Neuron-specific enolase as a novel biomarker reflecting tuberculosis activity and treatment response.

BACKGROUND/AIMS: It is not clear which tests are indicative of the activity and severity of tuberculosis (TB). This study aimed to investigate the predictive value of neuron-specific enolase (NSE) and to determine the origin of NSE in TB patients. METHODS: A single-center retrospective analysis was conducted on newly diagnosed TB patients between January and December 2010. Patients were categorized into one of two disease groups (focal segmental or extensive) based on chest X-ray. Pre- and post-treatment NSE concentrations were evaluated. To determine the origin of serum NSE concentration, NSE staining was compared with macrophage-specific CD68 staining in lung tissues and with a tissue microarray using immunohistochemistry and immunofluorescence. RESULTS: A total of 60 newly diagnosed TB patients were analyzed. In TB patients, NSE serum concentration was significantly increased and NSE level decreased after treatment (p < 0.001). In proportion to serum high-sensitivity C-reactive protein concentration, the mean serum concentration of NSE in the extensive group (25.12 ng/mL) was significantly higher than that in the focal segmental group (20.23 ng/mL, p = 0.04). Immunohistochemical staining revealed a large number of macrophages that stained positively for both NSE and CD68 in TB tissues. In addition, NSE signals mostly co-localized with CD68 signals in the tissue microarray of TB patients. CONCLUSIONS: Our results suggest that NSE may be a practical parameter that can be used to monitor TB activity and treatment response. Elevated serum NSE level originates, at least in part, from macrophages in granulomatous lesions.

In vivo real-time imaging of airway dynamics during bronchial challenge test.

BACKGROUND AND OBJECTIVE: Asthmatic patients exhibit airway hyper-responsiveness, which induces bronchoconstriction and results in a ventilation defect. The bronchial challenge test using methacholine is a useful way to measure airway hyper-responsiveness with airway constriction. Anatomical optical coherence tomography has been used to image airway hyper-responsiveness of medium sized bronchus with the aid of an endoscopic probe. Recently, a thoracic window was reported that allows direct visualization of terminal airway such as alveolus. A multi-scale integrated airway dynamics was assessed in this study. We imaged in vivo changes in the right intermedius bronchus and alveolar structure during the bronchial challenge test using two optical coherence tomography systems and correlated the changes with airway resistance. MATERIALS AND METHODS: Rabbits intubated with a non-cuffed endotracheal tube on a ventilator sequentially inhaled normal saline and methacholine (2 or 5 µg/ml). The airway resistance was measured by mechanical ventilation and airway structures were monitored by a commercial endoscopic optical coherence tomography system (1,310 nm) and a house-made table-top spectral-domain optical coherence tomography system (850 nm). RESULTS: We demonstrated an early decrease in the size of the right intermedius bronchus and alveoli in accordance with increased airway resistance after methacholine inhalation. OCT image after inhalation of 2 µg/ml methacholine showed some segmental narrowing of the right intermedius bronchus and the image after inhalation of 5 µg/ml methacholine showed even greater segmental narrowing. The cross-sectional areas were 7.2 ± 3.3 mm2 (normal saline), 3.7 ± 2.1 mm2 (2 µg/ml methacholine), and 2.4 ± 1.1 mm2 (5 µg/ml methacholine), respectively (P = 0.04). Most of the alveolar space was collapsed under elevated airway resistance with methacholine inhalation. The averaged areas per alveolus at the end of inspiration were 0.0244 ±0.0142 mm2 (normal saline), 0.0046 ±0.0026 mm2 (2 µg/ml methacholine), and 0.0048 ±0.0028 mm2 (5 µg/ml methacholine), respectively (P = 0.03). Methacholine induced a dose-dependent increase in airway resistance (1.1 ± 0.3 cm H2O sec/ml for 2 µg/ml methacholine, 1.5 ± 0.5 cm H2O sec/ml for 5 µg/ml methacholine) (P = 0.03). These results were obtained from normal rabbits during the bronchial challenge test with a non-cuffed endotracheal tube on a ventilator. With this setup increased airway resistance possibly resulted in larger leakage around the endotracheal tube, decreased inhaled volumes, and, in turn, alveolar collapse. CONCLUSION: We performed a feasibility study of in vivo visualization of real-time airway dynamics. To our best knowledge, this is the first report of real-time integrated airway dynamics including the right intermedius bronchus and alveoli during a bronchial challenge test. OCT showed bronchial constriction and alveolar collapse with a higher methacholine dose. OCT images correlated with the measured airway resistance. Therefore, OCT could be a potential diagnostic device for airway hyper-responsiveness and airway remodeling.

