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Biomedical subjects

Y Ohashi

Publications and source records attributed to Y Ohashi.

At least 145 records · Page 8Linked to original sources
PubMed2000

Effect of troglitazone on the liver of a Gunn rat model of genetic enzyme polymorphism.

There is a possibility that serious liver dysfunction rarely observed in diabetic patients given troglitazone is attributable to idiosyncratic abnormalities in liver drug-metabolism. In addition, the results of blood biochemical examinations in serious cases of liver dysfunction showed a tendency for a high level of total bilirubin (T-Bil) over a long period compared with other indicators of liver dysfunction. Thus, we focused on genetic variation of UDP-glucuronosyltransferases (UGTs) that are involved in the conjugation of troglitazone and bilirubin. In this study, Gunn rats, which are hereditarily deficient in the UGT1 family of UGT isozymes, and Wistar rats, the parent strain of Gunn rats, were treated with troglitazone for 3 months at dose levels of 0, 100 or 400 mg/kg to investigate two possibilities: first, whether the genetic deficiency in UGT1s induces an alteration of the metabolic profile of troglitazone followed by liver dysfunction, and second, whether the dosing of troglitazone to Gunn rats which show hyperbilirubinemia result in liver dysfunction. As a result, the metabolic profile of troglitazone in Gunn rats was much the same as that of Wistar rats, suggesting that genetic deficiencies in UGT1s did not influence the metabolic profile of troglitazone. Moreover, no elevation of blood biochemical parameters, such as asparate aminotransferase (AST) and alanine aminotransferase (ALT), or histopathological liver injuries, such as hepatocellular degeneration and necrosis, were observed in either strain of rats, and hyperbilirubinemia in Gunn rats was not aggravated by the dosing of troglitazone. These results strongly suggest that troglitazone was not metabolized by UGT1s but by other UGT isozyme (s) in rats, and that glucuronidation of troglitazone did not compete with glucuronidation of bilirubin in vivo. Thus, it is suggested that high levels of total bilirubin in patients with liver dysfunction induced by troglitazone are attributable to hypofunction due to hepatocellular injury, not to metabolic competition of bilirubin with troglitazone. Moreover, it is also suggested that the deficiency in the UGT1 family of UGT isozymes itself may not be the cause of liver dysfunction associated with troglitazone treatment.

Animals↗
PubMed2000

Experimental corneal endotheliitis in rabbit.

PURPOSE: Corneal endotheliitis may cause permanent visual loss due to endothelial decompensation. The pathogenesis underlying this distinct clinical entity is not known. In the current study, a rabbit herpetic corneal endotheliitis model was made of induced anterior chamber-associated immune deviation (ACAID). METHODS: One group of rabbits received left-eye intracameral inoculation of UV-inactivated herpes simplex virus (HSV)-1 (strain McKrae). The second group received cell medium in the same manner as the first group. The third group subcutaneously received the same inoculum as the first group. Seven days later, all right eyes were intracamerally infected with 2.5 x 10(4) plaque-forming units of infectious HSV-1. Eyes were evaluated by slit lamp examination. Two weeks after infection, rabbits were killed, and right eyes were examined by immunohistochemical staining and electron microscopy. Aqueous humor was detected for HSV-1 DNA and antibody. RESULTS: Nonspecific inflammation occurred in the anterior segments of the eyes from the second and third groups. In contrast, at 14 days after infection, the first group of rabbits showed a specific pattern of inflammation that greatly resembled clinical features of corneal endotheliitis. Viral antigen was detected only in the endothelial layer. Electron microscopy revealed enlarged intercellular gaps and infiltration of inflammatory cells that are characteristic of endothelial defects. HSV-1 DNA was detected at a significantly higher number in the aqueous humor aspirates from endotheliitis rabbits. In addition, ACAID was shown to be induced in the rabbits with corneal endotheliitis. CONCLUSIONS: HSV-1 infection can induce corneal endotheliitis and ACAID may play the pivotal role in this entity.

Animals↗
PubMed2000

[A pilot trial of high dose CEP (cyclophosphamide, epirubicin, cis-platinum) therapy in patients with advanced and recurrent ovarian cancer].

