Die basolaterale Aufnahme von organischen Anionen in die Leber wird durch Transportproteine der Oatp-Familie vermittelt. In der Rattenleber werden die basolateralen Transportproteine Oatp1 (Slc21a1), Oatp2 (Slc21a5) und Oatp4 (Slca10) exprimiert und unter pathophysiologischen Bedingungen (z.B. Cholestase) unterschiedlich reguliert. Ziel dieser Arbeit war es, den Einfluss von Cholat (CA) und Ursodeoxycholat (UDCA) auf die Expression von Oatp4 im Vergleich zu Ntcp, Oatp1 und Oatp2 zu untersuchen.

Micro-aggregation is a frequently used strategy to anonymize data before they are released to the scientific public. A sample of a continuous random variable is individually micro-aggregated by first sorting and grouping the data into groups of equal size and then replacing the values of the variable in each group by their group mean. In a similar way, data with more than one variable can be anonymized by individual micro-aggregation. Data thus distorted may still be used for statistical analysis. We show that if probabilities and quantiles are estimated in the usual way by computing relative frequencies and sample quantiles, respectively, these estimates are consistent and asymptotically normal under mild conditions.

A bridge connects and efficiently transfers the chirality from the backbone of a N-heterocyclic carbene (NHC) to the metal center. The result is excellent enantioselectivities in the ruthenium-catalyzed, asymmetric ring-opening cross-metathesis of norbornenes with allyltrimethylsilane (see scheme). Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Eine Brücke verbindet …︁ und überträgt damit die Chiralität effizient vom Rückgrat eines N-heterocyclischen Carbens auf das Metallzentrum in einem neuartigen Olefinmetathesekatalysator. Damit wurden exzellente Enantioselektivitäten in der Ruthenium-katalysierten asymmetrischen Ringöffnungskreuzmetathese von Norbornenen mit Allyltrimethylsilan erzielt (siehe Schema). Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

AbstractRing‐opening cross metathesis reaction of norbornene derivatives with styrene derivatives proceeds smoothly in the presence of a novel Ru catalyst.

Einhändig sehr effizient sind nicht nur Winkerkrabben, sondern auch chirale Ruthenium-Metathese(prä)katalysatoren mit einem C-monosubstituierten N-heterocyclischen Carben. S. Blechert und Mitarbeiter zeigen in ihrer Zuschrift auf S. 4064 ff., dass durch die Ligandenkombination hoch stabile Katalysatoren erreicht werden, die asymmetrische Ringöffnungs-Kreuzmetathesen rasch initiieren und hohe E- sowie Enantioselektivitäten liefern. (Foto: Thorsten Stegmann.)

Einfach (substituiert) geht's besser: Die Titelsysteme sind in Lösung hochstabil, initiieren die Metathese leicht und liefern bei der asymmetrischen Ringöffnungskreuzmetathese hohe ee-Werte bei ausgezeichneter E-Selektivität. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background & Aims: In patients with primary sclerosing cholangitis (PSC) treated with ursodeoxycholic acid (UDCA), dominant stenoses are associated with reduced survival free of liver transplantation and the role of inflammatory bowel disease (IBD) in such patients is unclear. In the present study the influence of IBD on the outcome in patients with and without dominant stenosis has been evaluated.Methods: In a prospective study, 171 patients were followed for up to 20 years. All patients were treated with ursodeoxycholic acid; patients with dominant stenosis in addition were treated endoscopically.Results:A total of 97 out of 171 patients had or developed dominant bile duct stenoses and 96 out of 97 were treated endoscopically. In patients with dominant stenosis without IBD, no carcinoma was found whereas all six bile duct and two gallbladder carcinomas and 6/7 cob-rectal carcinomas were found in patients with dominant stenosis with IBD (p = 0.012). In patients without dominant stenosis but with IBD, 1 out of 7 had colo-rectal carcinoma. In patients with dominant stenosis without IBD (n = 30), actuarial survival free of liver transplantation at 18 years was 77.8% and in those with dominant stenosis and inflammatory bowel disease (n = 67) it was 23.0% (p = 0.045). In PSC patients without dominant stenosis and without IBD (n = 21), actuarial survival free of liver transplantation at 18 years was 68.2% and in those with inflammatory bowel disease (n = 53) it was 78.4% (n.s.).Conclusions: In patients without dominant stenosis, IBD had no effect on the incidence of carcinomas and survival. Only patients with dominant stenosis with additional IBD had an increased carcinoma rate. This may contribute to the reduced survival free of liver transplantation in such patients. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

