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Using the NA49 main TPC, the central production of hyperons has been measured in CERN SPS Pb - Pb collisions at 158 GeV c-1. The preliminary ratio, studied at 2.0 < y < 2.6 and 1 < pT < 3 GeV c-1, equals ~ (13 ± 4)% (systematic error only). It is compatible, within errors, with the previously obtained ratios for central S + S [1], S + W [2], and S + Au [3] collisions. The fit to the transverse momentum distribution resulted in an inverse slope parameter T of 297 MeV. At this level of statistics we do not see any noticeable enhancement of hyperon production with the increased volume (and, possibly, degree of equilibration) of the system from S + S to Pb + Pb. This result is unexpected and counterintuitive, and should be further investigated. If confirmed, it will have a significant impact on our understanding of mechanisms leading to the enhanced strangeness production in heavy-ion collisions.
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.
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.
We present the first measurement of fluctuations from event to event in the production of strange particles in collisions of heavy nuclei. The ratio of charged kaons to charged pions is determined for individual central Pb+Pb collisions. After accounting for the fluctuations due to detector resolution and finite number statistics we derive an upper limit on genuine non-statistical fluctuations, perhaps related to a first or second order QCD phase transition. Such fluctuations are shown to be very small.
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.
We report measurements of Xi and Xi-bar hyperon absolute yields as a function of rapidity in 158 GeV/c Pb+Pb collisions. At midrapidity, dN/dy = 2.29 +/- 0.12 for Xi, and 0.52 +/- 0.05 for Xi-bar, leading to the ratio of Xi-bar/Xi = 0.23 +/- 0.03. Inverse slope parameters fitted to the measured transverse mass spectra are of the order of 300 MeV near mid-rapidity. The estimated total yield of Xi particles in Pb+Pb central interactions amounts to 7.4 +/- 1.0 per collision. Comparison to Xi production in properly scaled p+p reactions at the same energy reveals a dramatic enhancement (about one order of magnitude) of Xi production in Pb+Pb central collisions over elementary hadron interactions.
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
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.
The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers (‘average reader’) was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI.
Natural products (NPs) from microorganisms have been important sources for discovering new therapeutic and chemical entities. While their corresponding biosynthetic gene clusters (BGCs) can be easily identified by gene-sequence-similarity-based bioinformatics strategies, the actual access to these NPs for structure elucidation and bioactivity testing remains difficult. Deletion of the gene encoding the RNA chaperone, Hfq, results in strains losing the production of most NPs. By exchanging the native promoter of a desired BGC against an inducible promoter in Δhfq mutants, almost exclusive production of the corresponding NP from the targeted BGC in Photorhabdus, Xenorhabdus and Pseudomonas was observed including the production of several new NPs derived from previously uncharacterized non-ribosomal peptide synthetases (NRPS). This easyPACId approach (easy Promoter Activated Compound Identification) facilitates NP identification due to low interference from other NPs. Moreover, it allows direct bioactivity testing of supernatants containing secreted NPs, without laborious purification.
Rezensionen [2018]
(2018)
Verzeichnis
Einzelrezensionen
154 Beauvais, Clémentine: The Mighty Child. Time and Power in Children’s Literature (Thomas Kullmann)
155 Dean-Ruzicka, Rachel: Tolerance Discourse and Young Adult Holocaust Literature. Engaging Difference and Identity (Susanne Blumesberger)
157 Dolle-Weinkauff, Bernd (Hrsg.): Geschichte im Comic. Befunde – Theorien – Erzählweisen (Caroline Wittig)
159 Ewers, Hans-Heino (Hrsg.): Erster Weltkrieg: Kindheit, Jugend und Literatur. Deutschland, Österreich, Osteuropa, England, Belgien und Frankreich (Kurt Franz)
