[CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

Guidelines in the Register of the Association of Scientific Medical Societies in Germany - A Quality Improvement Campaign.

The Association of Scientific Medical Societies in Germany (AWMF) is the umbrella organization of medical scientific societies in Germany. The development of guidelines goes back to an initiative of the medical scientific societies and is coordinated by the AWMF. Rules for the inclusion of guidelines in the AWMF Guideline Register have been defined including how guidelines are classified. S1 guidelines are based only on recommendations by experts, whereas S2 guidelines require a structured consensus process or a systematic literature review. S3 guidelines include both elements. In addition to compulsory disclosure of any potential conflict of interest, transparent handling of potential conflicts of interest is an important confidence-building measure. For years, the trend has been to develop higher order (S2/S3) guidelines, and the German Society for Gynecology and Obstetrics (DGGG) has been no exception to the trend. In addition to its responsibility for specific S2 and S3 guidelines, the DGGG is also involved in numerous other interdisciplinary guidelines. When developing a guideline, it is essential to define the guideline's scope, identify aspects which require improvement and agree on the goals. Target groups affected by the guidelines should be involved if they are interested. Different formats (long and short versions, practical instructions, conventional or electronic decision aids, patient versions) are useful to disseminate the guideline. The guideline can be adapted to local circumstances to encourage implementation of its recommendations. Implementation can be measured using quality indicators. Feedback from practitioners is important as this highlights areas which require improvement. The medical scientific societies in Germany can look back on almost two decades of work spent on developing guidelines, most of it done by unpaid voluntary contributors, making this a very successful quality initiative.

[S3 guidelines on diagnostics and therapy of bipolar disorders: development process and essential recommendations]. / S3-Leitlinie zur Diagnostik und Therapie bipolarer Störungen: Entwicklungsprozess und wesentliche Empfehlungen.

Bipolar disorders are severe psychiatric disorders with extensive individual and health economic consequences. Starting in 2007 the first German evidence and consensus based guideline for diagnostics and treatment of bipolar disorders was developed which holds the potential of increasing confidence of therapists, patients and relatives in the decision-making process and improving healthcare service experiences of patients and relatives. Apart from recommendations for diagnostics and treatment the guidelines provide those for trialogue action, knowledge transfer and self-help and for strategies for healthcare provision of this complex disorder. In the present article the methodology and essential recommendations are outlined and complemented in specific topics by corresponding articles in this special issue. Due to restrictions of the length of this presentation there is the need to refer to the comprehensive version of the guidelines at several points also regarding a detailed discussion of the limitations.

[Inflammatory bowel diseases as multi-focal disorders: results from a multi-regional survey on bodily and psychosocial problems in IBD patients]. / Chronisch entzündliche Darmerkrankungen als multifokale Erkrankungen: körperliche und psychosoziale Probleme von Patienten mit CED. Ergebnisse eines Fragebogen-Surveys.

BACKGROUND: Patients with inflammatory bowel diseases (IBD) experience various bodily and psychosocial impairments. We report data from a recent German questionnaire survey. METHODS: The cross-sectional study was conducted in 2005 as a postal survey in three regions in West (Kiel and Luebeck, Regensburg) and East (Halle/Saale) Germany. Patients with Crohn's disease and ulcerative colitis (CD, UC) were recruited from specialized gastroenterological practices, university outpatient clinics, and the registry of a prominent patient organization (DCCV). The questionnaire followed the concept and distinctions of WHO's ICF and incorporated (inter-)nationally established items and scales (i. a. HADS). RESULTS: Survey responders (n = 1083, CD: 58 %, 65 % female) had a mean age of 42 years with an average disease duration of 13 years. 25 % suffered severely or very severely from their disease in general, one third stated at least severe fatigue, and 52 % felt profoundly affected by stress. A clinically relevant anxiety was observed in 24 % with no relevant difference between males and females. Depression was more common in men (29 %) than in women (21 %). Restrictions in social participation (family life, work) were actually prominent in at least a quarter of the responders. CONCLUSIONS: Beside somatic ailments typical for the disease, patients also reported multiple psychosocial impairments and participation restrictions and should hence profit from a multi- and interdisciplinary team care.

