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Opioid inhibition of nociceptive stimuli varies in individuals and is difficult to titrate. We have reported the vascular stiffness value (K) as a standard monitor to quantify sympathetic response with high accuracy. On the contrary, among individuals, a considerable variation in the rate of change in K for constant pain has been observed. In this study, we proposed a new index, the minimum stimulus intensity value that evoked the response on K (MECK: Minimum Evoked Current of K), and evaluated its accuracy in predicting sympathetic response to nociceptive stimuli under constant opioid administration. Thirty patients undergoing open surgery under general anesthesia were included. After anesthetic induction, remifentanil was administered at a constant concentration of 2 ng/ml at the effect site followed by tetanus stimulation. MECK was defined as the minimal current needed to produce a change in K. MECK significantly (P BP). Bland–Altman plot analysis using the predicted ROCBP calculated from MECK and the measured ROCBP showed that the prediction equation for ROCBP was highly accurate. This study showed the potential of MECK to predict blood pressure change during surgical incision under opioid analgesia.Clinical trial registration Registry: University hospital medical information network; Registration number: UMIN000041816; Principal investigator's name: Satoshi Kamiya; Date of registration: July 9th, 2019.

Fish oil-derived long-chain monounsaturated fatty acids (LCMUFAs) with a carbon chain length longer than 18 units ameliorate cardiovascular risk in mice. In this study, we investigated whether LCMUFAs could improve endothelial functions in mice and humans. In a double-blind, randomized, placebo-controlled, parallel-group, multi-center study, healthy subjects were randomly assigned to either an LCMUFA oil (saury oil) or a control oil (olive and tuna oils) group. Sixty subjects were enrolled and administrated each oil for 4 weeks. For the animal study, ApoE-/- mice were fed a Western diet supplemented with 3% of either gadoleic acid (C20:1) or cetoleic acid (C22:1) for 12 weeks. Participants from the LCMUFA group showed improvements in endothelial function and a lower trimethylamine-N-oxide level, which is a predictor of coronary artery disease. C20:1 and C22:1 oils significantly improved atherosclerotic lesions and plasma levels of several inflammatory cytokines, including IL-6 and TNF-α. These beneficial effects were consistent with an improvement in the gut microbiota environment, as evident from the decreased ratio of Firmicutes and/ or Bacteroidetes, increase in the abundance of Akkermansia, and upregulation of short-chain fatty acid (SCFA)-induced glucagon-like peptide-1 (GLP-1) expression and serum GLP-1 level. These data suggest that LCMUFAs alter the microbiota environment that stimulate the production of SCFAs, resulting in the induction of GLP-1 secretion. Fish oil-derived long-chain monounsaturated fatty acids might thus help to protect against cardiovascular disease.

Background Previous studies showed that remifentanil-induced anesthesia can inhibit surgical stress response in non-diabetic adult patients and that low-dose glucose loading during anesthesia may attenuate fat catabolism. However, little is known about the influence of glucose loading on metabolism in elderly patients, whose condition may be influenced by decreased basal metabolism and increased insulin resistance. We hypothesized that, in elderly patients, intraoperative low glucose infusion may attenuate the catabolism of fat without causing harmful hyperglycemia during remifentanil-induced anesthesia. Methods Elderly, non-diabetic patients scheduled to undergo elective surgery were enrolled and randomized to receive no glucose (0G group) or low-dose glucose infusion (0.1 g/kg/hr. for 1 h followed by 0.05 g/kg/hr. for 1 h; LG group) during surgery. Glucose, adrenocorticotropic hormone (ACTH), 3-methylhistidine (3-MH), insulin, cortisol, free fatty acid (FFA), creatinine (Cr), and ketone body levels were measured pre-anesthesia, 1 h post-glucose infusion, at the end of surgery, and on the following morning. Results A total of 31 patients (aged 75–85) were included (0G, n = 16; LG, n = 15). ACTH levels during anesthesia decreased significantly in both groups. In the LG group, glucose levels increased significantly after glucose loading but hyperglycemia was not observed. During surgery, ketone bodies and FFA were significantly lower in the LG group than the 0G group. There were no significant differences in insulin, Cr, 3-MH, and 3-MH/Cr between the two groups. Conclusion Remifentanil-induced anesthesia inhibited surgical stress response in elderly patients. Intraoperative low-dose glucose infusion attenuated catabolism of fat without inducing hyperglycemia. Trial registration This study has been registered with the University hospital Medical Information Network Center (http://www.umin.ac.jp/english/). Trial registration number: UMIN000016189. The initial registration date: January 12th 2015.

Prolonged postoperative neuromuscular respiratory paralysis after administration of a nondepolarizing neuromuscular blocking agent is a serious concern during anesthetic management of patients with Charcot-Marie-Tooth disease (CMTD). Some recent reports have described rocuronium use without respiratory paralysis in CMTD patients when sugammadex was used for its reversal. We report a case in which an induction dose of rocuronium caused a prolonged respiratory paralysis in a patient with undiagnosed type 1A CMTD (CMT1A).A 63-yr-old-male with an American Society of Anesthesiologists Physical Status score of III underwent a left hip arthroplasty under general anesthesia for osteoarthritis. Preoperative pulmonary function testing indicated a restrictive impairment. Anesthesia was induced with fentanyl, remifentanil, propofol, and 0.73 mg·kgOur case shows that rocuronium can cause a prolonged neuromuscular respiratory paralysis refractory to sugammadex in patients with CMT1A and impaired respiratory function. Our case may also indicate that restrictive pulmonary impairment and low nerve conduction velocity of 20 m·secRéSUMé: OBJECTIF: La paralysie respiratoire neuromusculaire postopératoire prolongée après l’administration d’un bloqueur neuromusculaire non dépolarisant est une préoccupation sérieuse lors de la prise en charge anesthésique des patients atteints de la maladie de Charcot-Marie-Tooth (CMT). Certains comptes rendus récents ont décrit l’utilisation de rocuronium sans paralysie respiratoire chez les patients atteints de CMT lorsque le sugammadex était utilisé pour le neutraliser. Nous rapportons un cas dans lequel une dose d’induction de rocuronium a provoqué une paralysie respiratoire prolongée chez un patient atteint de CMT de type 1A (CMT1A) non diagnostiquée. CARACTéRISTIQUES CLINIQUES: Un homme de 63 ans avec un score de statut physique III selon la classification de l’American Society of Anesthesiologists a bénéficié d’une arthroplastie de la hanche gauche sous anesthésie générale pour son ostéo-arthrite. Les tests préopératoires de la fonction pulmonaire ont indiqué un syndrome restrictif. L’anesthésie a été induite avec du fentanyl, du rémifentanil, du propofol et 0,73 mg·kg-1 de rocuronium. Le décompte du train-de-quatre (TdQ) était de 0 pour toute la durée de la chirurgie, soit 273 minutes. Après l’échec de doses répétées de sugammadex qui n’ont pas réussi à rétablir un TdQ normal ni la respiration spontanée, un total de 1200 mg (17,3 mg·kg-1) de sugammadex (une quantité qu’on a présumé suffisante pour neutraliser le rocuronium résiduel) a été administré. Bien que le patient ait exprimé qu’il était éveillé en clignant des yeux, il ne pouvait pas respirer. Il a donc été placé sous ventilation mécanique pendant 18 heures après l’opération. Une consultation postopératoire en neurologie a révélé une vitesse de conduction nerveuse retardée de 20 m·sec-1 et une duplication mutée du gène PMP22; un diagnostic de CMT1A a été posé. CONCLUSIONS: Notre cas montre que le rocuronium peut provoquer une paralysie respiratoire neuromusculaire prolongée réfractaire au sugammadex chez les patients atteints de CMT1A et d’une altération de la fonction respiratoire. Notre cas pourrait également indiquer qu’un syndrome restrictif pulmonaire et une faible vitesse de conduction nerveuse de 20 m·sec-1 constituent des facteurs prédictifs provoquant une paralysie respiratoire neuromusculaire prolongée réfractaire au sugammadex dans les cas de CMT1A.

