Mouse precision-cut liver slices as an ex vivo model to study drug-induced cholestasis

Drugs are often withdrawn from the market due to the manifestation of drug-induced liver injury (DILI) in patients. Drug-induced cholestasis (DIC), defined as obstruction of hepatic bile flow due to medication, is one form of DILI. Because DILI is idiosyncratic, and the resulting cholestasis complex, there is no suitable in vitro model for early DIC detection during drug development. Our goal was to develop a mouse precision-cut liver slice (mPCLS) model to study DIC and to assess cholestasis development using conventional molecular biology and analytical chemistry methods. Cholestasis was induced in mPCLS through a 48-h-incubation with three drugs known to induce cholestasis in humans, namely chlorpromazine (15, 20, and 30 µM), cyclosporin A (1, 3, and 6 µM) or glibenclamide (25, 50, and 65 µM). A bile-acid mixture (16 µM) that is physiologically representative of the human bile-acid pool was added to the incubation medium with drug, and results were compared to incubations with no added bile acids. Treatment of PCLS with cholestatic drugs increased the intracellular bile-acid concentration of deoxycholic acid and modulated bile-transporter genes. Chlorpromazine led to the most pronounced cholestasis in 48 h, observed as increased toxicity; decreased protein and gene expression of the bile salt export pump; increased gene expression of multidrug resistance-associated protein 4; and accumulation of intracellular bile acids. Moreover, chlorpromazine-induced cholestasis exhibited some transition into fibrosis, evidenced by increased gene expression of collagen 1A1 and heatshock protein 47. In conclusion, we demonstrate that mPCLS can be used to study human DIC onset and progression in a 48 h period. We thus propose this model is suited for other similar studies of human DIC

Constraints on the Existence of Chiral Fermions in Interacting Lattice Theories

It is shown that an interacting theory, defined on a regular lattice, must have a vector-like spectrum if the following conditions are satisfied: (a)~locality, (b)~relativistic continuum limit without massless bosons, and (c)~pole-free effective vertex functions for conserved currents. The proof exploits the zero frequency inverse retarded propagator of an appropriate set of interpolating fields as an effective quadratic hamiltonian, to which the Nielsen-Ninomiya theorem is applied.Comment: LaTeX, 9 pages, WIS--93/56--JUNE--P

Remark on Pauli-Villars Lagrangian on the Lattice

It is interesting to superimpose the Pauli-Villars regularization on the lattice regularization. We illustrate how this scheme works by evaluating the axial anomaly in a simple lattice fermion model, the Pauli-Villars Lagrangian with a gauge non-invariant Wilson term. The gauge non-invariance of the axial anomaly, caused by the Wilson term, is remedied by a compensation among Pauli-Villars regulators in the continuum limit. A subtlety in Frolov-Slavnov's scheme for an odd number of chiral fermions in an anomaly free complex gauge representation, which requires an infinite number of regulators, is briefly mentioned.Comment: 14 pages, Phyzzx. The final version to appear in Phys. Rev.

Anomalous Chiral Symmetry Breaking above the QCD Phase Transition

We study the anomalous breaking of U_A(1) symmetry just above the QCD phase transition for zero and two flavors of quarks, using a staggered fermion, lattice discretization. The properties of the QCD phase transition are expected to depend on the degree of U_A(1) symmetry breaking in the transition region. For the physical case of two flavors, we carry out extensive simulations on a 16^3 x 4 lattice, measuring a difference in susceptibilities which is sensitive to U_A(1) symmetry and which avoids many of the staggered fermion discretization difficulties. The results suggest that anomalous effects are at or below the 15% level.Comment: 10 pages including 2 figures and 1 tabl

