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Biomedical subjects

Masaharu Nishimura

Publications and source records attributed to Masaharu Nishimura.

At least 19 recordsLinked to original sources
PubMed2007

Virtual bronchoscopic navigation system shortens the examination time--feasibility study of virtual bronchoscopic navigation system.

Computed tomography (CT)-guided transbronchial biopsy (TBB) using an ultrathin bronchoscope with simulation by virtual bronchoscopy (VB) is effective for diagnosing small peripheral pulmonary lesions. However, we occasionally lose the proper bronchi to the lesion when a bronchoscope is inserted into peripheral bronchi with severe rotation. To overcome this problem, the virtual bronchoscopic navigation system that can display real-time VB images during TBB procedures in comparison with actual bronchi has been developed. We evaluated the usefulness of the virtual bronchoscopic navigation system for CT-guided TBB using an ultrathin bronchoscope (navigation method) to diagnose small peripheral pulmonary lesions, and compared the results to those with previous method that uses VB images in a simulation (simulation method). We performed CT-guided TBB using an ultrathin bronchoscope for 69 patients with 71 small peripheral pulmonary lesions (mean diameter, 13.7 mm) between November 2002 and November 2005 with the navigation method. CT-guided TBB with the navigation method was performed safely without any serious complications for all patients. Mean time to the initial scan, time to the first biopsy and total examination time were 5.3, 8.5 and 24.5 min, respectively. Fifty lesions (70%) were diagnosed by this procedure. Compared to simulation method, diagnostic sensitivity was higher in the navigation method, but the difference was not significant. However, the time to the first biopsy and total examination time were significantly shorter in the navigation method than in the simulation method (p<0.05). In summary, the virtual bronchoscopic navigation system was safely used, effective for diagnosing small peripheral pulmonary lesions, and useful for shortening the examination time of CT-guided TBB using an ultrathin bronchoscope.

Aged↗
PubMed2007

Increase in soluble CD138 in bronchoalveolar lavage fluid of multicentric Castleman's disease.

Multicentric Castleman's disease (MCD) is a rare and often incurable lymphoproliferative disorder. It is typically a systemic illness, but occasionally manifests primarily as a pulmonary parenchymal disease with massive infiltration of CD138 (syndecan-1)-positive plasma cells. This is the first report to demonstrate a marked elevation of soluble CD138, despite the absence of plasma cells, in BAL fluid in an MCD patient with pulmonary involvement. This finding suggests that the quantitative measurement of soluble CD138 in BAL fluid may reflect plasma cell infiltration and disease activity in the lungs of patients with MCD.

Biomarkers↗
PubMed2006

Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S768I and V769L.

Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) are associated with clinical responsiveness to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancers (NSCLCs). However, certain rare EGFR mutations including S768I are reported to confer less in vitro sensitivity to gefitinib, an EGFR-TKI, than major mutations such as exon 19 deletions and L858R and even the wild-type counterpart. Here, we report the first case of adenocarcinoma of the lung in which the patient had rare mutations S768I and V769L and was treated with gefitinib. Disease progressed during 6 weeks of treatment. This case suggests that in vitro sensitivity to gefitinib correlates with distinct clinical responsiveness to gefitinib in various types of EGFR mutations.

Adenocarcinoma↗
PubMed2006

Genetic impact of functional single nucleotide polymorphisms in the 3'-UTR region of the chemoattractant receptor expressed on Th2 cells (CRTH2) gene on asthma and atopy in a Japanese population.

