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Hidekata Yasuoka

Publications and source records attributed to Hidekata Yasuoka.

16 recordsLinked to original sources
PubMed2006

Increase in circulating endothelial precursors by atorvastatin in patients with systemic sclerosis.

OBJECTIVE: To evaluate whether atorvastatin can increase bone marrow-derived circulating endothelial precursors (CEPs) and improve the vascular symptoms in patients with systemic sclerosis (SSc; scleroderma). METHODS: The study was designed as an open-label, prospective study involving 14 patients with SSc who received 10 mg/day of atorvastatin for 12 weeks and were followed up for the subsequent 4 weeks. CEPs were quantified at weeks 0 (pretreatment), 4, 8, 12 (during treatment), and 16 (posttreatment) by cell sorting followed by 3-color flow cytometry. Raynaud's phenomenon variables, global measures, and psychological scales as well as circulating angiogenic factors and endothelial activation/injury markers were serially assessed. The potential of CEPs to differentiate into mature endothelial cells was examined in cultures with angiogenic stimuli. RESULTS: None of the patients experienced an adverse event, but 1 dropped out because of an excessive decrease in serum total cholesterol. Atorvastatin treatment resulted in a 1.7- to 8.0-fold increase in CEPs from baseline levels (P < 0.0001), but the numbers returned to within baseline levels at posttreatment. However, 8 patients (62%) experienced a gradual decrease in the number of CEPs, even while taking atorvastatin. Variables indicating the extent of Raynaud's phenomenon improved significantly, and up-regulated levels of angiogenic factors and vascular endothelial activation/injury markers decreased significantly during atorvastatin treatment. These variables returned to within baseline levels after discontinuation of the drug. In contrast, atorvastatin failed to improve the in vitro maturation potential of CEPs. CONCLUSION: The results of this pilot study suggest that atorvastatin treatment can increase CEPs and may be effective in improving Raynaud's phenomenon, even in SSc patients who have CEP dysfunction intrinsically.

Adult↗
PubMed2006

Insulin-like growth factor binding protein 5 induces skin fibrosis: A novel murine model for dermal fibrosis.

OBJECTIVE: To determine the role of insulin-like growth factor binding protein 5 (IGFBP-5) in the development of skin fibrosis in vivo, by examining the effect of overexpression of IGFBP-5 in mouse skin. METHODS: Wild-type C57BL/6J mice were injected subcutaneously with replication-deficient serotype 5 adenovirus expressing human IGFBP-3 (Ad3), IGFBP-5 (Ad5), or no complementary DNA (cAd). Mice were killed 3, 8, or 22 days postinjection. The dermal thickness and dermal collagen bundle thickness in skin sections were measured. The deposition of collagen in the extracellular matrix (ECM) was quantified using the Sircol assay. Expression of proliferating cell nuclear antigen (PCNA) and fibronectin, as determined by immunohistochemical analysis, was used to evaluate fibroblast activation, and vimentin and alpha-smooth muscle actin (alpha-SMA) were used to evaluate the fibroblast phenotype. RESULTS: Adenovirally expressed IGFBP was detected in dermal fibroblasts, endothelial cells, epithelial cells, and muscle bundles in Ad3- and Ad5-injected mice. Increased collagen deposition, denser dermal connective tissue, and increased collagen bundle thickness were observed in IGFBP-5-overexpressing mice. Dermal thickness and collagen bundle thickness were significantly increased in Ad5-injected mice compared with cAd- and Ad3-injected mice. Treatment with Ad5 resulted in a dose-dependent increase in dermal and collagen bundle thickness. Increased deposition of collagen and fibronectin, increased numbers of PCNA-positive fibroblasts, as well as increased numbers of vimentin- and alpha-SMA-double-positive fibroblasts were detected in the dermis of IGFBP-5-overexpressing mouse skin. CONCLUSION: IGFBP-5 is a key mediator of fibrosis. IGFBP-5 mediates its profibrotic effects through fibroblast activation, increased ECM deposition, and myofibroblastic transformation of dermal fibroblasts. Overexpression of IGFBP-5 provides a novel model for studying the pathogenesis of skin fibrosis in systemic sclerosis.

