Synergistic effect of phosphodiesterase 4 inhibitor and serum on migration of endotoxin-stimulated macrophages.

Macrophage migration is an essential step in host defense against infection and wound healing. Elevation of cAMP by inhibiting phosphodiesterase 4 (PDE4), enzymes that specifically degrade cAMP, is known to suppress various inflammatory responses in activated macrophages, but the role of PDE4 in macrophage migration is poorly understood. Here we show that the migration of Raw 264.7 macrophages stimulated with LPS was markedly and dose-dependently induced by the PDE4 inhibitor rolipram as assessed by scratch wound healing assay. Additionally, this response required the involvement of serum in the culture medium as serum starvation abrogated the effect. Further analysis revealed that rolipram and serum exhibited synergistic effect on the migration, and the influence of serum was independent of PDE4 mRNA expression in LPS-stimulated macrophages. Moreover, the enhanced migration by rolipram was mediated by activating cAMP/exchange proteins directly activated by cAMP (Epac) signaling, presumably via interaction with LPS/TLR4 signaling with the participation of unknown serum components. These results suggest that PDE4 inhibitors, together with serum components, may serve as positive regulators of macrophage recruitment for more efficient pathogen clearance and wound repair.

Engineering Nanostructural Routes for Enhancing Thermoelectric Performance: Bulk to Nanoscale.

Thermoelectricity is a very important phenomenon, especially its significance in heat-electricity conversion. If thermoelectric devices can be effectively applied to the recovery of the renewable energies, such as waste heat and solar energy, the energy shortage, and global warming issues may be greatly relieved. This review focusses recent developments on the thermoelectric performance of a low-dimensional material, bulk nanostructured materials, conventional bulk materials etc. Particular emphasis is given on, how the nanostructure in nanostructured composites, confinement effects in one-dimensional nanowires and doping effects in conventional bulk composites plays an important role in ZT enhancement.

Surface-dominated transport and enhanced thermoelectric figure of merit in topological insulator Bi(1.5)Sb(0.5)Te(1.7)Se(1.3).

We report the observation of an order of magnitude enhancement of the thermoelectric figure of merit (ZT = 0.36) in topological insulator Bi1.5Sb0.5Te1.7Se1.3 nanowires at 300 K as compared with the bulk specimen (ZT = 0.028). The enhancement was primarily due to an order of magnitude increase in the electrical conductivity of the surface-dominated transport and thermally activated charge carriers in the nanowires. Magnetoresistance analysis revealed the presence of Dirac electrons and determined that the Fermi level was near the conduction band edge. This may be the first thermoelectric measurement of samples with a chemical potential in the gap of a topological insulator without gate tuning, and provides an opportunity to study the contribution of surface states to the Seebeck coefficient and resistivity without concern for the complex effect of band bending.

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

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.

Chronic obstructive pulmonary disease in stage I non-small cell lung cancer that underwent anatomic resection: the role of a recurrence promoter.

BACKGROUND: Despite the use of anatomic resection, the post-surgical recurrence rate remains high in early-stage non-small cell lung cancer (NSCLC). Chronic inflammation plays a role in the mechanism that promotes tumor initiation. This study aimed to investigate the association between recurrence outcome and chronic inflammation-related co-morbidities in early-stage resected NSCLC. METHODS: A review of medical records for recurrence outcome and co-morbidities, in terms of chronic obstructive pulmonary disease (COPD), DM, asthma and cardiovascular diseases, was performed with 181 patients with stage I NSCLC that underwent anatomic resection. RESULTS: Subjects with T descriptors as T2a disease (49.5 vs. 28.0%, p < 0.05) and the presence of COPD (42.4 vs. 20.7%, p < 0.01) had a higher risk of tumor recurrence. Univariate analysis for recurrence-free survival showed T descriptor as T2a (21.5 months vs. NR, p < 0.05) and the presence of COPD (20.5 months vs. NR, p < 0.01) as significant factors predicting reduced survival. The presence of COPD (HR: 1.98; 95% CI, 1.29-.02, p < 0.01) and T descriptor as T2a (HR: 2.01; 95% CI, 1.04-3.91, p < 0.05) remain independent predictors of reduced recurrence-free survival in the Cox regression model. Patients with COPD were at higher risk of brain recurrence (OR: 7.88; 95% CI, 1.50-41.3, p < 0.01). In contrast, patients without COPD showed a tendency toward recurrence in bone and liver (OR: 4.13; 95% CI, 1.08-15.8, p = 0.05). CONCLUSION: Subjects with COPD and T2a disease had a higher risk of recurrence. The role of COPD as a recurrence promoter merits further prospective investigation.

