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Biomedical subjects

Y Takeda

Publications and source records attributed to Y Takeda.

At least 397 records · Page 22Linked to original sources
PubMed1998

[Clinical features and treatment of sarcoidosis involving the central nervous system].

PURPOSE: The purpose of this study was to investigate the clinical features, diagnosis, and treatment modalities of three cases with neurosarcoidosis, which involved the central nervous system (CNS). CASES: Three men with neurosarcoidosis, aged 27, 29 and 60 years, are presented. Two of them had previously been given a diagnosis of sarcoidosis. The clinical symptoms of these cases included diabetes insipidus, pituitary dysfunction, seizure, mental disorder, visual field disturbance and pyramidal tract signs. In these cases, CT scan and MRI showed the presence of a tumor near the pituitary gland, diffuse nodules in the subarachnoid space or meningoencephalitis associated with angitis. The level of angiotensin converting enzyme (ACE) in the sera and in the cerebrospinal fluid, were elevated in the two cases who had no brain biopsy. All three cases were treated with steroids; two of them received pulse steroid therapy. RESULTS: The two cases who received pulse steroid therapy responded quickly, with improvement in clinical features, serum ACE levels and neuroradiological findings. Under oral administration of steroids, all three cases recovered with complete remission of neurosarcoidosis except for endocrinological symptoms. DISCUSSION: The main pathological changes of neurosarcoidosis are granulomatous angitis of the venular walls and occasionally, of the capillaries near the meninx and Virchow-Robin space. The patients also had symptoms of secondary meningoencephalitis. These changes were mainly located in the hypothalamus and pituitary gland. The patients had complex symptoms resulting from endocrine system granuloma, as well as from cerebral ischemia. The severity of the disease and effectiveness of treatment, can be evaluated by measuring ACE levels in the cerebrospinal fluid (over 1. 0 IU/l), and by Gd-enhanced MRI. Early pulse steroid therapy with subsequent oral steroid administration is thought to be important for neurosarcoidosis treatment, in order to prevent irreversible damage in the CNS.

Adult↗
PubMed1997

Immunohistochemical localization of neurocan and L1 in the formation of thalamocortical pathway of developing rats.

We used immunohistochemistry to examine possible molecular interactions between the subplate and growing thalamocortical axons in rat fetuses. In the cortical anlage of embryonic day 16 (E16), the subplate first appeared below the cortical plate. Among chondroitin sulfate proteoglycans, phosphacan was uniformly distributed throughout the cortical wall, whereas neurocan was localized only in the subplate at E16. Neural cell adhesion molecules, NCAM-H, TAG-1, and L1, were detected in the cortical anlage. Both cortical neurons and growing axons were diffusely immunopositive for NCAM-H, and TAG-1 immunoreactivity was found on immature neurons and cortical efferent axons but not on thalamocortical axons. L1 immunoreactivity was specifically localized on the growing thalamocortical axons. When the locations of neurocan and L1 were compared in the developing cortex, L1-bearing axons were found to extend to neurocan-immunopositive regions; neurocan immunoreactivity was intense in the subplate at E16, when small numbers of L1-immunoreactive thalamocortical axons began to invade the cortex. At E17, many L1-positive axons were observed in the subplate that expressed neurocan specifically. Double immunostaining showed that L1-positive axons and neurocan immunoreactivity overlapped in the subplate at E17. After E18, neurocan expression gradually extended to the lower part of the cortical plate; it extended to the entire cortex by E21, 1 day before birth. By E21, L1-bearing axons had invaded the lower part of the cortical plate. The present study demonstrated that the neurocan expression precedes growth of L1-bearing thalamocortical afferent fibers. Because neurocan can bind to L1 molecule in vitro, these results suggest that neurocan and L1 play some important roles in pathfinding of the thalamocortical afferent fibers during rat corticogenesis.

Animals↗
PubMed1997

A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity.

