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Objectives To compare the effects of nicorandil and nitroglycerin on arterial oxygenation during two-lung ventilation (TLV) and one-lung ventilation (OLV) in patients with risk factors for myocardial ischemia. Design A prospective, randomized, double-blind study. Setting A tertiary care hospital. Participants Fifty-six patients scheduled for elective video-assisted thoracic surgery were assigned randomly to either the nicorandil group or the nitroglycerin group. Interventions Patients in the nicorandil group received a bolus dose of nicorandil, 0.08 mg/kg during induction of anesthesia, followed by a continuous infusion at a rate of 0.08 mg/kg/h. Patients in the nitroglycerin group received a continuous infusion of nitroglycerin at a rate of 1 µg/kg/min from the induction of anesthesia. Measurements and Main Results Arterial blood gas analysis was performed at the following points: before induction of anesthesia; during TLV; at 5, 10, 20, and 30 minutes after the initiation of OLV. PaO2 at TLV (479.7 ± 57.1 v 408.2 ± 70.9 mmHg, p Conclusion This study demonstrated that oxygenation during TLV and OLV was significantly higher in patients receiving nicorandil than in those receiving nitroglycerin.

Background: We investigated the effects of a novel method of anesthesia combining propofol and volatile anesthesia on the incidence of postoperative nausea and vomiting in patients undergoing laparoscopic gynecological surgery. Methods: Patients were randomly divided into three groups: those maintained with sevoflurane (Group S, n = 42), propofol (Group P, n = 42), or combined propofol and sevoflurane (Group PS, n = 42). We assessed complete response (no postoperative nausea and vomiting and no rescue antiemetic use), incidence of nausea and vomiting, nausea severity score, vomiting frequency, rescue antiemetic use, and postoperative pain at 2 and 24 h after surgery. Results: The number of patients who exhibited a complete response was greater in Groups P and PS than in Group S at 0–2 h (74%, 76% and 43%, respectively, p = 0.001) and 0–24 h (71%, 76% and 38%, respectively, p

Purpose : Activation of the mitochondrial calcium-activated potassium (mKCa) channel reportedly confers resistance to myocardial ischemic stress. However, the role of the mKCa channel in postconditioning induced by volatile anesthetic remains unclear. Methods :Male Japanese white rabbits underwent coronary artery occlusion for 30 min followed by reperfusion for 3 h. Volatile anesthetic, isoflurane, was administered at 3min prior to reperfusion for 5 min. Rabbits were injected with the mKCa channel blocker, iberiotoxin, or the mKCa channel opener, NS1619, at 8 min prior to reperfusion. Myocardial infarct size and the area at risk (AAR) were measured at the end of the experiment. Results : Isoflurane significantly reduced infarct size (23.0±9.8% of the AAR, P

Peutz–Jeghers syndrome (PJS) is a dominantly inherited human disorder characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. LKB1 (STK11) serine/threonine kinase is the product of the causative gene of PJS, which has been mapped to chromosome 19p13.3. However, several studies have produced results that are not consistent with a link between LKB1 gene mutation and PJS. We constructed a knockout gene mutation of Lkb1 to determine whether it is the causative gene of PJS and to examine the biological role of the Lkb1 gene. Lkb1 −/− mice died in utero between 8.5 and 9.5 days postcoitum. At 9.0 days postcoitum, Lkb1 −/− embryos were generally smaller than their age-matched littermates, showed developmental retardation, and did not undergo embryonic turning. Multiple gastric adenomatous polyps were observed in 10- to 14-month-old Lkb1 +/− mice. Our results indicate that functional Lkb1 is required for normal embryogenesis and that it is related to tumor development. The Lkb1 +/− mouse is suitable for studying molecular mechanism underlying the development of inherited gastric tumors in PJS.

