Castalagin and vescalagin purified from leaves of Syzygium samarangense (Blume) Merrill & L.M. Perry: Dual inhibitory activity against PARP1 and DNA topoisomerase II.

Inhibition of poly(ADP-ribose) polymerase 1 (PARP1) is one of the most promising strategies for cancer chemotherapy, and a number of inhibitors possessing nicotinamide-like structures are being developed. To discover new types of PARP1 inhibitors, we screened a large number of substances of plant origin and isolated two inhibitory substances from the leaves of Syzygium samarangense (Blume) Merrill & L.M. Perry. The inhibitory substances were identified as vescalagin and its epimer castalagin by analyses using nuclear magnetic resonance and mass spectrometry. The IC50 of purified vescalagin and castalagin for PARP1 inhibition were 2.67 and 0.86 µM, respectively. Unlike most of synthetic PARP1 inhibitors, castalagin showed a mixed type inhibition, of which Ki was 1.64 µM. When SH-SY5Y cells were treated with these ellagitannins at concentrations of less than 5 µM, cellular poly(ADP-ribosyl)ation was obviously attenuated. Castalagin and vescalagin also possessed inhibitory activity against DNA topoisomerase II, implying that they function as dual inhibitors in cells.

Anestheic Management of a Patient with Intravenous Leiomyomatosis Extending into the Right Atrium.

Intravenous leiomyomatosis (IVL) is a condition in which leiomyoma originating from uterine myoma or intrauterine venous walls develops intravenously. A single-stage operation was planned by the departments of gynecology and cardiovascular surgery for a patient in which the IVL was extended across the tricuspid valve. It was possible to safely perform perioperative care with continued evaluation of the tumor position and intravascular volume through the use of transesophageal echocardiography (TEE). TEE can be useful in the intraoperative care of patients with intracardiac tumor extension as in this case.

Effect of Intraoperative Glucose Infusion on Catabolism of Adipose Tissue and Muscle Protein in Patients Anesthetized With Remifentanil in Combination With Sevoflurane During Major Surgery: A Randomized Controlled Multicenter Trial.

BACKGROUND: A harmful effect of stress hormone secretion during surgery is lipolysis and proteolysis to maintain normal blood glucose levels. A well-titrated general anesthetic improves blood glucose control by suppressing secretion of these stress hormones. The aim of this study was to explore the effect of intraoperative glucose infusion on lipolysis and proteolysis in patients undergoing a general anesthetic consisting of sevoflurane and remifentanil during long (>6 hours) major surgery. METHODS: In this prospective, single-blinded, randomized, multicenter trial, 80 patients with an expected duration of anesthesia of >6 hours were allocated to either the glucose group, consisting of 40 patients who were infused with acetated Ringer's solution with glucose (2 mg/kg/min), or the no glucose group, consisting of 40 patients who were infused with the same solution, but without glucose. After oxygenation, general anesthesia was induced with propofol, fentanyl, and rocuronium and was maintained with sevoflurane, oxygen, rocuronium, and remifentanil infusions. The rates of remifentanil infusion were titrated based on systolic arterial blood pressure, maintaining this parameter within 10% of its postanesthesia values. Seventy-four patients completed the study. Urinary 3-methylhistidine/creatinine (3-MH/Cre) ratio, acetoacetic acid, 3-hydroxybutyric acid, blood glucose, insulin, and cortisol were measured 3 times: at anesthesia induction (0 hour) and at 3 and 6 hours after anesthesia induction. Urinary 3-MH/Cre ratio was the primary study outcome. RESULTS: In the no glucose group, the urinary 3-MH/Cre ratio at 6 hours was increased compared with that at 0 hour (213 [range, 42-1903] vs 124 [18-672] nmol/µmol; the difference in medians, 89; the 95% confidence interval [CI] of the difference, 82-252; P = .0002). Acetoacetic acid and 3-hydroxybutyric acid levels in the no glucose group were greater than those in the glucose group at 6 hours (110 [8-1036] vs 11 [2-238] µmol/L; the difference in medians, 99; the 95% CI of the difference, 92-196; P < .0001 and 481 [15-2783] vs 19 [4-555] µmol/L; the difference in medians, 462; the 95% CI of the difference, 367-675; P < 0.0001, respectively). Blood glucose and insulin levels in the glucose group were greater than those in the no glucose group at 3 hours (146 [103-190] vs 93 [72-124] mg/dL; the difference in medians, 53; the 95% CI of the difference, 47-55; P < .0001 and 9.8 [1.2-25.4] vs 3.2 [0.4-15.0] µU/mL; the difference in medians, 6.5; the 95% CI of the difference, 4.8-6.8; P < .0001) and 6 hours (139 [92-189] vs 87 [68-126] mg/dL; the difference in medians, 52; the 95% CI of the difference, 44-58; P < .0001 and 8.1 [1.2-22.3] vs 3.2 [0.4-10.1] µU/mL; the difference in medians, 4.9; the 95% CI of the difference, 4.0-5.9; P < .0001). Cortisol levels in both groups were similarly within normal levels at 0, 3, and 6 hours. CONCLUSIONS: The study showed that intraoperative glucose infusion suppressed lipolysis and proteolysis in patients anesthetized with remifentanil in combination with sevoflurane during surgery of >6 hours in length.

