The roles of transforming growth factor-ß1 and vascular endothelial growth factor in the tracheal granulation formation.

BACKGROUND: Acquired tracheal stenosis is common in patients with a long-term tracheostomy and granulation is one of the most commonly observed lesions in benign airway stenosis. The aim of this study was to investigate the mechanisms of tracheal granulation formation and find the potential therapeutic targets to prevent the granulation formation. RESULTS: In granulation tissue obtained from patients during interventional bronchoscopy for the relief of airway obstruction, increased expression of transforming growth factor (TGF)-ß1 and vascular endothelial growth factor (VEGF), as well as increased numbers of fibroblasts, was found by immunohistochemical staining. TGF-ß1 expression was detected in both the epithelial and submucosal layers. The highest levels of VEGF and vimentin expression occurred in the submucosal layers. In comparison with the control, significantly increased numbers of small vessels were observed in the submucosal layers of the granulation tissue. In vitro, TGF-ß1 stimulated production of VEGF by cultured fibroblasts at both the mRNA and protein level. VEGF siRNA treatment resulted in a significant decrease of TGF-ß1-induced VEGF production. SIS3, a selective Smad3 inhibitor, and UO126 both inhibited p44/42 MAP kinase phosphorylation and attenuated subsequent VEGF production by fibroblasts. A low concentration of erythromycin (1 µg/ml), but not dexamethasone (100 µM), inhibited TGF-ß1-induced VEGF production. CONCLUSION: This study provides important information that facilitates an understanding, at least in part, of the mechanisms of granulation formation. Targeting these mediators and cells may help to prevent the formation of granulation tissue in long-term tracheostomy or prolonged endotracheal intubation patients.

Budesonide/formoterol combination as a maintenance and rescue therapy: physicians' perspectives.

BACKGROUND: To investigate the rationale of clinicians when treating asthmatics with combined budesonide/formoterol in a single inhaler as a maintenance and rescue therapy (BFMRT). METHODS: A questionnaire was used to investigate, from the perspective of outpatient clinic physicians, why, how, and for whom BFMRT should be prescribed. Participants (N = 274) were employed in medical centers, regional hospitals, district hospitals, and private clinics; the majority of the clinicians were pulmonologists (75.5%). RESULTS: Most participants (84.9%) prescribed BFMRT primarily because of its convenience; 60.4% prescribed 1 puff (budesonide/formoterol, 160/4.5 microg/puff) twice daily and as needed and 38.5% 2 puffs twice daily and as needed; 70.4% did not insist that patients use budesonide/formoterol as a rescue treatment. There was no agreement on the dose (1 or 2 puffs as needed) or interval (5, 10, or 20 min) required for rescue treatment. Almost half (48.2%) of the physicians reported that they would not prescribe BFMRT because of patients' lack of understanding of the treatment. Further analysis showed that physicians practicing in medical centers, those specializing in chest medicine, and those working in higher socioeconomic regions may appreciate the benefits of BFMRT more than non-pulmonologists, those working in settings other than medical centers, and those employed in lower socioeconomic areas. CONCLUSIONS: More effort needs to be expended in the education of physicians responsible for asthma management, non-pulmonologists, those working outside of medical centers, and those practicing in rural areas in new treatment concepts to achieve optimal asthma control throughout the country.

Clinical impact of Mycobacterium tuberculosis W-Beijing genotype strain infection on aged patients in Taiwan.

The impact of W-Beijing genotype Mycobacterium tuberculosis on treatment outcome was evaluated in 249 newly diagnosed tuberculosis patients. No significant difference in the treatment outcome was found between the W-Beijing and non-W-Beijing groups. However, a poor outcome was more common in the elderly patients (>or=65 years) infected with the W-Beijing strain.

Bile acids induce CCN2 production through p38 MAP kinase activation in human bronchial epithelial cells: a factor contributing to airway fibrosis.

BACKGROUND AND OBJECTIVE: Bile acid aspiration occurs in a variety of acute and chronic airway disorders. The consequence of bile acid aspiration and lung disease remains unclear. It was hypothesized that airway epithelium exposure to bile acids would induce fibrosis via production of connective tissue growth factor (CCN2), CCN2 is essential for transforming growth factor-beta (TGFbeta)-induced fibrogenesis and functions as a downstream mediator of TGF-beta action on fibroblasts. METHODS: Human bronchial epithelial cells were grown on air-liquid interface culture inserts. Cells were stimulated with the major components of bile acids, chenodeoxycholic acid (CD) and glycochenodeoxycholic acid (GCD). RT-PCR and real-time quantitative PCR were used to detect mRNA expression. ELISA and western blotting were used to measure protein. RESULTS: CD-stimulated airway epithelial cells produce CCN2 at both mRNA and protein levels in a dose-dependent manner. GCD failed to increase CCN2 production. CCN2 expression occurred via activation of p38 mitogen-activated protein (MAP) kinase and the downstream transcription factor ATF-2. Dexamethasone and the selective p38 MAP kinase inhibitor SB203580 successfully inhibited p38 MAP kinase, ATF-2 phosphorylation and subsequent CCN2 production. CD induced TGF-beta1 release from airway epithelium via the same signalling pathway. TGF-beta1 therefore enhanced CCN2production in an autocrine manner. CONCLUSION: Early intervention to stop these processes may be useful in preventing fibrogenesis in chronic airway diseases associated with bile acid exposure.

