Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil

Aim To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. Methods Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. Results The best base model was a two-compartment model with a lag time (apparent oral clearance was 271 h(-1), and apparent volume of the central compartment 981). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. Conclusions The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

Semi-analytical solution for nonlinear vibration of laminated FGM plates with geometric imperfections

This paper investigates the nonlinear vibration of imperfect shear deformable laminated rectangular plates comprising a homogeneous substrate and two layers of functionally graded materials (FGMs). A theoretical formulation based on Reddy's higher-order shear deformation plate theory is presented in terms of deflection, mid-plane rotations, and the stress function. A semi-analytical method, which makes use of the one-dimensional differential quadrature method, the Galerkin technique, and an iteration process, is used to obtain the vibration frequencies for plates with various boundary conditions. Material properties are assumed to be temperature-dependent. Special attention is given to the effects of sine type imperfection, localized imperfection, and global imperfection on linear and nonlinear vibration behavior. Numerical results are presented in both dimensionless tabular and graphical forms for laminated plates with graded silicon nitride/stainless steel layers. It is shown that the vibration frequencies are very much dependent on the vibration amplitude and the imperfection mode and its magnitude. While most of the imperfect laminated plates show the well-known hard-spring vibration, those with free edges can display soft-spring vibration behavior at certain imperfection levels. The influences of material composition, temperature-dependence of material properties and side-to-thickness ratio are also discussed. (C) 2004 Elsevier Ltd. All rights reserved.

Synthesis, characterization and DFT studies of the cobalt(III) complex of a tetrapodal pentadentate N4S donor ligand

The synthesis of the pentadentate ligand 2,6-bis(3,3-dimethyl-2,4-dioxocyclohexanyl)-4-thiaheptane (N(4)Samp) is described. The synthetic pathway involves the coupling of two 1,3-(dimethylenedioxy)-2-methyl-2-(methylene-p-toluenesulfonyl)propane moieties with sodium sulfide and subsequent synthetic elaboration to prepare the final N4S donor system. The cobalt(III) complex [Co(N(4)Samp)Cl](2+) has been prepared and subsequently crystallized as the tetrachlorozincate salt. The X-ray structure analysis confirms the pentadentate nature of the ligand and shows the thioether donor occupying one apex with four equivalent amine donors effectively occupying the equatorial plane of the molecule. The sixth coordination site is occupied by a chloro ligand. The electronic absorption and C-13 NMR spectra have been studied. DFT calculations have been employed to explore structural and mechanistic comparisons between [Co(N(4)Samp)Cl](2+) and an analogous pentaamine complex.

Nonlinear quantum optical computing via measurement

We show how the measurement induced model of quantum computation proposed by Raussendorf and Briegel ( 2001, Phys. Rev. Letts., 86, 5188) can be adapted to a nonlinear optical interaction. This optical implementation requires a Kerr nonlinearity, a single photon source, a single photon detector and fast feed forward. Although nondeterministic optical quantum information proposals such as that suggested by KLM ( 2001, Nature, 409, 46) do not require a Kerr nonlinearity they do require complex reconfigurable optical networks. The proposal in this paper has the benefit of a single static optical layout with fixed device parameters, where the algorithm is defined by the final measurement procedure.

Measurement of quantum weak values of photon polarization

We experimentally determine weak values for a single photon's polarization, obtained via a weak measurement that employs a two-photon entangling operation, and postselection. The weak values cannot be explained by a semiclassical wave theory, due to the two-photon entanglement. We observe the variation in the size of the weak value with measurement strength, obtaining an average measurement of the S-1 Stokes parameter more than an order of magnitude outside of the operator's spectrum for the smallest measurement strengths.

Quantitative photoluminescence of broad band absorbing melanins: a procedure to correct for inner filter and re-absorption effects

We report methods for correcting the photoluminescence emission and excitation spectra of highly absorbing samples for re-absorption and inner filter effects. We derive the general form of the correction, and investigate various methods for determining the parameters. Additionally, the correction methods are tested with highly absorbing fluorescein and melanin (broadband absorption) solutions; the expected linear relationships between absorption and emission are recovered upon application of the correction, indicating that the methods are valid. These procedures allow accurate quantitative analysis of the emission of low quantum yield samples (such as melanin) at concentrations where absorption is significant. (c) 2004 Elsevier B.V. All rights reserved.

