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Biomedical subjects

Klaus F Rabe

Publications and source records attributed to Klaus F Rabe.

At least 37 records · Page 2Linked to original sources
PubMed2005

Endoscopic ultrasound added to mediastinoscopy for preoperative staging of patients with lung cancer.

CONTEXT: Up to 40% of thoracotomies performed for non-small cell lung cancer are unnecessary, predominantly due to inaccurate preoperative detection of lymph node metastases and mediastinal tumor invasion (T4). Mediastinoscopy and the novel, minimally invasive technique of transesophageal ultrasound-guided fine-needle aspiration (EUS-FNA) target different mediastinal lymph node stations. In addition, EUS can identify tumor invasion in neighboring organs if tumors are located adjacent to the esophagus. OBJECTIVE: To investigate the additional value of EUS-FNA to mediastinoscopy in the preoperative staging of patients with non-small cell lung cancer. DESIGN, SETTING, AND PATIENTS: Prospective, nonrandomized multicenter trial performed in 1 referral and 5 general hospitals in the Netherlands. During a 3-year period (2000-2003), 107 consecutive patients with potential resectable non-small cell lung cancer underwent preoperative staging by both EUS-FNA and mediastinoscopy. Patients underwent thoracotomy with tumor resection if mediastinoscopy was negative. Surgical-pathological staging was compared with preoperative findings and the added benefit of the combined strategy was assessed. INTERVENTION: The EUS-FNA examination was performed as an additional staging test to mediastinoscopy in all patients. MAIN OUTCOME MEASURE: Detection of mediastinal tumor invasion (T4) and lymph node metastases (N2/N3) comparing the combined staging by both EUS-FNA and mediastinoscopy with staging by mediastinoscopy alone. RESULTS: The combination of EUS-FNA and mediastinoscopy identified more patients with tumor invasion or lymph node metastases (36%; 95% confidence interval [CI], 27%-46%) compared with either mediastinoscopy alone (20%; 95% CI, 13%-29%) or EUS-FNA (28%; 95% CI, 19%-38%) alone. This indicated that 16% of thoracotomies could have been avoided by using EUS-FNA in addition to mediastinoscopy. However, 2% of the EUS-FNA findings were false-positive. CONCLUSION: These preliminary findings suggest that EUS-FNA, when added to mediastinoscopy, improves the preoperative staging of lung cancer due to the complementary reach of EUS-FNA in detecting mediastinal lymph node metastases and the ability to assess mediastinal tumor invasion.

Biopsy, Fine-Needle↗
PubMed2005

Markers of disease severity in chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVES: Diagnosis and assessment of treatment effect in chronic obstructive pulmonary disease (COPD) have relied primarily on the examination of a complex set of symptoms and the use of spirometry. However, these methods require long periods of assessment to determine whether patients show clinically relevant improvements after intervention. We therefore wanted to determine how existing clinical and laboratory measures change with COPD severity and identify disease markers that can serve as better endpoints for diagnosis and assessment of COPD progression and treatment effect. METHODS: Using standard COPD keywords and terms, we searched PubMed, ISI Web of Science, and Cochrane Review databases for retrospective and prospective clinical studies published since 1966. We identified 652 studies (n = 146,255) from 1978 to September 2003 based on the availability of spirometric and demographic data, investigation of possible markers, absence of acute exacerbations and co-morbidities, and the withdrawal of standard COPD medication. Central tendencies and dispersions of subject baseline measures were collected according to study sample size, smoking status, and mild, moderate and severe COPD stages. A fixed effect meta-analysis was then conducted on each measure at various disease stages. RESULTS: Arterial oxygen tension, sputum neutrophils and IL-8, and serum TNF-alpha and C-Reactive Protein showed a trend toward separation between COPD stages. Other measures such as pack-years and St George's Respiratory Questionnaire only distinguished between disease and disease-free states. CONCLUSIONS: We observed little separation between disease stages for many measures used in COPD diagnosis and clinical trials. This demonstrates the poor sensitivity of such endpoints to define a patient's clinical status and to quantify treatment effect. Therefore, we recommend that longitudinal studies and disease modelling be the primary methods for assessing whether potential markers of disease progression can be used for COPD diagnosis and clinical trials.

