Weighted gene co-expression network analysis reveals specific modules and hub genes related to neuropathic pain in dorsal root ganglions.

Neuropathic pain is a common, debilitating clinical issue. Here, the weighted gene co-expression network analysis (WGCNA) was used to identify the specific modules and hub genes that are related to neuropathic pain. The microarray dataset of a neuropathic rat model induced by tibial nerve transection (TNT), including dorsal root ganglion (DRG) tissues from TNT model (n=7) and sham (n=8) rats, was downloaded from the ArrayExpress database (E-MTAB-2260). The co-expression network modules were identified by the WGCNA package. The protein-protein interaction (PPI) network was constructed, and the node with highest level of connectivity in the network were identified as the hub gene. A total of 1739 genes and seven modules were identified. The most significant module was the brown module, which contained 215 genes that were primarily associated with the biological process (BP) of the defense response and molecular function of calcium ion binding. Furthermore, C-C motif chemokine ligand 2 (Ccl2), Fos and tissue inhibitor of metalloproteinase 1 (Timp1) which were identified as the hub genes in the PPI network and two subnetworks separately. The in vivo studies validated that mRNA and protein levels of Ccl2, Fos and Timp1 were up-regulated in DRG and spinal cord tissues after TNT. The present study offers novel insights into the molecular mechanisms of neuropathic pain in the context of peripheral nerve injury.

Differential gene expression profiling of the sciatic nerve in type 1 and type 2 diabetic mice.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). The pathogenic mechanisms of DPN and the therapeutic interventions required may be distinct between type 1 (T1) and type 2 (T2) DM. However, the molecular mechanisms underlying the pathogenesis of DPN in both types of diabetes remain unclear. The aim of the current study was to identify the changes in genes and pathways associated with DPN in sciatic nerves of T1- and T2DM mice using bioinformatics analysis. The microarray profiles of sciatic nerves of T1DM (GSE11343) and T2DM (GSE27382) mouse models were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) in each. DEGs in the two types of DM (with fold change ≥2 and P<0.05) were identified with BRB-ArrayTools. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins and visualized using Cytoscape. Compared with control samples, 623 and 1,890 DEGs were identified in sciatic nerves of T1- and T2DM mice, respectively. Of these, 75 genes were coordinately dysregulated in the sciatic nerves of both models. Many DEGs unique to T1DM mice were localized to the nucleoplasm and were associated with regulation of transcription processes, while many unique to T2DM mice were localized at cell junctions and were associated with ion transport. In addition, certain DEGs may be associated with the different treatment strategies used for the two types of DM. This analysis provides insight into the functional gene sets and pathways operating in sciatic nerves in T1- and T2DM. The results should improve understanding of the molecular mechanisms underlying the pathophysiology of DPN, and provide information for the development of therapeutic strategies for DPN specific to each type of DM.

A study of anaesthesia-related cardiac arrest from a Chinese tertiary hospital.

BACKGROUND: The present survey evaluated the incidence of perioperative cardiac arrests in a Chinese tertiary general teaching hospital over ten years. METHODS: The incidence of cardiac arrest that occurred within 24 h of anaesthesia administration was retrospectively identified in the Third Affiliated Hospital of Sun Yat-Sen University between August 2007 and October 2017. Overall, 152,513 anaesthetics were included in the study period. Data collected included patient characteristics, American Society of Anaesthesiologists (ASA) physical status score, surgical specialty and anaesthesia technique. Cardiac arrests were assigned to one of three groups: "anaesthesia-related", "anaesthesia-contributing" or "anaesthesia-unrelated". RESULTS: In total, 104 cardiac arrests (6.8:10,000) and 34 deaths (2.2:10,000) were obtained. Among them, eleven cardiac arrests events were anaesthesia-related, resulting in an incidence of 0.7 per 10,000 anaesthetics. Sixteen cardiac arrests events were found to be anaesthesia-contributing, resulting in an incidence of 1.0 per 10,000 anaesthetics. Cardiovascular adverse events were the major events that contributed to anaesthesia-related cardiac arrest. Differences were found between events related and unrelated to anaesthesia with regard to ASA physical status and anaesthesia technique (P < 0.05). CONCLUSIONS: Anaesthesia-related cardiac arrest occurred in 11 of 104 cardiac arrests within 24 h of anaesthesia administration. Most cardiac arrests related to anaesthesia were due to cardiovascular events, including arrhythmia and hypotension after intravenous narcotic, as well as haemorrhage. ASA physical status of at least 3 and subarachnoid block appeared to be relevant risk factors for anaesthesia-related cardiac arrest.

