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Masataka Kuwana

Publications and source records attributed to Masataka Kuwana.

At least 19 recordsLinked to original sources
PubMed2007

Evaluation of platelet kinetics in patients with liver cirrhosis: similarity to idiopathic thrombocytopenic purpura.

BACKGROUND: Thrombocytopenia is a common manifestation of liver cirrhosis (LC), but its underlying mechanism is not fully understood. The purpose of the present paper was to evaluate the platelet kinetics in LC patients by examining several non-invasive convenient markers. METHODS: Fifty-seven LC patients, 32 patients with idiopathic thrombocytopenic purpura (ITP), 12 with aplastic anemia (AA), and 29 healthy individuals were studied. Plasma thrombopoietin was measured by enzyme-linked immunosorbent assay. Absolute reticulated platelet (RP) count and plasma glycocalicin were used as indices for thrombopoiesis, and the indices for platelet turnover were the RP proportion and the plasma glycocalicin normalized to the individual platelet count (GCI). RESULTS: There was no difference in thrombopoietin levels between LC patients and healthy controls. The RP proportion and GCI were significantly higher and the absolute RP count and glycocalicin significantly lower in LC patients than in healthy controls. These markers in ITP and LC patients were comparable, but significantly different from those in AA patients. The bone marrow megakaryocyte density in LC and ITP patients was similar, and significantly higher than in AA patients. CONCLUSIONS: Cirrhotic thrombocytopenia is a multifactorial condition involving accelerated platelet turnover and moderately impaired thrombopoiesis. Thrombopoietin deficiency is unlikely to be the primary contributor to cirrhotic thrombocytopenia.

Aged↗
PubMed2006

Effects of a Helicobacter pylori eradication regimen on anti-platelet autoantibody response in infected and uninfected patients with idiopathic thrombocytopenic purpura.

Thirty-seven patients with idiopathic thrombocytopenic purpura (ITP) were treated with a standard Helicobacter pylori eradication regimen irrespective of H. pylori infection. Our results indicate that platelet recovery results from the disappearance of H. pylori itself, and is mediated, in part, through suppression of anti-platelet autoantibody production.

Adult↗
PubMed2006

T helper type 2-biased natural killer cell phenotype in patients with pemphigus vulgaris.

Pemphigus vulgaris (PV) is an autoantibody-mediated bullous disease, but the role of natural killer (NK) cells in its pathogenic process has never been examined in detail. Circulating CD56+ CD3- NK cells as well as CD69+-activated NK cells were increased in PV patients compared with healthy controls and patients with other autoantibody-mediated autoimmune diseases, including immune thrombocytopenic purpura and myasthenia gravis. Gene expression analysis of highly purified NK cells demonstrated an increased expression of IL-10 and decreased expression of IL-12Rbeta2, perforin, and granzyme B ex vivo in PV patients versus healthy controls. The NK cells from PV patients also showed impaired signal transducer and activator of transduction4 phosphorylation upon in vitro IL-12 stimulation. Moreover, NK cells from PV patients exhibited reduced IL-10 production in response to in vitro stimulation with IL-2/IL-12. Finally, IL-5 expression in NK cells was exclusively detected ex vivo in PV patients with active disease, and was lost in subsequent analyses performed during disease remission. Together these findings suggest that NK cells contribute to a T helper type 2-biased immune response in PV patients through impaired IL-12 signaling and an upregulation of IL-10 and IL-5.

Adult↗
PubMed2006

Endothelial differentiation potential of human monocyte-derived multipotential cells.

We previously reported a unique CD14(+)CD45(+)CD34(+) type I collagen(+) cell fraction derived from human circulating CD14(+) monocytes, named monocyte-derived multipotential cells (MOMCs). This primitive cell population contains progenitors capable of differentiating along the mesenchymal and neuronal lineages. Here, we investigated whether MOMCs can also differentiate along the endothelial lineage. MOMCs treated with angiogenic growth factors for 7 days changed morphologically and adopted a caudate appearance with rod-shaped microtubulated structures resembling Weibel-Palade bodies. Almost every cell expressed CD31, CD144, vascular endothelial growth factor (VEGF) type 1 and 2 receptors, Tie-2, von Willebrand factor (vWF), endothelial nitric-oxide synthase, and CD146, but CD14/CD45 expression was markedly downregulated. Under these culture conditions, the MOMCs continued to proliferate for up to 7 days. Functional characteristics, including vWF release upon histamine stimulation and upregulated expression of VEGF and VEGF type 1 receptor in response to hypoxia, were indistinguishable between the MOMC-derived endothelial-like cells and cultured mature endothelial cells. The MOMCs responded to angiogenic stimuli and promoted the formation of mature endothelial cell tubules in Matrigel cultures. Finally, in xenogenic transplantation studies using a severe combined immunodeficient mouse model, syngeneic colon carcinoma cells were injected subcutaneously with or without human MOMCs. Cotransplantation of the MOMCs promoted the formation of blood vessels, and more than 40% of the tumor vessel sections incorporated human endothelial cells derived from MOMCs. These findings indicate that human MOMCs can proliferate and differentiate along the endothelial lineage in a specific permissive environment and thus represent an autologous transplantable cell source for therapeutic neovasculogenesis.

