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S Higuchi

Publications and source records attributed to S Higuchi.

At least 37 records · Page 2Linked to original sources
PubMed2002

Binding evaluation of the combination between the superconductor and matrix by ultrasonic spectra.

Combination of the superconductor and high conductive normal metal is now indispensable in the practical use of superconducting magnet. And the binding property of both materials is one of the key points whether superconductive characteristics are fully attained or the current fails prematurely in the practical magnet. But this binding evaluation is not so easy, because even in the mechanically well-jointed conductor, it often appears poor in electric and magnetic joint in cryogenic temperature. Since we have examined and reported fundamental AE properties of superconductor from UI-91, UI-93, UI-95, and UI-97, we have found the simple but important discovery for getting new information about the binding evaluation. Here we report a new technique for evaluating these bindings by observing ultrasonic spectra when a normal transition is propagated along the superconductor. We have discovered that a good contacting conductor has an emission of this sound with sharp resonating frequency peak or peaks at around the highest spectrum area; from 0.5 to 1.0 MHz. Our interpretation of the evaluations are so simple that we can say that binding degrees are best, good or bad, according to the resonating Q-value at around the highest spectrum of the ultrasonic sound.

Journal Article↗
PubMed2002

Localization of [14C]clarithromycin in rat gastric tissue when administered with lansoprazole and amoxicillin.

After oral and intravenous administration of [14C]clarithromycin to rats, c. 60-70% of the radioactivity in the gastric tissue was found to be distributed in the mucosal layer. Co-administration of lansoprazole and amoxicillin had no apparent effect on this distribution pattern of [14C]clarithromycin. The amount of unchanged [14C]clarithromycin in gastric contents increased with co-administration of lansoprazole and amoxicillin. Microautoradiograms of the gastric mucosa showed that [14C]clarithromycin was highly distributed in the mucous layer and in surface epithelial cells following oral administration. Homogeneous distribution of radioactivity was evident in the fundic gland. With iv administration, [14C]clarithromycin seemed to be secreted by both secreting cells in the gland base and surface epithelial cells.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2002

Pharmacokinetic and pharmacodynamic analysis of TS-943, a selective non-peptide platelet glycoprotein-IIb/IIIa (GPIIb/IIIa) receptor antagonist, using a nonlinear mixed effect model in dogs.

A simultaneous analysis of the pharmacokinetics and pharmacodynamics of TS-943, a selective nonpeptide platelet glycoprotein-IIb/IIIa (GPIIb/IIIa) receptor antagonist, was made in dogs using a nonlinear mixed effect model. Plasma concentrations of TS-943 were determined after bolus intravenous injection, constant infusion and bolus plus constant infusion. Pharmacokinetic/pharmacodynamic data were fitted using NONMEM software. The pharmacokinetics of TS-943 fitted a two-compartment open model with first-order elimination. The pharmacodynamic model that best fitted platelet aggregation was an inhibitory sigmoid Emax model. The final estimates for E0 (baseline effect), Emax (maximum effect), IC50 (50% inhibitory concentration) and gamma (Hill coefficient) were 66.3%, 64.3%, 104 ng mL(-1) and 1.37, respectively. Correlations between TS-943 plasma concentration and extension of template bleeding time were examined by fitting with an exponential model. The TS-943 plasma concentration necessary to double bleeding time (C2-BTE) was approximately 209 ng mL(-1). The model estimated that the C2-BTE/IC50 (inhibition of platelet aggregation) ratio was approximately 2.0-fold in dogs. Our results suggest that the ratio values for dogs and man are comparable. A nonlinear mixed effect model was a useful tool for exploring the concentration-effect relationship for both efficacy and safety of TS-943 in dogs and man. In this study, the dog was found to be a useful model for screening of efficacy and safety of TS-943 in man.

Amidines↗
PubMed2001

Alcoholism, ALDH2*2 allele and the A1 allele of the dopamine D2 receptor gene: an association study.

