Drop to Gate Nasal Drops Attenuates Sepsis-Induced Cognitive Dysfunction.

Nasal administration can bypass the blood-brain barrier and directly deliver drugs to the brain, providing a non-invasive route for central nervous system (CNS) diseases. Inspired by the appearance that a gate can block the outside world and the characteristics of the sol-gel transition can form a "gate" in the nasal cavity, a Drop to Gate nasal drop (DGND) is designed to set a gate in nose, which achieves protecting role from the influence of nasal environment. The DGND demonstrates the efficiency and application prospect of delivering drugs to the brain through the N-to-B. The effective concentration of single administration is increased through the hydrophobic interaction between C8-GelMA and SRT1720 (SA), and then cross-linked under UV to form nanogel, which can respond to MMP in the inflammatory microenvironment of sepsis-induced cognitive dysfunction. Finally, the SA/nanogel is compounded into the thermogel, which can respond to the nasal cavity temperature to form DGND in situ, increasing the residence time and delivery efficiency of drugs in the nasal cavity. In vitro, the DGND alleviates lipopolysaccharides (LPS)-induced BV2 inflammation. In vivo, DGND effectively targets the nasal mucosa and deliver drugs to the brain, which activate Sirt1 to alleviate inflammation mediated by microglia and improve cognitive dysfunction in sepsis mice.

Cortical changes in the brain of patients with hemifacial spasm.

OBJECTIVE: Hemifacial spasm (HFS) is a movement disorder characterized by involuntary muscle contractions on one side of the face. It is associated with disturbances in the brain's functional architecture. Despite this, the structural alterations in the brain related to HFS remain poorly understood. In this study, we investigated the cortical morphology changes in patients with HFS compared to healthy controls (HCs). METHODS: We analyzed 3D T1-weighted MRI images from 33 patients with left-sided primary HFS and 33 age- and sex-matched HCs. Measurements of cortical thickness (CTh), sulcal depth, local gyrification index (lGI), and fractal dimension were taken using a computational anatomy toolbox. A general linear model, accounting for age, gender, and total brain volume, was applied for statistical analyses. Significant clusters were then assessed for correlations with clinical parameters. RESULTS: The HFS patients displayed several cortical abnormalities when compared to HCs, including reduced CTh in the contralateral precentral gyrus and left orbitofrontal cortex, decreased sulcal depth in the left orbitofrontal cortex, and increased lGI in the right insula and superior temporal cortex. However, fractal dimension did not differ significantly between the groups. Additionally, in HFS patients, a notable negative correlation was found between the sulcal depth in the left orbitofrontal cortex and the Beck Depression Inventory-II scores. CONCLUSIONS: Our findings reveal that HFS is associated with specific surface-based morphological changes in the brain. These alterations contribute to a deeper understanding of the neurophysiological mechanisms involved in HFS and may have implications for future research and treatment strategies.

Regulation and drug modulation of a voltage-gated sodium channel: Pivotal role of the S4-S5 linker in activation and slow inactivation.

Voltage-gated sodium (NaV) channels control excitable cell functions. While structural investigations have revealed conformation details of different functional states, the mechanisms of both activation and slow inactivation remain unclear. Here, we identify residue T140 in the S4-S5 linker of the bacterial voltage-gated sodium channel NaChBac as critical for channel activation and drug effects on inactivation. Mutations at T140 either attenuate activation or render the channel nonfunctional. Propofol, a clinical anesthetic known to inhibit NaChBac by promoting slow inactivation, binds to a pocket between the S4-S5 linker and S6 helix in a conformation-dependent manner. Using 19F-NMR to quantify site-specific binding by saturation transfer differences (STDs), we found strong STDs in inactivated, but not activated, NaChBac. Molecular dynamics simulations show a highly dynamic pocket in the activated conformation, limiting STD buildup. In contrast, drug binding to this pocket promotes and stabilizes the inactivated states. Our results provide direct experimental evidence showing distinctly different associations between the S4-S5 linker and S6 helix in activated and inactivated states. Specifically, an exchange occurs between interaction partners T140 and N234 of the same subunit in activation, and T140 and N225 of the domain-swapped subunit in slow inactivation. The drug action on slow inactivation of prokaryotic NaV channels seems to have a mechanism similar to the recently proposed "door-wedge" action of the isoleucine-phenylalanine-methionine (IFM) motif on the fast inactivation of eukaryotic NaV channels. Elucidating this gating mechanism points to a possible direction for conformation-dependent drug development.