Animals↗
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

Altered peptide ligands control type II collagen-reactive T cells from rheumatoid arthritis patients.

We previously reported that peripheral blood mononuclear cells from HLA-DRB1*0101 Japanese patients with rheumatoid arthritis (RA) were highly reactive to 256-271 peptide of type II collagen (CII). In this report, we tried to regulate the CII reactivity of T cells from RA patients with HLA-DRB1*0101 by altered peptide ligand (APL), which is a single amino acid substitution of the T-cell epitope on CII 256-271 peptide. Antagonistic activity of 21 APLs was assessed using three different T-cell lines. Results showed that 262 (G-->A) APL of CII 256-271 exhibited antagonistic activity in all T-cell lines and it was suggested that the application of CII APL might be a new therapeutic strategy in the regulation of RA.

Amino Acid Sequence↗
PubMed2006

Potential benefit of statins for vascular disease in systemic sclerosis.

PURPOSE OF REVIEW: Microvascular abnormality is a dominant feature of systemic sclerosis. There is increasing evidence that statins, developed as lipid-lowering drugs, yield profound benefits beyond their lipid-lowering effects. These 'pleiotropic' effects suggest that statins may be beneficial for treating SSc vasculopathy. This review focuses on the action of statins on endothelial functions and their potential use in treating SSc. RECENT FINDINGS: The initial event in the pathogenesis of vascular involvement in SSc has been thought to be endothelial injury, but recent studies have led to another theory--that insufficient vascular repair due to defective vasculogenesis contributes to this process. Statins inhibit cholesterol synthesis, but they also suppress the synthesis of other lipid intermediates, resulting in protection of the endothelium through improvements in endothelial function, mobilization of endothelial precursors, suppression of the inflammatory response, and inhibition of fibrosis. Only a few studies evaluating the clinical benefits of statins have been conducted in SSc patients to date, but one open-label study showed that statins might be effective in improving vascular symptoms. SUMMARY: Statins display numerous effects that may be of potential benefit in preventing endothelial dysfunction in SSc patients. Further clinical trials of statins in SSc patients are warranted.

Blood Vessels↗
PubMed2006

Neurogenic potential of progenitors derived from human circulating CD14+ monocytes.

We previously reported a primitive cell fraction derived from human circulating CD14+ monocytes, named monocyte-derived multipotential cells (MOMC), that can differentiate along mesenchymal lineages, including bone, cartilage, fat, skeletal muscle and cardiac muscle. In this study, we investigated whether MOMC can differentiate into the neuronal lineage. MOMC were fluorescently labelled and cocultivated with a primary culture of rat neurons for up to 4 weeks. The protein and gene expressions of neuron-specific markers in the human MOMC were evaluated over time using immunohistochemistry, in situ hybridization and reverse transcription followed by PCR. Shortly after cocultivation with rat neurons, nearly all the MOMC expressed early neuroectodermal markers, Mash1, Neurogenin2 and NeuroD, together with nestin, an intermediate filament expressed in neurogenesis. After 14 days of coculture, a subpopulation of MOMC displayed a multipolar morphology with elongated neurites and expressed mature neuron-specific markers, including neurofilament, microtubule-associated protein type 2, beta3-tubulin, NeuN and Hu. Transdifferentiation of monocytes into the neuroectodermal lineage was shown by the simultaneous expression of proneural markers and CD45/CD14 early in the differentiation process. The cocultivated MOMC retained their proliferative capacity for at least 16 days. Finally, the neuronal differentiation of MOMC was observed when they were cultured with neurons without cell-to-cell contact. The capacity of MOMC to differentiate into both mesodermal and neuroectodermal lineages suggests that circulating CD14+ monocytes are more multipotential than previously thought.

Animals↗
PubMed2006

Helicobacter pylori and immune thrombocytopenic purpura: unsolved questions and controversies.

