High temporal and spatial quality petawatt-class Ti:sapphire chirped-pulse amplification laser system.

Optical parametric chirped-pulse amplification (OPCPA) operation with low gain by seeding with high-energy, clean pulses is shown to significantly improve the contrast to better than 10(-10) to 10(-11) in a high-intensity Ti:sapphire laser system that is based on chirped-pulse amplification. In addition to the high-contrast broadband, high-energy output from the final amplifier is achieved with a flat-topped spatial profile of filling factor near 77%. This is the result of pump beam spatial profile homogenization with diffractive optical elements. Final pulse energies exceed 30 J, indicating capability for reaching peak powers in excess of 500 TW.

Electropharmacologic effects of a new phosphodiesterase III inhibitor, toborinone (OPC-18790), assessed in an in vivo canine model.

Electropharmacologic effects of a new phosphodiesterase (PDE) III inhibitor toborinone (OPC-18790) were assessed in a halothane-anesthetized, closed-chest canine model. Toborinone, 0.03 mg/kg, increased ventricular contractility, decreased total peripheral resistance, and inhibited intraventricular conduction without changing other cardiovascular parameters. A clinically relevant dose of 0.3 mg/kg increased heart rate, systolic blood pressure, and cardiac output, decreased preload to the left ventricle, enhanced atrioventricular nodal conduction, and shortened repolarization and the vulnerable period of the ventricle, in addition to enhancing the effects observed after the low dose. A high dose of 3 mg/kg of toborinone decreased systolic, mean, and diastolic pressures and prolonged the effective refractory period (ERP) in addition to the effects observed after the middle dose. No further change was detected in ventricular repolarization. Most of the cardiohemodynamic effects can be explained by the PDE III inhibition by toborinone. With regard to electrophysiologic properties, the prolongation of intraventricular conduction time and ERP by toborinone suggests sodium channel inhibition. The lack of the prolongation of ventricular repolarization suggests that previously demonstrated inhibition of I(Kr) and I(K1) and increased I(Ca-L) by toborinone might be counteracted by factors such as the cyclic AMP-dependent outward currents, I(Ks) and I(C1).

The anti-inflammatory effect of FR188582, a highly selective inhibitor of cyclooxygenase-2, with an ulcerogenic sparing effect in rats.

The anti-inflammatory and ulcerogenic effects of FR188582, 3-chloro-5-[4-(methylsulfonyl) phenyl]-1-phenyl-1H-pyrazole, were investigated. In a recombinant human cyclooxygenase (COX) enzyme activity, FR188582 inhibited COX-2 with an IC50 value of 0.017 microM, and the inhibition of prostaglandin (PG) E2 formation by FR188582 was over 6000 times more selective for COX-2 than COX-1. Oral administration of FR188582 dose-dependently inhibited adjuvant arthritis. This effect was threefold more potent than that of indomethacin. FR188582 and indomethacin dose-dependently suppressed the formation of immunoreactive PGE2, but not immunoreactive leukotriene (LT) B4, in arthritic paw. Unlike indomethacin, FR188582 did not induce visible gastric lesions in rats at doses up to 32 mg/kg, p.o. Furthermore, FR188582 did not inhibit the level of immunoreactive PGE2 and immunoreactive 6-keto PGF1alpha in rat gastric mucosa. These results suggest that FR188582, a highly selective COX-2 inhibitor, has a potent anti-inflammatory effect mediated by inhibition of PGE2 in inflamed tissues. The safety profile of FR188582 appears to be improved over the safety profile of indomethacin.

Effect of magnesium sulfate on the haloperidol-induced QT prolongation assessed in the canine in vivo model under the monitoring of monophasic action potential.

