The effect of intraoperative midazolam on postoperative delirium in older surgical patients: a prospective, multicentre cohort study.

BACKGROUND: Midazolam is a short-acting benzodiazepine frequently used in the perioperative setting. This study aimed to investigate the potential impact of intraoperative midazolam on postoperative delirium (POD) in older patients undergoing non-cardiac surgery. METHODS: This study included patients aged ≥ 65 years who received general anaesthesia between April 2020 and April 2022 in multiple hospitals across China. POD occurring within 7 days was assessed using the 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM). Univariable and multivariable logistic regression models based on the random effects were used to determine the association between midazolam administration and the occurrence of POD, presented as risk ratio (RR) and 95% confidence intervals (CI). Kaplan-Meier cumulative incidence curve was plotted to compare the distribution of time to POD onset between patients who received midazolam and those who did not. Subgroup analyses based on specific populations were performed to explore the relationship between midazolam and POD. RESULTS: In all, 5,663 patients were included, of whom 723 (12.8%) developed POD. Univariate and multivariable logistic regression analyses based on random effects of different hospitals showed no significant association between midazolam medication and POD among older population (unadjusted RR=0.96, 95% CI: 0.90-1.30, P=0.38; adjusted RR=1.09, 95% CI: 0.91-1.33, P=0.35). Kaplan-Meier curve showed no difference in the distribution of time to POD onset (Hazard ratio [HR]=1.02, 95%CI: 0.88-1.18, P=0.82). The results of subgroup analyses found that intraoperative midazolam treatment was not associated with POD in the specific subgroups of patients. CONCLUSIONS: Intraoperative administration of midazolam may not be associated with an increased risk of POD in older patients undergoing non-cardiac surgery.

Association of sleep quality on the night of operative day with postoperative delirium in elderly patients: A prospective cohort study.

BACKGROUND: Sleep disturbances in the peri-operative period have been associated with adverse outcomes, including postoperative delirium (POD). However, research on sleep quality during the immediate postoperative period is limited. OBJECTIVES: This study aimed to investigate the association between sleep quality on the night of the operative day assessed using the Sleep Quality Numeric Rating Scale (SQ-NRS), and the incidence of POD in a large cohort of surgical patients. DESIGN: A prospective cohort study. SETTING: A tertiary hospital in China. PATIENTS: This study enrolled patients aged 65 years or older undergoing elective surgery under general anaesthesia. The participants were categorised into the sleep disturbance and no sleep disturbance groups according to their operative night SQ-NRS. MAIN OUTCOME MEASURES: The primary outcome was delirium incidence, whereas the secondary outcomes included acute kidney injury, stroke, pulmonary infection, cardiovascular complications and all-cause mortality within 1 year postoperatively. RESULTS: In total, 3072 patients were included in the analysis of this study. Among them, 791 (25.72%) experienced sleep disturbances on the night of operative day. Patients in the sleep disturbance group had a significantly higher risk of developing POD (adjusted OR 1.43, 95% CI 1.11 to 1.82, P  = 0.005). Subgroup analysis revealed that age 65-75 years; male sex; ASA III and IV; haemoglobin more than 12 g l -1 ; intra-operative hypotension; surgical duration more than 120 min; and education 9 years or less were significantly associated with POD. No interaction was observed between the subgroups. No significant differences were observed in the secondary outcomes, such as acute kidney injury, stroke, pulmonary infection, cardiovascular complications and all-cause mortality within 1 year postoperatively. CONCLUSIONS: The poor subjective sleep quality on the night of operative day was independently associated with increased POD risk, especially in certain subpopulations. Optimising peri-operative sleep may reduce POD. Further research should investigate potential mechanisms and causal relationships. TRIAL REGISTRY: chictr.org.cn: ChiCTR1900028545.

TMEM59 protects against cerebral ischemic stroke by suppressing pyroptosis and microglial activation.