BACKGROUND: The human chemoattractant receptor expressed on Th2 cells (CRTH2), the receptor for prostaglandin D2, induces cell migration in eosinophils, basophils, and Th2 cells. The gene encoding CRTH2 is located on chromosome 11q13. Several groups, including ours, have reported significant associations between this region and various traits associated with allergic diseases such as asthma and atopy. Two single nucleotide polymorphisms in the 3'-UTR of the CRTH2 gene (1544G-->C and 1651G-->A) are associated with the mRNA stability of the gene; they have also been associated with asthma in both African American and Chinese populations. METHODS: Because CRTH2 is a biologically important candidate gene on chromosome 11q13, we conducted a case-control analysis using 787 Japanese subjects (384 asthmatics and 403 controls) to evaluate the genetic impact of the CRTH2 gene on asthma and asthma-related traits. Four polymorphisms [1544G-->C (rs11571288), 1651G-->A (rs545659), 11336T-->C (rs2074422), and 12375G-->T (rs561285)] were studied. RESULTS: The allele, genotype, or haplotype frequencies for 2 functional polymorphisms in our Japanese population were significantly different from those in the Chinese or African American populations. No association was found between any polymorphisms or haplotypes in the CRTH2 gene and asthma, atopy, or total serum IgE levels in a Japanese population. CONCLUSIONS: Our data failed to support previous associations of functional polymorphisms at the 3'-UTR of the CRTH2 gene implicated in asthma. We did show a significant difference in the allele and genotype frequencies as well as different haplotype frequencies among African American, Chinese, and Japanese populations, suggesting that the genetic impacts of these functional polymorphisms on asthma and asthma-related phenotypes may vary in different populations.

Adolescent↗
PubMed2006

Polymorphisms in the muscarinic receptor 1 gene confer susceptibility to asthma in Japanese subjects.

RATIONALE: The human cholinergic receptor muscarinic-1 (CHRM1) is widely distributed in the lungs. In patients with asthma, CHRM1 may be involved in airway constriction, airway epithelial cell proliferation, and airway inflammation. The CHRM1 gene is located on chromosome 11q13, which is one of the candidate loci for asthma and atopy. OBJECTIVES: To determine the role of the CHRM1 gene polymorphisms in asthma. METHODS: We studied nine single-nucleotide polymorphisms (-18379G > A, -9697C > T, -6965T > C, -4953A > G, +267A > C, +1353C > T, +3970C > G, +5418C > G, and +5455G > T) in a case-control study using 326 patients with asthma and 333 healthy control subjects. We also examined functional consequences of the -9697C > T and -4953A > G polymorphisms at the regulatory region using an mRNA reporter assay. MEASUREMENTS AND MAIN RESULTS: Two common single-nucleotide polymorphisms (-9697C > T and -4953A > G) were associated with asthma. The odds ratio for the TT homozygotes at the -9697C > T polymorphism was 0.29 compared with the CC homozygotes (95% confidence interval, 0.12-0.73; p = 0.008), and the odds ratio for the GG homozygotes at the -4953A > G polymorphism was 1.86 compared with the AA homozygotes (95% confidence interval, 1.04-3.34; p = 0.038). Haplotype analysis showed that the -9697T/-6965T/-4953A haplotype was associated with a lower risk of asthma (p = 0.00055) and the -9697C/-6965T/-4953G haplotype was associated with an increased risk of asthma (p = 0.020). The -9697T/-4953A haplotype was also associated with lower luciferase activity in vitro compared with the -9697C/-4953G haplotype. CONCLUSIONS: This study, together with an in vitro functional study, suggests that the CHRM1 gene is an important susceptibility locus for asthma on chromosome11q13.

Adolescent↗
PubMed2006

Multiple myeloma associated with sialyl salivary-type amylase.

