An Amino Acids and Dipeptide Injection Inhibits the TNF-α/HMGB1 Inflammatory Signaling Pathway to Reduce Pyroptosis and M1 Microglial Polarization in POCD Mice: the Gut to the Brain.

Peripheral surgery-induced neural inflammation is a key pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the mechanism underlying neuroinflammation and associated neural injury remains elusive. Surgery itself can lead to gut damage, and the occurrence of POCD is accompanied by high levels of TNF-α in the serum and blood‒brain barrier (BBB) damage. Reductions in stress, inflammation and protein loss have been emphasized as strategies for enhanced recovery after surgery (ERAS). We designed an amino acids and dipeptide (AAD) formula for injection that could provide intestinal protection during surgery. Through the intraoperative infusion of AAD based on the ERAS concept, we aimed to explore the effect of AAD injection on POCD and its underlying mechanism from the gut to the brain. Here, we observed that AAD injection ameliorated neural injury in POCD, in addition to restoring the function of the intestinal barrier and BBB. We also found that TNF-α levels decreased in the ileum, blood and hippocampus. Intestinal barrier protectors and TNF-α inhibitors also alleviated neural damage. AAD injection treatment decreased HMGB1 production, pyroptosis, and M1 microglial polarization and increased M2 polarization. In vitro, AAD injection protected the impaired gut barrier and decreased TNF-α production, alleviating damage to the BBB by stimulating cytokine transport in the body. HMGB1 and Caspase-1 inhibitors decreased pyroptosis and M1 microglial polarization and increased M2 polarization to protect TNF-α-stimulated microglia in vitro. Collectively, these findings suggest that the gut barrier-TNF-α-BBB-HMGB1-Caspase-1 inflammasome-pyroptosis-M1 microglia pathway is a novel mechanism of POCD related to the gut-brain axis and that intraoperative AAD infusion is a potential treatment for POCD.

SS-31 inhibits mtDNA-cGAS-STING signaling to improve POCD by activating mitophagy in aged mice.

BACKGROUND: Neuroinflammation is crucial in the development of postoperative cognitive dysfunction (POCD), and microglial activation is an active participant in this process. SS-31, a mitochondrion-targeted antioxidant, is widely regarded as a potential drug for neurodegenerative diseases and inflammatory diseases. In this study, we sought to explore whether SS-31 plays a neuroprotective role and the underlying mechanism. METHODS: Internal fixation of tibial fracture was performed in 18-month-old mice to induce surgery-associated neurocognitive dysfunction. LPS was administrated to BV2 cells to induce neuroinflammation. Neurobehavioral deficits, hippocampal injury, protein expression, mitophagy level and cell state were evaluated after treatment with SS-31, PHB2 siRNA and an STING agonist. RESULTS: Our study revealed that SS-31 interacted with PHB2 to activate mitophagy and improve neural damage in surgically aged mice, which was attributed to the reduced cGAS-STING pathway and M1 microglial polarization by decreased release of mitochondrial DNA (mtDNA) but not nuclear DNA (nDNA). In vitro, knockdown of PHB2 and an STING agonist abolished the protective effect of SS-31. CONCLUSIONS: SS-31 conferred neuroprotection against POCD by promoting PHB2-mediated mitophagy activation to inhibit mtDNA release, which in turn suppressed the cGAS-STING pathway and M1 microglial polarization.

Rutin prevents pyroptosis and M1 microglia via Nrf2/Mac-1/caspase-1-mediated inflammasome axis to improve POCD.

