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Kang-Yun Lee,1,2,* Tzu-Tao Chen,1,* Ling-Ling Chiang,1,3 Hsiao-Chi Chuang,1,3 Po-Hao Feng,1,2 Wen-Te Liu,1–3 Kuan-Yuan Chen,1 Shu-Chuan Ho1,3 1Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 2Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, 3School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan *These authors contributed equally to this work Background: COPD is a debilitating disease that affects patients’ daily lives. One’s daily physical activity (DPA) decreases due to multifactorial causes, and this decrease is correlated with a poor prognosis in COPD patients. Muscle wasting may at least be partly due to increased activity of the ubiquitin proteasome pathway and apoptosis.Methods: This study investigated the relationships among DPA, circulating proteasome activity, and protein carbonyl in COPD patients and healthy subjects (HSs). This study included 57 participants (42 patients and 15 healthy subjects). Ambulatory DPA was measured using actigraphy, and oxygen saturation was measured with a pulse oximeter.Results: COPD patients had lower DPA, lower 6 min walking distance (6MWD), lower delta saturation pulse oxygenation (SpO2) during the 6MWT, and lower delta SpO2 during DPA than HSs. COPD patients had higher proteasome activity and protein carbonyl than HSs. Circulating proteasome activity was significantly negatively correlated with DPA (r=−0.568, P

Kang-Yun Lee,1,2,* Ling-Ling Chiang,1,3,* Shu-Chuan Ho,1,3 Wen-Te Liu,1–3 Tzu-Tao Chen,1 Po-Hao Feng,1,2 Chien-Ling Su,1,3 Kai-Jen Chuang,4,5 Chih-Cheng Chang,1,2 Hsiao-Chi Chuang1–3 1Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, 2Department of Internal Medicine, School of Medicine, 3School of Respiratory Therapy, 4Department of Public Health, School of Medicine, College of Medicine, 5School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei City, Taiwan *These authors contributed equally to this work Abstract: Although traffic exposure has been associated with the development of COPD, the role of particulate matter

Kang-Yun Lee,1,2 Hsiao-Chi Chuang,1,3 Tzu-Tao Chen,1 Wen-Te Liu,1,3 Chien-Ling Su,1,3 Po-Hao Feng,1,2 Ling-Ling Chiang,1,3 Mauo-Ying Bien,3,4 Shu-Chuan Ho3 1Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; 2Department of Internal Medicine, School of Medicine, 3School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan Introduction: The measurement of C-reactive protein (CRP) to confirm the stability of COPD has been reported. However, CRP is a systemic inflammatory biomarker that is related to many other diseases.Objective: The objective of this study is to discover a diagnostic biomarker for COPD.Methods: Sixty-one subjects with COPD and 15 healthy controls (10 healthy non-smokers and 5 smokers) were recruited for a 1-year follow-up study. Data regarding the 1-year acute exacerbation frequency and changes in lung function were collected. CRP and the identified biomarkers were assessed in the validation COPD cohort patients and healthy subjects. Receiver operating characteristic values of CRP and the identified biomarkers were determined. A validation COPD cohort was used to reexamine the identified biomarker. Correlation of the biomarker with 1-year lung function decline was determined.Results: Proteoglycan 4 (PRG4) was identified as a biomarker in COPD. The serum concentrations of PRG4 in COPD Global initiative for chronic Obstructive Lung Disease (GOLD) stages 1+2 and 3+4 were 10.29 ng/mL and 13.20 ng/mL, respectively; 4.99 ng/mL for healthy controls (P

Wen-Te Liu,1,2,* Han-Pin Kuo,3,* Tien-Hua Liao,4 Ling-Ling Chiang,1 Li-Fei Chen,3 Min-Fang Hsu,5 Hsiao-Chi Chuang,1 Kang-Yun Lee,2,6 Chien-Da Huang,3 Shu-Chuan Ho11School of Respiratory Therapy, College of Medicine, Taipei Medical University, 2Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, 3Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 4Department of Respiratory Therapy, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, 5Department of Healthcare Administration, Asia University, Wufeng, Taichung, 6Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan*These authors contributed equally to this workAbstract: COPD patients have an increased prevalence of osteoporosis (OP) compared with healthy people. Physical inactivity in COPD patients is a crucial risk factor for OP; the COPD assessment test (CAT) is the newest assessment tool for the health status and daily activities of COPD patients. This study investigated the relationship among daily physical activity (DPA), CAT scores, and bone mineral density (BMD) in COPD patients with or without OP. This study included 30 participants. Ambulatory DPA was measured using actigraphy and oxygen saturation by using a pulse oximeter. BMD was measured using dual-energy X-ray absorptiometry. OP was defined as a T-score (standard deviations from a young, sex-specific reference mean BMD) less than or equal to -2.5 SD for the lumbar spine, total hip, and femoral neck. We quantified oxygen desaturation during DPA by using a desaturation index and recorded all DPA, except during sleep. COPD patients with OP had lower DPA and higher CAT scores than those of patients without OP. DPA was significantly positively correlated with (lumbar spine, total hip, and femoral neck) BMD (r=0.399, 0.602, 0.438, respectively, all P

Background: Patients undergoing bronchoscopic procedures may develop hypoxemia and severe complications. High-flow nasal cannula (HFNC) may prevent hypoxemic events during bronchoscopy. We conducted a systematic review of randomized controlled trials (RCTs) to evaluate the effectiveness of HFNC in these patients., Methods: We conducted a search in PubMed, Embase, and the Cochrane Library for RCTs published before November 2021. Individual effect sizes were standardized, and a meta-analysis was performed to calculate the pooled effect size using random-effects models. The primary outcome was the incidence of hypoxemic events (oxygen saturation [SpO2] < 90%) during bronchoscopy. Secondary outcomes included the incidence of interrupted bronchoscopy due to desaturation, lowest SpO2 during bronchoscopy, partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), end-tidal CO2 (EtCO2) at the end of bronchoscopy, and the incidence of intubation after the procedure., Results: Five trials involving 257 patients were reviewed. The incidence of hypoxemic events was lower in the HFNC group than in the conventional oxygen therapy group (risk ratio, 0.25; 95% confidence interval [CI], 0.14-0.42). The lowest SpO2 during the procedure was significantly higher in the HFNC group than in the conventional oxygen therapy group (weighted mean difference [WMD], 7.12; 95% CI, 5.39-8.84). PaO2 at the end of the procedure was significantly higher in the HFNC group than in the conventional oxygen therapy group (WMD, 20.36; 95% CI, 0.30-40.42). The incidence of interrupted bronchoscopy due to desaturation, PaCO2 and EtCO2 at the end of the procedure, and the incidence of intubation after the procedure were not significantly different between groups., Conclusions: HFNC may reduce the incidence of hypoxemic events and improve oxygenation in patients undergoing bronchoscopy., Competing Interests: The authors have no conflicts of interest or financial associations to disclose.

Air pollution is associated with sleep-related breathing disorders; however, the effects of air pollution on depression in patients with SRBDs remain unclear. A cross-sectional study was conducted to collect polysomnographic (PSG) data and Beck Depression Inventory-IA (BDI-IA) responses from 568 subjects with SRDBs in a sleep center in 2015 to 2017. Exposure to air pollution, including particulate matter with an aerodynamic diameter of ≤10 μm (PM 10 ), particulate matter with an aerodynamic diameter of ≤2.5 μm (PM 2.5 ), nitrogen (NO 2 ), sulfur dioxide (SO 2 ), carbon monoxide (CO) and ozone (O 3 ), in 1-month averages was collected. Associations of air pollution with the respiratory disturbance index (RDI), oxygen desaturation index (ODI), arousal index (ARI), sleep architecture, and BDI-IA were examined. We observed that interquartile range (IQR) increases in 1-month PM 2.5 , PM 10 , and NO 2 levels were respectively associated with 4.1/hour (h) (95% confidence interval (CI): 1.7/h to 6.4/h), 3.7/h (95% CI: 1.4/h to 6.0/h) and 1.9/h (95% CI: 0.1/h to 3.7/h) increases in the ARI. For sleep architecture, IQR increases in 1-month PM 2.5 and CO levels were respectively associated with a 6.2% (95% CI: 6.1% to 6.3%) increase in non-rapid eye movement sleep 1 (N1) and a 2.0% (95% CI: -3.8% to -0.1%) decrease in non-rapid eye movement sleep 2 (N2). For depression, an IQR change in the 1-month CO was associated a moderate/severe depressive status according to the BDI-IA (odds ratio, OR: 2.981, p < 0.05; 95% CI: 1.032 to 8.611). Short-term exposure to air pollution increased the risk of arousal and light sleep as well as depression in patients with SRBDs. The results suggest that SRBD patients could be a population at risk for depression due to short-term exposure to air pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The coronavirus disease 2019 (COVID-19) is spreading around the world, and Taiwan is no exception. Faced with the outbreak of the epidemic, the Taiwan government immediately ordered a policy banning indoor dining. The main purpose of the present research is to extend a Theory of Planned Behavior (TPB) theoretical framework to explore the public perception toward banning indoor dining policy on restaurant avoidance behavior during the COVID-19 outbreak. An online survey was administered in Taiwan during the COVID-19 pandemic from 25 May to 8 June 2021; a total of 326 responses were collected by a convenience sampling method, and partial least square (PLS) analysis was deployed to examine the hypothesized relationships. The results showed that perception toward banning indoor dining policy had independent significant associations with attitude, perceived behavioral control, and restaurant avoidance behavior. Moreover, attitude, perceived behavioral control, and subjective norm had independent significant associations with restaurant avoidance behavior. This study provides theoretical and practical insights into the psychological and behavioral processes involved in policy by the general public during the COVID-19 pandemic, thus helping policymakers to better understand public opinion and responses to policy issues.

