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1.  Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial 
Sakata, Yasuhiko | Shiba, Nobuyuki | Takahashi, Jun | Miyata, Satoshi | Nochioka, Kotaro | Miura, Masanobu | Takada, Tsuyoshi | Saga, Chiharu | Shinozaki, Tsuyoshi | Sugi, Masafumi | Nakagawa, Makoto | Sekiguchi, Nobuyo | Komaru, Tatsuya | Kato, Atsushi | Fukuchi, Mitsumasa | Nozaki, Eiji | Hiramoto, Tetsuya | Inoue, Kanichi | Goto, Toshikazu | Ohe, Masatoshi | Tamaki, Kenji | Ibayashi, Setsuro | Ishide, Nobumasa | Maruyama, Yukio | Tsuji, Ichiro | Shimokawa, Hiroaki | Shimokawa, H. | Fukuchi, M. | Goto, T. | Hiramoto, T. | Inoue, K. | Kato, A. | Komaru, T. | Ohe, M. | Sekiguchi, N. | Shiba, N. | Shinozaki, T. | Sugi, M. | Tamaki, K. | Hiramoto, T. | Inoue, K. | Kato, A. | Ogata, M. | Sato, S. | Sugi, M. | Ishide, N. | Ibayashi, S. | Maruyama, Y. | Ohno, I. | Tamaki, K. | Ogawa, H. | Kitakaze, M. | Tsuji, I. | Watanabe, T. | Sugiyama, K. | Oyama, S. | Nozaki, E. | Nakamura, A. | Takahashi, T. | Endo, H. | Fukui, S. | Nakajima, S. | Nakagawa, M. | Nozaki, T. | Yagi, T. | Horiguchi, S. | Fushimi, E. | Sugai, Y. | Takeda, S. | Fukahori, K. | Aizawa, K. | Ohe, M. | Tashima, T. | Sakurai, K. | Kobayashi, T. | Goto, T. | Matsui, M. | Tamada, Y. | Yahagi, T. | Fukui, A. | Takahashi, K. | Takahashi, K. | Kikuchi, Y. | Akai, K. | Kanno, H. | Kaneko, J. | Suzuki, S. | Takahashi, K. | Akai, K. | Katayose, D. | Onodera, S. | Hiramoto, T. | Komatsu, S. | Chida, M. | Iwabuchi, K. | Takeuchi, M. | Yahagi, H. | Takahashi, N. | Otsuka, K. | Koseki, Y. | Morita, M. | Shinozaki, T. | Ishizuka, T. | Onoue, N. | Yamaguchi, N. | Fujita, H. | Katoh, A. | Namiuchi, S. | Sugie, T. | Saji, K. | Takii, T. | Sugimura, A. | Ohashi, J. | Fukuchi, M. | Ogata, M. | Tanikawa, T. | Kitamukai, O. | Matsumoto, Y. | Inoue, K. | Koyama, J. | Tomioka, T. | Shioiri, H. | Ito, Y. | Kato, H. | Takahashi, C. | Kawana, A. | Sakata, Y. | Ito, K. | Nakayama, M. | Fukuda, K. | Takahashi, J. | Miyata, S. | Sugimura, K. | Sato, K. | Matsumoto, Y. | Nakano, M. | Shiroto, T. | Tsuburaya, R. | Nochioka, K. | Yamamoto, H. | Aoki, T. | Hao, K. | Miura, M. | Kondo, M. | Tatebe, S. | Yamamoto, S. | Suzuki, H. | Nishimiya, K. | Yaoita, N. | Sugi, M. | Yamamoto, Y. | Toda, S. | Minatoya, Y. | Takagi, Y. | Hasebe, Y. | Nihei, T. | Hanawa, K. | Fukuda, K. | Sakata, Y. | Takahashi, J. | Miyata, S. | Nochioka, K. | Miura, M. | Tadaki, S. | Ushigome, R. | Yamauchi, T. | Sato, K. | Tsuji, K. | Onose, T. | Abe, R. | Saga, C. | Suenaga, J. | Yamada, Y. | Kimura, J. | Ogino, H. | Oikawa, I. | Watanabe, S. | Saga, M. | Washio, M. | Nagasawa, K. | Nagasawa, S. | Kotaka, S. | Komatsu, W. | Hashimoto, R. | Ikeno, Y. | Suzuki, T. | Hamada, H.
European Heart Journal  2015;36(15):915-923.