Ischemic stroke is a common disease worldwide with high mortality and disability rates. Nevertheless, pathogenesis of ischemic stroke is still vague, and finding novel therapeutic target is urgently necessary. TMEM59 (also known as dendritic cell-derived factor 1, DCF1), a type I transmembrane protein, contains a minimal 19-amino-acid peptide in its intracellular domain, and has been involved in neurological pathology. However, its biological impacts on ischemic stroke are still unknown. In this study, we provided new evidence that TMEM59 expression was significantly down-regulated upon ischemia/reperfusion (I/R). The effect of stroke insult on TMEM59 expression change was only detected in microglial cells by in vitro studies. We observed that TMEM59 knockout markedly accelerated cerebral I/R in mice induced by middle cerebral artery occlusion (MCAO), as evidenced by the elevated infarction volume, neurological deficit scores, brain water contents and neuronal death, further contributing to the abnormal behaviors for mice. We then found that microglial activation reflected by the enhanced expression of Iba-1 was dramatically potentiated by TMEM59 knockout in MCAO-treated mice. Pyroptosis was highly triggered in mice with cerebral I/R, while being further aggravated in mice with TMEM59 deletion, as proved by the considerably increased expression of NLRP3, ASC, cleaved Caspase-1, GSDMD-N, mature-IL-1ß and mature-IL-18. Additionally, TMEM59 knockout mice exhibited accelerated activation of NF-κB signaling pathway compared with the wild type group of mice after MCAO operation, indicating the anabatic neuroinflammation. The effects of TMEM59 suppression on ischemic stroke were confirmed in microglial cells with exposure to oxygen-glucose deprivation/reoxygenation (OGD/R). In contrast, the in vitro studies verified that improving TMEM59 expression effectively hindered pyroptosis and inflammation in microglial cells upon OGD/R treatment. Taken together, these findings illustrated protective effects of TMEM59 against ischemic stroke through restraining pyroptosis and inflammatory response.

Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity.

BACKGROUND: Considerable evidence has shown that neuroinflammation and oxidative stress play an important role in the pathophysiology of postoperative cognitive dysfunction (POCD) and other progressive neurodegenerative disorders. Increasing evidence suggests that acetaminophen (APAP) has unappreciated antioxidant and anti-inflammatory properties. However, the impact of APAP on the cognitive sequelae of inflammatory and oxidative stress is unknown. The objective of this study is to explore whether APAP could have neuroprotective effects on lipopolysaccharide (LPS)-induced cognitive impairment in mice. METHODS: A mouse model of LPS-induced cognitive impairment was established to evaluate the neuroprotective effects of APAP against LPS-induced cognitive impairment. Adult C57BL/6 mice were treated with APAP half an hour prior to intracerebroventricular microinjection of LPS and every day thereafter, until the end of the study period. The Morris water maze was used to assess cognitive function from postinjection days 1 to 3. Animal behavioural tests as well as pathological and biochemical assays were performed to evaluate LPS-induced hippocampal damage and the neuroprotective effect of APAP. RESULTS: Mice treated with LPS exhibited impaired performance in the Morris water maze without changing spontaneous locomotor activity, which was ameliorated by treatment with APAP. APAP suppressed the accumulation of pro-inflammatory cytokines and microglial activation induced by LPS in the hippocampus. In addition, APAP increased SOD activity, reduced MDA levels, modulated glycogen synthase kinase 3ß (GSK3ß) activity and elevated brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Moreover, APAP significantly decreased the Bax/Bcl-2 ratio and neuron apoptosis in the hippocampus of LPS-treated mice. CONCLUSIONS: Our results suggest that APAP may possess a neuroprotective effect against LPS-induced cognitive impairment and inflammatory and oxidative stress via mechanisms involving its antioxidant and anti-inflammatory properties, as well as its ability to inhibit the mitochondrial permeability transition (MPT) pore and the subsequent apoptotic pathway.

Deferoxamine attenuates lipopolysaccharide-induced neuroinflammation and memory impairment in mice.

BACKGROUND: Neuroinflammation often results in enduring cognitive impairment and is a risk factor for postoperative cognitive dysfunction. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that the iron chelator deferoxamine (DFO) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of DFO on the cognitive sequelae of neuroinflammation is unknown. METHODS: A mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effects of DFO against LPS-induced memory deficits and neuroinflammation. Adult C57BL/6 mice were treated with 0.5 µg of DFO 3 days prior to intracerebroventricular microinjection of 2 µg of LPS. Cognitive function was assessed using a Morris water maze from post-injection days 1 to 3. Animal behavioral tests, as well as pathological and biochemical assays were performed to evaluate the LPS-induced hippocampal damage and the neuroprotective effect of DFO. RESULTS: Treatment of mice with LPS resulted in deficits in cognitive performance in the Morris water maze without changing locomotor activity, which were ameliorated by pretreatment with DFO. DFO prevented LPS-induced microglial activation and elevations of IL-1ß and TNF-α levels in the hippocampus. Moreover, DFO attenuated elevated expression of caspase-3, modulated GSK3ß activity, and prevented LPS-induced increases of MDA and SOD levels in the hippocampus. DFO also significantly blocked LPS-induced iron accumulation and altered expression of proteins related to iron metabolism in the hippocampus. CONCLUSIONS: Our results suggest that DFO may possess a neuroprotective effect against LPS-induced neuroinflammation and cognitive deficits via mechanisms involving maintenance of less brain iron, prevention of neuroinflammation, and alleviation of oxidative stress and apoptosis.

