Metabolomic Analysis in Saliva and Different Brain Regions of Older Mice with Postoperative Delirium Behaviors.

Objective: Postoperative delirium (POD) has become a critical challenge with severe consequences and increased incidences as the global population ages. However, the underlying mechanism is yet unknown. Our study aimed to explore the changes in metabolites in three specific brain regions and saliva of older mice with postoperative delirium behavior and to identify potential non-invasive biomarkers. Methods: Eighteen-month-old male C57/BL6 mice were randomly assigned to the anesthesia/surgery or control group. Behavioral tests were conducted 24 h before surgery and 6, 9, and 24 h after surgery. Complement C3 (C3) and S100 calcium-binding protein B protein (S100beta) levels were measured in the hippocampus, and a metabolomics analysis was performed on saliva, hippocampus, cortex, and amygdala samples. Results: In total, 43, 33, 38, and 14 differential metabolites were detected in the saliva, hippocampus, cortex, and amygdala, respectively. "Pyruvate" "alpha-linolenic acid" and "2-oleoyl-1-palmitoy-sn-glycero-3-phosphocholine" are enriched in one common pathway and may be potential non-invasive biomarkers for POD. Common changes were observed in the three brain regions, with the upregulation of 1-methylhistidine and downregulation of D-glutamine. Conclusion: Dysfunctions in energy metabolism, oxidative stress, and neurotransmitter dysregulation are implicated in the development of POD. The identification of changes in the level of salivary metabolite biomarkers could aid in the development of noninvasive diagnostic methods for POD.

Effect of individualized positive end-expiratory pressure based on electrical impedance tomography guidance on pulmonary ventilation distribution in patients who receive abdominal thermal perfusion chemotherapy.

Background: Electrical impedance tomography (EIT) has been shown to be useful in guiding individual positive end-expiratory pressure titration for patients with mechanical ventilation. However, the appropriate positive end-expiratory pressure (PEEP) level and whether the individualized PEEP needs to be adjusted during long-term surgery (>6 h) were unknown. Meanwhile, the effect of individualized PEEP on the distribution of pulmonary ventilation in patients who receive abdominal thermoperfusion chemotherapy is unknown. The primary aim of this study was to observe the effect of EIT-guided PEEP on the distribution of pulmonary ventilation in patients undergoing cytoreductive surgery (CRS) combined with hot intraperitoneal chemotherapy (HIPEC). The secondary aim was to analyze their effect on postoperative pulmonary complications. Methods: A total of 48 patients were recruited and randomly divided into two groups, with 24 patients in each group. For the control group (group A), PEEP was set at 5 cm H2O, while in the EIT group (group B), individual PEEP was titrated and adjusted every 2 h with EIT guidance. Ventilation distribution, respiratory/circulation parameters, and PPC incidence were compared between the two groups. Results: The average individualized PEEP was 10.3 ± 1.5 cm H2O, 10.2 ± 1.6 cm H2O, 10.1 ± 1.8 cm H2O, and 9.7 ± 2.1 cm H2O at 5 min, 2 h, 4 h, and 6 h after tracheal intubation during CRS + HIPEC. Individualized PEEP was correlated with ventilation distribution in the regions of interest (ROI) 1 and ROI 3 at 4 h mechanical ventilation and ROI 1 at 6 h mechanical ventilation. The ventilation distribution under individualized PEEP was back-shifted for 6 h but moved to the control group's ventral side under PEEP 5 cm H2O. The respiratory and circulatory function indicators were both acceptable either under individualized PEEP or PEEP 5 cm H2O. The incidence of total PPCs was significantly lower under individualized PEEP (66.7%) than PEEP 5 cm H2O (37.5%) for patients with CRS + HIPEC. Conclusion: The appropriate individualized PEEP was stable at approximately 10 cm H2O during 6 h for patients with CRS + HIPEC, along with better ventilation distribution and a lower total PPC incidence than the fixed PEEP of 5 cm H2O.Clinical trial registration: identifier ChiCTR1900023897.

