Sub-anesthetic dose of esketamine decreases postoperative opioid self-administration after spine surgery: a retrospective cohort analysis.

The use of intraoperative sub-anesthetic esketamine for postoperative analgesia is controversial. In this study, the impact of sub-anesthetic esketamine on postoperative opioid self-administration was determined. Patients who underwent spinal surgery with patient-controlled analgesia (PCA) from January 2019 to December 2021 were respectively screened for analysis. Postoperative PCA was compared between patients who received a sub-anesthetic esketamine dose and patients who were not treated with esketamine (non-esketamine group) with or without propensity score matching. Negative binomial regression analysis was used to identify factors associated with postoperative PCA. Patients who received intraoperative sub-anesthetic esketamine self-administered less PCA (P = 0.001). Azasetron, esketamine, and dexamethasone lowered the self-administration of PCA (IRR with 95% confidential interval, 0.789 [0.624, 0.993]; 0.581 [0.458, 0.741]; and 0.777 [0.627, 0.959], respectively). Fixation surgery and drinking were risk factors for postoperative PCA (1.737 [1.373, 2.188] and 1.332 [1.032, 1.737] for fixation surgery and drinking, respectively). An intraoperative sub-anesthetic dose of esketamine decreases postoperative opioid self-administration. Azasetron and dexamethasone also decrease postoperative opioid consumption. The study is registered at www.chictr.org.cn (ChiCTR2300068733).

Acute pituitary crisis after lumbar surgery: A case report.

RATIONALE: Patients with hypopituitarism often have no specific symptoms; that frequently results in missed diagnosis. An acute hypopituitarism crisis can be induced under stressful conditions. Here, we report a rare case of an acute pituitary crisis after lumbar surgery. PATIENT CONCERNS: We describe a 62-year-old female who presented with refractory electrolyte disorders after lumbar surgery. In addition, she developed anorexia, nausea, vomiting, chest cavity effusion, ascites, pericardial effusion, anemia, low blood pressure, bradycardia, and unconsciousness after surgery. MRI showed an empty sella turcica. DIAGNOSES: She was diagnosed with postoperative acute hypopituitary crisis. INTERVENTIONS: The patient received hormone replacement therapy. OUTCOMES: Her symptoms improved significantly following the initiation of hormone replacement therapy and was well 6 months after surgery. LESSONS: Refractory postoperative complications, including electrolyte disorders, infection, nausea, vomiting, circulatory collapse, anemia, and coma, indicate an acute postoperative hypopituitary crisis.

Development and validation of a prediction tool for intraoperative blood transfusion in brain tumor resection surgery: a retrospective analysis.

Early identification of a patient with a high risk of blood transfusion during brain tumor resection surgery is difficult but critical for implementing preoperative blood-saving strategies. This study aims to develop and validate a machine learning prediction tool for intraoperative blood transfusion in brain tumor resection surgery. A total of 541 patients who underwent brain tumor resection surgery in our hospital from January 2019 to December 2021 were retrospectively enrolled in this study. We incorporated demographics, preoperative comorbidities, and laboratory risk factors. Features were selected using the least absolute shrinkage and selection operator (LASSO). Eight machine learning algorithms were benchmarked to identify the best model to predict intraoperative blood transfusion. The prediction tool was established based on the best algorithm and evaluated with discriminative ability. The data were randomly split into training and test groups at a ratio of 7:3. LASSO identified seven preoperative relevant factors in the training group: hemoglobin, diameter, prothrombin time, white blood cell count (WBC), age, physical status of the American Society of Anesthesiologists (ASA) classification, and heart function. Logistic regression, linear discriminant analysis, supporter vector machine, and ranger all performed better in the eight machine learning algorithms with classification errors of 0.185, 0.193, 0.199, and 0.196, respectively. A nomogram was then established, and the model showed a better discrimination ability [0.817, 95% CI (0.739, 0.895)] than hemoglobin [0.663, 95% CI (0.557, 0.770)] alone in the test group (P = 0.000). Hemoglobin, diameter, prothrombin time, WBC, age, ASA status, and heart function are risk factors of intraoperative blood transfusion in brain tumor resection surgery. The prediction tool established using the logistic regression algorithm showed a good discriminative ability than hemoglobin alone for predicting intraoperative blood transfusion in brain tumor resection surgery.

