Biomedical subjects

Y Nishimura

Publications and source records attributed to Y Nishimura.

At least 469 records · Page 26Linked to original sources

PubMed1996

Molecular mechanisms underlying HLA-DR-associated susceptibility to autoimmunity.

We analyzed structural motifs of peptides bound to HLA-DR4 (DRB1*0405 and DRB1*0406) and DR9 (DRB1*0901) and found that: (a) AxxBxC motif where A, B, and C are hydrophobic, hydrophobic, and neutral, respectively, is important for binding to DR4; (b) Gln (Q) or Ser at position C allow high-affinity binding specific to DRB1*0406 which is strongly associated with insulin autoimmune syndrome; (c) among human insulin-derived peptide fragments, the TSICSLYQLE of the human insulin alpha chain, which is exposed only under reducing conditions, has the highest affinity specific to DRB1*0406 by binding with the IxxLxQ motif; (d) a short-term human insulin-specific T cell line recognizes a peptide fragment containing the IxxLxQ motif as a major T cell epitope; and (e) in the AxxB motif, where A and B need to be hydrophobic for binding to DR9, neutral Ser is exceptionally allowed at position B. The implications of our results are discussed in light of the HLA-DR4-associated susceptibility to insulin autoimmune syndrome and HLA-DR9-associated susceptibility to juvenile-onset myasthenia gravis and systemic lupus erythematosus with antiphospholipid syndrome, in particular T cell responses to autoantigens.

Amino Acid Sequence↗

PubMed1996

Anti-CD4 monoclonal antibody reduces the dose of cyclophosphamide required to induce tolerance to H-2 haplotype identical skin allografts in mice.

Cyclophosphamide (CP)-induced tolerance which consists of a single i.p. injection of 200 mg/kg CP 2 days after priming with 1 x 10(8) donor spleen cells (SC), leads to long-lasting donor-specific skin allograft tolerance in H-2 compatible, multiminor antigen incompatible, murine strain combinations. In this system, the optimal dose of CP has been suggested to be 200 mg/kg, however, such a dose of CP causes strong myelosuppression. In the present study, we therefore attempted to reduce the dose of CP by administering anti-CD4 monoclonal antibody (mAb) before donor cell priming in this tolerance-inducing system. When C3H/He (C3H; H-2k, Mls-1b) mice were injected i.p. with 200 micrograms anti-CD4 mAb on day -3, 1 x 10(8) AKR/J (AKR; H-2k, Mls-1a) SC plus 3 x 10(7) bone marrow cells (BMC) i.v. on day -2 and then 100 mg/kg CP i.p. on day 0, a long-lasting donor-specific skin allograft tolerance was established; furthermore, the decreases in the number of leukocytes and the concentration of hemoglobin (Hb) in the peripheral blood were all less in the C3H mice treated with this new combined protocol than in the C3H mice injected with 200 mg/kg CP following the previous protocol. In the periphery of these tolerant mice, the number of donor-reactive V beta 6+CD4+ T cells decreased and mixed chimerism was observed on both days 14 and 80. On the other hand, in the mice injected with AKR SC, BMC plus 100 mg/kg CP without anti-CD4 mAb, the number of V beta 6+CD4+ T cells decreased on day 14, and then recovered by day 80 when the mixed chimerism disappeared. These results therefore suggest that the combined use of anti-CD4 mAb with CP can reduce the dose of CP without affecting the efficiency of inducing donor-specific tolerance, probably due to the enhancement of the destruction effect of donor-reactive T cells by CP.

Anemia↗

PubMed1996

Combined effects of an angiogenesis inhibitor (TNP-470) and hyperthermia.