We have characterized a nontoxic mutant of cholera toxin (CT) as a mucosal adjuvant in mice. The mutant CT was made by substitution of serine with phenylalanine at position 61 of the A subunit (S61F), which resulted in loss of ADP ribosyltransferase activity and toxicity. Mice were intranasally immunized with ovalbumin, tetanus toxoid, or influenza virus either alone or together with mutant CT S61F, native CT, or recombinant CT-B. Mice immunized with these proteins plus S61F showed high serum titers of protein-specific IgG and IgA antibodies that were comparable to those induced by native CT. Further, high protein-specific IgA antibody responses were observed in nasal and vaginal washes, saliva, and fecal extracts as well as increased numbers of IgG and IgA antibody forming cells in cervical lymph nodes and lung tissues of mice intranasally immunized with these proteins and S61F or native CT, but not with recombinant CT-B or protein alone. Both S61F and native CT enhanced the induction of ovalbumin-specific CD4(+) T cells in lung and splenic tissues, and these T cells produced a Th2-type cytokine pattern of interleukin 4 (IL-4), IL-5, IL-6, and IL-10 as determined by analysis of secreted proteins and by quantitation of cytokine-specific mRNA. These results have shown that mutant CT S61F is an effective mucosal adjuvant when administrated intranasally and induces mucosal and systemic antibody responses which are mediated by CD4(+) Th2-type cells.

Animals↗
PubMed1997

Mutants in the ADP-ribosyltransferase cleft of cholera toxin lack diarrheagenicity but retain adjuvanticity.

Cholera toxin (CT), the most commonly used mucosal adjuvant in experimental animals, is unsuitable for humans because of potent diarrhea-inducing properties. We have constructed two CT-A subunit mutants, e.g., serine-->phenylalanine at position 61 (S61F), and glutamic acid-->lysine at 112 (E112K) by site-directed mutagenesis. Neither mutant CT (mCT), in contrast to native CT (nCT), induced adenosine diphosphate-ribosylation, cyclic adenosine monophosphate formation, or fluid accumulation in ligated mouse ileal loops. Both mCTs retained adjuvant properties, since mice given ovalbumin (OVA) subcutaneously with mCTs or nCT, but not OVA alone developed high-titered serum anti-OVA immunoglobulin G (IgG) antibodies (Abs) which were largely of IgG1 and IgG2b subclasses. Although nCT induced brisk IgE Ab responses, both mCTs elicited lower anti-OVA IgE Abs. OVA-specific CD4+ T cells were induced by nCT and by mCTs, and quantitative analysis of secreted cytokines and mRNA revealed a T helper cell 2 (Th2)-type response. These results now show that the toxic properties of CT can be separated from adjuvanticity, and the mCTs induce Ab responses via a Th2 cell pathway.

Adjuvants, Immunologic↗
PubMed1997

Depolymerized holothurian glycosaminoglycan (DHG) prevents neointimal formation in balloon-injured rat carotid artery.

The in vivo activity of depolymerized holothurian glycosaminoglycan (DHG), a newly developed polysaccharide anticoagulant, on neointimal formation induced by a balloon catheter in the left common carotid artery of rats was investigated. In every Sprague-Dawley rat weighing approximately 400 g, a Forgaty 2Fr balloon catheter was inserted from the left femoral artery to the left common carotid artery, and was passed through three times in order to denude the endothelium of the artery. These rats were divided into four groups by the following treatment protocols; DHG was given to rats by daily subcutaneous injection into their abdomens at a dose of 3 mg/kg or 10 mg/kg (D3 or D10 group). For controls, 250 microl saline was injected daily (C group). Furthermore, 1 mg/kg of unfractionated heparin was also injected daily as a comparison to DHG (H group). Each treatment was performed in six rats, and the injections were continued for two weeks after the catheterization. The area ratio of thickened intima/media (I/M ratio) treated with DHG decreased in a dose-dependent manner compared to the control. In addition, the ratio in the D10 group was significantly lower than in the control (P < 0.01). However, the ratio in the H group did not decrease. By anti-a smooth muscle actin antibody staining the intimal thickening layers were seen to be completely occupied by proliferated smooth muscle cells, and their amount in these layers was attenuated by the DHG treatment. This indicated that DHG has an inhibitory effect on intimal thickening induced by balloon catheterization, and that this might be due to the inactivation of aberrant smooth muscle cells by this agent.

Angioplasty, Balloon, Coronary↗
PubMed1997

BAYw6228 suppresses accumulation of macrophages in balloon-induced intimal thickening of rabbit carotid artery.