Gastroesophageal reflux disease (GERD) is one of the most common diseases. It mainly causes the stomach contents to flow back to the esophagus, thereby stimulating the esophagus and causing discomfort. From the results of our research, we intend to provide the general public with information related to preventing gastroesophageal reflux disease and medical personnel with information on the treatment and care of patients with gastroesophageal reflux disease. This study aimed to investigate the association of lifestyle habits and perceived symptoms on GERD in patients who underwent routine health check-ups. This study was conducted as a retrospective cross-sectional design to collect GERD cases from the medical records containing the health questionnaires and the report of endoscopic findings on the day of the health check-up. A total of 5653 patients were enrolled between 1 January 2016, and 31 December 2018. About 60.2% ( n = 3404) of patients with GERD were diagnosed based on endoscopic findings. Descriptive and multivariate logistic regression analyses were performed to identify the risk factors of the development of GERD. The results of the multivariate logistic regression analysis showed that age, sex, waist circumference, Areca catechu chewing habit, sleep disorders, otolaryngology symptoms, and hepatobiliary and gastrointestinal symptoms were significantly associated with GERD. In this study, our results can be used as a reference for public health care and clinicians. Because most GERD cases can be controlled and prevented by lifestyle modifications, health professionals should always obtain a detailed history regarding symptoms and lifestyle habits associated with GERD.

Takotsubo cardiomyopathy (TCM) is characterized by temporary wall motion abnormality of the left ventricle. There is much debate upon the prognostic parameters. We conducted a systematic review and meta-analysis to investigate whether LVEF and the presence of apical ballooning predict long-term mortality in TCM. PubMed and Embase were searched through to October 30, 2017 without language restrictions, followed by an additional search through to February 2, 2020. Our search identified 18 studies that met the inclusion criteria, with a total of 5168 patients. Reduced LVEF as a categorical variable was associated with more than threefold increase in mortality risk in TCM patients (HR 3.10; 95% CI 1.78-5.42; P < 0.0001; I 2  = 57%). Further subset analyses with the exclusion of studies consisting of patients with coronary artery disease revealed another significant relationship between LVEF and mortality (HR 3.13; 95% CI 1.392-7.031; P < 0.006; I 2  = 58%). LVEF as a continuous variable was also found to be associated with increased mortality risk. However, this relationship only retained significance when computing odds ratios instead of hazard ratios (OR 0.95; 95% CI 0.93-0.98; P < 0.001; I 2  = 0%). Finally, the existence of apical ballooning failed to demonstrate any link with an increased risk of mortality (HR 1.26; 95% CI 0.97-1.64; P = 0.09; I 2  = 34%). LVEF and apical ballooning are both potential prognostic markers for mortality.

Background: Patients with amyotrophic lateral sclerosis (ALS) develop respiratory failure and progressive muscle weakness. The effects of pulmonary rehabilitation on the lung function of patients with ALS are unclear., Objective: Through this meta-analysis of randomized controlled trials (RCTs), we evaluated the effects of pulmonary rehabilitation, such as type of treatment, on patients with ALS and compared the effectiveness of this treatment., Methods: PubMed, EMBASE, Web of Science, and Cochrane databases were searched until December 2020. The methodological quality of each study was assessed using the updated Cochrane Risk of Bias tool (RoB 2.0). Data were analyzed using Review Manager version 5.4 (Cochrane Collaboration, Oxford, England), and the meta-analysis was performed in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines., Results: Of 2168 articles, 10 trials were reviewed; among these trials, two focused on respiratory training and eight on physical exercise, three of which involved a combination of aerobic and resistance training. Our meta-analysis demonstrated no difference in the ALSFRS-R score and % FVC among patients with ALS., Conclusions: Respiratory training or physical exercise did not significantly affect the ALSFRS-R score and % FVC of patients with ALS. At 12 months after intervention, the ALSFRS-R score in the physical exercise group was higher than that in the usual care group. Further clinical trials are warranted to develop approaches for improving the lung function of patients with ALS.

Background: We aim to elucidate the disease impact by accounting the prevalence, survival rate, genetics, mTOR inhibitor use and direct costs of tuberous sclerosis complex (TSC) in our local setting. TSC patients with documented visits to our local public hospitals in 1995-2018 were identified. The public hospitals captured most if not all local TSC patients. Demographics such as age, sex, death, genetic profiles were retrieved from the central electronic database. Data including prevalence, age distribution and survival rate were analysed. Direct cost was calculated with reference to the drug use and number of visits to various public hospital facilities., Results: We identified 284 surviving TSC patients (55.3% male) in Hong Kong. The age range was from 4.5 months to 89.9 years, with a median age of 27.2 years. Paediatrics (< 18 years) to adult (≥18 years) ratio was 1:2.84. The overall prevalence of TSC patients was 3.87 in 100,000 (i.e. 1 in 25,833). Genetically, TSC1:TSC2 ratio is 1:2.7. Thirty seven patients died within the study period. The age of death ranged from 7.6 years to 77.8 years, with a median age of death at 36.6 years (IQR: 24.7-51.1 years). Most patients survived till adulthood. Survival rate at 20 and 50 years follow-up was 98.6 and 79.5% respectively. Two hundred and twenty nine TSC patients (71.3%) had neurological manifestations, sixteen patients (5.0%) had chronic kidney diseases and five patients (1.6%) had pulmonary lymphangioleiomyomatosis. Forty seven (16.5%) TSC patients were prescribed with mTOR inhibitors within the study period. Healthcare facility utilization was further analysed in the 2008-2018 cohort. In particular, the mean number of specialist out-patient clinic visits per patient-year was 9.23 per patient-year, which was 4.91 times more than that of local general population., Conclusions: Prevalence of local TSC patients is within the range of that reported in the literature. Local TSC patients have fair long term survival, but they require disproportionally high healthcare cost when compared with the general population, particularly in terms of outpatient (OP) visits. Although effective disease-modifying agent (i.e. mTOR inhibitor) is available, it was not widely used yet in Hong Kong despite the fact that Government approved and supported its use recently. Further research on quality of life and setting up a comprehensive patient registry are necessary for more accurate assessment of cost and benefit.

Noninvasive positive pressure ventilation (NPPV) has been widely applied in patients with high-risk extubation failure, including heart failure. High-flow nasal cannula (HFNC) has been demonstrated to benefit patients with heart failure by reducing cardiac preload. This study aimed to compare the effectiveness of HFNC to NPPV for preventing extubation failure in patients with heart failure. This 3-year retrospective and single-center cohort study included patients with heart failure with left ventricular ejection fraction <50% who received prophylactic HFNC or NPPV after scheduled extubation from January 2015 to January 2018 from a medical center with four adult intensive care units. Demographics, comorbidities, diagnosis, and weaning status were collected. The primary outcome was treatment failure within 72 hours after extubation, which was defined as escalation to NPPV or reintubation in the HFNC group and was defined as requiring reintubation in the NPPV group. Secondary outcomes were reintubation within 72 hours, reintubation, duration of stay, and mortality during the intensive care unit and hospital stay. Of the 104 patients analyzed, characteristics of 58 patients in the HFNC group and 46 patients in the NPPV group were compared. The treatment failure within 72 hours in the two groups was not significantly different (25.9% vs 13%, p =0.106). Hypoxemic respiratory failure related treatment failure was significantly higher in the HFNC group. Prophylactic HFNC as first-line therapy had a comparable rate of reintubation within 72 hours to the prophylactic NPPV alone (17.2% vs 13%, p =0.556). Other secondary outcomes were similar between the two groups. Among patients with heart failure, HFNC was not inferior to NPPV for preventing extubation failure and reintubation. However, in case of an impending respiratory failure, selective patients may benefit from rescue NPPV., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Che-Jung Chang et al.)

