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Biomedical subjects

R M Huber

Publications and source records attributed to R M Huber.

At least 19 recordsLinked to original sources
PubMed2006

Bronchial hyperreactivity is correlated with increased baseline airway tone.

Physiologically, airways are not completely relaxed but maintain a baseline airway tone (BAT). Although not fulfilling the criteria for obstructive airway disease, increased BAT may nevertheless be important because the same amount of airway narrowing can be well tolerated or can cause severe airway obstruction depending on the starting point of the narrowing. In this study, we aimed at studying if BAT is correlated with bronchial hyperreactivity (BHR). For in vitro studies, airways in murine lung slices were digitally recorded and the change in cross-sectional area with time was quantified. BAT was measured by the amount of relaxation induced by permeabilization of the cell membrane with beta-escin in zero external calcium. BHR was induced by incubation of lung slices with interleukin-13 (IL-13). T-bet knock-out mice served as an additional model for BHR. T-bet knock-out mice show a shift towards TH2-lymphocytes and display histological as well as functional characteristics of asthma. In vivo, the specific airway resistance of healthy non-smoking volunteers was assessed before and after inhalation of formoterol and bronchial challenge was performed using methacholin. In murine lung slices that had been cultivated without serum, only a minimal BAT could be observed. But, after cultivation with 10 % new born calve serum, airways showed a BAT of approximately 13 % that could be reduced by incubation with an IL-13 receptor antagonist. Atropine, isoproterenol and indomethacin failed to relax airways regardless of cultivation with serum. Incubation of lung slices without serum but with IL-13 increased BAT as well as airway responsiveness to acetylcholine and both effects were more pronounced in small compared to large airways. In lung slices from T-bet knock-out mice, airways were hyperreactive compared to airways in slices from wild type mice and BAT was found to be increased. Again, both effects were more pronounced in small compared to large airways. In human non-smokers without airway obstruction, increased BAT was correlated with bronchial hyperreactivity. We therefore conclude that although not fulfilling the criteria for obstructive airway disease, increased airway tone may yet be relevant in asthma.

Acetylcholine↗
PubMed2006

Efficacy of a toxicity-adjusted topotecan therapy in recurrent small cell lung cancer.

The present prospective multicentre trial investigated whether topotecan, given at a starting dose of 1.25 mg.m(-2) with individual dose adjustment, can improve safety in patients with relapsed/refractory small cell lung cancer without loss of efficacy. Patients received topotecan intravenously on days 1-5, every 21 days, for up to six courses. In the absence of relevant haematotoxicities, topotecan was increased to 1.5 mg.m(-2) and reduced to 1.0 mg.m(-2) in case of severe haematotoxicities. Of 170 recruited patients, 73.2% had stage IV disease and 63.4% had platinum-containing pre-treatment. Patients received a total of 521 courses. In 72.6% of those courses, the dose remained at 1.25 mg.m(-2); in 9.1% it was reduced and in 18.3% it increased. Overall response rate was 14.1% including one complete response; 28.8% had stable disease. Median duration of response was 13.6 weeks and median survival was 23.4 weeks. Clinical benefit was obvious for sensitive as well as for refractory patients. Haematotoxicity of grade 3 or 4 was clearly lower compared with the standard dose of 1.5 mg.m(-2). In conclusion, topotecan at a dose of 1.25 mg.m(-2) appears to be as effective as the dose of 1.5 mg.m(-2), but with reduced toxicity. Since patients with recurrent small cell lung cancer have a poor prognosis, they benefit especially from good tolerability.

Aged↗
PubMed2006

[Lung cancer].

Although various benign and malignant tumors can occur in the bronchi and lungs, lung cancer is by far the most common tumor and the leading cause of tumor death worldwide. For therapeutic reasons lung cancer is classified currently as small cell (SCLC) or non small cell lung cancer (NSCLC). The main cause is smoking. There are no specific symptoms that enable early detection. Staging is according to the international TNM-system. As the results of therapy to date are disappointing and many questions remain unsolved, as many patients as possible should be included in further prospective trials. In SCLC polychemotherapy is mandatory; in local tumor stages radiotherapy should be combined early on with chemotherapy, and in cases of complete remission, prophylactic cranial irradiation is indicated. In operable stages of NSCLC adjuvant chemotherapy demonstrates a survival benefit. In locally advanced NSCLC, radiochemotherapy is now the standard of care. Advanced stages require chemotherapy usually with two drugs, second-line chemotherapy is indicated in cases of relapse.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

[Ca2+-signaling in smooth muscles cells of the airways in T-bet knock-out mice].

