Masaru Nishitsuji

Potentiation of allergic bronchoconstriction by repeated exposure to formaldehyde in guinea‐pigs in vivo

Background Indoor formaldehyde (FA) might worsen allergies and be an underlying factor for the increasing incidence and severity of asthma; the exact mechanism, however, remains unclear.

Longitudinal decline in pulmonary function in atopic cough and cough variant asthma

Objective Cough variant asthma and atopic cough are different clinical manifestations of eosinophilic airway inflammation presenting with isolated chronic non‐productive cough. The aim of this study was to examine the longitudinal change in pulmonary function in cough variant asthma and atopic cough.

Attenuating effect of H+K+ATPase inhibitors on airway cough hypersensitivity induced by allergic airway inflammation in guinea‐pigs

Background Gastrooesophageal reflux (GER) is a frequent cause of chronic cough. Several investigators have indicated that inhibitors of H+K+ATPase (proton pump inhibitors; PPIs) could relieve coughing via inhibition of acid reflux. However, we considered that PPIs might directly inhibit increased cough reflex sensitivity.

Long-term probucol treatment results in regression of xanthomas, but in progression of coronary atherosclerosis in a heterozygous patient with familial hypercholesterolemia

A 66-year-old male heterozygous familial hypercholesterolemia (FH) patient with significant coronary atherosclerosis has been treated by us with probucol (1000 mg daily) for eight years. This treatment has produced significant reductions in the cholesterol levels of his serum, low density lipoprotein (LDL), and high density lipoprotein (HDL) from 237 +/- 20 mg/dl (mean +/- S.D.) to 156 +/- 15, from 175 +/- 8 to 111 +/- 16 mg/dl, and from 23 +/- 4 to 19 +/- 2 mg/dl, respectively. These reductions have been maintained for eight years. Serum triglyceride levels also decreased, from 220 +/- 54 to 146 +/- 36 md/dl. During this period, marked regression of xanthomas on the eyelids and finger extensor tendons was observed, while thickness of the Achilles tendons was reduced from 21.0 mm to 13.0 mm. On other hand, effort-induced anginal symptoms requiring additional antianginal medication have been noticed, and angiographically-demonstrated coronary atherosclerosis has progressed significantly during these eight years. These observations lead us to suggest that maintaining low levels of HDL cholesterol with probucol, even though resulting in satisfactory reduction of LDL cholesterol and marked regression of xanthomas, appears to be associated with the progression of atherosclerosis in the coronary arteries.

A guinea pig model for cough variant asthma and role of tachykinins.

Cough variant asthma is known as a major cause of chronic cough. Fundamental features of cough variant asthma are prolonged nonproductive cough responding to bronchodilator therapy, no history of wheezing or dyspnea attack, normal cough sensitivity, and slightly increased bronchial responsiveness. Animal model of cough variant asthma has not been reported. The aim of this study was to establish an animal model for studying detailed pathophysiology of cough variant asthma. Bronchial responsiveness to methacholine and cough reflex sensitivity to capsaicin were measured 72 hours after antigen (ovalbumin, OA) inhalation in actively sensitized guinea pigs. Next, cough number and specific airway resistance (sRaw) were measured during 20 minutes following reinhalation of OA solution, which was carried out 72 hours after the first OA inhalation, and then total cell number and cell differentials in bronchoalveolar lavage fluid (BALF) were measured. Bronchial responsiveness to methacholine, but not cough reflex sensitivity to capsaicin, was significantly increased 72 hours after the first inhalation of OA solution. Number of coughs, sRaw and total cell number in BALF increased significantly by the OA reinhalation, and the cough number and the increase in sRaw were significantly suppressed by β2 agonist, procaterol. FK224, a specific neurokinin (NK) receptor antagonist, did not significantly influence the OA reinhalation–induced cough and increase in sRaw and total cell number in BALF in this model. In conclusion, pathophysiologic feature of this animal model is similar to that of clinical cough variant asthma. Tachykinins may not play an important part in antigen-induced cough associated with bronchoconstriction and airway inflammation in cough variant asthma.

Usefulness of transesophageal bronchoscopic ultrasound-guided fine-needle aspiration in the pathologic and molecular diagnosis of lung cancer lesions adjacent to the esophagus.

Background:The discovery of driver oncogenes has increased the need to obtain a sufficient amount of tissue specimens for lung cancer diagnosis. Although endoscopic ultrasound (with bronchoscope)-guided fine-needle aspiration (EUS-B-FNA) is reportedly a feasible and well-tolerated modality, additional advantages of EUS-B-FNA are yet to be thoroughly investigated. The purpose of this study was to evaluate the ability of EUS-B-FNA to obtain sufficient tissue specimens for pathologic and molecular diagnoses of lung cancer. Methods:Among lung cancer patients who were diagnosed between December 2010 and December 2012 in our institute, patients who underwent EUS-B-FNA to diagnose lung cancer were enrolled (n=26). EUS-B-FNA was performed when bronchoscopic diagnosis was impossible or difficult to obtain sufficient samples. Epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule-associated protein-like 4 and the anaplastic lymphoma kinase (EML4-ALK) fusion gene were evaluated using EUS-B-FNA samples of non–small cell lung cancer. Results:EUS-B-FNA was performed on 28 lesions in 26 patients. Among the target lesions, 23 were mediastinal lymph nodes including nodal stations 2L, 4L, 7, 8, and 10L. The remaining 5 were intrapulmonary lesions. EUS-B-FNAs were completed without complications in all the patients. The diagnostic yield of EUS-B-FNA in diagnosing lung cancer was 100% (26/26). Additional diagnostic gain of EUS-B-FNA was 69.2% (18/26) as compared to bronchoscopy alone. EGFR mutations and EML4-ALK fusion gene could be evaluated in all patients with non–small cell lung cancer (n=20) using EUS-B-FNA samples. One case with EGFR mutation and 1 case with ALK fusion gene were diagnosed. Six non–small cell carcinomas were also diagnosed by bronchoscopy, but all bronchoscopic samples were insufficient to evaluate mutation analyses. Conclusions:EUS-B-FNA is a practical and feasible method to obtain abundant tumorous tissue samples for pathologic diagnosis and molecular analysis, particularly when the target lesions are inaccessible by other modalities because of their locations or because of the patient’s poor physical condition.