Phenomenology with Wilson fermions using smeared sources

We investigate the use of two types of non-local (``smeared'') sources for quark propagators in quenched lattice QCD at $\beta=6.0$ using Wilson fermions at $\kappa=0.154$ and $0.155$. We present results for the hadron mass spectrum, meson decay constants, quark masses, the chiral condensate and the quark distribution amplitude of the pion. The use of smeared sources leads to a considerable improvement over previous results. We find a disturbing discrepancy between the baryon spectra obtained using Wuppertal and wall sources. We find good signals in the ratio of correlators used to calculate the quark mass and the chiral condensate and show that the extrapolation to the chiral limit is smooth.Comment: (revised), 57 pages (29 pages of PostScript in landscape mode, 765924 bytes

Information Technology in the Service Economy: Challenges and Possibilities for the 21 st Century

Abstract Nursing work is intertwined with a number of technologies. This paper explores the work practices in a pediatri

Magnetoconductivity of quantum wires with elastic and inelastic scattering

We use a Boltzmann equation to determine the magnetoconductivity of quantum wires. The presence of a confining potential in addition to the magnetic field removes the degeneracy of the Landau levels and allows one to associate a group velocity with each single-particle state. The distribution function describing the occupation of these single-particle states satisfies a Boltzmann equation, which may be solved exactly in the case of impurity scattering. In the case where the electrons scatter against both phonons and impurities we solve numerically - and in certain limits analytically - the integral equation for the distribution function, and determine the conductivity as a function of temperature and magnetic field. The magnetoconductivity exhibits a maximum at a temperature, which depends on the relative strength of the impurity and electron-phonon scattering, and shows oscillations when the Fermi energy or the magnetic field is varied.Comment: 21 pages (revtex 3.0), 5 postscript figures available upon request at [email protected] or [email protected]

Investigation of the Domain Wall Fermion Approach to Chiral Gauge Theories on the Lattice

We investigate a recent proposal to construct chiral gauge theories on the lattice using domain wall fermions. We restrict ourselves to the finite volume case, in which two domain walls are present, with modes of opposite chirality on each of them. We couple the chiral fermions on only one of the domain walls to a gauge field. In order to preserve gauge invariance, we have to add a scalar field, which gives rise to additional light mirror fermion and scalar modes. We argue that in an anomaly free model these extra modes would decouple if our model possesses a so-called strong coupling symmetric phase. However, our numerical results indicate that such a phase most probably does not exist. ---- Note: 9 Postscript figures are appended as uuencoded compressed tar file.Comment: 27p. Latex; UCSD/PTH 93-28, Wash. U. HEP/93-6

Manifestly Gauge Covariant Treatment of Lattice Chiral Fermions. II

We propose a new formulation of chiral fermions on a lattice, on the basis of a lattice extension of the covariant regularization scheme in continuum field theory. The species doublers do not emerge. The real part of the effective action is just one half of that of Dirac-Wilson fermion and is always gauge invariant even with a finite lattice spacing. The gauge invariance of the imaginary part, on the other hand, sets a severe constraint which is a lattice analogue of the gauge anomaly free condition. For real gauge representations, the imaginary part identically vanishes and the gauge invariance becomes exact.Comment: 15 pages, PHYZZX. The title is changed. The final version to appear in Phys. Rev.

Analysis of Granular Packing Structure by Scattering of THz Radiation

Scattering methods are widespread used to characterize the structure and constituents of matter on small length scales. This motivates this introductory text on identifying prospective approaches to scattering-based methods for granular media. A survey to light scattering by particles and particle ensembles is given. It is elaborated why the established scattering methods using X-rays and visible light cannot in general be transferred to granular media. Spectroscopic measurements using Terahertz radiation are highlighted as they to probe the scattering properties of granular media, which are sensitive to the packing structure. Experimental details to optimize spectrometer for measurements on granular media are discussed. We perform transmission measurements on static and agitated granular media using Fourier-transform spectroscopy at the THz beamline of the BessyII storage ring. The measurements demonstrate the potential to evaluate degrees of order in the media and to track transient structural states in agitated bulk granular media.Comment: 12 Pages, 9 Figures, 56 Reference