Metabolite mean transit times in the liver as predicted by various models of hepatic elimination

Predicted area under curve (AUC), mean transit time (MTT) and normalized variance (CV2) data have been compared for parent compound and generated metabolite following an impulse input into the liver, Models studied were the well-stirred (tank) model, tube model, a distributed tube model, dispersion model (Danckwerts and mixed boundary conditions) and tanks-in-series model. It is well known that discrimination between models for a parent solute is greatest when the parent solute is highly extracted by the liver. With the metabolite, greatest model differences for MTT and CV2 occur when parent solute is poorly extracted. In all cases the predictions of the distributed tube, dispersion, and tasks-in-series models are between the predictions of the rank and tube models. The dispersion model with mixed boundary conditions yields identical predictions to those for the distributed tube model (assuming an inverse gaussian distribution of tube transit times). The dispersion model with Danckwerts boundary conditions and the tanks-in series models give similar predictions to the dispersion (mixed boundary conditions) and the distributed tube. The normalized variance for parent compound is dependent upon hepatocyte permeability only within a distinct range of permeability values. This range is similar for each model but the order of magnitude predicted for normalized variance is model dependent. Only for a one-compartment system is the MIT for generated metabolite equal to the sum of MTTs for the parent compound and preformed metabolite administered as parent.

Individual and household willingness to pay for public goods

The issue of whether willingness to pay (WTP) for the benefits generated by a public good should be elicited on an individual or on a household basis is addressed. Differences between individual and household WTP may arise when members of the household are mutually altruistic. It is shown that, for general specifications of altruism, household WTP is less than the sum of household members' individual WTP. Implications for the choice between household and individual measures of WTP are considered, and issues in the elicitation of household WTP are addressed.

Kinetic analysis of vascular marker distribution in perfused rat livers after regeneration following partial hepatectomy

Background/Aims: Liver clearance models are based on information (or assumptions) on solute distribution kinetics within the microvasculatory system, The aim was to study albumin distribution kinetics in regenerated livers and in livers of normal adult rats, Methods: A novel mathematical model was used to evaluate the distribution space and the transit time dispersion of albumin in livers following regeneration after a two-thirds hepatectomy compared to livers of normal adult rats. Outflow curves of albumin measured after bolus injection in single-pass perfused rat livers were analyzed by correcting for the influence of catheters and fitting a long-tailed function to the data. Results: The curves were well described by the proposed model. The distribution volume and the transit time dispersion of albumin observed in the partial hepatectomy group were not significantly different from livers of normal adult rats. Conclusions: These findings suggest that the distribution space and the transit time dispersion of albumin (CV2) is relatively constant irrespective of the presence of rapid and extensive repair. This invariance of CV2 implies, as a first approximation, a similar degree of intrasinusoidal mixing, The finding that a sum of two (instead of one) inverse Gaussian densities is an appropriate empirical function to describe the outflow curve of vascular indicators has consequences for an improved prediction of hepatic solute extraction.

Likelihood-based estimation of the regression model with scrambled responses

A significant problem in the collection of responses to potentially sensitive questions, such as relating to illegal, immoral or embarrassing activities, is non-sampling error due to refusal to respond or false responses. Eichhorn & Hayre (1983) suggested the use of scrambled responses to reduce this form of bias. This paper considers a linear regression model in which the dependent variable is unobserved but for which the sum or product with a scrambling random variable of known distribution, is known. The performance of two likelihood-based estimators is investigated, namely of a Bayesian estimator achieved through a Markov chain Monte Carlo (MCMC) sampling scheme, and a classical maximum-likelihood estimator. These two estimators and an estimator suggested by Singh, Joarder & King (1996) are compared. Monte Carlo results show that the Bayesian estimator outperforms the classical estimators in almost all cases, and the relative performance of the Bayesian estimator improves as the responses become more scrambled.

Novel solitons in parametric amplifiers and atom lasers

We review recent developments in quantum and classical soliton theory, leading to the possibility of observing both classical and quantum parametric solitons in higher-dimensional environments. In particular, we consider the theory of three bosonic fields interacting via both parametric (cubic) and quartic couplings. In the case of photonic fields in a nonlinear optical medium this corresponds to the process of sum frequency generation (via chi((2)) nonlinearity) modified by the chi((3)) nonlinearity. Potential applications include an ultrafast photonic AND-gate. The simplest quantum solitons or energy eigenstates (bound-state solutions) of the interacting field Hamiltonian are obtained exactly in three space dimensions. They have a point-like structure-even though the corresponding classical theory is nonsingular. We show that the solutions can be regularized with the imposition of a momentum cut-off on the nonlinear couplings. The case of three-dimensional matter-wave solitons in coupled atomic/molecular Bose-Einstein condensates is discussed.

Projecting mammographic screens

Objective-The purpose of mammographic screening is to reduce mortality from breast cancer. This study describes a method for projecting the number of screens to be performed by a mammographic screening programme, and applies this method in the context of New South Wales, Australia. Method-The total number of mammographic screens was projected as the sum of initial screens and re-screens, and is based on projections of the population, rates of new recruitment, rates of attrition within the programme, and the mix of screening intervals. The baseline scenario involved: 70% participation of women aged 50-69 years, 90% return rate for the second and subsequent re-screens, 5% annual screens (95% biennial screens), and a specified population projection. The results were assessed with respect to variations in these assumptions. Results-The projections were strongly influenced by: the rate of screening of the target age group; the proportion of women re-screened annually; and the rates of attrition within the programme. Although demographic change had a notable effect, there was little difference between different population projections. Standard assumptions about attrition within the programme suggest that the current target participation rates in NSW may not be achieved in the long term. Conclusions-A practical model for projecting mammographic screens for populations is described which is capable of forecasting the number of screens under different scenarios. Implications-Projections of mammographic screens provide important information for the planning and financing of equipment and personnel, and for testing the effects of variations in important operational parameters. Re-screening attrition is an important contributor to screening viability.

