Yu-Chin Lee

IV Delivery of Induced Pluripotent Stem Cells Attenuates Endotoxin-Induced Acute Lung Injury in Mice

BACKGROUND Induced pluripotent stem (iPS) cells are novel stem cell populations, but the role of iPS cells in acute lung injury (ALI) is not currently known. We investigated the effect of iPS cells in modifying the pathophysiology of endotoxin-induced ALI. METHODS Male C57BL/6 8- to 12-week-old mice were enrolled in this study. Mouse iPS cells were delivered through the tail veins of mice 4 h after intratracheal instillation of endotoxin. Lung histopathologic findings, the pulmonary levels of cytokines, and functional parameters were analyzed after either 24 h or 48 h. RESULTS More iPS cells integrated into the lungs of mice with ALI than those of the control mice, as demonstrated by in vivo radionuclide imaging and in vitro Hoechst-labeled fluorescent staining. iPS cells significantly diminished the histopathologic changes of ALI and the lung injury score. There was also a significant reduction in the activity of nuclear factor-κB (NF-κB) and neutrophil accumulation in the lung, confirmed by immunostaining, electrophoretic mobility shift assays, and the decrease of myeloperoxidase activity, in the iPS-cell-treated mice with ALI. These protective effects were not replicated by the control cell therapy with fibroblasts. iPS cells mediated a downregulation of the proinflammatory response to endotoxin (reducing tumor necrosis factor-α, IL-6, and macrophage inflammatory peptide-2). In addition, iPS cells rescued the hypoxemia and pulmonary function of ALI. Treatment with a conditioned medium of iPS cells showed effects similar to those of iPS cells, which may suggest the therapeutic benefits of iPS mediated by paracrine factors. CONCLUSIONS IV delivery of iPS cells provides a beneficial effect to attenuate the severity of endotoxin-induced ALI and improve physiologic impairment, which is partly mediated by a reduction in NF-κB activity and neutrophils accumulation. The conditioned medium of iPS cells demonstrated effects equal to those of iPS cells.

Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD

The anti-inflammatory effects of salmeterol/fluticasone (SFP), tiotropium/fluticasone (Tio+FP) and tiotropium (Tio) alone were investigated on the inflammatory cells and mediators in sputum induced from chronic obstructive pulmonary disease patients. Subjects were either newly diagnosed or had not taken any medication for 3 months prior to the study. Subjects (n = 99) were randomised (not double blinded) and received either SFP (100/1,000 μg daily), Tio+FP (18/1,000 μg daily) or Tio (18 μg daily) for 12 weeks. Induced sputum and serum C-reactive protein (CRP) were analysed prior to and at the end of treatment. The results showed that treatment with SFP caused a significant reduction in interleukin (IL)-8 and matrix metalloprotease (MMP)-9 in induced sputum, compared with treatment with Tio alone. There were no treatment differences between the SFP and Tio+FP groups in decreasing IL-8 and MMP-9 levels. The reduction in IL-8 showed significant association with the reduction in MMP-9. All treatment groups failed to significantly reduce the numbers of total cells, neutrophils, macrophages and eosinophils in induced sputum; in addition, there were no treatment differences in terms of improvement of forced expiratory volume in one second, forced vital capacity, CRP or quality of life between the three groups. The anti-inflammatory effects of salmeterol/fluticasone probably contribute to the clinical benefits seen in chronic obstructive pulmonary disease patients.

