Understanding the Neural Mechanisms of General Anesthesia from Interaction with Sleep-Wake State: A Decade of Discovery.

The development of cutting-edge techniques to study specific brain regions and neural circuits that regulate sleep-wake brain states and general anesthesia (GA), has increased our understanding of these states that exhibit similar neurophysiologic traits. This review summarizes current knowledge focusing on cell subtypes and neural circuits that control wakefulness, rapid eye movement (REM) sleep, non-REM sleep, and GA. We also review novel insights into their interactions and raise unresolved questions and challenges in this field. Comparisons of the overlapping neural substrates of sleep-wake and GA regulation will help us to understand sleep-wake transitions and how anesthetics cause reversible loss of consciousness. SIGNIFICANCE STATEMENT: General anesthesia (GA), sharing numerous neurophysiologic traits with the process of natural sleep, is administered to millions of surgical patients annually. In the past decade, studies exploring the neural mechanisms underlying sleep-wake and GA have advanced our understanding of their interactions and how anesthetics cause reversible loss of consciousness. Pharmacotherapies targeting the neural substrates associated with sleep-wake and GA regulations have significance for clinical practice in GA and sleep medicine.

Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer.

Morphine, a mu-opioid receptor (MOR) agonist, has been extensively used to treat advanced cancer pain. In particular, in patients with cancer metastasis, both morphine and anticancer drugs are given simultaneously. However, evidence showed that morphine might be a risk factor in promoting the tumor's malignant potential. In this study, we report that treatment with morphine could activate MOR and lead to the promotion of proliferation, migration, and invasion in HCT116 and DLD1 colorectal cancer (CRC) cells with time-concentration dependence. Moreover, morphine can also contribute to cetuximab's drug resistance, a targeted drug widely used to treat advanced CRC by inducing the activation of epidermal growth factor receptor (EGFR). The cell phenotype includes proliferation, migration, invasion, and drug resistance, which may be reversed by MOR knockdown or adding nalmefene, the MOR receptor antagonist. Receptor tyrosine kinase array analysis revealed that morphine selectively induced the transactivation of EGFR. EGFR transactivation resulted in the activation of ERK1/2 and AKT. In conclusion, morphine induces the transactivation of EGFR via MOR. It activates the downstream signal pathway AKT-MTOR and RAS-MAPK, increases proliferation, migration, and invasion, and promotes resistance to EGFR inhibitors in a CRC cell line. Furthermore, we verified that EGFR inhibition by cetuximab strongly reversed the protumoral effects of morphine in vitro and in vivo. Collectively, we provide evidence that morphine-EGFR signaling might be a promising therapeutic target for CRC patients, especially for cetuximab-resistant CRC patients.

Pain management after ambulatory surgery: a prospective, multicenter, randomized, double-blinded parallel controlled trial comparing nalbuphine and tramadol.

BACKGROUND: Postoperative pain in ambulatory surgery is a multifactorial issue affecting patient satisfaction, time of discharge, and rehospitalization. This study evaluated the efficacy and safety of nalbuphine for the treatment of postoperative pain after ambulatory surgery, relative to tramadol. METHODS: This multi-center, randomized, double blind, and controlled study was conducted at 10 centers. In accordance with the inclusion criteria, 492 ambulatory surgery patients were recruited. These patients had moderate to severe pain after ambulatory surgery, with a visual analogue scale (VAS) score > 3 cm. They were randomly divided into an experimental (n = 248) or control (n = 244) group and treated for analgesia with 0.2 mg/kg of nalbuphine or 2 mg/kg of tramadol, respectively. VAS scores, adverse events, and vital signs of the patients were recorded before administration (baseline; T1); and 30 min (T2), 2 h (T3), 4 h (T4), and 6 h (T5) after administration of analgesia. A decrease in pain intensity of more than 25% compared with the baseline was used as an indicator of analgesic efficacy. The experimental and control groups were compared with regard to this indicator of efficacy at each timepoint. RESULTS: The VAS scores of the experimental and control groups were statistically comparable at timepoints T1-T4. At T5, the VAS scores of the experimental group were significantly lower than that of the control. The pain intensity was significantly higher in the experimental group compared with the control at T2 and T3. Adverse events and vital signs were similar for the two groups at each timepoint. CONCLUSIONS: Nalbuphine can provide effective and safe pain relief in patients after ambulatory surgery. TRIAL REGISTRATION: The registration number is ChiCTR-IOR-16010032 , the date of registration was 2016-11-28.

Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca2+/CAMK II/ERK/NF-κB signaling pathway.

Metalloproteinase 9 (MMP-9) is able to degrade collagen IV, an important component of blood-brain barrier (BBB). Expression of MMPs, especially MMP-9, correlates with BBB disruption during central nervous system inflammation. Propofol has been reported to have anti-inflammation effects. In this study, we investigated the effects of propofol on TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells (hCMEC/D3 cells) and explored the underlying mechanisms. The hCMEC/D3 cells were treated with propofol (25 µM), followed by TNF-α (25 ng/mL). We showed that TNF-α treatment markedly increased MMP-9 expression and decreased collagen IV expression in hCMEC/D3 cells, which was blocked by pretreatment with propofol. TNF-α-induced downregulation of collagen IV was also reversed by MMP-9 knockdown with siRNA. We revealed that TNF-α upregulated MMP-9 expression in hCMEC/D3 cells through activation of Ca2+/CAMK II/ERK/NF-κB signaling pathway; co-treatment with inhibitors of CaMK II (KN93), ERK (LY3214996), NF-κB (PDTC) or Ca2+chelator (BAPTA-AM) abrogated the effect of TNF-α on MMP-9 expression. We further established an in vitro BBB model by co-culturing of hCMEC/D3 cells and human astrocytes for 6 days and measuring trans-endothelial electrical resistance (TEER) to reflect the BBB permeability. TNF-α treatment markedly decreased TEER value, which was attenuated by pretreatment with propofol (25 µM) or MMP-9 knockdown with siRNA. In conclusion, propofol inhibits TNF-α-induced MMP-9 expression in hCMEC/D3 cells via repressing the Ca2+/CAMKII/ERK/NF-κB signaling pathway. TNF-α-impaired BBB integrity could be reversed by propofol, and propofol attenuates the inhibitory effect of TNF-α on collagen IV.

General anesthesia combined with epidural anesthesia ameliorates the effect of fast-track surgery by mitigating immunosuppression and facilitating intestinal functional recovery in colon cancer patients.

PURPOSE: The purpose of this study is to investigate the influence of anesthetic methods on markers of anti-tumor immunity and intestinal functions in fast-track surgery in colon cancer (CC) patients during the perioperative period. PATIENTS AND METHODS: A total of 53 patients with American Society of Anesthesiologists (ASA) I-II status randomly received general anesthesia (G group, n = 27) or general anesthesia combined with epidural anesthesia (E group, n = 26) for surgical tumor resection. The recovery times of intestinal function were evaluated in both groups postoperatively. The frequencies of different subsets of CD4+ T cells and myeloid-derived suppressor cells and C-reactive protein (CRP) were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively, before anesthesia (t0), 1 h after the beginning of surgery (t1), 1 h after the end of surgery (t2), and on day 2 (t3) and day 5 (t4) post-surgery. RESULTS: There was no significant difference in demographic characteristics between the two groups, but the E group of patients received significantly lower amounts of morphine and sevoflurane. In comparison with those in the G group, significantly greater numbers of lymphocytes and elevated frequencies of Th1 cells were detected at t3 and t4 post-surgery in the E group (p < 0.01). Significantly lower percentages of Th2 cells and regulatory T cells were detected in the E group at t2-4 post-surgery. Whereas the levels of plasma CRP increased post-surgery in both groups, the levels of CRP were significantly lower in the E group than those in the G group at t3-4 post-surgery (p < 0.05). The times to the first flatus and to tolerate a full diet were significantly shorter in the E group than those in the G group (p < 0.01). CONCLUSION: General anesthesia combined with epidural anesthesia plays an important role in fast-track surgery, mitigating the surgical stress-related impairment of anti-tumor immune responses and hastening the recovery of intestinal function. This combination might also help to improve long-term outcomes for CC patients.

Dexmedetomidine renders a brain protection on hippocampal formation through inhibition of nNOS-NO signalling in endotoxin-induced shock rats.