Effect of dexmedetomidine for attenuation of propofol injection pain in electroconvulsive therapy: a randomized controlled study.

PURPOSE: Current analgesic strategies for propofol injection pain may cause adverse reactions during electroconvulsive therapy (ECT), such as shortening seizure duration. This study investigated whether dexmedetomidine could attenuate propofol injection pain in ECT. METHODS: Participants were randomly allocated to receive 0.2 µg/kg dexmedetomidine (Dex-0.2 group), 0.5 µg/kg dexmedetomidine (Dex-0.5 group) or saline (control group) prior to ECT. The composite pain scale and objective Surgical Pleth Index (SPI) were used to measure the intensity of injection pain, and the percentage of patients with pain score > 2 was the primary outcome. RESULTS: Of 137 patients recruited, 46 were assigned to each of the Dex-0.2 or Dex-0.5 groups, while 45 were in the control group. The percentage of pain score > 2 was reduced from 68.9% (31/45) in the control group to 34.8% (16/46) in the Dex-0.2 group (P < 0.001) and 15.2% (7/46) in the Dex-0.5 group (P < 0.001). The pain score and SPI at 5 s after propofol injection were greater in the control group than in the Dex-0.2 [pain scores 3 (2-4) vs. 1 (1-3), P < 0.001, SPI 76.6 ± 10.0 vs. 58.0 ± 11.0, P < 0.001] and Dex-0.5 groups [pain scores 3 (2-4) vs. 1 (0-1), P < 0.001, SPI 76.6 ± 10.0 vs. 51.2 ± 12.3, P < 0.001]. There were no significant differences in seizure duration between the three groups. No patients developed bradycardia and hypotension. CONCLUSIONS: Pretreatment with dexmedetomidine was able to reduce the propofol injection pain in ECT without interfering with the seizure duration and causing adverse effects such as bradycardia and hypotension. In addition, close monitoring of hemodynamic variables and preparation of a treatment plan and drugs for bradycardia are essential.

Identification of key genes and pathways associated with neuropathic pain in uninjured dorsal root ganglion by using bioinformatic analysis.

PURPOSE: Neuropathic pain is a complex chronic condition occurring post-nervous system damage. The transcriptional reprogramming of injured dorsal root ganglia (DRGs) drives neuropathic pain. However, few comparative analyses using high-throughput platforms have investigated uninjured DRG in neuropathic pain, and potential interactions among differentially expressed genes (DEGs) and pathways were not taken into consideration. The aim of this study was to identify changes in genes and pathways associated with neuropathic pain in uninjured L4 DRG after L5 spinal nerve ligation (SNL) by using bioinformatic analysis. MATERIALS AND METHODS: The microarray profile GSE24982 was downloaded from the Gene Expression Omnibus database to identify DEGs between DRGs in SNL and sham rats. The prioritization for these DEGs was performed using the Toppgene database followed by gene ontology and pathway enrichment analyses. The relationships among DEGs from the protein interactive perspective were analyzed using protein-protein interaction (PPI) network and module analysis. Real-time polymerase chain reaction (PCR) and Western blotting were used to confirm the expression of DEGs in the rodent neuropathic pain model. RESULTS: A total of 206 DEGs that might play a role in neuropathic pain were identified in L4 DRG, of which 75 were upregulated and 131 were downregulated. The upregulated DEGs were enriched in biological processes related to transcription regulation and molecular functions such as DNA binding, cell cycle, and the FoxO signaling pathway. Ctnnb1 protein had the highest connectivity degrees in the PPI network. The in vivo studies also validated that mRNA and protein levels of Ctnnb1 were upregulated in both L4 and L5 DRGs. CONCLUSION: This study provides insight into the functional gene sets and pathways associated with neuropathic pain in L4 uninjured DRG after L5 SNL, which might promote our understanding of the molecular mechanisms underlying the development of neuropathic pain.

Effects of small-dose dexmedetomidine on hyperdynamic responses to electroconvulsive therapy.