Efficacy of abdominal computed tomography and nasogastric tube in acute poisoning patients.

Abdominal computed tomography aids in the evaluation of the conditions in the stomach and will decrease needless gastric lavage in acute poisoning patients. A 16-year-old girl with a history of schizophrenia with depressive disorder was taken to our hospital. Her Glasgow Coma Scale was 8. Symptoms related to anticholinergic effects were strongly present. Her electrocardiogram showed sinus tachycardia with 60 milliseconds of QRS duration. Computed tomography images showed that the patient had a large amount of debris derived from tablets in her stomach and duodenum. We performed gastric aspiration through a nasogastric tube and not gastric lavage, and it took 5 minutes to complete the procedure. We administered activated charcoal 3 times. Intubation was not performed. Other than tonic-clonic seizure that was observed once, neither cardiovascular nor neurologic symptoms were observed. She recovered fully and admitted that she had ingested more than a hundred tablets almost 10 hours before being brought to our hospital. Computed tomography images show a cluster of tablets and debris to be of a higher density than tissues; this allows quantitative and qualitative evaluations to be performed. We were able to treat the patient with effective use of nasogastric tube.

Anesthetic management of two cases of Beckwith-Wiedemann syndrome.

Two cases of children with Beckwith-Wiedemann syndrome are presented. This syndrome consists of various abnormalities, including macroglossia, visceromegaly, omphalocele, and gigantism. These abnormalities frequently require operative correction during the neonatal period. We anesthesiologists should make plans for difficult airway managements in patients with this syndrome. Our two patients also showed larger sized tracheas than those estimated by their age and height. A cuffed tube, though still controversial, has recently been used in children. We recommend using a cuffed tube in patients with this syndrome, because the appropriate tracheal size may not be predictable, tracheal intubation might be difficult, and risks incurred during changing of a tracheal tube should be avoided.

Ropivacaine-induced toxicity with overdose suspected after axillary brachial plexus block.

Ropivacaine has a high threshold for systemic toxicity. We report and highlight a rare case in which an overdose of ropivacaine was suspected of leading to a generalized convulsion following the injection of this agent for axillary brachial plexus block (ABPB). A 25-year-old woman (height, 153 cm; weight, 48 kg; American Society of Anesthesiologists physical status I) was scheduled for finger surgery with ABPB. The perivascular sheath was identified by fascial clicks. We administered 300 mg (6.25 mg x kg(-1)) ropivacaine, while confirming that no blood flow was observed in the injection line by repeated negative aspiration tests. Ten minutes after the injection, most sensory and motor nerves were blocked effectively. Thirteen minutes after the administration, the patient lost consciousness and convulsed suddenly. No severe symptoms of cardiovascular toxicity occurred. The concentration of ropivacaine in a venous blood sample taken 28 min after the ropivacaine injection was 3.65 microg x ml(-1). She recovered with no sequelae. Limited cases have indicated high efficacy and sufficient safety for the use of 300 mg ropivacaine for ABPB. However, the toxic threshold of ropivacaine remains unclear, and the dose should be calculated in relation to the weight of the patient to prevent severe toxic complications.

[Cerebral hemorrhage following ovariectomy in a woman undergoing a gamma knife treatment for intracranial arteriovenous malformation].