Dexmedetomidine Promotes Angiogenesis and Vasculogenic Mimicry in Human Hepatocellular Carcinoma through α 2-AR/HIF-1α/VEGFA Pathway.

Objective: Dexmedetomidine (DEX), the most specific α 2-adrenergic receptor agonist widely used for its sedative and analgesic properties, has been reported to upregulate HIF-1α expression to protect hypoxic and ischemic tissues. However, it is largely unclear whether DEX can also upregulate Hypoxia-inducible factor-1 alpha (HIF-1α) expression and its downstream vascular endothelial growth factor-A (VEGFA) in cancer tissues with oxygen-deficient tumor microenvironment. Methods: We used SMMC-7721 cells, MHCC97-H cells, and a mouse model of orthotopic hepatic carcinoma to explore the effect of DEX on angiogenesis and vasculogenic mimicry (VM) and its mechanism. Under normoxic (20% O 2) and hypoxic (1% O 2) conditions, DEX was used to intervene cells, and yohimbine was used to rescue them. Results: The results showed that DEX promoted angiogenesis and VM in human liver cancer cells within a certain dose range, and the addition of yohimbine inhibited this effect. DEX could activate HIF-1α/VEGFA pathway, which was further verified by silencing HIF-1α. Consistently, in vivo results also showed that DEX can up-regulate HIF-1α/VEGFA expression, and enhance the number of VM channels and microvessel density (MVD). Conclusion: We believe that HIF-1α/VEGFA might be an important signaling pathway by which DEX promotes angiogenesis and VM formation in human hepatocellular carcinoma, whereas α 2-adrenergic receptor mediation might be the critical mechanisms.

Morphine pretreatment protects against cerebral ischemic injury via a cPKCγ-mediated anti-apoptosis pathway.

It has been reported that morphine pretreatment (MP) can exert neuroprotective effects, and that protein kinase C (PKC) participates in the initiation and development of ischemic/hypoxic preconditioning in the brain. However, it remains unknown whether PKC is involved in MP-induced neuroprotection. The aim of the present study, which included in vivo and in vitro experiments, was to determine whether the conventional γ isoform of PKC (cPKCγ) was involved in the protective effects of MP against cerebral ischemic injury. The present study included an in vivo experiment using a mouse model of middle cerebral artery occlusion and an in vitro experiment using neuroblastoma N2a cells with oxygen-glucose deprivation (OGD). Furthermore, a cPKCγ antagonist, Go6983, was used to determine the involvement of cPKCγ in the protective effects of MP against cerebral ischemic injury. In the in vivo experiment, neurological deficits, ischemic infarct volume, neural cell damage, apoptosis and caspase-3 activation were evaluated. In the in vitro experiment, flow cytometry was used to determine the activation of caspase-3 in N2a cells with OGD. It was found that MP protected against cerebral ischemic injury. However, intracerebroventricular injection of the cPKCγ antagonist before MP attenuated the neuroprotective effect of MP and increased the activation of cleaved caspase-3. These findings suggested that MP may provide protection against cerebral ischemic injury via a cPKCγ-mediated anti-apoptosis pathway.

Repeated propofol exposure-induced neuronal damage and cognitive impairment in aged rats by activation of NF-κB pathway and NLRP3 inflammasome.

