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Biomedical subjects

Kimiyoshi Arimura

Publications and source records attributed to Kimiyoshi Arimura.

At least 19 recordsLinked to original sources
PubMed2006

Serum VEGF--as a prognostic factor of atherosclerosis.

Vascular endothelial growth factor (VEGF) has been noted in the pathogenesis of atherosclerosis. To examine the usefulness of the serum concentration of VEGF as an index of atherosclerosis, we analyzed the serum VEGF concentrations in 443 adults who underwent a medical checkup. The mean serum VEGF concentration of men (229+/-147 pg/ml) was significantly higher than that of women (182+/-112 pg/ml). The platelet count showed a slight correlation with the serum VEGF concentration in both genders (men R=0.287, women R=0.296), corresponding with the results of experiments that platelets are the major source of VEGF in circulating peripheral blood. In men, the serum VEGF concentrations correlated with platelet counts, body fat percentages, leukocyte counts, and HDL-cholesterol concentrations (negative correlation). In the multiple regression analysis performed for men's serum VEGF concentrations, the decision coefficient (R2) was maximized (R2=0.173) when the leukocyte count, the body fat percentage, and the HDL-cholesterol concentration were taken into account besides the platelet count. Male smokers' serum VEGF concentrations were higher than non-smokers'. Smoking in men significantly affected the sex difference in the serum VEGF concentration, leukocyte count, and HDL-cholesterol concentration. We concluded that the serum VEGF concentration might be closely related to atherosclerosis accelerating factor, especially in men.

Adult↗
PubMed2006

Voltage-gated potassium channel antibodies associated limbic encephalitis in a patient with invasive thymoma.

Recently, limbic encephalitis (LE) associated with Voltage-gated potassium channel antibody (VGKC-Ab) has been postulated as a new autoimmune disorder. Most previously reported cases of VGKC-Ab-associated LE were non-paraneoplastic, and reports of a paraneoplastic type are rare. Here we describe a 59-year-old woman with paraneoplastic VGKC-Ab-associated LE preceding the recurrence of invasive thymoma. There was a close temporal relationship between the clinical course and the changes of the VGKC-Ab titer. Unlike many of the non-paraneoplastic VGKC-Ab-associated LE cases, our cases showed the more extensive high intensity lesions on MRI and the absence of seizure and hyponatremia.

Autoantibodies↗
PubMed2006

Discoidin domain receptor 1 contributes to eosinophil survival in an NF-kappaB-dependent manner in Churg-Strauss syndrome.

Churg-Strauss syndrome (CSS) is a systemic disease that shows marked eosinophilia along with eosinophil infiltration in the tissue. Prolonged eosinophil survival plays an important role in the pathogenesis of CSS; however, its detailed molecular mechanism remains unclear. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase, and its ligand is collagen. DDR1 was expressed in human leukocytes and fibroblasts, and it plays an important role in leukocyte cytokine production and fibroblast survival in an NF-kappaB-dependent manner. In this study, we examined in vitro and in vivo eosinophil DDR1 expression and its function in CSS patients. The expression level of DDR1 was significantly higher in the eosinophils of CSS patients, and the predominant isoform was DDR1b. Immunohistochemical findings revealed that the tissue-infiltrating eosinophils expressed endogenous DDR1. In CSS patients, DDR1 activation inhibited Fas agonistic antibody-induced apoptosis and up-regulated Fas agonistic antibody-induced cytokine production of eosinophils in an NF-kappaB-dependent manner. Suppression of DDR1 expression in the eosinophils by using RNA interference and addition of the DDR1-blocking protein abolished these effects. We propose that DDR1 contributes to the eosinophil survival in the tissue microenvironment of CSS and that it might be involved in the development of CSS.

Adult↗
PubMed2006

MRI studies of spinal visceral larva migrans syndrome.

We report serial MR findings in four patients with myelitis caused by visceral larva migrans syndrome due to Toxocara canis or Ascaris suum infection. MR imaging revealed spinal cord swelling with or without gadolinium enhancement in three patients. T2-weighted images showed high signal intensities preferentially located in both lateral and posterior columns. Antihelmintic and corticosteroid treatment yielded improvement in neurologic deficits and spinal lesions. However, one patient with T. canis infection relapsed associated with reappearance of MRI abnormalities.

