Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer.

While statin intake has been proven to reduce the risk of colorectal cancer (CRC), the mechanism of antitumor effects and clinical significance in survival benefits remain unclear. Statin-induced antiproliferative effects and its underlying mechanism were examined using six CRC cell lines. Statins except pravastatin showed antiproliferative effects (simvastatin ≥ fluvastatin > atorvastatin) even though both of simvastatin and pravastatin could activate mevalonate pathways, suggesting the statin-mediated antiproliferative effects depended on non-mevalonate pathway. Indeed, statin induced p27(KIP1) expression by downregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2), which acts as an epigenetic gene silencer. Additionally, the use of simvastatin plus classII histone deacetylase (HDAC) inhibitor (MC1568) induced further overexpression of p27(KIP1) by inhibiting HDAC5 induction originated from downregulated EZH2 in CRC cells and synergistically led to considerable antiproliferative effects. In the clinical setting, Statin intake (except pravastatin) displayed the downregulated EZH2 expression and inversely upregulated p27(KIP1) expression in the resected CRC by immunohistochemical staining and resulted in the significantly better prognoses both in overall survival (p = 0.02) and disease free survival (p < 0.01) compared to patients without statin intake. Statins may inhibit tumor progression via an EZH2-mediated epigenetic alteration, which results in survival benefits after resected CRC. Furthermore, statin plus classII HDAC inhibitor could be a novel anticancer therapy by their synergistic effects in CRC.

Malignant pheochromocytoma with multiple hepatic metastases treated by chemotherapy and transcatheter arterial embolization.

A 62-year-old Japanese male developed multiple hepatic metastases two years after resection of pheochromocytoma of the right adrenal gland. Transcatheter arterial embolization (TAE) was performed for the purpose of the treatment of hepatic metastases resistant to 27 cycles of combined chemotherapy consisting of cyclophosphamide, vincristine, and dacarbazine. After TAE, the hepatic metastatic lesions decreased in size and hypertension passed its crisis. The present case suggests the utility of TAE for multiple hepatic metastases under careful blood pressure monitoring.

[Interaction of cardiovascular effect of calcium channel blocking drugs and those of inhalation anesthetics in humans].

The hemodynamics in the patients undergoing craniotomy was studied to evaluate the interaction of cardiovascular effects of calcium blocking drugs (nicardipine NCR or diltiazem DL) and those of inhalation anesthetics (0.6% isoflurane Iso or 0.9% sevoflurane Sevo). (Group I = NCR alone, Group II = NCR+Iso, Group III = NCR+Sevo, Group IV = DL alone, Group V = DL+Iso, Group VI = DL+Sevo) Anesthesia was maintained with neuroleptanesthesia (N2O 60%). A 30% reduction in systolic blood pressure was achieved and this was maintained for 60 minutes in each groups. The following effects were observed during induced hypotension. 1) Heart rate increased in the group I and II, but decreased in the group IV, V and VI. 2) Cardiac output increased in the group I and II, but significantly decreased in the group VI. 3) Systemic vascular resistance and left ventricular stroke work decreased in all the groups. 4) Pulmonary vascular resistance decreased slightly in all the groups. 5) Cardiac arrhythmias were observed in 4 cases of the group IV and VI. These results suggest that the presence of Iso or Sevo at low concentrations does not have a marked effect on the pharmacologic action of NCR or DL in humans.

[Differential lung ventilatory management during bronchoplasty].

We compared two methods of respiratory managements during bronchoplasty surgery. In one lung ventilation group (OLV-G), 10 patients were ventilated with Broncho-cath tube or Univent tube. On another 10 patients, ventilation was performed with Univent tube following insertion of bronchial blocker into main bronchus of dependent lung. Dependent lung was then ventilated using high frequency jet ventilation (HFJV) through bronchial blocker superimposed with low tidal volume IPPV (selective HFJV, S-HFJV-G). Oxygenation index (O.I.) of S-HFJV-G was significantly higher than that of OLV-G when bronchus was open. These phenomena might have occurred through prevention of pulmonary blood flow shift to the non-dependent lung when S-HFJV was used.

[The effect of nitroglycerin ointment on cardiovascular functions in hypertensive patients during emergence from anesthesia].

The present study was designed to investigate the effect of nitroglycerin (TNG) ointment to attenuate the cardiovascular response of hypertensive patients during emergence from anesthesia compared with the effects of TNG infusion and nifedipine instillation in the nose. In addition, plasma TNG concentration was measured in the TNG ointment group and TNG infusion group. TNG 30 mg in ointment reduced the arterial pressure during extubation without producing hypotension and tachycardia. There was no significant difference in plasma TNG concentration between TNG ointment group and TNG infusion group each receiving 0.3 micrograms.kg-1.min-1. The study suggests that TNG ointment is useful for regulation of arterial pressure in hypertensive patients during emergence from anesthesia.