Coronary heart disease is a major global health concern. Further, severity of this condition is greatly influenced by myocardial ischemia/reperfusion (I/R) injury. Branched-chain amino acids (BCAAs) have cardioprotective effects against I/R via mammalian target of rapamycin (mTOR) activity, wherein Leu is considered to particularly regulate mTOR activation. However, the mechanism underlying cardioprotective effects of Leu via mTOR activity is not fully elucidated. Here, we aimed to study the signaling pathway of cardioprotection and mitochondrial function induced by Leu treatment.Cardiac myocytes isolated from adult male Wistar rats were incubated and exposed to simulated I/R (SI/R) injury by replacing the air content. Cardiac myocytes were treated with Leu and subsequently, their survival rate was calculated. To elucidate the signaling pathway and mitochondrial function, immunoblots and mitochondrial permeability transition pore were examined. Cell survival rate was decreased with SI/R but improved by 160 μM Leu (38.5 ± 3.6% vs. 64.5 ± 4.2%, respectively, p 0.001). Although rapamycin (mTOR inhibitor) prevented this cardioprotective effect induced by Leu, wortmannin (PI3K inhibitor) did not interfere with this effect. In addition, we indicated that overexpression of Opa-1 and mitochondrial function are ameliorated via Leu-induced mitochondrial biogenesis. In contrast, knockdown of Opa-1 suppressed Leu-induced cardioprotection.Leu treatment is critical in rendering a cardioprotective effect exhibited by BCAAs via mTOR signaling. Furthermore, Leu improved mitochondrial function.

The objective of this study was to examine the impact of around-the-clock (ATC) administration of intravenous (IV) acetaminophen following robot-assisted radical prostatectomy (RARP). Intravenous infusion of acetaminophen was started on the day of the operation at 1000 mg/dose every 6 h, and the infusion was continued on a fixed schedule until postoperative day 2 a.m. In a retrospective observational study, we compared 127 patients who were administered IV acetaminophen on a fixed schedule (ATC group) with 485 patients who were administered analgesic drugs only as needed (PRN group). We investigated postoperative pain intensity and additional analgesic consumption on postoperative day 0, 1, 2, 3, and 5 between the two groups. Postoperative pain scores were significantly lower in the ATC group than in the PRN group at 1 and 2 days, and this period matched the duration of ATC administration of IV acetaminophen. Postoperative frequency of rescue analgesia was significantly lower in the ATC group than in the PRN group at postoperative 0, 1, and 2 days. ATC administration of IV acetaminophen has the potential to be a very versatile and valuable additional dose to achieve appropriate postoperative analgesia in patients with RARP.

Robot-assisted laparoscopic radical prostatectomy (RALRP) is commonly performed in the surgical treatment of prostate cancer. However, the steep Trendelenburg position (25) and pneumoperitoneum required for this procedure can sometimes cause hemodynamic changes. Although blood pressure is traditionally monitored invasively during RALRP, the ClearSight system (BMEYE, Amsterdam, The Netherlands) enables a totally noninvasive and simple continuous blood pressure and cardiac output monitoring based on finger arterial pressure pulse contour analysis. We therefore investigated whether noninvasive continuous arterial blood pressure measurements using the ClearSight system were comparable to those obtained invasively in patients undergoing RALRP. Ten patients scheduled for RALRP with American Society of Anesthesiologists physical status I-II were included in this study. At each of the seven defined time points, noninvasive and invasive blood pressure measurements were documented and compared in each patient using Bland-Altman analysis. Although the blood pressure measured with the ClearSight system correlated with that measured invasively, a large difference between the values obtained by the two devices was noted. The ClearSight system was unable to detect blood pressure accurately during RALRP, suggesting that blood pressure monitoring using this device alone is not feasible in this small patient population. J. Med. Invest. 65:69-73, February, 2018.

To investigate the outcomes of patients with in-hospital cardiac arrest (IHCA) who underwent cardiopulmonary resuscitation (CPR) using an automated external defibrillator (AED) in non-monitored areas. Additionally, to detect correlated factors associated with rate of return of spontaneous circulation (ROSC) and survival rate, among collected data.This study included 109 patients. After investigating patient characteristics and resuscitation-related factors, the correlated factors associated with ROSC rates and survival rate were analyzed using univariate and multivariate analyses.The rate of survival to hospital discharge was 21.1%. CPR with AED performed since 2013 was associated with a higher ROSC rate (adjusted odds ratio [AOR] 3.24, 95% confidence interval [CI]: 1.21 to 9.52, p 0.05), but not with the survival rate after ROSC. Tracheal intubation was significantly associated with a higher ROSC rate (AOR 3.62, 95% CI: 1.27 to 11.7, p 0.05) and a lower survival rate after ROSC (hazard ratio 6.6, 95% CI: 1.2 to 43.3, p 0.05). Dysrhythmia as the cause of cardiac arrest and intensive care unit (ICU) admission after ROSC were associated with higher survival rates (hazard ratio 0.056, 95% CI: 0.004 to 0.759, p 0.05, and hazard ratio 0.072, 95% CI: 0.017 to 0.264, p 0.0001, respectively).The factors associated with ROSC rate and those associated with the survival rate after ROSC were different. Although initial shockable rhythms on AED were not associated with the survival rate, dysrhythmia as the etiology of cardiac arrest, and ICU admission were significantly associated with higher survival rates after ROSC.

Study Objective : the incidence of postoperative nausea and vomiting (PONV) following single-injection intraarticular anesthesia was compared to that following continuous epidural anesthesia. Design : Prospective, double-blind, randomized study. Setting : University-affiliated teaching hospital. Patients : Forty-eight patients finally participated in this study, and each group contained twenty-four patients. Interventions : Patients scheduled to undergo lower limb surgery under general anesthesia were randomly allocated into two groups, to receive either single-injection intraarticular or continuous epidural anesthesia for postoperative analgesia. Measurements : The incidence and severity of PONV, complete response rates (i.e., no vomiting or rescue antiemetic use), and pain scores were recorded 2, 24, and 48 h postoperatively. Main results : No significant differences between groups were observed in the incidence and severity of PONV, rescue antiemetic use, or complete response rate at any of the time points, but only the use of rescue analgesics was significantly less in continuous epidural anesthesia group during the 2-24h postoperative period (P=0.04). Conclusion : While the use of single-injection intraarticular anesthesia following lower limb surgery did not prevent PONV more than continuous epidural anesthesia in this study, the intraarticular technique still provides greater simplicity, safety, and cost-effectiveness. J. Med. Invest. 66 : 303-307, August, 2019.