Animals↗
PubMed2006

Insulin-like growth factor-binding protein-5 induces pulmonary fibrosis and triggers mononuclear cellular infiltration.

We have recently shown that insulin-like growth factor-binding protein (IGFBP)-5 is overexpressed in idiopathic pulmonary fibrosis lung tissues and increases collagen and fibronectin deposition. Here, we further examined the effect of IGFBP-5 in vivo by intratracheal administration of replication-deficient adenovirus expressing human IGFBP-5 (Ad5), IGFBP-3 (Ad3), or no cDNA (cAd) to wild-type mice. Increased cellular infiltration and extracellular matrix deposition were observed in mice after Ad5 administration compared with Ad3 and cAd. Mononuclear cell infiltration consisted predominantly of T lymphocytes at day 8. By day 14, the number of infiltrating T cells decreased, whereas that of B cells and monocytes/macrophages increased. IGFBP-5 also induced migration of peripheral blood mononuclear cells in vitro, suggesting that in vivo mononuclear cell infiltration may be the direct result of IGFBP-5 expression. alpha-Smooth muscle actin and Mucin-1 co-localized in cells of mice treated with Ad5, suggesting that IGFBP-5 induced epithelial-mesenchymal transition. In addition, exogenous IGFBP-5 induced alpha-smooth muscle actin expression in primary fibroblasts and epithelial-mesenchymal transition of pulmonary epithelial cells in vitro. In conclusion, our results suggest that overexpression of IGFBP-5 in mouse lung results in fibroblast activation, increased extracellular matrix deposition, and myofibroblastic changes. Thus, the IGFBP-5-induced fibrotic phenotype in vivo may represent a novel model to better understand the pathogenesis of fibrosis.

Animals↗
PubMed2005

Novel autoantibodies to a voltage-gated potassium channel Kv1.4 in a severe form of myasthenia gravis.

Sera from patients with myasthenia gravis (MG) were screened for autoantibodies to skeletal muscle-specific antigens by immunoprecipitation assay, using rhabdomyosarcoma and leukemia cell lines. Eleven of 61 MG sera immunoprecipitated a rhabdomyosarcoma-specific 70-kDa protein, which was identified as the voltage-gated K+ channel 1.4 (Kv1.4). This antibody specificity was not detected in 30 patients with polymyositis/dermatomyositis, 9 with thymoma alone, or 30 healthy controls. Clinical features associated with anti-Kv1.4 antibody included bulbar involvement, myasthenic crisis, thymoma, myocarditis, and QT prolongation on electrocardiogram. These findings suggest that anti-Kv1.4 antibody is a novel autoantibody associated with a severe MG subset and thymoma.

Adult↗
PubMed2005

Mortality in systemic sclerosis: an international meta-analysis of individual patient data.

PURPOSE: Studies on mortality associated with systemic sclerosis have been limited by small sample sizes. We aimed to obtain large-scale evidence on survival outcomes and predictors for this disease. METHODS: We performed a meta-analysis of individual patient data from cohorts recruited from seven medical centers in the United States, Europe, and Japan, using standardized definitions for disease subtype and organ system involvement. The primary outcome was all-cause mortality. Standardized mortality ratios and predictors of mortality were estimated. The main analysis was based only on patients enrolled at each center within 6 months of diagnosis (incident cases). RESULTS: Among 1645 incident cases, 578 deaths occurred over 11,521 person-years of follow-up. Standardized mortality ratios varied by cohort (1.5 to 7.2). In multivariate analyses that adjusted for age and sex, renal (hazard ratio [HR] = 1.9; 95% confidence interval [CI]: 1.4 to 2.5), cardiac (HR = 2.8; 95% CI: 2.1 to 3.8), and pulmonary (HR = 1.6; 95% CI: 1.3 to 2.2) involvement, and anti-topoisomerase I antibodies (HR = 1.3; 95% CI: 1.0 to 1.6), increased mortality risk. Renal, cardiac, and pulmonary involvement tended to occur together (P <0.001). For patients without adverse predictors for 3 years after enrollment, the subsequent risk of death was not significantly different from that for the general population in three cohorts, but was significantly increased in three cohorts that comprised mostly referred patients. Analyses that included all cases in each center (n = 3311; total follow-up: 19,990 person-years) yielded largely similar results. CONCLUSION: Systemic sclerosis confers a high mortality risk, but there is considerable heterogeneity across settings. Internal organ involvement and anti-topoisomerase I antibodies are important determinants of mortality.

