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Biomedical subjects

K Yanagihara

Publications and source records attributed to K Yanagihara.

At least 19 recordsLinked to original sources
PubMed2006

Effects of macrolides on pneumolysin of macrolide-resistant Streptococcus pneumoniae.

To clarify the discrepancy between increasing resistance and conservative clinical effects of macrolides on macrolide-resistant Streptococcus pneumoniae, the authors evaluated the effects of sub-minimum inhibitory concentrations of macrolides on pneumolysin. In vitro, S. pneumoniae was incubated with 1, 2 and 4 microg.mL(-1) of clarithromycin (CLR) and azithromycin (AZM) for 8 h. Western blot analysis and haemolytic assay were performed to examine the production and activities of pneumolysin. In vivo, mice were infected with S. pneumoniae intra-nasally and treated with CLR (40 or 200 mg.kg(-1) twice daily) or AZM (40 or 200 mg.kg(-1) once daily) orally for 7 days. After 72 h post-infection, western blot analysis was performed to examine pneumolysin production in lungs. Survival rates were observed for 10 days. In vitro, every concentration of macrolide inhibited pneumolysin production more than the control. CLR (2 and 4 microg.mL(-1)) and AZM (4 microg.mL(-1)) reduced the pneumolysin activities more than the control. In vivo, macrolides (200 mg.kg(-1)) reduced pneumolysin in murine lungs more than the control. CLR (40 and 200 mg.kg(-1)) and AZM (200 mg.kg(-1)) improved the survival rates more than the control. The study results show that sub-minimum inhibitory concentrations of macrolides reduced pneumolysin. This might be related to the effectiveness of macrolides against pneumonia caused by high-level macrolide-resistant Streptococcus pneumoniae. Further investigations are necessary to evaluate the effects of macrolides on macrolide-resistant Streptococcus pneumoniae.

Bacterial Proteins↗
PubMed2004

GP2/THP gene family of self-binding, GPI-anchored proteins forms a cluster at chromosome 7F1 region in mouse genome.

We investigated the genomic organization of pancreatic zymogen granule membrane-associated protein GP2, a GPI-anchored protein exhibiting self-aggregation at acidic pH, in order to construct a gene-knockout mouse. Cloning and analysis of lambda clones encoding GP2 from 129 Svj mouse genomic DNA libraries showed that the GP2 gene spans about 16.8 kb and includes 11 exons. Identifiable functional domains including a signal sequence, an EGF-like motif, a putative condensing ZP domain, a GPI-anchor attachment site, and a transmembrane sequence for GPI anchoring are encoded in separate exons. Using FISH, the GP2 gene was mapped to mouse chromosome 7F1 near the gene for THP, a GP2 homolog expressed in the cells of thick ascending loop of Henle (TALH) in the kidney. Further analysis of the mouse genome revealed that the THP and GP2 genes are adjacent to one another and are separated by only 3.5 kb in the 7F1 locus. Additionally, the overall structure of the THP gene, 16.2kb with 11 exons, was strikingly similar to that of GP2. This finding suggests that the GP2 and THP genes were generated by gene duplication and evolved separately to acquire regulatory elements leading to tissue-specific expression. Comparative analysis revealed that the 5' flanking region of the THP gene is similar to the first intron of NKCC2, a TALH cell-specific ion-transporter gene. The promoter region of the GP2 gene shares cis-elements found in other pancreas-specific genes. Using this genetic information, a GP2 null mutation was successfully introduced into an ES cell line, and an animal model was established without disruption of THP expression.

Animals↗
PubMed2004

Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients.