Objective Enhanced recovery after surgery is increasingly desired nowadays, and preoperative nutrient intake may be beneficial for this purpose. In this study, we investigated whether the intake of preoperative carbohydrate with amino acid (ONS) solution can improve starvation status and lipid catabolism before the induction of anesthesia. Methods This randomized, prospective clinical trial included 24 patients who were divided into two groups before surgery under general anesthesia: a control group, comprising patients who fasted after their last meal the day before surgery (permitted to drink only water), and an ONS group, comprising patients who consumed ONS solution 2 h before surgery. Biochemical markers, the respiratory quotient, and psychosomatic scores were assessed at the initiation of anesthesia. Results Compared with the control group, the ONS group showed significantly lower serum free fatty acid levels [control group: 828 (729, 1004) µEq/L, ONS group: 479 (408, 610) µEq/L, P = 0.0002, median (25th, 75th percentile)] and total ketone bodies [control group: 119 (68, 440) µmol/L, ONS group: 40 [27, 64] µmol/L, P = 0.037]. In addition, analysis using the Visual Analog Scale showed higher preoperative scores for anxiety, hunger, and thirst for the control group, with no differences in any other measure of subjective well-being between groups. Conclusions The results of this study suggest that preoperative ONS intake improves lipid catabolism and starvation status before the induction of anesthesia. Furthermore, it can provide better preoperative mental health compared with complete fasting.

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

Aims: Amino acids, especially branched chain amino acids (BCAAs), have important regulatory roles in protein synthesis. Recently studies revealed that BCAAs protect against ischemia/reperfusion (I/R) injury. We studied the signaling pathway and mitochondrial function affecting a cardiac preconditioning of BCAAs. Main methods: An in vivo model of I/R injury was tested in control, mTOR+/+, and mTOR+/−. Mice were randomly assigned to receive BCAAs, rapamycin, or BCAAs + rapamycin. Furthermore, isolated cardiomyocytes were subjected to simulated ischemia and cell death was quantified. Biochemical and mitochondrial swelling assays were also performed. Key findings: Mice treated with BCAAs had a significant reduction in infarct size as a percentage of the area at risk compared to controls (34.1 ± 3.9% vs. 44.7 ± 2.6%, P = 0.001), whereas mice treated with the mTOR inhibitor rapamycin were not protected by BCAA administration (42.2 ± 6.5%, vs. control, P = 0.015). This protection was not detected in our hetero knockout mice of mTOR. Western blot analysis revealed no change in AKT signaling whereas activation of mTOR was identified. Furthermore, BCAAs prevented swelling which was reversed by the addition of rapamycin. In myocytes undergoing simulated I/R, BCAA treatment significantly preserved cell viability (71.7 ± 2.7% vs. 34.5 ± 1.6%, respectively, p < 0.0001), whereas rapamycin prevented this BCAA-induced cardioprotective effect (43.5 ± 3.4% vs. BCAA, p < 0.0001). Significance: BCAA treatment exhibits a protective effect in myocardial I/R injury and that mTOR plays an important role in this preconditioning effect., This work was supported by JSPS KAKENHI, Japan [grant number 19K09353].

We investigated the effectiveness of the ClearSight system for hemodynamic management during kidney transplantation for a recipient. The recipient was to receive a kidney transplant from his mother under general anesthesia. We used continuous noninvasive finger-cuff-based monitoring of blood pressure, provided by the ClearSight system, and stroke volume variation to predict fluid responsiveness. We used of a balanced anesthetic technique and stringent monitoring standards to ensure a successful outcome for the patient. This case demonstrated that ClearSight has the potential to improve patient monitoring in hemodynamically stable patients who received kidney transplantation under general anesthesia. J. Med. Invest. 65:139-141, February, 2018.

Postoperative nausea and vomiting (PONV) is the most common complication after surgery, and opioid administration increases its incidence. We compared the preventive effects of fosaprepitant, a neurokinin-1 (NK1) receptor antagonist, with those of ondansetron on PONV in patients who underwent lower limb surgery with postoperative epidural opioid administration.This prospective, double-blind, randomized study included 38 patients who underwent lower limb surgery. They were randomly allocated to receive intravenous fosaprepitant 150 mg (n = 19; NK1 group) or ondansetron 4 mg (n = 19; ONS group) before general anesthesia. All patients received postoperative epidural fentanyl for pain control. The incidence of nausea and vomiting, complete response rate (no vomiting and no rescue antiemetic use), rescue antiemetic use, nausea score (0-3), and visual analog scale (VAS 0-10) score for pain were recorded at 2, 24, and 48 h after surgery.No patient in the NK1 group experienced vomiting (0%) during the first 24 and 48 h after surgery, while 5 of 19 (26%) patients in the ONS group experienced this complication, indicating a significant difference between groups. There were no significant differences in the incidence of PONV, complete response rate, rescue antiemetic use, nausea score, and VAS score for pain between the NK1 and ONS groups during the study period.Fosaprepitant was more effective than ondansetron in decreasing the incidence of vomiting after lower limb surgery with postoperative opioid administration. Meanwhile, fosaprepitant was not inferior to ondansetron in decreasing the incidence and severity of PONV.

Aims Geranylgeranylacetone (GGA) is commonly utilized to protect the gastric mucosa in peptic ulcer disease. Recently GGA has been shown to protect the myocardium from ischemia/reperfusion by activating heat shock proteins. However, the exact mechanism as to how GGA activates these protective proteins is unknown. Caveolae and caveolin-3 (Cav-3) have been implicated in ischemia, anesthetic, and opioid induced cardiac protection. Given the lipophilic nature of GGA it is our hypothesis that GGA induced cardiac protection requires caveolae and Cav-3. Main methods We used an in vivo mouse model of ischemia–reperfusion injury and performed biochemical assays in excised hearts. Key findings GGA treated control mice revealed increased caveolae formation and caveolin-3 in buoyant fractions, mediating heat shock protein 70 activation. Furthermore, control mice treated with GGA were protected against ischemia/reperfusion injury whereas Cav-3 knockout (Cav-3 KO) mice were not. Troponin levels confirmed myocardial damage. Finally, Cav-3 KO mice treated with GGA were not protected against mitochondrial swelling whereas control mice had significant protection. Significance This study showed that caveolae and caveolin-3 are essential in facilitating GGA induced cardiac protection by optimizing spatial and temporal signaling to the mitochondria.