An Fgr kinase inhibitor attenuates sepsis-associated encephalopathy by ameliorating mitochondrial dysfunction, oxidative stress, and neuroinflammation via the SIRT1/PGC-1α signaling pathway.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is characterized by diffuse brain dysfunction, long-term cognitive impairment, and increased morbidity and mortality. The current treatment for SAE is mainly symptomatic; the lack of specific treatment options and a poor understanding of the underlying mechanism of disease are responsible for poor patient outcomes. Fgr is a member of the Src family of tyrosine kinases and is involved in the innate immune response, hematologic cancer, diet-induced obesity, and hemorrhage-induced thalamic pain. This study investigated the protection provided by an Fgr kinase inhibitor in SAE and the underlying mechanism(s) of action. METHODS: A cecal ligation and puncture (CLP)-induced mouse sepsis model was established. Mice were treated with or without an Fgr inhibitor and a PGC-1α inhibitor/activator. An open field test, a novel object recognition test, and an elevated plus maze were used to assess neurobehavioral changes in the mice. Western blotting and immunofluorescence were used to measure protein expression, and mRNA levels were measured using quantitative PCR (qPCR). An enzyme-linked immunosorbent assay was performed to quantify inflammatory cytokines. Mitochondrial membrane potential and morphology were measured by JC-1, electron microscopy, and the MitoTracker Deep Red probe. Oxidative stress and mitochondrial dysfunction were analyzed. In addition, the regulatory effect of Fgr on sirtuin 1 (SIRT1) was assessed. RESULTS: CLP-induced sepsis increased the expression of Fgr in the hippocampal neurons. Pharmacological inhibition of Fgr attenuated CLP-induced neuroinflammation, the survival rate, cognitive and emotional dysfunction, oxidative stress, and mitochondrial dysfunction. Moreover, Fgr interacted with SIRT1 and reduced its activity and expression. In addition, activation of SIRT1/PGC-1α promoted the protective effects of the Fgr inhibitor on CLP-induced brain dysfunction, while inactivation of SIRT1/PGC-1α counteracted the benefits of the Fgr inhibitor. CONCLUSIONS: To our knowledge, this is the first report of Fgr kinase inhibition markedly ameliorating SAE through activation of the SIRT1/PGC-1α pathway, and this may be a promising therapeutic target for SAE.

Dexamethasone inhibits IL-8 via glycolysis and mitochondria-related pathway to regulate inflammatory pain.

BACKGROUND: Dexamethasone (Dexa) has been recently found to exert an analgesic effect, whose action is closely related to IL-8. However, whether dexamethasone induces antinociception via glycolysis and mitochondria-related pathways is still unclear. METHODS: Right hind paw inflammatory pain in mice was induced by intraplantar injection of Freund's Complete Adjuvant (FCA). Von Frey test was then used to measure the paw withdrawal threshold. The detection of glycolysis and mitochondrial pathway-related proteins and IL-8 were determined by Western blot and ELISA. The potential interaction between Dexa and fructose-1,6-bisphosphate (FBP, a PKM2 activator) was examined by simulation predictions using molecular docking. RESULTS: Intrathecal administration of Dexa (20 µg/20 µL) had an obvious analgesic effect in FCA-treated mice, which was counteracted by the glycolysis inhibitor 2-deoxyglucose (2-DG, 5 mg/20 µL) or the mitochondria-related pathway inhibitor oligomycin complex (Oligo, 5 µg/20 µL). In the glycolysis pathway, Dexa decreased GLUT3 and had no impact on HIF-1α expression during FCA-induced inflammation. Additionally, Dexa further increased the PKM2 level, accompanied by the formation of hydrogen bonds between Dexa and the PKM2 activator fructose-1,6-bisphosphate (FBP). In the mitochondrial pathway, Dexa downregulated the expression of Mfn2 protein but not the PGC-1α and SIRT-1 levels in the spinal cord. Moreover, both 2-DG and Oligo decreased Mfn2 expression. Finally, IL-8 level was reduced by the single or combined administration of Dexa, 2-DG, and Oligo. CONCLUSION: Dexa attenuated IL-8 expression via glycolysis and mitochondrial pathway-related proteins, thus mediating the analgesic effect during inflammatory pain.

Influence of different regimens of volumetric therapy on perioperative intestinal flora in the surgical patients with pancreas tumor, a randomized controlled trial study.