Objectives: Patients with obstructive sleep apnea (OSA) (an obstructed airway and intermittent hypoxia) negatively affect their respiratory muscles. We evaluated the effects of a 12-week threshold inspiratory muscle training (TIMT) program on OSA severity, daytime sleepiness, and pulmonary function in newly diagnosed OSA., Methods: Sixteen patients with moderate-to-severe OSA were randomly assigned to a TIMT group and 6 to a control group. The home-based TIMT program was 30-45 min/day, 5 days/week, for 12 weeks using a TIMT training device. Their apnea-hypopnea index (AHI), Epworth sleepiness scale (ESS), and forced vital capacity (FVC) scores were evaluated pre- and post-treatment. Polysomnographic (PSG) analysis showed that 9 TIMT-group patients had positively responded (TIMT-responder group: post-treatment AHI < pre-treatment) and that 7 had not (TIMT non-responder group: post-treatment AHI > pre-treatment)., Results: Post-treatment AHI and ESS scores were significantly (both P < 0.05) lower 6% and 20.2%, respectively. A baseline AHI ≤ 29.0/h predicted TIMT-responder group patients (sensitivity 77.8%; specificity 85.7%). FVC was also significantly (P < 0.05) higher 7.2%. Baseline AHI and FEV 6.0 were significant predictors of successful TIMT-responder group intervention. OSA severity and daytime sleepiness were also significantly attenuated., Conclusions: Home-based TIMT training is simple, efficacious, and cost-effective.

The cantharidinimide derivatives, 5a-h, including sulfanilamides containing pyrimidyl, pyrazinyl, hydrogen, thiazolyl, and oxazolyl groups were synthesized. Modification of cantharidinimide by means of the reaction of activated aziridine ring opening led to the discovery of a novel class of antitumor compounds. The analogues 10i-k, 11l-n, 12o-p, and 16q-s were obtained from treating cantharidinimide 6 and analogues (7, 8, and 13) with activated aziridines, which produced a series of ring-opened products including normal and abnormal types. Some of these compounds showed cytotoxic effects in vitro against HL-60, Hep3B, MCF7, and MDA-MB-231 cancer cells. The most potent cytostatic compound, N-cantharidinimido-sulfamethazine (5a), exhibited anti-HL-60 and anti-Hep3B cell activities. Two compounds 5g and 5h displayed slight effects on the Hep3B cell line, while the other compounds produced no response in these four cell lines.

Background/purpose: Primary antibody deficiency is the most common disorder among primary immunodeficiencies. Recurrent infection and chronic lung change often lead to mortality and morbidity., Methods: This study focused on the clinical presentation, molecular diagnosis, and outcomes of primary antibody deficiency in Taiwan pediatric group. Medical records of patients with primary antibody deficiency during the period 1990-2010 were retrospectively reviewed in one medical center., Results: Among the 34 patients evaluated, X-linked agammaglobulinemia (XLA) (29.4%) and common variable immunodeficiency diseases (CVIDs) (29.4%) were the most common disorders presented with respiratory and skin infections. Some genotype/phenotype discordance was found in one family. Patients with XLA, CVID, and hyper-IgM syndrome without complications had higher trough and initial IgG levels, and shorter delays in diagnosis. Patients with trough IgG levels >700 mg/dL had less occurrence of bronchiectasis., Conclusion: These results summarized clinical manifestations of primary antibody deficiency in pediatric group in Taiwan. Clinicians should strive to shorten delays in diagnosis and maintain higher trough IgG levels to decrease subsequent mortality and morbidity., (Copyright © 2012. Published by Elsevier B.V.)

Objective: Patients with sleep apnea syndrome (SAS) carry a higher stroke risk. The differential stroke risk between sex and among different age groups has not yet been specifically addressed in previous studies., Methods: Using a universal insurance claims database, we identified a large cohort of SAS patients from 1997 to 2010 and assessed the sex- and age-specific stroke risk compared with a control cohort matched for age, sex, and index date. Cox regression analyses were performed to assess the hazard ratio (HR) of stroke and the corresponding 95% confidence interval (CI). Stroke-free probabilities were computed using the Kaplan-Meier method and differences between both cohorts were examined using the log-rank test., Results: We identified 29,961 patients with SAS and a control cohort of 119,844 subjects without SAS. The overall incidence of stroke in the SAS cohort was 37% higher compared to the non-SAS cohort (54.6 per 10,000 individual-years vs 39.8 per 10,000 individual-years). After controlling for sex and comorbidities, the SAS cohort exhibited a 19% higher risk for stroke compared to the control cohort (adjusted HR, 1.19 [95% CI, 1.09-1.30]). Women with SAS ages 35 years or younger had the highest stroke risk compared to older age groups of the same sex and their risk for stroke was relatively higher compared to their male counterparts., Conclusion: Women aged 35 years or younger with SAS have a higher stroke risk., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Mutations in epidermal growth factor receptor ( EGFR ) commonly occur in non-small-cell lung cancer (NSCLC) patients characterized by female gender, never-smoker status and adenocarcinoma histology. The aim of this study was to determine whether gender is a confounding factor for EGFR mutations in NSCLC. To elucidate the confounding effect, Pearson's χ 2 test and logistic regression models were used to correlate these characteristics with EGFR mutations in 426 NSCLC patients treated at our institutes. Of those 426 NSCLC patients, 47% were females, 57% were non-smokers and 84% had adenocarcinomas. The multivariate logistic regression analysis demonstrated that never-smoker status [odds ratio (OR)=3.49, 95% confidence interval (CI): 1.99-6.13; P<0.001)] and adenocarcinoma (OR=9.43, 95% CI 3.62-24.56; P<0.001) were associated with EGFR mutations; however, gender was not (OR=1.25, 95% CI: 0.73-2.15; P=0.416). Furthermore, gender was not associated with EGFR mutation subtypes (OR=1.19, 95% CI: 0.56-2.50; P=0.650). The frequency of EGFR mutations among females and males was not different in non-smokers (64.8 vs. 55.8%, P=0.204) or ever-smokers (27.8 vs. 24.2%, P=0.775). Therefore, if the assessment for EGFR mutation status was limited to non-smoking females with adenocarcinoma, up to 40% of the patients harboring EGFR mutations would be precluded from the benefit of EGFR inhibitor therapy. Our results indicated that gender is a confounding factor for EGFR mutations in NSCLC and suggested that gender may not be associated with tumorigenesis in NSCLC-harboring EGFR mutations.

A considerable amount of studies have been conducted to investigate the interactions of biological fluids with nanoparticle surfaces, which exhibit a high affinity for proteins and particles. However, the mechanisms underlying these interactions have not been elucidated, particularly as they relate to human health. Using bovine serum albumin (BSA) and mice bronchoalveolar lavage fluid (BALF) as models for protein-particle conjugates, we characterized the physicochemical modifications of carbon blacks (CB) with 23nm or 65nm in diameter after protein treatment. Adsorbed BALF-containing proteins were quantified and identified by pathways, biological analyses and protein classification. Significant modifications of the physicochemistry of CB were induced by the addition of BSA. Enzyme modulators and hydrolase predominately interacted with CB, with protein-to-CB interactions that were associated with the coagulation pathways. Additionally, our results revealed that an acute-phase response could be activated by these proteins. With regard to human health, the present study revealed that the CB can react with proteins (∼55kDa and 70kDa) after inhalation and may modify the functional structures of lung proteins, leading to the activation of acute-inflammatory responses in the lungs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background/purpose: Long-term oxygen therapy has become standard treatment for patients with chronic respiratory insufficiency. However, patterns of long-term home oxygen therapy have not been well studied in Taiwan. Oxygen concentrator systems are commonly used in Taiwan, but liquid oxygen delivery systems are portable and may provide advantages over the concentrator system. This study compared oxygen usage between patients from a liquid oxygen group (LOG) and an oxygen concentrator group (OCG). The authors also assessed the physiologic responses of patients with chronic obstructive pulmonary disease (COPD) to ambulatory oxygen use at home., Methods: The study used a retrospective, cross-sectional, observational survey design. The LOG comprised 42 patients, and the OCG comprised 102 patients. We recruited participants in northern Taiwan from July 2009 to April 2010. The questionnaire instruments that were used to collect data consisted of three parts: demographic characteristics, devices used in respiratory care, and activity status with portable oxygen. Two-minute walking tests were performed on COPD patients in their homes., Results: COPD was the most common diagnosis in our study, with more than 50% of patients who received oxygen long term in both groups having received this diagnosis. The LOG used oxygen for an average of 21.7 hours per day, whereas OCG averaged 15.2 hours per day (p<0.001). In the OCG, 92.2% of patients used a concentrator alone, whereas 23.8% of the LOG used liquid oxygen alone (p<0.001). The LOG patients were involved in significantly more outdoors activities (p=0.002) and reported traveling with oxygen more often (p<0.001) than the OCG patients. For patients with the same dyspnea level of COPD severity, those using liquid oxygen had a lower increase in pulse rate after the walking test, in comparison with the concentrator users., Conclusion: Patients in the LOG used oxygen for longer hours, went on more outings, and were more likely to travel with oxygen than patients in the OCG. Being ambulatory with liquid oxygen might enable patients with COPD to walk more effectively., (Copyright © 2012. Published by Elsevier B.V.)

Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been associated with favorable progression free survival (PFS) in patients with non-small cell lung cancers (NSCLC) harboring EGFR mutations. However, a subset of this population doesn't respond to EGFR-TKI treatment. Therefore, the present study aimed to elucidate survival outcome in NSCLC EGFR-mutant patients who were treated with EGFR TKIs., Methods: Among the 580 consecutive NSCLC patients who were treated at our facility between 2008 and 2012, a total of 124 treatment-naïve, advanced NSCLC, EGFR-mutant patients treated with EGFR TKIs were identified and grouped into non-responders and responders for analyses., Results: Of 124 patients, 104 (84%) responded to treatment, and 20 (16%) did not; and the overall median PFS was 9.0 months. Notably, the PFS, overall survival (OS) and survival rates were significantly unfavorable in non-responders (1.8 vs. 10.3 months, hazard ratio (HR) = 29.2, 95% confidence interval (CI), 13.48-63.26, P<0.0001; 9.4 vs. 17.3 months, HR = 2.74, 95% CI, 1.52-4.94, P = 0.0008; and 58% vs. 82% in 6, 37% vs. 60% in 12, and 19 vs. 40% at 24 months, respectively). In multivariate analysis, treatment efficacy strongly affected PFS and OS, independent of covariates (HR = 47.22, 95% CI, 17.88-124.73, P<0.001 and HR = 2.74, 95% CI, 1.43-5.24, P = 0.002, respectively). However, none of the covariates except of the presence of EGFR exon 19 deletion in the tumors was significantly associated with better treatment efficacy., Conclusions: A subset of NSCLC EGFR-mutant patients displayed unfavorable survival despite EGFR TKI administration. This observation reinforces the urgent need for biomarkers effectively predicting the non-responders and for drug development overcoming primary resistance to EGFR TKIs. In addition, optimal therapeutic strategies to prolong the survival of non-responders need to be investigated.

Considerable evidence shows a key role for protein modification in the adverse effects of chemicals; however, the interaction of diesel exhaust particles (DEP) with proteins and the resulting biological activity remains unclear. DEP and carbon black (CB) suspensions with and without bovine serum albumin (BSA) were used to elucidate the biological effects of air pollutants. The DEP and CB samples were then divided into suspensions and supernatants. Two important goals of the interaction of DEP with BSA were as follows: (1) understanding BSA modification by particles and (2) investigating the effects of particles bound with BSA and the corresponding supernatants on cellular oxidative stress and inflammation. We observed significant free amino groups production was caused by DEP. Using liquid chromatography-mass spectrometry (LC-MS), we observed that BSA was significantly oxidised by DEP in the supernatants and that the peptides ETYGDMADCCEK, MPCTEDYLSLILNR and TVMENFVAFVDK, derived BSA-DEP conjugates, were also oxidised. In A549 cells, DEP-BSA suspensions and the corresponding supernatants reduced 8-hydroxy-2'-deoxyguanosine (8-OHdG) production and increased interleukin-6 (IL-6) levels when compared to DEP solutions without BSA. Our findings suggest that oxidatively modified forms of BSA caused by DEP could lead to oxidative stress and the activation of inflammation., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Superoxide dismutase (SOD) is a free radical scavenger and a broad-spectrum antioxidant. Its anti-inflammatory and immunomodulatory effects have recently been noted. We studied the effects of this antioxidant on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Sprange-Dawley rats (n = 40). Animals were randomized and evenly divided into two experimental groups, low tidal volume (V(T)) ventilation (V(T) = 9 ml/kg) and high V(T) ventilation (V(T) = 28 ml/kg). Each group was evenly divided into two subgroups: ten animals were treated with superoxide dismutase (SOD; 10,000 U/kg i.v., 2 h prior to the ventilation) and the rests were treated with vehicle. Lung injury was evaluated by histological examination, and cells counts of red blood cells (RBC) and white blood cells (WBC) in the alveoli and the septal wall thickness in lung tissues and serum lactate dehydrogenase (LDH). The lung permeability was assessed by the wet-to-dry weight ratio (W/D), lung weight to body weight ratio (LW/BW) and protein concentration in broncholavage fluid (BALF). Levels of oxidative stress and lipid peroxidation in the lungs were evaluated by tissue malondialdehyde (MDA) and methylguanidine (MG) in BALF, respectively. SOD pretreatment significantly decreased WBC counts in systemic circulation and in alveoli, and effectively attenuated high V(T) ventilation induced lung injury by reducing hyaline membrane development, septal wall thickness, lung W/D and LW/BW and serum LDH in relation to those of the control. In addition, lung tissues MDA and MG in BALF were also notably reduced.

Inhaled cigarette smoke (CS) triggers airway reflexes that are thought to result from the activation of lung vagal C-fiber afferents (LVCAs) via the action of reactive oxygen species in rats. We investigated the role of transient receptor potential vanilloid 1 (TRPV1) and P2X receptors in LVCA activation. Activities of LVCAs were recorded in anesthetized and artificially ventilated rats. Airway challenge of CS produced a concentration-dependent fiber stimulation. Pretreatment with dimethylthiourea [DMTU; a scavenger of hydroxyl radical (OH)], capsazepine (CPZ; a TRPV1 receptor antagonist) and iso-pyridoxalphosphate-6-azophenyl-2',5'-disulphonate (iso-PPADS; a P2X receptor antagonist) separately reduced the fiber responses by 64, 40 and 44%, respectively, whereas pretreatment with hexamethonium (a nicotinic acetylcholine receptor antagonist) failed to alter the response. A combination of CPZ and iso-PPADS exerted a greater inhibitory effect compared with the effect of either single pretreatment. However, a combination of DMTU, CPZ and iso-PPADS did not further reduce the fiber response compared with the combined effect of CPZ and iso-PPADS. It was concluded that both TRPV1 and P2X receptors, but not nicotinic acetylcholine receptors, participate in the stimulation of LVCAs by inhaled CS, possibly through the action of OH.

Background: Children represent 10-20% of all systemic lupus erythematosus (SLE) patients. Their clinical manifestations and outcomes vary with age. We aim to clarify the relationship between pubescent status and the clinical manifestations of pediatric SLE., Methods: In this study, pediatric SLE patients were divided into three groups, based on age at disease onset (≦8, 8-13 & 13-18 years), defined as prepubescent, pubescent and postpubescent, respectively. Initial clinical manifestations and laboratory characteristics at diagnosis were analyzed., Results: Ninety-six patients were entered into the study: 8 had disease onset before age 8, while 49 were between 8-13 and 39 of them were 13-18. Female predominance was noted in all three groups (2.5-7.0:1). Postpubescents showed significantly more renal involvement and lymphopenia, along with lower levels of C3 and C4, when compared with prepubescents. They also showed significantly more lymphopenia when compared with pubescents. Pubescents showed significantly more renal involvement, leukopenia and lupus anticoagulant (LAC) positivity, along with lower C3 and C4 levels, when compared with prepubescents. Pubescents also showed significantly higher anti-Sm antibody positivity when compared with postpubescents. Prepubescents showed significantly more splenomegaly and anti-Jo-1 antibody positivity when compared with those of pubescents. The results showed that the disease activity (SLEDAI-2K score) correlated positively with age at disease onset and negatively with disease duration before diagnosis (p = 0.011)., Conclusions: Age at disease onset is related to initial manifestations in pediatric SLE patients at our center. Certain parameters such as renal involvement, splenomegaly, low C3 level, low C4 level, lymphopenia, leukopenia, and anti-Sm & anti-Jo-1 antibody were found to be significantly different among the age groups. Renal involvement might be the key symptom that varies with age.

