Epidermal iontophoresis: I. Development of the ionic mobility-pore model

Purpose, An integrated ionic mobility-pore model for epidermal iontophoresis is developed from theoretical considerations using both the free volume and pore restriction forms of the model for a range of solute radii (r(j)) approaching the pore radii (r(p)) as well as approximation of the pore restriction form for r(j)/r(p) < 0.4. In this model, we defined the determinants for iontophoresis as solute size (defined by MV, MW or radius), solute mobility, solute shape, solute charge, the Debye layer thickness, total current applied, solute concentration, fraction ionized, presence of extraneous ions (defined by solvent conductivity), epidermal permselectivity, partitioning rates to account for interaction of unionized and ionized lipophilic solutes with the wall of the pore and electroosmosis. Methods, The ionic mobility-pore model was developed from theoretical considerations to include each of the determinants of iontophoretic transport. The model was then used to reexamine iontophoretic flux conductivity and iontophoretic flux-fraction ionized literature data on the determinants of iontophoretic flux. Results. The ionic mobility-pore model was found to be consistent with existing experimental data and determinants defining iontophoretic transport. However, the predicted effects of solute size on iontophoresis are more consistent with the pore-restriction than free volume form of the model. A reanalysis of iontophoretic flux-conductivity data confirmed the model's prediction that, in the absence of significant electroosmosis, the reciprocal of flux is linearly related to either donor or receptor solution conductivity. Significant interaction with the pore walls, as described by the model, accounted for the reported pH dependence of the iontophoretic transport for a range of ionizable solutes. Conclusions. The ionic mobility-pore iontophoretic model developed enables a range of determinants of iontophoresis to be described in a single unifying equation which recognises a range of determinants of iontophoretic flux.

Epidermal iontophoresis: II. Application of the ionic mobility-pore model to the transport of local anesthetics

Purpose, An in vitro study was carried out to determine the iontophoretic permeability of local anesthetics through human epidermis. The relationship between physicochemical structure and the permeability of these solutes was then examined using an ionic mobility-pore model developed to define quantitative relationships. Methods. The iontophoretic permeability of both ester-type anesthetics (procaine, butacaine, tetracaine) and amide-type anesthetics (prilocaine, mepivacaine, lidocaine, bupivacaine, etidocaine, cinchocaine) were determined through excised human epidermis over 2 hrs using a constant d.c. current and Ag/AgCl electrodes. Individual ion mobilities were determined from conductivity measurements in aqueous solutions. Multiple stepwise regression was applied to interrelate the iontophoretic permeability of the solutes with their physical properties to examine the appropriateness of the ionic mobility-pore model and to determine the best predictor of iontophoretic permeability of the local anesthetics. Results. The logarithm of the iontophoretic permeability coefficient (log PCj,iont) for local anesthetics was directly related to the log ionic mobility and MW for the free volume form of the model when other conditions are held constant. Multiple linear regressions confirmed that log PCj,iont was best defined by ionic mobility (and its determinants: conductivity, pK(a) and MW) and MW. Conclusions. Our results suggest that of the properties studied, the best predictors of iontophoretic transport of local anesthetics are ionic mobility (or pK(a)) and molecular size. These predictions are consistent with the ionic mobility pore model determined by the mobility of ions in the aqueous solution, the total current, epidermal permselectivity and other factors as defined by the model.

Off-diagonal long-range order in a supersymmetric integrable model of correlated electrons

A new model for correlated electrons is presented which is integrable in one-dimension. The symmetry algebra of the model is the Lie superalgebra gl(2\1) which depends on a continuous free parameter. This symmetry algebra contains the eta pairing algebra as a subalgebra which is used to show that the model exhibits Off-Diagonal Long-Range Order in any number of dimensions.

Subantarctic Macquarie Island - a model ecosystem for studying animal-derived nitrogen sources using N-15 natural abundance

