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Biomedical subjects

K Tahara

Publications and source records attributed to K Tahara.

At least 55 records · Page 3Linked to original sources
PubMed1999

Selective binding of thyrotropin receptor autoantibodies to recombinant extracellular domain of thyrotropin/lutropin-chorionic gonadotropin receptor chimeric proteins.

The extracellular domain of the glycosylated human thyrotropin receptor (ET-gp) contains epitopes that can adsorb pathogenic antibodies from sera of patients with Graves' disease (GD). In an attempt to define the regions within the ETSHR with which autoantibodies interact, we expressed extracellular domains of eight thyrotropin receptor/chorionic gonadotropin receptor (TSHR/LH-CGR) chimeric proteins in insect cells. The levels of expression were high and chimeric proteins were glycosylated. Chimeric proteins designated as EMc2+4 and EMc2+3+4, in which amino acids (aa) 90-165 and 261-370, and aa 90-370, respectively, of TSHR were replaced with corresponding aa of LH-CGR, partially reversed the thyrotropin binding inhibitory immunoglobulin (TBII) activity of experimental anti-TSHR antisera (anti-ET-gp). The other six chimeras almost completely reversed the TBII activity of these anti-ET-GP antisera. Next, we tested the ability of these chimeric proteins to reverse the TBII activity of GD patients' sera. Similar to our earlier study, ET-gp protein reversed the TBII activity of all eight GD patients' sera tested. Chimera EMc2, in which aa 90-165 of TSHR has been replaced with corresponding aa of LH-CGR, and EMc2+4 partially reversed the TBII activity of only three of the eight GD patients' sera. However, the other six chimeric proteins failed to neutralize the TBII activity of any of GD patients' sera. These data showed the following: (1) There is considerable heterogeneity amongst autoantibodies in GD patients' sera, (2) The TBII activity of some, but not others, is dependent on aa 90-165 and 261-370, and (3) Most Graves' sera, with TBII activity, failed to react with chimeric proteins in which either N-terminal or C-terminal regions of the extra cellular domain of the TSHR were replaced with corresponding regions of LH-CGR. These results suggest that the TBII activity of GD patients' sera is dependent on conformational epitopes and replacement of certain regions of TSHR with homologous regions of LH-CGR results in sufficient alteration in the conformation of the protein leading to loss of reactivity.

Animals↗
PubMed1999

Graves' immunoglobulins activate phospholipase A2 by recognizing specific epitopes on thyrotropin receptor.

Thyroid-stimulating IgG from Graves' patients bind to the TSH receptor and activate both adenylyl cyclase (AC) and phospholipase A2 (PLA2) in FRTL5 thyroid cells. Both activities have been associated with increased thyroid cell growth and function; evidence exists that subpopulations of Graves' IgG can stimulate either AC or PLA2 cascades and that the activation of both is associated with the largest goiters in patients. Studies using chimeras of the human TSHR receptor (hTSHR) and the LH-CG receptor show that most patients with Graves' disease have cAMP-stimulating IgG that require epitopes on the N-terminal portion of the TSHR extracellular domain; epitopes associated with PLA2 activation are not clear. To address this question we used stably transfected Chinese hamster ovary (CHO) cells containing the wild-type hTSHR and the hTSHR chimera with residues 8-165 (Mc1+2) substituted by equivalent residues of the LH-CG receptor. PLA2 activity, measured as arachidonic acid (AA) release, was determined in 32 patients with Graves' disease. We show that 72% of Graves' patients have IgG able to stimulate PLA2 in CHO cells transfected with the TSHR and that AA release induced by Graves' IgG was significantly reduced (P = 0.022) in the CHO-Mc1+2-transfected cells (193 +/- 88% vs. 131 +/- 67%, respectively). Unlike IgG, the effect of TSH was not modified in the CHO-Mc1+2-transfected cells. When we compared the AC- and PLA2-stimulating activities of these 32 IgG in wild-type TSHR transfectants, we found that 63% of Graves' patients have antibodies able to stimulate both PLA2 and AC, whereas some patients' IgG were active only in AC or PLA2 assays. Of the patients with IgG having activity in both assays in wild-type TSHR transfectants, 50% of the IgG lost their stimulatory activities in both AA release and cAMP assays in Mc1+2 cells. Of the remainder, some IgG maintained their activity in one (AA release) or the other (cAMP) assay when measured in Mc1+2 chimeras. Thus, our data show that the N-terminal portion of extracellular domain of the TSHR is required for PLA2 as well as AC activation by IgG from patients with Graves' disease. These data also demonstrate that patients with Graves' disease have heterogeneous autoantibodies that selectively activate AC and PLA2 pathways and suggest that patients with autoantibodies active in both assays have more severe disease, with higher thyroid hormone levels and larger goiters.

