[Linguistic Validation of the "German Lung Fibrosis Health Related Quality of Life Questionnaire"]. / Sprachliche Validierung des Fibrose-Fragebogens zur Erfassung der Lebensqualität bei Patienten mit idiopathischer Lungenfibrose und idiopathischer nichtspezifischer interstitieller Pneumonie.

Health status and quality of life are impaired in patients with idiopathic pulmonary fibrosis (IPF) and idiopathic non-specific interstitial fibrosis (iNSIP). In Germany exists only the K-BILD questionnaire for patients with ILD 1 in a professional translation by Kreuter et al. 2 This questionnaire focuses on the main problems in patients with progressive lung fibrosis in a limited manner. Therefore a new quality of life questionnaire for patients with idiopathic pulmonary fibrosis was developed and linguistically validated. METHODS: The linguistic validation of our questionnaire was carried out in a multistage process in collaboration with the developer of the questionnaire and bilingual, professional translators. Review by the developers and back translations as well as clinical assessment by IPF- and iNSIP-patients ensured that the translated questionnaire reflected the intention of the original English version of our questionnaire.Cross-validation was carried out with the St. Georges Respiratory Questionnaire (SGRQ). RESULTS: The new questionnaire concerning the health status was composed in English and German language. The questions cover five scales (sensitivity, selectivity and symptoms like breathlessness and cough and a visual analog scale on general health status) with 23 items. CONCLUSIONS: The results show that the FFB maps the special needs of the patients with IPF and iNSIP well and can support clinical and scientific questions and can be helpful in monitoring the clinical course.

[Exercise Testing in Respiratory Medicine - DGP Recommendations]. / Belastungsuntersuchungen in der Pneumologie ­ Empfehlungen der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V.

This document replaces the DGP recommendations published in 1998 and 2013. Based on recent studies and a consensus conference, the indications, choice and performance of the adequate exercise testing method and its necessary technical and staffing setting are discussed. Detailed recommendations are provided: for blood gas analysis and right heart catheterization during exercise, walk tests, spiroergometry, and stress echocardiography. The correct use of different exercise tests is discussed for specific situations in respiratory medicine: exercise induced asthma, obesity, monitoring of rehabilitation or therapeutical interventions, preoperative risk stratification, and evaluation in occupational medicine.

[DGP Interstitial Lung Disease Patient Questionnaire]. / Patientenfragebogen zur Erfassung der Ursachen interstitieller und seltener Lungenerkrankungen ­ klinische Sektion der DGP.

BACKGROUND: Interstitial lung diseases (ILD) encompass different heterogeneous, mainly chronic diseases of the pulmonary interstitium and/or alveoli with known and unknown reasons. The diagnostic of ILD is challenging and should be performed interdisciplinary. The medical history is of major importance and therefore, in German-speaking countries the Frankfurter Bogen (published in 1985) was utilised to scrutinise the medical history of the patient. This by now more than 30-years-old questionnaire requires a revision with regard to content and language. METHOD: Under the auspices of the clinical section of the DGP the new Interstitial Lung Disease Patient Questionnaire was developed in collaboration amongst pulmonologist, occupational medicine physicians and psychologists and supported by patient support groups. The questionnaire was finally optimised linguistically with the help of patients. RESULTS: The newly developed patient questionnaire for interstitial and rare lung diseases encompasses different domains: initial and current symptoms, medical history questions including prior drug treatments, previous pulmonary and extrapulmonary diseases, potential exposition at home, work and leisure time as well as family history and travelling. CONCLUSION: The newly developed questionnaire can facilitate the diagnosis in patients with suspicion on interstitial lung disease in clinical routine.

[Postpyloric feeding tubes for surgical intensive care patients. Pilot series to evaluate two methods for bedside placement]. / Postpylorische Ernährungssonden bei operativen Intensivpatienten. Pilotserie zur Bewertung von zwei Methoden zur bettseitigen Anlage.

