Orange Leafhopper Cicadulina bipunctata Feeding Induces Gall Formation Nitrogen Dependently and Regulates Gibberellin Signaling.

Orange leafhopper Cicadulina bipunctata feeding induces wallaby ear symptoms, namely growth suppression and gall formation characterized by severe swelling of leaf veins, on various Poaceae, thereby leading to low crop yields. Here, we investigated the development of wallaby ear symptoms on rice seedlings due to C. bipunctata feeding. After confirming that C. bipunctata feeding induces growth suppression and gall formation on rice seedlings, we further demonstrated that gall formation score decreased with decreasing levels of nitrogen in the medium and that C. bipunctata feeding induces the expression levels of nitrogen transporter genes. These gene expression changes may participate in the nutrient accumulation observed in galled tissues and in gall formation. In addition, these expression changes should induce growth promotion but the inhibition of gibberellin signaling by C. bipunctata feeding might be the reason why growth is suppressed. Treatment with plant growth regulators did not affect gall formation, suggesting the existence of a complex gall formation mechanism by C. bipunctata feeding.

Altered tolbutamide pharmacokinetics by a decrease in hepatic expression of CYP2C6/11 in rats pretreated with 5-fluorouracil.

1. We investigated the change in the pharmacokinetic profile of tolbutamide (TB), a substrate for CYP2C6/11, 4 days after single administration of 5-fluorouracil (5-FU), and the hepatic gene expression and activity of CYP2C6/11 were also examined in 5-FU-pretreated rats. 2. Regarding the pharmacokinetic parameters of the 5-FU group, the area under the curve (AUC) was significantly increased, and correspondingly, the elimination rate constant at the terminal phase (ke) was significantly decreased without significant change in the volume of distribution at the steady state (Vdss). 3. The metabolic production of 4-hydroxylated TB in hepatic microsomes was significantly reduced by the administration of 5-FU. 4. The expression level of mRNAs for hepatic CYP2C6 and CYP2C11 was significantly lower than in the control group when the rats were pretreated with 5-FU. 5. These results demonstrated that the pharmacokinetic profile of TB was altered by the treatment with 5-FU through a metabolic process, which may be responsible for the decreased CYP2C6/11 expression at mRNA levels.

Overexpression of microRNA-155 suppresses chemokine expression induced by Interleukin-13 in BEAS-2B human bronchial epithelial cells.

BACKGROUND: MicroRNAs are non-coding small RNAs that regulate expression of target genes by binding to 3' untranslated regions. In this study, we used bronchial epithelial cells to investigate in vitro the role of the microRNA miR-155 in the expression of chemokines associated with airway inflammation. miR-155 has previously been reported to regulate allergic inflammation. METHODS: BEAS-2B bronchial epithelial cells were cultured and transfected with mimic or inhibitor oligonucleotides to overexpress or downregulate miR-155, as confirmed by real-time PCR. Cells were then stimulated with tumor necrosis factor-alpha, interleukin-13 (IL-13), and a double stranded RNA that binds Toll-like receptor 3. Expression and secretion of the chemokines CCL5, CCL11, CCL26, CXCL8, and CXCL10 were then quantified by real-time PCR and ELISA, respectively. Phosphorylation of signal transducer and activator of transcription 6 (STAT6), a target of the IL-13 receptor, was analyzed by ELISA. RESULTS: miR-155 overexpression significantly suppressed IL-13-induced secretion of CCL11 and CCL26. These effects were specific, and were not observed for other chemokines, nor in cells with downregulated miR-155. miR-155 overexpression also suppressed CCL11 and CCL26 mRNA, but did not affect expression of the IL-13 receptor or phosphorylation of STAT6. CONCLUSIONS: miR-155 specifically inhibits IL-13-induced expression of eosinophilic chemokines CCL11 and CCL26 in bronchial epithelial cells, even though the 3'-untranslated region of these genes do not contain a consensus binding site for miR-155.

Step-down therapy in well-controlled asthmatic patients using salmeterol xinafoate/fluticasone propionate combination therapy.