Recent experimental studies have revealed that tumour-associated stromal macrophages as well as tumour cells express vascular endothelial growth factor C (VEGF-C), which plays important roles in lymphangiogenesis, which is a critical factor in the progression of many malignant tumours including non-small-cell lung cancer (NSCLC). However, no clinical study on VEGF-C expression in both stromal macrophages and tumour cells has been reported, and we conducted the present study to address the issue in resected NSCLC. A total of 206 patients with completely resected pathologic stage I-IIIA NSCLC were retrospectively reviewed. Expression of VEGF-C in primary lung tumour was assessed immunohistochemically. Expression of VEGF-C in tumour cells was high in 125 patients (60.7%), and that in stromal macrophages was positive in 136 patients (71.2%). The status of VEGF-C in tumour cells or in stromal macrophages was not correlated with nodal status or angiogenesis. The 5-year survival rate of high tumoral VEGF-C patients (60.7%) was significantly lower than that of low tumoral VEGF-C patients (39.3%) (P=0.046), and a multivariate analysis confirmed that tumoral VEGF-C status was a significant and independent prognostic factor. Moreover, tumour showing high VEGF-A and VEGF-C expression in tumour cells showed the poorest prognosis (5-year survival rate, 45.1%). The status of VEGF-C in stromal macrophages was not correlated with the prognosis. In conclusion, tumoral VEGF-C status, not stromal VEGF-C status, was a significant prognostic factor in resected NSCLC.

Aged↗
PubMed2004

Acute infection with influenza virus enhances susceptibility to fatal pneumonia following Streptococcus pneumoniae infection in mice with chronic pulmonary colonization with Pseudomonas aeruginosa.

We established a mouse model in which fatal pneumonia was induced by pneumococcal superinfection following influenza virus infection in chronic Pseudomonas aeruginosa infected mice. In this mouse model, influenza virus infection caused a significant increase in inflammatory cells, cytokines and severe tissue damage in the lungs of these P. aeruginosa infected mice, before pneumococcal infection. Intrapulmonary virus titres were significantly increased in mice with chronic P. aeruginosa infection, compared with control mice. Neutrophil function analysis showed significant reduction of myeloperoxidase (MPO) activity and lysozyme secretion by influenza virus infection in these mice. Our results suggest that influenza virus infection may play an important role in inducing pneumococcal pneumonia in chronic P. aeruginosa infected mice. Our results suggested that our mouse model is useful for investigating the pathogenesis of influenza virus infection in patients with chronic lung infection.

Acute Disease↗
PubMed2004

Virulence of metallo-beta-lactamase-producing Pseudomonas aeruginosa in vitro and in vivo.

We evaluated the virulence of Pseudomonas aeruginosa carrying bla(IMP), a metallo-beta-lactamase gene, and the efficacy of ceftazidime, imipenem-cilastatin, and ciprofloxacin in the endogenous bacteremia model. The presence of bla(IMP) did not practically change the virulence of the parent strain, and ciprofloxacin was effective against infection with P. aeruginosa carrying bla(IMP).

Animals↗
PubMed2004

Immunokinetics in severe pneumonia due to influenza virus and bacteria coinfection in mice.

Coinfections of bacteria and influenza are a major cause of excessive mortality during influenza epidemics. However, the mechanism of the synergy between influenza virus and bacteria are poorly understood. In this study, mice were inoculated with influenza virus, followed 2 days later by inoculation with Streptococcus pneumoniae. The kinetics of viral titres, bacterial numbers and the immune response (cytokine and chemokine production) were also analysed. Short-term survival correlated with pathological changes in the lungs of infected mice. Influenza virus or S. pneumoniae infection alone induced moderate pneumonia; however, severe bronchopneumonia with massive haemorrhage in coinfected mice, which caused death of these mice approximately 2 days after inoculation with S. pneumoniae, was noted. Intrapulmonary levels of inflammatory cytokines/chemokines, type-1 T-helper cell cytokines and Toll-like receptors, and the related mitogen-activated protein kinase signalling molecules (phosphorylated extracellular signal-regulated kinase -1 and - 2, p38 and c-Jun N-terminal kinase), were increased in coinfected mice. These results suggest that immune mediators, including cytokines and chemokines, through Toll-like receptors/mitogen-activated protein kinase pathways, play important roles in the pathology of coinfection caused by influenza virus and Streptococcus pneumoniae.

Animals↗
PubMed2003

Detection of Legionella DNA by PCR of whole-blood samples in a mouse model.