BACKGROUND: Airway smooth muscle cells (ASMC) play a key role in bronchial hyperresponsiveness (BHR). A major component of the signalling cascade leading to ASMC contraction is calcium. T-bet knock-out (KO) mice show the key features of allergic asthma such as a shift towards T (H2)-lymphocytes and display a broad spectrum of asthma-like histological and functional characteristics. In this study, we aimed at investigating whether Ca (2+)-homeostasis of ASMC is altered in T-bet KO-mice as an experimental model of asthma. METHODS: Lung slices of 100 to 200 microm thickness were obtained from T-bet KO- and wild-type mice. Airway contractions in response to acetylcholine (ACH) were measured by video-microscopy and Ca (2+)-signaling in single ASMC of lung slices was assessed using two-photon microscopy. RESULTS: Airways from T-bet KO-mice showed increased baseline airway tone (BAT) and BHR compared to those of wild-type mice. The increased BAT was correlated with an increased incidence of spontaneous changes in intracellular Ca (2+)-concentrations, whereas BHR correlated with higher ACH-induced Ca (2+)-transients and an increased proportion of ASMC showing Ca (2+)-oscillations. Emptying intracellular Ca (2+)-stores using caffeine or cyclopiazonic acid induced higher Ca (2+)-elevations in ASMC from T-bet KO compared to wild-type mice. CONCLUSIONS: Altered Ca (2+)-homeostasis of ASMC contributes to increased BAT and BHR in lung slices from T-bet KO mice as a murine asthma model. We propose that a higher Ca (2+)-content of the intracellular Ca (2+)-stores is involved in the pathophysiology of these changes.

Animals↗
PubMed2006

Place of cryotherapy, brachytherapy and photodynamic therapy in therapeutic bronchoscopy of lung cancers.

Cryotherapy, brachytherapy and photodynamic therapy (PDT) are three different methods proposed in the endoluminal treatment of lung cancers. The current article presents an overview of the specific indications and limits of each technique. These three methods were first proposed with palliative intent in inoperable patients with centrally located lung cancers. Now, the best indication is a curative intent in early stage lung cancers. Of the three, cryotherapy is the cheapest method. It induces cell necrosis in a 3-mm radius around the probe, and is suitable for treatment of superficial tumours. However, clinical trials are limited. In contrast, many clinical studies have confirmed the efficacy of PDT in treatment of superficial lung cancers. Brachytherapy can cure more aggressive tumours with deeper invasion into the bronchial wall. Unfortunately, no comparative studies have been published. Each of these methods induces a delayed tumour necrosis, and thus neither is indicated in the treatment of obstructive tumours with acute dyspnoea. In many situations, these methods should be complementary, particularly cryotherapy and brachytherapy or PDT and brachytherapy. The combination of these endoscopic methods with chemotherapy should be widely tested to promote the adjuvant role of the endoscopic methods in the treatment of lung cancers.

Animals↗
PubMed2005

Monitoring of expiratory flow rates and lung volumes during a high altitude expedition.

BACKGROUND: Data on lung volumes and changes in flow-volume spirometry at high altitude are few and do not provide comprehensive assessment of the occurring changes. This study characterizes alterations of the forced expiratory flow-volume curve (FEFV-curve) and lung volumes at increasing altitude. METHODS: FEFV-curve and lung volumes at increasing altitude were characterized by daily assessment of peak expiratory flow (PEF), forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and maximal expiratory flow rates (MEF 25, 50, 75) at 25%, 50% and 75% of the FEFV-curve with a portable spirometer (turbinometric method) three times a day during an expedition to Mustagh Ata (7545m) in 15 healthy mountaineers. RESULTS: With increasing altitude FVC and FEV1 were reduced by up to 25% (74.8% / 74.6% of baseline) and MEF25 was reduced to 81.5% of baseline values. PEF initially increased up to 4451m and returned to baseline values above 5000m. After descent below 2000m, all values normalized within one day. There were weak negative correlations between AMSS and FEV1, FVC and PEF (r = -0.23, p<0.001). CONCLUSIONS: We found increasing pulmonary restriction at high altitude without a marked reduction of PEF. Assessment of the FEFV-curve at high altitudes with a portable spirometer is a practical method reflecting the true field situation and may provide clinically relevant information (impending pulmonary edema).