BACKGROUND: It is not clear whether the perioperative intestinal microenvironment of patients undergoing pancreatic tumor surgery is affected by intraoperative fluid therapy. METHOD: Fifty-eight patients who underwent a confined excision of pancreas mass at this center were enrolled. The patients were grouped according to the random number table in these two groups: the liberal fluid infusion (LFI) group and the goal-directed fluid therapy (GDFT) group. Perioperative anesthesia management was carried out by the same team of anesthesiologists according to a preset anesthetic protocol. Fecal samples were collected twice: within 2 days before the surgery and at 6 to 8 days postoperatively. The collected fecal samples were sequenced through microbial diversity high-throughput 16 s-rDNA; and the differential changes of intestinal flora were analyzed. RESULTS: Main components of flora in the sample were significantly different between LFI and GDFT groups. As shown by the difference in species, in GDFT group, more constituent bacteria participated in the metabolism inside human body and the restoration of coagulation function, including: prevotella, roseburia, lachnospiracea, dialister and clostridium (P < 0.05); in LFI group, more constituent bacteria were opportunistic pathogenic bacteria, including: enterococcus, pseudomonas aeruginosa, and acinetobacter baumannii (P < 0.05). CONCLUSION: For surgical patients with pancreas tumor, there are significant differences of intestinal flora in diversity between GDFT and LFI. GDFT seems to play a more important role in protection and restoration of intestinal flora. CLINICAL TRIAL REGISTRATION: ChiCTR2000035187 .

Phosphorylation at Ser 727 Increases STAT3 Interaction with PKCε Regulating Neuron-Glia Crosstalk via IL-6-Mediated Hyperalgesia In Vivo and In Vitro.

METHODS: A rat hyperalgesia model was induced using an intraplantar injection of Freund's complete adjuvant (FCA) or an intrathecal injection of IL-6. Mechanical allodynia was evaluated using von Frey filament tests after intrathecal injections of T-5224 (c-Fos/AP-1 inhibitor), minocycline (Mino, a specific microglia inhibitor), L-2-aminoadipic acid (LAA, an astroglial toxin), PKCε inhibitor peptide, APTSTAT3-9R (STAT3 inhibitor), or anti-IL-6 antibody. The c-Fos, GFAP, Iba-1, PKCε, STAT3, pSTAT3Tyr705 and pSTAT3Ser727, and IL-6 expression at the spinal cord level was assessed by Western blot analysis. The interactive effects of PKCε and STAT3 were determined using immunofluorescence staining and immunoprecipitation in vivo and in vitro. Interleukin-6 promoter activity was examined using luciferase assays. RESULTS: T-5224, Mino, and LAA attenuated FCA- or IL-6-mediated inflammatory pain, with a decrease in c-Fos, GFAP, Iba-1, PKCε, and IL-6 expression. PKCε inhibitor peptide and APTSTAT3-9R reversed FCA-induced nociceptive behavior, while decreasing pSTAT3Ser727, IL-6, c-Fos, GFAP, and Iba-1 expression and PKCε and STAT3 coexpression. Interleukin-6 promoter activity increased in the presence of PKCε and STAT3. The interaction with PKCε increased on phosphorylating STAT3 at Ser727 but not at Tyr705. CONCLUSION: STAT3 phosphorylation at Ser 727 and the interaction with PKCε contribute to hyperalgesia via the IL-6-mediated signaling pathway, thus regulating neuron-glia crosstalk during inflammatory pain.

Efficacy of scopolamine plus propofol in the treatment of recalcitrant psoriasis: A pilot study.

Accumulating evidence suggests that botulinum neurotoxins (BoNTs), which inhibit acetylcholine release, can be used for treating plaque psoriasis. The therapeutic effects of scopolamine occur through antagonism of central muscarinic acetylcholine receptors. Thus, scopolamine has potential for the treatment of psoriasis. We aimed to evaluate the efficacy and safety of scopolamine plus propofol for the treatment of recalcitrant psoriasis. Twelve patients with recalcitrant psoriasis were enrolled. Patients received intravenous injection of scopolamine plus propofol for 5 consecutive days per month for a total of 3 months. Clinical efficacy was evaluated using a Psoriasis Area and Severity Index (PASI) score. Efficacy outcome was ≥75% reduction in PASI score (PASI75) from baseline. Two patients were lost to follow-up. At week 8, two of 10 patients (20%) achieved PASI75, and at week 12, seven of 10 (70%) achieved PASI75. Treatment was well tolerated, with no reported adverse events. Our study revealed the efficacy and safety of scopolamine plus propofol for the treatment of recalcitrant psoriasis. Scopolamine plus propofol therapy may be a new treatment for recalcitrant psoriasis.

Understanding Diseases from Single-Cell Sequencing and Methylation.

