PubMed Health⌕ Search

Biomedical subjects

S Hirohata

Publications and source records attributed to S Hirohata.

At least 19 recordsLinked to original sources
PubMed2003

Myocardial infarction caused by rheumatoid vasculitis: histological evidence of the involvement of T lymphocytes.

Rheumatoid arthritis (RA) is a chronic joint disease that can be complicated with extra-articular manifestations due to vasculitis. We describe a patient with RA who developed systemic vasculitis and died of myocardial infarction. Autopsy demonstrated vasculitis of the left anterior descendent and circumflex coronary arteries, which were narrowed or occluded with organizing thrombosis. Formation of granuloma with multinucleated giant cells was also observed in media of the circumflex artery. There was no microscopic evidence of atheroma formation in the coronary arteries. Of note, there was a follicle-like infiltration of CD45RO-positive T lymphocytes in interna of the left coronary arteries and the right renal artery. Although not frequently reported, coronary vasculitis as a cause of myocardial infarction should be considered in patients with RA. Moreover, our results suggest that infiltration of T lymphocytes might be involved in the development of rheumatoid vasculitis.

Aged↗
PubMed2003

Autoimmune hepatitis in a patient with systemic lupus erythematosus.

We report a female patient with systemic lupus erythematous (SLE), hyperbilirubinemia and high serum value of ALT. International autoimmune hepatitis (AIH) score showed definite AIH before treatment, but autoantibodies could not make a differential diagnosis of AIH and SLE-associated hepatitis. Liver biopsy showed periportal hepatitis with lymphoplasmacytic infiltration, but neither parenchymal collapse nor rosette formation could be found. Pericarditis, pleuritis and nephritis were improved as well as liver injury after administration of prednisolone, and no repeated attack has been present these 4 years. Our case suggested invalidity of AIH score among patients of SLE, and liver histology should be inferred most important at present to make a differential diagnosis of lupus hepatitis or AIH in patients with SLE.

Biopsy, Needle↗
PubMed2003

Differential regulation of Th1 responses and CD154 expression in human CD4+ T cells by IFN-alpha.

Like interleukin (IL)-12, interferon (IFN)-alpha has been shown to play an important role in inducing human Th1 responses. Recent studies have shown that human Th1 responses driven by IL-12 are associated with enhanced expression of CD154. The present study examined the effects of IFN-alpha on CD154 expression in human CD4+ T cells, with special attention to the relationship with Th1 responses. Highly purified CD4+ T cells from healthy donors were stimulated with immobilized anti-CD3 with or without IFN-alpha and IL-12 in the complete absence of accessory cells. IFN-alpha suppressed CD154 protein and mRNA expression in CD4+ T cells at the initial phase of activation with immobilized anti-CD3, but enhanced it in the subsequent maturation phase irrespective of the presence of IL-12. By contrast, IFN-alpha by itself did not enhance IFN-gamma production or mRNA expression in CD4+ T cells in the absence of IL-12 even in the presence of stimulation with anti-CD28, but enhanced it in the presence of IL-12. Accordingly, IFN-alpha enhanced IL-12Rbeta2 mRNA expression in anti-CD3-stimulated CD4+ T cells. Neither IFN-alpha nor IL-12 influenced the stability of CD154 mRNA in anti-CD3-activated CD4+ T cells. These results indicate that IFN-alpha by itself enhances CD154 expression in CD4+ T cells independently of the induction of IFN-gamma mRNA expression. The data also suggest that the optimal induction of human Th1 responses by IFN-alpha might require the presence of IL-12 and that the induction of Th1 responses and CD154 expression in human CD4+ T cells might be regulated through different mechanisms.

Adult↗
PubMed2003

Association of transporter associated with antigen processing genes with Behçet's disease in Japanese.