Bedside placement of postpyloric feeding tubes in surgical intensive care patients: a pilot series to evaluate two methods. Early enteral feeding is thought to be a key factor in maintaining the integrity of the gastrointestinal tract mucosal barrier associated with less bacterial translocation and decreased stimulation of the systemic inflammatory response and subsequent improved outcome in intensive care patients. Thus enteral feeding by nasogastric tubes is the preferred route of nutritional support for most surgical intensive care patients. However, intensive care patients with delayed gastric emptying and poor intestinal motility may not tolerate gastric feeding and may therefore benefit from postpyloric feeding. Postpyloric feeding tube placement may be achieved by endoscopic procedures or different bedside techniques with variable success. In the present study two feeding tubes for bedside postpyloric placement without endoscopic assistance were compared. The time to successful positioning was compared for jejunal feeding tubes from the companies Cook (Tiger 2™) and PortaMedical (Corflo-Tube®). The description for the Tiger 2™ states that because of its design slight residual peristalsis can cause it to migrate from the stomach to the jejunum. The Corflo-Tube® is also positioned at the bedside with the help of a detector and a monitor which maps the movements of the magnetic tip of the mandrin as it is pushed forward. Patients receiving early enteral nutrition through a gastric tube and exhibiting enhanced reflux, in spite of the head of the bed being raised and the administration of prokinetics randomly received either a Tiger 2™ or a Corflo-Tube®. The study included 41 patients from an intensive care ward for surgical patients and 13 out of 20 Tiger 2™-Tubes (65%) and 16 out of 21 Corflo-Tubes® (76%) were successfully positioned (p>0.05). The median time to successful positioning with the Corflo-Tubes® was 0.83 h (range 0.06-2.5 h), which was significantly shorter than the 24 h (range 2-72 h) found with the Tiger 2™ (p<0.001). There was no significant difference between the groups with respect to the period between the insertion of the tubes and the attainment of complete enteral nutrition, corresponding to the calculated individual calorie requirements. These tubes offer a good alternative to more demanding procedures as they are easy to handle and rapidly available. They confer clinical and cost advantages in terms of the early establishment of enteral feeding, no routine X-ray confirmation in the case of the Corflo-Tube® and avoidance of endoscopic guidance for tube placement or parenteral nutrition. In addition they are always justified in the event of a lack of endoscopic positioning.

[Pulmonary hypertension due to chronic lung disease. Recommendations of the Cologne Consensus Conference 2010]. / Pulmonale Hypertonie bei chronischen Lungenerkrankungen. Empfehlungen der Kölner Konsensus-Konferenz 2010.

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of pulmonary hypertension which may affect quality of life and survival of these patients in a similar manner. In June 2010, a group of German experts met in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology. One of the working groups was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Evidence for a solar system-size accretion disk around the massive protostar G192.16-3.82.

Seven-millimeter continuum observations of a massive bipolar outflow source, G192.16-3.82, were made at a milli-arc-second resolution with a capability that links the National Radio Astronomy Observatory's Very Large Array radio interferometer with the Very Long Baseline Array antenna, located in Pie Town, New Mexico. The observations provide evidence for a true accretion disk that is about the size of our solar system and located around a massive star. A model of the radio emission suggests the presence of a binary protostellar system. The primary protostar, G192 S1, at the center of the outflow, with a protostar mass of about 8 to 10 times the solar mass, is surrounded by an accretion disk with a diameter of 130 astronomical units (AU). The mass of the disk is on the order of the protostar mass. The outflow is poorly collimated with a full opening angle of about 40 degrees; there is no indication of a more highly collimated jetlike component. The companion source, G192 S2, is located 80 AU north of the primary source.

[Pulmonary arterial hypertension in collagenoses]. / Pulmonal arterielle Hypertonie bei Kollagenosen.

Pulmonary arterial hypertension is a rare disease of small pulmonary arteries of unknown origin characterised by endothelial dysfunction and cellular proliferation throughout all vessel layers, resulting in progressively elevated pulmonary arterial resistance with increasing right heart strain and finally right heart failure. The condition may develop in connective tissue diseases with variable frequency leading to a substantial worsening of prognosis. However, the spectrum of therapeutic options has broadened significantly in recent years. Several compounds have gained approval that act mainly as pulmonary vasodilators. Further drugs are under investigation, some of which target pulmonary vascular remodeling. Echocardiography remains the primary examination for disease detection. To classify pulmonary hypertension definite hemodynamic evaluation by means of right heart catheterisation and a thorough differential diagnosis are essential to provide the basis for further treatment. For differential therapy and assessment of follow-up profound knowledge is required, pointing to the need for close cooperation with specialised centres.

