Biomedical subjects

Roland Buhl

Publications and source records attributed to Roland Buhl.

33 records · Page 2Linked to original sources

PubMed2004

Increased concentrations of glutathione in induced sputum of patients with mild or moderate allergic asthma.

BACKGROUND: Oxidative stress is involved in the pathogenesis of allergic inflammatory diseases, such as rhinitis and asthma. Glutathione is a vital intracellular and extracellular protective pulmonary antioxidant. It plays a key role in regulating oxidant-induced lung epithelial cell function and also in the control of proinflammatory processes. OBJECTIVE: To quantify oxidative stress in sputum of asthmatic patients compared with healthy subjects. METHODS: We quantified induced sputum supernatant concentrations of total and oxidized glutathione in 20 patients with mild asthma without inhaled corticosteroid treatment, 19 patients with moderate-persistent asthma treated with inhaled corticosteroids (median dose, 900 microg/d of beclomethasone equivalent), and 15 healthy, nonatopic, nonsmoking subjects. RESULTS: Total glutathione levels were significantly increased in mild and persistent asthma compared with healthy subjects [geometric mean (95% confidence interval), 9.2 microM (7.1-12 microM) and 8.7 microM (5.9-12.5 microM) vs 4 microM (2.7-6 microM); P = .039 and .042, respectively]. In contrast, there were no differences in total and oxidized glutathione levels between steroid-naïve and steroid-treated asthmatic patients (P > .20 for all comparisons). Persistent, steroid-treated asthmatic patients had higher sputum counts of neutrophils than steroid-naïve asthmatic patients [geometric mean (95% confidence interval), 35.6% (28.2%-42.7%) vs 17.7% (11.7%-27.1%), P = .04]. There was a positive correlation of total glutathione with sputum total cells (rho = 0.32, P = .02). CONCLUSIONS: Total glutathione is increased in induced sputum of patients with mild and moderate asthma. These data underline the contribution of oxidative stress to the pathogenesis of allergic asthmatic inflammation.

Adolescent↗

PubMed2004

Increased glutathione disulfide and nitrosothiols in sputum supernatant of patients with stable COPD.

STUDY OBJECTIVES: Increased oxidant burden is involved in the pathogenesis of COPD. Glutathione (GSH) is a major antioxidant scavenging reactive oxygen and nitrogen species. We studied the concentrations of total and reduced GSH, glutathione disulfide (GSSG), and nitrosothiols in sputum supernatant of patients with COPD. DESIGN: Twenty-five patients with moderate-to-severe COPD (FEV(1) 61 +/- 12% of predicted) and 25 healthy nonsmoking control subjects underwent sputum induction. Sputum total GSH and GSSG were measured spectrophotometrically, and nitrosothiols were quantified by enzyme assay. Exhaled nitric oxide (eNO) was also measured to correlate eNO with nitrosothiols in induced sputum. MEASUREMENTS AND RESULTS: Compared with healthy subjects, patients with COPD had increased sputum neutrophils (geometric mean, 65%; 95% confidence interval [CI], 57.5 to 71; vs 21%; 95% CI, 13.2 to 31.6; p < 0.001); total GSH (geometric mean, 7.1 micromol/L; 95% CI, 2.95 to 17; vs 5.1 micromol/L; 95% CI, 3.2 to 8.1; p = 0.024); GSSG (geometric mean, 4.1 micromol/L; 95% CI, 1.7 to 10; vs 0.84 micromol/L; 95% CI, 0.35 to 1.99; p = 0.002); and nitrosothiols (geometric mean, 60.4 micromol/L; 95% CI, 40 to 95.5; vs 38 micromol/L; 95% CI, 31.6 to 43.6; p = 0.04). Sputum GSSG was positively correlated with neutrophils (rho = 0.47, p = 0.016) and nitrosothiols (rho = 0.49, p = 0.024) in patients with COPD, whereas there was no correlation of eNO with nitrosothiols (rho = 0.38, p = 0.1). CONCLUSIONS: Sputum concentrations of GSSG and nitrosothiols are increased in patients with COPD and associated with neutrophilic inflammation. These data underline the role of oxidative stress in the pathogenesis of COPD, and suggest that GSH is important to scavenge both reactive oxygen and nitrogen species.

