The Value of Additional Conventional Transbronchial Biopsy in the Negative Results of Rapid On-site Evaluation During Endobronchial Ultrasound With Guide Sheath to Diagnose Small Peripheral Lung Cancer.

Objective: The accuracy of rapid on-site evaluation (ROSE) during endobronchial ultrasonography with guide sheath (EBUS-GS) was reported to be approximately 90% for diagnosing small peripheral pulmonary lesions (PPLs). When ROSE during EBUS-GS for diagnosing small peripheral lung cancer is carried out and does not include malignant cells in a position whereby the probe was located within or adjacent to the lesion, the best technique for overcoming the lower diagnostic yield remains unknown. This study aimed to evaluate factors affecting positive results of ROSE during EBUS-GS in such a probe position. Moreover, when the results of ROSE were consistently negative, we evaluated the effectiveness of conventional transbronchial biopsy (TBB) in addition to EBUS-GS alone. Methods: We performed a retrospective analysis of consecutive patients who underwent EBUS-GS combined with ROSE for diagnosing small peripheral lung cancer (≤30 mm). We classified the results of ROSE into two groups based on the presence of malignant cells: the ROSE positive group (included malignant cells) and the ROSE negative group (did not include malignant cells). The significant predictors of positive ROSE results during EBUS-GS were analyzed using multivariate logistic regression analyses. Results: We identified 67 lesions (43 lesions in the ROSE positive group and 24 lesions in the ROSE negative group, respectively). Multivariate logistic analysis revealed that the significant factor affecting positive ROSE results was lesion size (>15 mm) (OR = 9.901). The diagnostic yield of additional conventional TBB to EBUS-GS was significantly higher than that of EBUS-GS alone (75.0% vs 33.3%, P = .041). Conclusion: The positive results of ROSE during EBUS-GS were significantly influenced by lesion size (>15 mm). When the results of ROSE during EBUS-GS were consistently negative in a position whereby the probe was located within or adjacent to the lesion, additional conventional TBB was effective to improve the diagnostic yield compared with EBUS-GS alone.

Endobronchial ultrasound-guided transbronchial needle aspiration under non-invasive positive pressure for the diagnosis of lung metastasis due to renal cell carcinoma in a patient with respiratory failure.

A 65-year-old man with chronic respiratory failure caused by chronic obstructive pulmonary disease, had a pulmonary nodule adjacent to the inlet of right B1 and B3. The patient had undergone a surgery for right renal cell carcinoma and colon cancer 6 years prior. We attempted endobronchial ultrasound-guided transbronchial needle aspiration under non-invasive positive pressure ventilation for diagnosis, with rapid on-site cytology, which was performed without complications. The histological findings revealed lung metastasis involving renal cell carcinoma. Endobronchial ultrasound-guided transbronchial needle aspiration under non-invasive positive pressure ventilation is useful for diagnosing lesions that require access up to the segmental bronchus in patients with respiratory failure.

Health-care-associated pneumonia among hospitalized patients in a Japanese community hospital.

BACKGROUND: Health-care-associated pneumonia (HCAP) is a relatively new concept. Epidemiologic studies are limited, and initial empirical antibiotic treatment is still under discussion. This study aimed to reveal the differences in mortality and pathogens between HCAP and community-acquired pneumonia (CAP) in each severity class, and to clarify the strategy for the treatment of HCAP. METHODS: We conducted a retrospective observational study of patients with HCAP and CAP who were hospitalized between November 2005 and January 2007, and compared baseline characteristics, severity, pathogen distribution, antibiotic regimens, and outcomes. In each severity class (mild, moderate, and severe) assessed using the A-DROP scoring system (ie, age, dehydration, respiratory failure, orientation disturbance, and low BP), we investigated the in-hospital mortality and occurrence of potentially drug-resistant (PDR) pathogens. RESULTS: A total of 371 patients (141 HCAP patients, 230 CAP patients) were evaluated. The proportion of patients in the severe class was higher in the HCAP patients than in CAP patients. In the moderate class, the in-hospital mortality proportion of HCAP patients was significantly higher than that of CAP patients (11.1% vs 1.9%, respectively; p = 0.008). In moderate-class patients in whom pathogens were identified, PDR pathogens were isolated more frequently from HCAP patients than from CAP patients (22.2% vs 1.9%, respectively; p = 0.002). The occurrence of PDR pathogens was associated with initial treatment failure and inappropriate initial antibiotic treatment. CONCLUSIONS: The present study provides additional evidence that HCAP should be distinguished from CAP, and suggests that the therapeutic strategy for HCAP in the moderate class holds the key to improving mortality. Physicians may need to consider PDR pathogens in selecting the initial empirical antibiotic treatment of HCAP.