BACKGROUND: There have been several reports describing a notable hyperamylasaemia in patients with multiple myeloma. Such amylase-producing myelomas have been mainly described in the context of concomitant salivary-type hyperamylasaemia, with sialyl salivary-type amylase identified in a portion of those cases. We investigated the incidence of the production of sialyl salivary-type amylase in serum of multiple myeloma patients. METHODS: Eleven patients (6 male and 5 female) who had been diagnosed as having multiple myeloma were enrolled in this study. Sialyl salivary-type amylase was detected by isoamylase electrophoresis and HPLC analysis, and identified by detecting either abnormal neuraminidase-sensitive band through isoamylase electrophoresis or abnormal extra-elution peak of amylase by means of HPLC analysis. RESULTS: Sialyl salivary-type amylase was detected in 7 out of 11 (63.6%) patients. Median total amylase activity was 154 U/l (range 109-43020). Isoamylase electrophoretic patterns of patients' serum were normal in 5 patients (71.4%) out of 7 patients and salivary-dominant in 2 (50.0%) out of 4 patients. CONCLUSIONS: We consider that there is no significant relationship between total serum amylase level and amylase isoenzyme pattern in the incidence of production of sialyl salivary-type amylase with multiple myeloma.

Aged↗
PubMed2006

Pharmacokinetics of telithromycin using bronchoscopic microsampling after single and multiple oral doses.

OBJECTIVES: Bronchoscopic microsampling (BMS) is a new technique for repeated sampling of bronchial epithelial lining fluid (ELF) to obtain the pharmacokinetic profile of drugs. We analyzed the time versus concentration profiles of telithromycin in bronchial ELF obtained by BMS and compared these finding to those in plasma and alveolar ELF obtained by bronchoalveolar lavage (BAL). METHODS: Bronchial ELF samples were obtained from five healthy subjects using BMS probe at 0, 2, 3, 4, 6, 10 and 24h after single or multiple oral doses of 600 mg of telithromycin. Alveolar ELF was also obtained by BAL 3h after single or multiple oral doses of 600 mg of telithromycin. RESULTS: The areas under the concentration-time curve from 0 to 24h (AUC0-24) of telithromycin in plasma and bronchial ELF were 2.86+/-0.60 and 19.5+/-10.4 mg h/l after single treatment and 3.60+/-0.49 and 42.2+/-22.7 mg h/l after multiple treatments, respectively. Single and multiple oral doses of telithromycin produced significantly (p<0.05) higher AUC0-24 in bronchial ELF compared to those in plasma. While concentrations in bronchial ELF obtained by BMS were significantly lower than those in alveolar ELF obtained by BAL, they tended to be higher than those in plasma after multiple administration. The telithromycin concentrations obtained by BMS method were very consistent in bronchial ELF at different bronchi at one time point and at the same bronchus at different time points. CONCLUSIONS: Using the BMS technique, we could describe the pharmacokinetics of telithromycin in bronchial ELF. Furthermore, BMS was reasonably validated and reconfirmed to be a feasible and reliable method for measuring antimicrobial concentrations in bronchial ELF.

Administration, Oral↗
PubMed2006

Extracellular matrix metalloproteinase inducer in interstitial pneumonias.

Extracellular matrix metalloproteinase inducer (EMMPRIN), a glycosylated transmembrane protein that induces matrix metalloproteinases (MMPs), is minimally expressed in the normal adult lung. We previously reported that it is up-regulated in murine bleomycin-induced lung injury. In this study, we determined the expression of EMMPRIN and its association with MMP-2, MMP-7, and MMP-9 in interstitial pneumonias (IPs). We performed immunohistochemistry for EMMPRIN and MMPs on lung tissue from 22 subjects with various IPs. We did bronchoalveolar lavage (BAL) on 9 of these subjects and 13 others with IPs to measure the soluble EMMPRIN in BAL fluid. For comparison, immunohistochemistry or BAL was done on 14 subjects without IPs. The staining intensity for each protein was scored from 0 to 3 in various epithelial cell types. Soluble EMMPRIN in BAL fluid was measured by an enzyme-linked immunosorbent assay. Extracellular matrix metalloproteinase inducer was prominent in abnormal epithelial cells. It was more prominent in hyperplastic type II cells, compared with epithelium in alveolar bronchiolization. It was also elevated in BAL fluid from the subjects with IPs. Matrix metalloproteinases were expressed in cells expressing EMMPRIN, although the profile of MMPs varied among the different abnormal epithelial cell types with MMP-2 and MMP-7 in hyperplastic type II cells and MMP-7 and MMP-9 in cells showing squamous metaplasia and cells comprising bronchiolization. These results suggest a role of EMMPRIN in reepithelialization in IPs.

