Melatonin-mediated mitophagy protects against long-term impairments after repeated neonatal sevoflurane exposures.

BACKGROUND: Melatonin is known to have protective effects in aging, neurodegenerative disorders and mitochondria-related diseases, while there is a poor understanding of the effects of melatonin treatment on mitophagy in neonatal cognitive dysfunction after repeated sevoflurane exposures. This study explores the protective effects of melatonin on mitophagy and cognition in developing rats exposed to sevoflurane. METHODS: Postnatal day six (P6) neonatal rats were exposed to 3 % sevoflurane for 2 h daily from P6 to P8. In the intervention groups, rats received 3-Methyladenine (3-MA) intracerebroventricularly from P6 to P8 and melatonin intraperitoneally from P6 to P8 following water drinking once daily from P21 to P41, respectively. Behavioral tests, including open field (OF), novel object recognition (NOR), and fear conditioning (FC) tests, were performed to assess cognitive function during young adulthood. In another experiment, rat brains were harvested for biochemical, histopathological, and electron microscopy studies. RESULTS: Rats exposed to sevoflurane showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mitophagy marker proteins (microtubule-associated protein 1 light chain 3 (LC3) II/I, and parkin), decreased autophagy marker protein (sequestosome 1 (P62/SQSTM1)), electron transport chain (ETC) proteins and ATP levels. Immunofluorescent staining of LC3 was co-localized mostly with a neuronal marker and microglial marker but was not co-localized with a marker for astrocytes in rats exposed to sevoflurane. These rats had poorer performance in the NOR and FC tests than control rats during young adulthood. Melatonin treatment reversed the abnormal expression of mitophagy proteins, mitochondrial energy metabolism, the activity of microglia, and impaired cognition. These ameliorations were blocked by an autophagy inhibitor, 3-MA, except for the activation of microglia. CONCLUSION: We have demonstrated that melatonin inhibits microglial activation by enhancing mitophagy and finally significantly reduces sevoflurane-induced deficits in cognition in neonatal rats. These results suggest that melatonin might be beneficial if considered when the anesthesia must be administered at a very young age.

Cuproptosis-related genes prediction feature and immune microenvironment in major depressive disorder.

Background: Major depressive disorder (MDD) is a severe, unpredictable, ill-cured, relapsing neuropsychiatric disorder. A recently identified type of death called cuproptosis has been linked to a number of illnesses. However, the influence of cuproptosis-related genes in MDD has not been comprehensively assessed in prior study. Aim: This investigation intends to shed light on the predictive value of cuproptosis-related genes for MDD and the immunological microenvironment. Methods: GSE38206, GSE76826, GSE9653 databases were used to analyze cuproptosis regulators and immune characteristics. To find the genes that were differently expressed, weighted gene co-expression network analysis was employed. We calculated the effectiveness of the random forest model, generalized linear model, and limit gradient lifting to arrive at the best machine prediction model. Nomogram, calibration curve, and decision curve analysis were used to show the anticipated MDD's accuracy. Results: This study found that there were activated immune responses and cuproptosis-related genes that were dysregulated in people with MDD compared to healthy controls. Considering the test performance of the learned model and validation on subsequent datasets, the RF model (including OSBPL8, VBP1, MTM1, ELK3, and SLC39A6) was considered to have the best discriminative performance. (AUC = 0.875). Conclusion: Our study constructed a prediction model to predict MDD risk and clarified the potential connection between cuproptosis and MDD.

Lactate Improves Long-term Cognitive Impairment Induced By Repeated Neonatal Sevoflurane Exposures Through SIRT1-mediated Regulation of Adult Hippocampal Neurogenesis and Synaptic Plasticity in Male Mice.