Plants collected from diverse sites on subantarctic Macquarie Island varied by up to 30 parts per thousand in their leaf delta(15)N values. N-15 natural abundance of plants, soils, animal excrement and atmospheric ammonia suggest that the majority of nitrogen utilised by plants growing in the vicinity of animal colonies or burrows is animal-derived. Plants growing near scavengers and animal higher in the food chain had highly enriched delta(15)N values (mean = 12.9 parts per thousand), reflecting the highly enriched signature of these animals' excrement, while plants growing near nesting penguins and albatross, which have an intermediate food chain position, had less enriched delta(15)N values (> 6 parts per thousand). Vegetation in areas affected by rabbits had lower delta(15)N values (mean = 1.2 parts per thousand), while the highly depleted delta(15)N values (below -5 parts per thousand) of plants at upland plateau sites inland of penguin colonies, suggested that a portion of their nitrogen is derived from ammonia (mean N-15 = -10 parts per thousand) lost during the degradation of penguin guano. Vegetation in a remote area had delta(15)N values near -2 parts per thousand. These results contrast with arctic and subarctic studies that attribute large variations in plant N-15 values to nitrogen partitioning in nitrogen-limited environments. Here, plant N-15 reflects the N-15 Of the likely nitrogen sources utilised by plants.

Algebraic Bethe ansatz for integrable Kondo impurities in the one-dimensional supersymmetric t-J model

An integrable Kondo problem in the one-dimensional supersymmetric t-J model is studied by means of the boundary supersymmetric quantum inverse scattering method. The boundary K matrices depending on the local moments of the impurities are presented as a nontrivial realization of the graded reflection equation algebras in a two-dimensional impurity Hilbert space. Further, the model is solved by using the algebraic Bethe ansatz method and the Bethe ansatz equations are obtained. (C) 1999 Elsevier Science B.V.

Integrability of a t - J model with impurities

A t - J model for correlated electrons with impurities is proposed. The impurities are introduced in such a way that integrability of the model in one dimension is not violated. The algebraic Bethe ansatz solution of the model is also given and it is shown that the Bethe states are highest weight states with respect to the supersymmetry algebra gl(2/1).

Inhibition of NK cells by murine CMV-encoded class I MHC homologue m144

Murine cytomegalovirus (CMV)-encoded protein m144 is homologous to class I MHC heavy-chain and is thought to regulate NK-cell-mediated immune responses in vivo. To examine the effects of m144 on Nh cytotoxicity in vitro, various cell lines were transfected with wild-type m144 or a chimeric construct in which the cytoplasmic domain of m144 was replaced with green fluorescence protein. Burkitt lymphoma line Raji expressed a significant level of m144 as determined by anti-m144 mAb binding or the green fluorescence of the fusion protein. The level of m144 expression was relatively low compared with that of transfected murine class I MHC Dd. However, m144 on Raji cells partially inhibited antibody-dependent cell-mediated cytotoxicity of IL-2-activated NK cells. NK cells from the CMV-susceptible BALB/c as well as those from the resistant C57BL/6 mice were inhibited by m144. Antibodies against the known murine NK inhibitory receptors Ly-49A, C, G, and I did not affect the inhibitory effect of m144. These results suggest that the murine CMV class I MHC homologue m144 partially inhibits MZ cells by interacting with a novel inhibitory receptor. (C) 1999 Academic Press.

A mathematical model for estimating the extent of solute- and water-flux heterogeneity in multiple sample percolation experiments

Multiple sampling is widely used in vadose zone percolation experiments to investigate the extent in which soil structure heterogeneities influence the spatial and temporal distributions of water and solutes. In this note, a simple, robust, mathematical model, based on the beta-statistical distribution, is proposed as a method of quantifying the magnitude of heterogeneity in such experiments. The model relies on fitting two parameters, alpha and zeta to the cumulative elution curves generated in multiple-sample percolation experiments. The model does not require knowledge of the soil structure. A homogeneous or uniform distribution of a solute and/or soil-water is indicated by alpha = zeta = 1, Using these parameters, a heterogeneity index (HI) is defined as root 3 times the ratio of the standard deviation and mean. Uniform or homogeneous flow of water or solutes is indicated by HI = 1 and heterogeneity is indicated by HI > 1. A large value for this index may indicate preferential flow. The heterogeneity index relies only on knowledge of the elution curves generated from multiple sample percolation experiments and is, therefore, easily calculated. The index may also be used to describe and compare the differences in solute and soil-water percolation from different experiments. The use of this index is discussed for several different leaching experiments. (C) 1999 Elsevier Science B.V. All rights reserved.

Integrable Kondo impurities in the one-dimensional supersymmetric U model of strongly correlated electrons

Integrable Kondo impurities in the one-dimensional supersymmetric U model of strongly correlated electrons are studied by means of the boundary graded quantum inverse scattering method. The boundary K-matrices depending on the local magnetic moments of the impurities are presented as non-trivial realizations of the reflection equation algebras in an impurity Hilbert space. Furthermore, the model Hamiltonian is diagonalized and the Bethe ansatz equations are derived. It is interesting to note that our model exhibits a free parameter in the bulk Hamiltonian but no free parameter exists on the boundaries. This is in sharp contrast to the impurity models arising from the supersymmetric t-J and extended Hubbard models where there is no free parameter in the bulk but there is a free parameter on each boundary.

