Recommendations of the German Central Committee against Tuberculosis (DZK) and the German Respiratory Society (DGP) for the Diagnosis and Treatment of Non-tuberculous Mycobacterioses.

Non-tuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis-complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide, a rising prevalence and significance of non-tuberculous mycobacterioses is recognized. The present recommendations summarise current aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of non-tuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

[Recommendations for diagnosis and treatment of nontuberculous mycobacterioses of the German Central Committee against tuberculosis and the German Respiratory Society]. / Empfehlungen zur Diagnostik und Therapie nichttuberkulöser Mykobakteriosen des Deutschen Zentralkomitees zur Bekämpfung der Tuberkulose (DZK) und der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

Nontuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide a rising prevalence and significance of nontuberculous mycobacterioses can be recognized. The present recommendations summarise actual aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of nontuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

[German guideline for diagnosis and management of idiopathic pulmonary fibrosis]. / S2K-Leitlinie zur Diagnostik und Therapie der idiopathischen Lungenfibrose.

Idiopathic pulmonary fibrosis is a fatal lung disease with a variable and unpredictable natural history and limited treatment options. Since publication of the ATS-ERS statement on IPF in the year 2000 diagnostic standards have improved and a considerable number of randomized controlled treatment trials have been published necessitating a revision. In the years 2006 - 2010 an international panel of IPF experts produced an evidence-based guideline on diagnosis and treatment of IPF, which was published in 2011. In order to implement this evidence-based guideline into the German Health System a group of German IPF experts translated and commented the international guideline, also including new publications in the field. A consensus conference was held in Bochum on December 3rd 2011 under the protectorate of the "Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP)" and supervised by the "Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften" (AWMF). Most recommendations of the international guideline were found to be appropriate for the german situation. Based on recent clinical studies "weak negative" treatment recommendations for pirfenidone and anticoagulation were changed into "weak positive" for pirfenidone and "strong negative" for anticoagulation. Based on negative results from the PANTHER-trial the recommendation for the combination therapy of prednisone plus azathiorpine plus N-acetlycsteine was also changed into strong negative für patients with definite IPF. This document summarizes essential parts of the international IPF guideline and the comments and recommendations of the German IPF consensus conference.

Pulmonary haptoglobin and CD163 are functional immunoregulatory elements in the human lung.

BACKGROUND: The acute-phase protein haptoglobin (Hp) and its receptor CD163 serve as immunomodulators and possess anti-inflammatory besides antioxidant functions. OBJECTIVES: To further understand the role of the recently described pulmonary Hp (pHp) and its receptor CD163 in case of inflammation and infection, pHp and CD163 were investigated on mRNA and protein level to gain insight into the cellular events taking place upon stimulation with the inflammatory mediators LPS, Pam3, cytokine IL-6 and dexamethasone, and upon infection with respiratory pathogens (Haemophilus influenzae, Streptococcuspneumoniae and Chlamydia pneumoniae) by use of a human ex vivo tissue culture model and cell cultures of A549 and alveolar epithelial cells type II. In addition, pHp and CD163 expression in COPD and sarcoidosis was assessed. METHODS: We conducted experiments using 942 ex vivo cultured lung samples applying immunohistochemistry, immunocytochemistry, in situ hybridization, immunofluorescence, real-time PCR, RT-PCR, slot and Western immunoblot analyses with tissue lysates and culture supernatants as well as ELISA and cytometric bead array analyses. RESULTS: This study describes for the first time the expression, regulation and secretion of pHp and its receptor CD163 in the human lung. The release of soluble mediators from A549 cell line and human monocyte-derived macrophages was observed indicating that Hp differentially activates the release of soluble mediators and major chemoattractants. CONCLUSIONS: The findings indicate a native function of pHp and CD163 as functional pulmonary defense elements due to local expression, regulation and secretion during lung infection and as part of the inflammatory immune response of the respiratory system.

