Phase II Clinical Trial of Combination Therapy with Favipiravir and Methylprednisolone for COVID-19 with Non-Critical Respiratory Failure.

INTRODUCTION: The administration of systemic corticosteroids is a key strategy for improving COVID-19 outcomes. However, evidence is lacking on combination therapies of antiviral agents and systemic corticosteroids. The objective of this study was to investigate the efficacy and safety of the combination therapy of favipiravir and methylprednisolone in preventing respiratory failure progression in patients with COVID-19 and non-critical respiratory failure. METHODS: We conducted a multicenter, open-label, single-arm phase II study. The patients received favipiravir 3600 mg on the first day, followed by 1600 mg for a total of 10-14 days. Methylprednisolone was administered intravenously at 1 mg/ideal body weight (IBW)/day from days 1 to 5, followed by 0.5 mg/IBW/day from days 6 to 10 if clinically indicated. The primary endpoint was the proportion of patients requiring mechanical ventilation (MV) (including noninvasive positive pressure ventilation) or those who met the criteria for tracheal intubation within 14 days of the study treatment initiation (MVCTI-14). RESULTS: Sixty-nine patients were enrolled and underwent the study treatment. Of them, the MVCTI-14 proportion was 29.2% (90% confidence interval 20.1-39.9, p = 0.200). The proportion of patients who required MV or who died within 30 days was 26.2%, and 30-day mortality was 4.9%. The most significant risk factor for MVCTI-14 was a smoking history (odds ratio 4.1, 95% confidence interval 1.2-14.2). The most common grade 3-4 treatment-related adverse event was hyperglycemia, which was observed in 21.7%. CONCLUSION: The MVCTI-14 proportion did not reach a favorable level in the clinical trial setting with the threshold of 35%. However, the proportion of MV or death within 30 days was 26.6%, which might be close to the findings (28.1%) of the RECOVERY trial, which showed the efficacy of dexamethasone for patients with COVID-19 and non-critical respiratory failure. Further evaluation of this combination therapy is needed. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) identifier jRCTs041200025.

Changes in exercise capacity, muscle strength, and health-related quality of life in esophageal cancer patients undergoing esophagectomy.

BACKGROUND: Surgery for cancer of the thoracic esophagus is a challenging procedure associated with high morbidity and mortality. Perioperative rehabilitation has been introduced to promote early mobilization of the patients and to prevent postoperative pulmonary complications. The purpose of the present study was to characterize the preoperative functional exercise capacity, muscle strength, anxiety, depression, and health-related quality of life (QOL) in patients with esophageal cancer, and to evaluate the impact of radical esophagectomy on these parameters. METHODS: We performed a retrospective review of 34 consecutive patients with newly diagnosed resectable esophageal cancer who underwent esophagectomy followed by postoperative rehabilitation from January to December 2014. Patients were tested for 6-min walk distance (6MWD), knee-extensor muscle strength, hand grip strength, the Hospital Anxiety and Depression Scale (HADS), and the chronic obstructive pulmonary disease (COPD) assessment test (CAT) before and two weeks after the surgery. Before surgery, the pulmonary function test, and components of the MOS 36-item Short-Form Health Survey (SF-36) Questionnaire for general health were assessed. RESULTS: The mean age was 67.3 ± 8.1 years. The patients were predominantly male (76.4 %), had high rates of smoking history (91.2 %), and squamous cell carcinoma (97.1 %). The predicted value for forced expiratory volume in 1 s was 94.0 ± 15.9 %, and 12 patients (35.3 %) had COPD. The clinical stage was 0-I in 12 patients, II in 4 patients, III in 16 patients, and IV in 2 patients. Thirty-one patients (91.2 %) underwent open surgery. At the baseline, components of the SF-36 scores significantly correlated with CAT and HADS scores, and the physical status was significantly poorer in patients with COPD than those without. Comparisons between the preoperative and postoperative values revealed significant decreases in 6MWD, hand grip strength, isometric knee extensor muscle strength, and a significant increase in CAT scores but not in HADS scores after surgery. In multiple regression analysis, decreases in 6MWD after the surgery significantly correlated with the preoperative physical component summary of SF-36. CONCLUSIONS: Our results indicate that surgery remained detrimental to health outcomes at two weeks. Further research should investigate whether prehabilitation would improve the postoperative outcomes, QOL, and physical fitness.

