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Biomedical subjects

M Mihara

Publications and source records attributed to M Mihara.

At least 109 records · Page 6Linked to original sources
PubMed1996

In vitro and in vivo biological activities of a novel nonpolyglutamable anti-folate, MX-68.

MX-68 is a newly synthesized anti-folate, chemically designed not to undergo intracellular polyglutamation and to have increased affinity to dihydrofolate reductase (DHFR). In the present study, we examined the in vitro and in vivo biological activities of MX-68 compared with methotrexate (MTX) which forms several polyglutamates intracellularly. MX-68 dose-dependently inhibited the proliferation of PHA-, anti-CD3-, or PMA plus ionomycin-stimulated peripheral blood mononuclear cells (PBMC) and endothelial cells (EC) from normal subjects as well as IL-1 beta- or TNF alpha-stimulated synovial fibroblastic cells (SC) from rheumatoid arthritis (RA) patients. Coaddition of folinic acid completely reversed the anti-proliferative effects of both MX-68 and MTX. Although the anti-proliferative activities of MX-68 were almost comparable to those of MTX, the washout study clearly showed the characteristic nature of MX-68. When drugs were removed during culture, the suppressive effect of MX-68 completely disappeared, whereas suppression by MTX was merely weakened. MX-68 dramatically suppressed the onset of collagen-induced arthritis (CIA) in mice when the drug was orally administered three times a week. starting from the day of first immunization. In this model, 2 mg/kg of MX-68 was sufficient to completely suppress arthritis, whereas suppression by the same dose of MTX was partial. These lines of evidence suggest that polyglutamation is not always a prerequisite in the anti-rheumatic effects of anti-folate. In addition, since intracellular accumulation of polyglutamates is thought to have adverse effects, MX-68 may become a more potent and less toxic anti-rheumatic drug than MTX.

2-Aminoadipic Acid↗
PubMed1996

IL-6-soluble IL-6 receptor complex inhibits the proliferation of dermal fibroblasts.

A number of investigators has reported that there is increased production of interleukin-6 (IL-6) by fibroblasts and monocytes from the patients with systemic sclerosis (SS). However, the precise role of IL-6 in the pathogenesis of SS remains unclear. On the basis of our previous study showing that the complex of IL-6 and soluble IL-6 receptor (sIL-6R) could induce synovial fibroblast proliferation, we examined whether the IL-6-sL-6R complex could induce the proliferation of normal dermal fibroblastic cells (DF). IL-6 suppressed DF proliferation, and, in the presence of sIL-6R, dose-dependently showed much stronger suppressive effects on DF proliferation. This suppression was completely blocked by either anti-IL-6 or anti-sIL-6R antibody. Furthermore, the IL-6-sIL-6R complex significantly suppressed IL-1 beta-, TNF alpha- and PDGF-AA-induced DF proliferation. These lines of evidence suggest that the IL-6-sIL-6R complex may have potential as a useful agent for the treatment of SS.

Antigens, CD↗
PubMed1996

UV-induced apoptosis in rat skin.

Sunburn cells appear in the epidermis after UVB irradiation and are histologically suggested to be keratinocytes undergoing apoptosis. We here show a known biochemical process of apoptosis, genomic DNA fragmentation, in rat skin. UVB irradiation induced sunburn cells in the epidermis of rat skin at a lower dosage and the cleavage of genome DNA to nucleosomal size units at dosages of more than 0.3 J/cm2. The fragmented DNA observed could be driven from the epidermis though the involvement of DNA in dermal cells cannot be neglected. PUVA treatment also induced sunburn cells and the fragmentation of genome DNA. The extent of DNA fragmentation by UVB irradiation was enhanced depending on the dosage and peaked at 12-24 h after the irradiation. The induction of the DNA fragmentation observed in this study indicates the presence of a common pathway related to the DNA damage-induced apoptosis in the skin, and might become a useful marker in the course of in vivo studies on the physiological role of apoptotic process in the skin.

Animals↗
PubMed1996

Subcutaneous granuloma annulare with Hodgkin's disease.

We report an 85-year-old woman with subcutaneous granuloma annulare. Three nodules developed on her scalp and sacral regions and gradually increased with tenderness. Histologically, a biopsy specimen of the nodule was interpreted as subcutaneous granuloma annulare because palisading granuloma was present in the dermis and subcutaneous fatty tissue. Laboratory tests, including RA, showed no remarkable changes except for hyperglycemia and glycosuria. These nodules spontaneously regressed without medication. One year later, she noted swelling of some lymph nodules in the left axillary region. These were diagnosed as Hodgkin's disease (mixed cellularity type). She was treated with chemotherapy, but died after two months. Subcutaneous granuloma annulare which occurs suddenly in the elderly may be a dermadrome of malignant blood disease.

Aged↗
PubMed1996

Detection of hepatocellular carcinoma by intraarterially enhanced ultrasonography with CO2 microbubbles. Comparison with DSA, dynamic CT, and Lipiodol CT.