BACKGROUND: Neuroinflammation following peripheral surgery plays a key role in postoperative cognitive dysfunction (POCD) development and there is no effective therapy to inflammation-mediated cognitive impairment. Recent studies showed that rutin, a natural flavonoid compound, conferred neuroprotection. However, the effects and mechanisms of rutin on cognition of surgical and aged mice and LPS-induced BV2 need deeper exploration. METHODS: The effect of rutin in vivo and vitro were evaluated by Morris water maze test, HE stainin, Golgi-Cox staining, IF, IHC, RT-PCR, Flow Cytometer and Western blotting. In vivo, aged mice were treated with rutin and surgery. In vitro, rutin, Nrf2 knockdown, MAC-1 overexpression and VX765, a caspase-1 inhibitor, were administration on BV2 microglial cells. RESULTS: Surgery led to compensatory increase in nuclear Nrf2 and rutin could further increase it. Neural damage was accompanied with high level in MAC-1, caspase-1-mediated pyroptosis and M1 microglia, while rutin recovered the process. Nrf2 inhibition abolished the effect of rutin with the increase of MAC-1, caspase-1-mediated pyroptosis and M1 microglia. Activation of MAC-1 abrogated protection of rutin by increase in pyroptosis and M1 microglia. Finally, we found that treatment with VX765 improved injury and increased M2 microglia against overexpression of MAC-1. CONCLUSIONS: Our study indicated that rutin may be a potential therapy in POCD and exerted neural protection via Nrf2/ Mac-1/ caspase-1-mediated inflammasome axis to regulate pyroptosis and microglial polarization.

The effects of vitamin B6 on the nutritional support of BCAAs-enriched amino acids formula in rats with partial gastrectomy.

BACKGROUND: Total parenteral nutrition with the formula of amino acids enriched branched-chain amino acids (BCAAs) could promote patients' recovery after gastrointestinal surgery. Previous studies reported that vitamin B6 could promote amino acid metabolism and enhance protein synthesis. The aim of this study was to determine if the addition of vitamin B6 to BCAAs-enriched formula can enhance postoperative nutritional status and intestinal function in rats undergoing partial gastrectomy, and the appropriate compatibility concentration of vitamin B6. METHODS: Fifty-six male rats were randomly divided into seven groups (n = 8 per group): (I) Control, (II) BCAAs-enriched formula group (BCAA), (III) BCAA plus vitamin B6 (50 mg/L), (IV) BCAA plus vitamin B6 (100 mg/L), (V) BCAA plus vitamin B6 (200 mg/L), (VI) BCAA plus vitamin B6 (500 mg/L), and (VII) BCAA plus vitamin B6 (1000 mg/L). All animals were performed partial gastrectomy and placed a jugular vein catheter. During enteral nutrition, blood and urine samples were repeatedly collected. Gastrocnemius muscle and small intestine were also collected at the end of experiment. RESULTS: The addition of vitamin B6 to BCAAs-enriched formula improved negative nitrogen balance after gastrectomy compared to the BCAAs-enriched formula group at POD1 (first postoperative day) and POD3 (third postoperative day), and 100 mg/L was an appropriate concentration of vitamin B6 to enhance the effects of BCAAs-enriched formula. The 3-methylhistidine/creatinine in BCAA plus vitamin B6 groups were significantly lower than that in the BCAA group at POD3. Moreover, BCAA plus vitamin B6 group significantly increased the cross-sectional area of the muscle fibers compared to the BCAA group. Transcriptome sequencing, GO and KEGG enhancement analysis also showed that BCAA plus vitamin B6 group showed muscle organ development and PI3K/AKT pathway enhancement compared to BCAA group. Moreover, AKT/mTOR/4EBP1 pathway was activated in BCAA plus vitamin B6 group. In addition, the results also showed that BCAA plus vitamin B6 decreased D-lactate, and exerted synergistic effects on intestinal morphology. CONCLUSION: The addition of vitamin B6 to BCAAs-enriched formula could improve nitrogen balance, promote muscle protein synthesis through AKT/mTOR/4EBP1 pathway, and alleviate intestinal mucosa damage after partial gastrectomy in rats. Overall, the results from this pre-clinical study support the use of vitamin B6 as an ingredient to BCAAs-enriched formula, and 100 mg/L may be an optimal concentration for rats.

Caloric Restriction Can Ameliorate Postoperative Cognitive Dysfunction by Upregulating the Expression of Sirt1, MeCP2 and BDNF in the Hippocampal CA1 Region of Aged C57BL/6 Mice.

