Safety and efficacy of non-reduced use of caspofungin in patients with Child-Pugh B or C cirrhosis: a real-world study.

BACKGROUND AND PURPOSE: The need for dose adjustment of caspofungin in patients with hepatic impairment is controversial, especially for those with Child-Pugh B or C cirrhosis. The purpose of this study was to investigate the safety and efficacy of standard-dose caspofungin administration in Child-Pugh B and C cirrhotic patients in a real-world clinical setting. PATIENTS AND METHODS: The electronic medical records of 258 cirrhotic patients, including 67 Child-Pugh B patients and 191 Child-Pugh C patients, who were treated with standard-dose of caspofungin at the Second Affiliated Hospital of Chongqing Medical University, China, from March 2018 to June 2023 were reviewed retrospectively. The white blood cells (WBC), hepatic, renal and coagulation function results before administration and post administration on days 7, 14 and 21 were collected, and the efficacy was assessed in all patients at the end of caspofungin therapy. RESULTS: Favorable responses were achieved in 137 (53.1%) patients while 34 (13.2%) patients died. We observed that some patients experienced an increase of prothrombin time (PT) or international normalized ratio (INR), or a decrease of WBC, but no exacerbation of hepatic or renal dysfunction were identified and no patient required dose interruption or adjustment because of an adverse drug reaction during treatment with caspofungin. CONCLUSIONS: Standard-dose of caspofungin can be safely and effectively used in patients with Child-Pugh B or C cirrhosis, and we appealed to re-assess the most suitable dosing regimen in this population to avoid a potential subtherapeutic exposure.

Effect of volatile versus propofol anaesthesia on major complications and mortality after cardiac surgery: a multicentre randomised trial.

BACKGROUND: The comparative effectiveness of volatile anaesthesia and total intravenous anaesthesia (TIVA) in terms of patient outcomes after cardiac surgery remains a topic of debate. METHODS: Multicentre randomised trial in 16 tertiary hospitals in China. Adult patients undergoing elective cardiac surgery were randomised in a 1:1 ratio to receive volatile anaesthesia (sevoflurane or desflurane) or propofol-based TIVA. The primary outcome was a composite of predefined major complications during hospitalisation and mortality 30 days after surgery. RESULTS: Of the 3123 randomised patients, 3083 (98.7%; mean age 55 yr; 1419 [46.0%] women) were included in the modified intention-to-treat analysis. The composite primary outcome was met by a similar number of patients in both groups (volatile group: 517 of 1531 (33.8%) patients vs TIVA group: 515 of 1552 (33.2%) patients; relative risk 1.02 [0.92-1.12]; P=0.76; adjusted odds ratio 1.05 [0.90-1.22]; P=0.57). Secondary outcomes including 6-month and 1-yr mortality, duration of mechanical ventilation, length of ICU and hospital stay, and healthcare costs, were also similar for the two groups. CONCLUSIONS: Among adults undergoing cardiac surgery, we found no difference in the clinical effectiveness of volatile anaesthesia and propofol-based TIVA. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IOR-17013578).

Nongenetic and genetic predictors of haemodynamic instability induced by propofol and opioids: A retrospective clinical study.

AIM: Propofol and opioids are commonly used in anaesthesia, but are highly susceptible to haemodynamic instability, thereby threatening the patient's surgical safety and prognosis. The purpose of this study was to investigate the predictors of haemodynamic instability and establish its predictive model. METHODS: A total of 150 Chinese patients undergoing thyroid or breast surgery participated in the study, with target-controlled infusion concentrations of propofol, opioids dosage, heart rate (HR), mean arterial pressure (MAP) and Narcotrend Index recorded at key points throughout the procedure. The Agena MassARRAY system was used to genotype candidate single nucleotide polymorphisms related to pharmacodynamics and pharmacokinetics of propofol and opioids. RESULTS: Among nongenetic factors, baseline HR (R = -.579, P < .001) and baseline MAP (R = -.725, P < .001) had a significant effect on the haemodynamic instability. Among genetic factors, the CT/CC genotype of GABRB1 rs4694846 (95% confidence interval [CI]: -11.309 to -3.155), AA/AG of OPRM1 rs1799971 (95%CI: 0.773 to 10.290), AA of CES2 rs8192925 (95%CI: 1.842 to 9.090) were associated with higher HR instability; the AA/GG genotype of NR1I2 rs6438550 (95%CI: 0.351 to 7.761), AA of BDNF rs2049046 (95%CI: -9.039 to -0.640) and GG of GABBR2 rs1167768 (95%CI: -10.146 to -1.740) were associated with higher MAP instability. The predictive models of HR and MAP fluctuations were developed, accounting for 45.0 and 59.2% of variations, respectively. CONCLUSION: We found that cardiovascular fundamentals and genetic variants of GABRB1, GABBR2, OPRM1, BDNF, CES2 and NR1I2 are associated with cardiovascular susceptibility, which can provide a reference for haemodynamic management in clinical anaesthesia.