Objective: Hypoxic pulmonary vasoconstriction (HPV) is a well known phenomenon to temporarily offset a ventilation-perfusion mismatch. Sustained HPV may lead to pulmonary hypertension. In this protocol, we studied the relationships between the HPV response and inducible cyclooxygenase II (COX II) activation after hypoxia-reoxygenation (H-R) challenge in an isolated perfused lung model., Methods: An in situ isolated perfused rat lung model underwent inaction of hypoxia by ventilation with 5% CO(2)-95% N(2) for 10 minutes instead of 5% CO(2)-95% air; they were then reoxygenated with 5% CO(2)-95% air. We measured pulmonary arterial pressure (PAP) changes before, during, and after H-R challenge. We also estimated changes in blood concentrations of hydroxyl radicals, nitric oxide (NO) and thromboxane B(2) (TxB(2)) before and after H-R as well as mRNA expressions of COX II in lung tissue thereafter. A COX II inhibitor, celecoxib (10 mg/kg), was administered between 2 consecutive challenges., Results: Hypoxia induced pulmonary vasoconstriction by increasing PAP (4.1 ± 0.8 mm Hg). Consecutive hypoxic challenges did not show tachyphylaxis (P > .05). H-R of lung tissues induced significant increases in blood concentrations of hydroxyl radicals (48.5 ± 7.6 vs 75.8 ± 11.5 mmol/L; P < .01), NO (54.3 ± 12.3 vs 77.7 ± 15.7 pmol; P < .05), and TxB(2) (42.3 ± 6.9 vs 58.7 ± 8.6 pg/mL; P < .05). Lung tissue H-R also significantly increased COX II mRNA expression compared with sham tissues (1 ± 0 vs 4.0 ± 2.8; P < .001). The COX II inhibitor celecoxib significantly attenuated HPV responses (P < .05) and attenuated the elevated blood concentrations of TxB(2) (P < .05), hydroxyl radicals (P < .01), nitric oxide (P < .05), and COX II mRNA expression (P < .05) after H-R challenge., Conclusions: Lung tissue H-R induced significant increases blood concentrations of inflammatory mediators and tissue mRNA expression of COX related to elevation of HPV responses. COX II inhibitor celecoxib attenuated the HPV responses by reducing TxB(2) release., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Reperfusion of the ischemic liver results in the generation of oxidative and nitrosative stresses and reaction product of peroxynitrite, which induce rapid cytotoxicity and liver injury. In this study we demonstrated that curcumin, an antioxidant, attenuated ischemia/reperfusion (I/R)-induced liver injury., Materials and Methods: Ischemia was induced by clamping the common hepatic artery and portal vein of rats for 30 minutes. Thereafter, flow was restored and the liver was reperfused for 80 minutes. Blood samples collected prior to ischemia and after reperfusion were analyzed for methyl guanidine (MG), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and adenosphate triphosphate (ATP). Blood levels of serum glutamic oxaloacetic transaminase (sGOT), serum glutamate pyruvate transaminase (sGPT), and lactic dehydrogenase (LDH), which served as indexes of liver injury, were measured., Results: The protocol resulted in elevation of blood NO (P < .001), TNF-α (P < .001), and MG (P < .001). sGOT, sGPT, and LDH were elevated significantly (P < .001), whereas ATP was significantly diminished (P < .001). Pretreatment with curcumin (25 mg/kg) significantly attenuated the reperfusion liver injury, while the ATP content reversed. In addition, MG, TNF-α, and NO release were attenuated., Conclusions: These results indicated that curcumin exerted potent anti-inflammatory effects in I/R-induced liver injury due to its antioxidant effects., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The effectiveness of noninvasive ventilation (NIV) after extubation in preventing post-extubation respiratory failure is still controversial., Methods: We conducted a prospective, multicenter randomized controlled study involving patients on mechanical ventilation for > 48 hours who tolerated a 2-hour spontaneous breathing trial and were subsequently extubated. The patients were randomized to NIV or standard medical therapy. Re-intubation rate within 72 hours was the primary outcome measure. Multivariable logistic regression analysis was used to determine predictors for extubation failure., Results: We randomized 406 patients to either NIV (no. = 202) or standard medical therapy (no. = 204). The 2 groups had similar baseline clinical characteristics. There were no differences in extubation failure (13.2% in control and 14.9% in NIV), intensive care unit or hospital mortality. Cardiac failure was a more common cause of extubation failure in control than in NIV. There was no difference in rapid shallow breathing index (RSBI) in extubation failure patients between control (80) and NIV (73). When using data from all patients, we found Acute Physiology and Chronic Health Evaluation (APACHE II) scores (odds ratio [OR] 1.13, 95% CI 1.07-1.20, P < .001), maximal inspiratory pressure (OR 1.04, 95% CI 1.00-1.08, P = .03), and RSBI (OR 1.03, 95% CI 1.02-1.05, P < .001) to be predictors of extubation failure. Abundant secretions were the most common reason (35.1%) for extubation failure identified by attending physicians., Conclusions: Preventive use of NIV after extubation in patients who passed spontaneous breathing trial did not show benefits in decreasing extubation failure rate or the mortality rate.

Background/purpose: Early physical training is necessary for severely deconditioned patients undergoing prolonged mechanical ventilation (PMV), because survivors often experience prolonged recovery. Long-term outcomes after physical training have not been measured; therefore, we investigated outcome during a 1-year period after physical training for the PMV patients., Methods: We conducted a prospective randomized control trial in a respiratory care center. Thirty-four patients were randomly assigned to the rehabilitation group (n = 18) and the control group (n = 16). The rehabilitation group participated in supervised physical therapy training for 6 weeks, and continued in an unsupervised maintenance program for 6 more weeks. The functional independence measurement (FIM) was used to assess functional status. Survival status during the year after enrollment, the number of survivors discharged, and the number free from ventilator support were collected. These outcome parameters were assessed at entry, immediately after the 6 weeks physical therapy training period, after 6 weeks unsupervised maintenance exercise program, and 6 months and 12 months after study entry., Results: The scores of total FIM, motor domain, cognitive domain, and some sub-items, except for the walking/wheelchair sub-item, increased significantly in the rehabilitation group at 6 months postenrollment, but remained unchanged for the control group. The eating, comprehension, expression, and social interaction subscales reached the 7-point complete independence level at 6 months in the rehabilitation group, but not in the control group. The 1-year survival rate for the rehabilitation group was 70%, which was significantly higher than that for the control group (25%), although the proportion of patients discharged and who were ventilator-free in the rehabilitation and control groups did not differ significantly., Conclusion: Six weeks physical therapy training plus 6 weeks unsupervised maintenance exercise enhanced functional levels and increased survival for the PMV patients compared with those with no such intervention. Early physical therapy interventions are needed for the PMV patients in respiratory care centers., (Copyright © 2011. Published by Elsevier B.V.)

Background: Post-cardiopulmonary bypass (CPB) lung injury is the combination of whole body inflammatory response and local ischemia-reperfusion (IR) injury. We investigated the benefit of pulmonary perfusion with L-arginine in protection against post-CPB lung injury., Methods: New Zealand white rabbits (n = 50, weight, 2.5-2.8 kg) were divided into five groups (n = 10 each): sham (sham sternotomy), CPB (CPB without pulmonary perfusion), perfusion (CPB with pulmonary perfusion), L-arginine (CPB with perfusion + L-arginine), and L-NAME (CPB with perfusion + L-NAME). The duration of CPB was 60 min followed by 2 h of reperfusion. Pulmonary perfusion was performed every 20 min through the pulmonary artery during CPB. Checking parameters included: (1) pulmonary vascular resistance, (2) pulmonary artery endothelium relaxation (organ chamber study), and (3) IR marker (myeloperoxidase) and inflammatory markers (TNF-α, IL-B, NF-κB)., Results: CPB induced pulmonary artery endothelium dysfunction manifested by increased pulmonary vascular resistance and impaired pulmonary artery relaxation. Pulmonary perfusion could significantly reverse the phenomenon (P < 0.01) while provision of NO precursor-L-arginine with pulmonary perfusion together further possessed significant relaxation ability for pulmonary arterial endothelium compared with perfusion alone (P < 0.05). Accordingly, lung parenchyma myeloperoxidase activity and inflammatory cytokine level were also markedly increased after CPB (P < 0.05). Pulmonary perfusion could partially decrease the response, whereas additional L-arginine further attenuated inflammatory cytokine release (P < 0.05)., Conclusions: Pulmonary perfusion during CPB partially ameliorates CPB-induced lung injury. Pulmonary perfusion with L-arginine could further attenuate lung injury by restoring endothelial function and decreasing inflammatory response., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Colonic perforation is an extremely rare complication following ventriculoperitoneal (VP) shunting. Laparotomy to repair the perforation site is usually required for patients with peritonitis. Here we report colonic perforation due to VP shunt in a 4-year-old girl, presenting with a distal catheter protruding out of the anus as well as symptoms and signs of peritonitis. The distal catheter was removed and the perforation site was repaired successfully via the anus. Postoperative course was uneventful. Trans-anal repair of the colonic perforation after removal of the distal shunt may be considered an alternative choice for managing this kind of complication., (Copyright (c) 2010 Formosan Medical Association & Elsevier. Published by Elsevier B.V. All rights reserved.)

There is growing evidence that increased expression of cyclooxygenase-2 (COX-2) in the lungs of patients is a key event in the pathogenesis of lung diseases. In this study, we investigated the involvement of the extracellular signal-regulated kinase (ERK), IkappaB kinase alpha/beta (IKKalpha/beta), and nuclear factor-kappaB (NF-kappaB) signaling pathways in thrombin-induced COX-2 expression in human lung fibroblasts (WI-38). Treatment of WI-38 cells with thrombin caused increased COX-2 expression in a concentration- and time-dependent manner. Treatment of WI-38 cells with PD 98059 (2-[2-amino-3-methoxyphenyl]-4H-1-benzopyran-4-one, a MEK inhibitor) inhibited thrombin-induced COX-2 expression and COX-2-luciferase activity. Stimulation of cells with thrombin caused an increase in ERK phosphorylation in a time-dependent manner. In addition, treatment of WI-38 cells with Bay 117082, an IkappaB phosphorylation inhibitor, and pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, inhibited thrombin-induced COX-2 expression. The thrombin-induced increase in COX-2-luciferase activity was also blocked by the dominant negative IkappaBalpha mutant (IkappaBalphaM). Treatment of WI-38 cells with thrombin induced IKKalpha/beta and IkappaBalpha phosphorylation, IkappaBalpha degradation, and kappaB-luciferase activity. The thrombin-mediated increases in IKKalpha/beta phosphorylation and kappaB-luciferase activity were inhibited by PD 98059. Taken together, these results suggest that the ERK-dependent IKKalpha/beta/NF-kappaB signaling pathway plays an important role in thrombin-induced COX-2 expression in human lung fibroblasts.