Haloperidol has been reported to induce polymorphic ventricular arrhythmias associated with QT prolongation. The present study examined the effects of magnesium sulfate on the cardiovascular system suffering from haloperidol overdose. Beagle dogs were anesthetized with halothane inhalation under the monitoring of monophasic action potential (n=6). After intravenous administration of an intentionally high dose of haloperidol (3 mg/kg), the heart rate (HR), left ventricular contraction and mean blood pressure (BP) decreased, and the ventricular repolarization phase and effective refractory period (ERP) were prolonged, the increment in the former being than in the latter, indicating an increase in electrical vulnerability. However, preload of the left ventricle, cardiac output (CO) and cardiac conduction were hardly affected. An additional intravenous dose of 100 mg/kg of magnesium sulfate increased the preload of the left ventricle, and decreased the HR, mean BP, left ventricular contraction and CO, suppressed atrioventricular as well as intraventricular conduction, and prolonged the ventricular repolarization phase and ERP, in which the increment of the repolarization phase was similar to that of ERP. These results suggest that magnesium sulfate hardly affects the electrical vulnerability of the heart during haloperidol overdose, but may block the calcium, potassium and sodium channels, which may explain its antiarrhythmic action.

Antiarrhythmic and cardiohemodynamic effects of a novel Ca(2+) channel blocker, AH-1058, assessed in canine arrhythmia models.

The antiarrhythmic profile and cardiohemodynamic effect of a novel Ca(2+) channel blocker, 4-(5H-Dibenzo[a, d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-p ropeny l]piperidine hydrochloride (AH-1058), were analyzed using the epinephrine-, digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmia models. Intravenous administration of AH-1058 (100 microg/kg) effectively suppressed each of the ventricular arrhythmias accompanied by weak hypotensive effects. The results contrast well with those of a typical Ca(2+) channel blocker, verapamil, which suppresses only the epinephrine-induced ventricular arrhythmia with severe hypotension. These results indicate that AH-1058 may possess a more selective inhibitory action on Ca(2+) channels in the heart than on those in the vessels. Furthermore, the antiarrhythmic actions of AH-1058 were slower in onset and longer-lasting, than those in our previous studies using other antiarrhythmic drugs, including Na(+) and Ca(2+) channel blockers. The antiarrhythmic effects of AH-1058 did not correlate with its plasma concentrations when administered either intravenously or orally. These results suggest that AH-1058 can become a long-acting Ca(2+) channel blocker with unique antiarrhythmic properties, and that AH-1058 may be used in certain pathological processes, for which selective inhibition of the cardiac Ca(2+) channels is essential.

Protective effect of aged garlic extract on the small intestinal damage of rats induced by methotrexate administration.

The methotrexate (MTX) administration to rats causes the damage of small intestine. The small intestinal damage was evaluated by measuring the intestinal permeability of the poorly absorbable compound, fluorescein isothiocyanate (FITC)-labeled dextran (average molecular weight, 4,400) (FD-4) using the in vitro everted intestine technique and by determining the FD-4 that appeared in plasma using the in situ closed loop intestine technique. The MTX administration to rats fed with the standard laboratory diet increased the small intestinal permeability of FD-4 due to the damage of the small intestine. Interestingly, the permeability of FD-4, when MTX was administered to rats fed with the aged garlic extract containing diet, was depressed almost to the level of control rats without the MTX treatment. The present study showed that the aged garlic extract protected the small intestine from the damage induced by the action of MTX on the crypt cells.

Characteristic transfer of colostral components into cerebrospinal fluid via serum in neonatal pigs.

In order to evaluate the possibility of modification of brain function by colostral suckling, the characteristic transfer of colostral components into serum and cerebrospinal fluid (CSF) has been studied by SDS electrophoresis, immunoblot and ELISA methods in nonsuckling pigs. Total protein concentrations in the serum increased immediately after oral administration of bovine colostrum, reaching a peak value (7.0 +/- 0.7 g/dl) at 24 h after administration, corresponding to a 3-fold increase compared to preinfusion levels. IgG and other macromolecular components (MW 19, 000-58,000) were recognized in serum by electrophoretic and ELISA analysis. Total protein concentrations in the CSF collected from the cisterna magna also increased steeply after colostral administration, reaching a maximal value (54.1 +/- 5.0 mg/dl) at 4 h, corresponding to a 4-fold increase compared to preinfusion levels. Two colostral components (MW 19,000 and 31,000) in serum were confirmed to be present in the CSF by electrophoresis. The component of MW 19,000 was identified by immunoblot as beta-lactoglobulin. IgG in serum transferred from colostrum could not be detected in the CSF by ELISA. Lactoferrin administered into the intestine was also detected in the CSF via serum. These results indicate that some components of colostrum can be transported into the CSF via the serum, suggesting the possibility of modification of immature brain functions by colostral suckling in neonatal pigs.

