Are Selective Serotonin Reuptake Inhibitors Associated With Hepatocellular Carcinoma in Patients With Hepatitis C?

BACKGROUND AND AIMS: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for patients with chronic hepatitis C virus (HCV) infection. Research suggests that serotonin promotes the development and growth of hepatocellular carcinoma (HCC). We tested the hypothesis whether exposure to SSRIs is associated with an increased risk of HCC in HCV patients. METHOD: Patients who entered the United States Veterans Affairs (VA) Hepatitis C Clinical Case Registry in 2000 to 2009 were analyzed. During the 8 years of follow-up, 36,192 patients filled at least 1 SSRI prescription. Cases of HCC were identified by diagnosis codes (ICD-9 155.0). Multivariable Cox regression analyses estimated adjusted HCC hazard ratios (HRs) for SSRI-exposed versus SSRI-unexposed subjects and categories of average SSRI doses. RESULTS: The annual incidence of HCC in the VA registry cohort of 109,736 patients was 0.5% and significantly greater in the 8% with cirrhosis at baseline (HR = 5.2; 95% CI, 4.7-5.7). There was no evidence for significant interactions between the effect of SSRI-exposure and cirrhosis. Baseline characteristics of the exposed (n = 36,192) and unexposed (n = 73,544) subjects were similar. The median (interquartile range [IQR]) follow-up period after SSRI-exposure began was 44 (20-74) months with 18 (3-49) months between the first and last prescription. The median average SSRI dose during follow-up expressed as a fraction of initial recommended doses for depression was 0.94 (IQR, 0.5 to 1.3). The risk of HCC was not significantly increased after SSRI exposure (HR = 0.96; 95% CI, 0.87-1.05) or with increasing SSRI doses. CONCLUSIONS: Analysis of a large cohort of HCV patients did not support the hypothesis that SSRIs increase the risk of developing HCC.

Evaluation of treatment response after chemoembolisation (TACE) in hepatocellular carcinoma using real time image fusion of contrast-enhanced ultrasound (CEUS) and computed tomography (CT)--preliminary results.

OBJECTIVE To evaluate treatment response of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with a new real-time imaging fusion technique of contrast-enhanced ultrasound (CEUS) with multi-slice detection computed tomography (CT) in comparison to conventional post-interventional follow-up. MATERIAL AND METHODS 40 patients with HCC (26 male, ages 46-81 years) were evaluated 24 hours after TACE using CEUS with ultrasound volume navigation and image fusion with CT compared to non-enhanced CT and follow-up contrast-enhanced CT after 6-8 weeks. Reduction of tumor vascularization to less than 25% was regarded as "successful" treatment, whereas reduction to levels >25% was considered as "partial" treatment response. Homogenous lipiodol retention was regarded as successful treatment in non-enhanced CT. RESULTS Post-interventional image fusion of CEUS with CT was feasible in all 40 patients. In 24 patients (24/40), post-interventional image fusion with CEUS revealed residual tumor vascularity, that was confirmed by contrast-enhanced CT 6-8 weeks later in 24/24 patients. In 16 patients (16/40), post-interventional image fusion with CEUS demonstrated successful treatment, but follow-up CT detected residual viable tumor (6/16). Non-enhanced CT did not identify any case of treatment failure. Image fusion with CEUS assessed treatment efficacy with a specificity of 100%, sensitivity of 80% and a positive predictive value of 1 (negative predictive value 0.63). CONCLUSIONS Image fusion of CEUS with CT allows a reliable, highly specific post-interventional evaluation of embolization response with good sensitivity without any further radiation exposure. It can detect residual viable tumor at early state, resulting in a close patient monitoring or re-therapy.

Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.

BACKGROUND & AIMS Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. METHODS PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD. RESULTS Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001). CONCLUSIONS Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.

Virus-like particle-mediated intracellular delivery of mRNA cap analog with in vivo activity against hepatocellular carcinoma.

