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Biomedical subjects

K Takeyama

Publications and source records attributed to K Takeyama.

At least 19 recordsLinked to original sources
PubMed2006

Fatal hepatitis B virus reactivation in a chronic myeloid leukemia patient during imatinib mesylate treatment.

Reactivation of chronic hepatitis B virus (HBV) infection in patients undergoing chemotherapy is well-documented, but reactivation during imatinib mesylate treatment has not been reported. This study reports a 54-year-old man, without prior liver dysfunction but with chronic HBV infection, in whom fatal HBV reactivation occurred during treatment of chronic myeloid leukemia (CML) with imatinib mesylate. He developed fulminant hepatitis followed by marked elevation of HBV DNA polymerase, probably from the lymphocytopenic and immunosuppressive status induced by imatinib mesylate. Imatinib mesylate is widely used to treat CML patients. Although therapy with imatinib mesylate is generally well tolerated, the case presented here suggests that viral reactivation should be considered, even when using imatinib mesylate to treat CML.

Antineoplastic Agents↗
PubMed2001

Validity and safety of sputum induction by inhaled uridine 5'-triphosphate.

UNLABELLED: Inhalation of hypertonic saline during sputum induction causes bronchoconstriction. We studied the validity and safety of sputum induction by uridine 5'-triphosphate (UTP). Sputum was induced by a 5-min inhalation of hypertonic saline (3%) on Day 1 and UTP (5 mg/ml in 0.9% saline) on Days 8 and 15 in 16 healthy subjects and 16 patients with mild-to-moderate asthma. Inhaled UTP produced twofold greater amounts of sputum than did hypertonic saline. There were significant differences in oxygen desaturation and bronchoconstriction during the procedure between the two methods: the maximal fall in Sa(O(2)), the AUC of the Sa(O(2))-time response, and the fall in PEF were less in the subjects who received UTP than in those who received hypertonic saline. Sputum total cell and differential cell counts, with a high proportion of eosinophils in asthmatics, were similar between specimens obtained by hypertonic saline and UTP. When we compared two consecutive measurements on the UTP-induced sputum samples, the reproducibility calculated by the intraclass correlation coefficient was high for the proportion of eosinophils, neutrophils, and macrophages. Therefore, inhalation of UTP aerosols may provide an effective, relatively noninvasive, valid, and reproducible method of sputum induction for the assessment of airway inflammation in asthma. KEYWORDS: uridine triphosphate; induced sputum; airway inflammation; bronchoconstriction; asthma

Administration, Inhalation↗
PubMed2001

A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA.

One class of the nuclear receptor AF-2 coactivator complexes contains the SRC-1/TIF2 family, CBP/p300 and an RNA coactivator, SRA. We identified a subfamily of RNA-binding DEAD-box proteins (p72/p68) as a human estrogen receptor alpha (hER alpha) coactivator in the complex containing these factors. p72/p68 interacted with both the AD2 of any SRC-1/TIF2 family protein and the hER alpha A/B domain, but not with any other nuclear receptor tested. p72/p68, TIF2 (SRC-1) and SRA were co-immunoprecipitated with estrogen-bound hER alpha in MCF7 cells and in partially purified complexes associated with hER alpha from HeLa nuclear extracts. Estrogen induced co-localization of p72 with hER alpha and TIF2 in the nucleus. The presence of p72/p68 potentiated the estrogen-induced expression of the endogenous pS2 gene in MCF7 cells. In a transient expression assay, a combination of p72/p68 with SRA and one TIF2 brought an ultimate synergism to the estrogen-induced transactivation of hER alpha. These findings indicate that p72/p68 acts as an ER subtype-selective coactivator through ER alpha AF-1 by associating with the coactivator complex to bind its AF-2 through direct binding with SRA and the SRC-1/TIF2 family proteins.

Amino Acid Motifs↗
PubMed2001

Staphylococcus aureus bacteriuria and surgical site infections by methicillin-resistant Staphylococcus aureus.