Immune thrombocytopenic purpura (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies. Recent accumulating evidence indicates that eradication of Helicobacter pylori (H pylori) is effective in increasing platelet count in nearly half of ITP patients infected with this bacterium. The H pylori eradication therapy for adult ITP is becoming very popular in Japan and is now chosen as an initial treatment in H pylori-infected patients. The lack of efficacy of the H pylori eradication regimen in H pylori-negative ITP patients clearly indicates that platelet recovery results from the disappearance of H pylori itself. Despite extensive efforts, clinical features characteristic to H pylori-related ITP and factors predicting the response after the H pylori eradication therapy have not been identified. Great variability in the efficacy of the H pylori eradication therapy in ITP patients exists among countries: a higher response rate has been found in Japan and Italy than in the United States and non-Italian European countries. Some children infected with H pylori show the platelet response after successful eradication of H pylori, but the H pylori eradication therapy is ineffective in patients with secondary ITP. The pathogenesis of ITP associated with H pylori remains obscure; the mechanisms are not simple and may involve multiple steps, including cross-reactivity between H pylori antigen and platelets, and suppression of the reticuloendothelial system. Further studies to evaluate the mechanisms responsible for the platelet response in ITP patients after successful eradication of H pylori may be useful in clarifying the pathogenesis of ITP and developing new therapeutic strategies for ITP.

Anti-Bacterial Agents↗
PubMed2006

[A case of Good syndrome accompanied by myasthenia gravis: immunological evaluations].

Good syndrome, characterized by both thymoma and hypogammaglobulinemia, is a rare immunodeficient disorder. We experienced a case of Good syndrome accompanied by myasthenia gravis (MG). A 58-year-old man was admitted to our hospital because of muscle weakness and fatigability. Based on the presence of anti-acetylcholine receptor (AChR) antibody and thymoma, he was diagnosed as having MG. Peripheral blood lymphocyte count was normal, but gammaglobulin levels were markedly decreased (IgG 283 mg/dl, IgA 17 mg/dl, IgM 1 mg/dl). Clinical remission of MG was achieved by thymectomy followed by high-dose corticosteroids. Despite monthly intravenous immunoglobulin supplementation, he suffered from repeated respiratory tract infections and candidiasis. Body CT revealed adrenal tumor and pancreatic cancer with liver metastasis, and he died of bacterial pneumonia. Immunological evaluations showed complete lack of CD19+ B cell in the peripheral blood and responses of peripheral blood mononuclear cells to mitogens. Peripheral blood T cells responded to a suboptimal concentration of a recombinant AChR fragment: this pattern of AChR-induced T cell response was typical of MG patients. We failed to detect IgG autoantibodies reactive with B cells in his serum. Patients with Good syndrome represent imbalance of immune responses, leading to both immunodeficiency and autoimmunity.

Agammaglobulinemia↗
PubMed2005

Immune responses to DNA mismatch repair enzymes hMSH2 and hPMS1 in patients with pancreatic cancer, dermatomyositis and polymyositis.

To identify tumor antigens useful for diagnosis and immunotherapy of patients with pancreatic ductal adenocarcinoma, we applied a SEREX approach with a cDNA library made from 5 pancreatic cancer cell lines and sera obtained from 8 patients with pancreatic cancer, and isolated total 32 genes, including 14 previously characterized genes and 18 genes with unknown functions. Among these isolated antigens, serum IgG antibodies for 2 isolated DNA mismatch repair enzymes, Homo sapiens mutS homolog 2 (hMSH2) and Homo sapiens postmeiotic segregation increased 1 (hPMS1), were detected in patients with pancreatic ductal adenocarcinoma and dermatomyositis (DM), and polymyositis (PM), but not in sera from healthy individuals. Immunohistochemical study demonstrated that hMSH2 and hPMS1 were over-expressed in pancreatic ductal adenocarcinoma compared to normal pancreatic ducts. These results suggested that hMSH2 and hPMS1 may be useful as CD4+ helper T cell antigens for immunotherapy of pancreatic cancer patients and that serum IgG antibodies may be useful for diagnosis of patients with pancreatic ductal adenocarcinoma and DM/PM.

Adenocarcinoma↗
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

Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis.

