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Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A4 (LXA4), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15+/+ and Alox12/15−/− mice, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA4 significantly lowered transaminase levels only in Alox12/15−/− mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA4 injection attenuated selected parameters of disease progression in Alox12/15−/− mice, its beneficial impact on immunity was also apparent in Alox12/15+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.
Apheresis therapies for NMOSD attacks : a retrospective study of 207 therapeutic interventions
(2018)
Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).
Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.
Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).
Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.
Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
Consensus on definition and severity grading of lymphatic complications after kidney transplantation
(2020)
Background: The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy.
Methods: Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high-volume transplant centres.
Results: Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty-three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non-invasive impact on the clinical management of the patient; grade B complications require non-surgical intervention; and grade C complications require invasive surgical intervention.
Conclusion: A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.
In den Untersuchungen des Intergovernmental Panel on Climate Change (IPCC) wird für das 21. Jahrhundert in Mitteleuropa von einem Temperaturanstieg zwischen 2, 5°C und 3,5°C ausgegangen. Auf der lokalen Ebene (Sachsen) wird ebenfalls eine Veränderung des Niederschlagsregimes erwartet. Leicht zunehmende Winter- und abnehmende Sommerniederschläge führen zu einer Reduzierung des verfügbaren Bodenwassers in der Vegetationsperiode. Diese Veränderungen führen zu einer Veränderung des Bestandes- Innenklimas, das wiederum von den Beständen selbst beeinflusst wird. Diese Abschätzung der Bedeutung der Rückkopplung zwischen dem Mikroklima und der Bestandesentwicklung ist dabei eine wesentliche Herausforderung. In dieser Studie wird mit Hilfe modellgestützter Untersuchungen (Vegetations-Atmosphären Grenzschichtmodell HIRVAC) die Variabilität des Bestandes-Innenklimas quantifiziert. Hierbei wurden Modellbestände für den Ist-Zustand und für die IPCC Szenarien B1 und A2 sowie für unterschiedliche Altersklassen als Output des Waldwachstumsmodells BALANCE herangezogen. Die Ergebnisse zeigen, wie sich unter diesen Voraussetzungen das Bestandes-Innenklima und dessen Variabilität verändert. So kann unter der Annahme der Erhöhung der mittleren Sommertemperaturen und einer Reduzierung des Niederschlags von einer Verschärfung der Extreme von Luft- und Vegetationsoberflächentemperaturen in den Beständen ausgegangen werden. Durch Optimierung der Bestandesstruktur konnten jedoch maximale Dämpfungsraten der Temperaturen im Kronenbereich zwischen 5,4° C und 6, 2° C in Abhängigkeit der betrachteten Klimaszenarien mit HIRVAC berechnet werden. Damit stellt der Waldumbau möglicherweise ein wichtiges Instrument zur Klimaregulierung innerhalb der Bestände der Zukunft dar.
Die in Amerika heimische Kolumbianische Zwergwasserlinse (Wolffia columbiana) tritt neuerdings in Europa als Neophyt auf und konnte in Niedersachsen zum ersten Mal im Jahr 2016 nachgewiesen werden. Im Hintergrund stehen die für den Naturschutz relevanten Fragen, wie viele vermeintliche Vorkommen von Wolffia arrhiza in Wirklichkeit Wolffia columbiana repräsentieren und ob dieser Neophyt die heimische und gefährdete Art Wolffia arrhiza verdrängen kann.
The directed and elliptic flow of protons and charged pions has been observed from the semi-central collisions of a 158 GeV/nucleon Pb beam with a Pb target. The rapidity and transverse momentum dependence of the flow has been measured. The directed flow of the pions is opposite to that of the protons but both exhibit negative flow at low pt. The elliptic flow of both is fairly independent of rapidity but rises with pt. PACS numbers: 25.75.-q, 25.75.Ld
Hintergrund
In Anbetracht ihres bedeutenden Potenzials zur Verbesserung der medizinischen Versorgung wird Telemedizin weiterhin zu wenig genutzt. Trotz einiger erfolgreicher Pilotprojekte in den vergangenen Jahren ist insbesondere über die Hindernisse der Etablierung und Verstetigung von Telemedizin wenig bekannt. Diese Studie hatte das Ziel, die Einstellung niedergelassener Neurologen hinsichtlich der Nutzung von Telemedizin in der Epileptologie und resultierende Hinderungsgründe zu verstehen. Gleichzeitig werden mögliche Lösungsansätze präsentiert.