Generation and evaluation of a monoclonal antibody, designated MAdL, as a new specific marker for adenocarcinomas of the lung.

BACKGROUND: Different therapy regimens in non-small-cell lung cancer (NSCLC) are of rising clinical importance, and therefore a clear-cut subdifferentiation is mandatory. The common immunohistochemical markers available today are well applicable for subdifferentiation, but a fraction of indistinct cases still remains, demanding upgrades of the panel by new markers. METHODS: We report here the generation and evaluation of a new monoclonal antibody carrying the MAdL designation, which was raised against primary isolated human alveolar epithelial cells type 2. RESULTS: Upon screening, one clone (MAdL) was identified as a marker for alveolar epithelial cell type II, alveolar macrophages and adenocarcinomas of the lung. In a large-scale study, this antibody, with an optimised staining procedure for formalin-fixed tissues, was then evaluated together with the established markers thyroid transcription factor-1, surfactant protein-A, pro-surfactant protein-B and napsin A in a series of 362 lung cancer specimens. The MAdL displays a high specificity (>99%) for adenocarcinomas of the lung, together with a sensitivity of 76.5%, and is capable of delivering independent additional diagnostic information to the established markers. CONCLUSION: We conclude that MAdL is a new specific marker for adenocarcinomas of the lung, which helps to clarify subdifferentiation in a considerable portion of NSCLCs.

[Efficacy and safety in the treatment of pleural effusions with the PleurX catheter: a retrospective analysis]. / Nutzen und Sicherheit der Behandlung von Pleuraergüssen mit dem PleurX-Katheter: eine retrospektive Analyse.

BACKGROUND: The purpose of this retrospective study was to investigate the efficacy and safety of an indwelling pleural device (PleurX, Denver Biomedical, USA) for the treatment of recurrent pleural effusions. In cases when life expectancy tends to be very short and also surgical decortication is not recommended, pleurodesis is another treatment option but requires complete drainage of the whole pleural fluid for optimal results which is sometimes hard to achieve. The PleurX catheter is an alternative therapeutic option. METHODS AND RESULTS: We retrospectively analysed the clinical data from a total of 21 patients who were treated with a PleurX alone (11 patients) or who initially received pleurodesis and afterwards a PleurX catheter (10 patients). Mean survival was 25 weeks after initial diagnosis of the underlying disease. The mean amount of pleural effusion drained per week was 725 mL. 16 patients used the catheter until they died at least 1 - 2 times a week. The complication rate was 19 % and thus within a reasonable range when compared to other treatment options for recurrent pleural effusions. There was no statistically significant difference in clinical outcome in both groups (pleurodesis and subsequent PleurX vs. PleurX alone). The amount of evacuated pleural effusion was inversely correlated with the remaining life time. CONCLUSION: The use of an indwelling pleural device is a safe alternative treatment option for patients with chronic pleural effusions and trapped lung signs. We should be aware of this device and propagate its use at an earlier stage of malignant diseases with recurrent pleural effusions, especially when the remaining life time is short.

Low-frequency ultrasound permeates the human thorax and lung: a novel approach to non-invasive monitoring.

PURPOSE: Conventional sonography at 2 - 10 MHz cannot permeate the chest because ultrasound at this frequency is strongly scattered and reflected by air inclusions in the lungs. Therefore, sonography is considered impracticable for thoracic imaging. However, human thoraxes and lungs in situ were never rigorously probed with ultrasound at frequencies below 1 MHz. In addition, ultrasound is commonly applied as echo imaging rather than sound transmission. MATERIALS AND METHODS: Human subjects were studied with a transducer detector pair or an elastic thorax belt equipped with 12 sensors 5 cm apart that was wrapped around the thorax and a single pulse transmitter attached to the sternum. We focused on fast ultrasound transmission from 1 kHz to 1 MHz, coupled over thoracic sonotrodes. RESULTS: Between 1 Hz to 1 MHz, sound transmission through thorax and lungs shows three distinct bands: < 1 kHz sound is transmitted at 30 - 50 m/sec, between 1 - 10 kHz sound transmission is absent and > 10 kHz sound is transmitted with a speed of 1500 m/sec. We demonstrate that low-frequency ultrasound (10 - 750 kHz) can permeate the thorax and permits monitoring of the air and water content of human lungs. In healthy subjects at 15 kHz, the difference in sound transmission through thorax and lungs between inspiration and expiration was dynamic and spanned several decades. Sound transmission during expiration was strongly decreased in patients suffering from pulmonary emphysema or pneumothorax, but increased in patients with pleural effusions. CONCLUSION: Sound transmission in the lungs is characterized by three distinct frequency bands. Low frequency ultrasound is transmitted through the lungs and may offer a novel non-invasive approach to real time diagnostics.