Contribution of transporter associated with antigen processing (TAP) genes to the pathogenesis of Behçet's disease (BD) was studied. Restriction fragment length polymorphic analysis of TAP genes was carried out in 46 Japanese patients with BD and 95 healthy subjects. There were no significant differences in allele frequencies of TAP1 and TAP2 genes between whole patients with BD and control population. No significant differences in the frequencies of TAP alleles were observed, when patients of BD with complete type or incomplete type were compared with control population, respectively. An allele frequency of TAP2C was, however, slightly but significantly high in patients with BD who had symptom of erythema nodosum (24.1%) as compared to the control group (11.6%). [p < .05, RR = 2.4]. The allele frequency of TAP2C was slightly high in HLA*B5101 positive patients with BD (28.6%) as compared to HLA*B5101 negative patients (10.9%), but the difference did not reach statistical significance. The absence of genotype TAP2B/C was observed in whole patients group, though it was present in control subjects (14.7%). [p = 0.003, RR = 0.06]. A genotype frequency of TAP2C/H was high in patients with BD who had symptom of skin lesions (7.5%) as compared to the control group (0.0%). [p = 0.03, RR = 15.4]. These results suggest the possibility that TAP molecule play some part in formation of skin lesion, such as erythema nodosum in BD in Japanese.

ATP-Binding Cassette Transporters↗
PubMed2001

Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter.

Because the apoptotic pathway is often disrupted in tumor cells, its genetic restoration is a very attractive approach for the treatment of tumors. To treat malignant gliomas with this approach, it would be preferred to restrict induction of apoptosis to tumor cells by establishing a tumor-specific expression system. Telomerase is an attractive target because the vast majority of malignant gliomas have telomerase activity whereas normal brain cells do not. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit [human telomerase reverse transcriptase, (hTERT)]. Therefore, we hypothesized that using a hTERT promoter-driven vector system, an apoptosis-inducible gene may be preferentially restricted to telomerase- or hTERT-positive tumor cells. In this study, we constructed an expression vector consisting of the constitutively active caspase-6 (rev-caspase-6) under the hTERT promoter (hTERT/rev-caspase-6) and then investigated its antitumor effect on malignant glioma cells. The rationale for using the rev-caspase-6 gene is because it induces apoptosis independent of the initiator caspases. We demonstrated that the hTERT/rev-caspase-6 construct induced apoptosis in hTERT-positive malignant glioma cells, but not in hTERT-negative astrocytes, fibroblasts, and alternative lengthening of telomeres cells. In addition, the growth of s.c. tumors in nude mice was significantly suppressed by the treatment with hTERT/rev-caspase-6 construct. The present results strongly suggest that the telomerase-specific transfer of the rev-caspase-6 gene under the hTERT promoter is a novel targeting approach for the treatment of malignant gliomas.

Animals↗
PubMed2001

Procollagen II amino propeptide processing by ADAMTS-3. Insights on dermatosparaxis.

The amino and carboxyl propeptides of procollagens I and II are removed by specific enzymes as a prerequisite for fibril assembly. Null mutations in procollagen I N-propeptidase (ADAMTS-2) cause dermatosparaxis in cattle and the Ehlers-Danlos syndrome (dermatosparactic type) in humans by preventing proteolytic excision of the N-propeptide of procollagen I. We have found that procollagen II is processed normally in dermatosparactic nasal cartilage, suggesting the existence of another N-propeptidase(s). We investigated such a role for ADAMTS-3 in Swarm rat chondrosarcoma RCS-LTC cells, which fail to process the procollagen II N-propeptide. Stable transfection of RCS-LTC cells with bovine ADAMTS-2 or human ADAMTS-3 partially rescued the processing defect, suggesting that ADAMTS-3 has procollagen II N-propeptidase activity. Human skin and skin fibroblasts showed 30-fold higher mRNA levels of ADAMTS-2 than ADAMTS-3, whereas ADAMTS-3 mRNA was 5-fold higher than ADAMTS-2 mRNA in human cartilage. We propose that both ADAMTS-2 and ADAMTS-3 process procollagen II, but ADAMTS-3 is physiologically more relevant, given its preferred expression in cartilage. The findings provide an explanation for the sparing of cartilage in dermatosparaxis and, perhaps, for the relative sparing of some procollagen I-containing tissues.

ADAM Proteins↗
PubMed2001

Systemic sclerosis complicated with nephrotic syndrome: relevance with antiribosomal P antibody.

The nephrotic syndrome is an extremely rare occurrence in systemic sclerosis (SSc). Here we describe a 39-year-old woman with SSc who developed the nephrotic syndrome along with the expression of antiribosomal P antibody but not of anti-double-stranded DNA antibody in her serum. Although a renal biopsy specimen showed minimal changes on light microscopy, immunofluorescence studies showed granular deposition of C3 and IgM in the glomeruli. The patient recovered from the nephrotic syndrome with the decrease in serum antiribosomal P antibody after the daily administration of 60 mg of prednisolone. It is strongly suggested that antiribosomal P antibody might have been involved in the development of the nephrotic syndrome in our patient.