Adrenal Cortex Hormones↗
PubMed2006

Molecular mechanism of rigid spine with muscular dystrophy type 1 caused by novel mutations of selenoprotein N gene.

Mutations of selenoprotein N, 1 gene (SEPN1) cause rigid spine with muscular dystrophy type 1 (RSMD1), multiminicore disease, and desmin-related myopathy. We found two novel SEPN1 mutations in two Japanese patients with RSMD1. To clarify the pathomechanism of RSMD1, we performed immunohistochemical studies using a newly developed antibody for selenoprotein N. Selenoprotein N was diffusely distributed in the cytoplasm of the control muscle, but was reduced and irregularly expressed in the cytoplasm of a patient with RSMD1. The expression pattern was very similar to that of calnexin, a transmembrane protein of the endoplasmic reticulum. Selenoprotein N seems to be an endoplasmic reticulum glycoprotein, and loss of this protein leads to disturbance of muscular function. One of the families had the SEPN1 homozygous mutation in the initiation codon 1_2 ins T in exon 1 and showed truncated protein expression. The other had a homozygous 20-base duplication mutation at 80 (80_99dup, frameshift at R27) which, in theory, should generate many nonsense mutations including TGA. These nonsense mutations are premature translation termination codons and they degrade immediately by the process of nonsense-mediated decay (NMD). However, truncated selenoprotein N was also expressed. A possible mechanism behind this observation is that SEPN1 mRNAs may be resistant to NMD. We report on the possible molecular mechanism behind these mutations in SEPN1. Our study clarifies molecular mechanisms of this muscular disorder.

Adult↗
PubMed2006

Association of AKT1 haplotype with the risk of schizophrenia in Iranian population.

AKT-glycogen synthase kinase 3beta (GSK3beta) signaling is a target of lithium and has been implicated in the pathogenesis of mood disorders and schizophrenia. AKT1 protein level is decreased in the peripheral lymphocytes and brains of schizophrenic patients. The SNP2/3/4 TCG haplotype of AKT1 was associated with schizophrenia in patients with Northern European origin. In the present study, we genotyped five single nucleotide polymorphisms (SNP1-5) of AKT1 gene according to the original study in Iranians comprising of 321 schizophrenic patients and 383 controls, all residing in Mashhad city, Northeastern Iran. Haplotype analysis showed that the frequency of a five-SNP haplotype (AGCAG) was significantly higher in schizophrenic patients (0.068) than that of controls (0.034) (P = 0.03 after Bonferroni correction, OR = 2.04, CI = 1.2-3.4). In stratified analysis by schizophrenia subtypes, the frequency of the same haplotype was significantly higher in disorganized subtype (n = 78, frequency of haplotype=0.081) when compared with normal controls (P = 0.04 after Bonferroni correction, OR = 2.59, CI = 1.3-5.2). Our findings did not confirm the association of AKT1 SNP2/3/4 TCG haplotype with the risk of schizophrenia as reported in the original study but showed the evidence of association with a different haplotype, AKT1 five-SNP AGCAG haplotype, with the risk of schizophrenia in Iranian population.

Alleles↗
PubMed2006

Increased serum vascular endothelial growth factor levels in microscopic poly angiitis with pulmonary involvement.

Microscopic polyangiitis (MPA) is a systemic necrotizing vasculitis that affects small vessels, resulting in a wide spectrum of organ involvement including the lungs. However, there are little serological markers that predict its prognosis or severity of pulmonary involvement. Vascular endothelial growth factor (VEGF) is an angiogenic mediator, which has been reported to be elevated in systemic vasculitis. In this study, we measured serum VEGF levels in 22 MPA patients with pulmonary involvement. We also investigated VEGF expression in pulmonary cells using flow cytometry analysis. We found that serum VEGF levels in MPA patients were significantly higher than those in respiratory or urinary tract infection. The serum VEGF levels decreased in parallel with the improvement of MPA symptoms. The serum VEGF levels in MPA patients who died within 5 years were significantly higher than those who survived more than 5 years. The sensitivity of VEGF levels to distinguish MPA patient with poor prognosis from those with good prognosis was 90.9%, and specificity was 81.8% (cutoff value = 802.5 pg/ml). The serum VEGF levels showed significant positive correlation with the composite physiological index, which indicates the severity of pulmonary lesion. In flow cytometry analysis, CD11b positive bronchoalveolar lavage fluid cells expressed VEGF. Immunohistochemically, alveolar macrophages, tissue infiltrating inflammatory cells and alveolar epithelial cells stained positive for VEGF. Measurement of serum VEGF levels in MPA might become one of the markers for prognosis and the severity of pulmonary involvement in MPA. VEGF might contribute to the development of pulmonary lesion of MPA.