Small area population disease burden

Small area health statistics has assumed increasing importance as the focus of population and public health moves to a more individualised approach of smaller area populations. Small populations and low event occurrence produce difficulties in interpretation and require appropriate statistical methods, including for age adjustment. There are also statistical questions related to multiple comparisons. Privacy and confidentiality issues include the possibility of revealing information on individuals or health care providers by fine cross-tabulations. Interpretation of small area population differences in health status requires consideration of migrant and Indigenous composition, socio-economic status and rural-urban geography before assessment of the effects of physical environmental exposure and services and interventions. Burden of disease studies produce a single measure for morbidity and mortality - disability adjusted life year (DALY) - which is the sum of the years of life lost (YLL) from premature mortality and the years lived with disability (YLD) for particular diseases (or all conditions). Calculation of YLD requires estimates of disease incidence (and complications) and duration, and weighting by severity. These procedures often mean problematic assumptions, as does future discounting and age weighting of both YLL and YLD. Evaluation of the Victorian small area population disease burden study presents important cross-disciplinary challenges as it relies heavily on synthetic approaches of demography and economics rather than on the empirical methods of epidemiology. Both empirical and synthetic methods are used to compute small area mortality and morbidity, disease burden, and then attribution to risk factors. Readers need to examine the methodology and assumptions carefully before accepting the results.

Using biplots to interpret gene expression patterns in plants

Sum: Plant biologists in fields of ecology, evolution, genetics and breeding frequently use multivariate methods. This paper illustrates Principal Component Analysis (PCA) and Gabriel's biplot as applied to microarray expression data from plant pathology experiments. Availability: An example program in the publicly distributed statistical language R is available from the web site (www.tpp.uq.edu.au) and by e-mail from the contact. Contact: scott.chapman@csiro.au.

The land assembly problem revisited

As in the standard land assembly problem, a developer wants to buy two adjacent blocks of land belonging to two different owners. The value of the two blocks of land to the developer is greater than the sum of the individual values of the blocks for each owner. Unlike the land assembly literature, however, our focus is on the incentive that each lot owner has to delay the start of negotiations, rather than on the public goods nature of the problem. An incentive for delay exists, for example, when owners perceive that being last to sell will allow them to capture a larger share of the joint surplus from the development. We show that competition at point of sale can cause equilibrium delay, and that cooperation at point of sale will eliminate delay. This suggests that strategic delay is another source for the inefficient allocation of land, in addition to the public-good type externality pointed out by Grossman and Hart [Bell Journal of Economics 11 (1980) 42] and O'Flaherty [Regional Science and Urban Economics 24 (1994) 287]. (C) 2004 Elsevier B.V. All rights reserved.

Analysis and implementation of a new constant acceleration subcycling algorithm

An algorithm for explicit integration of structural dynamics problems with multiple time steps is proposed that averages accelerations to obtain subcycle states at a nodal interface between regions integrated with different time steps. With integer time step ratios, the resulting subcycle updates at the interface sum to give the same effect as a central difference update over a major cycle. The algorithm is shown to have good accuracy, and stability properties in linear elastic analysis similar to those of constant velocity subcycling algorithms. The implementation of a generalised form of the algorithm with non-integer time step ratios is presented. (C) 1997 by John Wiley & Sons, Ltd.

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.

Chemical characterization of soils of a tropical humid forest zone: A methodology

A methodology, based on a combination of routinely performed analyses and investigation of fundamental charge and anion sorption properties, was used to characterize the soils of the humid forest zone of Cameroon, In general, the soils have about 2 cmol kg(-1) permanent negative charge, with about 1 cmol kg(-1) from variable-charge sources at current soil pH values, Furthermore, they are impoverished with respect to Ca, Mg, and K, while Al frequently dominates the exchange complex. Thus, the ability of these soils to retain base cations is more limited than is suggested by the cation-exchange capacity (CEC), Therefore we propose the concept of a degradation index (DI) defined as: DI = 100(CEC5.5 - sum of basic cations)/CEC5.5, where CEC5.5 is the CEC measured at pH 5.5, This index encompasses degradation a soil may have experienced from natural or man-made causes, Extractable PO4 concentrations are considered very low and the soils have a moderate to high capacity to fix added PO4. Surface soil SO4 concentrations are considered marginal to deficient for plant growth, though adequate reserves of SO4 are held in the subsoil by SO4 sorption, The approach used demonstrated that the five morphologically different soil profile classes identified in the zone have similar chemical characteristics. Thus, the results of experimentation conducted on one of the soil profile classes will be applicable throughout the zone, Furthermore, the approach has provided a means of identifying comparable soil types in other parts of the world and will guide technology transfer, The analytical methods used in this study are relatively simple and require no specialized equipment, and are therefore within the capabilities of many laboratories in the developing world.

Commercialisation of agriculture in Kenya: Case study of urban bias on food availability in farm households

This study investigates the effect of cash cropping on food availability and examines the determinants of the proportion of income allocated for food expenditures in the Nyeri district in Kenya. Using a Tobit model, the results suggest that in general food expenditure allocations suffer due to cash cropping in Kenya as the lump-sum income flows from this may be used for purchases other than food. Food expenditure also suffers when remittances are irregular. On the other hand, earnings from outside employment for married women living with husbands are positively associated with food expenditure allocations. Amounts of non-cash food output as well as ownership of livestock are negatively associated with food expenditure allocations. These findings indicate that lump sum income may not lead to improved welfare of women and children. Thus, there may be social reasons for increasing non-cash food production especially by women, instead of over emphasizing cash cropping as now seems to be so in public policy.