Effect of perioperative dexmedetomidine on the endocrine modulators of stress response: a meta-analysis.

This study examined the effects of perioperative dexmedetomidine treatment on physiological modulators of surgical stress response. The quality of the included studies was assessed prior to performing meta-analyses of the weighted mean differences in the changes from baseline of stress hormones and interpreted in the light of statistical heterogeneity between the studies. Nineteen studies (844 surgical subjects) data were used for this meta-analysis. Dexmedetomidine administration significantly decreased blood cortisol levels (µg/dL) postoperatively (mean difference with 95% confidence interval (CI) from controls: -18.78 (-28.45, -9.10); P < 0.05). In the subgroup analysis, the mean difference between dexmedetomidine-treated and saline-treated subjects in the changes from baseline of the cortisol levels was -20.10 (-30.96, -9.25; P < 0.05) but, between dexmedetomidine- and comparator-treated subjects, it was not statistically significantly different (-15.13 (-49.78, 19.52); P < 0.05). Compared with controls, dexmedetomidine treatment also decreased adrenaline and noradrenaline levels significantly (mean difference in the percent changes from baseline: -90.41 (-145.79, -35.03)%; P < 0.05 and -62.82 (-85.47, -0.40.17)%; P < 0.05, respectively). Dexmedetomidine also decreased prolactin levels with a mean difference of -19.42 (-39.37, 0.52) µg/L (P = 0.06). In conclusion, perioperative use of dexmedetomidine reduces serum catecholamine and cortisol levels but the decrease in cortisol levels was not statistically different from the comparator anaesthetics. More data will be required to assess the effects of dexmedetomidine on corticotropin, prolactin, and growth hormone.

Gut microbiota and cognitive performance: A bidirectional two-sample Mendelian randomization.

PURPOSE: Previous studies have suggested a potential association between gut microbiota and neurological and psychiatric disorders. However, the causal relationship between gut microbiota and cognitive performance remains uncertain. METHODS: A two-sample Mendelian randomization (MR) study used SNPs linked to gut microbiota (n = 18,340) and cognitive performance (n = 257,841) from recent GWAS data. Inverse-variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were employed. Heterogeneity was assessed via Cochran's Q test for IVW. Results were shown with funnel plots. Outliers were detected through leave-one-out method. MR-PRESSO and MR-Egger intercept tests were conducted to address horizontal pleiotropy influence. LIMITATIONS: Limited to European populations, generic level, and potential confounding factors. RESULTS: IVW analysis revealed detrimental effects on cognitive perfmance associated with the presence of genus Blautia (P = 0.013, 0.966[0.940-0.993]), Catenibacterium (P = 0.035, 0.977[0.956-0.998]), Oxalobacter (P = 0.043, 0.979[0.960-0.999]). Roseburia (P < 0.001, 0.935[0.906-0.965]), in particular, remained strongly negatively associated with cognitive performance after Bonferroni correction. Conversely, families including Bacteroidaceae (P = 0.043, 1.040[1.001-1.081]), Rikenellaceae (P = 0.047, 1.026[1.000-1.053]), along with genera including Paraprevotella (P = 0.044, 1.020[1.001-1.039]), Ruminococcus torques group (P = 0.016, 1.062[1.011-1.115]), Bacteroides (P = 0.043, 1.040[1.001-1.081]), Dialister (P = 0.027, 1.039[1.004-1.074]), Paraprevotella (P = 0.044, 1.020[1.001-1.039]) and Ruminococcaceae UCG003 (P = 0.007, 1.040[1.011-1.070]) had a protective effect on cognitive performance. CONCLUSIONS: Our results suggest that interventions targeting specific gut microbiota may offer a promising avenue for improving cognitive function in diseased populations. The practical application of these findings has the potential to enhance cognitive performance, thereby improving overall quality of life.