Biomarkers↗
PubMed2005

Host defense effector molecules in mucosal secretions.

Mucosal secretions contain a range of defense effector molecules including antimicrobial peptides and proteinase inhibitors. These molecules play a central role in host defense against infection, and in a variety of immune and inflammatory reactions. The aim of this study was to analyze the levels of neutrophil defensins, the cathelicidin hCAP-18/LL-37, and the proteinase inhibitors secretory leukocyte proteinase inhibitor, SKALP/elafin and cystatin M/E in various mucosal secretions and urine. We show here that especially seminal plasma is characterized by high concentrations of hCAP-18/LL-37, SLPI, SKALP/elafin and cystatin M/E. The results of this study demonstrate that each mucosal secretion is characterized by a unique profile of effector molecules, which may supply individual mucosal secretions with specific properties related to the control of local infection and inflammation.

Antimicrobial Cationic Peptides↗
PubMed2005

Obtaining optimal control in mild asthma: theory and practice.

BACKGROUND: Studies have shown that asthma severity is easily under-estimated and as a result, patients may be under-treated with reduced asthma control. OBJECTIVE: This study, performed in the General Practice Research Database (GPRD), investigates asthma control in patients treated as intermittent asthmatics (short-acting beta agonist (SABA) alone), or persistent asthmatics (additional inhaled cortico-steroid (ICS), no other medication). METHODS: Patients (0-45 years) diagnosed with asthma between 1 January 1995 and 31 December 2001 taking > or =2 scripts for SABA (SABA only group) or > or =3 scripts for ICS (ICS group) in the first six months following diagnosis were selected. Factors associated with drug prescriptions were assessed. RESULTS: SABA script rates were 3.6 and 5.1 per year in the SABA and ICS group respectively, i.e. >1 dose/day. 10.5% of SABA group and 13.4% of ICS group used oral steroids. Within the SABA group, 37% were stepped up to ICS, the time to first ICS script being significantly associated with prior hospitalization (RR 2.26, CI 1.65-3.10) and atopy (RR 1.47, CI 1.33-1.63). A higher rate of oral steroid use was significantly associated with using ICS, being female, adult and smoking. Smokers and atopic individuals had increased risk of obtaining an earlier script for oral steroid (RR 1.32, CI 1.10-1.59 and RR 1.28, CI 1.10-1.49, respectively). CONCLUSIONS: Asthma control was sub-optimal in a substantial proportion of patients using relatively high doses of SABA, or SABA and ICS from the outset of asthma treatment in general practice. Being female, atopic, a smoker and prior hospitalization were all associated with lack of asthma control and could guide physicians in treatment prescribing.

Administration, Inhalation↗
PubMed2005

Transcriptional response of bronchial epithelial cells to Pseudomonas aeruginosa: identification of early mediators of host defense.

The airway epithelium responds to microbial exposure by altering expression of a variety of genes to increase innate host defense. We aimed to delineate the early transcriptional response in human primary bronchial epithelial cells exposed for 6 h to a mixture of IL-1beta and TNF-alpha or heat-inactivated Pseudomonas aeruginosa. Because molecular mechanisms of epithelial innate host defense are not fully understood, the open-ended expression-profiling technique SAGE was applied to construct gene expression profiles covering 30,000 genes: 292 genes were found to be differentially expressed. Expression of seven genes was confirmed by real-time qPCR. Among differentially expressed genes, four classes or families were identified: keratins, proteinase inhibitors, S100 calcium-binding proteins, and IL-1 family members. Marked transcriptional changes were observed for keratins that form a key component of the cytoskeleton in epithelial cells. Expression of antimicrobial proteinase inhibitors SLPI and elafin was elevated after microbial or cytokine exposure. Interestingly, expression of numerous S100 family members was observed, and eight members, including S100A8 and S100A9, were among the most differentially expressed genes. Differential expression was also observed for the IL-1 family members IL-1beta, IL-1 receptor antagonist, and IL-1F9, a newly discovered IL-1 family member. Clustering of differentially expressed genes into biological processes revealed that the early inflammatory response in airway epithelial cells to IL-1beta-TNF-alpha and P. aeruginosa is characterized by expression of genes involved in epithelial barrier formation and host defense.