Surgical site infection (SSI) remains an important cause of morbidity among hospitalized patients. We reviewed 421 patients who underwent open urological operations between January 1993 and December 1997 in our institute. Group I consisted of 259 patients who received uncontrolled antimicrobial prophylaxis (AMP) between 1993 and 1995. Group II consisted of 162 patients who received controlled AMP between 1996 and 1997. In group II, penicillins or first to second-generation cephalosporins was used and the duration of use for these agents regulated according to the wound class of each operation. The operations with clean wounds showed the lowest rate of SSI in both groups; the operations with contaminated wounds showed the highest rate of SSI (32.0% in group I and 33.3% in group II). There was no significant difference in the total rates of SSI between the two groups (P=0.216). The most frequently isolated bacterial species was methicillin-resistant Staphylococcus aureus (MRSA), isolated in 73.3% of the cases in group I and in 93.3% in group II. There was no significant difference in the incidence of MRSA isolation between the two groups (P=0.114). The controlled AMP could not lower the incidence of MRSA-induced SSIs. In SSI patients, 22.7% of group I and 35.7% in group II, had MRSA bacteriuria before operation. The prohibition of third-generation cephalosporins and shorter duration of AMP did not reduce the incidence of SSI induced by MRSA because MRSA was not the emerging microorganism but rather a resident in the urological ward. On the other hand, the total incidence of SSI did not increase after regulation of AMP. This finding suggests that older antibacterial agents can prevent infection, except those caused by resistant microorganisms such as MRSA. The effective counter-measure for the prevention of MRSA-induced SSI is needed.

Anti-Infective Agents, Urinary↗
PubMed2001

IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils.

Mucus hypersecretion contributes to the morbidity and mortality in acute asthma. Both T helper 2 (Th2) cytokines and epidermal growth factor receptor (EGFR) signaling have been implicated in allergen-induced goblet cell (GC) metaplasia. Present results show that a cascade of EGFR involving neutrophils is implicated in interleukin (IL)-13-induced mucin expression in GC. Treatment with a selective EGFR tyrosine kinase inhibitor prevented IL-13-induced GC metaplasia dose dependently and completely. Instillation of IL-13 also induced tumor necrosis factor-alpha protein expression, mainly in infiltrating neutrophils. Control airway epithelium contained few leukocytes, but intratracheal instillation of IL-13 resulted in time-dependent leukocyte recruitment by IL-13-induced IL-8-like chemoattractant expression in airway epithelium. Pretreatment with an inhibitor of leukocytes in the bone marrow (cyclophosphamide) or with a blocking antibody to IL-8 prevented both IL-13-induced leukocyte recruitment and GC metaplasia. These findings indicate that EGFR signaling is involved in IL-13-induced mucin production. They suggest a potential therapeutic role for inhibitors of the EGFR cascade in the hypersecretion that occurs in acute asthma.

Animals↗
PubMed2001

Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke.

Mucus hypersecretion from hyperplastic airway goblet cells is a hallmark of chronic obstructive pulmonary disease (COPD). Although cigarette smoking is thought to be involved in mucus hypersecretion in COPD, the mechanism by which cigarette smoke induces mucus overproduction is unknown. Here we show that activation of epidermal growth factor receptors (EGFR) is responsible for mucin production after inhalation of cigarette smoke in airways in vitro and in vivo. In the airway epithelial cell line NCI-H292, exposure to cigarette smoke upregulated the EGFR mRNA expression and induced activation of EGFR-specific tyrosine phosphorylation, resulting in upregulation of MUC5AC mRNA and protein production, effects that were inhibited completely by selective EGFR tyrosine kinase inhibitors (BIBX1522, AG-1478) and that were decreased by antioxidants. In vivo, cigarette smoke inhalation increased MUC5AC mRNA and goblet cell production in rat airways, effects that were prevented by pretreatment with BIBX1522. These effects may explain the goblet cell hyperplasia that occurs in COPD and may provide a novel strategy for therapy in airway hypersecretory diseases.

Animals↗
PubMed2001

Relationship of epidermal growth factor receptors to goblet cell production in human bronchi.