Adult↗
PubMed1999

Additive triple DMARD combination therapy of a low dose of sulfhydryl compounds, sulfasalazine and methotrexate in the treatment of rheumatoid arthritis: a clinical trial.

To evaluate the efficacy and safety of additive triple disease modifying anti-rheumatic drug (DMARD) combination therapy of a low dose of sulfhydryl compounds ¿D-penicillamine, bucillamine or tiopronin¿, sulfasalazine (SSZ) and methotrexate (MTX) as a treatment for rheumatoid arthritis (RA) patients, we studied a total of 33 Japanese RA patients (6 males, 27 females). At 1 or 2 months after simultaneous administration of the 3 above-mentioned DMARDs was begun, significant improvements were seen in markers of joint inflammation, i.e., erythrocyte sedimentation rate and C-reactive protein in sera. At 6 months, clinical improvement judged by the physicians' overall assessment of joint symptoms and laboratory data was observed in 29 (88%) of the 33 RA patients. No marked effect was observed in the other 4 (12%) patients, however. We observed no significant adverse reaction to this therapy. This suggests that additive triple DMARD combination therapy of a low dose of sulfhydryl compounds, SSZ and MTX could be a useful drug therapy for the treatment of RA patients, even those who are refractory.

Adult↗
PubMed1999

[Anti-myeloperoxidase and anti-lactoferrin antibodies in patients with IgA nephropathy and Henoch-Schönlein purpura].

Antineutrophil cytoplasmic antibodies (ANCA) for two antigens, i.e. myeloperoxidase (MPO) and lactoferrin (LF) in sera from 19 IgA nephropathy (IgAN), 3 adult Henoch-Schönlein purpura (HSP) and 8 child HSP patients were examined by enzyme-linked immunoabsorbent assay (ELISA) for immunoglobulin isotypes. All of child HSP patients showed negative ANCA. On the other hand, one IgAN patient and two adult HSP patients showed weak positivity for IgA class anti-MPO antibody. There was no patients who showed positivity for IgG and IgM class anti-MPO antibody. In anti-LF antibody, one IgAN and one adult HSP showed positivity in IgG class; 2 IgAN and 2 HSP in IgA class and 2 IgAN and one HSP in IgM class. These results indicate that adult HSP patients have higher prevalence of IgA class anti-MPO antibody and anti-LF antibody than IgAN or child HSP.

Adult↗
PubMed1999

[A case of secondary systemic amyloidosis associated with rheumatoid arthritis after 3-year disease duration].

A 63-year-old woman who started to have polyarthralgia in December 1993 has been diagnosed as rheumatoid arthritis (RA) and treated with muscular injection of gold sodium thiomalate. She began to have nausea, vomiting, anorexia and watery diarrhea in October 1995. A year later, she had to receive intravenous infusion on admission since more frequent watery diarrhea occurred more than ten times within a day. On admission in our hospital in December 1996, she had proteinuria in addition to gastrointestinal symptoms. The biopsy specimen from stomach, duodenum and kidney proved systemic amyloidosis associated with RA. In spite of steroid-pulse, dimethyl sulfoxide (DMSO) and colchicine therapy, profound proteinuria in nephrotic syndrome was continued in association with hypoproteinemia, anasarca and renal failure. She was treated on hemodialysis and intravenous hyperalimentation (IVH) until November 1997 when A-V shunt operation on left forearm was performed. However, the shunt was not available for HD and she suffered from septicemia and died on December 1997. This patient was a rare case of secondary systemic amyloidosis associated with RA in early clinical course.

