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Biomedical subjects

K Takehara

Publications and source records attributed to K Takehara.

At least 145 records · Page 8Linked to original sources
PubMed1996

Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders.

Connective tissue growth factor (CTGF) is a novel peptide that exhibits platelet-derived growth factor-like activities and is produced by skin fibroblasts after activation with transforming growth factor-beta. Coordinate expression of transforming growth factor-beta followed by CTGF during wound repair suggests a cascade process for control of tissue regeneration. We recently reported a significant correlation between CTGF mRNA expression and histologic sclerosis in systemic sclerosis. To confirm the relation between CTGF and skin fibrosis, we investigated CTGF gene expression in tissue expression in tissue sections from patients with localized scleroderma, keloid, other sclerotic skin disorders using nonradioactive in situ hybridization. In localized scleroderma, the fibroblasts with positive signals for CTGF mRNA were scattered throughout the sclerotic lesions with no preferential distribution around the inflammatory cells or perivascular regions, whereas the adjacent nonaffected dermis was negative for CTGF mRNA. In keloid tissue, the fibroblasts positive for CTGF mRNA were diffusely distributed, especially in the peripheral expanding lesions. In scar tissue, however, the fibroblasts in the fibrotic lesions showed partially positive signals for CTGF mRNA. In eosinophilic fasciitis, nodular fasciitis, and Dupuytren's contracture, CTGF mRNA was also expressed partially in the fibroblasts of the fibrotic lesions. Our findings reinforce a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-beta plays an important role in the pathogenesis of fibrosis, as it is the only inducer for CTGF identified to date.

Adolescent↗
PubMed1996

Epidemiological analysis of prognosis of 496 Japanese patients with progressive systemic sclerosis (SSc). Scleroderma Research Committee Japan.

For the first time, we performed an epidemiological study of SSc in Japan to study the factors influencing prognosis, survival rate and cause of death of Japanese SSc patients and to compare our data with those from foreign countries. Prognosis of 496 Japanese patients with progressive systemic sclerosis (SSc) was analyzed based on clinical data described in case cards provided by the members of the Scleroderma Research Committee of the Japanese Ministry of Health and Welfare. The essential observation period was from 5 to 20 years, at ending in 1994. Ninety patients died (males 11, females 79). The age of onset of the deceased patients was significantly higher than that of surviving patients (deceased, 45.6 yrs, surviving 41.3 yrs). Statistically significant factors for a poor prognosis were as follows: Barnett type III > type II > type I, positive for anti-Scl-70 antibody, negative for anti-centromere antibody. The survival rate at 5 years after the onset of the disease was 0.937, followed by 0.82 at 10 years, 0.567 at 20 years and 0.40 at 30 years after the onset. Sex was not a predictor for prognosis, although male patients died at an earlier stage of the disease. The most common causes of death were heart failure, pulmonary insufficiency, lung fibrosis, and renal failure. Twenty-four patients had cancer of which 13 were lung cancers. The current status of the survival rate and prognostic factors of 496 Japanese SSc patients is summarized. In future, more well-controlled studies using the same criteria should be performed for the better understanding and management of SSc.

Adult↗
PubMed1996

Anti-ribosomal P protein antibodies in a Japanese patient with systemic sclerosis.

A 56-year-old Japanese woman developed Raynaud's phenomenon and digital ulcerations at the age of 50. She showed rapid and diffuse skin sclerosis; visceral involvement was mild. She showed no symptoms or laboratory findings suggestive of other collagen diseases, including systemic lupus erythematosus and Sjögren's syndrome. Based on the clinical and histological findings, she was diagnosed as having diffuse cutaneous systemic sclerosis (SSc). The patient's serum produced nucleolar and cytoplasmic staining by indirect immunofluorescence analyses on HEp-2 cell substrate and reacted with P0, P1 and P2 proteins in immunoblotting using purified ribosomal antigens. She was negative for anti-topoisomerase I, centromere, and U1RNP antibodies. Antiribosomal P protein antibodies are considered highly specific for systemic lupus erythematosus; this is the first case report of an SSc patient with anti-ribosomal P protein antibodies. The clinical features of SSc patients with these antibodies need to be clarified by an accumulation of cases.

