Association between the variability of cerebral oxygen saturation during cardiopulmonary bypass and delayed postoperative neurocognitive recovery in cardiac valve surgical patients: A pilot study.

AIMS OF THE STUDY: The association between regional cerebral oxygen saturation (rSO2) and postoperative cognitive decline is controversial. In this study, we investigated the association between the real variability of regional cerebral oxygen saturation during cardiopulmonary bypass (CPB) and postoperative delayed neurocognitive recovery in patients undergoing heart valve surgery. METHODS USED TO CONDUCT THE STUDY: A total of 71 patients who underwent cardiac valve surgery were enrolled in this study. Patients were assessed for cognitive function using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment Scale (MOCA) on the day before surgery and the 7th day after surgery. The real variability of regional cerebral oxygen saturation (rSO2), real variability of the brain bispectral index of EEG (BIS), real variability of mean arterial pressure (MAP) and body temperature were monitored during CPB. Patients were divided into two groups according to neural cognitive function scores to explore the relationship between postoperative delayed neurocognitive recovery and the real variability of cerebral oxygen saturation, BIS, MAP, and body temperature during CPB. RESULTS OF THE STUDY: Twenty-seven patients were diagnosed with postoperative delayed neurocognitive recovery. The occurrence of postoperative delayed neurocognitive recovery after surgery was closely related to the large variability of rSO2 during the rewarming phase of CPB (P < .05). Logistic analysis showed that preoperative arrhythmia, a lower level of serum albumin after surgery and greater rSO2 variability during the rewarming phase were risk factors for postoperative delayed neurocognitive recovery (P < .05). In this study, there was no correlation between postoperative delayed neurocognitive recovery and BIS, MAP or body temperature variability (P > .05). CONCLUSIONS DRAWN FROM THE STUDY AND CLINICAL IMPLICATIONS: The real variability of rSO2 during the CPB rewarming phase was related to postoperative delayed neurocognitive recovery in patients who underwent cardiac surgery.

Outcomes of Infant Cardiac Surgery for Congenital Heart Disease Concomitant With Persistent Pneumonia: A Retrospective Cohort Study.

OBJECTIVES: There is still controversy about whether an infant should have cardiac surgery concomitant with ongoing persistent pneumonia. This study analyzes the outcome of surgical treatment for infants with left-to-right shunt congenital heart disease accompanied with persistent pneumonia and discusses the perioperative management strategies for these cases. DESIGN: This is a retrospective cohort study. SETTING: This study was conducted in an academic hospital and is a single-center study. PARTICIPANTS: In this study, the authors analyzed the data of 94 infants admitted to our hospital from January 2014 to May 2016 who underwent surgical correction for left-to-right shunt congenital heart disease. INTERVENTIONS: Fifty cases without pneumonia were included as a control group, and 44 cases with unresolved persistent pneumonia were included as a study group. The clinical characteristics between the 2 groups were compared, and the perioperative safety and short-term prognosis were evaluated. MEASUREMENTS AND MAIN RESULTS: There was no significant difference in sex composition between the 2 groups. Infants in the pneumonia group were younger and had a lower body weight (p < 0.001). There was a significant difference in types of congenital heart disease between the 2 groups (p < 0.001). Preoperative body temperature and heart rate of infants in the pneumonia group were higher than those in the control group (p < 0.001). The cardiopulmonary bypass time in the pneumonia group was significantly longer than that of the control group (p = 0.001). Perioperative major complications were not significantly different between the 2 groups. The postoperative ventilator-assisted time, duration of intensive care unit stay, and length of hospital stay were longer in the pneumonia group (p < 0.001). Only 1 patient in the control group died of severe low cardiac output syndrome. CONCLUSION: The authors conclude that in the presented cases, no mortality or major morbidity was observed related to the practice of performing surgery in infants with signs of persistent pneumonia. The authors conclude that it is likely to be safe and effective for infants to receive cardiac surgery for left-to-right shunt congenital heart disease in the presence of persistent pneumonia.

Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-ɤ.