Bronchi↗
PubMed2005

EUS-guided FNA of centrally located lung tumours following a non-diagnostic bronchoscopy.

OBJECTIVE: To assess the feasibility and yield of endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) in diagnosing centrally located lung tumours after a previously non-diagnostic bronchoscopy. BACKGROUND AND HYPOTHESIS: Bronchoscopy fails to establish a diagnosis in up to 30% of patients with suspected lung cancer. Intrapulmonary tumours located near or adjacent to the esophagus might be visualized and biopsied under real-time ultrasound guidance by EUS-FNA. DESIGN: Patients with suspected lung cancer and an intrapulmonary tumour located near or adjacent to the esophagus who had undergone a non-diagnostic bronchoscopy, underwent EUS-FNA for diagnostic purposes. Surgical-pathological verification occurred when EUS-FNA was non-diagnostic and in those patients diagnosed with non-small-cell lung cancer by EUS-FNA who were surgical candidates. RESULTS: EUS-FNA diagnosed lung cancer in 31 of 32 patients (97%). No complications occurred. The diagnosis obtained by EUS-FNA was confirmed in all 11 patients who were operated. In one case, in which EUS-FNA was non-diagnostic, a lymphoma was diagnosed after pneumonectomy. CONCLUSIONS AND SIGNIFICANCE: EUS-FNA qualifies as the next diagnostic step in patients with suspected lung cancer and a non-diagnostic bronchoscopy if the intrapulmonary mass is located adjacent or near the esophagus. In these cases, EUS-FNA may replace computed tomography of the chest (CT)-guided biopsies and reduce the number of exploratory thoracotomies.

Adult↗
PubMed2005

Eotaxin-2 and eotaxin-3 expression is associated with persistent eosinophilic bronchial inflammation in patients with asthma after allergen challenge.

BACKGROUND: Eotaxin-1, eotaxin-2, and eotaxin-3 are chemokines involved in the activation and recruitment of eosinophils through activation of their main receptor, CC chemokine receptor 3. The differential roles of these chemokines still remain to be established. It has been suggested that eotaxin-1 is an important mediator in the early phase of allergen-induced recruitment of eosinophils into the airways. Eotaxin-2 and eotaxin-3 might play a role in the subsequent persistence of allergen-induced bronchial eosinophilia. OBJECTIVE: The aim of this study was to determine the expression of eotaxins and eosinophil counts in the bronchial mucosa of subjects with mild asthma after resolution of the late-phase asthmatic response (LAR). METHODS: The expression of eotaxins and eosinophil counts were determined in bronchial biopsy specimens obtained from 10 subjects with mild asthma 48 hours after diluent and allergen challenge by using immunohistochemistry. Positively stained cells were counted in a 125-mum-deep zone of the lamina propria. RESULTS: Eotaxin-2 and eotaxin-3 expression in bronchial mucosa was significantly increased 48 hours after allergen challenge ( P = .001 and P = .013, respectively). At this time point, when marked tissue eosinophilia was still present, these increases were positively correlated with the magnitude of the LAR ( r = 0.72, P = .019 and r = 0.64, P = .046, respectively). Furthermore, eotaxin-2 expression was associated with the number of eosinophils after allergen challenge ( r = 0.72, P = .018). CONCLUSION: Our findings suggest that eotaxin-2 and eotaxin-3 might account for the persistence of bronchial eosinophilia after resolution of the LAR.

Adult↗
PubMed2005

Expression of the anaphylatoxin receptors C3aR and C5aR is increased in fatal asthma.

