On the validity of the dispersion model of hepatic drug elimination when intravascular transit time densities are long-tailed

The dispersion model with mixed boundary conditions uses a single parameter, the dispersion number, to describe the hepatic elimination of xenobiotics and endogenous substances. An implicit a priori assumption of the model is that the transit time density of intravascular indicators is approximated by an inverse Gaussian distribution. This approximation is limited in that the model poorly describes the tail part of the hepatic outflow curves of vascular indicators. A sum of two inverse Gaussian functions is proposed as ail alternative, more flexible empirical model for transit time densities of vascular references. This model suggests that a more accurate description of the tail portion of vascular reference curves yields an elimination rate constant (or intrinsic clearance) which is 40% less than predicted by the dispersion model with mixed boundary conditions. The results emphasize the need to accurately describe outflow curves in using them as a basis for determining pharmacokinetic parameters using hepatic elimination models. (C) 1997 Society for Mathematical Biology.

Relative dispersion of intravascular transit times during isolated human limb perfusions for recurrent melanoma

Aims We have characterized the relative dispersion of vascular and extravascular markers in the limbs of three patients undergoing isolated limb perfusions with the cytotoxic melphalan for recurrent malignant melanoma both before and after melphalan dosing. Methods A bolus of injectate containing [Cr-51] labelled red blood cells, [C-14]-sucrose and [H-3]-water was injected into an iliac or femoral artery and outflow samples collected at 1 s intervals by a fraction collector. The radioactivity due to each isotype was analysed by either gamma [Cr-51] or beta [C-14 and H-3] counting. The moments of the outflow fraction-time profiles were estimated by a nonparametric (numerical integration) method and a parametric model (sum of two inverse Gaussian functions). Results The availability, mean transit time and normalised variance (CV2) obtained for labelled red blood cells, sucrose and water were similar before and after melphalan dosing and with the two methods of calculation but varied between the patients. Conclusions The vascular space is not well-stirred but characterized by a CV2 similar that reported previously for in situ rat hind limb and rat liver perfusions. A flow-limited blood-tissue exchange was observed for the permeating indicators. Administration of melphalan did not influence the distribution characteristics of the indicators.

On building a principled framework for evaluating and testing evolutionary algorithms: A continuous landscape generator

In this paper, we address some issue related to evaluating and testing evolutionary algorithms. A landscape generator based on Gaussian functions is proposed for generating a variety of continuous landscapes as fitness functions. Through some initial experiments, we illustrate the usefulness of this landscape generator in testing evolutionary algorithms.

Commentary: Using the convection-dispersion model and transit time density functions in the analysis of organ distribution kinetics

The convection-dispersion model and its extended form have been used to describe solute disposition in organs and to predict hepatic availabilities. A range of empirical transit-time density functions has also been used for a similar purpose. The use of the dispersion model with mixed boundary conditions and transit-time density functions has been queried recently by Hisaka and Sugiyanaa in this journal. We suggest that, consistent with soil science and chemical engineering literature, the mixed boundary conditions are appropriate providing concentrations are defined in terms of flux to ensure continuity at the boundaries and mass balance. It is suggested that the use of the inverse Gaussian or other functions as empirical transit-time densities is independent of any boundary condition consideration. The mixed boundary condition solutions of the convection-dispersion model are the easiest to use when linear kinetics applies. In contrast, the closed conditions are easier to apply in a numerical analysis of nonlinear disposition of solutes in organs. We therefore argue that the use of hepatic elimination models should be based on pragmatic considerations, giving emphasis to using the simplest or easiest solution that will give a sufficiently accurate prediction of hepatic pharmacokinetics for a particular application. (C) 2000 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 89:1579-1586, 2000.