The inactive form of aldehyde dehydrogenase-2 (ALDH2) is regarded as a protective factor against the development of alcoholism, and alcoholics with inactive ALDH2 are considered to be relatively homogeneous. This examination of a possible allelic association of the dopamine D2 receptor (DRD2) gene TaqI A polymorphism failed to detect significant differences between 583 Japanese alcoholics and 295 unrelated Japanese controls, or between alcoholic subjects with different ALDH2 genotypes. Despite the significantly higher frequency of the DRD2 A1 allele in the 207 alcoholics with inactive ALDH2 than in the 376 alcoholics with active ALDH2, multiple logistic regression analysis (controlled for the ALDH2 genotype) revealed no association between the TaqI A polymorphism and alcoholism. Nor did the frequency of the DRD2 TaqI A polymorphism differ in alcoholic subjects grouped by several pertinent clinical characteristics, including severity of alcoholism. Although there remains a possibility that the DRD2 TaqI A polymorphism plays some role in modifying the phenotype of the disease, these results suggest that neither the A1 allele nor the homozygous A1 genotype is associated with alcoholism.

Adult↗
PubMed2001

Effects of histamine and interleukin-4 synthesized in arterial intima on phagocytosis by monocytes/macrophages in relation to atherosclerosis.

We investigated the localization of histidine decarboxylase (HDC), which is the rate-limiting enzyme that generates histamine from histidine, in human aorta/coronary artery. RT-PCR and immunohistochemical staining revealed that the HDC gene was expressed in monocytes/macrophages and T cells in the arterial intima but not in smooth muscle cells in either the arterial intima or the media. A luciferase promoter assay with U937 and Jurkat cells demonstrated that interleukin-4 (IL-4) inhibited the expression of the HDC gene. In contrast, among a scavenger receptor family, IL-4 as well as histamine up-regulated U937 cells to express the LOX-1 gene but not the SR-A gene, which genes encode receptors that scavenge oxidized lipids. These findings suggest that histamine synthesized in the arterial wall participates in the initiation and progression of atherosclerosis and that IL-4 can act as an important inhibitory and/or stimulatory factor in the function of monocytes/macrophages modulated by histamine in relation to the process of atherosclerosis.

Arteriosclerosis↗
PubMed2001

Association between 5HT2A receptor gene promoter region polymorphism and eating disorders in Japanese patients.

BACKGROUND: Evidence from family and twin studies suggests a genetic contribution to the etiology of eating disorders (EDs). Recently, researchers have reported genetic associations between the MspI polymorphism (-1438A/G) of the promoter region of the 5HT2A receptor gene and EDs; however, reports of evidence against these findings make the association controversial. METHODS: The authors examined the prevalence of the -1438A/G polymorphism of the 5HT2A receptor gene among 182 Japanese patients with EDs and 374 normal control subjects. Interactions of the association of this polymorphism with subtypes of anorexia nervosa (AN), bulimia nervosa (BN), and various clinical characteristics were also assessed. RESULTS: In contrast to previous studies reporting elevated A allele frequencies in patients with AN, the G allele had a significantly higher frequency in patients with BN but not in patients with AN, than in control subjects. Examination of the interactions revealed that the presence of the binge eating and/or purging behavior and comorbid borderline personality disorder (BPD) tended to be associated with increased frequency of the G allele. CONCLUSIONS: Though preliminary, these results can be interpreted as suggesting that the G allele of the 5HT2A receptor gene -1438A/G polymorphism may be associated with pathological features that EDs and BPD have in common, especially disinhibition in eating behavior and personality trait.

Adult↗
PubMed2001

Association study of serotonin transporter gene regulatory region polymorphism and alcoholism.

Previous studies have indicated associations between a functional biallelic repetitive element in the 5' regulatory region of the serotonin transporter gene (5-HTTLPR) and alcoholic subjects who have either dissocial personality disorder or severe withdrawal symptoms. To replicate these associations under the hypothesis that genetic polymorphism plays some role in the susceptibility or vulnerability of some subgroup of alcoholics, the associations between alcoholic subjects' genetic polymorphisms, clinical characteristics, and personality traits were examined. This case control study comprised 697 alcoholic and 270 control subjects. A questionnaire focusing on family and social background, history of drinking and alcohol withdrawal, DSM-III-R criteria for the evaluation of psychiatric conditions, and Feighner's criteria for the lifetime diagnosis and assessment of overall severity of alcoholism was administered to 373 alcoholic subjects. Temperament and Character Inventory (TCI) and Sensation Seeking Scale (SSS) were used to evaluate the other 324 alcoholics. The frequency of the homozygous short allele was significantly higher in alcoholic binge drinkers than in nonbinge drinking alcoholics. There were no significant differences in the frequencies of either the 5-HTTLPR genotype or the short vs. long allele in alcoholic and control subjects. The alcoholics' 5-HTTLPR genotype and allele frequencies did not differ significantly by the severity of withdrawal symptoms or by the number of positive Feighner's diagnostic criteria. Although these results indicate an association between 5-HTTLPR and a subgroup of alcoholics characterized by binge drinking, the authors found no differences in SSS and TCI subscale scores for alcoholics with different 5-HTTLPR genotypes. Future studies of the association in other alcoholic population should take into account personality traits.