BACKGROUND: Elderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent propofol exposure remains unclear. Thus, we used aged rats to investigate the effect of propofol on cognition. METHODS: The study included two parts. In the first part, aged (18-20 months old) male Sprague-Dawley rats underwent intermittent intraperitoneal injection of propofol (200 mg/kg) or intralipid, every 9 days or once a day. In the second part, some aged rats received intraperitoneal injection of Bay 11-7082 (1 mg/kg), a specific inhibitor of NF-κB, 30 min before propofol injection. Memory tests were performed to evaluate cognition 24 h after the entire treatment. The hippocampal neuronal damage was assessed by TUNEL staining. The hippocampal levels of p-NF-κB p65, NLRP3, caspase-1 p20, and cleaved caspase-3 were detected by western blotting. The hippocampal and serum levels of IL-1ß, IL-6, and TNF-α were evaluated using ELISA. RESULTS: There were no differences in the behavioral tests, hippocampal neuronal damage, and neuroinflammation between groups given intralipid and propofol treatment every 9 days. However, repeated propofol treatment once a day promoted activation of NF-κB and the NLRP3 inflammasome, inducing cognitive impairment and neuroinflammation. Interestingly, pretreatment with Bay-11-7082 not only inhibited NF-κB/NLRP3 inflammasome activation, but also attenuated neuronal damage and cognitive dysfunction in aged rats exposed to daily propofol treatment. CONCLUSIONS: Intermittent propofol treatment every 9 days may be safe for aged rats. However, propofol treatment once a day could impair the cognition of aged rats, partly through the activation of the NF-κB pathway and NLRP3 inflammasome, which may be a potential targets for the treatment of cognitive impairment in elderly patients.

Fisetin Alleviates Lipopolysaccharide-Induced Acute Lung Injury via TLR4-Mediated NF-κB Signaling Pathway in Rats.

Acute lung injury (ALI), a common component of systemic inflammatory disease, is a life-threatening condition without many effective treatments. Fisetin, a natural flavonoid from fruits and vegetables, was reported to have wide pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. The aim of this study was to detect the effects of fisetin on lipopolysaccharide (LPS)-induced acute lung injury and investigate the potential mechanism. Fisetin was injected (1, 2, and 4 mg/kg, i.v.) 30 min before LPS administration (5 mg/kg, i.v.). Our results showed that fisetin effectively reduced the inflammatory cytokine release and total protein in bronchoalveolar lavage fluids (BALF), decreased the lung wet/dry ratios, and obviously improved the pulmonary histology in LPS-induced ALI. Furthermore, fisetin inhibited LPS-induced increases of neutrophils and macrophage infiltration and attenuated MPO activity in lung tissues. Additionally, fisetin could significantly inhibit the Toll-like receptor 4 (TLR4) expression and the activation of NF-κB in lung tissues. Our data indicates that fisetin has a protective effect against LPS-induced ALI via suppression of TLR4-mediated NF-κB signaling pathways, and fisetin may be a promising candidate for LPS-induced ALI treatment.

Daidzein attenuates lipopolysaccharide-induced acute lung injury via toll-like receptor 4/NF-kappaB pathway.

Daidzein, a diphenolic isoflavone from many plants and herbs, has been reported to have anti-inflammatory properties. However, the effects of daidzein on lipopolysaccharide (LPS)-induced acute lung injury have not been determined. The aim of this study was to detect the effects of daidzein on LPS-induced acute lung injury and investigate the molecular mechanisms. Daidzein was intraperitoneally injected (2, 4, 8 mg/kg) 30 min after intratracheal instillation of LPS (5 mg/kg) in rats. The results showed that daidzein treatment remarkably improved the pulmonary histology and decreased the lung wet/dry weight ratios. We also found that daidzein significantly inhibited LPS-induced increases of macrophages and neutrophils infiltration of lung tissues, as well as markedly attenuated MPO activity. Moreover, daidzein effectively reduced the inflammatory cytokines release and total protein in bronchoalveolar lavage fluids (BALF). Furthermore, daidzein significantly inhibited LPS-induced toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) protein up-expressions and NF-κB activation in lung tissues. In vitro, daidzein obviously inhibited the expressions of TLR4 and MyD88 and the activation of NF-κB in LPS-stimulated A549 alveolar epithelial cells. In conclusion, these data indicate that the anti-inflammatory effects of daidzein against LPS-induced ALI may be due to its ability to inhibit TLR4-MyD88-NF-κB pathway and daidzein may be a potential therapeutic agent for LPS-induced ALI.

[The evaluation of Apneic anesthesia with intermittent ventilation for juvenile-onset recurrent laryngeal papillomatosis].