We evaluated the feasibility of high-dose CEP (cyclophosphamide 750 mg/m2, epirubicin 90 mg/m2, cis-platinum 70 mg/m2) therapy, with granulocyte colony-stimulating factor support every 21 days, in 18 patients with advanced and recurrent ovarian cancer. Ten patients (56%) received 6 cycles of this regimen as planned. Toxicities more than grade 3/4 on' the WHO scale of neutropenia and thrombocytopenia were observed in all cases. Nausea, vomiting, mucositis, malaise, alopecia, hepatotoxicity, and fever were common adverse effects. The average relative dose intensity of cyclophosphamide, epirubicin, cis-platinum was 0.77, 0.77, 0.79 respectively, and each RDI decreased in the last two cycles. These data suggest that this regimen could be performed safely with careful consideration on hepatotoxicity and thrombocytopenia.

Adult↗
PubMed2000

Squid nerve sphingomyelin containing an unusual sphingoid base.

A new methodology has been developed to determine sphingolipid structures by positive-ion fast atom bombardment tandem mass spectrometry (FAB-MS/MS). The method was verified by application to a structurally known glycosphingolipid, and then used in the structural study of an unusual sphingomyelin isolated from squid (Loligo pealei) nerve. Our previous study of this squid sphingomyelin indicated that the major base had a branched C(19) alkyl chain with three double bonds, two of which were conjugated. The positions of the branching as well as the double bonds of this base were unambiguously determined by directly comparing the product ion spectra of the long-chain base ion (LCB(+)) of two ceramides, one derived from squid nerve sphingomyelin and another, glucosylceramide, obtained from starfish spermatozoa. The latter served as the standard because the structure had already been determined by nuclear magnetic resonance (NMR). The precursor ion here was LCB(+), that is, [CH(2) - C(NH(2)) = CHR](+), rather than [M + H](+), where R represents the backbone hydrocarbon chain counting from C-4. The results clearly showed that the squid nerve base is identical to the base derived from starfish (Asterias amurensis), that is, 2-amino-9-methyl-4,8,10-octadecatriene-1,3-diol. This is the first report in which the detailed structure of a branched polyunsaturated sphingoid base was studied by tandem mass spectrometry without derivatization or the aid of NMR. The occurrence of such an unusual sphingoid base in various phyla and tissues suggests the conjugated polyunsaturated branched sphingoid base plays a significant role in animals.

Animals↗
PubMed2000

Study of dose escalation and sequence switching of administration of the combination of docetaxel and doxorubicin in advanced breast cancer.

The objectives of the present study were to evaluate whether a schedule-dependent pharmacokinetic and/or pharmacodynamic interaction exists between two sequences of docetaxel and doxorubicin administration and to determine the maximal tolerated dose (MTD) of this combination. Patients with chemotherapy-naïve metastatic or recurrent advanced breast cancer were enrolled. In the crossover design, tandem dose escalation of docetaxel and doxorubicin was performed. Docetaxel, in doses ranging from 50-70 mg/m2, was administered for 1 h by drip infusion either just before or after a 5-min bolus i.v. injection of doxorubicin at dosages from 40-50 mg/ m2. The sequence of drug administration was switched after the first course in each patient, and the sequence of drug administration thereafter depended on the patient's choice. Twenty-five patients were initially assessable for toxicity. The MTD in the sequence of doxorubicin after docetaxel was 40 and 50 mg/m2, respectively, with the dose-limiting toxicity of neutropenia. On the other hand, the MTD of the sequence of docetaxel after doxorubicin was 70 and 50 mg/m2, respectively. The dose-limiting toxicities in this sequence were neutropenia and diarrhea. Duration of grade 4 neutropenia in the sequence of docetaxel followed by doxorubicin was significantly longer than that in the alternate sequence (P = 0.0062). However, there was no difference in pharmacokinetic parameters of docetaxel, doxorubicin, and doxorubicinol between the two sequences. The sequence of 50 mg/m2 doxorubicin followed by 60 mg/m2 docetaxel is recommended for subsequent clinical trials for practical reasons.

