Direct paraventricular thalamus-basolateral amygdala circuit modulates neuropathic pain and emotional anxiety.

The comorbidity of chronic pain and mental dysfunctions such as anxiety disorders has long been recognized, but the underlying mechanisms remained poorly understood. Here, using a mouse model of neuropathic pain, we demonstrated that the thalamic paraventricular nucleus (PVT) played a critical role in chronic pain-induced anxiety-like behavioral abnormalities. Fiber photometry and electrophysiology demonstrated that chronic pain increased the activities in PVT glutamatergic neurons. Chemogenetic manipulation revealed that suppression of PVT glutamatergic neurons relieved pain-like behavior and anxiety-like behaviors. Conversely, selective activation of PVT glutamatergic neurons showed algesic and anxiogenic effects. Furthermore, the elevated excitability of PVT glutamatergic neurons resulted in increased excitatory inputs to the basolateral complex (BLA) neurons. Optogenetic manipulation of the PVT-BLA pathway bilaterally modulates both the pain-like behavior and anxiety-like phenotypes. These findings shed light on how the PVT-BLA pathway contributed to the processing of pain-like behavior and maladaptive anxiety, and targeting this pathway might be a straightforward therapeutic strategy to both alleviate nociceptive hypersensitivity and rescue anxiety behaviors in chronic pain conditions.

ED90 of Sufentanil in Epidural Initiation for Labor Analgesia in Latent Phase and Active Phase During the First Labor Stage.

BACKGROUND: The standard solutions for epidural labor analgesia include both local anesthetics and opioids. The concept of the standard epidural use of local anesthetics in labor analgesia has shifted from high concentrations to high volumes with low concentrations. However, the optimal dosage of opioids needed to initiate and maintain epidural labor analgesia in different phases during the first labor stage has rarely been studied. OBJECTIVE: The present study aimed to determine the optimal sufentanil dose for epidural initiation in the latent and active phases during the first stage of labor. STUDY DESIGN: A prospective, double-blind, sequential dose-finding study. SETTING: A Class A tertiary obstetrics and gynecology hospital. METHODS: The study included 80 nulliparae with cervical dilatation of 2-4 cm and 5-6 cm, with 40 nulliparae in each group. A research dose of sufentanil combined with ropivacaine 13 mg in epidural initiation with a volume of 15 mL was administered to the puerperant. A 1-microgram sufentanil dose and a 2.5-micrograms sufentanil dose were used for the first puerperant of each group. The dose of sufentanil for the subsequent puerperant was determined by the response of the previous puerperant according to the biased coin up-and-down design in each trial. The primary outcome was a visual analog scale score of <= 3 at 15, 30, and 45 minutes after epidural administration, including the given dose of sufentanil. According to the response of each puerperant, the 90% effective doses and their 95% confidence intervals were estimated by isotonic regression and bootstrapping according to the response of each puerperant. RESULTS: The 90% effective doses of sufentanil for puerperants were 1.91 micrograms (95% confidence intervals 1.82-2.35 micrograms) and 4.90 micrograms (95% confidence intervals 4.82-5.35 micrograms) in epidural initiation in the latent and active phases, respectively. The 90% effective doses were 62.5% (95% confidence intervals 50.8-64.0%) lower in the latent phase than that in the active phase during the first stage of labor. LIMITATIONS: Both spontaneous labor and induced labor were included in this study, and the degree of pain in these 2 types of labor is different. Further, only nulliparae were recruited in the study. CONCLUSIONS: Different sufentanil doses should be adopted in epidural initiation in different phases during the first stage of labor due to the large differences in the demand for sufentanil.

Optimum dose of spinal ropivacaine with or without single intravenous bolus of S-ketamine during elective cesarean delivery: a randomized, double-blind, sequential dose-finding study.