This study aimed to investigate the impact of caloric restriction (CR) on cognitive function in aged C57BL/6 mice after surgery, as well as the underlying mechanisms. Forty 14-month-old male C57BL/6 mice were randomly assigned to the ad libitum (AL, n = 20) group and the CR (n = 20) group. After feeding for 12 weeks, they were subdivided into four groups: AL control (ALC, n = 10), AL with surgery (ALS, n = 10), CR control (CRC, n = 10), and CR with surgery (CRS, n = 10). The Morris Water Maze (MWM) test was used to assess learning and memory capacity. By using western blot and immunofluorescence, the expression of Sirt1, MeCP2, and BDNF in the hippocampus and hippocampal CA1 region was quantified. According to the behavioral test, the CRC and CRS groups had significantly better learning and memory abilities than the ALC and ALS groups, respectively. Sirt1, MeCP2, and BDNF expression in the hippocampus and CA1 region in the hippocampus of the ALC and CRC groups of mice were correlated with cognitive improvement. In conclusion, CR could enhance the postoperative cognitive function in aged mice, most likely by increasing the expression of Sirt1, MeCP2, and BDNF in the CA1 region of the hippocampus.

Obesity aggravated hippocampal-dependent cognitive impairment after sleeve gastrectomy in C57/BL6J mice via SIRT1/CREB/BDNF pathway.

Postoperative cognitive dysfunction (POCD) is characterized by cognitive impairments following anesthesia/surgery, but the role of obesity and the underlying mechanisms are not known. We investigated the impact of obesity on POCD. Eighty male C57BL/6 J mice were assigned randomly to two groups fed a normal chow diet (ND, n = 40) or a high-fat diet (HD, n = 40) for 20 weeks. Then, they were divided randomly into eight subgroups of 10: ND control (NDC), ND with surgery (NDS), HD control (HDC), HD with surgery (HDS); NDS + DMSO (NDS + DS), NDS + SRT1720 (NDS + SRT), HDS + DMSO (HDS + DS), and HDS + SRT1720 (HDS + SRT). Body weight, blood glucose level, and serum lipid levels were measured. Staining methods on liver tissues were used to determine hepatic steatosis. A POCD model was established by sleeve gastrectomy (SG) under isoflurane anesthesia. Cognitive function was assessed using the Morris water maze test (MWMT). Expression of sirtuin1 (SIRT1), phosphorylated cAMP-responsive element binding protein (p-CREB), CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured. High-fat diet-fed mice for 20 weeks could establish an obesity model with hyperlipidemia and hepatic steatosis. Cognitive impairment was significantly worse in the HDC and HDS groups than that in the NDC and NDS groups, respectively. Hippocampal expression of SIRT1, p-CREB, and BDNF in the HDS group was significantly lower than that of the HDC group. SRT1720 (SIRT1 activator) pretreatment could attenuate cognitive impairment by upregulating SIRT1 expression. These data suggest that obesity exacerbated postoperative hippocampal-dependent cognitive impairment via a SIRT1 pathway, and SRT1720 pretreatment could alleviate it.

An Opioid-Sparing Strategy for Laparoscopic Sleeve Gastrectomy: A Retrospective Matched Case-Controlled Study in China.

Background: Opioid-sparing anesthesia may enhance postoperative recovery by reducing opioid-related side effects. The present study was to evaluate the effect of an opioid-sparing strategy in bariatric surgery. Methods: This study was conducted as a retrospective matched case-controlled (1:1) study. A total of 44 patients receiving either an opioid-based approach (OBA group) or an opioid-sparing strategy (OSA group) who under laparoscopic sleeve gastrectomy were included between May 2017 and October 2020. The primary outcome was the postoperative hospital length of stay (PLOS). Secondary outcomes were the hospital costs, operative opioid consumption, time to recovery, postoperative pain score at rest and rescue antiemetic administered in the PACU. Results: The clinical demographic and operative data in both groups were comparable. There were no significant differences between the two groups in the PLOS (OSA vs. OBA: 6.18 ± 0.23 days vs. 6.73 ± 0.39 days, p = 0.24). Compared to the OBA group, opioid consumption in the OSA group was significantly decreased (48.79 ± 4.85 OMEs vs. 10.57 ± 0.77 OMEs, p < 0.001). There were no significant differences in the hospital costs, time to recovery, and rescue antiemetic administered, the incidence of intravenous opioids and vasopressor use in the PACU. Conclusion: The opioid-sparing anesthesia for laparoscopic sleeve gastrectomy was feasible but did not decrease the PLOS.