To determine the in vivo activity of BAYw6228 (BAYw), a newly developed 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, we examined its effect on balloon catheterization-induced carotid arterial intimal thickening in Japanese white rabbits. In all rabbits weighing approximately 3.5 kg, a balloon catheter was inserted from a peripheral branch of the left external carotid artery to the aorta in order to denude the endothelium of the left common carotid artery. At day 12, they were divided into control and BAYw groups. The latter were subcutaneously injected with BAYw, 1 mg/kg/day, for the following 17 days. At day 15, the second balloon catheterization was performed in the same left common carotid artery in both groups. After another two weeks, the left common carotid artery was removed and stained with Elastica-Masson (EM) and anti-rabbit macrophage antibody (RAM 11). With RAM 11 staining, the number of positive cells in the intimal thickening was markedly decreased in the BAYw group compared with the control group (P < 0.01). Compared with the area ratio of the thickened intima/media layer of the control group, that of the BAYw group was significantly decreased to 45% (P < 0.05). These results indicate that BAYw prevents accumulation of macrophages and consequently contributes to the inhibition of intimal thickening induced by balloon catheterization.

Animals↗
PubMed1997

Ceramide-induced translocation of protein kinase C-delta and -epsilon to the cytosol. Implications in apoptosis.

Ceramide is now recognized as an intracellular lipid signal mediator, which induces various kinds of cell functions including apoptosis. Ceramide-induced apoptosis was reported to be blocked by 12-O-tetradecanoylphorbol 13-acetate, a protein kinase C (PKC) activator, but its mechanism remained unclear. Therefore, we investigated whether ceramide has any effects on PKC in the induction of apoptosis. We here report that N-acetylsphingosine (synthetic membrane-permeable ceramide) induced translocation of PKC-delta and -epsilon isozymes from the membrane to the cytosol within 5 min in human leukemia cell lines. Treatment with sphingomyelinase, tumor necrosis factor-alpha, or anti-Fas antibody, all of which can induce apoptosis by generating natural ceramide, similarly induced cytosolic translocation of PKC-delta and -epsilon. In Fas-resistant cells anti-Fas antibody did not induce cytosolic translocation of PKC-delta and -epsilon because of no generation of ceramide, whereas N-acetylsphingosine induced apoptosis with cytosolic translocation of PKC-delta and -epsilon. Furthermore, both 12-O-tetradecanoylphorbol 13-acetate and a nonspecific kinase inhibitor, staurosporine, prevented ceramide-induced apoptosis by inhibiting cytosolic translocation of PKC-delta and -epsilon. These data suggest that cytosolic translocation of PKC-delta and -epsilon plays an important role in ceramide-mediated apoptosis.

Antibodies, Monoclonal↗
PubMed1997

Antirheumatic agents: novel methotrexate derivatives bearing a benzoxazine or benzothiazine moiety.

Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H-1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro. Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68) were comparable to that of MTX in these in vitro assays. Compounds 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.

Animals↗
PubMed1997

Apoptosis and in vivo distribution and clearance of eosinophils in normal and Trichinella spiralis-infected rats.

We examined apoptosis of eosinophils obtained from normal rats and rats infected with Trichinella spiralis (T. spiralis). A considerable percentage of normal rats underwent apoptosis within a few hours, however, the apoptosis rate of infected rats was significantly lower. This rate began decreasing only 12 h after infection, reached its lowest level on day 3, and was restored to normal by day 40. We also studied the effects on eosinophil apoptosis of culture supernatants from concanavalin A-stimulated spleen cells from infected rats and found that supernatants from days 3, 7, and 18 of infection inhibited apoptosis eosinophils from normal rats. We then examined the distribution and clearance of eosinophils in vivo. In normal rats, the largest numbers of eosinophils were found in the spleen, liver, and bone marrow. In the infected rats, however, by day 3, by which time the worms had begun to migrate, there was a striking increase in these cells in the intestines. In summary, normal eosinophils are unexpectedly sensitive to apoptosis, whereas infected eosinophils become resistant to this form of cell death.

Animals↗
PubMed1997

Amelioration of sinusoidal endothelial cell damage by Kupffer cell blockade during cold preservation of rat liver.