Adult↗
PubMed2005

Cost-effectiveness analysis of budesonide/formoterol compared with fluticasone in moderate-persistent asthma.

In this economic evaluation, conducted alongside a randomized, double-blind clinical trial, economic data were collected from 339 patients with moderate-persistent asthma randomized to receive twice-daily, double-blind treatment with budesonide/formoterol 160/4.5 microg in a single inhaler (n=166) or fluticasone propionate 250 microg (n=173) for 12 weeks. The mean number of episode-free days (EFD) per patient was significantly greater in the budesonide/formoterol group than the fluticasone group (48.71 compared with 42.34, P=0.0185). Data on medication use, visits to healthcare professionals, and hospitalization were pooled across all six countries and combined with German and Dutch unit cost data to calculate total healthcare costs. Using German unit costs, budesonide/formoterol was associated with significantly lower total healthcare costs per patient over the 12-week period compared with fluticasone (euro 131 compared with euro 210, P=0.0043). Using Dutch unit costs, total healthcare costs were slightly numerically lower in the budesonide/formoterol group than the fluticasone group (euro 102 compared with euro 104), but the difference did not reach statistical significance. Budesonide/formoterol in a single inhaler is more effective than a higher microgram dose of fluticasone alone. It is cost-neutral and may provide cost-savings in some countries.

Adult↗
PubMed2005

Detection of cancerous endobronchial lesions by autofluorescence bronchoscopy combined with mutation analysis of p53.

Early lung cancer screening failed to reduce lung cancer mortality. New techniques such as autofluorescence bronchoscopy (AF) and the identification of specific genetic alteration might change future outcomes of lung cancer screening. It was the aim of our study to combine p53 analysis with white-light bronchoscopy (WL) or WL and AF to improve the diagnostic yield in a series of 36 patients with histologically proven lung cancer, pulmonary metastasis or suspected lung cancer. - Endobronchial sites were analysed by WL (n = 71), AF (Storz) (n = 34), histopathology (n = 71) and p53 mutations were examined by SSCP analysis on additional biopsies (n = 69). The overall frequency of cancerous lesions was 19, of which 14 were macroscopically visible lesions. The addition of p53 and autofluorescence improved the yield to 17 of 19 cases. In 7 preinvasive lesions (dysplasia/metaplasia) 4 were identified macroscopically and 5 of 7 lesions by all 3 methods. In the WL/p53 group the diagnostic yield was 7 of 9 cancerous lesions compared to 10 of 10 cancerous lesions in the AF group. It should be noted that all methods were associated with false positive results. However, the combination of conventional with autofluorescence bronchoscopy and mutation analysis is a promising approach which is applicable to clinical routine and may be further enhanced by the inclusion of a panel of markers of tumour progression.

Bronchoscopy↗
PubMed2005

Inhaled glutathione decreases PGE2 and increases lymphocytes in cystic fibrosis lungs.

Reduced glutathione (GSH), a major antioxidant and modulator of cell proliferation, is decreased in the bronchoalveolar lavage fluid (BALF) of cystic fibrosis (CF) patients. We previously have shown that GSH inhalation in CF patients significantly increased GSH levels in BALF and improved lung function (M. Griese et al., 2004, Am. J. Respir. Crit. Care Med.169, 822-828). GSH depletion in vitro enhances susceptibility to oxidative stress, increases inflammatory cytokine release, and impairs T cell responses. We therefore hypothesized that an increase in GSH in BALF reduces oxidative stress, decreases inflammation, and modulates T cell responses in lungs of CF patients. BALF from 17 CF patients (median FEV1 67% (43-105%) of predicted) was assessed before and after GSH inhalation for total protein, markers of oxidative stress (8-isoprostane, myeloperoxidase, and ascorbic and uric acid), pattern of protein oxidation, prostaglandin E2 (PGE2), and proinflammatory cytokines. BALF cells were differentiated using cytospin slides, and lymphocytes were further analyzed by flow cytometry. Inhalation of GSH decreased BALF levels of PGE2 and increased CD4+ and CD8+ lymphocytes in BALF significantly but had no effect on markers of oxidative stress. BALF lymphocytes correlated positively with lung function, whereas levels of PGE2 showed an inverse correlation. The patients with the greatest improvement in lung function after GSH treatment also had the largest decline in PGE2 levels. We conclude that GSH inhalation in CF patients increases lymphocytes and suppresses PGE2 in the bronchoalveolar space. Thus, GSH primarily affected the pulmonary immune response rather than the oxidative status in CF patients. The effect of GSH inhalation on PGE2 levels and lymphocytes in CF warrants further investigation.

