Publications by authors named "Chien-Da Huang"

48 Publications

Active learning of medical students in Taiwan: a realist evaluation.

BMC Med Educ 2020 Dec 3;20(1):487. Epub 2020 Dec 3.

Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taipei, Taiwan.

Background: Active learning is defined as any instructional method that engages students in the learning process. Cultural differences in learning patterns can play an important role in engagement with active learning. We aimed to examine process models of active learning to understand what works, for whom and why.

Methods: Forty-eight sixth- and seventh-year medical students with experience of active learning methods were purposively selected to participate in ten group interviews. Interactions around active learning were analysed using a realist evaluation framework to unpack the 'context-mechanism-outcome' (CMO) configurations.

Results: Three core CMO configurations, including cultural, training and individual domains, were identified. In the cultural context of a strong hierarchical culture, the mechanisms of fear prompted students to be silent (outcome) and dare not give their opinions. In the training context of teacher-student familiarity alongside teachers' guidance, the mechanisms of learning motivation, self-regulation and enthusiasm were triggered, prompting positive learning outcomes and competencies (outcome). In the individual context of learning how to learn actively at an early stage within the medical learning environment, the mechanisms of internalisation, professional identity and stress resulted in recognising active learning and advanced preparation (outcomes).

Conclusions: We identified three CMO configurations of Taiwanese medical students' active learning. The connections among hierarchical culture, fear, teachers' guidance, motivation, the medical environment and professional identity have been shown to affect the complex interactions of learning outcomes. Fear derived from a hierarchical culture is a concern as it is a significant and specific contextual factor, often sparking fear with negative outcomes.
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http://dx.doi.org/10.1186/s12909-020-02392-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713042PMC
December 2020

The influence of narrative medicine on medical students' readiness for holistic care practice: a realist synthesis protocol.

BMJ Open 2019 08 2;9(8):e029588. Epub 2019 Aug 2.

Chang Gung Medical Education Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan

Introduction: Holistic healthcare considers the whole person-their body, mind, spirit and emotions-and has been associated with narrative medicine practice. Narrative medicine is medicine performed with narrative skill and has been offered as a model for humanism and effective medical practice. Narrative medicine interventions have been associated with physicians' increased empathy and more meaningful interactions with patients about managing their illness and preventative medicine. However, while there is some evidence that certain groups are more open to narrative practices (eg, traditional vs Western medical students), the extent to which narrative medicine interventions during undergraduate medical education impacts on students' readiness for holistic care, as well as the underlying reasons why, is unknown.

Methods And Analysis: Realist review is a theory-driven approach to evaluate complex interventions. It focuses on understanding how interventions and programmes work (or not) in their contextual setting. This realist synthesis aimed to formulate a theory around the influence of narrative medicine medical students' readiness for holistic care practice. We will follow Pawson's five steps: locate existing theories, search strategy, study selection, data extraction, data analysis and synthesis. We will use the following electronic databases: Web of Science, Medline, Scopus and Embase. Articles between January 2008 and September 2018 will be included. Results will be written according to the RAMESES (Realist And Meta-narrative Evidence Syntheses: Evolving Standards) standard for reporting realist syntheses.

Ethics And Dissemination: Ethics approval was obtained from the Chang Gung Memorial Hospital for the wider study. The findings of this review will provide useful information for academics and policymakers, who will be able to apply the findings in their context when deciding whether and how to introduce narrative medicine programmes into medical students' curricula. We will publish our findings in peer-reviewed journals and international conferences.

Prospero Registration Number: CRD42018115447.
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http://dx.doi.org/10.1136/bmjopen-2019-029588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687057PMC
August 2019

Reduced suppressive effect of β-adrenoceptor agonist on fibrocyte function in severe asthma.

Respir Res 2017 Nov 21;18(1):194. Epub 2017 Nov 21.

Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.

Background: Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β-AR agonists, alone or in combination with corticosteroids, on fibrocyte function.

Methods: Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I/CD45 cells) and differentiating fibrocytes (α-smooth muscle actin cells), and the expression of CC chemokine receptor 7 and of β-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram.

Results: Salmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface β-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased β-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation.

Conclusions: Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.
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http://dx.doi.org/10.1186/s12931-017-0678-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697384PMC
November 2017

Impact of a narrative medicine programme on healthcare providers' empathy scores over time.

BMC Med Educ 2017 Jul 5;17(1):108. Epub 2017 Jul 5.

Department of Medical Education, Chang Gung University, College of Medicine, Taipei, Taiwan.

Background: The cultivation of empathy for healthcare providers is an important issue in medical education. Narrative medicine (NM) has been shown to foster empathy. To our knowledge, there has been no research that examines whether a NM programme affects multi-professional healthcare providers' empathy. Our study aims to fill this gap by investigating whether a NM programme effects multi-professional healthcare providers' empathy.

Methods: A pre-post questionnaire method was used.142 participants (n = 122 females) who attended the NM programme were divided into single (n = 58) and team groups (n = 84) on the basis of inter-professional education during a period of 2 months. Perceptions of the NM programme were collected using our developed questionnaire. Empathy levels were measured using the Chinese version of Jefferson Scale of Empathy - Healthcare Providers Version (JSE-HP) - at three time points: prior to (Time 1), immediately after (T2), and 1.5 years (T3) after the programme.

Results: Participants' perceptions about the NM programme (n = 116; n = 96 females) suggested an in enhancement of empathy (90.5%). Empathy scores via the JSE-HP increased after the NM programme (T1 mean 111.05, T2 mean 116.19) and were sustainable for 1.5 years (T3 mean 116.04) for all participants (F(2297) = 3.74, p < .025). A main effect of gender on empathy scores was found (F(1298) = 5.33, p < .022). No significant effect of gender over time was found but there was a trend that showed females increasing empathy scores at T2, sustaining at T3, but males demonstrating a slow rise in empathy scores over time.

Conclusions: NM programme as an educational tool for empathy is feasible. However, further research is needed to examine gender difference as it might be that males and females respond differently to a NM programme intervention.
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http://dx.doi.org/10.1186/s12909-017-0952-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499008PMC
July 2017

Different perceptions of narrative medicine between Western and Chinese medicine students.

BMC Med Educ 2017 May 10;17(1):85. Epub 2017 May 10.

Neurosurgery, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taipei, Taiwan.