BACKGROUND: Acute hemodynamic responses to electroconvulsive therapy (ECT) may increase the risk of cardiovascular complications in vulnerable patients. The aim of the current study was to assess the effect of small-dose dexmedetomidine on hyperdynamic responses to ECT. METHODS: Seventy-eight patients were enrolled and randomly allocated to receive either 0.2 µg/kg dexmedetomidine (Dex group, n = 39) or saline (Control group, n = 39) prior to ECT. Heart rate (HR) and mean arterial pressure (MAP) were recorded immediately after the administration of dexmedetomidine (T1), and 0, 1, 3, 5 and 10 min after the electrical stimuli ended (T2, T3, T4, T5 and T6). In addition, the peak HR after ECT, seizure duration, recovery time, and incidence rates of post-ECT adverse effects (agitation, headache and nausea) were also recorded. RESULTS: HR and MAP in the Dex group were significantly lower than those in the Control group from T2 to T5. In addition, peak HR was significantly lower in the Dex group compared with that in the Control group. Seizure length and time to spontaneous breathing, eye opening, and obeying commands in the Dex group were similar to those in the Control group. The incidence rates of post-ECT agitation and headache in the Dex group were significantly lower than that in the Control group. CONCLUSION: The administration of 0.2 µg/kg dexmedetomidine to patients receiving ECT leads to a significant reduction in HR, MAP, and peak HR responses to ECT without altering seizure duration or delaying recovery. Furthermore, dexmedetomidine effectively reduced the incidence rates of post-ECT adverse effects such as agitation and headache.

Dexmedetomidine Combined With Intravenous Anesthetics in Electroconvulsive Therapy: A Meta-analysis and Systematic Review.

OBJECTIVE: The aim of this study was to investigate how the combined use of dexmedetomidine with intravenous anesthetics influences seizure duration and circulatory dynamics in electroconvulsive therapy (ECT). METHODS: A literature search was performed to identify studies that evaluated the effect of dexmedetomidine on motor- or electroencephalogram (EEG)-based seizure durations and maximum mean arterial pressure (MAP) and heart rate (HR) after ECT. Moreover, recovery time and post-ECT agitation were evaluated. RESULTS: Six studies enrolling 166 patients in 706 ECT sessions were included. There was no significant difference in motor or EEG seizure duration between dexmedetomidine and nondexmedetomidine groups [motor: 6 studies; mean difference (MD), 1.62; 95% confidence interval (CI), -2.24 to 5.49; P = 0.41; EEG: 3 studies; MD, 2.34; 95% CI, -6.03 to 10.71; P = 0.58]. Both maximum MAP and HR after ECT were significantly reduced in the dexmedetomidine group (MAP: 6 studies; MD, -4.83; 95% CI, -8.43 to -1.22; P = 0.009; HR: 6 studies; MD, -6.68; 95% CI, -10.74 to -2.62; P = 0.001). Moreover, the addition of dexmedetomidine did not significantly prolong recovery time when the reduced-dose propofol was used (4 studies; MD, 63.27; 95% CI, -15.41 to 141.96; P = 0.12). CONCLUSIONS: The use of dexmedetomidine in ECT did not interfere with motor and EEG seizure durations but could reduce maximum MAP and HR after ECT. Besides, the addition of dexmedetomidine in ECT did not prolong recovery time when reduced-dose propofol was used. It might be worthwhile for patients to receive dexmedetomidine before the induction of anesthesia in ECT.

Pharmacodynamic analysis of target-controlled infusion of propofol in patients with hepatic insufficiency.

The effect of liver dysfunction on target-controlled infusion (TCI) of propofol remains poorly documented. The pharmacodynamic performance of propofol TCI was evaluated in a cohort of Chinese patients with hepatic insufficiency. Fifty-three patients with hepatic insufficiency were enrolled in the current prospective, observational study. Anesthesia was induced with propofol via TCI to a plasma concentration of 3 µg/ml. Following loss of consciousness (LOC), fentanyl and cisatracurium were administered. Pharmacodynamic parameters were recorded during TCI, including time to LOC, bispectral index (BIS), heart rate (HR) and blood pressure. Patients were divided into two groups based on model of end stage liver disease (MELD) score: Those with a MELD score of ≤9 and those with a MELD score of ≥10. BIS, mean arterial pressure and HR were demonstrated to vary according to time, but were not affected by liver dysfunction. Hypotension was prominent in patients with a MELD score of ≥10 30 min after induction. The proportion of bradycardia and hypotension at the other time points was not significantly different between MELD scores of ≤9 and ≥10. Notably, no bradycardia was observed in MELD of ≥10. Thus, bradycardia and hypotension was observed in patients with hepatic insufficiency over time, although patients with different severities of hepatic insufficiency did not present with different depths of anesthesia. TCI of propofol to 3 µg/ml may be not suitable for patients with hepatic insufficiency, particularly those with severe liver dysfunction. Predictive concentrations (Cp) of TCI propofol requires further investigation and adjustment in patients with hepatic insufficiency (trial registration no. ChiCTR-OCH-12002255).

Intestinal injury following liver transplantation was mediated by TLR4/NF-κB activation-induced cell apoptosis.