Antineutrophil Cytoplasmic Antibody-associated Vasculitis Superimposed on Infection-related Glomerulonephritis Secondary to Pulmonary Mycobacterium avium Complex Infection.

A 73-year-old woman was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection and received no treatment. Disease progression was evident one year later with the development of myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA) titers and systemic symptoms of a fever, polyarthritis, purpura, and rapidly progressive glomerulonephritis. Her symptoms did not improve with antibiotic treatment. A renal biopsy revealed crescentic glomerulonephritis with immunodeposition. According to these findings, she was diagnosed with ANCA-associated vasculitis (AAV) superimposed on infection-related glomerulonephritis (IRGN). Although there was a risk of aggravating an underlying infection, the combination therapy of corticosteroid and antibiotics improved AAV, IRGN, and even the lung radiological findings. To the best of our knowledge, this is the first case of AAV and IRGN secondary to pulmonary MAC infection.

Factors Affecting the Diagnostic Yield of Transbronchial Biopsy Using Endobronchial Ultrasonography with a Guide Sheath in Peripheral Lung Cancer.

Objective Endobronchial ultrasonography with a guide sheath (EBUS-GS) and virtual bronchoscopic navigation (VBN) improves the diagnostic yield in patients with peripheral pulmonary lesions (PPLs). Most previous reports on EBUS-GS-guided transbronchial biopsy (TBB) have included patients with benign and malignant diseases. We aimed to determine the factors that predicted a successful diagnosis by EBUS-GS-guided TBB diagnostic in patients with small peripheral lung cancer, with a focus on the high-resolution computed tomography (HRCT) findings before bronchoscopy. Methods We retrospectively reviewed the medical records of 173 consecutive patients with 175 small (≤30 mm) PPLs who were diagnosed with primary lung cancer between June 2010 and October 2013 at Nagoya University Hospital. All patients underwent EBUS-GS-guided TBB with VBN using a ZioStation computer workstation (Ziosoft, Osaka, Japan). We analyzed the patient characteristics, HRCT findings, diagnostic yield, and the diagnostic factors in small peripheral lung carcinoma. Results The EBUS probe position was within the PPL in 83 of the 175 lesions (47%) and 112 (64.0%) cases were successfully diagnosed by EBUS-GS-guided TBB. A univariate analysis revealed that the following factors were associated with a significantly higher diagnostic yield: CT bronchus sign positivity, a lesion of >20 mm in diameter, a solid nodule, and a probe position that was within the lesion. The following factors were not significant: the lesion location, the number of biopsies, and the lung cancer histology. A multivariate analysis revealed that the following factors significantly affected the diagnostic yield: CT bronchus sign positivity [odds ratio (OR) =2.479]; a probe position that was within the lesion (OR=2.542); and a solid nodule (OR=2.304). Conclusion The significant factors that were significantly associated with a successful diagnosis using EBUS-GS-guided TBB in small peripheral lung carcinoma were as follows: CT bronchus sign positivity, a solid nodule, and a probe position that was within the lesion.

Respiratory mechanics measured by forced oscillation technique in rheumatoid arthritis-related pulmonary abnormalities: frequency-dependence, heterogeneity and effects of smoking.