BACKGROUND: The mechanisms leading to death from asthma are not completely understood. Recent studies suggest the involvement of the anaphylatoxins C3a and C5a, generated during complement activation, and their receptors C3aR and C5aR in the pathogenesis of asthma. OBJECTIVE: The aim of our study was to investigate the expression of C3aR and C5aR in fatal asthma. METHODS: We analyzed lung tissue from 14 subjects who died of asthma (fatal asthma; FA) and 14 subjects who died of nonpulmonary causes (controls) and bronchial biopsy specimens from 16 subjects with mild intermittent asthma (MIA). C3aR and C5aR expression was evaluated by immunohistochemistry, and a semiquantitative analysis of the intensity of staining was performed according to a visual analogue scale (score, 0-3). RESULTS: C3aR was expressed on airway epithelium, smooth muscle, submucosal, and parenchymal vessels. C5aR was expressed on myeloid cells infiltrating the submucosa and on airway epithelium. Statistical analysis demonstrated higher expression of C3aR on submucosal vessels in FA compared with controls and MIA (median [minimum-maximum], controls, 0.24 [0-1.48]; MIA, 0.0 [0-1.00]; FA, 1.56 [0.13-3]; P = .002). C3aR was also increased on parenchymal vessels in FA (controls, 0.56 [0-2.00]; FA, 1.81 [0.5-3]; P = .0004). C5aR expression on airway epithelium was increased in FA compared with controls and MIA (controls, 1.25 [0.25-3]; MIA, 1.00 [0-2.00]; FA, 3.00 [1.13-3.00]; P = .001). CONCLUSION: The results of our study suggest a role of complement in FA.

Adult↗
PubMed2005

The human cathelicidin LL-37: a multifunctional peptide involved in infection and inflammation in the lung.

Antimicrobial peptides play an important role in innate immunity of the lung by acting as effector molecules in host defence against inhaled pathogens. Various families of antimicrobial peptides have been identified, including the cathelicidins. Cathelicidins are characterized by a conserved N-terminal cathelin domain and a variable C-terminal antimicrobial domain that can be released from the precursor protein after cleavage by proteinases. LL-37 is the C-terminal part of the only human cathelicidin identified to date called human cationic antimicrobial protein (hCAP-18), which is mainly expressed by neutrophils and epithelial cells. In addition to killing a broad spectrum of microorganisms, LL-37 was demonstrated to display various cellular activities related to inflammation including cytotoxicity to host cells, chemotaxis, epithelial cell activation, angiogenesis and epithelial wound repair. Focussing on this recent information, this review discusses the role of LL-37 in infection and inflammation in the lung. In addition, the importance of the fact that antimicrobial peptides such as LL-37 display a range of activities for the design and development of antimicrobial peptides for therapeutic use is discussed.

Antimicrobial Cationic Peptides↗
PubMed2004

Diagnosis of IPA in HIV: the role of the chest X-ray and radiologist.

The role of clinical information and chest film for the discrimination between invasive pulmonary aspergillosis (IPA) and its differential diagnoses in human immunodeficiency virus (HIV) infection was studied. The diagnostic performance of clinical information and chest film alone and in combination was studied for eight internists and eight radiologists with regular exposure to IPA patients. The multicenter case sample consisted of 25 patients with proven IPA and 25 with other pulmonary diseases typical for HIV. The cases were presented on a CD-ROM. Receiver operating characteristics (ROC) methodology was employed. With clinical information alone, internists achieved the highest diagnostic performance (area under curve/AUC=0.84). Viewing the chest films did not contribute to their performance (AUC=0.80, P=0.26). The radiologist's performance on the basis of viewing the chest film (AUC=0.75) increased significantly ( P=0.012) when clinical information (AUC=0.83) was supplied. IPA cases with characteristic radiological appearance were correctly identified in 90% with chest film. For radiologists with regular exposure to HIV patients, chest films hold relevant information and contribute to the determination in cases with characteristic radiological appearance. Overall and especially in cases with less characteristic radiological appearance, they have significant profit from full access to the clinical data. For internists with regular exposure to HIV patients, chest films do not provide information essential for the verification or differentiation of potential IPA.

AIDS-Related Opportunistic Infections↗
PubMed2004

"Refractory" eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids.

It has been suggested that patients with refractory eosinophilic airway inflammation represent a separate "eosinophilic" asthma phenotype associated with increased morbidity and a poor prognosis. To investigate whether persistent eosinophilia in these patients is a fixed feature or can still be modified by treatment, we investigated the effect of high-dose intramuscular corticosteroids on eosinophils in induced sputum. Twenty-two patients with stable severe asthma (15 women, aged 21-73 years) participated in this double-blind, placebo-controlled study. All were using inhaled corticosteroids (> or = 1,600 microg/day) or chronic oral prednisone. They were included if the percentage of eosinophils in induced sputum was above the upper limit of normal (> or = 2%). Two weeks after treatment with triamcinolone, but not placebo, sputum eosinophils almost completely disappeared from a median of 12.6-0.2% (p < 0.001). In 82% of patients, no eosinophils could be observed at all. In addition, the rescue medication score decreased from 1.4 to 0.8 (p = 0.01), and FEV1 improved from a median of 73.8-88.3% predicted (p = 0.001). We conclude that persistent sputum eosinophilia despite extensive antiasthma treatment is not a refractory phenomenon but is still sensitive to high-dose systemic corticosteroids. This implies that these patients with severe asthma need additional or alternative antiinflammatory treatment to combat the eosinophilia and associated poor prognosis.