Dexmedetomidine Pretreatment Protects Against Myocardial Ischemia/Reperfusion Injury by Activating STAT3 Signaling.

BACKGROUND: Myocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can protect against cardiac IRI, but the mechanism is still insufficiently understood. METHODS: In vivo, myocardial ischemia/reperfusion (30 minutes/120 minutes) was induced via ligation and then reperfusion of the left anterior descending coronary artery (LAD) in mice. Intravenous infusion of 10 µg/kg DEX was performed 20 minutes before ligation. Moreover, the α2-adrenoreceptor antagonist Yohimbine and STAT3 inhibitor Stattic were applied 30 minutes ahead of DEX infusion. In vitro, hypoxia/reoxygenation (H/R) with DEX pretreatment for 1 hour was performed in isolated neonatal rat cardiomyocytes. In addition, Stattic was applied before DEX pretreatment. RESULTS: In the mouse cardiac ischemia/reperfusion model, DEX pretreatment lowered the serum creatine kinase-MB isoenzyme (CK-MB) levels (2.47 ± 0.165 vs 1.55 ± 0.183; P < .0001), downregulated the inflammatory response ( P ≤ .0303), decreased 4-hydroxynonenal (4-HNE) production and cell apoptosis ( P = .0074), and promoted the phosphorylation of STAT3 (4.94 ± 0.690 vs 6.68 ± 0.710, P = .0001), which could be blunted by Yohimbine and Stattic. The bioinformatic analysis of differentially expressed mRNAs further confirmed that STAT3 signaling might be involved in the cardioprotection of DEX. Upon H/R treatment in isolated neonatal rat cardiomyocytes, 5 µM DEX pretreatment improved cell viability ( P = .0005), inhibited reactive oxygen species (ROS) production and calcium overload (both P ≤ .0040), decreased cell apoptosis ( P = .0470), and promoted STAT3 phosphorylation at Tyr705 (0.102 ± 0.0224 vs 0.297 ± 0.0937; P < .0001) and Ser727 (0.586 ± 0.177 vs 0.886 ± 0.0546; P = .0157), which could be abolished by Stattic. CONCLUSIONS: DEX pretreatment protects against myocardial IRI, presumably by promoting STAT3 phosphorylation via the α2-adrenoreceptor in vivo and in vitro.

Propofol Does Not Reduce Pyroptosis of Enterocytes and Intestinal Epithelial Injury After Lipopolysaccharide Challenge.

BACKGROUND: To date, mechanisms of sepsis-induced intestinal epithelial injury are not well known. P2X7 receptor (P2X7R) regulates pyroptosis of lymphocytes, and propofol is usually used for sedation in septic patients. AIMS: We aimed to determine the occurrence of enterocyte pyroptosis mediated by P2X7R and to explore the effects of propofol on pyroptosis and intestinal epithelial injury after lipopolysaccharide (LPS) challenge. METHODS: A novel regimen of LPS challenge was applied in vitro and in vivo. Inhibitors of P2X7R (A438079) and NLRP3 inflammasome (MCC950), and different doses of propofol were administered. The caspase-1 expression, caspase-3 expression, caspase-11 expression, P2X7R expression and NLRP3 expression, extracellular ATP concentration and YO-PRO-1 uptake, and cytotoxicity and HMGB1 concentration were detected to evaluate enterocyte pyroptosis in cultured cells and intestinal epithelial tissues. Chiu's score, diamine oxidase and villus length were used to evaluate intestinal epithelial injury. Moreover, survival analysis was performed. RESULTS: LPS challenge activated caspase-11 expression and P2X7R expression, enhanced ATP concentration and YO-PRO-1 uptake, and led to increased cytotoxicity and HMGB1 concentration. Subsequently, LPS resulted in intestinal epithelial damage, as evidenced by increased levels of Chiu's score and diamine oxidase, and shorter villus length and high mortality of animals. A438079, but not MCC950, significantly relieved LPS-induced enterocyte pyroptosis and intestinal epithelial injury. Importantly, propofol did not confer the protective effects on enterocyte pyroptosis and intestinal epithelia although it markedly decreased P2X7R expression. CONCLUSION: LPS attack leads to activation of caspase-11/P2X7R and pyroptosis of enterocytes. Propofol does not reduce LPS-induced pyroptosis and intestinal epithelial injury, although it inhibits P2X7R upregulation.