161 Franz, Kurt / Lange, Günter (Hrsg.): Der Stoff, aus dem Geschichten sind. Intertextualität im Werk Otfried Preußlers (sabine fuchs)
163 Glasenapp, Gabriele von/Kagelmann, Andre/Giesa, Felix (Hrsg.): Die Zeitalter werden besichtigt. Aktuelle Tendenzen der Kinder- und Jugendliteraturforschung. Festschrift für Otto Brunken (Karin Richter)
165 Josting, Petra/Schmideler, Sebastian (Hrsg.): Bonsels’ Tierleben. Insekten und Kriechtiere in Kinder- und Jugendmedien (Kurt Franz)
167 Kriegleder, Wynfrid/ Lexe, Heidi / Loidl, Sonja/ Seibert, Ernst (Hrsg.): Jugendliteratur im Kontext von Jugendkultur (Lena Hoffmann)
169 Kurwinkel, Tobias: Bilderbuchanalyse. Narrativik – Ästhetik – Didaktik (Annette Kliewer)
171 Langenhorst, Georg/Naurath, Elisabeth (Hrsg.): Kindertora – Kinderbibel – Kinderkoran. Neue Chancen für (inter-)religiöses Lernen (Renate Grubert)
172 Lathey, Gillian: Translating Children’s Literature (heike Elisabeth Jüngst)
174 Mairbäurl, Gunda/Seibert, Ernst (Hrsg.): Kulturelle Austauschprozesse in der Kinder- und Jugendliteratur. Zur genrespezifischen Transformation von Themen, Stoffen und Motiven im medialen Kontext (Sarah Terhorst)
176 Maiwald, Klaus /Meyer, Anna-Maria/Pecher, Claudia Maria (Hrsg.): »Klassiker« des Kinderund Jugendfilms (Michael Stierstorfer)
177 Mills, Claudia (Hrsg.): Ethics in Children’s Literature (Thomas Kullmann)
179 Nast, Mirjam: »Perry Rhodan« lesen. Zur Serialität der Lektürepraktiken einer Heftromanserie (Wolfgang Biesterfeld)
181 O’Sullivan, Emer / Immel, Andrea (Hrsg.): Imagining Sameness and Difference in Children’s Literature. From the Enlightenment to the Present Day (Iris Schäfer)
182 Oetken, Mareile: Wie Bilderbücher erzählen. Analysen multimodaler Strukturen und bimedialen Erzählens im Bilderbuch (Katharina Egerer)
184 Schmideler, Sebastian (Hrsg.): Wissensvermittlung in der Kinder- und Jugendliteratur der DDR. Themen, Formen, Strukturen, Illustrationen (Sabine Planka)
186 Standke, Jan (Hrsg.): Wolfgang Herrndorf lesen. Beiträge zur Didaktik der deutschsprachigen Gegenwartsliteratur (Sabine Planka)
187 Viel, Bernhard: Der Honigsammler. Waldemar Bonsels, Vater der Biene Maja. Eine Biografie (Renate Grubert)
189 Zellerhoff, Rita: Komplexe sprachliche Strukturen in der Jugendliteratur. Aufgezeigt an Beispielen preisgekrönter Werke der Jugendjury des Deutschen Jugendliteraturpreises (Susanne Riegler)
Sammelrezensionen
191 Anker, Martin u.a. (Hrsg.): Grimms Märchenwelten im Bilderbuch. Beiträge zur Entwicklung des Märchenbilderbuches seit Mitte des 20. Jahrhunderts. – Brinker-von der Heyde, Claudia u. a. (Hrsg.): Märchen, Mythen und Moderne. 200 Jahre Kinder- und Hausmärchen der Brüder Grimm. – Joosen, Vanessa/ Lathey, Gillian (Hrsg.): Grimms’ Tales around the Globe. The Dynamics of their International Reception (Thomas Bitterlich)
194 Böhm, Kerstin: Archaisierung und Pinkifizierung. Mythen von Weiblichkeit und Männlichkeit in der Kinder- und Jugendliteratur. – Dangendorf, Sarah: Kleine Mädchen in High Heels. Über die visuelle Sexualisierung frühadoleszenter Mädchen (Annette Kliewer)
197 Gordon, Ian: Kid Comic Strips. A Genre Across Four Countries. – Kupczynska, Kalina/Renata Makarska (Hrsg.): Comic in Polen. Polen im Comic. – Kutch, Lynn Marie (Hrsg.): Novel Perspectives on German-Language Comics Studies. History, Pedagogy, Theory. – Reddition. Zeitschrift für Graphische Literatur (66) 2017: Ein halbes Jahrhundert Carlsen Comics. – Rosenfeldt, Reginald: ComicPioniere. Die deutschen Comic-Künstler der 1950er Jahre (Felix Giesa)
Objectives: The SAVI-TF (Symetis ACURATE neo Valve Implantation Using Transfemoral Access) registry was initiated to study the ACURATE neo transcatheter heart valve in a large patient population treated under real-world conditions.
Background: The self-expanding, supra-annular ACURATE neo prosthesis is a transcatheter heart valve that gained the Conformité Européene mark in 2014, but only limited clinical data are available so far.
Methods: This prospective, multicenter registry enrolled 1,000 patients at 25 European centers who were followed for 1 year post-procedure.