[Evidence-based and consented pathways for patients with inflammatory bowel diseases (IBD)]. / Evidenzbasierte und interdisziplinär konsentierte Versorgungspfade für Patientinnen und Patienten mit Morbus Crohn oder Colitis ulcerosa.

Crohn's disease and ulcerative colitis are diseases characterized by remission and relapse, an early age of onset and restrictions on activities and participation. IBD patients need a comprehensive, easily accessible and problem-oriented health care. This requires the integration and coordination of different health care sectors, medical and non-medical professionals, social and health care facilities and funding agencies. The pathways to guide patients through integrated health care were based on clinical considerations, interviews with patients and specialists, systematically searched evidence and results of a questionnaire survey. Within a systematic assessment-assignment approach relevant problems were identified and subsequently related to different medical and non-medical professionals, health care services and medical sectors. The pathways further imply (1) medical care according to evidence-based guideline recommendations, (2) patient education programs to foster shared decision making and self-management and (3) suggestions for further research. The pathways were consented in a consensus conference using nominal group process methods. Their feasibility and effect will be evaluated within a regional implementation project.

Systematic review and evidence-based consensus guideline on prevention of allergy and atopic eczema of the German Network on Allergy Prevention (ABAP).

Allergies are a meaningful public-health problem. Until now no evidence-based recommendations for allergy prevention exist. An evidence based guideline for primary and secondary prevention of allergies was developed in the course of the German Network on Allergy Prevention (Aktionsbündnis Allergiepräven-tion, ABAP) with support of the German Ministry of Health. Results of the systematic evidence search and the consented recommendations are presented here. After an appropriate search strategy was developed, a systematic literature search was performed in electronic databases (Cochrane library, MEDLINE, EMBASE). Furthermore four selected journals were hand-searched and reference lists of actual reviews as well as grey literature was screened. Some 3 500 references were retrieved initially and a two-stage filter process on the relevance was applied by screening titles and abstracts and subsequently full-text papers. For the critical methodological appraisal modifications of international checklists were used. A total of 323 studies were included and evaluated. These comprised 3 Cochrane Reviews, 7 meta-analyses, 37 randomized controlled trials (RCTs) as well as 102 cohort and 174 case-control-studies. The following levels of evidence were applied: 3x1a, 21x1b, 5x2a, 59x2b, 1x3a, 45x3b, 189x4. These studies were summarized in a form of a systematic review and corresponding recommendations were formulated. The latter were consented by members of the abap steering committee in two consensus meeting where the method of a nominal group process was applied. For the first time recommendations for the prevention of allergies were developed on a high methodological standard. The content and modifications reflect the existing evidence.

Characterization of human non-small cell lung cancer (NSCLC) cell lines for expression of MHC, co-stimulatory molecules and tumor-associated antigens.

A panel of 31 long-term non-small cell lung cancer (NSCLC) cell lines was examined for the expression of protein and/or mRNA transcripts for 11 distinct immune response related molecules or tumor associated antigens (TAA). To assess whether cytokine stimulation might up-regulate expression of the genes of interest, cells were cultured in 500 U/ml of gamma-interferon (gamma-IFN) for 48-72 h prior to analysis. Major histocompatibility complex (MHC) Class I antigens were detected by indirect immunofluorescence and were constitutively expressed on all of the cell lines. The average of the mean fluorescence intensity (MFI) measured 222+/-22. gamma-IFN stimulation produced a significant increase to 482+/-36. For MHC Class II only 7/31 cell lines (23%) exhibited constitutive expression, while gamma-IFN treatment had a dramatic effect and yielded 18/31 (58%) positive cell lines. The co-stimulatory molecules CD80 and CD86 were examined by direct immunofluorescence for cell surface expression and RT-PCR amplification for mRNA. CD80 protein was not detected at all, while an insignificant percentage of cells were positive (mean 2%) for CD86 in all cell lines tested. gamma-IFN had no apparent effect on CD80 or CD86 protein expression. Constitutive CD80 or CD86 mRNA levels were observed in 45 and 61% of the NSCLC lines, respectively. These percentages increased to 77% and 90% with gamma-IFN. Cell surface phenotypic analysis for TAA revealed positive populations in 28/31 cell lines (90%) for Her-2/neu, 18/31 (58%) for CEA and 8/31 (26%) for GD-2, with gamma-IFN having no effect. After gamma-IFN stimulation, RT-PCR amplification for Mage-1, -2, -3 and WT-1 detected mRNA in 33%, 33%, 44% and 70% of the cell lines, respectively. Overall, gamma-IFN stimulation led to the up-regulation of MHC Class I molecules and class II molecules as well as CD80 and CD86 mRNA transcripts. This survey represents the first comprehensive analysis of NSCLC cell lines for a variety of molecules that could play an important role in the generation of an NSCLC anti-tumor CD8+ cytotoxic T lymphocyte (CTL) response.

Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-kappaB and NFAT.

Pre-T cell antigen receptor (pre-TCR) signaling plays a crucial role in the development of immature T cells. Although certain aspects of proximal pre-TCR signaling have been studied, the intermediate signal transducers and the distal transcription modulators have been poorly characterized. We report here a correlation between pre-TCR signaling and a biphasic rise in the cytosolic Ca2+ concentration. In addition, we show that constitutive pre-TCR signaling is associated with an increased rate of Ca2+ influx through store-operated plasma membrane Ca2+ channels. We show also that the biphasic nature of the observed pre-TCR-induced rise in cytosolic Ca2+ differentially modulates the activities of the transcription factors NF-kappaB and NFAT in developing T cells.

Truncated elongation factor G lacking the G domain promotes translocation of the 3' end but not of the anticodon domain of peptidyl-tRNA.

The mechanism by which elongation factor G (EF-G) catalyzes the translocation of tRNAs and mRNA on the ribosome is not known. The reaction requires GTP, which is hydrolyzed to GDP. Here we show that EF-G from Escherichia coli lacking the G domain still catalyzed partial translocation in that it promoted the transfer of the 3' end of peptidyl-tRNA to the P site on the 50S ribosomal subunit into a puromycin-reactive state in a slow-turnover reaction. In contrast, it did not bring about translocation on the 30S subunit, since (i) deacylated tRNA was not released from the P site and (ii) the A site remained blocked for aminoacyl-tRNA binding during and after partial translocation. The reaction probably represents the first EF-G-dependent step of translocation that follows the spontaneous formation of the A/P state that is not puromycin-reactive [Moazed, D. & Noller, H. F. (1989) Nature (London) 342, 142-148]. In the complete system--i.e., with intact EF-G and GTP--the 50S phase of translocation is rapidly followed by the 30S phase during which the tRNAs together with the mRNA are shifted on the small ribosomal subunit, and GTP is hydrolyzed. As to the mechanism of EF-G function, the results show that the G domain has an important role, presumably exerted through interactions with other domains of EF-G, in the promotion of translocation on the small ribosomal subunit. The G domain's intramolecular interactions are likely to be modulated by GTP binding and hydrolysis.

Deposition and clearance of 2 micron particles in the tracheobronchial tree of normal subjects--smokers and nonsmokers.

Deposition and clearance of inhaled particles of iron oxide labeled with (198)Au were studied in 19 normal subjects (10 nonsmokers and 9 smokers). For this purpose, monodisperse aerosols of particles with a 2 mu diameter were produced in a spinning disc atomizer. Thoracic counts and images with a scintillation camera were begun immediately after inhalation of the aerosol and continued for 6 hr. In all subjects, smokers and nonsmokers, the deposition of the particles was uniform throughout both lung fields, with approximately half of the particles deposited in the ciliated airways (tracheobronchial deposition) and half in the nonciliated airways (alveolar deposition). Tracheobronchial clearance in nonsmokers occurred immediately after inhalation, first at a fast rate for particles deposited in the largest and most central airways, and then at a slower rate for particles from the smaller and more peripheral airways. Photoscintigrams showed that the particles cleared steadily with no retention in any area. The general pattern of clearance may be likened to a model of multiple conveyor belts with speed increasing from the peripheral to the central airways in such a way as to prevent "particle jams" at airway confluence points. In smokers, tracheobronchial clearance was delayed for periods of 1-4 hr after inhalation. Furthermore, in contrast with the findings in nonsmokers, significant clearance was still occurring in many of the smokers in the 5th and 6th hr after inhalation. Also, photoscintigrams showed an abnormal accumulation of particles in the large airways several hours after inhalation of the aerosol.