We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19–2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11–1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01–2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24–2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at
PMCID: PMC4466154  PMID: 25637937
Heart failure; Hypertension; Angiotensin II receptor blocker; Olmesartan
2.  PARVB overexpression increases cell migration capability and defines high risk for endophytic growth and metastasis in tongue squamous cell carcinoma 
British Journal of Cancer  2014;112(2):338-344.
Tongue squamous cell carcinoma (TSCC) is highly diverse, even in its early stages. This cancer is classified into three subtypes (superficial, exophytic, and endophytic) based on macroscopic appearance. Of these subtypes, the endophytic tumours have the worst prognosis because of their invasiveness and higher frequency of metastasis.
To understand the molecular mechanism underlying the endophytic subtype and to identify biomarkers, we performed a comprehensive gene expression microarray analysis of clinical biopsy samples and also confirmed the clinical relevance of differential gene expression.
Expression of the parvin-beta (PARVB) gene and its encoded protein was significantly upregulated in endophytic-type TSCC. PARVB is known to play a critical role in actin reorganization and focal adhesions. Knockdown of PARVB expression in vitro caused apparent decreases in cell migration and wound healing, implying that PARVB has a crucial role in cell motility. Moreover, metastasis-free survival was significantly lower in patients with higher tumour expression of PARVB.
These findings suggest that PARVB overexpression is a candidate biomarker for endophytic tumours and metastasis. This protein may be a clinically useful target for adjuvant TSCC therapy.
PMCID: PMC4453450  PMID: 25422907
PARVB; tongue cancer; endophytic growth; subtype; migration; metastasis; microarray
4.  Enhancement of the radiation response of EMT-6 tumours by a copper octabromotetracarboranylphenylporphyrin 
The British Journal of Radiology  2012;85(1012):443-450.
The carborane-containing porphyrin, copper (II) 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(3-[1,2-dicarba-closo-dodecaboranyl]methoxyphenyl)-porphyrin (CuTCPBr), was investigated as a potential radiation enhancing agent for X-ray radiotherapy (XRT) in a subcutaneously implanted EMT-6 murine carcinoma.
The biodistribution and toxicological profile of this porphyrin has been shown to be favourable for another bimodal radiotherapy technique, boron neutron-capture therapy. For the XRT studies, CuTCPBr was formulated in either 9% Cremophor® (BASF Corporation, Ludwigschafen, Germany) EL and 18% propylene glycol (9% CRM) or a revised formulation comprising 1% Cremophor ELP, 2% Tween 80® (JT Baker, Mansfield, MA), 5% ethanol and 2.2% PEG 400 (CTEP formulation), which would be more clinically acceptable than the original 9% CRM formulation. Using the 9% CRM formulation of CuTCPBr, doses of 100, 210 or 400 mg kg−1 of body weight were used in combination with single doses of 25–35 Gy 100 kVp X-rays.
While doses of 100 mg kg−1 and 210 mg kg−1 did not result in any significant enhancement of tumour response, the 400 mg kg−1 dose did. A dose modification factor of 1.20±0.10 was obtained based on the comparison of doses that produced a 50% local tumour control probability. With the CTEP formulation of CuTCPBr, doses of 83 and 170 mg kg−1 produced significant radiation enhancement, with dose modification factors based on the TCP50 of 1.29±0.15 and 1.84±0.24, respectively.
CuTCPBr significantly enhanced the efficacy of XRT in the treatment of EMT-6 carcinomas in mice. The CTEP formulation showed a marked improvement, with over 9% CRM being associated with higher dose modification factors. Moreover, the radiation response in the skin was not enhanced.
PMCID: PMC3486664  PMID: 22096223
5.  Disease control using low-dose-rate brachytherapy is unaffected by comorbid severity in oral cancer patients 
The British Journal of Radiology  2011;84(1006):930-938.
The aim of this study was to evaluate the outcome and complications of low-dose-rate brachytherapy (LDR-BT) for oral cancer according to comorbidity.
The records of a total of 180 patients who received LDR-BT for T1-2N0M0 oral cancers between January 2005 and December 2007 were analysed. The comorbidities of the patients were retrospectively graded according to the Adult Comorbidity Evaluation-27, and the relationships between the comorbidity grades and survival, disease control and the incidence of complications were analysed.
