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Biomedical subjects

Y Tada

Publications and source records attributed to Y Tada.

At least 73 records · Page 4Linked to original sources
PubMed2000

Inhibition of intracellular cathepsin activities and suppression of immune responses mediated by helper T lymphocyte type-2 by peroral or intraperitoneal administration of vitamin B6.

We reported that pyridoxal phosphate (PAP), a coenzyme form of vitamin B6, strongly inhibits activities of cathepsin B and weakly inhibits those of cathepsins S, K, and C in vitro. Either intraperitoneal injection or peroral administration of medication doses of vitamin B6 in the diet caused dose-dependent inhibition of hepatic cathepsins B, L, S, and C, and the inhibition was exhibited much more significantly in the case of a high protein diet than in a low protein diet. Administration of vitamin B6 induced the suppression of immune responses against ovalbumin (OVA) mediated by helper T lymphocyte type-2, based on the suppression of antigen processing by cathepsin B inhibition, as in the case of CA-074 administration, a cathepsin B specific inhibitor. Ovalbumin-dependent production of immunoglobulins IgE, IgG1 and interleukin IL-4 was suppressed by administration of medication doses of pyridoxal (PA) or pyridoxine (PI), while the production of IgG2alpha and interferon (INF)-gamma mediated by helper T lymphocyte type 1 was not changed. Administration of medication doses of vitamin B6 caused the inhibition of intracellular cathepsin B activity due to suppression of the functions of helper T lymphocyte type-2.

Administration, Oral↗
PubMed2000

Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosides.

A new class of 5-halogenated pyrimidine analogs substituted at the 6-position was evaluated as competitive inhibitors of thymidine phosphorylase (TPase). The most potent member of the series was 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidine dio ne hydrochloride (TPI), which has an apparent K(i) value of 1.7 x 10(-8) M. TPI selectively inhibited the activity of TPase, but not that of uridine phosphorylase, thymidine kinase, orotate phosphoribosyltransferase, or dihydropyrimidine dehydrogenase. In vitro inhibition studies of TPI using a thymidine analogue, 5-trifluoromethyl-2'-deoxyuridine (F(3)dThd), as the substrate demonstrated that F(3)dThd phosphorolytic activity was inhibited markedly by TPI (1 x 10(-6) M) in extracts from the liver, small intestine, and tumors of humans, from the liver and small intestine of cynomolgus monkeys, and from the liver of rodents, but not from the liver or small intestine of dogs or the small intestine of rodents, suggesting that the distribution of TPase differs between humans and animal species, and that TPI could contribute to the modulation of TPase in humans. When F(3)dThd or 5-iodo-2'-deoxyuridine (IdUrd) was coadministered to mice with TPI at a molar ratio of 1:1, the blood levels of F(3)dThd (or IdUrd) were about 2-fold higher than when F(3)dThd (or IdUrd) was administered alone. In monkeys, the maximum concentration (C(max)) and the area under the concentration-time curve (AUC) after oral F(3)dThd alone were 0.23 microg/mL and 0.28 microg. hr/mL, respectively, but markedly increased to 15.18 microg/mL (approximately 70-fold) and 28.47 microg. hr/mL (approximately 100-fold), respectively, when combined with equimolar TPI. Combined oral administration of TPI significantly potentiated the antitumor activity of F(3)dThd on AZ-521 human stomach cancer xenografts in nude mice. In conclusion, TPI may contribute not only to inhibition of TPase-mediated biological functions but also to potentiation of the biological activity of various 2'-deoxyuridine and thymidine derivatives by combining with them.

Administration, Oral↗
PubMed2000

Granulocyte/macrophage colony-stimulating factor inhibits IL-12 production of mouse Langerhans cells.

We investigated the capacity of mouse Langerhans cells (LC) to produce IL-12, a central cytokine in a Th1 type of immune responses. We prepared purified LC (>95%) from BALB/c mouse skin by the panning method using anti-I-Ad mAb. An ELISA showed that purified LC spontaneously produced IL-12 p40, and that its production was up-regulated following simultaneous stimulation with anti-CD40 mAb and IFN-gamma. Surprisingly, GM-CSF strikingly inhibited IL-12 p40 production by anti-CD40/IFN-gamma-stimulated LC (% inhibition = 97.0 +/- 0.9% at 1 ng/ml GM-CSF). Supernatants of 48-h cultured keratinocytes (KC) also caused the inhibition of LC IL-12 p40 secretion, and this effect was neutralized by anti-GM-CSF mAb. IL-1alpha (1 ng/ml)-stimulated KC produced much more GM-CSF than unstimulated KC (60.9 +/- 0.2 pg/ml vs 20.9 +/- 1.7 pg/ml), and IL-1alpha-stimulated KC supernatants strongly inhibited IL-12 p40 production by anti-CD40/IFN-gamma-stimulated LC (% inhibition = 89.4 +/- 1.4%). A bioassay using an IL-12-dependent T cell line demonstrated the correlation of the level of IL-12 p40 with the bioactivity of IL-12. These results provide important implications for the pathogenesis of atopic dermatitis, which involves the participation of LC and KC with the capacity to produce IL-12 and GM-CSF, respectively.