Intestinal motility and barriers are often impaired due to intestinal congestion during liver transplantation. Intestinal bacteria and enterogenous endotoxins enter into the blood stream or lymphatic system and translocate to other organs, which can result in postoperative multi-organ dysfunction (MODF) and systemic inflammatory reaction syndrome (SIRS) severely affecting patient survival. However, the mechanisms underlying liver transplantation-induced intestinal injury remain unclear and effective therapies are lacking. Thus, the present study investigated whether these effects were associated with endotoxin-mediated apoptosis. Rat autologous orthotopic liver transplantation (AOLT) models were established to observe dynamic intestinal injuries at different time-points following reperfusion. Changes in the levels of endotoxins and the primary receptor, toll-like receptor 4 (TLR4), as well as its downstream signaling molecule, nuclear factor-κB (NF-κB) were all determined. Finally, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were conducted to detect caspase-3 expression and intestinal cell apoptosis, respectively. AOLT resulted in significant pathological intestinal injury, with the most serious intestine damage apparent four or eight hours following reperfusion. Furthermore, the levels of endotoxins and inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, peaked during this time period and gradually decreased to the normal level. Notably, TLR4 and downstream NF-κB expression, as well as NF-κB-mediated caspase-3 activation and intestinal cell apoptosis coincided with the intestinal pathological damage. Thus, the possible mechanism of post-liver transplantation intestinal injury was demonstrated to be associated with NF-κB activation-induced cell apoptosis.

In Vivo Evaluation of the Ameliorating Effects of Small-Volume Resuscitation with Four Different Fluids on Endotoxemia-Induced Kidney Injury.

Acute kidney injury associated with renal hypoperfusion is a frequent and severe complication during sepsis. Fluid resuscitation is the main therapy. However, heart failure is usually lethal for those patients receiving large volumes of fluids. We compared the effects of small-volume resuscitation using four different treatment regimens, involving saline, hypertonic saline (HTS), hydroxyethyl starch (HES), or hypertonic saline hydroxyethyl starch (HSH), on the kidneys of rats treated with lipopolysaccharide (LPS) to induce endotoxemia. LPS injection caused reduced and progressively deteriorated systemic (arterial blood pressure) and renal hemodynamics (renal blood flow and renal vascular resistance index) over time. This deterioration was accompanied by marked renal functional and pathological injury, as well as an oxidative and inflammatory response, manifesting as increased levels of tumor necrosis factor-α, nitric oxide, and malondialdehyde and decreased activity of superoxide dismutase. Small-volume perfusion with saline failed to improve renal and systemic circulation. However, small-volume perfusion with HES and HSH greatly improved the above parameters, while HTS only transiently improved systemic and renal hemodynamics with obvious renal injury. Therefore, single small-volume resuscitation with HES and HSH could be valid therapeutic approaches to ameliorate kidney injury induced by endotoxemia, while HTS transiently delays injury and saline shows no protective effects.

Ulinastatin prevents acute lung injury led by liver transplantation.

BACKGROUND: Little is known regarding the effect of ulinastatin (UTI) on acute lung injury (ALI) induced by orthotopic liver transplantation. This study aims to investigate the protective effect of UTI on ALI induced by orthotopic autologous liver transplantation (OALT) in a rat model and to explore the potential underlying mechanism. MATERIALS AND METHODS: Rats were randomly allocated into the following four groups (n = 8 each): (i) sham control group (group sham); (ii) model group (underwent OALT) (group model); (iii) low-dose UTI-treated group (group u1), with UTI (50 U/g) administered intravenously both before the portal vein was occluded and after liver reperfusion started; and (iv) high-dose UTI-treated group (group uh), with UTI (100 U/g) given in the same way as group ul. The lung pathologic parameters, lung water content, and levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, malondialdehyde (MDA), superoxide dismutase (SOD) activity, RanBP-type and C3HC4-type zinc finger-containing protein 1 (RBCK1), and peroxiredoxin-2 (Prx-2) were assessed 8 h after OALT was performed. RESULTS: According to histology, there was severe damage in the lung of group model accompanied by increases in the TNF-α, IL-1ß, IL-6, and MDA levels and decreases in SOD activity and the expression of RBCK1 and Prx-2. UTI treatment significantly reduced the pathologic scores, lung water content, and TNF-α, IL-1ß, IL-6, and MDA levels while restoring the SOD activity and expression of RBCK1 and Prx-2. Furthermore, compared with group u1, treatment with a high dose of UTI resulted in a better protective effect on the lung when assessed by the TNF-α, IL-1ß, IL-6, and MDA levels and SOD activity. CONCLUSIONS: UTI dose-dependently attenuates ALI that is induced by OALT in this rat model, which is mainly due to the suppression of the inflammatory response and oxidant stress, which may, in turn, be mediated by the upregulation of RBCK1 and Prx-2 expression.