Association of pre-operative troponin levels with major adverse cardiac events and mortality after noncardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Circulating cardiac troponin levels are powerful predictors of prognosis in many clinical settings, but their association with outcomes after noncardiac surgery is unclear. OBJECTIVES: The aim of this systematic review was to summarise current evidence on the association of pre-operative troponin elevation with postoperative major adverse cardiac events (MACE) and mortality in patients undergoing noncardiac surgery. DESIGN: Systematic review of observational studies with meta-analysis. DATA SOURCES: PubMed, EMBASE and Science Citation Index Expanded (ISI Web of Science) from their inception to 1 October 2017. ELIGIBILITY CRITERIA: Observational studies reporting the associations between pre-operative troponin levels and MACE and all-cause mortality after noncardiac surgeries were included. RESULTS: Ten studies met the eligibility criteria. The entire body of evidence addressing the research question was based on a total of 10 371 patients: 4.7 to 68.3% (median 23.8%) of patients had elevated troponin levels before surgery. Elevated pre-operative troponin was significantly associated with short-term MACE (seven studies, 5180 patients: odds ratio (OR) 6.92, 95% confidence interval (CI) 3.85 to 12.42), short-term mortality (five studies, 6103 patients: OR 4.23, 95% CI 2.27 to 7.89) and long-term mortality (two studies, 760 patients: OR 2.51, 95% CI 1.47 to 4.29). The associations remained significant when only multivariate-adjusted results were analysed. Overall, the reviewers' certainty about the summary estimates of the associations was very low. CONCLUSION: Current evidence suggests that pre-operative high troponin levels are significantly associated with adverse cardiac events and mortality after noncardiac surgery. TRIAL REGISTRATION: This systematic review was registered in the International Prospective Register of Systematic Reviews (Centre for Reviews and Dissemination 42017077837).

TGF-ß1 improves mucosal IgA dysfunction and dysbiosis following intestinal ischaemia-reperfusion in mice.

Intestinal ischaemia/reperfusion (I/R) severely disrupts gut barriers and leads to high mortality in the critical care setting. Transforming growth factor (TGF)-ß1 plays a pivotal role in intestinal cellular and immune regulation. However, the effects of TGF-ß1 on intestinal I/R injury remain unclear. Thus, we aimed to investigate the effects of TGF-ß1 on gut barriers after intestinal I/R and the molecular mechanisms. Intestinal I/R model was produced in mice by clamping the superior mesenteric artery for 1 hr followed by reperfusion. Recombinant TGF-ß1 was intravenously infused at 15 min. before ischaemia. The results showed that within 2 hrs after reperfusion, intestinal I/R disturbed intestinal immunoglobulin A class switch recombination (IgA CSR), the key process of mucosal IgA synthesis, and resulted in IgA dysfunction, as evidenced by decreased production and bacteria-binding capacity of IgA. Meanwhile, the disruptions of intestinal microflora and mucosal structure were exhibited. Transforming growth factor-ß1 activated IgA CSR as evidenced by the increased activation molecules and IgA precursors. Strikingly, TGF-ß1 improved intestinal mucosal IgA dysfunction, dysbiosis and epithelial damage at the early stage after reperfusion. In addition, SB-431542, a specific inhibitor of activating mothers against decapentaplegic homologue (SMAD) 2/3, totally blocked the inductive effect of TGF-ß1 on IgA CSR and almost abrogated the above protective effects on intestinal barriers. Taken together, our study demonstrates that TGF-ß1 protects intestinal mucosal IgA immunity, microbiota and epithelial integrity against I/R injury mainly through TGF-ß receptor 1/SMAD 2/3 pathway. Induction of IgA CSR may be involved in the protection conferred by TGF-ß1.