Preoperative prognostic nutritional index predicts postoperative delirium in aged patients after surgery: A matched cohort study.

OBJECTIVE: Prognostic nutritional index (PNI) is an indicator to evaluate the nutritional immune status of patients. This study aimed to assess whether preoperative PNI could predict the occurrence of postoperative POD in aged patients undergoing non-neurosurgery and non-cardiac surgery. METHOD: The aged patients undergoing non-neurosurgery and non-cardiac surgery between January 2014 and August 2019 were included in the retrospective cohort study. The correlation between POD and PNI was investigated by univariate and multivariable logistic regression analysis, propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and subgroup analysis. RESULTS: In the cohort (n = 29,814), the cutoff value of PNI was 46.01 determined by the receiver operating characteristic (ROC) curve. In univariate and three multivariable regression analysis, the ORs of PNI ≤ 46.01 was 2.573(95% CI:2.261-2.929, P < 0.001),1.802 (95% CI:1.567-2.071, P < 0.001),1.463(95% CI:1.246-1.718, P < 0.001),1.370(95% CI:1.165-1.611, P < 0.001). In the PSM model and IPTW model, the ORs of PNI ≤ 46.01 were 1.424(95% CI:1.172-1.734, P < 0.001) and 1.356(95% CI:1.223-1.505, P < 0.001). CONCLUSION: The PNI was found to have a predictive value for POD in patients undergoing non-neurosurgery and non-cardiac surgery. Improving preoperative nutritional status may be beneficial in preventing POD for aged patients.

Development and validation of a nomogram to predict postoperative delirium in older patients after major abdominal surgery: a retrospective case-control study.

BACKGROUND: Postoperative delirium is a common complication in older patients, with poor long-term outcomes. This study aimed to investigate risk factors and develop a predictive model for postoperative delirium in older patients after major abdominal surgery. METHODS: This study retrospectively recruited 7577 patients aged ≥ 65 years who underwent major abdominal surgery between January 2014 and December 2018 in a single hospital in Beijing, China. Patients were divided into a training cohort (n = 5303) and a validation cohort (n = 2224) for univariate and multivariate logistic regression analyses and to build a nomogram. Data were collected for 43 perioperative variables, including demographics, medical history, preoperative laboratory results, imaging, and anesthesia information. RESULTS: Age, chronic obstructive pulmonary disease, white blood cell count, glucose, total protein, creatinine, emergency surgery, and anesthesia time were associated with postoperative delirium in multivariate analysis. We developed a nomogram based on the above 8 variables. The nomogram achieved areas under the curve of 0.731 and 0.735 for the training and validation cohorts, respectively. The discriminatory ability of the nomogram was further assessed by dividing the cases into three risk groups (low-risk, nomogram score < 175; medium-risk, nomogram score 175~199; high-risk, nomogram score > 199; P < 0.001). Decision curve analysis revealed that the nomogram provided a good net clinical benefit. CONCLUSIONS: We developed a nomogram that could predict postoperative delirium with high accuracy and stability in older patients after major abdominal surgery.

Risk factors prediction of 6-month mortality after noncardiac surgery of older patients in China: a multicentre retrospective cohort study.

BACKGROUND: Identifying the risk factors associated with perioperative mortality is crucial, particularly in older patients. Predicting 6-month mortality risk in older patients based on large datasets can assist patients and surgeons in perioperative clinical decision-making. This study aimed to develop a risk prediction model of mortality within 6 months after noncardiac surgery using the clinical data from 11 894 older patients in China. MATERIALS AND METHODS: A multicentre, retrospective cohort study was conducted in 20 tertiary hospitals. The authors retrospectively included 11 894 patients (aged ≥65 years) who underwent noncardiac surgery between April 2020 and April 2022. The least absolute shrinkage and selection operator model based on linear regression was used to analyse and select risk factors, and various machine learning methods were used to build predictive models of 6-month mortality. RESULTS: The authors predicted 12 preoperative risk factors associated with 6-month mortality in older patients after noncardiac surgery. Including laboratory-associated risk factors such as mononuclear cell ratio and total blood cholesterol level, etc. Also including medical history associated risk factors such as stroke, history of chronic diseases, etc. By using a random forest model, the authors constructed a predictive model with a satisfactory accuracy (area under the receiver operating characteristic curve=0.97). CONCLUSION: The authors identified 12 preoperative risk factors associated with 6-month mortality in noncardiac surgery older patients. These preoperative risk factors may provide evidence for a comprehensive preoperative anaesthesia assessment as well as necessary information for clinical decision-making by anaesthesiologists.