Background: Western medicine is an evidence-based science, whereas Chinese medicine is more of a healing art. To date, there has been no research that has examined whether students of Western and Chinese medicine differentially engage in, or benefit from, educational activities for narrative medicine. This study fills a gap in current literature with the aim of evaluating and comparing Western and Chinese Medicine students' perceptions of narrative medicine as an approach to learning empathy and professionalism.

Methods: An initial 10-item questionnaire with a 5-point Likert scale was developed to assess fifth-year Western medical (MS) and traditional Chinese medical (TCMS) students' perceptions of a 4-activity narrative medicine program during a 13-week internal medicine clerkship. Exploratory factor analysis was undertaken.

Results: The response rate was 88.6% (412/465), including 270 (65.5%) MSs and 142 (34.5%) TCMSs, with a large reliability (Cronbach alpha = 0.934). Three factors were extracted from 9 items: personal attitude, self-development/reflection, and emotional benefit, more favorable in terms of enhancement of self-development/reflection. The perceptions of narrative medicine by scores between the two groups were significantly higher in TCMSs than MSs in all 9-item questionnaire and 3 extracted factors.

Conclusions: Given the different learning cultures of medical education in which these student groups engage, this suggests that undertaking a course in Chinese medicine might enhance one's acceptance to, and benefit from, a medical humanities course. Alternatively, Chinese medicine programmes might attract more humanities-focused students.
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http://dx.doi.org/10.1186/s12909-017-0925-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424351PMC
May 2017

Obstructive sleep apnoea accelerates FEV decline in asthmatic patients.

BMC Pulm Med 2017 03 21;17(1):55. Epub 2017 Mar 21.

Pulmonary Disease Research Centre, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, 199 Tun-Hwa N. Rd., Taipei, Taiwan.

Background: Although the prevalence of both obstructive sleep apnoea (OSA) and asthma are both increasing, little is known about the impact of OSA on the natural history of lung function in asthmatic patients.

Methods: A total of 466 patients from our sleep laboratory were retrospectively enrolled. Of them, 77 patients (16.5%) had asthma with regular follow-up for more than 5 years. Their clinical characteristics, pulmonary function, emergency room visits, and results of polysomnography results were analysed.

Results: The patients were divided into three groups according to the severity of the apnoea-hypopnea index (AHI). The decline in FEV among asthma patients with severe OSA (AHI > 30/h) was 72.4 ± 61.7 ml/year (N = 34), as compared to 41.9 ± 45.3 ml/year (N = 33, P = 0.020) in those with mild to moderate OSA (5 < AHI ≤ 30) and 24.3 ± 27.5 ml/year (N = 10, P = 0.016) in those without OSA (AHI ≤ 5). For those patients with severe OSA, the decline of FEV significantly decreased after continuous positive airway pressure (CPAP) treatment. After multivariate stepwise linear regression analysis, only AHI was remained independent factor for the decline of FEV decline.

Conclusions: Asthmatic patients with OSA had substantially greater declines in FEV than those without OSA. Moreover, CPAP treatment alleviated the decline of FEV in asthma patients with severe OSA.
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http://dx.doi.org/10.1186/s12890-017-0398-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361857PMC
March 2017

Mid-arm and calf circumferences are stronger mortality predictors than body mass index for patients with chronic obstructive pulmonary disease.

Int J Chron Obstruct Pulmon Dis 2016 31;11:2075-80. Epub 2016 Aug 31.

Department of Nursing, Yuanpei University of Medical Technology, Hsinchu City, Taiwan.

Background: Chronic obstructive pulmonary disease (COPD) is currently the third most common cause of death in the world. Patients with COPD experience airflow obstruction, weight loss, skeletal muscle dysfunction, and comorbidities. Anthropometric indicators are risk factors for mortality in geriatric assessment.

Purpose: This study examined and compared the associations of anthropometric indicators, such as low body mass index (BMI), low mid-arm circumference (MAC), and low calf circumference (CC), with the prediction of a 3-year follow-up mortality risk in patients with COPD.

Methods: We recruited nonhospitalized patients with COPD without acute conditions from a general hospital in Taiwan. The BMI, MAC, and CC of all patients were measured, and they were followed for 3 years through telephone interviews and chart reviews. The Kaplan-Meier survival curves stratified by BMI, MAC, and CC were analyzed. Variables univariately associated with survival were entered into a multivariate Cox regression model. The Bayesian information criterion was used to compare the predictive ability of the three anthropometric indicators to predict mortality rate.

Results: In total, 104 patients were included (mean ± standard deviation age, 74.2±6.9 years; forced expiratory volume in 1 second [%], 58.4±20.4 predicted; males, 94.2%); 22 patients (21.2%) died during the 36-month follow-up. During this long-term follow-up, the three anthropometric indicators could predict mortality risk in patients with COPD (low BMI [<21 kg/m(2)], hazard ratio [HR] =2.78, 95% confidence interval [CI] =1.10-7.10; low MAC [<23.5 cm], HR =3.09, 95% CI =1.30-7.38; low CC [<30 cm], HR =4.40, 95% CI =1.82-10.63). CC showed the strongest potential in predicting the mortality risk, followed by MAC and BMI.

Conclusion: Among the three anthropometric variables examined, CC can be considered a strong predictor of mortality risk in patients with COPD.
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http://dx.doi.org/10.2147/COPD.S107326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012597PMC
August 2017

Efficacy of omalizumab (Xolair®) in patients with moderate to severe predominately chronic oral steroid dependent asthma in Taiwan: a retrospective, population-based database cohort study.

BMC Pulm Med 2016 Jan 8;16. Epub 2016 Jan 8.

Department of Thoracic Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taipei, Taiwan.

Background: Omalizumab (Xolair®), a recombinant monoclonal anti-IgE antibody, has demonstrated efficacy in clinical trials conducted in patients with moderate to severe persistent allergic asthma. We aimed to investigate the efficacy, discontinuation and medical resource utilization of omalizumab in the real-life setting in Taiwan.

Methods: This study was a retrospective, population-based database cohort study using the Taiwan NHIRD from 2007 to 2011 assessing the efficacy of omalizumab therapy over 4 months on changes in asthma medication, asthma control, frequency of exacerbations and hospitalization rates at baseline and after omalizumab discontinuation.