Pharmacological preconditioning, including that with geranylgeranylacetone (GGA) and volatile anesthetics, has been shown to confer cardiac protection from ischemia/reperfusion injury although the mechanisms for this protection are poorly understood. Caveolins, integral membrane proteins that act as scaffolding proteins in caveolar membranes, localize molecules involved in cardiac protection. We have tested the hypothesis that caveolin-3 (Cav-3), the predominant isoform in cardiac myocytes, is essential for the synergistic effect observed between GGA and volatile anesthetics.Mice were randomly assigned to receive GGA, isoflurane [0.5 and 1.0 minimum alveolar concentration (MAC)], or GGA + isoflurane (0.5 MAC). An in vivo mouse model of ischemia/reperfusion injury was tested in wild-type and Cav-3 knockout mice, and the infarct size was determined. Biochemical assays were also performed in excised hearts.Geranylgeranylacetone and therapeutic isoflurane (1.0 MAC) independently reduced infarct size (31.6 ± 6.1 and 28.0 ± 5.0% of the area at risk, respectively; n = 10) as compared to the controls (45.8 ± 9.4%; n = 10). The combination GGA + sub-therapeutic isoflurane (0.5 MAC) further decreased the infarct size to 19.3 ± 5.1% (n = 10). Preconditioning [GGA, isoflurane (1.0 MAC), and GGA + isoflurane] increased the amount of Cav-3 protein in the discontinuous sucrose-gradient buoyant fractions. Additionally, cardiac protection was not observed in Cav-3 knockout mice following the administration of GGA, isoflurane, and GGA + isoflurane.Combined administration of GGA + isoflurane had a synergistic effect, enhancing the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by Cav-3 expression.

The incidence of postoperative nausea and vomiting (PONV) is 30–50% after surgery. PONV occurs frequently, especially after craniotomy. In this study, we investigated the preventive effects on PONV in a randomized study by comparing patients who had been administered fosaprepitant, a neurokinin-1 (NK1) receptor antagonist, or ondansetron intravenously. Sixty-four patients undergoing craniotomy were randomly allocated to receive fosaprepitant 150 mg i.v. (NK1 group,n= 32) or ondansetron 4 mg i.v. (ONS group,n= 32) before anesthesia. The incidence of vomiting was significantly less in the NK1 group, where 2 of 32 (6%) patients experienced vomiting compared to 16 of 32 (50%) patients in the ONS group during the first 24 and 48 hours following surgery. Additionally, the incidence of complete response (no vomiting and no rescue antiemetic use) was significantly higher in the NK1 group than in the ONS group, and was 66% versus 41%, respectively, during the first 24 hours, and 63% versus 38%, respectively, during the first 48 hours. In patients undergoing craniotomy, fosaprepitant is more effective than ondansetron in increasing the rate of complete response and decreasing the incidence of vomiting at 24 and 48 hours postoperatively.

The aim of the present study was to evaluate the usefulness of a closed-loop system (STG-55; Nikkiso, Tokyo, Japan), a type of artificial endocrine pancreas for the continuous monitoring and control of intraoperative blood glucose, for preventing postoperative acute kidney injury (AKI) in patients undergoing hepatectomy. Thirty-eight patients were enrolled in this study. Glucose concentrations were controlled with either a manual injection of insulin based on a commonly used sliding scale (manual insulin group, n = 19) or the programmed infusion of insulin determined by the control algorithm of the artificial endocrine pancreas (programmed insulin group, n = 19). After the induction of anesthesia, a 20-G intravenous catheter was inserted into the peripheral forearm vein of patients in the programmed insulin group and connected to an artificial endocrine pancreas (STG-55). The target range for glucose concentrations was set to 100–150 mg/dL. The mean serum creatinine concentrations of preoperative, postoperative 24 and 48 h were 0.72, 0.78, and 0.79 mg/dL in the programmed insulin group, and 0.81, 0.95, and 1.03 mg/dL in the manual insulin group, respectively. Elevations in serum creatinine concentrations postoperative 48 h were significantly suppressed in the programmed insulin group. The STG-55 closed-loop system was effective for maintaining strict blood glucose control during hepatectomy with minimal variability in blood glucose concentrations and for suppressing elevations in serum creatinine concentrations. Strict blood glucose control by an artificial endocrine pancreas during hepatectomy may prevent postoperative AKI.

Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH2-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to produce cardiac protection from ischemia-reperfusion injury.

Background Caveolae are small, flask-like invaginations of the plasma membrane. Caveolins are structural proteins found in caveolae that have scaffolding properties to allow organization of signaling. The authors tested the hypothesis that delayed cardiac protection induced by volatile anesthetics is caveolae or caveolin dependent. Methods An in vivo mouse model of ischemia-reperfusion injury with delayed anesthetic preconditioning (APC) was tested in wild-type, caveolin-1 knockout, and caveolin-3 knockout mice. Mice were exposed to 30 min of oxygen or isoflurane and allowed to recover for 24 h. After 24 h recovery, mice underwent 30-min coronary artery occlusion followed by 2 h of reperfusion at which time infarct size was determined. Biochemical assays were also performed in excised hearts. Results Infarct size as a percent of the area at risk was reduced by isoflurane in wild-type (24.0 +/- 8.8% vs. 45.1 +/- 10.1%) and caveolin-1 knockout mice (27.2 +/- 12.5%). Caveolin-3 knockout mice did not show delayed APC (41.5 +/- 5.0%). Microscopically distinct caveolae were observed in wild-type and caveolin-1 knockout mice but not in caveolin-3 knockout mice. Delayed APC increased the amount of caveolin-3 protein but not caveolin-1 protein in discontinuous sucrose-gradient buoyant fractions. In addition, glucose transporter-4 was increased in buoyant fractions, and caveolin-3/glucose transporter-4 colocalization was observed in wild-type and caveolin-1 knockout mice after APC. Conclusions These results show that delayed APC involves translocation of caveolin-3 and glucose transporter-4 to caveolae, resulting in delayed protection in the myocardium.

Summary Background Maintenance of a competent permeability barrier in the face of external and internal stressors requires signals between the stratum corneum interface and the metabolic machinery in the underlying nucleated layers. For example, reductions in the ion gradients for Ca2+ after acute barrier disruption stimulate lamellar body (LB) secretion, a response required to restore barrier homeostasis. Although alterations in external K+ levels also regulate barrier recovery after acute insults, the mechanisms whereby K+ regulates barrier function remain unknown. Objectives To evaluate effects of regulators of K+ channels on barrier homeostasis in hairless mice. Methods We tested a number of chemically different drugs that alter intracellular K+ levels. Results Single applications of either K+ channel openers (i.e. 1-EBIO, minoxidil, diazoxide) or the K+ ionophore, valinomycin, accelerated barrier recovery after acute insults to murine skin, paralleled by a reduction in intracellular K+ levels in cultured human keratinocytes. In contrast, applications of K+ channel blockers (i.e. gilbenclamide, dequalinium) delayed barrier recovery. Alterations in intracellular K+ regulated barrier homeostasis by either stimulating (reduced K+) or inhibiting (elevated K+) LB secretion. Finally, development of epidermal hyperplasia, a downstream consequence of barrier disruption, was also inhibited by agents that reduce intracellular K+ levels. Conclusions These results demonstrate that changes in K+ levels that can be presumed to occur after barrier disruption signal metabolic responses, i.e. LB secretion, which accelerates normalization of barrier function.