To determine the relationship of epidermal growth factor receptor (EGFR) expression to mucin synthesis in human airways, we examined EGFR and MUC5AC expression at both gene and protein levels using in situ hybridization and immunohistochemical analysis in human bronchi. Bronchial mucosal biopsy specimens were obtained from 12 asthmatic subjects and 11 healthy subjects. In asthmatic airways, EGFR mRNA was expressed in the airway epithelium. EGFR immunoreactivity staining patterns varied among the asthmatic airways: staining was positive mainly in goblet cells, in basal cells, or in both. In contrast, healthy airways showed little expression of EGFR mRNA; EGFR immunoreactivity was observed mainly in goblet cells. In parallel to EGFR expression, MUC5AC mRNA expression was greater in asthmatic airways; mucous glycoconjugates that stained positively with Alcian blue/PAS were also increased in asthmatic airways. Ciliated cells were negative for EGFR and MUC5AC both in asthmatic and in healthy subjects at both mRNA and protein levels. There was a significant positive correlation between EGFR immunoreactivity and the area of MUC5AC-positive staining in both asthmatics and healthy subjects. These findings suggest a sequence of events by which EGFR activation is involved in mucin expression in asthmatic airway epithelium.

Adult↗
PubMed2001

The molecular basis of vitamin D-dependent rickets type I.

Vitamin D 1alpha-hydroxylase is a key enzyme for the vitamin D-calcium homeostasis. Recently, 1alpha-hydroxylase cDNA and gene were cloned. Human 1alpha-hydroxylase gene is located at chromosome 12q13.3. Several inactivating mutations in the 1alpha-hydroxylase gene were found in VDDR I patients, and it was established that 1alpha-hydroxylase gene is responsible for VDDR I. To date, various mutations spreading over all exons have been reported. The cloning of 1alpha-hydroxylase gene will further lead to the better understanding of vitamin D regulation in both normal and pathological states. In addition, 1alpha-hydroxylase knock-out mice, which is recently generated, would be a useful model animal for VDDR I.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2001

Influence of body fat on the onset of vecuronium induced neuromuscular blockade.

The onset time of vecuronium, a muscle relaxant, was measured after a bolus intravenous injection of 0.15 mg kg(-1) of vecuronium into 40 surgical patients aged 59-64 years. The onset time was then compared between male and female patients and the relationship between onset time and body fat (% of body weight) was analyzed. Arterial plasma concentrations of vecuronium were measured at 75, 195, and 375 sec after administration of vecuronium to 8 patients. The female patients (n = 23) showed a shorter onset time and more body fat than the male patients (n = 17). The onset time significantly decreased with increasing body fat in both groups. When only females with body fat of less than 30% (n = 10) were compared with the male group (all male patients had body fat of less than 30%), the body fat, onset time, and regression lines between the onset time and the body fat did not differ significantly. Except in the patient with the highest body fat, plasma concentrations at 195 and 375 sec significantly increased with increasing body fat. We concluded that the higher body fat in females is largely responsible for the faster onset of vecuronium action in females. A smaller distribution volume of vecuronium may also be one of the reasons for the faster onset of vecuronium in females.

Adipose Tissue↗
PubMed2001

Valsalva maneuver prevents guide wire trouble associated with 22-gauge safe guide.

UNLABELLED: The Safe guide is a central venous puncture needle that serves as both a pilot needle and as an introducer. A guide wire can be inserted into a vein through the side port at the hub of the 22-gauge Safe guides needle initially inserted as a pilot needle. However, guide wire insertion may fail due to kinking or locking at the side port. Increasing airway pressure to 20 cm H2O by squeezing a respiratory bag during insertion of the guide wire together with venous puncture was attempted to determine if would decrease guide wire trouble. SUBJECTS AND METHODS: A total of 120 patients scheduled for central venous catheterization by right internal jugular puncture were divided into two groups. Patients in group-A (n = 60) were catheterized by the conventional method and those in group-B (n = 60) were catheterized by applying the Valsalva maneuver. Three observations were made: 1) Frequency of cases in which blood back-flow occurred during withdrawal only and not upon advancement of the puncture needle. 2) Frequency of cases in which kinking and/or locking of the guide wire occurred at the hub during its insertion. And 3) the occurrence of complications. RESULTS: 1) The patency of the vein was preserved and blood back-flow was obtained during advancement of the puncture needle in all cases in which the Valsalva maneuver was applied. 2) The incidence of kinking and/or locking during insertion of the guide wire decreased from 16.7% to 3.4% by applying positive airway pressure during the Valsalva maneuver. And 3) complications were negligible. Additionally, the application of the Valsalva maneuver allowed successful guide wire insertion in 6 out of 9 cases (67%) in group-A, in which the initial attempt using the conventional method had failed. CONCLUSION: The application of positive airway pressure using the Valsalva maneuver may prevent the guide wire trouble associated with the 22-gauge Safe guide.

