Vasoaktive Effekte von Brain Natriuretic Peptide auf den Lungenkreislauf im Modell der isoliert ventilierten und blutfrei perfundierten Kaninchenlunge

Die pulmonal-arterielle Hypertonie stellt eine schwere Erkrankung mit einer stark eingeschränkten Prognose dar. Bedeutende pathophysiologische Mechanismen sind die Vasokonstriktion sowie der fortschreitende Umbau des pulmonalen Gefäßbetts. Im Verlauf der Erkrankung kommt es zu ansteigenden Plasmaspiegeln des B-Type Natriuretic Peptides (BNP). Diese korrelieren mit der Schwere der Erkrankung und gelten als prognostische Indikatoren. BNP bewirkt über den Natriuretischen Peptid Rezeptor Typ-A (NPR-A) die Generierung von zyklischem GMP. Die vasodilatierende und antiproliferative Wirkung zyklischer Nukleotide hat zur therapeutischen Anwendung cGMP und cAMP-generierender Substanzen wie NO, Sildenafil und Iloprost im Rahmen der PAH geführt. Zudem kann über die inhalative Verabreichung eine pulmonale Selektivität mit Vermeidung systemischer Nebenwirkungen erzielt werden. Zielsetzung der vorliegenden Arbeit war es, die hämodynamischen Auswirkungen von BNP auf die Lungenzirkulation zu untersuchen. Es galt zu prüfen, ob die Beeinflussung des pulmonal-arteriellen Drucks durch sowohl intravasale als auch inhalative Applikation möglich ist. Der Klärung bedurfte es, ob die beobachteten Effekte über cGMP vermittelt werden. Die Studien wurden an einer experimentell erzeugten akuten pulmonalen Hypertonie am etablierten Modell der isoliert ventilierten und blutfrei perfundierten Kaninchenlunge durchgeführt. Untersucht wurden der pulmonal-arterielle Druck, das relative Lungengewicht als Maß der Ödementwicklung sowie die zirkulierende cGMP-Konzentration, die mittels eines kommerziellen Radioimmunoessays bestimmt wurde. In der vorliegenden Arbeit wurde die pulmonal-arteriell drucksenkende Wirkung von BNP gezeigt. Der Effekt wurde sowohl unmittelbar nach intravasaler als auch – etwas geringer ausgeprägt - inhalativer Applikation beobachtet. Damit gelang erstmalig der Nachweis einer erhaltenen Vasoaktivität von BNP nach Aerosolierung und inhalativer Applikation. Die Drucksenkung wurde jeweils von einem signifikanten Anstieg der zirkulierenden cGMP-Konzentration begleitet. Die beobachteten Effekte und Konzentrationverläufe von cGMP legen nahe, dass die vasodilatierende Wirkung von BNP unabhängig vom Applikationsmodus, über den NPR-A-cGMP-Signalweg vermittelt wird

Home noninvasive ventilatory support for patients with chronic obstructive pulmonary disease:patient selection and perspectives

Long-term or home mechanical noninvasive ventilation (Home-NIV) has become a well-established form of therapy over the last few decades for chronic hypercapnic COPD patients in European countries. However, meta-analyses and clinical guidelines do not recommend Home-NIV for COPD patients on a routine basis. In particular, there is ongoing debate about Home-NIV in chronic hypercapnic COPD regarding the overall effects, the most favorable treatment strategy, the selection of eligible patients, and the time point at which it is prescribed. The current review focuses on specific aspects of patient selection and discusses the various scientific as well as clinical-guided perspectives on Home-NIV in patients suffering from chronic hypercapnic COPD. In addition, special attention will be given to the topic of ventilator settings and interfaces