STIM2 Suppression Blocks Glial Activation to Alleviate Brain Ischemia Reperfusion Injury via Inhibition of Inflammation and Pyroptosis.

Cerebral ischemia/reperfusion injury (CIRI) involves various pathogenic mechanisms, including cytotoxicity, apoptosis, inflammation, and pyroptosis. Stromal interactive molecule 2 (STIM2) is implicated in cerebral ischemia. Consequently, this study investigates the biological functions of STIM2 and its related mechanisms in CIRI progression. Middle cerebral artery occlusion/reperfusion (MCAO/R) mouse models and oxygen-glucose deprivation/reoxygenation (OGD/R) cellular models were established. STIM2 level was upregulated in experimental CIRI models, as shown by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and immunofluorescence staining. Brain infarction and edema were attenuated by STIM2 knockdown, as 2,3,5-triphenyltetrazolium chloride (TTC) staining and brain water content evaluation revealed. STIM2 knockdown relieved neuronal apoptosis, microglia activation, inflammation and pyroptosis in MCAO/R mice, as detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, enzyme-linked immunosorbent assay (ELISA) and western blotting. Results of flow cytometry, ELISA, western blotting and cell counting kit-8 (CCK-8) assays also showed that STIM2 knockdown inhibited inflammation, apoptosis and pyroptosis in OGD/R-treated BV2 cells. Moreover, STIM2 knockdown inhibited apoptosis and pyroptosis in PC12 cells incubated with conditioned medium collected from OGD/R-exposed BV2 cells. Mechanistically, lncRNA Malat1 (metastasis associated lung adenocarcinoma transcript 1) positively regulated STIM2 expression by sponging miR-30d-5p. Their binding relationship was confirmed by luciferase reporter assays. Finally, lncRNA Malat1 elevation or miR-30d-5p knockdown abolished the sh-STIM2-induced inhibition in cell damage. In conclusion, STIM2 knockdown in microglia alleviates CIRI by inhibiting microglial activation, inflammation, apoptosis, and pyroptosis.

Development and validation of nomograms to predict preoperative anxiety and postoperative pain in patients undergoing gynecological surgery: An observational analysis.

BACKGROUND: Perioperative anxiety and pain are associated with patient dissatisfaction, postoperative complications, and prolonged hospital stay. Early identification of high-risk patients with preoperative anxiety and postoperative pain will be useful for the implementation of preventive management. METHODS: Patients, who underwent gynecological surgery in our hospital between March 2022 and September 2022, were consecutively enrolled. Perioperative anxiety and pain were evaluated with the Visual Analogue Scale of Anxiety (VAA) and Visual Analogue Scale of Pain (VAS), respectively. Step Akaike Information Criterion analysis was performed to identify risk factors and logistic regression was used to establish nomograms, followed by discrimination, calibration, and clinical utility evaluation. RESULTS: A total of 197 patients were included for analysis, including 116 and 81 patients who were randomized to training and test groups, respectively. The prediction model of preoperative moderate to severe anxiety identified four preoperative relevant factors: age, sleep duration, preoperative pain, and regular exercise before gynecological surgery. The model had an area under the receiver operating characteristics curve of 0.808 (0.729, 0.887) and 0.754 (0.634, 0.875) in the training and test groups, respectively. The prediction model of postoperative moderate to severe pain identified four relevant factors: preoperative pain, surgery type, VAA before anesthesia, and patient-controlled analgesia. The model had an area under the receiver operating characteristics curve of 0.867 (0.798, 0.935) and 0.852 (0.761, 0.943) in the training and test groups, respectively. CONCLUSIONS: The established nomograms accurately identified high-risk patients with preoperative anxiety and postoperative pain before gynecological surgery. Clinical registration at: www.chictr.org.cn (ChiCTR2200057757).