Amyloidosis↗
PubMed1999

[Photostimulation that induces flattening of photopic electroretinograms--first report. An apparatus for slope photostimulation].

PURPOSE: We developed a new photostimulation system for electroretinograms (ERGs). This apparatus is capable of varying the transients during stimulus on and off (up-slope and down-slope times, respectively) as well as the stimulus and background intensities. We applied this system to evaluate the photopic ERG in human eyes. CASES AND METHODS: Seven normal volunteers and a 43-year-old patient with pre-proliferative diabetic retinopathy served as test subjects. We recorded ERGs with relatively long intervals of up-slope and down-slope times for photostimulation. RESULTS: As the up-slope and down-slope times were increased, the amplitude was reduced and the peak latency was prolonged for both the on and off responses. When the normal subjects' retinas were stimulated with a 341-msec up-slope time and a 34.1-msec down-slope time, the ERG waves showed complete flattening in both on and off responses. The ERGs of a patient with pre-proliferative diabetic retinopathy showed much longer peak latency than that of the normal volunteers as the up-slope time was prolonged. When the patient's retina was stimulated for a prolonged up-slope time, the average of the amplitude of ERG waves was similar to that of the normal volunteers. CONCLUSION: These results suggest that this new type of photostimulation might potentially uncover some novel aspect of clinical ERGs and might be useful for testing retinal functions of patients with diabetic retinopathy.

Adult↗
PubMed1999

Neuropeptide Y Y1 receptor polymorphism as a prognostic predictor in Japanese patients with IgA nephropathy.

BACKGROUND: Neuropeptide Y exhibits a vasoconstricting action and regulates systemic blood pressure as well as noradrenalin. There are 5 types of NPY receptors, Y1 - Y5, which were introduced by pharmacological differences. Recently, a single point mutation in the first intron of the NPY Y1 receptor (NPYY1R) was reported. SUBJECTS AND METHODS: In this study, we investigated the relationship between NPYY1R gene polymorphism and clinical characteristics in patients with IgA nephropathy using polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Distribution of the NPYY1R genotypes which were defined as YY, Yy and yy genotypes, did not differ between 60 normal control subjects and 68 patients with IgA nephropathy (15 : 36 : 9 versus 21 : 40 : 7, respectively). In IgA nephropathy patients, the incidence of hypertension and the rate of urinary protein excretion were slightly higher in the non-YY genotype than in the YY genotype group (23% versus 5% and 1.1 +/- 1.2 versus 0.6 +/- 0.4 g/24 h, p = 0.09 and p = 0.05, respectively). The reciprocal of the serum creatinine level was estimated to determine the deterioration in renal function during follow-up after the renal biopsy. The level was lower in the non-YY genotype than in the YY genotype group (-0.002 +/- 0.064 vs 0.033 +/- 0.053/month, respectively, p < 0.01). Multiple regression analysis for the reciprocal of the serum creatinine level revealed that the NPYY1R genotype was an effective variable (p < 0.01). CONCLUSION: In conclusion, we propose that the NPYY1R gene polymorphism may be a novel prognostic predictor in patients with IgA nephropathy.

Adult↗
PubMed1999

[A case of systemic lupus erythematosus associated with severe acute pancreatitis].

A 22-year-old woman began to have the symptoms of anorexia, high fever, cough and general fatigue from June of 1997. She was admitted in our hospital on Aug. 8th, 1997 for the further detail examination because of pancytopenia and positive antinuclear antibody (ANA). Her laboratory findings and clinical symptoms were compatible with systemic lupus erythematosus (SLE) such as leukopenia, proteinuria, hypocomplementemia, positive ANA, elevated titer of autoantibodies including anti-DNA, anti-Sm, anti-RNP antibodies, polyarthralgia and photosensitivity. The administration of oral prednisolone (40 mg/day) was started on Aug. 15th, 1997 under the diagnosis of SLE. However, she had severe abdominal pain in epigastrium with elevated serum amylase, ascites and dull shape of pancreas tail by CT scan compatible with acute pancreatitis. On Aug. 18th, her general condition was worsening with fever, epigastralgia, abdominal distension, anemia, weak palpation of radial artery, hypotension, tachycardia, shallow breathing and cold sensation on both extremities as shock. In spite of steroid pulse therapy with nafamostat mesilate intraarterial infusion, her condition was not improved. The dose of 50 mg/day of cyclophosphamide was added to the regimen on Aug. 22nd. Then, gradually her condition started to be restored. Anemia, leukopenia, hypocomplementemia continued. Second steroid pulse therapy was done on Sep. 5th. After then, she became better in her clinical symptoms and laboratory data. The dose of PSL was tapered to 15 mg/day and 7.5 mg/day update of Oct. 1998 without the pseudcysts found after pancreatitis. She is a rare case who recovered from severe acute pancreatitis due to SLE itself.