Repeated neonatal exposures to sevoflurane induce long-term cognitive impairment that has been reported to have sex-dependent differences. Exercise promotes learning and memory by releasing lactate from the muscle. The study tested the hypothesis that lactate may improve long-term cognitive impairment induced by repeated neonatal exposures to sevoflurane through SIRT1-mediated regulation of adult hippocampal neurogenesis and synaptic plasticity. C57BL/6 mice of both genders were exposed to 3% sevoflurane for 2 h daily from postnatal day 6 (P6) to P8. In the intervention experiments, mice received lactate at 1 g/kg intraperitoneally once daily from P21 to P41. Behavioral tests including open field (OF), object location (OL), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function. The number of 5-Bromo-2'- deoxyuridine positive (BrdU+) cells and BrdU+/DCX+ (doublecortin) co-labeled cells, expressions of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), early growth response 1 (Egr-1), SIRT1, PGC-1α and FNDC5, and long-term potentiation (LTP) were evaluated in the hippocampus. Repeated exposures to sevoflurane induced deficits in OL, NOR and contextual FC tests in male but not female mice. Similarly, adult hippocampal neurogenesis, synaptic plasticity-related proteins and hippocampal LTP were impaired after repeated exposures to sevoflurane in male but not female mice, which could rescue by lactate treatment. Our study suggests that repeated neonatal exposures to sevoflurane inhibit adult hippocampal neurogenesis and induce defects of synaptic plasticity in male but not female mice, which may contribute to long-term cognitive impairment. Lactate treatment rescues these abnormalities through activation of SIRT1.

Reduced inhibitory and excitatory input onto parvalbumin interneurons mediated by perineuronal net might contribute to cognitive impairments in a mouse model of sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is commonly defined as diffuse brain dysfunction and can manifest as delirium to coma. Accumulating evidence has suggested that perineuronal net (PNN) plays an important role in the modulation of the synaptic plasticity of central nervous system. We here investigated the role of PNN in SAE induced by lipopolysaccharide (LPS) injection. Behavioral tests were performed by open field, Y-maze, and fear conditioning tests at the indicated time points. The densities of vesicular γ-aminobutyric acid transporter, vesicular glutamate transporter 1, PNN, and parvalbumin (PV) in the hippocampus were evaluated by immunofluorescence. Matrix metalloproteinases-9 (MMP-9) expression and its activity were detected by Western blot and gel zymography, respectively. Local field potential was recorded by in vivo electrophysiology. LPS-treated mice displayed significant cognitive impairments, coincided with activated MMP-9, decreased PNN and PV densities, reduced inhibitory and excitatory input onto PV interneurons enwrapped by PNN, and decreased gamma oscillations in hippocampal CA1. Notably, MMP-9 inhibitor SB-3CT treatment rescued most of these abnormalities. Taken together, our study demonstrates that active MMP-9 mediated PNN remodeling, leading to reduced inhibitory and excitatory input onto PV interneurons and abnormal gamma oscillations in hippocampal CA1, which consequently contributed to cognitive impairments after LPS injection.

Diagnosis and prognostic value of circDLGAP4 in acute ischemic stroke and its correlation with outcomes.

Rationale and aims: Circular RNAs are a subclass of noncoding RNAs in mammalian cells and highly expressed in the central nervous system. Although their physiological functions are not yet completely defined, they are thought to promise as stroke biomarkers because of their stability in peripheral blood.Sample Size Estimate: 222 participants. Methods and design: The plasma of patients with acute ischemic stroke (AIS) (n = 111) and non-stroke controls (n = 111) from November 2017 to February 2019 were enrolled in our research. The expression of circDLGAP4 in plasma was evaluated using real-time PCR. Study outcomes: In patients with AIS, circDLGAP4 was significantly decreased in comparison with non-stroke controls. The CircDLGAP4 level had a significant AUC of 0.7896 with 91.72% sensitivity and 64.83% specificity in diagnosing AIS. Furthermore, the circDLGAP4 level was related to smoking history and previous transient ischemic attack/stroke/myocardial infarction in all samples. The change rate in circDLGAP4 within the first 7 days showed an AUC curve of 0.960 in predicting an stroke outcome. Conclusion: circDLGAP4 could serve as biomarker for AIS diagnosis and prediction of stroke outcomes.

2,2',4,4'-Tetrabromodiphenyl ether disrupts spermatogenesis in mice by interfering with the ER-Nrf1-Tfam-mitochondria pathway.

