Kun-Ming Tao

Remifentanil Preconditioning Reduces Hepatic Ischemia― Reperfusion Injury in Rats via Inducible Nitric Oxide Synthase Expression

BACKGROUND Opioid preconditioning against ischemia reperfusion injury has been well studied in myocardial and neuronal tissues. The objective of this study was to determine whether remifentanil could attenuate hepatic injury and to investigate the mechanisms. METHODS A rat model of hepatic ischemia reperfusion injury and a hepatocyte hypoxia reoxygenation (HR) injury model were used, respectively, in two series of experiments. Remifentanil was administered before ischemia or hypoxia and the experiments were repeated with previous administration of naloxone, L-arginine and N-ω-nitro-L-arginine methyl ester, a nonselective opioid receptor antagonist, a nitric oxide donor, and nitric oxide synthase (NOS) inhibitor, respectively. Serum aminotransferase, cytokines, and hepatic lipid peroxidation were measured. Histopathology examination and apoptotic cell detection were assessed. For the in vitro study, cell viability, intracellular nitric oxide, apoptosis, and NOS expression were evaluated. RESULTS Remifentanil and L-arginine pretreatment reduced concentrations of serum aminotransferases and cytokines, decreased the concentrations of hepatic malondialdehyde and myeloperoxidase activity, and increased superoxide dismutase, nitric oxide, and inducible NOS expression in vivo. Decreased histologic damage and apoptosis were also seen in these two groups. These changes were prevented by previous administration of N-ω-nitro-L-arginine methyl ester but not naloxone. There was an increase in inducible NOS protein expression but not endogenous NOS in remifentanil and L-arginine pretreated groups compared with control, naloxone, and N-ω-nitro-L-arginine methyl ester groups. CONCLUSION Pretreatment with remifentanil can attenuate liver injury both in vivo and in vitro. Inducible NOS but not opioid receptors partly mediate this effect by exhausting reactive oxygen species and attenuating the inflammatory response.

From QUOROM to PRISMA: A Survey of High-Impact Medical Journals' Instructions to Authors and a Review of Systematic Reviews in Anesthesia Literature

Background The PRISMA (Preferred Reporting Items of Systematic reviews and Meta-Analyses) Statement was published to help authors improve how they report systematic reviews. It is unknown how many journals mention PRISMA in their instructions to authors, or whether stronger journal language regarding use of PRISMA improves author compliance. Methodology/Principal Findings An Internet-based investigation examined the extent to which 146 leading medical journals have incorporated the PRISMA Statement into their instructions to authors. Results were analyzed using descriptive statistics. Also, systematic reviews published in the leading anesthesiology journals and the QUOROM (QUality Of Reporting Of Meta-analyses) Statement were used to explore the hypothesis that indicating compliance with the QUOROM Statement in the manuscript is associated with improved compliance with the reporting guideline. In a sample of 146 journals publishing systematic reviews, the PRISMA Statement was referred to in the instructions to authors for 27% (40/146) of journals; more often in general and internal medicine journals (7/14; 50%) than in specialty medicine journals (33/132; 25%). In the second part of the study, 13 systematic reviews published in the leading anesthesiology journals in 2008 were included for appraisal. Mention of the QUOROM Statement in the manuscript was associated with higher compliance with the QUOROM checklist (P = 0.022). Conclusions/Significance Most of the leading medical journals used ambiguous language regarding what was expected of authors. Further improvement on quality of reporting of systematic reviews may entail journals clearly informing authors of their requirements. Stronger directions, such as requiring an indication of adherence to a research quality of reporting statement in the manuscript, may improve reporting and utility of systematic reviews.