Acute Disease↗
PubMed1999

[Correlation of serum IgA levels with serum IgG levels, erythrocyte sedimentation rate and platelet counts in 98 patients with rheumatoid arthritis].

Rheumatoid arthritis (RA) is an autoimmune disease with unknown etiology. Polyclonal B cell activation (PBA) is one of immunological abnormalities commonly found in RA patients. We examined serum IgG, IgA, IgM levels in 98 RA patients and compared 31 patients with high serum IgA levels (group B) with 67 patients with normal serum IgA levels (group A) in clinical background. Group B patients had significantly higher mean values of serum IgG levels, erythrocyte sedimentation rate (ESR), and platelet counts than group A. However, there was no correlation between serum IgA levels and X-ray stage, class of ADL or disease duration of RA. These results indicate that high serum IgA levels reflect for disease activity of RA. Serum IgA levels did not correlate with interleukin (IL)-6 levels in 53 RA patients studied. It is speculated that high serum IgA levels might be caused by the following evidences 1) that transforming growth factor (TGF) beta, a known cytokine to increase IgA production by human splenic B cells, gene expression is enhanced in mononuclear cells from synovial fluid and 2) that iron deposition is found in RA synovial and high serum IgA levels are found in iron overload like thalassemia intermedia.

Arthritis, Rheumatoid↗
PubMed1999

Identification of a MAGE-2-encoded human leukocyte antigen-A24-binding synthetic peptide that induces specific antitumor cytotoxic T lymphocytes.

Because MAGE-2 gene is expressed in a wide variety of malignant tumors and HLA-A24 is the most common allele in the Japanese population and is also frequently present in Caucasians, the identification of MAGE-2-encoded peptide presented by HLA-A24 is, therefore, considered to be important in order to develop specific immunotherapy for malignant tumors using peptides as a vaccine. By using a MHC-binding assay, eight peptides derived from MAGE-2 were found to bind with sufficient affinity to the HLA-A24 molecule. When the induction of specific cytotoxic T lymphocytes (CTLs) was examined using a simplified method, the highest human lymphocyte antigen (HLA) binder (EYLQLVFGI) in these peptides was able to elicit CTLs from unseparated peripheral blood mononuclear cells in HLA-A24 healthy donors by stimulation with freshly isolated, peptide-pulsed peripheral blood mononuclear cells as antigen-presenting cells and also by using interleukin 7 and keyhole-limpet hemocyanin in a primary culture. The induced CTL could, thus, lyse HLA-A24 tumor cells expressing MAGE-2, as well as the peptide-pulsed target cells, with antigen specificity in a HLA class I-restricted manner. The identification of this peptide may, thus, be of therapeutic value in peptide-based vaccines for the treatment of several types of malignant tumors expressing MAGE-2.

Amino Acid Sequence↗
PubMed1999

Effect of a polymorphism of endothelial nitric oxide synthase gene in Japanese patients with IgA nephropathy.