2,2',4,4' -tetrabromodiphenyl ether (BDE47), a well-known endocrine disruptor of the estrogen receptor (ER) is toxic to the mitochondria and spermatogenesis. This study aimed to explore the mechanism of BDE47 on spermatogenesis in mammals. Adult male Institute of Cancer Research (ICR) mice were gavaged daily with BDE47 (0, 1, or 10 mg/kg bw) for 8 weeks. Testicular weight, sperm production and motility, morphology of spermatogenic cells, nuclear respiratory factor 1 (Nrf1) level, and its expression in testes were determined. In vitro, cell viability, and key molecules in the ER-Nrf1-mitochondrial transcription factor A (Tfam)-mitochondria pathway in the immortalized mouse spermatogonia line (GC1) were determined at 48 h and 0-5 h after exposure; RNA interference (RNAi) was also performed to verify that the decreased Nrf1 was associated with mitochondrial dysfunction and the impaired viability of germ cells. The results indicated that BDE47 impaired testis weight and spermatogenesis, impaired mitochondria and germ cells, and decreased Nrf1 in the testes of mice. In vitro, after 48 h exposure, BDE47 reduced cell viability, Nrf1 protein, and mRNA of Nrf1, Tfam, ATP synthase subunit ß (Atp5b), and cytochrome c oxidase subunit I (mt-CO1) in GC1 while also reducing mRNA of Nrf1 and Tfam promptly (from 1 to 5 h) after exposure. Furthermore, Nrf1 RNA interference decreased viability and mitochondrial function in GC1. These results indicated that BDE47 disrupts spermatogenesis in mice, probably by interfering with the ER-Nrf1-Tfam-mitochondria pathway, and Nrf1 is a target molecule of BDE47 estrogen receptor.

The effects of volume-controlled ventilation versus pressure-controlled ventilation on hemodynamic and respiratory parameters in patients undergoing lumbar spine fusion surgery: a randomized controlled trial.

BACKGROUND: Hypotension is a common event in patients under general anesthesia during lumbar spine fusion surgery. The reduction of venous drainage followed by the postural changes is the main reason. The venous return reduced when the intrathoracic pressure is positive. Volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) are two traditional ventilation modes in operating room, with different respiratory mechanics. The two ventilation modes have different influences on intrathoracic pressure and consequently venous return. A double-blinded, randomized, parallel group controlled clinical trial was conducted to examine the hemodynamic and respiratory effects of two different ventilation modes in lumbar spine fusion surgery. METHODS: Forty-eight patients scheduled for posterior lumbar spine fusion surgery at Zhongda Hospital, Southeast University were randomly allocated into two groups to receive either the VCV mode or PCV mode [vital volume (VT) 8 mL/kg, and partial pressure of end-tidal carbon dioxide (PETCO2) 35-45 mmHg]. The respiratory mechanics [peak airway pressure (Ppeak) and dynamic compliance (Cdyn)] and hemodynamic changes were measured every 10 min for 120 min. All participants and relevant staff were blinded to the randomization. RESULTS: The data of 19 of 22 patients in the VCV group and 18 of 20 in the PCV group were analyzed. Compared to VCV group, cardiac output (CO) and central venous pressure (CVP) in the PCV group were higher; however, the difference was not significant. There's no statistically difference in systemic vascular resistance index (SVRI) values of both the groups. The mean blood pressure (MBP) of the PCV group was higher than that of the VCV group from 90 min after the patients were turned to the prone position until the endpoint. The Cdyn and Ppeak of the PCV group were higher than those of the VCV group. Additionally, there was a positive correlation between Cdyn and CO (r=0.744, P=0.006). CONCLUSIONS: With better respiratory mechanic and hemodynamic stability, PCV was a better choice for patients undergoing lumbar spine fusion surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-14005086.

Key proteins of proteome underlying sperm malformation of rats exposed to low fenvalerate doses are highly related to P53.

