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Biomedical subjects

A Nakashima

Publications and source records attributed to A Nakashima.

At least 19 recordsLinked to original sources
PubMed2001

Determination of fluvastatin and its five metabolites in human plasma using simple gradient reversed-phase high-performance liquid chromatography with ultraviolet detection.

A simple gradient reversed-phase high-performance chromatographic method with ultraviolet detection for the determination of fluvastatin (FV) and its five metabolites, (M-2, M-3, M4, M-5 and M-7) in human plasma was developed and validated. The limit of quantification of FV and its five metabolites in human plasma was 10 ng ml(-1). The assay had satisfactory selectivity, recovery, linearity and precision accuracy. Stability studies showed that FV and its five metabolites were stable in plasma up to at least 1 month of storage at -30 degrees C.

Anticholesteremic Agents↗
PubMed2001

Inhibitory effects of fluvastain and its metabolites on the formation of several reactive oxygen species.

We investigated the inhibitory effects of fluvastain (FV) and its metabolites (M-2, M-3, M-4, M-5, and M-7) on the formation of several reactive oxygen species (ROS), such as singlet oxygen (1O2), superoxide anion (O2-), hydroxy radical (*OH), hypochlorite ion (OCL-), and linoleic acid peroxide (LOO*). Inhibitory effects of pravastatin (PV), simvastatin (SV), probucol (PR) and alpha-tocopherol (TOC) were also tested. The inhibitory effects of 5-hydroxy FV (M-2) and 6-hydroxy FV (M-3) on the formation of 1O2, O2-, *OH, and OCL- were strongest. Scavenging of 1O2 by M-4, M-5, (+)-FV, and (-)-FV was also noted. The inhibitory effects of (+)-FV on the formation of 1O2 were comparable to those of (-)-FV, PV, SV, PR and M-7 had little or no inhibitory effect on the formation of several ROS. In conclusion, FV and its metabolites, particulary M-2 and M-3, have the potential to protect against oxidative stress mediated by several ROS.

Animals↗
PubMed2001

Distribution and behavior of nonylphenol, octylphenol, and nonylphenol monoethoxylate in Tokyo metropolitan area: their association with aquatic particles and sedimentary distributions.

Distributions of alkylphenols (APs) [i.e., nonylphenol (NP), octylphenol (OP)], and nonylphenol monoethoxylate (NP1EO) in wastewater effluents, river water, and riverine and bay sediments in the Tokyo metropolitan area were demonstrated. During sewage treatments, NP and OP were efficiently removed from the sewage effluents through activated sludge treatments. Greater removal for NP (93% on average) than OP (84% on average) was consistent with their partitioning behavior to particles in primary and secondary effluents. NP concentrations in the river water samples ranged from 0.051 to 1.08 microg/L with higher concentrations in summer and spring than in colder seasons. In the river water samples, approximately 20% of NP was found in the particulate phase. Organic carbon-normalized apparent partition coefficients (K'OC) for NP (10(5.22 +/- 0.38)) and OP (10(4.65 +/- 0.42)) were 1 order of magnitude higher than those expected from their octanol-water partition coefficients (K(OW)), indicating strong affinity of APs to aquatic particles. Among NP isomers, no significant differences in their K'OC values were suggested. This is consistent with surprisingly uniform isomer peak profiles among the technical standard and all the environmental samples analyzed. NP and OP were widely distributed in the river sediments in Tokyo, and relatively high concentrations (0.5-13.0 microg/g dry) of NP were observed in a long reach (approximately 10 km) in the Sumidagawa River. In situ production of APs in the river sediment was suggested. Seaward decreasing trend in APs concentration was observed from the estuary to the Tokyo Bay. APs were well preserved in a sediment core collected from the bay. The profile shows subsurface maximum of AP concentrations in the layer deposited around the mid-1970s. The recent decrease in AP concentrations can be attributed to the legal regulation of industrial wastewater in the early 1970s.

Cities↗
PubMed2001

Expression of GTP cyclohydrolase I in murine locus ceruleus is enhanced by peripheral administration of lipopolysaccharide.