Rheumatoid arthritis (RA)-related pulmonary disorders specifically airway abnormalities and interstitial pneumonia (IP) are important extra-articular manifestations. The forced oscillation technique (FOT) is a useful method to assess respiratory impedance, respiratory resistance (Rrs) and reactance (Xrs), at different oscillatory frequencies during tidal breathing. The aim of this study was to characterize the respiratory mechanics of patients with RA and to relate them to parameters of the pulmonary function test and findings of chest CT images. Respiratory impedance of RA patients (n = 69) was measured as a function of frequency from 4 to 36 Hz using the FOT device and compared with that of healthy subjects (n = 10). Data were retrospectively reviewed. Patients were female-dominant (60.9 %) and 95.7 % had abnormal CT findings including airway and parenchymal abnormalities. Thirty-seven of 69 patients (53.6 %) were smokers. Rrs was significantly frequency-dependent in RA patients but not in the healthy subjects. Xrs were significantly frequency-dependent in both RA and healthy groups. Rrs was significantly higher during an expiratory phase in both RA and healthy groups. Xrs was significantly lower (more negative) during an expiratory phase than that during an inspiratory phase in RA patients but not in healthy subjects. Xrs of the RA group was significantly more negative than that of the normal control. There was no difference in impedance parameters between the airway lesion dominant (n = 27) and IP dominant groups (n = 23) in the RA group. The impedance parameters of the RA group significantly correlated with most parameters of the pulmonary function test. In pulmonary function test results, % of the predicted value for forced expiratory flow from 25 to 75 % of forced vital capacity was significantly lower and % of the predicted value for diffusing capacity of the lung for carbon monoxide was higher in the airway lesion dominant group than those in the IP dominant group. Krebs von den Lungen-6, a serum indicator of IP, was significantly higher in the IP group than that in the airway lesion dominant group. Taken together, the impedance results reflect abnormalities in pulmonary functions and structures in patients with RA.

Impact of airflow limitation on carotid atherosclerosis in coronary artery disease patients.

BACKGROUND: Both airflow limitation and smoking are established cardiovascular risk factors. However, their interaction as risk factors for the development of atherosclerosis in coronary artery disease patients remains unclear. OBJECTIVES: To evaluate the effect of the interaction between airflow limitation and smoking status on the severity of carotid atherosclerosis. METHODS: We categorized the 234 enrolled patients with coronary artery disease into four groups: never-smokers with normal pulmonary function (group A), never-smokers with airflow limitation (group B), ever-smokers with normal pulmonary function (group C), and ever-smokers with airflow limitation (group D). RESULTS: The prevalence of airflow limitation in the enrolled patients was 23.1% (ever-smokers: 15.8%, never-smokers: 7.3%). The prevalence of severe carotid atherosclerosis was 28.2, 29.4, 41.3, and 45.9%, respectively, in the four groups (group D vs. group A, p = 0.035). Even after multivariate adjusting for confounding factors, ever-smokers with airflow limitation were independently associated with severe carotid atherosclerosis (odds ratio 2.89, 95% confidence interval, 1.19-7.00, p = 0.019). CONCLUSIONS: Ever-smokers with airflow limitation were significantly associated with severe carotid atherosclerosis among patients with coronary artery disease. These findings also provide additional insight into the correlation between airflow limitation and poor cardiovascular clinical outcomes.

Ca2+ influx and ATP release mediated by mechanical stretch in human lung fibroblasts.

One cause of progressive pulmonary fibrosis is dysregulated wound healing after lung inflammation or damage in patients with idiopathic pulmonary fibrosis and severe acute respiratory distress syndrome. The mechanical forces are considered to regulate pulmonary fibrosis via activation of lung fibroblasts. In this study, the effects of mechanical stretch on the intracellular Ca(2+) concentration ([Ca(2+)]i) and ATP release were investigated in primary human lung fibroblasts. Uniaxial stretch (10-30% in strain) was applied to fibroblasts cultured in a silicone chamber coated with type I collagen using a stretching apparatus. Following stretching and subsequent unloading, [Ca(2+)]i transiently increased in a strain-dependent manner. Hypotonic stress, which causes plasma membrane stretching, also transiently increased the [Ca(2+)]i. The stretch-induced [Ca(2+)]i elevation was attenuated in Ca(2+)-free solution. In contrast, the increase of [Ca(2+)]i by a 20% stretch was not inhibited by the inhibitor of stretch-activated channels GsMTx-4, Gd(3+), ruthenium red, or cytochalasin D. Cyclic stretching induced significant ATP releases from fibroblasts. However, the stretch-induced [Ca(2+)]i elevation was not inhibited by ATP diphosphohydrolase apyrase or a purinergic receptor antagonist suramin. Taken together, mechanical stretch induces Ca(2+) influx independently of conventional stretch-sensitive ion channels, the actin cytoskeleton, and released ATP.