Adult↗
PubMed2000

[A combined effect of fadrozole and tamoxifen in postmenopausal patients with recurrent breast cancer: a preliminary report: Japanese Cooperative Study Group of Fadrozole and Tamoxifen].

To elucidate the combined effects of fadrozole (nonsteroidal aromatase inhibitor) and tamoxifen, 11 postmenopausal patients with recurrent breast cancer were examined between October 1996 and June 1998. One patient, 49 years old, was ineligible due to the short period after castration. The patients were aged 53-71 years (mean 63.5). PS was 0-1. Six patients were pre-treated with tamoxifen and 6 with oral 5-FU derivatives. One had no previous treatment. The target lesions were soft tissues in 5, bone in 4, lungs in 6 and liver in 1. The response was CR in 2, PR in 2, SD (longer than 24 weeks) in 2, NC in 1 and PD in 3. Consequently, the response rate was 60% (6 out of 10 eligible cases). Hormonal concentration was measured before and after administration of two drugs in weeks 2, 4, 6, 8 and at the end of the treatment, and significant decreases in estrogens in peripheral blood were observed. Adverse effects (4 cases of low grade headache, dizziness and elevation of GOT, GPT, gamma-GTP) did not influence the continuous administration of the drugs. We conclude that combined administration of fadrozole (2nd generation aromatase inhibitor) and tamoxifen produces a good response in postmenopausal recurrent breast cancer patients, and can be a useful treatment for patients with breast cancer.

Aged↗
PubMed2000

[Complications related to arterial infusion chemotherapy in patients with hepatic metastasis from colorectal cancer].

Complications of hepatic arterial infusion chemotherapy were analyzed in 30 cases with hepatic metastasis from colorectal cancer from July 1993 to February 2000 in our department. Thirty patients were treated with three kinds of arterial infusion course that mainly consisted of 5-FU. Complications resulting in interruption of therapy occurred in 10 patients (33%), and there was no difference in the incidence rate of complications among the three chemotherapy regimens. The complications with our therapy were hepatic arterial occlusion in two patients, catheter tip dislocation in four patients, fistulus between the hepatic artery and common bile duct in two patients, and fistulus between the hepatic artery and duodenal bulb in two patients. Four patients who had severe complications with fistulus all underwent hepatectomy, especially right hepatic lobectomy in two cases. Sixty percent of our patients had complications after hepatectomy, so regular GIF and DSA are necessary to prevent severe complications after hepatectomy.

Adult↗
PubMed1999

Intravesical chemotherapy for maximum prophylaxis of new early phase superficial bladder carcinoma treated by transurethral resection: a combined analysis of trials by the Japanese Urological Cancer Research Group using smoothed hazard function.

BACKGROUND: The effect of intravesical instillation of doxorubicin or epirubicin after transurethral resection (TUR) was estimated from the data of five randomized clinical trials in Japan. The authors provided the estimated hazard function plots with a smoothing technique, to evaluate the prophylactic effect of an intravesical therapy over time and to estimate the natural history of superficial bladder carcinoma. METHODS: Data on a total of 1732 patients from 5 studies of the Japanese Urological Cancer Research Group who were eligible to receive doxorubicin and epirubicin were analyzed. The patients were divided into four subgroups based on their background characteristics. Their tumors were categorized as "primary and solitary," "primary and multiple," "recurrent and solitary," or "recurrent and multiple." RESULTS: Multivariate analysis revealed that intravesical instillation reduced the risk of recurrence to about one-half to two-thirds compared with the controls. The shapes of the graphs that estimated the hazard function for patients with no prophylaxis indicated that multiple tumors showed an earlier peak of recurrence than solitary tumors and recurrent tumors had a higher hazard of recurrence than primary tumors. Graphic presentation of the hazard function in each subgroup suggested that the effect of prophylaxis continued for 500 days after TUR but not for longer. CONCLUSIONS: This analysis indicated that there are two patterns of tumor recurrence of superficial bladder carcinoma after TUR, namely, early phase and late phase. Intravesical chemotherapy may be effective mainly in reducing the hazard for recurrence in the early phase.

Administration, Intravesical↗
PubMed1999

Systematic isolation of genes expressed at low levels in inflorescence apices of Arabidopsis thaliana.