Results: Mean patient age was 81.1 ± 5.2 years; mean logistic European System for Cardiac Operative Risk Evaluation I score, European System for Cardiac Operative Risk Evaluation II score, and Society of Thoracic Surgeons score were 18.1 ± 12.5%, 6.6 ± 7.5%, and 6.0 ± 5.6%, respectively. At 1 year, 8.0% (95% confidence interval [CI]: 6.3% to 9.7%) of patients had died, 2.3% (95% CI: 1.3% to 3.2%) had disabling strokes, and 9.9% (95% CI: 8.1% to 11.8%) had permanent pacemaker implantations. Through 1 year, 5 reinterventions (0.5%; 95% CI: 0.1% to 1.0%) were performed: 3 valve-in-valve and 2 surgical aortic valve replacements. Mean effective orifice area was 1.84 ± 0.43 cm2, mean gradient was 7.3 ± 3.7 mm Hg, and greater than mild paravalvular leakage was observed in 3.6% of patients.
Conclusions: Transfemoral implantation of the ACURATE neo prosthesis resulted in favorable 1-year clinical and echocardiographic outcomes with very low mortality and new pacemaker rates.
Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions: From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (~ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
Bei einer Prüfung von 153 Gewässern in Frankfurt am Main wurden neben den heimischen Typha-Arten Typha angustifolia und T. latifolia Verwilderungen von Typha shuttleworthii und Pflanzungen von Typha laxmannii gefunden. Auch Typha ×glauca die Hybride zwischen Typha angustifolia und T. latifolia wurde mehrfach gefunden.
Previous studies detected an influence of urban characteristics on song traits in passerine birds, that is, song adjustments to ambient noise in urban areas. Several studies already described the effect of weather conditions on the behavior of birds, but not the effect on song traits. We investigate, if song trait variability changes along a continuous urbanity gradient in Frankfurt am Main, Germany. We examined, for the first time on a larger scale, the influence of weather on song parameters. We made song recordings of three common passerine species: the blue and great tit (Cyanistes caeruleus (Linnaeus, 1758) and Parus major Linnaeus, 1758) and the European blackbird (Turdus merula Linnaeus, 1758). We measured different song traits and performed statistical analyses and modeling on a variety of variables—among them urbanity and weather parameters. Remarkably, we found only few cases of a significant influence of urbanity parameters on song traits. The influence of weather parameters (air pressure, atmospheric humidity, air and soil temperatures) on song traits was highly significant. Birds in Frankfurt face high noise pollution and might show different adaptations to high noise levels. The song trait variability of the investigated species is affected more by weather conditions than by urban characteristics in Frankfurt. However, the three species react differently to specific weather parameters. Smaller species seem to be more affected by weather than larger species.
Background: The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has established a multigene panel (TruRisk®) for the analysis of risk genes for familial breast and ovarian cancer. Summary: An interdisciplinary team of experts from the GC-HBOC has evaluated the available data on risk modification in the presence of pathogenic mutations in these genes based on a structured literature search and through a formal consensus process. Key Messages: The goal of this work is to better assess individual disease risk and, on this basis, to derive clinical recommendations for patient counseling and care at the centers of the GC-HBOC from the initial consultation prior to genetic testing to the use of individual risk-adapted preventive/therapeutic measures.
Eine Erkrankung zählt in der Europäischen Union zu den Seltenen Erkrankungen (SE), wenn diese nicht mehr als 5 von 10.000 Menschen betrifft. Derzeit existiert mit mehr als 6000 SE eine sowohl große als auch heterogene Menge an unterschiedlichen Krankheitsbilder, die in ihrer Symptomatik komplex, vielschichtig und damit im medizinischen Alltag schwierig einzuordnen sind. Dies erschwert Diagnosefindung und Behandlung sowie das Auffinden eines passenden Ansprechpartners, da es nur wenige Experten für jede einzelne SE gibt. Der medizinische Versorgungsatlas für Seltene Erkrankungen www.se-atlas.de ermöglicht anhand von Erkrankungsnamen die Suche nach Versorgungseinrichtungen und Selbsthilfeorganisationen zu bestimmten SE und stellt die Suchergebnisse geografisch dar. Ebenso gibt er einen Überblick über alle deutschen Zentren für SE, die eine Anlaufstelle für betroffene Personen mit unklarer Diagnose darstellen. Der se-atlas dient als Kompass durch die heterogene Menge an Informationen über Versorgungseinrichtungen für SE und stellt niederschwellig Informationen für eine breite Nutzergruppe von Betroffenen bis hin zu Mitgliedern des medizinischen Versorgungsteams bereit.