Real-time imaging of ATP release induced by mechanical stretch in human airway smooth muscle cells.

Airway smooth muscle (ASM) cells within the airway walls are continually exposed to mechanical stimuli, and exhibit various functions in response to these mechanical stresses. ATP acts as an extracellular mediator in the airway. Moreover, extracellular ATP is considered to play an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease. However, it is not known whether ASM cells are cellular sources of ATP secretion in the airway. We therefore investigated whether mechanical stretch induces ATP release from ASM cells. Mechanical stretch was applied to primary human ASM cells cultured on a silicone chamber coated with type I collagen using a stretching apparatus. Concentrations of ATP in cell culture supernatants measured by luciferin-luciferase bioluminescence were significantly elevated by cyclic stretch (12 and 20% strain). We further visualized the stretch-induced ATP release from the cells in real time using a luminescence imaging system, while acquiring differential interference contrast cell images with infrared optics. Immediately after a single uniaxial stretch for 1 second, strong ATP signals were produced by a certain population of cells and spread to surrounding spaces. The cyclic stretch-induced ATP release was significantly reduced by inhibitors of Ca(2+)-dependent vesicular exocytosis, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester, monensin, N-ethylmaleimide, and bafilomycin. In contrast, the stretch-induced ATP release was not inhibited by a hemichannel blocker, carbenoxolone, or blockade of transient receptor potential vanilloid 4 by short interfering RNA transfection or ruthenium red. These findings reveal a novel property of ASM cells: mechanically induced ATP release may be a cellular source of ATP in the airway.

Predictors of the need to initiate noninvasive ventilation in stable outpatients with acute exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: Predictors of the need to initiate noninvasive ventilation (NIV) in stable COPD outpatients with acute exacerbation of chronic obstructive pulmonary disease (COPD-AE) are insufficiently defined. The objective of this study was to investigate predictors of the need to initiate NIV in stable COPD-AE outpatients. METHODS: A total of 140 consecutive stable COPD outpatients who were hospitalized for COPD-AE for the first time were retrospectively examined. Demographic and clinical parameters measured in the stable state were evaluated, including data for arterial blood gases, the pulmonary function, body mass index and dyspnea scores. RESULTS: Of the 140 patients included, NIV was used in 32 (23%) patients. In a univariate Cox proportional hazards analysis, the baseline partial pressure of arterial carbon dioxide (PaCO2) (hazard ratio (HR), 1.14 per mmHg; 95% confidence interval (CI), 1.08-1.21) and forced expiratory volume in one second (FEV1)% predicted (HR, 1.03 per %; 95% CI, 1.01-1.05) were identified to be significant predictors. A multivariate logistic regression analysis showed only the PaCO2 (HR, 1.18 per mmHg; 95% CI, 1.12-1.26) to be a significant predictor. CONCLUSION: Our results suggest that the PaCO2 measured in the stable state is an independent significant predictor of the need to initiate NIV in COPD-AE patients who are hospitalized for the first time.

Endobronchial ultrasound transbronchial needle aspiration in older people.