The 2 year overall survival rates of patients with no comorbidity, Grade 1, Grade 2 and Grade 3 comorbidity were 87%, 85%, 76% and 65%, respectively, and the reduction in the survival rate according to comorbid severity was significant in a univariate analysis (p = 0.032) but not in a multivariate analysis including other clinical factors. Cause-specific survival, locoregional control and local control were not related to the comorbidity grade, or any other clinical factors. Grade 2 or 3 complications developed in 27% of the patients. The incidence of complications was unrelated to the comorbidity grade.
The disease control of oral cancer and the incidence of complications after LDR-BT were not related to comorbid severity. LDR-BT is a useful and safe treatment for patients regardless of the presence of severe comorbidity.
PMCID: PMC3473764  PMID: 21224307
6.  Surgical Results of Patients with Peritoneal Carcinomatosis Treated with Cytoreductive Surgery Using a New Technique Named Aqua Dissection 
During 2004 to 2011, 81, 420, and 166 patients with colorectal cancer (CRC), epithelial appendiceal neoplasm (APN), and gastric cancer (GC) with PC were treated with cytoreductive surgery (CRS) plus perioperative chemotherapy. CRS was performed by peritonectomy techniques using an aqua dissection. Results. Complete cytoreduction was done in 62/81 (76.5%), 228/420 (54.3%), and 101/166 (60.8%) of patients with CRC, APN, and GC. The main reasons of incomplete resections were involvement of all peritoneal regions and diffuse involvement of small bowel. The incidence (64%, 302/470) of CC-0 resection after introduction of an aqua dissection was significantly higher than before (42%, 82/197). A total of 41 (6.1%) patients died postoperatively. Major complication (grade 3-4 complications) occurred in 126 patients (18.9%). A reoperation was necessary in 36 patients (5.4%). By the multivariate analysis, PCI scores capable of serving as thresholds for favorable versus poor prognosis in each group and CC scores demonstrated as the independent prognostic factors. Conclusions. Peritonectomy using an aqua dissection improves the incidence of complete cytoreduction, and improves the survival of patients with PC. Patients with PCI larger than the threshold values should be treated with chemotherapy to improve the incidences of complete cytoreduction.
PMCID: PMC3362043  PMID: 22666235
7.  Adverse effects of methylprednisolone pulse therapy in refractory Kawasaki disease 
Archives of Disease in Childhood  2005;90(10):1096-1097.
PMCID: PMC1720131  PMID: 16177169
8.  Coronary risk factors in Kawasaki disease treated with additional gammaglobulin 
Archives of Disease in Childhood  2004;89(8):776-780.
Aims: To assess the hypothesis that an additional intravenous gammaglobulin (IVGG) infusion, if administered early, may prevent coronary artery lesions (CAL) in patients with Kawasaki disease (KD) who do not respond to initial IVGG therapy.
Methods: Forty four KD patients (17 with CAL and 27 without CAL), treated with additional IVGG because of persistent or recrudescent fever after initial IVGG therapy, were studied. Main outcome measures were the presence of CAL by echocardiography and the number of febrile days before and after start of additional IVGG infusion (pre- and post-additional IVGG).
Results: In univariate analyses, risk factors for CAL were the number of febrile days pre-additional IVGG, the number of febrile days post-additional IVGG, the number of days that initial IVGG was divided over, the white blood cell count pre- and post-additional IVGG, and the C reactive protein concentration pre-additional IVGG. In a multivariate analysis, the only independent risk factor was the number of febrile days pre-additional IVGG (⩾10 days; odds ratio 7.86; 95% CI 1.44 to 42.8; p = 0.02).
Conclusions: Among KD patients with persistent or recrudescent fever after initial IVGG therapy, administration of additional IVGG before the first 10 febrile days was associated with a decreased prevalence of CAL, when compared with the prevalence in those who were retreated later. An additional IVGG infusion, if administered early, may prevent CAL in initial IVGG non-responders.
PMCID: PMC1720042  PMID: 15269082
9.  Relationship between foveal birefringence and visual acuity in neovascular age-related macular degeneration 
Eye (London, England)  2006;21(3):353-361.
Purpose To investigate the relationship between visual acuity and foveal birefringence in patients with neovascular age-related macular degeneration.
Methods In total, 40 patients with choroidal neovascularization underwent macular imaging with scanning laser polarimetry. Bowtie patterns, typically seen in birefringence images of the macula, were evaluated and classified into three categories: (1) regular bowtie present; (2) bowtie present, but disrupted; and (3) no bowtie present. The relation of the bowtie appearance to the best-corrected logMAR visual acuities was tested (ANOVA).