Fenvalerate (Fen) is an endocrine disruptor, capable of interfering with the activity of estrogen and androgen. Our objective was to explore the molecular mechanisms of Fen on sperm in vivo. Adult male Sprague-Dawley rats were orally exposed to 0, 0.00625, 0.125, 2.5, 30 mg/kg/day Fen for 8 weeks. Sperm morphology, differential proteomics of sperm and testes, bioinformatic analysis, western blotting (WB), and RT-PCR were used to explore the mechanism of Fen on sperm. Data showed that low Fen doses significantly induced sperm malformations. In sperm proteomics, 47 differentially expressed (DE) proteins were enriched in biological processes (BPs) related to energy metabolism, response to estrogen, spermatogenesis; and enriched in cellular components (CCs) relating to energy-metabolism, sperm fibrous sheath and their outer dense fibers. In testicular proteomics, 56 DE proteins were highly associated with mRNA splicing, energy metabolism; and enriched in CCs relating to vesicles, myelin sheath, microtubules, mitochondria. WB showed that the expression of selected proteins was identical to their tendency in 2D gels. Literature indicates that key DE proteins in proteomic profiles (such as Trap1, Hnrnpa2b1, Hnrnpk, Hspa8, and Gapdh) are involved in P53-related processes or morphogenesis or spermatogenesis. Also, P53 mRNA and protein levels were significantly increased by Fen; bioinformatic re-analysis showed that 88.5% DE proteins and P53 formed a complex interacting network, and the key DE proteins were coenriched with P53-related BPs. Results indicate that key DE proteins of proteome underlying sperm malformations of rats exposed to low Fen doses are highly related to P53.

Effects of dezocine for the prevention of postoperative catheter-related bladder discomfort: a prospective randomized trial.

Purpose: To evaluate the effects of dezocine on the prevention of postoperative catheter-related bladder discomfort (CRBD). Patients and methods: Ninety-six adult patients undergoing abdominal surgery with urinary catheterization under general anesthesia were randomized into dezocine and control (flurbiprofen) groups. The postoperative CRBD, pain score, sedation score and adverse effects were evaluated at 0, 1, 2 and 6 hrs after tracheal extubation. Results: The primary outcome showed a lower incidence of CRBD at 1 hr post-extubation in the dezocine group (29.17%) than the control group (58.33%, P<0.01). The incidences at 0 and 2 hrs post-extubation and the overall incidence were also lower in the dezocine group than the control group (all P<0.05). The severity of CRBD at 0, 1, 2 and 6 hrs and the pain, sedation score and other adverse effects were comparable between the two groups (P>0.05); however, the overall severity of CRBD was decreased in the dezocine group compared with the control group (P<0.05). Conclusion: Intraoperative dezocine reduces the incidence and severity of postoperative CRBD without clinically relevant adverse effects.

Two-hit model of postintensive care syndrome induced by lipopolysaccharide challenge and subsequent chronic unpredictable stress in mice.

Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness. However, there is still a lack of a clinically relevant animal model. Thus, development of a PICS model is essential for understanding the mechanism underlying PICS and screening treatment methods for this neuropsychiatric disorder. The purpose of this study was to establish a clinically relevant PICS model based on the two-hit concept, in which lipopolysaccharide (LPS, 3 mg/kg) injection was served as the first hit and subsequent modified chronic unpredictable stress as the second hit. In order to pharmacologically verify the proposed model of PICS, we studied the effectiveness of fluoxetine to reverse the behavioral and molecular abnormalities in this model. In the present study, body- and adrenal weight changes proved our model was effective, as reflected by body weight loss, increased adrenals weight, and a significantly increased level of plasma corticosterone. Moreover, our PICS model displayed reproducible anxiety- and depression like behavior and cognitive impairments. Neurobiological investigations revealed a significant up-regulation of the microglial marker CD68 and pro-inflammatory cytokine IL-6 in the hippocampus of stressed mice. Notably, chronic treatment with fluoxetine for three weeks reversed most of the affected parameters. In summary, we believe that we have developed a new model of PICS that is clinically relevant, which could advance the mechanism research and the development of therapeutic strategies.

