo for 2 h. On postnatal day 14, mouse brains were dissected, and oligodendrocyte precursor cell line level lentivirus knockdown of GABRB3, immunofluorescence, and transwell migration assays were performed. Finally, behavioral tests were conducted. Multiple Sevo exposure groups exhibited increased neuronal apoptosis levels and decreased neurofilament protein levels in the mouse cortex compared with the control group. Sevo exposure inhibited the proliferation, differentiation, and migration of the oligodendrocyte precursor cells, thereby affecting their maturation process. Electron microscopy revealed that Sevo exposure reduced myelin sheath thickness. The behavioral tests showed that multiple Sevo exposures induced cognitive impairment. GABAAR and NKCC1 inhibition provided protection against Sevo-induced neurotoxicity and cognitive dysfunction. Thus, bicuculline and bumetanide can protect against Sevo-induced neuronal injury, myelination impairment, and cognitive dysfunction in neonatal mice. Furthermore, GABAAR and NKCC1 may be mediators of Sevo-induced myelination impairment and cognitive dysfunction.

Lipid accumulation product is an effective predictor of metabolic syndrome in non-obese women with polycystic ovary syndrome.

Objective: To explore the correlation of lipid accumulation product (LAP) with metabolic syndrome (MS) and to assess the predictive value of LAP for MS risk in polycystic ovary syndrome (PCOS) with different body mass index (BMI). Methods: A total of 242 PCOS patients and 150 controls were recruited and divided into normal-weight, overweight, and obese groups, then further divided into MS and without MS subgroups. Clinical and anthropometric variables and laboratory results were recorded. LAP was calculated from waist circumference (WC) and triglyceride using sex-specific formulae. Logistic regression analysis and receiver operating characteristic (ROC) curve were applied to determine and analyze the predictive value of LAP for MS. Results: The prevalence of MS among PCOS patients was 45.04%, which was significantly higher than that of the controls (10%). Stratified by BMI, the incidence of MS in the normal-weight, overweight, and obese PCOS groups were 15.58%, 41.43%, and 71.58%, respectively. Logistic regression analysis indicated that LAP was an independent risk factor for MS in both normal-weight and overweight groups; however, the results were not significant in the obese group. ROC curve analysis showed that LAP had an outstanding discrimination index for MS in normal-weight (AUC=0.960, cut-off value=42.5) and overweight (AUC=0.937, cut-off value=47.93) PCOS patients, with a sensitivity of 0.917/0.931 (normal-weight/overweight) and a specificity of 0.969/0.854 (normal-weight/overweight), respectively. Conclusion: Normal-weight and overweight PCOS patients also have a fairly high incidence of MS and should receive as much attention as obese patients. Compared to applying multiple clinical indicators, LAP is more convenient and facilitates acquiring early and accurate diagnoses of MS among non-obese PCOS patients using fewer MS markers.

The research landscape of ferroptosis in the brain: A bibliometric analysis.

Background: Ferroptosis is a newly proposed concept of programmed cell death and has been widely studied in many diseases during the past decade. However, a bibliometric study that concentrates on publication outputs and research trends of ferroptosis related to the brain is lacking. Methods: We retrieved publication data in the field of ferroptosis in the brain from the Web of Science Core Collection on 31 December 2021. A bibliometric analysis was performed using VOSviewer and CiteSpace software. Results: Six hundred fifty-six documents focusing on ferroptosis in the brain were published from 2012 to 2021. The number of publications in this field has shown a steady increase in recent years. Most publications were from China (338) and the United States (166), while the most productive organizations were at the University of Melbourne (34) and University of Pittsburgh (23). Ashley I. Bush was the most productive author, while Scott J Dixon was the most co-cited author. The journal Free Radical Biology and Medicine published the most articles in this field, while Cell was the most cited journal. Among 656 publications, top 10 cited documents were cited at least 300 times. Among the top 20 references with the strongest citation bursts, half of the papers had a burst until 2021. The keywords analysis suggests that the top 20 keywords appeared at least 40 times. Additionally, "amyloid precursor protein" was the keyword with strongest bursts. Conclusion: Research on ferroptosis in the brain will continue to be highly regarded. This study analyzed the research landscape of ferroptosis in the brain and offers a new reference for researchers in this field.

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity.