Population balance model of in vivo neutrophil formation following bone marrow rescue therapy

In this paper, we develop a simple four parameter population balance model of in vivo neutrophil formation following bone marrow rescue therapy. The model is used to predict the number and type of neutrophil progenitors required to abrogate the period of severe neutropenia that normally follows a bone marrow transplant. The estimated total number of 5 billion neutrophil progenitors is consistent with the value extrapolated from a human trial. The model provides a basis for designing ex vivo expansion protocols.

Phase diagram of a Heisenberg spin-Peierls model with quantum phonons

Using a new version of the density-matrix renormalization group we determine the phase diagram of a model of an antiferromagnetic Heisenberg spin chain where the spins interact with quantum phonons. A quantum phase transition from a gapless spin-fluid state to a gapped dimerized phase occurs at a nonzero value of the spin-phonon coupling. The transition is in the same universality class as that of a frustrated spin chain, to which the model maps in the diabatic limit. We argue that realistic modeling of known spin-Peierls materials should include the effects of quantum phonons.

Extended integrability regime for the supersymmetric U model

An extension of the supersymmetric U model for correlated electrons is given and integrability is established by demonstrating that the model can he constructed through the quantum inverse scattering method using an R-matrix without the difference property. Some general symmetry properties of the model are discussed and from the Bethe ansatz solution an expression for the energies is presented.

Integrable Kondo impurities in the one-dimensional supersymmetric extended Hubbard model

An integrable Kondo problem in the one-dimensional supersymmetric extended Hubbard model is studied by means of the boundary graded quantum inverse scattering method. The boundary K-matrices depending on the local moments of the impurities are presented as a non-trivial realization of the graded reflection equation algebras in a two-dimensional impurity Hilbert space. Further, the model is solved by using the algebraic Bethe ansatz method and the Bethe ansatz equations are obtained.

Rectification of the olfactory cyclic nucleotide-gated channel by intracellular polyamines

Polyamine-induced inward rectification of cyclic nucleotide-gated channels was studied in inside-out patches from rat olfactory neurons. The polyamines, spermine, spermidine and putrescine, induced an 'instantaneous' voltage-dependent inhibition with K-d values at 0 mV of 39, 121 mu M and 2.7 mM, respectively. Hill coefficients for inhibition were significantly < 1, suggesting an allosteric inhibitory mechanism. The Woodhull model for voltage-dependent block predicted that all 3 polyamines bound to a site 1/3 of the electrical distance through the membrane from the internal side. Instantaneous inhibition was relieved at positive potentials, implying significant polyamine permeation. Spermine also induced exponential current relaxations to a 'steady-state' impermeant level. This inhibition was also mediated by a binding site 1/3 of the electrical distance through the pore, but with a K-d of 2.6 mM. Spermine inhibition was explained by postulating two spermine binding sites at a similar depth. Occupation of the first site occurs rapidly and with high affinity, but once a spermine molecule has bound, it inhibits spermine occupation of the second binding site via electrostatic repulsion. This repulsion is overcome at higher membrane potentials, but results in a lower apparent binding affinity for the second spermine molecule. The on-rate constant for the second spermine binding saturated at a low rate (similar to 200 sec(-1) at +120 mV), providing further evidence for an allosteric mechanism. Polyamine-induced inward rectification was significant at physiological concentrations.

On modifications to the long-term survival mixture model in the presence of competing risks

A mixture model for long-term survivors has been adopted in various fields such as biostatistics and criminology where some individuals may never experience the type of failure under study. It is directly applicable in situations where the only information available from follow-up on individuals who will never experience this type of failure is in the form of censored observations. In this paper, we consider a modification to the model so that it still applies in the case where during the follow-up period it becomes known that an individual will never experience failure from the cause of interest. Unless a model allows for this additional information, a consistent survival analysis will not be obtained. A partial maximum likelihood (ML) approach is proposed that preserves the simplicity of the long-term survival mixture model and provides consistent estimators of the quantities of interest. Some simulation experiments are performed to assess the efficiency of the partial ML approach relative to the full ML approach for survival in the presence of competing risks.