Autoantibodies↗
PubMed1996

Changes in gastric HCO-3 secretory response to NG-nitro-L-arginine methyl ester in rats following repeated administration.

The effect of repeated administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on gastric HCO-3 secretion was examined using ex vivo chambered stomachs of anaesthetized rats. Intravenous administration of L-NAME (5 mg/kg) increased gastric HCO-3 secretion with a concomitant rise in arterial blood pressure (BP). The HCO-3 stimulatory action of L-NAME diminished when rats were pretreated with L-NAME (20 mg/kg, p.o., twice daily) for 1 or 3 days and an inverse relationship was found between the degree of secretory stimulation and the period of pretreatment. The increased BP response to L-NAME was also significantly lessened following repeated pretreatment; basal BP showed a stepwise increase during repeated pretreatment and did not change at all in response to i.v. L-NAME after 3 days pretreatment. When delta HCO-3 output induced by i.v. L-NAME was plotted against delta BP (from basal values) during repeated pretreatment with L-NAME, a significant relationship was found between these two factors. The reduction in the HCO3 secretory response to L-NAME was restored when animals were pretreated with L-arginine (500 mg/kg, i.p., twice daily) together with L-NAME. However, prostaglandin E2 (300 micrograms/kg, i.v.) caused a gastric HCO-3 secretory response similar to L-NAME, regardless of whether rats had been pretreated with L-NAME or not. In contrast, the attenuation by L-NAME of the acid (0.2 nmol/L HCl)-induced gastric hyperaemic response was not influenced by repeated pretreatment with L-NAME. We conclude that repeated p.o. pretreatment with L-NAME reduces the HCO-3 stimulatory action of i.v. L-NAME and that this phenomenon may be explained by the lack of further elevation of BP in response to i.v. L-NAME following repeated pretreatment with this agent. Thus, the stimulation of HCO-3 secretion by i.v. L-NAME may be causally related with increased BP in response to this agent.

Administration, Oral↗
PubMed1996

Antiubiquitin antibody in localised and systemic scleroderma.

OBJECTIVE: To determine the presence of antiubiquitin antibody (AUbA) in localised scleroderma and systemic sclerosis, as it is frequently found in the sera of patients with systemic lupus erythematosus (SLE) and has also been shown to have a close relationship with antihistone antibodies that have an important role in scleroderma. METHODS: Serum samples from patients with localised scleroderma (n = 48) and systemic sclerosis (n = 52) were examined by enzyme linked immunosorbent assay. Twenty samples from patients with SLE, 20 from patients with dermatomyositis, and 30 samples from healthy individuals were used as controls. RESULTS: AUbA was demonstrated in 44% of patients with localised scleroderma and in 42% of those with systemic sclerosis. The presence of AUbA correlated with the presence of antihistone antibodies in both localised scleroderma and systemic sclerosis. CONCLUSIONS: AUbA is frequently present in patients with localised scleroderma and systemic sclerosis. Induction of AUbA is closely associated with that of antihistone antibodies, suggesting that ubiquitinated histone may be the target in autoimmune responses of these disorders.

Adolescent↗
PubMed1996

Diethyldithiocarbamate, a superoxide dismutase inhibitor, reduces indomethacin-induced gastric lesions in rats.