Sub-Anesthesia Dose of S-Ketamine Reduces Postoperative Pain and Anxiety in Patients Receiving Breast and Thyroid Surgery: A Randomized, Controlled Trial.

BACKGROUND: Postoperative pain and anxiety affect patients' recovery and increase the family burden. S-ketamine presents analgesic effects and anti-depressive effects in clinics. The effect of a sub-anesthesia dose of S-ketamine on postoperative pain and anxiety remains to be clarified. OBJECTIVES: This study aimed to evaluate the analgesic and anxiolytic effects of a sub-anesthesia dose of S-ketamine on postoperative pain and anxiety and explored the risk factors for postoperative pain in patients receiving breast or thyroid surgery under general anesthesia. STUDY DESIGN: A randomized, double-blind, controlled trial. SETTING: A university hospital. METHODS: One hundred twenty patients receiving breast or thyroid surgery, stratified by surgery type, were randomized to S-ketamine and control groups in a 1:1 ratio. S-ketamine (0.3 mg/kg) or an equal volume of normal saline was administrated after anesthesia induction. Visual analog scale (VAS) of pain and self-rating anxiety scale (SAS) were tested before surgery and on postoperative day 1, 2, and 3. VAS and SAS score between the 2 groups were compared, and the risk factors for postoperative moderate to severe pain were explored with logistic regression analysis. RESULTS: Intraoperative S-ketamine decreased VAS and SAS scores on postoperative day 1, 2, and 3 (P < 0.05, 2-way ANOVA for repeated measurements followed by Bonferroni post-analysis). Subgroup analysis showed S-ketamine decreased VAS and SAS scores both in breast surgery and thyroid surgery patients on postoperative day 1, 2, and 3. Logistic regression identified S-ketamine and regular exercise are protective factors, and anxiety before surgery is a risk factor for postoperative moderate to severe pain (P < 0.05). LIMITATIONS: The anxiety score in our study is not so high, which may under-evaluate the anxiolytic effect of S-ketamine. However, S-ketamine decreased the SAS scores postoperatively in our study. CONCLUSIONS: Intraoperative sub-anesthesia dose of S-ketamine reduces postoperative pain and anxiety intensity. Anxiety before surgery is a risk factor, and S-ketamine and regular exercise are protective factors for postoperative pain. The study was registered at www.chictr.org.cn with the number: ChiCTR2200060928.

Development and validation of a nomogram for blood transfusion during intracranial aneurysm clamping surgery: a retrospective analysis.

PURPOSE: Intraoperative blood transfusion is associated with adverse events. We aimed to establish a machine learning model to predict the probability of intraoperative blood transfusion during intracranial aneurysm surgery. METHODS: Patients, who underwent intracranial aneurysm surgery in our hospital between January 2019 and December 2021 were enrolled. Four machine learning models were benchmarked and the best learning model was used to establish the nomogram, before conducting a discriminative assessment. RESULTS: A total of 375 patients were included for analysis in this model, among whom 108 received an intraoperative blood transfusion during the intracranial aneurysm surgery. The least absolute shrinkage selection operator identified six preoperative relative factors: hemoglobin, platelet, D-dimer, sex, white blood cell, and aneurysm rupture before surgery. Performance evaluation of the classification error demonstrated the following: K-nearest neighbor, 0.2903; logistic regression, 0.2290; ranger, 0.2518; and extremely gradient boosting model, 0.2632. A nomogram based on a logistic regression algorithm was established using the above six parameters. The AUC values of the nomogram were 0.828 (0.775, 0.881) and 0.796 (0.710, 0.882) in the development and validation groups, respectively. CONCLUSIONS: Machine learning algorithms present a good performance evaluation of intraoperative blood transfusion. The nomogram established using a logistic regression algorithm showed a good discriminative ability to predict intraoperative blood transfusion during aneurysm surgery.

An Efficient Self-Organized Detection System for Algae.