Results: There was a reduction in asthma medication post omalizumab therapy and severe exacerbations and hospitalizations from baseline (31.2%, n = 282) to the end of follow-up (11.8%, n = 144, p < 0.001). Nearly all the patients received chronic oral corticosteroids at baseline (92.4%). The number of ER visits decreased from 1.13 ± 2.04 to 0.29 ± 0.83, and the mean number of admissions decreased from 5.93 ± 16.16 to 2.75 ± 12.02 from baseline to the end of follow-up (p < 0.001). After discontinuation of omalizumab, the cost of ER medical expenses decreased from New Taiwan dollars (NTD) 3934 at 2 months to NTD 2860 at 12 months.

Conclusions: Patients who received omalizumab therapy for over 4 months were more likely to reduce the use of other asthma medications and less likely to experience an asthma exacerbation, ER visits, and hospitalization, even after the discontinuation of omalizumab. These data suggest that omalizumab has efficacy in improving health outcomes in patients with moderate to severe predominately chronic oral steroid dependent asthma in the real-life setting in Taiwan.
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http://dx.doi.org/10.1186/s12890-015-0156-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706688PMC
January 2016

Low bone mineral density in COPD patients with osteoporosis is related to low daily physical activity and high COPD assessment test scores.

Int J Chron Obstruct Pulmon Dis 2015 1;10:1737-44. Epub 2015 Sep 1.

School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.

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<0.05) and T-score (r=0.471, 0.531, 0.459, respectively, all P<0.05), whereas CAT scores were significantly negatively correlated with (total hip and femoral neck) BMD (r=-0.412, -0.552, respectively, P<0.05) and (lumbar spine, total hip, and femoral neck) T-score (r=-0.389, -0.429, -0.543, respectively, P<0.05). Low femoral neck BMD in COPD patients was related to high CAT scores. Our results show no significant difference in desaturation index, low SpO2, and inflammatory markers (IL-6, TNF-α, IL-8/CXCL8, CRP, and 8-isoprostane) between the two groups. Chest physicians should be aware that COPD patients with OP have low DPA and high CAT scores.
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http://dx.doi.org/10.2147/COPD.S87110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562728PMC
April 2016

Circulating angiopopietin-1 correlates with the clinical course of multiple organ dysfunction syndrome and mortality in patients with severe sepsis.

Medicine (Baltimore) 2015 May;94(20):e878

From the Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taipei, Taiwan.

To determine plasma concentrations of angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) in patients with sepsis-induced multiple organ dysfunction syndrome (MODS) and determine their association with mortality.The study prospectively recruited 96 consecutive patients with severe sepsis in a l intensive care unit of a tertiary hospital. Plasma Ang-1, Ang-2, Tie-2, and VEGF levels and MODS were determined in patients on days 1, 3, and 7 of sepsis. Univariate and Cox proportional hazards analysis were performed to develop a prognostic model.Days 1, 3, and 7 plasma Ang-1 concentrations were persistently decreased in MODS patients than in non-MODS patients (day1: 4.0 ± 0.5 vs 8.0 ± 0.5 ng/mL, P < 0.0001; day 3, 3.2 ± 0.6 vs 7.3 ± 0.5 ng/mL, P < 0.0001, day 7, 2.8 ± 0.6 vs 10.4 ± 0.7 ng/mL, P < 0.0001). In patients with resolved MODS on day 7 of sepsis, Ang-1 levels were increased from day 1 (4.7 ± 0.6 ng/mL vs 9.1 ± 1.4 ng/mL, n = 43, P = 0.004). Plasma Ang-1 levels were lower in nonsurvivors than in survivors on days 1 (4.0 ± 0.5 vs 7.1 ± 0.5 ng/mL, P < 0.0001), 3 (3.8 ± 0.6 vs 7.1 ± 0.5 ng/mL, P < 0.0001), and 7 (4.7 ± 0.7 vs 11.0 ± 0.8 ng/mL, P < 0.0001) of severe sepsis. In contrast, plasma Ang-2 levels were higher in nonsurvivors than in survivors only on day 1 (15.8 ± 2.0 vs 9.5 ± 1.2 ng/mL, P = 0.035). VEGF and Tie-2 levels were not associated with MODS and mortality. Ang-1 level less than the median value was the only independent predictor of mortality (hazard ratio, 2.57; 95% CI 1.12-5.90, P = 0.025).Persistently decreased Ang-1 levels are associated with MODS and subsequently, mortality in patients with sepsis.
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http://dx.doi.org/10.1097/MD.0000000000000878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602874PMC
May 2015

Medical record review for faculty promotion: A cohort analysis.

Biomed J 2015 Sep-Oct;38(5):456-61

Department of Medical Education; Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Background: A medical record is an important source of information regarding medical care and medical record review plays an important role in the evaluation of the teaching proficiency. The study analyzed the difference between internal and external auditing when conducting medical record review for faculty promotion in a study institute.

Methods: We analyzed the scores related to the medical records maintained by applicants for the faculty promotion of attending physicians during the period between 2008 and 2010 at the Chang Gung Memorial Hospital. The scores were obtained from one internal reviewer of the study institute and two external reviewers from other medical centers, and routine scores were obtained from the Committee of Medical Record 1 year before application. Pearson's correlation coefficient was used to analyze the correlation and statistical significance.

Results: There were 259 applicants for faculty promotion enrolled in this study [professors (n = 33, 13%), associate professors (n = 63, 24%), assistant professors (n = 90, 35%), lecturers (n = 73, 28%)]. The scores of the external reviewers 1 and 2 were correlated with routine scores (r = 0.187, p = 0.002; r = 0.198, p = 0.001; N= 259), respectively. The correlation between external reviewers' average and ordinary scores was significant for assistant professor (r = 0.334, p = 0.001, n = 90) and professor grades (r = 0.469, p = 0.006, n = 33). However, the internal reviewer scores did not correlate with the routine scores (r = 0.073, p = 0.241, N = 259).

Conclusions: The scores from external reviewers correlated more with routine scores than the scores from internal reviewers, suggesting that utilizing an external auditing system of medical records for the faculty promotion of attending physicians is quite feasible and balanced.
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http://dx.doi.org/10.4103/2319-4170.151028DOI Listing
December 2016

Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma.

J Allergy Clin Immunol 2015 May 6;135(5):1186-95.e1-6. Epub 2014 Dec 6.

Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; NIHR Respiratory Biomedical Research Unit, Royal Brompton NHS Foundation Trust, London, United Kingdom. Electronic address:

Background: Patients with severe asthma are less responsive to corticosteroid therapy and show increased airway remodeling. The mesenchymal progenitors, fibrocytes, may be involved in the remodeling of asthmatic airways. We propose that fibrocytes in severe asthma are different from those in nonsevere asthma.