UNLABELLED Adenovirus dodecahedron (Dd), a nanoparticulate proteinaceous biodegradable virus-like particle (VLP), was used as a vector for delivery of an oncogene inhibitor to hepatocellular carcinoma (HCC) rat orthotopic model. Initiation factor eIF4E is an oncogene with elevated expression in human cancers. Cell-impermeant eIF4E inhibitor, cap structure analog (cap) and anti-cancer antibiotic doxorubicin (Dox) were delivered as Dd conjugates. Dd-cap and Dd-dox inhibited cancer cell culture proliferation up to 50 and 84%, respectively, while with free Dox similar results could be obtained only at a 5 times higher concentration. In animal HCC model the combination treatment of Dd-cap/Dd-dox caused 40% inhibition of tumor growth. Importantly, the level of two pro-oncogenes, eIF4E and c-myc, was significantly diminished in tumor sections of treated rats. Attachment to Dd, a virus-like particle, permitted the first demonstration of cap analog intracellular delivery and resulted in improved doxorubicin delivery leading to statistically significant inhibition of HCC tumor growth. FROM THE CLINICAL EDITOR Adenovirus dodecahedron, a nanoparticulate proteinaceous biodegradable virus-like particle was used in this study as a vector for the concomitant delivery of cap structure analog and doxorubicine to hepatocellular carcinoma in a rat model, resulting in significant inhibition of tumor growth.

Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis.

BACKGROUND & AIMS Unhealthy lifestyles predispose to non-alcoholic steatohepatitis (NASH), which may further result in the development of hepatocellular carcinoma (HCC). Although NASH patients benefit from physical activity, it is unknown whether regular exercise reduces the risk of developing HCC. Therefore, we studied the effect of regular exercise on the development of HCC in male hepatocyte-specific PTEN-deficient mice (AlbCrePten(flox/flox)), which develop steatohepatitis and HCC spontaneously. METHODS Mice were fed a standardized 10% fat diet and were randomly divided into exercise or sedentary groups. The exercise group ran on a motorized treadmill for 60 minutes/day, 5 days/week during 32 weeks. RESULTS After 32 weeks of regular exercise, 71% of exercised mice developed nodules larger than 15 mm(3) vs 100% of mice in the sedentary group. The mean number of tumors per liver was reduced by exercise, as well as the total tumoral volume per liver. Exercise did not affect steatosis and had no effect on the Non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). Exercise decreased tumor cell proliferation. Mechanistically, exercise stimulated the phosphorylation of AMPK and its substrate raptor, which decreased the kinase activity of mTOR. CONCLUSIONS These data show a benefit of regular exercise on the development of HCC in an experimental model of NASH and offer a rationale for encouraging predisposed patients to increase their physical activity for the prevention of HCC.

Total Tumor Volume and Alpha Fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation.

The selection of liver transplant candidates with hepatocellular carcinoma (HCC) is currently validated based on Milan criteria. The use of extended criteria has remained a matter of debate, mainly because of the absence of prospective validation. The present prospective study recruited patients according to the previously proposed Total Tumor Volume (TTV ≤115 cm(3) )/alpha fetoprotein (AFP ≤400 ng/ml) score. Patients with AFP >400 ng/ml were excluded, and as such the Milan group was modified to include only patients with AFP <400 ng/ml; these patients were compared to patients beyond Milan, but within TTV/AFP. From January 2007 to March 2013, 233 patients with HCC were listed for liver transplantation. Of them, 195 patients were within Milan, and 38 beyond Milan but within TTV/AFP. The average follow-up from listing was 33,9 ±24,9 months. The risk of drop-out was higher for patients beyond Milan but within TTV/AFP (16/38, 42,1%), than for patients within Milan (49/195, 25,1%, p=0,033). In parallel, intent-to-treat survival from listing was lower in the patients beyond Milan (53,8% vs. 71,6% at four years, p<0,001). After a median waiting time of 8 months, 166 patients were transplanted, 134 patients within Milan criteria, and 32 beyond Milan but within TTV/AFP. They demonstrated acceptable and similar recurrence rates (4,5% vs. 9,4%, p=0,138) and post-transplant survivals (78,7% vs. 74,6% at four years, p=0,932). CONCLUSION Based on the present prospective study, HCC liver transplant candidate selection could be expanded to the TTV (≤115 cm(3) )/AFP (≤400 ng/ml) criteria in centers with at least 8-month waiting time. An increased risk of drop-out on the waiting list can be expected but with equivalent and satisfactory post-transplant survival. This article is protected by copyright. All rights reserved.