Among the enzymes involved in the system for catecholamine biosynthesis, GTP cyclohydrolase I (GCH) contributes to the system as the first and rate-limiting enzyme for the de novo biosynthesis of tetrahydrobiopterin (BH4), which is the cofactor for tyrosine hydroxylase (TH). Therefore, we investigated whether the endotoxemia caused by an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) can modulate BH4 production in the norepinephrine nuclei, i.e. the locus ceruleus (LC; A6) and central caudal pons (A5), in C3H/HeN mice and whether such a change in BH4, if any, can result in the modification of norepinephrine production in these nuclei. After a 5-microg i.p. injection of LPS, the protein expression of GCH and TH in both nuclei was examined by immunohistochemistry. The staining intensity of GCH-positive cells increased at 6 h, whereas no significant change in the staining intensity of TH-positive cells was detected. Next, we measured the contents of BH4, norepinephrine, and its metabolites 4-hydroxy-3-methoxyphenylglycol (MHPG) and DL-4-hydroxy-3-methoxymandelic acid (VMA) in these nuclei after LPS i.p. injection. The BH4 content increased to a statistically significant level at 2 and 4 h after the injection. The contents of MHPG and VMA also showed a time-course similar to that of BH4. These data can be rationalized to indicate that an increased supply of BH4 in the LC increased TH activity and resulted in an increase in norepinephrine production rate at the site. This is the first report that sheds light on BH4 as a molecule that intervenes during endotoxemia to increase norepinephrine production rate in the LC.

Animals↗
PubMed2001

Risk stratification analysis of operative mortality in coronary artery bypass surgery.

OBJECTIVE: We assessed the operative mortality of coronary artery bypass grafting (CABG) surgery using risk stratification. METHODS: In 294 consecutive patients who underwent CABG with or without concomitant surgery from August 1994 to December 1999, we compared operative mortality calculated conventionally and by risk stratification. Scores for each patient were calculated using the Parsonnet additive model and stratified based on the probability of operative mortality. RESULTS: Overall crude hospital mortality was 4.8%-4.0% among patients younger than 80 years and 14% among those 80 years of age or older (p = 0.0692). Hospital mortality was 12% in urgent/emergency surgery, and 1.5% in elective surgery (p < 0.0002), and 4.5% in CABG alone and 7.4% in CABG with concomitant surgery (p = 0.3763), and 25% in patients receiving vein grafts only and 3.0% in those receiving at least 1 artery graft (p = 0.0003). Overall patient distribution was 32% good, 20% fair, 20% poor, 11% high-risk, and 16% extremely high-risk. Predicted mortality was 2.2% for patients who were a good risk, 6.7% for fair-risk, 12% for poor-risk, 16% for high-risk, and 25% for extremely high-risk patients. Actual operative mortality was 1.0% for good-risk, 0% for fair-risk, 3.4% for poor-risk, 6.3% for high-risk, and 18% for extremely high-risk patients, making actual mortality significantly lower than that predicted. CONCLUSION: Comparing predicted mortality and actual mortality enabled us to objectively calculate operative results and assess operative quality.

Age Factors↗
PubMed2001

Anti-arthritic effects of KF20444, a new immunosuppressive compound inhibiting dihydroorotate dehydrogenase, on rat collagen-induced arthritis.

OBJECTIVE AND DESIGN: A newly synthesized inhibitor of pyrimidine de novo biosynthesis, KF20444 (6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5H-benzo [6,7] cyclohepta [1,2-b] quinoline-8-carboxylic acid), was evaluated as an inhibitor of dihydroorotate dehydrogenase (DHO-DHase) and tested in the rat collagen-induced arthritis (CIA) model. MATERIAL AND METHODS: Female Sprague Dawley rats, 5 weeks-old, were used for evaluation of KF20444 in the CIA model. Arthritis was evaluated by arthritis score, serum anti-type II collagen antibody titer, body weight loss, radiographical and histological changes. TREATMENT: KF20444 was orally administered 5 times per week (0.3, 1, 3 mg/kg/day). RESULTS: KF20444 inhibited rat liver dihydroorotate dehydrogenase in vitro with Ki = 8.5 +/- 3.2 nM, which was a comparable effect to that of brequinar sodium (Ki = 25.3 +/- 5.3 nM). The anti-proliferative effect of KF20444 was caused by cell cycle arrest at the S-phase. Treatment with 3 mg/kg/day of KF20444 completely prevented the development of CIA based on reduction of the arthritis score. The 50% effective dose (ED50) of KF20444 on arthritis score was 0.64 mg/kg. KF20444 ameliorated body weight loss associated with disease onset. The compound also inhibited the increase in serum anti-type II collagen antibody level, and reduced both pannus formation and bone erosion. Importantly, KF20444 suppressed the development of arthritis, even when it was administered after booster immunization of collagen. CONCLUSIONS: KF20444 is a novel immunosuppressant which inhibits DHO-DHase and its effects in CIA suggest that it could be useful in the treatment of rheumatoid arthritis.