Modal functions of future tenses in French

The paper disputes two influential claims in the Romance Linguistics literature. The first is that the synthetic future tenses in spoken Western Romance are now rivalled, if not supplanted, as temporal functors by the more recently developed GO futures. The second is that these synthetic futures now have modal rather than temporal meanings in spoken Romance. These claims are seen as reflecting a universal cycle of diachronic change, in which verb forms originally expressing modal (or aspectual) values take on future temporal reference, becoming tenses. The new modal meanings supplant the temporal, which are then taken up by new forms. Challenges to this theory for French are raised on the basis of empirical evidence of two sorts. Positively, future tenses in spoken Romance continue to be used with temporal meaning. Negatively, evidence of modal meaning for these forms is lacking. The evidence comes froma corpora of spoken French, native speaker judgements and verb data from a daily broadsheet. Cumulatively, it points to the reverse of the claims noted above: the synthetic future in spoken French has temporal but little modal meaning.

Fast evolution strategies

Evolution strategies are a class of general optimisation algorithms which are applicable to functions that are multimodal, nondifferentiable, or even discontinuous. Although recombination operators have been introduced into evolution strategies, the primary search operator is still mutation. Classical evolution strategies rely on Gaussian mutations. A new mutation operator based on the Cauchy distribution is proposed in this paper. It is shown empirically that the new evolution strategy based on Cauchy mutation outperforms the classical evolution strategy on most of the 23 benchmark problems tested in this paper. The paper also shows empirically that changing the order of mutating the objective variables and mutating the strategy parameters does not alter the previous conclusion significantly, and that Cauchy mutations with different scaling parameters still outperform the Gaussian mutation with self-adaptation. However, the advantage of Cauchy mutations disappears when recombination is used in evolution strategies. It is argued that the search step size plays an important role in determining evolution strategies' performance. The large step size of recombination plays a similar role as Cauchy mutation.

Cost functions and duality for stochastic technologies

Cost functions dual to stochastic production technologies are derived and their properties are discussed. These cost functions are shown to be consistent with expected-utility maximization without placing serious structural restrictions on the underlying technology.

The dimerization and topological specificity functions of MinE reside in a structurally autonomous C-terminal domain

Correct placement of the division septum in Escherichia coli requires the co-ordinated action of three proteins, MinC, MinD and MinE. MinC and MinD interact to form a non-specific division inhibitor that blocks septation at all potential division sites. MinE is able to antagonize MinCD in a topologically sensitive manner, as it restricts MinCD activity to the unwanted division sites at the cell poles, Here, we show that the topological specificity function of MinE residues in a structurally autonomous, trypsin-resistant domain comprising residues 31-88, Nuclear magnetic resonance (NMR) and circular dichroic spectroscopy indicate that this domain includes both alpha and beta secondary structure, while analytical ultracentrifugation reveals that it also contains a region responsible for MinE homodimerization. While trypsin digestion indicates that the anti-MinCD domain of MinE (residues 1-22) does not form a tightly folded structural domain, NMR analysis of a peptide corresponding to MinE(1-22) indicates that this region forms a nascent helix in which the peptide rapidly interconverts between disordered (random coil) and alpha-helical conformations, This suggests that the N-terminal region of MinE may be poised to adopt an alpha-helical conformation when it interacts with the target of its anti-MinCD activity, presumably MinD.

Protein fold recognition score functions: Unusual construction strategies

We describe two ways of optimizing score functions for protein sequence to structure threading. The first method adjusts parameters to improve sequence to structure alignment. The second adjusts parameters so as to improve a score function's ability to rank alignments calculated in the first score function. Unlike those functions known as knowledge-based force fields, the resulting parameter sets do not rely on Boltzmann statistics, have no claim to representing free energies and are purely constructions for recognizing protein folds. The methods give a small improvement, but suggest that functions can be profitably optimized for very specific aspects of protein fold recognition, Proteins 1999;36:454-461. (C) 1999 Wiley-Liss, Inc.