Adult↗
PubMed2005

Cardiomyogenic potential of mesenchymal progenitors derived from human circulating CD14+ monocytes.

Previously, we reported a unique CD14+CD45+CD34+type I collagen+ cell fraction derived from human circulating CD14+ monocytes, named monocyte-derived mesenchymal progenitors (MOMPs). These primitive cells differentiate along mesenchymal lineages, including bone, cartilage, fat, and skeletal muscle. Here, we demonstrate that CD14+ monocytes generate MOMPs that differentiate into cardiomyocytes. MOMPs labeled with a fluorescent marker and co-cultivated with rat cardiomyocytes for 4 weeks expressed the cardiomyocyte-specific transcription factors Nkx2.5, GATA-4, eHAND, and MEF2 and the hematopoietic/monocytic markers CD45 and CD14 within 10 days and retained their proliferative capacity for up to 16 days. A subpopulation of MOMPs subsequently expressed the cardiomyocyte-specific markers micro-sarcomeric actinin, troponin I, and atrial natriuretic peptide on day 21. Furthermore, fluorescence-labeled, spontaneously beating cells that formed gap junctions with adjacent rat cardiomyocytes appeared in these cultures and these cells exhibited electrophysiological properties typical of ventricular myocytes. The co-cultivation of human MOMPs with rat GFP-tagged cardiomyocytes resulted in the generation of human cardiomyocytes lacking green fluorescent protein (GFP) staining, suggesting that our observations could not solely be explained by cell fusion. Our results demonstrate for the first time that human circulating CD14+ monocytes include progenitors capable of proliferating and differentiating along the cardiomyogenic lineage via their differentiation into MOMPs.

Animals↗
PubMed2005

Donor fibroblast chimerism in the pathogenic fibrotic lesion of human chronic graft-versus-host disease.

PURPOSE: Tissue atrophy and excessive fibrosis are prominent histologic features of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation, but the underlying mechanism remains unknown. The current study was undertaken to investigate whether the increase in fibroblasts at the site of pathogenic fibrosis originated from transplanted donor cells in patients with chronic GVHD. METHODS: Lacrimal gland biopsy specimens were obtained from nine patients with chronic GVHD. The male-specific sequences detected by fluorescein in situ hybridization (FISH) and in situ hybridization (ISH) were used as markers for the donor cells in seven female patients who had received a transplant from male donors. Primary fibroblast cultures were generated from lacrimal gland biopsy specimens and examined for mismatched genetic markers between recipients and donors. RESULTS: In lacrimal gland specimens obtained from seven female patients who received a sex-mismatched transplant, 13.4% to 26.7% of CD34+ fibroblasts that accumulated in the fibrotic lesion were donor derived, as determined by FISH for the Y-chromosome. The male-specific mRNA was also detected in the lacrimal gland fibroblasts by ISH. Primary lacrimal gland fibroblast cultures were generated from four patients with chronic GVHD and further examined for mismatched genetic markers between recipients and donors. As a result, the presence of donor origin of the fibroblasts was demonstrated by detecting the Y-chromosome sequence and donor-specific microsatellite genetic markers. CONCLUSIONS: These findings together indicate the chimeric status of accumulated CD34+ fibroblasts in the lacrimal gland of patients with chronic GVHD. Fibroblasts originating from circulating donor-derived precursors may participate in the excessive fibrosis in these patients.

Adult↗
PubMed2004

Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Behçet's disease.