We have previously prepared monoclonal antibodies (MAbs) against tumor vasculature using cultured rat tumor endothelial cells (TECs) isolated from solid KMT-17 tumors and identified 40 and 80 kDa antigens recognized by TES-17 and TES-23 MAbs, respectively. To clarify the nature of antigens on tumor vasculature, molecular cloning was conducted by screening the rat TEC cDNA library. Two antigens were detected: a 40 kDa OTS-8 antigen, which had been defined as a differentiation marker for osteoblastic lineage, and an 80 kDa CD44H antigen. Northern blots showed that OTS-8 mRNA was expressed exclusively in the lung, in addition to TECs, while CD44H mRNA was detected in the lung, intestine, spleen, thymus and peripheral blood cells, in addition to TECs. Immuno-histochemistry of KMT-17 tumors revealed that OTS-8 and CD44 were expressed on sprouting TECs. In addition, TES-23 MAb stained TECs of tubular vessels as well as sprouting TECs, but anti-rat CD44 MAbs stained only sprouting TECs. PCR showed that CD44 cDNA with a splice in exon 6 (CD44ex6) was present in rat TECs at low levels. Our results indicate that OTS-8 and CD44 are expressed on rat sprouting TECs and that TES-23 MAb recognizes CD44H on sprouting TECs as well as an unknown epitope on TECs of tubular vessels that could not be recognized by anti-rat CD44 MAbs.

We have isolated a serine protease, halystase, from Agkistrodon halys blomhoffii venom by chromatography on DEAE-Sepharose, heparin-Sepharose and Q-Sepharose columns, and have determined the complete amino acid sequence by Edman degradation and by mass spectral analysis of peptides generated by enzymatic and chemical cleavage. The 238-residue sequence of halystase, containing N-linked carbohydrates (about 13%) at two sites showed significant similarity to other thrombin-like snake venom serine proteases (66-72%), mammalian tissue kallikrein (42%) and thrombin (26%). Halystase contained the tentative catalytic triad of His43, Asp88 and Ser184 common to all serine proteases and Asp178 in the primary substrate-binding site. Although halystase contained an RGD sequence at residues 181-183, it did not inhibit platelet aggregation induced by ADP or collagen. It hydrolyzed most efficiently a tissue-kallikrein substrate, prolylphenylalanylarginyl-4-methyl-coumaryl-7-amide, and released bradykinin from bovine kininogen. Halystase did not coagulate human plasma, but it cleaved the fibrinogen B beta chain at the carboxyl side of Arg42 and cleaved slowly the fibrogen A alpha chain. Fibrinogen thus treated gradually became insensitive to thrombin. The proteolytic activity was inhibited with diisopropyl fluorophosphate, phenylmethylsulfonyl fluoride or leupeptin. These results indicate that halystase is a serine protease structurally similar to coagulating thrombin-like snake venom proteases, but it specifically cleaves fibrinogen at sites different from thrombin without inducing fibrin clotting, and hydrolyzes kininogen to produce bradykinin, resulting in the reduction of blood pressure.

Background Cardiac protection by volatile anesthetic-induced preconditioning and ischemic preconditioning have similar signaling pathways. Recently, it was reported that augmentation of protein modified with O-linked β-N-acetylglucosamine (O-GlcNAc) contributes to cardiac protection. This study investigated the role of O-GlcNAc in cardiac protection induced by anesthetic-induced preconditioning. Methods O-GlcNAc-modified proteins were visualized by immunoblotting. Tolerance against ischemia or reperfusion was tested in vivo (n = 8) and in vitro (n = 6). The opening of the mitochondrial permeability transition pore (mPTP) upon oxidative stress was examined in myocytes treated with calcein AM (n = 5). Coimmunoprecipitation and enzymatic labeling were performed to detect the mitochondrial protein responsible for the mPTP opening. Results Isoflurane treatment and the consequent augmentation of O-GlcNAc concentrations reduced the infarct size (26 ± 5% [mean ± SD], P < 0.001) compared with the control. The protective effect of O-GlcNAc was eliminated in the group pretreated with the O-GlcNAc transferase inhibitor alloxan (39 ± 5%, P < 0.001). Myocyte survival also showed the same result in vitro. Formation of the mPTP was abrogated in the isoflurane-treated cells (86 ± 4%, P < 0.001) compared with the control and alloxan-plus-isoflurane-treated cells (57 ± 7%, P < 0.001). Coimmunoprecipitation and enzymatic labeling studies revealed that the O-GlcNAc-modified, voltage-dependent anion channel restained the mPTP opening. Conclusions Isoflurane induced O-GlcNAc modification of mitochondrial voltage-dependent anion channel. This modification inhibited the opening of the mPTP and conferred resistance to ischemia-reperfusion stress.