Administration, Inhalation↗
PubMed2005

[Lung cancer screening -- state of the art].

Besides smoking as the main risk factor for lung cancer several occupational risk factors like exposure to asbestos, polycyclic aromatic hydrocarbons, uranium and dust containing nickel or silica have to be considered. Due to lack of effort in smoking prevention and cessation, lung cancer screening is an important issue. A number of pitfalls has to be considered when evaluating the efficacy of screening procedures. In this paper, we summarize the results of the major studies including chest X-ray, sputum cytology and low dose computed tomography. Randomized controlled studies involving low dose CT in about 100 000 subjects are on the way. Around the year 2010 we will be able to define whether or not lung cancer screening including new techniques and standardized algorithms yields a decrease in mortality. If diagnostic algorithms are used which have been applied in published feasibility studies, the mean percentage of invasive diagnostic measures revealing benign lesions is about 34 % and thus below those obtained in, e. g., breast cancer screening trials.

Germany↗
PubMed2005

Lung function in adults with cystic fibrosis at altitude: impact on air travel.

Current guidelines for air travel state that patients with chronic respiratory diseases are required to use oxygen if their in-flight arterial oxygen tensions (Pa,O2) drop below 6.6 kPa. This recommendation may not be strictly applicable to cystic fibrosis patients, who may tolerate lower Pa,O2 for several hours without clinical symptoms. Lung function, symptoms, blood gas levels and signs of pulmonary hypertension were studied in 36 cystic fibrosis patients at altitudes of 530 m and, after 7 h, 2,650 m. A hypoxia inhalation test (inspiratory oxygen fraction 0.15) was performed at low altitude in order to predict high-altitude hypoxaemia. Median Pa,O2 dropped from 9.8 kPa at low altitude to 7.0 kPa at high altitude. Mild exercise at a workload of 30 W further decreased Pa,O2. Two-thirds of all patients exhibited Pa,O2 of <6.6 kPa during exercise and, except for one patient, were asymptomatic. Patients were significantly less obstructed at an altitude of 2,650 m. Low forced expiratory volume in one second at baseline was associated with a low Pa,O2 at altitude. It is concluded that cystic fibrosis patients with baseline arterial oxygen tensions of >8.0 kPa safely tolerate an altitude of 2,650 m for several hours under resting conditions. The risk assessment of low in-flight oxygenation should encompass the whole clinical situation of cystic fibrosis patients, with special attention being paid to the presence of severe airway obstruction.

Adult↗
PubMed2005

Cell cycle effects of radiation on human bronchial epithelium and lung carcinoma cells in monolayer cultures and a three-dimensional co-culture system.

The aim of this study was to investigate whether the three-dimensional structure of the bronchial tissue and the contact of non-malignant with malignant cells influence the effectiveness of radiotherapy. Monolayer cultures of cells of the human bronchial epithelial cell line BEAS 2B, monolayer co-cultures of BEAS 2B cells and cells of the GFP-transfected lung carcinoma cell line EPLC 32M1, organ cultures of human bronchial epithelium, and organ co-cultures with EPLC 32M1 cells were irradiated with 10 Gy, and the DNA content was analyzed using flow cytometry. In non-malignant epithelial cells, BEAS 2B monolayer cultures without tumor cells were highly radiosensitive. However, contact with tumor cells in monolayer co-cultures markedly reduced radiosensitivity. Non-malignant cells in three-dimensional organ cultures and organ co-cultures with tumor cells showed moderate radiosensitivity. In EPLC 32M1 tumor cells, proliferation was increased without irradiation when the cells were in contact with epithelial cells in both organ and monolayer co-cultures. Radiosensitivity was higher in organ co-cultures than in monolayer cultures and monolayer co-cultures. These data indicate that organ co-cultures in combination with flow cytometry allow investigation of the effects of radiation in an in vivo-like environment and that both the spatial organization and the interaction of non-malignant and tumor cells are crucial for the effectiveness of radiotherapy.

Bronchi↗
PubMed2004

[High prevalence of osteoporosis in adult cystic fibrosis patients].