Diagnosis and prognosis of neutrophil gelatinase-associated lipocalin for acute kidney injury with sepsis: a systematic review and meta-analysis.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) has been identified as an early biomarker for prediction of acute kidney injury (AKI). However, the utility of NGAL to predict the occurrence of AKI in septic patients remains controversial. We performed a systematic review and meta-analysis to evaluate the evidence on diagnosis of sepsis AKI and the prediction of other clinical outcomes. METHOD: The MEDLINE, EMBASE, Cochrane Library, Wanfang, and CNKI databases were systematically searched up to August 19, 2015. Quality assessment was applied by using the Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) tool. The diagnostic performance of NGAL for the prediction of AKI in sepsis was evaluated using pooled estimates of sensitivity, specificity, likelihood ratio, and diagnostic odds ratio (DOR), as well as summary receiver operating characteristic curves (SROC). RESULTS: Fifteen studies with a total of 1,478 patients were included in the meta-analysis. For plasma NGAL, the pooled sensitivity and specificity with corresponding 95% confidence intervals (CI) were 0.83 (95% CI: 0.77 - 0.88) and 0.57 (95% CI: 0.54 - 0.61), respectively. The pooled positive likelihood ratio (PLR) was 3.10 (95% CI: 1.57 - 6.11) and the pooled negative likelihood ratio (NLR) was 0.24 (95% CI: 0.13 - 0.43). The pooled DOR was 14.72 (95% CI: 6.55 - 33.10) using a random effects model. The area under the curve (AUC) for SROC to summarize diagnostic accuracy was 0.86. For urine NGAL, the pooled sensitivity, specificity, PLR, NLR, DOR, and AUC values were 0.80 (95% CI: 0.77 - 0.83), 0.80 (95% CI: 0.77 - 0.83), 4.42 (95% CI: 2.84 - 6.89), 0.21 (95% CI: 0.13 - 0.35), 24.20 (95% CI: 9.92 - 59.05) and 0.90, respectively. Significant heterogeneity was explored as a potential source. There was no notable publication bias observed across the eligible studies. NGAL for prediction of renal replacement therapy (RRT) and mortality associated with AKI in septic patients were also evaluated. CONCLUSION: To a certain extent, NGAL is not only an effective predictive factor for AKI in the process of sepsis, but also shows potential predictive value for RRT and mortality. However, future trials are needed to clarify this controversial issue.

Propofol-induced rhabdomyolysis: a case report.

OBJECTIVE: To report a case of propofol-induced rhabdomyolysis. In this case, widespread myolysis was detected after induction of anesthesia. CASE SUMMARY: A 54-year-old female patient was scheduled for a hysterectomy. Beginning shortly after the induction of anesthesia with propofol, several episodes of ventricular fibrillation occurred. Despite intensive care, the patient failed to recover. During most episodes of ventricular fibrillation, marked hyperthermia or hyperkalemia were not observed. Unexplained, widespread myolysis affecting both skeletal and cardiac muscle was observed at autopsy. DISCUSSION: In this patient, the evidence for rhabdomyolysis is robust. Clinical characteristics are similar to those observed in propofol infusion syndrome. The absence of a body temperature over 40 °C precludes the possibility of malignant hyperthermia. Widespread rhabdomyolysis locations cannot be explained by precordial electric shocks. Propofol is the only drug used in this case that has been reported to induce rhabodomyolysis. CONCLUSIONS: Signs of propofol-induced rhabdomyolysis may be different from those of malignant hyperthermia. Even a regular induction dose of propofol for adults could possibly trigger rhabdomyolysis similar to what is observed in children diagnosed with propofol infusion syndrome. Though rare, care should still be taken when administering propofol.

Pretreatment of parecoxib attenuates hepatic ischemia/reperfusion injury in rats.

BACKGROUND: Previous studies showed that cyclooxygenase(COX) was involved in ischemia/reperfusion (I/R) injuries. Parecoxib, a selective inhibitor for COX -2, has been shown to have protective properties in reducing I/R injury in the heart, kidney and brain. The aim of this study was to investigate the effects of parecoxib on hepatic I/R and to explore the underlying mechanisms. METHODS: Fifty-two Sprague-Dawley rats were randomly divided into three groups: the sham-operation (Sham) group, the hepatic ischemia/reperfusion (I/R) group, and the parecoxib pretreated I/R (I/R + Pare) group. Partial warm ischemia was produced in the left and middle hepatic lobes of Sprague-Dawley rats for 60 min, followed by 6 h of reperfusion. Rats in the I/R + Pare group received parecoxib (10 mg/kg) intraperitoneally twice a day for three consecutive days prior to ischemia. Blood and tissue samples from the groups were collected 6 h after reperfusion, and a survival study was performed. RESULTS: Pretreatment with parecoxib prior to I/R insult significantly reduced I/R-induced elevations of aminotransferases, and significantly improved the histological status of the liver. Parecoxib significantly suppressed inflammatory cascades, as demonstrated by attenuations in TNF-α and IL-6. Parecoxib significantly inhibited iNOS and nitrotyrosine expression after I/R and significantly attenuated I/R-induced apoptosis. The 7-day survival rate was increased by pre-administration of parecoxib. CONCLUSIONS: Administration of parecoxib prior to hepatic I/R attenuates hepatic injury through inhibition of inflammatory response and nitrosative stress.