We report a case of cerebral hemorrhage following ovariectomy in a 39-year-old woman undergoing a gamma knife treatment for intracranial arteriovenous malformation (AVM). She underwent bilateral ovariectomy with combined spinal-epidural anesthesia. Tracheal intubation was not performed so that severe changes in blood pressure, partial carbon dioxide pressure, and partial pressure of oxygen could be avoided. There were no complications during surgical anesthesia, but the AVM ruptured soon after her being discharged. AVM is errors in the development of the vasculature that, together with the effects of blood flow, may lead to a focal arteriovenous shunt. In some cases, aneurysms may coexist with AVM. It is said that radiosurgery significantly decreases the risk of hemorrhage in patients with AVM, even before there is angiographic evidence of obliteration. But it should be kept in mind that anesthetic management must be performed carefully.

[Case of papillary muscle rupture diagnosed by preoperative transesophageal echocardiography].

A 46-year-old man with severe mitral regurgitation (MR) was scheduled for emergency surgery for chordae tendae repairment. Preoperative transesophageal echocardiography (TEE) revealed massive MR due to a rupture in the antero-lateral papillary muscle. We changed the operation procedure to mitral valve replacement. It is difficult to diagnose papillary muscle rupture. Therefore, we should perform TEE on the patient with acute MR of unknown origin.

Antihypertensive effect of an extract of Passiflora edulis rind in spontaneously hypertensive rats.

Orally administered methanol extract of Passiflora edulis rind (10 mg/kg or 50 mg/kg) or luteolin (50 mg/kg), which is one of consistent polyphenols of the extract, significantly lowered systolic blood pressure in spontaneously hypertensive rats (SHRs). Quantitative analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) showed that the extract contained 20 microg/g dry weight of luteolin and 41 microg/g dry weight of luteolin-6-C-glucoside. It also contained gamma-aminobutyric acid (GABA, 2.4 mg/g dry weight by LC-MS/MS or 4.4 mg/g dry weight by amino acid analysis) which has been reported to be an antihypertensive material. Since the extract contained a relatively high concentration of GABA, the antihypertensive effect of the extract in SHRs might be due mostly to the GABA-induced antihypertensive effect and partially to the vasodilatory effect of polyphenols including luteolin.

The tumor specific cytotoxicity of dihydronitidine from Toddalia asiatica Lam.

PURPOSE: In recent years, a number of reports have shown the anticancer activity of plant extracts and phytoalkaloid. METHODS: We have evaluated the cytotoxicity profiles of 157 extracts prepared from dietary or medical plants growing in the Okinawa island, using 10 different cell lines. In vitro cytotoxicity screening indicated the presence of a highly selective cytotoxic compound in the extract of Toddalia asiatica Lam. The known alkaloid (1,3)benzodioxolo(5,6-c)phenanthridine, 12,13-dihydro-2,3-dimethoxy-12-methyl-(dihydronitidine) was identified as an active material from this plant. This alkaloid had highly specific cytotoxicity to human lung adenocarcinoma (A549) cells. RESULTS: The results of the fluorescence activated cell sorter (FACS) analysis and the measurement of caspase-3 activity showed that dihydronitidine induced specific apoptotic cell death in A549 cells. Gene expression analysis in the apoptotic cells found that dihydronitidine variously regulated the cell cycle related genes (CDK2 and CCNE), and up-regulated the cell death related genes specifically in tumor cells. Thus dihydronitidine manifested its characteristics in the tumor selective cytotoxicity, contrasting with the case of a known anticancer agent camptothecin (CPT). Microscopic observation further revealed the specific accumulation of dihydronitidine within the cytosolic organelle, but not in the nuclei of adenocarcinoma. No accumulation was observed with CPT in all cell lines. CONCLUSION: The data suggested that dihydronitidine toxicity targeted a particular intracellular organelle in the tumor cells.

Luteolin inhibits endothelin-1 secretion in cultured endothelial cells.

We discovered that luteolin, a typical flavonoid contained in various kinds of plants, inhibits the secretion and gene expression of endothelin-1 (ET-1), a potent vasoconstrictor regulating blood pressure, in porcine aortic endothelial cells. Its ED50 was about 10 microM. In addition, the inhibition of ET-1 by a glycoside compound of luteolin (luteolin-6-C-glucoside) was weak.

Single-channel activity of L-type Ca2+ channels reconstituted with the beta2c subunit cloned from the rat heart.