Results Mean visual acuity was best for the group that had regular bowties (mean logMAR = 0.34) and differed statistically significantly from the disrupted bowtie group and no bowtie group (P = 0.01 and 0.0007). Ages for the three groups did not differ (P = 0.31).
Conclusions Appearance of a regular bowtie indicates a substantially intact Henle fibre layer with the potential for good visual function, despite the presence of underlying pathology. Conversely, disruption or absence of a bowtie may indicate severe damage to the photoreceptors, consistent with the finding of poorer visual acuity.
PMCID: PMC1808494  PMID: 16397620
scanning laser polarimetry; age-related macular degeneration
10.  Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death 
Heart  2003;89(1):66-70.
Objective: To investigate the clinical outcome, ECG characteristics, and optimal treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), a malignant and rare ventricular tachycardia.
Patients and methods: Questionnaire responses and ECGs of 29 patients with CPVT were evaluated. Mean (SD) age of onset was 10.3 (6.1) years.
Results: The initial CPVT manifestations were syncope (79%), cardiac arrest (7%), and a family history (14%). ECGs showed sinus bradycardia and a normal QTc. Mean heart rate during CPVT was 192 (30) beats/min. Most cases were non-sustained (72%), but 21% were sustained and 7% were associated with ventricular fibrillation. The morphology of CPVT was polymorphic (62%), polymorphic and bidirectional (21%), bidirectional (10%), or polymorphic with ventricular fibrillation (7%). There was 100% inducement of CPVT by exercise, 75% by catecholamine infusion, and none by programmed stimulation. No late potential was recorded. Onset was in the right ventricular outflow tract in more than half the cases. During a follow up of 6.8 (4.9) years, sudden death occurred in 24% of the patients, 7% of whom had anoxic brain damage. Autosomal dominant inheritance was seen in 8% of the patients’ families. β Blockers completely controlled CPVT in only 31% of cases. Calcium antagonists partially suppressed CPVT in autosomal dominant cases.
Conclusions: CPVT may arise in certain distinct areas but the prognosis is poor. The onset of CPVT may be an indication for an implanted cardioverter-defibrillator.
PMCID: PMC1767500  PMID: 12482795
ventricular tachycardia; calcium channel blocker; ventricular fibrillation; sudden death
11.  Role of ICAM-1 in the aggregation and adhesion of human alveolar macrophages in response to TNF-alpha and INF-gamma. 
Mediators of Inflammation  2001;10(6):309-313.
Intracellular adhesion molecule-1 (ICAM-1)-mediated cell-cell adhesion is thought to play an important role at sites of inflammation. Recent evidence suggests that ICAM-1 surface expression on alveolar macrophages is increased in pulmonary sarcoidosis and that inflammatory granuloma formation is characterized by the aggregation of macrophages. The present study shows that ICAM-1 expression is significantly elevated on alveolar macrophages from patients with sarcoidosis in response to tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (INF-gamma) compared with healthy controls. Aggregation and adhesion were significantly increased in alveolar macrophages treated with TNF-alpha and INF-gamma, and significantly inhibited in those pretreated with a monoclonal antibody to ICAM-1. Similarly, aggregation and adhesion were inhibited in macrophages treated with heparin, which then exhibited a wide range of biological activities relevant to inflammation. These results suggested that the surface expression of ICAM-1 on alveolar macrophages in response to TNF-alpha and INF-gamma is important in mediating aggregation and adhesion. Additionally, heparin may be useful for developing novel therapeutic agents for fibrotic lung disease.
PMCID: PMC1781738  PMID: 11817671
12.  Erythromycin and clarithromycin modulation of growth factor-induced expression of heparanase mRNA on human lung cancer cells in vitro. 
Mediators of Inflammation  2001;10(5):259-267.