Objectives: To examine the survival, myofibroblastic differentiation, and C-C chemokine receptor 7 (CCR7) expression in blood fibrocytes from patients with severe and nonsevere asthma and study the effect of corticosteroids on fibrocyte function.

Methods: The nonadherent non-T-cell fraction of blood mononuclear cells was isolated from healthy subjects and patients with nonsevere and severe asthma. Total and differentiating fibrocytes were identified by their expression of CD45, collagen I, and α-smooth muscle actin using flow cytometry. The expression of CCR7 and of the glucocorticoid receptor was measured by using flow cytometry.

Results: Increased numbers of circulating fibrocytes, with greater myofibroblastic differentiation potential, were observed in patients with severe asthma. Dexamethasone induced apoptosis, leading to reduction in the number of cultured fibrocytes and total nonadherent non-T cells from healthy subjects and patients with nonsevere asthma but not from patients with severe asthma. Dexamethasone reduced CCR7 expression in fibrocytes from patients with nonsevere asthma but not from patients with severe asthma. Glucocorticoid receptor expression was attenuated in fibrocytes from patients with severe asthma.

Conclusions: Patients with severe asthma have elevated numbers of circulating fibrocytes that show enhanced myofibroblastic differentiation and that are less responsive to the effects of corticosteroids.
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http://dx.doi.org/10.1016/j.jaci.2014.10.031DOI Listing
May 2015

A biologically inspired lung-on-a-chip device for the study of protein-induced lung inflammation.

Integr Biol (Camb) 2015 Feb;7(2):162-9

Institute of NanoEngineering and MicroSystems, National Tsing Hua University, Hsinchu, Taiwan, Republic of China.

This study reports a biomimetic microsystem that reconstitutes the lung microenvironment for monitoring the role of eosinophil cationic protein (ECP) in lung inflammation. ECP induces the airway epithelial cell expression of CXCL-12, which in turn stimulates the migration of fibrocytes towards the epithelium. This two-layered microfluidic system provides a feasible platform for perfusion culture, and was used in this study to reveal that the CXCL12-CXCR4 axis mediates ECP induced fibrocyte extravasation in lung inflammation. This 'lung-on-a-chip' microdevice serves as a dynamic transwell system by introducing a flow that can reconstitute the blood vessel-tissue interface for in vitro assays, enhancing pre-clinical studies. We made an attempt to develop a new microfluidic model which could not only simulate the transwell for studying cell migration, but could also study the migration in the presence of a flow mimicking the physiological conditions in the body. As blood vessels are the integral part of our body, this model gives an opportunity to study more realistic in vitro models of organs where the blood vessel i.e. flow based migration is involved.
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http://dx.doi.org/10.1039/c4ib00239cDOI Listing
February 2015

Fibrocyte trafficking in patients with chronic obstructive asthma and during an acute asthma exacerbation.

J Allergy Clin Immunol 2015 May 24;135(5):1154-62.e1-5. Epub 2014 Oct 24.

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan; Department of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Background: Fibrocytes express several chemokine receptors (CCR7 and CXCR4) that regulate their recruitment and trafficking into tissue-damage sites in response to specific chemokine gradients (CCL19 and CXCL12).

Objective: We investigated whether these chemoattractants and S100A9, through the receptor for advanced glycation end-products (RAGE; ie, its receptor), are involved in fibrocyte trafficking in patients with chronic obstructive asthma (COA) and during an acute exacerbation (AE) in patients without airflow obstruction (Asthma AE group).

Methods: We collected peripheral blood from 14 asthmatic patients with normal pulmonary function, 14 patients with COA, 11 patients in the Asthma AE group, and 14 healthy subjects. Isolated circulating fibrocytes were used for migration assay. Expression of CCR7, CXCR4, S100A9, and RAGE in fibrocytes was measured by using flow cytometry. CCL19 and CXCL12 expression in bronchial tissues was determined by using immunohistochemistry and RT-PCR.

Results: There were higher numbers of circulating fibrocytes in patients in the Asthma AE group and patients with COA. The expression of CXCL12 in bronchial tissues and CXCR4 in circulating fibrocytes was higher in the Asthma AE group and, to a lesser extent, in patients with COA. The expression of CCL19 in bronchial tissues and CCR7 in fibrocytes was higher in patients with COA. CXCL12/CXCR4 and CCL19/CCR7 enhanced fibrocyte transmigration in the Asthma AE group and in patients with COA, respectively. The upregulated expression of S100A9 and RAGE in fibrocytes of patients in the Asthma AE group and those with COA contributes to the enhanced basal migratory motility of fibrocytes.

Conclusion: The CXCR4/CXCL12 axis contributes to chemotaxis of fibrocytes in patients in the Asthma AE group, whereas the CCR7/CCL19 axis plays an important role in patients with COA. S100A9 enhances the basal migratory motility of fibrocytes from patients in the Asthma AE group and patients with COA.
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http://dx.doi.org/10.1016/j.jaci.2014.09.011DOI Listing
May 2015

Mobile-phone-based home exercise training program decreases systemic inflammation in COPD: a pilot study.

BMC Pulm Med 2014 Aug 30;14:142. Epub 2014 Aug 30.

Department of Thoracic Medicine, Chang Gung Memorial Hospital, 199 Tun-Hwa North Road, Taipei, Taiwan.

Background: Moderate-intensity exercise training improves skeletal muscle aerobic capacity and increased oxidative enzyme activity, as well as exercise tolerance in COPD patients.

Methods: To investigate whether the home-based exercise training program can reduce inflammatory biomarkers in patients with COPD, twelve patients using mobile phone assistance and 14 with free walk were assessed by incremental shuttle walk test (ISWT), spirometry, strength of limb muscles, and serum C-reactive protein (CRP) and inflammatory cytokines.

Results: Patients in the mobile phone group improved their ISWT walking distance, with decrease in serum CRP after 2 months, and sustained at 6 months. Patients in the control group had no improvement. Serum IL-8 in the mobile phone group was significantly reduced at 2, 3 and 6 months after doing home exercise training compared to baseline. IL-6 and TNF-α were significantly elevated at 3 and 6 months in control group, while there were no changes in mobile phone group. The strength of limb muscles was significantly greater compared to baseline at 3 and 6 months in the mobile phone group.