BACKGROUND/AIMS: Recent researches highlighted the protective potential of pioglitazone, a PPAR-γ agonist, in the progression of cerebral ischemia-reperfusion injury. However, there has been no study on the application of pioglitazone in treating ischemic stroke through mechanisms involving pyroptosis. METHODS: The cerebral injury was established by middle cerebral artery occlusion (MCAO). in vitro ischemia in primary cultured astrocytes was induced by the oxygen-glucose deprivation (OGD). ELISA and Western Blot analysis were employed to the levels of PPAR-γ, pyroptosis-related biomarkers and cytoplasmic translocation of HMGB-1 and RAGE expression as well as Rac1 activity, respectively. RESULTS: We demonstrated that repeated intraperitoneal administration of pioglitazone remarkably reduced the infarct volume, improved neurological deficits and suppressed the Rac1 activity with significant reduction of excessive ROS in rat model of middle cerebral artery occlusion (MCAO). Moreover, pioglitazone alleviated the up-regulation of pyroptosis-related biomarkers and the increased cytoplasmic translocation of HMGB-1 and RAGE expression in cerebral penumbra cortex. Similarly, the protective effects of pioglitazone on cultured astrocytes were characterized by reduced Rac1 activity, pyroptosis related protein expressions and lactate dehydrogenase (LDH) release. However, these protective effects of pioglitazone were neutralized with the use of GW9662, a PPAR-γ inhibitor. Interestingly, Rac1 knockdown in lentivirus with the Rac1 small hair RNA (shRNA) could inhibit the OGD-induced pyroptosis of primary cultured astrocytes. Furthermore, the combination of Rac1-shRNA and pioglitazone can further strengthen the inhibitory effects on pyroptosis induced by OGD. CONCLUSION: The neuroprotection of pioglitazone was attributable to the alleviated ischemia/hypoxia-induced pyroptosis and was also associated with the PPARγ-mediated suppression of HGMB-1/RAGE signaling pathway. Moreover, the inhibition of Rac1 promoted this function.

[Perioperative safety of Tibetan children with congenital heart disease undergoing cardiac surgery and anesthesia in low-altitude area].

OBJECTIVE: To observe the clinical parameters and short-term prognosis of Tibetan high-altitude area children with congenital heart disease undergoing surgery and anaesthesia in low-altitude area, and to investigate the perioperative safety of the treatment.
 Methods: From January, 2016 to December, 2016, 14 children with congenital heart disease who underwent surgery were assigned into 2 groups (n=7 each): the high-altitude area group (X group, children from Tibetan Autonomous Region) and the low-altitude area group (H group, children from Hunan Province). Echocardiography data, perioperative hemodynamic changes, postoperative recovery, complication and perioperative serum N terminal pro B type natriuretic peptide (NT-proBNP) levels were recorded.
 Results: There were no significant differences in cardiac structure and function between the 2 groups, while the incidence of pulmonary hypertension in the X group was significantly higher than that in the H group (P<0.05). There were no significant differences in perioperative hemodynamics between the 2 groups (P>0.05), while the duration in ICU in the X group was longer than that in the H group and the serum NT-proBNP level in the X group was higher than that in the H group (P<0.05).
 Conclusion: For children with congenital heart disease in Tibetan high-altitude area, undergoing surgery in low-altitude area contributes to a steady perioperative hemodynamics and helps to increase the perioperative safety. There may be a higher risk of postoperative cardiac dysfunction in Tibetan children than that in low-altitude area.

5-HT receptors exert differential effects on seizure-induced respiratory arrest in DBA/1 mice.

Both clinical and animal studies demonstrated that seizure-induced respiratory arrest (S-IRA) contributes importantly to sudden unexpected death in epilepsy (SUDEP). It has been shown that enhancing serotonin (5-HT) function relieves S-IRA in animal models of SUDEP, including DBA/1 mice. Direct activation of 5-HT3 and 5-HT4 receptors suppresses S-IRA in DBA/1 mice, indicating that these receptors are involved in S-IRA. However, it remains unknown if other subtypes of 5-HT receptors are implicated in S-IRA in DBA/1 mice. In this study, we investigated the action of an agonist of the 5-HT1A (8-OH-DPAT), 5-HT2A (TCB-2), 5-HT2B (BW723C86), 5-HT2C (MK-212), 5-HT6 (WAY-208466) and 5-HT7 (LP-211) receptor on S-IRA in DBA/1 mice. An agonist of the 5-HT receptor or a vehicle was intraperitoneally administered 30 min prior to acoustic simulation, and the effect of each drug/vehicle on the incidence of S-IRA was videotaped for offline analysis. We found that the incidence of S-IRA was significantly reduced by TCB-2 at 10 mg/kg (30%, n = 10; p < 0.01, Fisher's exact test) but was not altered by other agonists compared with the corresponding vehicle controls in DBA/1 mice. Our data demonstrate that 5-HT2A receptors are implicated in S-IRA, and 5-HT1A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 receptors are not involved in S-IRA in DBA/1 mice.