Algal blooms have seriously affected the production and life of people and real-time detection of algae in water samples is a powerful measure to prevent algal blooms. The traditional manual detection of algae with a microscope is extremely time-consuming. In recent years, although there have been many studies using deep learning to classify and detect algae, most of them have focused on the relatively simple task of algal classification. In addition, some existing algal detection studies not only use small datasets containing limited algal species, but also only prove that object detection algorithms can be applied to algal detection tasks. These studies cannot implement the real-time detection of algae and timely warning of algal blooms. Therefore, this paper proposes an efficient self-organized detection system for algae. Benefiting from this system, we propose an interactive method to generate the algal detection dataset containing 28,329 images, 562,512 bounding boxes and 54 genera. Then, based on this dataset, we not only explore and compare the performance of 10 different versions of state-of-the-art object detection algorithms for algal detection, but also tune the detection system we built to its optimum state. In practical application, the system not only has good algal detection results, but also can complete the scanning, photographing and detection of a 2 cm × 2 cm, 0.1 mL algal slide specimen within five minutes (the resolution is 0.25886 µm/pixel); such a task requires a well-trained algal expert to work continuously for more than three hours. The efficient algal self-organized detection system we built makes it possible to detect algae in real time. In the future, with the help of IoT, we can use various smart sensors, actuators and intelligent controllers to achieve real-time collection and wireless transmission of algal data, use the efficient algal self-organized detection system we built to implement real-time algal detection and upload the detection results to the cloud to realize timely warning of algal blooms.

Efficacy of quadratus lumborum block on postoperative pain and side effects in patients who underwent urological surgery: A meta-analysis.

BACKGROUND: Ultrasound-guided quadratus lumborum block (QLB) is considered a novel nerve block for postoperative pain control. However, its efficacy after urological surgery remains unclear. OBJECTIVES: The purpose of the current meta-analysis was to evaluate the effects of the QLB block versus control (placebo or no injection) on postoperative pain and other adverse outcomes after urological surgery, providing extensive evidence of whether quadratus lumborum block is suitable for pain management after urological surgery. STUDY DESIGN: Systematic review with meta-analysis of randomized clinical trials. METHODS: We searched PubMed, Cochrane Library, Embase, Web of Science, and ClinicalTrials.gov to collect studies investigating the effects of QLB on analgesia after urological surgery. The primary outcomes included visual analog scale (VAS) at rest and during movement, 24-h postoperative morphine consumption, and the incidence of postoperative nausea and vomiting (PONV). RESULTS: Overall, 13 randomized controlled trials (RCTs) were reviewed, including 751 patients who underwent urological surgery. The QLB group exhibited a lower VAS score postoperatively at rest or on movement at 0, 6, 12, and 24 h, with less 24-h postoperative morphine consumption and lower incidence of PONV. LIMITATIONS: Although the result is stable, heterogeneity exists in the current research. CONCLUSIONS: QLB exhibited a favorable effect of postoperative analgesia with reduced postoperative complications at rest or during movement after urological surgery. However, it is still a novel technology at a primary stage, which needs further research to develop.

Tropisetron Preconditioning Decreases Myocardial Biomarkers in Patients Undergoing Heart Valve Replacement Surgery.