Objectives: A conometric concept was recently introduced in which conical implant abutments hold the matching crown copings by friction alone, eliminating the need for cement or screws. The aim of this in vitro study was to assess the presence of microgap formation and bacterial leakage at the Acuris conometric restorative interface of three different implant abutment systems. Material and methods: A total of 75 Acuris samples of three implant-abutment systems (Ankylos, Astra Tech EV, Xive) were subjected to microbiological (n = 60) and scanning electron microscopic (SEM) investigation (n = 15). Bacterial migration into and out of the conical coupling system were analyzed in an anaerobic workstation for 48, 96, 144, and 192 h. Bacterial DNA quantification using qrt-PCR was performed at each time point. The precision of the conometric coupling and internal fit of cemented CAD/CAM crowns on corresponding Acuris TiN copings were determined by means of SEM. Results: qrt-PCR results failed to demonstrate microbial leakage from or into the Acuris system. SEM analysis revealed minute punctate microgaps at the apical aspect of the conometric junction (2.04 to 2.64 µm), while mean cement gaps of 12 to 145 µm were observed at the crown-coping interface. Conclusions: The prosthetic morse taper connection of all systems examined does not allow bacterial passage. Marginal integrity and internal luting gap between the ceramic crown and the coping remained within the clinically acceptable limits. Clinical relevance: Conometrically seated single crowns provide sufficient sealing efficiency, relocating potential misfits from the crown-abutment interface to the crown-coping interface.
In the current study we compared the molecular signature of expanded mesenchymal stromal cells (MSCs) derived from selected CD271+ bone marrow mononuclear cells (CD271-MSCs) and MSCs derived from non-selected bone marrow mononuclear cells by plastic adherence (PA-MSCs). Transcriptome analysis demonstrated for the first time the upregulation of 115 and downregulation of 131 genes in CD271-MSCs. Functional enrichment analysis showed that the upregulated genes in CD271-MSCs are significantly enriched for extracellular matrix (tenascin XB, elastin, ABI family, member 3 (NESH) binding protein, carboxypeptidase Z, laminin alpha 2 and nephroblastoma overexpressed) and cell adhesion (CXCR7, GPNMB, MYBPH, SVEP1, ARHGAP6, TSPEAR, PIK3CG, ABL2 and NCAM1). CD271-MSCs expressed higher gene transcript levels that are involved in early osteogenesis/chondrogenesis/adipogenesis (ZNF145, FKBP5). In addition, increased transcript levels for early and late osteogenesis (DPT, OMD, ID4, CRYAB, SORT1), adipogenesis (CTNNB1, ZEB, LPL, FABP4, PDK4, ACDC), and chondrogenesis (CCN3/NOV, CCN4/WISP1, CCN5/WISP2 and ADAMTS-5) were detected. Interestingly, CD271-MSCs expressed increased levels of hematopoiesis associated genes (CXCL12, FLT3L, IL-3, TPO, KITL). Down-regulated genes in CD271-MSCs were associated with WNT and TGF-beta signaling, and cytokine/chemokine signaling pathways. In addition to their capacity to support hematopoiesis, these results suggest that CD271-MSCs may contain more osteo/chondro progenitors and/or feature a greater differentiation potential.
The German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh) : a success story
(2016)
This article gives a comprehensive overview on the strategy, the development and the progress of the German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh). The program soon prompted positive results: more than 10 years now the courses had an average enrolment rate of 90 %, and employment-seeking graduates from the first courses mostly succeeded in quickly finding employment relevant to their training. With over 450 students enrolled to date, the degree program contributes significantly to the field of Environmental Chemistry and Ecotoxicology.
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced.
(2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored.
(3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%.
(4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
Dieser Bericht stellt die wesentlichen Ergebnisse der sozialwissenschaftlichen und ökologischen Begleitforschung in der Modellregion Elektromobilität Rhein-Main (SÖB) dar. Dabei wird zunächst das Projektumfeld vorgestellt, indem auf die Rahmenbedingungen des Förderprogramms sowie weitere Programme und Projekte im Bereich Elektromobilität eingegangen wird. Im zweiten Kapitel wird das Projektkonsortium und dessen Einbettung in die Modellregion Rhein-Main erläutert, sowie die Verknüpfung mit der überregionalen Begleitforschung der Nationalen Organisation Wasser- und Brennstoffzellentechnologie (NOW). Im Kapitel 3 wird das Forschungsdesign der SÖB skizziert. Dazu werden einige Erkenntnisse aus der ersten Förderperiode beleuchtet, die für die Forschungsziele der aktuellen Förderperiode ausschlaggebend waren. Des Weiteren erfolgt eine Ausführung der methodischen Vorgehensweisen der Projektpartner. Das darauf folgende Kapitel 4 stellt die wesentlichen Ergebnisse des Projekts dar. Dabei wurde bewusst versucht, die verschie¬denen Erkenntnisse der einzelnen Partner thematisch miteinander zu verknüpfen. Aus den Ergeb¬nissen wurden Handlungsempfehlungen für verschiedene Bereiche und Akteure generiert, die in Kapitel 5 einfließen. Abschließend rundet ein Fazit mit zusammenfassenden Erkenntnissen den Bericht ab.