microRNA Expression Profile of Purified Alveolar Epithelial Type II Cells

Alveolar type II (ATII) cells are essential for the maintenance of the alveolar homeostasis. However, knowledge of the expression of the miRNAs and miRNA-regulated networks which control homeostasis and coordinate diverse functions of murine ATII cells is limited. Therefore, we asked how miRNAs expressed in ATII cells might contribute to the regulation of signaling pathways. We purified "untouched by antibodies" ATII cells using a flow cytometric sorting method with a highly autofluorescent population of lung cells. TaqMan® miRNA low-density arrays were performed on sorted cells and intersected with miRNA profiles of ATII cells isolated according to a previously published protocol. Of 293 miRNAs expressed in both ATII preparations, 111 showed equal abundances. The target mRNAs of bona fide ATII miRNAs were used for pathway enrichment analysis. This analysis identified nine signaling pathways with known functions in fibrosis and/or epithelial-to-mesenchymal transition (EMT). In particular, a subset of 19 miRNAs was found to target 21 components of the TGF-β signaling pathway. Three of these miRNAs (miR-16-5p, -17-5p and -30c-5p) were down-modulated by TGF-β1 stimulation in human A549 cells, and concomitant up-regulation of associated mRNA targets (BMPR2, JUN, RUNX2) was observed. These results suggest an important role for miRNAs in maintaining the homeostasis of the TGF-β signaling pathway in ATII cells under physiological conditions

Obesity hypoventilation syndrome treated with non-invasive ventilation:Is a switch to CPAP therapy feasible?

Background and objective: Obesity hypoventilation syndrome (OHS) can be treated with either continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) therapy; the device choice has important economic and operational implications. Methods: This multicentre interventional trial investigated the safety and short-term efficacy of switching stable OHS patients who were on successful NIV therapy for ≥3 months to CPAP therapy. Patients underwent an autotitrating CPAP night under polysomnography (PSG); if the ensuing parameters were acceptable, they were sent home on a fixed CPAP for a 4–6-week period. It was hypothesized that blood gas analysis, PSG parameters and lung function tests would remain unchanged. Results: A total of 42 OHS patients were recruited, of whom 37 patients were switched to CPAP therapy. All patients had a history of severe obstructive sleep apnoea syndrome; chronic obstructive pulmonary disease (COPD) (Global Initiative for Obstructive Lung Disease (GOLD) I/II) was present in 52%. Regarding the primary outcome, 30 of 42 patients (71%, 95% CI: 55–84%) maintained daytime partial pressure of carbon dioxide (PaCO2) levels ≤45 mm Hg after the home CPAP period. There was no further impairment in quality of life, sleep parameters or lung function. Interestingly, 24 patients (65%) preferred CPAP as their long-term therapy, despite the high pressure levels used (mean: 13.8 ± 1.8 mbar). After the CPAP period, 7 of 37 patients were categorized as CPAP failure, albeit only due to mild hypercapnia (mean: 47.9 ± 2.7 mm Hg). Conclusion: It is feasible to switch most stable OHS patients from NIV to CPAP therapy, a step that could significantly reduce health-related costs. The auto-adjusted CPAP device, used in combination with the analysis of the PSG and capnometry, is a valid titration method in OHS patients

Cell-binding IgM in CSF is distinctive of multiple sclerosis and targets the iron transporter SCARA5

Intrathecal IgM production in multiple sclerosis (MS) is associated with a worse disease course. To investigate pathogenic relevance of autoreactive IgM in MS, CSF from two independent cohorts, including MS patients and controls, were screened for antibody binding to induced pluripotent stem cell-derived neurons and astrocytes, and a panel of CNS- related cell lines. IgM binding to a primitive neuro-ectodermal tumour cell line discriminated 10% of MS donors from controls. Transcriptomes of single IgM producing CSF B cells from patients with cell-binding IgM were sequenced and used to produce recombinant monoclonal antibodies for characterisation and antigen identification. We produced 5 cell-binding recombinant IgM antibodies, of which one, cloned from an HLA-DR + plasma-like B cell, mediated antigen-dependent complement activation. Immunoprecipitation and mass spectrometry, and biochemical and transcriptome analysis of the target cells identified the iron transport scavenger protein SCARA5 as the antigen target of this antibody. Intrathecal injection of a SCARA5 antibody led to an increased T cell infiltration in an EAE model. CSF IgM might contribute to CNS inflammation in MS by binding to cell surface antigens like SCARA5 and activating complement, or by facilitating immune cell migration into the brain