Wie über Wolken. Jüdische Lebens- und Denkwelten in Stadt und Region Bern, 1200 – 2000

Der bildhafte Titel dieses Buches ist einem Brief der Lyrikerin Else Lasker-Schüler aus den 1930er Jahren entnommen und schildert ihre hohe Stimmung beim Flanieren durch die ruhige Stadt Bern. «Solche Spaziergänge, schwebend, lassen das Leben ertragen», schreibt sie weiter. Dass das Leben zu ertragen sei, ja mitunter «stratosphärisch» leicht sich anfühle, verweist jedoch auch auf die Lasten und die Bedrängnis jener Jahre, die Anfechtungen, denen Juden und Jüdinnen vielerorts in Europa ausgesetzt waren. Der Titel verdeutlicht, dass hier Texte versammelt sind, die ein breites Spektrum an jüdischen Erfahrungen, Denkvorgängen und Erinnerungsfiguren aus verschiedenen Epochen dokumentieren: vom mittelalterlichen Privileg über die stigmatisierende Ausschliessung bis zur gewaltsamen Vertreibung, von der bürgerlichen Emanzipation im 19. Jahrhundert über die Ohnmacht während der Zeit der Schoah bis zur öffentlich-rechtlichen Anerkennung der jüdischen Religionsgemeinschaft. Durch die Verbindungen jüdischer Intellektueller mit Bern ergeben sich Einblicke in Sternstunden des europäischen Geisteslebens. Die jüdische künstlerische und politische Moderne war geprägt von Aufbruchstimmung und Exilerfahrung. Für viele wurde Bern zum Ort, wo ihr Traum vom Studium in Erfüllung ging. Und immer wieder spiegelt das Bild von der Wolkenstadt den Wechsel des Klimas: zwischen Judenhut und Alpenparadies, Schwermut und Traumhaftigkeit, Eigensinn und Höhenflug, Bangen und Bürgerlichkeit, liberalem Empfinden und Streben nach sozialer Beteiligung.

Le temps de la défiguration. À propos de la versification dans Les Pâques à New York

Cet article est une première contribution à une nouvelle compréhension de la versification de Cendrars, qui a été décrite comme appartenant au «vers libre classique» (Roubaud). Dans Les Pâques à New York, la fréquence des alexandrins réguliers incite à ramener des vers apparemment non réguliers au schéma de l’alexandrin. Il s’ensuit une défiguration de l’alexandrin qui fait écho sur le plan thématique à celle du Christ, dont les Pâques n’indiquent que la passion et non la résurrection.

Stress-induced cortisol secretion impairs detection performance in x-ray baggage screening for hidden weapons by screening novices

Aviation security strongly depends on screeners' performance in the detection of threat objects in x-ray images of passenger bags. We examined for the first time the effects of stress and stress-induced cortisol increases on detection performance of hidden weapons in an x-ray baggage screening task. We randomly assigned 48 participants either to a stress or a nonstress group. The stress group was exposed to a standardized psychosocial stress test (TSST). Before and after stress/nonstress, participants had to detect threat objects in a computer-based object recognition test (X-ray ORT). We repeatedly measured salivary cortisol and X-ray ORT performance before and after stress/nonstress. Cortisol increases in reaction to psychosocial stress induction but not to nonstress independently impaired x-ray detection performance. Our results suggest that stress-induced cortisol increases at peak reactivity impair x-ray screening performance.

itw : im dialog - Forschungen zum Gegenwartstheater

Die Reihe itw : im dialog – Forschungen zum Gegenwartstheater widmet sich den Ästhetiken, Themen und Tendenzen gegenwärtigen Theaterschaffens und will Impulse zu seiner Erforschung geben. Ausgehend von der besonderen Position des Gegenwartstheaters als Ort der unmittelbaren Konfrontation mit gesellschaftlichen und politischen Fragen, wird dieses zum Gegenstand wissenschaftlicher Problematisierung und Reflexion. Die neugegründete Reihe gibt den teils von Inszenierungsanalysen ausgehenden theatertheoretischen sowie theaterhistorischen Reflexionen und den Gesprächen mit Künstlerinnen und Künstlern ein erweitertes wissenschaftliches Forum. Die Bände der Reihe werden zeitnah zu den »itw : im dialog«-Veranstaltungen produziert. So können die aus dem internationalen Austausch mit den Theaterforschenden und Theaterschaffenden gewonnenen Erkenntnisse und Anregungen umgehend in den akademischen Diskurs zum Gegenwartstheater einfließen.

Kants Wette. Von Kants starkem Glauben an ausserirdisches Leben, der Geschichte dieser Fragestellung und ihrer Herausforderung für die Theologie heute.

