Systemic epidermal nevus with involvement of the oral mucosa due to FGFR3 mutation

Our results show that activating FGFR3 mutations can also affect the oral mucosa and that extracutaneous manifestations of EN syndrome can be subtle. We highlight the theoretical risk of the patient having an offspring with thanatophoric dysplasia as gonadal mosaicism for the R248C mutation cannot be excluded

Duration of invasive mechanical ventilation prior to extracorporeal membrane oxygenation is not associated with survival in acute respiratory distress syndrome caused by coronavirus disease 2019

BACKGROUND: Duration of invasive mechanical ventilation (IMV) prior to extracorporeal membrane oxygenation (ECMO) affects outcome in acute respiratory distress syndrome (ARDS). In coronavirus disease 2019 (COVID-19) related ARDS, the role of pre-ECMO IMV duration is unclear. This single-centre, retrospective study included critically ill adults treated with ECMO due to severe COVID-19-related ARDS between 01/2020 and 05/2021. The primary objective was to determine whether duration of IMV prior to ECMO cannulation influenced ICU mortality. RESULTS: During the study period, 101 patients (mean age 56 [SD ± 10] years; 70 [69%] men; median RESP score 2 [IQR 1–4]) were treated with ECMO for COVID-19. Sixty patients (59%) survived to ICU discharge. Median ICU length of stay was 31 [IQR 20.7–51] days, median ECMO duration was 16.4 [IQR 8.7–27.7] days, and median time from intubation to ECMO start was 7.7 [IQR 3.6–12.5] days. Fifty-three (52%) patients had a pre-ECMO IMV duration of > 7 days. Pre-ECMO IMV duration had no effect on survival (p = 0.95). No significant difference in survival was found when patients with a pre-ECMO IMV duration of < 7 days (< 10 days) were compared to ≥ 7 days (≥ 10 days) (p = 0.59 and p = 1.0). CONCLUSIONS: The role of prolonged pre-ECMO IMV duration as a contraindication for ECMO in patients with COVID-19-related ARDS should be scrutinised. Evaluation for ECMO should be assessed on an individual and patient-centred basis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13613-022-00980-3

The POM Monoclonals: A Comprehensive Set of Antibodies to Non-Overlapping Prion Protein Epitopes

PrPSc, a misfolded and aggregated form of the cellular prion protein PrPC, is the only defined constituent of the transmissible agent causing prion diseases. Expression of PrPC in the host organism is necessary for prion replication and for prion neurotoxicity. Understanding prion diseases necessitates detailed structural insights into PrPC and PrPSc. Towards this goal, we have developed a comprehensive collection of monoclonal antibodies denoted POM1 to POM19 and directed against many different epitopes of mouse PrPC. Three epitopes are located within the N-terminal octarepeat region, one is situated within the central unstructured region, and four epitopes are discontinuous within the globular C-proximal domain of PrPC. Some of these antibodies recognize epitopes that are resilient to protease digestion in PrPSc. Other antibodies immunoprecipitate PrPC, but not PrPSc. A third group was found to immunoprecipitate both PrP isoforms. Some of the latter antibodies could be blocked with epitope-mimicking peptides, and incubation with an excess of these peptides allowed for immunochromatography of PrPC and PrPSc. Amino-proximal antibodies were found to react with repetitive PrPC epitopes, thereby vastly increasing their avidity. We have also created functional single-chain miniantibodies from selected POMs, which retained the binding characteristics despite their low molecular mass. The POM collection, thus, represents a unique set of reagents allowing for studies with a variety of techniques, including western blotting, ELISA, immunoprecipitation, conformation-dependent immunoassays, and plasmon surface plasmon resonance-based assays

„Daumen hoch“ für das virtuelle Klassenzimmer. Zur Förderung mündlicher Interaktion in studienvorbereitenden Online-Sprachkursen durch den Einsatz eines virtuellen Klassenzimmers mit ergonomischer Benutzeroberfläche

Grammatik und Wortschatz, Lesen, Hören und Schreiben gehören zu den Kompetenzen, die sich sehr gut für die mediale Vermittlung in Online-Sprachkursen eignen. Zweifel bestehen aber bezüglich der Frage, ob mündliche Kompetenzen ebenso gut ausgebildet werden können, verlangen sie doch synchrone, direkte Kommunikation. Virtuelle Klassenzimmer setzen genau hier an und versuchen die mündliche Interaktion medial zu vermitteln. Sie können deshalb eine sinnvolle Ergänzung gängiger Lernprogramme sein. Die Sprachdidaktiker der Deutsch-Uni Online (DUO), einer multimedialen Sprach lernplattform, versuchen diesen Herausforderungen durch den Einsatz der am Fraunhofer Institut entwickelten Software vitero (virtual team room) zu begegnen. Der vorliegende Artikel beschreibt die verschiedenen Schritte bei der Implementierung des virtuellen Klassenzimmers in die Kurse der Deutsch-Uni Online sowie die Ergebnisse der ersten Erprobungsphase der Arbeit im virtuellen Klassenzimmer. Dabei zeichnet sich ab, dass die angestrebte Verbesserung vor allen Dingen in den Bereichen Sprechen, Hören, Wortschatz liegt und die Treffen insgesamt zu einem besseren Verständnis der Themen im Online-Kurs führen. (DIPF/Orig.