U-q[(sl(2)over-cap vertical bar 1)] vertex operators, screen currents, and correlation functions at an arbitrary level

Bosonized q-vertex operators related to the four-dimensional evaluation modules of the quantum affine superalgebra U-q[sl((2) over cap\1)] are constructed for arbitrary level k=alpha, where alpha not equal 0,-1 is a complex parameter appearing in the four-dimensional evaluation representations. They are intertwiners among the level-alpha highest weight Fock-Wakimoto modules. Screen currents which commute with the action of U-q[sl((2) over cap/1)] up to total differences are presented. Integral formulas for N-point functions of type I and type II q-vertex operators are proposed. (C) 2000 American Institute of Physics. [S0022-2488(00)00608-3].

The human papillomavirus E7 protein is able to inhibit the antiviral and anti-growth functions of interferon-alpha

It is now well recognized that cervical cancer is caused by infection with certain human papillomavirus (HPV) subtypes and while interferon-alpha (IFN-alpha) is used to treat HPV-infected lesions, HPV appears to have developed a means to avoid the effects of IFN-alpha. Clinically, resistance appears to be associated with the expression of the E7 oncoprotein. Here we investigated the effects of expression in cells of the E7 protein from high- and low-risk papillomavirus subtypes on a range of responses to IFN-alpha. 2fTGH, a cell line dependent on IFN-alpha for growth in selection medium, grew significantly less well in the presence of E7, and the antiproliferative effects of IFN-alpha upon epithelial cells was lost upon E7 expression. The antiviral effects of IFN-alpha were abrogated in E7-expressing cells. Loss of response to IFN-alpha was found to occur in both high- and low-risk papillomaviruses. Finally, deletion of amino acids 21-24 of HPV type 16 E7 protein partially reversed repression. We conclude that E7 inhibits the functional effects of IFN-alpha and that this property is shared by all HPV subtypes tested. (C) 2000 Academic Press.

Determining complicated winding patterns for shim coils using stream functions and the target-field method

In a magnetic resonance imaging equipment, gradient and shim coils are needed to produce a spatially varying magnetic field throughout the sample being imaged. Such coils consist of turns of wire wound on the surface of a cylindrical tube. Shim coils in particular, must sometimes be designed to produce complicated magnetic fields to correct for impurities. Streamline patterns for shim coils are much more complicated than those for gradient coils, In this work we present a detailed analysis of streamline methods and their application to shim coil design, A method is presented for determining the winding patterns to generate these complicated fields. (C) 2002 John Wiley & Sons, Inc.

A method for the design of MRI radiofrequency coils based on triangular and pulse basis functions

This paper presents a numerical technique for the design of an RF coil for asymmetric magnetic resonance imaging (MRI) systems. The formulation is based on an inverse approach where the cylindrical surface currents are expressed in terms of a combination of sub-domain basis functions: triangular and pulse functions. With the homogeneous transverse magnetic field specified in a spherical region, a functional method is applied to obtain the unknown current coefficients. The current distribution is then transformed to a conductor pattern by use of a stream function technique. Preliminary MR images acquired using a prototype RF coil are presented and validate the design method. (C) 2002 Elsevier Science B.V. All rights reserved.

Group theory and quasiprobability integrals of Wigner functions

The integral of the Wigner function of a quantum-mechanical system over a region or its boundary in the classical phase plane, is called a quasiprobability integral. Unlike a true probability integral, its value may lie outside the interval [0, 1]. It is characterized by a corresponding selfadjoint operator, to be called a region or contour operator as appropriate, which is determined by the characteristic function of that region or contour. The spectral problem is studied for commuting families of region and contour operators associated with concentric discs and circles of given radius a. Their respective eigenvalues are determined as functions of a, in terms of the Gauss-Laguerre polynomials. These polynomials provide a basis of vectors in a Hilbert space carrying the positive discrete series representation of the algebra su(1, 1) approximate to so(2, 1). The explicit relation between the spectra of operators associated with discs and circles with proportional radii, is given in terms of the discrete variable Meixner polynomials.