Implication of clinical pathway care for community-acquired pneumonia in a community hospital: early switch from an intravenous beta-lactam plus a macrolide to an oral respiratory fluoroquinolone.

OBJECTIVE: The effect of clinical pathway (CP) care and early switch from intravenous to oral antibiotics therapy on community-acquired pneumonia (CAP) has been well documented. However, limited studies have evaluated the effects of CP on reducing time taken for attaining clinical stability and duration of antibiotics prescriptions. This study was aimed to investigate the use of a CP and its implication for CAP in a community hospital. METHODS: We conducted a retrospective cohort study of CAP patients hospitalized between November 2005 and January 2007. The patients were divided into two groups, those for whom CP was adopted and those for whom CP was not adopted on admission. We compared the outcomes of three risk classes assessed using the severity scoring system (A-DROP). CP included switching from an intravenous beta-lactam plus a macrolide to an oral respiratory fluoroquinolone, when the patients exhibited risk factors for drug-resistant pneumococci. RESULTS: One hundred thirty-five patients were evaluated, and sixty received CP care. Patients in the CP group had a lower A-DROP score. Although clinical cure proportions were similar, the CP group in the mild and moderate classes (A-DROP score,

Comparison of severity scoring systems A-DROP and CURB-65 for community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: The initial assessment of the severity of community-acquired pneumonia (CAP) is important for patient management. The Japanese Respiratory Society (JRS) has proposed a 6-point scale (0-5) to assess the clinical severity of CAP. The A-DROP scoring system assesses the following parameters: (i) Age (male >or= 70 years, female >or= 75 years); (ii) Dehydration (blood urea nitrogen (BUN) >or= 210 mg/L); (iii) Respiratory failure (SaO(2) 7 mmol/L (200 mg/L), respiratory rate >or= 30/min, low blood pressure (diastolic or= 65 years) proposed by the British Thoracic Society. However, validation of A-DROP has not been attempted nor has it been compared with CURB-65. The aim of this study was to confirm that A-DROP is equivalent to CURB-65 for predicting severity of CAP. METHODS: A retrospective observational study was conducted of patients with CAP hospitalized at a single centre between November 2005 and January 2007. The 30-day mortality after admission was compared following assessment of severity using the A-DROP and CURB-65 scoring systems. RESULTS: Three-hundred and twenty-nine patients were evaluated. The areas under the receiver operating characteristic curves were 0.846 (95% confidence interval (CI): 0.790-0.903) and 0.835 (95% CI: 0.763-0.908) for A-DROP and CURB-65, respectively. CONCLUSION: The JRS A-DROP can be used to assess severity of CAP, and gives similar results to CURB-65.

Dual pathway activated by tert-butyl hydroperoxide in human airway anion secretion.