OBJECTIVE: To detect and characterize the autoreactive CD8+ T cells to major histocompatibility complex class I chain-related gene A (MICA), a stress-inducible antigen preferentially expressed on the epithelium and endothelium, in patients with Behcet's disease (BD). METHODS: A candidate for the antigenic MICA peptide was selected based on its predicted binding affinity for HLA-B51 and proteasomal cleavage sites. Peripheral blood T cells from 14 patients with BD and 15 healthy controls were repeatedly stimulated with the MICA peptide, and the specific T cell response was measured by peptide-induced interferon-gamma. Cytotoxic T lymphocyte activity was examined by chromium-51 release from an HLA-B51-transfected B cell line in the presence of the MICA peptide. RESULTS: A 9-mer peptide AAAAAIFVI (termed MICA transmembrane [MICA-TM]) was selected as a candidate for the antigenic peptide presented by HLA-B51. A specific T cell response to MICA-TM was detected in 4 patients with BD (29%) but in none of the 15 healthy donors. All 4 responders had HLA-B51 and active disease, and the specific T cell response was lost after the BD-related symptoms disappeared. The MICA-induced T cell response was specifically inhibited by anti-HLA class I antibody or by CD8+ cell depletion. MICA-reactive T cells recognized an HLA-B51-transfected B cell line pulsed with MICA-TM or a B cell line transfected with both HLA-B51 and MICA in the absence of exogenous peptides. Finally, MICA-stimulated T cell lines lysed the HLA-B51-expressing B cell line in the presence of MICA-TM. CONCLUSION: HLA-B51-restricted cytotoxic T lymphocytes autoreactive to MICA may be involved in the pathogenesis of BD.

Autoimmunity↗
PubMed2004

Single nucleotide polymorphisms of the inflammatory cytokine genes in adults with chronic immune thrombocytopenic purpura.

Single nucleotide polymorphisms (SNPs) of inflammatory cytokine genes were examined in 84 adult Japanese patients with chronic immune thrombocytopenic purpura (ITP) and 56 race-matched healthy controls. The SNPs examined were within the genes encoding tumour necrosis factor (TNF)-alpha (-238 G/A and -308 G/A), TNF-beta (+252 G/A), and interleukin (IL)-1beta (-511 C/T and +3953 T/C). Of these SNPs, the frequency of the TNF-beta (+252) G/G phenotype was significantly higher in ITP patients than in healthy controls (21% vs. 7%, P = 0.04, odds ratio = 3.6, 95% confidence interval 1.1-11.1), while no significant association was detected for the other SNPs. The distribution of the TNF-beta (+252) phenotype was not associated with human leucocyte antigen class II alleles or the therapeutic response in ITP patients. The frequency of circulating anti-glycoprotein IIb/IIIa antibody-producing B cells was significantly higher in ITP patients with the TNF-beta (+252) G/G phenotype than in those with the G/A or A/A phenotype (11.9 +/- 4.9 vs. 6.8 +/- 4.9 and 3.7 +/- 2.8 per 10(5) peripheral blood mononuclear cells; P = 0.02 and P < 0.001, respectively). These findings suggest that the SNP located at TNF-beta (+252) contributes to susceptibility to chronic ITP by controlling the autoreactive B-cell responses to platelet membrane glycoproteins.

Adult↗
PubMed2004

[A case of mixed connective tissue disease successfully treated for hemophagocytic syndrome with intermittent intravenous injection of cyclophosphamide].

A 52 year-old woman noticed general fatigue, polyarthralgia, and muscle weakness of lower extremities in October 2001. In December, she felt difficulty in walking due to muscle weakness. In January 2002, she admitted another hospital because of dyspnea on exertion and edema of lower extremities. Laboratory test revealed leukocytopenia, the elevation of creatine kinase and positive anti-U1-RNP antibodies. Her chest computed tomography (CT) showed severe interstitial pneumonia. Cardiac echogram revealed that she had pericardial effusion and pulmonary hypertension. Then she was transferred to Keio University Hospital and she was diagnosed as having mixed connective tissue disease (MCTD) manifestating myositis, interstitial pneumonia, pulmonary hypertension and pericarditis. Prednisolone (PSL) 60mg daily following to methylprednisolone (mPSL) pulse therapy was begun and her symptoms were gradually improved. In middle of February, she complained of high fever over 39.0 degrees C. Bacterial culture tests were negative and laboratory data indicated pancytopenia and a high level of serum ferritin. Bone marrow aspiration revealed hemophagocytosis in bone marrow specimens and she was diagnosed as having hemophagocytic syndrome associated with MCTD. mPSL pulse therapy was not effective and intermittent cyclophosphamide pulse therapy (IV-CY) was performed resulting in improvement of the symptoms. This case suggested the effectiveness of IV-CY therapy in patients with corticosteroid-resistant HPS associated with connective tissue diseases.