TNP-470, a synthetic analogue of fumagillin first isolated from Aspergillus fumigatus, is known to be a potent anti-angiogenic compound. The combined effects on tumour growth and tumour angiogenesis of TNP-470 and hyperthermia were investigated. The tumour used was SCCVII carcinoma of the C3H/He mouse. The tumour response was evaluated by the tumour growth (TG) time assay. The TG time is the time required for one-half of the treated tumours to reach three times the initial tumour volume. Significant delay of tumour growth was observed by TNP-470 alone (100 mg kg-1 x 2 or x 4), indicating that TNP-470 alone has antitumour effect in vivo. When TNP-470 (100 mg kg-1 x 2 or x 4) was administered after hyperthermia at 44 degrees C, the TG times of the combined treatment were significantly longer than those of heat alone (44 degrees C) or TNP-470 (100 mg kg-1 x 2 or x 4) alone. However, the TG time of combined treatment with TNP-470 and hyperthermia at 42 degrees C was quite similar to that of TNP-470 alone. This conflicting result on the combined effect of TNP-470 and hyperthermia may be related to the temperature-dependent vascular damage by hyperthermia. Dose-dependent inhibition of angiogenesis by TNP-470 was demonstrated in microangiograms obtained 4 days and 7 days after hyperthermia (44 degrees C for 30 min). It is, thus, suggested that the combined effect of TNP-470 and hyperthermia is attributable to the inhibition of angiogenesis by TNP-470 following heat-induced vascular damage.

Animals↗

PubMed1996

The cavity in the hydrophobic core of Myb DNA-binding domain is reserved for DNA recognition and trans-activation.

The DNA-binding domain of Myb consists of three imperfect repeats, R1, R2 and R3, each containing a helix-turn-helix motif variation. Among these repeats, R2 has distinct characteristics with high thermal instability. The NMR structure analysis found a cavity inside the hydrophobic core of R2 but not in R1 or R3. Here, we show that R2 has slow conformational fluctuations, and that a cavity-filling mutation which stabilizes the R2 structure significantly reduces specific Myb DNA-binding activity and trans-activation. Structural observations of the free and DNA-complexed stages suggest that the implied inherent conformational flexibility of R2, associated with the presence of the cavity, could be important for DNA recognition by Myb.

Amino Acid Sequence↗

PubMed1996

Overproduction of penicillin-binding protein 7 suppresses thermosensitive growth defect at low osmolarity due to an spr mutation of Escherichia coli.

Escherichia coli delta prc mutants lacking periplasmic protease Prc, which was originally found involved in the C-terminal processing of penicillin-binding protein (PBP) 3, show thermosensitive growth at low osmolarity. We isolated thermoresistant revertants containing extragenic suppressor (spr) mutations. In the prc+ background the mutations also caused thermosensitivity at low osmolarity. They were all mapped at about 48 min on the chromosome and most probably allelic to one another. From this chromosomal region we cloned a gene that could correct the thermosensitive defect of an spr mutant, which turned out to be a multicopy suppressor of spr. Analysis of the nucleotide sequence predicted that the gene would code for a low-molecular-weight PBP, and penicillin-binding experiments revealed the product to be PBP 7. Disruption of the gene on the chromosome caused no apparent growth defect. PBP 7 seemed to be degraded by protease Prc. Overproduction of mutant PBP 7 that had the active site serine residue replaced with alanine did not correct the spr thermosensitivity, suggesting importance of the DD-endopeptidase activity in the multicopy suppression.

Alleles↗

PubMed1996

HLA-DQ-binding peptide motifs. 1. Comparative binding analysis of type II collagen-derived peptides to DR and DQ molecules of rheumatoid arthritis-susceptible and non-susceptible haplotypes.

The frequency of the HLA-DR4-DQ4 haplotype (DRB1(*)0405-DQA1(*)0302-DQB1(*)0401) is significantly increased in Japanese patients with rheumatoid arthritis (RA) and DRB1(*)0405-binding peptide motifs were identified in our previous studies. To clarify the DQ4-binding peptide motifs, the primary structure of DQ4-binding peptides was determined by affinity-based selection of a phage random peptide library. Analog peptides of a high-affinity DQ4 binder revealed that two major anchors (VxxxxxxxR; where x is any amino acid) play an essential role in binding to DQ4. The affinity of synthetic VAAAAAAAR-based analog peptides showed that substituting V to W, G, L, I, M, P, F, Y or A and R to H, M, L, I or V allows binding. The involvement of the ninth residue of the peptides, especially Arg, was critical for high-affinity binding. In comparison with other class II-binding peptide motifs reported to date, peptide motifs for DQ4 were unique, in that Gly and Pro are allowed as low-affinity N-terminal anchors. Interestingly, 94 putative DQ4-binding motifs were detected in the human type II collagen molecule, since it is composed of (Gly-X1-X2)n and is rich in R and P at positions X2. However, no significant differences were observed between the affinities of the collagen-derived peptides with DR or DQ molecules of RA-susceptible DR4-DQ4 and with those of non-susceptible DR4-DQ8 (DRB1(*)0406-DQA1(*)0301-DQB1(*)0302) haplotypes, indicating that the susceptibility to RA is not a simple immune response gene phenomenon specific to collagen. The immunogenetic implications of the unique peptide motifs for DQ are discussed.