Catheterization, Central Venous↗
PubMed2000

Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators.

The nuclear peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily and acts as a ligand-dependent transcription factor mediating adipocyte differentiation, cell proliferation and inflammatory processes, and modulation of insulin sensitivity. Members of the 160-kDa protein (SRC-1/TIF2/AIB-1) family of coactivators, CBP/p300 and TRAP220/DRIP205, are shown to interact directly with PPARgamma and potentiate nuclear receptor transactivation function in a ligand-dependent fashion. Because PPARgamma ligands exert partially overlapping but distinct subsets of biological action through PPARgamma binding, we wished to examine whether interactions between PPARgamma and known coactivators were induced to the same extent by different classes of PPARgamma ligand. The natural ligand 15-deoxy-Delta12,14-prostaglandin J(2) induced PPARgamma interactions with all coactivators tested (SRC-1, TIF2, AIB-1, p300, TRAP220/DRIP205) in yeast and mammalian two-hybrid assays, as well as in a glutathione S-transferase pull-down assay. However, under the same conditions troglitazone, a synthetic PPARgamma ligand that acts as an antidiabetic agent, did not induce PPARgamma interactions with any of the coactivators. Our findings suggest that ligand binding may alter PPARgamma structure in a ligand type-specific way, resulting in distinct PPARgamma-coactivator interactions.

Animals↗
PubMed2000

Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils.

Oxidative stress has been implicated in the pathogenesis of inflammatory diseases of airways. Here we show that oxidative stress causes ligand-independent activation of epidermal growth factor receptors (EGFR) and subsequent activation of mitogen-activated protein kinase kinase (MEK)-p44/42 mitogen-activated protein kinase (p44/42mapk), resulting in mucin synthesis in NCI-H292 cells. Exogenous hydrogen peroxide and neutrophils activated by IL-8, FMLP, or TNF-alpha increased EGFR tyrosine phosphorylation and subsequent activation of p44/42mapk and up-regulated the expression of MUC5AC at both mRNA and protein levels in NCI-H292 cells. These effects were blocked by selective EGFR tyrosine kinase inhibitors (AG1478, BIBX1522) and by a selective MEK inhibitor (PD98059), whereas a selective platelet-derived growth factor receptor tyrosine kinase inhibitor (AG1295), a selective p38 MAPK inhibitor (SB203580), and a negative compound of tyrosine kinase inhibitors (A1) were without effect. Neutrophil supernatant-induced EGFR tyrosine phosphorylation, activation of p44/42mapk, and MUC5AC synthesis were inhibited by antioxidants (N-acetyl-cysteine, DMSO, dimethyl thiourea, or superoxide dismutase); neutralizing Abs to EGFR ligands (EGF and TGF-alpha) were without effect, and no TGF-alpha protein was found in the neutrophil supernatant. In contrast, the EGFR ligand, TGF-alpha, increased EGFR tyrosine phosphorylation, activation of p44/42mapk, and subsequent MUC5AC synthesis, but these effects were not inhibited by antioxidants. These results implicate oxidative stress in stimulating mucin synthesis in airways and provide new therapeutic approaches in airway hypersecretory diseases.

Antioxidants↗
PubMed2000

Cardiac conduction abnormalities in patients with breast cancer undergoing high-dose chemotherapy and stem cell transplantation.