Animals↗
PubMed2000

Structure-based development of pyridoxal propionate derivatives as specific inhibitors of cathepsin K in vitro and in vivo.

We found that pyridoxal phosphate shows considerable inhibition of cathepsins. CLIK-071, in which the phosphate ester of position 3 of pyridoxal phosphate was replaced by propionate, strongly inhibited cathepsin B. Three new types of synthetic pyridoxal propionate derivatives showing specific inhibition of cathepsin K were developed. New synthetic pyridoxal propionate derivatives, -162, -163, and -164, in which the methyl arm of position 6 of CLIK-071 was additionally modified, strongly inhibited cathepsin K and cathepsin S weakly, but other cathepsins were not inhibited. CLIK-166, in which the position 4 aldehyde of CLIK-071 is replaced by a vinyl radical and position 5 is additionally modified, showed cathepsin K-specific inhibition at 10(-5) M. Pit formation due to bone collagen degradation by cathepsin K of rat osteoclasts was specifically suppressed by administration of CLIK-164, but not by inhibitors of cathepsin L or B.

Animals↗
PubMed2000

Inhibition of cathepsin activities by vitamin B6 derivatives.

We found that pridoxal phosphate (PLP), a coenzyme form of vitamin B6, inhibited the activity of cathepsins B, K, S and L in vitro. Cathepsins activities in cultured splenocytes were suppressed by the addition of pridoxal (PL) or pridoxine (PI) in to the culture medium. A newly synthesized artificial vitamin B6 derivative, a pridoxal propionate derivative, CLIK-164, showed selective inhibition of cathepsin O/K.

Cathepsins↗
PubMed2000

Partial left ventriculectomy in a 3-year-old boy with dilated cardiomyopathy.

A 3-year-old boy suffered severe heart failure 2 months after ventricular septal defect repair. The cardiothoracic ratio was 67% and the ejection fraction 13%. Echocardiography showed a dilated left ventricle and thin myocardium. After thorough study, we made a diagnosis of dilated cardiomyopathy. Because conventional therapy was unsuccessful, we conducted partial left ventriculectomy with Alfieri repair of the mitral valve. The postoperative cardiothoracic ratio was 57% at 1 year of follow-up and the ejection fraction 40%. The New York Heart Association functional class improved from IV to I. In conclusion, the role of partial left ventriculectomy is both as a bridge to transplantation and as a definitive repair in dilated cardiomyopathy during childhood.

Cardiomyopathy, Dilated↗
PubMed2000

Stress and coping behavior in patients with diabetes mellitus.

Diabetes mellitus is a disease which must be controlled over the lifetime of a patient. We investigated the issues of stress and coping for diabetes mellitus which may influence self-management. In addition, we examined the association of these factors with blood glucose control, in order to review self-management instructions for diabetes mellitus. The study included 153 patients with diabetes mellitus. The patients were divided into two subgroups: good-control group, comprising patients with glycohemoglobin (HbA1c) values less than 7.0%; and poor-control group, comprising those with HbA1c values of 7.0% or more. All patients responded to a questionnaire regarding stress tolerance, Jalowiec and Power's coping scale and awareness of diabetes mellitus. Stress tolerance was not significantly different between the good-control and poor-control groups. No significant gender differences in coping score were evident for the good-control group. However, in the poor-control group, the coping score in men was significant higher than that in women. The problem-oriented coping score for men in the poor-control group was significantly higher than that for the good-control group (p < 0.01). In a comparison of awareness of diabetes mellitus, the proportion of patients who replied that they were rigidly following diabetes treatment was higher in the poor-control group than the good-control group. Patients with diabetes mellitus may have a knowledge of the disease and a strong will to resolve problems. This is especially true for male patients in that their will appeared to be stronger, but they may not have the resolve to establish appropriate behavior patterns. In the future, methods for evaluating self-management should be included in diabetes education.