BACKGROUND: Endotoxin shock (ES) and its severe complications, such as brain injury, remain a handicap clinically. Therefore, it is a clinical significance of developing a new drug to treat brain damage induced by ES. AIM: The present study aimed to observe the protective effect of dexmedetomidine (Dex) on hippocampal formation in endotoxin-induced shock rats and explore its possible mechanism. METHODS: High and low doses of Dex were tail intravenously administered slowly. After a 5-minute interval, lipopolysaccharide was tail intravenous injected slowly to establish the ES rats. Six hours after Dex administration, these rats were immediately sacrificed. Then, the brain water content was determined. NO amounts in homogenate, cerebrospinal fluid and serum were detected by Griess Reagent assay. nNOS mRNA in hippocampal formation was measured by RT-PCR and nNOS protein was determined by Western blotting and immunohistochemistry. RESULTS: ES rats showed that cerebral water contents were significantly increased, NO concentrations in brain tissues, serum and cerebrospinal fluid were each obviously raised and meanwhile expressions of nNOS mRNA and its protein in hippocampal formation were notably augmented. Treatment of these rats with Dex evidently decreased cerebral water contents, NO concentrations and nNOS mRNA and its protein expressions. CONCLUSION: These results demonstrated that Dex exerted a brain protection on hippocampal formation through inhibition of the nNOS-NO signalling in ES rats and Dex may have a favourably therapeutic value in treating brain damage in patients with endotoxin shock.

Efficacy and safety of patient-controlled epidural analgesia versus patient-controlled intravenous analgesia following open hepatectomy: A single-center retrospective study.

Background: Postoperative analgesia is an essential component of enhanced recovery after surgery following abdominal surgery. Studies comparing the effectiveness of epidural analgesia with that of other analgesic modalities after liver surgery have reported inconsistent results. Consequently, the use of epidural analgesia for open hepatectomy is controversial. Objective: The present single-center retrospective study aimed to compare the efficacy and safety of patient-controlled epidural analgesia (PCEA) and patient-controlled intravenous analgesia (PCIA) in adults undergoing open hepatectomy. Methods: Patients who underwent open hepatectomy between January 2018 to December 2019 at Zhongshan Hospital, Fudan University were retrospectively analyzed. Propensity score matching was used to adjust baseline information between the PCEA and PCIA groups. The primary outcome measure was scores of the numeric rating scales (NRSs) for resting, exercise, and nocturnal pain at postoperative 24 h (postoperative day 1 [POD1]) and 48 h (POD2). The secondary outcome indicators included postoperative nausea and vomiting (PONV), hypotension, pruritus, respiratory depression, functional activity score (FAS), effective analgesic pump compression ratio, analgesic relief rate, discontinuation of the analgesic pump, reasons for discontinuation of the analgesic pump, and patient satisfaction with postoperative analgesia. Results: The NRS scores of the PCEA group on POD1 were significantly lower than those of the PCIA group (P < 0.05). On POD2, the difference between the two groups was significant only for motion NRS scores (P < 0.05). The PCIA group had significantly more patients with lower FAS functional class than the PCEA group (P < 0.001). The effective analgesic pump compression ratio and the analgesic relief rate at 2 days after the surgery were lower in the PCEA group than in the PCIA group (P < 0.001). The incidence of pump discontinuation was higher in the PCEA group than in the PCIA group on POD2 (P = 0.044). Moreover, on POD1 and POD2, the PCEA group showed a higher incidence of pruritus and hypotension than the PCIA group (P < 0.001). Both groups showed no significant difference in PONV incidence. Conclusion: In patients undergoing open hepatectomy, PCEA was more effective than PCIA in relieving moderate to severe pain on POD1. However, improving the safety and effectiveness of PCEA remains a challenge.

Individualized positive end-expiratory pressure with and without recruitment maneuvers in obese patients during bariatric surgery.