[DNA barcoding and its utility in commonly-used medicinal snakes].

Identification accuracy of traditional Chinese medicine is crucial for the traditional Chinese medicine research, production and application. DNA barcoding based on the mitochondrial gene coding for cytochrome c oxidase subunit I (COI), are more and more used for identification of traditional Chinese medicine. Using universal barcoding primers to sequence, we discussed the feasibility of DNA barcoding method for identification commonly-used medicinal snakes (a total of 109 samples belonging to 19 species 15 genera 6 families). The phylogenetic trees using Neighbor-joining were constructed. The results indicated that the mean content of G + C(46.5%) was lower than that of A + T (53.5%). As calculated by Kimera-2-parameter model, the mean intraspecies genetic distance of Trimeresurus albolabris, Ptyas dhumnades and Lycodon rufozonatus was greater than 2%. Further phylogenetic relationship results suggested that identification of one sample of T. albolabris was erroneous. The identification of some samples of P. dhumnades was also not correct, namely originally P. korros was identified as P. dhumnades. Factors influence on intraspecific genetic distance difference of L. rufozonatus need to be studied further. Therefore, DNA barcoding for identification of medicinal snakes is feasible, and greatly complements the morphological classification method. It is necessary to further study in identification of traditional Chinese medicine.

Adverse outcomes after major surgery in patients with systemic lupus erythematosus: a nationwide population-based study.

OBJECTIVES: To investigate the postoperative adverse outcomes among surgical patients with preoperative systemic lupus erythematosus (SLE) in a nationwide population-based study. METHODS: We used Taiwan's National Health Insurance Research Database to identify 4321 surgical inpatients with SLE and 17 284 sex- and age-matched controls receiving major surgery. Sociodemographic characteristics, preoperative comorbidities, postoperative 30-day in-hospital major complications and mortality were analysed among surgical patients with and without SLE. RESULTS: Surgical patients with SLE had a higher prevalence of preoperative coexisting medical conditions and postoperative major complications. The OR of 30-day postoperative mortality for surgical patients with SLE was 1.71 (95% CI 1.09 to 2.67) after adjustment. Surgical patients who had received more recent (within 6 months) preoperative SLE-related inpatient care had higher risks of 30-day postoperative acute renal failure (OR=7.23, 95% CI 4.52 to 11.6), pneumonia (OR=2.60, 95% CI 1.82 to 3.72), pulmonary embolism (OR=4.86, 95% CI 1.20 to 19.7), septicaemia (OR=3.43, 95% CI 2.48 to 4.74), stroke (OR=2.01, 95% CI 1.38 to 2.92), overall complications (OR=2.30, 95% CI 1.89 to 2.80) and 30-day postoperative mortality (OR=2.39, 95% CI 1.28 to 4.45) than surgical patients without SLE. SLE-related preoperative steroid injections showed a dose-dependent relationship with postoperative complications and mortality. CONCLUSIONS: SLE significantly increased the risks of surgical patients for overall major complications and mortality after major surgery. Our findings demonstrated the need for integrated care and revised protocols for perioperative management to improve outcomes for surgical patients with SLE.

Limb remote ischemic preconditioning attenuates lung injury after pulmonary resection under propofol-remifentanil anesthesia: a randomized controlled study.