The extracellular matrix is rapidly emerging as a prominent contributor to various fundamental processes of tumorigenesis. In particular, decorin, a member of the small leucine-rich proteoglycan gene family, is assuming a central role as a potent soluble tumor repressor. Decorin binds and antagonizes various receptor tyrosine kinases and inhibits downstream oncogenic signaling in several solid tumors. Among other functions, decorin evokes cell cycle arrest, apoptosis, and antimetastatic, and antiangiogenic programs. Recent work has revealed a paradigmatic shift in our understanding of the molecular mechanisms underlying its tumoricidal properties. Decorin adversely compromises the genetic signature of the tumor microenvironment and induces endothelial cell autophagy downstream of VEGFR2. Moreover, decorin selectively evokes destruction of tumor cell mitochondria downstream of Met through mitophagy. Acting as a partial agonist, decorin signals via proautophagic receptors and triggers procatabolic processes that parallel the classical tumoricidal properties of this multifaceted proteoglycan.
Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that decorin protein core modulated the differential expression of 374 genes within the stromal compartment of the tumor xenograft. Further, our top gene ontology classes strongly suggests an unexpected and preferential role for decorin protein core to inhibit genes necessary for immunomodulatory responses while simultaneously inducing expression of those possessing cellular adhesion and tumor suppressive gene properties. Rigorous verification of the top scoring candidates led to the discovery of three genes heretofore unlinked to malignant breast cancer that were reproducibly found to be induced in several models of tumor stroma. Collectively, our data provide highly novel and unexpected stromal gene signatures as a direct function of systemic administration of decorin protein core and reveals a fundamental basis of action for decorin to modulate the tumor stroma as a biological mechanism for the ascribed anti-tumorigenic properties.
The highly conserved eukaryotic process of macroautophagy (autophagy) is a non-specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis.
The highly conserved eukaryotic process of macroautophagy (autophagy) is a non-specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis.
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Endothelium-dependent vasodilation is thought to be mediated primarily by the NO/cGMP signaling pathway whereas cAMP-elevating vasodilators are considered to act independent of the endothelial cell layer. However, recent functional data suggest that cAMP-elevating vasodilators such as β-receptor agonists, adenosine or forskolin may also be endothelium-dependent. Here we used functional and biochemical assays to analyze endothelium-dependent, cGMP- and cAMP-mediated signaling in rat aorta. Acetylcholine and sodium nitroprusside (SNP) induced a concentration-dependent relaxation of phenylephrine-precontracted aorta. This response was reflected by the phosphorylation of the vasodilator-stimulated phosphoprotein (VASP), a validated substrate of cGMP- and cAMP-dependent protein kinases (cGK, cAK), on Ser157 and Ser239. As expected, the effects of acetylcholine were endothelium-dependent. However, relaxation induced by the β-receptor agonist isoproterenol was also almost completely impaired after endothelial denudation. At the biochemical level, acetylcholine- and isoproterenol-evoked cGK and cAK activation, respectively, as measured by VASP Ser239 and Ser157 phosphorylation, was strongly diminished. Furthermore, the effects of isoproterenol were repressed by eNOS inhibition when endothelium was present. We also observed that the relaxing and biochemical effects of forskolin were at least partially endothelium-dependent. We conclude that cAMP-elevating vasodilators, i.e. isoproterenol and to a lesser extent also forskolin, induce vasodilation and concomitant cyclic nucleotide protein kinase activation in the vessel wall in an endothelium-dependent way.
Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA).
Patients and methods: Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1–3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1–7) plus daunorubicin (45 mg/m2 days 3–5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone.
Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33–45] versus 55% (95% CI: 49–61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513).
Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.
