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.

The anti-tumor activity of IL-12: Mechanisms of innate immunity that are model and dose dependent

IL-12 has been demonstrated to have potent anti-tumor activities in a variety of mouse tumor models, but the relative roles of NK, NKT, and T cells and their effector mechanisms in these responses have not been fully addressed. Using a spectrum of gene-targeted or Ab-treated mice we have shown that for any particular tumor model the effector mechanisms downstream of IL-12 often mimic the natural immune response to that tumor. For example, metastasis of the MHC class I-deficient lymphoma, EL4-S3, was strictly controlled by NK cells using perforin either naturally or following therapy with high-dose IL-12. Intriguingly, in B16F10 and RM-1 tumor models both NK and NKT cells contribute to natural protection from tumor metastasis, In these models, a lower dose of IL-12 or delayed administration of IL-12 dictated a greater relative role of NKT cells in immune protection from tumor metastasis. Overall, both NK and NKT cells can contribute to natural and IL-12-induced immunity against tumors, and the relative role of each population is turner and therapy dependent.

Change in the rate of shell deposition and shell microstructure in response to shell borers in the abalone Haliotis rubra

Gastropod shells consist of two crystal types of calcium carbonate, an outer, prismatic calcite layer and an inner nacreous layer made of aragonite. In cross-section, the nacre of the nacreous layer appears to have a regular brick-like microstructure composed of thin laminae of aragonite crystals, separated by very thin sheets of protein (Lutz and Rhoads, 1980; Nakahara, 1983). In abalone (Genus, Haliotis) and other gastropods, thin layers of non-lamellar pigmented material occur within the nacre and have been termed alternatively, fine lines, growth rings or growth lines (Shepherd et al., 1995). It has been suggested that these pigmented layers are small, prismatic, calcite layers (Shepherd and Avalos-Borja, 1997; Zaremba et al., 1996) but investigations using a Raman laser in Haliotis rubra show that they contain aragonite rather than calcite (Hawkes et al, 1996). Day and Fleming (1992) suggest that the occurrence of pigmented layers is correlated with regular exogenous cues such as reproduction or temperature changes and indeed in some species, pigmented layers in the shell can be used to age abalone (review: Shepherd and Triantafillos, 1997). However, McShane and Smith (1992) suggest that pigmented layers can occur irregularly and therefore may be unreliable indicators of age.

Efficient discovery of immune response targets by cyclical refinement of QSAR models of peptide binding

Peptides that induce and recall T-cell responses are called T-cell epitopes. T-cell epitopes may be useful in a subunit vaccine against malaria. Computer models that simulate peptide binding to MHC are useful for selecting candidate T-cell epitopes since they minimize the number of experiments required for their identification. We applied a combination of computational and immunological strategies to select candidate T-cell epitopes. A total of 86 experimental binding assays were performed in three rounds of identification of HLA-All binding peptides from the six preerythrocytic malaria antigens. Thirty-six peptides were experimentally confirmed as binders. We show that the cyclical refinement of the ANN models results in a significant improvement of the efficiency of identifying potential T-cell epitopes. (C) 2001 by Elsevier Science Inc.

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.

Diffusion- and perfusion-weighted MRI response to thrombolysis in stroke

Diffusion- and perfusion-weighted magnetic resonance imaging provides important pathophysiological information in acute bra-in ischemia. We performed a prospective study in 19 sub-6-hour stroke patients using serial diffusion- and perfusion-weighted imaging before intravenous thrombolysis, with repeat studies, both subacutely and at outcome. For comparison of ischemic lesion evolution and clinical outcome, we used a historical control group of 21 sub-6-hour ischemic stroke patients studied serially with diffusion- and perfusion-weighted imaging. The two groups were well matched for the baseline National Institutes of Health Stroke Scale and magnetic resonance parameters. Perfusion-weighted imaging-diffusion-weighted imaging mismatch was present in 16 of 19 patients treated with tissue plasminogen activator, and 16 of 21 controls. Perfusion-weighted imaging-diffusion-weighted imaging mismatch patients treated with tissue plaminogen activator had higher recanalization rates and enhanced reperfusion at day 3 (81% vs 47% in controls), and a greater proportion of severely hypoperfused acute mismatch tissue not progressing to infarction (82% vs -25% in controls). Despite similar baseline diffusion-weighted imaging lesions, infarct expansion was less in the recombinant tissue plaminogen activator group (14cm(3) vs 56cm(3) in controls). The positive effect of thrombolysis on lesion growth in mismatch patients translated into a greater improvement in baseline to outcome National Institutes of Health Stroke Scale in the group treated with recombinant tissue plaminogen activator, and a significantly larger proportion of patients treated with recombinant tissue plaminogen activator having a clinically meaningful improvement in National Institutes of Health Stroke Scale of;2:7 points. The natural evolution of acute perfusion-weighted imaging-diffusion-weighted imaging mismatch tissue may be altered by thrombolysis, with improved stroke outcome. This has implications for the use of diffusion- and perfusion-weighted imaging in selecting and monitoring patients for thrombolytic therapy.

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.

The role of the church in developing the law: response to commentators

Three of the four commentators endorse our concerns about intervention by the Roman Catholic church as an omicus curiae in civil litigation, with few reservations. One commentary rejects our arguments in We deal first with the three commentaries that support our arguments; secondly, with the reservations and qualifications in those commentaries, and thirdly, with the commentary that totally rejects our arguments.

Heroin-assisted treatment as a response to the public health problem of opiate dependence

Injection drug use (involving the injection of illicit opiates) poses serious public health problems in many countries. Research has indicated that injection drug users are at higher risk for morbidity in the form of HIV/AIDS and Hepatitis B and C, and drug-related mortality, as well as increased criminal activity. Methadone maintenance treatment is the most prominent form of pharmacotherapy treatment for illicit opiate dependence in several countries, and its application varies internationally with respect to treatment regulations and delivery modes. In order to effectively treat those patients who have previously been resistant to methadone maintenance treatment, several countries have been studying and/or considering heroin-assisted treatment as a complementary form of opiate pharmacotherapy treatment. This paper provides an overview of the prevalence of injection drug use and the opiate dependence problem internationally, the current opiate dependence treatment landscape in several countries, and the status of ongoing or planned heroin-assisted treatment trials in Australia, Canada and certain European countries.

Human response to environmental noise: The role of perceived control

Negative impacts of noise exposure on health and performance may result in part from learned helplessness, the syndrome of deficits typically produced by exposure to uncontrollable events. People may perceive environmental noise to be uncontrollable, and several effects of noise exposure appear to parallel learned helplessness deficits. In the present socioacoustic survey (N = 1,015), perceived control over aircraft noise correlated negatively with some effects of noise (though not others). Furthermore, these effects were better predicted by perceived control than by noise level. These observational data support the claim that learned helplessness contributes to the effects of noise exposure.