We constructed an equalized cDNA library from Arabidopsis inflorescence shoot apices including inflorescence meristem, floral meristem and flower tissue collected before stage 5 of flower development. The cDNA clones were arrayed on membranes and were differentially screened using cDNA pools from vegetative and inflorescence tissues as probes. Each clone was classified by expression specificity and expression level. By removing the clones that displayed hybridization signals, 384 out of 3264 clones in this library remained as candidates for inflorescence-specific mRNAs expressed at low levels. Sequence analysis of all selected clones indicated that 53 were identical and 120 were homologous to genes in public protein databases. The remaining 211 selected clones had no significant amino acid sequence similarities with those deduced from any reported genes, though 62 of them appeared in Arabidopsis expressed sequenced tags (ESTs). About 40% of the selected clones were novel, validating the present approach for gene discovery. Northern blot analysis of 22 randomly selected clones confirmed that most were expressed preferentially in inflorescence tissues. In addition, many clones were transcribed at relatively low levels. We demonstrate that the screening method of the present study is useful for systematic classification of cDNA species based on expression specificity.

Animals↗
PubMed1999

Tyrosine phosphorylation of Crk-associated substrate lymphocyte-type is a critical element in TCR- and beta 1 integrin-induced T lymphocyte migration.

Crk-associated substrate (Cas) lymphocyte-type (Cas-L) is a 105-kDa cytoplasmic protein consisting of Src homology-3 domain and multiple YXXP motifs (substrate domain). Our previous studies showed that Cas-L is tyrosine-phosphorylated following the ligation of TCR and beta 1 integrins in T lymphocytes. Here we show that Cas-L is involved in T cell motility following the ligation of TCR and beta 1 integrin. Peripheral T lymphocytes showed a marked increase of migration on fibronectin (FN) after the ligation of TCR. In contrast, the migrating Jurkat cells, in which Cas-L was marginally expressed, were less than one-tenth in number on the same condition. Transfection of wild-type Cas-L into Jurkat cells resulted in restoring CD3 plus FN-induced cell migration. Furthermore, following the ligation of beta 1 integrin alone, the Cas-L transfectants significantly migrated better than the vector control. Mutational analysis of Cas-L revealed that the substrate domain is required for both FN- and CD3-induced tyrosine phosphorylation of Cas-L and cell migration caused by FN alone and CD3 plus FN. In contrast, the Src homology-3 domain is required only for the FN-induced tyrosine phosphorylation of Cas-L and cell migration, but not for CD3-induced tyrosine phosphorylation or CD3 plus FN-induced cell migration. These data strongly suggest that Cas-L is a key molecule in T cell migration induced by the ligation of CD3 and beta 1 integrins and that tyrosine phosphorylation of Cas-L is essential for T cell migration.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Investigating centre effects in a multi-centre clinical trial of superficial bladder cancer.

This paper examines the amount of variation among centres and estimates the overall effect of therapy in a multi-centre cancer clinical trial with censored failure time data. To investigate the centre effects, the variation in the treatment effect must be taken into consideration in addition to the variation in the baseline risk. We treat centre effects as random ones and extend the penalized partial likelihood approach proposed by McGilchrist to estimate the treatment-by-centre interaction as well as the baseline risk. This method is applied to data from a superficial bladder cancer clinical trial investigating the efficacy of intravesical chemotherapy after transurethral resection. In this trial, although there exists some degree of centre variation, especially in the baseline risk, the treatment is effective in preventing recurrence among the participating centres. This result indicates that the treatment effect is generalizable to the target population.

Administration, Intravesical↗
PubMed1999

Daily fluctuation of 7-alkoxycoumarin O-dealkylase activities in the liver of male F344 rats under ad libitum-feeding or fasting condition.