Bronchoconstriction-triggered Cough Is Impaired in Typical Asthmatics

Background and objective. Cough is an essential innate protective behavior, which is experienced by even healthy individuals. The mechanism of cough triggered by bronchoconstriction is not yet clear. The aim of this study was to investigate the relation between bronchoconstriction and cough caused by methacholine (Mch) inhalation in typical asthmatics and normal healthy subjects. Methods. We measured bronchial responsiveness to Mch and counted the number of coughs induced by Mch inhalation in 15 typical asthmatics and 20 normal subjects. Results. After inhalation of Mch at the concentration causing 20% or more decrease in forced expiratory volume in 1 second (FEV1) (PC20-FEV1), coughs were provoked in normal subjects (number of cough: 22.5/32 min, range: 3.3–45). Conversely, coughs were hardly provoked in typical asthmatics (median number of cough: 2/32 min, range: 0–4). Conclusions. Although typical asthmatics have increased airway responsiveness, their cough response to bronchoconstriction is impaired.

Predictors for Typical Asthma Onset from Cough Variant Asthma

Cough variant asthma is recognized to be a precursor of asthma or preasthmatic state because nearly 30% patients with cough variant asthma develop typical asthma within several years. However, predictors for risk of typical asthma onset from cough variant asthma are unknown. Forty-one patients with cough variant asthma (median age 50 years, 13 men and 28 women), who had undertaken spirometry, bronchial reversibility test, methacholine provocation test, measurements of peripheral blood eosinophil count, serum total IgE, and specific IgE to common allergens, and induced sputum eosinophil count at presentation, were followed up with special emphasis on typical asthma onset during 1 year or more (median 4 years, range 1–12.4). Long-term inhaled corticosteroids (ICS) were taken in 27 patients. Univariate and multivariate logistic analyses were performed to determine the predictors for typical asthma onset. Asthma onset was recognized in 7 patients. Bronchial hyperresponsiveness, peripheral blood eosinophil count, and no use of ICS were significant predictors for the typical asthma onset by univariate analysis. However, only bronchial hyperresponsiveness was the significant predictor when multivariate analysis was used (adjusted OR 0.028, 95% CI 0.001–0.783, p = 0.0355). Bronchial hyperresponsiveness may be the most important predictor for risk of typical asthma onset from cough variant asthma.

Bronchodilator effect of deep inspiration and bronchoconstriction-triggered cough.

BackgroundCough in the patients with cough variant asthma is triggered by bronchoconstriction, which responds to bronchodilator therapy. Following airway narrowing induced by inhaled methacholine, deep inspiration (DI) causes dilation of the airways in both asthmatic and non-asthmatic subjects. The aim of the present study was to investigate the relationship between bronchodilator effect of DI and bronchoconstriction-triggered cough.MethodsWe measured airway responsiveness to methacholine using partial and full flow-volume curves in 28 healthy adults. The expiratory flow at 40% above residual volume from the full forced vital capacity (MEF40) was obtained and the volume was used as the reference volume to determine the isovolume flow from the partial curve (PEF40). Coughs were counted for 32 min during and following the inhalation of methacholine at the provocative concentration which produced a 20% fall or more in FEV1from the post-saline value (PC20-FEV1). The bronchodilator effect of DI on bronchoconstriction induced by methacholine at the PC20-FEV1 concentration was expressed as the ratio of (MEF40-PEF40)/PEF40 (DI index).ResultsThe number of coughs for 32 min during and following the inhalation of PC20-FEV1 concentration of methacholine was 39.3 ± 29.7 (mean ± SD)/32 min. The number of coughs during and following the inhalation was correlated with DI index (r = 0.57, p = 0.0015), but not with PC20-FEV1 or change in FEV1 or PEF40 by inhalation of the PC20-FEV1 concentration of methacholine.ConclusionWe found that methacholine-induced cough was associated with the bronchodilator effect of DI on methacholine induced-bronchoconstriction in normal subjects.

Paradoxical reaction to antituberculosis therapy after 6 months of treatment for pulmonary tuberculosis: A case report.

Paradoxical reactions (PRs) to antituberculosis (anti-TB) drugs during treatment are well known phenomena, but a PR presenting as a new pulmonary lesion after completion of treatment is extremely rare, and little is known about the management of such cases. A 44-year-old man was diagnosed with pulmonary TB. His sputum cultures became negative 45 days after the initiation of standard anti-TB treatment. Upon the patients completion of 6 months of anti-TB therapy, computed tomography revealed a new irregularly shaped mass in the lower left pulmonary lobe. A transbronchial lung biopsy (TBLB) revealed caseous necrosis and granulomatosis surrounded by epithelioid and multinucleated giant cells. Cultures of both the TBLB specimen and bronchoalveolar lavage fluid remained negative for TB. The CT shadow disappeared 6 months later without further administration of anti-TB drugs. Careful observation without therapy may be sufficient for a patient treated for TB who develops a PR upon completion of treatment, if the patient has achieved a bacteriological remission.