Effects of anti-histamine treatment on liver injury triggered by small intestinal ischemia reperfusion in rats.

Mast cell (MC) degranulation has been implicated in small intestinal ischemia reperfusion (IIR) injury, therein, inhibiting overproduction of histamine released from activated MC may provide promising strategies against IIR-mediated liver injuries. The aim of the present study was to explore whether anti-histamine treatment contribute to attenuating IIR-mediated liver injury. Adult SD rats were randomized into sham-operated group (S group), sole IIR group (IIR group), and IIR treated with Ketotifen, a histamine antagonist (IIR+K group), Cromolyn Sodium, a MC stabilizer (IIR+C group), and Compound 48/80, a MC degranulator (IIR+CP group), respectively. IIR was induced by superior mesenteric artery occlusion for 75 min followed by 4 h of reperfusion. The agents were intravenously administrated 5 min before reperfusion to induce different levels of histamine. Subsequently, serum concentrations of ALT, AST and histamine; levels of LDH,TNF-α, IL-8 and MDA as well as SOD activities in the liver were assessed. Histopathologic changes were also evaluated. IIR resulted in severe liver injury as demonstrated by significant increases in injury scores, with concomitant significant increases in serum ALT, AST and histamine levels, as well as LDH, TNF-α, IL-8, and MDA levels in the liver, accompanied by reduction in SOD activities (all P < 0.05, IIR vs. S). Treatments by Ketotifen and Cromolyn Sodium similarly markedly alleviated IIR-mediated liver injury as confirmed by significant reduction of the above biomedical changes whereas Compound 48/80 further aggravated IIR-mediated liver injury by dramatically enhancing the above biomedical changes. Data of our study suggest that anti-histamine treatments may provide promising benefits in alleviating liver injury triggered by IIR.

[Effects of cromolyn sodium on intestinal ischemia-reperfusion injury by inhibiting PAR-2 expression in rats].

OBJECTIVE: To explore the effects of cromolyn sodium (CS) on intestinal ischemia-reperfusion (IIR) and its relationship with mast cell activation and protease-activated receptor 2 (PAR-2) expression. METHODS: A total of 32 SD rats were randomly divided into 4 groups: sham-operated (S), intestinal ischemia reperfusion (IIR), CS (a mast cell stabilizer, CS, 25 mg/kg) and compound 48/80 (a mast cell degranulation, CP, 0.75 mg/kg) (n = 8 each). IIR was induced by clamping superior mesenteric artery for 75 min followed by reperfusion for 3 hours. The above agents were intravenously administrated at 5 min pre-reperfusion. Rats were then sacrificed and intestinal issues harvested for histological examinations. The tryptase expression and mast cell count were analyzed by immunohistochemistry. PAR-2 was analyzed by Western blot. RESULTS: The Chiu's score (0.75 ± 0.21), mast cell count (10 ± 3), tryptase expression (125 ± 15) and PAR-2 expression (109 ± 10) of group S were the least while those of group CP the most (all P < 0.05). The Chiu's score (2.14 ± 0.64), mast cell count (15 ± 4), tryptase expression (138 ± 17) and PAR-2 expression (124 ± 12) of group CS were less than those of groups IIR and CP (all P < 0.05). CONCLUSION: Cromolyn sodium may reduce IIR injury by stabilizing mast cell membrane and inhibiting the expressions of tryptase and PAR-2.

[Peri-operative characteristics of cerebral oxygen metabolism in patients with encephalopathy after orthotopic liver transplantation].