Endorsement of the CONSORT Statement by High-Impact Medical Journals in China: A Survey of Instructions for Authors and Published Papers

Background The CONSORT Statement is a reporting guideline for authors when reporting randomized controlled trials (RCTs). It offers a standard way for authors to prepare RCT reports. It has been endorsed by many high-impact medical journals and by international editorial groups. This study was conducted to assess the endorsement of the CONSORT Statement by high-impact medical journals in China by reviewing their instructions for authors. Methodology/Principal Findings A total of 200 medical journals were selected according to the Chinese Science and Technology Journal Citation Reports, 195 of which publish clinical research papers. Their instructions for authors were reviewed and all texts mentioning the CONSORT Statement or CONSORT extension papers were extracted. Any mention of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals (URM) developed by the International Committee of Medical Journal Editors (ICMJE) or ‘clinical trial registration’ was also extracted. For journals endorsing the CONSORT Statement, their most recently published RCT reports were retrieved and evaluated to assess whether the journals have followed what the CONSORT Statement required. Out of the 195 medical journals publishing clinical research papers, only six (6/195, 3.08%) mentioned ‘CONSORT’ in their instructions for authors; out of the 200 medical journals surveyed, only 14 (14/200, 7.00%) mentioned ‘ICMJE’ or ‘URM’ in their instructions for authors, and another five journals stated in their instructions for authors that clinical trials should have trial registration numbers and that priority would be given to clinical trials which had been registered. Among the 62 RCT reports published in the six journals endorsing the CONSORT Statement, 20 (20/62, 32.26%) contained flow diagrams and only three (3/62, 4.84%) provided trial registration information. Conclusions/Significance Medical journals in China endorsing either the CONSORT Statement or the ICMJEs URM constituted a small percentage of the total; all of these journals used ambiguous language regarding what was expected of authors.

Isoflurane Preconditioning at Clinically Relevant Doses Induce Protective Effects of Heme Oxygenase-1 on Hepatic Ischemia Reperfusion in Rats

BackgroundActivation of heme oxygenase-1 (HO-1) has been proved to reduce damages to the liver in ischemia reperfusion injury. The objective of present study was to determine whether clinic relevant doses of isoflurane treatment could be sufficient to activate HO-1 inducing, which confers protective effect against hepatic ischemia-reperfusion injury.MethodsThe hepatic artery and portal vein to the left and the median liver lobes of forty male Sprague-Dawley rats were occluded for 60 minutes. Reperfusion was allowed for 4 hours before the animal subjects were sacrificed. Six groups (n = 12) were included in the study. A negative control group received sham operation and positive control group a standard ischemia-reperfusion regimen. The third group was pretreated with isoflurane prior to the ischemia-reperfusion. The fourth group received an HO-1 inhibitor zinc protoporphyrin (Znpp) prior to the isoflurane pretreatment and the ischemia-reperfusion. The fifth group received Znpp alone before ischemia-reperfusion procedure, and the sixth group was administrated with a HO-1 inducer hemin prior to IR. HO-1 in the liver was measured using an enzymatic activity assay, a Western blot analysis, as well as immunohistochemical method. Extent of liver damage was estimated by determination of the serum transaminases, liver lipid peroxidation and hepatic histology. Infiltration of the liver by neutrophils was measured using a myeloperoxidase activity assay. TNFα mRNA in the liver was measured using RT-PCR.ResultsIsoflurane pretreatment significantly attenuated the hepatic injuries and inflammatory responses caused by the ischemia reperfusion. Selectively inhibiting HO-1 with ZnPP completed blocked the protective effects of isoflurane. Inducing HO-1 with hemin alone produced protective effects similar in magnitude to that of isoflurane.ConclusionsClinic relevant doses of isoflurane attenuate ischemia reperfusion injury in rats by increasing the HO-1 expression and activity.