A detection system for Legionella DNA in blood samples based on the PCR was developed and evaluated in A/J mice with experimentally induced Legionella pneumonia. Primers were designed to amplify a 106 bp DNA fragment of the 16S rRNA gene specific to Legionella species. The PCR system could detect clinically relevant Legionella species including Legionella pneumophila, Legionella micdadei, Legionella bozemanae, Legionella dumoffii, Legionella longbeachae, Legionella gormanii and Legionella jordanis. The sensitivity of the PCR system was 20 fg extracted DNA. In the mouse model, the blood PCR was compared with results obtained by PCR on bronchoalveolar lavage fluid (BALF) samples, cultures of blood and BALF and detection of Legionella urinary antigen. Blood PCR was positive until 8 days after infection, while BALF PCR became negative on day 4. These results indicate that PCR using blood samples may be a useful, convenient and non-invasive method for the diagnosis of Legionella pneumonia.

Animals↗
PubMed2002

DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers.

Death-associated protein kinase is a positive regulator of programmed cell death induced by interferon gamma. To investigate the role of epigenetic inactivation of death-associated protein kinase in gastrointestinal cancer, we examined the methylation status of the 5' CpG island of the death-associated protein kinase gene. Methylation of the 5' CpG island was detected in 3 of 9 colorectal and 3 of 17 gastric cancer cell lines, while among primary tumours, it was detected in 4 of 28 (14%) colorectal and 4 of 27 (15%) gastric cancers. By contrast, methylation of the edge of the CpG island was detected in virtually every sample examined. Death-associated protein kinase expression was diminished in four cell lines that showed dense methylation of the 5' CpG island, and treatment with 5-aza-2'-deoxycitidine, a methyltransferase inhibitor, restored gene expression. Acetylation of histones H3 and H4 in the 5' region of the gene was assessed by chromatin immunoprecipitation and was found to correlate directly with gene expression and inversely with DNA methylation. Thus, aberrant DNA methylation and histone deacetylation of the 5' CpG island, but not the edge of the CpG island, appears to play a key role in silencing death-associated protein kinase expression in gastrointestinal malignancies.

Apoptosis Regulatory Proteins↗
PubMed2002

Long-term response to zonisamide in patients with West syndrome.

The long-term effectiveness of zonisamide (ZNS) was evaluated in 11 patients with West syndrome (7 symptomatic) who had cessation of spasms with ZNS monotherapy. During the follow-up period (24 to 79 months, mean = 53 months), this response was maintained in 7 patients (3 symptomatic, relapse rate = 36%), including 2 children in whom ZNS was successfully discontinued. No serious adverse reactions were noted. ZNS may be both effective and well tolerated for the treatment of West syndrome.

Adolescent↗
PubMed2001

Effect of transforming growth factor-beta1 on the cell growth and Epstein-Barr virus reactivation in EBV-infected epithelial cell lines.

Transforming growth factor (TGF)-beta1 is a multifunctional cytokine that plays important roles in regulating cell growth and differentiation in many biological systems. In this study, we found that gastric tissue-derived Epstein-Barr virus (EBV)-infected epithelial cell lines GT38 and GT39 had resistance to TGF-beta1-mediated growth inhibition and apoptosis compared to a TGF-beta1-susceptible gastric carcinoma cell line HSC-39. However, TGF-beta1 partially induced EBV reactivation in GT38 and GT39 cells, as shown by the induction of EBV immediate-early BZLF1 RNA and its protein product ZEBRA and early antigen-D. The expressions of TGF-beta receptor I and II were detected in GT38 and GT39 cells by Northern and Western blot analyses. Both cell lines spontaneously produced the TGF-beta1, which was sufficient for inhibiting cell growth of HSC-39 cells. Taken together, these data suggest that TGF-beta1 may be a key factor for EBV reactivation and selective growth of EBV-infected epithelial cells in vivo.

Activin Receptors, Type I↗
PubMed2001

Single nucleotide instability without microsatellite instability in rat mammary carcinomas.