Spatial and ontogenetic variation in growth of nursery-bound juvenile lemon sharks, Negaprion brevirostris: a comparison of two age-assigning techniques

We compared growth rates of the lemon shark, Negaprion brevirostris, from Bimini, Bahamas and the Marquesas Keys (MK), Florida using data obtained in a multi-year annual census. We marked new neonate and juvenile sharks with unique electronic identity tags in Bimini and in the MK we tagged neonate and juvenile sharks. Sharks were tagged with tiny, subcutaneous transponders, a type of tagging thought to cause little, if any disruption to normal growth patterns when compared to conventional external tagging. Within the first 2 years of this project, no age data were recorded for sharks caught for the first time in Bimini. Therefore, we applied and tested two methods of age analysis: ( 1) a modified 'minimum convex polygon' method and ( 2) a new age-assigning method, the 'cut-off technique'. The cut-off technique proved to be the more suitable one, enabling us to identify the age of 134 of the 642 previously unknown aged sharks. This maximised the usable growth data included in our analysis. Annual absolute growth rates of juvenile, nursery-bound lemon sharks were almost constant for the two Bimini nurseries and can be best described by a simple linear model ( growth data was only available for age-0 sharks in the MK). Annual absolute growth for age-0 sharks was much greater in the MK than in either the North Sound (NS) and Shark Land (SL) at Bimini. Growth of SL sharks was significantly faster during the first 2 years of life than of the sharks in the NS population. However, in MK, only growth in the first year was considered to be reliably estimated due to low recapture rates. Analyses indicated no significant differences in growth rates between males and females for any area.

Divergent selection and the evolution of signal traits and mating preferences

Mating preferences are common in natural populations, and their divergence among populations is considered an important source of reproductive isolation during speciation. Although mechanisms for the divergence of mating preferences have received substantial theoretical treatment, complementary experimental tests are lacking. We conducted a laboratory evolution experiment, using the fruit fly Drosophila serrata, to explore the role of divergent selection between environments in the evolution of female mating preferences. Replicate populations of D. serrata were derived from a common ancestor and propagated in one of three resource environments: two novel environments and the ancestral laboratory environment. Adaptation to both novel environments involved changes in cuticular hydrocarbons, traits that predict mating success in these populations. Furthermore, female mating preferences for these cuticular hydrocarbons also diverged among populations. A component of this divergence occurred among treatment environments, accounting for at least 17.4% of the among- population divergence in linear mating preferences and 17.2% of the among-population divergence in nonlinear mating preferences. The divergence of mating preferences in correlation with environment is consistent with the classic by- product model of speciation in which premating isolation evolves as a side effect of divergent selection adapting populations to their different environments.

Measuring nonlinear functionals of quantum harmonic oscillator states

Using only linear interactions and a local parity measurement we show how entanglement can be detected between two harmonic oscillators. The scheme generalizes to measure both linear and nonlinear functionals of an arbitrary oscillator state. This leads to many applications including purity tests, eigenvalue estimation, entropy, and distance measures-all without the need for nonlinear interactions or complete state reconstruction. Remarkably, experimental realization of the proposed scheme is already within the reach of current technology with linear optics.

Assessment of epidermal cell viability by near infrared multi-photon microscopy following ballistic delivery of gold micro-particles

The use of gene guns in ballistically delivering DNA vaccine coated gold micro-particles to skin can potentially damage targeted cells, therefore influencing transfection efficiencies. In this paper, we assess cell death in the viable epidermis by non-invasive near infrared two-photon microscopy following micro-particle bombardment of murine skin. We show that the ballistic delivery of micro-particles to the viable epidermis can result in localised cell death. Furthermore, experimental results show the degree of cell death is dependant on the number of micro-particles delivered per unit of tissue surface area. Micro-particles densities of 0.16 +/- 0.27 (mean +/- S.D.), 1.35 +/- 0.285 and 2.72 +/- 0.47 per 1000 mu m(2) resulted in percent deaths of 3.96 +/- 5.22, 45.91 +/- 10.89, 90.52 +/- 12.28, respectively. These results suggest that optimization of transfection by genes administered with gene guns is - among other effects - a compromise of micro-particle payload and cell death. (c) 2005 Elsevier Ltd. All rights reserved.