OBJECTIVE: To investigate the feature of cerebral oxygen metabolism during peri-operative stage of orthotopic liver transplantation (OLT), in order to identify the difference between the patients with or without complicating encephalopathy after OLT, and the relationship between the cerebral oxygen metabolism and encephalopathy after OLT. METHODS: Thirty patients undergoing OLT were studied. The patients were divided into two groups according to occurrence or not of encephalopathy after OLT: encephalopathy group and non-encephalopathy group. Blood samples were taken from radial artery and jugular vein simultaneously for blood gas analysis before operation, 25 minutes after onset of anhepatic phase, 30 minutes after graft reperfusion , 3 hours after graft reperfusion , and 24 hours after graft reperfusion. Cerebral arterial oxygen content (CaO(2)), oxygen content of jugular vein blood (CjvO(2)), cerebral arterial-venous oxygen content difference (Ca-jvO(2)), cerebral oxygen extraction ratio (CERO(2)) and cerebral blood flow/cerebral metabolic rate of oxygen ratio (CBF/CMRO(2)) were calculated, and the levels of blood glucose and lactic acid were recorded. RESULTS: There were 11 patients (36.7%) complicated by encephalopathy after OLT. The quantity of red blood cell infusion, blood loss and the dosage of noradrenalin in encephalopathy group were significantly larger compared with non-encephalopathy group. The overall tendency of change in cerebral oxygen metabolism index was about the same for both groups, while CaO(2) and Ca-jvO(2) at 25 minutes after onset of anhepatic phase, 30 minutes after graft reperfusion and 3 hours after graft reperfusion , and CERO(2) at 30 minutes after graft reperfusion and 3 hours after graft reperfusion were significantly decreased compared with those before operation [CaO(2) (ml/L) in encephalopathy group: 132.4 ± 23.5 , 125.9 ± 17.6, 133.4 ± 11.1 vs. 148.5 ± 28.8, in non-encephalopathy group: 135.7 ± 22.4, 130.5 ± 20.0, 139.9 ± 21.2 vs. 148.9 ± 28.2; Ca-jvO(2) (ml/L) in encephalopathy group: 42.9 ± 13.2, 31.4 ± 12.3 , 32.3 ± 6.5 vs. 52.9 ± 23.5, in non-encephalopathy group: 33.0 ± 14.1, 26.6 ± 9.1, 30.6 ± 10.3 vs. 50.2 ± 23.2; CERO(2) in encephalopathy group: (24.9 ± 9.7)%, (24.4 ± 5.5)% vs. (35.4 ± 11.5)%, in non-encephalopathy group: (20.6 ± 7.3)%, (21.9 ± 7.0)% vs. (33.4 ± 13.1)%, all P < 0.05], and they returned to the levels before operation at 24 hours after graft reperfusion. Jugular venous oxygen saturation (SjvO(2)) and CBF/CMRO(2) ratio were significantly increased at 30 minutes after graft reperfusion and 3 hours after graft reperfusion compared with the levels before operation [SjvO(2) in encephalopathy group: 0.838 ± 0.105, 0.835 ± 0.065 vs. 0.709 ± 0.125, in non-encephalopathy group: 0.854 ± 0.074, 0.824 ± 0.074 vs. 0.713 ± 0.138; CBF/CMRO(2) ratio in encephalopathy group: 37.8 ± 16.6, 31.9 ± 6.8 vs. 20.9 ± 6.7 , in non-encephalopathy group: 37.8 ± 14.1, 35.7 ± 13.7 vs. 24.3 ± 14.0, all P <0.05], and they returned to the levels before operation at 24 hours after graft reperfusion. The overall tendency of change in blood glucose and lactic acid was about the same in both groups, while the levels of blood glucose increased significantly from anhepatic phase to 24 hours after graft reperfusion compared with the levels before operation , and the levels of lactic acid increased significantly from anhepatic phase to 3 hours after graft reperfusion compared with the levels before operation and returned to the levels before operation at 24 hours after graft reperfusion. CONCLUSION: There are significant changes in the features of cerebral oxygen metabolism during OLT, but there is no difference between encephalopathy group and non-encephalopathy group. The occurrence of encephalopathy can be attributed to many factors, so the prevention and treatment should be comprehensive considered.

Efficient derivation of functional hepatocytes from mouse induced pluripotent stem cells by a combination of cytokines and sodium butyrate.

BACKGROUND: Hepatocyte transplantation has been proposed as an alternative to whole-organ transplantation to support many forms of hepatic insufficiency. Unfortunately, the lack of donor livers makes it difficult to obtain enough viable human hepatocytes for hepatocyte-based therapies. Therefore, it is urgent to find new ways to provide ample hepatocytes. Induced pluripotent stem (iPS) cells, a breakthrough in stem cell research, may terminate these hinders for cell transplantation. For the promise of iPS cells to be realized in liver diseases, it is necessary to determine if and how efficient they can be differentiated into functional hepatocytes. METHODS: In this study, we directly compared the hepatic-differentiation capacity of mouse iPS cells and embryonic stem (ES) cells with three different induction approaches: conditions via embryonic body (EB) formation plus cytokines, conditions by combination of dimethyl sulfoxide and sodium butyrate and chemically defined, serum free monolayer conditions. Among these three induction conditions, more homogenous populations can be promoted under chemically defined, serum free conditions. The cells generated under these conditions exhibited hepatic functions in vitro, including glycogen storage, indocynine green (ICG) uptake and release as well as urea secretion. Although efficient hepatocytes differentiation from mouse iPS cells were observed, mouse iPS cells showed relatively lower hepatic induction efficiency compared with mouse ES cells. RESULTS: Mouse iPS cells would be efficiently differentiated into functional hepatocytes in vitro, which may be helpful in facilitating the development of hepatocytes for transplantation and for research on drug discovery. CONCLUSION: We demonstrate that mouse iPS cells retain full potential for fetal liver development and describe procedures that facilitates the efficient generation of highly differentiated human hepatocyte-like cells from iPS cells in vitro.