Comparison of logistic regression and machine learning methods for predicting postoperative delirium in elderly patients: A retrospective study.

AIMS: To compare the performance of logistic regression and machine learning methods in predicting postoperative delirium (POD) in elderly patients. METHOD: This was a retrospective study of perioperative medical data from patients undergoing non-cardiac and non-neurology surgery over 65 years old from January 2014 to August 2019. Forty-six perioperative variables were used to predict POD. A traditional logistic regression and five machine learning models (Random Forest, GBM, AdaBoost, XGBoost, and a stacking ensemble model) were compared by the area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, and precision. RESULTS: In total, 29,756 patients were enrolled, and the incidence of POD was 3.22% after variable screening. AUCs were 0.783 (0.765-0.8) for the logistic regression method, 0.78 for random forest, 0.76 for GBM, 0.74 for AdaBoost, 0.73 for XGBoost, and 0.77 for the stacking ensemble model. The respective sensitivities for the 6 aforementioned models were 74.2%, 72.2%, 76.8%, 63.6%, 71.6%, and 67.4%. The respective specificities for the 6 aforementioned models were 70.7%, 99.8%, 96.5%, 98.8%, 96.5%, and 96.1%. The respective precision values for the 6 aforementioned models were 7.8%, 52.3%, 55.6%, 57%, 54.5%, and 56.4%. CONCLUSIONS: The optimal application of the logistic regression model could provide quick and convenient POD risk identification to help improve the perioperative management of surgical patients because of its better sensitivity, fewer variables, and easier interpretability than the machine learning model.

Mental health changes in elderly patients undergoing non-cardiac surgery during the COVID-19 pandemic in China.

BACKGROUND: The COVID-19 pandemic has a heavy impact on the mental health of elderly surgical patients worldwide. In particular, the elderly patients faced considerable psychological stress due to various environmental and medical factors during the outbreak. This study aims to examine changes in mental health trends among non-cardiac surgical patients aged 65 and above in China during the COVID-19 pandemic. METHODS: This multi-center, convenient sampling, longitudinal observational study was conducted from April 1, 2020 to April 30, 2022. Primary outcome was the prevalence of postoperative depression. Secondary outcome was the prevalence of postoperative anxiety. Follow-up was conducted separately at 7 days and 30 days after surgery. Depression symptoms were assessed using the Patient Health Questionnaire 9 (PHQ-9) scale. Anxiety symptoms were assessed using Generalized Anxiety Disorder-7 (GAD-7) scale, with scores of ≥5 defining positive depression or anxiety symptoms. Multivariate logistic regression analysis was used to investigate risk factors of mental health status in more elderly patients undergoing non-cardiac surgery. RESULTS: A total of 4639 patients were included, of whom 2279 (46.0 %) were male, 752 (15.2 %) were over the age of 75, and 4346 (93.7 %) were married. The monthly prevalence trends demonstrated that compared to the outbreak period, a significant reduction in the prevalence of depression and anxiety symptoms in elderly patients who underwent surgery during the post-pandemic period. In post-pandemic period, a statistically significant decrease in the prevalence of all severity depression and anxiety patients was noted at the 7-day follow-up, but no significant decrease was observed for severe depression and anxiety in the 30-day follow-up. In COVID-19 low-risk area, a significant overall decrease in prevalence of mental health was observed during the post-pandemic period compared to the outbreak period, including 7-day depression, 7-day anxiety, 30-day depression, and 30-day anxiety (all with P < 0.001). Female and patients with ≥2 comorbidities appeared to be more susceptible to postoperative depression and anxiety during the pandemic. LIMITATION: The absence of data from the early days of the COVID-19 outbreak. CONCLUSIONS: This study analyzed the prevalence of depression and anxiety in elderly non-cardiac patients during and after the COVID-19 pandemic, focusing on dimensions such as severity, risk-areas, gender, and comorbidity. Our findings revealed a significant decrease in the prevalence of depression and anxiety in elderly surgery patients during the post-pandemic period.

Intraoperative allogeneic transfusion is associated with postoperative delirium in older patients after total knee and hip arthroplasty.