Alcoholism↗
PubMed2001

Pharmacokinetic properties of a novel tissue-type plasminogen activator pamiteplase after single intravenous administration to rats, dogs, and monkeys.

The pharmacokinetics of pamiteplase and recombinant tissue-type plasminogen activator (rt-PA) in rats, dogs, and monkeys were examined using a newly developed enzyme-linked immunosorbent assay (ELISA). Plasma concentrations after intravenous administration of pamiteplase to rats declined in a triphasic manner. Plasma concentrations after intravenous administration of pamiteplase to dogs or monkeys declined in a biphasic manner. The area under the plasma concentration-time curve from zero to infinity (AUC(0-->infinity)) in rats and dogs increased with increasing dose. The half-life and mean residence time of pamiteplase in rats, dogs, and monkeys were shown to be longer than those of rt-PA. Total clearance (CL(total)) of pamiteplase was only 7-16% that of rt-PAs, suggesting that concentrations of pamiteplase in plasma were higher and more continuous than those of rt-PA in these experimental animals. The data suggest that a bolus administration of pamiteplase shows the same thrombolytic activity as continuous infusion of rt-PA in experimentally induced thrombosis in rats and dogs. The pharmacokinetic parameters distribution volume at the steady state and CL(total) calculated by immunoreactive concentration after administration of pamiteplase to rats, dogs, and monkeys show high correlation with body weights (r(2)=.7728 and .9039).

Animals↗
PubMed2001

Large-scale domain movements and hydration structure changes in the active-site cleft of unligated glutamate dehydrogenase from Thermococcus profundus studied by cryogenic X-ray crystal structure analysis and small-angle X-ray scattering.

Here we describe the large-scale domain movements and hydration structure changes in the active-site cleft of unligated glutamate dehydrogenase. Glutamate dehydrogenase from Thermococcus profundus is composed of six identical subunits of M(r) 46K, each with two distinct domains of roughly equal size separated by a large active-site cleft. The enzyme in the unligated state was crystallized so that one hexamer occupied a crystallographic asymmetric unit, and the crystal structure of the hexamer was solved and refined at a resolution of 2.25 A with a crystallographic R-factor of 0.190. In that structure, the six subunits displayed significant conformational variations with respect to the orientations of the two domains. The variation was most likely explained as a hinge-bending motion caused by small changes in the main chain torsion angle of the residue composing a loop connecting the two domains. Small-angle X-ray scattering profiles both at 293 and 338 K suggested that the apparent molecular size of the hexamer was slightly larger in solution than in the crystalline state. These results led us to the conclusion that (i) the spontaneous domain motion was the property of the enzyme in solution, (ii) the domain motion was trapped in the crystallization process through different modes of crystal contacts, and (iii) the magnitude of the motion in solution was greater than that observed in the crystal structure. The present cryogenic diffraction experiment enabled us to identify 1931 hydration water molecules around the hexamer. The hydration structures around the subunits exhibited significant changes in accord with the degree of the domain movement. In particular, the hydration water molecules in the active-site cleft were rearranged markedly through migrations between specific hydration sites in coupling strongly with the domain movement. We discussed the cooperative dynamics between the domain motion and the hydration structure changes in the active site of the enzyme. The present study provides the first example of a visualized hydration structure varying transiently with the dynamic movements of enzymes and may form a new concept of the dynamics of multidomain enzymes in solution.

Binding Sites↗
PubMed2001

Relationship between diurnal rhythm of cell cycle and interferon receptor expression in implanted-tumor cells.

Whether the diurnal rhythm of cell cycle is associated with that of interferon-alpha/beta receptor (IFNAR) expression was investigated in implanted-tumor cells. The expression of IFNAR mRNA significantly increased when the proportion of tumor cells in DNA synthesis (S) phase increased in vitro. A diurnal rhythm was observed for cell cycle distribution in implanted-tumor cells. The specific binding of interferon-alpha to receptor and IFNAR mRNA increased when the proportion of tumor cells in S phase increased in vivo. The time-dependent expression of IFNAR was supported by that of transcription factor level induced by interferon-beta. The present result suggests that the rhythm of IFNAR expression is closely related to that of cell cycle distribution in implanted-tumor cells.