We recently cloned the beta(2c) subunit of the L-type Ca(2+) channel as a functional type of beta subunit from the rat heart. In order to clarify the contribution of the beta(2c) subunit to native Ca(2+) channel function, we investigated the single-channel properties of Ca(2+) channels reconstituted with beta(2a) or beta(2c) subunits and compared them with the properties of native channels. In contrast to the Ca(2+) channel with beta(2a) subunit, long-lasting closings were dominant in the Ca(2+) channel with beta(2c) subunit and the native channel. The ensemble-averaged current of the cells with beta(2c) subunits was comparable to that of the native cardiomyocytes. Many high P(o) sweeps (mode 2) were observed in the cells with beta(2a) subunits, while only a few high P(o) sweeps were observed in the cells with beta(2c) subunits and the native cells. These findings suggest that the beta(2c) subunit is one of the functional beta subunits in the rat heart.

A truncated splice variant of KCNQ1 cloned from rat heart.

KCNQ1 encodes a pore-forming subunit of potassium channels. Mutations in this gene cause inherited diseases, i.e., Romano-Ward syndrome and Jervell and Lange-Nielsen syndrome. A truncated isoform of KCNQ1 was reported to be expressed physiologically and to suppress a delayed rectifier potassium current dominant-negatively in human heart. However, it is not known whether this way of modulation occurs in other species. We cloned another truncated splice variant of KCNQ1 (tr-rKCNQ1) from rat heart. Judging from the deleted sequence of the tr-rKCNQ1, the genomic structure of rat in this portion might be different from those of human and mouse. Otherwise, an unknown exon might exist. RT-PCR analysis demonstrated that the tr-rKCNQ1 was expressed in fetal and neonatal hearts. When this gene was expressed along with a full-length KCNQ1, it suppressed potassium currents, whether a regulatory subunit minK was co-expressed or not.

Sevoflurane inhibits contraction of uterine smooth muscle from pregnant rats similarly to halothane and isoflurane.

PURPOSE: The present study was designed to clarify the direct effects of the volatile anesthetics halothane, isoflurane and sevoflurane on oxytocin-induced uterine smooth muscle contraction from pregnant rats. METHODS: Longitudinal smooth muscle layers were obtained from pregnant rats. Intracellular concentration of free Ca++ ([Ca++](i)) was measured, using a fluorescence technique, simultaneously with muscle tension. Inward Ba++ current (I(Ba)) through voltage-dependent Ca++ channels (VDCCs) was measured using a whole cell patch clamp technique. After incubation with 20 nM oxytocin, halothane, isoflurane or sevoflurane (1, 2, and 3%) was introduced into the tissue bath. RESULTS: All volatile anesthetics significantly inhibited muscle contraction concomitant with a decrease in [Ca++](i). Volatile anesthetics also inhibited the peak I(Ba). When the anesthetic concentrations were expressed as multiples of minimum alveolar concentrations, there were no differences in the inhibitory potencies of the three volatile agents tested for muscle tension and VDCC. CONCLUSIONS: Volatile anesthetics halothane, isoflurane and sevoflurane reduce the oxytocin-induced contraction of pregnant uterine smooth muscle. Inhibition of the contraction by the volatile anesthetics is due, at least in part, to the decrease in [Ca++](i), and the decrease in [Ca++](i) may be mediated by inhibition of VDCC activity.

Evaluation of four techniques of warming intravenous fluids.

PURPOSE: This study was conducted to compare the fluid warming capabilities at different flow rates in four different warming systems. METHODS: The intravenous (i.v.) fluid warmers used in this study were a water-bath warmer, a forced-air warmer, a dry-heat plate warmer, and an i.v. fluid tube warmer. Ringer's solution at room temperature or at ice-cold temperature (120-3000 ml.h(-1)) was used as an i.v. fluid, and the i.v. fluid temperatures were measured with thermocouples at the end of a 1-m tube connected to the warmer. RESULTS: The temperature of the i.v. fluid delivered by the water bath and the forced-air warming system increased as the flow rate increased up to 1200 ml.h(-1) but decreased with further increase of the flow rate. The temperature of the i.v. fluid delivered by the dry-heat plate warmer significantly increased as the flow rate increased within the range studied. The delivered temperature did not depend on the flow rate within the range studied when the i.v. fluid tube warmer was used. CONCLUSION: It is important to choose a warmer according to its characteristics as well as its performance.