Cyclophosphamide↗
PubMed2003

A novel protein highly expressed in testis is overexpressed in systemic sclerosis fibroblasts and targeted by autoantibodies.

Nearly all autoantibody specificities in sera from patients with systemic sclerosis (SSc) target proteins distributed ubiquitously, and Abs against proteins whose expression is restricted to the affected sites have not been identified. In this study we describe SSc-specific autoantibody to a novel testicular Ag, termed protein highly expressed in testis (PHET), which is ectopically overexpressed in SSc dermal fibroblasts. A partial cDNA encoding PHET was isolated by immunoscreening of a HepG2 cDNA library with an SSc serum. PHET appeared to be a member of the UniGene cluster Hs.129872, but had a unique exon composition and a characteristic mRNA expression profile restricted to the testis. Serum Abs to a recombinant PHET fragment were detected in nine (8.4%) of 107 SSc patients, but in none of 50 systemic lupus erythematosus patients or 77 healthy controls. In SSc patients, the presence of anti-PHET Abs was associated with diffuse cutaneous SSc and lung involvement (p = 0.02 and 0.01, respectively). PCR-based quantitative analysis of PHET mRNA expression in cultured dermal fibroblasts showed increased expression of PHET mRNA in SSc fibroblasts compared with control fibroblasts. PHET-reactive Abs purified from SSc sera stained the cytoplasm of SSc dermal fibroblasts, and the staining intensity tended to be more prominent on SSc compared with control fibroblasts. These findings suggest that the autoantibody response to PHET can be induced by ectopic overexpression of PHET in dermal fibroblasts in SSc patients.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiation.

Circulating CD14+ monocytes are precursors of phagocytes, such as macrophages and dendritic cells. Here we report primitive cells with a fibroblast-like morphology derived from human peripheral blood CD14+ monocytes that can differentiate into several distinct mesenchymal cell lineages. We named this cell population monocyte-derived mesenchymal progenitor (MOMP). MOMPs were obtained in vitro from human peripheral blood mononuclear cells cultured on fibronectin in the presence of fetal bovine serum alone as a source of growth factors. MOMPs had a unique molecular phenotype-CD14+CD45+CD34+type I collagen+-and showed mixed morphologic and molecular features of monocytes and endothelial and mesenchymal cells. MOMPs were found to be derived from a subset of circulating CD14+ monocytes, and their differentiation required that they bind fibronectin and be exposed to one or more soluble factors derived from peripheral blood CD14- cells. MOMPs could be expanded in culture without losing their original phenotype for up to five passages. The induction of MOMPs to differentiate along multiple limb-bud mesodermal lineages resulted in the expression of genes and proteins specific for osteoblasts, skeletal myoblasts, chondrocytes, and adipocytes. Our findings represent the first evidence that human circulating CD14+ monocytes are a source of progenitors that exhibit mesenchymal cell differentiation.

Alkaline Phosphatase↗
PubMed2003

Autoreactive T cells to the P3A+ isoform of AChR alpha subunit in myasthenia gravis.

In vitro T cell proliferative response to an alternative splicing variant of acetylcholine receptor alpha subunit (AChR alpha) with the P3A exon-encoded region was examined in peripheral blood samples from 28 myasthenia gravis (MG) patients and 14 healthy donors using recombinant fragments and synthetic peptides. T cells responsive to the P3A region-specific sequences were detected in five MG patients, all of whom were late-onset disease with thymoma, but in none of healthy donors. These autoreactive T cells may be involved in the pathogenic process in a subset of MG patients.

