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Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules. However, a significant part of the mutant DYRK1B protein accumulated in detergent-insoluble cytoplasmic aggregates and was underphosphorylated on tyrosine. The mutant DYRK1B variants were more vulnerable to the HSP90 inhibitor ganetespib and showed enhanced binding to the co-chaperone CDC37 as compared to wild type DYRK1B. These results support the hypothesis that the mutations in the DH box interfere with the maturation of DYRK1B by tyrosine autophosphorylation and compromise the conformational stability of the catalytic domain, which renders the kinase susceptible to misfolding.
Dryopteris lacunosa – eine neue Art des Dryopteris-affinis-Aggregats (Dryopteridaceae, Pteridophyta)
(2011)
Eine weitere Sippe des Dryopteris-affinis-Aggregats wird als Art, D. lacunosa S. JESS., ZENNER, CH. STARK & BUJNOCH beschrieben. Sie lässt sich morphologisch von den anderen bisher beschriebenen Taxa des Aggregats unterscheiden, ist triploid und zeigt spezifische Phloroglucid- und RAPD- Bandenmuster. Bisher sind Funde aus Norditalien, Österreich, der Schweiz, Frankreich, Deutschland, Großbritannien und Irland belegt.
Background: Does the dogma of nephron sparing surgery (NSS) still stand for large renal masses? Available studies dealing with that issue are considerably biased often mixing imperative with elective indications for NSS and also including less malignant variants or even benign renal tumors. Here, we analyzed the oncological long-term outcomes of patients undergoing elective NSS or radical tumor nephrectomy (RN) for non-endophytic, large (≥7cm) clear cell renal carcinoma (ccRCC).
Methods: Prospectively acquired, clinical databases from two academic high-volume centers were screened for patients from 1980 to 2010. The query was strictly limited to patients with elective indications. Surgical complications were retrospectively assessed and classified using the Clavien-Dindo-classification system (CDS). Overall survival (OS) and cancer specific survival (CSS) were analyzed using the Kaplan-Meier-method and the log-rank test.
Results: Out of in total 8664 patients in the databases, 123 patients were identified (elective NSS (n = 18) or elective RN (n = 105)) for ≥7cm ccRCC. The median follow-up over all was 102 months (range 3–367 months). Compared to the RN group, the NSS group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04).
Conclusions: In large renal masses, NSS can be performed safely with acceptable complication rates. In terms of long-term OS and CSS, NSS was at least not inferior to RN. Our findings suggest that NSS should also be performed in patients presenting with renal tumors ≥7cm whenever technically feasible. Limitations include its retrospective nature and the limited availability of data concerning long-term development of renal function in the two groups.
In dieser Arbeit wurde deutlich, dass die Multilevel Monte Carlo Methode eine signifikante Verbesserung gegenüber der Monte Carlo Methode darstellt. Sie schafft es den Rechenaufwand zu verringern und in fast allen Fällen die gewollte Genauigkeit zu erreichen. Die Erweiterung durch Richardson Extrapolation brachte immer eine Verringerung des Rechenaufwands oder zumindest keine Verschlechterung, auch wenn nicht in allen Fällen die schwache Konvergenzordnung verdoppelt wurde.
Im Falle der Optionssensitivitäten ist eine Anwendung des MLMC-Algorithmus problematisch. Das Funktional, das auf den Aktienkurs angewendet wird, darf keine Unstetigkeitsstelle besitzen, bzw. im Falle des Gammas muss es stetig differenzierbar sein. Die Anwendung der MLMC Methode macht dann vor allem Sinn, wenn sich die Sensitivität als Funktion des Aktienkurses umformen lässt, so dass nur der Pfad der Aktie simuliert werden muss. Nur wenn dies nicht möglich ist, wäre es sinnvoll, die in Kapitel 6.5 am Beispiel des Deltas vorgestellte Methode zu benutzen, in der man einen zweiten Pfad für das Delta simuliert.