AIM: The usefulness and safety of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) have been established recently, but no study has evaluated whether or not aging increases the risk of the procedure. In the present study, we aimed to assess the usefulness and safety of EBUS-TBNA in older patients. METHODS: The medical records and database of 109 patients who received EBUS-TBNA between 2008 and 2011 at Nagoya University Hospital, Nagoya, Japan were reviewed retrospectively. All patients underwent bronchoscopy under light sedation with midazolam. A total of 34 patients were aged 70 years or older (the older group) and 75 were aged 69 years or younger (the younger group). We analyzed patients' characteristics, changes of clinical parameters, usage doses of midazolam and lidocaine, procedure duration, geographic data of biopsied lymph nodes, diagnostic yield, and complications in both groups. RESULTS: There were more comorbidities in the older group. Four patients (11.8%) in the older group had poor performance status (2-3). Systolic blood pressure at baseline was significantly higher in the older group. There were no statistical differences between the two groups in some clinical parameters (minimum oxygen saturation [SpO2 ], reduction in SpO2 , maximum oxygen supplementation, elevation of systolic blood pressure, increase of heart rate) during the procedure. Diagnostic performance in older patients was similar to that found in younger patients. There was no difference in the frequency of complications between both groups. CONCLUSION: Safety and usefulness of EBUS-TBNA in older people were comparable with those in younger people.

Differential regulation of airway smooth muscle cell migration by E-prostanoid receptor subtypes.

Migration of airway smooth muscle (ASM) cells plays an important role in the pathophysiology of airway hyperresponsiveness and remodeling in asthma. It has been reported that prostaglandin (PG)E2 inhibits migration of ASM cells. Although PGE2 regulates cellular functions via binding to distinct prostanoid EP receptors, the role of EP receptor subtypes in mechanisms underlying cell migration has not been fully elucidated. We investigated the role of EP receptors in the inhibitory effects of PGE2 on the migration of human ASM cells. Migration induced by platelet-derived growth factor (PDGF)-BB (10 ng/ml, 6 h) was assessed by a chemotaxis chamber assay. PDGF-BB-induced cell migration was inhibited by PGE2, the specific EP2 agonist ONO-AE1-259-01, the specific EP4 agonist ONO-AE1-329, and cAMP-mobilizing agents. The inhibition of cell migration by PGE2 was significantly reversed by a blockade of EP2 and EP4 receptors using antagonists or transfection with siRNAs. Moreover, PGE2, the EP2 agonist, and the EP4 agonist significantly increased phosphorylation of small heat shock protein 20, one of the protein substrates for protein kinase A (PKA), with depolymerization of actin. In contrast, the EP3 agonist ONO-AE-248 significantly promoted baseline cell migration without affecting PDGF-BB-induced cell migration. In summary, activation of EP2 and EP4 receptors and subsequent activation of the cAMP/PKA pathway are the main mechanisms of inhibition of ASM cell migration by PGE2. HSP20 phosphorylation by PKA is possibly involved in this mechanism. Conversely, EP3 is potent in promoting cell migration. EP receptor subtypes may be novel therapeutic target molecules in airway remodeling and asthma.

Pulmonary hypertension as a prognostic indicator at the initial evaluation in idiopathic pulmonary fibrosis.

BACKGROUND: The impact of pulmonary hypertension (PH) on survival has been demonstrated in severe cases with idiopathic pulmonary fibrosis (IPF) who were referred for transplantation. However, whether PH is a predictor of survival remains unclear in milder cases. OBJECTIVES: To evaluate the survival impact of pulmonary artery pressure measured during the initial evaluation in patients with IPF. METHODS: We retrospectively analyzed the initial evaluation data of 101 consecutive IPF patients undergoing right heart catheterization. Patients evaluated with supplemental oxygen were excluded. Predictors of 5-year survival were analyzed using the Cox proportional model. RESULTS: The mean forced vital capacity (FVC) % predicted, diffusing capacity of the lung for carbon monoxide (DLCO) % predicted, and mean pulmonary artery pressure (MPAP) were 70.2 ± 20.1%, 47.9 ± 19.5%, and 19.2 ± 6.5 mm Hg, respectively. A univariate Cox proportional hazard model showed that the body mass index, %FVC, %DLCO, baseline PaO2, modified Medical Research Council score, 6-min walk distance, and lowest SpO2 of the 6-min walk test were significantly predictive of survival. The MPAP and pulmonary vascular resistance of right heart catheterization were also significant. With stepwise, multivariate Cox proportional analysis, MPAP (HR = 1.064; 95% CI 1.015-1.116, p = 0.010) and %FVC (HR = 0.965, 95% CI 0.949-0.982, p < 0.001) were independent determinants of survival. Analysis of the receiver operating curve revealed MPAP >20 mm Hg to be optimal for predicting the prognosis. CONCLUSIONS: Higher MPAP and lower %FVC at the initial evaluation were significant independent prognostic factors of IPF. The current results suggested the importance of the initial evaluation of PH for patients with IPF.