Recent studies have shown that Kupffer cell function is enhanced in the cold-preserved liver, and blockade of Kupffer cells attenuates the injury induced by cold preservation with subsequent reperfusion. This study was designed to investigate the contribution of Kupffer cell blockade with gadolinium chloride (GdCl3) to the rescue of sinusoidal endothelial cell (SEC) damage by comparing the time-related morphological and ultrastructural changes. GdCl3 injection reduced the number of Kupffer cells reactive with monoclonal antibodies ED2 and Ki-M2R directed against macrophage. Scanning electron microscopy revealed the prominent string-like appearance of the SEC processes at 24 hr of preservation in the control; the SECs were better preserved in the GdCl3-pretreated group. Transmission electron microscopy showed detachment of the sinusoidal epithelia at 12 hr of preservation in the control; it was not seen in the GdCl3-pretreated group. At 24 hr of preservation, the SECs were better preserved in the GdCl3-pretreated group. Microvascular casts from the control group showed a disturbance in the radial arrangement of the sinusoids, significant dilation of the sinusoidal caliber at 24 hr, and discontinuity of the sinusoids with extravasation of the casting material at 36 hr of preservation. These changes were also minimized in the GdCl3-pretreated group. In conclusion, the present study demonstrates that Kupffer cells are strongly involved in the morphological integrity of SECs and that blockade of the activation of Kupffer cells would be effective for the prevention of damage to SECs and maintenance of the sinusoidal architecture during cold preservation of the liver tissure.

Animals↗
PubMed1997

Loss of biological activity due to Glu-->Arg mutation at residue 11 of the B subunit of cholera toxin.

Since it has been reported that a single amino acid mutation of Gly-->Arg in the CAGYC region of the beta chain of human thyroid stimulating hormone (hTSH) was responsible for congenital isolated TSH deficiency, and that the same amino acid substitution in this site of hTSH and human chorionic gonadotropin (hCG) introduced by site-directed mutagenesis resulted in loss of activity, the authors studied the role of glutamic acid at position 11 (Glu-11) from the N-terminus of the B subunit of cholera toxin (CT), which corresponds to the glycine in the CAGYC region of the beta chain of hTSH and hCG. A mutant CT constructed by site-directed mutagenesis in which Glu-11 was replaced by Arg (CT-E11R) did not induce either morphological changes or accumulation of cytosolic cyclic AMP in Chinese hamster ovary cells, although it formed the holotoxin AB5, retained the ability to bind to GM1-ganglioside and showed ADP-ribosyltransferase activity. Weak assembly of the B subunits in mutant CT-E11R demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under non-heating conditions might explain the loss of biological activity.

Amino Acid Substitution↗
PubMed1997

Regulation of mouse immuno-responses by a natural suppressor cell clone from bone marrow.

Natural suppressor (NS) activity is mediated by several kinds of cell lineages in bone marrow. We demonstrated that a NS cell, clone 7-31, was obtained after limiting dilution with bone marrow culture supplemented with WEHI supernatant. Clone 7-31, was capable of non-specific suppression of the generation of cytotoxic T lymphocytes without major histocompatibility complex restriction. Suppression of cytotoxic thymus-dependent lymphocyte (CTL) generation was also induced with a cell-free supernatant from the 7-31 cells. Interleukin-2 (IL-2) containing concanavallin-A-conditioned medium could not reverse the suppression. The supernatant did not inhibit the proliferation of IL-2-dependent CTLL-2 cells and rapidly growing tumour cells and fibroblasts. Thus, this bone marrow suppressor cell produces a soluble factor that inhibits the generation of CTL in vitro, and prolongs the acceptance of skin allografts in in vivo.

Animals↗
PubMed1997

Ultrasound biomicroscopy in the diagnosis of persistent hypotony after vitrectomy.

PURPOSE: To describe a case of persistent hypotony after an otherwise successful vitreous surgery for epiretinal membrane, in which ciliochoroidal detachment was detected by ultrasound biomicroscopy but not by ophthalmoscopy. METHOD: We used ultrasound biomicroscopy to determine the cause of persistent postoperative hypotony. RESULTS: Ultrasound biomicroscopy clearly disclosed ciliochoroidal detachment. In an attempt to resolve ciliochoroidal detachment, we performed vitrectomy and fluid-gas exchange combined with diathermy around the sites of sclerotomy. Postoperatively, the regression of ciliochoroidal detachment was confirmed by ultrasound biomicroscopy. CONCLUSIONS: Using ultrasound biomicroscopy, we were able to visualize ciliochoroidal detachment and its regression clearly, which we had not observed during ophthalmoscopy.