Repeated neonatal isoflurane exposure facilitated stress-related fear extinction impairment in male mice and was associated with ΔFosB accumulation in the basolateral amygdala and the hippocampal dentate gyrus.

Volatile anesthetics elicit neurodevelopmental toxicity in rodents and primates and lead to more exaggerated anxiety-like behavior in response to future stress. Anxiety and fear are closely correlated and maladaptive fear-associated learning is regarded as the core mechanism underlying anxiety-related disorders. However, little is known about the interaction between early-life anesthetic exposure and future stress and the accompanying effect on fear-associated learning. In the present study, we evaluated the alterations in fear-associated learning (fear acquisition and extinction) occurring in mice receiving repeated neonatal isoflurane exposure and chronic variable stress (CVS) successively through a series of fear conditioning, fear reinforcing, and fear extinction paradigms. The corticosterone (CORT) response during CVS and the immunohistochemical levels of ΔFosB and c-Fos expression in the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG) after the extinction retrieval test were also investigated. The results showed that neonatal isoflurane exposure could increase CORT levels following the first diurnal CVS procedure, but not after completion of the whole CVS paradigm. Neonatal isoflurane exposure exerted a repressive effect on fear acquisition, in contrast to that seen with CVS. Neonatal isoflurane exposure and CVS both exerted suppressive effects on fear extinction and there was a significant synergy between them. Furthermore, neonatal isoflurane exposure facilitated CVS-mediated ΔFosB accumulation in the BLA and the hippocampal DG, which may have been responsible for c-Fos expression deficits and fear extinction impairment. Collectively, these findings contribute to the understanding of the interaction between early-life anesthetic exposure and future stress, as well as the accompanying behavioral alterations.

Microinjection of HSV-1 amplicon vector-mediated human proenkephalin into the periaqueductal grey attenuates neuropathic pain in rats.

We investigated the antinociceptive effect of microinjection of HSV-1 amplicon vector-mediated human proenkephalin (hPPE) into the ventral periaqueductal grey (PAG) on neuropathic pain in rats. Male Sprague-Dawley rats with chronic constriction injury (CCI)-induced neuropathic pain were microinjected into the ventral PAG with normal saline (NS), pHSVIRES-lacZ (SHZ), or HSV-1 amplicon vector pHSVIRES-hPPE-lacZ (SHPZ), respectively. Pain thresholds in the SHPZ-treated rats were significantly higher at day 3, then reached peak at day 14 and lasted until day 35 after PAG administration, and these effects were reversed by naloxone. In contrast, NS or SHZ-treated rats did not significantly affect pain thresholds. These results demonstrated that microinjection of HSV-1 amplicon vector-mediated hPPE into the ventral PAG attenuates neuropathic pain in rats.

Incidence and risk factors of intraoperative awareness during general anesthesia.

OBJECTIVE: To investigate the incidence of awareness during general anesthesia and analyze the risk factors in anesthetic practice and patient populations. METHODS: A total of 2 300 patients who underwent general anesthesia were included. Perioperative data and anesthetic drugs were collected prospectively. Patients were interviewed twice postoperatively with the same structured questionnaire. Each patient was classified into categories as no awareness, possible awareness, and awareness. RESULTS: Twenty-one patients (0.91%) definitely reported awareness, and another 205 (8.91%) reported possible awareness. Few of the patients with awareness required psychological intervention. ASA physical status III-IV and propofol maintenance were associated risk factors of awareness. CONCLUSION: The incidence of intraoperative awareness is high in the clinical practice in major medical centers.

PDTC ameliorates neuropathic pain by inhibiting microglial activation via blockage of the TNFα-CX3CR1 pathway.