Scientific Publications from Mainland China, Taiwan, and Hong Kong in Integrative and Complementary Medicine Journals: A Ten-Year Literature Survey

Practitioners and researchers from China, the largest user of complementary and alternative medicine (CAM), have been publishing an increasing number of scientific articles in world-famous CAM journals in recent years. However, the status of CAM research in the three major regions of China, the Mainland, Taiwan and Hong Kong has, until now, not been reported. In this study, we compared articles from these three regions published in international CAM journals from 2000 to 2009 using PubMed database and the Journal Citation Reports. The study results showed that the number of published articles from Mainland China increased significantly from 2000 to 2009, particularly since 2005. Meanwhile, the number of published articles from Taiwan also increased, whereas those from Hong Kong remained steady. Clinical trials and randomized controlled trials from Chinese authors both took a small percentage of the total. The impact factors of the journals in which these articles were published suggested similar academic levels whereas the average number of citation of articles from the Mainland was less than those from the other two regions. Journal of Ethnopharmacology, American Journal of Chinese Medicine, Journal of Alternative and Complementary Medicine and Evidence-based Complementary and Alternative Medicine were the most popular journals for Chinese authors.

Protective effects of hydrogen enriched saline on liver ischemia reperfusion injury by reducing oxidative stress and HMGB1 release

BackgroundThe nuclear protein high-mobility group box 1 (HMGB1) is a key trigger for the inflammatory reaction during liver ischemia reperfusion injury (IRI). Hydrogen treatment was recently associated with down-regulation of the expression of HMGB1 and pro-inflammatory cytokines during sepsis and myocardial IRI, but it is not known whether hydrogen has an effect on HMGB1 in liver IRI.MethodsA rat model of 60 minutes 70% partial liver ischemia reperfusion injury was used. Hydrogen enriched saline (2.5, 5 or 10 ml/kg) was injected intraperitoneally 10 minutes before hepatic reperfusion. Liver injury was assessed by serum alanine aminotransferase (ALT) enzyme levels and histological changes. We also measured malondialdehyde (MDA), hydroxynonenal (HNE) and 8-hydroxy-guanosine (8-OH-G) levels as markers of the peroxidation injury induced by reactive oxygen species (ROS). In addition, pro-inflammatory cytokines including TNF-α and IL-6, and high mobility group box B1 protein (HMGB1) were measured as markers of post ischemia-reperfusion inflammation.ResultsHydrogen enriched saline treatment significantly attenuated the severity of liver injury induced by ischemia-reperfusion. The treatment group showed reduced serum ALT activity and markers of lipid peroxidation and post ischemia reperfusion histological changes were reduced. Hydrogen enriched saline treatment inhibited HMGB1 expression and release, reflecting a reduced local and systemic inflammatory response to hepatic ischemia reperfusion.ConclusionThese results suggest that, in our model, hydrogen enriched saline treatment is protective against liver ischemia-reperfusion injury. This effect may be mediated by both the anti-oxidative and anti-inflammatory effects of the solution.

Comparison of registered and published primary outcomes in randomized controlled trials of gastroenterology and hepatology

Abstract Objectives. The need for trial registration as well as the benefits it has brought for the transparency of medical research has been recognized for years. Trial registration has turned from an exception to a mandatory guideline in recent years. The present study aimed to examine the characteristics of registered randomized controlled trials (RCTs) in a sample of recently published gastroenterology RCTs, and to assess the consistency of registered and published primary outcome (PO) in RCTs. Methods. Articles published in the top five “general and internal journals” and top five “gastroenterology and hepatology journals” categories between 2009 and 2012 were searched in PubMed. Basic characteristics and the registration information were identified and extracted from the included RCTs. PO consistency analysis was conducted to compare between the registered and published format. Results. A total of 305 RCTs were included; among them 252 could be identified with a registration number. Nearly half of these RCTs were funded solely by industry (141/305, 46.3%). ClinicalTrials.gov was the most popular registry for these RCTs (214/252, 84.9%). A total of 155 RCTs were included in the PO consistency analysis. Among them, 22 (14.2%) RCTs had discrepancies between POs registered in the trial registry compared to the published article. Conclusions. Based on the results of the present study, selective outcome reporting of gastroenterology RCTs published in leading medical journals has been much improved over the past years. However, there might be a sampling bias to say that consistency of registered and published POs of gastroenterology RCTs has been better than before.

Volatile anesthetics might be more beneficial than propofol for postoperative liver function in cirrhotic patients receiving hepatectomy.