PURPOSE: A combination therapy with inhaled corticosteroid (ICS) and a long-acting ß agonist (LABA) is the standard treatment for asthmatic patients, and step-down treatment is recommended once control has been achieved. However, little data exist that evaluate the long-term outcomes after step-down treatment. OBJECTIVE: To compare the long-term outcomes of step-down therapy with ICS/LABA or ICS alone for asthmatic patients who have achieved well-controlled asthma by the ICS (250 µg fluticasone)/LABA (50 µg salmeterol) combination (SFC, two puffs per day). PATIENTS AND METHODS: We randomized 40 well-controlled patients with asthma receiving SFC (250 µg) to two groups; one group of patients received step-down therapy with low-dose SFC (100 µg, two puffs daily) and another group of patients received step-down therapy with high-dose fluticasone propionate (FP) alone (500 µg, daily). The two groups were monitored over 12 months for changes in asthma control test scores, respiratory function (percent forced expiratory volume in 1 second, maximal expiratory flow rate at 50% of the vital capacity [%FEF50], and maximal expiratory flow rate at 25% of the vital capacity [%FEF25]), and the concentration of fractional exhaled nitric oxide. RESULTS: There was no significant difference in the dropout rate between the SFC and FP groups. Low-dose SFC maintained the stability of all parameters over 12 months, whereas the FP group exhibited a rapid 5% decrease in forced expiratory volume in 1 second within 2 months after discontinuation of salmeterol; furthermore, after 10 months, there was a gradual decrease in %FEF50 and %FEF25. CONCLUSION: This study suggests that a balanced step-down protocol, including both ICS and LABA, is essential in providing long-term stability to patients with mild-to-moderate well-controlled asthma.

Decreased elimination clearance of midazolam by doxorubicin through reductions in the metabolic activity of hepatic CYP3A in rats.

1. We examined the effects of doxorubicin (DOX) on the expression level and metabolic activity of CYP3A in the liver as well as on the pharmacokinetics of midazolam (MDZ), a probe for CYP3A, in rats. Changes in the hepatic status of DOX-treated rats were confirmed. 2. Serum levels of the biomarkers of hepatic impairment were elevated by the DOX treatment, which was consistent with the results obtained from a histopathological evaluation of the liver. 3. No significant difference was observed in the expression of proteins for hepatic CYP3A1 and CYP3A2 between the DOX and control groups. The metabolic production of 1'-hydroxylated and 4'-hydroxylated MDZ by hepatic microsomes was significantly lower in DOX-treated rats than in control rats. 4. The area under the curve (AUC) and the half-life (t1/2) of intravenously administered MDZ were significantly increased, and the total clearance (CLtot) and the elimination rate constant at the terminal phase (ke) were significantly decreased without significant changes in the volume of distribution at a steady state (Vdss). 5. These results indicated that a DOX-induced depression in the metabolic activity, but not expression level of CYP3A contributed to a decrease in the elimination clearance of MDZ, and also that reduced CYP3A function may be associated with the hepatotoxicity of DOX.

Comparison of physicians' compliance, clinical efficacy, and drug cost before and after introduction of Asthma Prevention and Management Guidelines in Japan (JGL2003).

BACKGROUND: This study investigated the variations in the clinical efficacy and drug cost following the introduction of the Asthma Prevention and Management Guidelines in Japan (JGL2003). METHODS: The medical charts of fifty outpatients treated continuously for asthma, aged 16-50 years, from October 2002 to October 2004 at Showa University Hospital were analyzed for physicians' compliance with asthma guidelines, symptom severity, episodes in various occasions, prescriptions and drug costs. RESULTS: Physicians' compliance with the guidelines, which were defined as the number of patient visits treated in conformity with the JGL over the total number of patient visits, was found to be high before (89.4%) and after (90.3%) the introduction of JGL2003, without a statistical difference. On the other hand, the distribution of asthma symptom severity varied significantly (P<0.0001). Fewer patients were recognized as having more severe asthma symptoms after the introduction of JGL2003. Significantly more patients with severe asthma symptoms were detected in the physicians' noncompliant group than in the compliant group (P<0.0001). The number of patients prescribed with oral corticosteroids, long-acting beta2-agonists containing patches, long-acting oral beta2-agonists, short-acting inhaled beta2-agonists, sustained-released theophylline and leukotriene receptor antagonists decreased after the introduction of JGL2003. Furthermore, the total annual drug cost per patient decreased significantly by an average of 16,259 yen (P=0.006). CONCLUSIONS: The JGL2003 was judged to have improved criteria, which thus resulted in the high compliance of physicians with the guidelines, in the remission of asthma symptoms and in the reduction in the total annual drug cost per patient.

Survey on the handling of chronic obstructive pulmonary disease by annual health check in Japan.