Methoden
Mithilfe eines individuell erstellten 14-Item-Fragebogens befragten wir prospektiv alle Neurologen, die zuvor die Teilnahme an einem transregionalen Telemedizinpilotprojekt im Bereich der Epileptologie abgelehnt oder keine Rückmeldung gegeben hatten, zu Gründen für und gegen den generellen Einsatz von bzw. die Teilnahme an Telemedizin.
Ergebnisse
Von 58 kontaktierten Neurologen antworteten 33 (57 %). Die häufigsten Gründe für die fehlende Nutzung der Telemedizin waren ein vermuteter Zeitmangel oder ein vermuteter zu großer organisatorischer Aufwand (49 %). Zudem wurden Bedenken bezüglich der technischen Ausstattung (30 %) und eine Präferenz für alternative Wege der intersektoralen Kommunikation (30 %) angegeben. Befürchtete Probleme in Bezug auf die Kostenerstattung für telemedizinische Leistungen waren für 27 % ein Hindernis. Neurologen in ländlichen Gebieten waren signifikant häufiger bereit, zunächst eine telemedizinische Konsultation anzufordern, bevor sie eine Überweisung ausstellen (p = 0,006).
Schlussfolgerungen
Die flächendeckende Etablierung von Telemedizinstrukturen ist immer noch durch Hindernisse erschwert, die meist im organisatorischen Bereich liegen. Die bestehenden Herausforderungen im Gesundheitswesen in ländlichen Gebieten sind eine besondere Chance für die Implementierung von Telemedizin. Die meisten Probleme der Telemedizin können gelöst werden, sollten aber bereits bei der Konzeptionierung von Projekten mitbedacht werden, um ihre Verstetigung zu erleichtern.
Two-particle correlation functions of negative hadrons over wide phase space, and transverse mass spectra of negative hadrons and deuterons near mid-rapidity have been measured in central Pb+Pb collisions at 158 GeV per nucleon by the NA49 experiment at the CERN SPS. A novel Coulomb correction procedure for the negative two-particle correlations is employed making use of the measured oppositely charged particle correlation. Within an expanding source scenario these results are used to extract the dynamic characteristics of the hadronic source, resolving the ambiguities between the temperature and transverse expansion velocity of the source, that are unavoidable when single and two particle spectra are analysed separately. The source shape, the total duration of the source expansion, the duration of particle emission, the freeze-out temperature and the longitudinal and transverse expansion velocities are deduced.
The large acceptance TPCs of the NA49 spectrometer allow for a systematic multidimensional study of two-particle correlations in different part of phase space. Results from Bertsch-Pratt and Yano-Koonin-Podgoretskii parametrizations are presented differentially in transverse pair momentum and pair rapidity. These studies give an insight into the dynamical space-time evolution of relativistic Pb+Pb collisions, which is dominated by longitudinal expansion.
During SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) we performed measurements of a wide range of trace gases with different lifetimes and sink/source characteristics in the northern hemispheric upper troposphere (UT) and lowermost stratosphere (LMS). A large number of in-situ instruments were deployed on board a Learjet 35A, flying at altitudes up to 13.7 km, at times reaching to nearly 380 K potential temperature. Eight measurement campaigns (consisting of a total of 36 flights), distributed over all seasons and typically covering latitudes between 35° N and 75° N in the European longitude sector (10° W–20° E), were performed. Here we present an overview of the project, describing the instrumentation, the encountered meteorological situations during the campaigns and the data set available from SPURT. Measurements were obtained for N2O, CH4, CO, CO2, CFC12, H2, SF6, NO, NOy, O3 and H2O. We illustrate the strength of this new data set by showing mean distributions of the mixing ratios of selected trace gases, using a potential temperature – equivalent latitude coordinate system. The observations reveal that the LMS is most stratospheric in character during spring, with the highest mixing ratios of O3 and NOy and the lowest mixing ratios of N2O and SF6. The lowest mixing ratios of NOy and O3 are observed during autumn, together with the highest mixing ratios of N2O and SF6 indicating a strong tropospheric influence. For H2O, however, the maximum concentrations in the LMS are found during summer, suggesting unique (temperature- and convection-controlled) conditions for this molecule during transport across the tropopause. The SPURT data set is presently the most accurate and complete data set for many trace species in the LMS, and its main value is the simultaneous measurement of a suite of trace gases having different lifetimes and physical-chemical histories. It is thus very well suited for studies of atmospheric transport, for model validation, and for investigations of seasonal changes in the UT/LMS, as demonstrated in accompanying and elsewhere published studies.
During SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) we performed measurements of a wide range of trace gases with different lifetimes and sink/source characteristics in the northern hemispheric upper troposphere (UT) and lowermost stratosphere (LMS). A large number of in-situ instruments were deployed on board a Learjet 35A, flying at altitudes up to 13.7 km, at times reaching to nearly 380 K potential temperature. Eight measurement campaigns (consisting of a total of 36 flights), distributed over all seasons and typically covering latitudes between 35° N and 75° N in the European longitude sector (10° W–20° E), were performed. Here we present an overview of the project, describing the instrumentation, the encountered meteorological situations during the campaigns and the data set available from SPURT. Measurements were obtained for N2O, CH4, CO, CO2, CFC12, H2, SF6, NO, NOy, O3 and H2O. We illustrate the strength of this new data set by showing mean distributions of the mixing ratios of selected trace gases, using a potential temperature – equivalent latitude coordinate system. The observations reveal that the LMS is most stratospheric in character during spring, with the highest mixing ratios of O3 and NOy and the lowest mixing ratios of N2O and SF6. The lowest mixing ratios of NOy and O3 are observed during autumn, together with the highest mixing ratios of N2O and SF6 indicating a strong tropospheric influence. For H2O, however, the maximum concentrations in the LMS are found during summer, suggesting unique (temperature- and convection-controlled) conditions for this molecule during transport across the tropopause. The SPURT data set is presently the most accurate and complete data set for many trace species in the LMS, and its main value is the simultaneous measurement of a suite of trace gases having different lifetimes and physical-chemical histories. It is thus very well suited for studies of atmospheric transport, for model validation, and for investigations of seasonal changes in the UT/LMS, as demonstrated in accompanying and elsewhere published studies.
Background: Glucose metabolism in the tumor-microenvironment is a fundamental hallmark for tumor growth and intervention therein remains an attractive option for anti-tumor therapy. Whether tumor-derived factors such as microRNAs (miRs) regulate glucose metabolism in stromal cells, especially in tumor-associated macrophages (TAMs), to hijack them for trophic support, remains elusive.
Methods: Ago-RIP-Seq identified macrophage lactate dehydrogenase B (LDHB) as a target of tumor-derived miR-375 in both 2D/3D cocultures and in murine TAMs from a xenograft mouse model. The prognostic value was analyzed by ISH and multiplex IHC of breast cancer patient tissues. Functional consequences of the miR-375-LDHB axis in TAMs were investigated upon mimic/antagomir treatment by live metabolic flux assays, GC/MS, qPCR, Western blot, lentiviral knockdown and FACS. The therapeutic potential of a combinatorial miR-375-decoy/simvastatin treatment was validated by live cell imaging.
Results: Macrophage LDHB decreased in murine and human breast carcinoma. LDHB downregulation increase aerobic glycolysis and lactagenesis in TAMs in response to tumor-derived miR-375. Lactagenesis reduced fatty acid synthesis but activated SREBP2, which enhanced cholesterol biosynthesis in macrophages. LDHB downregulation skewed TAMs to function as a lactate and sterol/oxysterol source for the proliferation of tumor cells. Restoring of LDHB expression potentiated inhibitory effects of simvastatin on tumor cell proliferation.
Conclusion: Our findings identified a crucial role of LDHB in macrophages and established tumor-derived miR-375 as a novel regulator of macrophage metabolism in breast cancer, which might pave the way for strategies of combinatorial cancer cell/stroma cell interventions.
Lambda and Antilambda reconstruction in central Pb+Pb collisions using a time projection chamber
(1997)
The large acceptance time projection chambers of the NA49 experiment are used to record the trajectory of charged particles from Pb + Pb collisions at 158 GeV per nucleon. Neutral strange hadrons have been reconstructed from their charged decay products. To obtain distributions of Λ, and Ks0 in discrete bins of rapidity, y, and transverse momentum, pT, calculations have been performed to determine the acceptance of the detector and the efficiency of the reconstruction software as a function of both variables. The lifetime distributions obtained give values of cτ = 7.8 ± 0.6 cm for Λ and cτ = 2.5 ± 0.3 cm for Ks0, consistent with data book values.