Adaptation, Psychological↗
PubMed2000

Anomalies of inferior vena cava and left renal vein: risks in aortic surgery.

Although most aortic surgery is now routinely performed without incident, major venous anomalies can cause unexpected bleeding. In the last 6 years, 4 of 166 patients undergoing abdominal aortic surgery at our institution were found to have a major venous anomaly, including a double inferior vena cava (2), a preaortic iliac vein confluence (1), and a circumaortic renal collar (1). The 3 men and 1 woman had a mean age of 62.3 years (range, 56 to 68 years). All four patients underwent surgery for an abdominal aortic aneurysm. Preoperative imaging revealed all of the venous anomalies except for the renal collar. Unexpected venous injuries complicated the operation in one patient who had a double inferior vena cava and an inflammatory abdominal aortic aneurysm and in the patient with the circumaortic renal collar. Major venous anomalies are rarely encountered in patients undergoing aortic surgery. Preoperative assessment and intraoperative awareness are important to prevent unexpected venous injuries. Patients with an anomaly of the left renal vein and an inflammatory abdominal aortic aneurysm are at a particularly high risk.

Aged↗
PubMed2000

Age-related changes in the magnitude of ventricular depolarization vector: analyses by magnetocardiogram.

The magnetocardiogram has the beneficial feature that permits the strength and location of the current dipole to be estimated. This study examines the issue of whether the magnitude of the heart current during depolarization phase was influenced by the age of healthy subjects. The magnetocardiograms were recorded by means of a second-derivative SQUID (superconducting quantum interference device) magnetometer (BT Corp, Model BMP, San Diego, CA) in 150 healthy subjects. The subjects were subgrouped into 5 age-based categories according to the age. The current dipole of the maximum QRS complex was determined from isofield contour maps during the ventricular depolarization phase, and no significant differences were observed in the magnitude in the current source for any age category. However, the amplitudes of the RV5 and SV1 + RV5 in the standard electrocardiogram were larger in 65 to 74-year-old women than other age groups, and the SV1 + RV5 was smaller for the 45 to 74-year-old men than for the men aged 25 to 44 years. These findings suggest that the age-associated changes in the QRS complex observed by the electrocardiogram are caused by increased electric resistance and not by the heart current itself. The results additionally suggest that no effects of aging were observed in the actual heart current of the heart during the depolarization phase.

Action Potentials↗
PubMed2000

Subchronic toxicity of chlorpropham (CIPC) in ICR mice.

Male and female ICR mice were given 0, 1875, 7500 or 30,000 ppm of chlorpropham (CIPC) in the diet for 13 weeks. Methemoglobin levels of male and female mice in the 7500 and 30,000 ppm groups were significantly elevated. Hemoglobin concentration, packed cell volume, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and white blood cell count of male and female mice in the 30,000 ppm group were significantly increased. Dose-dependent splenomegaly was observed in male and female mice in the 7500 and 30,000 ppm group. Congestion, increased hemosiderin deposition and increased extramedullary hematopoiesis in the spleen, hematopoietic cell hyperplasia and hemosiderin deposition in bone marrow was observed dose dependently in male and female mice in the 7500 or 30,000 ppm group. Eosinophilic granular cytoplasm of hepatocytes, sinusoidal dilatation, hemosiderin deposition, extramedullary hematopoiesis and necrosis of hepatocytes were observed in the liver of male and female mice in the 30,000 ppm group. Hemosiderin deposition was increased in the kidney of male and female mice in the 30,000 ppm group. Administration of CIPC in diet for 13 weeks caused methemoglobinemia and splenomegaly in ICR mice.

Animals↗
PubMed2000

Gene expression and immunohistochemical localization of biglycan in association with mineralization in the matrix of epiphyseal cartilage.

This study has used in situ hybridization, Northern blot analysis, and immunohistochemistry at the light and electron microscope levels to localize mRNAs and core proteins of biglycan in developing tibial epiphyseal cartilage of 10-day old Wistar rats. The expression of mRNAs and core proteins of biglycan appeared prominent in hypertrophic and degenerative chondrocytes associated with the epiphyseal ossification centre and the growth plate cartilage, but was not seen in the rest of epiphyseal cartilage. Northern blot analysis confirmed biglycan mRNA expression in the epiphyseal cartilage. Ultrastructural immunogold cytochemistry of the growth plate revealed that prominent immunolabelling was confined to the Golgi apparatus and cisternae of rough-surfaced endoplasmic reticulum of the hypertrophic and the degenerating chondrocytes, the early mineralized cartilage matrices of the longitudinal septum of the lower hypertrophic and the calcifying zones, and fully mineralized cartilage mitrices, which were present in the metaphyseal bone trabeculae. Furthermore, Western blot analysis of biglycan in extracts of fresh epiphyseal cartilage revealed that an EDTA extract, after chondroitinase ABC digestion, contains core proteins of biglycan, indicating the presence of biglycan in mineralized cartilage matrices. These results indicate that the distribution of biglycan is associated with cartilage matrix mineralization.