Mutation frequencies (MnFs) of the lacI transgene and mutation rates (MRs) of the endogenous hprt gene were analyzed in two mammary carcinoma cell lines that we established from mammary carcinomas that had been induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in female lacI-transgenic rats. Using the lacI transgene, corrected MnF, which is the number of independent lacI mutations that occurred while 102 cells expanded into 10(7) cells and which reflect the dynamic increase of point mutations, was measured. The corrected MnFs in the two mammary carcinoma cell lines (59 x 10(-6) and 72 x 10(-6) mutations) were significantly higher than that in the primary culture of normal mammary epithelium (4.7 x 10(-6)). MRs of the hprt gene in the two mammary carcinoma cell lines (8.2 x 10(-7) and 11 x 10(-7) mutations/hprt/cell division) were also higher than the same control (1.4 x 10(-7)). A:T to C:G transversion was observed at significantly higher frequencies in the two cell lines (6 of 24 and 6 of 25 for lacI; 10 of 67 and 19 of 92 for hprt) than in the control (0 of 6 for lacI; 0 of 4 for hprt). Taking advantage of the lacI transgene, high frequencies of A:T to C:G transversion (6 of 38 and 8 of 33, respectively) was also confirmed in the primary carcinomas of the two cell lines, which indicated the presence of a common abnormality in the cell lines and in the primary carcinomas. Both the established cell lines and their primary carcinomas were negative for microsatellite instability, which is known to be caused mainly by mismatch repair insufficiency and to increase point mutations, and for p53 mutations. These findings showed that the two cell lines, and possibly their primary carcinomas, had increases in the MRs of point mutations attributable to a mechanism(s) different from mismatch repair insufficiency, and we would suggest that such a state be designated as single nucleotide instability (SNI).

Animals↗
PubMed2001

Prognostic significance of polysialic acid expression in resected non-small cell lung cancer.

Polysialic acid (PSA) is a carbohydrate attached mainly to the neural cell adhesion molecule. Because PSA is composed of a linear homopolymer of alpha-2-8-linked sialic acid residues and has a large negative charge, the presence of PSA attenuates the adhesive property of neural cell adhesion molecule and increases cellular motility. In an earlier study, we demonstrated that PSA and STX, a polysialyltransferase, were associated with tumor progression in non-small cell lung cancer (NSCLC) (F. Tanaka et al., Cancer Res., 60: 3072-3080, 2000). Therefore, in the present study, to assess the prognostic significance of PSA in resected NSCLC, a total of 236 patients who underwent complete resection for pathological (p)-stage I-IIIa disease were reviewed retrospectively. PSA was expressed in 44 of 236 (18.6%) patients, and the expression was correlated with p-stage disease. For all p-stage patients, 5-year survival rates for those with PSA-positive and PSA-negative tumors were 52.1% and 71.3%, respectively, demonstrating a significantly worse prognosis for the PSA-positive patients (P = 0.012). Analysis for only p-stage I patients also demonstrated a significantly worse prognosis for the PSA-positive patients; 5-year survival rates of the PSA-positive and the PSA-negative patients were 45.1% and 83.5%, respectively, (P < 0.001). In addition, there proved to be no difference in the postoperative survival among p-stage I, II, and IIIa patients when PSA expression was positive. Multivariate analysis confirmed that PSA expression was an independent factor to predict poor prognosis in resected NSCLC. These results suggested that PSA could be an important clinical marker and that preoperative induction and/or postoperative adjuvant therapies should be performed for PSA-positive NSCLC, even if the disease is classified as p-stage I.

Biomarkers, Tumor↗
PubMed2001

Clinical significance of caspase-3 expression in pathologic-stage I, nonsmall-cell lung cancer.

Caspase-3 is a cysteine protease that plays an important role in the process of apoptotic cell death. Whereas many studies on the clinical significance of apoptosis in the therapy of malignant tumors have been reported, little has been studied clinically on caspase-3. In the present study, the clinical significance of caspase-3 expression in resected nonsmall-cell lung cancer (NSCLC) and its correlation with incidence of apoptosis were examined. A total of 118 consecutive patients who had undergone complete resection for pathologic Stage I NSCLC were retrospectively reviewed. Caspase-3 expression was examined immunohistochemically using a polyclonal antibody that recognized uncleaved caspase-3. The 5-year survival rate for patients with strong expression of caspase-3 (66.6%) was significantly lower than that for patients with weak expression (82.1%, P = 0.021). Expression of caspase-3 was not correlated with incidence of apoptosis, proliferative activity, or p53 status. Multivariate analysis confirmed that strong expression of caspase-3 was a significant factor to predict poor prognosis. These results suggest that enhanced expression of "uncleaved" caspase-3, that is, inactivated caspase-3, was correlated with poor prognosis in resected NSCLC.

Aged↗
PubMed2001

Inflammatory endobronchial stenosis.