Basal cell carcinoma of the nipple-areola complex: a case report.

Basal cell carcinoma (BCC) of the nipple-areola complex is very rare. Only 24 cases were reported in the literature and 17 (70.8%) of these cases arose in men. Most of the cases were treated with simple excision. We report on a case of BCC of the nipple-areola complex in a 46-year-old woman, treated with partial mastectomy. Metastasis to the axillary lymph nodes had been noted in 3 (12.5%) of the 24 reported cases of BCC of the nipple-areola complex. Thus, we applied the concept of the sentinel lymph node to detect possible metastases of axillary lymph nodes, letting us avoid the unnecessary axillary lymph node dissection and possible future morbidity.

Preliminary report of using FDG-PET to detect extrapelvic lesions in cervical cancer patients with enlarged pelvic lymph nodes on MRI/CT.

PURPOSE: To evaluate, in a prospective study, the effects of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) on the detection of extrapelvic lesions, the design of whole pelvis or extended field radiotherapy, and subsequent failure patterns for patients with cervical cancer and enlarged pelvic lymph nodes (LNs) shown on MRI or CT. METHODS AND MATERIALS: Between April and December 2001, 19 consecutive patients underwent an additional FDG-PET examination before concurrent chemoradiotherapy. The inclusion criteria for the study were at least one enlarged pelvic LN > or =10 mm in its maximal dimension as shown on radiologic images and no extrapelvic tumors detected by conventional examination. The PET findings of the primary tumor, pelvic LNs, and extrapelvic lesions were investigated and compared with the MRI/CT findings. Tumor FDG uptake was quantitated with the maximal pixel standardized uptake value. RESULTS: Except for 1 patient with diabetes mellitus who was excluded from analysis, 18 cervical tumors had significant FDG uptake (maximal pixel standardized uptake value >8). A total of 39 pelvic LNs were reported, and the agreement of positive pelvic LNs between MRI/CT and PET was 79.5%. Five patients (28%) had positive paraaortic LNs on FDG-PET, and their treatment fields were extended to include the paraaortic region. In addition to the paraaortic LNs, 1 patient also had metastasis at the left supraclavicular node. After a minimum follow-up of 12 months (median 15.9), 4 patients (22.2%) developed new extrapelvic metastases. The disease-free survival rate was 78% at 12 months. CONCLUSION: FDG-PET is a useful tool to detect paraaortic LN metastasis and determine the appropriate treatment field for cervical cancer with enlarged pelvic LNs on MRI/CT. The preliminary data suggest that pretreatment FDG-PET can supplement conventional imaging studies, but still has limitations in the detection of microscopic disease.

Imaging early-stage corticobasal degeneration with [99mTc]TRODAT-1 SPET.

AIM: The aim of this study was to investigate the nigrostriatal dopaminergic function in patients with corticobasal degeneration (CBD) using [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2',S2,S2']oxo-[1R-(exo-exo)]-[99mTc]technetium ([99mTc]TRODAT-1) brain single-photon emission tomography (SPET). METHODS: Five patients with probable CBD, 10 age- and duration-matched patients with idiopathic Parkinson's disease (IPD) and 10 age-matched healthy volunteers completed the SPET study. The images were obtained 4 h after intravenous injection of 925 MBq of [99mTc]TRODAT-1. Using a magnetic resonance imaging atlas of the striatum, the ratios of specific striatal binding to non-specific occipital binding were calculated. RESULTS: Clinical analysis showed that the CBD patients obtained significantly higher scores on the Unified Parkinson's Disease Rating Scale and a significantly worse score for activities of daily living. In the CBD and IPD groups, striatum-occipital/occipital, caudate nucleus-occipital/occipital and putamen-occipital/occipital ratios decreased significantly relative to those of healthy subjects. No statistical difference could be found between the CBD and IPD groups for these ratios, although relatively even, decreased uptakes in the caudate nucleus and putamen were found in the CBD group. On further analysis of the index of binding reduction, the differences between the caudate nucleus and putamen were significantly lower in the CBD group than in the IPD group. The striatal uptake of [99mTc]TRODAT-1 showed a distinct asymmetry in both the CBD and IPD patients. CONCLUSION: From this study, it can be concluded that early-stage CBD patients have a worse performance and more difficulties with daily activities than IPD patients. CBD patients demonstrated essentially similar patterns of [99mTc]TRODAT-1 binding as those with IPD. However, there was relatively more homogeneous involvement of the caudate nucleus and putamen in the CBD patients. This provides information about the differences between these patients in the early stages.