Duodenal duplication cysts are rare congenital lesions usually diagnosed in infancy, although they may present in adulthood. Prenatal diagnosis is difficult, and postnatal diagnosis relies on ultrasonography, barium swallow, contrast-enhanced computerized tomography, magneticresonance imaging (MRI), and magnetic resonance cholangiopancreatography. A female newborn was diagnosed with an abdominal cyst (size around 6 x 5 x 4 cm) at gestational age (GA) 24 weeks, by regular prenatal examination. After her birth at GA 37 weeks, we performed abdominal ultrasonography and RI, but there was no definite diagnosis. The usual management of an abdominal cyst involves resection by laparotomy (requiring a large incision) or laparoscopy (requiring several small incisions). We performed an exploratory trans-umbilical minimal laparotomy excision for surgery, and the pathology revealed duodenal duplication. In our case, there was no recurrence of the cyst after 18 months follow-up, and the operation scar was almost undetectable. Trans-umbilical minimal laparotomy excision may be considered as an alternative choice for the management of abdominal and duodenal duplication cysts.

Sigmoid volvulus is a rare but potentially life-threatening condition in childhood. Colectomy is usually required to prevent recurrent volvulus, which carries a high risk of morbidity and mortality. Here, we report a non-resection method based on the concept of Ladd's procedure to treat a sigmoid volvulus in a 15-year-old boy. After reduction of the volvulus, the distance between the sigmoid-rectal junction and the sigmoid-descending colon junction was widened by dissecting the meso-sigmoid colon along the course of the long axis. No colon resection was performed. The total operation time was less than an hour. The post-operative recovery was uneventful. There was no recurrent volvulus during a follow-up of 1 year. Widening the base of the mesosigmoid according to the concept of Ladd's procedure may be considered as a more simple and safe alternative treatment to prevent recurrent sigmoid volvulus in children.

Objective: White cell activation in the lung plays a critical role to induce lung injury and lymphocytes in the thoracic duct system may also participate. We evaluated the effect of cyclosporine on phorbol myristate acetate (PMA)-induced lung injury., Materials and Methods: We used an in situ isolated, blood perfused rat lung model to measure pulmonary arterial pressure (PAP) and lung weight gain (LWG; g) for 50 minutes after a bolus injection of PMA (0.05 microg/mL). Oxygen radical release was estimated by an LKB 1251 luminometer and by nitric oxide (NO) release as measured by an ENO-20 NO analyzer., Results: In the group exposed to PMA alone, the mean PAP increased from 16.53 +/- 1.28 to 43.33 +/- 3.40 mm Hg (P < .001), and lung weight increased by 4.35 +/- 0.67 g during the 50-minute perfusion after PMA challenge (P < .001). In vitro measurement showed that PMA induced a significant increase in oxygen radical release (P < .001). PMA attenuated NO release (P < .001) into the perfusion system. Pretreatment with cyclosporine (3 mg/kg) for 3 days prevented the increases in both PAP (P < .01) and LWG (P < .001). NO release was maintained in cyclosporine-pretreated rats. Cyclosporine also showed dose-dependent attenuation of oxygen radical release by PMA-activated white blood cells., Conclusion: The mechanisms responsible for the protective effect of cyclosporine on the lung injury induced by phorbol may be related to an attenuation of oxygen radical production with maintenance of NO release.

Objective: The phagocytic recognition and clearance of the recruited inflammatory cells with prolonged survival play a pivotal role in relieving tissue inflammation and maintaining tissue homeostasis. Transgenic mice expressing Bcl-2 in mature neutrophils demonstrated that Bcl-2 attenuated neutrophil apoptosis, while the homeostasis of the neutrophil population was essentially unaffected. This result suggests that clearance of neutrophils with prolonged survival operates independently from apoptosis. Owing to the constitutive and inducible expression of Bcl-2 homologue, A1 in human neutrophils and the intolerance of preparation for the isolated human neutrophils with prolonged survival, the human promyelocytic HL60-A1 transfectants were established to study the mechanism of phagocytic recognition/clearance of the cells with prolonged survival., Materials and Methods: The non-apoptotic cells with prolonged survival were enriched by serum withdrawal for five days and negatively isolated by annexin V-binding beads. Then, the cells were labeled with a fluorogenic marker. Monocyte-derived macrophages (MDM) were co-cultured to perform the phagocytosis assay, and flow cytometry was employed to determine the phagocytic index., Results: In the serum-free condition, the phagocytic index of HL60-A1 transfectants was little different from that of the HL60-EGFP control, despite showing a significantly lower degree of apoptosis. While the phagocytic index of HL60-EGFP control was significantly correlated with the degree of apoptosis, the index of the HL60-A1 transfectants was less relevant to it. The phagocytic index for the annexin V-positive cells did not distinguish the two cell types. However, the phagocytic index for the annexin V-negative cells from the HL60-A1 transfectants was increased with age in days. Preincubation of MDM with the scavenger receptor inhibitor, Oxi-LDL, and the inhibitory antibodies against alphavbeta3, CD14 and CD36 surface molecules could attenuate the phagocytic recognition of the annexin V-positive HL60 cells but not the annexin V-negative A1 transfectants with prolonged survival., Conclusions: This study thus suggests that a mechanism unrelated to apoptosis exists, which mediates the phagocytic clearance of the non-apoptotic cells with prolonged survival and may be associated with A1 function in the myeloid cells.

A previous report showed that transforming growth factor-beta1 (TGF-beta1) can induce heme oxygenase-1 (HO-1) expression, attenuate cellular injury, and maintain tissue homeostasis. In this study, we investigated the involvement of phosphoinositide-3-OH-kinase (PI3K)/Akt and the nuclear factor-kappaB (NF-kappaB) signaling pathway in TGF-beta1-induced HO-1 expression in human lung epithelial cells (A549). Treatment of A549 cells with TGF-beta1 caused HO-1 to be expressed in a concentration- and time-dependent manner. Treatment of A549 cells with LY 294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, a PI3K inhibitor), an Akt inhibitor, and the dominant negative mutant of Akt (Akt DN) inhibited TGF-beta1-induced HO-1 expression and HO-1-luciferase activity. Stimulation of cells with TGF-beta1 caused an increase in Akt phosphorylation in a time-dependent manner, which was inhibited by wortmannin and LY 294002 (PI3K inhibitors). In addition, treatment of A549 cells with Bay 117082 ((E)-3-[4-methylphenylsulfonyl]-2-propenenitrile, an IkappaB phosphorylation inhibitor), pyrrolidine dithiocarbamate (PDTC, an NF-kappaB inhibitor), and the dominant negative mutant of IkappaBalpha (IkappaBalphaM) inhibited TGF-beta1-induced HO-1 expression and HO-1-luciferase activity. Treatment of A549 cells with TGF-beta1-induced IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 Ser536 phosphorylation, and kappaB-luciferase activity. The TGF-beta1-mediated increases in IKKalpha/beta phosphorylation, p65 Ser536 phosphorylation, and kappaB-luciferase activity were inhibited by LY 294002, an Akt inhibitor, and Akt DN. Taken together, these results suggest that the PI3K/Akt dependent IKKalpha/beta/NF-kappaB signaling pathway plays an important role in TGF-beta1-induced HO-1 expression in A549 cells.

Background/purpose: This study assessed how positive expiratory pressure (PEP) affected pulmonary function, functional capacity, and subjective cough difficulty in individuals with chronic obstructive pulmonary diseases (COPD)., Methods: This was a prospective, randomized, controlled study. Subjects were recruited from an outpatient department at a university hospital. Thirty-two patients with COPD were allocated to either PEP + FET (forced expiratory technique) group (n = 16) or FET only group (n = 16). Subjects in PEP + FET and FET groups were in a clinically stable condition before and during the study. Subjects in the PEP + FET group received PEP breathing using a mouth adjunct to FET, and the FET group was administered FET for 4 weeks only. Patients received weekly follow-up during the study period. Pulmonary function, 6-minute walk tests, and subjective cough difficulty scores were measured before and after the 4-week interventions., Results: Subjects in the PEP + FET group had a significantly increased diffusing capacity (DLCO) compared to preintervention (p < 0.05) and after intervention in the FET group (p < 0.05). DLCO significantly increased in the PEP + FET group from 18.0 +/- 7.3 to 20.1 +/- 7.2 mL/min/mmHg. The 6-minute walking distance (6MWD) also increased significantly from 516.8 +/- 94.1 to 570.6 +/- 60.4 m in the PEP + FET group (p < 0.001) after intervention, compared to that for the FET group (p < 0.05). Additionally, the PEP + FET group had significantly lower cough difficulty scores compared to those at baseline and in the FET group., Conclusion: Four-week PEP therapy as an adjunct to FET further enhanced DLCO and 6MWD, and reduced cough difficulty compared to FET only in COPD patients with mucus hypersecretion.