We encountered a 71-year-old woman with inoperable bronchial stenosis of the right main bronchus, which was caused by inflammatory granulation infected with Pseudomonas aeruginosa in posttuberculous bronchiectasis. Two months after placement of self-expanding nitinol stents, fiberoptic bronchoscopic examination to investigate hemosputum revealed endobronchial granuloma formation. Endobronchial granulation has disappeared with long-term oral administration of tranilast.

Administration, Oral↗
PubMed2001

Diffuse panbronchiolitis--pathophysiology and treatment mechanisms.

Diffuse panbronchiolitis (DPB) is a chronic, potentially life-threatening lower respiratory tract disease that is particularly common in Japanese people. It is characterized by chronic infiltration of inflammatory cells, and Pseudomonas aeruginosa is isolated from sputum in some cases. Bronchoalveolar lavage fluid from DPB patients contains high concentrations of neutrophils, lymphocytes and inflammatory cytokines compared with levels found in other chronic lung diseases. If left untreated, DPB progresses rapidly and is usually fatal, but long-term, low-dose macrolide therapy improves the prognosis. Macrolides are effective against DPB even in the absence of a P. aeruginosa infection. There is evidence that these antibiotic agents may have an anti-inflammatory mode of action in DPB.

Anti-Bacterial Agents↗
PubMed2001

Prognostic factors in patients with resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC).

OBJECTIVES: To clarify prognostic factors in resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC). METHODS: A total of 95 consecutive patients who underwent complete tumor resection and mediastinal dissection for pT1-2N1M0 NSCLC between 1976 and 1997 were retrospectively reviewed. p53 status and proliferative activity were evaluated immunohistochemically. RESULTS: The extent of N1 stations and p53 status proved to be significant prognostic factors. The 5-year survival rate for tumor without hilar node (#10) involvement was 66%, significantly higher than that for tumor with #10 involvement (39%, P<0.01). The 5-year survival rate for tumor with aberrant p53 expression was 37%, significantly lower than that for tumor without aberrant p53 expression (74%, P<0.01). There proved to be no significant difference in the prognosis between pT1 disease and pT2 disease; the 5-year survival rates for pT1 and pT2 diseases were 62 and 56%, respectively. Age, gender, performance status, grade of tumor differentiation, histological type, or proliferative activity were not significant factors. Multivariate analysis of prognostic factors using Cox's proportional hazard model confirmed these results. CONCLUSIONS: Involvement of the hilar node and aberrant p53 expression were significant factors to predict a worse prognosis in resected T1-2N1M0 NSCLC.

Biomarkers, Tumor↗
PubMed2001

Quinapril with high affinity to tissue angiotensin-converting enzyme reduces restenosis after percutaneous transcatheter coronary intervention.

Experimental studies have demonstrated that vascular injury resulted in an induction of vascular angiotensin-converting enzyme (ACE), and have suggested that inhibition of vascular ACE might be important in the prevention of restenosis. The present study aimed to determine the effect of quinapril, an ACE inhibitor with high affinity to tissue ACE, on restenosis following coronary intervention. The design of this study was a prospective, randomized, open, and non-placebo controlled trial. Patients with ischemic heart disease were enrolled after successful percutaneous transluminal coronary angioplasty or stent implantation at 7 participating institutions. Two hundred and fifty-three patients with 294 lesions were randomly assigned to the quinapril (10-20 mg per day) group or control group. Administration of quinapril was continued for 3-6 months of the follow-up. Quantitative coronary angiography was performed before and after angioplasty and at follow-up. Core laboratory measurements were performed independently and blinded. Follow-up angiography was performed in 108 patients with 124 lesions in the quinapril group and in 107 patients with 130 lesions in the control group. The baseline characteristics and findings of angioplasty showed no significant differences between the two groups. However, in the quinapril group, restenosis per patient and per lesion was significantly lower (34.3% vs. 47.7%, p < 0.05 and 30.6% vs. 43.8%, p < 0.05). Multivariable analysis revealed that administration of quinapril independently contributed to reducing the restenosis per patient and per lesion (odds ratio, 0.73; 95% confidence interval, 0.54-0.99 and odds ratio, 0.75; 95% confidence interval, 0.57-0.99). In conclusion, quinapril significantly reduces restenosis following coronary intervention.

Aged↗