Adult↗
PubMed2003

Effect of intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis in Japanese patients with connective tissue disease: 3 year followup.

OBJECTIVE: A 3 year prospective randomized study was conducted to clarify the efficacy of intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis. METHODS: A group of 102 Japanese patients were enrolled, each taking > 7.5 mg of prednisolone daily for at least 90 days. Patients were randomly divided into 2 treatment groups: Group E (etidronate) took 200 mg etidronate disodium per day for 2 weeks with 3.0 g calcium lactate and 0.75 microg alphacalcidol daily; Group C (control) took 3.0 g calcium lactate and 0.75 microg alphacalcidol daily. Outcome measurements included changes from baseline in bone mineral density (BMD) of the lumbar spine and the rate of new vertebral fractures at 48 and 144 weeks. RESULTS: The mean (+/- SD) lumbar spine BMD increased 3.7 +/- 5.6% (p < 0.01) and 1.5 +/- 4.1% (NS) from baseline at 48 weeks and 4.8 +/- 6.9% (p < 0.005) and 0.4 +/- 5.0% (NS) from baseline at 144 weeks in Group E and Group C, respectively. The improvement of BMD in Group E was significantly greater than in Group C at 144 weeks (p < 0.01). In 3 subgroups, men and premenopausal and postmenopausal women, the postmenopausal women showed the greatest improvement. Mean percentage change in this subgroup was 10.1 +/- 8.0% and 1.35 +/- 6.4% in Group E and Group C, respectively. We noted that 2 patients in Group C had new vertebral fractures, whereas no fractures were observed in Group E. CONCLUSION: These results indicate that intermittent cyclical etidronate therapy is effective for the prevention and treatment of corticosteroid induced osteoporosis in patients with connective tissue diseases.

Adult↗
PubMedDate not supplied

Defective vasculogenesis in systemic sclerosis.

BACKGROUND: Typical vascular features of systemic sclerosis include low capillary density and vascular obliteration. The formation and repair of blood vessels in adults involve vasculogenesis, which is mediated through the recruitment of bone-marrow-derived circulating endothelial precursors (CEP). We investigated whether vasculogenesis is impaired in patients with systemic sclerosis. METHODS: Peripheral blood was obtained from 11 patients with systemic sclerosis, 11 with rheumatoid arthritis, and 11 healthy controls. Factors potentially affecting the CEP number were matched among the three groups. CEP (identified as circulating cells positive for CD34, CD133, and the type 2 receptor for vascular endothelial growth factor) were quantified by cell sorting and three-colour flow cytometry. The circulating concentrations of angiogenic factors were measured by ELISA. The potential of CEP to differentiate into endothelial cells was assessed by the upregulation of von Willebrand factor after in-vitro maturation treatment. Findings The absolute number of CEP was much lower in patients with systemic sclerosis than in patients with rheumatoid arthritis or healthy controls (median 274 [IQR 178-395] vs 1154 [653-1524] and 1074 [713-1186] per 20 mL peripheral blood, respectively; p<0.0001 by Kruskal-Wallis test. Paradoxically, circulating concentrations of most angiogenic factors were significantly higher in patients with systemic sclerosis than in healthy controls. The proportion of CEP that differentiated into endothelial cells was significantly lower in patients with systemic sclerosis than in healthy controls (p<0.0001, Mann-Whitney test). INTERPRETATION: Insufficient vascular repair machinery due to defective vasculogenesis might contribute to vasculopathy in systemic sclerosis. RELEVANCE TO PRACTICE: As well as providing an important insight into the pathogenesis of this disorder, these findings suggest that dysregulated vasculogenesis might be important in other disorders with abnormalities in vascular formation, including those with excessive formation of new vessels such as cancer and those with deficient vessel formation such as atherosclerosis. Circulating endothelial precursors could be a novel target for therapeutic strategies for ischaemic complications in patients with systemic sclerosis.

AC133 Antigen↗