Complex attosecond waveform synthesis at fel fermi

Free-electron lasers (FELs) can produce radiation in the short wavelength range extending from the extreme ultraviolet (XUV) to the X-rays with a few to a few tens of femtoseconds pulse duration. These facilities have enabled significant breakthroughs in the field of atomic, molecular, and optical physics, implementing different schemes based on two-color photoionization mechanisms. In this article, we present the generation of attosecond pulse trains (APTs) at the seeded FEL FERMI using the beating of multiple phase-locked harmonics. We demonstrate the complex attosecond waveform shaping of the generated APTs, exploiting the ability to manipulate independently the amplitudes and the phases of the harmonics. The described generalized attosecond waveform synthesis technique with an arbitrary number of phase-locked harmonics will allow the generation of sub-100 as pulses with programmable electric fields

Roadmap on photonic, electronic and atomic collision physics: I. Light-matter interaction

We publish three Roadmaps on photonic, electronic and atomic collision physics in order to celebrate the 60th anniversary of the ICPEAC conference. In Roadmap I, we focus on light-matter interaction. In this area, studies of ultrafast electronic and molecular dynamics have been rapidly growing, with the advent of new light sources such as attosecond lasers and X-ray free electron lasers. In parallel, experiments with established synchrotron radiation sources and femtosecond lasers using cutting- edge detection schemes are revealing new scientific insights that have never been exploited. Relevant theories are also being rapidly developed. Target samples for photon-impact experiments are expanding from atoms and small molecules to complex systems such as biomolecules, fullerene, clusters and solids. This Roadmap aims at looking back along the road, explaining the development of these fields, and looking forward, collecting contributions from twenty leading groups from the field

Evolving Epidemiology of Home Mechanical Ventilation: A Rapidly Growing Challenge for Patient Care

Zusammenfassung Hintergrund Die au ss erklinische Beatmung erfahrt in Deutschland eine rasante Entwicklung. Patienten mit chronischer respiratorischer Insuffizienz werden in deutlich zunehmender Zahl nichtinvasiv oder invasiv in einem hauslichen Setting beatmet. Diese Patienten mussen im Rahmen von Kontrolluntersuchungen oder Akut-Problemen immer wieder stationar behandelt werden. Die fur die Steuerung des Gesundheitswesens wichtige Entwicklung der stationaren Behandlungsfalle ist bislang ebenso unbekannt wie die Morbiditat und Krankenhaussterblichkeit der hauslich beatmeten Patienten. Methode Von 2006-2016 wurden alle stationaren Aufnahmen analysiert, bei denen eine Langzeit-Abhangigkeit vom Respirator (mindestens 3 Monate) bestand (Daten des Deutschen Statistischen Bundesamtes). Ergebnisse Es zeigte sich eine exponentielle Zunahme von stationaren Behandlungsfallen, wobei 2006 noch 24845 Patienten stationar behandelt werden mussten, im Jahr 2016 hingegen 86117 Patienten. Im gleichen Zeitraum zeigte sich eine Abnahme der Krankenhaussterblichkeit von 13,2% (2006) auf 5,7% (2016). Im Jahr 2016 wurden zudem 47% der Patienten auf einer Intensiv-, Weaning- oder uberwachungsstation behandelt. Es bestand eine Vielzahl von internistischen und neurologischen Komorbiditaten, welche in Verbindung mit der chronischen respiratorischen Insuffizienz die gro ss e Patientenkohorte als schwer krankes Patientenkollektiv charakterisierte. Fuhrende Diagnosen waren die COPD mit 58% und eine Vielzahl kardiologischer Diagnosen. Auffallig viele Patienten (24%) zeigten eine Einschrankung der Nierenfunktion bis hin zur Dialysepflichtigkeit. Diskussion Die rasante Zunahme der au ss erklinischen Beatmung hat wesentlichen Einfluss auf die Entwicklung der Krankenhauslandschaft in Deutschland. Der exponentielle Anstieg der sehr pflegeintensiven Patienten stellt das Gesundheitssystem vor extreme Herausforderungen und erfordert eine gesundheitspolitische Diskussion uber die Grenzen des Systems. Abstract Background Home mechanical ventilation is dramatically evolving in Germany. Patients with non-invasive and invasive ventilation are increasingly treated at home. In-hospital treatment of these patients is also necessary either for control visits or the management of acute medical problems. However, the development of in-hospital patient care, morbidity and mortality of these patients is unknown. Methods All patients with long-term dependence on mechanical ventilation for more than three months requiring hospitalisation between 2006 and 2016 were analysed (data obtained from the Federal Statistical Office of Germany). Results There was an exponential increase in the number of in-patients with long-term dependence of mechanical ventilation. While 24845 patients were treated in-hospital in 2006, 86117 patients were treated in 2016. Correspondingly, mortality decreased from 13.2% (2006) to 5.7% (2016). In addition, in 2016 47% of all patients were treated on the intensive care or high dependency care unit. Overall, patients had been severely ill, as there were plenty of medical and neurological co-morbidities. The most common diagnosis was COPD with 58% of all cases, followed by several cardiology diagnosis. A high number of patients had an impairment of renal function (24%), in part requiring dialysis. Conclusions The rapid development of home mechanical ventilation substantially impacts on the development of the hospital landscape in Germany. The exponential increase of these care-intensive patients is challenging for the health care system and requires a discussion about its limits