Endobronchial ultrasound-guided transbronchial biopsy and brushing: a comparative evaluation for the diagnosis of peripheral pulmonary lesions.

OBJECTIVES: The diagnosis of peripheral pulmonary lesions (PPLs) often involves endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB), washing and brushing. Certain echoic features of PPL have been associated with biopsy yield. This study compared yields of TBB and bronchial washing (TBBW) with those of TBBW plus bronchial brushing and analysed the associations between clinical and echoic features and yield. METHODS: We performed a retrospective review of 271 patients undergoing TBB for PPL. TBBW was performed in 139 patients and 132 underwent TBBW plus brushing. RESULTS: The diagnostic yield of TBBW plus brushing was superior to that of TBBW (80.3 vs 66.2%, P < 0.01). In TBBW patients, lesions <3 cm (57.1 vs 73.7%, P < 0.05), EBUS probe adjacent to the lesion (47.6 vs 74.2%, P < 0.01), continuous margin (56.5 vs 75.7%, P < 0.01) and homogeneous echogenicity (51.0 vs 75.0%, P < 0.01) predicted lower yields, but adding bronchial brushing rendered the diagnostic yields similar, irrespective of EBUS echoic features, leaving lesion size of <3 cm (odds ratio 2.81; 95% confidence interval 1.08-7.31, P < 0.05) as the single independent predictor of lower yield by multivariate regression analysis. TBB plus brushing was not inferior to TBBW plus brushing (78.8 vs 80.3%, P = 0.88). CONCLUSIONS: Bronchial brushing boosted diagnostic yields, particularly for PPLs with echoic features previously associated with a reduced biopsy yield.

Algorithmic approach by endobronchial ultrasound-guided transbronchial needle aspiration for isolated intrathoracic lymphadenopathy: a study in a tuberculosis-endemic country.

BACKGROUND/PURPOSE: Isolated intrathoracic lymphadenopathy (IT-LAP) is clinically challenging because of the difficult anatomic location and wide range of associated diseases, including tuberculosis (TB). Although sampling via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for histopathology is a major development, there is still room for improvement. This study aimed to investigate an algorithmic approach driven by EBUS-TBNA and conventional bronchoscopy to streamline the management of IT-LAP. METHODS: Eighty-three prospectively enrolled patients with IT-LAP were subjected to an EBUS-TBNA diagnostic panel test (histopathology, cytology, and microbiology) and underwent conventional bronchoscopy for bronchoalveolar lavage. The results were structured into an algorithmic approach to direct patient treatment, workup, or follow-up. RESULTS: The diagnostic yields of EBUS-TBNA based on histopathology were similar for each disease entity: 77.8% for malignancy, 70.0% for TB, 75.0% for sarcoidosis, 80.0% for anthracosis, and 70.0% for lymphoid hyperplasia (p = 0.96). The incidence of malignancy was 10.8% for total IT-LAP patients, and 12.0% and 33.7% for patients with TB and sarcoidosis, respectively. Thirty-five (42.2%) patients were symptomatic. The leading diagnosis was sarcoidosis (60%), followed by TB (20%), malignancy (11.4%), lymphoid hyperplasia (5.7%), and anthracosis (2.9%). By logistic regression analysis, granulomatous disease (odds ratio: 13.45; 95% confidence interval: 4.45-40.67, p < 0.001) was an independent predictor of symptoms. Seven (8.4%) and three (3.6%) IT-LAP patients diagnosed active TB and suggestive of TB with household contact history, respectively, were all placed on anti-TB treatment. CONCLUSION: The algorithmic approach streamlines patient management. It enables early detection of malignancy, correctly places nonmalignant patients on an appropriate treatment regimen, and particularly identifies candidates at high risk of TB reactivation for anti-TB chemoprophylaxis.