Weitere Verbesserungsmöglichkeiten könnten in der Wahl von anderen varianzreduzierenden Methoden liegen oder durch Verwendung von Diskretisierungsverfahren mit höherer starker Ordnung als das Euler-Verfahren (vgl. [7], Verwendung des Milstein-Verfahrens). In diesem Fall ist theoretisch ein Rechenaufwand der Größenordnung O(ϵexp-2) möglich, da die Anzahl der zu erstellenden Samples nicht mehr mit steigendem L erhöht wird. Somit könnte das L so groß gewählt werden, dass der Bias verschwindet und der MSE ausschließlich von der Varianz des Schätzers abhängt. Um diese auf eine Größenordnung von O(ϵexp2) zu bringen, ist es nötig, O(ϵexp2) Pfade zu erstellen (siehe Gleichung (3.6)), was den Rechenaufwand begründet.
Objectives: Rising prevalence of multidrug-resistant organisms (MDRO) is a major health problem in patients with liver cirrhosis. The impact of MDRO colonization in liver transplantation (LT) candidates and recipients on mortality has not been determined in detail.
Methods: Patients consecutively evaluated and listed for LT in a tertiary German liver transplant center from 2008 to 2018 underwent screening for MDRO colonization including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant gram-negative bacteria (MDRGN), and vancomycin-resistant enterococci (VRE). MDRO colonization and infection status were obtained at LT evaluation, planned and unplanned hospitalization, three months upon graft allocation, or at last follow-up on the waiting list.
Results: In total, 351 patients were listed for LT, of whom 164 (47%) underwent LT after a median of 249 (range 0–1662) days. Incidence of MDRO colonization increased during waiting time for LT, and MRDO colonization was associated with increased mortality on the waiting list (HR = 2.57, p<0.0001. One patients was colonized with a carbapenem-resistant strain at listing, 9 patients acquired carbapenem-resistant gram-negative bacteria (CRGN) on the waiting list, and 4 more after LT. In total, 10 of these 14 patients died.
Conclusions: Colonization with MDRO is associated with increased mortality on the waiting list, but not in short-term follow-up after LT. Moreover, colonization with CRGN seems associated with high mortality in liver transplant candidates and recipients.
Eine Hybride zwischen Asplenium septentrionale (L.) Hoffm. subsp. septentrionale und A. viride (L.) HUDS. wird beschrieben. Der Bastard wurde in einem Exemplar bei Bosco-Gurin im Schweizer Kanton Tessin gefunden. Die morphologische Mittelstellung sowie Sporen-, Cytologische und Molekulargenetische Untersuchungen bestätigten die vermutete Abstammung.
Was verstehen Lehramtsstudierende unter Inklusion? Eine Untersuchung subjektiver Definitionen
(2019)
Der Begriff der Inklusion ist ein mehrdimensionales Konstrukt, das sowohl in Theorie als auch in Praxis unterschiedlich definiert ist. Für angehende Lehrkräfte bedeutet dies, dass sie sich mit unterschiedlichen Konnotationen dieses Begriffs auseinandersetzen müssen und dadurch möglicherweise eigene Begriffsdefinitionen vornehmen. Im Mittelpunkt dieses Beitrages steht die Frage nach den subjektiven Begriffsdefinitionen zum Begriff Inklusion. Im Rahmen einer schriftlichen Befragung wurden 290 Lehramtsstudierende mit Hilfe einer offenen Fragestellung zu ihrem Inklusionsverständnis befragt. Das Material wurde mittels qualitativer Inhaltsanalyse ausgewertet. Die Ergebnisse verweisen auf ein differenziertes Begriffsverständnis angehender Lehrkräfte. Es können vier Verständnistypen unterschieden werden, ausgehend von einem sehr engen bis hin zu einem sehr weiten und offenen Begriffsverständnis.