[Monitored anesthesia care for a patient with malignant pheochromocytoma].

Monitored anesthesia care (MAC) is being increasingly used in the 1990s for a wide variety of diagnostic and therapeutic procedures. The primary objective in providing MAC is to ensure patients' comfort and safety, whether in the operating room or in other places. We experienced MAC for a patient with pheochromocytoma. A 63-year-old man with hepatic metastasis of malignant pheochromocytoma, received transcatheter arterial embolization (TAE) in the angiographic room. Hypertension and ventricular arrhythmia occurred during the hepatic arterial embolization. However, we successfully controlled the hemodynamic changes using phentolamine and propranolol under the close monitoring. He showed an uneventful recovery during postoperative period except for mild hypotension on the third day which needed temporary norepinephrine infusion.

[Endoscopic resection of the thoracic sympathetic trunk for the treatment of frequent syncopal attack of idiopathic long QT syndrome].

A 22 year old man was diagnosed as having Jervell and Lange-Nielsen syndrome (JLNS), which includes a prolonged QTc, congenital neural deafness, and syncopal attacks or sudden death. In spite of medication with beta blocker, syncopal attack increased in frequency since his sister suddenly had died of JLNS. Because left stellate ganglion block improved the QTc dispersion, left cardiac sympathectomy was scheduled under the video-assisted thoracic surgery. After the premedication with midazolam, anesthesia was induced with thiamylal, and maintained with nitrous oxide, sevoflurane, and fentanyl. Serious arrhythmias were not observed throughout the perioperative period. Sympathetic trunk was successfully resected from the top of 1st ganglion to the bottom of 4th ganglion of left thoracic sympathetic trunk. Horner's sign did not appear after the surgery. Although the shortening of QTc was not significant, QTc dispersion during exercise was improved, and syncopal attack was not observed until 6 months after the surgery.

Comparative analysis of systemic and coronary hemodynamics during sevoflurane- and isoflurane-induced hypotension in dogs.

We studied the effects of sevoflurane on myocardial contractility and systemic and coronary hemodynamics, as compared with the effects of isoflurane in dogs under the same cardiac work conditions. Sixteen mongrel dogs were anesthetized with alpha-chloralose. Heart was paced at 100 beats/min after producing a complete atrioventricular (A-V) block. Controlled hypotension to a mean arterial pressure (MAP) of 60 mm Hg was induced and maintained by inhalation of either anesthetic, lasting for 60 min. Measurements were made at baseline, 15 min (T1), and 60 min (T2) after starting hypotension, and 30 min after discontinuing equihypotension (T3). Although left ventricular systolic segment shortening (%SS) decreased approximately 20% in both groups, cardiac output (CO) decreased only in sevoflurane during equihypotension (-27.6% at T2). Sevoflurane decreased the coronary blood flow (CBF; -34.8% at T2) with no significant change of coronary vascular resistance (CVR), whereas isoflurane produced a significant decrease in CVR resulting in no change of CBF despite of decreased coronary perfusion pressure (-37.4% at T2). These systemic and coronary vascular effects were continued even at T3. In conclusion, myocardial depressant effects were comparable between sevoflurane and isoflurane. Both systemic and coronary vasodilatory effects of isoflurane are greater than those of sevoflurane.

[Investigation of limulus test during and after cardiopulmonary bypass. Part II. Effect of washing of the bypass circuit].

Previously we reported the presence of Limulus positive substance (LPS) in blood and urine for several days following cardiopulmonary bypass (CPB), and foreign particles in the primining fluids. The purpose of this study was to evaluate the effect of washing of the CPB circuit on appearance of LPS and to define the nature of it. Semi-quantitative Limulus test was performed in patients using washed CPB circuit (n = 54) and without washing (n = 41). LPS in the blood were negative in all patients before CPB. LPSs in the priming fluids did not disappear after washing, however the amounts of it in the blood were significantly lower than those without washing. Especially at second postoperative day. Limulus test were positive in 10% of patients with washed CPB circuit and 60% of those without it (p less than 0.01), and all the urine samples of patients with washed CPB circuit were negative to Limulus test at 1st postoperative day. The number of foreign particles decreased in parallel with the smaller pore size of the filter. Since reactions of Pregell to ethylene oxide gas, ethylene chlorohydrin and ethylene glycol were negative, ethylene oxides did not seem to be the LPS. These results indicate the superiority of employment of washed CPB circuit with micropore filter. However, further exploration is still mandatory to elucidate the LPSs.