OBJECTIVE: Since mild COPD can be detected in the annual health check by lung function tests, we conducted a questionnaire survey on how such examinations are used to assess chronic obstructive pulmonary disease (COPD). METHODS: We mailed questionnaires to 633 facilities performing comprehensive medical check-up from June to July 2005 and obtained responses from 254 (40.1%). RESULTS: At participating facilities, the proportion of full or part-time physicians specializing in respiratory diseases was low [40 of 366 full timers (10.9%) and 114 of 2,044 part-timers (5.6%)], with very few physicians certified by the Japanese Respiratory Society (6.8%). Non respiratory physicians were involved in evaluating the results of thoracic diagnostic imaging at 32 facilities. Lung function tests were carried out at 98.2% of facilities though relatively few facilities evaluated test results with COPD in mind. All stages (mild, moderate, severe) of COPD were diagnosed in patients at 85 facilities (39.2%), while only severe COPD was targeted by chest imaging at 97 facilities (44.7%), disregarding mild and moderate cases. Counseling for smoking cessation was provided at 113 facilities (20.6%), while 30 facilities (14.4%) provided no form of smoking cessation. CONCLUSION: At most facilities performing a comprehensive medical check-up, there was not a sufficient number of respirologists to ensure early diagnosis of COPD and this may have compromised COPD diagnosis. The newly proposed Japan Society of Comprehensive Medical Check-up (Ningen-dock) Standards based on the Japanese Respiratory Society may be useful to reveal early stages of COPD.

[Case of primary cavitary sarcoidosis: exacerbation after 16 years from onset].

A 46-year-old man presented with the complaint of cough, fever and dyspnea on exercise. Sixteen years previously stage II sarcoidosis was diagnosed, with an ocular lesion. So far, he had had no respiratory symptoms and was followed up without medication. Two months before his visit, he had a cough. He gradually developed a fever and felt dyspnea on exercise. Chest X-ray showed an infiltrative shadow with a cavity in the right upper lobe. Bronchofiberscopy was performed and the biopsy specimen from the cavity wall revealed noncaseating epitheloid cell granulomas, suggesting primary cavitary sarcoidosis. Corticosterid therapy was started. His symptoms improved rapidly, and the infiltrative shadow on the right upper lobe decreased within one month. The cavity wall was thin on the following computed tomography. Thirty-two cases of primary cavity sarcoidosis were reported in Japan from 1975-2005. The mean age of the patients was 26.5 years old and the ratio of males to females was 13:3. In most cases, corticosteroid therapy was effective and nine spontaneously improved cases were reported. To determine the indications for steroid therapy, further examination is needed.

[Serum amyloid protein A was a useful marker for steroid tapering in a case of MPO-ANCA-associated vasculitis].

A 55-year-old man was admitted complaining of hemosputa, fever and dyspnea. The chest radiographs and computed tomography showed a diffuse alveolar filling pattern; suggesting alveolar hemorrhage. Laboratory data demonstrated renal dysfunction with hematuria and proteinuria and serum MPO-ANCA was also elevated. Respiratory failure progressed rapidly within two days. Steroid pulse therapy and plasmapheresis was performed. Thereafter, symptoms and chest radiograph findings improved dramatically. However proteinuria persisted as steroid administration was tapered. Renal biopsy demonstrated gromeluronephritis and interstitial lymphocyte infiltration. After administering a second course of steroid semi-pulse therapy, her proteinuria improved. C-reactive protein and MPO-ANCA decreased to normal levels after the initial steroid therapy, but serum amyloid A protein (SAA) gradually elevated. The second course of steroid pulse therapy normalized SAA, and proteinuria improved. Based on these findings, SAA seems to be a more sensitive marker for steroid tapering than either CRP or MPO-ANCA.

Structural changes of the airway wall impair respiratory function, even in mild asthma.

STUDY OBJECTIVES: To clarify whether structural changes of the airway wall impair respiratory function in patients with mild asthma, and to determine whether mild asthma should be treated with inhaled steroids. SETTING: Showa University Hospital in Tokyo. PATIENTS: Thirteen healthy nonatopic volunteers (control subjects), 26 patients with mild asthma treated with a bronchodilator alone without oral or inhaled corticosteroids or antiallergic agents, and 10 patients with mild-to-moderate asthma treated with inhaled corticosteroids. MEASUREMENTS: We measured the thickness of the epithelial reticular basement membrane (Rbm) of the airway wall in bronchial biopsy specimens from patients with asthma and from healthy control subjects. We also performed spirometry and histamine challenge tests to evaluate airflow obstruction and airway hyperresponsiveness. RESULTS: The thickness of the Rbm in patients with mild asthma was significantly greater than that in healthy control subjects and was negatively correlated with the FEV(1) as a percentage of FVC and the provocative concentration of histamine that caused a 20% decrease in FEV(1) from the post-saline solution baseline value. Moreover, the Rbm was thicker in patients with mild asthma not treated with inhaled steroids than in patients with mild-to-moderate asthma treated with inhaled steroids. CONCLUSIONS: The thickness of the Rbm is increased even in mild asthma and is correlated with airway obstruction and hyperresponsiveness. Our results suggests that anti-inflammatory treatment with inhaled steroids should be started in the early stage of bronchial asthma to prevent structural changes from occurring in the airway wall.