Basigin↗
PubMed2006

Airflow limitation and airway dimensions in chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation caused by emphysema and/or airway narrowing. Computed tomography has been widely used to assess emphysema severity, but less attention has been paid to the assessment of airway disease using computed tomography. OBJECTIVES: To obtain longitudinal images and accurately analyze short axis images of airways with an inner diameter>or=2 mm located anywhere in the lung with new software for measuring airway dimensions using curved multiplanar reconstruction. METHODS: In 52 patients with clinically stable COPD (stage I, 14; stage II, 22; stage III, 14; stage IV, 2), we used the software to analyze the relationship of the airflow limitation index (FEV1, % predicted) with the airway dimensions from the third to the sixth generations of the apical bronchus (B1) of the right upper lobe and the anterior basal bronchus (B8) of the right lower lobe. MEASUREMENTS AND MAIN RESULTS: Airway luminal area (Ai) and wall area percent (WA%) were significantly correlated with FEV1 (% predicted). More importantly, the correlation coefficients (r) improved as the airways became smaller in size from the third (segmental) to sixth generations in both bronchi (Ai: r=0.26, 0.37, 0.58, and 0.64 for B1; r=0.60, 0.65, 0.63, and 0.73 for B8). CONCLUSIONS: We are the first to use three-dimensional computed tomography to demonstrate that airflow limitation in COPD is more closely related to the dimensions of the distal (small) airways than proximal (large) airways.

Adult↗
PubMed2006

Recovery of protein-losing enteropathy after living-donor lobar lung transplantation in primary pulmonary hypertension.

The patient investigated was a 43-year-old woman with primary pulmonary hypertension (PPH) and refractory protein-losing enteropathy (PLE). She underwent living-donor lobar lung transplantation (LDLLT), which led to remarkable improvement in both pulmonary hypertension and PLE. Although there have been no reports, to our knowledge, that have demonstrated PLE as a complication of PPH, the present case clearly shows how PLE could complicate PPH. In addition, and more importantly, hypo-proteinemia due to PLE should not necessarily be an exclusion criterion for lung transplantation when PPH is involved, because it could markedly improve after transplantation.

Adult↗
PubMed2006

IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity.

BACKGROUND: IL-17F is a recently discovered cytokine that plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. Upregulated IL17F gene expression has been observed at sites of allergen challenge in the airways of patients with asthma, suggesting that IL-17F is involved in the pathophysiology of asthma. OBJECTIVE: To investigate the role of IL-17F in asthma pathogenesis, we conducted genetic analyses of association of asthma with the common variants of IL17F, using 867 unrelated Japanese subjects. METHODS: Five polymorphisms were studied, including the coding-region sequence variant single nucleotide polymorphism rs763780 (7488T/C), which causes a His-to-Arg substitution at amino acid 161 (H161R). Functional consequences of the H161R substitution were examined by using recombinant wild-type and mutant IL-17F proteins. RESULTS: Homozygosity of the H161R variant was inversely associated with asthma; the odds ratio (95% CI) for asthma was 0.06 (0.01-0.43) for the H161R homozygote compared with the wild-type homozygote (P = .0039). This result remains significant (P = .0079) after adjustment for the presence of atopy using the Mantel-Haenszel chi2 test. In addition, in vitro functional experiments demonstrated that the H161R variant of IL-17F lacks the ability to activate the mitogen-activated protein kinase pathway, cytokine production, and chemokine production in bronchial epithelial cells, unlike wild-type IL-17F. Furthermore, the H161R variant blocked induction of IL-8 expression by wild-type IL-17F. CONCLUSION: The current findings indicate that the IL-17F H161R variant influences the risk of asthma and is a natural IL-17F antagonist, suggesting a potential role for IL-17F in the etiology of asthma.