[Investigation of Limulus test during and after cardiopulmonary bypass--analysis of Limulus positive substance and particles in the cardiopulmonary bypass circuit].

Patients undergoing heart surgery with cardiopulmonary bypass (CPB) frequently have positive Limulus test without any remarkable signs of endotoxemia. CPB circuit could be one of the possible causes of this phenomenon, but the exact mechanism has not been studied. Accordingly, a prospective study was made in 41 patients undergoing heart surgery with CPB. Limulus test were performed on the samples of priming fluids of CPB including the plasma and urine of those patients during and after surgery. Besides the Limulus test, the CPB fluids were analysed by the false positive test. Microscopic examinations were carried out on the priming fluids before and after using a 40 microns filter during recirculation without washing the CPB circuit and the fluid from a 4 microns filter been washed by 2000 ml of Martose-10 in order to find out the presence of any foreign particles in the CPB circuit. The size and the number of particles were measured by coulter counter. The studies revealed the following facts, 1) Limulus test; most of the samples from priming fluids (31/35), plasma circulating the CPB (36/36), urine during CPB (22/25) and plasma (34/35) and urine (21/30) just after the surgery revealed positive. However, only 4 samples from plasma at 3POD and 2 samples from urine at 2POD revealed positive, 2) false positive test of the samples from priming fluids was negative meaning the Limulus positive substances are not endotoxin, 3) under microscopic analysis and coulter counter, there were about 40 particles over 50 microns per ml of priming fluids before washing the CPB circuit.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbachol, norepinephrine, and hypocapnia stimulate phosphatidylinositol turnover in rat tracheal slices.

BACKGROUND: The intracellular mechanisms involved in the alpha-adrenoceptor- or hyperventilation-induced bronchoconstriction remain unknown. Because there is a direct relationship between phosphatidylinositol (PI) metabolism and airway smooth muscle contraction induced by muscarinic agonists, the authors examined the effects of carbachol (CCh), norepinephrine (NE), and hypocapnia on PI turnover in the airway smooth muscle. METHODS: Rat tracheal slices were incubated in Krebs-Henseleit solution containing LiCl and [3H]myo-inositol in the presence of NE, CCh, or neither. The PCO2 in the solution was 36 +/- 3 mmHg (normocapnia), 19 +/- 2 mmHg (moderate hypocapnia), or 5 +/- 2 mmHg (severe hypocapnia), respectively. [3H]inositol monophosphate (IP1) formed was counted with a liquid scintillation counter. RESULTS: Basal IP1 formed was greater at severe hypocapnia than at normocapnia. Norepinephrine- and CCh-induced IP1 formation were also greater at hypocapnia than at normocapnia. CONCLUSIONS: These results indicate that CCh, NE, and hypocapnia stimulate PI turnover in the airway smooth muscle, which would cause bronchoconstriction, and hypocapnia also augments NE- and CCh-induced PI turnover, which could cause worsening of exercise-induced asthma and vagotonic asthma, respectively.

Sevoflurane protects stunned myocardium through activation of mitochondrial ATP-sensitive potassium channels.

UNLABELLED: We sought to determine the hemodynamic and cardioprotective effects of sevoflurane in canine stunned myocardium. Forty-nine dogs were allocated to one of seven groups (n = 7 for each). In six separate groups, dogs received vehicle, glibenclamide (a nonselective adenosine triphosphate-dependent potassium [K(ATP)] channel antagonist) (0.3 mg/kg IV) or 5-hydroxydecanoic acid (a mitochondrial K(ATP) channel antagonist) (5 mg/kg IV) in the presence or absence of 1 minimum alveolar concentration (1 MAC) sevoflurane. In an additional group, dogs received 1 MAC sevoflurane with hemodynamic correction. Regional myocardial contractility was evaluated with segment shortening. Measurements were made before and during 15-min ischemia and 90-min reperfusion. Recovery of segment shortening 90 min after reperfusion was significantly improved in the dogs anesthetized with sevoflurane either with or without hemodynamic correction (70.1 +/- 4.2 and 75.9 +/- 3.1% of baseline, respectively), whereas the recovery was poor in control and glibenclamide or 5-hydroxydecanoic acid pretreated dogs (33.3 +/- 4.3, 33.8 +/- 6.8, and 45.0 +/- 5.5% of baseline, respectively). Regional myocardial perfusion showed no significant difference among groups. The results indicate that sevoflurane has a cardioprotective effect mediated through activation of mitochondrial K(ATP) channels and independent of coronary blood flow or reduction in cardiac work. IMPLICATIONS: Sevoflurane exerts a cardioprotective effect that is mediated via activation of adenosine triphosphate-sensitive potassium channels in ischemic canine hearts.