Effects of magnesium sulfate on the canine cardiovascular system complicating astemizole overdose.

Polymorphic ventricular arrhythmias induced by astemizole overdose have been reported to be successfully managed with intravenous magnesium sulfate. This study was designed to assess the effects of magnesium sulfate on the cardiovascular system, complicating astemizole overdose, the better to understand the therapeutic utility and undesirable effects of magnesium sulfate. Beagle dogs were anesthetized with halothane inhalation (n = 6). Monophasic action potential of the right ventricle, electrocardiogram, and systemic and left ventricular pressure were continuously monitored. Cardiac output was measured by a thermodilution method. Effective refractory period of the right ventricle was assessed by programmed electrical stimulation. An intentionally high dose of astemizole (3 mg/kg, i.v.) prolonged the repolarization and refractory period, while it decreased the sinus automaticity, ventricular contraction, and conduction. A canine antiarrhythmic dose of magnesium sulfate (100 mg/kg, i.v.) was additionally injected 1 h after i.v. astemizole. Magnesium sulfate increased the atrioventricular conduction time, electrical vulnerability, and preload of the left ventricle, while it decreased the blood pressure and cardiac output, besides the effects similar to those observed after i.v. astemizole. The plasma concentration of astemizole was at least 10 times higher than its therapeutic concentration during the experimental period. Magnesium sulfate could be expected to act as a calcium channel blocker during astemizole overdose; however, it may not antagonize the proarrhythmic effects of astemizole.

Hepatic arterial infusion chemotherapy combined with hyperthermia for metastatic liver tumors of colorectal cancer.

The efficacy of combined hepatic arterial infusion chemotherapy and hyperthermia for unresectable hepatic tumors of colorectal cancer was retrospectively compared with hepatic arterial infusion chemotherapy alone. Nine cases were treated with combination therapy and eight cases were treated with hepatic arterial infusion alone. The response rate in the combined hepatic arterial infusion/hyperthermia group was higher (44% v 25%) and the survival period longer (2-year survival, 35% v 12%) than in the group treated with hepatic arterial infusion alone. The toxicity was not severe, with the exception of gastrointestinal symptoms, suggesting that this combination of modalities is useful in the treatment of metastatic liver tumors.

Molecular cloning and functional expression of a cDNA for rat phospholipid hydroperoxide glutathione peroxidase: 3'-untranslated region of the gene is necessary for functional expression.

A full-length cDNA clone for phospholipid hydroperoxide glutathione peroxidase (PHGPx) was isolated from a rat brain. The cDNA was 0.761 kb in length and encoded 170 amino acids, which included a TGA-encoded selenocysteine at residue 46. The protein has a calculated molecular mass of 19,473 Da. We succeeded in the transient functional expression of a full-length cDNA for PHGPx, which includes the 3'-UTR, in COS-7 cells at the first attempt. Deletion of the 3'-UTR prevented the expression of the PHGPx activity and the incorporation of [75Se]selenious acid into the monomeric 19.7 kDa PHGPx protein. Thus, the 3'-UTR of the cDNA for PHGPx was required for the functional expression of PHGPx. Northern blot analysis demonstrated that the mRNA for PHGPx was widely expressed in normal rat tissues, especially in the testis. The mRNA levels of PHGPx in the cultured cells such as hepatomas, neuronal cells, nephroblastoma, and mammary myo-epithelial cells were higher than those of the tissues. The ratio of PHGPx to cytosolic glutathione peroxidase (cGPx) was significantly high in the testis and relatively high in the cultured cells. The mRNA levels of PHGPx in tissues were lower than those of cGPx.

Utilization of an isolated, blood-perfused canine papillary muscle preparation as a model to assess efficacy and adversity of class I antiarrhythmic drugs.