We examined the effect of diethyldithiocarbamate (DDC), the superoxide dismutase (SOD) inhibitor, on the development of gastric lesions induced by indomethacin in rats. Indomethacin (25 mg/kg) was given subcutaneously, and gastric acid secretion, motility, lipid peroxidation, vascular permeability, and myeloperoxidase as well as gastric lesions were measured. Indomethacin produced high-amplitude contractions of the stomach and caused hemorrhagic lesions in the corpus mucosa with significant increase in neutrophil-related processes such as myeloperoxidase activity, vascular permeability and lipid peroxidation. These changes caused by indomethacin were all significantly inhibited by prior administration of atropine (3 mg/kg s.c.). Pretreatment of the animals with DDC (75-1,000 mg/kg s.c.) prevented these lesions induced by indomethacin in the corpus mucosa in a dose-dependent manner (> 100 mg/kg), though at high doses (> 750 mg/kg) some damage was found in both the antrum and duodenum. DDC showed a significant inhibition against the gastric mucosal SOD activity (> 400 mg/kg), yet potently suppressed the increase of lipid peroxidation, vascular permeability, and myeloperoxidase activity caused by indomethacin. DDC dose-dependently (> 75 mg/kg) inhibited the enhancement of gastric motility caused by indomethacin and showed a weak antisecretory effect at high doses (> 750 mg/kg). These results showed that DDC reduced indomethacin-induced gastric lesions by suppressing gastric motility, despite inhibiting SOD activity. This study also indicates the prime importance of gastric hypercontraction in the pathogenesis of this lesion model and suggests that other events including the neutrophil-related processes may be secondary to gastric hypercontraction caused by indomethacin.

Animals↗
PubMed1996

Successful treatment of livedo vasculitis with beraprost sodium: a possible mechanism of thrombomodulin upregulation.

BACKGROUND: Livedo vasculitis is thought to be a thrombogenic disorder. We demonstrated that thrombomodulin (TM) expression on the endothelial cells in livedo vasculitis was markedly reduced, while blood tests of coagulation and fibrinolytic activities were within the normal range. OBJECTIVE: Since prostacyclin (PGI2) upregulates the TM expression of endothelial cells, we tried a PGI2 analogue for the treatment of livedo vasculitis. METHOD: Four patients with livedo vasculitis were started on a regimen of beraprost sodium (120 micrograms daily). Additional intake of low-dose aspirin was combinated with a maintenance dose of beraprost sodium (60 micrograms daily). RESULT: All 4 patients experienced a clinical improvement with a combination therapy with beraprost sodium and low-dose aspirin. CONCLUSION: We propose that PGI2 analogue therapy is useful for the treatment of livedo vasculitis, since the drug upregulates TM expression in this disorder.

Adolescent↗
PubMed1996

Clinical significance of serum levels of soluble interleukin-2 receptor in patients with localized scleroderma.

Localized scleroderma has been reported to be accompanied by abnormal immune reactions, including autoantibody production and lymphocyte activation. Lymphocyte activation can be quantitatively detected by measuring soluble interleukin-2 receptor (sIL-2R) in serum samples. In this study, serum sIL-2R levels were assayed by a sensitive enzyme-linked immunosorbent assay, in 48 patients with localized scleroderma, in 20 with systemic sclerosis (SSc) and in 20 healthy controls. Serum levels of sIL-2R were significantly higher in patients with localized scleroderma than in healthy controls. The serum levels of sIL-2R were correlated with the number of sclerotic lesions, the number of involved areas, the levels of anti-ssDNA, and the levels of antihistone antibody immunoglobulin M. Moreover, sIL-2R levels in sera from patients with SSc were also significantly higher than in healthy controls. Elevated serum levels of sIL-2R in localized scleroderma suggest that lymphocyte activation is one of the early processes in the development of this disease.

Adolescent↗
PubMed1996

Hepatocellular carcinoma with pleural metastasis complicated by hemothorax.

Hemothorax can be caused by rupture of hepatocellular carcinoma (HCC). Hemoperitoneum is a well-known cause of death caused by rupture of a primary HCC lesion. Rupture of a HCC metastasis has not been adequately described. This is the first report of a HCC patient who died of hemothorax due to rupture of a pleural metastasis. The patient, a woman, died in respiratory failure 2 wk after rupture of her HCC metastasis in the pleura. Autopsy revealed moderately differentiated HCC in the liver, lung, and pleura. We discuss treatment options for ruptured pleura-based HCC metastases.

Adult↗
PubMed1996

[Local immune responses in uterine cervical carcinogenesis].