Amino Acid Sequence↗

PubMed1996

IL-4 and anti-CD40 protect against Fas-mediated B cell apoptosis and induce B cell growth and differentiation.

Most Th2 clones, when activated, produce IL-4 and express CD40 ligand (CD40L) on their cell surface. Therefore, they can induce growth and differentiation of B cells by cognate help. In contrast, activated Th1 clones, which produce IFN-gamma and express both CD40L and Fas ligand (FasL) on their cell surface, often induce B cell apoptotic cell death. To understand the mechanism by which Th2 cells can induce B cell growth and differentiation in the presence of FasL-positive cells, we stimulated B cells with IL-4, anti-IgM and/or anti-CD40 in the presence of anti-Fas. We report here that addition of anti-Fas strongly inhibited anti-CD40-induced B cell proliferation without affecting anti-IgM-induced B cell proliferation. Furthermore we showed that stimulation of B cells with anti-CD40 induced the expression of Fas molecules on the B cells (approximately 30%) and rendered them highly sensitive to anti-Fas-mediated apoptotic cell death. Indeed, over 23% of anti-CD40-stimulated B cells showed hypodiploid DNA after being incubated with anti-Fas, while h2 cells could dominate over FasL-positive Th1 cells by production of CD40L and IL-4, which in combination induce antibody production and inhibit the Th1 cell-mediated immune response.

Animals↗

PubMed1996

Clinical usefulness of determining the rate of thermal clearance within heated tumors.

Between June 1987 and June 1988, 28 patients (28 tumors) with liver, retroperitoneal, intrapelvic, or superficial tumors were treated with hyperthermia combined with radiotherapy and/or chemotherapy. Hyperthermia was administered once or twice a week for 30-60 min per session, up to a total of 2-11 sessions, with an 8-MHz RF capacitive heating device. Blood flow in the tumors was evaluated from the rate of thermal clearance (TCR) using the bio-heat transfer equation. The TCR was measured in the middle of the first heating session and at the end of the last heating session by turning off the output power of the heating device. For 9 patients, contrast-enhanced CT scans were taken and CT numbers at the centers of tumors were measured before and after the entire course of hyperthermia. Changes in TCR were closely related to average tumor center temperature, changes in CT number, and tumor response. When smaller and more superficial tumors were treated by hyperthermia combined with radiotherapy and/or chemotherapy that consisted of many heating sessions and during which a high average tumor center temperature was achieved, a better tumor response was obtained. The better the tumor response, the higher the local control rate became. The cause-specific survival rate of patients who achieved good tumor responses was higher than that of patients who showed poor tumor responses. Changes in TCR and CT number in heated tumors were useful and important indicators of tumor response to hyperthermia.

Adolescent↗

PubMed1996

Preservative effects of trehalose on rat muscle flaps.

In this experiment, the effect of trehalose on the preservation of rat gracilis muscle flaps was studied. The muscle flaps were preserved in 4 degrees C Euro-Collins solution or 4 degrees C trehalose-Euro-Collins solution for 6, 12, 24, 48, 72, and 96 hours, and then replanted in the same rats using microsurgical techniques. Immediately after preservation and 1 week after replantation, the levels of adenosine triphosphate and creatine phosphate in flaps preserved in the trehalose-Euro-Collins solution were significantly higher than those in flaps preserved in the Euro-Collins solution. In the 4 degrees C Euro-Collins solution group 1 week after replantation, focal necrosis, hyaline degeneration, and proliferation of fibroblasts were seen after 12 hours of preservation, and, after 48 hours of preservation, there were no surviving flaps. In the 4 degrees C trehalose-Euro-Collins group, focal necrosis, hyaline degeneration, and proliferation of fibroblasts were seen only after 24 hours of preservation, and, after 96 hours of preservation, two of eight flaps survived. These findings indicate that trehalose was effective in the preservation of muscle flaps.