Rezensionen [2019]
(2019)
Verzeichnis
Einzelrezensionen
163 Babenhauserheide, Melanie: Harry Potter und die Widersprüche der Kulturindustrie. Eine ideologiekritische Analyse (DAVID N. SCHMIDT)
165 Ballis, Anja/Pecher, Claudia Maria/ Schuler, Rebecca (Hrsg.): Mehrsprachige Kinder- und Jugendliteratur. Überlegungen zur Systematik, Didaktik und Verbreitung (SVETLANA VISHEK)
167 Bannasch, Bettina/Matthes, Eva (Hrsg.): Kinder- und Jugendliteratur. Historische, erzähl- und medientheoretische, pädagogische und therapeutische Perspektiven (susanne blumesberger)
169 Batzke, Ina/ Erbacher, Eric C. /Heß, Linda M. / Lenhardt, Corinna (Hrsg.): Exploring the Fantastic. Genre, Ideology, and Popular Culture (THOMAS BITTERLICH)
170 Bertling, Maria: All-Age-Literatur. Die Entdeckung einer neuen Zielgruppe und ihrer Rezeptionsmodalitäten (NICOLA KÖNIG)
172 Blümer, Agnes: Mehrdeutigkeit übersetzen. Englische und französische Kinderliteraturklassiker der Nachkriegszeit in deutscher Übertrag (MARTINA SEIFERT)
174 Blumesberger, Susanne/Thunecke, Jörg (Hrsg.): Deutschsprachige Kinder- und Jugendliteratur während der Zwischenkriegszeit und im Exil. Schwerpunkt Österreich (KURT FRANZ)
176 Busch, Nathanael /Velten, Hans Rudolf (Hrsg.): Die Literatur des Mittelalters im Fantasyroman (SONJA LOIDL)
178 Cave, Roderick/Ayad, Sara (Hrsg.): Die Geschichte des Kinderbuches in 100 Büchern (ERNST SEIBERT)
180 Dettmar, Ute/Pecher, Claudia Maria/Schlesinger, Ron (Hrsg.): Märchen im Medienwechsel. Zur Geschichte und Gegenwart des Märchenfilms (MICHAEL STIERSTORFER)
182 Dommermuth, Clarissa: Wir sind dagegen – denn ihr seid dafür. Zur Tradition literarischer Jugendbewegungen im deutschsprachigen Raum (SUSANNE BLUMESBERGER)
184 Ellerbach, Benoît: L’Arabie contée aux Allemands. Fictions interculturelles chez Rafik Schami (ANNETTE KLIEWER)
185 Enklaar, Jattie/ Ester, Hans /Tax, Evelyne (Hrsg.): Studien über Kinder- und Jugendliteratur im europäischen Austausch von 1800 bis heute (IRIS SCHÄFER)
187 Ewers, Hans-Heino: Michael Ende neu entdecken. Was »Jim Knopf«,»Momo« und »Die unendliche Geschichte« Erwachsenen zu sagen haben (MARKUS JANKA)
189 Flegel, Monica/Parkes, Christopher (Hrsg.): Cruel Children in Popular Texts and Cultures (LENA HOFFMANN)
191 Garbe, Christine/Gürth, Christina et al. (Hrsg.): Attraktive Lesestoffe (nicht nur) für Jungen. Erzählmuster und Beispielanalysen zu populärer Kinder- und Jugendliteratur (THOMAS BITTERLICH)
193 Goga, Nina/Kümmerling-Meibauer, Bettina (Hrsg.): Maps and Mapping in Children’s Literature. Landscapes, Seascapes, and Cityscapes (Wolfgang Biesterfeld)
195 Hamer, Naomi /Nodelman, Perry / Reimer, Mavis (Hrsg.): More Words about Pictures. Current Research on Picturebooks and Visual/Verbal Texts for Young People (FARRIBA SCHULZ)
196 Hoffmann, Lena: Crossover. Mehrfachadressierung in Text, Markt und Diskurs (HEIDI LEXE)
198 Josting, Petra/Reuter, Frank/Roeder, Caroline/Wolters, Ute (Hrsg.): »Denn sie rauben sehr geschwind jedes böse Gassenkind.« ›Zigeuner‹-Bilder in Kinder- und Jugendmedien (KURT FRANZ)
200 Langemeyer, Peter /Knutsen, Karen Patrick (Hrsg.): Narratology Plus. Studies in Recent International Narratives for Children and
Young Adults / Narratologie Plus. Studien zur Erzählweise in aktueller internationaler Kinder- und Jugendliteratur (NADINE BIEKER)
202 Museumsinsel Lüttenheid (Hrsg.): Rudolf Dirks. Zwei Lausbuben und die Erfindung des modernen Comics (LUKAS SARVARI)
204 Oeste, Bettina/Preußer, Ulrike (Hrsg.): Neuvermessung deutschsprachiger Erinnerungsstrategien in der Kinder- und Jugendliteratur nach 1990 (annette kliewer)
206 Planka, Sabine (Hrsg.): Berlin. Bilder einer Metropole in erzählenden Medien für Kinder und Jugendliche (KATHARINA EGERER)
208 Press, Alexander: Die Bilder des Comics. Funktionsweisen aus kunst- und bildwissenschaftlicher Perspektive (RALF VOLLBRECHT)
209 Schenk, Klaus /Zeisberg, Ingold (Hrsg.): Fremde Räume. Interkulturalität und Semiotik des Phantastischen (ANNETTE KLIEWER)
211 Schweizerisches Institut für Kinder- und Jugendmedien SIKJM (Hrsg.): Atlas der Schweizer Kinderliteratur. Expeditionen und
Panoramen (SUSANNE RIEGLER)
Sammelrezensionen
213 Heinemann, Caroline: Produktionsräume im zeitgenössischen Kinder- und Jugendtheater. – Hentschel, Ingrid: Theater zwischen Ich und Welt. Beiträge zur Ästhetik des Kinder- und Jugendtheaters. Theorien – Praxis – Geschichte (PHILIPP SCHMERHEIM)
215 Janka, Marcus /Stierstorfer, Michael (Hrsg.): Verjüngte Antike. Griechisch-römische Mythologie in zeitgenössischen Kinder- und Jugendmedien. – Stierstorfer, Michael: Antike Mythologie in der Kinder- und Jugendliteratur der Gegenwart. Unsterbliche Götter- und Heldengeschichten? (KARINA BECKER)
218 Josting, Petra/Kruse, Iris (Hrsg.): Paul Maar. Bielefelder Poet in Residence 2015 | Paderborner Kinderliteraturtage 2016. – Wicke, Andreas /Roßbach, Nikola (Hrsg.): Paul Maar. Studien zum kinder- und jugendliterarischen Werk (SONJA MÜLLER-CARSTENS)
Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.