[Protective effects of ulinastatin during orthotopic liver transplantation on kidney function with decreasing acute renal failure after liver transplantation in patients with severe hepatitis].

OBJECTIVE: To study whether using ulinastatin (UTI) during orthotopic liver transplantation (OLT) can decrease acute renal failure after liver transplantation in patients with Severe Hepatitis. METHOD: Thirty-one patients with Severe Hepatitis undergoing orthotopic liver transplantation (OLT) were studied. They were devided into two groups: determination of serumbeta(2) microglobulin (beta(2) MG), BUN and Cr before operation and 24 h after operation, at the same time, urine samples were taken for determination of urine beta(2) MG. Data of HR, ABPM, CVP, CO were recorded during operation. The Incidence of renal failure affiliated liver transplantation (RFALT) and prognosis of these patients were also recorded in the two groups after operation. RESULTS: (1) 4 cases in group U while 10 cases in group C developed RFALT at 24 h after operation (P < 0.05). In these patients who developed RFALT at 24 h after operation, 4 cases were all rehabilitation discharge in group U, while in group C, 2 cases died, 3 cases didn't cure but required discharge, only 5 cases were rehabilitation discharge. (2) Compared with baseline before operation, serum beta(2) MG, Urine beta(2) MG, BUN and Cr increased significantly at 24 h after operation both in two groups, (P < 0.05, P < 0.01). (3) Compared with group C, serum beta(2) MG, Urine beta(2) MG, BUN increased significantly at 24 h after operation in group U (P < 0.05, P < 0.01). CONCLUSION: Protective effects of ulinastatin during orthotopic liver transplantation on kidney function in patients with Severe Hepatitis can decrease acute renal failure after liver transplantation.

Effects of propofol intravenous injection bolus on the left ventricular function and the myocardial beta-adrenoceptor in rats.

Propofol bolus injection has been reported to influence cardiovascular functions. However, the detailed mechanism underlying this action has not been elucidated. This study was designed to investigate the effects of propofol i.v. bolus on the left ventricular function, the myocardial beta-adrenoceptor (beta-AR) binding-site density (Bmax) and Kd (apparent dissociation constant) in a 30-minute period. One hundred and four male Wistar rats were randomly divided into four groups: group C (control group), group I (intralipid group), group P1 (5 mg/kg propofol) and group P2 (10 mg/kg propofol). The results showed a significant downregulation of HR, LVSP, +dp/dtmax and -dp/dtmax in both groups P1 and P2 (especially after bolus injection in 7 min) than those of group C (P < 0.05), whereas no significant difference was found between the P1 and P2 groups (P > 0.05). Likely, Bmax was remarkably upregulated in both groups P1 and P2 (P < 0.05, vs. groups C and I), and there was no significant difference between these two groups (P > 0.05). Of note, the Kd value in group P2 (10 mg/kg propofol) was found dramatically increased in 30 min than that in the low-dose propofol-treated group (group P1) as well as in groups C and I (P < 0.05). In conclusion, these results indicate that intravenous injection of propofol bolus can inhibit the cardiac function partially via upregulation of Bmax and downregulation of the beta-AR affinity at higher-dose injection of propofol bolus.

[Changes of systemic and pulmonary hemodynamics and plasma levels of inducible nitric oxide synthase and endothelin-1 in patients with hepatopulmonary syndrome].

OBJECTIVE: To observe the changes of systemic and pulmonary hemodynamics and the plasma levels of inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) and investigate their association in patients with hepatopulmonary syndrome (HPS). METHODS: Twenty-six patients with HPS undergoing orthotopic liver transplantation (OLT) were enrolled in this study with 20 patients without hypoxemia as the control group. Blood samples were taken one day before OLT to measure the plasma levels of iNOS and ET-1 using fluorescence quantitative polymerase chain reaction (FQ-PCR) and radioimmunoassay, respectively, with 10 healthy volunteers serving as the healthy control group. Before the operation for OLT, the parameters of systemic and pulmonary hemodynamics were monitored after anesthesia induction. RESULTS: The systemic and pulmonary hemodynamics in patients without hypoxemia was characterized by high cardiac output and low resistance, and by comparison, the patients with HPS showed even higher cardiac output and lower mean pulmonary artery pressure, pulmonary artery wedge pressure, systemic vascular resistance and pulmonary vascular resistance. The two patient groups had comparable plasma iNOS and ET-1 levels, which were both higher than those in the healthy control group. CONCLUSION: The hemodynamics in patients with end-stage liver disease exhibit a pattern of high cardiac output and low resistance, which is more obvious in HPS patients possibly in association with elevated plasma levels of iNOS and ET-1.