Conclusions: A mobile-phone-based system can provide an efficient home endurance exercise training program with improved exercise capacity, strength of limb muscles and a decrease in serum CRP and IL-8 in COPD patients. Decreased systemic inflammation may contribute to these clinical benefits. (Clinical trial registration No.: NCT01631019).
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http://dx.doi.org/10.1186/1471-2466-14-142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236722PMC
August 2014

PPARγ ligand ciglitazone inhibits TNFα-induced ICAM-1 in human airway smooth muscle cells.

Biomed J 2014 Jul-Aug;37(4):191-8

Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Background: Modification of human airway smooth muscle (ASM) function by proinflammatory cytokines has been regarded as a potential mechanism underlying bronchial hyperresponsiveness in asthma. Human ASM cells express intercellular adhesion molecule (ICAM)-1 in response to cytokines. Synthetic ligands for peroxisome proliferator-activated receptor (PPAR)γ reportedly possess anti-inflammatory and immunomodulatory properties. In this study, we examined whether ciglitazone, a synthetic PPARγ ligand, can modulate the basal and tumor necrosis factor (TNF)α-induced ICAM1 gene expression in human ASM cells.

Methods: Human ASM cells were treated with TNFα. ICAM-1 expression was assessed by flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. PPARγ activity was inhibited by target-specific small interfering (si) RNA targeting PPARγ and GW9662, a PPARγ antagonist. Activity of nuclear factor (NF)-κB was assessed by using immunoblot analysis, immune-confocal images, and electrophoretic mobility shift assay (EMSA).

Results: By flow cytometry, ciglitazone alone had no effect on ICAM-1 expression in ASM cells, but inhibited ICAM-1 expression in response to TNFα (10 ng/ml) in a dose-dependent manner (1-10 μM). It also inhibited TNFα-induced ICAM1 gene expression by RT-PCR analysis. Knockdown of PPARγ gene by target-specific siRNA targeting PPARγ enhanced ICAM-1 expression and the inhibitory effect of ciglitazone on TNFα-induced ICAM-1 expression was reversed by PPARγ siRNA and GW9662. SN-50 (10 μg/ml), an inhibitor for nuclear translocation of NF-κB, inhibited TNFα-induced ICAM-1 expression. Ciglitazone did not prevent TNFα-induced degradation of the cytosolic inhibitor of NF-κB (IκB), but inhibited the nuclear translocation of p65 induced by TNFα and suppressed the NF-κB/DNA binding activity.

Conclusion: These findings suggest that ciglitazone inhibits TNFα-induced ICAM1 gene expression in human ASM cells through the ligand-dependent PPARγ activation and NF-κB-dependent pathway.
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http://dx.doi.org/10.4103/2319-4170.132890DOI Listing
May 2015

Clinical characteristics and treatment outcomes of patients with low- and high-concentration isoniazid-monoresistant tuberculosis.

PLoS One 2014 22;9(1):e86316. Epub 2014 Jan 22.

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taipei, Taiwan.

Background: Isoniazid (INH) resistance is now the most common type of tuberculosis (TB) infection resistance worldwide. The aim of this study was to evaluate the clinical characteristics and treatment outcomes of patients with low- and high-concentration INH-monoresistant TB.

Methods: One hundred and thirty-four patients with culture-confirmed INH-monoresistant TB during 2006 January to 2007 December were retrospectively enrolled. INH resistance was classified as either low-concentration or high-concentration resistance according to the critical concentrations of 0.2 µg/mL or 1 µg/mL of INH, respectively. The patients' clinical outcomes, treatment regimens, and treatment duration were analyzed.

Results: The treatment success rates between low- and high-concentration INH-resistant TB were similar (81.8% vs. 86.7%). The treatment regimens and treatment duration were similar between both groups. Only a minor percentage of the patients in both groups received 6-month treatment regimens (low vs. high concentration resistance, 9.1% vs. 13.3%; respectively, p = 0.447) The most common reason for treatment duration longer than 6 months was pyrazinamide given for less than 6 months, followed by a delay in clinical response to treatment. Multivariable analysis showed that prior tuberculosis treatment (Odds ratio, 2.82, 95% C.I., 1.02-7.77, p = 0.045) was the only independent risk factor for unsuccessful treatment outcome.

Conclusion: Different levels of INH resistance did not affect the treatment outcomes of patients with INH-monoresistant tuberculosis. Prolonged Rifampin-containing regimens may achieve those good outcomes in patients with low- and high-concentration INH-monoresistant TB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086316PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899226PMC
November 2014

Vocal cord dysfunction diagnosed by four-dimensional dynamic volume computed tomography in patients with difficult-to-treat asthma: A case series.

J Formos Med Assoc 2015 Dec 15;114(12):1285-90. Epub 2013 Nov 15.

Department of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan; Department of Thoracic Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address:

Patients with asthma may also have vocal cord dysfunction (VCD), which leads to poor control of the asthma. Once patients are diagnosed with difficult-to-treat asthma with poor control, VCD should be excluded or treated accordingly. The gold standard for diagnosis of VCD is to perform a laryngoscopy. However, this procedure is invasive and may not be suitable for patients with difficult-to-treat asthma. Four-dimensional (4D) dynamic volume computed tomography (CT) is a noninvasive method for quantification of laryngeal movement, and can serve as an alternative for the diagnosis of VCD. Herein, we present a series of five cases with difficult-to-treat asthma patients who were diagnosed with VCD by 4D dynamic volume CT. Clinicians should be alert to the possibility of VCD when poor control is noted in patients with asthma. Early diagnosis by noninvasive 4D dynamic volume CT can decrease excessive doses of inhaled corticosteroids.
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http://dx.doi.org/10.1016/j.jfma.2013.10.008DOI Listing
December 2015

The endothelin A receptor mediates fibrocyte differentiation in chronic obstructive asthma. The involvement of connective tissue growth factor.

Am J Respir Crit Care Med 2013 Aug;188(3):298-308

Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Rationale: Fibrocytes possess increased differentiability into α-smooth muscle actin (α-SMA)(+) myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin-1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear.

Objectives: To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA.

Methods: Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or α-SMA were identified by flow cytometry.

Measurements And Main Results: We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serum levels of ET-1 and the expression of the ETAR in fibrocytes were significantly higher in patients with COA compared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and α-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated α-SMA expression induced by ET-1 in fibrocytes from normal participants.