Administration, Oral↗
PubMed2001

Increased expression of biglycan mRNA in pressure-overloaded rat heart.

Biglycan mRNA expression in rat myocardium after abdominal aortic banding with renal ischemia was examined. The Northern blot analysis demonstrated that expression of biglycan mRNA in the pressure-overloaded hearts on days 2, 7, 14 and 28 was 2.88 +/- 0.89, 2.32 +/- 0.49, 2.17 +/- 0.57 and 1.81 +/- 0.46-fold higher, respectively, than that in the sham-operated hearts. In situ hybridization showed an increased density of biglycan mRNA signal-positive cells in the pressure-overloaded hearts. The cells with positive signals were spindle-shaped mesenchymal cells in the myocardial interstitium. A marked increase in biglycan mRNA signal expression was also observed in endothelial cells and smooth muscle cells of the thickened myocardial capillary wall. These results demonstrated an increase in biglycan mRNA in the pressure-overloaded heart in mesenchymal cells in the myocardial interstitium, and in endothelial and smooth muscle cells of the capillaries, indicating that biglycan contributes to the ventricular and vascular remodeling in response to pressure overload.

Animals↗
PubMed2001

Antiribosomal P protein antibody in human systemic lupus erythematosus reacts specifically with activated T cells.

We examined the presence of the epitope recognized by antiribosomal P protein antibody (anti-P) on the cell surface of human immunocompetent cells. Highly purified CD4+ and CD8+ T cells, and B cells from normal healthy individuals were reacted with affinity-purified IgG anti-P, and were stained with FITC-conjugated F(ab)2, fragment goat anti-human IgG, followed by analysis on flow cytometry with gating for viable cells by propidium iodide staining. The presence of an epitope that is antigenically related to the carboxyl-terminal 22-amino-acid sequence of ribosomal P protein was not demonstrated on the surface of fresh CD4+ and CD8+ T cells, or fresh B cells. However, the expression of the ribosomal P epitope was induced on CD4+ and CD8+ T cells after activation with immobilized anti-CD3, whereas the epitope was not expressed on activated B cells. These results indicate that anti-P is an antilymphocyte antibody, which reacts specifically with activated T cells but not with resting T cells or B cells, suggesting possible direct effects of anti-P on the immune dysregulation in systemic lupus erythematosus.

Antibodies, Monoclonal↗
PubMed2001

Characterization of a protease responsible for truncated actin increase in neutrophils of patients with Behçet's disease.

As described previously (Yamashita S. et al., Biol. Pharm. Bull., 23, 519-522 (2000)), high levels of a truncated actin with an N-terminus of Met-44 were detected in neutrophils of patients with Behcet's disease. Since the increase of the truncated actin in neutrophils of patients may be important for understanding the pathology of Behçet's disease, the mechanism of the truncated actin formation was studied. First, to investigate the presence of a specific protease, which cleaves the actin at the site between Val-43 and Met-44, a peptide with a partial amino acid sequence of actin from the N-terminal Pro-38 to Asp-51 was synthesized as the protease substrate. The synthesized peptide was digested with cytosolic fractions of neutrophils from patients and healthy volunteers, and digestion products were analyzed by C18-reverse phase HPLC. The chromatograms of these samples showed that an endoprotease, which cleaved the peptide at a specific site, was present in cytosolic fractions of neutrophils from patients with Behçet's disease. Then, the effects of various kinds of protease inhibitors on the digestion of the peptide were investigated in order to identify the responsible endoprotease. The digestion of the peptide was suppressed by 4-(2-aminoethyl) benzenesulfonylfluoride (AEBSF, a serine protease inhibitor) and N-methoxysuccinyl-Ala-Ala-Pro-Val chloromethylketone (CMK, a polymorphonuclear (PMN)-elastase inhibitor) in the presence of EDTA. Furthermore, PMN-elastase was found to cleave the substrate peptide and actin at the site between Val-43 and Met-44. These results lead to the conclusion that the PMN-elastase is responsible for cleavage of actin at the N-terminal site between Val-43 and Met-44 in neutrophils from patients with Behçet's disease.