Animals↗
PubMed2001

Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity.

Caveolin-3 is the muscle-specific isoform of the caveolin protein family, which is a major component of caveolae, small membrane invaginations found in most cell types. Caveolins play important roles in the formation of caveola membranes, acting as scaffolding proteins to organize and concentrate lipid-modified signaling molecules, and modulate a signaling pathway. For instance, caveolin-3 interacts with neuronal nitric oxide synthase (nNOS) and inhibits its catalytic activity. Recently, specific mutations in the caveolin-3 gene, including the Pro104Leu missense mutation, have been shown to cause an autosomal dominant limb-girdle muscular dystrophy (LGMD1C), which is characterized by the deficiency of caveolin-3 in the sarcolemma. However, the molecular mechanism by which these mutations cause the deficiency of caveolin-3 and muscle cell degeneration remains elusive. Here we generated transgenic mice expressing the Pro104Leu mutant caveolin-3. They showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, indicating a dominant negative effect of mutant caveolin-3. Interestingly, we also found a great increase of nNOS activity in their skeletal muscle, which, we propose, may play a role in muscle fiber degeneration in caveolin-3 deficiency.

Animals↗
PubMed2001

Uptake by vascular smooth muscle cells plays an important role in targeting of lipid microspheres incorporating prostaglandin E1 into a thickened intima.

A study was done to determine how lipid microspheres (LM) containing prostaglandin E1 (lipo PGE1) accumulate in injured arterial tissue. After administration of lipo PGE1 labeled with a fluorescence probe, 1,1'-dioctadecyl-3, 3, 3',3'-tetramethyl-indocarbocyanine perchlorate (DiI-lipo PGE1) to rats 14 of days after balloon injury of the carotid artery, localization into the injured site was examined using a fluorescence confocal laser scanning microscope (CLSM). In contrast with the normal carotid artery, DiI-lipo PGE1 accumulated remarkably in neointima of the injured site which was occupied mainly by the migration of the proliferating and quiescent vascular smooth muscle cells (SMC). In vitro cellular uptake of DiI-lipo PGE1 was semi-quantitatively measured using CLSM, regarding differentiated and proliferative phenotypes of human vascular SMC, compared with the human endothelial cells (EC) and mouse fibroblasts. The differentiated SMC incorporated DiI-lipo PGE1 to equal or a higher level of the proliferative phenotype, and was significantly higher than EC and fibroblasts. The uptake of DiI-lipo PGE1 by both SMC and EC was inhibited at 4 degrees C, by dansylcadaverine and excessive LM, but was unaffected by cytochalasin B. These results suggest that the uptake of DiI-lipo PGE1 by SMC plays an important role in localization of DiI-lipo PGE1 at the injured site, and that the uptake seems to be a receptor mediated endocytosis.

3T3 Cells↗
PubMed2001

Highly sensitive determination of TS-962 (HL-004), a novel acyl-CoA:cholesterol acyltransferase inhibitor, in rat and rabbit plasma by liquid chromatography and atmospheric pressure chemical ionization-tandem mass spectrometry combined with a column-switching technique.

A quantitative bioanalytical method with excellent specificity using liquid chromatography (LC) atmospheric pressure chemical ionization-tandem mass spectrometry (APCI-MS-MS) combined with a column-switching technique has been developed for the highly sensitive and reliable determination of TS-962 (HL-004), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, in rat and rabbit plasma. The method involves protein precipitation of a 25-microl aliquot of plasma sample with eight volumes of methanol containing a deuterium-labeled internal standard, the direct injection of a methanolic supernatant into the analytical instrumentation with no sample evaporation and reconstitution steps, automated on-line clean-up on a C18 short trapping column (10 mm x 4.0 mm I.D.) followed by separation on a C18 analytical column (50 mm x 4.6 mm I.D.), and detection with APCI-MS-MS using m/z 448 ([M+H]+) as a precursor ion and m/z 178 as a product ion in a selected reaction monitoring mode. The lower limit of quantification was 1 ng/ml, and good linearity of the calibration graph was obtained in the range of 1 to approximately 490 ng/ml with excellent reliability. The developed method enabled pharmacokinetic profiles to be determined for rats and rabbits with sequential plasma collection from an individual animal.