Clinical single-cell biomedicine has become a new emerging discipline, which integrates single-cell RNA and DNA sequencing, proteomics, and functions with clinical phenomes, therapeutic responses, and prognosis. It is of great value to discover disease-, phenome-, and therapy-specific diagnostic biomarkers and therapeutic targets on the basis of the principle of clinical single-cell biomedicine. This book reviews the roles of single-cell sequencing and methylation in diseases and explores disease-specific alterations of single-cell sequencing and methylation, especially focusing on potential applications of methodologies on human single-cell sequencing and methylation, on potential correlations between those changes with pulmonary diseases, and on potential roles of signaling pathways that cause heterogeneous cellular responses during treatment. This book also emphasizes the importance of methodologies in clinical practice and application, the potential of perspectives, challenges and solutions, and the significance of single-cell preparation standardization. Alterations of DNA and RNA methylation, demethylation in lung diseases, and a deep knowledge about the regulation and function of target gene methylation for diagnosing and treating diseases at the early stage are also provided. Importantly, this book aims to apply the measurement of single-cell sequencing and methylation for clinical diagnosis and treatment and to understand clinical values of those parameters and to headline and foresee the potential values of the application of single-cell sequencing in non-cancer diseases.

Drug-selective Anesthetic Insensitivity of Zebrafish Lacking γ-Aminobutyric Acid Type A Receptor ß3 Subunits.

BACKGROUND: Transgenic mouse studies suggest that γ-aminobutyric acid type A (GABAA) receptors containing ß3 subunits mediate important effects of etomidate, propofol, and pentobarbital. Zebrafish, recently introduced for rapid discovery and characterization of sedative-hypnotics, could also accelerate pharmacogenetic studies if their transgenic phenotypes reflect those of mammals. The authors hypothesized that, relative to wild-type, GABAA-ß3 functional knock-out (ß3) zebrafish would show anesthetic sensitivity changes similar to those of ß3 mice. METHODS: Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 mutagenesis was used to create a ß3 zebrafish line. Wild-type and ß3 zebrafish were compared for fertility, growth, and craniofacial development. Sedative and hypnotic effects of etomidate, propofol, pentobarbital, alphaxalone, ketamine, tricaine, dexmedetomidine, butanol, and ethanol, along with overall activity and thigmotaxis were quantified in 7-day postfertilization larvae using video motion analysis of up to 96 animals simultaneously. RESULTS: Xenopus oocyte electrophysiology showed that the wild-type zebrafish ß3 gene encodes ion channels activated by propofol and etomidate, while the ß3 zebrafish transgene does not. Compared to wild-type, ß3 zebrafish showed similar morphology and growth, but more rapid swimming. Hypnotic EC50s (mean [95% CI]) were significantly higher for ß3 versus wild-type larvae with etomidate (1.3 [1.0 to 1.6] vs. 0.6 [0.5 to 0.7] µM; P < 0.0001), propofol (1.1 [1.0 to 1.4] vs. 0.7 [0.6 to 0.8] µM; P = 0.0005), and pentobarbital (220 [190 to 240] vs. 130 [94 to 179] µM; P = 0.0009), but lower with ethanol (150 [106 to 213] vs. 380 [340 to 420] mM; P < 0.0001) and equivalent with other tested drugs. Comparing ß3 versus wild-type sedative EC50s revealed a pattern similar to hypnosis. CONCLUSIONS: Global ß3 zebrafish are selectively insensitive to the same few sedative-hypnotics previously reported in ß3 transgenic mice, indicating phylogenetic conservation of ß3-containing GABAA receptors as anesthetic targets. Transgenic zebrafish are potentially valuable models for sedative-hypnotic mechanisms research.

High-throughput Screening in Larval Zebrafish Identifies Novel Potent Sedative-hypnotics.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Many general anesthetics were discovered empirically, but primary screens to find new sedative-hypnotics in drug libraries have not used animals, limiting the types of drugs discovered. The authors hypothesized that a sedative-hypnotic screening approach using zebrafish larvae responses to sensory stimuli would perform comparably to standard assays, and efficiently identify new active compounds. METHODS: The authors developed a binary outcome photomotor response assay for zebrafish larvae using a computerized system that tracked individual motions of up to 96 animals simultaneously. The assay was validated against tadpole loss of righting reflexes, using sedative-hypnotics of widely varying potencies that affect various molecular targets. A total of 374 representative compounds from a larger library were screened in zebrafish larvae for hypnotic activity at 10 µM. Molecular mechanisms of hits were explored in anesthetic-sensitive ion channels using electrophysiology, or in zebrafish using a specific reversal agent. RESULTS: Zebrafish larvae assays required far less drug, time, and effort than tadpoles. In validation experiments, zebrafish and tadpole screening for hypnotic activity agreed 100% (n = 11; P = 0.002), and potencies were very similar (Pearson correlation, r > 0.999). Two reversible and potent sedative-hypnotics were discovered in the library subset. CMLD003237 (EC50, ~11 µM) weakly modulated γ-aminobutyric acid type A receptors and inhibited neuronal nicotinic receptors. CMLD006025 (EC50, ~13 µM) inhibited both N-methyl-D-aspartate and neuronal nicotinic receptors. CONCLUSIONS: Photomotor response assays in zebrafish larvae are a mechanism-independent platform for high-throughput screening to identify novel sedative-hypnotics. The variety of chemotypes producing hypnosis is likely much larger than currently known.