Actins↗
PubMed2001

Possible physiological roles of proteolytic products of actin in neutrophils of patients with Behçet's disease.

A truncated actin with an N-terminus of Met-44 is known to be selectively increased in neutrophils of patients with Behçet's disease and to be generated proteolytically by PMN-elastase (Yamashita S. et al., Biol. Pharm. Bull., 23, 519-522 (2000); Biol. Pharm. Bull., 24, 119-122 (2001)). In this study, the functions of the N-terminal peptide consisting of Asp-2 to Val-43 of beta-actin (42-merP) and the truncated actin with an N-terminus of Met-44 were examined. We first confirmed that the 42-merP existed in the patient plasma. The motility of human peripheral blood neutrophils and neutrophilic granulocytes differentiated from HL-60 cells was suppressed by the 42-merP. Furthermore, when neutrophil-like cells from HL-60 cells were preincubated with 10 nm 42-merP, migration of the cells induced by chemotactic factors such as fMLP and IL-8 was suppressed. The release of PMN-elastase, which is a neutrophil granular enzyme that is responsible for the production of the 42-merP and truncated actin, was suppressed by pretreating the neutrophils with 42-merP before fMLP-stimulation. The truncated actin was unable to polymerize in 0.1 M KCl, suggesting that the increase of truncated actin damages the reconstitution capacity of actin in neutrophils of the patients. These results suggest that the increase of 42-merP and truncated actin in patients with Behçet's disease changes functions of neutrophils

Actins↗
PubMed2001

A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter.

Telomerase activity has a close relationship with malignancies in many cell types and it is tightly regulated at the transcriptional level of human telomerase reverse transcriptase (hTERT). Utilizing the hTERT promoter, the authors developed a gene delivery system of Fas associated protein with death domain (FADD) (hTERT/FADD). FADD is a protein which plays an important role in the apoptotic pathway of Fas. Over-expression of FADD induces apoptosis in the cells regardless of Fas expression on the cell surface. We hypothesized that we might be able to restrict the expression of FADD in malignant glioma cells if we use the gene transfer system under the control of hTERT promoter. This study was designed to investigate whether the hTERT/FADD construct induces apoptosis effectively in malignant glioma cells while keeping normal cells intact. First, using the reverse transcription-polymerase chain reaction (RT-PCR) technique, we confirmed that hTERT mRNA was expressed in human malignant glioma cells (U373-MG, A172 and GB-1), but not in cultured astrocytes (TEN) or fibroblasts (MRC5). After transient transfection with the hTERT/FADD construct, a significant number of FADD-positive cells and apoptotic cells were detected in hTERT-positive malignant glioma cells. In contrast, hTERT-negative astrocytes and fibroblasts remained intact. Furthermore, subcutaneously implanted U373-MG tumors treated with the hTERT/FADD construct reduced in volume significantly compared to the conrol treatment (p=0.0001). Gene transfer of FADD under the control of the hTERT promoter may be a novel and promising therapy to kill hTERT-positive malignant glioma cells while sparing normal brain cells lacking hTERT.

Animals↗
PubMed2001

Induction of fibroblast-like cells from CD34(+) progenitor cells of the bone marrow in rheumatoid arthritis.

To assess the role of bone marrow in the pathogenesis of rheumatoid arthritis (RA), we examined the capacity of CD34(+) cells from bone marrow to generate fibroblast-like type B synoviocytes. CD34(+) cells from the bone marrow of 22 RA patients differentiated into cells with fibroblast-like morphology, which expressed prolyl 4-hydroxylase, in the presence of stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-alpha), much more effectively than CD34(+) cells from bone marrow of 15 control subjects (10 patients with osteoarthritis and 5 healthy individuals). The generation of fibroblast-like cells was not at all observed in cultures with SCF, GM-CSF, and interleukin 4 (IL-4) with or without TNF-alpha. Generation of fibroblast-like cells was correlated with matrix metalloproteinase (MMP)-1 levels in culture supernatants. Thus, MMP-1 levels were significantly higher in TNF-alpha-stimulated cultures of bone marrow CD34(+) cells from patients with RA than in those from the control group. These results indicate that bone marrow CD34(+) cells from patients with RA have abnormal capacities to respond to TNF-alpha and to differentiate into fibroblast-like cells producing MMP-1, suggesting that bone marrow CD34(+) progenitor cells might generate type B synoviocytes and thus could play an important role in the pathogenesis of RA.