Background: Cardioplegic arrest during the heart valve replacement surgery frequently leads to myocardial damage. Tropisetron (TRP) has been demonstrated to reduce myocardial ischemia-reperfusion injury and inflammation in animals. We examined the efficacy of TRP in lowering myocardial biomarkers in patients undergoing heart valve replacement surgery. Methods: A total of seventy-five patients, scheduled for elective heart valve replacement surgery, were randomly chosen to receive either 10 ml of normal saline or 10 mg/10 ml of TRP immediately after anesthesia induction. Blood samples for the measurement of cardiac troponin I (cTnI), creatine kinase (CK-MB), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-10 (IL-10) were taken before anesthesia, as well as 4, 12, and 24 h after aortic cross-clamp release to evaluate myocardial injury using two-way ANOVA for repeated measurements. The study was registered at www.chictr.org.cn (number, ChiCTR-1800018681). Results: Treatment with TRP decreased the increment of cTnI (Fgroup = 4.911, p = 0.030; Ftime = 55.356, p = 0.001; Fgroup × time = 5.340, p = 0.002) at 12 and 24 h; of CK-MB (Fgroup = 6.552, p = 0.013; Ftime = 49.276, p = 0.001; Fgroup × time = 7.627, p = 0.003) at 4, 12, and 24 h; of TNF-α (Fgroup = 4.153, p = 0.046; Ftime = 28.244, p = 0.002; Fgroup × time = 4.692, p = 0.006) at 4 and 12 h; and of LDH (Fgroup = 4.275, p = 0.043; Ftime = 63.225, p = 0.001; Fgroup × time = 2.501, p = 0.083) at 24 h after the release of the aortic cross-clamp. It increased IL-10 (Fgroup = 5.958, p = 0.018; Ftime = 31.226, p = 0.002; Fgroup × time = 1.464, p = 0.236) at 12 h after the release of the aortic cross-clamp. Multiple linear regression analysis showed that cardiopulmonary bypass (CPB) time was a risk factor, and that TRP treatment was a protective factor for postoperative cTNI change (ß = 4.449, 95% CI [0.97-7.92], p = 0.013 for CPB time; and ß = -381, 95% CI [-613.4 to -148.5], p = 0.002 for TRP treatment). Conclusions: Tropisetron had cardioprotective and anti-inflammatory effects in patients undergoing heart valve replacement surgery with cardioplegic arrest. The addition of TRP and reduction of CPB time should be considered for myocardial protection in heart valve replacement surgery. Clinical Trial Registration: [www.chictr.org.cn/index.aspx], identifier [ChiCTR1800018681].

Tropisetron attenuates neuroinflammation and chronic neuropathic pain via α7nAChR activation in the spinal cord in rats.

OBJECTIVES: Tropisetron is an alpha 7 nicotinic acetylcholine receptor (α7nAChR) agonist and is a commonly used antiemetic clinically. α7nAChRs activation modulating nociception transmissions and cholinergic anti-inflammation may decrease neuropathic pain. This study was set to investigate the effects of tropisetron on neuropathic pain and neuroinflammation as well as the underlying mechanisms in rats. METHODS: Neuropathic pain behavior was assessed in rats using the paw mechanical withdrawal threshold and paw thermal withdrawal latency before and after the establishment of a spared nerve injury (SNI) pain model in rats treated with tropisetron treatment in the presence or absence of the α7nAChR antagonist methyllycaconitine (MLA) through intrathecal injection. Their spinal cords were then harvested for inflammatory cytokines, the α7nAChR, p38 mitogen-activated protein kinase (p-p38MAPK) and cAMP-response element binding protein (CREB) measurement. RESULTS: Tropisetron effectively alleviated mechanical allodynia and thermal hyperalgesia; decreased IL-6, IL-1ß and TNF-a; and down-regulated the phosphorylation of p38MAPK and CREB. Pre-treatment with MLA abolished these effects of tropisetron. CONCLUSION: Our data indicate that tropisetron alleviates neuropathic pain may through inhibition of the p38MAPK-CREB pathway via α7nAChR activation. Thus, tropisetron may be a potential new therapeutic strategy for chronic neuropathic pain.

Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure.

Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity. As a major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections. Spinal microglial activation and the production of pro-inflammatory cytokines have been implicated in the pathogenesis of LPS-induced hyperalgesia in neonatal rats. Dexmedetomidine (DEX) possesses potent anti-neuroinflammatory and neuroprotective properties through the inhibition of microglial activation and microglial polarization toward pro-inflammatory (M1) phenotype and has been widely used in pediatric clinical practice. However, little is known about the effects of DEX on LPS-induced spinal inflammation and hyperalgesia in neonates. Here, we investigated whether systemic LPS exposure has persistent effects on spinal inflammation and hyperalgesia in neonatal rats and explored the protective role of DEX in adverse effects caused by LPS injection. Systemic LPS injections induced acute mechanical hyperalgesia, increased levels of pro-inflammatory cytokines in serum, and short-term increased expressions of pro-inflammatory cytokines and M1 microglial markers in the spinal cord of neonatal rats. Pretreatment with DEX significantly decreased inflammation and alleviated mechanical hyperalgesia induced by LPS. The inhibition of M1 microglial polarization and microglial pro-inflammatory cytokines expression in the spinal cord may implicate its neuroprotective effect, which highlights a new therapeutic target in the treatment of infection-induced hyperalgesia in neonates and preterm infants.