Spontaneous breathing trial needs to be prolonged in critically ill and older patients requiring mechanical ventilation

PURPOSE To investigate a modified weaning procedure to predict extubation outcome in critically older and ventilated patients. METHODS We retrospectively analyzed extubation outcome in older (≥ 70 years) and ventilated patients. In period I (2007), patients passing a 2-hour spontaneous breathing trial (SBT) were extubated. In period II (2008), patients underwent an 8-hour SBT on day 1 and a 2-hour SBT, followed by extubation on day 2. Weaning parameters were recorded at baseline (T(0)) (periods I and II), 2 and 8 (T(8)) hours after SBT (period II). RESULTS The demographic data of patients in each period (n = 64 and 67, respectively) were similar. Patients in period II demonstrated a higher rate of SBT failure but a significantly lower rate of extubation failure and reintubation mortality. In period II, successfully extubated patients demonstrated a significantly lower value of rapid shallow breathing index (RSBI) at T(8). The ratio of RSBI at T(8) over T(0) (T(8)/T(0) ≤ 1.4) demonstrated good diagnostic value (sensitivity 89.5%, specificity 80.0%, accuracy 88.4%) in predicting successful extubation. CONCLUSIONS For critically older and ventilated patients, a prolonged SBT in conjunction with evolution of the RSBI ratio over baseline during SBT may serve as a useful procedure to predict extubation outcome.

Decoy Receptor 3 Levels in Peripheral Blood Predict Outcomes of Acute Respiratory Distress Syndrome

RATIONALE Acute respiratory distress syndrome (ARDS), a serious inflammatory reaction to acute lung injury, is associated with high mortality rates. Decoy receptor (DcR) 3 is a soluble protein with immunomodulatory effects. Biomarkers that reliably predict outcomes in ARDS are not currently available. OBJECTIVES Comparing DcR3 with the Acute Physiology and Chronic Health Evaluation (APACHE) II scores and three other plasma markers to explore the association of DcR3 and the clinical outcome in ARDS. METHODS Eighty-eight patients with ARDS were studied. Baseline APACHE II scores and clinical data were recorded. Plasma levels of DcR3, soluble triggering receptor expressed on myeloid cells (sTREM)-1, tumor necrosis factor (TNF)-alpha, and IL-6 were measured on Day 1 and later time points, and correlated with the survival status on Day 28 after the onset of ARDS. For validation, 59 patients with ARDS from another medical center were studied. MEASUREMENTS AND MAIN RESULTS Among the biomarkers evaluated, only DcR3 discriminated the survivors and nonsurvivors at all time points in the first week of ARDS. DcR3 independently associated with and best predicted the 28-day mortality of patients with ARDS. Plasma DcR3 levels most correlated to multiple-organ dysfunction and ventilator dependence. Compared with survivors, the nonsurvivors had higher DcR3 levels regardless of the APACHE II scores. Kaplan-Meier survival analysis showed higher mortality in patients with ARDS with higher DcR3 levels. The outcome prediction of patients with ARDS by plasma DcR3 levels was recapitulated by the validation cohort. CONCLUSIONS High plasma DcR3 levels correlate with development of multiple-organ dysfunction and independently predict the 28-day mortality in patients with ARDS.

Sleep Apnea and Risk of Deep Vein Thrombosis: A Non-randomized, Pair-matched Cohort Study

BACKGROUND Patients with sleep apnea have been reported to be associated with increased prevalence of deep vein thrombosis (DVT) in some papers, which were criticized for either a small sample size or lack of a prospective control. Our study strived to explore the relationship of sleep apnea and the subsequent development of DVT using a nationwide, population-based database. METHODS From 2000 to 2007, we identified a study cohort consisting of newly diagnosed sleep apnea cases in the National Health Insurance Research Database. A control cohort without sleep apnea, matched for age, sex, comorbidities, major operation, and fractures, was selected for comparison. The 2 cohorts were followed-up, and we observed the occurrence of DVT by registry of DVT diagnosis. RESULTS Of the 10,185 sampled patients (5680 sleep apnea patients vs. 4505 control), 40 (0.39%) cases developed DVT during a mean follow-up period of 3.56 years, including 30 (0.53%) from the sleep apnea cohort and 10 (0.22 %) from the control group. Subjects with sleep apnea experienced a 3.113-fold (95% confidence interval, 1.516-6.390; P=.002) increase in incident DVT, which was independent of age, sex, and comorbidities. Kaplan-Meier analysis also revealed the tendency of sleep apnea patients toward DVT development (log-rank test, P=.001). The risk of DVT was even higher in sleep apnea cases who needed continuous positive airway pressure treatment (hazard ratio 9.575; 95% confidence interval, 3.181-28.818; P <.001). CONCLUSION Sleep apnea may be an independent risk factor for DVT.