OBJECTIVE: To identify novel autoantibodies specific for dermatomyositis (DM), especially those specific for clinically amyopathic DM (C-ADM). METHODS: Autoantibodies were analyzed by immunoprecipitation in 298 serum samples from patients with various connective tissue diseases (CTDs) or idiopathic pulmonary fibrosis (IPF). Antigen specificity of the sera was further examined by immunoblotting and indirect immunofluorescence (IF). The disease specificity and clinical features associated with the antibody of interest were determined. RESULTS: Eight sera recognized a polypeptide of approximately 140 kd (CADM-140 autoantigen) by immunoprecipitation and immunoblotting. Immunoreactivity was detected in the cytoplasm, and indirect IF revealed a granular or reticular pattern. Anti-CADM-140 antibodies were detected in 8 of 42 patients with DM, but not in patients with other CTDs or IPF. Interestingly, all 8 patients with anti-CADM-140 antibodies had C-ADM. Among 42 patients with DM, those with anti-CADM-140 autoantibodies had significantly more rapidly progressive interstitial lung disease (ILD) when compared with patients without anti-CADM-140 autoantibodies (50% versus 6%; P = 0.008). CONCLUSION: These results indicate that the presence of anti-CADM-140 autoantibodies may be a novel marker for C-ADM. Further attention should be directed to the detection of rapidly progressive ILD in those patients with anti-CADM-140 autoantibodies.

Adult↗
PubMed2005

Enzyme-linked immunosorbent assay for detection of anti-RNA polymerase III antibody: analytical accuracy and clinical associations in systemic sclerosis.

OBJECTIVE: We have recently developed an enzyme-linked immunosorbent assay (ELISA) for detection of anti-RNA polymerase III (anti-RNAP III) antibody, using a recombinant fragment containing the immunodominant epitope as the antigen source. This study was conducted to assess the analytical accuracy and clinical associations of the anti-RNAP III ELISA in patients with systemic sclerosis (SSc). METHODS: To evaluate analytical sensitivity and specificity of the ELISA, both immunoprecipitation tests and ELISA were used to detect anti-RNAP III antibody in 534 SSc sera from patients at 3 medical centers. Sera from 522 SSc patients and 516 controls, including patients with other connective tissue diseases and blood bank donors, were also evaluated to assess the clinical sensitivity and specificity of the ELISA. Clinical findings in anti-RNAP III antibody-positive SSc patients were compared between patient groups stratified according to anti-RNAP III antibody levels determined by the ELISA. RESULTS: In SSc patients, our ELISA showed analytical sensitivity of 91% and analytical specificity of 99% compared with the immunoprecipitation assay (a gold standard for detection of anti-RNAP III antibody). The additional analysis using a large series of SSc and control sera showed that clinical sensitivity and specificity of the ELISA with respect to the diagnosis of SSc were 17% and 98%, respectively. A high level of anti-RNAP III antibody was associated with diffuse cutaneous SSc, higher maximum total skin score, and increased frequency of tendon friction rubs. CONCLUSION: The anti-RNAP III ELISA is analytically accurate and clinically specific. With this assay, testing for anti-RNAP III antibody can be made routinely available.

Antibodies, Antinuclear↗
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

Initial laboratory findings useful for predicting the diagnosis of idiopathic thrombocytopenic purpura.

PURPOSE: To identify initial laboratory findings useful for the later diagnosis of idiopathic thrombocytopenic purpura (ITP) in adult patients with thrombocytopenia. SUBJECTS AND METHODS: We studied 62 consecutive adult patients who had thrombocytopenia and whose peripheral blood film was normal except for thrombocytopenia at presentation. Each patient underwent physical examination and routine laboratory tests and was prospectively followed for 22.5 +/- 9.8 months (range, 8 to 41 months). The frequency of antiglycoprotein (GP) IIb/IIIa antibody-producing B cells, the presence of platelet-associated and plasma anti-GPIIb/IIIa antibodies, the percentage of reticulated platelets, and the plasma thrombopoietin level were examined at the first visit. The final diagnosis was based on the clinical history, physical examination, complete blood test, bone marrow findings, and the clinical course at last observation. RESULTS: Forty-six patients were diagnosed as having ITP and 16 as having another disorder, including myelodysplastic syndrome, aplastic anemia, amegakaryocytic thrombocytopenia, and reduced platelet production, with or without other cytopenias, and without dysplasia or evidence for destruction. Six initial laboratory findings discriminated ITP from other diagnoses: the absence of anemia, absence of leukocytopenia, increased frequency of anti-GPIIb/IIIa antibody-producing B cells, increased platelet-associated anti-GPIIb/IIIa antibodies, elevated percentage of reticulated platelets, and a normal or slightly increased plasma thrombopoietin level. Three or more of these ITP-associated findings were found at presentation in 44 patients (96%) with thrombocytopenia later diagnosed as ITP, compared with only 1 patient (6%) whose disorder was non-ITP. CONCLUSION: Initial laboratory findings can well predict future diagnosis of ITP. Further studies prospectively evaluating these same diagnostic criteria on another, independent set of patients are necessary.

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↗