Adrenal Cortex Hormones↗
PubMed2004

Lymphocytic inflammation in childhood bronchiolitis obliterans.

Childhood bronchiolitis obliterans (CBO) is an infrequent, severe disorder characterized by persistent obstructive respiratory symptoms after an acute episode of bronchiolitis. The viral etiology is most common, and adenovirus is the most frequently identified causative agent. Pathologically, the disease is characterized as constrictive type BO, with variable degrees of chronic inflammation and fibrosis in the bronchioles. The nature of the cellular infiltrate is largely unknown, and its characterization may provide better understanding of the disease and offer clues for therapy. Therefore, the aim of the present study was to characterize the inflammatory infiltrate in the bronchioles of 23 open lung biopsies of children with CBO and to compare this to the infiltrate in histologically normal airways. Our results show that CD3+ T cells were the most frequent cell type observed in CBO, with a predominance of the CD8+ T-cell subtype. When compared to the control group, there was a larger number of CD8+, CD4+, CD20+, granzyme B+, and perforin+ lymphocytes in the CBO group. Further studies are needed to address the role of different cell types in the development of CBO.

Adolescent↗
PubMed2004

Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys.

BACKGROUND: In 1995, the Global Initiative for Asthma (GINA) guidelines recommended goals for the management of asthma, which were updated in 2002. However, there are no recent international surveys on the real management of asthma. OBJECTIVE: The Asthma Insights and Reality surveys are the first large-scale surveys aimed at determining international variations in the severity, control, and management of asthma in children and adults. METHODS: A cross-section of households in 29 countries in North America, Europe, and Asia were surveyed to identify from the general population asthmatic patients with symptoms within the last year or who were taking current asthma medication. A standard questionnaire was administered to 7786 adults, and, through a proxy, to 3153 children with asthma. Objective and subjective patient perception of asthma control and severity were assessed, including access to medical care, health care use, missed work-school, and medication use. RESULTS: Despite variations at a country level, a substantial effect of asthma on patients' lives was observed, with considerable loss of schooldays and workdays. The current level of asthma control worldwide falls far short of the goals for long-term management in international guidelines. A significant proportion of patients continue to have symptoms and lifestyle restrictions and to require emergency care. The proportion of adult asthmatic patients who were current smokers was also high. However, the use of anti-inflammatory preventative medication, even in patients with severe persistent asthma, was low, ranging from 26% in Western Europe to 9% in Japan, as was the use of objective lung function testing. The correlation between self-perceived severity of asthma and objective assessment of severity on the basis of GINA criteria was consistently poor in all areas. CONCLUSION: We conclude that there is direct evidence for suboptimal asthma control in many patients worldwide, despite the availability of effective therapies, with long-term management falling far short of the goals set in the GINA guidelines.

Adult↗
PubMed2004

TGF-beta differentially regulates TH2 cytokine-induced eotaxin and eotaxin-3 release by human airway smooth muscle cells.