BACKGROUND: Nitric oxide (NO) is synthesized by endothelial cell NO synthase (ecNOS) on vascular endothelium, and it plays a key role in the regulation of blood flow and pressure. A polymorphism of the ecNOS gene was recently shown to be associated with the development of cardiovascular disease. PATIENTS AND METHODS: We investigated the ecNOS gene polymorphism in 68 Japanese patients with IgA nephropathy (IgAN) and 134 normal controls. RESULTS: The genotype distributions were not different between the normal controls and the IgAN patients (ecNOS4b/b: ecNOS4b/a: ecNOS4a/a = 106:27:1 and 50:18:0, respectively). There was no significant difference in the renal histopathological grading between the patients with ecNOS4b/a and ecNOS4b/b. However, among the subgroup of patients whose duration of illness was two or more years, the advanced histopathological grading was more frequent in the patients with the ecNOS4b/a genotype (than in those with the ecNOS4b/b (p = 0.04)). The incidence of hypertension was also higher in the patients with the ecNOS4b/a genotype (50% in ecNOS4b/a versus 12% in ecNOS4b/b, p = 0.04). CONCLUSION: These results suggest that the ecNOS4b/a genotype (or ecNOS4a allele) of the ecNOS gene polymorphism may be involved in the progression of IgAN.

Adult↗
PubMed1998

Focal, high dose, and fractionated modified stereotactic radiation therapy for lung carcinoma patients: a preliminary experience.

BACKGROUND: Stereotactic radiation therapy is highly effective in the treatment of small brain metastases, regardless of the histology. This suggests that small extracranial malignancies may be curable with similar radiation therapy. The authors developed a novel treatment unit for administering such therapy. METHODS: The unit consisted of a linear accelerator (linac), an X-ray simulator (X-S), computed tomography (CT), and a table. The gantry axes of the three machines were coaxial and could be matched by rotating the table. Patients were instructed to perform shallow respiration with oxygen. The motion of the tumor was monitored with the X-S. When the motion was slight enough, the table was rotated to the CT. To include all geometric movement on the CT images, each scan was made while the patient was performing shallow respiration. After the CT positioning, the table was rotated to the linac, and non-coplanar treatment was given. Beginning in October 1994, 45 patients with 23 primary or 43 metastatic lung carcinomas were treated. Radiation doses at the 80% isodose line were 30-75 gray in 5-15 fractions over 1-3 weeks with or without conventional radiation therapy. RESULTS: The treatment was performed with no or minimal adverse acute symptoms. The daily treatment time was short. During a median follow-up of 11 months, local progression occurred in 2 of 66 lesions. Interstitial changes in the lung were limited. CONCLUSIONS: With this unit and procedure, focal radiation therapy similar to stereotactic radiation therapy is possible for extracranial sites. The preliminary experience appeared safe and promising, and further exploration of this approach is warranted.

Adenocarcinoma↗
PubMed1998

Acanthamoeba keratitis with symbiosis of Hartmannella ameba.

PURPOSE: To report a case of severe amebic keratitis in which both Hartmannella and Acanthamoeba were isolated simultaneously from the same lesion. METHOD: Case report. The deep corneal lesion was scraped for cytopathology and isolation of the pathogens. We tested the in vitro sensitivities of the pathogens to several drugs. RESULTS: Cultures of the corneal scrapings and of the solution in the patient's contact lens storage case were positive for Acanthamoeba E9 cysts and trophozoites. Hartmannella ameba coexisted with Acanthamoeba in the cornea. When tested in vitro, Acanthamoeba trophozoites were sensitive to both miconazole nitrate and natamycin, while cysts were sensitive only to natamycin. However, the patient did not respond to these antiamebic drugs. CONCLUSIONS: This case suggests that Acanthamoeba is not the only origin of amebic keratitis. Hartmannella may also cause severe drug-resistant keratitis.

Acanthamoeba↗
PubMed1998

Down regulation by iron of prostaglandin E2 production by human synovial fibroblasts.

OBJECTIVE: To examine the effect of iron on the prostaglandin (PG) E2 production by human synovial fibroblasts in vitro. METHODS: Human synovial fibroblasts were isolated from synovial tissue of rheumatoid arthritis (RA) and osteoarthritis (OA) patients and cultured in medium. Synovial fibroblasts were stimulated by human recombinant interleukin (IL) 1 beta (0.1-10 ng/ml) with or without ferric citrate (Fe-citrate, 0.01-1 mM). The amount of PGE2 in the culture medium was measured by an enzyme linked immunosorbent assay. RESULTS: The production of PGE2 by the synovial fibroblasts was increased by stimulation with IL1 beta at all concentrations tested. Fe-citrate but not sodium citrate (Na-citrate) down regulated the production of PGE2 by the synovial fibroblasts, both with and without stimulation by IL1 beta. Fe-citrate inhibited the spontaneous PGE2 production by the cells in a dose dependent manner, and a maximum inhibition by Fe-citrate was observed at the concentration of 0.1 mM with IL1 beta stimulation. The down regulation by iron was reversed by the co-addition of desferrioxamine (100 micrograms/ml), an iron chelator. CONCLUSION: Iron down regulates the PGE2 production by synovial fibroblasts in vitro.