Acute ketamine administration attenuates lipopolysaccharide-induced depressive-like behavior by reversing abnormal regional homogeneity in the nucleus accumbens.

Ketamine has rapid antidepressant effects, but no study to date has investigated changes in resting-state brain activity following ketamine administration in inflammation-induced depression. The purpose of this study was to use blood oxygen level-dependent functional MRI to explore changes in the resting-state brain activity in a rat model of depression induced by lipopolysaccharide (LPS, 1 mg/kg) challenge and to examine whether acute ketamine administration can reverse LPS-induced depressive-like behavior. Here, we showed LPS-induced depressive-like behavior as evidenced by significantly reduced motility in the forced swim test. In addition, LPS-induced increases in plasma levels of proinflammatory cytokines were not completely reversed by acute ketamine administration, suggesting that ketamine exerts its antidepressant effects independently of a possible interference with LPS-induced inflammatory signaling. However, increased regional homogeneity (ReHo) was observed in some brain regions of LPS-exposed animals, including bilateral caudate putamen and nucleus accumbens, which were parts of the mood-regulating circuit. Moreover, ReHo values of bilateral caudate putamen and nucleus accumbens showed significant positive correlations with immobility time. Notably, the LPS-induced depressive-like behavior and increase of ReHo value in the right nucleus accumbens was reversed by acute ketamine administration. In summary, this study suggests that acute ketamine administration is capable of attenuating LPS-induced depressive-like behavior, at least partially by reversing abnormal ReHo in the right nucleus accumbens.

Altered functional connectivity within the default mode network in two animal models with opposing episodic memories.

Memory enhancement and memory decline are two opposing cognitive performances commonly observed in clinical practice, yet the neural mechanisms underlying these two different phenomena remain poorly understood. Accumulating evidence has demonstrated that the default-mode network (DMN) is implicated in diverse cognitive, social, and affective processes. In the present study, we used the retrosplenial cortex as a seed region to study the functional connectivity within the DMN in two animal models with opposing episodic memories, of which memory enhancement was induced by footshocks to mimic posttraumatic stress disorder (PTSD) and memory decline was induced by lipopolysaccharide (LPS) challenge to mimic sepsis-associated encephalopathy (SAE). Our results showed that LPS challenge and footshocks induced opposing episodic memories. With regard to the imaging data, there were significant differences in the functional connectivity between the retrosplenial cortex and the medial prefrontal cortex (mPFC), insular lobe, left piriform cortex, left sensory cortex, and right visual cortex among the three groups. Post-hoc comparisons showed the LPS group had a significantly increased functional connectivity between the retrosplenial cortex and mPFC as compared with the control group. Compared with the LPS group, the PTSD group displayed significantly decreased functional connectivity between the retrosplenial cortex and the right visual cortex, retrosplenial cortex, insular lobe, left piriform cortex, and left sensory cortex. In summary, our study suggests that there is a significant difference in the functional connectivity within the DMN between SAE and PTSD rats.

The p75 neurotrophin receptor might mediate sepsis-induced synaptic and cognitive impairments.

Systemic inflammation induces cognitive impairment, yet the mechanism involved in this process is unclear. Neurotrophin receptor p75 (p75NTR) signaling is a key pathological factor contributing to neurobehavioral abnormalities in many neurodegenerative diseases. However, the role of p75NTR signaling in the regulation of sepsis-induced cognitive impairment remains largely to be elucidated. In this study, systemic inflammation was induced by cecal ligation and puncture (CLP). Neurobehavioral performances were evaluated by open field, novel object recognition, and fear conditioning tests. The expressions of proinflammatory cytokines (tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-10), apoptosis marker cleaved caspase-3, ionized calcium binding adaptor molecule 1 (IBA1), proBDNF, p75NTR, c-Jun N-terminal kinase (JNK), and pJNK in the hippocampus were determined by enzyme-linked immunosorbent assay, western blot analysis, and immunofluorescence. The synaptic marker in the CA1 region of the hippocampus was assessed by Golgi staining. In the present study, we showed that systemic inflammation induced cognitive impairment, which was accompanied by increased expressions of hippocampcal proBDNF and p75NTR. Of note, we found that LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75NTR signaling modulator significantly reversed the sepsis-induced cognitive impairment and restored most of the abnormal biochemical parameters. Taken together, our study suggests that proBDNF/p75NTR signaling pathway might play a key role in the development of sepsis-induced cognitive impairment, whereas specific p75NTR inhibitor may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases.