In order to investigate the role of local immune response in uterine cervical carcinogenesis, lymphocyte phenotypes infiltrating the cervical region were studied by indirect immunoperoxidase staining for natural killer (NK) cells, macrophages. Langerhans cells (LC), memory T cells, CD4-positive cells and CD8-positive cells. The specimens used in this study were 9 normal ectocervical epithelium samples, 28 with mild dysplasia, 28 with moderate dysplasia, 31 with severe dysplasia and 9 with carcinoma in situ (CIS). A quantitative study was conducted in 23 patients with persistent cervical dysplasia and a comparable control group of 17 patients with regressive dysplasia. Human papillomavirus (HPV) types 16 and 18 DNA was analyzed by using polymerase chain reaction techniques, and differences in local immune responses between cases with and others without HPV types 16 and 18 were studied. The results are as follows. 1) The numbers, of NK cells and macrophages increased as the grade of cervical dysplasia increased and the numbers of these cells in cases of cervical dysplasia were greater than in normal ectocervical epithelium and CIS. 2) The numbers of LC, memory T cells and CD4-positive cells also increased with the grade of cervical dysplasia. The number of memory T cells was significantly greater in severe cervical dysplasia than in normal ectocervical epithelium or mild dysplasia (p < 0.05). 3) There were statistically significant correlations between the number of white blood cells and those of stroma-infiltrating memory T cells (r = 0.98) and CD4-positive cells (r = 0.88). A positive correlation was found between the numbers of lymphocytes in epithelium and in subepithelium. 4) A significant reduction in CD4-positive cells was founded in persistent dysplasia compared with regressive dysplasia (p < 0.05). 5) Cases with and without HPV types 16 and 18 did not differ significantly with respect to local immune responses. It is therefore considered that the increased number of lymphocytes in cervical dysplasia and the decreased number in CIS might reflect active local immunosurveillance in the process of carcinogenesis. Lymphocytes, especially CD4-positive cells, may play an important role in surveillance against the development and progression of cervical cancer.

Cell Count↗
PubMed1995

Differential chemotactic responses mediated by platelet-derived growth factor alpha- and beta-receptors.

We have performed a modified Boyden chamber chemotaxis assay using NRK-49F cells under serum-free condition, in order to characterize the chemotactic activity of recombinant platelet-derived growth factor (PDGF)-AA, -AB, and -BB. All three PDGF isoforms showed similar chemotactic activity on NRK cells expressing both PDGF alpha- and beta-receptors. A checkerboard analysis revealed that PDGF-AA was a true chemoattractant for NRK cells, indicating that alpha-receptors could transduce signals for the chemotactic response. We then examined the inhibitory effects of PDGF isoforms in the upper chamber on NRK cell migration to PDGF in the lower chamber. When higher concentrations of PDGF-AB or -BB were present in the upper chamber, cell migration to any of the PDGF isoforms was completely blocked, whereas PDGF-AA in the upper chamber could not induce complete inhibition of the chemotactic migration to PDGF-AB or -BB. Even when 100 ng/ml of PDGF-AA was present in the upper chamber, NRK cell migration to 5 ng/ml of PDGF-AB in the lower chamber was not completely blocked. These findings suggest that the chemotactic response induced by ligand binding to PDGF beta-receptor may be different from that induced by ligand binding to PDGF alpha-receptors.

Blotting, Western↗
PubMed1995

Thrombospondin-related adhesive protein (TRAP) of Plasmodium falciparum: expression during sporozoite ontogeny and binding to human hepatocytes.

Plasmodium sporozoites collected from oocysts, haemocoel and salivary glands of the mosquito show profound differences in their biological properties such as motility, ability to induce protective immune response and infectivity for vertebrate host cells. Sporozoites from salivary glands are much more infectious than those from oocysts and haemocoel. Differential expression of proteins, such as the circumsporozoite (CS) protein and the thrombospondin-related adhesive protein (TRAP), implicated in sporozoite recognition and entry into hepatocytes may account for the development of infectivity during ontogeny. We have carried out a series of experiments to: (i) analyse the expression and localization of TRAP in P.falciparum sporozoites during development in the mosquito; and (ii) elucidate the biochemical and adhesive properties of recombinant TRAP. Our data indicate that TRAP is not expressed in oocysts, whereas variable amounts of CS protein are found in this parasite developmental stage. Hemocoel sporozoites display the distinct phenotypes TRAP- CS protein+ and TRAP+ CS protein+ at a frequency of 98.5 and 1.5% respectively. Salivary gland sporozoites are all TRAP+ CS protein+. We also provide experimental evidence showing that recombinant TRAP binds to the basolateral cell membrane of hepatocytes in the Disse's space and that sulfated glycoconjugates function as TRAP ligands on human hepatocytes.