Expression analysis of EML4 in normal lung tissue and non-small cell lung cancer (NSCLC) in the absence and presence of chemotherapeutics.

Despite considerable progress in the development of individualized targeted therapies of tumor diseases, identification of additional reliable target molecules is still mandatory. One of the most recent targets is microtubule-associated human EML4 generating a fusion-type oncogene with ALK demonstrating marked transforming activity in lung cancer. Since EML4 is a poorly characterized protein with regard to expression, function and regulation in human tissue, specimens of human tumor and tumor-free tissues obtained from patients with NSCLC were analyzed to determine the cellular localization. All tissue samples have been previously fixed with the novel HOPE-technique and paraffin embedded. Determination of both gene expression and protein levels of EML4 were performed using RT-PCR, in situ hybridization as well as immunohistochemistry, respectively. In human NSCLC tissue samples, possible regulation of EML4 transcription upon chemotherapy with combinations of most established cytotoxic drugs for NSCLC treatment was also studied employing the recently established ex vivo tissue culture model STST. In normal lung, both marked mRNA and protein levels of EML4 were localized in alveolar macrophages. In contrast, lung tumor tissues always showed consistent transcriptional expression in situ and by RT-PCR. Stimulation of NSCLC tissues with chemotherapeutics revealed heterogeneous effects on EML4 mRNA levels. Based on its expression patterns in both tumor-free lung and NSCLC tissues, human EML4 is likely to be closely associated with processes involved in local inflammation of the lung as well as with tumor behavior. Thus, our results suggest that EML4 may have the potential as a therapeutic target molecule in NSCLC chemotherapy.

[Pathophysiology and pathogens of sepsis]. / Pathophysiologie und Keimspektrum der Sepsis.

The pathophysiology of sepsis is not completely understood. Bacteria are the main cause of sepsis. Activated receptors of the innate immune system lead to an exaggerated immune response. Immune cells including activated neutrophils and macrophages express and are controlled by a variety of cytokines, chemokines, complement factors and other mediators. These proinflammatory factors induce the expression of secondary mediators such as lipids and reactive oxygen species leading to further amplification of inflammation. Due to loss of control mechanisms in sepsis the immune response causes damage of the own organism. The early phase of sepsis is characterized by a proinflammatory response. In contrast, in the late stage of sepsis an anti-inflammatory milieu is observed that can cause severe immunosuppression. An overview will be given on the recent advances in understanding the interaction of different pathophysiological mechanisms and potential therapeutic interventions in the complex and dynamic syndrome of sepsis.

Yield of dwarf tomatoes grown with a nutrient solution based on recycled synthetic urine.