Association between preoperative nutritional status, inflammation, and intestinal permeability in elderly patients undergoing gastrectomy: a prospective cohort study.

Background: Malnutrition is relatively common among elderly patients with gastric cancer. This study sought to analyze whether preoperative nutritional status, inflammatory cytokines, and intestinal permeability were correlated in elderly gastric cancer patients undergoing surgery, and their effects on postoperative recovery. Methods: This study was a single-center prospective cohort study. Patients aged 65-90 years who underwent gastrectomy were included. Preoperative nutritional status was assessed by the Mini Nutritional Score (MNA), Nutritional Risk Screening-2002 (NRS2002), body mass index (BMI), free fatty acids (FFAs), albumin, and prealbumin concentrations. Intestinal permeability was assessed by D-lactate and intestinal fatty acid-binding protein (i-FABP). The inflammatory factors included interleukin (IL)-6, IL-10, neutrophil, and lymphocyte counts. The time to first defecation, time to first liquid diet, length of hospital stay (LOS), and postoperative complications were recorded. Results: A total of 134 patients were included. According to the MNA, 50.7% and 32.1% of the cohort had mild to moderate malnutrition, and severe malnutrition, respectively. According to the NRS2002, 38.8% of the patients scored >4 points. I-FABP was significantly negatively correlated with albumin (r=-0.409, P<0.001) and prealbumin (r=-0.397, P<0.001), and significantly positively correlated with MNA (r=0.291, P=0.001), the NRS2002 (r=0.284, P=0.001), and LOS (r=0.245, P=0.004). D-lactate was significantly negatively correlated with BMI (r=-0.229, P=0.008), albumin (r=-0.426, P<0.001), and prealbumin (r=-0.358, P<0.001), and significantly positively correlated with the NRS2002 (r=0.187, P=0.030), time to first defecation (r=0.264, P=0.002), and LOS (r=0.409, P<0.001). There were significant differences in BMI, prealbumin, FFAs, i-FABP, time to first defecation, and time to first fluid diet (P<0.05) among groups based on MNA score. The multivariate logistic analysis showed that D-lactate was an independent risk factor of postoperative complications [odds ratio (OR) =1.354, 95% confidence interval (CI): 1.099-1.669, P=0.004]. Conclusions: The preoperative intestinal permeability indicators (i.e., D-lactate and i-FABP) are significantly correlated with some nutritional indicators and postoperative recovery indicators. The preoperative D-lactate level is an independent risk factor of postoperative complications, suggesting that altered gut barrier function before surgery could to some extent influence postoperative recovery in the elderly.

Preoperative Nutritional Status and Risk Factors Associated with Delayed Discharge in Geriatric Patients Undergoing Gastrectomy: A Single-Center Retrospective Study.