Cardiac toxicities in 39 consecutive patients with breast cancer receiving high-dose chemotherapy (HDC) with stem cell transplantation were reviewed. All 39 patients received various anthracycline-containing regimens in adjuvant settings and/or for metastatic disease before HDC. As a cytoreductive regimen, all received cyclophosphamide 2000 mg/m2 and thiotepa 200 mg/m2 for 3 consecutive days. No immediate fatal toxicities were observed, but one patient developed chronic congestive heart failure and two had transient left ventricular dysfunction. Pericardial effusion was observed in another three patients. ST-T abnormalities during HDC were observed in two patients and arrhythmias were observed in nine, four of which occurred during stem cell infusion (SCI). There were three atrial arrhythmias, two ventricular arrhythmias, and four atrioventricular (AV)-block episodes. Two patients developed advanced and complete AV-block with an asystolic pause. Notably, three patients experienced AV-block with uncontrolled vomiting. No relationship was observed between the cumulative dose of anthracycline and cardiac toxicities during HDC. These results suggest that abnormalities in the conduction system during HDC may be more frequent than previously reported. Vagal reflex secondary to emesis may play an important role in the development of AV-block. Bone Marrow Transplantation (2000) 25, 185-189.

Adult↗
PubMed2000

Prognostic significance of the cell cycle inhibitor p27Kip1 in acute myeloid leukemia.

There are few molecular biologic determinants that are prognostic for patients with acute myeloid leukemia (AML). Hence, we examined whether cellular levels of the cyclin-dependent kinase inhibitor p27Kip1 in acute myeloid leukemia could be used to predict clinical outcome in AML. Using immunoblot analysis, levels of p27 were assessed in blast cells from 72 AML patients who were registered and treated by the identical chemotherapy protocol. AML cases were classified into three groups on the basis of the percentage of the expression level of p27 compared to a control cell line. AML cases exhibiting p27 expression at low, moderate, and high levels were 43, 9, and 20 cases, respectively. No significant differences in the rates of complete remission (CR) were observed among the three groups. Although the level of p27 expression was not correlated with any other possible prognostic markers, such as age, white blood cell count, chromosome abnormalities, and FAB subclasses, patients with high p27 expression had a significantly increased disease-free survival (DFS) (78% vs 19%, P = 0.004). We further examined the expression of cyclin E at the protein level in all 72 AML cases. We observed a statistically significant correlation between a high cyclin E level and a high p27 level (P < 0.005). However, we failed to find any correlation between the rates of CR or DFS and cyclin E expression. The present study reveals that levels of p27 expression can be one of the useful prognostic molecular markers for AML. Leukemia (2000) 14, 28-33.

Acute Disease↗
PubMed2000

Suplatast tosilate inhibits goblet-cell metaplasia of airway epithelium in sensitized mice.

BACKGROUND: IL-4 and IL-13 play a putative role in mucus hypersecretion in asthma. Suplatast tosilate prevents the synthesis of T(H2) cytokines. OBJECTIVE: Because suplatast tosilate inhibits T(H2) cytokines but does not inhibits IFN-gamma production, we examined the effect of suplatast on IL-4- or IL-13- and ovalbumin (OVA)-induced mucin synthesis in NCI-H292 cells in vitro and in bronchi of pathogen-free BALB/c mice in vivo. METHODS: In vitro, NCI-H292 cells were preincubated with suplatast tosilate (0.1-100 microgram/mL) 1 hour before adding human recombinant IL-4 (10 ng/mL). In vivo, mouse recombinant IL-4 or IL-13 (250 ng per/mouse) was instilled intranasally in mice pretreated with suplatast tosilate (50 mg.kg(-1).d(-1)). Mucous glycoconjugates were stained with Alcian blue (AB)/periodic acid-Schiff (PAS) stain. To evaluate effects of suplatast tosilate on goblet-cell metaplasia in OVA-sensitized mice, animals were pretreated with suplatast tosilate (1-50 mg.kg(-1).d(-1)) intragastrically. IL-4 and IL-13 were measured, and allergic inflammatory cells were analyzed in bronchoalveolar lavage fluid of OVA-sensitized mice. RESULTS: Pretreatment with suplastast did not prevent IL-4- or IL-13-induced increase in mucous glycoconjugate production in NCI-H292 cells or in mice. OVA sensitization increased AB/PAS-stained area of the epithelium (48.1% +/- 2.4%, P <.01 compared with control mice). Suplatast tosilate inhibited OVA-induced goblet-cell metaplasia in airway epithelium in a dose-dependent fashion; 50 mg.kg(-1).d(-1) decreased the AB/PAS area to 22.7% +/- 2.7% (P <.05 compared with OVA sensitization alone). Pretreatment with suplatast tosilate also prevented OVA-induced increase in IL-4 and IL-13 levels and decreased the number of lymphocytes and eosinophils in bronchoalveolar lavage fluid (P <.05 compared with values of mice given OVA alone). CONCLUSION: These results indicate that suplatast tosilate prevents allergen-induced goblet-cell metaplasia and the recruitment of eosinophils and lymphocytes into the airways. These results suggest that this effect is due to the prevention of the production of T(H2) cytokines in airways.