Adenosine Monophosphate↗

PubMed1996

Proposal for a new comprehensive classification of V-Y plasty and its analogues: the pros and cons of inverted versus ordinary Burow's triangle excision.

Burow's triangle excision is often used in V-Y plasty to facilitate the advancement of the V flap. The technique also seems to help reduce unsightly scarring. We devised an alternative technique to Burow's triangle excision, i.e., an inverted Burow's triangle excision. Sometimes the inverted Burow's triangle excision seems to be more effective for both purposes. In this paper we propose a new comprehensive classification of V-Y plasty and its analogues such as V-M, V-W, or five Z-plasty based on a new concept, the appropriate use of Burow's and inverted Burow's triangle excision and other criteria. The applications of these designs are discussed.

Burns↗

PubMed1996

Changes in cell proliferative parameters of SCCVII and EMT6 murine tumors after single-dose irradiation.

To understand better the repopulation kinetics of tumor cells after radiotherapy, we investigated changes in cell proliferative parameters after single-dose irradiation of SCCVII tumors in C3H/He mice and EMT6 tumors in Balb/c mice. The following parameters were determined 0-15 days after single irradiation at 20 or 30 Gy; dividing fraction (DF), potential doubling time (Tpot), number of clonogenic cells per tumor (Ncln), and volume doubling time (Tvol). DF and Tpot were determined by in vivo-in vitro cytokinesis-block assay with cytochalasin B, Ncln was measured by in vivo-in vitro colony-forming assay, and Tvol was determined by growth delay assay. In both tumors, longer Tpot and lower DF and Ncln were obtained for 3-4 days after irradiation, but in SCCVII tumors these values returned to the pretreatment levels 9 days after irradiation. In EMT6 tumors, Tpot, DF, and Ncln did not return to the pretreatment levels even 12 days after irradiation. In the regrowth phase of both tumors following irradiation at 20 Gy, Tvol was longer than the pretreatment level, although Tpot was similar in SCCVII and only slightly longer in EMT6. Therefore, the cell loss factor in the regrowth phase was considered to be higher than the pretreatment level in both tumors. From the results, recruitment of previously quiescent cells into the proliferative pool in these tumors was suggested to contribute to repopulation after radiation.

Animals↗

PubMed1996

Epitope analysis of HLA-DR-restricted helper T-cell responses to Der p II, a major allergen molecule of Dermatophagoides pteronyssinus.

T-cell epitopes of Der p II, a major allergen of Dermatophagoides pteronyssinus, were analyzed by using human T-cell clones. We tested 38 cloned T cells from two Japanese patients with allergic rhinitis, and identified at least two peptides (K33-T47 and I58-C73) as helper T-cell epitopes. The former epitope was shown to be restricted by HLA-DRB1*1502, and the latter by HLA-DRB1*0405, both of which are typical Japanese HLA-DR alleles, suggesting that those T-cell epitopes might be important for the onset of house-dust mite allergy in the Japanese population. We prepared 15 analog peptides of the HLA- DRB1*1502-restricted 15-mer peptide. Of those 15 residues, five (F35, L37, A39, F41, and E42) were critical for the epitope activity, and three residues (F35, A39, and E42) seemed to be included in anchor motifs for HLA-DRB1*1502. The epitope peptide was also recognized by HLA-DRB1*1502-positive healthy donors; however, only allergic T cells showed Th2 functions. Antigen-presenting cells of nonallergic donors were able to activate allergic T cells to express Th2 function. This seemed to suggest that antigen recognition of T cells, as well as additional unknown factors which promote Th2, rather than Th1, responses, might be important for the onset of house-dust mite allergy.

Allergens↗

PubMed1996

Immunodominance of seven regions of a major allergen, Cry j 2, of Japanese cedar pollen for T-cell immunity.