Adult↗

PubMed2004

Current and future pharmacologic therapy of exacerbations in chronic obstructive pulmonary disease and asthma.

Exacerbations are an important cause of the morbidity and mortality associated with asthma and chronic obstructive pulmonary disease. Newer therapies include long-acting beta(2)-agonists, which are more effective than short-acting bronchodilators. Inhaled corticosteroids and, in asthma, leukotriene receptor antagonists may have roles in the early phase of exacerbation as an alternative to or added to oral prednisolone. In the future, combinations of long-acting beta(2)-agonists and anticholinergic bronchodilators may offer additive clinical benefits. However, although the treatment and prevention of exacerbations of chronic obstructive pulmonary disease and asthma have been improved by using combinations of known therapies, further research addressing the underlying etiology as well as molecular and pathophysiologic mechanisms of exacerbation is needed to better target novel therapies to the appropriate patient populations and to develop new therapeutic strategies.

Adrenal Cortex Hormones↗

PubMed2003

Synthesis and preliminary evaluation of (R,R)(S,S) 5-(2-(2-[4-(2-[(18)F]fluoroethoxy)phenyl]-1-methylethylamino)-1-hydroxyethyl)-benzene-1,3-diol ([(18)F]FEFE) for the in vivo visualisation and quantification of the beta2-adrenergic receptor status in lung.

The (18)F-labeled beta2-adrenergic receptor ligand (R,R)(S,S) 5-(2-(2-[4-(2-[(18)F]fluoroethoxy)phenyl]-1-methylethylamino)-1-hydroxyethyl)-benzene-1,3-diol, a derivative of the original highly selective racemic fenoterol, was synthesized in an overall radiochemical yield of 20% after 65 min with a radiochemical purity higher than 98%. The specific activity was in the range of 50-60 GBq/micromol. In vitro testing of the non-radioactive fluorinated fenoterol derivative with isolated guinea pig trachea was conducted to obtain an IC(50) value of 60 nM. Preliminary ex vivo organ distribution and in vivo experiments with positron emission tomography (PET) on guinea pigs were performed to study the biodistribution as well as the displacement of the radiotracer to prove specific binding to the beta2-receptor.

Animals↗

PubMed2003

SeroGRID: an improved method for the rapid selection of antigens with disease related immunogenicity.

Screening of cDNA expression libraries derived from human tumors with autologous sera (SEREX) permits the definition of immunogenic antigens in individual cancer patients. However, only a minority of SEREX-derived cDNA clones show a clear cancer-relatedness in the sense that circulating autoantibodies to them occur exclusively in the sera of tumor patients but not in healthy individuals. Evaluation of multiple SEREX-defined clones in serological assays using panels of allogeneic sera from cancer patients as well as appropriate control groups is an important step towards focussing on the relevant antigens. This in turn is the basis for defining disease parameters of diagnostic and prognostic significance.Here, we show that seroreactivity of multiple SEREX-derived antigens can be simultaneously evaluated using a rapid and versatile high throughput procedure, which we call SeroGRID.

Antigens, Neoplasm↗

PubMed2003

Dissimilarity between seasonal changes in airway responsiveness to adenosine-5'-monophosphate and methacholine in patients with grass pollen allergic rhinitis: relation to induced sputum.