Conclusions: Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.
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http://dx.doi.org/10.1164/rccm.201301-0132OCDOI Listing
August 2013

Amplified Mycobacterium tuberculosis direct test for diagnosing tuberculous pleurisy--a diagnostic accuracy study.

PLoS One 2012 10;7(9):e44842. Epub 2012 Sep 10.

Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan.

Background: The study was designed to investigate the clinical usefulness of Amplified Mycobacterium Tuberculosis Direct (AMTD) tests for diagnosing TB pleurisy.

Methods: One hundred and fifty-two patients for whom the exclusion of tuberculous pleural effusion was necessary were retrospectively analyzed.

Results: The sensitivity of AMTD in diagnosing pleural TB was 36.4% (20 of 55). Combining sputum and pleural effusion AFB smear, pleural biopsy, and AMTD test of pleural effusion increased sensitivity to 82.5% (33/40). There were significantly higher percentages of neutrophils in the pleural effusion in the positive than in the negative AMTD group (38.0 ± 6.7% vs. 11.1 ± 3.7%, p<0.001). Patients with symptom duration <18 days prior to pleural effusion studies had more positive AMTD tests than those with symptom >18 days (70% vs. 31.4%; OR 5.09; 95% CI 1.54-16.79; p = 0.011).

Conclusions: Combining AMTD tests with conventional diagnostic methods offer good sensitivity for pleural TB diagnosis. Patients in the early course of the disease are better candidates for AMTD tests.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044842PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438172PMC
March 2013

CD14(+)S100A9(+) monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer.

Am J Respir Crit Care Med 2012 Nov 6;186(10):1025-36. Epub 2012 Sep 6.

Pulmonary Research Center, Chang Gung Medical Foundation, Chang Gung University, 199, Tun-Hwa North Road, Taipei, Taiwan.

Rationale: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T-cell immunity in tumor-bearing hosts. Their clinical relevance remains unclear.

Objectives: To identify subtypes of myeloid-derived suppressor cells in patients with non-small cell lung cancer (NSCLC) and their clinical relevance.

Methods: CD11b(+)CD14(-) and CD11b(+)CD14(+) cells, determined and phenotyped by fluorescence-activated cell sorter analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naive patients with advanced NSCLC were correlated with clinical data. T-cell activation in response to CD3/CD28 costimulation was determined by carboxy-fluorescein diacetate succinimidyl ester (CFSE) staining and ELISA analysis of IFN-γ. The percentage of CD11b(+)CD14(+)S100A9(+) cells in PBMCs was correlated with and tested as a predictor for treatment response in a cohort of patients prospectively receiving first-line cisplatin-based chemotherapy.

Measurements And Main Results: Patients with NSCLC had a significantly higher ratio of CD11b(+)CD14(+) cells than healthy subjects, which was correlated with poor performance status and poor response to chemotherapy. The depletion of these cells in the PBMC reversed the suppression of CD8(+) and CD4(+) T cells. Isolated CD11b(+)CD14(+) cells suppressed CD8(+) T-cell proliferation and IFN-γ production, and the former effect was attenuated by the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine hydrochloride, arginase inhibitor N-hydroxy-nor-l-arginine (nor-NOHA), and blocking antibodies for IL-4Rα(+) and IL-10. CD11b(+)CD14(+) cells were monocyte-like, expressing CD33(+), CD15(-/low), IL-4Rα(+), and S100A9(+) and producing iNOS, arginase, and several cytokines. The ratio of S100A9(+) cells positively correlated with the suppressive ability of the CD11b(+)CD14(+) cells, was associated with poor response to chemotherapy, and predicted shorter progression-free survival.

Conclusions: CD14(+)S100A9(+) inflammatory monocytes in patients with NSCLC are a distinct subset of MDSCs, which suppress T cells by arginase, iNOS, and the IL-13/IL-4Rα axis. The amount of these inflammatory monocytes is associated with poor response to chemotherapy. Clinical trial registered with www.clinicaltrials.gov (NCT 01204307).
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http://dx.doi.org/10.1164/rccm.201204-0636OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132576PMC
November 2012

Reduced nuclear factor-κB repressing factor: a link toward systemic inflammation in COPD.

Eur Respir J 2012 Oct 22;40(4):863-73. Epub 2012 Mar 22.

Dept of Thoracic Medicine Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199 Tun-Hwa North Road, Taipei, Taiwan.

Chronic systemic inflammation is implicated in the systemic manifestations and, probably, the excess mortality risk of chronic obstructive pulmonary disease (COPD). The role of nuclear factor (NF)-κB repressing factor (NRF), a DNA-binding, protein-inhibiting NF-κB response gene, in human diseases has not been explored. We hypothesised that the NRF-negative regulatory mechanism is impaired in COPD peripheral blood mononuclear cells (PBMCs) leading to excessive interleukin (IL)-8/CXCL8 production. NRF expression, NF-κB activation, IL-8/CXCL8 release and intracellular oxidative stress were assessed in PBMCs of normal subjects and stable COPD patients. Primary PBMCs with NRF overexpression, NRF knockdown and exposure to H(2)O(2) were used to elucidate the mechanisms. Stable COPD patients, especially those with severe COPD, showed decreased NRF expression, enhanced NF-κB activation and increased IL-8/CXCL8 release in PBMCs compared with normal subjects. This was associated with reduced NRF and increased RNA polymerase II occupancy at the IL-8/CXCL8 promoter. NRF knockdown enhanced IL-8/CXCL8 production in normal PBMCs, whilst NRF overexpression attenuated IL-8/CXCL8 production. Intracellular oxidative stress was increased in COPD PBMCs. H(2)O(2)-decreased NRF expression and -enhanced IL-8/CXCL8 production was augmented in COPD PBMCs. NRF expression is reduced in PBMCs of stable COPD patients, probably through oxidative stress, leading to increased production of IL-8/CXCL8 and potentially chronic systemic inflammation.
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http://dx.doi.org/10.1183/09031936.00146811DOI Listing
October 2012

Increased activation of fibrocytes in patients with chronic obstructive asthma through an epidermal growth factor receptor-dependent pathway.

J Allergy Clin Immunol 2012 May 9;129(5):1367-76. Epub 2012 Feb 9.

Pulmonary Disease Research Center, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.

Background: Fibrocytes are circulating progenitor cells that are increased in asthmatic patients with chronic obstructive asthma (COA) and rapid decrease in lung function. Fibrocytes from patients with COA have a greater capacity for proliferation and differentiation.