To develop a model to predict the efficacy and adversity of class I antiarrhythmic drugs, intraventricular conduction time (IVCT), coronary blood flow (CBF), developed tension of papillary muscle (DT) and idioventricular automaticity rate (VR) were measured following drug administration in an isolated canine papillary muscle preparation cross-circulated with the heparinized blood of a donor dog. Tetrodotoxin, the prototypic fast Na+ channel blocker, and class I drugs increased IVCT and CBF, but decreased DT and VR, in a dose-dependent manner. The profiles of known class I drugs, procainamide, disopyramide, lidocaine, mexiletine and flecainide were similar, but the potencies of each drug were different. Two new class I drugs, ME3202 and AN-132, were also tested and found to have effects that were similar to that of tetrodotoxin. There was a good correlation between the doses of drugs prolonging IVCT by 50% and the canine antiarrhythmic plasma concentrations in our previous study. This model can also be used to estimate the use-dependency and the kinetics of use-dependent sodium channel block; however, it is not suitable for extensive investigation of cellular and molecular mechanisms. Thus, the use of this model facilitates the comparison of multiple cardiac effects of class I drugs and may be an effective way to better assess new antiarrhythmic drugs.

A case-matched control study of intrahepatoarterial chemotherapy in combination with or without regional hyperthermia for treatment of primary and metastatic hepatic tumours.

The efficacy of the combined application of intrahepatoarterial (IHA) chemotherapy and regional hyperthermia for the treatment of unresectable hepatic tumours was studied in a case-matched, retrospective control study. Well-matched pairs of patients with the same or similar background factors, who had been treated with IHA chemotherapy plus hyperthermia (group A; n = 32) and with IHA chemotherapy alone (group B; n = 32) were included in this study. In group A, partial responses (PRs) were found in 2 of 8, 4 of 8, and 5 of 16 patients with hepatocellular carcinoma, metastatic gastric cancer, and metastatic colorectal cancer, respectively. In group B, PRs were found in 1 of 8, 3 of 8, and 5 of 16 patients with those diseases, respectively. Overall, PRs were found in 12 (37%) and 9 (28%) of 32 patients in groups A and B, respectively; progressive disease was found in 6 (19%) in group A and in 12 (38%) in group B. These results indicate that this combination therapy is of therapeutic benefit in the treatment of unresectable hepatic tumours.

Chronotropic and inotropic effects of kampo extracts in the canine isolated, blood-perfused heart preparations.

Cardiac effects of drugs used for circulatory disorders in traditional Japanese medicine based on ancient Chinese medicine (Kampo Medicine): Saikoka-ryukotsu-borei-to, Oren-gedoku-to, Toki-shakuyaku-san, Shimbu-to, Moku-boi-to, Ryo-kei-jutsu-kan-to, Sha-kanzo-to, Keishi-ninjin-to, Toki-to and Ryo-kan-kyo-mi-shin-ge-nin-to were investigated using canine isolated, blood-perfused sinoatrial node and papillary muscle preparations. Single injections of small doses of Oren-gedoku-to, Moku-boi-to and Ryo-kan-kyo-mi-shin-ge-nin-to (0.1 to 3 mg) dose-dependently increased the sinoatrial rate and the developed tension of papillary muscle, while other drugs showed almost no effect on these parameters. All the drugs had almost no effect on the blood flow through the nutrient arteries of each preparation. The positive chronotropic and inotropic effects induced by Oren-gedoku-to, Moku-boi-to and Ryo-kan-kyo-mi-shin-ge-nin-to did not show tachyphylaxis and were not affected after pharmacological denervation by tetrodotoxin treatment or by reserpine pretreatment, but were significantly suppressed by atenolol. These results indicate that these three drugs act as beta-adrenoceptor agonists to produce clinically useful cardiac effects.

Antiarrhythmic plasma concentrations of pirmenol on canine ventricular arrhythmias.

Using two-stage coronary ligation-, digitalis- and adrenaline-induced canine ventricular arrhythmias, antiarrhythmic effects of pirmenol were examined, and the minimum effective plasma concentration for each arrhythmia model was determined. Pirmenol suppressed all the arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 24 hr coronary ligation, 48 hr coronary ligation, digitalis and adrenaline were 1.1 +/- 0.3 (by 3 mg/kg, i.v.), 1.1 +/- 0.3 (by 3 mg/kg, i.v.), 1.1 +/- 0.2 (by 3 mg/kg, i.v.) and 2.5 +/- 1.5 (by 3 mg/kg, i.v.) microgram/ml, respectively (mean +/- S.D.M., n = 6-7). The concentration for adrenaline-induced arrhythmia was significantly higher than those for the other types of arrhythmias. This pharmacological profile is similar to those of mexiletine, tocainide and cibenzoline. Since pirmenol had no deleterious effects on the blood pressure and sinus node activity, its clinical usefulness is expected.