To investigate the cardioprotective effects of isoflurane and exendin-4 against myocardial ischemia/reperfusion injury and the signaling pathways through which these effects are mediated.For infarct size measurements, anesthetized mice were subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion. Wild-type or caveolin-3 knockout mice received isoflurane, exendin-4, or isoflurane with exendin-4 before ischemia index determination. Caveolin-3 expression in the heart was measured by immunoblotting.Myocardial infarct size was smaller in the isoflurane- [1.0 minimum alveolar concentration (MAC)] or exendin-4- (30 ng/kg i.v.) treated groups than the controls. Infarct size was not affected by isoflurane at 0.5 MAC or 3 ng/kg i.v. exendin-4, but the combination of these treatments reduced infarct size. Pharmacological preconditioning (isoflurane at 1.0 MAC, 30 ng/kg i.v. exendin-4, or isoflurane at 0.5 MAC with 3 ng/kg i.v. exendin-4) increased caveolin-3 protein expression in the heart after infarct induction. The cardioprotective effects of isoflurane, exendin-4, and isoflurane with exendin-4 were abolished in caveolin-3 knockout mice.The combination of isoflurane and exendin-4 reduced infarct size, but it was not more effective than either agent alone, and the cardioprotective effects of these agents are mediated by caveolin-3 expression.

Background Isoflurane reduces myocardial ischemia-reperfusion injury within hours to days of reperfusion. Whether isoflurane produces sustained cardiac protection has never been examined. The authors studied isoflurane-induced cardiac protection in the intact mouse after 2 h and 2 weeks of reperfusion and determined the dependence of this protection on adenosine triphosphate-dependent potassium channels and the relevance of this protection to myocardial function and apoptosis. Methods Mice were randomly assigned to receive oxygen or isoflurane for 30 min with 15 min of washout. Some mice received mitochondrial (5-hydroxydecanoic acid) or sarcolemmal (HMR-1098) adenosine triphosphate-dependent potassium channel blockers with or without isoflurane. Mice were then subjected to a 30-min coronary artery occlusion followed by 2 h or 2 weeks of reperfusion. Infarct size was determined at 2 h and 2 weeks of reperfusion. Cardiac function and apoptosis were determined 2 weeks after reperfusion. Results Isoflurane did not change hemodynamics. Isoflurane reduced infarct size after reperfusion when compared with the control groups (27.7 +/- 6.3 vs. 41.7 +/- 6.4% at 2 h and 19.6 +/- 5.9 vs. 28.8 +/- 9.0% at 2 weeks). Previous administration of 5-hydroxydecanoic acid, but not HMR-1098, abolished isoflurane-induced cardiac protection. At 2 weeks, left ventricular end-diastolic diameter was decreased significantly and end-systolic pressure and maximum and minimum dP/dt were improved by isoflurane. Isoflurane-treated mice subjected to ischemia and 2 weeks of reperfusion showed less expression of proapoptotic genes, significantly decreased expression of cleaved caspase-3, and significantly decreased deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling-positive nuclei compared with the control group. Conclusions Cardiac protection induced by isoflurane against necrotic and apoptotic cell death is associated with an acute memory period that is sustained and functionally relevant 2 weeks after ischemia-reperfusion injury in mice in vivo.

Background Activation of adenosine triphosphate-sensitive potassium (K(ATP)) channels produces cardioprotective effects during ischemia. Because propofol is often used in patients who have coronary artery disease undergoing a wide variety of surgical procedures, it is important to evaluate the direct effects of propofol on K(ATP) channel activities in ventricular myocardium during ischemia. Methods The effects of propofol (0.4-60.1 microg/ml) on both sarcolemmal and mitochondrial K(ATP) channel activities were investigated in single, quiescent rat ventricular myocytes. Membrane currents were recorded using cell-attached and inside-out patch clamp configurations. Flavoprotein fluorescence was measured to evaluate mitochondrial oxidation mediated by mitochondrial K(ATP) channels. Results In the cell-attached configuration, open probability of K(ATP) channels was reduced by propofol in a concentration-dependent manner (EC(50) = 14.2 microg/ml). In the inside-out configurations, propofol inhibited K(ATP) channel activities without changing the single-channel conductance (EC(50) = 11.4 microg/ml). Propofol reduced mitochondrial oxidation in a concentration-dependent manner with an EC(50) of 14.6 microg/ml. Conclusions Propofol had no effect on the sarcolemmal K(ATP) channel activities in patch clamp configurations and the mitochondrial flavoprotein fluorescence induced by diazoxide at clinically relevant concentrations (< 2 microm), whereas it significantly inhibited both K(ATP) channel activities at very high, nonclinical concentrations (> 5.6 microg/ml; 31 microm).

Background Exendin-4, an exogenous glucagon-like peptide-1 receptor (GLP-1R) agonist, protects the heart from ischemia/reperfusion injury. However, the mechanisms for this protection are poorly understood. Caveolae, sarcolemmal invaginations, and caveolins, scaffolding proteins in caveolae, localize molecules involved in cardiac protection. We tested the hypothesis that caveolae and caveolins are essential for exendin-4 induced cardiac protection using in vitro and in vivo studies in control and caveolin-3 (Cav-3) knockout mice (Cav-3 KO). Methods Myocytes were treated with exendin-4 and then incubated with methyl-β-cyclodextrin (MβCD) to disrupt caveolae formation. This was then followed by simulated ischemia/reperfusion (SI/R). In addition, cardiac protection in vivo was assessed by measuring infarct size and cardiac troponin levels. Results Exendin-4 protected cardiac myocytes (CM) from SI/R [35.6 ± 12.6% vs. 64.4 ± 18.0% cell death, P = 0.034] and apoptosis but this protection was abolished by MβCD (71.8 ± 10.8% cell death, P = 0.004). Furthermore, Cav-3/GLP-1R co-localization was observed and membrane fractionation by sucrose density gradient centrifugation of CM treated with MβCD + exendin-4 revealed that buoyant (caveolae enriched) fractions decreased Cav-3 compared to CM treated with exendin-4 exclusively. Furthermore, exendin-4 induced a reduction in infarct size and cardiac troponin relative to control (infarct size: 25.1 ± 8.2% vs. 41.4 ± 4.1%, P

During perioperative fasting, lipid metabolism gradually increases, resulting in free fatty acids (FFA) and/or ketone bodies. Suppression of surgical stress by remifentanil may allow the safe administration of glucose infusions, avoiding both hyperglycemia and ketogenesis. The effects of glucose infusion on glucose and lipid metabolism were therefore investigated in patients undergoing minor surgery with remifentanil anesthesia.Thirty-four patients were randomized 1 : 1 to receive no glucose (0G group) or low-dose glucose (0.1 g/kg/h for 1 h followed by 0.05 g/kg/h for 1 h; LG group). The concentrations of glucose, adrenocorticotropic hormone (ACTH), 3-methylhistidine (3-MH), insulin, cortisol, FFA, creatinine (Cr), and ketone bodies were measured before anesthetic induction, 1 and 2 h after glucose infusion, at the end of surgery, and the next morning.The concentrations of cortisol and ACTH decreased during surgery in both groups when compared with the concentrations before anesthesia and at the end of surgery (P 0.05). Glucose and insulin concentrations were significantly higher in the LG than in the 0G group at 1 and 2 h after infusion. No patient experienced hyperglycemia. The concentrations of FFA and ketone bodies were lower in the LG than in the 0G group during surgery, but there were no significant between group differences in 3-MH/Cr.Infusion of low-dose glucose attenuated fat catabolism without causing hyperglycemia, indicating that infusion of low-dose glucose during remifentanil-induced anesthesia may be safe for patients.