OBJECTIVE: To evaluate the feasibility of Apneic anesthesia with intermittent ventilation (AAIV) during laryngeal papillomatosis removal in children. METHODS: The clinical data of 30 patients with laryngeal papillomatosis treated in the Tong Ren Hospital of Capital University of Medical Sciences, between 10 - 12 2011 were analyzed. Thirty ASA physical status I or II patients who were scheduled for elective surgery. The patients were ventilated with 100% oxygen and the period of intermittent apnea were guided by pulse oximetry, the endotracheal tube was removed when SpO2 was 100% and reinserted when SpO2 was 95%. RESULT: The average duration of apnea was (232 ± 32) s. This technique provided a good visualization and immobile field for operation. No significant complications have occurred with AAIV. CONCLUSION: Apneic anesthesia with intermittent ventilation could be used without any serious adverse outcome for juvenile-onset recurrent laryngeal papillomatosis, 232 seconds can provided for surgery every AAIV.

Shikani™ Seeing Optical Stylet-aided tracheal intubation in patients with a large epiglottic cyst.

Large epiglottic cysts can block the glottis, leading to serious consequences. This condition presents a challenge in terms of airway management for anesthesiologists during induction of anesthesia. We report the use of a Shikani™ Seeing Optical Stylet combined with a Macintosh laryngoscope to aid tracheal intubation in seven patients with large epiglottic cysts. Use of this technique can avoid cyst rupture and allow smooth, safe intubation.

[Effects of cPKCßII/γ membrane translocation ischemic/hypoxic tolerance induced by morphine postconditioning in hippocampal slices].

OBJECTIVE: To determine whether or not morphine postconditioning can induce ischemic/hypoxic tolerance in neurons subjected to reperfusion injury after oxygen-glucose deprivation (OGD). METHODS: Hippocampal slices of 400 µm thickness were prepared from healthy adult male BALB/c mice. The slices were incubated in oxygen-saturated ACSF without or with calcium, then were subjected to OGD for 20 min. After recovery, the samples were immersed in oxygenated artificial fluid for 2 hours in the presence or absence of morphine postconditioning at 3 µmol/L during the first 5 - 60 min. The assessment of slices injury was performed by a determination of the intensity of slice stain incubated with TTC (2% 2, 3, 5-triphenyltetrazolium chloride) and the leakage rate of LDH also evaluated. At the designated periods during incubation, some slices were immersed into liquid nitrogen for a later analysis of Western blot. The frozen slices were homogenized, sonicated and centrifuged to separate soluble and particulate proteins. 10% SDS-PAGE Western blot was used to identify the changes of membrane-specific translocation of cPKCßII/γ. RESULTS: After reperfusion, the cell survival significantly decreased with the elongation of OGD (51.4%). The release rate of LDH (184.05%) significantly increased simultaneously. In hippocampal slices postconditioned with morphine for 20 - 60 min, the release rate of LDH (136%, 142%, 144%) significantly decreased as compared with the group OGD. In the hippocampal slices postconditioned with morphine for 10 - 30 min, the cell survival rate (64.9%, 69.9%, 63.5%) significantly increased as compared with reperfusion alone. cPKCγ of particulate fraction increased versus the control. And there was a corresponding decrease of cytosolic fraction. Morphine postconditioning significantly inhibited the cPKCγ isoform-specific membrane translocation. It declined from 136% in the group OGD to 123%, 118%, 114% in the group morphine 20 - 60 min. cPKCßII membrane translocation had no change. CONCLUSION: Morphine postconditioning can induce ischemic tolerance in nerons. The protective mechanism may be through inhibiting the cPKCγ isoform-specific membrane translocation.

[Effects of intraoperative application of radical scavenger edaravone in severe elderly cases].