Animals↗
PubMed2001

Fission yeast tor1 functions in response to various stresses including nitrogen starvation, high osmolarity, and high temperature.

A target of rapamycin (TOR) protein is a protein kinase that exerts cellular signal transduction to regulate cell growth in response to extracellular nutrient conditions. In the Schizosaccharomyces pombe genome database, there are two genes encoding TOR-related proteins, but their functions have not been analyzed. Here we report that one of the genes, referred to as tor1+, is required for sexual development induced by nitrogen starvation. Ste11 is a key transcription factor for the initiation of sexual development. The expression of ste11+ is normally regulated in tor1- cells; and overexpression of ste11+ hardly rescues the defect in fertility in tor1-. Upon nitrogen starvation, tor1+ cells promote two rounds of the cell cycle to become arrested at the G1 phase before initiation of sexual development. The tor1- cells do not promote such a cell cycle, suggesting that Tor1 is necessary for the response to nitrogen starvation. The tor1- cells show no growth or very slow growth under various stress conditions, including external high pH, high concentrations of salts or sorbitol, and high temperature. These results suggest that Tor1 is necessary for any response to a wide range of stresses. The vegetative growth of tor1- cells is inhibited by rapamycin, although tor1+ cells are resistant to the drug. The tor1- cells are hypersensitive to fluphenazine and cyclosporin A, which specifically inhibit calmodulin and calcineurin, respectively.

Amino Acid Sequence↗
PubMed2001

Error correcting memorization learning for noisy training examples.

In order to avoid overfitting, we propose error correcting memorization learning. This method is derived from minimization of error between outputs of a trained neural network and correct values for noisy training examples, although the correct values are unknown. We show that noise is adequately suppressed by error correcting memorization learning. The noise suppression mechanism is theoretically clarified. It is found that redundancy plays an essential role for noise suppression and depends on a set of training inputs. We give the condition for the training inputs to provide the redundancy. Moreover, by clarifying the relationships between the proposed method and the weighted least squares estimation with the Mahalanobis norm, we reveal effectiveness of the weighted least squares estimation on noise suppression.

Models, Theoretical↗
PubMed2001

Noise suppression in training examples for improving generalization capability.

For the supervised learning problem, error correcting memorization learning was proposed in order to suppress noise in teacher signals. In this paper, generalization capability of the learning method is discussed. Generalization capability is evaluated based on the projection learning criterion. We give a necessary and sufficient condition for error correcting memorization learning to provide the same level of generalization as projection learning, and suggest how to choose a training set so as to satisfy the obtained condition. Moreover, it is revealed that noise suppression based on the error correcting memorization learning criterion always has a good effect on improving generalization to the level of projection learning.

Artifacts↗
PubMed2001

Risk stratification analysis of operative mortality in heart and thoracic aorta surgery: comparison between Parsonnet and EuroSCORE additive model.

OBJECTIVE: Our purpose was to compare the performance of risk stratification model between Parsonnet and European System for Cardiac Operative Risk Evaluation (EuroSCORE) in our patient database. METHODS: From August 1994 to December 2000, 803 consecutive patients have undergone heart and thoracic aorta surgery using cardiopulmonary bypass and scored according to Parsonnet and EuroSCORE algorithm. The population was divided into five clinically relevant risk categories. We compared correlation of predicted mortality and observed mortality between these two models. Score validity was assessed by calculating the area under the receiver operating characteristic (ROC) curve. RESULTS: Overall hospital mortality was 4.5%. In Parsonnet model, predicted mortality was 2.4% for 0-4% risk, 6.7% for 5-9% risk, 12% for 10-14% risk, 17% for 15-19% risk, 25% for 20% plus risk, and 10.4% for overall patients. Observed mortality was 2.4, 0.4, 5.9, 8.7, 11, and 4.5%, respectively. The thoracic aorta and valve cohort indicated poor correlation between predicted and observed mortality compared to coronary cohort. In the EuroSCORE model, predicted mortality was 1.4% for 0-2% risk, 4.0% for 3-5% risk, 6.7% for 6-8% risk, 9.7% for 9-11% risk, 13% for 12% plus risk, and 5.3% for overall patients. Actual mortality was 0, 1.5, 6.8, 11, 21, and 4.5%, respectively. Each of the thoracic aorta, valve, and coronary cohort indicated good correlation between predicted and observed mortality. Areas under the ROC curves were 0.72 in Parsonnet and 0.82 in EuroSCORE. CONCLUSIONS: The EuroSCORE additive model yielded good predictive value for hospital mortality of Japanese patients undergoing not only cardiac but also thoracic aortic surgery.