PURPOSE: To evaluate the diagnostic value of contrast-enhanced US with CO2 microbubbles (EU) for HCCs. Detectability was compared with DSA, dynamic CT, and Lipiodol CT. MATERIAL AND METHODS: Forty-seven histologically proven HCCs detected with US were evaluated with EU, DSA, and dynamic CT. In 23 patients (35 lesions), Lipiodol CT was also performed. The size of the tumors ranged from 8 to 71 mm (average 28.1 mm); 24 lesions were smaller than 20 mm and 23 lesions were larger than 20 mm. RESULTS: Overall detection was possible in 40 of 47 lesions (85%) by EU, in 32 of 47 (68%) by DSA, in 33 of 47 (74%) by dynamic CT, and in 27 of 35 (77%) by Lipiodol CT. In tumors smaller than 20 mm, detection was possible in 21 of 24 lesions (88%) by EU, 14 of 24 (58%) by DSA, 14 of 24 (58%) by dynamic CT, and 11 of 17 (65%) by Lipiodol CT. CONCLUSION: EU has significant diagnostic value for detection of HCCs, particularly tumors smaller than 20 mm.

Angiography, Digital Subtraction↗
PubMed1996

Antirheumatic agents. I. Novel methotrexate derivatives bearing an indoline moiety.

Various novel methotrexate (MTX) derivatives bearing an indoline moiety were synthesized and tested for biological activities using human peripheral blood mononuclear cell (hPBMC) and human synovial cells (hSC) derived from patients with rheumatoid arthritis (RA). Compounds having potent activity in vitro were further evaluated using an adjuvant arthritis model in vivo. N-[1-(2,4-Diamino-6-pteridinylmethyl)indoline-5-carbonyl]-L-glutam ic acid 2f showed more potent activities than MTX in vitro and in vivo, and N-[1-(2,4-diamino-6-pteridinylmethyl)-indoline-5-carbonyl]-L-2-ami noadipic acid 2d exhibited fairly good activities in vitro and considerable activity in vivo. Compound 2d was, as expected, not sensitive to folyl-polyglutamate synthetase (FPGS) and did not undergo polyglutamation, a process which may be responsible for a side-effect during MTX therapy.

Animals↗
PubMed1996

Antirheumatic agents. II. Novel methotrexate derivatives bearing an alkyl-substituted benzene ring.

Novel methotrexate (MTX) derivatives with either a mono- or dialkyl-substituted benzene ring were synthesized and initially tested for in vitro anti-proliferative activities using human peripheral blood mononuclear cells (hPBMC) derived from healthy volunteers and synovial cells (hSC) derived from patients with rheumatoid arthritis (RA). Compounds with potent activities were further evaluated in an in vivo adjuvant arthritis model. In comparison with MTX, a glutamate derivative 3a was more potent as a suppressor of the in vitro cell proliferation and the in vivo experimental arthritis, and a homoglutamate derivative, 3e, exhibited fairly good activities in vitro and considerable activity in vivo in a dose-dependent manner. As expected, 3e did not act as a substrate of folylpolyglutamate synthetase (FPGS), and thus did not undergo polyglutamation, which is thought to be responsible for side-effects that occur during MTX therapy.

Antirheumatic Agents↗
PubMed1996

Nodular localized cutaneous amyloidosis: detection of monoclonality of infiltrating plasma cells by polymerase chain reaction.

We report nodular localized cutaneous amyloidosis arising in a 74-year-old woman as a single nodule at the left angle of the mouth. Histological examination revealed eosinophilic material deposited in the dermis, identified as amyloid by staining with Dylon stain, and antiamyloid P component, and by electron microscopy. The amyloid material was further determined immunohistochemically to be of AL fibril protein type derived from lambda light chains. Infiltrating plasma cells, around blood vessels in the dermis, stained monotypically with anti-lambda antibody, suggesting plasma cell monoclonality. Semi-nested polymerase chain reaction (PCR), for rearrangement of immunoglobulin heavy chain gene using paraffin-embedded sections, yielded two distinct amplified bands, indicating monoclonality of the infiltrating plasma cells. These findings support the hypothesis that primary localized nodular amyloidosis involves local accumulation of monoclonal plasma cells and their secreted products. The two amplified bands observed on PCR may, in the present case, reflect abnormal secretion of immunoglobulin light chains.

Aged↗
PubMed1996

[Comparative study of sustained-release in theophylline (Slobid, Theolong, Theodur) by pharmacokinetics].