Purpose: The role of obesity in glioblastoma remains unclear, as previous analyses have reported contradicting results. Here, we evaluate the prognostic impact of obesity in two trial populations; CeTeG/NOA-09 (n = 129) for MGMT methylated glioblastoma patients comparing temozolomide (TMZ) to lomustine/TMZ, and GLARIUS (n = 170) for MGMT unmethylated glioblastoma patients comparing TMZ to bevacizumab/irinotecan, both in addition to surgery and radiotherapy.
Methods: The impact of obesity (BMI ≥ 30 kg/m2) on overall survival (OS) and progression-free survival (PFS) was investigated with Kaplan–Meier analysis and log-rank tests. A multivariable Cox regression analysis was performed including known prognostic factors as covariables.
Results: Overall, 22.6% of patients (67 of 297) were obese. Obesity was associated with shorter survival in patients with MGMT methylated glioblastoma (median OS 22.9 (95% CI 17.7–30.8) vs. 43.2 (32.5–54.4) months for obese and non-obese patients respectively, p = 0.001), but not in MGMT unmethylated glioblastoma (median OS 17.1 (15.8–18.9) vs 17.6 (14.7–20.8) months, p = 0.26). The prognostic impact of obesity in MGMT methylated glioblastoma was confirmed in a multivariable Cox regression (adjusted odds ratio: 2.57 (95% CI 1.53–4.31), p < 0.001) adjusted for age, sex, extent of resection, baseline steroids, Karnofsky performance score, and treatment arm.
Conclusion: Obesity was associated with shorter survival in MGMT methylated, but not in MGMT unmethylated glioblastoma patients.
Background: Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC.
Methods: A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019).
Results: We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18–78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533–7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780–1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503–3840) among working-age individuals (< 67 years in Germany). Multiple regression analyses revealed mTOR inhibitor use and persistent seizures as independent cost-driving factors for total direct costs. Older age and disability were independent cost-driving factors for total indirect costs, whereas epilepsy, psychiatric disease, and disability were independent cost-driving factors for nursing care costs.
Conclusions: This three-month study revealed substantial direct healthcare, indirect healthcare, and medication costs associated with TSC in Germany. This study highlights the spectrum of organ manifestations and their associated treatment needs in the German healthcare setting. Trial registration: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.
Encouraging clinical results were reported on a novel cone-in-cone coupling for the fixation of dental implant-supported crowns (Acuris, Dentsply Sirona Implants, Mölndal, Sweden). However, the presence or absence of a microgap and a potential bacterial leakage at the conometric joint has not yet been investigated. A misfit and a resulting gap between the conometric components could potentially serve as a bacterial reservoir that promotes plaque formation, which in turn may lead to inflammation of the peri-implant tissues. Thus, a two-fold study set-up was designed in order to evaluate the bidirectional translocation of bacteria along conometrically seated single crowns. On conometric abutments filled with a culture suspension of anaerobic bacteria, the corresponding titanium nitride-coated (TiN) caps were fixed by friction. Each system was sterilized and immersed in culture medium to provide an optimal environment for microbial growth. Positive and negative controls were prepared. Specimens were stored in an anaerobic workstation, and total and viable bacterial counts were determined. Every 48 h, samples were taken from the reaction tubes to inoculate blood agar plates and to isolate bacterial DNA for quantification using qrt-PCR. In addition, one Acuris test system was subjected to scanning electron microscopy (SEM) to evaluate the precision of fit of the conometric coupling and marginal crown opening. Throughout the observational period of one week, blood agar plates of the specimens showed no viable bacterial growth. qrt-PCR, likewise, yielded a result approaching zero with an amount of about 0.53 × 10−4 µg/mL DNA. While the luting gap/marginal opening between the TiN-cap and the ceramic crown was within the clinically acceptable range, the SEM analysis failed to identify a measurable microgap at the cone-in-cone junction. Within the limits of the in-vitro study it can be concluded that the Acuris conometric interface does not allow for bacterial translocation under non-dynamic loading conditions.