Choroid Diseases↗
PubMed1997

Impaired expression of neural cell adhesion molecule L1 in the extrinsic nerve fibers in Hirschsprung's disease.

Immunohistochemical studies on the ganglionic and aganglionic segment in Hirschsprung's disease (HD) were carried out using antibodies against three neural membrane proteins, Thy-1, integrin alpha5, and L1. Enteric neural elements were immunostained with antibodies against neurofilament, which is the neuronal cytoskeletal protein. In ganglionic segments, neurofilament-immunoreactivity was detected in neuronal cell bodies and fine nerve fibers of the myenteric and submucosal plexuses. All of these neural elements were immunopositive for Thy-1, integrin alpha5, and L1. In aganglionic segments, no intrinsic neurons were detected, and instead, hypertrophied nerve bundles were observed in intermuscular space, in submucosa, and in circular muscle layer by immunochemistry for neurofilament. These hypertrophied nerve bundles were immunopositive with anti-Thy-1 and anti-integrin alpha5 antibodies. However, they were not immunostained with anti-L1 in all five cases. These findings indicate that the expression of L1 molecule, which plays an important role in cell adhesion, neural cell migration, and neurite outgrowth, is impaired in the extrinsic nerve fibers in aganglionic colon. And this may perturb neural crest migration and adequate neurite outgrowth, with resulting aganglionic segment and abnormal nerve bundles of extrinsic fibers in HD.

Antigens, CD↗
PubMed1997

Estrogen and parathyroid hormone regulate insulin-like growth factor binding protein-4 in SaOS-2 cells.

The effect of 17beta-estradiol and parathyroid hormone (PTH) on the expression of insulin-like growth factor-binding protein-4 (IGFBP-4) messenger RNA (mRNA) was studied in the cultured human osteoblast-like SaOS-2 cells. Treatment of SaOS-2 cells with PTH for 3 h caused 3.3-fold increase in IGFBP-4 mRNA levels which was determined by reverse transcription-polymerase chain reaction. 17beta-Estradiol had no effect on either the stimulation of mRNA level by PTH or the basal level. Together with our previous report that 17beta-estradiol inhibits the PTH-induced reduction of IGFBP-4 proteolysis in these cells, the results obtained may help to explain the mechanisms of determining IGFBP-4 availability by systemic hormones in osteoblast cells.

Blotting, Western↗
PubMed1997

Megastigmane glycosides from Salvia nemorosa.

From the aerial parts of Salvia nemorosa, three new megastigmane glycosides, salvionosides A-C, were isolated, along with the known compounds, (6S,9R)- and (6S,9R)-roseosides, (6R,9R)- and (6R,9S)-3-oxo-alpha-ionol glucosides and blumeol C glucoside. The structures of the new compounds were elucidated on the basis of spectral and chemical evidence.

Carbohydrates↗
PubMed1997

Preventive effect of a novel antifolate, MX-68, in murine systemic lupus erythematosus (SLE).

We evaluated the preventive effects of a novel nonpolyglutamatable antifolate, MX-68, on two experimental murine models of systemic lupus erythematosus (SLE); NZBxNZW F1 (BWF1) mice and chronic graft-versus-host disease (GVHD) mice, in comparison with classical antifolate methotrexate (MTX). The oral administration of 2 mg/kg MX-68, three times a week from 12 to 40 or 60 weeks of age, significantly delayed the onset of proteinuria and prolonged the life-span of BWF1 mice. The elevation of serum blood urea nitrogen (BUN) and cholesterol levels resulting from the development of lupus nephritis was also inhibited. However, MX-68 did not suppress the increase of serum anti-DNA or anti-TNP antibodies or total IgG isotype (IgG1, IgG2 and IgG3) levels. In chronic GVHD mice, MX-68 given three times a week from the day of first cell injection, for 9 weeks, dose-dependently delayed the appearance of proteinuria. The elevation of BUN and cholesterol levels was also inhibited. Furthermore, in the 4 mg/kg MX-68 group, the production of IgG anti-DNA and anti-TNP antibodies was significantly inhibited, but this was not observed in the 2 mg/kg MX-68 and the 4 mg/kg MTX groups. These beneficial effects of MX-68 were much greater than those of MTX in both models. These results suggest that MX-68 might be a more useful drug for the treatment of SLE.

2-Aminoadipic Acid↗