Exercise Reduces Morphine-Induced Hyperalgesia and Antinociceptive Tolerance.

Chronic morphine intake for treating various pain is frequently concomitant with morphine-induced hyperalgesia and tolerance. The mechanisms can be explained by the activation of p38-MAPK proteins in microglia in the spinal cord horn. Exercise has been shown to prevent the development of microglia overactivation. Thus, we designed to test whether exercise prevents the morphine-induced hyperalgesia and tolerance as well as suppression of p38 phosphorylation. A p38 inhibitor SB203580, exercise, and exercise preconditioning were used for treating morphine-induced hyperalgesia and tolerance development in the present study. The behavior tests for hyperalgesia and tolerance were performed in male Wistar rats before and after morphine administration. Western blotting and immunostaining for examining phosphorylated-p38 expression were performed after the behavior tests. Our results showed that SB203580 and exercise, but not exercise preconditioning, prevented the occurrence of morphine-induced hyperalgesia and tolerance. Meanwhile, exercise decreased morphine-induced phosphorylated-p38 overexpression. In summary, exercise prevented the development of morphine-induced hyperalgesia and tolerance. The mechanism may be related to inhibition of p38 phosphorylation.

Survival and Clinicopathological Significance of SIRT1 Expression in Cancers: A Meta-Analysis.

Background: Silent information regulator 2 homolog 1 (SIRT1) is an evolutionarily conserved enzymes with nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity. SIRT1 is involved in a large variety of cellular processes, such as genomic stability, energy metabolism, senescence, gene transcription, and oxidative stress. SIRT1 has long been recognized as both a tumor promoter and tumor suppressor. Its prognostic role in cancers remains controversial. Methods: A meta-analysis of 13,138 subjects in 63 articles from PubMed, EMBASE, and Cochrane Library was performed to evaluate survival and clinicopathological significance of SIRT1 expression in various cancers. Results: The pooled results of meta-analysis showed that elevated expression of SIRT1 implies a poor overall survival (OS) of cancer patients [Hazard Ratio (HR) = 1.566, 95% CI: 1.293-1.895, P < 0.0001], disease free survival (DFS) (HR = 1.631, 95% CI: 1.250-2.130, P = 0.0003), event free survival (EFS) (HR = 2.534, 95% CI: 1.602-4.009, P = 0.0001), and progress-free survival (PFS) (HR = 3.325 95% CI: 2.762-4.003, P < 0.0001). Elevated SIRT1 level was associated with tumor stage [Relative Risk (RR) = 1.299, 95% CI: 1.114-1.514, P = 0.0008], lymph node metastasis (RR = 1.172, 95% CI: 1.010-1.360, P = 0.0363), and distant metastasis (RR = 1.562, 95% CI: 1.022-2.387, P = 0.0392). Meta-regression and subgroup analysis revealed that ethnic background has influence on the role of SIRT1 expression in predicting survival and clinicopathological characteristics of cancers. Overexpression of SIRT1 predicted a worse OS and higher TNM stage and lymphatic metastasis in Asian population especially in China. Conclusion: Our data suggested that elevated expression of SIRT1 predicted a poor OS, DFS, EFS, PFS, but not for recurrence-free survival (RFS) and cancer-specific survival (CCS). SIRT1 overexpression was associated with higher tumor stage, lymph node metastasis, and distant metastasis. SIRT1-mediated molecular events and biological processes could be an underlying mechanism for metastasis and SIRT1 is a therapeutic target for inhibiting metastasis, leading to good prognosis.