Acute Hypervolemic Infusion Can Improve Splanchnic Perfusion in Elderly Patients During Laparoscopic Colorectal Surgery.

BACKGROUND There is no adequate evidence on how the long duration of laparoscopic surgery affects splanchnic perfusion in elderly patients or the efficacy of acute hypervolemic fluid infusion (AHFI) during the induction of anesthesia. Our aim was to observe the effects of AHFI during the induction of general anesthesia on splanchnic perfusion. MATERIAL AND METHODS Seventy elderly patients receiving laparoscopic colorectal surgery were randomly divided into three groups: lactated Ringer's solution group (group R), succinylated gelatin group (group G), and hypertonic sodium chloride hydroxyethyl starch 40 injection group (group H). Thirty minutes after the induction of general anesthesia, patients received an infusion of target dose of these three solutions. Corresponding hemodynamic parameters, arterial blood gas analysis, and gastric mucosal carbon dioxide tension were monitored in sequences. RESULTS In all three groups, gastric-arterial partial CO2 pressure gaps (Pg-aCO2) were decreased at several beginning stages and then gradually increased, Pg-aCO2 also varied between groups due to certain time points. The pH values of gastric mucosa (pHi) decreased gradually after the induction of pneumoperitoneum in the three groups. CONCLUSIONS The AHFI of succinylated gelatin (12 ml/kg) during the induction of anesthesia can improve splanchnic perfusion in elderly patients undergoing laparoscopic surgery for colorectal cancer and maintain good splanchnic perfusion even after a long period of pneumoperitoneum (60 minutes). AHFI can improve splanchnic perfusion in elderly patients undergoing laparoscopic colorectal surgery.

Sevoflurane Acts on Ubiquitination-Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice.

BACKGROUND: Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane, a commonly used anesthetic in children, has been reported to decrease levels of postsynaptic density 95 protein. However, the upstream mechanisms and downstream consequences of the sevoflurane-induced reduction in postsynaptic density 95 protein levels remains largely unknown. We therefore set out to assess whether sevoflurane acts on ubiquitination-proteasome pathway to facilitate postsynaptic density 95 protein degradation. METHODS: Six-day-old wild-type mice received anesthesia with 3% sevoflurane 2 h daily for 3 days starting on postnatal day 6. We determined the effects of the sevoflurane anesthesia on mRNA, protein and ubiquitinated levels of postsynaptic density 95 protein in neurons, and synaptosomes and hippocampus of young mice. Cognitive function in the mice was determined at postnatal day 31 by using a Morris water maze. Proteasome inhibitor MG132 and E3 ligase mouse double mutant 2 homolog inhibitor Nutlin-3 were used for the interaction studies. RESULTS: The sevoflurane anesthesia decreased protein, but not mRNA, levels of postsynaptic density 95, and reduced ubiquitinated postsynaptic density 95 protein levels in neurons, synaptosomes, and hippocampus of young mice. Both MG132 and Nutlin-3 blocked these sevoflurane-induced effects. Sevoflurane promoted the interaction of mouse double mutant 2 homolog and postsynaptic density 95 protein in neurons. Finally, MG132 and Nutlin-3 ameliorated the sevoflurane-induced cognitive impairment in the mice. CONCLUSIONS: These data suggest that sevoflurane acts on the ubiquitination-proteasome pathway to facilitate postsynaptic density 95 protein degradation, which then decreases postsynaptic density 95 protein levels, leading to cognitive impairment in young mice. These studies would further promote the mechanistic investigation of anesthesia neurotoxicity in the developing brain.

Tanshinone IIA Attenuates Sevoflurane Neurotoxicity in Neonatal Mice.