BACKGROUND: Maternal hypotension after spinal anaesthesia occurs at a high rate during caesarean delivery and can lead to adverse maternal or foetal outcomes. The aim of this study was to determine the optimal dose of spinal ropivacaine for caesarean section with or without intravenous single bolus of S-ketamine and to observe the rates of hypotension associated with both methods. METHODS: Eighty women undergoing elective caesarean delivery were randomly allocated into either a ropivacaine only or ropivacaine with intravenous S-ketamine group. If the upper sensory level of the patient reached T6 and the visual analogue scale (VAS) scores remained below 3 points before delivery, the next patient had a 1/9th chance of receiving a lower dose or an 8/9th chance of receiving the same dose as the previous patient. If the patient had VAS scores of more than 2 points or needed an extra epidural rescue bolus before delivery, a higher dose was used for the next patient. The primary outcome was the successful use of spinal ropivacaine to maintain patient VAS score of < 3 points before delivery and the incidence of post-spinal hypotension in both groups. Secondary outcomes included the rates of hypotension-related symptoms and interventions, upper sensory level of anaesthesia, level of sedation, neonatal outcomes, Edinburgh Postnatal Depression Scale scores at admission and discharge, and post-operative analgesic effect. The 90% effective dose (ED90) and 95% confidence interval (95% CI) were estimated by isotonic regression. RESULTS: The estimated ED90 of ropivacaine was 11.8 mg (95% CI: 11.7-12.7) with and 14.7 mg (95% CI: 14.6-16.0) without intravenous S-ketamine, using biased coin up-down sequential dose-finding method. The rates of hypotension and associated symptoms were significantly lower in S-ketamine group than in the ropivacaine only group. CONCLUSIONS: A spinal dose of ropivacaine 12 mg with a single intravenous 0.15 mg/kg bolus dose of S-ketamine may significantly reduce the risk of hypotension and induce sedation before delivery. This method may be used with appropriate caution for women undergoing elective caesarean delivery and at a high risk of hypotension or experiencing extreme nervousness. TRIAL REGISTRATION: http://www.chictr.org.cn ( ChiCTR2000040375 ; 28/11/2020).

Performance verification of a new domestic chemiluminescence detection system.

BACKGROUND: Procalcitonin (PCT) is an acute phase response protein, which can be used as an indicator for early diagnosis of infection. At present, the main detection methods for PCT are electrochemiluminescence and enzyme-linked immunofluorescence. We aimed to explore the accuracy of PCT determination in a domestic chemiluminescence detection system and its correlation with other systems. METHODS: Clinical specimens were collected, and the precision, linearity, biological reference interval, contamination rate, Clinical reportable scope, and methodological comparison of the determination of PCT in a Chinese chemiluminescence detection system were evaluated and preliminarily verified by referring to Clinical and Laboratory Standards Institute (CLSI) documents or industry standards. RESULTS: The results of precision verification showed that the coefficient of variation (CV) values of the variation coefficient of precision in the samples of low and high values were 2.07% and 0.83% respectively, while the CV values of the total variation coefficient of precision were 3.05% and 1.81% respectively; these findings all met the experimental requirements. The results of linear verification test showed that the linear range was 0.006-96.96 ng/mL, and the linear relationship was well within the detection range (R2 =0.9891). The biological reference interval and the carrying contamination rate were also verified. The clinical reportable range was 0.02-369.585 ng/mL. The results showed that the correlation coefficient between the Mindray CL900I and the Roche E602 was 0.9986, and that between the Mindray CL900I and the Snibe 2000 was 0.983. Meanwhile, when the PCT was higher than 0.1 ng/mL, the correlation coefficient was 100%. CONCLUSIONS: The domestic chemiluminescence detection system has a good performance in the determination of calcitonin, as indicated by the measures of precision, linearity, biological reference interval, carrying contamination rate, and Clinical reportable scope, and can thus be used for clinical specimen detection. The results of methodological comparison showed that the correlation coefficient between the Mindray CL900I and Roche E602 was 0.9986, while the correlation coefficient between the Mindray CL900I and the Snibe 2000 was 0.983. The test results were consistent with the experimental requirements.

Lithium chloride ameliorates cognition dysfunction induced by sevoflurane anesthesia in rats.

Postoperative cognitive dysfunction is a common complication in elderly patients after surgeries involving anesthesia, but the underlying mechanisms are poorly understood. Lithium is a conventional treatment for bipolar disorder, which exerts a neuroprotective role in various diseases by inhibiting glycogen synthase kinase-3ß (GSK-3ß) in the brain and spinal cord. However, it is not known whether lithium chloride (LiCl) can protect against cognitive dysfunction induced by sevoflurane (SEV) anesthesia. Here, we examined the effects of LiCl on SEV-induced cognitive dysfunction in rats and on SEV-induced neuron apoptosis. We report that anesthesia with SEV significantly impaired memory performance, induced oxidative stress and hippocampal neuron apoptosis, and stimulated GSK-3ß activity. Treatment with LiCl ameliorated SEV-induced cognitive disorder in rats by inhibiting the GSK-3ß/ß-catenin signaling pathway. In addition, LiCl reduced hippocampal neuron apoptosis and oxidative stress induced by SEV anesthesia. These results suggest that LiCl may have potential for development into a therapeutic agent for treatment of SEV anesthesia-induced cognitive dysfunction.

Norepinephrine intravenous prophylactic bolus versus rescue bolus to prevent and treat maternal hypotension after combined spinal and epidural anesthesia during cesarean delivery: a sequential dose-finding study.