Algorithms↗
PubMed2001

Determination of tetrahydrobiopterin in murine locus coeruleus by HPLC with fluorescence detection.

Tetrahydrobiopterin in the murine locus coeruleus was measured as its fully oxidized form, biopterin, using a HPLC coupled to a fluorescence detector, because tetrahydrobiopterin itself cannot be detected by such means. The differential oxidization method distinguished tetrahydrobiopterin-derived biopterin and dihydrobiopterin-derived biopterin. The protocol reported here is a rapid and sensitive method that facilitates the measurement of tissue and/or cellular tetrahydrobiopterin. Using this assay protocol, we were able to detect and quantify variations in the tetrahydrobiopterin content in the murine locus coeruleus.

Animals↗
PubMed2001

Exon 3 of tyrosine hydroxylase gene: lack of association with Japanese schizophrenic patients.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine (DA) biosynthesis. Exon 3 of the human TH gene encodes the sequence from Ser31 to Glu104 of type 1 enzyme, which contains the critical parts for regulation of the catalytic activity. The amino acid residues Gly36-Arg37-Arg38 were identified as a key sequence for DA to exert its inhibitory effect on catalytic activity. Therefore, we screened the nucleotide sequences of exon 3 from 201 Japanese patients with schizophrenia to explain the elevation in the synaptic or presynaptic DA concentrations in the schizophrenic brain, based on the hypothesis that any mutation changing the amino acid sequence Gly36-Arg37-Arg38 would result in the elevation of DA synthesis, due to a reduced inhibitory effect of DA on the catalytic activity. However, no mutated sequences of exon 3 and both exon-intron boundaries were detected in any of the patients examined. Polymorphisms generating Val81 and Met81 were compared of the distributions of genotype and allele between the patients and 175 Japanese healthy controls, which did not suggest an association between the polymorphism and schizophrenia. These results indicate that exon 3 of the human TH gene lacks association with schizophrenia in Japanese patients.

Adult↗
PubMed2001

[Antioxidative effects of fluvastatin, and its major metabolites [II]].

We investigated the antioxidative effects of fluvastatin (FV or (+/-)-FV), each enantiomer ((+)-FV, (-)-FV) and its major metabolites on lipid peroxidation using rat and human liver microsomes. The extent of NADPH induced microsomal (Ms) lipid peroxidation was determined by thiobarbituric acid (TBA) assay. The antioxidative effect of each compound was shown as the percentage of inhibition on the formation of TBA reactive substance (TBARS) against vehicle control. The antioxidative effects of alpha-tocopherol (Toc), a potent antioxidative vitamin, probucol (PR), a potent antioxidative drug, pravastatin (PV) and simvastatin (SV), HMG-CoA reductase inhibitors, were also tested. The (+/-)-FV inhibit the formation of TBARS by 40 to 70% depending on Ms concentrations. The antioxidative effects of PR and TOC were comparable to those of FV. The inhibitory effects of PV and SV on the formation of TBARS were less potent than (+/-)-FV, PR and TOC. (+)-FV, (-)-FV, and (+/-)-FV inhibited the formation of TBARS by approximately 50% using rat hepatic microsomes. The antioxidative effects of (+)-FV was comparable to that of (-)-FV using human hepatic microsomes. These results indicated that the antioxidative effects of (+)-FV were comparable to those of (-)-FV, although the HMG-CoA reductase inhibitory activity of (+)-FV was 30-fold higher than that of (-)-FV.

Animals↗
PubMed2001

[Early and mid-term results after cardiac or thoracic aortic surgery in patients aged 70 years and older--survival and quality of life].

The early and mid-term survival after cardiac or thoracic aortic surgery and influence of age to the operative mortality were examined in 168 consecutive patients aged 70 years and older from August 1994 to December 1998, together with assessment of postoperative quality of life (QOL). The mean age was 74.1 +/- 3.7 years old (70 to 86 years). 80 patients had IHD, 59 had VHD, 28 had TAA. Preoperative risk score was classified in 5 groups (good, fair, poor, high, extremely high) based on Parsonnet method. Current QOL of the survivors was assessed using Asanoi method with questionnaire by a letter. There were 9 early deaths (5.4%). Following the Parsonnet model observed mortality was absolutely lower than predicted mortality. When age score was excluded in the Parsonnet model, the observed mortality became almost equal with the predicted mortality. There were 22 late deaths (6.9%/P-Y). The actuarial survival rate of age 70 to 74 group was significantly higher than the age 75 years and older group (p = 0.0021). The actuarial survival rate of TAA group was significantly lower than the VHD or IHD group (p < 0.02). Postoperative NYHA and activity score of TAA group were better than VHD or IHD group. We got satisfactory answers for operation in 95% current survivors. Patients aged 70 years and older will be undergone cardiac or thoracic aortic surgery at a reasonable risk and well satisfaction.