BACKGROUND:Cholangiocellular carcinomas and gallbladder carcinomas are highly aggressive tumours with a poor prognosis and are generally regarded as chemoresistant tumours. Overexpression of ATP-binding cassette transporters of the multidrug resistance protein (MDR) and multidrug resistance-related protein (MRP) family in cancer cells is a major cause for the multidrug resistance phenotype in vitro and in vivo. To further define the role of MRP family members in biliary tract cancer, we studied the expression and localization of MRP2 and MRP3 in cholangiocellular carcinomas and gallbladder carcinomas.MATERIALS AND METHODS:The expression and cellular localization of the multidrug resistance proteins MRP2 and MRP3 in human cholangiocellular carcinomas and gallbladder carcinomas were analysed by immunohistochemistry using isoform-specific antibodies. Expression of MRP isoforms was studied in vitro in Mz-ChA-1 cells derived from gallbladder adenocarcinoma by reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting and immunofluorescence microscopy.RESULTS:Mz-ChA-1 cells constitutively expressed MDR P-glycoproteins, MRP1, MRP2 and MRP3 by RT-PCR, immunoblotting and immunofluorescence microscopy. MRP2 and MRP3 are expressed in the respective apical and basolateral membrane domains. MRP3 was the predominant MRP isoform in gallbladder carcinomas (93%) and cholangiocellular carcinomas (57%), whereas MRP2 expression was detected in only 29% of gallbladder carcinomas and was undetectable in cholangiocellular carcinomas.CONCLUSIONS:Our findings suggest that the intrinsic multidrug resistance of cholangiocellular and gallbladder carcinomas seems to be independent of MRP2 expression while the expression of MRP3 may contribute to the MDR phenotype.

Highly efficient formation of tetrasubstituted olefins is described by ring-closing metathesis (RCM) using catalyst 2 in presence of hexafluorobenzene. This combination with hexafluorobenzene shows an unexpected promoting effect, which requires low catalysts loadings and allows the conversion of deficient olefins in high yields and very short reaction times. (C) 2008 Elsevier Ltd. All rights reserved.

UNLABELLEDBile salts may initiate or aggravate cholestasis in man. Infusion of Taurochenodeoxycholate (TCDCA) represents a model of bile salt-induced cholestasis in rat. The events leading to cholestasis are incompletely understood. The canalicular conjugate export pump Mrp2 is the major driving force for the bile salt-independent bile flow. Redistribution of Mrp2 has been suggested to cause reduction in bile flow in others models of acute cholestasis (i.e. endotoxin, phalloidin, GSH-depletion). We have studied the effects of TCDCA on the distribution of Mrp2 and P-glycoproteins with respect to changes in the actin cytoskeleton and actin associated proteins radixin and ZO-1. Bile duct cannulated rats were infused with TCDCA (0.1 and 0.4 micromol/min/100g body weight) and bile flow was measured. After 30 min livers were removed and distribution of Mrp2, P-glycoproteins, actin, actin-associated radixin and ZO1 were studied by immunofluorescence analysis. TCDCA at subcholestatic amounts (0.1 micromol/min/100 g body weight) led to distortion and dilation of the canaliculi which was apparent in actin, ZO-1, and Mrp2 fluorescence. Administration of higher amounts of TCDCA (0.4 micromol/min/100g body weight) led to a reduction of bile flow to 31 % of control bile flow. Radixin, which localized strictly to the plasmamembrane in controls, was detected in intracellular structures partially colocalizing with actin aggregates especially at the sinusoidal membranes as visualized by double-immunofluorescence staining. Mrp2 appeared in pericanalicular membrane structures in cholestatic animals whereas P-glycoproteins remained unchanged under these conditions.CONCLUSIONSBile salt-induced cholestasis is associated with changes of the actin cytoskeleton and actin binding protein radixin and a retrieval of the canalicular export pump Mrp2.

Gastrointestinale Nebenwirkungen gehören zu den häufigen und für den Patienten besonders belastenden Folgen einer zytostatischen Chemotherapie.

Background/Aims Cholangiocarcinoma represents a serious complication of primary sclerosing cholangitis. Ursodeoxycholic acid may possibly influence the incidence of cholangiocarcinoma in man. The aim of this study was to evaluate the incidence rate of cholangiocarcinoma in a large group of primary sclerosing cholangitis patients after long-time treatment with ursodeoxycholic acid. Patients and methods From May 1987 up to May 2005 a total of 150 patients with primary sclerosing cholangitis but without evidence of cholangiocarcinoma at entry were included in the study. All patients were treated with ursodeoxycholic acid and controls were performed in at least yearly intervals. Results The median treatment time of the 150 patients was 6.4 years. Altogether five patients developed a cholangiocarcinoma during treatment yielding a rate of 3.3%. The patients developed 0.58 cholangiocarcinoma per 100 patient-years in years 0–2.5, 0.59 cholangiocarcinoma in years 2.5–8.5, and no cholangiocarcinoma thereafter up to 18 years after entry into the study. The Kaplan–Meier estimate of cholangiocarcinoma incidence during ursodeoxycholic acid treatment reached a plateau after 8.3 years. Summary and conclusion The annual incidence rate of cholangiocarcinoma in primary sclerosing cholangitis treated with ursodeoxycholic acid is lower than expected and decreases with time of treatment.