Mass Cytometry of CSF Identifies an MS-Associated B-cell Population

OBJECTIVE To identify an MS-specific immune cell population by deep immune phenotyping and relate it to soluble signaling molecules in CSF. METHODS We analyzed surface expression of 22 markers in paired blood/CSF samples from 39 patients using mass cytometry (cytometry by time of flight). We also measured the concentrations of 296 signaling molecules in CSF using proximity extension assay. Results were analyzed using highly automated unsupervised algorithmic informatics. RESULTS Mass cytometry objectively identified a B-cell population characterized by the expression of CD49d, CD69, CD27, CXCR3, and human leukocyte antigen (HLA)-DR as clearly associated with MS. Concentrations of the B cell-related factors, notably FCRL2, were increased in MS CSF, especially in early stages of the disease. The B-cell trophic factor B cell activating factor (BAFF) was decreased in MS. Proteins involved in neural plasticity were also reduced in MS. CONCLUSION When analyzed without a priori assumptions, both the soluble and the cellular compartments of the CSF in MS were characterized by markers related to B cells, and the strongest candidate for an MS-specific cell type has a B-cell phenotype

Clinical evidence for respiratory insufficiency type II predicts weaning failure in long-term ventilated, tracheotomised patients: a retrospective analysis

Abstract Background Patients who require a prolonged weaning process comprise a highly heterogeneous group of patients amongst whom the outcome differs significantly. The present study aimed to identify the factors that predict whether the outcome for prolonged weaning will be successful or unsuccessful. Methods Data from tracheotomised patients who underwent prolonged weaning on a specialised weaning unit were assessed retrospectively via an electronic and paper-bound patient chart. Factors for weaning success were analysed by univariate and multivariate analyses. Results Out of the 124 patients examined, 48.4% were successfully weaned (n = 60). Univariate analysis revealed that long-term home mechanical ventilation prior to current weaning episode; time between intubation and the first spontaneous breathing trial (SBT); time between intubation and the first SBT of less than 30 days; lower PaCO2 prior to, and at the end of, the first SBT; and lower pH values at the end of the first SBT were predictors for successful weaning. Following multivariate analysis, the absence of home mechanical ventilation prior to admission, a maximum time period of 30 days between intubation and the first SBT, and a non-hypercapnic PaCO2 value at the end of the first SBT were predictive of successful weaning. Conclusions The current analysis demonstrates that the evidence for respiratory insufficiency type II provided by clinical findings serves as a predictor of weaning failure