Previous studies have suggested that pyrrolidine dithiocarbamate (PDTC), a nuclear factor κB (NF-κB) inhibitor, play a role in deterring nerve injury-induced neuropathic pain (NP) The activation of NF-κB pathway may contribute to spinal microglial activation, CX3CR1 and tumor necrosis factor-alpha (TNF-a) up-regulation. The aim of this study was to clarify whether PDTC could inhibit the development of neuropathic pain via decreasing TNF-a-induced CX3CR1 up-regulation. Sprague-Dawley rats were randomly divided into sham group and NP group. Rats in each group were treated with intrathecal infusion of PDTC (100 or 1000 pmol/d) or saline. The sciatic nerve chronic constriction injury (CCI) model was used to induce NP in rats. Mechanical stimuli and radiant heat were used to evaluate mechanical allodynia and thermal hyperalgesia. Spinal microglial marker OX42 and TNF-a were detected by immunohistochemistry. In vitro BV-2 microglia activation was induced by TNF-a incubation, and the levels of CX3CR1 were assessed by Western blot and reverse transcription-polymerase chain reaction. Pain behavior and immunohistochemistry results showed that intrathecal infusion of PDTC at 100 or 1000 pmol/d prevented the development of mechanical and thermal hyperalgesia, spinal microglial activation and TNF-a expression induced by sciatic nerve CCI in rats. In vitro experiment results showed that PDTC inhibited the TNF-a-induced CX3CR1 up-regulation in BV-2 microglial cells. In conclusion, intrathecal infusion of PDTC could attenuate the pain-related behaviors induced by sciatic nerve CCI through suppressing the spinal microglia activation and TNF-a up-regulation in rats. The NF-κB activation might be responsible for TNF-a-induced CX3CR1 up-regulation in microglia.

A network meta-analysis of the long- and short-term efficacy of sleep medicines in adults and older adults.

BACKGROUND: This study focuses on seven commonly used hypnotics to comprehensively analyze the effects of long- and short-term use on sleep outcomes among adults and older adults. METHODS: A network meta-analysis was performed. The insomnia medications were classified into seven categories: benzodiazepines, z-drugs, melatonin, H1-antagonists, orexin receptor antagonists (ORAs), antidepressants, and anticonvulsants. We compared their efficacy of total sleep time, sleep latency, sleep efficiency and wake after sleep onset in subgroups short-term, long-term, elderly, and adults. RESULTS: A total of 111 RCTs involving 25,923 participants were included in this study. CONCLUSIONS: ORAs can be widely used in adults and the elderly, and both short-term and long-term use are effective for primary insomnia. H1-antagonists are more effective in adults than in the elderly. Although benzodiazepines have a more obvious effect on sleep maintenance, it is best to reduce their use due to their side effects, especially for the elderly. As a food supplement, melatonin has little effect on adults, but it still has a certain effect on the elderly.

PPAR γ Prevents Neuropathic Pain by Down-Regulating CX3CR1 and Attenuating M1 Activation of Microglia in the Spinal Cord of Rats Using a Sciatic Chronic Constriction Injury Model.

BACKGROUND: Previous studies have proved that peripheral nerve injury is involved in the pathogenesis of neuropathic pain (NP). The peripheral nerve injury primes spinal M1 microglia phenotype and produces pro-inflammatory cytokines, which are responsible for neurotoxic and neuronal hyper-excitable outcomes. Spinal peroxisome proliferator-activated receptor gamma (PPAR γ) has been shown to play an anti-inflammatory role in the development of NP. However, the role of PPAR γ in attenuating the pathological pathway of spinal microgliosis is still unknown. METHODS: Sprague-Dawley rats (male, aged 8-10 weeks) were randomly divided into three groups, i.e., a control group, a NP group, and a NP + lentivirus encoding PPAR γ (LV-PPAR γ) group. The sciatic chronic constriction injury (CCI) model was used to induce NP in rats. Pain behavior was assessed by monitoring the rat hind-paw withdrawal threshold to mechanical stimuli and withdrawal latency to radiant heat. The LV-PPAR γ was intrathecally infused 1 day before CCI. Western blot analysis and real-time qPCR were used to detect the microglia phenotypic molecules and CX3CR1 expression in the spinal cord. In vitro, BV-2 microglia cells were transfected with LV-PPAR γ and incubated with lipopolysaccharides (LPS), and the levels of M1 microglia phenotypic molecules and CX3CR1 in BV-2 microglia cells were assessed by western blot analysis, real-time qPCR, and enzyme-linked immunosorbent assay. RESULTS: Preoperative intrathecal infusion of LV-PPAR γ attenuated pain in rats 7 days post-CCI. The M1-microglia marker, CX3CR1, and pro-inflammatory signaling factors were increased in the spinal cord of CCI rats, while the preoperative intrathecal infusion of LV-PPAR γ attenuated these changes and increased the expression of IL-10. In vitro, the overexpression of PPAR γ in BV-2 cells reduced LPS-induced M1 microglia polarization and the levels of CX3CR1 and pro-inflammatory cytokines. CONCLUSION: Intrathecal infusion of LV-PPAR γ exerts a protective effect on the development of NP induced by CCI in rats. The overexpression of PPAR γ may produce both analgesic and anti-inflammatory effects due to inhibition of the M1 phenotype and CX3CR1 signaling pathway in spinal microglia.