This study aimed to determine whether regular recruitment maneuvers (RMs) are essential for obese patients (OPs) undergoing elective laparoscopic bariatric surgery (LBS) during intraoperative ventilation with individualized positive end-expiratory pressure (PEEP). Patients were randomly assigned to two arms: the RM + PEEP-EIT arm consisted of individualized PEEP titrated by electrical impedance tomography (EIT) with two regular RMs and the PEEP-EIT arm consisted of individualized PEEP titrated by EIT without additional RMs. For these two arms together, EIT-guided PEEP varied among individuals. The partial pressure of oxygen in arterial blood to fractional inspired oxygen (PaO2 /FiO2 ) ratio in the RM + PEEP-EIT arm was higher than that in the PEEP-EIT arm at 1 h after pneumoperitoneum (p = 0.024) and at the end of surgery (p = 0.035). There was no great difference in the PaO2 /FiO2 ratio between these two arms when measured 5 min prior to postanesthesia care unit (PACU) departure and on postoperative day 1. Compared with the PEEP-EIT arm, patients in the RM + PEEP-EIT arm had significantly higher intraoperative dynamic respiratory system compliance (p < 0.001) but consumed more vasopressors (p = 0.036). Postoperative pulmonary complications occurred in 1 of 29 patients in the RM + PEEP-EIT arm compared with 2 of 31 patients in the PEEP-EIT arm. Regular lung RMs can improve intraoperative oxygenation and respiratory system compliance among OPs undergoing LBS with EIT-guided individual PEEP. However, the improvement might disappear before leaving the PACU, and regular RMs resulted in more vasopressor consumption.

Dexmedetomidine Preserves Activity of Neurons in Primary Somatosensory Cortex Compared to Propofol and Ketamine.

General anesthesia has been shown to induce significant changes in the functional connectivity of the cerebral cortex. However, traditional methods such as electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) lack the spatial resolution to study the effects of general anesthesia on individual cortical neurons. This study aimed to use high-resolution two-photon imaging, which can provide single-neuron resolution, to investigate the characteristics of consciousness under general anesthesia. We used C57BL/6J and Thy1-GCamp6s mice and found that at similar levels of sedation, as measured by EEG, dexmedetomidine did not significantly inhibit the spontaneous activity of neuronal somata in the S1 cortex, but preserved the frequency of calcium events in neuronal spines. In contrast, propofol and ketamine dramatically inhibited the spontaneous activity of both neuronal somata and spines. The S1 cortex still responded to whisker stimulation under dexmedetomidine anesthesia, but not under propofol or ketamine anesthesia. Our results suggest that dexmedetomidine anesthesia has unique neuronal properties associated with its ability to facilitate easy awakening in the clinic. These findings provide insights into the development of more effective strategies for monitoring consciousness during general anesthesia.

[Effects of isoflurane, sevoflurane and desflurane on expression of ICAM-1 and VCAM-1 in LPS-induced rat lung microvascular endothelial cells].

OBJECTIVE: To investigate the effect of isoflurane, sevoflurane and desflurane on the expression of ICAM-1 and VCAM-1 in LPS-induced rat lung microvascular endothelial cells (RLMVECs). METHODS: Cultured LPS-treated RLMVECs were exposed to 0.7, 1.0 or 2.0 minimum alveolar concentration (MAC) iosoflurane, sevoflurane or desflurane in 6 h. The protein expression of ICAM-1 and VCAM-1 was determined by Western blot analysis. The expression of ICAM-1 mRNA was detected by reverse-transcription polymerase chain reaction (RT-PCR). RESULT: Isoflurane at concentration of 1.0 MAC up-regulated the expression of ICAM-1 in LPS-induced RLMVECs (P <0.05); while same concentrations of sevoflurane and desflurane down-regulated the expression of ICAM-1 (P<0.05). Desflurane at concentration of 2.0 MAC up-regulated the expression of ICAM-1 in non-LPS-induced RLMVECs. All the volatile anesthetics down-regulated the expression of VCAM-1 in a dose-dependent manner. CONCLUSION: Compared to isoflurane, 1.0 MAC sevoflurane and desflurane down-regulate the expression of ICAM-1, which may be the molecule mechanism of their protective effect in acute lung injury.

Dezocine regulates the malignant potential and aerobic glycolysis of liver cancer targeting Akt1/GSK-3ß pathway.