Adolescent↗
PubMed2006

Tetramer-blocking assay for defining antigen-specific cytotoxic T lymphocytes using peptide-MHC tetramer.

Peptide-MHC tetramers have been engineered to allow accurate detection of antigen-specific cytotoxic C lymphocytes (CTL) by flow cytometry. Here, we propose a novel use for peptide-MHC tetramers in the specific and sensitive analysis of the cytotoxic function of antigen-specific CTL by blocking MHC-restricted antigen-specific cytotoxicity. We found that pretreatment of ovalbumin (OVA)-specific CD8(+) CTL (OT-1 CTL), derived from OT-1 T-cell receptor (TCR)-transgenic mice, with OVA(257-264) peptide-H-2K(b) tetramer caused a marked inhibition of the cytotoxicity against OVA-expressing EG-7 tumor cells. OVA(257-264) peptide-H-2K(b) tetramer did not block the cytotoxicity mediated by 2C mouse (H-2(b))-derived CD8(+) CTL, which recognize allo (H-2L(d)) antigens. Moreover, OT-I CTL activity was not inhibited by an irrelevant HBV(208-216) peptide-H-2K(b) tetramer. These results indicate that the blocking of CTL activity with peptide-MHC tetramer was caused by interference with the interaction between the TCR and H-2K(b)-OVA(257-264) peptide complex, but not with the CD8-MHC class I interaction. The blocking activity of OVA(257-264) peptide-H-2K(b) tetramer was reversible because OT-I CTL pretreated with the tetramer recovered their cytotoxicity after culturing with interleukin-2 for 24 h. The same results were also demonstrated in freshly isolated, in vivo-primed OT-1 CTL sorted by the tetramer. These results demonstrate that peptide-MHC tetramer is a useful tool for defining MHC-restricted antigen-specific CTL function. Moreover, our finding implies that the measurement of CTL activity immediately after tetramer-guided sorting is not a suitable method for evaluating the function of in vivo-induced tetramer-positive CTL. We believe that the tetramer-blocking assay presented here will be useful for functionally monitor the induction of MHC-restricted antigen-specific CTL during vaccination therapy against tumor and infectious diseases.

Animals↗
PubMed2006

Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis.

OBJECTIVE: Circulating levels of KL-6, a high MW glycoprotein (MUC1 mucin), are elevated in a majority of patients with a number of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). However, KL-6 levels vary from patient to patient. The aim of the present study was to determine whether the serum KL-6 level at the time of diagnosis predicts prognosis in IPF. METHODS: The relationship between clinical variables and prognosis in 27 patients with IPF were analysed retrospectively. The diagnosis was made by histological examination (n = 16) or on clinical findings including high-resolution CT scanning (n = 11). All patients were followed up for at least 3 years. Variables such as age, FVC%, PaO(2) at rest, initial LDH level, C-reactive protein and KL-6 were used for analysis. RESULTS: At the cut-off level determined by receiver operating characteristic curves, LDH and KL-6 showed a significant correlation with the patient's prognosis by univariate analysis. However, multivariate analysis revealed that only KL-6 was a predictor of prognosis. The patients were categorized by their serum KL-6 levels (as above or below the cut-off level of 1000 U/mL) and their survival estimated using the Kaplan-Meier method. The difference in median survival between the two groups was significant. The median survival of patients with low KL-6 was more than 36 months, whereas that of patients with high KL-6 was only 18 months. CONCLUSION: These results suggest that initial evaluation of serum KL-6 level can predict survival in patients with IPF.

Antigens, Neoplasm↗
PubMed2006

Epithelioid sarcoma presenting as pulmonary cysts with cancer antigen 125 expression.