article i nfo Article history: Received 15 June 2010 Accepted 27 October 2010 Aims: Volatile anesthetics, such as isoflurane, reverse glucose-induced inhibition of pancreatic adenosine triphosphate-sensitive potassium (KATP) channel activity, resulting in reduced insulin secretion and impaired glucose tolerance. No previous studies have investigated the effects of intravenous anesthetics, such as propofol, on pancreatic KATP channels. We investigated the cellular mechanisms underlying the effects of isoflurane and propofol on pancreatic KATP channels and insulin secretion. Main methods: Intravenous glucose tolerance tests (IVGTT) were performed on male rabbits. Pancreatic islets were isolated from male rats and used for a perifusion study, measurement of intracellular ATP concentration ((ATP)i), and patch clamp experiments. Key findings: Glucose stimulus significantly increased insulin secretion during propofol anesthesia, but not isoflurane anesthesia, in IVGTT study. In perifusion experiments, both islets exposed to propofol and control islets not exposed to anesthetic had a biphasic insulin secretory response to a high dose of glucose. However, isoflurane markedly inhibited glucose-induced insulin secretion. In a patch clamp study, the relationship between ATP concentration and channel activity could be fitted by the Hill equation with a half-maximal inhibition of 22.4, 15.8, and 218.8 μM in the absence of anesthetic, and with propofol, and isoflurane, respectively. (ATP)i and single KATP channel conductance did not differ in islets exposed to isoflurane or propofol. Significance: Our results indicate that isoflurane, but not propofol, decreases the ATP sensitivity of KATP channels and impairs glucose-stimulated insulin release. These differential actions of isoflurane and propofol on ATP sensitivity may explain the differential effects of isoflurane and propofol on insulin release.

ResumoJustificativaInvestigamos os efeitos de um novo método de anestesia, que combina propofol e anestesia volátil, sobre a incidência de náusea e vômito no período pós‐operatório de pacientes submetidas à laparoscopia ginecológica.MétodosAs pacientes foram randomicamente divididas em três grupos: manutenção com sevoflurano (Grupo S, n = 42), com propofol (Grupo P, n = 42) ou com a combinação de propofol e sevoflurano (Grupo PS, n = 42). Avaliamos as respostas completas (sem náusea e vômito no pós‐operatório e sem uso de antiemético de resgate), incidência de náusea e vômito, escore de gravidade da náusea, frequência de vômitos, uso de antiemético de resgate e dor no pós‐operatório em duas e 24horas após a cirurgia.ResultadosO número de doentes que apresentou uma resposta completa foi maior nos grupos P e PS do que no Grupo S em 0‐duashoras (74%, 76% e 43%m respectivamente, p = 0,001) e 0‐24horas (71%, 76% e 38%, respectivamente, p < 0,0005). A incidência de náusea em 0‐duashoras (Grupo S = 57%, Grupo P = 26% e Grupo PS = 21%, p = 0,001) e 0‐24horas (Grupo S = 62%; Grupo P = 29% e grupo PS = 21%, p < 0,0005) também foi significativamente diferente entre os grupos. Porém, não houve diferença significativa entre os grupos em relação à incidência ou frequência de vômitos ou uso de antiemético de resgate em 0‐24horas.ConclusãoA combinação de propofol e anestesia volátil durante a laparoscopia ginecológica efetivamente diminui a incidência de náusea no pós‐operatório.AbstractBackgroundWe investigated the effects of a novel method of anesthesia combining propofol and volatile anesthesia on the incidence of postoperative nausea and vomiting in patients undergoing laparoscopic gynecological surgery.MethodsPatients were randomly divided into three groups: those maintained with sevoflurane (Group S; n = 42), propofol (Group P; n = 42), or combined propofol and sevoflurane (Group PS; n = 42). We assessed complete response (no postoperative nausea and vomiting and no rescue antiemetic use), incidence of nausea and vomiting, nausea severity score, vomiting frequency, rescue antiemetic use, and postoperative pain at 2 and 24h after surgery.ResultsThe number of patients who exhibited a complete response was greater in Groups P and PS than in Group S at 0‐2h (74%; 76% and 43%; respectively, p = 0.001) and 0‐24h (71%; 76%, and 38%; respectively, p < 0.0005). The incidence of nausea at 0‐2h (Group S = 57%; Group P = 26% and Group PS = 21%; p = 0.001) and 0‐24h (Group S = 62%; Group P = 29% and Group PS = 21%; p < 0.0005) was also significantly different among groups. However, there were no significant differences among groups in the incidence or frequency of vomiting or rescue antiemetic use at 0‐24h.ConclusionCombined propofol and volatile anesthesia during laparoscopic gynecological surgery effectively decreases the incidence of postoperative nausea.