Objective: Preoperative malnutrition is an independent risk factor for postoperative complications and survival for gastric cancer patients. The study is aimed at investigating the prevalence of malnutrition, perioperative nutritional support, and the risk factors associated with delayed discharge of geriatric patients undergoing gastrectomy. Methods: A retrospective study of gastric cancer patients (age ≥ 65) who underwent gastrectomy at Zhongshan Hospital from January 2018 to May 2020 was conducted. Clinical data, including demographic information, medical history, surgery-related factors, and perioperative nutritional management, were collected and analyzed. Postoperative complications were assessed according to the Clavien-Dindo grading system, and the prognostic nutritional index (PNI) was calculated. The risk factors affecting the prolongation of postoperative hospital stay were analyzed. Results: A total of 783 patients were reviewed. The overall frequency of malnutrition was 31.3% (249/783). The albumin, prealbumin, and hemoglobin levels were lower in the malnutrition group than in the well-nourished group. The proportion of patients who received preoperative total parenteral nutritional support in the malnutrition group was significantly higher than in the well-nourished group (12.4% vs. 3.7%, P < 0.001). All patients received postoperative parenteral nutrition (PN); the proportion of patients who received total nutrient admixture (TNA) in the malnutrition group was lower than in the well-nourished group (22.1% vs. 33.5%, P = 0.001). No significant difference was found in the duration of postoperative nutrition between groups (P > 0.05). The malnutrition group was associated with a higher rate of postoperative complications (P < 0.001). Univariate and multivariate regressions revealed that age > 70 years (OR = 1.216, 95% CI 1.048-1.411, P = 0.010), operation time > 180 min (OR = 1.431, 95% CI 1.237-1.656, P < 0.001), PNI < 44.5 (OR = 1.792, 95% CI 1.058-3.032, P = 0.030), and postoperative complications (OR = 2.191, 95% CI 1.604-2.991, P < 0.001) were significant risk factors associated with delayed discharge. Conclusion: Malnutrition is relatively common in elderly patients undergoing gastrectomy. Advanced age, duration of surgery, lower levels of PNI, and postoperative complications were risk factors associated with delay discharge. Elderly gastric cancer patients with risk factors urgently require specific attention for reducing hospital stay.

Modified protocol for Enhanced Recovery After Surgery is beneficial for achalasia patients undergoing peroral endoscopic myotomy: a randomized prospective trial.

INTRODUCTION: Enhanced Recovery After Surgery (ERAS) protocols have been proven to promote postoperative recovery. However, limited evidence is available on ERAS protocols in patients undergoing peroral endoscopic myotomy (POEM). AIM: To study the safety and effectiveness of an ERAS protocol in terms of the standard postoperative length of stay (LOS) and QoR-15 (Quality of Recovery) score of patients undergoing POEM. MATERIAL AND METHODS: Eighty patients were randomly divided into the ERAS or conventional group. The ERAS group received ERAS management, while the conventional group received normal management. The ERAS protocol included sufficient preoperative education, shortening time of preoperative fasting, maintaining intraoperative normothermia, intraoperative fluid management, and improving analgesia. We compared the results between the two groups in term of standard postoperative LOS and cost, QoR-15 score, postoperative pain and complications. RESULTS: Patients showed an improvement in the ERAS group in terms of earlier readiness for hospital discharge (40.21 ±8.42 h vs. 48.63 ±10.42 h; p < 0.001), earlier resumption of oral feeding (31.80 ±8.7 h vs. 42.35 ±10.80 h; p < 0.001), lower VAS, and higher QoR-15 score (139.29 ±2.21 vs. 137.03 ±3.77; p = 0.002) on postoperative day 2. For post-operative complications, there was no significant difference between the two groups. CONCLUSIONS: The ERAS protocol is feasible and safe for POEM, and may decrease standard postoperative LOS, shorten recovery of gastrointestinal function, and improve postoperative patient satisfaction.

Effect of perioperative use of parecoxib on chronic post-surgical pain in elderly patients after hepatectomy: a prospective randomized controlled study.

BACKGROUND: Chronic post-surgical pain (CPSP) has a negative impact on the recovery, quality of life, and physical functioning of elderly patients. This study aimed to test the superiority of parecoxib vs. placebo in preventing chronic post-hepatectomy pain in elderly patients under combined general-epidural anesthesia. METHODS: A total of 105 elderly patients undergoing hepatectomy under combined general-epidural anesthesia were randomized into the parecoxib or placebo group. The primary outcome was the proportion of patients with CPSP 3 months postoperatively. The secondary outcomes included the Short-Form McGill Pain Questionnaire score in CPSP-positive responders, acute pain intensity, postoperative analgesic demand, inflammatory markers change, and postoperative complications within 28 days. RESULTS: The parecoxib group provided a non-significant absolute 9.1% reduction in the rate of CPSP compared to the placebo group (P = 0.34). The average chronic pain visual analog scale in the parecoxib group was lower than that in the placebo group (P = 0.04). Significantly less moderate-to-severe acute pain at rest (P = 0.04) and with coughing (P < 0.001), less patient-controlled epidural analgesia (PCEA) consumption (P = 0.01), and less rescue analgesia (P < 0.001) were observed in the parecoxib group compared to the placebo group. Furthermore, no between-group difference was observed in inflammatory markers (P > 0.05) and postoperative complications (P = 0.65). CONCLUSIONS: Parecoxib reduced the prevalence of CPSP in elderly patients after hepatectomy under combined general-epidural anesthesia from 44.4 to 35.3% with no statistical significance. Moreover, significantly alleviated CPSP intensity and improved acute pain management were observed. TRIAL REGISTRATION: This study was retrospectively registered in the Chinese Clinical Trial Registry (URL: http://www.chictr.org.cn/edit.aspx?pid=56961&htm=4 ) on August 3, 2020 ( ChiCTR-2,000,035,198 ).