Animals↗
PubMed2000

Relation of epidermal growth factor receptor expression to goblet cell hyperplasia in nasal polyps.

BACKGROUND: Because the epidermal growth factor receptor (EGFR) system regulates mucin production in airway epithelium, we hypothesized a role for this system in mucus hypersecretion that occurs in nasal polyposis. OBJECTIVE: We examined the relationship between goblet cell hyperplasia, EGFR expression, and inflammatory mediators produced by eosinophils and neutrophils in nasal polyp tissues. METHODS: Nasal polyp tissue samples from 8 patients and nasal turbinate biopsy specimens from 6 normal control subjects were examined for alcian blue/PAS staining, mucin MUC5AC (MUC5AC), and EGFR immunoreactivity and EGFR gene expression (in situ hybridization). We also examined the role of eosinophils and neutrophils in goblet cell hyperplasia. RESULTS: In control nasal mucosa alcian blue/periodic acid-Schiff- and MUC5AC-stained areas were 18.40% +/- 1.31% and 21.89% +/- 1.43%, respectively. In polyps the alcian blue/periodic acid-Schiff- and MUC5AC-stained areas were 51.30% +/- 5.85% and 52.07% +/- 6.58%, which was significantly larger than that found in control subjects (each comparison, P <.01). Four of 6 control specimens expressed EGFR messenger RNA and protein weakly in the epithelium. In polyps 4 of 8 specimens expressed EGFR gene and EGFR protein strongly; the EGFR-stained area was greater in hyperplastic than in pseudostratified epithelium. TNF-alpha immunoreactivity, expressed in eosinophils, was increased in EGFR-positive polyps compared with EGFR-negative polyps, suggesting a role for TNF-alpha in EGFR expression. Neutrophils were increased in the epithelium of EGFR-positive compared with EGFR-negative polyps, suggesting a role for these cells in mucin expression and in goblet cell degranulation. CONCLUSION: These data suggest a role for EGFR cascade in the regulation of goblet cell mucins in nasal polyps. Proof of concept will require clinical studies using selective EGFR inhibitors.

Cell Movement↗
PubMed2000

Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways.

We hypothesized that foreign bodies in airways cause inflammation leading to goblet cell metaplasia. Instilled agarose plugs lodged in the bronchi of pathogen-free rats caused a time-dependent increase in Alcian blue-periodic acid-Schiff staining that was detected within 24 h and markedly increased at 72 h. Control bronchi contained no pregoblet or goblet cells, but plugged bronchi contained many pregoblet and goblet cells and a decrease in nongranulated secretory cells. In situ hybridization showed no expression of MUC5AC in control airways, but plugged airways showed a marked expression. Control bronchi showed sparse staining for epidermal growth factor receptor (EGFR) protein, but plugged bronchi showed intense EGFR staining in the epithelium. Pretreatment with an EGFR tyrosine kinase inhibitor (BIBX1522) prevented Alcian blue-periodic acid-Schiff staining and MUC5AC gene expression in plugged bronchi. Pretreatment with tumor necrosis factor-alpha neutralizing antibody or pretreatment with cyclophosphamide abolished plug-induced EGFR protein expression and goblet cell metaplasia. Thus instillation of agarose plugs induces profound goblet cell metaplasia by causing EGFR expression and activation.

Animals↗