Effects of oxygen oscillations on human myocardial and endothelial cell cultures

Das akute Lungenversagen hat eine Mortalitätsrate von 35-46%, häufig auf Basis eines sekundären Multiorganversagens. Während das klassische Konzept die systemische Inflammation als Ursache für sekundäre Organschäden beschreibt, werden Sauerstoffoszillationen, welche durch die Blutbahn zu Endorganen fortgeleitet werden, aktuell als Pathomechanismus in Betracht gezogen. Intermittierende hypoxische Situationen treten zudem auch beim obstruktiven Schlafapnoesyndrom auf. Obwohl sich die zugrundeliegenden Mechanismen unterscheiden, kommt es bei beiden Syndromen zu sekundären Organschäden. Aufgrund der eingeschränkten Gasdiffusion in herkömmlichen Zellkulturmodellen, sind die Auswirkungen auf zellulärer Ebene noch unzureichend untersucht. Aus diesem Grund hatte die vorliegende Doktorarbeit zum Ziel die Effekte von Oszillationen auf humane Endothelzellen aus Nabelschnüren (human umbilical vein endothelial cells, HUVECs) sowie humane adulte Kardiomyozyten (human adult cardiomyocytes, HACMs) in in vitro Experimenten zu analysieren. In vier einzelnen Projekten wurden HUVECs und HACMs in einem neu entwickelten Bioreaktor unterschiedlichen Sauerstoffbedingungen ausgesetzt. Die Analysen erfolgen zu Beginn sowie nach definierten Expositionszeitpunkten in Hinblick auf die Freisetzung von Interleukinen, Zellzytotoxizität, -vitalität und der Expression von Genen und Proteinen. Die intermittierende (0-21% O2) und konstante schwere Hypoxie (0%) führte in HACMs zur Zellschädigung und Inflammation. Desweiteren wurde ein Unterschied in der Expression von Genen des oxidativen Stresses sowie der Signalisierung von Hypoxie unter repetitiver Hypoxie detektiert. Die moderate Hyperoxie (40%) und zyklische Anoxie/moderate Hyperoxie (0-40%) induzierten in HUVECs Apoptose und Nekrose. Weiters aktivierte die wiederkehrende Anoxie/moderate Hyperoxie kompensatorische Mechanismen der Zellregulierung. Die intermittierende (5-95%) und die konstante schwere Hyperoxie (95%) hatten in HUVECs und HACMs Zellschädigung und die Freisetzung von Zytokinen zur Folge. In der vorliegenden Arbeit führten die Oszillationen zur Zellschädigung und Freisetzung von inflammatorischen Zytokinen in HUVECs und HACMs. Diese Ergebnisse weisen darauf hin, dass Sauerstoffschwankungen für die schädlichen Folgen im Rahmen des akuten Lungenversagens und dem obstruktiven Schlafapnoesyndrom verantwortlich sein könnten.The acute respiratory distress syndrome has a mortality rate of around 35-46%, mostly due to secondary multi-organ failure. Whereas the classical concept describes the systemic inflammatory response as the potential cause for this failure, oxygen oscillations, which are forwarded to the organs with the bloodstream, are currently considered as a novel patho-mechanism. Additionally, repetitive hypoxic episodes can be detected in patients suffering from obstructive sleep apnea syndrome. Although the underlying mechanisms differ, both syndromes induce secondary organ failure. However, due to the limitation of gas diffusion in a conventional cell-culture model, the effects at the cellular level have not been hitherto adequately investigated. Therefore, the present PhD thesis was aimed at analyzing the effects of oxygen oscillations in cultures of human umbilical vein endothelial cells (HUVECs) and human adult cardiomyocytes (HACMs) in in vitro experiments. In four separate projects, HUVECs and HACMs were exposed to various oxygen concentrations using a novel bioreactor. Measurements were performed before intervention as well as after an exposure of defined lengths with regard to the release of interleukines, cell cytotoxicity, -viability, and the pattern of expression of genes and proteins. It was demonstrated in HACMs that intermittent (0-21% O2) and constant severe hypoxia (0%) resulted in cell injury and inflammation. Moreover, gene regulation was modified for hypoxia signaling and oxidative stress under repetitive hypoxia. In addition, moderate hyperoxia (40%) and cyclic anoxia/moderate hyperoxia (0-40%) in HUVECs induced apoptosis and necrosis in comparison to constant anoxia (0%). Furthermore, recurrent anoxia/moderate hyperoxia activated compensatory mechanisms for cell survival. Additionally, intermittent (5-95%) and constant hyperoxia (95%) in cultures of HUVECs and HACMs demonstrated cell injury and cytokine release. In the present work, intermittent hypoxia and hyperoxia induced in HUVECs and HACMs cell death and an inflammatory response. These experiments indicated that oscillations of oxygen, which are present in patients suffering from acute respiratory distress syndrome and obstructive sleep apnea, may be responsible for the detrimental effects in the context of multi-organ failure.submitted by Christina Maria HafnerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Dissertation, 2017OeBB(VLID)246738