Laparoscopic sleeve gastrectomy under general anesthesia in severely obese patients: a single-centered retrospective study.

BACKGROUND: This study aims to summarize and analyze the clinical characteristics and outcomes of severely obese patients who underwent laparoscopic sleeve gastrectomy (LSG) under general anesthesia with multidisciplinary collaboration. METHODS: A retrospective analysis was performed for 100 severely obese patients who were hospitalized in Zhongshan Hospital, Fudan University from January 2017 to December 2019, and included preoperative general information, laboratory examinations, anesthesia and outcomes. RESULTS: A total of 100 patients (46 males, 54 females) were admitted to the department of endocrinology: 100 had hepatic steatosis (100%), 43 had sleep apnea hypopnea syndrome (43%), 25 had hypertension (25%), 11 had type 2 diabetes (11%) and 8 had polycystic ovary syndrome (14% of women). The mean age and BMI were 31.52 ± 10.53 years and 43.31 ± 6.80 kg/m2, respectively. Visual laryngoscope intubation was successfully performed with routine intravenous induction in the optimum sniffing position at one time. The surgeries were successfully performed under general anesthesia, without conversion, and the operation time was 140.92 ± 31.23 min. The follow-up data for 41 patients were obtained. The postoperative BMI showed a downward trend. The BMI at 1 month and 3 months after surgery were 38.40 ± 6.77 kg/m2and 35.52 ± 7.94 kg/m2, respectively. CONCLUSIONS: Multidisciplinary collaboration may contribute to better management and recovery during the perioperative period. Visual laryngoscope intubation with intravenous induction was performed successfully in the optimum sniffing position at one time.

Awake fiberoptic orotracheal intubation: a protocol feasibility study.

OBJECTIVE: To assess the feasibility of an awake fiberoptic intubation (AFOI) protocol. METHODS: We enrolled 40 patients with simulated difficult intubation. The protocol consisted of conscious sedation (midazolam, 0.03 mg/kg and sufentanil, 0.1 µg/kg), regional anesthesia, and intubation. The time, first-attempt intubation success rate, hemodynamic parameters, blood oxygen saturation (SpO2), intubation amnesia rate, patient satisfaction, and relative complications were recorded. RESULTS: AFOI was completed in all patients. The average total AFOI time was 14.17 ± 1.47 minutes, and the time to placing the landmark-guided bilateral superior laryngeal nerve block was 1.24 ± 0.42 minutes. The first-attempt intubation success rate was 97.5%, and patient satisfaction was 90%. Blood pressure changed (<20%) briefly after administering conscious sedation. Heart rates did not change significantly, and SpO2 remained stable and ≥95%. Three patients had a sore throat, which resolved on postoperative day 1 without other complications. On postoperative day 1, 82.5% (33/40) of the patients had no recall of AFOI, and 17.5% (7/40) had only an indistinct memory. CONCLUSIONS: The protocol was feasible with a high first-attempt intubation success rate and low complications rate. Hemodynamic parameters and respiration remained stable, with high patient satisfaction and effective amnesia.

Ultrasound-guided versus Shikani optical stylet-aided tracheal intubation: a prospective randomized study.