Binarity and Accretion in AGB Stars: HST/STIS Observations of UV Flickering in Y Gem.

Binarity is believed to dramatically affect the history and geometry of mass loss in AGB and post-AGB stars, but observational evidence of binarity is sorely lacking. As part of a project to search for hot binary companions to cool AGB stars using the GALEX archive, we discovered a late-M star, Y Gem, to be a source of strong and variable UV and X-ray emission. Here we report UV spectroscopic observations of Y Gem obtained with the Hubble Space Telescope that show strong flickering in the UV continuum on time-scales of ≲ 20 s, characteristic of an active accretion disk. Several UV lines with P-Cygni-type profiles from species such as Si IV and C IV are also observed, with emission and absorption features that are red- and blue-shifted by velocities of ~500 km s-1 from the systemic velocity. Our model for these (and previous) observations is that material from the primary star is gravitationally captured by a companion, producing a hot accretion disk. The latter powers a fast outflow that produces blue-shifted features due to absorption of UV continuum emited by the disk, whereas the red-shifted emission features arise in heated infalling material from the primary. The outflow velocities support a previous inference by Sahai et al. (2015) that Y Gem's companion is a low-mass main-sequence star. Blackbody fitting of the UV continuum implies an accretion luminosity of about 13 L⊙, and thus a mass-accretion rate > 5 × 10-7M⊙ yr-1; we infer that Roche lobe overflow is the most likely binary accretion mode for Y Gem.

Luteolin protects rat PC12 and C6 cells against MPP+ induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway.

Oxidative stress is central to neuronal damage in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. In consequence, activation of the cerebral oxidative stress defence is considered as a promising strategy of therapeutic intervention. Here we demonstrate that the flavone luteolin confers neuroprotection against oxidative stress via activation of the nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor central to the maintenance of the cellular redox homeostasis. Luteolin protects rat neural PC12 and glial C6 cells from N-methyl-4-phenyl-pyridinium (MPP+) induced toxicity in vitro and effectively activates Nrf2 as shown by ARE-reporter gene assays. This protection critically depends on the activation of Nrf2 since downregulation of Nrf2 by shRNA completely abrogates the protection of luteolin in vitro. Furthermore, the neuroprotective effect of luteolin is abolished by the inhibition of the luteolin-induced ERK1/2-activation. Our results highlight the relevance of Nrf2 for neural cell survival conferred by flavones. In particular, we identified luteolin as a promising lead for the search of orally available, blood brain barrier permeable compounds to support the therapy of neurodegenerative disorders.

[Pulmonary hypertension due to chronic lung disease: Recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Lungenkrankheiten: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Membrane fluidity and lipid composition of rat small intestinal brush-border membranes during postnatal maturation.

Fluidity and lipid composition of rat small intestinal brush-border membranes (BBM) were studied during maturation in five age groups: newborns, sucklings (1-3 weeks), weaned (4-6 weeks), juveniles (8-10 weeks), and adults (12 weeks). Brush-border membrane fluidity was measured by steady-state fluorescence polarization. Fluorescent probes used were: 1,6-diphenyl-1,3,5-hexatriene, 1-(4-trimethylammonium)phenyl)-6-phenyl-1,3,5-hexatriene, and a set of n-(9-anthroyloxy) fatty acids. Fluorescence anisotropy measured with all fluorophores was increased in adult versus newborn rats (P less than 0.004). The weight ratio of saturated to cis-unsaturated fatty acids increased from birth to the suckling age (P less than 0.0004). The cholesterol to phospholipid molar ratio increased from birth to the weaned age (P less than 0.0001). Cholesterol to protein ratio and phospholipid to protein ratio decreased after the weaned age (P less than 0.004). The results not only describe maturational changes of brush-border membranes but also give a better understanding of the correlations between biophysical and biochemical data in biological membranes.

Regulation of insulin-like growth factor (IGF)-binding protein-6 and mannose 6-phosphate/IGF-II receptor expression in IGF-IL-overexpressing NIH 3T3 cells.