Der «bestirnte Himmel» über uns hat nicht erst seit Kant Bewunderung und Ehrfurcht befördert. Für ihn, der mit der Existenz von Bewohnern anderer Welten fest gerechnet hat, war dieser Himmel bewohnt. Er ist sich sicher: «Wenn es möglich wäre durch irgend eine Erfahrung auszumachen, so möchte ich wohl alles das Meinige darauf verwetten, daß es wenigstens in irgend einem von den Planeten, die wir sehen, Einwohner gebe. Daher sage ich, ist es nicht bloß Meinung, sondern ein starker Glaube (auf dessen Richtigkeit ich schon viele Vorteile des Lebens wagen würde), daß es auch Bewohner anderer Welten gebe.» In dieser Aussage Kants, die sich an keinem geringeren Ort als in der Kritik der reinen Vernunft findet, kann man einerseits einen Reflex früherer Überzeugungen und Darlegungen Kants erkennen, andererseits sind der Kontext der zitierten Stelle und der zeitgeschichtliche Hintergrund natürlich relevant. An Kants Beispiel wird dem Sinn solcher Überlegungen über Bewohner fremder Welten nachgegangen, die aufgrund des Fortschritts der planetaren Astronomie heute von neuem auf der Tagesordnung stehen. Das Nachdenken darüber stellt auch für die Theologie eine Herausforderung dar.

A study of the time complexity of an Elitist Genetic Algorithm used for associating optical observations of MEO and GEO Space Debris

Currently several thousands of objects are being tracked in the MEO and GEO regions through optical means. The problem faced in this framework is that of Multiple Target Tracking (MTT). In this context both the correct associations among the observations, and the orbits of the objects have to be determined. The complexity of the MTT problem is defined by its dimension S. Where S stands for the number of ’fences’ used in the problem, each fence consists of a set of observations that all originate from dierent targets. For a dimension of S ˃ the MTT problem becomes NP-hard. As of now no algorithm exists that can solve an NP-hard problem in an optimal manner within a reasonable (polynomial) computation time. However, there are algorithms that can approximate the solution with a realistic computational e ort. To this end an Elitist Genetic Algorithm is implemented to approximately solve the S ˃ MTT problem in an e cient manner. Its complexity is studied and it is found that an approximate solution can be obtained in a polynomial time. With the advent of improved sensors and a heightened interest in the problem of space debris, it is expected that the number of tracked objects will grow by an order of magnitude in the near future. This research aims to provide a method that can treat the correlation and orbit determination problems simultaneously, and is able to e ciently process large data sets with minimal manual intervention.

[Ventricular assist device – Possibilities of long-term mechanical circulatory support]

In Switzerland 200’000 people suffer from congestive heart failure. Approximately 10’000 patients find themselves in an advanced state of the disease. When conservative treatment options are no longer available heart transplantation is the therapy of choice. Should this not be an option due to long waiting lists or medical issues assist device therapy becomes an option. Assist device therapy is separated in short-term and long-term support. Long-term support is nowadays performed with ventricular assist devices (VADs). The native heart is still in place and supported in parallel to the remaining function of the heart. The majority of patients are treated with a left ventricular assist device (LVAD). The right ventrical alone (RVAD) as well as bi-ventricular support (BiVAD) is rarely needed. The modern VADs are implantable and create a non-pulsative bloodflow. A percutaneous driveline enables energy supply and pump-control. Indication strategies for VAD implantations include bridge to transplant (short term support), bridge to candidacy and bridge to transplant. VADs become more and more a definite therapeutic option (destination therapy). VAD therapy might be a realistic alternative to organ transplantation in the near future.

Wien, Deutschland und Europa

Boberach: Über eine Reichsverfassung und den Sitz der Zentralgewalt soll in Wien verhandelt werden. Dort kann die Verbindung Österreichs mit Deutschland am ehesten realisiert werden. Die Staatsform des Bundesstaates muß die Republik sein, die über die demokratische Monarchie und die monarchische Demokratie als Übergangsformen geschaffen werden kann. Eine Zentralgewalt in Wien kann günstig auf die West- und Südslawen wirken. Preußen kann in seine Provinzen zerfallen. - Wentzke: "Der Sitz der zentralen Gewalten des Staatensystems, in welches sich Deutschland im weiteren Verlaufe seiner Revolution umwandeln wird, muß Wien sein", der "Ort des Verkehrs und der Wechselwirkung zwischen den vier großen Völkermassen unseres Weltteils, der romanischen, germanischen, slavischen und tartarischen". Der preußische Staat kann in seine Provinzen zerfallen, ohne daß deutsche Interessen darunter leiden; das Zerfallen des österreichischen Staates ist nur wünschenswert bei Bildung eines mitteleuropäischen Staatenbundes. Soll Wien nicht unter russischen Einfluß kommen, so muß es der Mittelpunkt dieses demokratischen Bundes werden