Objective: To determine whether intraoperative transfusion of allogeneic or autologous blood is associated with an increased incidence of postoperative delirium (POD) after total knee arthroplasty (TKA) and total hip arthroplasty (THA). Methods: The medical records of 1,143 older (≥65 years old) patients who received an intraoperative blood transfusion while undergoing total knee or hip arthroplasty at the First Medical Center of Chinese PLA General Hospital from 2014 to 2019 were reviewed; of these patients, 742 (64.92%) received allogeneic blood, while 401 (35.08%) received autologous blood. Patients who received autologous transfusion were paired with those received allogeneic transfusion using 1:1 propensity score matching method. The primary outcome was POD. The secondary outcomes were postoperative complications, including heart failure, deep vein thrombosis, myocardial infarction, stroke, and lung infection. Multivariable nominal logistic regression was used to identify any independent associations between intraoperative blood transfusions and POD, and secondary postoperative complications, respectively. Results: Postoperative delirium occurred in 6.6% (49/742) of patients who had received an allogeneic blood transfusion and in 2.0% (8/401) of patients who had received an autologous blood transfusion. It is noteworthy that the multivariable logistic regression demonstrated a significant association between intraoperative allogeneic blood transfusion and POD (odds ratio [OR]: 4.11; 95% confidence interval [CI]: 1.95-9.77; p < 0.001). After PSM, Allogeneic transfusion was also the strongest predictor for POD (OR: 4.43; 95% CI: 2.09-10.58; p < 0.001). Conclusions: In the patients who had received THA or TKA, intraoperative allogeneic blood transfusions were associated with an increased risk of POD.

Using preoperative N-terminal pro-B-type natriuretic peptide levels for predicting major adverse cardiovascular events and myocardial injury after noncardiac surgery in Chinese advanced-age patients.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is often viewed as an indicator for heart failure. However, the prognostic association and the predictive utility of NT-proBNP for postoperative major adverse cardiovascular events (MACEs) and myocardial injury after noncardiac surgery (MINS) among older patients are unclear. METHODS: In this study, we included 5033 patients aged 65 years or older who underwent noncardiac surgery with preoperative NT-proBNP recorded. Logistic regression was adopted to model the associations between preoperative NT-proBNP and the risk of MACEs and MINS. The receiver operating characteristic curve was used to determine the predictive value of NT-proBNP. RESULTS: A total of 5033 patients were enrolled, 63 patients (1.25%) and 525 patients (10.43%) had incident postoperative MACEs and MINS, respectively. Analysis of the receiver operating characteristic curve indicated that the cutoff values of ln (NT-proBNP) for MACEs and MINS were 5.16 (174 pg/mL) and 5.30 (200 pg/mL), respectively. Adding preoperative ln (NT-proBNP) to the Revised Cardiac Risk Index score and the Cardiac and Stroke Risk Model boosted the area under the receiver operating characteristic curves from 0.682 to 0.726 and 0.787 to 0.804, respectively. The inclusion of preoperative NT-proBNP in the prediction models significantly increased the reclassification and discrimination. CONCLUSIONS: Increased preoperative NT-proBNP was associated with a higher risk of postoperative MACEs and MINS. The inclusion of NT-proBNP enhances the predictive ability of the preexisting models.

lncRNA BDNF-AS Attenuates Propofol-Induced Apoptosis in HT22 Cells by Modulating the BDNF/TrkB Pathway.

Propofol is widely used as an intravenous anesthetic in clinical practice. Previous studies have indicated that propofol induces apoptosis in neurons. Brain-derived neurotrophic factor (BDNF), a neurotrophic factor, is associated with neuronal apoptosis. BDNF-AS, a relatively conserved long non-coding RNA, can reverse the transcription of BDNF. This study aimed to investigate the involvement of BDNF-AS in propofol-induced apoptosis in HT22 cells. HT22 cells were treated with various concentrations of propofol at different time points. BDNF-AS was silenced using BDNF-AS-targeting siRNA. TrkB was antagonized by the TrkB inhibitor, ANA-12. Flow cytometry, quantitative reverse-transcription PCR, and western blotting were performed to analyze apoptosis and the expression of genes and proteins, respectively. In propofol-treated HT22 cells, BDNF-AS was upregulated, and BDNF was downregulated in a time- and dose-dependent manner. BDNF-AS downregulation mediated by siRNA mitigated apoptosis, upregulated the expression of Bcl-2, and downregulated the expression of Bax and caspase-3, 7, and 9. ANA-12 downregulated the expression of Bcl-2, upregulated the expression of Bax and caspase-3, 7, and 9, and increased apoptosis. Our study implied that inhibition of BDNF-AS can decrease propofol-induced apoptosis by activating the BDNF/TrkB pathway. Thus, the BDNF-AS-BDNF/TrkB signaling pathway may be a valuable target for treating propofol-induced neurotoxicity.