Heparanase activity is correlated with the metastatic potential of several cancer cells and is a key enzyme in the breakdown of tissue barriers. It is also involved in the regulation of growth factor and cytokine activity. However, little is known about the factors that induce heparanase in cancer cells. We investigated the effect of three growth factors, platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF), on heparanase mRNA induction in lung cancer cells in vitro. In addition, we examined the effect of erythromycin (EM) and clarithromycin (CAM), which are 14-membered ring macrolide antibiotics that act as biological response modifiers, on the expression of heparanase mRNA induced by growth factors. PDGF, HGF and bFGF stimulated cell migration activity and enhanced the expression of heparanase mRNA in the human lung adenocarcinoma cell line A549. Via different mechanisms, EM and CAM modulate the induction by these factors of heparanase mRNA expression on A549 cells. EM also significantly suppressed A549 cell migration induced by PDGF and HGF, and CAM significantly suppressed A549cell migration induced by bFGF. The results suggest that the growth factors PDGF, HGF and bFGF are important inducers of heparanase in potentially invasive and metastatic cancer cells. The suppressive effect of heparanase mRNA expression by EM and CAM may have interestingtherapeutic applications in the prevention of metastasis.
PMCID: PMC1781717  PMID: 11759110
14.  Differential regulation of metalloproteinase production, proliferation and chemotaxis of human lung fibroblasts by PDGF, interleukin-1beta and TNF-alpha. 
Mediators of Inflammation  2000;9(3-4):155-160.
Fibroblast migration, proliferation, extracellular matrix protein synthesis and degradation, all of which play important roles in inflammation, are themselves induced by various growth factors and cytokines. Less is known about the interaction of these substances on lung fibroblast function in pulmonary fibrosis. The goal of this study was to investigate the effects of PDGF alone and in combination with IL-1beta and TNF-alpha on the production of human lung fibroblast matrix metalloproteinases, proliferation, and the chemotactic response. The assay for MMPs activity against FITC labeled type I and IV collagen was based on the specificity of the enzyme cleavage of collagen. Caseinolytis and gelatinolytic activities of secreted proteinases were analyzed by zymography. Fibronectin in conditioned media was measured using human lung fibronectin enzyme immunoassay. Cell proliferation was measured by 3H-Thymidine incorporation assay. Cell culture supernatants were tested for PGE2 content by ELISA. Chemotactic activity was measured using the modified Boyden chamber. Matrix metalloproteinase assay indicated that IL-1beta, TNF-alpha and PDGF induced intestitial collagenase (MMP-1) production. MMP assay also indicated that IL-1beta and TNF-alpha had inhibitory effects on MMP-2,9(gelatinaseA,B) production. Casein zymography confirmed that IL-1beta stimulated stromlysin (matrix metalloproteinase 3; MMP-3) and gelatin zymography demonstrated that TNF-alpha induced MMP-9 production in human lung fibroblast, whereas PDGF alone did not. PDGF in combination with IL-1beta and TNF-alpha induced MMP-3 and MMP-9 activity, as demonstrated by zymography. PDGF stimulated lung fibroblast proliferation in a concentration-dependent manner, whereas IL-1beta and TNF-alpha alone had no effect. In contrast, the proliferation of human lung fibroblasts by PDGF was inhibited in the presence of IL-1beta and TNF-alpha, and this inhibition was not a consequence of any elevation of PGE2. PDGF stimulated fibroblast chemotaxis in a concentration-dependent manner, and this stimulation was augmented by combining PDGF with IL-1beta and TNF-alpha. These findings suggested that PDGF differentially regulated MMPs production in combination with cytokines, and further that MMP assay and zymography had differential sensitivity for detecting MMPs. The presence of cytokines with PDGF appears to modulate the proliferation and chemotaxis of human lung fibroblasts.
PMCID: PMC1781765  PMID: 11132772
15.  Effect of heparin and related glycosaminoglycan on PDGF-induced lung fibroblast proliferation, chemotactic response and matrix metalloproteinases activity. 
Mediators of Inflammation  2000;9(2):85-91.