Animals↗
PubMed2000

Use of oligotrophic bacteria for the biological monitoring of heavy metals.

Oligotrophic bacteria exhibited active growth even in nutritionally deficient medium made with nutrient broth that had been diluted with distilled water, 1 : 10 000. The oligotrophic bacteria, Sphingomonas paucimobilis KPS01 and Burkholderia cepacia KPC01 and KPC02 were found to be highly susceptible to heavy metals and to be potentially useful as sensors for the assessment of toxicity. The susceptibility of the bacteria to metals was measured by incubating the bacteria with metals of varying concentrations in the nutritionally deficient medium at 30 degrees C for 24 h. Bacteria were considered susceptible when the growth inhibition rate (EC50 was more than 50% of the control. The EC50 value of Ag+, Pb2+ and Cd2+ was 10(5)mmol l(-1) and Zn2+, Cr3+, Cr6+, Cu2+ and Hg2+ was 10(-4) mmol l(-1) in S. paucimobilis KPS01. Other strains also showed similar results. No difference in the EC50 was found using either the chloride or sulphate forms of these metals. The optimum incubation time was 24 h and a longer incubation time did not necessarily lead to more inhibition. The EC50 value rose in proportion to the concentration of nutrition in media. Environmental samples were tested and 14 out of 88 samples inhibited the growth of S. paucimobilis KPS01.

Burkholderia cepacia↗
PubMed2000

Origin of giant cells in osteoclast-like giant cell tumors of the pancreas.

To clarify the origin of giant cells in osteoclast-like giant cell tumors (OGCTs) of the pancreas, we performed microscopical, immunohistochemical, and K-ras gene mutation analyses with a microdissection approach in 3 cases, featuring 4 cellular components (osteoclast-like giant cells [OGCs], pleomorphic large cells [PLCs], mononuclear cells, and ductal carcinoma cells). Two cases had abundant OGCs, and 1 case contained large number of both OGCs and PLCs. In each, none of the microdissected OGCs contained any K-ras gene mutation while they were positive for a histiocytic marker (CD-68). In contrast, PLCs, when present, frequently harbored K-ras gene mutations and were negative for CD-68. In all cases, mononuclear cells, a mixture of histiocyte-like and atypical, from microscopic and immunohistochemical viewpoints, also frequently showed K-ras alteration. Histiocyte-like mononuclear cell was equipped with a regular and oval nucleus similar to those in OGCs and was positive for CD-68. Atypical mononuclear cell showed an irregular, pleomorphic, or sometimes bizarre nucleus similar to those in PLCs and was negative for CD-68. All of the K-ras gene mutations found in PLCs and mononuclear cells were the same as in the ductal carcinoma cells within the same tumor. Thus, OGCs differ in origin from ductal cells and are strongly suggested to be nonneoplastic and of mesenchymal origin, whereas PLCs, which harbor K-ras gene mutations, are neoplastic and presumably derived from ductal carcinoma cells. Moreover, mononuclear cells may be classified into 2 types, histiocyte-like and atypical.

Carcinoma, Pancreatic Ductal↗
PubMed2000

K-ras gene mutations and loss of heterozygosity at the p53 gene locus relative to histological characteristics of mucin-producing tumors of the pancreas.