BACKGROUND: To compare ultrasound-guided tracheal intubation (UGTI) versus Shikani optical stylet (SOS)-aided tracheal intubation in patients with anticipated normal airway. METHODS: Sixty patients aged 18-65 years old who presented for elective surgery under general anesthesia were recruited in this prospective randomized study. They were assigned into two equal groups, either an ultrasound-guided group (Group UG, n = 30) or an SOS-aided group (Group SOS, n = 30). After the induction of anesthesia, the tracheal intubation was performed by a specified skilled anesthesiologist. The number of tracheal intubation attempt and the duration of successful intubation on the first attempt were recorded. Complications relative to tracheal intubation including desaturation, hoarseness and sore throat were also recorded. RESULTS: The first-attempt success rate is 93.3% (28/30) in Group UG and 90% (27/30) in Group SOS (P = 0.640). The second-attempt was all successful for the 2 and 3 patients left in the two groups, and the overall success rate of both groups was 100%. The duration of successful intubation on the first attempt of Group UG was not significantly different from that of Group SOS (34.0 ± 20.8 s vs 35.5 ± 23.2 s, P = 0.784). One patient in Group SOS had desaturation (P = 0.313), and there was none hoarseness in the two groups. Sore throat was detected in both group (4 in Group UG, 5 in Group SOS, P = 0.718). CONCLUSION: Ultrasound-guided tracheal intubation was as effective as Shikani optical stylet-aided tracheal intubation in adult patients with anticipated normal airway. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IIC-17010875 . Date of Registration: 15 March 2017.

MECP2 Duplication Causes Aberrant GABA Pathways, Circuits and Behaviors in Transgenic Monkeys: Neural Mappings to Patients with Autism.

MECP2 gain-of-function and loss-of-function in genetically engineered monkeys recapitulates typical phenotypes in patients with autism, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remain unknown. Here we report a combination of gene-circuit-behavior analyses including MECP2 coexpression network, locomotive and cognitive behaviors, and EEG and fMRI findings in 5 MECP2 overexpressed monkeys (Macaca fascicularis; 3 females) and 20 wild-type monkeys (Macaca fascicularis; 11 females). Whole-genome expression analysis revealed MECP2 coexpressed genes significantly enriched in GABA-related signaling pathways, whereby reduced ß-synchronization within fronto-parieto-occipital networks was associated with abnormal locomotive behaviors. Meanwhile, MECP2-induced hyperconnectivity in prefrontal and cingulate networks accounted for regressive deficits in reversal learning tasks. Furthermore, we stratified a cohort of 49 patients with autism and 72 healthy controls of 1112 subjects using functional connectivity patterns, and identified dysconnectivity profiles similar to those in monkeys. By establishing a circuit-based construct link between genetically defined models and stratified patients, these results pave new avenues to deconstruct clinical heterogeneity and advance accurate diagnosis in psychiatric disorders.SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a complex disorder with co-occurring symptoms caused by multiple genetic variations and brain circuit abnormalities. To dissect the gene-circuit-behavior causal chain underlying ASD, animal models are established by manipulating causative genes such as MECP2 However, it is unknown whether such models have captured any circuit-level pathology in ASD patients, as demonstrated by human brain imaging studies. Here, we use transgenic macaques to examine the causal effect of MECP2 overexpression on gene coexpression, brain circuits, and behaviors. For the first time, we demonstrate that the circuit abnormalities linked to MECP2 and autism-like traits in the monkeys can be mapped to a homogeneous ASD subgroup, thereby offering a new strategy to deconstruct clinical heterogeneity in ASD.

Obesity caused by a high-fat diet regulates the Sirt1/PGC-1α/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice.