Different effects of immune stimulation on chronic unpredictable mild stress-induced anxiety- and depression-like behaviors depending on timing of stimulation.

Stressful life events are thought to be triggering factors of numerous neuropsychiatric disorders, including anxiety and depression. However, the interactions between chronic unpredictable mild stress (CUMS) and immune stimulation have not been thoroughly investigated. In the present study, we evaluated the effects of lipopolysaccharide (LPS) challenge at different time points on CUMS-induced anxiety- and depression-like behaviors. At 1 day before, 18 or 35 days following the initial of CUMS, mice were intraperitoneally given a single LPS (0.1 mg/kg). Neurobehavioral and biochemical studies were performed at the indicated time points. LPS challenge had different effects on CUMS-induced anxiety- and depression-like behaviors depending on the timing of stimulation. When given 1 day before CUMS, LPS restored brain-derived neurotrophic factor level and reversed anxiety- and depression-like behaviors. When given at 18 days after the initial of CUMS, LPS seemed to promote the immune response and even induce a slight exacerbation of neurobehavioral performance, although the difference did not reach statistical significance. Intriguingly, when given at the end of CUMS, LPS reversed some of the anxiety- and depression-like behavior. Taken together, our study highlights the complex interaction between stress and immune challenge, suggesting therapies that modulate immune responses should be tailored to the immune status of the individual.

Short- and Long-Term Protective Effects of Melatonin in a Mouse Model of Sepsis-Associated Encephalopathy.

Brain dysfunction is a common complication after sepsis and is an independent risk factor for a poor prognosis, which is partly attributed to the dysregulated inflammatory response and oxidative damage. Melatonin regulates the sleep-wake cycle and also has potent anti-inflammatory and antioxidant properties, yet the protective effects of melatonin on sepsis-induced neurobehavioral dysfunction remain to be elucidated. In the present study, melatonin was administered intraperitoneally daily at a dose of 10 mg/kg for three consecutive days immediately (early treatment) or 7 days (delayed treatment) after sham operation or cecal ligation and puncture (CLP), followed by an additional treatment in drinking water until the end of behavioral tests. The concentrations of pro-inflammatory cytokines (tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-10), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) were determined at the indicated time points. Compared with the CLP + vehicle group, we found that early melatonin treatment resulted in increased survival rate but not improvement in measures of neurobehavioral outcomes, which was accompanied by significantly lower plasma level of IL-1ß. Intriguingly, delayed melatonin treatment improved neurobehavioral dysfunction by normalization of hippocampal BDNF and GDNF expressions. In conclusion, our study suggests the beneficial effects of both early and delayed melatonin treatment after sepsis development, which implicates melatonin has a potential therapeutic value in sepsis-associated organ damage including brain dysfunction.

Effect of propofol combined with opioids on cough reflex suppression in gastroscopy: study protocol for a double-blind randomized controlled trial.