BACKGROUND: Sevoflurane is the most widely used inhalational anesthetic in pediatric medicine. Despite this, sevoflurane has been reported to exert potentially neurotoxic effects on the developing brain. Clinical interventions and treatments for these effects are limited. Tanshinone IIA (Tan IIA), extracted from Salvia miltiorrhiza (Danshen), has been documented to alleviate cognitive decline in traditional applications. Therefore, we hypothesized that preadministration of Tan IIA may attenuate sevoflurane-induced neurotoxicity, suggesting that Tan IIA is a new and promising drug capable of counteracting the effects of cognitive dysfunction produced by general anesthetics. METHODS: To test this hypothesis, neonatal C57 mice (P6) were exposed to 3% sevoflurane for 2 hours with or without Tan IIA pretreatment at a dose of 10 mg/kg or 20 mg/kg for 3 consecutive days. Cognitive behavior tests such as open field tests and fear conditioning were performed to evaluate locomotor and cognitive function at P31 and P32. At P8, other separate tests, including TdT mediated dUTP Nick End Labeling (TUNEL) assay, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay, and electron microscopy, were performed. The mean differences among groups were compared using 1-way analysis of variance followed by Bonferroni post hoc multiple comparison tests. RESULTS: Repeated exposure to sevoflurane leads to significant cognitive impairment in mice, which may be explained by increased apoptosis, overexpression of neuroinflammatory markers, and changes in synaptic ultrastructure. Interestingly, preadministration of Tan IIA ameliorated these neurocognitive deficits, as shown by increased freezing percentages on the fear conditioning test (sevoflurane+Tan IIA [20 mg/kg] versus sevoflurane, mean difference, 19, 99% confidence interval for difference, 6.4-31, P < .0001, n = 6). The treatment also reduced the percentage of TUNEL-positive nuclei (sevoflurane versus sevoflurane+Tan IIA [20 mg/kg], 2.6, 0.73-4.5, P = .0004, n = 6) and the normalized expression of cleaved caspase-3 (sevoflurane versus sevoflurane+Tan IIA [20 mg/kg], 0.27, 0.02-0.51, P = .0046, n = 5). Moreover, it attenuated the production of the neuroinflammatory mediators interleukin (IL)-1ß and IL-6 (normalized sevoflurane versus sevoflurane+Tan IIA [20 mg/kg]: IL-1ß: 0.75, 0.47-1.0; P < .0001; IL-6: 0.66, 0.35-0.97; P < .0001; n = 10 per group). Finally, based on measurements of postsynaptic density, the treatment preserved synaptic ultrastructure (sevoflurane+Tan IIA [20 mg/kg] versus sevoflurane, 42, 20-66; P < .0001; n = 12 per group). CONCLUSIONS: These results indicate that Tan IIA can alleviate sevoflurane-induced neurobehavioral abnormalities and may decrease neuroapoptosis and neuroinflammation.

Regional anesthesia and lipid resuscitation for local anesthetic systemic toxicity in China: results of a survey by the orthopedic anesthesia group of the Chinese Society Of Anesthesiology.

BACKGROUND: Intravenous lipid emulsions have been introduced for the management of patients with Local Anesthetic Systemic Toxicity (LAST). These emulsions have been stated as a first-line treatment in the guidelines of several international anesthesia organizations. Nevertheless, the adoption of lipid rescue therapy by Chinese practitioners remains unknown. We, therefore, evaluated the current approaches to treat LAST and the use of lipid rescue therapy among anesthesiologists in China. METHODS: In September 2013, a 23-question survey on regional anesthesia practice and availability of lipid emulsions was sent by e-mail to directors or designated individuals at 41 academic anesthesiology departments listed by the orthopedic anesthesia group of the Chinese Society of Anesthesiology. RESULTS: Responses were received from 36 of the 41 (88 %) anesthesiology departments. To simplify the analysis, responses were divided into two groups according to the annual percentage of patients who received regional anesthesia (RA) for orthopedic anesthesia: 14 departments (39%) with high-utilization (≥ 50%) and 22 departments (61%) low-utilization (<50%) of RA. Ropivacaine and bupivacaine were the common drugs used for RA, which were independent of RA utilization. Interestingly, ultrasound-guided techniques were much more frequently used in low-utilization institutions than in high-utilization institutions (P = 0.025). Lipid emulsion was readily available in 8 of the 36 (22%) responding institutions, with 7 of the other 28 (25%) institutions planning to stock lipid emulsion. No differences in lipid availability and storage plans were observed between high- and low-utilization institutions. Lipid resuscitation was performed in five of the eight departments that had lipid emulsion. Eleven patients were successfully resuscitated and one was not. CONCLUSION: Lipid emulsion is not widely available in China to treat LAST resulted from RA for orthopedic patients. Efforts are required to promote lipid rescue therapy nationwide. TRIAL REGISTRATION: Chinese Clinical Trail Registry (Registration number # ChiCTR-EOR-15006960; Date of Retrospective Registration on August 23rd, 2015) http://www.chictr.org.cn/showproj.aspx?proj=11703 .