[Regulation of inflammatory pain by NF-κB and CX3CR1 at the spinal cord of rats].

OBJECTIVE: To observe the effect of intrathecal injection of nuclear factor-κB (NF-κB) inhibitor of pyrrolidine dithiocarbamate (PDTC) on pain sensitivity thresholds and the expression of spinal cord CX3C chemokine receptor 1 (CX3CR1) in monoarthritis (MA) model in rats. METHODS: Forty-eight Sprague-Dawley rats were randomly divided into 4 groups (12 each) after successful intrathecal catheterization: (1) sham operation with physiological saline group (the sham group); (2) MA with normal saline group (the MA group); (3) 10 µL 100 µmol/L PDTC before MA (the PDTC pre-treatment group); (4)MA before 10 µL 100 µmol/L PDTC (the PDTC post-treatment group). Normal saline or PDTC was injected 5 d after the intrathecal catheterization. Pain sensitivity thresholds were measured in the 4 groups before and after the intrathecal injection at different time points. Rat monoarthritis model was subsequently built by injecting complete Freund's adjuvant (CFA) into the left ankle joint of the rats. On day 3 after the intrathecal injection, expression of microglia in the L5 spinal cord segment was observed by immunohistochemical method, and the lumbar segments L4-L5 of spinal cord were taken to perform RT-PCR to examine the expression of NF-κB mRNA and CX3CR1 mRNA. RESULTS: Compared with the MA group, the pain sensitivity thresholds in the sham group, the PDTC pre-treatment group and the PDTC post-treatment group at each time point after the intrathecal injection increased significantly (P<0.05), while microglia in the L5 spinal cord segment decreased significantly (P<0.05) and expression of CX3CR1 mRNA and NF-κB mRNA in the lumbar segments L4-L5 of spinal cord decreased significantly (P<0.05). CONCLUSION: The hyperalgesic effect of the CFA-induced model of monoarthritis can be relieved by intrathecal injection of NF-κB inhibitor PDTC. Its mechanism is possibly related to NF-κB signal pathway which is involved in the formation of inflammatory pain through regulating CX3CR1 expression.

[Sevoflurane preconditioning induced delayed neuroprotection against focal cerebral ischemia in rats].

OBJECTIVE: To investigate whether the reactive oxygen species (ROS) and mitochondrial ATP-sensitive potassium (mitoKATP) channels were involved in delayed neuroprotection induced by sevoflurane on tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels. METHODS: Eighty-four male SD rats weighing 250 approximately 280 g, undergoing thread embolism of the right middle cerebral artery occlusion (MCAO) to cause focal ischemia for 2 h and then undergoing 24 h reperfusion, were randomly divided into 7 groups (n=12, each): a sham group(S), an ischemia-reperfusion group (I/R), a sevoflurane preconditioning group (Sevo), a 2-mercaptopropionylglycine (ROS scavenger)+sevoflurane group (MPG+Sevo), a 5-hydroxydecanoate (a mitoK(ATP) blocker) + sevoflurane group (5-HD+Sevo), an MPG group, and a 5-HD group. The protein level of TNF-alpha and IL-1beta in the cerebral issue was detected by enzyme linked immunosorbent assay (ELISA) and the expression of mRNA was measured by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Apoptosis index (AI), the protein level and the mRNA expression of TNF-alpha and IL-1beta were significantly higher in the I/R group than those of Group S. Pre-administration of sevoflurane could inhibit the increase of the protein level and the expression of mRNA of TNF-alpha, and IL-1beta and attenuate the cerebral damage induced by ischemia-reperfusion. Neuroprotection of sevoflurane preconditioning was abolished by MPG and 5-HD. However, MPG and 5-HD alone had no effect. CONCLUSION: Sevoflurane can produce delayed protection against cerebral ischemia-reperfusion injury by down-regulating TNF-alpha, IL-1beta protein, and mRNA expression.