Aged↗
PubMed2006

Flow cytometry evaluation of the T-cell receptor Vbeta repertoire among human T-cell lymphotropic virus type-1 (HTLV-1) infected individuals: effect of interferon alpha therapy in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

Human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic inflammatory disease of the spinal cord characterized by perivascular lymphocytic cuffing and parenchymal lymphocytic infiltration. In this study using flow cytometry, we have investigated the T-cell receptor (TCR) Vbeta repertoire of peripheral blood T lymphocytes in 8 HAM/TSP patients, 10 HTLV-1 infected healthy carriers, and 11 uninfected healthy controls to determine if there is a biased usage of TCR Vbeta. We found that TCR Vbeta7.2 was under-utilized and Vbeta12 was over-utilized in CD4+ T cells of HTLV-1 infected individuals compared with healthy uninfected controls, whereas there were no such differences in CD8+ T cells. Comparison of Vbeta repertoire changes before and after interferon-alpha (IFN-alpha) treatment for HAM/TSP revealed that one out of five patients showed dramatic decrease of specific Vbeta in CD8+ T cells. Our results suggest that dominant Vbeta subpopulations in CD4+ T cells evolved associated with chronic HTLV-1 infection, and IFN-alpha treatment for HAM/TSP does not induce a specific pattern of TCR Vbeta changes.

Antiviral Agents↗
PubMed2006

Suppression of discoidin domain receptor 1 by RNA interference attenuates lung inflammation.

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase whose ligand is collagen. Recently, we have reported the association of DDR1 in the cytokine production of human leukocytes in in vitro and in vivo expression in idiopathic pulmonary fibrosis. However, its role in in vivo inflammation has not been fully elucidated. Small interference RNA (siRNA) can induce specific suppression of in vitro and in vivo gene expression. In this study, using a bleomycin-induced pulmonary fibrosis mouse model, we administered siRNA against DDR1 transnasally and evaluated histological changes, cytokine expression, and signaling molecule activation in the lungs. Histologically, siRNA against DDR1 successfully reduced in vivo DDR1 expression and attenuated bleomycin-induced infiltration of inflammatory cells. Furthermore, it significantly reduced inflammatory cell counts and concentrations of cytokines such as MCP-1, MIP-1alpha, and MIP-2 in bronchoalveolar lavage fluid. Subsequently, bleomycin-induced up-regulation of TGF-beta in bronchoalveolar lavage fluid was significantly inhibited, and collagen deposition in the lungs was reduced. Furthermore, siRNA against DDR1 significantly inhibited bleomycin-induced P38 MAPK activation in the lungs. Considered together, we propose that DDR1 contributes to the development of bleomycin-induced pulmonary inflammation and fibrosis.

Administration, Intranasal↗
PubMed2006

HTLV-I viral escape and host genetic changes in the development of adult T cell leukemia.