Investigating the performance analysis of EASI algorithm and EKENS algorithm in nonlinear model

This paper investigates the performance of EASI algorithm and the proposed EKENS algorithm for linear and nonlinear mixtures. The proposed EKENS algorithm is based on the modified equivariant algorithm and kernel density estimation. Theory and characteristic of both the algorithms are discussed for blind source separation model. The separation structure of nonlinear mixtures is based on a nonlinear stage followed by a linear stage. Simulations with artificial and natural data demonstrate the feasibility and good performance of the proposed EKENS algorithm.

Studies of solar radiation and its measurement

A mathematical model has been developed for predicting the spectral distribution of solar radiation incident on a horizontal surface. The solar spectrum in the wavelength range 0.29 to 4.0 micrometers has been divided in 144 intervals. Two variables in the model are the atmospheric water vapour content and atmospheric turbidity. After allowing for absorption and scattering in the atmosphere, the spectral intensity of direct and diffuse components of radiation are computed. When the predicted radiation levels are compared with the measured values for the total radiation and the values with glass filters RG715, RG630 and OG530, a close agreement (± 5%) has been achieved under clear sky conditions. A solar radiation measuring facility, close to the centre of Birmingham, has been set up utilising a microcomputer based data logging system. A suite of computer programs in the BASIC programming language has been developed and extensively tested for solar radiation data, logging, analysis and plotting. Two commonly used instruments, the Eppley PSP pyranometer and the Kipp and Zonen CM5 pyranometer, have been compared under different experimental conditions. Three models for computing the inclined plane irradiation, using total and diffuse radiation on a horizontal surface, have been tested for Birmingham. The anisotropic-alI-sky model, proposed by Klucher, provides a good agreement between the measured and the predicted radiation levels. Measurements of solar spectral distribution, using glass filters, are also reported for a number of inclines facing South.

Abnormal left and right amygdala-orbitofrontal cortical functional connectivity to emotional faces:state versus trait vulnerability markers of depression in bipolar disorder

Background - Amygdala-orbitofrontal cortical (OFC) functional connectivity (FC) to emotional stimuli and relationships with white matter remain little examined in bipolar disorder individuals (BD). Methods - Thirty-one BD (type I; n = 17 remitted; n = 14 depressed) and 24 age- and gender-ratio-matched healthy individuals (HC) viewed neutral, mild, and intense happy or sad emotional faces in two experiments. The FC was computed as linear and nonlinear dependence measures between amygdala and OFC time series. Effects of group, laterality, and emotion intensity upon amygdala-OFC FC and amygdala-OFC FC white matter fractional anisotropy (FA) relationships were examined. Results - The BD versus HC showed significantly greater right amygdala-OFC FC (p = .001) in the sad experiment and significantly reduced bilateral amygdala-OFC FC (p = .007) in the happy experiment. Depressed but not remitted female BD versus female HC showed significantly greater left amygdala-OFC FC (p = .001) to all faces in the sad experiment and reduced bilateral amygdala-OFC FC to intense happy faces (p = .01). There was a significant nonlinear relationship (p = .001) between left amygdala-OFC FC to sad faces and FA in HC. In BD, antidepressants were associated with significantly reduced left amygdala-OFC FC to mild sad faces (p = .001). Conclusions - In BD, abnormally elevated right amygdala-OFC FC to sad stimuli might represent a trait vulnerability for depression, whereas abnormally elevated left amygdala-OFC FC to sad stimuli and abnormally reduced amygdala-OFC FC to intense happy stimuli might represent a depression state marker. Abnormal FC measures might normalize with antidepressant medications in BD. Nonlinear amygdala-OFC FC–FA relationships in BD and HC require further study.

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.

Dispersion and nonlinearity-management in mode-locked fibre lasers

In this work we extend theory of dispersion-managed (DM) solitons to dissipative systems with the main focus on applications in mode-locked lasers. In general, pulses in mode-locked fibre lasers experience both nonlinear and dispersion management per cavity round trip. In stretched-pulse lasers, this concept was utilized to obtain high energy pulses. Here we model the pulse propagation in a mode-locked fibre laser with a distributed nonlinear and DM Ginzburg-Landau type equation. We extend existing results on DM solitons and investigate the impact on soliton properties of dissipative perturbations that occur due to the effects of gain amplification, saturable absorption, and loss. In conclusion, in contrast to standard DM solitons in Hamiltonian systems, dissipative DM solitons do exist at high map strengths, thus opening a way for the generation of stable, short pulses with high energy.