Additive benefits of tiotropium in COPD patients treated with long-acting β2 agonists and corticosteroids

Objective and background:  The addition of an alternative class of long‐acting bronchodilator is recommended for COPD patients who do not respond satisfactorily to monotherapy. The aim of this study was to investigate the additive benefit of tiotropium in severe COPD and to establish whether the improvement in lung function in these patients can be predicted from their acute bronchodilator response to ipratropium or salbutamol.

Bile Acid Aspiration in Suspected Ventilator-Associated Pneumonia

AIMS The aims of this study were to measure the levels of bile acids in patients with suspected ventilator-associated pneumonia (VAP) and provide a possible pathway for neutrophilic inflammation to explain its proinflammatory effect on the airway. METHODS Bile acid levels were measured by spectrophotometric enzymatic assay, and liquid chromatography mass spectrometry was used to quantify the major bile acids. Alveolar cells were grown on modified air-liquid interface culture inserts, and bile acids were then employed to stimulate the cells. Reverse transcriptase polymerase chain reaction and Western blots were used to determine the involved gene expression and protein levels. RESULTS The mean (+/- SE) concentration of total bile acids in tracheal aspirates was 6.2 +/- 2.1 and 1.1 +/- 0.4 mumol/L/g sputum, respectively, for patients with and without VAP (p < 0.05). The interleukin (IL)-8 level was significantly higher in the VAP group (p < 0.05). The major bile acid, chenodeoxycholic acid, stimulated alveolar epithelial cells to increase IL-8 production at both the messenger RNA and protein level through p38 and c-Jun N-terminal kinase (JNK) activation. The selective p38 and JNK inhibitors, as well as dexamethasone, successfully inhibited IL-8 production. CONCLUSION These data suggest that early intervention to prevent bile acid aspiration may reduce the intensity of neutrophilic inflammation in intubated and mechanically ventilated patients in the ICU.

Role of 2-month sputum smears in predicting culture conversion in pulmonary tuberculosis

Sputum smears and culture conversion are frequently used to evaluate treatment response in pulmonary tuberculosis patients. Limited data are available on the evaluation of the correlation between under-treatment sputum smear results and culture conversion. This prospective study included sputum culture-proven pulmonary tuberculosis patients at six hospitals in Taiwan. At least two sets of sputum were collected at the completion of 8 weeks of TB treatment. The sensitivities and specificities of 2-month sputum smears were estimated based on culture conversion status. A total of 371 patients were enrolled for analysis. Factors associated with culture conversion included having a smear positive before treatment, presence of a cavity on radiography, rifampicin resistance and usage of the DOTS (directly observed therapy, short course) strategy. The sensitivities of 2-month sputum smears for culture conversion among all patients, initially smear-positive patients and initially smear-negative patients were 64.3, 71.4 and 38%, respectively, and the specificities were 81.6, 69.9 and 92.8%, respectively. In patients who were 2-month sputum smear-positive, the 2-month culture conversion rate was 80% if the patients were under DOTS and without cavitary lesions in radiograms. The predictive value of 2-month sputum smears in culture conversion was limited and highly influenced by clinical factors in pulmonary tuberculosis patients.