BACKGROUND: In patients with allergic rhinitis, bronchial hyperresponsiveness (BHR) and airway inflammation may increase during pollen exposure. BHR can be assessed by adenosine-5'-monophosphate (AMP) or methacholine challenge. It has been suggested that BHR to AMP is more closely related to airway inflammation than BHR to methacholine. Seasonal allergic rhinitis offers a dynamic model to study changes in BHR and airway inflammation during natural allergen exposure. METHODS: We measured BHR [provocative concentration causing a 20% fall (PC(20)) in forced expiratory volume in 1 s (FEV(1))] to AMP and methacholine, and induced sputum cells in 16 rhinitis patients before and during the 2001 grass pollen season. RESULTS: There was a decrease in PC(20) methacholine during pollen exposure (geometric mean PC(20) from 3.22 to 1.73 mg/ml, p = 0.0023), whereas no reduction was observed for PC(20) AMP (p = 0.11). There was no increase in sputum eosinophils [pre: 0.69% (95% confidence interval 0.22-2.07); during: 1.85 (0.55- 5.6), p = 0.31]. Although the correlation of log PC(20) methacholine and log PC(20) AMP at baseline was good (r = 0.76, p = 0.001), individual seasonal changes (doubling concentrations) in PC(20) methacholine were not correlated with changes in PC(20) AMP (rho = 0.21, p = 0.44). There was no correlation between baseline log PC(20) methacholine or seasonal changes in PC(20) methacholine and sputum eosinophils (p > 0.12, all correlations). In contrast, there was a significant correlation between seasonal changes in PC(20) AMP and changes in sputum eosinophils (rho = -0.59, p = 0.025). CONCLUSIONS: These data show dissimilarity between seasonal changes in PC(20) AMP and methacholine in patients with seasonal allergic rhinitis. Moreover, PC(20) AMP seems to be more closely related to sputum eosinophils than PC(20) methacholine. The clinical significance of this discrepancy is unclear.

Adenosine Monophosphate↗

PubMed2003

Long-term repeatability of induced sputum cells and inflammatory markers in stable, moderately severe COPD.

STUDY OBJECTIVES: Neutrophilic inflammation is a major feature of COPD. Induced sputum is increasingly used to monitor inflammatory airway diseases. Although short-term repeatability of selected sputum markers has been extensively studied in several populations, data on the long-term repeatability of induced sputum markers in stable COPD are scant. DESIGN: Sputum supernatant of 12 patients with stable COPD was analyzed on three separate occasions with 4-weekly intervals. Sputum cells and inflammatory markers interleukin (IL)-8 and soluble intercellular adhesion molecule (sICAM)-1 were measured in supernatant using enzyme-linked immunosorbent assay. Repeatability of sputum markers was expressed by intraclass correlation coefficients (Ri). MEASUREMENTS AND RESULTS: Sputum induction was safe in all patients. None of the sputum parameters analyzed changed significantly throughout the study. The repeatability for cell differential counts in stable COPD was as follows: total cells, Ri = 0.07; neutrophils, Ri = 0.66; macrophages, Ri = 0.47; eosinophils, Ri = 0.49; and lymphocytes, Ri = 0.58. The repeatability of soluble markers was as follows: IL-8, Ri = 0.50; and sICAM, Ri = 0.58. Sputum neutrophils were negatively correlated with lung function on each separate occasion, whereas soluble markers were not correlated with sputum cells (p > 0.16, all correlations) or lung function (p > 0.24, all correlations). CONCLUSIONS: Clinically stable, moderate COPD is associated with equally stable sputum inflammatory markers. Repeatability of induced-sputum markers of neutrophilic inflammation in stable COPD is satisfactory, even over extended periods of time. These data support the usefulness of serial monitoring of induced-sputum inflammatory markers in COPD.

Analysis of Variance↗

PubMed2003

Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4.

STUDY OBJECTIVES: Neutrophilic inflammation is a major feature of COPD. Several factors in bronchial secretions have been identified as chemoattractants for neutrophils. The present study was designed to assess the contribution of interleukin (IL)-8 and leukotriene B(4) (LTB(4)) to neutrophil chemotaxis evoked by sputum obtained from patients with established COPD. DESIGN: Sputum supernatant of 20 patients with COPD was used as chemoattractant in a 96-well chemotaxis chamber, with subsequent quantification of migrated cells by a luminescence assay. The contribution of IL-8 and LTB(4) to chemotaxis was determined by addition of a neutralizing antibody and a selective receptor antagonist, respectively. MEASUREMENTS AND RESULTS: COPD sputum caused neutrophil chemotaxis in a concentration-dependent manner, with a maximum response evoked with a 10-fold dilution of the original sample. Pretreatment of sputum or neutrophils with either an anti-IL-8 antibody or the LTB(4) antagonist, SB 201146, led to a concentration-dependent inhibition of sputum-induced neutrophil chemotaxis, with a maximum suppression (mean +/- SEM) of 29.2 +/- 4.9% (p < 0.001) from baseline by 100 ng/mL of anti-IL-8 antibody, and 45.6 +/- 7% (p < 0.02) by 10 micro mol/L of SB 201146. The combination of the anti-IL-8 antibody and SB 201146 inhibited neutrophil chemotaxis, but this was not significantly greater than the effect of SB 201146 or anti-IL-8 alone. CONCLUSIONS: These data confirm the importance of IL-8 and LTB(4) as chemoattractants for neutrophils in bronchial secretions from patients with COPD, and suggest that specific inhibitors may have therapeutic potential in COPD.