BACKGROUND: Due to the "ceiling effect" of respiratory depression and the non-addictiveness, the consumption of dezocine is increasing quickly in the cancer surgery perioperative period for security and comfort reasons in China. Former studies find dezocine inhibits the norepinephrine transporters (NET) and serotonin transporters (SERT) and sigma-1opioid receptors. Given the complexity of the molecular mechanism, the effect of dezocine on tumor cells need to be studied. In this study, we investigated the effect of dezocine on HepG2 and Hep 3B liver cancer cell lines growth and glycolysis, and the molecular mechanisms behind. METHODS: HepG2 and Hep 3B cells viability and migration were measured by CCK8, Wound healing and transwell assay, Extracellular acidification rate (ECAR) was used to index the aerobic glycolysis of liver cancer cells and western blot analysis showed protein expression levels in the cells. SC79, an agonist of Akt, and the siRNA silence of Akt1 aimed to regulate Akt1 activity and expression in the reverse experiments. RESULTS: Dezocine played opposite roles in HepG2 and Hep 3B cells viability and migration in a concentration-dependent manner (P<0.01). Dezocine has diverse effects on aerobic glycolysis and adjusts the serine/threonine kinase 1 (Akt1)-glycogen synthase kinase-3ß (GSK-3ß) pathway. The effects of SC79 and the siRNA silence of Akt1 could reverse the effects of dezocine on HepG2 and Hep 3B cells. CONCLUSIONS: As an analgesic drug widely used in clinical practice, dezocine play reversed roles on HepG2 and Hep 3B cells viability and migration targeting Akt1/GSK-3ß pathway then the glycolysis in a concentration-dependent manner.

Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression.

Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.

Propofol improved hypoxia-impaired integrity of blood-brain barrier via modulating the expression and phosphorylation of zonula occludens-1.

AIMS: Hypoxia may damage blood-brain barrier (BBB). The neuroprotective effect of propofol has been reported. We aimed to identify whether and how propofol improved hypoxia-induced impairment of BBB integrity. METHODS: Mouse brain microvascular endothelial cells (MBMECs) and astrocytes were cocultured to establish in vitro BBB model. The effects of hypoxia and propofol on BBB integrity were examined. Further, zonula occludens-1 (ZO-1) expression and phosphorylation, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression, intracellular calcium concentration and Ca2+ /calmodulin-dependent protein kinase II (CAMKII) activation were measured. RESULTS: Hypoxia-impaired BBB integrity, which was protected by propofol. Hypoxia-reduced ZO-1 expression, while induced ZO-1 phosphorylation. These effects were attenuated by propofol. The expression of HIF-1α and VEGF was increased by hypoxia and was alleviated by propofol. The hypoxia-mediated suppression of ZO-1 and impaired BBB integrity was reversed by HIF-α inhibitor and VEGF inhibitor. In addition, hypoxia increased the intracellular calcium concentration and induced the phosphorylation of CAMKII, which were mitigated by propofol. The hypoxia-induced phosphorylation of ZO-1 and impaired BBB integrity was ameliorated by calcium chelator and CAMKII inhibitor. CONCLUSION: Propofol could protect against hypoxia-mediated impairment of BBB integrity. The underlying mechanisms may involve the expression and phosphorylation of ZO-1.

High Glucose Stimulates Expression of MFHAS1 to Mitigate Inflammation via Akt/HO-1 Pathway in Human Umbilical Vein Endothelial Cells.

Hyperglycemia is a highly dangerous factor to various diseases, even resulting in death of people. Inflammation plays a key role in this process. The aim of this study was to explore the role of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) in high-glucose induced inflammation. Our research showed that high glucose stimulated the expression of MFHAS1, and overexpression of MFHAS1 can attenuate high-glucose induced inflammation in endothelial cells by decreasing the secretion of cytokines interleukin-1ß (IL-1ß), interleukin-1α (IL-1α), adhesion molecule intercellular adhesion molecule-1 (ICAM), interleukin-6 (IL-6), interleukin-8 (IL-8), and chemokine ligand 1 (CXCL-1). Furthermore, we found that MFHAS1 promoted the phosphorylation of Akt and the expression of heme oxygenase-1 (HO-1). Our results indicated that MFHAS1 deadened high-glucose induced inflammation by activating AKT/HO-1 pathway, suggesting that MFHAS1 may act as a new therapeutic target of diabetes mellitus.

