Combined Blockade of ADP Receptors and PI3-Kinase p110β Fully Prevents Platelet and Leukocyte Activation during Hypothermic Extracorporeal Circulation

Extracorporeal circulation (ECC) and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K) p110β. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P2Y12 and P2Y1 blockade and PI3K p110β inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P2Y12 antagonist 2-MeSAMP, the P2Y1 antagonist MRS2179, the PI3K p110β inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls). Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX-221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28°C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P2Y blockers (p<0.05), while no effect of hypothermic ECC or antiplatelet agents on GPIIb/IIIa and GPIbα expression and von Willebrand factor binding was observed. Sole P2Y and PI3K blockade or a combination thereof inhibited P-selectin expression on platelets and platelet-derived microparticles during hypothermic ECC (p<0.05). P2Y blockade alone or combined with TGX-221 prevented ECC-induced platelet-granulocyte aggregate formation (p<0.05). Platelet adhesion to the ECC surface, platelet loss and Mac-1 expression on granulocytes were inhibited by combined P2Y and PI3K blockade (p<0.05). Combined blockade of P2Y12, P2Y1 and PI3K p110β completely inhibits hypothermic ECC-induced activation processes. This novel finding warrants further studies and the development of suitable pharmacological agents to decrease ECC- and hypothermia-associated complications in clinical applications

Familienangehörige spielerisch zusammenführen – Systemkonzept

Immer mehr ältere Menschen leben von ihren Angehörigen getrennt und können über Kommunikationsmedien wie Telefon und Skype nur eingeschränkt gemeinsame Erlebnisse erzeugen. In diesem Paper wird die technische Umsetzung eines Konzeptes vorgestellt, das es Familienmitgliedern ermöglicht über das Internet gemeinsam „Mensch-ärgere-dich-nicht“ zu spielen. Durch Videotelefonie und eine besondere Anordnung der Hardware werden die Spieler trotz räumlicher Trennung virtuell an einen Tisch gebracht und dadurch ein gemeinsames Erlebnis erzeugt. Die Clientanwendung wird dabei als plattformunabhängiger Webservice und die Videotelefonie mittels verschiedener Standards und Server realisiert

Thermal history of Northwest Africa 5073--A coarse-grained Stannern-trend eucrite containing cm-sized pyroxenes and large zircon grains

International audienceWe report on the bulk chemical composition, petrology, oxygen isotopic composition, trace element composition of silicates, and degree of self-irradiation damage on zircon grains of the eucrite Northwest Africa (NWA) 5073 to constrain its formation and postcrystallization thermal history, and to discuss their implications for the geologic history of its parent body. This unequilibrated and unbrecciated meteorite is a new member of the rare Stannern-trend eucrites. It is mainly composed of elongated, zoned pyroxene phenocrysts up to 1.2 cm, plagioclase laths up to 0.3 cm in length, and is rich in mesostasis. The latter contains zircon grains up to 30 μm in diameter, metal, sulfide, tridymite, and Ca-phosphates. Textural observations and silicate compositions, coupled with the occurrence of extraordinary Fe-rich olivine veins that are restricted to large pyroxene laths, indicate that NWA 5073 underwent a complex thermal history. This is also supported by the annealed state of zircon grains inferred from μ-Raman spectroscopic measurements along with U and Th data obtained by electron probe microanalyses

Publikationsbasierte Dissertation?! Argumente. Aktueller Stand. Offene Fragen.

Die Frage “Dissertation als Monographie oder als kumulative Dissertation?” wird aktuell an vielen Standorten und im Rahmen der GDM-Nachwuchsvertretung kontrovers und oft auch leidenschaftlich diskutiert.Auslösende Faktoren dieser Diskussion sind Anforderungen an Promovierende, bereits während der Promotionszeit wissenschaftlich zu publizieren, um die Sichtbarkeit der eigenen Forschung zu erhöhen, eventuelle Ansprüche von Drittmittelgebern zu erfüllen oder gut vorbereitet zu sein für die aktuelle wissenschaftliche Praxis.Angeregt durch konkrete Anfragen an den GDM-Beirat haben wir uns als Kleingruppe zusammengefunden. Uns vereint, dass wir die Möglichkeit einer publikationsbasierten Dissertation befürworten, ohne dass diese die monographische Form ersetzen sollte. Mit diesem Artikel möchten wir die bisherigen Diskussionen öffnen und transparent machen. Deshalb beginnen wir mit einer Sammlung von Argumenten aus dem aktuellen Diskurs. Im Anschluss stellen wir die Ergebnisse einer informellen Abfrage vor, die Silke Ruwisch bei Kolleg/-innen verschiedener mathematikdidaktischer Standorte durchgeführt hat und mit der sich ein grober Überblick über gängige einschlägige Praxen gewinnen ließ. Wir schließen mit offenen Fragen zur Thematik, die zur gemeinsamen Diskussion anregen sollen. Deshalb laden wir herzlich ein zum gemeinsamen Austausch im Rahmen des Diskussionsforums “Publikationsbasierte Dissertation?!” auf der GDM-Jahrestagung in Frankfurt. Weitere Informationen dazu entnehmen Sie bitte der Tagungsseite https://www.gdm-tagung.de