Acrylates↗

PubMed2003

Budesonide/formoterol for the treatment of asthma.

Budesonide/formoterol (Symbicort), AstraZeneca plc) is a novel treatment for asthma, combining an inhaled corticosteroid - budesonide, and a long-acting beta(2)-agonist - formoterol, in a single inhaler, the Turbuhaler. Randomised, clinical studies in patients with asthma have demonstrated that budesonide/formoterol is more effective than the inhaled corticosteroids, budesonide and fluticasone alone, and at least as effective as both monocomponents in separate inhalers. Results from clinical studies suggest a synergistic effect when both drugs are administered via one inhaler, although the mechanisms for this are not fully understood. Budesonide/formoterol has a rapid onset of effect, apparent within 1 min of treatment, which is largely because of the properties of formoterol. Once- and twice-daily dosing with budesonide/formoterol are effective treatment options for patients with mild or moderate asthma. Studies have also shown that the beneficial safety profiles and dose relationships of both budesonide and formoterol allow dose adjustments of budesonide/formoterol in response to variations in the patient's asthma. Findings from the budesonide/formoterol adjustable maintenance dosing programme, comparing fixed and adjustable, symptom-guided dosing regimens, demonstrate that patients achieve equally good asthma control with adjustable dosing (from one inhalation twice-daily to more than four inhalations twice-daily), but at a significantly lower overall drug load. Adverse events, mainly expected inhaled corticosteroid and long-acting beta(2)agonist class effects, have been few in number and mild in nature. In addition, there is growing evidence that budesonide/formoterol is also effective in patients with chronic obstructive pulmonary disease. The future for treatment with budesonide/formoterol may include as-needed administration in addition to maintenance therapy.

Anti-Asthmatic Agents↗

PubMed2003

Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications.

PURPOSE: The tyrosine-kinase receptor c-kit and its ligand stem cell factor are coexpressed in many small cell lung cancer (SCLC) cell lines, leading to the hypothesis that this coexpression constitutes an autocrine growth loop. To further evaluate the frequency and pathogenic relevance of c-kit expression, tumor tissue together with the corresponding clinical data of SCLC patients was analyzed. EXPERIMENTAL DESIGN: Tumor tissue of 102 consecutive SCLC cancer patients was analyzed immunohistochemically using an affinity-purified polyclonal c-kit antibody. Immunostaining data were correlated with survival and other relevant clinical parameters. RESULTS: A positive c-kit expression was observed in 37% of patients. c-kit expression was associated with decreased survival in the likelihood-ratio-forward selection model of the Cox regression including clinically relevant risk factors (c-kit expression, age, gender, stage, tumor stage, node stage, metastasis stage, weight loss, performance status, response to chemotherapy, lactate dehydrogenase, neuronspecific enolase, hemoglobin). Only c-kit expression [hazard ratio, 2.00; confidence interval (CI), 1.17-3.41; P = 0.012], response to chemotherapy (hazard ratio, 4.49; CI, 2.36-8.55; P < 0.001), and tumor stage (hazard ratio, 2.11; CI, 1.18-3.74; P = 0.008) were explanatory prognostic factors. These factors and all possible interactions between them were further analyzed in a second Cox regression model. As expected, response to chemotherapy had the highest impact on survival (hazard ratio, 3.06; CI, 1.69-5.54; P < 0.001). In patients with extensive disease, minor response to chemotherapy, and positive c-kit expression, the risk to die increased to 8.4 (hazard ratio, 2.74; CI, 1.52-4.91; P = 0.002). In a Kaplan-Meier analysis median survival of patients with minor response to chemotherapy and extensive stage was 288 days (CI, 255-321 days) when c-kit expression was negative compared with only 71 days (CI, 0-237 days) for c-kit-positive patients (log rank test: P = 0.003). CONCLUSIONS: c-kit represents a new prognostic factor in SCLC. c-kit expression is of particular clinical relevance in patients with advanced disease and poor response to chemotherapy. Given the very limited therapeutic options and unfavorable prognosis of these patients, clinical studies aimed at targeting c-kit (e.g., STI571) are clearly warranted.