Twenty-one monkeys (cynomolgus, rhesus, African green) were fed cyclamate (100 mg/kg and 500 mg/kg) in the diet five times per week from a few days after birth and continuing for up to 24 years. Malignant tumors were diagnosed in three 24-year-old cyclamate monkeys; these were metastatic colon carcinoma (rhesus; 500 mg/kg), metastatic hepatocellular carcinoma (cynomolgus; 500 mg/kg), and a small, well differentiated adenocarcinoma of the prostate (cynomolgus; 100 mg/kg). Benign tumors were found at necropsy in three females; these were adenoma of the thyroid gland (rhesus; 100 mg/kg) and two cases of leiomyoma of the uterus (rhesus; 100 mg/kg and 500 mg/kg). No tumors were detected in an age-matched control group of 16 monkeys. Examination of the testes revealed complete testicular atrophy in one of the old cyclamate monkeys, and focal germ cell aplasia (Sertoli-only tubules) in two other cyclamate monkeys. Focal spermatogenic interruption (maturation arrest) at various germ cell levels mixed with normal spermatogenesis was observed in both the cyclamate-treated and the control monkeys, all of which were over 20 years old. Measurements of terminal cyclohexylamine concentrations showed that three of the males dosed with cyclamate at 500 mg/kg were high converters, with plasma concentrations comparable to the levels that produce testicular atrophy in rats. However, only one of the three high converters showed histologic evidence of irregular spermatogenesis. The overall conclusion is that the testicular abnormalities and the sporadic cases of different malignancies found after more than 20 years of dosing do not provide clear evidence of a toxic or carcinogenic effect of sodium cyclamate in monkeys.

Patients with renal failure often experience decreased serum zinc that remains uncorrected after dialysis. A complication of this depletion is taste impairment, which can detrimentally influence diet and nutrition. However, because more than half of all serum zinc is bound to albumin, we hypothesized that normalizing serum zinc to albumin levels may be associated with taste impairment. A total of 65 patients undergoing dialysis but not receiving supplementary zinc and 120 control patients not undergoing dialysis (60 malnourished patients and 60 healthy controls) were tested for their receptiveness to saltiness using various salt concentrations. Patients' total protein and albumin levels were measured, and linear regressions were extrapolated between serum zinc levels and total protein or albumin. Patients undergoing dialysis had significantly lower levels of total serum zinc compared with control patients. However, uncorrected zinc levels were not correlated with taste impairment. Normalizing zinc levels against total protein or albumin resulted in extrapolated equations that revealed a significant correlation with taste impairment. Our data suggest a statistical correlation between zinc and albumin in both healthy subjects and patients undergoing maintenance hemodialysis, or protein-energy malnutrition without hemodialysis, allowing for a quantitative measure for taste impairment.

Lubag disease is a genetic X-linked dystonia-parkinsonism syndrome afflicting Filipino men. This disease is characterized by dystonia dominating the first 10-15 years of the disorder, which is associated with or replaced by parkinsonian features in later years of life. A 49-year-old man with Lubag disease underwent general anesthesia for deep brain stimulation (DBS) surgery. Anesthesia was maintained mainly with propofol, remifentanil, rocuronium bromide, and sevoflurane. During magnetic resonance imaging, the patient was anesthetized with midazolam, fentanyl, and rocuronium bromide. The surgery was completed safely using these anesthetic agents. After DBS, some symptoms including involuntary movement improved within 10 days.

Anaphylaxis during anesthesia is a rare but life-threatening event. Sugammadex is a recently introduced drug that was specifically designed for the reversal of rocuroium and vecuronium-induced neuromuscular block. We describe the cases of a 74-year-old man and a 29-year-old man who developed an anaphylactoid reaction to sugammadex, presenting with cardiovascular collapse. Initial management consisted of fluid administration and intermittent i.v. ephedrine, epinephrine, and hydrocortisone. The patients made uncomplicated recovery and were discharged.

We describe anesthetic management of a patient with airway stenosis due to a tracheal tumor involving the carina. A 68-year-old man developed dyspnea and was scheduled for YAG laser surgery under general anesthesia. Awake fiberoptic intubation was selected for anesthesia induction, and percutaneous cardiopulmonary support (PCPS) was ready to be established prior to induction of anesthesia. Anesthesia was maintained with remifentanil (0.05 microg x kg(-1) x min(-1)) and propofol (2 mg x kg(-1) x hr(-1)), and spontaneous breathing was preserved throughout the surgical procedure. The operation was completed successfully without any adverse events, and PCPS was not used. In this patient, preservation of spontaneous breathing using remifentanil was found to be useful for airway management.

Brugada syndrome is characterized by an electrocardiograph pattern of right bundle-branch block and has an increased risk for cardiac arrest due to malignant arrhythmia. We describe the successful anesthetic management for electroconvulsive therapy in a patient with Brugada electrocardiograph pattern. Patients with Brugada ECG pattern are not recommended to use neostigmine which augments ST elevation. Sugammadex was administered as a neuromuscular reversal agent in this case. Sugammadex provides rapid reversal of profound rocuronium-induced neuromuscular blockade under propofol anesthesia.

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.

We experienced anesthetic management of a patient with Becker muscular dystrophy. He had advanced dilated cardiomyopathy and high serum CK in the preoperative examinations. Anesthesia was planned to avoid triggering malignant hyperthermia or rhabdomyolysis and hemodynamic changes. Propofol, remifentanil and a minimum dose of rocuronium bromide were used for anesthetic induction and maintainance. Arterial pressure, cardiac output and stroke volume variation were monitored by Flotrac sensor. There were no adverse events observed during the anesthetic management. In conclusion, total intravenous anesthesia with the administration of rocuronium and circulatory monitoring by Flotrac sensor could be safe and efficient for anesthetic management of patients with Becker muscular dystrophy.