Lymphoscintigraphy and intraoperative gamma probe-directed sentinel lymph node mapping in patients with malignant melanoma.

BACKGROUND AND PURPOSE: Lymphoscintigraphy has been considered a useful tool for sentinel lymph node (SLN) mapping for malignant melanoma. This study evaluated the usefulness of SLN detection by lymphoscintigraphy and excision with intraoperative gamma probe in Taiwanese patients with malignant melanoma. METHODS: Thirty six malignant melanoma patients in clinical stage I and II were enrolled. The Breslow thickness of the primary melanomas was /= 4 mm in 3 patients, and unknown in 4 patients who were transferred from other hospitals and had no nodal or distant metastasis. SLN lymphoscintigraphy was performed with filtered 99mTc-sulfur colloid. An intraoperative gamma probe was used to identify the SLN for dissection. RESULTS: A total of 44 SLNs were detected in 36 patients, with a mean of 1.22 SLNs per patient. The SLN detection rate by lymphoscintigraphy was 100%. During surgery, 39 of the 44 SLNs (88.6%) in 33 of 36 patients (91.7%) were identified. SLN metastasis was found in 8 of 39 dissected SLNs (20.5%) or in 8 of 36 patients (22.2%). The SLN metastatic rate in the patients with primary melanoma with Breslow thickness 2.0 mm was 41.7% (5/12). CONCLUSIONS: Lymphoscintigraphy and intraoperative gamma probe are useful in localizing and dissecting SLN in patients with malignant melanoma. SLN mapping changed the clinical stage in 22.2% of melanoma patients.

The value of Tc-99m red blood cell SPECT in differentiating giant cavernous hemangioma of the liver from other liver solid masses.

PURPOSE: Giant cavernous hemangioma (GCH) of the liver has the potential risk for rupture and bleeding, which may cause sudden death. The purpose of this retrospective study was to compare the value of Tc-99m-labeled red blood cell (RBC) SPECT with ultrasound (US) in differentiating GCH from other solid liver masses. METHODS: Twenty-two patients with giant solid liver masses, equal to or greater than 8 cm in at least one dimension, identified by US were examined by Tc-99m RBC SPECT. Final diagnoses were based on findings of surgery, biopsy or follow-up by US for a minimum of 24 months after the scan. RESULTS: In all, US detected 23 giant liver masses in 22 patients (3 men, 19 women). Eighteen GCHs were detected in 17 patients by Tc-99m RBC SPECT. Nine showed a homogeneously increased blood pool; 9 revealed peripheral high, but central low, uptake. The US patterns in these 18 GCHs were mixed-echoic in 12, hyperechoic in 4, and hypoechoic in 2. The other five large liver tumors, all proved by operation, had no increased uptake area with Tc-99m RBC SPECT. The US patterns of these were mixed-echoic in 3, hyperechoic in 1, and hypoechoic in 1. CONCLUSIONS: Our study showed that there was no specific US pattern that would differentiate GCHs from other giant liver masses. Tc-99m RBC SPECT appeared to separate them clearly.

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.

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.

The impact of image fusion in resolving discrepant findings between FDG-PET and MRI/CT in patients with gynaecological cancers.

This study was performed to prospectively investigate the impact of image fusion in resolving discrepant findings between fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) or X-ray computed tomography (CT) in patients with gynaecological cancers. Discrepant findings were defined as lesions where the difference between the FDG-PET and MRI/CT images was assigned a value of at least 2 on a 5-point probability scale. The FDG-PET and MRI/CT images were taken within 1 month of each other. Image fusion between FDG-PET and CT was performed by automatic registration between the two images. During an 18-month period, 34 malignant lesions and seven benign lesions from 32 patients who had undergone either surgical excision or a CT-guided histopathological investigation were included for analysis. Among these cases, image fusion was most frequently required to determine the nature and/or the extent of abdominal and pelvic lesions (28/41, 68%), especially as regards peritoneal seeding (8/41, 20%). Image fusion was most useful in providing better localisation for biopsy (16/41, 39%) and in discriminating between lesions with pathological versus physiological FDG uptake (12/41, 29%). Image fusion changed the original diagnosis based on MRI/CT alone in 9/41 lesions (22%), and the original diagnosis based on FDG-PET alone in 5/41 lesions (12%). It led to alteration of treatment planning (surgery or radiotherapy) in seven of the 32 patients (22%). In patients with gynaecological cancers, the technique of image fusion is helpful in discriminating the nature of FDG-avid lesions, in effectively localising lesions for CT-guided biopsy and in providing better surgical or radiotherapy planning.