Dysfunction of EAAT3 Aggravates LPS-Induced Post-Operative Cognitive Dysfunction.

Numerous results have revealed an association between inhibited function of excitatory amino acid transporter 3 (EAAT3) and several neurodegenerative diseases. This was also corroborated by our previous studies which showed that the EAAT3 function was intimately linked to learning and memory. With this premise, we examined the role of EAAT3 in post-operative cognitive dysfunction (POCD) and explored the potential benefit of riluzole in countering POCD in the present study. We first established a recombinant adeno-associated-viral (rAAV)-mediated shRNA to knockdown SLC1A1/EAAT3 expression in the hippocampus of adult male mice. The mice then received an intracerebroventricular microinjection of 2 µg lipopolysaccharide (LPS) to construct the POCD model. In addition, for old male mice, 4 mg/kg of riluzole was intraperitoneally injected for three consecutive days, with the last injection administered 2 h before the LPS microinjection. Cognitive function was assessed using the Morris water maze 24 h following the LPS microinjection. Animal behavioral tests, as well as pathological and biochemical assays, were performed to clarify the role of EAAT3 function in POCD and evaluate the effect of activating the EAAT3 function by riluzole. In the present study, we established a mouse model with hippocampal SLC1A1/EAAT3 knockdown and found that hippocampal SLC1A1/EAAT3 knockdown aggravated LPS-induced learning and memory deficits in adult male mice. Meanwhile, LPS significantly inhibited the expression of EAAT3 membrane protein and the phosphorylation level of GluA1 protein in the hippocampus of adult male mice. Moreover, riluzole pretreatment significantly increased the expression of hippocampal EAAT3 membrane protein and also ameliorated LPS-induced cognitive impairment in elderly male mice. Taken together, our results demonstrated that the dysfunction of EAAT3 is an important risk factor for POCD susceptibility and therefore, it may become a promising target for POCD treatment.

Anti-PTSD Effects of Hypidone Hydrochloride (YL-0919): A Novel Combined Selective 5-HT Reuptake Inhibitor/5-HT1A Receptor Partial Agonist/5-HT6 Receptor Full Agonist.

Posttraumatic stress disorder (PTSD) is a debilitating trauma and stressor-related disorder that has become a major neuropsychiatric problem, leading to substantial disruptions in individual health and societal costs. Our previous studies have demonstrated that hypidone hydrochloride (YL-0919), a novel combined selective 5-HT reuptake inhibitor/5-HT1A receptor partial agonist/5-HT6 receptor full agonist, exerts notable antidepressant- and anxiolytic-like as well as procognitive effects. However, whether YL-0919 exerts anti-PTSD effects and its underlying mechanisms are still unclear. In the present study, we showed that repeated treatment with YL-0919 caused significant suppression of contextual fear, enhanced anxiety and cognitive dysfunction induced by the time-dependent sensitization (TDS) procedure in rats and by inescapable electric foot-shock in a mouse model of PTSD. Furthermore, we found that repeated treatment with YL-0919 significantly reversed the accompanying decreased expression of the brain-derived neurotrophic factor (BDNF) and the synaptic proteins (synapsin1 and GluA1), and ameliorated the neuroplasticity disruption in the prefrontal cortex (PFC), including the dendritic complexity and spine density of pyramidal neurons. Taken together, the current study indicated that YL-0919 exerts clear anti-PTSD effects, which might be partially mediated by ameliorating the structural neuroplasticity by increasing the expression of BDNF and the formation of synaptic proteins in the PFC.

[Protective effects of propofol combined with reserpine on cultured PC12 cells impaired by ischemia and reperfusion].