Ghrelin inhibits proinflammatory responses and prevents cognitive impairment in septic rats.

OBJECTIVES: A novel stomach-derived peptide, ghrelin, is down-regulated in sepsis and its IV administration decreases proinflammatory cytokines and mitigates organ injury. In this study, we wanted to investigate the effects of ghrelin on proinflammatory responses and cognitive impairment in septic rats. DESIGN: Prospective, randomized, controlled experiment. SETTING: Animal basic science laboratory. SUBJECTS: Sprague-Dawley rats, weighing 250-300 g. INTERVENTIONS: Sepsis was induced by cecal ligation and puncture. Animals were randomly divided into four groups: sham, sham + ghrelin, cecal ligation and puncture, and cecal ligation and puncture + ghrelin. Saline was given subcutaneously (30 mL/kg) at 4 and 16 hours after surgery for all rats. Septic rats were treated with ceftriaxone (30 mg/kg) and clindamycin (25 mg/kg) subcutaneously at 4 and 16 hours after surgery. Ghrelin (80 µg/kg) was administrated intraperitoneally 4 and 16 hours after surgery in sham + ghrelin group and cecal ligation and puncture + ghrelin group. MEASUREMENTS AND MAIN RESULTS: The levels of proinflammatory cytokines in hippocampus were measured by enzyme-linked immunosorbent assay, and cleaved caspase-3 was detected by Western blot 24 hours after surgery. Neuronal apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining 48 hours after surgery. Additional animals were monitored to record survival and body weight changes for 10 days after surgery. Survival animals underwent behavioral tasks 10 days after surgery: open-field, novel object recognition, and continuous multiple-trial step-down inhibitory avoidance task. Ghrelin significantly decreased the levels of proinflammatory cytokines and inhibited the activation of caspase-3 in the hippocampus after cecal ligation and puncture. The density of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive apoptotic neurons was significantly lowered by ghrelin. In addition, ghrelin improved the survival rates after cecal ligation and puncture. There were no differences in the distance and move time between groups in open-field task. However, the survivors after cecal ligation and puncture were unable to recognize the novel object and required more training trials to reach the acquisition criterion. All these long-term impairments were prevented by ghrelin. CONCLUSIONS: Ghrelin inhibited proinflammatory responses, improved the survival rate, and prevented cognitive impairment in septic rats.

The ventrolateral preoptic nucleus is required for propofol-induced inhibition of locus coeruleus neuronal activity.

The mechanisms underlying the unconsciousness of general anesthesia are not completely understood. Accumulating evidence indicates the ventrolateral preoptic nucleus (VLPO) in the endogenous sleep circuits may contribute to loss of consciousness (LOC) induced by GABA-enhancing anesthetics. However, there are few studies that look into distinct sleep pathway in the sleep-wake system. In the neural pathway from VLPO to the locus coeruleus (LC), we compared the inhibition effect of propofol on the LC activity before and after VLPO lesion in vivo rats. Systemic administration of propofol (20 mg/kg, i.p.) in normal rats caused a fast and obvious inhibition of LC neurons spontaneous firing (from 0.24 ± 0.06 to 0.12 ± 0.03 Hz). The LC neuronal firing rate of VLPO lesion rats only decreased to 0.18 ± 0.05 Hz (P = 0.021 vs. non-VLPO rats) after the propofol injection, and the time to reach the maximal inhibition level was also prolonged in VLPO lesion rats (2.3 ± 0.7 vs. 5.8 ± 1.2 min, P = 0.037). Microinjections of a selective GABAA receptor antagonist (SR95531) into the LC fully reversed the inhibitory effect of propofol on the LC neuronal activity, but did not significantly affect the latency to loss of righting reflex of rats after propofol administration (3.4 ± 0.9 vs. 3.7 ± 1.2 min, P = 0.639). Our results indicated that VLPO is necessary for the propofol-induced inhibition of LC activity, but the LC may not play an important role in the propofol-induced LOC.

Propofol Provides More Effective Protection for Circulating Lymphocytes Than Sevoflurane in Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery.