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It is of great significance to study agroecosystem health in major grain producing areas based on the theory and method of ecosystem health. This paper selected Jilin Province as the study area, and an evaluation index system of agroecosystem health was built based on the SSI-VOR conceptual framework model. Using the optimal combined weights method, comprehensive evaluation assessment, GIS spatial analysis and grey slope similarity incidence models, the spatial-temporal pattern of agroecosystem health and influence factors were analyzed from 2000 to 2011 in Jilin Pro-vince. The results indicated that, temporally, the composite index of agroecosystem health showed a rising trend in Jilin Province from 1995 to 2011, and the agroecosystem health level changed from not healthy to relatively healthy; spatially, the spatial discrepancy of agroecosystem health level tended to become larger, which remained unchanged in central area, while was gradually improved in southeast and west. The main contributors which improved the agroecosystem health level were economic driving force, environmental management and social development, while the main 'dragging' factors were ecological pressure, organization structure and input capacity. Finally, relevant measures were put forward to improve the agroecosystem health condition.

Protective effects of oridonin on the sepsis in mice.

This study aimed to investigate the protective effects of oridonin (ORI) on cecal ligation and puncture (CLP)-induced sepsis in mice. Male C57BL/6 mice weighing 22-30 g and aged 8-10 weeks were randomly assigned to three groups: Sham group, CLP group, or CLP plus ORI group. In the CLP group and ORI group, CLP was induced, and intraperitoneal injection of normal saline and oridonin (100 µg/kg) was conducted, respectively. The survival rate was determined within the following 7 days. The blood, liver, and lung were collected at 24 hours after injury. Hematoxylin-eosin staining of the lung, detection of lung wet-to-dry ratio, and serum cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-6), and examination of intraperitoneal and blood bacterial clearance were conducted to evaluate the therapeutic efficacy. Results showed that ORI treatment significantly reduced the lung wet-to-dry ratio, decreased serum TNF-α and IL-6, and improved liver pathology compared with the CLP group (p < 0.05). Moreover, the intraperitoneal and blood bacterial clearance increased markedly after ORI treatment (p < 0.05). The 7-day survival rate in the ORI group was also dramatically higher than in the CLP group (p < 0.05). Our findings indicate that ORI can attenuate liver and lung injuries and elevate bacterial clearance to increase the survival rate of sepsis mice.

MFHAS1 Is Associated with Sepsis and Stimulates TLR2/NF-κB Signaling Pathway Following Negative Regulation.

Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) has a potential immunoregulatory role dependent on Toll-like receptors (TLRs). TLR2, associated with deleterious systemic inflammation, cardiac dysfunction, and acute kidney injury, acts synergistically in sepsis. The role of MFHAS1 in targeting TLR2 involved in sepsis has not been examined thus far. This study aimed to examine the relationship of MFHAS1 and sepsis, and the effect of MFHAS1 on the TLR2 signaling pathway. Blood samples were collected from eight sepsis patients after surgery and eight patients undergoing selective surgery to determine blood MFHAS1 levels. HEK 293 cells, RAW 264.7 macrophages and THP-1 monocytes were used to confirm the effect of MFHAS1 on TLR2 signaling pathway. Our study showed that blood MFHAS1 was significantly elevated in septic patients, and MFHAS1 was more increased in mononuclear cells from septic patients. Pam3CSK4 (TLR2 ligand) was found to induce MFHAS1 production in RAW 264.7 murine macrophages and THP-1 human monocytes in a time-dependent manner. MFHAS1 has dual effects on TLR2 signaling pathway and inflammation, i.e., inhibitory effect at 6 hours, and then stimulatory effect after 24 hours through the activation of TLR2/NF-κB signaling pathway, and MFHAS1 induced the phosphorylation of JNK and p38 after TLR2 stimulation.

Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: an updated systematic review with meta-regression.