BACKGROUND: As a relatively new drug in obstetrical anesthesia, norepinephrine is less likely to induce bradycardia and decrease cardiac output, which makes it a potential alternative to phenylephrine. The purpose of this study was to determine the optimal norepinephrine bolus dose needed to either prevent or reverse hypotension after the use of combined spinal and epidural (CSE) anesthesia in 90% of women during elective cesarean delivery (CD). METHODS: Eighty women undergoing elective CD were randomly allocated into either a prophylactic group or a rescue group in this dose finding study. If the women's systolic blood pressure (SBP) was maintained above 80% of their baseline, the next patient had an 8/9th chance of receiving the same dose or a 1/9th chance of receiving a lower dose. If the patient's SBP was not maintained, a higher dose was used for next patient. The primary outcome was the successful use of the norepinephrine bolus dose to maintain SBP above 80% of the baseline until after delivery. Secondary outcomes included nausea, vomiting, breathlessness, dizziness, hypertension, bradycardia due to hypotension and supplemental use of atropine and norepinephrine, upper sensory level of anesthesia, umbilical vein (UV) blood gases, and 1- and 5-minute Apgar scores. The 90% effective dose (ED90) and 95% confidence interval (95% CI) were estimated using isotonic regression methods. RESULTS: The estimated ED90 of the norepinephrine prophylactic bolus was 10.85 µg (95% CI, 9.20-11.67 µg) and that of the norepinephrine rescue bolus was 12.3 µg (95% CI, 10.0-12.8 µg) using isotonic regression methods. CONCLUSIONS: For norepinephrine, either a prophylactic bolus dose of 11 µg or a rescue bolus dose of 12 µg was recommended for clinical practices.

Emulsified isoflurane induces release of cytochrome C in human neuroblastoma SHSY-5Y cells via JNK (c-Jun N-terminal kinases) signaling pathway.

A large number of studies have demonstrated that inhalation anesthetic isoflurane induced neural cell death by apoptosis in various cell and animal models. Emulsified isoflurane (EIso) is a new type of intravenous preparation of isoflurane that attracts increasing research attention as a promising clinical agent due to its both advantages as an intravenous and inhalation anesthetics medication. However, its safety and underlying molecular mechanism of neurotoxicity largely remain unknown. Therefore, it is meaningful to investigate the safety of EIso and to further elucidate its mechanism of anesthetic neurotoxicity. Human neuroblastoma SHSY-5Y cells were cultured, followed by a random exposure to one of three doses of EIso (0.56mmol/l, 1.12mmol/l, and 2.24mmol/l) or the corresponding intralipid as vehicle (0.3956µl/ml, 0.7912µl/ml and 1.5824µl/ml) for 6h, 12h or 24h. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) assay and the morphological changes were determined by a light microscope. We detect JNK, p-JNK and cytochrome C (cyto C) protein levels by western blotting. SP600125, a specific inhibitor of JNK, was used to detect the role of JNK pathway in the neurotoxicity of EIso. Our study showed that EIso reduced the viability of SHSY-5Y cells in a dose- and time-dependent manner. 0.56mmol/l EIso has no significant effects on cell viability, while 1.12mmol/l of EIso with 24-h and 2.24mmol/l of EIso with over 12-h exposure notably reduced cell viability. EIso dramatically increased the levels of p-JNK and cyto C. The JNK pathway inhibitor SP600125 significantly increased the cell viability of SHSY-5Y cells induced by EIso. These findings suggest that EIso induces damage in human neuroblastoma SHSY-5Y cells by JNK signaling pathway activation and cyto C release. SP600125 protects neural cells against EIso-induced injury. Our findings provide a new insight in the exploration of potential novel therapeutic strategies for the treatment of EIso-induced neurotoxicity and other neurodegenerative diseases.

JNK inhibitor alleviates apoptosis of fetal neural stem cells induced by emulsified isoflurane.