Inhibition of Rac1 ameliorates neuronal oxidative stress damage via reducing Bcl-2/Rac1 complex formation in mitochondria through PI3K/Akt/mTOR pathway.

Although the neuroprotective effects of Rac1 inhibition have been reported in various cerebral ischemic models, the molecular mechanisms of action have not yet been fully elucidated. In this study, we investigated whether the inhibition of Rac1 provided neuroprotection in a diabetic rat model of focal cerebral ischemia and hyperglycemia-exposed PC-12 cells. Intracerebroventricular administration of lentivirus expressing the Rac1 small hairpin RNA (shRNA) and specific Rac1 inhibitor NSC23766 not only decreased the infarct volumes and improved neurologic deficits with a correlated significant activation of mitochondrial DNA specific proteins, such as OGG1 and POLG, but also elevated Bcl-2 S70 phosphorylation in mitochondria. Furthermore, the levels of p-PI3K, p-Akt and p-mTOR increased, while 8-OHdG, ROS production and Bcl-2/Rac1 complex formation in mitochondria reduced in both Rac1-shRNA- and NSC23766-treated rats. Moreover, to confirm our in vivo observations, inhibition of Rac1 activity by NSC23766 suppressed the interactions between Bcl-2 and Rac1 in the mitochondria of PC-12 cells cultured in high glucose conditions and protected PC-12 cells from high glucose-induced neurotoxicity. More importantly, these beneficial effects of Rac1 inhibition were abolished by PI3K inhibitor LY294002. In contrast to NSC23766 treatment, LY294002 had little effect on the decrement of p-PTEN level. Taken together, these findings revealed novel neuroprotective roles of Rac1 inhibition against cerebral ischemic reperfusion injury in vivo and high glucose-induced neurotoxicity in PC-12 cells in vitro, by reducing Bcl-2/Rac1 complex formation in mitochondria through the activation of PI3K/Akt/mTOR survival pathway.

Identification of lncRNA expression profiles and ceRNA analysis in the spinal cord of morphine-tolerant rats.

Morphine tolerance is a challenging clinical problem that limits the use of morphine in pain treatment, but the mechanisms of morphine tolerance remain unclear. Recent research indicates that long noncoding RNAs (lncRNAs) might be a novel and promising target in the pathogeneses of diseases. Therefore, we hypothesized that lncRNAs might play a role in the development of morphine tolerance. Male Sprague-Dawley rats were intrathecally injected with 10 µg morphine twice daily for 7 consecutive days. The animals were then sacrificed for lncRNA microarray tests, and the results were validated by RT-qPCR. Next, functional predictions for the differentially expressed mRNAs (DEmRNAs) were made with the Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG), and predictions for the differentially expressed lncRNAs (DElncRNAs) were made based on competitive endogenous RNA (ceRNA) analyses. The rats successfully developed morphine tolerance. LncRNA microarray analysis revealed that, according to the criteria of a log2 (fold change) > 1.5 and a P-value < 0.05, 136 lncRNAs and 278 mRNAs were differentially expressed in the morphine tolerance group (MT) compared with the normal saline group (NS). The functions of the DEmRNAs likely involve in the processes of the ion channel transport, pain transmission and immune response. The ceRNA analysis indicated that several possible interacting networks existed, including (MRAK150340, MRAK161211)/miR-219b/Tollip.Further annotations of the potential target mRNAs of the miRNAs according to the gene database suggested that the possible functions of these mRNAs primarily involved the regulation of ubiquitylation, G protein-linked receptors, and Toll-like receptors, which play roles in the development of morphine tolerance. Our findings revealed the profiles of differentially expressed lncRNAs in morphine tolerance conditions, and among these lncRNAs, some DElncRNAs might be new therapeutic targets for morphine tolerance.

Suppression of HDAC2 in Spinal Cord Alleviates Mechanical Hyperalgesia and Restores KCC2 Expression in a Rat Model of Bone Cancer Pain.