Incidence and outcome of healthcare-associated Acinetobacter baumannii in chronically ventilated patients in a tertiary care hospital in Taiwan.

INTRODUCTION: Most studies related to healthcare-associated infection with Acinetobacter baumannii (HAIA) are on acutely ventilated patients. Little is known regarding the incidence and outcomes of HAIA in chronically ventilated patients. METHODS: A retrospective study of chronically ventilated patients covering the period May 2002 to May 2008 was conducted to determine the incidence of patients with HAIA. The Cox proportional hazard model was used to estimate differences in the 30-day mortality between those with and those without HAIA by case-control study after controlling for confounders. RESULTS: Of 240 patients who were chronically ventilated for 49,207 days, 78 (32.5%) acquired HAIA at a rate of 1.59/1,000 patient day. The central venous catheter-related bloodstream infections rate was 8.78 per 1,000 catheter days; the ventilator-associated pneumonia rate was 1.26 per 1,000 ventilator days; and the catheter-associated urinary tract infections rate was 0.17 per 1,000 catheter days. Fifty (64.1%) HAIA and 58 (64.4%) non-HAIA patients were treated well and survived without ICU admission. After univariate and multivariate analyses, prolonged ventilation days (odds ratio: 3.4; 95% confidence interval: 1.7-6.1; P = 0.01] and inappropriate empiric antibiotics within 48 hours (odds ratio: 7.9; 95% confidence interval: 3.9-9.8; P = 0.02) were independent factors that predicted the 30-day mortality of HAIA among chronically ventilated patients. CONCLUSIONS: Although chronically ventilated patients with HAIA have longer ventilator days, higher antibiotics resistance, and high rate per 100 patients of ventilator-associated pneumonia, most patients are treated well. Compared with patients without HAIA, prolonged ventilation days and inappropriate empiric antibiotics within 48 hours are independent factors of the 30-day mortality.

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

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.

Delayed suspicion, treatment and isolation of tuberculosis patients in pulmonology/infectious diseases and non-pulmonology/infectious diseases wards.

BACKGROUND/PURPOSE: Delayed diagnosis and isolation increases the risk of nosocomial transmission of tuberculosis (TB). To assess the risk of delayed management of TB, we analyzed the risk factors of prolonged delay in isolation of smear-positive TB patients in pulmonology/infectious diseases and other wards in a tertiary teaching hospital. METHODS: We enrolled smear-positive TB patients aged > 16 years with delayed respiratory isolation following hospitalization. Medical records were reviewed retrospectively. Time intervals between admission, order of sputum acid-fast staining, initiation of anti-tuberculous treatment and isolation were compared between pulmonology/infectious diseases wards (PIWs) and other wards. Risk factors were analyzed in patients with prolonged isolation delay of > 7 days in individual groups. RESULTS: Isolation was delayed in 191 (73.7%) of 259 hospitalized smear-positive TB patients. Median suspicion, treatment and isolation delays were 0, 3 and 4 days in PIWs and 1, 5 and 7 days in other wards. For patients admitted to non-PIWs, atypical chest radiographs, symptoms without dyspnea or not being admitted from the emergency department (ED) were risk factors for prolonged isolation delay exceeding 7 days. The only risk factor for delayed isolation in patients admitted to PIWs was age >or= 70 years. CONCLUSION: Delays in suspicion, treatment and isolation of TB patients were longer in non-PIWs. Clinicians should be alert to those admitted to non-PIWs with atypical chest radiographs, atypical symptoms, or not admitted from the ED.