Insulin-like growth factor II (IGF-II)-overexpressing NIH 3T3 cells were used to examine regulation of insulin-like growth factor binding protein (IGFBP) and mannose 6-phosphate (M6P)/IGF-II receptor expression. Ligand blot analysis of conditioned media indicated a predominant IGFBP of 26-28 kilodaltons the abundance of which is 3- to 10-fold higher in media of IGF-II-overexpressing cells. The IGFBP level in control cell medium was increased by incubation in the presence of IGF-II, IGF-I, and mutant IGF-II forms with reduced affinities for IGF-I or M6P/IGF-II receptors. Further proof that IGF-II regulated the IGFBP was obtained by incubation of IGF-II overexpressing cells in the presence of antisense IGF-II oligomers or anti-IGF-II antibodies, which resulted in significant reduction of the IGFBP in conditioned medium. Mouse IGFBP-6 mRNA expression was increased in IGF-II-overexpressing or IGF-II-treated control cells. The IGFBP contained O-linked carbohydrate residues and was recognized by an antiserum to rat IGFBP-6. To determine whether IGFs were influencing proteolytic degradation of IGFBPs, cell-free conditioned media were incubated at 37 C with recombinant human IGFBPs. At neutral pH proteolysis of IGFBP-5 occurred during incubation in conditioned media from control and IGF-II-overexpressing cells. Upon acidification of the medium samples, only the degradation of IGFBP-6 was prevented in IGF-II-overexpressing cell-conditioned medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Proteolysis of insulin-like growth factor binding protein-5 by pregnancy serum and amniotic fluid.

Incubation of iodinated recombinant human insulin-like growth factor binding protein (rhIGFBP)-5 with pregnancy serum or amniotic fluid resulted in the formation of 22- and 15 kDa fragments. Non-pregnancy serum did not contain IGFBP-5 proteolytic activity. Size fractionation revealed the proteolytic activity both in serum and amniotic fluid in a > 100 kDa fraction which co-eluted in gel filtration with proteins of approx. 200 kDa. The IGFBP-5 protease activity was inhibited by EDTA, phenanthroline and PMSF. The formation of proteolytic fragments was also observed using 125I labeled rhIGFBP-3 and -4 but not with rhIGFBP-1 or -6 as substrate. The data demonstrate that pregnancy serum and amniotic fluid contain a very similar cation-dependent serine protease which degrades IGFBP-3, -4 and -5.

Proteolysis of insulin-like growth factors (IGF) and IGF binding proteins by cathepsin D.

Various proteinases have been postulated to function in limited proteolysis of insulin-like growth factor binding proteins (IGFBPs) contributing to the regulation of IGF bioavailability. In this study, we report on the in vitro degradation of IGFs and IGFBPs by the purified acidic aspartylprotease cathepsin D that has been shown to proteolyze IGFBP-3. Recombinant human [125I] IGFBP-1 to -5 were processed by cathepsin D to fragments of defined sizes in a concentration dependent manner, whereas IGFBP-6 was not degraded. Ligand blotting revealed that none of the IGFBP-1 or -3 fragments formed by cathepsin D retain their ability to bind IGF. By N-terminal sequence analysis of nonglycosylated IGFBP-3 fragments produced by cathepsin D, at least four different cleavage sites were identified. Some of these cleavage sites were identical or differed by one amino acid from sites used by other IGFBP proteases described. The IGFBP-3 and -4 cleavage sites produced by cathepsin D are located in the nonconserved central region. IGF-I and -II, but not the unrelated platelet-derived growth factor BB, were degraded by cathepsin D in a time and concentration-dependent manner. We speculate that the major functional site of cathepsin D is intracellular and may be involved 1) in the selected clearance either of IGFBP or IGFs via different endocytic pathways or 2) in the general lysosomal inactivation of the IGF system.

Biodegradation of phenol and p-cresol by the hyphomycete Scedosporium apiospermum.

A hyphomycete with the ability to utilize phenol and p-cresol as carbon and energy source was isolated from soil and subsequently identified as Scedesporium apiospermum. The identification of degradation metabolites and the detection of the corresponding catabolic enzymes in crude extracts enabled us to propose different pathways for the degradation of both phenol and p-cresol in this organism. Generally, the catabolism proceeded via three different dihydroxylated intermediates (catechol, hydroxyhydroquinone and protocatechuate) which were intradiolically cleaved by the corresponding inducible dioxygenases and further catabolized via the 3-oxoadipate pathway.

Biodegradation of phenylbenzoate and some of its derivatives by Scedosporium apiospermum.