Isoflurane can provide both neuroprotection and neurotoxicity in various culture models and in rodent developing brains. Emulsified Isoflurane (EI) is an emulsion formulation of isoflurane, while its underlying molecular mechanism of developemental nerve toxicity largely remains unclear. We hypothesized that EI induced fetal neural stem cells (FNSCs) apoptosis, endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK) activation. FNSCs were isolated from the cortex of SD rats during 14 days of gestation. The cell viability, cell apoptotic rates and the expression of apoptosis-related protein Caspase3, inositol requiring enzyme 1 (IRE1), poly (adenosine diphosphate-ribose) polymerase (PARP), Bax, Bcl-2, JNK, p-JNK and XBP1 were determined. Specific inhibition was performed by siRNA-targeting of JNK in FNSCs. EI could increase the p-JNK, JNK and caspase3 protein expression, the JNK pathway was activated by EI, and EI-induced apoptosis was blocked by inhibiting JNK pathway with SP600125 or JNK-small interfering RNA (siRNA), EI enhanced the level of IRE1, PARP, Bax/Bcl-2 and XBP1, which led FNSCs to apoptosis and ER stress. Meanwhile, dilatation of the ER lumens in FNSCs treated by EI for 24 h was significant. Green fluorescent protein (GFP) positive cell ratios were significantly decreased by FNSCs transfecting with JNK gene silencing. JNK was efficiently silenced in siRNA-JNK1 group. The results provided in-vitro evidence which supports that the underlying mechanisms of EI-induced apoptosis are the induction of ER stress and sequent JNK activation. Together, these data suggest that JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity. HIGHLIGHTS: 1. Prolonged treatment with high-dose EI decreased the survival level of FNSCs by inducing apoptosis and inhibiting proliferation via the JNK signaling pathway. 2. EI induced ER stress and sequent JNK activation. 3. JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity.

Risk assessment of morbidly obese parturient in cesarean section delivery: A prospective, cohort, single-center study.

BACKGROUND: Up to 40% of women gain excessive weight during pregnancy. Obesity complications and risks in parturient women undergoing cesarean section (CS) with different anesthetic methods remain unknown. This study aimed to assess the safety and risk of obese women undergoing CS delivery with various perioperative anesthetic methods. METHODS: Seven hundred ninety parturient women underwent CS under general anesthesia (GA), intraspinal anesthesia including epidural anesthesia (EA) and combined spinal-epidural anesthesia (CSEA). They were divided into morbid (n = 255), severe (n = 274), and non-obesity (n = 261) groups. This study is registered with ClinicalTrials.gov (number NCT03002636). RESULT: Between 2013 and 2016, 790 pregnant were assessed. Compared with the non-obesity group, there were significantly more fetal distress and higher body mass index (BMI) in the morbid obesity group (P = .0001 and P = .001, respectively). Significantly more patients showed preeclampsia, multifetation, amniotic fluid abnormality, and high bleeding amounts in the morbid obesity group compared with the non-obesity group (P = .0001, P = .048, P = .017, and P = .018, respectively); more patients were administered EA and GA compared with the non-obesity group (P = .0001 and P = .0001, respectively). More post-anesthesia care unit (PACU) patients were found in the severe obesity group no more than the non-obesity group. Significantly increased anesthesia puncture times for 5 > n ≥ 3 and n ≥ 5 were obtained in the morbid obesity group (P = .0001 and P = .0001, respectively), with more patients in the puncture sitting position, compared with the non-obesity group (P = .0001). CONCLUSION: GA, EA, and CSEA are safe and effective in severely or morbidly obese patients. Morbidly obese parturient show increased likelihood for fetal distress, PACU, sitting position puncture, puncture difficulty, and other pregnancy complications. There were more anesthesia puncture times in morbidly obese patients.

Suitable depth of epidural puncture in nulliparous pregnant woman.

We study the suitable depth for epidural puncture in primiparas so as to decrease epidural complications and provide anesthesiologists with an appropriate insertion guide. A prospective study of 87 primipara patients receiving labor analgesia who had epidural punctures in the course of vaginal delivery were randomly divided into 3 groups: the L 3,4 group (N = 27), the L 2,3 group (N = 29), and the L 1,2 group (N = 26). Predictive statistical models were used for the formulation of the ideal epidural puncture needle depth. Eighty two patients who had non-traumatic epidural punctures were studied. There were no significant changes in age, weight, height, weight/height ratio, gestational weeks, fetus weight, pregnancy weight, weight difference, and fetus weight (P > 0.05). Compared with L 3,4 intervertebral space, the puncture depth in L 1,2 and L 2,3 was significantly shorter (P < 0.05) and (P < 0.001), respectively; Regression equation: PD (cm) = 0.351 [LHZ] + 0.147 [BMI] + 0.017. The correlation coefficient for LHZ was 0.351 (95 % CI 0.278-0.424; P < 0.001), the correlation coefficient for BMI was 0.147 (95 % CI 0.123-0.171; P < 0.001). This formula is accurate and practical with less complex calculations. However, further validation through a prospective study will be required. It is an accurate way to localize the puncture site in parturients and improve the efficiency of puncture in parturients for analgesia labor.Epidural puncture depth prediction in L 1,2, L 2,3, and L 3,4 can supply with a related reference.