Epigenetic modulation participates in the mechanism of multiple types of pathological pain, so targeting the involved regulators may be a promising strategy for pain treatment. Our previous research identified the analgesic effect of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on mechanical hyperalgesia in a rat model of bone cancer pain (BCP) via restoration of µ-opioid receptor (MOR) expression. However, the specific types of HDACs contributing to BCP have not been explored. The present study investigated the expression pattern of some common HDACs and found that HDAC2 was up-regulated in a time-dependent manner in the lumbar spinal cord of BCP rats. TSA application suppressed HDAC2 expression in cultured PC12 cells and reversed the augmented HDAC2 in BCP rats. An RNA-interfering strategy confirmed the essential role of HDAC2 in the modulation of mechanical hyperalgesia following tumor cell inoculation, and we further examined its possible downstream targets. Notably, HDAC2 knock-down did not restore MOR expression, but it robustly reversed the down-regulation of potassium-chloride cotransporter 2 (KCC2). The impaired KCC2 expression is a vital mechanism of many types of pathological pain. Therefore, our results demonstrated that HDAC2 in spinal cord contributed to the mechanical hyperalgesia in BCP rats, and this effect may be associated with KCC2 modulation.

Sevoflurane inhibits cardiac function in pulmonary fibrosis mice through the TLR4 signaling pathway.

Pulmonary fibrosis is often concomitant with myocardial injury. We studied sevoflurane's effects on cardiac function and the expression of the TLR4/inducible nitric oxide synthase (iNOS) signaling pathway on a pulmonary fibrosis model. C57BL/6J wild-type (WT) and TLR4-deficient (TLR4-/-) mice were randomly divided into a control group and a pulmonary fibrosis group. The model of pulmonary fibrosis was induced by treatment with paraquat (PQ; 20 mg/kg). Four weeks after PQ administration, mice were tested for body weight changes, and histopathology and hydroxyproline in lung. Left ventricular function in each group of mice was measured by echocardiogram before and after sevoflurane inhalation. The expression of TLR4 and iNOS protein were analyzed. Pulmonary fibrosis mice were fed lenalidomide (50 mg/kg/day) for three days and cardiac function was assessed before and after sevoflurane inhalation. WT pulmonary fibrosis mice showed pathological damage and excessive deposition of collagen in the lung and heart. Left ventricular function decreased after four weeks of PQ exposure. TLR4-/- mice were resistant to pulmonary fibrosis like pathological damage and the effect of sevoflurane on heart rate and ejection fraction than that of WT mice. TLR4 and iNOS expression in WT pulmonary fibrosis mice increased significantly after sevoflurane inhalation. Lenalidomide treatment alleviated the effect of sevoflurane on heart rate and ejection fraction in WT pulmonary fibrosis mice. Sevoflurane inhibits cardiac function in pulmonary fibrosis mice through the TLR4/iNOS pathway. Lenalidomide attenuated the sevoflurane's effect on the cardiac function of mice with pulmonary fibrosis.

Enhanced recovery after surgery pathway for patients undergoing cardiac surgery: a randomized clinical trial.

OBJECTIVES: Enhanced recovery after surgery (ERAS) pathways have not been reported in cardiac surgery. The aim of this study was to evaluate the clinical effectiveness and safety profile of ERAS pathways compared with routine care for patients undergoing cardiac valvular surgery. METHODS: A randomized clinical trial was conducted between July 2015 and November 2016. A total of 226 patients who underwent elective valvular surgery were randomly assigned to the ERAS pathway or routine care (control) group. The ERAS protocol consisted of an evidence-based systematic optimization approach for managing perioperative patients. The control group received routine care. The primary end-point was readiness for hospital discharge. The secondary outcomes were duration of intensive care unit (ICU) stay, length of postoperative vasoactive drug support, duration of mechanical ventilation, time to first bowel movement, removal of surgical drain, overall medical costs and complication rate. RESULTS: Postoperative time to readiness for discharge was significantly shorter in the ERAS group (6.0 (2.0∼14.0) days) than the control group (7.0 (4.0∼16.0) days, P = 0.01), and the duration of ICU stay and duration of mechanical ventilation were significantly shorter in the ERAS group (20.9 (13.5∼69.3) h, 7.2 (0.0∼22.3) h, respectively) than the control group (22.0 (13.4∼212.3) h, P = 0.001; 8.8 (3.7∼44.9) h, respectively; P < 0.0001). The overall treatment cost of the ERAS group (69202 (52089∼123823) CNY) was significantly lower than that of the control group (77058 (51390∼144290) CNY, P = 0.002). CONCLUSIONS: ERAS pathways reduce the length of ICU and hospital stay, postoperative complications and cost for patients undergoing cardiac surgery. Clinical trial registration: ClinicalTrials.gov: NCT02479581.