BACKGROUND AND OBJECTIVE: In adult patients with cystic fibrosis bone metabolism may be altered by multiple mechanisms, such as abnormal calcium homeostasis, malnutrition, chronic inflammation or inactivity in the course of respiratory failure. In contrast to the high prevalence of osteoporosis in CF patients before lung transplantation, data from different CF collectives show great variation. It was the purpose of our cross-sectional study to determine changes in bone metabolism by measuring bone mineral density, and assessing calcium metabolism and clinical characteristics in adult patients (mean age 32 years) with cystic fibrosis. PATIENTS AND METHODS: Bone mineral density (quantitative digital radiography), parameters of calcium homeostasis and clinical characteristics were determined in 34 adult patients with cystic fibrosis. RESULTS: The mean age of the study population was 32 years (range 20 to 47; 21m: 13f). 13 patients had normal T-values (mean bone mineral density in young adults), whereas 11 patients (32 %) had osteopenia and 10 (29 %) had osteoporosis. Calcium homeostasis was abnormal in only one case. In contrast T-values were positively correlated with a low body mass index (p = 0.01) and a low one-second forced expiratory volume (FEV1) (p < 0.05). CONCLUSION: Decreased mineral bone density is a frequent complication in adult patients with cystic fibrosis, but does not occur inevitably even in long-standing disease (up to 47 years). In our cohort measurable alterations of calcium homeostasis could be avoided by consistent substitution policy. The main determinants of a low T-value were poor nutritional status, lowered serum calcium or phosphate concentrations and severely impaired lung function as indicator of the progression of the disease. Screening of adult patients with CF can be recommended especially in presence of malnutrition or poor lung function.

Adult↗
PubMed2004

5-Aminolevulinic acid-induced fluorescence in bronchial tumours: dependency on the patterns of tumour invasion.

5-ALA-induced protoporphyrin IX (PPIX) fluorescence kinetics was quantified by fluorescence microscopy in three-dimensional organ co-cultures of human bronchial epithelium, which were infiltrated by four different lung tumour cell lines (EPLC-M31, LCLC-103H, NCI-H125 and NCI-H841). Corresponding fluorescence measurements were performed in monolayer cultures of these tumour cell lines and BEAS-2B cells as a model for normal bronchial epithelium by flow cytometry. Significant differences of fluorescence intensities (FI) between the tumours were detected in organ co-cultures as well as in single cell measurements. Relative FI values in organ co-cultures (FI(EPLC-32M1)>FI(LCLC-H103)>FI(NCI-H125)>FI(NCI-H841)) did not correspond to the measurements in single cells (FI(LCLC-H103)>FI(NCI-H125)>FI(NCI-H841)>FI(EPLC-32M1)). Histology of organ co-cultures revealed different patterns of invasion and tumour cell densities depending on the tumour type. After correction of FI in the co-cultures to tumour cell density the correlation coefficient for fluorescence values between both models increased considerably. Thus, additionally to distinctive features of 5-ALA metabolism, patterns of tumour invasion may be a factor determining 5-ALA-induced fluorescence. Considering these results, a pronounced heterogeneity of 5-ALA-induced fluorescence might be expected in different bronchial tumours in vivo. This could interfere with the diagnostic reliability of 5-ALA-induced fluorescence for early tumour detection.

Aminolevulinic Acid↗
PubMed2004

Molecular oncology--perspectives in lung cancer.

Despite novel therapies in lung cancer treatment the 5-year survival rate still remains poor. Furthermore, screening concepts for early diagnosis, based on conventional sputum cytology and chest radiography, have so far not demonstrated an impact on decreasing lung-cancer mortality. More specific molecular markers allow new insights in the process of lung carcinogenesis. Furthermore they raise the hope that they provide new tools for early diagnosis and screening of high-risk individuals, determination of prognosis, and identification of innovative treatments. In this review, these perspectives of molecular targets in lung cancer will be discussed and summarised. Angiogenesis-stimulating factors (VEGF, FGF, MMP, etc.), parameters concerning tumour cell proliferation and apoptosis (EGFR, p53, K-ras, rb, bcl-2, etc.) are well known. Several of these genetic factors have already been investigated, but no single parameter has yet gained a sufficient selectivity regarding prognostic significance or therapeutic efficacy. New aspects in the complex tumour-stroma interaction and the interactive, cross-talking signal transduction pathways and recently developed functional genomic approaches, such as DNA microarrays and proteomics might lead to further progress in biological staging models and treatment concepts.

Antineoplastic Agents↗