Extended human spaceflight missions require not only the processing, but also the recycling of human waste streams in bio-regenerative life support systems, which are rich in valuable resources. The Combined Regenerative Organic food Production® project of the German Aerospace Center aims for recycling human metabolic waste products to produce useful resources. A biofiltration process based on natural communities of microorganisms has been developed and tested. The processed aqueous solution is, among others, rich in nitrogen present as nitrate. Nitrate is one of the main nutrients required for plant cultivation, resulting in strong synergies between the developed recycling process and plant cultivation. The latter is envisaged as the basis of future bio-regenerative life support systems, because plants do consume carbon dioxide, water and nutrients in order to produce oxygen, water, food and inedible biomass. This paper describes a series of plant cultivation experiments performed with synthetic urine processed in a bioreactor. The aim of the experiments was to investigate the feasibility of growing tomato plants with this solution. The results of the experiments show that such cultivation of tomato plants is generally feasible, but that the plants are less productive. The fruit fresh weight per plant is less compared to plants grown with the half-strength Hoagland reference solution. This lack in production is caused by imbalances of sodium, chloride, potassium, magnesium and ammonium in the solution gained from recycling the synthetic urine. An attempt on adjusting the produced bioreactor solution with additional mineral fertilizers did not show a significant improvement in crop yield.

[Infection diagnostics in pneumology. Part 1. Survey and methods]. / Infektionsdiagnostik in der Pneumologie. Teil 1. Ubersicht und Methoden.

Lower respiratory tract infections rank among the most important illnesses in medicine. However, the identification of a causative microbiological agent is often difficult. Pulmonary infections must be differentiated from non-infectious causes of pulmonary diseases with similar symptoms and infiltrates on chest imaging. Among the important novel developments ranks the analysis of serum procalcitonin for a better identification and treatment monitoring of bacterial pneumonias compared to conventional tests and a simple scoring system, like the CRB-65/CURB score, for a rapid risk stratification. A rational diagnostic approach is necessary to identify causative microorganisms of pulmonary infectious diseases depending on the severity of the illness, the exposition and predisposition of the patient. In addition to the classical microbiological methods, rapid test systems for the identification of microorganisms are becoming increasingly important. The first part of this review gives a detailed survey of the methods for the diagnosis of pulmonary infectious diseases. In the second part of the manuscript, we will focus on special pulmonary infectious diseases.

[Immunisation strategies for the management of severe acute respiratory syndrome (SARS)]. / Impfstrategien bei Schwerem Akutem Respiratorischem Syndrom (SARS).

Most patients with severe acute respiratory syndrome (SARS) develop antibodies against the SARS coronavirus and survive the infection. This suggests that active or passive immunisation might be an effective option in preventing or treating SARS. Therefore, the development of SARS vaccination strategies belongs to the most important targets of SARS research. The present study analyses data-bases for the current knowledge on vaccination strategies. Both, passive and active immunisation protocols are presently being developed. Passive immunisation with sera from surviving patients leads to partial success. Whereas the passive immunisation exhibits a promising therapeutic tool, only active immunisation can successfully prevent infection. A number of approaches has been used on the basis of inactivated SARS coronaviruses, recombinant subunits, recombinant DNA, and viral vectors. However, all recently developed candidates need to be evaluated critically before clinical use. The so-called "antibody-dependent enhancement" can improve viral uptake into host cells resulting in increased viral load and exacerbation of disease.

Disseminated mycobacterium bovis infection in an immunocompetent host.

We report about a rare case of disseminated Mycobacterium bovis infection in a 61 year old female immunocompetent patient with involvement of the lung, the brain, the spleen and spine. The patient had intracerebral tuberculomas with paradoxical enlargement during the first weeks of therapy. We reviewed the data of our microbiological department and found five other patients with Mycobacterium bovis infection diagnosed between 1999 and 2004, which are 5.8 % of all diagnoses of tuberculosis during this period.

Review and analysis of over 40 years of space plant growth systems.

The cultivation of higher plants occupies an essential role within bio-regenerative life support systems. It contributes to all major functional aspects by closing the different loops in a habitat like food production, CO2 reduction, O2 production, waste recycling and water management. Fresh crops are also expected to have a positive impact on crew psychological health. Plant material was first launched into orbit on unmanned vehicles as early as the 1960s. Since then, more than a dozen different plant cultivation experiments have been flown on crewed vehicles beginning with the launch of Oasis 1, in 1971. Continuous subsystem improvements and increasing knowledge of plant response to the spaceflight environment has led to the design of Veggie and the Advanced Plant Habitat, the latest in the series of plant growth systems. The paper reviews the different designs and technological solutions implemented in higher plant flight experiments. Using these analyses a comprehensive comparison is compiled to illustrate the development trends of controlled environment agriculture technologies in bio-regenerative life support systems, enabling future human long-duration missions into the solar system.