Fibroblast migration, proliferation, extracellular matrix protein synthesis and degradation are the key events in various biological and pathological processes in pulmonary fibrosis. In addition, biopsy specimens from the lungs of patients with pulmonary fibrosis show increased numbers of mast cells which have metachromatic granules containing heparin, histamine and proteases. Little is known about how these products influence pulmonary fibrosis. In the present study, we investigated the effect of heparin and related glycosaminoglycans on PDGF-induced lung fibroblast proliferation and chemotactic response in vitro. In addition, we examined the effect of heparin on both the induction of matrix metalloproteinases (MMPs) and MMPs activity in lung fibroblasts in vitro. Heparin, de-N-sulphated heparin but not heparan sulphate inhibited PDGF-induced lung fibroblast proliferation. In contrast, only heparin inhibited PDGF-stimulated human lung fibroblast chemotaxis. Negatively charged poly-L-glutamic acid had no effect on either fibroblast proliferation or chemotaxis. Thus the negative charge alone cannot account for the ant-proliferative and anti-chemotactic effects of heparin. Furthermore, heparin and heparan sulphate also had no inhibitory effect on induction of MMPS, including MMP-1 (interstitial collagenase), MMP-2 (gelatinase A) and MMP-9 (gelatinase B). Only heparin inhibited both MMP-1 and MMP-2/MMP-9 activity. Additionally, tissue inhibitor of metalloproteinase type 1 (TIMP-1) and type 2 (TIMP-2) inhibited PDGF-stimulated human lung fibroblast chemotaxis. The ability of heparin to inhibit fibroblast chemotaxis may account for the inhibitory effect of heparin on MMP activity. The above results suggested that heparin and related glycosaminoglycans differentially regulate PDGF-induced lung fibroblast proliferation, chemotaxis and MMPs activity and further that these effects may have a key role in extracellular matrix remodeling in inflammatory lung disease.
PMCID: PMC1781749  PMID: 10958381
16.  Angiotensin converting enzyme (ACE) inhibitor-induced cough and substance P. 
Thorax  1996;51(2):199-201.
BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors cause coughing in 5-10% of patients, but the exact mechanisms of this effect are still unclear. In the airways ACE degrades substance P so the cough mechanism may be related to this peptide. METHODS: Nine patients who developed a cough and five patients who did not develop a cough when taking the ACE inhibitor enalapril (2.5 or 5.0 mg/day) for hypertension were enrolled in the study. No subjects had respiratory disease and the respiratory function of all subjects was normal. One month after stopping enalapril, inhalation of hypertonic saline (4%) was performed using an ultrasonic nebuliser for 15-30 minutes to induce sputum. The concentration of substance P in the sputum sample was measured by radioimmunoassay. In four of the nine cases with a cough enalapril was given again for 1-2 weeks and the concentration of substance P in the induced sputum was again measured. RESULTS: One month after stopping enalapril the mean (SE) concentration of substance P in the sputum of the group with a cough was 16.6 (3.0) fmol/ml, significantly higher than that in the subjects without a cough (0.9 (0.5) fmol/ml). All four subjects in the group with a cough who were given a repeat dose of enalapril developed a cough again, but the concentrations of substance P in the induced sputum while taking enalapril (17.9 (3.2) fmol/ml) were similar to the values whilst off enalapril (20.0 (2.5) fmol/ml). CONCLUSIONS: The mechanisms of ACE inhibitor-induced coughing may involve substance P mediated airway priming. However, the final triggering of the ACE inhibitor-induced coughing is unlikely to be due to this peptide.
PMCID: PMC473042  PMID: 8711657
17.  Characterization of manganese peroxidases from the hyperlignolytic fungus IZU-154. 
Applied and Environmental Microbiology  1996;62(11):4066-4072.
Four isozymes of manganese peroxidase (MnP) were identified in the culture fluid of the hyperlignolytic fungus IZU-154 under nitrogen starvation conditions. One of them was purified and characterized kinetically. The specific activity and Kcat/K(m) value of the MnP from IZU-154 were 1.6 times higher than those of the MnP from a typical lignin-degrading fungus, Phanerochaete chrysosporium. Two cDNAs encoding MnP isozymes from IZU-154 were isolated. The coding sequence of the two cDNAs, IZ-MnP1 cDNA and IZ-MnP2 cDNA, were 1,152 (384 amino acids) and 1,155 (385 amino acids) bp in length, respectively. They exhibit 96.2% identity at the nucleotide level and 95.1% identity at the amino acid level. Southern blot analysis indicated that two MnP isozyme genes exist in IZU-154 genomic DNA. The primary structures of two MnPs from IZU-154 were similar to those of MnPs from P. chrysosporium. The amino acid sequences including the important residues identified in MnPs from P. chrysosporium, such as the manganese-binding residues, the calcium-binding residues, the disulfide bonds, and the N-glycosylation site, were conserved in the two deduced IZ-MnPs. However, several discrepancies were found in the context around the distal histidine residue between MnP from IZU-154 and MnP from P. chrysosporium, which likely led to the difference in the kinetic parameters for MnP function.
PMCID: PMC168228  PMID: 8899997
18.  Involvement of apamin-sensitive K+ channels in antigen-induced spasm of guinea-pig isolated trachea. 
British Journal of Pharmacology  1994;112(3):958-962.
