Year of publication
- Physik (16)
- Medizin (5)
- Exzellenzcluster Die Herausbildung normativer Ordnungen (1)
- Geowissenschaften (1)
- Pharmazie (1)
- Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivo tacrolimus perfusion (2013)
- Background: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts. Methods/Design: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients. Discussion: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage. Trial register: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095
- A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma (2010)
- Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 3-year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. (trial registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)
- ATXN2-CAG42 sequesters PABPC1 into insolubility and induces FBXW8 in cerebellum of old ataxic knock-in mice (2012)
- Spinocerebellar Ataxia Type 2 (SCA2) is caused by expansion of a polyglutamine encoding triplet repeat in the human ATXN2 gene beyond (CAG)31. This is thought to mediate toxic gain-of-function by protein aggregation and to affect RNA processing, resulting in degenerative processes affecting preferentially cerebellar neurons. As a faithful animal model, we generated a knock-in mouse replacing the single CAG of murine Atxn2 with CAG42, a frequent patient genotype. This expansion size was inherited stably. The mice showed phenotypes with reduced weight and later motor incoordination. Although brain Atxn2 mRNA became elevated, soluble ATXN2 protein levels diminished over time, which might explain partial loss-of-function effects. Deficits in soluble ATXN2 protein correlated with the appearance of insoluble ATXN2, a progressive feature in cerebellum possibly reflecting toxic gains-of-function. Since in vitro ATXN2 overexpression was known to reduce levels of its protein interactor PABPC1, we studied expansion effects on PABPC1. In cortex, PABPC1 transcript and soluble and insoluble protein levels were increased. In the more vulnerable cerebellum, the progressive insolubility of PABPC1 was accompanied by decreased soluble protein levels, with PABPC1 mRNA showing no compensatory increase. The sequestration of PABPC1 into insolubility by ATXN2 function gains was validated in human cell culture. To understand consequences on mRNA processing, transcriptome profiles at medium and old age in three different tissues were studied and demonstrated a selective induction of Fbxw8 in the old cerebellum. Fbxw8 is encoded next to the Atxn2 locus and was shown in vitro to decrease the level of expanded insoluble ATXN2 protein. In conclusion, our data support the concept that expanded ATXN2 undergoes progressive insolubility and affects PABPC1 by a toxic gain-of-function mechanism with tissuespecific effects, which may be partially alleviated by the induction of FBXW8.
- Lavender Oil-Potent Anxiolytic Properties via Modulating Voltage Dependent Calcium Channels (2013)
- Recent clinical data support the clinical use of oral lavender oil in patients suffering from subsyndromal anxiety. We identified the molecular mechanism of action that will alter the perception of lavender oil as a nonspecific ingredient of aromatherapy to a potent anxiolytic inhibiting voltage dependent calcium channels (VOCCs) as highly selective drug target. In contrast to previous publications where exorbitant high concentrations were used, the effects of lavender oil in behavioral, biochemical, and electrophysiological experiments were investigated in physiological concentrations in the nanomolar range, which correlate to a single dosage of 80 mg/d in humans that was used in clinical trials. We show for the first time that lavender oil bears some similarities with the established anxiolytic pregabalin. Lavender oil inhibits VOCCs in synaptosomes, primary hippocampal neurons and stably overexpressing cell lines in the same range such as pregabalin. Interestingly, Silexan does not primarily bind to P/Q type calcium channels such as pregabalin and does not interact with the binding site of pregabalin, the α2δ subunit of VOCCs. Lavender oil reduces non-selectively the calcium influx through several different types of VOCCs such as the N-type, P/Q-type and T-type VOCCs. In the hippocampus, one brain region important for anxiety disorders, we show that inhibition by lavender oil is mainly mediated via N-type and P/Q-type VOCCs. Taken together, we provide a pharmacological and molecular rationale for the clinical use of the oral application of lavender oil in patients suffering from anxiety.