BACKGROUND: Several epidemiological studies have been conducted to address the later effect of anesthesia on neurodevelopment in children. However, the results are still inconclusive. METHODS: We here conducted a systematic review and meta-analysis to summarize the currently available clinical and epidemiologic evidence on the association of anesthesia/surgery with neurodevelopmental outcomes in children by searching PubMed, EMBASE, and Web of Science database (from January-1 2000 to February-1, 2013). The evaluation of neurodevelopment includes language and learning disabilities, cognition, behavioral development, and academic performance. Both retrospective and prospective studies were included. Data were abstracted from seven eligible studies. We estimated the synthesized hazard ratios (HR) and 95% confidence interval (CI) according to inter-study heterogeneity. RESULTS: The pooled HR for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.25 (95% CI, 1.13-1.38, P<0.001; random-effects model) in children undergoing the first anesthesia before the age of 4-year. Then we analyzed the factors for this association using meta-regression method. It showed that it was the number of times of exposure (HR = 1.75, 95% CI 1.31-2.33; P<0.001) rather than the time at exposure before 4-year (HR = 1.08, 95% CI 0.87-1.34 for the effect of per 1-year early exposure; P = 0.47) is a risk factor for neurodevelopmental impairment. CONCLUSION: The current clinical evidence suggests modestly elevated risk of adverse neurodevelopmental outcomes in children who were exposed to anesthesia/surgery during early childhood, especially for those with multiple times of exposure. Due to limitation of retrospective studies, prospective investigations are needed to determine whether anesthesia/surgery is causative.

Simvastatin attenuates the lipopolysaccharideinduced inflammatory response of rat pulmonary microvascular endothelial cells by downregulating toll-like receptor 4 expression.

OBJECTIVE: The therapeutic potential of simvastatin as an anti-inflammatory agent was explored by investigating its effect on the lipopolysaccharide (LPS)-induced inflammatory response in rat pulmonary microvascular endothelial cells (RPMVECs). METHODS: RPMVECs were isolated and the mRNA and protein levels of different toll-like receptors (TLR) were assessed by qRT-PCR and western blotting. The LPS-induced expressions of TLR4, TNF-α and iNOS were analyzed in RPMVECs treated with different concentrations of simvastatin for different times. NF-κB activation was examined by immuofluroscence, luciferase reporter assay and western blotting. RESULTS: TLR4 is abundantly expressed in RPMVECs, and its expression is induced by LPS stimulation. Simvastatin inhibited LPS-induced TLR4 expression at the mRNA and protein levels in a time-dependent manner (p<0.01), and alleviated inflammation in RPMVECs by inhibiting the release of inflammatory factors such as TNF-α and iNOS. Further study indicated that simvastatin significantly attenuated NF-κB activity by inhibiting the degradation of IκB-α. Pretreatment with pyrrolidine dithiocarbamate (PDTC) and knock-down of TLR4 expression by RNA interference down-regulated the LPS-induced inflammatory response in RPMVECs. CONCLUSION: Simvastatin inhibits the LPS-induced inflammatory response in RPMVECs by down-regulating TLR4 expression, suggesting its role as a potential inhibitor of LPS-induced inflammation.

The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies.

Animal models have shown that regional anesthesia (combined with or without general anesthesia) would attenuate the surgical stress response by preserving immune function and result in better long-term outcome. In order to test the hypothesis that cancer patients who had surgery with epidural anesthesia (EA) would have better outcome (either overall survival [OS] or recurrence-free survival [RFS]) than those who were general anesthesia (GA), we performed this meta-analysis. By searching relevant literature, a total of 14 studies containing 18 sub-studies (seven in OS analysis and eleven in RFS analysis) were identified and meta-analyzed. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the strength of association. For OS, the random-effects model was used to analyze the data and demonstrated an OS benefit in favor of EA compared with GA alone (HR = 0.84, 95% CI 0.74-0.96, P = 0.013). The influence analysis showed the robustness of the results. Specifically, a significantly positive association between EA and improved OS was observed in colorectal cancer (HR = 0.65, 95% CI 0.43-0.99, P = 0.045). For RFS, the random-effects model was used to analyze the data and no significant relationship between RFS benefit and EA (HR = 0.88, 95% CI 0.64-1.22, P = 0.457) was detected. In conclusion, our meta-analysis suggests that epidural anesthesia and/or analgesia might be associated with improved overall survival in patients with operable cancer undergoing surgery (especially in colorectal cancer), but it does not support an association between epidural anesthesia and cancer control. Prospective studies are needed to determine whether the association between epidural use and survival is causative.