Titanium dioxide exposure induces acute eosinophilic lung inflammation in rabbits.

Titanium dioxide (TiO2) is increasingly widely used in industrial, commercial and home products. TiO2 aggravates respiratory symptoms by induction of pulmonary inflammation although the mechanisms have not been well investigated. We aimed to investigate lung inflammation in rabbits after intratracheal instillation of P25 TiO2. One ml of 10, 50 and 250µg of P25 TiO2 was instilled into one of the lungs of rabbits, chest computed-tomography was performed, and bronchoalveolar lavage (BAL) fluid was collected before, at 1 and 24 h after P25 TiO2 exposure. Changes in inflammatory cells in the BAL fluids were measured. Lung pathological assay was also carried out at 24 h after P25 TiO2 exposure. Ground glass opacities were noted in both lungs 1 h after P25 TiO2 and saline (control) instillation. Although the control lung showed complete resolution at 24 h, the lung exposed to P25 TiO2 showed persistent ground glass opacities at 24 h. The eosinophil counts in BAL fluid were significantly increased after P25 TiO2 exposure. P25 TiO2 induced a dose dependent increase of eosinophils in BAL fluid but no significant differences in neutrophil and lymphocyte cell counts were detected. The present findings suggest that P25 TiO2 induces lung inflammation in rabbits which is associated with eosinophilic inflammation.

Over-expression of thymosin ß4 in granulomatous lung tissue with active pulmonary tuberculosis.

Recent studies have shown that thymosin ß4 (Tß4) stimulates angiogenesis by inducing vascular endothelial growth factor (VEGF) expression and stabilizing hypoxia inducible factor-1α (HIF-1α) protein. Pulmonary tuberculosis (TB), a type of granulomatous disease, is accompanied by intense angiogenesis and VEGF levels have been reported to be elevated in serum or tissue inflamed by pulmonary tuberculosis. We investigated the expression of Tß4 in granulomatous lung tissues at various stages of active pulmonary tuberculosis, and we also examined the expression patterns of VEGF and HIF-1α to compare their Tß4 expression patterns in patients' tissues and in the tissue microarray of TB patients. Tß4 was highly expressed in both granulomas and surrounding lymphocytes in nascent granulomatous lung tissue, but was expressed only surrounding tissues of necrotic or caseous necrotic regions. The expression pattern of HIF-1α was similar to that of Tß4. VEGF was expressed in both granulomas and blood vessels surrounding granulomas. The expression pattern of VEGF co-localized with CD31 (platelet endothelial cell adhesion molecule, PECAM-1), a blood endothelial cell marker, and partially co-localized with Tß4. However, the expression of Tß4 did not co-localize with alveolar macrophages. Stained alveolar macrophages were present surrounding regions of granuloma highly expressing Tß4. We also analyzed mRNA expression in the sputum of 10 normal and 19 pulmonary TB patients. Expression of Tß4 was significantly higher in patients with pulmonary tuberculosis than in normal controls. These data suggest that Tß4 is highly expressed in granulomatous lung tissue with active pulmonary TB and is associated with HIF-1α- and VEGF-mediated inflammation and angiogenesis. Furthermore, the expression of Tß4 in the sputum of pulmonary tuberculosis patients can be used as a potential marker for diagnosis.