Thermoradiotherapy of refractory malignant tumors: an experience with microwave and RF capacitive hyperthermia.

Basic and clinical evidence that hyperthermia with radiation therapy or selected chemotherapy could significantly improve therapeutic ratios has attracted considerable interest. A variety of heating equipment and techniques have been used in many early clinical studies, with encouraging results: 60-70% with complete tumor regression without concomitant increase of normal-tissue toxicity. New generations of hyperthermia systems being developed should improve results significantly. However, since tumor response is directly related to hyperthermic temperature and the uniformity of the temperature distribution within target tissues, adequate characterization of the temperature profile within tumors as well as normal tissues is of primary importance. Clinical experience with microwave hyperthermia treatment combined with radiotherapy has been encouraging (complete regression response rate of 68% in 63 tumors in 50 patients) at Duke and VA Medical Centers, as have the results obtained (complete regression in 21 of 40 tumors treated in one clinic; 13 of 20 tumors treated in another clinic) with an 8-MHz RF capacitive hyperthermia system being evaluated in Japan.

[Hemispheric lateralization of EEG in early infantile autism].

Autoregressive (AR) analysis and component analysis were applied to EEGs during sleep stage 2 of normal and autistic children, since AR-coefficients of EEG characterize the autocovariance and power spectral density of EEG. In addition, as the Mahalanobis' generalized distance of the average AR coefficient vector of an EEG group at one side from that at the opposite side follows a F-distribution, the statistical inferences were carried out, whether or not there is hemispheric specialization in EEG in 21 right handed autistic children and whether there is difference between AR-spectral pattern of EEG in the autistic children and that of 28 normal children of the same age range or not. The results obtained were as follows: 1) The significant hemispheric lateralization in EEG at the significant level of 0.01 was observed in normals, whereas none of the lateralization was confirmed in autistic children. 2) The random click stimulation caused a cumulative effect on the hemispheric lateralization in the normals, but not in the autistic children. On the contrary, the effects of random flash light stimulation on hemispheric asymmetry were verified in the autistic children as well as in the normals. 3) The EEG components of autistic children were significantly different from the normal ones in frequency range of alpha-2 component wave at bilateral frontal (F1 and F2) regions and the activity of these component waves were higher in the autistic children than in the normal ones over 5 years-old. 4) These findings suggest that autistic children are not only less responsive to external stimuli, but also neurophysiologically less active in the internal regulatory mechanism.

Ontogenic development of EEG-asymmetry in early infantile autism.

Autoregressive (AR) analysis and component analysis were done on EEGs during sleep stage 2 in normal and autistic children, since AR-coefficients of EEG characterize the autocovariance and power spectral density of EEG. In addition, as the generalized distance of the average AR-coefficient vector of an EEG group at one side from that at the opposite side exhibits an F-distribution, the statistical inferences were determined, as to whether there is hemispheric specialization in EEG in 21 right-handed autistic children and whether there is a difference between the AR-spectral pattern of EEG in the autistic children and that of 28 normal children of the same age range. The results obtained are as follows: 1. Significant hemispheric lateralization in EEG at the significant level of 0.01 was observed in normal children, whereas no lateralization was confirmed in autistic children. 2. Random click stimulation had cumulative effects on the hemispheric lateralization in the normal children, but not in the autistic children. On the contrary, the effects of random flash light stimulation on hemispheric asymmetry were verified in the autistic children as well as in the normal children. 3. The EEG components of autistic children were significantly different from the normal ones in the frequency range of alpha-2 component waves at bilateral frontal (Fp1 and Fp2) regions and the activity of these component waves was higher in the autistic children than in the normal ones over 5 years old. 4. These findings suggest that autistic children are not only less responsive to external stimuli, but also neurophysiologically less active in the internal regulatory mechanism.