Activation of alpha7 acetylcholine receptors reduces neuropathic pain by decreasing dynorphin A release from microglia.

Dynorphin A is increased in neuropathic pain models. Activation of α7 n acetylcholine receptor (nAchR) reduces inflammation and pain. Whether activation of α7 nAchR affects dynorphin A release is unknown. The experiments evaluated the proinflammatory effect of dynorphin A in the spinal nerve ligation-induced neuropathic pain models and the effect of α7 nAchR activation on the dynorphin A content. α7 nAchR agonist, PHA-543613 and its antagonist, methyllycaconitine citrate were used and dynorphin A content was measured after spinal nerve ligation and in microglia cultures to test the analgesic mechanisms of α7 nAchR activation. The results showed that dynorphin A content peaked 3 to 7 days after nerve injury, and dynorphin A anti-serum intrathecal injection decreased IL-ß and TNF-α content a week after nerve injury. Activation of α7 nAchR by PHA-543613 alleviated neuropathic pain behaviors and decreased dynorphin A concentration in the ipsilateral spinal cords. Also, PHA-543613 decreased dynorphin A release from the microglia cultures to LPS stimulation by activation of α7 nAchR. Our results suggest that dynorphin A contribute to the development and maintenance of neuropathic pain and that decreasing dynorphin A content by activation of α7 AchR of microglia is a potential therapeutic target for treating neuropathic pain.

An eight-lncRNA signature predicts survival of breast cancer patients: a comprehensive study based on weighted gene co-expression network analysis and competing endogenous RNA network.

PURPOSE: To identify a lncRNA signature to predict survival of breast cancer (BRCA) patients. METHODS: A total of 1222 BRCA case and control datasets were downloaded from the TCGA database. The weighted gene co-expression network analysis of differentially expressed mRNAs was performed to generate the modules associated with BRCA overall survival status and further construct a hub on competing endogenous RNA (ceRNA) network. LncRNA signatures for predicting survival of BRCA patients were generated using univariate survival analyses and a multivariate Cox hazard model analysis and validated and characterized for prognostic performance measured using receiver operating characteristic (ROC) curves. RESULTS: A prognostic score model of eight lncRNAs signature was identified as Prognostic score = (0.121 × EXPAC007731.1) + (0.108 × EXPAL513123.1) + (0.105 × EXPC10orf126) + (0.065 × EXPWT1-AS) + (- 0.126 × EXPADAMTS9-AS1) + (- 0.130 × EXPSRGAP3-AS2) + (0.116 × EXPTLR8-AS1) + (0.060 × EXPHOTAIR) with median score 1.088. Higher scores predicted higher risk. The lncRNAs signature was an independent prognostic factor associated with overall survival. The area under the ROC curves (AUC) of the signature was 0.979, 0.844, 0.99 and 0.997 by logistic regression, support vector machine, decision tree and random forest models, respectively, and the AUCs in predicting 1- to 10-year survival were between 0.656 and 0.748 in the test dataset from TCGA database. CONCLUSIONS: The eight-lncRNA signature could serve as an independent biomarker for prediction of overall survival of BRCA. The lncRNA-miRNA-mRNA ceRNA network is a good tool to identify lncRNAs that is correlated with overall survival of BRCA.

Environmental enrichment reduces adolescent anxiety- and depression-like behaviors of rats subjected to infant nerve injury.