Amino Acid Sequence↗
PubMed1995

Impaired growth response to endothelin-1 in scleroderma fibroblasts.

Systemic sclerosis (SSc) is characterized by vascular damage and dermal fibrosis. In this study, we examined the endothelin (ET) receptor subtype involved in mitogenic signaling in scleroderma and normal skin fibroblasts. ET-1 stimulated DNA synthesis of normal fibroblasts in serum-deprived cultures. ET-3 had lesser effects on DNA synthesis of normal fibroblasts than ET-1. The growth response to ET-1 in scleroderma fibroblasts was decreased compared to normal fibroblasts. [125I]-ET-1 binding to normal fibroblasts was significantly blocked by excessive amount of unlabeled ET-1 and BQ-123. [125I]-ET-1 binding to scleroderma fibroblasts was significantly decreased compared with normal controls. Immunoblotting analysis showed that the expression of ETA receptor in scleroderma fibroblasts was diminished compared with normal controls. ETA mRNA expression in scleroderma fibroblasts was decreased compared with that of normal fibroblasts. From these results, we conclude that the mitogenic effects of ET in human dermal fibroblasts are mainly mediated through ETA receptors, and that down-regulation of ETA receptors caused the decreased growth response of ET-1 in scleroderma fibroblasts.

Biopsy↗
PubMed1995

Matrix/integrin interaction activates the mitogen-activated protein kinase, p44erk-1 and p42erk-2.

Cell adhesion to extracellular matrix proteins is a dynamic process leading to dramatic changes in the cell phenotype. Integrins are one of the major receptor families that mediate cell-matrix contact. Evidence that integrins can act as signal transducing molecules has accumulated over the past few years. We report here that p44erk-1 and p42erk-2 mitogen-activated protein (MAP) kinases are rapidly phosphorylated on tyrosine residues upon adhesion of human skin fibroblasts to fibronectin or upon cross-linking of beta 1 integrins with antibody. The tyrosine phosphorylation of both kinases is associated with increased enzymatic activity. Pretreatment of the cells with cytochalasin D, which selectively disrupts the network of the actin filaments, completely inhibits this adhesion-mediated MAP kinase activation. Thus, our findings indicate that ligation of beta 1 integrins induces an increase in both tyrosine phosphorylation and enzymatic activity of p44erk-1 and p42erk-2 MAP kinases, and that the integrity of the actin cytoskeleton is essential in this process. Since MAP kinase behaves as a convergence point for diverse receptor-initiated signaling events at the plasma membrane, this serine/threonine kinase plays a key role and helps to account for the diversity of integrin-dependent cell functions.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1995

Autoantibodies to pyruvate dehydrogenase complex in patients with systemic sclerosis. Possible role of anti-E1 alpha antibody as a serologic indicator for development of primary biliary cirrhosis.

OBJECTIVE: To determine the prevalence and clinical significance of anti-pyruvate dehydrogenase complex (anti-PDC) antibodies in systemic sclerosis (SSc). METHODS: Serum samples from patients with limited cutaneous SSc (n = 81) or diffuse cutaneous SSc (n = 63) were examined for anti-PDC antibodies by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. RESULTS: IgG- and/or IgM-isotype anti-PDC antibodies were demonstrated by ELISA in 26 of 144 patients with SSc (18%). By immunoblotting, 19 patients had IgG anti-PDC antibodies. Among these patients with IgG anti-PDC antibodies, antibody to the E1 alpha subunit was significantly associated with the presence of laboratory abnormalities typical of primary biliary cirrhosis (PBC). CONCLUSION: Antibody to the E1 alpha subunit of PDC may be a serologic indicator for the development of PBC in patients with SSc.

Adult↗