A 39-year-old Japanese woman presented with a swollen right hand and a right-sided pneumothorax. Chest CT revealed bilateral multiple pulmonary thin-walled cysts measuring<or=1 cm in diameter and small nodules. An initial skin biopsy led to a misdiagnosis of metastatic adenocarcinoma, as tumour cells were positive for cytokeratin, epithelial membrane antigen, carcinoembryonic antigen and cancer antigen 125. However, chemotherapy proved ineffective, and the skin biopsy was repeated. A final diagnosis of epithelioid sarcoma (ES) was made. Open lung biopsy showed that the pulmonary nodules represented metastases of ES. Although the pulmonary cyst walls did not contain tumour cells, bronchiolar wall adjacent to the cysts had been infiltrated by tumour cells. These findings suggested that pulmonary cysts, a rare form of pulmonary metastases from soft tissue sarcomas, had developed through a ball-valve effect of metastatic tumour in small airways. However, presence of cancer antigen 125 hindered obtaining a correct diagnosis of ES.

Adenocarcinoma↗
PubMed2006

Association between nonspecific airway hyperresponsiveness and Arg16Gly beta2-adrenergic receptor gene polymorphism in asymptomatic healthy Japanese subjects.

BACKGROUND: Nonspecific airway hyperresponsiveness (AHR), a cardinal feature of asthma, is thought to result from several genetic and environmental factors. Asymptomatic AHR in nonasthmatic healthy subjects might be a risk factor for the development of asthma. Genetic variations in codons 16 and 27 of the human beta(2)-adrenergic receptor (beta(2)-AR) alter receptor function in vitro and are associated with various asthma-related phenotypes, including asthma severity and AHR. To date, however, few reports have examined the impact of beta(2)-AR gene polymorphism on AHR in asymptomatic healthy subjects. OBJECTIVE: To determine whether polymorphism of the beta(2)-AR gene (Arg16Gly and Gln27Glu) might influence nonspecific AHR in asymptomatic healthy Japanese subjects. DESIGN AND PARTICIPANTS: A cohort of 120 asymptomatic healthy subjects was analyzed using a stepwise linear regression model. Nonspecific airway responsiveness was measured using a continuous methacholine inhalation method (Astograph; Chest; Tokyo, Japan). We used values of the cumulative dose of inhaled methacholine measured at the inflection point at which respiratory conductance starts to decrease (Dmin) as an index of AHR. Genotyping to identify polymorphisms at codons 16 and 27 was conducted using an assay combining kinetic real-time quantitative polymerase chain reaction with allele-specific amplification. RESULTS: The Gly16Gly genotype was associated with lower Dmin values. The log Dmin value of asymptomatic healthy subjects carrying the Arg16 allele (Arg16/Arg or Arg16/Gly, n = 90) was 1.09 +/- 0.56 (mean +/- SD), while those homozygous for the Gly16 allele (n = 30) yielded a log Dmin value of 0.85 +/- 0.56 (p < 0.05). CONCLUSION: This study indicates that a specific beta(2)-AR polymorphism at codon 16 might be a genetic determinant of AHR, as judged by methacholine-induced bronchoconstriction in asymptomatic healthy subjects.

Administration, Inhalation↗
PubMed2006

Osteopontin: a potential biomarker for successful bee venom immunotherapy and a potential molecule for inhibiting IgE-mediated allergic responses.

Venom immunotherapy (VIT) is proven to be curative for insect allergy, but the mechanisms and the biomarkers associated with clinical efficacy remain elusive. We report herein the discovery of a leading candidate biomarker, osteopontin (OPN), for VIT. From cDNA microarray and clustering analyses, an increased expression of OPN was found in patients who completed 5-6 years of VIT and discontinued therapy for 3-6 years as compared with the untreated group. A significantly higher level of serum OPN was found in the completed treatment group as compared with the untreated group. Following VIT, kinetically increased levels of OPN associated with reduced venom specific IgE levels were noted in subjects with large local allergic reactions to venom. These findings together with the fact that OPN is involved in Th1-associated immune response strongly suggest a role of OPN as a functional biomarker for VIT.

Bee Venoms↗