BACKGROUND: Remote ischemic preconditioning (RIPC) may confer the protection in critical organs. The authors hypothesized that limb RIPC would reduce lung injury in patients undergoing pulmonary resection. METHODS: In a randomized, prospective, parallel, controlled trial, 216 patients undergoing elective thoracic pulmonary resection under one-lung ventilation with propofol-remifentanil anesthesia were randomized 1:1 to receive either limb RIPC or conventional lung resection (control). Three cycles of 5-min ischemia/5-min reperfusion induced by a blood pressure cuff served as RIPC stimulus. The primary outcome was PaO2/FIO2. Secondary outcomes included other pulmonary variables, the incidence of in-hospital complications, markers of oxidative stress, and inflammatory response. RESULTS: Limb RIPC significantly increased PaO2/FIO2 compared with control at 30 and 60 min after one-lung ventilation, 30 min after re-expansion, and 6 h after operation (238 ± 52 vs. 192 ± 67, P = 0.03; 223 ± 66 vs. 184 ± 64, P = 0.01; 385 ± 61 vs. 320 ± 79, P = 0.003; 388 ± 52 vs. 317 ± 46, P = 0.001, respectively). In comparison with control, it also significantly reduced serum levels of interleukin-6 and tumor necrosis factor-α at 6, 12, 24, and 48 h after operation and malondialdehyde levels at 60 min after one-lung ventilation and 30 min after re-expansion (all P < 0.01). The incidence of acute lung injury and the length of postoperative hospital stay were markedly reduced by limb RIPC compared with control (all P < 0.05). CONCLUSION: Limb RIPC attenuates acute lung injury via improving intraoperative pulmonary oxygenation in patients without severe pulmonary disease after lung resection under propofol-remifentanil anesthesia.

Limb remote ischemic preconditioning for intestinal and pulmonary protection during elective open infrarenal abdominal aortic aneurysm repair: a randomized controlled trial.

BACKGROUND: Remote ischemic preconditioning (RIPC) may confer the cytoprotection in critical organs. The authors hypothesized that limb RIPC would reduce intestinal and pulmonary injury in patients undergoing open infrarenal abdominal aortic aneurysm repair. METHODS: In this single-center, prospective, double-blinded, randomized, parallel-controlled trial, 62 patients undergoing elective open infrarenal abdominal aortic aneurysm repair were randomly assigned in a 1:1 ratio by computerized block randomization to receive limb RIPC or conventional abdominal aortic aneurysm repair (control). Three cycles of 5-min ischemia/5-min reperfusion induced by a blood pressure cuff placed on the left upper arm served as RIPC stimulus. The primary endpoint was arterial-alveolar oxygen tension ratio. The secondary endpoints mainly included the intestinal injury markers (serum intestinal fatty acid-binding protein, endotoxin levels, and diamine oxidase activity), the markers of oxidative stress and systemic inflammatory response, and the scores of the severity of intestinal and pulmonary injury. RESULTS: In limb RIPC group, a/A ratio was significantly higher than that in control group at 8, 12, and 24 h after cross-clamp release (66 ± 4 vs. 45 ± 4, P = 0.003; 60 ± 6 vs. 37 ± 4, P = 0.002; and 60 ± 5 vs. 47 ± 6, P = 0.039, respectively). All biomarkers reflecting intestinal injury increased over time, and there was significant differences between limb RIPC and control group (P < 0.001). The severity of intestinal and pulmonary injury was decreased by limb RIPC (P = 0.014 and P = 0.001, respectively). CONCLUSIONS: Limb RIPC attenuates intestinal and pulmonary injury in patients undergoing elective open infrarenal abdominal aortic aneurysm repair without any potential risk.

Augmenter of Liver Regeneration Monoclonal Antibody Promotes Apoptosis of Hepatocellular Carcinoma Cells.

Background and Aims: Hepatocellular carcinoma (HCC) is one of the most common types of cancer, often resulting in death. Augmenter of liver regeneration (ALR), a widely expressed multifunctional protein, has roles in liver disease. In our previous study, we reported that ALR knockdown inhibited cell proliferation and promoted cell death. However, there is no study on the roles of ALR in HCC. Methods: We used in vitro and in vivo models to investigate the effects of ALR in HCC as well as its mechanism of action. We produced and characterized a human ALR-specific monoclonal antibody (mAb) and investigated the effects of the mAb in HCC cells. Results: The purified ALR-specific mAb matched the predicted molecular weight of IgG heavy and light chains. Thereafter, we used the ALR-specific mAb as a therapeutic strategy to suppress tumor growth in nude mice. Additionally, we assessed the proliferation and viability of three HCC cell lines, Hep G2, Huh-7, and MHC97-H, treated with the ALR-specific mAb. Compared with controls, tumor growth was inhibited in mice treated with the ALR-specific mAb at 5 mg/kg, as shown by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling. Simultaneous treatment with the ALR-specific mAb and adriamycin promoted apoptosis, whereas treatment with the ALR-specific mAb alone inhibited cell proliferation. Conclusions: The ALR-specific mAb might be a novel therapy for HCC by blocking extracellular ALR.

Intestinal ischemia/reperfusion enhances microglial activation and induces cerebral injury and memory dysfunction in rats.