1. In order to examine whether K+ channels play a role in antigen-induced airway responses, the effect of K+ channel blockers on antigen-induced airway smooth muscle contraction and mediator release was examined in vitro in guinea-pigs actively sensitized with ovalbumin (OA). 2. Tracheal strips from sensitized animals were suspended in organ baths under a resting tension of 1 g and isometric tension was continuously measured. Cumulative concentration-response curves to OA (0.1-1000 ng ml-1) or histamine (10 nM-1 mM) were obtained in the presence and absence of K+ channel blockers. 3. OA (10, 100 or 1000 ng ml-1) was incubated with minced lung tissues from the same animals for 15 min in the presence and absence of K+ channel blockers, and released histamine and leukotriene C4 (LTC4) in the incubating medium were measured. 4. Apamin, a small conductance Ca(2+)-activated K+ channel (PK,Ca) blocker, (0.1, 0.3 and 1 microM) significantly inhibited OA-induced smooth muscle contraction, while charybdotoxin (ChTX, 10 nM), an intermediate and large conductance PK,Ca blocker, and iberiotoxin (IbTX, 3 nM), a large conductance PK,Ca blocker, were without effect. Apamin (0.3 microM) had no effect on exogenously administered histamine-induced airway smooth muscle contraction, suggesting that the inhibition of OA-induced contraction by apamin did not occur at the smooth muscle level. 5. The inhibition of OA-induced contraction by apamin (0.3 microM) was not significantly affected by pretreatment with a leukotriene antagonist, ONO-1078 (10 microM), but was abolished by pretreatment with a histamine H1-receptor blocker, pyrilamine (1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1910186  PMID: 7522863
19.  A functional insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the epidermal growth factor receptor. 
Molecular and Cellular Biology  1994;14(7):4588-4595.
When wild-type mouse embryo cells are stably transfected with a plasmid constitutively overexpressing the epidermal growth factor (EGF) receptor (EGFR), the resulting cells can grow in serum-free medium supplemented solely with EGF. Supplementation with EGF also induces in these cells the transformed phenotype (growth in soft agar). However, when the same EGFR expression plasmid is introduced and overexpressed in cells derived from littermate embryos in which the insulin-like growth factor I (IGF-I) receptor genes have been disrupted by homologous recombination, the resulting cells are unable to grow or to be transformed by the addition of EGF. Reintroduction into these cells (null for the IGF-I receptor) of a wild-type (but not of a mutant) IGF-I receptor restores EGF-mediated growth and transformation. Our results indicate that at least in mouse embryo fibroblasts, the EGFR requires the presence of a functional IGF-I receptor for its mitogenic and transforming activities.
PMCID: PMC358831  PMID: 8007963
20.  Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. 
Molecular and Cellular Biology  1994;14(6):3604-3612.
Fibroblast cell lines, designated R- and W cells, were generated, respectively, from mouse embryos homozygous for a targeted disruption of the Igf1r gene, encoding the type 1 insulin-like growth factor receptor, and from their wild-type littermates. W cells grow normally in serum-free medium supplemented with various combinations of purified growth factors, while pre- and postcrisis R- cells cannot grow, as they are arrested before entering the S phase. R- cells are able to grow in 10% serum, albeit more slowly than W cells, and with all phases of the cell cycle being elongated. An activated Ha-ras expressed from a stably transfected plasmid is unable to overcome the inability of R- cells to grow in serum-free medium supplemented with purified clones. Nevertheless, even in the presence of serum, R- cells stably transfected with Ha-ras, alone or in combination with simian virus 40 large T antigen, fail to form colonies in soft agar. Reintroduction into R- cells (or their derivatives) of a plasmid expressing the human insulin-like growth factor I receptor RNA and protein restores their ability to grow with purified growth factors or in soft agar. The signaling pathways participating in cell growth and transformation are discussed on the basis of these results.
PMCID: PMC358728  PMID: 8196606
21.  Bronchodilating effects of the novel potassium channel opener HOE 234 in human airways in vitro. 
Bronchodilating effects of the novel potassium channel opener HOE 234 were examined in human bronchi in vitro and compared with those of BRL 38227. HOE 234 produced concentration-dependent relaxations of spontaneous tone and of tone increased by methacholine (10(-6) M), with mean EC50 values of 11 nM and 47 nM, respectively (n = 5). The relaxation produced by HOE 234 was 7 and 3.5 fold more potent than that by BRL 38227 on spontaneous and induced tone, respectively, and was inhibited by glibenclamide (10(-5) M). These results suggest that HOE 234 is a potent bronchodilator which activates ATP-sensitive potassium channels in human airways.