Background: Sevoflurane is one of the most popular inhalational anesthetics during perioperative period but presenting neurotoxicity among pediatric and aged populations. Recent experiments in vivo and in vitro have indicated that ferroptosis may contribute to the neurotoxicity of sevoflurane anesthesia. However, the exact mechanism is still unclear. Methods: In current study, we explored the differential expressed genes (DEGs) in HT-22 mouse hippocampal neuronal cells after sevoflurane anesthesia using RNA-seq. Differential expressed ferroptosis-related genes (DEFRGs) were screened and analyzed by Gene Ontology (GO) and pathway enrichment analysis. Protein-to-protein interaction (PPI) network was constructed by the Search Tool for the Retrieval of Interacting Genes (STRING). Significant modules and the hub genes were identified by using Cytoscape. The Connectivity Map (cMAP) was used for screening drug candidates targeting the identified DEFRGs. Potential TF-gene network and drug-gene pairs were established towards the hub genes. In final, we validated these results in experiments. Results: A total of 37 ferroptosis-related genes (18 upregulated and 19 downregulated) after sevoflurane exposure in hippocampal neuronal cells were finally identified. These differentially expressed genes were mainly involved into the biological processes of cellular response to oxidative stress. Pathway analysis indicated that these genes were involved in ferroptosis, mTOR signaling pathway, and longevity-regulating pathway. PPI network was constructed. 10 hub genes including Prkaa2, Chac1, Arntl, Tfrc, Slc7a11, Atf4, Mgst1, Lpin1, Atf3, and Sesn2 were found. Top 10 drug candidates, gene-drug networks, and TFs targeting these genes were finally identified. These results were validated in experiments. Conclusion: Our results suggested that ferroptosis-related genes play roles in sevoflurane anesthesia-related hippocampal neuron injury and offered the hub genes and potential therapeutic agents for investigating and treatment of this neurotoxicity after sevoflurane exposure. Finally, therapeutic effect of these drug candidates and function of potential ferroptosis targets should be further investigated for treatment and clarifying mechanisms of sevoflurane anesthesia-induced neuron injury in future research.

Sevoflurane exposure induces neurotoxicity by regulating mitochondrial function of microglia due to NAD insufficiency.

Developmental neurons received with sevoflurane, the commonly used inhalational anesthetic agent in clinical surgery, several times tend to be destroyed. Microglia, the resident immune cells of the central nervous system (CNS), are activated after sevoflurane exposure, accompanied by releasing proinflammatory cytokines that damage developing neurons. The sevoflurane-induced neurotoxicity could be attributed to activated microglia presenting proinflammatory and anti-inflammatory functions. Proinflammatory microglia release cytokines to impair the CNS, while anti-inflammatory microglia engulf damaged neurons to maintain CNS homeostasis. Sevoflurane exposure promotes the secretion of proinflammatory cytokines by microglia, inhibiting the microglial phagocytic function. Microglia with poor phagocytic function cannot engulf damaged neurons, leading to the accumulation of damaged neurons. The mechanism underlying poor phagocytic function may be attributed to mitochondrial dysfunction of microglia induced by sevoflurane exposure, in which affected mitochondria cannot generate adequate ATP and NAD to satisfy the energy demand. We discovered that sevoflurane treatment impaired the mitochondrial metabolism of microglia, which resulted in NAD deficiency and couldn't produce sufficient energy to clear damaged neurons to maintain CNS development. Our findings provide an explanation of a new mechanism underlying sevoflurane-induced neurotoxicity.

Role of GABAA receptor depolarization-mediated VGCC activation in sevoflurane-induced cognitive impairment in neonatal mice.

Background: In neonatal mice, anesthesia with sevoflurane depolarizes the GABA Type A receptor (GABAAR), which leads to cognitive impairment. Calcium accumulation in neurons can lead to neurotoxicity. Voltage-gated calcium channels (VGCCs) can increase intracellular calcium concentration under isoflurane and hypoxic conditions. The underlying mechanisms remain largely unknown. Methods: Six-day-old mice were anesthetized with 3% sevoflurane for 2 h/day for 3 days. The Y-Maze, new object recognition (NOR) test, the Barnes maze test, immunoassay, immunoblotting, the TUNEL test, and Golgi-Cox staining were used to assess cognition, calcium concentration, inflammatory response, GABAAR activation, VGCC expression, apoptosis, and proliferation of hippocampal nerve cells in mice and HT22 cells. Results: Compared with the control group, mice in the sevoflurane group had impaired cognitive function. In the sevoflurane group, the expression of Gabrb3 and Cav1.2 in the hippocampal neurons increased (p < 0.01), the concentration of calcium ions increased (p < 0.01), inflammatory reaction and apoptosis of neurons increased (p < 0.01), the proliferation of neurons in the DG area decreased (p < 0.01), and dendritic spine density decreased (p < 0.05). However, the inhibition of Gabrb3 and Cav1.2 alleviated cognitive impairment and reduced neurotoxicity. Conclusions: Sevoflurane activates VGCCs by inducing GABAAR depolarization, resulting in cognitive impairment. Activated VGCCs cause an increase in intracellular calcium concentration and an inflammatory response, resulting in neurotoxicity and cognitive impairment.