Background and Purpose: Patients requiring prolonged mechanical ventilation (PMV) are frequently deconditioned because of respiratory failure precipitated by the underlying disease, the adverse effects of medications, and a period of prolonged immobilization. The effects of 6 weeks of physical training on the strength of respiratory and limb muscles, on ventilator-free time, and on functional status in patients requiring PMV were examined., Subjects: Thirty-nine patients with PMV were initially enrolled in the study and were assigned to either a treatment group (n=20) or a control group (n=19). Three subjects in the treatment group and 4 subjects in the control group died during the 6-week intervention period and thus their data were excluded from the final analysis., Methods: Subjects in the treatment group received physical training 5 days a week for 6 weeks. Strength of respiratory and limb muscles, ventilator-free time, and functional status, which was measured by the Barthel Index of Activities of Daily Living (BI) and Functional Independence Measure (FIM), were examined at baseline and at the third and sixth weeks of the study period., Results: Respiratory and limb muscle strength improved significantly at the third and sixth weeks in the treatment group compared with baseline measurements. Total BI and FIM scores increased significantly in the treatment group and remained unchanged in the control group. Effect sizes of the BI and FIM scores were 2.02 and 1.93, respectively, at the sixth week., Discussion and Conclusion: The results show that a 6-week physical training program may improve limb muscle strength and ventilator-free time and thus improve functional outcomes in patients requiring PMV.

Background/purpose: This study was designed to investigate the effects of 6 months of nocturnal nasal positive pressure ventilation (NNPPV) on respiratory muscle function and exercise capacity in patients with chronic respiratory failure., Methods: A prospective, randomized, controlled design was used. Twenty-nine patients with chronic respiratory failure were enrolled and allocated to either the NNPPV (n = 14) or control group (n = 15). Patients in the NNPPV group received bi-level positive pressure ventilation via nasal mask for 6 consecutive months. Arterial blood gas, respiratory muscle assessment and 6-minute walk test (6MWT) were performed before and after the 6-month NNPPV intervention. Respiratory muscle function was assessed using the variables of maximal inspiratory pressure (Pimax), maximal expiratory pressure (Pemax), and maximum voluntary ventilation (MVV)., Results: Subjects in the NNPPV group showed a significant improvement in blood gas exchange and increased 6-minute walk distance (6MWD) compared to baseline and the control group. The 6MWD was significantly increased from 257.1 +/- 114.1 to 345.2 +/- 109.9 m (34.3%) in the NNPPV group. NNPPV also significantly improved MVV and Pimax relative to baseline. MVV was significantly increased from 19.2 +/- 6.5 to 22.3 +/- 7.1 L/min (16.1%) in the NNPPV group (p < 0.05). Furthermore, there was a significant correlation between the magnitude of MVV improvement and 6MWD change., Conclusion: The 6-month NNPPV treatment significantly decreased the partial pressure of carbon dioxide and improved daytime respiratory muscle function, thus contributing to exercise-capacity increase in patients with chronic respiratory failure.

Background: The study objective was to investigate the efficacy of 6 months of nocturnal nasal positive pressure ventilation (NNPPV) on arterial blood gas, exercise capacity, respiratory muscle function, and the frequency of hospital admission in hypercapnic patients with severe obstructive lung diseases., Methods: This was a prospective, randomized, controlled study. Twenty-seven patients with hypercapnic obstructive lung diseases were randomized to either the NNPPV group (N = 13) or the control group (N = 14). Arterial blood gas, exercise capacity and respiratory muscle function were measured before and after 6 months of NNPPV intervention. The number of hospital admissions and the length of stay during the 6-month period before and after NNPPV intervention were recorded., Results: Subjects in the NNPPV group showed a significant reduction in arterial carbon dioxide partial pressure (PaCO2). bicarbonate (HCO3-), and base excess (BE), compared with those before intervention and of the control group. Six-minute walk distance (6MWD) also increased significantly from 232.2 +/- 79.3 m to 333.4 +/- 81.3 m in the NNPPV group after 6 months of intervention. The maximum voluntary ventilation (MVV) also increased significantly after NNPPV intervention. Moreover, the NNPPV group had significantly lower frequency of admission and fewer days of hospital stay during the intervention period compared with those before intervention and of the control group., Conclusion: Six months of NNPPV improved the arterial blood gas, increased exercise capacity and respiratory muscle endurance, and helped to reduce the frequency and the length of hospitalization in hypercapnic patients with severe obstructive lung disease.

This study investigates the signaling pathway involved in inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) release caused by Staphylococcus aureus lipoteichoic acid (LTA) in RAW 264.7 macrophages. A phosphatidylcholine-phospholipase C (PC-PLC) inhibitor (D-609) and a phosphatidylinositol-phospholipase C (PI-PLC) inhibitor (U-73122) attenuated LTA-induced iNOS expression and NO release. Two PKC inhibitors (Go 6976 and Ro 31-8220), an NF-kappaB inhibitor (pyrrolidine dithiocarbamate; PDTC), and long-term (24 h) 12-phorbol-13-myristate acetate (PMA) treatment each also inhibited LTA-induced iNOS expression and NO release. Treatment of cells with LTA caused an increase in PKC activity; this stimulatory effect was inhibited by D-609, U-73122, or Ro 31-8220. Stimulation of cells with LTA caused IkappaB-alpha phosphorylation and IkappaB-alpha degradation in the cytosol, and translocation of p65 and p50 NF-kappaB from the cytosol to the nucleus. Treatment of cells with LTA caused NF-kappaB activation by detecting the formation of NF-kappaB-specific DNA-protein complexes in the nucleus; this effect was inhibited by Go 6976, Ro 31-8220, long-term PMA treatment, PDTC, L-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK), and calpain inhibitor I. These results suggest that LTA might activate PC-PLC and PI-PLC to induce PKC activation, which in turn initiates NF-kappaB activation, and finally induces iNOS expression and NO release in RAW 264.7 macrophages.

We have investigated the role of protein kinase C (PKC) and nuclear factor-kappaB (NF-kappaB) in cyclooxygenase-2 (COX-2) expression caused by Staphylococcus aureus lipoteichoic acid in RAW 264.7 macrophages. A phosphatidylcholine-phospholipase C (PC-PLC) inhibitor (D-609) and a phosphatidylinositol-phospholipase C (PI-PLC) inhibitor (U-73122) attenuated lipoteichoic acid-induced COX-2 expression, while a phosphatidate phosphohydrolase inhibitor (propranolol) had no effect. Two PKC inhibitors (Go 6976 and Ro 31-8220) and the NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), also attenuated lipoteichoic acid-induced COX-2 expression. Lipoteichoic acid resulted in a decrease in PKC activity in the cytosol and an increase in PKC activity in membranes. The lipoteichoic acid-induced translocation of p65 NF-kappaB from the cytosol to the nucleus was inhibited by D-609, U-73122, Go 6976, Ro 31-8220, and PDTC, but not by propranolol. The results suggested that lipoteichoic acid might have activated PC-PLC and PI-PLC to induce PKC activation, which in turn initiated NF-kappaB activation, and finally induced COX-2 expression in RAW 264.7 macrophages.