Plasma soluble vascular endothelial growth factor receptor-1 levels predict outcomes of pneumonia-related septic shock patients: a prospective observational study

IntroductionDespite recent advances in the management of septic shock, mortality rates are still unacceptably high. Early identification of the high-mortality risk group for early intervention remains an issue under exploration. Vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR1) and urokinase plasminogen activator (uPA) have diverse effects in the pathogenesis of sepsis, which involve pro-inflammation, anti-inflammation, endothelial cell repair, and vascular permeability change. Their roles in predicting mortality and organ dysfunction remain to be clarified.MethodsPneumonia-related septic shock patients from medical intensive care units were enrolled for this prospective observational study. We also included 20 patients with pneumonia without organ dysfunction for comparison. Plasma levels of VEGF and sVEGFR1 and uPA activity within 24 hours of shock onset were measured. We compared plasma levels of these biomarkers with APACHE II scores between subgroups of patients, and evaluated their predictive value for 28-day mortality and organ dysfunction.ResultsA total of 101 patients, including 81 with pneumonia-related septic shock and 20 with pneumonia without organ dysfunction, were enrolled. Non-survivors of septic shock had significantly higher plasma sVEGFR1 levels (659.3 ± 1022.8 vs. 221.1 ± 268.9 pg/mL, respectively, P < 0.001) and uPA activity (47.2 ± 40.6 vs. 27.6 ± 17.2 units, respectively, P = 0.001) when compared with those of the survivors. Kaplan-Meier survival analysis demonstrated significantly higher mortality in patients with higher levels of sVEGFR1 (P < 0.001) and uPA activity (P = 0.031). In Cox regression analysis, plasma sVEGFR1 level was independently associated with, and best predicted, the 28-day mortality of septic shock (HR: 1.55, 95% CI: 1.05-2.30). Plasma sVEGFR1 level and uPA activity had good correlation with renal dysfunction, metabolic acidosis, and hematologic dysfunction; their levels significantly increased when the number of organ dysfunctions increased. In multivariate analysis, plasma sVEGFR1 level (HR: 2.82, 95% CI: 1.17-6.81) and uPA activity (HR: 2.75, 95% CI: 1.06-7.13) were independent predictors of the presence of concomitant multi-organ dysfunction. The predictive value of VEGF for mortality and organ dysfunction was limited in pneumonia-related septic shock patients.ConclusionsHigh plasma sVEGFR1 level in the early stage of pneumonia-related septic shock independently predicted 28-day mortality and multi-organ dysfunction.

Gender differences in treatment outcomes of tuberculosis patients in Taiwan: a prospective observational study

Gender disparities in tuberculosis (TB) cases are reported worldwide, and socio-cultural factors have been proposed as possible causes. To date, gender differences in treatment outcomes of TB patients remain controversial. In this prospective observational study, newly diagnosed, culture-proven TB patients from six hospitals in Taiwan were enrolled for analysis. Gender differences in demographic characteristics and treatment outcomes, including sputum conversion and on-treatment mortality, were analysed accordingly. From January 2007 through to December 2009, a total of 1059 patients were enrolled, including 819 (77.3%) males and 240 (22.7%) females. The ratio of male gender was around 50 ~ 60% in TB patients below 35 years and >80% for those older than 65 years. When compared with the female patients, the male patients were older, more likely to have the habit of smoking, chronic obstructive pulmonary disorder, malignancy and liver cirrhosis, and more likely to present with haemoptysis, body weight loss and pleural effusion. Regarding treatment outcomes, male gender is associated with a lower 2-month sputum culture conversion rate (78.8% vs. 89.3%, p 0.002) and higher on-treatment mortality (21.1% vs. 12.1%, p 0.002). Kaplan-Meier survival analysis demonstrated significantly higher mortality in the men (p 0.005). In multivariate analysis, male gender was an independent risk factor for 2-month sputum culture un-conversion (OR, 1.96; 95% CI, 1.12-3.41). Our findings suggest that male gender is associated with older age, more co-morbidities and worse treatment outcomes. Gender-specific strategies, including active case finding in elderly women and smoking cessation in male patients, are warranted to optimize TB management.