PMCID: PMC1381584  PMID: 8471412
22.  Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro. 
Journal of Clinical Investigation  1993;92(2):736-742.
Human airway smooth muscle possesses an inhibitory nonadrenergic noncholinergic neural bronchodilator response mediated by nitric oxide (NO). In guinea pig trachea both endogenous NO and vasoactive intestinal peptide (VIP) modulate cholinergic neural contractile responses. To identify whether endogenous NO or VIP can modulate cholinergic contractile responses in human airways in vitro, we studied the effects of specific NO synthase inhibitors and the peptidase alpha-chymotrypsin on contractile responses evoked by electrical field stimulation (EFS) at three airway levels. Endogenous NO, but not VIP, was shown to inhibit cholinergic contractile responses at all airway levels but this inhibition was predominantly in trachea and main bronchus and less marked in segmental and subsegmental bronchi. To elucidate the mechanism of this modulation we then studied the effects of endogenous NO on acetylcholine (ACh) release evoked by EFS from tracheal smooth muscle strips. We confirmed that release was neural in origin, frequency dependent, and that endogenous NO did not affect ACh release. These findings show that endogenous NO, but not VIP, evoked by EFS can inhibit cholinergic neural responses via functional antagonism of ACh at the airway smooth muscle and that the contribution of this modulation is less marked in lower airways.
PMCID: PMC294908  PMID: 8349813
23.  Tissue-specific in vitro transcription from the mouse myelin basic protein promoter. 
Molecular and Cellular Biology  1989;9(7):3122-3126.
The mouse myelin basic protein promoter was transcribed in brain nuclear extracts. The distal promoter region from -253 to -54 directed preferential transcription in brain extracts, whereas the same region repressed transcription activity in liver extracts. Stimulation of transcription was observed when the distal region was located only in a native orientation. The proximal region downstream from -53 alone still directed preferential transcription. It is suggested that cooperative function by the two promoter regions may be required for higher specificity.
PMCID: PMC362786  PMID: 2476662
24.  Measurement method of the anterior chamber volume by image analysis. 
A new computerised method of measurement of the anterior chamber in the human eye is described. Photographs of the anterior chamber were taken with a Zeiss slit-lamp 75-SL and converted from an optical image into a true image by computer with a digitiser. We obtained data on both the anterior chamber volume and also the anterior chamber depth, peripheral anterior chamber volume, the diameter of the anterior chamber, and the degree of the iridocorneal angle. These data were simultaneously displayed several seconds after in-put by the digitiser. In mensuration by digitiser on three occasions from a single photograph of a given eye the mean deviation rate was about 0.7%, and the mean deviation rate of 10 successive exposures of one eye was 3.5%. By this image analysis technique an accurate profile of the anterior chamber is displayed of the pupil margin, iris-root insertion, and central anteroposterior pupillary axis. These data help us to understand the mechanism of primary angle-closure glaucoma.
PMCID: PMC1040796  PMID: 3756123
25.  Analysis of transcription control elements of the mouse myelin basic protein gene in HeLa cell extracts: demonstration of a strong NFI-binding motif in the upstream region. 
Nucleic Acids Research  1988;16(24):11441-11459.
Promoter elements of the mouse myelin basic protein (MBP) gene were analyzed by in vitro transcription using HeLa cell extracts. We demonstrated the MBTE (MBP transcription element), GC-box core and TATA-box elements, at -130, -93 and -34, respectively. The TATA-box was indispensable for the promoter function. The GC-box was suggested to function co-operatively with far upstream sequences including the MBTE. The MBTE was crucial to direct maximal transcription, and also functioned with a heterologous promoter irrespective of its orientation. We identified a ubiquitous binding factor which interacted specifically with the MBTE and activated transcription. Intensive foot-printing studies demonstrated that the MBTE had a NFI-binding sequence. The MBTE was considered to be one of the strongest NFI-binding motif among known cellular genes. Interestingly, similar strong NFI-binding motifs were suggested to be present in the enhancer of JC virus whose gene is expressed like the MBP gene, in the nervous system.
PMCID: PMC339057  PMID: 2463515

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