Mucin-producing tumors (MPTs) of the pancreas accompanied by carcinomas usually include various grades of dysplasia in the ductal epithelium, and invasive areas are histologically similar to those of common invasive ductal carcinomas, suggesting that MPTs provide a good tool to investigate early stages of pancreatic carcinogenesis. Thus, to clarify genetic alterations in the early stage of pancreatic carcinogenesis, we analyzed K-ras gene mutations and loss of heterozygosity (LOH) at the p53 gene locus using 37 cases of MPTs harboring dysplastic epithelium. Further, we conducted an extended, multifocal microdissection analysis focusing on the histological features of ductal epithelium and the distribution of genetic alterations for 3 cases of MPT positive for LOH of the p53 gene to determine the relation to tumor progression. K-ras gene mutations were detected with high frequency in 50% or more cases of the adenomas (14 of 19), borderline tumors (4 of 7), and carcinomas (8 of 11), whereas LOH of the p53 gene was limited to carcinomas (3 of 5 informative cases, 60%) and always accompanied by K-ras gene mutation. Investigation of a total of 126 microdissection sites from 3 cases showed the presence of K-ras gene mutations in mild dysplasia and all (100%) regions of moderate or more marked dysplasia, whereas LOH of the p53 gene showed more gradual tendency to increase with grade from moderate dysplasia. In addition, the multifocal genetic analysis showed K-ras gene mutations to be widely distributed throughout tumors, whereas LOH of the p53 gene was localized to 1 or a few areas. Further, topographically delimited areas with the same histology in the same tumor did not always show the same genetic alteration. In conclusion, we could confirm that both the K-ras and p53 gene alterations occur in the intraductal stage of MPT, and the latter is superimposed on the former during the course of tumor progression. However, the pattern of association of histological features with genetic alteration differs from tumor to tumor.

Adult↗
PubMed2000

Novel therapeutic approach: organic arsenical melarsoprol) alone or with all-trans-retinoic acid markedly inhibit growth of human breast and prostate cancer cells in vitro and in vivo.

The organic arsenical known as melarsoprol (Mel-B) is used to treat African trypanosomiasis. Recently, another arsenical, As2O3 was shown to be effective in treatment of acute promyelocytic leukaemia. We have investigated the anti-tumour activities of Mel-B either with or without all-trans-retinoic acid (ATRA) using the MCF-7 human breast cancer cells, as well as the PC-3 and DU 145 human prostate cancer cells both in vitro and in vivo. The antiproliferative effects of Mel-B and/or ATRA against breast and prostate cancer were tested in vitro using clonogenic assays and in vivo in triple immunodeficient mice. Furthermore, the mechanism of action of these compounds was studied by examining the cell cycle, levels of bcl-2, apoptosis and antiproliferative potency using a pulse-exposure assay. Clonogenic assays showed that the cancer cell lines were sensitive to the inhibitory effect of Mel-B (effective dose that inhibited 50% clonal growth [ED50]: 7 x 10(-9) M for MCF-7, 2 x 10(-7) M for PC-3, 3 x 10(-7) M for DU145 cells. Remarkably, the combination of Mel-B and ATRA had an enhanced antiproliferative activity against all three cancer cell lines. Furthermore, the combination of Mel-B and ATRA induced a high level of apoptosis in all three cell lines. Treatment of PC-3 and MCF-7 tumours growing in triple immunodeficient mice with Mel-B and ATRA either alone or in combination markedly retarded tumour size and weight of the tumours without major side-effects. In conclusion, our results suggest that either Mel-B alone or with ATRA may be a useful, novel therapy for breast and prostate cancers.

Animals↗
PubMed2000

Identification of the intraparotid facial nerve on magnetic resonance imaging.

As a result of recent advances in magnetic resonance imaging (MRI) technology, direct imaging of the intraparotid facial nerve has become possible. The usefulness of MRI is well known in the diagnosis of parotid tumors. Using a 0.5 T midfield MR unit, this study aimed to visualize the intraparotid facial nerve in 5 normal volunteers and 14 patients with parotid tumors (on 24 normal sides and 14 affected sides). Under appropriate conditions for MRI, the facial nerve was detectable on 9 out of 10 affected sides and 17 out of 20 normal sides. The running course of the facial nerve was consistent with MRI findings in five patients who underwent surgery. The imaging conditions suitable for visualizing the intraparotid facial nerve are reported and the usefulness of MRI in the diagnosis of parotid tumors is discussed.

Adenolymphoma↗
PubMed2000

Magnetic resonance imaging findings in a patient with bilateral facial paralysis due to malignant lymphoma.

In malignant lymphomas, especially non-Hodgkin's lymphomas, invasion to the central nervous system (CNS) often occurs. A patient is reported here with bilateral facial paralysis due to invasion of a malignant lymphoma to the CNS. Contrast magnetic resonance imaging (MRI) revealed swelling of the entire length internal auditory meatus and enhancement in the entire length of the facial nerve. Transcranial magnetic stimulation and MRI revealed that later facial nerve injury was present before the onset of paralysis due to a malignant lymphoma. Therefore treatment should be performed with consideration given to the possible invasion of the tumor to the CNS.

Adult↗