Autophagy plays an essential role in maintaining an intricate balance between nutrient demands and energetic requirements during normal homeostasis. Autophagy recycles metabolic substrates from nonspecific bulk degradation of proteins and excess or damaged organelles. Recent work posits an active and dynamic signaling role for extracellular matrix-evoked autophagic regulation, that is, allosteric and independent of prevailing nutrient conditions. Several candidates, representing a diverse repertoire of matrix constituents (decorin, collagen VI, laminin α2, endostatin, endorepellin, and kringle V), can modulate autophagic signaling pathways. Importantly, a novel principle indicates that matrix constituents can differentially modulate autophagic induction and repression via interaction with specific receptors. Most of the matrix-derived factors described here appear to control autophagy in a canonical manner but independent of nutrient deprivation. Because the molecular composition and structure of the extracellular matrix are dynamically remodeled during various physiological and pathological conditions, we propose that matrix-regulated autophagy is key for maintaining proper tissue homeostasis and disease prevention, such as cancer progression and muscular dystrophies.
Endocannabinoids (ECs) are potent lipid mediators with high physiological relevance. They are involved in a wide variety of diseases like depression or multiple sclerosis and are closely connected to metabolic parameters in humans. Therefore, their suitability as a biomarker in different (patho-)physiological conditions is discussed intensively and predominantly investigated by analyzing systemic concentrations in easily accessible matrices like blood. Carefully designed pre-analytical sample handling is of major importance for high-quality data, but harmonization is not achieved yet. Whole blood is either processed to serum or plasma before the onset of analytical workflows and while knowledge about pre-analytical challenges in plasma handling is thorough they were not systematically investigated for serum.
Therefore, the ECs AEA and 2-AG, and closely related EC-like substances 1-AG, DHEA, and PEA were examined by LC-MS/MS in serum samples of nine healthy volunteers employing different pre-analytical sample handling protocols, including prolonged coagulation, and storage after centrifugation at room temperature (RT) or on ice. Furthermore, all analytes were also assessed in plasma samples obtained from the same individuals at the same time points to investigate the comparability between those two blood-based matrices regarding obtained concentrations and their 2-AG/1-AG ratio.
This study shows that ECs and EC-like substances in serum samples were significantly higher than in plasma and are especially prone to ex vivo changes during initial and prolonged storage for coagulation at RT. Storage on ice after centrifugation is less critical. However, storage at RT further increases 1-AG and 2-AG concentrations, while also lowering the already reduced 2-AG/1-AG ratio due to isomerization. Thus, avoidance of prolonged processing at RT can increase data quality if serum as the matrix of choice is unavoidable. However, serum preparation in itself is expected to initiate changes of physiological concentrations as standard precautionary measures like fast and cooled processing can only be utilized by using plasma, which should be the preferred matrix for analyses of ECs and EC-like substances.
The emerging disciplines of lipidomics and metabolomics show great potential for the discovery of diagnostic biomarkers, but appropriate pre-analytical sample-handling procedures are critical because several analytes are prone to ex vivo distortions during sample collection. To test how the intermediate storage temperature and storage period of plasma samples from K3EDTA whole-blood collection tubes affect analyte concentrations, we assessed samples from non-fasting healthy volunteers (n = 9) for a broad spectrum of metabolites, including lipids and lipid mediators, using a well-established LC-MS-based platform. We used a fold change-based approach as a relative measure of analyte stability to evaluate 489 analytes, employing a combination of targeted LC-MS/MS and LC-HRMS screening. The concentrations of many analytes were found to be reliable, often justifying less strict sample handling; however, certain analytes were unstable, supporting the need for meticulous processing. We make four data-driven recommendations for sample-handling protocols with varying degrees of stringency, based on the maximum number of analytes and the feasibility of routine clinical implementation. These protocols also enable the simple evaluation of biomarker candidates based on their analyte-specific vulnerability to ex vivo distortions. In summary, pre-analytical sample handling has a major effect on the suitability of certain metabolites as biomarkers, including several lipids and lipid mediators. Our sample-handling recommendations will increase the reliability and quality of samples when such metabolites are necessary for routine clinical diagnosis.