We made a comparative study of three kinds of sustained-release of theophylline compounds by means of analysis of plasma concentrations. The drugs were Slobid (SB) (Up-john) 11 patients (10 men, 1 women), Theolong (TL) (Eisai) 22 (10 men, 12 women), Theodur (TD) (Nikken chemicals) 34 (18 men, 16 women), who were hospitalized from January 1989 to November 1994. Theses patients were given oral theophylline, bid at 9:00 and 21:00, plasma concentration of theophylline was determined at 9:00, 12:00, 15:00, 18:00 and 21:00, after plasma concentration reached a plateau. There were no significant differences as to the zero absorption rate, clearance, the moment absorption rate, but there were significant differences to Cmax-Cmin of SB (3.34 micrograms) < TL (4.22) < TD (5.22) (P = 0.0150), the zero half life time (T1/2) of SB (18.9 hr) > TL (13.5) > TD (10.1) (P = 0.0061), the apparent distribution volume (V) of SB (0.811/ kg) > TL (0.78) > TD (0.55) (P = 0.0309), mean residence time (MRT) of SB (21.3 hr) > TL (16.7) > TD (15.2) (P = 0.0034), the moment half life time (Tm1/2) of SB (13.7 hr) > TL (10.6) > TD (9.55) (P = 0.009), by measurements analysis of variance. These results suggest that these sustained-release drugs have different pharmacokinetics judging from the important indices including Cmax-Cmin, T1/2, V, MRT and Tm1/2, and that the best one is the SB, the second is the TL, and the third is the TD for RTC therapy.

Administration, Oral↗
PubMed1995

Chemical form of selenium-containing metabolite in small intestine and liver of mice following orally administered selenocystine.

The chemical form of a selenium-containing metabolite in the small intestine following a single oral administration of selenocystine was investigated with ICR male mice. Selenium content in the small intestine of animals treated with 50 mg/kg selenocystine significantly increased 15 min, 1 h and 6 h after treatment. In contrast, selenocystine significantly depressed the intestinal reduced glutathione (GSH) level at 1 h after administration. A significant negative correlation between the selenium level and the level of GSH in the small intestine was observed (r = -0.83, p < 0.001). Analysis of the intestinal metabolite of selenocystine showed that selenium-containing metabolites elute in two fractions from a Sephadex G-25 column: the low-molecular fraction (peak I) contained the selenocystine, while the high-molecular fraction (peak II) contained selenocysteine-containing metabolite. An in vitro experiment was performed to gain insight into the mechanism for selenocysteine-containing metabolite production in the intestinal cytosol. When selenocystine or selenocysteine reacted with excess GSH in the presence of intestinal homogenate, the peak II fraction which involved the selenocysteine-containing metabolite was recognized in the Sephadex G-25 chromatogram. From an examination of the distribution of the selenocysteine-containing metabolite, it was recognized that this metabolite exists in plasma and liver cytosol of mice after oral administration of selenocystine. These results suggested that the mice treated with selenocystine produce selenocysteine-containing metabolite by reaction of selenocystine with excess GSH in the small intestine, and the metabolite is then transported to the liver through blood plasma.

Administration, Oral↗
PubMed1995

Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor.

A number of investigators have reported that there are detectably elevated levels of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) in the synovial fluids of rheumatoid arthritis (RA) patients. However, the precise role of IL-6 and sIL-6R in the pathogenesis of RA remains unclear. In the present study we examined whether IL-6 and/or sIL-6R could induce the proliferation of synovial fibroblastic cells (SFC) obtained from a RA patient. Co-existence of IL-6 and sIL-6R induced SFC proliferation without needing any further stimulation. This proliferation was completely blocked by either anti-IL-6 or anti-sIL-6 antibody. In contrast, neither IL-6 nor sIL-6R alone induced SFC proliferation. Although sIL-6R alone could not induce SFC proliferation, it did however augment IL-1 beta-induced SFC proliferation in a dose-dependent manner, but not tumour necrosis factor alpha-, platelet-derived growth factor-AB- or b-fibroblast growth factor-induced proliferation. This augmentation was completely neutralized by the addition of anti-IL-6 or anti-sIL-6R antibodies. This may be explained by the fact that an amount of IL-6 sufficient to induce SFC proliferation in the presence of sIL-6R was found to be detectable in the IL-1 beta-stimulated-culture supernatant. This evidence suggests that IL-6 is very likely to be involved in synovial cell proliferation in the synovium of RA patients in co-operation with sIL-6R.

Arthritis, Rheumatoid↗
PubMed1995

A case of Bowen's disease with tissue eosinophilia.

An 85-year-old Japanese man with Bowen's disease on the left inguinal area is reported. Most of the inflammatory cells adjacent to the tumor were eosinophils. Tissue eosinophilia spontaneously improved after biopsy.

Aged↗
PubMed1995

Primary cutaneous meningioma on the scalp: report of two siblings.

Primary cutaneous meningioma (PCM) is a rare tumor whose pathogenesis is quite obscure. We reported PCMs occurring on almost the same occipital region of two siblings studied by histology, immunohistochemistry, and electron microscopy. Both lesions were attached to duras, but extracranial. One lesion was histologically diagnosed as meningothelial meningioma; its tumor cells showed electron microscopically interdigitating cytoplasmic processes with junctional complexes. The other was interpreted as fibroblastic meningioma; its tumor cells were arranged linearly in a stepping-stone arrangement and had small dense bodies in the cytoplasm. The tumor cells stained positively with anti-vimentin antibody. Both lesions had adenomatous hyperplasia of the eccrine glands. Although the histologic and electron microscopic features of these two lesions slightly differed from each other, their pathogenesis was essentially considered to be acoelic or rudimentary meningocele.

Adolescent↗