Aged↗

PubMed2003

Neutrophilic inflammation in induced sputum of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology. Biopsy and bronchoalveolar lavage studies have shown, that accumulation of inflammatory cells, particularily neutrophils, in the alveolar space is a relevant feature of the pathogenesis of IPF. This paper adresses the issue of whether the safe and non-invasive method of sputum induction is a suitable tool to study respiratory tract inflammation in IPF. METHODS: In a cross-sectional analysis, 15 IPF patients and 14 healthy, non-smoking subjects underwent sputum induction. Total sputum cell counts, differentials, and the amount of interleukin (IL)-8, granulocyte-macrophage-colony stimulating factor (GM-CSF), and soluble ICAM-1 (sICAM) in sputum supernatant were analyzed. RESULTS: IPF patients had increased sputum neutrophils (60 +/- 6 vs 22 +/- 3%, p = 0.0003), and supernatant concentrations of IL-8 (19 +/- 3 vs. 7 +/- 1 ng/ml, p = 0.0002), GM-CSF (205 +/- 43 vs. 122 +/- 36 pg/ml, p = 0.08) and sICAM (12 +/- 3 vs. 5 +/- 3 ng/ml, p = 0.01), when compared with healthy controls. Sputum IL-8 was correlated with sputum neutrophils (rho = 0.61, p = 0.0006) in all patients. The extent of sputum neutrophilia was also correlated with lung function impairment (vital capacity, % of predicted) in IPF patients (rho = -0.68, p = 0.007). CONCLUSION: These data confirm the established role of neutrophilic inflammation in the pathogenesis of IPF, and show the potential of induced sputum to directly study inflammatory processes and surrogate markers in interstitial lung diseases like IPF.

Adult↗

PubMed2002

Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer--what limits limited disease?

Small cell lung cancer (SCLC) is usually classified into a two-stage system, limited (LD) and extensive disease (ED). However, the criteria for these two categories remain controversial. The widely used Veterans Administration Lung Study Group (VALG) definition of LD includes patients with primary tumor and nodal involvement limited to one hemithorax. In contrast, the International Association for the Study of Lung Cancer (IASLC) recommends that LD should additionally include all patients without distant metastasis. As a consequence, since treatment modalities for LD and ED could be different, individual clinical outcome of SCLC patients may be influenced by the staging system chosen. Among 109 consecutive SCLC patients treated in our clinic between 1989 and 1999 (mean age 68+/-9.1 years, 81% male) 23 patients (21%) could be either classified as LD or ED (LD-ED), depending on the staging system used. The prognosis of this overlapping group (LD-ED: median survival 291 days) was not statistically different from patients with limited disease defined by VALG criteria (LD-VALG: 385 days, log-rank test P = 0.42). On the other hand the survival difference between LD-ED patients and the ED-IASLC population was relevant (ED-IASLC: 208 days, P = 0.05), indicating that LD-ED patients should rather be included in the LD category. This is further supported by the results of a multivariate Cox regression analysis with all clinically relevant data. Only stage as defined by IASLC criteria was an independent prognostic factor in the likelihood-ratio-forward (hazard ratio = 1.94, CI = 1.26-2.99; P = 0.005) and backward model (hazard ratio = 1.76, CI: 1.12-2.76; P = 0.012), confirming the higher discriminatory power of the IASLC definition. In conclusion, the IASLC staging criteria for SCLC patients have a higher prognostic impact and are therefore preferable in clinical practice and future therapeutic trials.