New model of subconjunctival tumor development in rabbits.

Conjunctival squamous cell carcinoma (SCC) is an uncommon disease. However, SCC has recently become an important clinical problem due the identification of a significantly high incidence of SCC among a group of black African patients with AIDS. However, basic research concerning SCC, including both intraepithelial and invasive squamous neoplasia, is limited due to the lack of an ocular tumor animal model. Specifically, current ocular imaging and treatment modalities are insufficient for investigating currently available small animal models, because the conjunctival space is not comparable to that of humans. We describe the development of a reproducible model of subconjunctival squamous carcinoma in moderate-sized immunocompetent rabbits. Under optical coherence tomography guidance, 1×107 VX2 carcinoma cells are inoculated into the subconjunctival space of 3 to 4-kg New Zealand white rabbits. Malignant tumor involvement developed on the subconjunctival space after an average of 1 to 2 weeks. This subconjunctival tumor model induction method will likely facilitate a broad range of investigation of subconjunctival cancer diagnostics and therapeutics.

Thymosin ß4 and its degradation product, Ac-SDKP, are novel reparative factors in renal fibrosis.

Previously, we found thymosin ß4 (Tß4) is upregulated in glomerulosclerosis and required for angiotensin II-induced expression of plasminogen activator inhibitor-1 (PAI-1) in glomerular endothelial cells. Tß4 has beneficial effects in dermal and corneal wound healing and heart disease, yet its effects in kidney disease are unknown. Here we studied renal fibrosis in wild-type and PAI-1 knockout mice following unilateral ureteral obstruction to explore the impact of Tß4 and its prolyl oligopeptidase tetrapeptide degradation product, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), in renal fibrosis. Additionally, we explored interactions of Tß4 with PAI-1. Treatment with Ac-SDKP significantly decreased fibrosis in both wild-type and PAI-1 knockout mice, as observed by decreased collagen and fibronectin deposition, fewer myofibroblasts and macrophages, and suppressed profibrotic factors. In contrast, Tß4 plus a prolyl oligopeptidase inhibitor significantly increased fibrosis in wild-type mice. Tß4 alone also promoted repair and reduced late fibrosis in wild-type mice. Importantly, both profibrotic effects of Tß4 plus the prolyl oligopeptidase inhibitor, and late reparative effects of Tß4 alone, were absent in PAI-1 knockout mice. Thus, Tß4 combined with prolyl oligopeptidase inhibition is consistently profibrotic, but by itself has antifibrotic effects in late-stage fibrosis, while Ac-SDKP has consistent antifibrotic effects in both early and late stages of kidney injury. These effects of Tß4 are dependent on PAI-1.

Lung cancer probably related to talc exposure: a case report.

Industrial talc has been widely circulated in the world for a long time. The pure talc has little effects on humans, but inhalation of talc contaminated with asbestos can causes severe asbestos-related diseases such as lung cancer and malignant mesothelioma. Herein, we represent a case of lung cancer after occupational exposure to industrial talc in the rubber manufacturing industry.

Successful treatment of a tracheal squamous cell carcinoma with a combination of cryoablation and photodynamic therapy.

Malignant tumors of the trachea are rare, and account for less than 0.1% of all malignancies. Because there are no guidelines based on randomized clinical trials, the choice of treatment modalities and optimal sequences have not yet been established. In most cases of malignant airway obstruction, a single modality is chosen as the treatment of choice for management, but complete ablation becomes increasingly problematic with minimal residual lesions that require additional treatment. There were few case reports of the combined use of cryoablation and photodynamic therapy to treat tracheal cancer. Therefore, we present our experience of successful tracheal cancer treatment using this combination therapy. A bronchoscopic complete regression was obtained using these two modalities, and the procedures proved to be a safe and effective treatment option based on a one-year follow-up.