Scedosporium apiospermum, a recently isolated phenol-degrading hyphomycete, was shown to be able to productively utilise the diaryl ester phenylbenzoate as its sole source of carbon and energy. The characterisation of degradation intermediates together with the detection of the corresponding catabolic enzymes in crude extracts enabled us to propose a pathway for the degradation of this diaryl ester. According to our results, an inducible esterase initiated the biodegradation of phenylbenzoate by hydrolysing the ester bond to yield stoichiometric amounts of phenol and benzoate. While phenol was catabolised via catechol and hydroxyhydroquinone, the benzoate was further degraded via the protocatechuate branch of the ortho-pathway. In addition, the fungus utilised p-tolylbenzoate and 4-chlorophenylbenzoate by employing similar catabolic sequences.

Incidence of neuronal ceroid-lipofuscinoses in West Germany: variation of a method for studying autosomal recessive disorders.

The incidence of neuronal ceroid-lipofuscinoses (NCL) in West Germany was determined using a novel method which is applicable to other autosomal recessively inherited diseases. Questionnaires were sent to all pediatric departments (answer rate 189/276, 68%), schools for the blind (39/46, 85%), and neuropathological institutes (15/22, 68%). Diagnoses were accepted only when based on firm clinical and/or electron microscopic criteria; 207 such identified patients were sorted according to year of birth. Plotting the cumulative number of new cases per year against the year of birth resulted in a slightly S-shaped curve. Before the year 1962, the curve is relatively flat, probably due to inefficient case registration. Between 1968 and 1977, the slope of the curve is constant--a steep, nearly straight line. Thereafter the curve flattens out again, likely due to inefficient registration of young, still undiagnosed patients. We interpret the central segment of the curve, which is continuously straight over a period of 10 years and corresponds to 92 patients, as a period in which efficient registration of new cases occurred. The number of live births being 7,211,543 during the same period, the NCL incidence is calculated to be 1.28 per 100,000 live births (0.71 for juvenile NCL and 0.46 for late infantile NCL).

Leukodystrophy incidence in Germany.

Through a survey of all departments of pediatrics, neurology and neuropathology in Germany, we calculated the incidence of all major forms of leukodystrophy. Only diagnoses based on specific biochemical tests in association with typical findings and/or neuroradiologically proven white matter involvement were accepted. In accordance with these strict criteria, 617 cases of leukodystrophy were found (incidence of all forms: app. 2.0/100,000). Minimal incidence was estimated at 0.8/100,000 for adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN), 0.6/100,000 for metachromatic leukodystrophy (MLD), and 0.6/100,000 for Krabbe disease. Thus ALD/AMN is apparently underdiagnosed in Germany. A considerable proportion of leukodystrophies could not be classified in spite of adequate diagnostic procedures in experienced centers.

Increased plasma membrane fluidity and decreased receptor availability of nonmuscle cells in myotonic dystrophy.

Plasma membrane fluidity of intact nonmuscle cells from patients with myotonic dystrophy (MyD) was determined by fluorescence anisotropy measurements. Anisotropy values of the probe diphenylhexatriene were decreased in patient mononuclear cells (0.163 +/- 0.017, n = 13) versus controls (0.181 +/- 0.013, n = 13, P less than 0.01) and in patient platelets (0.087 +/- 0.017, n = 9) versus controls (0.137 +/- 0.015, n = 9, P less than 0.001) indicating increased plasma membrane fluidity in patient nonmuscle cells. Vasopressin plasma concentrations were increased in patients (7.4 +/- 2.1 pg/ml, n = 12) versus controls (4.5 +/- 1.4 pg/ml, n = 22, P less than 0.0005), whereas serum osmolality was normal. These data are compatible with a decreased vasopressin sensitivity in MyD patients. Specific binding of 125I-labelled vasoactive intestinal peptide (VIP) was decreased in patient mononuclear cells (2.9 +/- 0.9%/10(6) cells, n = 8) versus controls (5.2 +/- 1.6%/10(6) cells, n = 9, P less than 0.005) and receptor affinity for VIP was decreased in patient mononuclear cells (Kd = 0.26 +/- 0.05 nM, n = 8) versus controls (Kd = 0.19 +/- 0.02 nM, n = 9, P less than 0.005). In nonmuscle cells of MyD patients, increased membrane fluidity correlated with decreased receptor availability. This might explain the various endocrine defects described in MyD patients.