Hepatic inflow occlusion during the liver surgery may result in a transient ischemia period followed by reperfusion, and may initiate liver injury and lead to postoperative liver dysfunction. Especially in cirrhotic patients, the tolerance time of ischemia is much shorter and the outcome would be worse. Recently, clinical trials had proved that volatile anesthetics rather than propofol can protect myocardial cells from ischemia reperfusion (IR) injury in cardiac surgery. Meanwhile, animal studies had revealed that volatile anesthetics could induce some endogenous protective molecules in the liver such as hypoxia induced factor-1 (HIF-1), heme oxygenase (HO) enzyme system and inducible nitric oxide synthase (iNOS), which make the volatile anesthetics posing the extraordinary anti-oxidative, anti-inflammatory, anti-apoptotic, and vasodilatory characteristics. However, there is still lack of trials to compare the postoperative outcomes such as liver function in cirrhotic patients undergoing liver surgery with inflow occlusion between volatile anesthetics and propofol anesthesia. Hence we hypothesize that with its anti-IR injury characteristics, volatile anesthetics might be the more appropriate choice in cirrhotic patients undergoing liver surgery with occlusion.

Acute PAR2 activation reduces GABAergic inhibition in the spinal dorsal horn.

We investigated the mechanism underlying inhibition of spinal dorsal horn GABAergic neurotransmission to elucidate the role of protease-activated receptor-2 (PAR2). Initially, we confirmed that PAR2 agonist SL-NH(2) applied intrathecally produced mechanical hyperalgesia. Then we performed patch-clamp experiments in substantia gelatinosa neurons of spinal cord slice, and found that spontaneous inhibitory post-synaptic currents (sIPSCs) were significantly decreased in both frequency and amplitude when neurons were incubated with PAR2 agonist SL-NH(2) for a brief time period (2 min). The GABA-mediated currents were significantly reduced, and there was no impact on glycine-mediated currents during this SL-NH(2) treatment. These results suggest that PAR2 activation enhanced the pain response, potentially via inhibition of dorsal horn GABAergic neurotransmission.

Proteinase-activated receptor 1 contributed to up-regulation of enkephalin in keratinocytes of patients with obstructive jaundice.

Background:Skin synthesis of endogenous opioids such as enkephalin is considered to be increased in cholestatic rodents, which may induce antinociception in cholestatic liver disease. No studies have reported yet the expression of skin enkephalin in patients with cholestasis. Methods:Electrical pain threshold, postoperative morphine consumption, and skin enkephalin expression were measured in patients with jaundice (n = 18) and control patients (n = 16). Male Sprague–Dawley rats (n = 52) and human keratinocyte cell line HaCaT were used in vivo and in vitro studies, respectively. Nociceptive thresholds and plasma and skin levels of methionine-enkephalin were compared in protease-activated receptors-1–antagonized and control bile duct–ligated rats. In in vitro study, the effect on thrombin-induced enkephalin expression was examined and the role of extracellular regulated protein kinases 1/2 and p38 was investigated. Results:The authors found that: (1) the electrical pain threshold (mean ± SD) was 1.1 ± 0.1 mA in control patients, whereas it was significantly increased in patients with jaundice (1.7 ± 0.3 mA); 48-h postoperative morphine consumption was approximately 50% higher in the control group than that in the group with jaundice; (2) Skin keratinocytes enkephalin expression was increased in the patients with jaundice; (3) Protease-activated receptors-1 antagonist 1 &mgr;g·kg−1·day−1 treatment to the bile duct–ligated rats significantly reduced plasma levels of methionine-enkephalin, nociceptive thresholds, and keratinocytes enkephalin expression; and (4) protease-activated receptors-1 activation induced enkephalin expression through phosphorylation of extracellular regulated protein kinases 1/2 and p38 in keratinocytes. Conclusion:Protease-activated receptors-1 activation in peripheral keratinocytes may play an important role in the local synthesis of enkephalin during cholestasis.