Objective: We investigated whether epidermal growth factor receptor (EGFR) activation mediated the proliferation of fibrocytes in patients with COA and whether oxidative stress was involved in this activation.

Methods: Circulating fibrocytes from nonadherent non-T-cell mononuclear cell fractions from healthy subjects, asthmatic patients with normal pulmonary function, and patients with COA were determined by using flow cytometric coexpression of collagen I, CD45, and CD34 or EGFR or a disintegrin and metalloprotease domain 17 and placed in culture.

Results: Expression of EGFR was increased in fibrocytes from patients with COA compared with that seen in patients with NPF. AG1478 and gefitinib, inhibitors of EGFR tyrosine kinase, reduced fibrocyte proliferation and myofibroblast transformation. Increased expression of EGFR and fibrocyte proliferation and transformation were induced by hydrogen peroxide, and these effects were inhibited by N-acetylcysteine.

Conclusions: Enhanced fibrocyte proliferation and transformation found in patients with COA might be mediated through an oxidant-sensitive EGFR-dependent pathway.
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http://dx.doi.org/10.1016/j.jaci.2012.01.038DOI Listing
May 2012

Efficacy and tolerability of salmeterol/fluticasone propionate versus fluticasone propionate in asthma patients: a randomized, double-blind study.

Chang Gung Med J 2011 Jul-Aug;34(4):382-94

Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkuo, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Background: A combination of salmeterol and fluticasone propionate (SAL/FP) has been shown to be effective in the treatment of asthma. We compared the efficacy and tolerability of SAL/FP (50/250 μg) with fluticasone propionate (FP) 250 μg administrated twice daily for 2 weeks in treating patients with mild to moderate asthma.

Methods: This was a randomized, double-blind study in adult patients with symptomatic asthma that was not controlled by 1000 μg/d inhaled corticosteroids (ICS) alone. 48 asthmatics were randomized to receive 2 inhalations of SAL/FP 50/250 μg bis in die (BID) or 2 inhalations of FP 250 μg BID, both delivered via Accuhaler device, for 2 weeks. The primary objective was the mean change from baseline in the mean morning peak expiratory flow (PEF) over the two week period. Other parameters included lung function, daily asthma symptom scores, evening PEF, percentage of days free of rescue medication use and daily rescue medication use. Tolerability was assessed by adverse events spontaneously elicited at clinic visits.

Results: 46 patients provided evaluable efficacy for analysis. The morning PEF improved significantly throughout the two weeks of treatment compared with baseline in the SAL/FP group. Mean morning PEF was 23.0 L/min higher in SAL/FP group than in FP group (p = 0.013). The change of forced expiratory volume in one second (FEV1) from baseline was greater in SAL/FP group compared to FP group (p = 0.048). There were similar effects on day-time and night-time symptom scores, percentage symptom free days and nights and usage of salbutamol. 70.8% of the patients receiving SAL/FP were satisfied with the treatment, while only 26.1% of patients receiving FP alone were (p = 0.020). No death or acute exacerbation occurred.

Conclusion: SAL/FP 50/250 μg was safe and effective, and had a high level of patient satisfaction resulting in significantly greater increases in morning PEF and FEV1 compared to the use of FP 250 μg alone.
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January 2012

Inadequate antimicrobial treatment for nosocomial infection is a mortality risk factor for systemic lupus erythematous patients admitted to intensive care unit.

Am J Med Sci 2010 Jul;340(1):64-8

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan

Introduction: Infection is a frequent cause of death in patients with systemic lupus erythematous (SLE) admitted to the intensive care unit (ICU). Complicated clinical features of SLE patients may delay or cause inadequate antimicrobial treatment. This study aimed to determine if inadequate antimicrobial treatment is an independent risk factor for mortality in SLE patients in the ICU.

Methods: Fifty-eight SLE patients admitted to the ICU were evaluated in a retrospective analysis. Inadequate antimicrobial treatment was defined by patient receiving antibiotics > or =24 hours after the diagnostic criteria for nosocomial infection and/or the identified microorganism did not exhibit in vitro sensitivity to the antibiotics administered in the ICU.

Results: Multivariate logistic regression analysis identified the risk factors. Thirty-three (56.9%) SLE patients died during their ICU stay. The nonsurvivor group (n = 33), exhibited lower platelet count (P = 0.025), prolonged hospital stay before ICU admission (P = 0.015), higher Acute Physiology and Chronic Health Evaluation II score (P = 0.015), and higher prevalence of multiple organ failure (P = 0.044) and inadequate antimicrobial treatment (P = 0.002) compared with the survivor group (n = 25). In multivariate logistic regression analysis, inadequate antimicrobial treatment was the most significant factor for mortality (odds ratio = 12.02, 95% confidence interval = 1.24-116.10, P = 0.032). Patients with prolonged hospitalization prior ICU admission had a mild risk for mortality (odds ratio = 1.06, 95% confidence interval = 1.00-1.12, P = 0.045).

Conclusions: SLE patients in the ICU receiving inadequate antimicrobial treatment or with prior prolonged hospital stay have a higher risk of mortality. Clinical efforts should ensure adequate antimicrobial treatment in SLE patients with prior prolonged hospital stay before ICU admission.
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http://dx.doi.org/10.1097/MAJ.0b013e3181e0ef9bDOI Listing
July 2010

Erlotinib-associated near-fatal interstitial pneumonitis in a patient with relapsed lung adenocarcinoma.

Chang Gung Med J 2010 Jan-Feb;33(1):100-5

Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Erlotinib (Tarceva) is a human epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor used for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Interstitial lung disease, associated with gefitinib (Iressa) use, has been reported in approximately 1% of patients worldwide. However, the adverse pulmonary effects of erlotinib remain poorly documented. Reviewed English language publications in MEDLINE and PubMed suggest that this report is to be the first case report in English of a histologically-confirmed case of near-fatal interstitial pneumonitis with acute lung injury, associated with erlotinib, in East Asian patients. Physicians are hereby encouraged to promptly evaluate new or worsening pulmonary symptoms so that they can detect early radiographic signs of pulmonary toxicity in patients on erlotinib. If toxicity is confirmed, erlotinib should be discontinued and the patient treated appropriately. The case presented suggests that the outcome of erlotinib-associated pulmonary toxicity with acute respiratory failure may be favorable with adequate early management.
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June 2010

Cross-talk between bradykinin and epidermal growth factor in regulating IL-6 production in human airway smooth muscle cells.