OBJECTIVES: To compare the effects of propofol, sevoflurane, and the combination of the 2 on circulating lymphocytes in patients undergoing off-pump coronary artery bypass graft (OPCAB) surgery. DESIGN: A prospective, randomized study. SETTING: A university hospital. PARTICIPANTS: One hundred five patients undergoing elective OPCAB surgery. INTERVENTIONS: Participants were randomized to receive sevoflurane (group S), propofol (group P), or coadministration (group C) of sevoflurane- and propofol-maintained anesthesia. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained before, during, and after surgery. Caspase-3 and apoptosis-inducing factor in lymphocytes were evaluated by Western blot. During surgery, 5 minutes after revascularization of the left anterior descending artery, 5 minutes after all anastomoses (T4), and after the sternal closure (T5), caspase-3 expression of group S was higher than that of group P (p = 0.02) and group C (p = 0.02). At T4 and T5, expression of active apoptosis-inducing factor in group S was higher than that in the other 2 groups (p = 0.03 and p = 0.04, respectively). 24 hours after surgery, the lymphocyte count of group S (0.55/nL) was lower than that of group P (0.73/nL, p = 0.02) and group C (0.73/nL, p = 0.03). Intensive care unit stay of group S (3.0 days) was longer than that of the other 2 groups (2.2 days, p = 0.02 and 2.1 days, p = 0.01). CONCLUSIONS: OPCAB surgery was associated with postoperative lymphopenia. Regarding a protective effect for circulating lymphocytes, propofol and the combination of sevoflurane- and propofol-maintained anesthesia were both superior to sevoflurane-maintained anesthesia.

Anesthetic effects of propofol in the healthy human brain: functional imaging evidence.

Functional imaging methods, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have become important tools for studying how anesthetic drugs act in the human brain to induce the state of general anesthesia. Recent imaging studies using fMRI and PET techniques have demonstrated the regional effects of propofol on the brain. However, the pharmacological mechanism of the action of propofol in the intact human central nervous system is unclear. To explore the possible action targets of propofol in the human brain, a systematic review of the literature was performed. The literature search was performed with limiting factors of "propofol," "functional imaging," "positron emission tomography", and "functional magnetic resonance imaging" from 1966 to July 2013 (using Medline, EMBASE, CINAHL and hand searches of references). Studies meeting the inclusion criteria were reviewed and critiqued for the purpose of this literature research. Eighteen researches meeting the inclusion criteria were reviewed in terms of the appropriateness of valuation technique. In the unconscious state, propofol sharply reduces the regional glucose metabolism rate (rGMR) and regional cerebral blood flow (rCBF) in all brain regions, particularly in the thalamus. However, GMR, such as in the occipital, temporal, and frontal lobes, was obviously decreased at a sedative dosage of propofol, whereas, changes in the thalamus were not obvious. Using fMRI, several studies observed a decrease of connectivity of the thalamus versus an increase of connectivity within the pons of the brainstem during propofol-induced mild sedation. During deep sedation, propofol preserves cortical sensory reactivity, the specific thalamocortical network is moderately affected, whereas the nonspecific thalamocortical network is severely suppressed. In contrast, several recent fMRI studies are consistent on the systemic decreased effects of propofol in the frontoparietal network. Accumulating evidence suggest that propofol-induced unconsciousness is associated with a global metabolic and vascular depression in the human brain and especially with a significant reduction in the thalamocortical network and the frontoparietal network.

Correlation of cardiac output measured by non-invasive continuous cardiac output monitoring (NICOM) and thermodilution in patients undergoing off-pump coronary artery bypass surgery.

PURPOSE: This observational study was designed to evaluate the clinical value of cardiac output (CO) obtained via bioreactance (NICOM™) as compared with values of CO obtained via thermodilution (using pulmonary artery catheter, Vigilance™) and the thoracic bioimpedance (BioZ.com™), in patients undergoing off-pump coronary artery bypass surgery. METHODS: Fifty American Society of Anesthesiologists physical status I-III patients, aged 38-81 years, scheduled for off-pump coronary artery bypass surgery were enrolled in this study. CO data (NCO, BCO, PCO) were recorded during the operative period at ten time points after stable hemodynamic conditions were achieved. RESULTS: The equation of the relationship between the PCO and NCO is PCO = 0.945 × NCO + 0.328 (r = 0.77), and that of PCO and BCO is PCO = 0.965 × BCO + 0.729 (r = 0.63). Furthermore, no statistical difference was found between PCO versus NCO (mean (SD): 4.4 (1.1) versus 4.4 (0.9), p = 0.431). A significant correlation was found between PCO and NCO (r = 0.77, p < 0.001). Correlation was also found between PCO and BCO (r = 0.63, p < 0.001). CONCLUSIONS: The NICOM device is a safe, convenient, and reliable device for measuring continuous non-invasive cardiac output and cardiac index, and the trends of change in CO during the surgery are similar between NICOM and PAC.