[Cerebral state index the in monitoring and evaluating the induction of anesthesia with target-controlled infusion of propofol in adults].

OBJECTIVE: To evaluate the accuracy of cerebral state index (CSI) as an indicator of anesthesia depth in patients in the induction of anesthesia with target-controlled infusion of propofol. METHODS: Forty ASA (American Society of Anesthesiologists) I approximately II patients scheduled for an operation under general anesthesia were anesthetized with target-controlled infusion of propofol. Target plasma concentration was 0. 5 mg/L at the beginning, and increased by 0. 5 mg/L every 5 minutes, till 5 minutes after the level of MOAA/S (modified observer's assessment of alertness/sedation) was 0. The CSI, mean arterial pressure (MAP), heart rate (HR), MOAA/S level, and the effect-site concentration of propofol were recorded. RESULTS: (1) CSI values declined with the decrease of MOAA/S levels. CSI values were statistically different between level 0 and 1, level 1 and 2, level 3 and 4, level 4 and 5 of MOAA/S (P < 0.05). The difference of MAP had statistical significance between level 3 and level 2 of MOAA/S (P < 0.05). HR values had no statistical difference between the two levels of MOAA/S (P > 0.05). (2) The spearman rank correlation co-efficients between CSI, MAP, HR and the level of MOAA/S were 0.929, 0.421, and 0.085, respectively. The prediction probabilities (Pk) to differentiate different levels of MOAA/S for CSI, MAP, and HR were 0.94, 0.67, and 0.54, respectively. (3) There was linear regression relationship between CSI and the effect-site concentration of propofol (the coefficient of determination R2 was 0. 833, P < 0.01). CONCLUSION: During the induction of patients with target-controlled infusion of propofol, the CSI is accurate as an indicator of awakeness and different levels of consciousness after anesthesia, and can reliably predict the anesthesia depth.

[Bispectral index, cerebral state index and the predicted effect-site concentration at different clinical end-points during target-controlled infusion of propofol].

OBJECTIVE: To examine the predicted effect-site concentration of propofol at two clinical end-points: loss of verbal contact (LVC) and loss of consciousness (LOC), and to explore the relationship between bispectral index (BIS) values, cerebral state index (CSI) values and the predicted effect-site concentration during the target-controlled infusion of propofol. METHODS: In 20 patients during the target-controlled infusion of propofol, the propofol infusion was set at an initial effect-site concentration of 0.5 mg/L, and increased by 0.5 mg/L every 5 min until 5 min after the modified observer's assessment of alertness/sedation scale (OAA/S) values reached zero. The predicted effect-site concentration of propofol, the values of CSI and BIS were recorded, and the sedation level was examined by the modified OAA/S every 20s. The predicted effect-site concentrations of propofol in target-controlled infusion (TCI) system were recorded when they increased by more than 0.1 mg/L. The predicted effect-site concentrations of propofol and the values of BIS and CSI at LVC and LOC in 5%, 50% and 95% of the patients were calculated. RESULTS: There was good linearity between BIS and the predicted effect-site concentration of propofol (R(2)=0.787), as well as between CSI and the predicted effect-site concentration of propofol (R(2)=0.792). The predicted effect-site concentrations of propofol at LVC in 5%, 50% and 95% of the patients were 1.1,1.8 and 2.4 mg/L, respectively. The values of BIS and CSI at LVC in 5%, 50% and 95% of the patients were 79.2, 69.2 and 59.2; 74.9, 65.9 and 56.8, respectively. The predicted effect-site concentrations of propofol at LOC in 5%, 50% and 95% of the patients were 1.5, 2.5 and 3.4 mg/L, respectively. At LOC, the values of BIS and CSI in 5%, 50% and 95% of the patient were 73.6, 57.1 and 40.6; 65.2, 54.8 and 44.3, respectively. CONCLUSION: During target-controlled infusion of propofol, LVC and LOC occur within a definite range of predicted effect-site concentrations. There is the good linearity between BIS, CSI and the predicted effect-site concentrations of propofol. CSI may be more useful than BIS in predicting LVC and LOC.