The immunodominant regions of the Japanese cedar pollen allergen Cry j 2 for T-cell immunity were determined with whole peripheral blood lymphocytes (PBL) derived from seven allergic patients and three nonallergic subjects. Cry j 2-stimulated T-cell proliferation was inhibited by anti-HLA-DR, but not by anti-HLA-DQ antibody, indicating that the responding T cells recognized the allergen peptides associated with HLA-DR molecules. It was found that seven regions of Cry j 2, i.e., regions corresponding to amino acid numbers 1-26, 70-84, 151-167, 187-203, 252-279, 283-314, and 345-362, were immunodominant for T-cell proliferation. Thus, Cry j 2 bears a limited number of immunodominant regions despite polymorphic features of HLA-DR in the immune system. This suggests the possibility of molecularly designing Cry j 2 antagonists that could downregulate allergic reactions to Japanese cedar pollen.

Case-Control Studies↗

PubMed1996

Serum markers for fibrosis and plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma in comparison with patients with liver cirrhosis.

In order to elucidate collagen metabolism in hepatocellular carcinoma (HCC) tissue, we compared levels of different potential markers of collagen metabolism and plasma transforming growth factor-beta 1 in patients with HCC and in patients with liver cirrhosis. Serum levels of prolyl hydroxylase and the tissue inhibitor of metalloproteinase-1 in patients with HCC were significantly higher than those in patients with liver cirrhosis and increased with the size of the HCC tumour, whereas the serum levels of procollagen type III propeptide and type IV collagen 7S domain were similar in the two groups. In HCC, the increased plasma transforming growth factor-beta 1 levels were closely correlated with serum levels of prolyl hydroxylase and the tissue inhibitor of metalloproteinase-1. These findings suggest that, in HCC tissue, the intracellular biosynthesis of collagen is enhanced, whereas the secretion of procollagen is disturbed and the degradation of collagen is suppressed by the excess production of the tissue inhibitor of metalloproteinase-1. The results also suggest that plasma transforming growth factor-beta 1 plays an important role in the altered metabolism of collagen in HCC.

Aged↗

PubMed1996

Clinical significance of serum hyaluronan in patients with chronic viral liver disease.

In order to elucidate the clinical significance of serum hyaluronan in chronic viral hepatitis, serum hyaluronan concentrations were measured using a sandwich enzyme binding assay in 115 patients with chronic viral hepatitis. These findings were examined in relation to the results of laboratory liver tests, levels of serum markers for fibrosis and liver histological findings. Serum hyaluronan levels increased with the progress of liver disease, particularly in liver cirrhosis. There were no significant differences in serum hyaluronan levels among the cirrhotic patients according to Child's grade. Multivariate analysis showed that the significant independent predictors of serum hyaluronan were serum aspartate aminotransferase (P = 0.020), serum alanine aminotransferase (P = 0.008), serum cholinesterase (P < 0.001), particularly serum type IV collagen 7S domain (P < 0.0001), and the histological degree of liver fibrosis (P < 0.0001). These findings suggest that elevated serum hyaluronan levels are closely related to the severity of liver fibrosis. We assessed the predictive value of serum hyaluronan in differentiating cirrhosis from chronic hepatitis, constructing receiver operating curves; we found that serum hyaluronan was a better test for diagnosing cirrhosis than serum type IV collagen 7S domain and laboratory liver tests.

Adult↗

PubMed1996

Characterization of 5-hydroxytryptamine receptors mediating contractions in basilar arteries from stroke-prone spontaneously hypertensive rats.