Interaction of isoflurane and cromakalim, a KATP channel opener, on coronary and systemic haemodynamics in chronically instrumented dogs.

BACKGROUND: Although isoflurane has been shown to cause coronary and systemic vasodilation through KATP channel activation, the interaction of KATP channel openers and isoflurane has not been fully investigated. The present study was carried out to determine the haemodynamic actions of cromakalim, a KATP channel opener, under the conscious state and during isoflurane anaesthesia in chronically instrumented dogs. METHODS: Fourteen dogs were chronically instrumented to measure systemic and coronary haemodynamics. Each dog was randomly assigned to receive doses of either cromakalim, 4 and 10 microg x kg(-1) i.v., or isoflurane, 2.1% end-tidal (1.5 MAC), plus cromakalim, 4 and 10 microg x kg(-1) i.v. RESULTS: Cromakalim dose-relatedly decreased mean arterial pressure and systemic vascular resistance and increased coronary blood flow in both conscious and anaesthetized states. With isoflurane, the duration of effects of cromakalim were prolonged. Isoflurane exerted an additive effect on the increase in coronary blood flow induced by a low-dose cromakalim, whereas it did not influence the effect of a high-dose cromakalim. The maximum rate of increase in left ventricular pressure and segment shortening were increased by cromakalim in the conscious state but unchanged during isoflurane anaesthesia. CONCLUSION: The results suggest that the coronary vasodilating effects of isoflurane and cromakalim are basically additive until cromakalim exerts the maximal effect, and that the action of cromakalim on the coronary vasculature is prolonged by isoflurane.

Germinal center-associated nuclear protein (GANP) has a phosphorylation-dependent DNA-primase activity that is up-regulated in germinal center regions.

Antigen stimulation induces a rapid proliferation of B cells for expansion of specific B cell clones and their further differentiation into antibody-producing cells in germinal centers of T-dependent antigen-immunized mice. Previously, we identified a 210-kDa germinal center-associated nuclear protein (GANP) that is up-regulated selectively in germinal centers and carries an MCM-binding domain in the carboxyl-terminal side. In addition, here, we found a region (from 414 to 550 aa) in GANP molecule that is slightly similar to the known DNA-primase component p49. The recombinant GANP fragment covering this region synthesizes RNA primers for extension by DNA polymerase I with single-stranded DNA templates in vitro. GANP DNA-primase activity is controlled by phosphorylation at Ser(502) that is induced by CD40-mediated signaling in vitro and in the germinal center B cells stimulated with antigen in vivo. Overexpression of ganp cDNA in Daudi B cells caused the increased DNA synthesis more than the levels of the mock-transfectants. These evidences suggested that the novel DNA-primase GANP is involved in regulation of cell proliferation of antigen-driven B cells in germinal centers.

A novel nuclear phosphoprotein, GANP, is up-regulated in centrocytes of the germinal center and associated with MCM3, a protein essential for DNA replication.

Antigen (Ag) immunization induces formation of the germinal center (GC), with large, rapidly proliferating centroblasts in the dark zone, and small, nondividing centrocytes in the light zone. We identified a novel nuclear protein, GANP, that is up-regulated in centrocytes. We found that GANP was up-regulated in GC B cells of Peyer's patches in normal mice and in spleens from Ag-immunized mice. GANP-positive cells appeared in the light zone of the GC, with coexpression of the peanut agglutinin (PNA) (PNA)-positive B220-positive phenotype. The expression of GANP was strikingly correlated with GC formation because Bcl6-deficient mice did not show the up-regulation of GANP. GANP-positive cells were mostly surrounded by follicular dendritic cells. Stimulation with anti-micro and anti-CD40 induced up-regulation of ganp messenger RNA as well as GANP protein in B220-positive B cells in vitro. GANP is a 210-kd protein localized in both the cytoplasm and nuclei, with a homologous region to Map80 that is associated with MCM3, a protein essential for DNA replication. Remarkably, GANP is associated with MCM3 in B cells and MCM3 is also up-regulated in the GC area. These results suggest that the up-regulation of GANP might participate in the development of Ag-driven B cells in GCs through its interaction with MCM3.