Aged↗
PubMed1998

The formation of thyrotropin receptor (TSHR) antibodies in a Graves' animal model requires the N-terminal segment of the TSHR extracellular domain.

Immunization of AKR/N mice with murine fibroblasts, transfected with the TSH receptor (TSHR) and a murine major histocompatibility complex class II molecule having the same H-2k haplotype (but not either alone), induces immune thyroid disease with the humoral and histological features of human Graves', including the presence of two different TSHR antibodies (TSHRAbs): stimulating TSHRAbs, which cause hyperthyroidism; and TSH-binding-inhibiting immunoglobulins. The primary functional epitope for both types of antibodies in Graves' patients is on the N-terminal portion of the extracellular domain of the TSHR, residues 25 to 165; most require residues 90-165 to express TSHRAb activity, as evidenced in studies using chimeras of the TSHR and lutropin-choriogonadotropin receptor (LH-CGR). To evaluate the role of this region of the TSHR in the formation of Graves' TSHRAbs, we immunized AKR/N mice with fibroblasts transfected with three human TSHR chimeras with residues 9-165 (Mc1+2), 90-165 (Mc2), or 261-370 (Mc4) substituted by equivalent residues of the rat LH-CGR. Mice immunized with the Mc1+2 and Mc2 chimeras, with the N-terminal portion of the extracellular domain of the TSHR substituted by LH-CGR residues, did not develop TSHRAbs. Mice immunized with the Mc4 chimera, having a major portion of the C-terminal portion of the extracellular domain of the TSHR replaced by comparable LH-CGR residues, can develop TSHRAbs. The results suggest that the N-terminal segment of the TSHR extracellular domain is not only a critical functional epitope for Graves' TSHRAbs, but it is important also in their formation in a mouse model of Graves' disease.

Animals↗
PubMed1998

Thyrotropin receptor epitopes recognized by graves' autoantibodies developing under immunosuppressive therapy.

Abnormal modulation of the immune system is a prerequisite for the expression of Graves' disease. Thus, when hyperthyroidism developed in a renal transplant recipient under long term immunosuppression with cyclosporine A and prednisone, we carefully evaluated the basis for her hyperthyroidism and her state of immunosuppression. Immunosuppression was confirmed by finding markedly deficient lymphocyte responses to common mitogens. Lymphocyte phenotype frequencies were those previously found in Graves', i.e. elevated frequencies of CD3/DR, CD5/26, and CD3/25 lymphocytes. There was also reversal of the CD4/CD8 ratio due to increased CD8 frequency; this is not a typical finding in autoimmune hyperthyroidism, but has been seen in the intrathyroidal lymphocyte populations of some Graves' patients and is associated with other forms of autoimmunity. The patient's serum contained a broad spectrum of TSH receptor autoantibodies (TSHRAbs) characteristic of Graves' disease. To determine whether these were an unusual population of autoantibodies, we determined their functional epitopes before and for nearly 1 yr after radioiodine therapy. Stimulating TSHRAbs that increase cAMP levels were human receptor (TSHR) specific and consistently recognized functional epitopes located on TSHR residues 90-165. Stimulating TSHRAbs that increased arachidonate release and inositol phosphate levels recognized residues 25-90, as did TSH binding inhibitory Igs present in the patient. These data demonstrate that Graves' disease with a wide array of TSHRAbs can develop in a patient despite adequate immunosuppression. More importantly, they show that the cAMP-stimulating TSHRAb associated with disease expression in this patient had a homogeneous subtype dependent on TSHR residues 90-165. As persistence of this type of TSHRAb over time has been associated with resistance to methimazole therapy in Graves' patients, we speculate that the development and persistence of TSHRAb with this homogeneous epitope may be linked to resistance to immunosuppressive therapy.

Animals↗