Chang Gung Med J 2010 Jan-Feb;33(1):92-9

Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Background: Bradykinin (BK), a G-protein-coupled-receptor (GPCR) agonist via the B2 receptor induces interleukin (IL)-6 expression in airway smooth muscle (ASM) cells by involving the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. In some cell species, GPCR agonists have been shown to activate the ERK 1/2 pathway via transactivation of epidermal growth factor (EGF) receptor (EGFR). In this study, we tested whether there is cross-talk between BK and EGF in the regulation of IL-6 gene expression in ASM cells.

Methods: ASM cells were treated with BK, EGF, AG-1478 and genistein. IL-6 production was analyzed by enzyme-linked immunosorbent assay (ELISA). Immunoblot study was used for detection of ERK1/2 activation. Transactivation of EGFR phosphorylation was detected by immunoprecipitation.

Results: ELISA showed that EGF (10 ng/ml, 18 hr) increased IL-6 secretion (from 234 +/- 35 to 923 +/- 494 pg/ml, n = 5, p > 0.05), and significantly enhanced BK-induced IL-6 secretion (from 4383 +/- 296 to 8312 +/- 1267 pg/ml, n = 5, p < 0.05) in ASM. Moreover, AG-1478 (2 microM), reduced BK-induced IL-6 secretion by 28% and abrogated the synergic induction of IL-6 induced by BK plus EGF (from 8312 +/- 1267 to 3229 +/- 597 pg/ml, n = 5, p < 0.05). AG-1478 dual effects on IL-6 secretion induced by BK alone or BK plus EGF were also observed in cells treated with genistein, a tyrosine kinase inhibitor, and AG-825, an ErbB-2 inhibitor. Immunoblot analysis demonstrated that AG-1478 had no effect on ERK1/2 activation by BK (1 microM, 10 min). Immunoprecipitation studies showed that BK (1 muM for 2, 5 and 10 min) did not directly transactivate EGFR phosphorylation.

Conclusion: These data show that BK and EGF act in concert to regulate the expression of IL-6 in ASM cells possibly via transcriptional mechanisms involving EGFR-associated key signaling molecules.
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June 2010

Diagnostic value of endobronchial ultrasonography for pulmonary tuberculosis.

J Thorac Cardiovasc Surg 2009 Jul;138(1):179-84

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taipei, Taiwan.

Objectives: We sought to compare the diagnostic yields of acid-fast bacilli smears and Mycobacterium tuberculosis cultures in terms of bronchoalveolar lavage fluid and histologic examination of transbronchial lung biopsy specimens for pulmonary tuberculosis by using bronchoscopy with versus without endobronchial ultrasonography in patients with negative acid-fast bacilli smears or no sputum production.

Methods: From June 2005 to July 2006, a total of 451 patients were given diagnoses of and treated for pulmonary tuberculosis in a university-affiliated hospital. Among them, 121 patients who received bronchoscopy because of sputum-negative conditions were recruited. Of these, 73 patients received bronchoscopy with endobronchial ultrasonography, and 48 patients received conventional bronchoscopy.

Results: Patients who received bronchoscopy with endobronchial ultrasonography had higher diagnostic yields of acid-fast bacilli smears (31.5% vs 12.5%, P = .018) in bronchoalveolar lavage fluid, M tuberculosis in bronchoalveolar lavage fluid (67.1% vs 47.9%, P = .024), and pathologic reports of tuberculosis in transbronchial lung biopsy specimens (32.9% vs 4.2%, P < .0001) than patients who received conventional bronchoscopy. With the aid of endobronchial ultrasonography, the overall diagnostic yield for tuberculosis by using bronchoscopic procedures (smears and cultures of bronchoalveolar lavage fluid and transbronchial lung biopsy specimens) was higher (80.8%) than for those who did not undergo endobronchial ultrasonography (58.3%, P = .035).

Conclusions: The addition of endobronchial ultrasonography to diagnostic bronchoscopy increased the sensitivity for proving the presence of tuberculosis in a population of patients with negative acid-fast bacilli smears or no sputum production.
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http://dx.doi.org/10.1016/j.jtcvs.2009.04.004DOI Listing
July 2009

F-18 FDG PET/CT in pulmonary alveolar proteinosis.

Clin Nucl Med 2009 Feb;34(2):103-4

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.

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http://dx.doi.org/10.1097/RLU.0b013e318192c382DOI Listing
February 2009

Matrix metalloproteinase-1 polymorphism is associated with persistent airway obstruction in asthma in the Taiwanese population.

J Asthma 2009 Feb;46(1):41-6

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.

Background And Objective: Overexpression of matrix metalloproteinase (MMP)-1 has been demonstrated in asthma, and MMP polymorphisms are known to enhance disease susceptibility. We investigated whether MMP-1 polymorphism is associated with persistent airway obstruction in asthma in the Taiwanese population.

Methods: A total of 131 unrelated Taiwanese subjects were enrolled, age-matched, and divided as follows: (1) those who had asthma with persistent airway obstruction with forced expiratory volume in 1 second (FEV(1)) and FEV(1)/forced vital capacity (FVC) values less than 75% predicted (n = 41); (2) those with asthma without airway obstruction with FEV(1) and FEV(1)/FVC values > or = 75% predicted (n = 47); and (3) normal control subjects (n = 43). All were genotyped for the 1G/2G polymorphism of MMP-1 promoter (-1607 bp).

Results: 1G genotypes of MMP-1 containing at least one 1G allele were found in asthmatic patients with persistent airway obstruction (OR = 3.696, 95% CI: 1.489-9.173, p = 0.027), but not in asthmatic patients without airway obstruction (OR = 2.065, 95% CI: 0.890-4.790, p = 0.091) when compared with homozygous 2G (2G/2G). The heterozygous 1G genotype (1G/2G) was more associated with persistent airway obstruction than homozygous 2G (2G/2G) (OR: 4.727, 95% CI: 1.759-12.703, p = 0.012). The adjusted risk estimate of 1G genotypes for asthmatics with persistent airway obstruction was 4.416 (95% CI: 1.651-11.812, p = 0.003).

Conclusion: 1G genotypes of MMP-1 polymorphism are associated with asthma with persistent airway obstruction, and the heterozygous 1G genotype (1G/2G) poses the most susceptibility to persistent airway obstruction in asthma.
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http://dx.doi.org/10.1080/02770900802252077DOI Listing
February 2009