In the pathogenesis of adult T cell leukemia (ATL), an oncogenetic role of the human T cell lymphotropic virus type I (HTLV-I) Tax protein, viral escape from the host immune system, and host genetic changes have been proposed as contributory factors. We examined the premature stop codons in tax gene as one of the mutations that may lead to escape of HTLV-I from the cytotoxic T lymphocyte (CTL) response in HTLV-I carriers, to test whether a putative CTL escape mutant can emerge in the early stage of ATL development and whether HTLV-I infected cells with such a mutation can proliferate subsequently. We also examined deletion of cyclin-dependent kinase inhibitor 4 (INK4) genes and mutation of p53 gene in combination with changes in the HTLV-I genome in acute type ATL to test whether host genetic changes promoted the malignant transformation of ATL cells that carry putative CTL escape mutations. The premature stop codon in tax gene existed in many non-ATL HTLV-I carriers as a minor population but not in the commonest HTLV-I sequence of the individual. This minor population with a premature stop codon did not expand subsequently in 3 asymptomatic carriers tested. There were cases who had a mutation or deletion in HTLV-I who also have either deletion of INK4 genes or mutation in p53 gene. Our findings suggest that CTL escape mutation can occur at an early stage of ATL development, and that certain host genetic changes favor the development of the aggressive form of ATL.

Cell Proliferation↗
PubMed2006

Genetic variability in the extracellular matrix protein as a determinant of risk for developing HTLV-I-associated neurological disease.

Aggrecan, which is a well-known proteoglycan in joint cartilage, also exists in the spinal cord and plays an important role in maintaining water content in the extracellular matrix structure. In this study, we first examined the variable number of tandem repeat (VNTR) polymorphism of the aggrecan gene in 227 HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, in 217 HTLV-I-infected healthy carriers (HCs), and in 85 normal controls. The VNTR allele 28 (1,630 bp) was more frequently observed in HAM/TSP patients than in HCs (chi2=12.02, p=0.0005, odds ratio 1.79, 95% C.I. 1.29-2.50) and in controls (chi2=13.43, p=0.0002, odds ratio 2.54, 95% C.I. 1.52-4.25), although this allele was not related to disease progression or to HTLV-I provirus load. We also found that the aggrecan concentration in cerebrospinal fluid (CSF) from rapidly progressive HAM/TSP patients was significantly higher than in slowly progressive patients (corrected p=0.0145) but not in infected non-inflammatory neurological other disease controls (OND) (corrected p=0.078). We then analyzed this aggrecan VNTR polymorphism in the different set of patients with HAM/TSP (n=58) and healthy carriers (n=70). This analysis, again, revealed that allele 28 was detected more frequently in HAM/TSP group than in HCs (chi2=11.03, p=0.0009, odd ratio 3.04, 95% C.I. 1.55-5.97). The reproducibility of our study was regarded as a second- or third-class association by comparing combined p values and the Better Associations for Disease and GEnes (BADGE) system. Our results suggest that aggrecan polymorphism can be a novel genetic risk factor for developing HAM/TSP.

Aggrecans↗
PubMed2006

Abnormal expression of proteoglycans in Ullrich's disease with collagen VI deficiency.

Patients with Ullrich's disease have generalized muscle weakness, multiple contractures of the proximal joints, and hyperextensibility of the distal joints. Recently we found a marked reduction of fibronectin receptors in the skin and cultured fibroblasts of two patients with Ullrich's disease with collagen VI deficiency, and speculated that an abnormality of cell adhesion may be involved in the pathogenesis of the disease. In this study, we investigated the expression of proteoglycans and adhesion molecules in Ullrich's disease and other muscle diseases. We found a reduction of NG2 proteoglycan in the membrane of skeletal muscle but not in the skin in Ullrich's disease. By contrast, we found the upregulation of tenascin C in the extracellular matrix of skeletal muscle in Ullrich's disease. Our findings suggest that abnormal expression of proteoglycans and adhesion molecules may be involved in the pathogenesis of the dystrophic muscle changes in Ullrich's disease.

Adult↗
PubMed2006

Clinical symptoms and the odds of human T-cell lymphotropic virus type 1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) in healthy virus carriers: application of best-fit logistic regression equation based on host genotype, age, and provirus load.