Objectives: To investigate the effects of obesity caused by high-fat diet (HFD) on postoperative cognitive dysfunction (POCD) and expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus of older mice. Methods: Fifty-six 15-month-old male C57BL/6 mice were randomly divided into eight groups - ad libitum control (ALC), ad libitum surgery (ALS), ad libitum surgery with PBS (ALS + PBS), ad libitum surgery with resveratrol (ALS + Res), HFD control (HFC), HFD surgery (HFS), HFD surgery with PBS (HFS + PBS), HFD surgery with resveratrol (HFS + Res). Surgery group mice were exposed to isoflurane before tibial fracture internal fixation. Open field tests and fear conditioning were performed to test motor ability and memory. The levels of expression of Sirt1, PGC-1α, FNDC5, and BDNF were detected using western blot and immunofluorescence. Results: The results of the open field tests indicated there were no between-group differences in motor ability and anxiety. The results of the fear conditioning indicated that the memory of the HFC group and HFS group mice were significantly worse compared with the ALC group and ALS group mice, respectively. There were parallel decreases in expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampi of the HFC and HFS group mice. Resveratrol treatment attenuated the memory loss by increasing hippocampal Sirt1 expression. Expression of the PGC-1α/FNDC5/ BDNF pathway in the CA1 area of the hippocampus was upregulated after resveratrol treatment. Conclusion: An HFD exacerbates POCD in older mice. This change was related to HFD inhibition of expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus. Resveratrol pretreatment reversed the memory loss via upregulation of this pathway.

HSF1/HSP pathway in the hippocampus is involved in SIRT1-mediated caloric restriction-induced neuroprotection after surgery in aged mice.

Postoperative cognitive dysfunction is common in the elderly. Endoplasmic reticulum stress (ER-stress) increases neuronal apoptosis after surgery, and chaperone molecules, such as heat shock proteins (HSPs), help reduce unfolded protein reactions, thereby promoting protein homeostasis. Mammal sirtuin1 (SIRT1)-mediated deacetylation of heat shock factor 1 (HSF1) upregulates HSF1 binding to the HSP70 promoter. Caloric restriction (CR) improves cognition in many neurodegenerative models. In this study, we evaluated whether CR improves impaired learning and memory after surgery by attenuating ER-stress in an SIRT1-dependent manner. Male 18-month-old C57BL/6J mice receiving a 12-week CR or an ad libitum (AL) diet pre-intervention were challenged with tibial open fracture surgery and anesthesia or no treatment. We found a significant protective effect of CR on memory in contextual fear conditioning test after surgery compared with the AL group. CR alleviated ER-stress and neuronal apoptosis in the hippocampus induced by surgery. CR increased HSP70 expression through the HSF1/HSP pathway in a SIRT1-mediated manner, and inhibition of SIRT1 in the hippocampus by lentivirus injection partially reduced the benefits of CR (increased HSP70, deacetylated HSF1, reduced ER-stress, and improved memory). Taken together, our results showed that CR alleviates memory impairment postoperatively via attenuation of ER-stress in the hippocampus in an SIRT1-dependent manner, and the SIRT1/HSF1/HSP70 pathway is involved in this process.

Effects of resveratrol pretreatment on endoplasmic reticulum stress and cognitive function after surgery in aged mice.

BACKGROUND: Postoperative cognitive dysfunction (POCD) seriously reduces quality of life and is associated with increased morbidity and mortality. The causes and neuropathogenesis of POCD remain largely unknown. Resveratrol, a sirtuin 1 (Sirt1) activator, is a polyphenol compound found in red wine that has protective functions in neuropathology paradigms. Endoplasmic reticulum stress (ERS) is a primary cellular response that activates the unfolded protein response (UPR). ERS and UPR mediate molecular and biochemical mechanisms related to neurodegeneration; however, the roles of ERS and Sirt1 in POCD remain unclear. The properties of resveratrol might be useful in the setting of POCD. METHODS: In the present study, we investigated learning and memory function and ERS pathways in aged mice after surgery under local anesthesia, and we evaluated the effects of resveratrol pretreatment. RESULTS: We found that resveratrol attenuated postoperative learning and memory impairment in aged mice postoperatively but did not alter locomotor activity. Resveratrol significantly decreased postoperative expression of ERS pathway UPR-related proteins and inflammatory mediators including nuclear factor-κB (NF-κB) in the hippocampus. This was accompanied by higher Sirt1 protein expression levels. Pretreatment with resveratrol did not affect the number of hippocampal neurons in aged mice after surgery. CONCLUSION: Overall, resveratrol pretreatment attenuated short-term learning and memory impairment and the ERS pathway UPR in aged mice after surgery under local anesthesia.