Chronic hepatitis C virus (HCV) infection is a leading cause for orthotopic liver transplantation (OLT) in the U.S. We investigated characteristics of HCV-infected patients registered for OLT, and explored factors associated with mortality. Data were obtained from the United Network for Organ Sharing and Organ Procurement and Transplantation network (UNOS/OPTN) registry. Analyses included 41,157 HCV-mono-infected patients ≥18 years of age listed for cadaveric OLT between February 2002 and June 2014. Characteristics associated with pre- and post-transplant survival and time trends over the study period were determined by logistic and Cox proportional hazard regression analyses and Poisson regressions. Most patients were white (69.1%) and male (70.8%). At waitlist registration, mean age was 54.6 years and mean MELD was 16. HCC was recorded in 26.9% of the records. A total of 51.2% of the patients received an OLT, 21.0% died or were too sick; 15.6% were delisted and 10.4% were still waiting. Factors associated with increased waitlist mortality were older age, female gender, blood type 0, diabetes, no HCC and transplant region (p<0.001). OLT recipient characteristics associated with increased risk for post OLT mortality were female gender, age, diabetes, race (p<0,0001), and allocation MELD (p = 0.005). Donor characteristics associated with waitlist mortality included age, ethnicity (p<0.0001) and diabetes (p<0.03). Waitlist registrations and OLTs for HCC significantly increased from 14.4% to 37.3% and 27.8% to 38.5%, respectively (p<0.0001). Pre- and post-transplant survival depended on a variety of patient-, donor-, and allocation- characteristics of which most remain relevant in the DAA-era. Still, intensified HCV screening strategies and timely and effective treatment of HCV are highly relevant to reduce the burden of HCV-related OLTs in the U.S.
Aim: Cellular CD81 is a well characterized hepatitis C virus (HCV) entry factor, while the relevance of soluble exosomal CD81 in HCV pathogenesis is poorly defined. We performed a case-control study to investigate whether soluble CD81 in the exosomal serum fraction is associated with HCV replication and inflammatory activity.
Patients and Methods: Four cohorts were investigated, patients with chronic hepatitis C (n = 37), patients with chronic HCV infection and persistently normal ALT levels (n = 24), patients with long term sustained virologic response (SVR, n = 7), and healthy volunteers (n = 23). Concentration of soluble CD81 was assessed semi-quantitatively after differential centrifugation ranging from 200 g to 100,000 g in the fifth centrifugation fraction by immunoblotting and densitometry.
Results: Soluble CD81 was increased in patients with chronic hepatitis C compared to healthy subjects (p = 0.03) and cured patients (p = 0.017). Patients with chronic HCV infection and persistently normal ALT levels and patients with long term SVR had similar soluble CD81 levels as healthy controls (p>0.2). Overall, soluble CD81 levels were associated with ALT levels (r = 0.334, p = 0.016) and severe liver fibrosis (p = 0.027).
Conclusion: CD81 is increased in the exosomal serum fraction in patients with chronic hepatitis C and appears to be associated with inflammatory activity and severity of fibrosis.
Eosinophilic cholangitis is a potentially underdiagnosed etiology in indeterminate biliary stricture
(2017)
AIM: To investigate presence and extent of eosinophilic cholangitis (EC) as well as IgG4-related disease in patients with indeterminate biliary stricture (IBS).
METHODS: All patients with diagnosis of sclerosing cholangitis (SC) and histopathological samples such as biopsies or surgical specimens at University Hospital Frankfurt from 2005-2015 were included. Histopathological diagnoses as well as further clinical course were reviewed. Tissue samples of patients without definite diagnosis after complete diagnostic work-up were reviewed regarding presence of eosinophilic infiltration and IgG4 positive plasma cells. Eosinophilic infiltration was as well assessed in a control group of liver transplant donors and patients with primary sclerosing cholangitis.
RESULTS: one hundred and thirty-five patients with SC were included. In 10/135 (13.5%) patients, no potential cause of IBS could be identified after complete diagnostic work-up and further clinical course. After histopathological review, a post-hoc diagnosis of EC was established in three patients resulting in a prevalence of 2.2% (3/135) of all patients with SC as well as 30% (3/10) of patients, where no cause of IBS was identified. 2/3 patients with post-hoc diagnosis of EC underwent surgical resection with suspicion for malignancy. Diagnosis of IgG4-related cholangitis was observed in 7/135 patients (5.1%), whereas 3 cases were discovered in post-hoc analysis. 6/7 cases with IgG4-related cholangitis (85.7%) presented with eosinophilic infiltration in addition to IgG4 positive plasma cells. There was no patient with eosinophilic infiltration in the control group of liver transplant donors (n = 27) and patients with primary sclerosing cholangitis (n = 14).
CONCLUSION: EC is an underdiagnosed benign etiology of SC and IBS, which has to be considered in differential diagnosis of IBS.