Aged↗

PubMed2002

Pulmonary dysfunction in non-cirrhotic patients with chronic viral hepatitis.

Background: Hepatopulmonary syndrome (HPS), defined as hypoxemia and functional intrapulmonary right-to-left shunts in the presence of chronic liver disease, is a frequent complication of end-stage liver disease. The aim of this study was to determine the extent of pulmonary dysfunction and the prevalence of HPS in non-cirrhotic patients with chronic viral hepatitis. Methods: Lung function tests were carried out in 178 patients with chronic viral hepatitis (mean age 43.2 years, 95 smokers). To demonstrate intrapulmonary shunting, contrast echocardiography was performed in all patients with hypoxemia (paO(2)<70 mmHg) or a reduced diffusion capacity (DLCO<70% predicted). Results: The median results of lung function parameters (FVC, FEV(1), FEV(1)/FVC, TLC, DLCO, and blood gas analysis) were normal. Despite normal lung function, hypoxemia and/or DLCO reduction were observed in 17 of 178 patients (9.6%). A correlation with inflammatory activity, extent of fibrosis, or etiology was not found. Intrapulmonary shunting was observed in three of 17 patients. Two of these patients fulfilled the diagnostic criteria of HPS. Conclusions: Impaired gas exchange is a common finding even in non-cirrhotic patients with chronic viral hepatitis. HPS, however, was present in 1.1% of patients with chronic viral hepatitis and is thus not restricted to patients with liver cirrhosis, portal hypertension, or acute liver failure.

Journal Article↗

PubMed2002

Anticholinergics in the treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in the world. In the majority of cases, the disease is the result of years of cigarette smoking. Contributing factors leading to bronchial obstruction in COPD include mucus hypersecretion and an increase in bronchial muscle tone, which is triggered mainly by cholinergic mechanisms. Anticholinergic bronchodilators reduce vagal cholinergic tone, the main reversible component of COPD; hence they are the first-line treatment for bronchial obstruction in COPD. In addition to improving lung function, anticholinergics improve dyspnea, quality of life and exercise tolerance, and they reduce exacerbations. When compared with other bronchodilators, anticholinergics show at least equivalent bronchodilator potency, but with fewer side effects. In addition, due to their unique site of action, anticholinergics can be effectively combined with other bronchodilators. The introduction of new, long-acting anticholinergics is a promising addition to the treatment of COPD and is expected to lead to improved treatment outcomes and improved patient compliance.

Adrenergic beta-Agonists↗

PubMedDate not supplied

c-kit expression in adenocarcinomas of the lung.

The tyrosine-kinase receptor c-kit (CD117) and its ligand stem cell factor are considered to be co-expressed in various solid tumors, including adenocarcinomas of the lung. The frequency of c-kit expression and its association with clinical parameters has not yet been evaluated in a larger population of lung adenocarcinomas. Therefore, tumor tissue of 95 consecutive patients with adenocarcinoma of the lung was stained using a polyclonal c-kit antibody. c-kit expression was correlated with relevant clinical parameters obtained by chart review. Positive c-kit expression in tumor tissue was observed in 61 of 95 patients (64%). Univariate analysis showed a significant effect of T (p = 0.003), N (p = 0.001) and M stage (p < 0.001) as well as of performance status (p = 0.001), surgical resection (p < 0.001), and LDH serum levels (p = 0.016) on survival. In contrast, c-kit protein expression was non- significant (p = 0.913). However, multivariate Cox regression with the influential parameters revealed a significant effect of c-kit expression on survival. Forward stepwise selection showed a 1.77-fold increased risk to die (hazard ratio, HR; 95% confidence interval, CI: 1.00-3.14, p = 0.047) for patients with c-kit-positive tumors. Similar data for c-kit expression were obtained by backward stepwise selection (HR: 1.78; 95% CI: 1.00-3.16; p = 0.044). In conclusion, the receptor tyrosine kinase c-kit is frequently expressed in adenocarcinomas of the lung and has a relevant effect on patient survival. The results of this study support clinical trials targeting the c-kit receptor with specific c-kit inhibitors (e.g. imatinib).

Adenocarcinoma↗