- Shell structure of superheavy nuclei in self-consistent mean-field models (1999)
- We study the extrapolation of nuclear shell structure to the region of superheavy nuclei in self-consistent mean-field models—the Skyrme-Hartree-Fock approach and the relativistic mean-field model—using a large number of parametrizations which give similar results for stable nuclei but differ in detail. Results obtained with the folded-Yukawa potential which is widely used in macroscopic-macroscopic models are shown for comparison. We focus on differences in the isospin dependence of the spin-orbit interaction and the effective mass between the models and their influence on single-particle spectra. The predictive power of the mean-field models concerning single-particle spectra is discussed for the examples of 208Pb and the spin-orbit splittings of selected neutron and proton levels in 16O, 132Sn, and 208Pb. While all relativistic models give a reasonable description of spin-orbit splittings, all Skyrme interactions show a wrong trend with mass number. The spin-orbit splitting of heavy nuclei might be overestimated by 40%–80%, which exposes a fundamental deficiency of the current nonrelativistic models. In most cases the occurrence of spherical shell closures is found to be nucleon-number dependent. Spherical doubly magic superheavy nuclei are found at 184298114, 172292120, or 184310126 depending on the parametrization. The Z=114 proton shell closure, which is related to a large spin-orbit splitting of proton 2f states, is predicted only by forces which by far overestimate the proton spin-orbit splitting in 208Pb. The Z=120 and N=172 shell closures predicted by the relativistic models and some Skyrme interactions are found to be related to a central depression of the nuclear density distribution. This effect cannot appear in macroscopic-microscopic models or semiclassical approaches like the extended Thomas-Fermi-Strutinski integral approach which have a limited freedom for the density distribution only. In summary, our findings give a strong argument for 172292120 to be the next spherical doubly magic superheavy nucleus.
- Potential energy surfaces of superheavy nuclei (1998)
- We investigate the structure of the potential energy surfaces of the superheavy nuclei 158258Fm100, 156264Hs108, 166278112, 184298114, and 172292120 within the framework of self-consistent nuclear models, i.e., the Skyrme-Hartree-Fock approach and the relativistic mean-field model. We compare results obtained with one representative parametrization of each model which is successful in describing superheavy nuclei. We find systematic changes as compared to the potential energy surfaces of heavy nuclei in the uranium region: there is no sufficiently stable fission isomer any more, the importance of triaxial configurations to lower the first barrier fades away, and asymmetric fission paths compete down to rather small deformation. Comparing the two models, it turns out that the relativistic mean-field model gives generally smaller fission barriers.
- Dirac particles in Rindler space (1980)
- We show that a uniformly accelerated observer experiences a "thermal" flux of Dirac particles in the ordinary Minkowski vacuum.
- Fields nonlocal in Clifford space. I. Classical Gauge-invariant nonlinear field theory (1972)
- A fully gauge-invariant, Lorentz-covariant, nonlocal, and nonlinear theory, for coupled spin-½ fields, ψ, and vector fields, A, i.e., "electrons" and "photons," is constructed. The field theory is linear in the ψ fields. The nonlinearity in the A fields arises unambiguously from the requirement of gauge invariance. The coordinates are generalized to admit hypercomplex values, i.e., they are taken to be Clifford numbers. The nonlocality is limited to the hypercomplex component of the coordinates. As the size of the nonlocality is reduced toward zero, the theory goes over into the inhomogeneous Dirac theory. The nonlocality parameter corresponds to an inverse mass and induces self-regulatory properties of the propagators. It is argued that in a gauge-invariant theory a graph-by-graph convergence is impossible in principle, but it is possible that convergence may hold for the complete solution, or for sums over classes of graphs.
- Continuum nuclear structure of O16 in the Eigenchannel reaction theory (1967)
- The total particle-particle SJ matrix of O16 for spin J=1- and excitation energies between 15 and 27 MeV has been calculated in the eigenchannel reaction theory for several parameters of the Saxon-Woods potential and the two-body force. The many-body problem has been treated in the 1-particle-1-hole approximation. The photon channels have been included by perturbation theory. Surprisingly, the most important structure of the experimental cross sections is reproduced quite well in this simple approximation.
- Collective treatment of the giant resonances in spherical nuclei (1966)
- In a collective treatment the energies of the giant resonances are given by the boundary conditions at the nuclear surface, which is subject to vibration in spherical nuclei. The general form of the coupling between these two collective motions is given by angular-momentum and parity conservation. The coupling constants are completely determined within the hydrodynamical model. In the present treatment the influence of the surface vibrations on the total photon-absorption cross section is calculated. It turns out that in most of the spherical nuclei this interaction leads to a pronounced structure in the cross section. The agreement with the experiments in medium-heavy nuclei is striking; many of the experimental characteristics are reproduced by the present calculations. In some nuclei, however, there seem to be indications of single-particle excitations which are not yet contained in this work.