[Changes of hemodynamics and concentrations of nitric oxide, endothelin, prostacyclin, and thromboxane A2 during portal cavity clamping and opening in portal hypertensive canines].

OBJECTIVE: To observe the changes in systemic hemodynamics and their relations to the concentrations of nitric oxide, endothelin, prostacyclin, and thromboxane A2 after portal cavity clamping and opening in portal hypertensive canines. METHODS: Twelve canines were randomly divided into control group and model group, and partial ligation of the portal vein was performed in the model group. Portal cavity clamping and opening was performed 12 weeks later in the two groups. The hemodynamic parameters including cardiac output index (CI), heart rate (HR), mean artery blood pressure (MABP), central venous pressure (CVP), pulmonary arteriole wedge pressure (PAWP), and systemic vascular resistance index (SVRI) were measured during the operation. Samples were obtained from the central vein at 3 time points during the operation for measuring NO, ET, PGI2, and TXA2. RESULTS: Portal vein ligation and portal cavity clamping produced obvious changes in the systemic circulation of the dogs, and the alteration was milder in the control group. After obstruction of the portal vein, the NO levels in systemic circulation in portal hypertensive dogs declined obviously, but gradually recovered the normal level after reperfusion. CONCLUSION: Systemic circulation undergoes significant alterations after portal vein obstruction, but its changes in portal hypertensive dogs are milder than those in the control group, the mechanism of which needs further investigation.

Relationship between the expression of Toll-like receptor 2 and 4 in mononuclear cells and postoperative acute lung injury in orthotopic liver transplantation.

BACKGROUND: The aim of this study was to investigate the potential relationship between the dynamic expression of Toll-like receptor 2 and 4 (TLR2/4) in peripheral blood mononuclear cells as well as changes in serum concentration of inflammatory factors and acute lung injury (ALI) in patients after orthotopic liver transplantation (OLT). METHODS: The peripheral blood samples of 27 patients (23 men and 4 women with ASA III to IV) who received OLT were collected for measurement of TLR2/4 at T1 (after induction of anesthesia), T2 (25 minutes after anhepatic phase), T3 (3 hours after graft reperfusion) and T4 (24 hours after graft reperfusion). The expression of TLR2/4 in mononuclear cells was measured by flow cytometry. The serum concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-8 were measured by enzyme-linked immunosorbent assay (ELISA). Twenty-seven patients were assigned to ALI group (n = 9) and non-ALI group (n = 18) according to the diagnostic criteria of ALI. The expression of TLR2/4 in the ALI group or non-ALI group was analyzed. RESULTS: Compared to the non-ALI group, the volumes of blood loss, ascites, total output and transfused red blood cells were higher in the ALI group, and the anhepatic phase lasted longer (P < 0.05, P < 0.01). The expression of TLR2/4 in mononuclear cells increased significantly at T3 and T4, and serum concentrations of TNF-alpha, IL-1beta and IL-8 increased significantly too. There was no significant difference in Child-Turcotte-Pugh (CTP) scores between the ALI group and non-ALI group (P > 0.05). The expression of TLR2/4 in mononuclear cells increased significantly at T3 and T4 in the ALI group (P < 0.05, P < 0.01). A positive correlation was noted between the expression of TLR4 in mononuclear cells and the serum concentrations of TNF-alpha, IL-1beta (P = 0.041, P = 0.046) in the ALI group. In the non-ALI group, statistical results showed that the expression level of TLR2/4 in mononuclear cells was not significantly different during the peri-operative period of OLT (besides TLR4 expression at T4). Compared to the non-ALI group, the increasing amplitude of TLR2/4 expression in mononuclear cells was more significant in the ALI group. The patients whose TLR2/4 expression in mononuclear cells exceeded that at T1 by one time were more likely to suffer from ALI (P = 0.013), with a relative risk of 16. CONCLUSION: The expression level of TLR2/4 in mononuclear cells increases significantly in the peri-operative period of OLT, and it may be a high risk factor for occurrence of postoperative ALI.