Regional lung function determined by electrical impedance tomography during bronchodilator reversibility testing in patients with asthma.

The measurement of rapid regional lung volume changes by electrical impedance tomography (EIT) could determine regional lung function in patients with obstructive lung diseases during pulmonary function testing (PFT). EIT examinations carried out before and after bronchodilator reversibility testing could detect the presence of spatial and temporal ventilation heterogeneities and analyse their changes in response to inhaled bronchodilator on the regional level. We examined seven patients suffering from chronic asthma (49 ± 19 years, mean age ± SD) using EIT at a scan rate of 33 images s(-1) during tidal breathing and PFT with forced full expiration. The patients were studied before and 5, 10 and 20 min after bronchodilator inhalation. Seven age- and sex-matched human subjects with no lung disease history served as a control study group. The spatial heterogeneity of lung function measures was quantified by the global inhomogeneity indices calculated from the pixel values of tidal volume, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak flow and forced expiratory flow between 25% and 75% of FVC as well as histograms of pixel FEV1/FVC values. Temporal heterogeneity was assessed using the pixel values of expiration times needed to exhale 75% and 90% of pixel FVC. Regional lung function was more homogeneous in the healthy subjects than in the patients with asthma. Spatial and temporal ventilation distribution improved in the patients with asthma after the bronchodilator administration as evidenced mainly by the histograms of pixel FEV1/FVC values and pixel expiration times. The examination of regional lung function using EIT enables the assessment of spatial and temporal heterogeneity of ventilation distribution during bronchodilator reversibility testing. EIT may become a new tool in PFT, allowing the estimation of the natural disease progression and therapy effects on the regional and not only global level.

Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM.

Effects of human glucagon-like peptide I (GLP-I)(7-36)amide were examined in volunteers having insulin-dependent diabetes mellitus (IDDM) with residual C-peptide (CP) secretion (n = 8, 7 men and 1 woman; age, 31 +/- 1.4 years; body mass index, 24.7 +/- 0.7 kg/m2; duration of diabetes, 3.2 +/- 0.8 years; insulin dose, 0.41 +/- 0.05 U.kg-1.day-1; meal-stimulated CP, 1.0 +/- 0.2 nmol/l [means +/- SE]). After a mixed meal (Sustacal, 30 kJ/kg body wt), intravenous injection of GLP-I, 1.2 pmol.kg-1.min-1 through 120 min, virtually abolished increments of plasma glucose, CP, pancreatic polypeptide (PP), and glucagon concentrations, with no significant effect on plasma gastrin levels during the infusions. At reduced dosage (0.75 pmol.kg-1.min-1), GLP-I had lesser effects on plasma glucose and CP levels. On cessation of intravenous GLP-I infusions after the meals, plasma glucose, CP, PP, and glucagon concentrations rebounded toward control levels by 180 min, and the response of plasma gastrin was prolonged. These rebound responses are consistent with intestinal delivery of food retained in the stomach on escape from inhibition of gastric emptying by GLP-I. Infusion of 1.2 pmol.kg-1.min-1 GLP-I with 20 g glucose (10% dextrose in water) injected intravenously over 60 min enhanced plasma responses of immunoreactive CP; the mean incremental areas under concentration curves (0-60 min) increased sixfold, but the glycemic excursion was not affected. Thus, in CP-positive IDDM, pharmacological doses of GLP-I reduce glycemic excursions after meals by a mechanism(s) not dependent on stimulation of insulin secretion, presumably involving delayed gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)