Aims Compound K (C-K; 20-O- d -glucopyranosyl-20(S)-protopanaxadiol) is a novel ginsenoside metabolite formed by intestinal bacteria and does not occur naturally in ginseng. In this study, we investigated whether administration of C-K has protective effects on myocardial ischemia-reperfusion injury and its potential mechanisms. Main methods We used in vivo mouse models of ischemia-reperfusion injury and performed biochemical assays in excised hearts. Key findings C-K reduced infarct size compared with the control group after ischemia-reperfusion. Immunoblot analysis showed that C-K significantly enhanced protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) activity. Wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, blocked cardiac protection in vivo and attenuated phosphorylation of Akt and eNOS. Additionally, the hearts of C-K pretreated mice showed inhibition of mitochondrial swelling induced by Ca 2+ . Significance This study showed that Compound K pretreatment has protective effects on myocardial ischemia-reperfusion injury, partly by mediating the activation of PI3K pathway and phosphorylation of Akt and eNOS.

We tested the hypothesis that caveolin-3 (Cav-3) is essential for opioid-induced preconditioning in vivo. Cav-3 overexpressing mice, Cav-3 knockout mice (Cav-3 KO), and controls were exposed to myocardial ischemia/reperfusion (I/R) in the presence of SNC-121 (SNC), a delta-selective opioid agonist, or naloxone, a non-selective opioid antagonist. Controls were protected from I/R injury by SNC. No protection was produced by SNC in Cav-3 KO mice. Cav-3 over-expressing mice showed innate protection from I/R compared with controls that was abolished by naloxone. Our results show opioid-induced preconditioning is dependent on Cav-3 expression and endogenous protection in Cav-3 over-expressing mice is opioid dependent.

We evaluated Disposable Crystal Laryngoscope Blades in terms of preventing infection. Most anesthesiologists were satisfied with the view offered by the Disposable Crystal Laryngoscope Blade; however more force is necessary to lift the epiglottis during intubation. It may be more difficult to use by residents, inexperienced anesthesiologist, or emergency medical technicians, although the Disposable Crystal Laryngoscope blade is useful for preventing infection.

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.

Summary Background Previous studies have demonstrated that sex hormones modulate epidermal permeability barrier homeostasis, and when the balance of these hormones is altered at menopause or during the menstrual cycle, skin sensitivity or barrier function is changed. Objectives To observe the direct effects of sex hormones on epidermal homeostasis. Methods We examined the effects of topical application of sex hormones on permeability barrier recovery after tape stripping in the hairless mouse. To avoid the influence of systemic hormonal alteration, we employed male animals. Results Application of androgen (testosterone or androsterone) delayed the barrier recovery, and the delay was overcome by co-application of β-estradiol. Progesterone also delayed the barrier recovery, but in this case the delay was enhanced by β-estradiol. Conclusions These results suggest that changes in sex hormone balance might be associated with the skin dysfunction that often occurs during menopause, and at certain points during the menstrual cycle.

Reactive oxygen species (ROS) generated by ischemic and pharmacological preconditioning are known to act as triggers of cardiac protection; however, the involvement of ROS in ischemic and pharmacological postconditioning (PostC) in vivo and in vitro is unknown. We tested the hypothesis that ROS are involved in PostC in the mouse heart in vivo and in the isolated adult cardiac myocyte (ACM). Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion with or without ischemic or pharmacologic PostC (three cycles of 20 s reperfusion/ischemia; 1.4% isoflurane; 10 mg/kg SNC-121). Additional groups were treated with 2-mercaptopropionyl glycine (MPG), a ROS scavenger, 10 min before or after the PostC stimuli. Ischemia-, isoflurane-, and SNC-121- induced PostC reduced infarct size (24.1+/-3.2, 15.7+/-2.6, 24.9+/-2.6%, p0.05, respectively) compared to the control group (43.4+/-3.3%). These cardiac protective effects were abolished by MPG when administered before (40.0+/-3.6, 39.3+/-3.1, 38.5+/-1.6%, respectively), but not after the PostC stimuli (26.6+/-2.3, 17.0+/-2.2, 23.9+/-1.7%, respectively). Additionally, ACM were subjected to a simulated ischemia/reperfusion protocol with isoflurane and SNC PostC. Isoflurane- and SNC-induced PostC in vitro were abolished by prior treatment with MPG. These data indicate that ROS signaling is an essential trigger of ischemic and pharmacological PostC and this is occurring at the level of the cardiac myocyte.

Caveolae, small invaginations in the plasma membrane, contain caveolins (Cav) that scaffold signaling molecules including the tyrosine kinase Src. We tested the hypothesis that cardiac protection involves a caveolin-dependent mechanism. We used in vitro and in vivo models of ischemia-reperfusion injury, electron microscopy (EM), transgenic mice, and biochemical assays to address this hypothesis. We found that Cav-1 mRNA and protein were expressed in mouse adult cardiac myocytes (ACM). The volatile anesthetic, isoflurane, protected ACM from hypoxia-induced cell death and increased sarcolemmal caveolae. Hearts of wild-type (WT) mice showed rapid phosphorylation of Src and Cav-1 after isoflurane and ischemic preconditioning. The Src inhibitor PP2 reduced phosphorylation of Src (Y416) and Cav-1 in the heart and abolished isoflurane-induced cardiac protection in WT mice. Infarct size (percent area at risk) was reduced by isoflurane in WT (30.5+/-4 vs. 44.2+/-3, n=7, P

Insulin and nutrients activate hepatic p70 S6 kinase (S6K1) to regulate protein synthesis. Paradoxically, activation of S6K1 also leads to the development of insulin resistance. In this study, we investigated the effect of TRB3, which acts as an endogenous inhibitor of Akt, on S6K1 activity in vitro and in vivo. In cultured cells, overexpression of TRB3 completely inhibited insulin-stimulated S6K1 activation by mammalian target of rapamycin, whereas knockdown of endogenous TRB3 increased both basal and insulin-stimulated activity. In C57BL/6 mice, adenoviral overexpression of TRB3 inhibited insulin-stimulated activation of hepatic S6K1. In contrast, overexpression of TRB3 did not inhibit nutrient-stimulated S6K1 activity. We also investigated the effect of starvation, feeding, or insulin treatment on TRB3 levels and S6K1 activity in the liver of C57BL/6 and db/db mice. Both insulin and feeding activate S6K1 in db/db mice, but only insulin activates in the C57BL/6 strain. TRB3 levels were 3.5-fold higher in db/db mice than C57BL/6 mice and were unresponsive to feeding or insulin, whereas both treatments reduced TRB3 in C57BL/6 mice. Akt was activated by insulin alone in the C57BL/6 strain and but not in db/db mice. Both insulin and feeding activated mammalian target of rapamycin similarly in these mice; however, feeding was unable to activate the downstream target S6K1 in C57BL/6 mice. These results suggest that the nutrient excess in the hyperphagic, hyperinsulinemic db/db mouse primes the hepatocyte to respond to nutrients resulting in elevated S6K1 activity. The combination of elevated TRB3 and constitutive S6K1 activity results in decreased insulin signaling via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway.