INTRODUCTION: The best methods for inducing analgesia and sedation for gastroscopy are still debated but finding an adequate regimen of sedation/analgesia is important. Stimulation of the larynx under sedation can cause reflex responses. Propofol with opioids has been recommended for gastroscopy sedation but the effects on cough reflex suppression remain unclear. This trial will evaluate the effects of propofol combined with small doses of dezocine, oxycodone, sufentanil or fentanyl for gastroscopy. We hypothesise that better performance may be obtained with a combination of propofol and oxycodone. We will observe the incidence and degree of reflex coughing and gagging under sedation when using propofol combined with one of the above drugs or propofol alone. METHODS AND ANALYSIS: This will be a prospective, randomised, double-blind, controlled trial. ASA I-II level patients aged 18-65 years and scheduled for gastroscopy will be included. It is planned that 500 subjects will be randomised to intravenously receive 2-2.2 mg/kg propofol plus 0.5-0.8 µg/kg fentanyl (fentanyl group), 2-2.2 mg/kg propofol plus 0.05-0.08 µg/kg sufentanil (sufentanil group), 2-2.2 mg/kg propofol plus 0.04-0.05 mg/kg dezocine (dezocine group), 2-2.2 mg/kg propofol plus 0.04-0.05 mg/kg oxycodone (oxycodone group), or 2.4-3 mg/kg propofol plus 2-2.5 mL saline (control group) for sedation. The primary endpoint is the incidence and degree of reflex coughing and gagging. The secondary endpoints include the occurrence of discomfort or side effects, the use of jaw thrust, assisted ventilation or additional propofol, recovery time, duration of procedure and Steward score. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Ethics Committee for Clinical Research of Zhongda Hospital, Affiliated to Southeast University (No. 2015ZDSYLL033.0). The results of the trial will be published in an international peer-reviewed journal. TRIAL REGISTRATION: This study has been registered with the Chinese Clinical Trial Register (No. ChiCTR-ICR-15006952). TRIAL STATUS: At the time of manuscript submission, the study was in the recruitment phase.

The Combination of Long-term Ketamine and Extinction Training Contributes to Fear Erasure by Bdnf Methylation.

A combination of antidepressant drugs and psychotherapy exhibits more promising efficacy in treating fear disorders than either treatment alone, but underlying mechanisms of such treatments remain largely unknown. Here we investigated the role of DNA methylation of the brain-derived neurotrophic factor (Bdnf) gene in the therapeutic effects of ketamine in combination with extinction training in a mouse model of post-traumatic stress disorder (PTSD) induced by inescapable electric foot shocks (IFS). Male mice received ketamine for 22 consecutive days starting 1 h after the IFS (long-term ketamine treatment) or 2 h prior to the extinction training on days 15 and 16 after the IFS (short-term ketamine treatment). The Open Field (OF) and Elevated Plus Maze (EPM) tests were conducted on days 18 and 20. The spontaneous recovery and fear renewal tests were performed on day 23. Mice, subjected to IFS, exhibited anxiety-like behavior and fear relapse, accompanied by the increased levels of DNA methyltransferases, hyper-methylation of Bdnf gene, and decreased BDNF mRNA expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Long-term treatment with ketamine combined with extinction training alleviated the IFS-induced abnormalities. These results suggest that long-term ketamine treatment in combination with extinction training may ameliorate fear relapse in the murine model of PTSD, at least in part, by normalizing DNA methylation of Bdnf gene.

Hemodynamic effects of ephedrine and phenylephrine bolus injection in patients in the prone position under general anesthesia for lumbar spinal surgery.

Ephedrine and phenylephrine (PE) are vasoconstrictors commonly used to restore the blood pressure (BP) to normal values. The aim of the present study was to investigate the effects of ephedrine and PE bolus administration on intra-arterial systolic BP (ISBP), intra-arterial diastolic BP (IDBP) and cardiac output (CO) in patients undergoing lumbar spine surgery in the prone position under general anesthesia (GA). In this prospective, randomized, and double-blind study, a total of 60 patients aged 20-60 years and undergoing elective lumbar spine surgery were administered either a single dose of ephedrine (0.1 mg/kg) or PE (1 µg/kg) through a central venous catheter as a bolus injection following the achievement of a stable hemodynamic status for ≥10 min. Following bolus injection of ephedrine or PE, a significant increase in ISBP was observed in the two experimental groups compared with pre-ephedrine and pre-PE values. The duration of the increment in ISBP however was significantly longer in the ephedrine group compared with the PE group. A similar response was observed in IDBP. A significant increase in CO began 1 min following ephedrine injection and lasted for the entire observation period, whereas the increase was only sustained for 3 min following bolus injection in the PE group. The results of the present study demonstrated that bolus ephedrine produces a more persistent pressor response and durable increase in CO and CI compared with PE when patients are in the prone position with GA for spine surgery.