OBJECTIVE: The mortality of critically ill patients associated with intestinal ischemia/reperfusion remains very high, which results from multiorgan dysfunction or failure due to intestinal injury induced by intestinal ischemia/reperfusion. This study was carried out to investigate whether intestinal ischemia/reperfusion can cause cerebral injury and concomitant memory dysfunction, and explore the potential mechanisms. DESIGN: Prospective, controlled, and randomized animal study. SETTING: University research laboratory. SUBJECTS: Male, adult Sprague-Dawley rats (weighing 250-300 g). INTERVENTIONS: Intestinal ischemia/reperfusion was established by clamping the superior mesenteric artery for 90 mins followed by different reperfusion durations (2, 6, 12, 24, or 48 hrs). The sham surgical preparation including isolation of the superior mesenteric artery without occlusion was performed as control. MEASUREMENTS AND MAIN RESULTS: In comparison with sham control, intestinal ischemia/reperfusion caused severe intestinal injury, accompanied by notable cerebral damage evidenced by increased wet-to-dry brain weight ratio reflecting brain edema and neuronal cell apoptosis manifested by increased apoptotic cell number and cleaved caspase-3 protein expressions. All these changes were concomitant with reduced survival rates as well as impaired memory function determined by Morris water maze test at 24 and 48 hrs after reperfusion. In addition, intestinal ischemia/reperfusion resulted in significant increases in the levels of tumor necrosis factor-α and interleukin-6 both in the serum and in cortices and hippocampal Cornu Ammonis area 1 regions, concomitant with the activation of microglia, a key cellular mediator involved in neuroinflammation and neurodegeneration, which was evidenced by increased protein expressions of ionized calcium binding adaptor molecule 1. Furthermore, the releases of reactive oxygen species evidenced by increased malondialdehyde levels and decreased superoxide dismutase activities in cortices and hippocampal Cornu Ammonis area 1 regions were found after reperfusion. CONCLUSIONS: These findings indicate that intestinal ischemia/reperfusion-induced intestinal injury can lead to cerebral damage and memory dysfunction partly via microglia activation which further facilitates oxidative injury, inflammatory response, and neuronal cell apoptosis.

Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) injury is a devastating complication in the perioperative period. Dexmedetomidine is commonly applied in the perioperative period. The authors aimed to determine the effects of different doses of dexmedetomidine (given before or after intestinal ischemia) on intestinal I/R injury and to explore the underlying mechanisms. METHODS: Intestinal I/R injury was produced in rat by clamping the superior mesenteric artery for 1 h followed by 2 h reperfusion. Intravenous infusion of dexmedetomidine was performed at 2.5, 5, and 10 µg · kg(-1) · h(-1) for 1 h before or after ischemic insult. In addition, yohimbine hydrochloride was administered intravenously to investigate the role of α2 adrenoreceptor in the intestinal protection conferred by dexmedetomidine. RESULTS: Intestinal I/R increased mortality of rats and caused notable intestinal injury, as evidenced by statistically significant increases in Chiu's scores; serum diamine oxidase and tumor necrosis factor-α concentration, accompanied by increases in the intestinal mucosal malondialdehyde concentration; myeloperoxidase activity; and epithelial cell apoptosis (all P < 0.05 vs. Sham). Except malondialdehyde and myeloperoxidase, all changes were improved by the administration of 5 µg · kg(-1) · h(-1) dexmedetomidine before ischemia (all P < 0.05 vs. Injury) but not after ischemia. Infusion of 2.5 µg · kg(-1) · h(-1) dexmedetomidine before or after ischemia produced no beneficial effects, and infusion of 10 µg · kg(-1) · h(-1) dexmedetomidine led to severe hemodynamic suppression. Yohimbine abolished the intestinal protective effect of the 5 µg · kg(-1) · h(-1) dexmedetomidine infusion before ischemia and was accompanied by the disappearance of its antiapoptotic and antiinflammatory effect. CONCLUSION: Dexmedetomidine administration before, but not after, ischemia dose-dependently protects against I/R-induced intestinal injury, partly by inhibiting inflammatory response and intestinal mucosal epithelial apoptosis via α2 adrenoreceptor activation.

The antinociceptive effect of intrathecal tramadol in rats: the role of alpha 2-adrenoceptors in the spinal cord.