OBJECTIVE: To evaluate the protective action of propofol and reserpine, as well as a combination of the two drugs on cultured pheochromocytoma cells (PC12 cells) impaired by mimic ischemia reperfusion (IR), and its possible mechanisms. METHODS: PC12 cells were subjected to IR to reproduce the experimental model. They were divided into IR group, propofol (P) group, reserpine (R) group, and fospropofol/reserpine combined treatment (PR) group. The scale of cell impairment in each group was assessed by the content of lactate dehydrogenase (LDH) and by the absorption (A) at 570 nm with the methyl thiazolyl tetrazolium (MTT) assay. The change in [Ca2+]i was detected by Fura-2/AM fluorescence assay after the treatment of propofol, reserpine, or both. RESULTS: Compared with IR group, the release of LDH was decreased and the A values increased in P, R and PR groups (P < 0.05 or P < 0.01). When combined with reserpine (40 micromol/L), different concentrations of propofol (12.4, 37.3 and 112.0 micromol/L) rendered the cells to release less LDH, with an increase in A value (all P < 0.05). Both propofol (12.4 micromol/L and 37.3 micromol/L) and reserpine (40 micromol/L) could lessen the overload of intra-cellular calcium after IR [(279.66+/-18.00) nmol/L vs. (219.41+/-12.53) nmol/L, (279.66+/-18.00) nmol/L vs. (210.50+/-11.03) nmol/L, (279.66+/-18.00) nmol/L vs. (254.82+/-10.45) nmol/L,P < 0.05 or P < 0.01]. [Ca2+]i could be further lowered when the cells were treated with propofol and reserpine in combination [(191.19+/-10.36) nmol/L and (183.82+/-9.83) nmol/L, both P < 0.05]. CONCLUSION: Both propofol and reserpine can protect cells from IR injury, and attenuate [Ca2+]i overload induced by IR. The attenuation of [Ca2+]i overload in impaired cells may be one of the mechanisms for their protective actions.

Vitamin C alleviates LPS-induced cognitive impairment in mice by suppressing neuroinflammation and oxidative stress.

Neuroinflammation is believed to be one of the primary causes of cognitive impairment. Previous studies showed that the antioxidant vitamin C (Vit C) performs many beneficial functions such as immunostimulant and anti-inflammatory actions, but its role in inflammatory cognitive impairment is unclear. In the current study, we investigated the effect and possible mechanism of action of Vit C in lipopolysaccharide (LPS)-induced cognitive impairment. Intracerebroventricular LPS-induced memory impairment was used as the model for neuroinflammatory cognitive dysfunction. Vit C was administered by intracerebroventricular microinjection 30 min prior to LPS exposure. It was found that Vit C significantly protected animals from LPS-induced memory impairment as evidenced by improved performance in the Morris water maze and novel object recognition tests without changes in spontaneous locomotor activity. Vit C pretreatment inhibited the activation of microglia and the production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). Furthermore, Vit C pretreatment markedly decreased the malondialdehyde (MDA) level, increased superoxide dismutase (SOD) activity, and modulated the Bax/Bcl-2 ratio and p-p38 MAPK activation in the hippocampus of LPS-treated mice. Together, these results suggest that vitamin C pretreatment could protect mice from LPS-induced cognitive impairment, possibly through the modulation of oxidative stress and inflammatory responses.

Inhibition of N-methyl-D-aspartate receptor function appears to be one of the common actions for antidepressants.

In order to explore the possible common action mechanisms of three kinds of classical antidepressants, inhibition of drugs on the N-methyl-D-aspartate (NMDA)-Ca(2)-nitric oxide synthase (NOS) signal pathway was observed. With 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and lactic dehydrogenase (LDH) assay, classical antidepressants, desipramine (1, 10 microM), fluoxetine (0.625-10 microM) or moclobemide (2.5, 10 microM) antagonized NMDA 300 M induced-lesion in PC12 cells. Using fura-2/AM (acetoxymethyl ester) labelling assay, desipramine or fluoxetine at doses 1, 5 microM attenuated the intracellular Ca(2) overload induced by NMDA 200 microM for 24 h in PC12 cells. Meanwhile, using confocal microscope, it was also found that desipramine 5 microM, fluoxetine 2.5 microM or moclobemide 10 microM decreased the NMDA 20 microM induced intracellular Ca(2) overload in primarily cultured rat hippocampal neurons. Furthermore, desipramine (1, 5 microM), fluoxetine (1, 5 microM) or moclobemide (2.5, 10 microM) significantly inhibited NOS activity in NMDA (300 microM) treated PC12 cells for 4h. In summary, we suggest that inhibition on the function of NMDA-Ca(2) -NOS signal pathway appears to be one of the common actions for antidepressants despite their remarkably different structures, which is expected to have great implication for the evaluation and screening in vitro of new antidepressants.