Detection of functional protein domains by unbiased genome-wide forward genetic screening

Genetic and chemo-genetic interactions have played key roles in elucidating the molecular mechanisms by which certain chemicals perturb cellular functions. Many studies have employed gene knockout collections or gene disruption/depletion strategies to identify routes for evolving resistance to chemical agents. By contrast, searching for point-mutational genetic suppressors that can identify separation- or gain-of-function mutations, has been limited even in simpler, genetically amenable organisms such as yeast, and has not until recently been possible in mammalian cell culture systems. Here, by demonstrating its utility in identifying suppressors of cellular sensitivity to the drugs camptothecin or olaparib, we describe an approach allowing systematic, large-scale detection of spontaneous or chemically-induced suppressor mutations in yeast and in haploid mouse embryonic stem cells in a short timeframe, and with potential applications in essentially any other haploid system. In addition to its utility for molecular biology research, this protocol can be used to identify drug targets and to predict mechanisms leading to drug resistance. Mapping suppressor mutations on the primary sequence or three-dimensional structures of protein suppressor hits provides insights into functionally relevant protein domains, advancing our molecular understanding of protein functions, and potentially helping to improve drug design and applicability

Age independent survival benefit for patients with hepatocellular carcinoma (HCC) without metastases at diagnosis: a population-based study

OBJECTIVE Hepatocellular carcinoma (HCC) is a major cause of death worldwide and its incidence is expected to increase globally. Aim of this study was to assess whether the implementation of screening policies and the improvement of treatment options translated into a real-world survival benefit in HCC patients. DESIGN 4078 patients diagnosed with HCC between 1998 and 2016 from the Munich Cancer Registry were analysed. Tumour characteristics and outcome were analysed by time period and according to age and presence of metastases at diagnosis. Overall survival (OS) was analysed using Kaplan-Meier method and relative survival (RS) was computed for cancer-specific survival. Cox proportional hazard models were conducted to control for prognostic variables. RESULTS While incidence of HCC remained substantially stable, tumours were diagnosed at increasingly earlier stages, although the median age at diagnosis increased. The 3 years RS in HCC improved from 19.8% in 1998-2002, 22.4% in 2003-2007, 30.6% in 2008-2012 up to 31.0% in 2013-2016. Median OS increased from 6 months in 1998-2002 to 12 months in 2008-2016. However, analysis according to the metastatic status showed that survival improved only in patients without metastases at diagnosis whereas the prognosis of patients with metastatic disease remained unchanged. CONCLUSION These real-world data show that, in contrast to the current assumptions, the incidence of HCC did not increase in a representative German region. Earlier diagnosis, likely related to the implementation of screening programmes, translated into an increasing employment of effective therapeutic options and a clear survival benefit in patients without metastases at diagnosis, irrespective of age

Daytime sleepiness in patients with untreated restless legs syndrome

Background Restless legs syndrome (RLS), a disorder characterized by an urge to move one’s legs during sleep or rest, leads to impaired sleep quality. Many patients with RLS report increased daytime sleepiness, but this has seldom been the focus of clinical research. The current study empirically investigated the prevalence and severity of daytime sleepiness in RLS. Methods This prospective study included 29 newly diagnosed treatment-naïve patients with RLS and 31 healthy controls and assessed standardized subjective (tiredness symptom scale [TSS], Stanford Sleepiness Scale [SSS], Epworth Sleepiness Scale [ESS]), cognitive (psychomotor vigilance task [PVT], Mackworth Clock Test [MCT]), and physiological measures (pupillary unrest index [PUI]). RLS symptom severity was assessed, and the effects of RLS on general health aspects and subjective sleep quality (Pittsburgh Sleep Quality Index) were compared to control data. Results Patients had moderate to severe RLS with significant negative effects on general health, quality of life, and sleep quality. Patients with RLS showed more subjective daytime sleepiness (ESS) and current sleepiness (TSS, SSS) than controls. The objective performance of patients in sustained attention tasks (P VT, MCT) was significantly worse than that of controls. Additionally, patients showed higher PUI scores. Conclusion In the present study, RLS was associated with markedly impaired subjective sleep quality and with subjectively and objectively increased daytime sleepiness. Since daytime sleepiness can be a major factor leading to compromised quality of life, assessing and treating sleepiness should be incorporated into standard diagnostics and treatment