It has been reported that drug metabolizing enzyme activities in the liver fluctuate daily, though the daily fluctuation of 7-alkoxycoumarin O-dealkylase (ACD) activities catalyzed by P450 has not been examined. The ACD activities are known to be useful to clarify the extensive induction of P450-dependent oxygenases. In the present study, the hepatic ACD activities, as well as P450 content, were investigated periodically in male F344 rats under ad libitum-feeding or fasting condition. The ACD activities in ad libitum-fed rats were found to follow obvious daily fluctuations with high values during dark periods and with low values during light periods. This agreed with the other previous results of drug metabolizing enzyme activities measured with other substrates. Because the daily fluctuation was also observed in fasted rats, the fluctuation in ACD activities was clearly not affected by feeding, an external factor. P450 content, however, showed different fluctuation patterns from the ACD activities. This suggests that the fluctuation of ACD activities might not be related to the quantitative variation of P450 proteins.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1999

Animal cell-death suppressors Bcl-x(L) and Ced-9 inhibit cell death in tobacco plants.

In plants, events similar to programmed cell death have been reported [1] [2], although little is known of their mechanisms at the molecular level. To investigate the mechanism(s) involved, we overexpressed bcl-x(L), which encodes a mammalian suppressor of programmed cell death, in tobacco plants, under the control of a strong promoter [3]. In plants expressing Bcl-x(L), cell death induced by UV-B irradiation, paraquat treatment or the hypersensitive reaction (HR) to tobacco mosaic virus (TMV) infection was suppressed. The extent of suppression of cell death depended on the amount of Bcl-x(L) protein expressed. Similar enhanced resistance to cell death was found in transgenic tobacco plants overexpressing the ced-9 gene, a Caenorhabditis elegans homolog of bcl-x(L) [4], indicating that Bcl-x(L) and Ced-9 can function to inhibit cell death in plants.

Apoptosis Regulatory Proteins↗
PubMed1999

Cas-L is required for beta 1 integrin-mediated costimulation in human Tcells.

Beta 1 integrins provide a costimulus for TCR/CD3-driven T cell activation and IL-2 production in human peripheral T cells. However, this beta 1 integrin-mediated costimulation is impaired in a human T lymphoblastic line, Jurkat. We studied the molecular basis of this impaired costimulation and found that Cas-L, a 105-kDa docking protein, is marginally expressed in Jurkat T cells, whereas Cas-L is well expressed in peripheral T cells. Cas-L is a binding protein and a substrate for focal adhesion kinase and is tyrosine phosphorylated by beta 1 integrin stimulation. We here show that the transfection of wild-type Cas-L in Jurkat T cells restores beta 1 integrin-mediated costimulation. However, Cas-L transfection had no effect on CD28-mediated costimulation, indicating that Cas-L is specifically involved in the beta 1 integrin-mediated signaling pathway. Furthermore, transfection of the Cas-L Delta SH3 mutant failed to restore beta 1 integrin-mediated costimulation in Jurkat cells. Cas-L Delta SH3 mutant lacks the binding site for focal adhesion kinase and is not tyrosine phosphorylated after beta 1 integrin stimulation. These findings strongly suggest that the tyrosine phosphorylation of Cas-L plays a key role in the signal transduction in the beta 1 integrin-mediated T cell costimulation.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Daily rhythm of serum melatonin levels and effect of light exposure in patients with dementia of the Alzheimer's type.

BACKGROUND: Several studies have suggested that patients with dementia experience a deterioration of biological rhythms. We investigated the daily profile of serum melatonin levels in patients with dementia of the Alzheimer's type (AD), since daily melatonin rhythm is thought to reflect the functioning of the biological clock. METHODS: Seventeen inpatients with AD, 10 psychiatric inpatients without dementia, and 11 elderly healthy volunteers participated in this study. Serum melatonin was assessed every 3 hours by radioimmunoassay. RESULTS: A daily fluctuation of melatonin levels with a significant nocturnal increase was observed in all three subject groups. However, both the AD patients and psychiatric patients without dementia showed significantly higher levels of melatonin in the daytime compared with the healthy subjects. When the effect of bright light exposure on melatonin secretion was investigated in six AD patients and five psychiatric patients without dementia, the daytime levels were markedly decreased in the patients without dementia, while no change was observed in the AD patients. CONCLUSIONS: The high levels of melatonin in the daytime associated with a lack of response to light exposure in AD patients may be due to the neurodegenerative process of this disease.

Aged↗