Background and Purpose: Oxygen supplementation is the treatment most commonly used to relieve dyspnea in chronic obstructive pulmonary disease (COPD). There is a lack of data, however, on the response of the respiratory drive to low flow oxygen in severe stable COPD. The purpose of this investigation was to evaluate the magnitude of chemoresponsiveness to low flow supplemental oxygen in patients with COPD of variable severity in terms of mouth occlusion pressure at 100 msec (P0.1), P0.1 and minute ventilation (MV) response to CO2 stimulation, and blood gas tension., Methods: Twenty-six patients with stable COPD of variable severity were divided into two groups: those with mild airway obstruction and normocapnia (n = 14) and those with hyperinflation and hypercapnia (n = 12)., Results: Arterial oxygen tension, oxygen saturation, and arterial CO2 tension were significantly increased after oxygen therapy in COPD patients with or without hypercapnia (all p < 0.01). COPD patients with hypercapnia had a significantly higher P0.1 (0.7 +/- 0.07 kPa) than those with normocapnia (0.3 +/- 0.03 kPa, p < 0.01). Oxygen significantly decreased the P0.1 adjusted by end tidal CO2 pressure (delta P0.1/PETCO2) only in patients with hyperinflation and hypercapnia, from 0.2 +/- 0.05 to 0.1 +/- 0.03 kPa (p < 0.05). There was a weak correlation between P0.1/PETCO2 and forced vital capacity (FVC; r = 0.41, p < 0.05) or forced expiratory volume in 1 second (FEV1; r = 0.45, p < 0.05). In addition, the arterial CO2 tension (PaCO2) was inversely related to P0.1/PETCO2 (r = -0.57, p < 0.01). The MV with 6% CO2 (MVCO2) was also significantly decreased in the hypercapnic group from 17.9 +/- 3.7 to 14.8 +/- 4.9 L after oxygen therapy (p < 0.01). The maximum inspiratory pressure did not change after oxygen usage in either group., Conclusion: We conclude that short-term oxygen therapy may blunt respiratory response to CO2 in COPD with chronic hypercapnia. Cautious observation of respiratory response is needed during oxygen therapy in COPD patients with a higher magnitude of air-trapping and hypercapnia.

Background: We studied the correlation between exercise tolerance and pulmonary function, arterial blood gases, and ventilatory drive in patients with airflow limitation (AFL)., Methods: Forty-one patients (36 men, 5 women, mean age 63.6 +/- 10.3 years) with forced expiratory volume in one second (FEV1) < 75% and FEV1/forced vital capacity (FVC) < 75% were enrolled. All patients were clinically stable with no impairment of the lower extremities. On the first day of the study, pulmonary function test (PF), including FVC, FEV1, diffusion capacity (DLCO), and residual volume (RV)/total lung capacity (TLC) was measured by plethysmography. On the next day, ventilatory drive P0.1 were measured before drawing blood gases. Then, a 6-minute walking test with pulse-oxymetry and end tidal CO2 monitoring was performed. Ventilation efficiency (O2SATp & ETCO2) was recorded every 6 seconds during exercise., Results: The walking distance (WD) was significantly correlated to PF: FVC%, FEV1%, DLCO%, and RV/TLC. There was also a significant correlation between resting arterial blood gases (PaO2, PaCO2, SatO2) and PF (FVC%, FEV1%, DLCO% and RV/TLC). The SatO2 at the end of exercise was highly correlated to PF (FVC%, FEV1%, DLCO% and RV/TLC). Gas exchange parameters: PaO2, PaCO2, O2SATa, O2SATp at rest, and O2SATp at the end of exercise were also significantly related to WD., Conclusion: The magnitude of exercise intolerance in patients with AFL was not only significantly correlated to the impairment of pulmonary function, but also closely related to gas exchange during exercise. Therefore, limitation of ventilation could be identified earlier using an exercise test.

Background: Chronic obstructive airway diseases (COAD), characterized by mucus hypersecretion, lead to exercise intolerance. Incentive spirometry has been used to prevent postoperative pulmonary atelectasis., Methods: To compare the efficacy of two incentive spirometers, Coach (volume-oriented) and Triflo (flow-oriented), in the work of breathing in COAD patients, 22 patients were randomized in this study: 12 patients (Triflo-II group) initially used Triflo-II for 10 minutes and then Coach for the same period. In contrast, the Coach group, including 10 patients, started with Coach followed by Triflo-II. After receiving incentive spirometry, lung expansion and work of breathing were assessed., Results: Patients in the Coach group significantly increased chest wall expansion (p = 0.041), as compared with patients using Triflo-II. Similarly, there was also a significantly increased abdominal wall expansion in the Coach group (p = 0.0056), compared with that in the Triflo-II group. The need of accessory muscle assistance for breathing in the Coach group was significantly less than in the Triflo-II group (p = 0.047). It was easier for patients in the Coach group to start a breath (p = 0.0058) than for those in the Triflo-II group. For the entire group, 17 patients (77.3%) preferred Coach to assist their breathing, and only 4 patients (18.2%) favored Triflo-II., Conclusion: COAD patients achieved a larger expansion of the chest and abdomen with a Coach device. Our data provide a good rationale for an outcome study on the use of incentive spirometer in COAD patients.

Background: Chest physiotherapy is beneficial to patients with mucus hypersecretion. However, it is not risk-free. Chest physiotherapy may affect gastrointestinal motility and the competence of the gastroesophageal sphincter during the procedure. Our study was aimed to investigate whether gastroesophageal reflux is exacerbated or induced by chest physiotherapy., Materials and Methods: Thirty-two adult patients with chronic bronchitis or bronchiectasis received chest physiotherapy. An esophageal pH meter was placed 5 cm above the gastroesophageal junction and monitored the reflux episodes from 8 AM on the first day to 12 noon on the second day. Physiotherapy was performed with the patient in three different positions on the second day for one hour., Results: Thirteen patients were found to have gastroesophageal reflux disease. For the study group as a whole, neither the frequency nor the duration of having a pH < 4 during the physiotherapy was significantly different from the mean hourly frequency and mean hourly duration recorded on the first day or from those values recorded at a corresponding time on the first day. As for the patients with gastroesophageal reflux disease, the frequency and total duration of gastroesophageal reflux during physiotherapy were not significantly different from the mean hourly frequency and the mean hourly duration or from the values recorded at the corresponding time on the first day. There was no significant difference in the gastroesophageal reflux frequency or the duration in different body positions., Conclusion: Chest physiotherapy including postural drainage, percussion and forced expiration techniques in different positions did not induce or increase the incidence of gastroesophageal reflux in patients with chronic bronchitis and bronchiectasis.

Airflow limitation impairs exercise capacity in patients with chronic obstructive pulmonary disease (COPD). Bronchodilators have been shown to increase exercise tolerance in patients with COPD by mechanisms yet unclarified. We studied the effect of nebulized fenoterol (0.5 mg/ml) on the 6-minute walking test (WT) 60 mins after a control WT using a nebulized saline control in 16 patients with moderate to severe COPD. Before and immediately after each WT, the FEV1, FVC, O2, Saturation and dyspnea score (Borg breathlessness score,[BS]) were measured. Fenoterol had no significant effect on pre-exercise spirometry in our patients but maintained a significantly higher level of FEV1 (0.9 +/- 0.1L, p < 0.0001) and FVC (2.0 +/- 0.2L, p < 0.01) immediately after exercise than that after saline control nebulization (0.7 +/- 0.1L, 1.8 +/- 0.2L, respectively). Fenoterol significantly (p < 0.01) increased walking distance (WD) from 201.3 +/- 22.2m to 238.9 +/- 22.2m, but no difference was found in BS and oxygen saturation. The decline in FEV1 following the WT was shown to have an inverse relationship (r = - 0.74, p < 0.002) with the WD improvement (delta WD). Those who walked farther after fenoterol inhalation felt less dyspnea after exercise, also with an inverse correlation (r = -0.61, p < 0.02). These results suggest that fenoterol may improve exercise capacity by preventing airflow deterioration during exercise in patients with COPD. We also recommend the 6-minute walking test in the routine clinical assessment of COPD patients to evaluate the symptomatic benefit offered by betamimetic bronchodilators.

Although home mechanical ventilation is common in western countries, it is still extremely rare in Taiwan. The objectives of this study are (1) to review retrospectively the types of disorders and outcomes of these patients requiring prolonged mechanical ventilation (MV), and (2) to survey the home status of twelve patients on home mechanical ventilation. From January 1990 to April 1992, one hundred fifteen patients receiving prolonged MV ( > or = 30 days & > or = 8-10 hrs/day) were studied in the medical intensive care unit at Chang Gung Memorial Hospital. Eighty-two patients (71.3%) for whom long-term MV were thought to be beneficial were divided into three groups by disorder: (1)primary pulmonary disorder (N = 55, 67.07%) (2) neuromuscular disorder (N = 18, 21.95%), (3) brain stem disorder (N = 9, 10.98%). The outcomes of these eighty-two patients were as follows: expired, 37 (45.12%), completely weaned, 21 (25.61%), unweanable 24, including 12 (14.63%) hospitalized and 12 (14.63%) discharged home. The three outcomes of prolonged MV were significantly associated with the three types of disorder (P = 0.0035). Among these three disorders, duration of MV were longest in the neuromuscular group, whatever the outcome. There was significant difference in the duration of MV for the different outcomes of group I & group III. The mean duration at home for the twelve home MV patients (5 male and 7 female, mean age +/- SD = 46.08 +/- 20.83 years old) was 9.93 +/- 8.11 month, with the longest being 21.5 months. Four expired within two months of discharge to home, two patients had to be readmitted once (one C2-C5 spinal cord injury patient for pneumonia, and the other for brain stem deterioration). When comparing hospital stay, four patients improved in the maximal free time (the mean improvement, 5.75 +/- 3.11 hours/day), seven remained unchanged, while one regressed.(ABSTRACT TRUNCATED AT 250 WORDS)