We analyzed the mechanisms underlying the ion transport induced by tert-butyl hydroperoxide (t-BOOH), a membrane-permeant oxidant that has been widely used as a model of oxidative stress, in human airway epithelial cells (Calu-3). We found that t-BOOH induced a short-circuit current that was composed of two distinct components, a peaked component (PC) and a sustained component (SC). Both components were reduced by the presence of H-89 (N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline) [10 microM, a protein kinase A (PKA) inhibitor] and clofilium (100 microM, a cAMP-dependent K+ channel inhibitor) but not by charybdotoxin (50 nM, a human intermediate conductance Ca2+-activated K+ channel inhibitor), suggesting that both PC and SC were generated through a common PKA-dependent/Ca2+-independent pathway. Notwithstanding, analyses of the physiological properties revealed that PC and SC were attributable to different pathways. PC, but not SC, was correlated with apical membrane Cl- conductance and was inhibited by the cyclooxygenase (COX)-2 inhibitor NS-398 (N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide; 10 microM). In contrast, SC, but not PC, was composed of a component sensitive to bumetanide (50 microM), an inhibitor of the basolateral Na+-K+-2Cl- cotransporter (NKCC1), and was abolished by the cytoskeleton dysfunction induced by cytochalasin D (10 microM) and (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexane carboxamide (Y-27632; 20 microM). Collectively, t-BOOH induces PKA-related anion secretion through two independent pathways: rapid activation of apical anion efflux through a COX-2-dependent/cytoskeleton-independent pathway and relatively delayed activation of NKCC1 for basolateral anion uptake through a COX-2-independent/cytoskeleton-dependent pathway.

Paradoxical effects of hydrogen peroxide on human airway anion secretion.

The present study concerns intriguing effects of hydrogen peroxide (H2O2) on cAMP-mediated anion secretion in polarized human airway epithelia. Although H2O2 applied to the apical and basolateral membrane increases short-circuit currents (ISC) with analogous properties, it has opposite effects on subsequent cAMP-activated ISC responses. Namely, forskolin (FK)-induced ISC responses were down-regulated by the apical presence of H2O2, whereas they were up-regulated by its basolateral presence. Despite this contrasting effect, oxidative stimuli from either aspect of the monolayer hindered FK-induced increments in cytosolic cAMP levels and apical membrane Cl- conductance. The site-dependent effects of H2O2 were reproduced in the responses to 8-bromo-cAMP. Estimation of the anionic composition of the ISC revealed that the FK up-regulated both bumetanide [an Na+-K+-2Cl- cotransporter (NKCC1) inhibitor]-sensitive and 4,4'-dinitrostilbene-2,2'-disulfonic acid [an HCO3--dependent anion transporter (NBC1/AE2) inhibitor]-sensitive ISC in the control, whereas the up-regulation evidently favored bumetanide-sensitive ISC in the basolateral presence of H2O2. The FK-induced NKCC1 augmentation after exposure to basolateral H2O2 was counteracted by cytochalasin D, an inhibitor of microfilament function, but not by charybdotoxin, a blocker of the intermediate conductance Ca2+-activated K+ channel, whose activation could be related to NKCC1-mediated Cl- secretion. These observations suggest that basolaterally but not apically applied H2O2 potentiates subsequent cAMP-mediated Cl- secretion by an increase in Cl- uptake via basolateral NKCC1, whose sensitivities to cAMP/protein kinase A are up-regulated, overcoming the H2O2-induced inhibition of cAMP-mediated apical anion conductance. The basolateral membrane-specific effects of H2O2 may be relevant to the basolateral cytoskeleton, which is believed to interact with NKCC1.

Ion transport regulated by protease-activated receptor 2 in human airway Calu-3 epithelia.