Aelurostrongylus abstrusus antibody seroprevalence reveals that cats are at risk of infection throughout Germany

Cats infected with the metastrongylid nematode Aelurostrongylus abstrusus may show clinical signs ranging from mild to severe respiratory disease or remain unobserved, despite damages present in the lung tissue. This study aimed to determine the seroprevalence and distribution of A. abstrusus in cats by testing serum samples from all over Germany to identify potential risk areas and strengthen disease awareness accordingly. Sera of 2998 cats were screened for the presence of antibodies against A. abstrusus by ELISA, and the data were evaluated by a geographic information system to visualise the regional distribution of the analysed samples. Overall, 12.0% of the samples tested positive (361/2998 cats, 95% confidence interval: 10.9–13.3%). Seropositive cats were identified throughout the country, suggesting that all cats in Germany with outdoor access are at risk of A. abstrusus infection and that the infection is overall underdiagnosed. Increased testing for A. abstrusus infection would allow earlier detection of infected animals, hence improving the life quality and health of cats and preventing potential death under anaesthesia

A computational workflow for the expansion of heterologous biosynthetic pathways to natural product derivatives

Plant natural products (PNPs) and their derivatives are important but underexplored sources of pharmaceutical molecules. To access this untapped potential, the reconstitution of heterologous PNP biosynthesis pathways in engineered microbes provides a valuable starting point to explore and produce novel PNP derivatives. Here, we introduce a computational workflow to systematically screen the biochemical vicinity of a biosynthetic pathway for pharmaceutical compounds that could be produced by derivatizing pathway intermediates. We apply our workflow to the biosynthetic pathway of noscapine, a benzylisoquinoline alkaloid (BIA) with a long history of medicinal use. Our workflow identifies pathways and enzyme candidates for the production of (S)-tetrahydropalmatine, a known analgesic and anxiolytic, and three additional derivatives. We then construct pathways for these compounds in yeast, resulting in platforms for de novo biosynthesis of BIA derivatives and demonstrating the value of cheminformatic tools to predict reactions, pathways, and enzymes in synthetic biology and metabolic engineering

Enlightened&nbsp;Dictators? Good Governance In Autocratic International Organizations

In this paper, we argue that the consequences of democratic backsliding are not limited to the large and growing number of international organizations (IOs) made up and governed by illiberal or outright authoritarian regimes. Many of these authoritarian IOs (AIOs) formally adopt good governance mandates, linking goals like democracy promotion, anti-corruption policies and human rights to their broader mission. Why do AIOs adopt good governance mandates that appear to conflict with the norms and standards these regimes apply at home? We argue that AIOs adopt these standards when they face substantial pressure from inside or outside the IO to adopt them. Central to our argument is that not all aspects of good governance are inherently or equally threatening to autocratic regimes. They pursue strategies that minimize the threat by externalizing policy outside the membership and strategically defining the goals to avoid or enact. This allows autocratic governments to uptake good governance talk but lessen any deep commitment to the norms and sometimes even to use them strategically to project their own power outside of the organization. Using data on 48 regional IOs with primarily autocratic membership between 1945 and 2015, we demonstrate that AIOs facing pressure from external good governance promoters will adopt good governance mandates but strategically shape those mandates in their favor if they can form bargaining coalitions with likeminded governments. The findings have sobering implications for the future of good governance promotion through IOs

Aelurostrongylus abstrusus Antibody Seroprevalence Reveals That Cats Are at Risk of Infection throughout Germany

Cats infected with the metastrongylid nematode Aelurostrongylus abstrusus may show clinical signs ranging from mild to severe respiratory disease or remain unobserved, despite damages present in the lung tissue. This study aimed to determine the seroprevalence and distribution of A. abstrusus in cats by testing serum samples from all over Germany to identify potential risk areas and strengthen disease awareness accordingly. Sera of 2998 cats were screened for the presence of antibodies against A. abstrusus by ELISA, and the data were evaluated by a geographic information system to visualise the regional distribution of the analysed samples. Overall, 12.0% of the samples tested positive (361/2998 cats, 95% confidence interval: 10.9–13.3%). Seropositive cats were identified throughout the country, suggesting that all cats in Germany with outdoor access are at risk of A. abstrusus infection and that the infection is overall underdiagnosed. Increased testing for A. abstrusus infection would allow earlier detection of infected animals, hence improving the life quality and health of cats and preventing potential death under anaesthesia