PURPOSES: The alpha 2 (α(2))-adrenoceptor is highly important in the antinociception of tramadol administered systemically and intrathecally. However, it is unclear whether tramadol at the spinal level exerts an antinociceptive effect by directly binding with α(2)-adrenoceptors in the spinal cord. This study was conducted to investigate the relationship between α(2)-adrenoceptors and the antinociception of tramadol at the spinal level. METHODS: The rat formalin test was designed to determine whether the intrathecal α(2)-adrenoceptor antagonist yohimbine could reverse the antinociceptive effect of intrathecal tramadol. The binding affinity of tramadol for α(2)-adrenoceptors in the spinal cord was determined by radioligand binding assay using the labeled α(2)-adrenoceptor antagonist [(3)H]-yohimbine. RESULTS: The nociceptive test showed that intrathecal tramadol induced significant antinociception whereas pretreatment with intrathecal yohimbine partially reversed this antinociception. Scatchard analysis of the binding data showed [(3)H]-yohimbine had high affinity (K(d) = 1.79 nM: ) for the α(2)-adrenoceptor in the rat spinal cord, and that tramadol inhibited specific binding of [(3)H]-yohimbine with the spinal cord membranes with a high affinity constant (K(i) = 34.14 µM: ) and an IC50 of 68.25 µM: , which indicated that tramadol was much less potent than [(3)H]-yohimbine at binding with α(2)-adrenoceptors of the spinal cord. CONCLUSION: The results suggested that, with very weak binding affinity for α(2)-adrenoceptors, the antinociception of intrathecal tramadol is partially related to α(2)-adrenoceptors, and its intrathecal antinociception may mainly involve its indirect activation of α(2)-adrenoceptors in the spinal cord.

[Fast-track surgery accelerates the recovery of postoperative humoral immune function in elective operation for colorectal carcinoma: a randomized controlled clinical trial].

OBJECTIVE: To explore the effects of fast-track surgery on postoperative humoral immune function in patients undergoing elective colorectal resection. METHODS: Seventy patients with colorectal carcinoma requiring colorectal resection were randomized into fast-track group (n = 35) and conventional care group (n = 35). The clinical parameters and markers of humeral immune function were evaluated in both groups postoperatively. RESULTS: Sixty-two patients finally completed the study, including 32 in the fast-track group and 30 in the conventional care group. There was a significantly faster recovery of postoperative humoral immunity: blood levels of globulin (24.1 ± 2.4 vs 22.1 ± 3.3 g/L, P = 0.025), immunoglobulin G (10.79 ± 2.39 vs 8.66 ± 2.09 g/L, P = 0.007) and complement 4 (0.24 ± 0.09 vs 0.17 ± 0.05 g/L, P = 0.035) at Day 3 postoperation were higher in the fast-track group than in the conventional care group. And there was also a significantly shorter length of postoperative stay (6.0 ± 1.0 vs 11.7 ± 3.8 d, P < 0.001) in patients undergoing fast-track rehabilitation. CONCLUSION: Fast-track surgery accelerates the recovery of postoperative humoral immune function in elective surgery for colorectal carcinoma with a shorter length of postoperative hospital stay.

[Fast track surgery accelerates the postoperative rehabilitation and recovery of insulin sensitivity in elective operation for colorectal carcinoma: a randomized controlled clinical trial].

OBJECTIVE: To investigate the effects of fast track surgery on postoperative insulin sensitivity on the basis of clinical benefits in patients undergoing elective open colorectal resection. METHODS: During May 2008 to December 2008, Seventy patients with colorectal carcinoma requiring colorectal resection were randomized into two groups: a fast track group (35 cases) and a conventional care group (35 cases). All included patients received elective open colorectal resection with combined tracheal intubation and general anesthesia. Clinical parameters, stress markers and insulin sensitivity were evaluated in both groups. RESULTS: The 62 patients finally completed the study, 32 cases in the fast-track group and 30 cases in the conventional care group. The speed of recovery of postoperative insulin sensitivity on 7 days postoperative in the fast-track group (97% ± 9%) was significantly faster than the conventional care group (88.5% ± 9.0%, t = 2.552, P = 0.016). The hospitalization days in the fast-track group was 6 days (M(50)), and it was significantly shorter than the conventional care group ((11.7 ± 3.8) days, Z = 4.360, P = 0.000). The time of recovery of bowel function were faster in the fast-track group (time to pass flatus was 2 days (M(50))) than the conventional care group (4 days, Z = 3.976, P = 0.000). The Infectious complication rate in the fast-track group (2/32) is lower than the other group (8/30, P = 0.040). CONCLUSION: Fast track surgery accelerates recovery of postoperative insulin sensitivity in elective surgery for colorectal carcinoma with a lower rate of postoperative infectious complications and a shorter length of postoperative hospital stay.