We examined the mechanisms underlying anion secretion mediated by protease-activated receptor 2 (PAR2) and its role in the regulation of ion transport, using polarized human airway Calu-3 cells. PAR2 stimulation by trypsin and a PAR2-activating peptide (PAR2AP), especially from the basolateral aspect, caused transient Cl(-) secretion due to cytosolic Ca(2+) mobilization. Antagonists of PI-PLC (U73122, ET-18-OCH(3)) and inositol 1,4,5-triphosphate (xestospongin C (Xest C)) were without effect on the PAR2AP-mediated Cl(-) secretion, whereas it was attenuated by D609 (a PC-PLC inhibitor) and phorbol 12-myristate 13 acetate (PMA, a PKC activator). Even 30 min after removal of PAR2AP after a 10-min-exposure, cells were still poorly responsive to PAR2 stimulation, but the reduced responsiveness was upregulated by a PKC inhibitor, GF109203X (GFX). Pretreatment with PAR2AP did not affect responses to anion secretagogues, such as isoproterenol, forskolin, thapsigargin, 1-ethyl-2-benzimdazolinone, and adenosine, but ATP-induced responses were significantly reduced. Nystatin permeabilization studies revealed that the presence of PAR2AP prevented ATP-induced increments in basolateral membrane K(+) conductance without affecting apical membrane Cl(-) conductance. ATP-elicited Ca(2+) mobilization, which was sensitive to D609 and PMA, was inhibited by the pretreatment with PAR2AP, and this inhibition was blunted by the presence of GFX. Collectively, stimulation of PAR2 generates a brief response of Cl(-) secretion through PC-PLC-mediated pathway, followed by not only auto-desensitization of PAR2 itself but also cross-desensitization of a PC-PLC-coupled purinoceptor. The two types of desensitization seem likely to have PKC-mediated downregulation of PC-PLC in common.

Reduction of airway anion secretion via CFTR in sphingomyelin pathway.

The present study concerns the involvement of the ceramide produced through sphingomyelinase (SMase)-mediated catalysis in airway anion secretion of Calu-3 cells. Short-circuit current (Isc) measurement revealed that isoproterenol (ISO, 0.1 microM)-induced anion secretion was prevented by pretreatment with SMase (0.3 U/ml, for 30 min) from the basolateral but not the apical side, although basal and 1-ethyl-2-benzimidazolinone (1-EBIO, a Ca2+-activated K+ channel opener)-induced Isc were unaffected. The effects of SMase were reproduced in responses to forskolin (20 microM) or 8-bromo-cAMP (2 mM). C2-ceramide, a cell-permeable analog, also repressed the 8-bromo-cAMP-induced responses. Nystatin permeabilization studies confirmed that the SMase- and C2-ceramide-induced repressions were due to hindrance of augmentation of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated conductance across the apical membrane. Further, SMase failed to influence K+ conductance across the basolateral membrane. These results suggest that the ceramide originating from basolateral sphingomyelin acts on activated CFTR from the cytosolic side, hindering anion secretion.

Effects of fluoranthene, a polycyclic aromatic hydrocarbon, on cAMP-dependent anion secretion in human airway epithelia.

The human respiratory tract is constantly exposed to polycyclic aromatic hydrocarbons (PAHs) through inhalation of atmospheric pollutants. We examined the effects of three PAHs (benzo[a]pyrene, anthracene, and fluoranthene) on the airway ion transport, which is essential for lung defense and normal airway function, using human airway epithelia (Calu-3). These three PAHs had no significant effect on the basal short-circuit current (I(sc)). However, fluoranthene (1-100 microM) applied in the apical compartment potentiated I(sc) in response to cAMP-related agents (isoproterenol, forskolin, and 8-bromo-cAMP). The effects of fluoranthene were unaffected by ellipticine, a PAH receptor antagonist. Estimation of the anionic composition of I(sc) revealed that isoproterenol increased both HCO(3)(-) and Cl(-) transport in the control, whereas it potentiated only Cl(-) transport in the presence of fluoranthene. The fluoranthene-induced modulations of these anion transporters were counteracted by charybdotoxin (ChTx, a hIK-1 channel blocker). Fluoranthene gradually augmented the ChTx-sensitive K(+) current (I(K)) across the basolateral membrane, accompanied by a sustained increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)). In the presence of fluoranthene, however, a much larger hIK-1-dependent I(K) was identified by the application of 8-bromo-cAMP without concomitant elevation of [Ca(2+)](i). These results suggest that fluoranthene switches from cAMP-dependent HCO(3)(-) secretion to Cl(-) secretion through the hIK-1 channel, whose sensitivity to protein kinase A may be up-regulated by the sustained [Ca(2+)](i) elevation produced by this chemical.