Adult↗
PubMed2001

[Central nervous system involvement in Behçet's disease].

Central nervous system involvement in Behçet's disease, usually called neuro-Behçet's syndrome (NB), includes acute type and chronic progressive type. Acute NB is characterized by acute meningoencephalitis with focal lesions, presenting high intensity areas in T2-weightened images or FLAIR images on MRI scans. Cyclosporin A frequently causes acute NB. Acute NB responds to steroid therapy, and is usually self-limiting. By contrast, chronic progressive NB is characterized by intractable slowly progressive dementia, ataxia and dysarthria with persistent elevation of cerebrospinal fluid IL-6 activity (more than 20 pg/ml). In our series, most patients (approximately 90%) with chronic progressive NB were HLA-B51 positive, and had history of attacks of acute NB prior to the development of progressive neurological symptoms. Chronic progressive NB is resistant to conventional treatment with steroid, cyclophosphamide, or azathioprine. However, recent studies suggest the efficacy of low dose methotrexate in chronic progressive NB.

Acute Disease↗
PubMed2000

Cerebrospinal fluid beta(2)-microglobulin in neuro-Behçet's syndrome.

Paired serum and cerebrospinal fluid (CSF) specimens from 17 patients with Behçet's disease and central nervous system (CNS) involvement (neuro-Behçet's syndrome; NB) were studied for beta(2)-microglobulin (beta(2)MG) and albumin, using ELISA and single radial immunodiffusion, respectively. We also studied 29 patients with non-inflammatory neurological diseases for comparison. All of CSF beta(2)MG, serum beta(2)MG, Q albumin (an indicator of blood-brain barrier function), and CSF beta(2)MG index (an indicator of intrathecal beta(2)MG synthesis) were significantly elevated in patients with NB compared with the control patients. There were no significant differences in these parameters between 11 patients with chronic NB and six patients with acute NB. In nine patients with NB, CSF beta(2)MG and Q albumin were significantly decreased when the CNS manifestations were improved by successful treatment, whereas CSF beta(2)MG index and serum beta(2)MG were not significantly changed. The results indicate that the elevation of CSF beta(2)MG, which results from the transudation of serum beta(2)MG as well as the increased intrathecal synthesis presumably by infiltrating lymphocytes, is a good marker of CNS disease activity of NB. The data, however, also suggest that the intrathecal synthesis of beta(2)MG might not parallel to the CNS disease activity of NB, most likely due to the recovery of constitutive physiological intrathecal synthesis of beta(2)MG in spite of the withdrawal of pathological beta(2)MG synthesis at times of treatment-associated improvement.

Adult↗
PubMed2000

A novel telomerase-specific gene therapy: gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter.

Apoptosis is a genetically encoded cell death process and is a pathway that may be disrupted in tumor cells. Therefore, therapies that restore the ability to undergo apoptosis are promising for the treatment of tumor cells. We have demonstrated that the transfer of apoptosis-inducible genes inhibits the growth of tumors in vitro and in vivo through induction of apoptosis. However, to restrict induction of apoptosis to tumor cells, we need to explore a tumor-specific expression system of these genes. In the present study, we developed the telomerase-specific transfer system of apoptosis-inducible genes, utilizing the promoter of the human telomerase catalytic subunit (hTERT) gene. Approximately 90% of tumors have telomerase activity whereas most normal cells do not express the activity. These observations indicate that telomerase is a particularly attractive target for the tumor-specific expression system of vectors. We demonstrate here that by using the hTERT promoter-driven caspase-8 expression vector (hTERT/caspase-8), apoptosis is restricted to telomerase-positive tumor cells of wide range, and is not seen in normal fibroblast cells without telomerase activity. Furthermore, treatment of subcutaneous tumors in nude mice with the hTERT/caspase-8 construct inhibited tumor growth significantly because of induction of apoptosis (p < 0.01). The telomerase-specific expression of apoptosis-inducible genes afforded by the hTERT promoter, therefore, may be a novel and promising targeting approach for the treatment of tumors with telomerase activity.

Animals↗