STIM1 regulates platelet-derived growth factor-induced migration and Ca2+ influx in human airway smooth muscle cells.

It is suggested that migration of airway smooth muscle (ASM) cells plays an important role in the pathogenesis of airway remodeling in asthma. Increases in intracellular Ca(2+) concentrations ([Ca(2+)](i)) regulate most ASM cell functions related to asthma, such as contraction and proliferation. Recently, STIM1 was identified as a sarcoplasmic reticulum (SR) Ca(2+) sensor that activates Orai1, the Ca(2+) channel responsible for store-operated Ca(2+) entry (SOCE). We investigated the role of STIM1 in [Ca(2+)](i) and cell migration induced by platelet-derived growth factor (PDGF)-BB in human ASM cells. Cell migration was assessed by a chemotaxis chamber assay. Human ASM cells express STIM1, STIM2, and Orai1 mRNAs. SOCE activated by thapsigargin, an inhibitor of SR Ca(2+)-ATPase, was significantly blocked by STIM1 siRNA and Orai1 siRNA but not by STIM2 siRNA. PDGF-BB induced a transient increase in [Ca(2+)](i) followed by sustained [Ca(2+)](i) elevation. Sustained increases in [Ca(2+)](i) due to PDGF-BB were significantly inhibited by a Ca(2+) chelating agent EGTA or by siRNA for STIM1 or Orai1. The numbers of migrating cells were significantly increased by PDGF-BB treatment for 6 h. Knockdown of STIM1 and Orai1 by siRNA transfection inhibited PDGF-induced cell migration. Similarly, EGTA significantly inhibited PDGF-induced cell migration. In contrast, transfection with siRNA for STIM2 did not inhibit the sustained elevation of [Ca(2+)](i) or cell migration induced by PDGF-BB. These results demonstrate that STIM1 and Orai1 are essential for PDGF-induced cell migration and Ca(2+) influx in human ASM cells. STIM1 could be an important molecule responsible for airway remodeling.

Prostaglandin E2 enhances interleukin-8 production via EP4 receptor in human pulmonary microvascular endothelial cells.

Prostaglandin E(2) (PGE(2)) is a bioactive prostanoid implicated in the inflammatory processes of acute lung injury/acute respiratory distress syndrome. This study investigated whether PGE(2) can induce production of interleukin (IL)-8, the major chemokine for neutrophil activation, from human pulmonary microvascular endothelial cells (HPMVECs). PGE(2) significantly enhanced IL-8 protein production with increases in IL-8 mRNA expression and intracellular cAMP levels. HPMVECs expressed only EP4 receptor mRNA. The PGE(2) effects were mimicked by a selective EP4 receptor agonist, ONO-AE1-329, and inhibited by a selective EP4 receptor antagonist, ONO-AE3-208, or a protein kinase A inhibitor, Rp-adenosine 3',5'-cyclic monophosphorothioate triethylamine salt. The specific agonist for EP1, EP2, or EP3 receptor did not induce IL-8 production. PGE(2)-induced IL-8 production was accompanied by p38 phosphorylation and was significantly inhibited by a p38 inhibitor, SB-203580, but not by an ERK1/2 inhibitor, U-0126, or a JNK inhibitor, SP-600125. Additionally, PGE(2) increased cyclooxygenase-2 expression with no change in constitutive cyclooxygenase-1 expression, suggesting possible involvement of an autocrine or paracrine manner. In conclusion, PGE(2) enhances IL-8 production via EP4 receptor coupled to G(s) protein in HPMVECs. Activation of the cAMP/protein kinase A pathway, followed by p38 activation, is essential for these mechanisms. Because neutrophils play a critical role in the inflammation of acute lung injury/acute respiratory distress syndrome, IL-8 released from the pulmonary microvasculature in response to PGE(2) may contribute to pathophysiology of this disease.

Effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca(2+) concentrations in human airway smooth muscle cells.

Increased airway smooth muscle mass due to cell proliferation contributes to airway hyper-responsiveness and remodeling in patients with asthma. Prostaglandin E2 (PGE2) inhibits proliferation of airway smooth muscle cells, but the role of prostanoid EP receptor subtypes in mechanisms involved has not been fully elucidated yet. We investigated the effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca(2+) concentrations ([Ca(2+)]i) in human airway smooth muscle cells. Cell numbers were assessed by mitochondria-dependent reduction of 4-[3-(4-lodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1, 3-benzene disulfonate to formazan (WST-1 assay). RT-PCR data showed that human airway smooth muscle cells express EP2, EP3, and EP4 but not EP1 receptor mRNA. PGE2 (1nM-1µM) inhibited cell proliferation induced by 5% fetal bovine serum (FBS) in a concentration-dependent manner. (16S)-9-deoxy-9ß-chloro-15-deoxy-16-hydroxy-17, 17-trimethylene-19, 20-didehydro PGE2 sodium salt (ONO-AE1-259-01; EP2 receptor agonist) and 16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia PGE2 (ONO-AE1-329; EP4 receptor agonist) inhibited the 5% FBS-induced cell proliferation. ONO-AE1-259-01 and ONO-AE1-329 also significantly increased the cytosolic cAMP levels. In contrast, 11,15-O-dimethyl PGE2 (ONO-AE-248; EP3 receptor agonist) elicited an oscillatory increase in [Ca(2+)]i but did not affect the cell growth or cAMP levels. [(17S)-2,5-ethano-6-oxo-17,20-dimethyl PGE1] (ONO-DI-004; EP1 receptor agonist) did not affect cell growth, cAMP levels, or [Ca(2+)]i. In conclusion, PGE2 inhibits FBS-induced cell proliferation mostly via EP2 and EP4 receptor activation and subsequent cAMP elevation. The EP3 receptor agonist causes an increase in [Ca(2+)]i without affecting cell growth. There is no functional expression of the EP1 receptor. Research on prostanoid EP receptors may lead to novel therapeutic strategies for treatment of asthma.

Noninvasive ventilation in patients with acute exacerbation of pulmonary tuberculosis sequelae.

BACKGROUND: The efficacy of noninvasive ventilation (NIV) in acute exacerbation of pulmonary tuberculosis sequelae has not been fully studied. METHODS: We retrospectively reviewed 58 patients with acute exacerbation of pulmonary tuberculosis sequelae who were admitted to Tosei General Hospital and treated with NIV over a 9-year period. RESULTS: The 58 patients (mean age: 76.2±8.0) consisted of 39 males and 19 females. Arterial blood gas analysis on admission showed a mean pH of 7.28±0.07 and a mean PaCO(2) of 72.6±14.2 mmHg. After the start of NIV, significant improvement occurred in pH, to 7.32±0.06 after 2 h and 7.36±0.06 after 24 h, and in PaCO(2), to 66.4±11.2 mmHg after 2 h and 61.6±11.3 mmHg after 24 h. The success rate in weaning from NIV was 86.2%. There were statistically significant differences in pH, body mass index (BMI), blood leukocyte count and serum potassium between patients successfully and unsuccessfully weaned from NIV. CONCLUSION: We conclude that patients with acute exacerbation of pulmonary tuberculosis sequelae can be treated successfully with NIV. Lower pH, BMI, and serum potassium, and higher blood leukocyte count are related to NIV failure.

[Primary pulmonary cryptococcosis: a case series of 9 patients].