BACKGROUND: Infant nerve injury causes delayed adolescent neuropathic pain, but whether it also leads to psychiatric illness is unknown. Environmental enrichment (EE) increases social communication and activity. Thus, our goal was to test anxiety- and depression-like behaviors after infant peripheral nerve injury and evaluate the effect of environmental enrichment on these models of affective disorders. METHODS: Open field, elevated plus maze, sucrose preference, and pain behaviors (paw withdrawal threshold, spontaneous guarding score, and cold response to acetone) were measured in rats that received infant spared nerve injury (SNI). Enzyme-linked immune absorbent assay of cytokines was performed to evaluate the inflammatory response in the brain. Then, the ability of intracerebroventricular (ICV) injection of a microglia inhibitor, minocycline (MIN), and EE (a free-running wheel, a staircase, a plastic tunnel, a raised platform, and various colored balls) to reverse the infant SNI effects on behaviors and cytokines was examined. RESULTS: Infant nerve injury resulted in adolescent anxiety- and depression-like behaviors. The medial prefrontal cortex, basolateral amygdala, and ventral hippocampus were skewed to a pro-inflammatory profile. ICV injection of MIN reduced anxiety- and depression-like behaviors without affecting pain behaviors. In addition, ICV MIN skewed the brain towards an anti-inflammatory profile. Finally, environmental enrichment improved anxiety- and depression-like behaviors, as well as pain behaviors. EE increased brain IL-10 and decreased IL-1ß and TNF-α. CONCLUSIONS: Infant nerve injury induces adolescent anxiety- and depression-like behaviors and central nervous inflammation. Environmental enrichment reduces these behaviors by normalizing the inflammation balance in the brain.

Differential Inhibition of Nav1.7 and Neuropathic Pain by Hybridoma-Produced and Recombinant Monoclonal Antibodies that Target Nav1.7 : Differential activities of Nav1.7-targeting monoclonal antibodies.

The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na+ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7-expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na+ currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.

Infant nerve injury induces delayed microglial polarization to the M1 phenotype, and exercise reduces delayed neuropathic pain by modulating microglial activity.

Neuropathic pain is absent in infants and emergent years after injury. Adult spinal cord microglia play a key role in initiating neuropathic pain, and modulation of microglia is a potential target for treating neuropathic pain. In this study, we evaluated the role of microglia after infant peripheral nerve injury and the effect of exercise on the delayed-onset neuropathic pain. Rat pups received spared nerve injury, and behavior tests were performed to evaluate their pain threshold. qPCR, immunohistochemistry, and Western blot were used for M1 and M2 marker expression analysis. In contrast to the microglial polarization to the M1 phenotype observed in the adult spinal cord, in infant nerve injury, microglial polarization immediately shifted to the M2 phenotype. In adolescence, microglia polarized to the M1 phenotype, which was concomitant with the emergence of neuropathic pain. Exercise shifted spinal cord microglia polarization to the M2 phenotype and reduced neuropathic pain. In addition, IL-10 increased and TNF-α decreased after exercise, and intrathecal injection of the IL-10 antibody reduced the exercise-induced analgesia. Our study found that infant nerve injury induced delayed spinal cord microglia polarization to the M1 phenotype and that exercise was effective in the treatment of delayed adolescent neuropathic pain via the modulation of microglial polarization.

Noradrenergic transmission in the central medial thalamic nucleus modulates the electroencephalographic activity and emergence from propofol anesthesia in rats.

At present, the mechanisms by which general anesthetics causing loss of consciousness remain unclear. The central medial thalamic nucleus (CMT) is a rarely studied component of the midline thalamic complex, which is deemed to be a part of the nonspecific arousal system. Although the CMT participates in modulating arousal and receives excitatory noradrenergic projections from locus coeruleus, it remains unknown whether the noradrenergic pathway in the CMT takes part in modulating the arousal system. Therefore, we hypothesized that noradrenergic transmission in the CMT is involved in modulating induction and emergence of propofol anesthesia. First, we infused norepinephrine (NE) into the CMT to observe the role of CMT noradrenergic pathway in modulating the anesthetic state induced by propofol. The results showed that microinjection of NE into the CMT accelerated emergence from propofol anesthesia, but had no impact on the induction of or sensitivity to propofol anesthesia in rats. In addition, infusion of NE into the CMT caused electroencephalography changes in the prefrontal cortex and the anterior cingulate cortex. Finally, we used a whole-cell patch clamp to examine the effects of NE on neuronal excitability and GABAergic transmission in the CMT. In the CMT slices, propofol suppressed neuronal excitability and enhanced GABAergic transmission, while application of NE partly reversed these effects. These findings support the hypothesis that the CMT noradrenergic pathway plays an important role in modulating the emergence from general anesthesia.