Background Remifentanil enhances intraoperative hemodynamic stability, suggesting that it may decrease intraoperative blood loss when included as an adjuvant to general anesthesia. This retrospective study compared intraoperative blood loss during spinal surgery in patients administered either remifentanil or fentanyl as an opioid adjuvant. Methods We reviewed clinical and surgical data from 64 consecutive laminoplasty or laminectomy patients treated at National Hospital Organization Zentsuji Hospital between April 2010 and March 2011. Patients received either remifentanil (n = 35) or fentanyl (n = 29) as an opioid analgesic during general anesthesia. In addition to intraoperative blood loss, indices of hemodynamic stability, including heart rate as well as systolic, mean, and diastolic blood pressure (BP), were compared over the entire perioperative period between remifentanil and fentanyl groups. Results The remifentanil group exhibited significantly lower intraoperative arterial BP than the fentanyl group. Intraoperative blood loss was also significantly lower in the remifentanil group (125 ± 67 mL vs. 165 ± 82 mL, P = 0.035). Conclusions Intraoperative blood loss during spinal surgery was decreased in patients who received remifentanil as an opioid adjuvant, possibly because of lower intraoperative BP. A larger-scale prospective randomized controlled trial is warranted to confirm our results and to test whether remifentanil can decrease intraoperative blood loss during other surgical procedures.

Purpose : Post-operative nausea and vomiting (PONV) remains the most fre- quently reported patient complaint after anesthesia. Aprepitant is the first neurokinin- 1(NK1) receptor antagonism available for use as an antiemetic. We investigated whether aprepitant can effectively decrease PONV in patients undergoing laparoscopic gyneco- logical surgery. Methods : Sixty four patients receiving general anesthesia for laparoscopic gynecological surgery were randomly assigned to either receive a preoperative dose of 80 mg aprepitant or no drug. Efficacy was assessed in 2 and 24 hours after surgery. Primary and secondary endpoints were analyzed for the time intervals 0-2 hours (acute phase) and 2-24 hours (delayed phase). Vomiting, nausea, use of rescue anti-emetic, and visual analog scale (VAS) were assessed. Nausea was assessed on a 4-point scale, from 0 to 3. Results : Sixty patients participated in the study. At acute phase, PONV was present in both control and NK1 group and were 63% nd 43% respectively. The severity of nausea was much less in the NK1 group. PONV prevalence at delayed phase was present in control but absent in NK1 group 27% s. 0% respectively. The amount of pain medication used by patients in the NK1 group was significantly less for diclofenac and pentazocine sug- gesting increase pain tolerance. Conclusions : Neurokinin-1 receptor antagonism effec- tively lowered PONV increased pain tolerance, and expedited recovery in patients under- going laparoscopic gynecological surgery. J. Med. Invest. 58 : 246-251, August, 2011