We retrospectively reviewed 9 consecutive cases of primary pulmonary cryptococcosis having no comorbidity. At diagnosis, seven had no subjective symptoms and two had subtle symptom. Chest CT scan showed nodular shadows in 8, while 3 cases had infiltrative shadows. Eight of the nine were diagnosed with histopathology obtained by transbronchial lung biopsy or CT-guided needle aspiration biopsy. We also assessed PHA and Con A lymphocyte stimulation tests to measure cellular immune function in 6, four of whom showed decreased reaction of lymphocytes. We successfully treated seven of the nine with fluconazole alone and used fluconazole as a maintenance regimen in two. No relapse or treatment failure was seen after completion of antifungal treatment. Six cases were seropositive for serum cryptococcus antigen titer at diagnosis and only one showed seroconversion. We concluded that the duration of therapy for primary pulmonary cryptococcosis should not be necessarily determined by serum cryptococcus antigen seroconversion.

[Surgical lung biopsy for interstital lung diseases: complications, diagnostic yield and mortality].

We retrospectively reviewed 110 consecutive patients with interstitial lung diseases (ILDs) who underwent surgical lung biopsy over 13 years from 1989-2002. Surgical procedures, medical records, surgical complications and outcome including post-operative exacerbation of ILDs were assessed in order to clarify the safety and efficacy of surgical lung biopsy. Forty-one patients underwent open lung biopsy (OLB), while 69 patients received videothoracoscopic lung biopsy (VTLB). There was no significant difference in patient characteristics, pulmonary function, arterial oxygen pressure and therapy prior to surgery between the two groups. The mean number of biopsy specimens was 2.5. Left side was selected as the site of biopsy in 70 cases. Duration of surgery was not significantly different between 2 groups. Bleeding during operation was less in the VTLB group than in the OLB group, although the mean bleeding amount was only 16.5mL. The duration of thoracic drainage and length of hospital stay were shorter in the VTLB group. The overall rate of surgical complications was 10.9%, with no difference between the two groups. The overall 30-day post-SLB mortality was 6.4% and majority of these had a very poor prognosis pathologically. The diagnostic yield of all 110 cases was 98.2%. SLB is a relatively safe and efficient diagnostic method in the diagnosis of ILDs.

[Case of acute respiratory distress syndrome in which high-frequency oscillatory ventilation (HFOV) was effective for the management of severe hypoxemia].

A 69-year-old man was admitted to our hospital because of acute prostatitis. After admission he produced bloody sputum and chest radiograph showed bilateral infiltration of the upper lung fields. The fraction of neutrophils in the bronchoalveolar lavage fluid was 15.6%, lymphocytes were 33.6%, eosinophils were 26.6% and macrophages were 23.6%. No special findings were observed in the lung tissue obtained by transbronchial lung biopsy. After admission, he displayed acute respiratory distress syndrome with severe hypoxemia as dyspnea gradually progressed. We commenced treatment with high-dose pulse methylprednisolone and neutrophil elastase inhibitor under mechanical ventilation. Because severe hypoxemia was unresolved, HFOV was initiated on the 8th hospital day. His respiratory condition rapidly improved during HFOV. On the 17th hospital day, he was weaned from mechanical ventilation. HFOV seem to be safe and effective for patients with severe ARDS who failed conventional ventilation support.

[Quality of life as an independent prognostic factor in advanced non-small-cell lung cancer in general practice].

Although quality of life (QOL) has become an important aspect of lung cancer trials, it has rarely been evaluated in general practice. We have been assessing QOL in patients with advanced non-small-cell lung cancer in general practice. In this study, we retrospectively analyzed factors of the baseline QOL score in relation to response to chemotherapy and survival in 43 consecutive advanced non-small-cell lung cancer patients who received chemotherapy. QOL was evaluated with the QLQ-C30 of The European Organization for Research and Treatment of Cancer. In multivariate analysis, the cognitive functioning score was the only significant factor in both response to treatment and survival. In conclusion, the QOL score is an independent factor in both response to chemotherapy and survival even in general practice; and cognitive functioning is the most important factor.