Epileptiform EEG discharges during sevoflurane anesthesia in children: A meta-analysis.

OBJECTIVE: To investigate the overall incidence and associated factors of epileptiform discharges in children during sevoflurane anesthesia. METHODS: Our group systematically searched the PubMed, Cochrane library (Central) and EMBASE for the relevant trials from their inception until September 2020. The primary endpoint was the incidence of epileptiform discharges during sevoflurane induction. The secondary endpoints were the incidence of different types of epileptiform discharges, factors associated with these epileptiform events, and other adverse events such as seizure-like movements. RESULTS: After screening of 713 records, eleven studies involving 448 participants were included into the final analysis. Meta-analysis indicated that the overall incidence of Epileptiform EEG discharges was 38.1% (95%confidence interval [CI], 19.1%-59.2%) during sevoflurane anesthesia in children. Subgroup analysis showed that the incidence of these EEG patters was lower when participants were inducted by using the low initial concentration of sevoflurane, compared with the high initial concentration sevoflurane (1.7%, 95%CI, 0.0% to 8.4% versus 47.7%, 95%CI, 25.5% to 70.3%, P < 0.05). The longer exposure (>3 min) of high concentration sevoflurane during induction showed higher rate of epileptiform discharges than a shorter exposure (≤3 min) (48.4%, 95%CI, 20.1% to 77.3% versus 5.7%, 95%CI, 0.00% to 23.5%; P < 0.05). No significant difference for the incidence of epileptiform discharges was observed in subgroup analysis of addition of nitrous oxide (69.2%, 95%CI, 34.0% to 95.7% versus 41.3%, 95%CI, 15.6% to 69.7%, Pï¹¥0.05) and type of EEG monitoring (26.9%, 95%CI, 3.8% to 60.7% versus 53.1%, 95%CI, 25.4% to 79.8%, Pï¹¥0.05). CONCLUSIONS: The incidence of epileptiform EEG events in children during sevoflurane anesthesia varied from 19.1%-59.2%. The low initial concentration technique and shorter exposure time of high concentration sevoflurane may be associated with a decreased incidence of these epileptiform discharges in EEG. SIGNIFICANCE: Epileptiform EEG discharges during sevoflurane anesthesia in children should arouse clinicians' attention. The use of low initial concentration technique and shorter exposure time of high concentration sevoflurane may be associated with a lower occurrence of these paradoxical events.

The role of depolarizing activation of Na+-Ca2+ exchanger by oligodendrocyte progenitor cells in the effect of sevoflurane on myelination.

AIMS: The aim of this study was to investigate the role of depolarizing activation of Na+-Ca2+ exchanger (NCX) by oligodendrocyte progenitor cells (OPC) in the effect of sevoflurane on myelination. MAIN METHODS: On postnatal days 7, 8, and 9, mice were exposed to 3 % sevoflurane for 2 h per day. The proliferation, differentiation, and myelin sheath of OPC were observed with immunofluorescence, quantitative real-time polymerase chain reaction (QRT-PCR), and transmission electron microscopy (TEM) at various time points. The open field, Y maze, and new object recognition tests were used to measure spatial learning and memory. siRNA was used for the knockdown NCX1 in human OPC (HOPC) before sevoflurane exposure; the Transwell migration assay was used to measure cell migration ability and Fluo 4-AM was used to measure intracellular Ca2+ concentration. KEY FINDINGS: Pretreatment with an NCX inhibitor attenuated the proliferation and differentiation of OPC induced by sevoflurane and induced a remarkable increase in platelet-derived growth factor receptor-alpha (PDGFRα), 2, 3-cyclic nucleotide 3-phosphodiesterase (CNPase), oligodendrocyte transcription factor 2 (Olig2), and homeodomain protein NK2 homeobox 2 (NKX2.2) levels. Pretreatment with an NCX inhibitor alleviated the sevoflurane-induced myelination disorder and cognitive impairment. The decreased cell migration and increased intracellular Ca2+ concentration observed in the siRNA-negative control group was reversed in the sevoflurane plus siRNA-NCX1 group. SIGNIFICANCE: This study suggests that repeated sevoflurane exposure in newborn mice leads to depolarization of OPC, which leads to Ca2+ influx through NCX and affects OPC proliferation, migration, differentiation, and myelination, ultimately leading to cognitive impairment.