Aged↗
PubMed2000

Positive charge intrinsic to Arg(37)-Arg(38) is critical for dopamine inhibition of the catalytic activity of human tyrosine hydroxylase type 1.

Tyrosine hydroxylase (TH), which converts L-tyrosine to L-3, 4-dihydroxyphenylalanine, is a rate-limiting enzyme in the biosynthesis of catecholamines; its activity is regulated by the feedback inhibition of the catecholamine products including dopamine. To rationalize the significant role of the N-terminal sequence Arg(37)-Arg(38) of human TH type 1 (hTH1) in determining the efficiency of feedback inhibition, we produced mutants of which the positively charged Arg(37)-Arg(38) site was replaced by electrically neutral Gly and/or negatively charged Glu and analyzed the degree of inhibition of these mutant enzymes by dopamine. The replacement of Arg by Gly reduced the inhibitory effect of dopamine on the catalytic activity measured in the basic pH range and the replacement of Arg by Glu was enough to abolish the inhibitory effect, although these mutations brought no significant changes to the circular dichroism spectrum. The prediction of the secondary structure of N-terminal residues 1-60 by computer software specified the location of the Arg(37)-Arg(38) sequence in the turn intervening between the two alpha-helices (residues 16-29 and residues 41-59). These results suggest that the positive charge of the amino acid residues at positions 37 and 38 is one of the main factors that maintains the characteristic of the turn and is responsible for the enzyme inhibition by dopamine.

Amino Acid Sequence↗
PubMed2000

Risk factors for posttransfusion graft versus host disease, mediastinitis, and late cardiac tamponade in heart surgery. Survey of 119 Japanese institutions.

OBJECTIVE: Correlations and risk factors remain to be unclarified for post-heart-surgery posttransfusion graft-versus-host disease, mediastinitis, and late cardiac tamponade caused by deteriorated host-defense mechanisms due to cardiopulmonary bypass both with and without steroid usage. METHODS: We sent questionnaires to 298 Japanese cardiovascular institutions asking for institution profiles, including infection control, steroid use in cardiopulmonary bypass, and prevalence of mediastinitis, late cardiac tamponade, and posttransfusion graft-versus-host disease during 1994. The overall prevalence of posttransfusion graft-versus-host disease since the start of service (from establishment of institution to date) was also requested. RESULTS: The number of pump cases at the 119 institutions responding (40%) were 91.6 +/- 67.9 cases/institution (total = 10,904). The prevalence of mediastinitis was 1.2 +/- 1.8 and that of late cardiac tamponade 1.0 +/- 1.8%. Posttransfusion graft-versus-host disease occurred in 1 of 10,904 patients (0.01%) during 1994 at an institution where steroids and nonirradiated blood were used in surgery. The simple institutional mean prevalence of posttransfusion graft-versus-host disease since establishing institutions was 0.08 +/- 0.13%. Of the 119 institutions surveyed, 86 used steroids in all pump cases (72%); 11 institutions used steroids in a limited number of cases (9%). The institutional mean of methylprednisolone-converted steroid dose was 21.5 +/- 16.4 mg/kg (n = 119). In multivariate regression analysis, operation time (p = 0.005) for mediastinitis, steroid usage (all, limited, or no cases) (p = 0.01) and % aneurysm (p = 0.05) for late cardiac tamponade, and steroid dosage (p = 0.002) for posttransfusion graft-versus-host disease were identified as significant risk factors. CONCLUSION: Our results suggest that massive steroid administration for cardiopulmonary bypass may increase the risk of posttransfusion graft-versus-host disease and late cardiac tamponade, but not mediastinitis.

Aged↗
PubMed2000

Imaging features of myoepithelioma arising from the hard palate. A case report.

A 53-year-old Japanese woman presented with a mass of the hard palate that was histologically diagnosed as myoepithelioma. By CT, the well-demarcated ovoid isodense mass showed faint contrast enhancement. By MR imaging, the mass was homogeneous and isointense on T1-weighted images with homogeneous enhancement after administration of contrast material and markedly hyperintense on T2-weighted images. Myoepithelioma should be kept in mind as differential diagnosis of hard palatine tumors.

Actins↗