The authors have previously developed a logistic regression equation to predict the odds that a human T-cell lymphotropic virus type 1 (HTLV-1)-infected individual of specified genotype, age, and provirus load has HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in southern Japan. This study evaluated whether this equation is useful predictor for monitoring asymptomatic HTLV-1-seropositive carriers (HCs) in the same population. The authors genotyped 181 HCs for each HAM/TSP-associated gene (tumor necrosis factor [TNF]-alpha-863A/C, stromal cell-derived factor 1 (SDF-1) +801G/A, human leukocyte antigen [HLA]-A*02, HLA-Cw*08, HTLV-1 tax subgroup) and measured HTLV-1 provirus load in peripheral blood mononuclear cells using real-time polymerase chain reaction (PCR). Finally, the odds of HAM/TSP for each subject were calculated by using the equation and compared the results with clinical symptoms and laboratory findings. Although no clear difference was seen between the odds of HAM/TSP and either sex, family history of HAM/TSP or adult T-cell lenkemia (ATL), history of blood transfusion, it was found that brisk patellar deep tendon reflexes, which suggest latent central nervous system compromise, and flower cell-like abnormal lymphocytes, which is the morphological characteristic of ATL cells, were associated with a higher odds of HAM/TSP. The best-fit logistic regression equation may be useful for detecting subclinical abnormalities in HCs in southern Japan.

Adult↗
PubMed2006

Increased serum vascular endothelial growth factor level in Churg-Strauss syndrome.

BACKGROUND: Churg-Strauss syndrome (CSS) is a rare form of systemic vasculitis occurring in patients with asthma and hypereosinophilia. For optimal treatment, prompt distinction of CSS from asthma is necessary; however, there are few serologic screening markers for this purpose. Vascular endothelial growth factor (VEGF), a vascular permeability factor, has been associated with other systemic vasculitis such as Wegener granulomatosis and giant-cell arteritis. OBJECTIVE: The aim of this study was to clarify the clinical value of the measurement of serum VEGF for the distinction of CSS from asthma. METHODS: We investigated serum VEGF levels in 18 CSS patients, 19 asthma patients, and 12 acute bronchitis patients. We also performed immunohistochemical analysis for VEGF. RESULTS: The serum VEGF levels of CSS patients were significantly higher than those of asthma patients and acute bronchitis patients. The sensitivity and specificity to distinguish CSS from asthma were 93.3% and 81.8%, respectively (cutoff, 600 pg/mL). Infiltrating eosinophils stained intensely positive for VEGF, and serum VEGF levels showed a significant correlation with peripheral eosinophil counts. Serum VEGF levels decreased significantly after therapy (p < 0.001). The infiltrating eosinophils in the CSS lesion stained positive for VEGF in the immunohistochemical analysis. CONCLUSION: VEGF is one of the useful screening markers for the distinction of CSS from asthma. We suggest that VEGF might be associated with the pathogenesis of CSS.

Acute Disease↗
PubMed2006

Discoidin domain receptor 1 contributes to the survival of lung fibroblast in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-kappaB activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro DDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DDR1. The DDR1 expression level was significantly higher in fibroblasts from IPF patients, and the predominant isoform was DDR1b. In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-kappaB nuclear translocation. Suppression of DDR1 expression in fibroblasts by siRNA abolished these effects, and an NF-kappaB inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DDR1 up-regulation may occur in other fibroproliferative lung diseases as well.

Actins↗
PubMed2006

[A case of bronchiolitis obliterans syndrome successfully treated by Tiotropium bromide].

A 48-year-old woman was admitted with dyspnea on effort. She suffered from adult T-cell leukemia and received peripheral blood stem cell transplantation (PBSCT). Eight months after the PBSCT, she developed dyspnea on effort and was treated with bronchodilator, inhaled corticosteroid, anti-leukotriene drug, theophylline and oxytropium bromide. However her symptoms progressed and she was admitted. We diagnosed bronchiolitis obliterans syndrome (BOS) because of obstructive pulmonary dysfunction, diffuse patchy high density of the lung field on chest computed tomography and decreased ventilation with peripheral patchy accumulation on ventilation scintigraphy. She was treated with corticosteroid and cyclosporine A and her symptoms and her pulmonary function were improved. However, in parallel with corticosteroid tapering, her symptoms and pulmonary functions worsened. Treatment with Tiotropium bromide was started and her pulmonary function improved significantly. Her pulmonary function did not worsen and tapering steroid dose was successfully achieved. PBSCT was reported to up-regulate the muscarinic receptor activity in lung. Tiotropium bromide might become one additional option for the treatment of BOS.

Bronchiolitis Obliterans↗