Acetamides↗
PubMed2001

A strategy for quantitative bioanalysis of non-polar neutral compounds by liquid chromatography/electrospray ionization tandem mass spectrometry: determination of TS-962, a novel acyl-CoA:cholesterol acyltransferase inhibitor, in rabbit aorta and liver tissues.

A strategy for the sensitive and reliable quantitative determination of non-polar neutral compounds in biological matrices by liquid chromatography/electrospray ionization tandem mass spectrometry is described in the context of assay development for TS-962, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, in rabbit aorta and liver tissues. The electrospray ionization (ESI) mass spectrum of this compound with a mobile phase of water/acetonitrile did not give abundant [M + H]+ ions, but did give alkali metal cation adducts such as [M + Na]+, [M + CH3CN + Na]+ and [M + K]+ ions. The cationized species are acknowledged as unsuitable precursor ions for selected reaction monitoring (SRM) for various reasons, such as difficulty in obtaining characteristic product ions in low-energy collision-induced dissociation, and irreproducibility of the adduct-ion intensities. To overcome this problem, a solution of 3.4 mM trifluoroacetic acid in 2-propanol was added to the mobile phase as a postcolumn additive, resulting in a decrease of the undesirable adduct formation and significant enhancement of [M + H]+ ion intensity. An attempt was then made to prevent the matrix effect by employing a column-switching system, which allowed direct injection of a large volume of 2-propanolic tissue homogenate (950 microL) followed by sufficient clean-up, separation, and ESI-SRM on-line. This enabled development of a sensitive and reliable assay method for TS-962 in rabbit aorta and liver tissues in the concentration range of 5-500 ng/g wet tissue using a 25-mg aliquot of tissue sample. Application of this method to the determination of aortic TS-962 levels at 24 h after repeated oral administration of this compound (3 mg/kg) once a day for 12 weeks to 1% cholesterol-fed rabbits is also presented. Results showed that TS-962 is well distributed to both the thoracic and abdominal aorta tissues, at levels higher than the 50% inhibitory concentration value of this compound for microsomal ACAT activity from rabbit aorta.

Acetamides↗
PubMed2001

Cerebrospinal fluid amyloid beta(1-42) levels in the mild cognitive impairment stage of Alzheimer's disease.

Cerebrospinal fluid (CSF) levels of amyloid beta-protein ending at amino acid position 42 (CSF-A beta(1-42)) and CSF-tau levels were quantified by sandwich ELISAs in 19 patients with mild cognitive impairment (MCI) who eventually developed Alzheimer's disease (AD) on follow-up as well as in 15 age-matched normal controls and 54 AD patients at diverse stages of the disease. In the present study, the annual conversion rate was approximately 15%. The CSF-A beta(1-42) levels did not differ significantly between the normal control group and the MCI group, however, these values declined significantly once AD became clinically overt. In contrast to CSF-Abeta(1-42), CSF-tau levels were significantly increased in the MCI stage, and these values continued to be elevated thereafter, indicating that increased levels of CSF-tau may help in detecting MCI subjects who are predicted to develop AD. We propose that CSF-tau and CSF-A beta(1-42) must be used as two distinct biomarkers that should be applied appropriately in clinical settings.

Aged↗
PubMed2001

Population-based investigation of relative clearance of digoxin in Japanese neonates and infants by multiple-trough screen analysis.

OBJECTIVE: The steady-state concentrations of digoxin at trough levels were studied to establish the role of patient characteristics in estimating doses for digoxin using routine therapeutic drug monitoring data. METHOD: The data (n = 448) showing steady state after repetitive oral administration in 172 hospitalized neonates and infants were analyzed using Nonlinear Mixed Effect Model (NONMEM), a computer program designed to analyze pharmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of digoxin were investigated. RESULTS: Estimates generated using NONMEM indicated that clearance of digoxin (l.h-1) was influenced by the demographic variables of age, total body weight, serum creatinine, the coadministration of spironolactone, and the presence or absence of congestive heart failure. The interindividual variability in digoxin clearance was modeled with proportional errors with an estimated coefficient of variation of 32.1%, and the residual variability was 28.9%. In the validation set of 66 patients, the performance (bias, precision) of the final population model was good (mean prediction error -0.04 ng.ml-1; mean absolute prediction error 0.20 ng.ml-1).

Cardiotonic Agents↗