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
Due to an increasing awareness of the potential hazardousness of air pollutants, new laws, rules and guidelines have recently been implemented globally. In this respect, numerous studies have addressed traffic-related exposure to particulate matter using stationary technology so far. By contrast, only few studies used the advanced technology of mobile exposure analysis. The Mobile Air Quality Study (MAQS) addresses the issue of air pollutant exposure by combining advanced high-granularity spatial-temporal analysis with vehicle-mounted, person-mounted and roadside sensors. The MAQS-platform will be used by international collaborators in order 1) to assess air pollutant exposure in relation to road structure, 2) to assess air pollutant exposure in relation to traffic density, 3) to assess air pollutant exposure in relation to weather conditions, 4) to compare exposure within vehicles between front and back seat (children) positions, and 5) to evaluate "traffic zone"- exposure in relation to non-"traffic zone"-exposure. Primarily, the MAQS-platform will focus on particulate matter. With the establishment of advanced mobile analysis tools, it is planed to extend the analysis to other pollutants including including NO2, SO2, nanoparticles, and ozone.
Three-dimensional multicellular aggregates such as spheroids provide reliable in vitro substitutes for tissues. Quantitative characterization of spheroids at the cellular level is fundamental. We present the first pipeline that provides three-dimensional, high-quality images of intact spheroids at cellular resolution and a comprehensive image analysis that completes traditional image segmentation by algorithms from other fields. The pipeline combines light sheet-based fluorescence microscopy of optically cleared spheroids with automated nuclei segmentation (F score: 0.88) and concepts from graph analysis and computational topology. Incorporating cell graphs and alpha shapes provided more than 30 features of individual nuclei, the cellular neighborhood and the spheroid morphology. The application of our pipeline to a set of breast carcinoma spheroids revealed two concentric layers of different cell density for more than 30,000 cells. The thickness of the outer cell layer depends on a spheroid’s size and varies between 50% and 75% of its radius. In differently-sized spheroids, we detected patches of different cell densities ranging from 5 × 105 to 1 × 106 cells/mm3. Since cell density affects cell behavior in tissues, structural heterogeneities need to be incorporated into existing models. Our image analysis pipeline provides a multiscale approach to obtain the relevant data for a system-level understanding of tissue architecture.
Aims: Patients with aortic stenosis (AS) may have concomitant heart failure (HF) that determines prognosis despite successful transcatheter aortic valve implantation (TAVI). We compared outcomes of TAVI patients with low stroke volume index (SVI) ≤35 ml/m2 body surface area in different HF classes.
Methods and results: Patients treated by transfemoral TAVI at our center (n = 1822) were classified as 1) ‘HF with preserved ejection fraction (EF)’ (HFpEF, EF ≥50%), 2) ‘HF with mid-range EF’ (HFmrEF, EF 40–49%), or 3) ‘HF with reduced EF’ (HFrEF, EF <40%). Patients with SVI >35 ml/m2 served as controls. The prevalence of cardiovascular disease and symptoms increased stepwise from controls (n = 968) to patients with HFpEF (n = 591), HFmrEF (n = 97), and HFrEF (n = 166). Mortality tended to be highest in HFrEF patients 30 days post-procedure, and it became significant after one year: 10.2% (controls), 13.5% (HFpEF), 13.4% (HFmrEF), and 23.5% (HFrEF). However, symptomatic improvement in survivors of all groups was achieved in the majority of patients without differences among groups.
Conclusions: Patients with AS and HF benefit from TAVI with respect to symptom alleviation. TAVI in patients with HFpEF and HFmrEF led to an identical, favorable post-procedural prognosis that was significantly better than that of patients with HFrEF, which remains a high-risk population.
Preliminary data on phi production in central Pb + Pb collisions at 158 GeV per nucleon are presented, measured by the NA49 experiment in the hadronic decay channel phi - K+K-. At mid-rapidity, the kaons were separated from pions and protons by combining dE/dx and time-of-flight information; in the forward rapidity range only dE/dx identification was used to obtain the rapidity distribution and a rapidity-integrated mt-spectrum. The mid-rapidity yield obtained was dN/dy = 1.85 ± 0.3 per event; the total phi multiplicity was estimated to be 5.0 ± 0.7 per event. Comparison with published pp data shows a slight, but not very significant strangeness enhancement.