BACKGROUND: Human airway smooth muscle cells (HASMs) are involved in the pathogenesis of asthma. By producing chemokines, HASMs play a role in the inflammatory processes observed in this disease. Eotaxin, eotaxin-2, and eotaxin-3 are important chemoattractants for eosinophils, and these chemokines are expressed during different phases of the allergic reaction. TH2 cytokines and TGF-beta can be found in increased levels in patients with asthma, and these cytokines may be involved in the regulation of chemokine expression. OBJECTIVE: The aim of this study was to determine the effect of TH2 cytokines and TGF-beta on the regulation of expression of eotaxin, eotaxin-2, and eotaxin-3 by HASMs. METHODS: HASMs were incubated for 24 hours with IL-4, IL-13, TGF-beta1, or combinations of these cytokines. Protein and mRNA levels of eotaxin and eotaxin-3 were evaluated by sandwich ELISA and reverse transcriptase-PCR. RESULTS: IL-4 and IL-13 induced mRNA and protein for both eotaxin and eotaxin-3. Eotaxin-2 mRNA and protein were not detected in HASMs. TGF-beta alone did not induce expression of the eotaxins. However, in combination with IL-4 or IL-13, TGF-beta enhanced eotaxin production and inhibited TH2 cytokine-induced eotaxin-3 production. CONCLUSION: TGF-beta differentially regulates TH2 cytokine-induced eotaxin and eotaxin-3 release.

Bronchi↗
PubMed2004

A prospective clinical study of theophylline safety in 3810 elderly with asthma or COPD.

A large-scale prospective study was conducted in 3810 Japanese elderly (> or =65 years old) patients with asthma or chronic obstructive pulmonary disease (COPD) who had been treated with sustained-release theophylline tablets (THEODUR) at a dose of 400 mg/day for 1-6 months, in principle. Among 3798 protocol-complying patients (mean age: 73.8 +/- 0.10 years, 1997 with COPD), 261 theophylline-related adverse events were observed in 179 (4.71%) patients. The 5 most frequently observed adverse events were "nausea" (40 episodes, 1.05%), "loss of appetite" (22 episodes, 0.56%), "hyperuricemia" (16 episodes, 0.42%), "palpitation" (15 episodes, 0.39%), and "increased alkaline phosphatase" (11 episodes, 0.28%). No convulsions were reported. Six patients had serious adverse events. The incidence of theophylline-related adverse events was higher in patients with hepatic disease (odds ratio: 1:1.81) and in patients with arrhythmia (odds ratio: 1:1.88). Blood drug concentration measurements in 736 patients indicated that the drug levels were < or =15 microg/ml in 641 patients (87.1%), and no correlation was noted between dose and theophylline-related adverse events. These results suggest that sustained-release theophylline can be used safely in elderly patients with asthma or COPD.

Aged↗
PubMed2004

Histologic patterns of lung infiltration of B-cell, T-cell, and Hodgkin lymphomas.

Secondary lung infiltration by lymphomas occurs frequently. To our knowledge, however, no recent studies have attempted to discriminate histologic patterns of lung infiltration in the lymphoma subtypes. We retrospectively evaluated the frequency of lung infiltration and the respective infiltration patterns by lymphomas at autopsy, during an 11-year period. Lymphomas were classified according to the 2001 World Health Organization Classification of hematologic malignancies in B-cell, T-cell, and Hodgkin lymphomas (HLs). In 21,157 autopsies, 414 reports with lymphoma diagnosis were reviewed histologically, and 85 showed lung infiltration (20.5%). We studied 14 HLs, 43 B-cell lymphomas, and 20 T-cell lymphomas. Five infiltration patterns were identified: peribronchial-perivascular, nodular alveolar, interstitial, and pleural. Approximately half of the lymphomas had more than 1 infiltration pattern (mean, 1.7); peribronchial-perivascular and pleural were the most frequent. The frequency of nodular infiltration was larger in HL than in B-cell lymphomas. T-cell lymphomas had a larger frequency of the interstitial infiltration pattern compared with B-cell lymphomas. Recognizing the frequency and patterns of lung infiltration in the light of a more recent classification is certainly useful for physicians dealing with lymphoma diagnostic procedures, such as radiologists and pathologists.

Adolescent↗
PubMed2004

Mechanisms of bronchial hyperreactivity in asthma and chronic obstructive pulmonary disease.

Bronchial hyperreactivity has long been recognized as a hallmark of chronic asthma. Less is known about the prevalence and mechanisms of hyperreactivity in chronic obstructive pulmonary disease (COPD). Currently, it is unclear whether the role and mechanisms of hyperreactivity are similar in patients with asthma and COPD or whether the underlying pathophysiologic abnormalities are different for both diseases. The aim of this review is to present an overview of current knowledge of the mechanisms of bronchial hyperreactivity in asthma and COPD.

Asthma↗