Delayed cardiac protection mediated by 12-lipoxygenase (12-LO) expression and activity has been linked to opioid receptor stimulation. The role of 12-LO in volatile anesthetic-induced delayed cardiac protection has not been determined. We tested the hypothesis that expression and activity of 12-LO mediate delayed cardiac protection induced by isoflurane in the mouse heart in vivo. Mice were pretreated with 1.4% isoflurane for 30 min and allowed to recover for 1, 12, or 24 h. Immunoblot analysis showed isoflurane significantly enhanced 12-LO protein expression at 12 and 24 h after isoflurane exposure, and this induction of 12-LO was confirmed by immunohistochemistry of whole heart sections at 24 h. The induced protein expression appeared to be localized to intercalated disc regions adjoining adjacent cardiac myocytes. Additionally, mice ± isoflurane (24 h previously) were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion in the presence and absence of a 12-LO inhibitor. Isoflurane reduced infarct size (27.1 ± 2.2% of the area at risk; n = 8) compared with the control group (44.6 ± 3.6%, n = 8). Baicalein (3 mg/kg), a selective 12-LO inhibitor, blocked the delayed protective effects of isoflurane pretreatment on infarct size (40.6 ± 3.6%, n = 8). These data suggest that 12-LO is an important mediator of isoflurane-induced delayed preconditioning.

BACKGROUND AND PURPOSE: Because carotid plaque ulceration is associated with an increased risk of cerebral embolism, residual carotid plaque ulceration directly around a stent (peristent ulceration) after carotid angioplasty and stent placement (CAS) could still be a risk factor for a stroke. The purpose of this study is to understand the morphologic and clinical prognosis of peristent ulceration. PATIENTS AND TECHNIQUES: CAS was attempted on 91 consecutive stenotic lesions (80 patients). Of these, 54 lesions (48 patients) had ulceration before CAS. Angiograms were evaluated immediately after the procedure. Peristent ulceration was found in 34 lesions (30 patients). The mean depth and length of peristent ulcers were 2.1 mm (range, 1–4.7 mm) and 8.9 mm (range, 1.5–22 mm), respectively. All patients with peristent ulceration were followed with antiplatelet therapy. RESULTS: No ischemic event due to the lesions occurred during the mean follow-up period of 25.5 months (range, 3–48 months). Angiography on 25 lesions (21 patients) at a mean of 5.8 months (range, 1–21 months) after CAS showed that peristent ulceration disappeared in 12 lesions (48%), improved in 11 lesions (44%), and remained unchanged in 2 lesions (8%). Nine lesions (36%) showed restenosis, which were ≤30% and did not require any additional intervention. New ischemic lesions were not detected in any of the 14 patients (17 lesions) who underwent follow-up MR imaging at a mean of 9 months (range, 1–32 months) after CAS. CONCLUSION: We conclude that peristent ulceration after CAS improves spontaneously and is not a risk factor for cerebral embolism.

The purpose of the study was to evaluate the effectiveness of an oral health promotion programme at the workplace. The programme was given once a year at offices or factories, which was voluntary and free for all employees. The programme consisted of clinical examinations followed by oral health guidance, oral hygiene instruction and oral prophylaxis of anterior lower teeth. Oral health status was compared by the times of participation in the programme. It was shown that three times or more participants in the programme had fewer decayed, missing and filled teeth (DMFT) and lower percentage of Community Periodontal Index (CPI) sextants 3 and 4. The oral health promotion programme was effective in keeping or maintaining good oral health among workers. In addition to current activities, the programme should include education to motivate subjects to receive regular check-ups.

A 48-year-old male without marked blood coagulation disorder developed a pseudoaneurysm of the superficial temporal artery (STA) following craniotomy. Cerebral angiography revealed a pseudoaneurysm on the parietal branch of the STA. Total extirpation was performed, and the postoperative course was uneventful. Most pseudoaneurysms of the STA develop after trauma. Lesions rarely develop after craniotomy. However, pseudoaneurysm of the STA should be considered as a possible surgical complication.

Background Accumulating evidence suggests that mitochondrial rather than sarcolemmal adenosine triphosphate-sensitive K+ (K(ATP)) channels may have an important role in the protection of myocardium during ischemia. Because both lidocaine and mexiletine are frequently used antiarrhythmic drugs during myocardial ischemia, it is important to investigate whether they affect mitochondrial K(ATP) channel activities. Methods Male Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. The authors measured flavoprotein fluorescence to evaluate mitochondrial redox state. Lidocaine or mexiletine was applied after administration of diazoxide (25 microM), a selective mitochondrial K(ATP) channel opener. The redox signal was normalized to the baseline flavoprotein fluorescence obtained during exposure to 2,4-dinitrophenol, a protonophore that uncouples respiration from ATP synthesis and collapses the mitochondrial potential. Results Diazoxide-induced oxidation of flavoproteins and the redox changes were inhibited by 5-hydroxydecanoic acid, a selective mitochondrial K(ATP) channel blocker, suggesting that flavoprotein fluorescence can be used as an index of mitochondrial oxidation mediated by mitochondrial K(ATP) channels. Lidocaine (10(-3) to 10 mM) and mexiletine (10(-3) to 10 mM) reduced oxidation of the mitochondrial matrix in a dose-dependent manner with an EC50 of 98+/-63 microM for lidocaine and 107+/-89 microM for mexiletine. Conclusions Both lidocaine and mexiletine reduced flavoprotein fluorescence induced by diazoxide in rat ventricular myocytes, indicating that these antiarrhythmic drugs may produce impairment of mitochondrial oxidation mediated by mitochondrial K(ATP) channels.

It is important for dural arteriovenous fistula (DAVF) to evaluate venous ischemia in the brain related to venous hypertension, but only a few such studies have been performed. In this study, regional cerebral blood flow(rCBF) in DAVF was examined for venous ischemia by 123I-IMP SPECT. The subjects were eighteen patients with DAVF. Of the eighteen patients, nine had DAVF with low perfusion areas and venous ischemia. The factors affecting rCBF in DAVF are: 1) the presence of retrograde leptomeningeal venous drainage, 2) sinus occlusion, and 3) DAVF with high flow. The presence of retrograde leptomeningeal venous drainage was observed in nine patients, sinus occlusion in four patients, high flow in three patients. In two patients, pure leptomeningeal venous drainage was formed by patent sinus, and blood regurgitated from DAVF on the sinus wall to cortical vein. When DAVF was associated with LMVD, most patients had venous hypertension and concomitant venous congestion in the same areas due to reduced venous circulation, resulting in a decrease in rCBF and an increase in regional cerebral blood volume. These hemodynamics suggest venous ischemia in the brain. 123I-IMP SPECT was useful for evaluating rCBF and as a parameter of the treatment.

Leiomyosarcoma of the scrotum is a rare tumor. Up to 1999, only 29 cases have been reported in the literature worldwide. A 27-year-old man presented with a mass on the left side of the scrotum which had been painless and had gradually enlarged over the previous 10 years. During the following 3 months, however, it became painful and he was then referred to our hospital. Physical examination revealed a solid mass on the left side of the scrotum, measuring 7 cm in diameter, which was not adhering to the testis or to the vas deferens. The tumor was surgically resected. The histological examination confirmed the diagnosis of well differentiated leiomyosarcoma. Adjuvant therapy was considered unnecessary. The follow-up at 41 months revealed no local recurrence or distant metastasis.