OBJECTIVE: To observe the effects of intraoperative application of radical scavenger edaravone in severe elderly cases. METHODS: A total of 400 severe elderly patients scheduled for surgery were randomly assigned to receive edaravone 60 mg/40 ml (Group Y) or an equal volume of normal saline (Group C). The arterial blood samples were harvested at immediately after pricking, 1 hour after the beginning of surgery and before saturation to determine the levels of superoxide dismutase (SOD) and malondialdehyde (MDA). The operative duration, fluid volume, blood loss, blood transfusion volume, urine output, intraoperative adverse events, mortality rate, total hospital stay, intensive care unit (ICU) stay, postoperative mechanical ventilation time and complications were recorded. Patients undergoing off-pump coronary artery bypass graft (OPCABG) were evaluated for troponin I (cTnI) and left ventricular ejection fraction (LVEF) before and after 24 hours of surgery. RESULTS: SOD was higher and MDA lower in Group Y than those in Group C at 1 hour intraoperation and before saturation [SOD: (87 ± 14) U/ml vs (78 ± 14) U/ml, (83 ± 13) U/ml vs (77 ± 14) U/ml, P < 0.01, < 0.05; MDA: (11 ± 5) nmol/L vs (14 ± 7) nmol/L, (11 ± 5) nmol/L vs (14 ± 6) nmol/L, P < 0.05, < 0.01]. There were more intraoperative hypotension cases requiring a continuous application of vasoactive drugs in Group C (37 cases vs 19 cases), total hospital stay [(21 ± 9) d vs (23 ± 9) d, P < 0.05] and ICU stay [(10 ± 7) d vs (13 ± 9) d, P < 0.05] were also longer. Postoperative cTnI and LVEF of Group Y significantly improved in OPCABG cases (all P < 0.05). CONCLUSION: The intraoperative application of edaravone in severe elderly patients may prevent MDA increase and SOD decrease and reduce free radical damage. Especially in OPCABG patients, cTnIand LVEF improve significantly.

[Premedication with oral midazolam in children receive sevoflurane general anesthesia].

OBJECTIVE: To investigate the effect of oral midazolam on sedation, on perioperative emotion and on behavior in children with sevoflurane general anesthesia. METHODS: 48 children undergoing cataract surgeries were randomly divided into two groups and respectively received 0.5 mg/kg oral midazolam (Group I)and placebo (Group II) 30 minutes before the operation. Perioperative behavior and emotion status were assessed. RESULTS: Satisfactory sedation ratio in group I was better than that in group II (58.3% vs 12.5%, P < 0.05). There were no differences in emergence time, PACU stay and incidence of emergence agitation between two groups (P > 0.05). CONCLUSION: 0.5 mg/kg oral midazolam before sevoflurane general anesthesia in children is safe. It is effective on anxious relief, however it does not decrease the incidence of emergence agitation.

[Evaluation of retropalatal mechanical loads in patients with obstructive sleep apnea].

OBJECTIVE: To evaluate the mechanical load of retropalatal airway in obstructive sleep apnea patients, and to investigate the contributions of pharyngeal anatomy to upper airway collapsibility. METHODS: Static mechanical load of transpalatal pharynx was determined by opening pressure (Popen) of the segment during general anesthesia in 30 patients and 14 controls. Size of pharynx was measured while intraluminal pressure was controlled at 3-20 cm H2O (1 cm H2O = 0.09806 kPa) and the minimal intraluminal pressure that needed to compensate for the mechanical load of a retropalatal segment was determined. RESULTS: Pharyngeal cavity collapse at the level of the hard palate was observed in only one of the 30 subjects (3.3%), and in none of the 14 controls. At tongue base level, 23 subjects had a Popen > 0 cm H2O (76.7%) while in 7 of the controls (50.0%) had a Popen > 0 cm H2O. And at the level of the uvual and soft palate, pharyngeal collapses was observed in all subjects except in 9 of the controls (64.3%). The median of Popen was 8.3 [5.9;11.5] cm H2O in the patients group and was 2.7 [-3.9;6.0] cm H2O in the control group. Differences of Popen were significant between patients and controls (U = 58.500, P = 0.000). The correlation between Popen and AHI was also significant at 0.05 level (r = 0.377, P = 0.044). CONCLUSIONS: Patients with sleep apnea have more collapsible passive upper airway than controls. Retropalatal and retroglossal airway are the most collapsible segments and positive pressures are needed to compensate for the mechanical loads.