1. The 5-hydroxytryptamine (5-HT) induced-contraction in ring preparations of basilar arteries from Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) was pharmacologically characterized in vitro. 2. Contractile responses to 5-HT (1 nM-100 nM) and their pD2 values in arteries from SHRSP at 6 months of age were significantly greater than those in age-matched WKY, although the maximum response did not differ between the two groups. 3. There were no significant differences in contractile responses to U-44619, endothelin-1, neuropeptide Y, and angiotensin II between WKY and SHRSP arteries. 4. Spiperone (1 nM-1 microM, a 5-HT2 receptor antagonist), produced biphasic displacement of the 5-HT curves in WKY and SHRSP arteries. The response to high concentrations of 5-HT was concentration-dependently antagonized by spiperone, while the response to low concentrations of 5-HT was resistant to blockade by spiperone, and the spiperone-resistant contractile responses induced by 5-HT were greater in SHRSP than in WKY. Ketanserin (1-100 nM, 5-HT2) also produced a biphasic shift of the 5-HT curves for both arteries. 5. Methiothepin (10 and 100 nM, 5-HT1 and 5-HT2) potently inhibited 5-HT-induced contractions in both groups. In addition, methiothepin (100 nM) produced a parallel shift to the right of the component of 5-HT-induced contractile responses that was resistant to blockade by spiperone in both groups. 6. The contractile effects of 5-HT in WKY and SHRSP arteries were not affected by MDL 72222 (1 microM, 5-HT3) and SDZ 205-557 (1 microM, 5-HT4). In addition, cocaine (10 microM), pargyline (50 microM), prazosin (10 microM), indomethacin (3 microM) and SQ 29,548 (1 microM) did not affect the contractile effects of 5-HT in either artery. 7. Contractile responses to 5-carboxamidotryptamine, CGS 12066B, pindolol and propranolol were greater in SHRSP arteries than in WKY arteries, whereas contractions in response to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), alpha-methyl-5-HT and 2-methyl-5-HT did not differ between the two groups. Cisapride failed to contract basilar arteries in both groups. Furthermore, a correlation analysis showed a highly significant correlation between the pD2 values of 5-HT agonists in WKY and SHRSP arteries and their published binding affinities at the 5-HT1B subtype. 8. These findings suggest that 5-HT elicits vasoconstriction in rat basilar arteries by stimulation of a mixed receptor population of 5-HT2 and 5-HT1-like receptors (similar to the 5-HT1B receptor subtype), and that the contraction mediated by 5-HT1-like receptors is enhanced in the basilar artery from SHRSP.

Animals↗

PubMed1996

[A case of empyema caused by Salmonella enteritidis in a patient with sequela of pulmonary tuberculosis].

A 69-year-old male was admitted to our hospital on Jan. 10, 1995 complaining of bloody sputum, left back pain and fever of 39 degrees C. He had a history of pulmonary tuberculosis 45 years ago. His chest X-ray and CT showed the presence of air-fluid level in the left pleural cavity with thickening and calcification of the pleura. Salmonella Enteritidis was isolated from the sputum, bronchoalveolar lavage fluid and stool. He was diagnosed as suffering from Salmonella-empyema with an internal fistula. Based on the in vitro sensitivity test, sulfamethoxazole/trimethoprim was started. However, the efficacy of the antimicrobia was not sufficient. He then underwent left pleuropneumonectomy. Salmonella was cultured also from the specimen obtained at the operation. His course after operation was uneventful. Thus, although Salmonella Enteritidis is known as a common pathogen of food poisoning, it can cause empyema, especially in a case with an impaired host defence system.

Aged↗

PubMed1996

Relationship between bronchial hyperreactivity and symptoms of cardiac asthma in patients with non-valvular left ventricular failure.

To determine whether a relationship exists between bronchial hyperreactivity and cardiac asthma, which is commonly observed in patients with left heart failure, a methacholine inhalation test was performed in 15 patients with stable left ventricular failure (LVF) and 10 normal subjects. The subjects were divided into 3 groups based on symptoms of nocturnal coughing and/or wheezing in acute exacerbation of LVF. Group A consisted of 8 patients with nocturnal coughing and/or wheezing. Group B consisted of 7 patients without such symptoms, and Group C consisted of the 10 age-matched normal controls. Eleven of the 15 patients with LVF showed a significant increase in respiratory resistance in the methacholine inhalation test, as opposed to none of the normal subjects. The median cumulative dose which produced a 35% decrease in respiratory conductance (PD35Grs) was significantly lower in Group A than in Group B (1.45 log units and 1.90 log units, respectively, p < 0.05). The results of pulmonary function tests were not significantly different between Groups A and B. The minimum cumulative dose required to initiate a decrease in respiratory conductance from the baseline, as an index of bronchial sensitivity to methacholine, was significantly correlated with DLCO/VA (r = 0.710, p < 0.01). We conclude that bronchial hyperreactivity is responsible for cardiac asthma and that it might be related to pulmonary interstitial changes in stable patients with non-valvular LVF.

Adult↗