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This study aimed to develop a rapid, 1 mm3 isotropic resolution, whole-brain MRI technique for automatic lesion segmentation and multi-parametric mapping without using contrast by continuously applying balanced steady-state free precession with inversion pulses throughout incomplete inversion recovery in a single 6 min scan. Modified k-means clustering was performed for automatic brain tissue and lesion segmentation using distinct signal evolutions that contained mixed T1/T2/magnetization transfer properties. Multi-compartment modeling was used to derive quantitative multi-parametric maps for tissue characterization. Fourteen patients with contrast-enhancing gliomas were scanned with this sequence prior to the injection of a contrast agent, and their segmented lesions were compared to conventionally defined manual segmentations of T2-hyperintense and contrast-enhancing lesions. Simultaneous T1, T2, and macromolecular proton fraction maps were generated and compared to conventional 2D T1 and T2 mapping and myelination water fraction mapping acquired with MAGiC. The lesion volumes defined with the new method were comparable to the manual segmentations (r = 0.70, p < 0.01; t-test p > 0.05). The T1, T2, and macromolecular proton fraction mapping values of the whole brain were comparable to the reference values and could distinguish different brain tissues and lesion types (p < 0.05), including infiltrating tumor regions within the T2-lesion. Highly efficient, whole-brain, multi-contrast imaging facilitated automatic lesion segmentation and quantitative multi-parametric mapping without contrast, highlighting its potential value in the clinic when gadolinium is contraindicated.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

The in vivo performances of most drugs after extravascular administration are fitted well with the two-compartment pharmacokinetic (PK) model, but the estimation of absorption rate constant (ka) for these drugs becomes difficult during unavailability of intravenous PK data. Herein, we developed a novel method, called the direct method, for estimating the ka values of drugs without using intravenous PK data, by proposing a new PK parameter, namely, maximum apparent rate constant of disposition (kmax). The accuracy of the direct method in ka estimation was determined using the setting parameters (k12, k21, and k10 values at high, medium, and low levels, respectively) and clinical data. The results showed that the absolute relative error of ka estimated using the direct method was significantly lower than that obtained using both the Loo-Riegelman method and the statistical moment method for the setting parameters. Human PK studies of telmisartan, candesartan cilexetil, and tenofovir disoproxil fumarate indicated that the ka values of these drugs were accurately estimated using the direct method based on good correlations between the ka values and other PK parameters that reflected the absorption properties of drugs in vivo (Tmax, Cmax, and Cmax/AUC0-t). This novelmethod can be applied in situations where intravenous PK data cannot be obtained and is expected to provide valuable support for PK evaluation and in vitro-in vivo correlation establishment. [ABSTRACT FROM AUTHOR]

With the aging population, osteoporosis has become an important public health issue. The purpose of this study was to establish a two-compartment model (TCM) to quantify the volumetric bone mineral density (vBMD) of the lumbar spine using abdominal computed tomography (CT) images. The TCM approach uses water as the bone marrow equivalent and K2HPO4 solution as the cortical bone equivalent. A phantom study was performed to evaluate the accuracy of vBMD estimation at 100 kVp and 120 kVp. The data of 180 patients who underwent abdominal CT imaging and dual-energy X-ray absorptiometry (DXA) within one month were retrospectively collected. vBMD of L1–L4 vertebrae were calculated, and the receiver-operating characteristic curve analysis was performed to establish the diagnostic thresholds for osteoporosis and osteopenia in terms of vBMD. The average difference between the measured vBMD following TCM and the theoretical vBMD of the self-made phantom was 0.2%, and the maximum difference was 0.5%. vBMD of lumbar vertebrae obtained from TCM and aBMD obtained by DXA had a significant positive correlation (r = 0.655 to 0.723). The average diagnostic threshold for osteoporosis was 0.116 g/cm3. The sensitivity, specificity, and accuracy were 95.7%, 75.6.5%, and 80.0%, respectively. The average diagnostic threshold for osteopenia was 0.126 g/cm3. The sensitivity, specificity, and accuracy were 81.3%, 82.5%, and 82.7%, respectively. The aforementioned threshold values were used to perform the diagnostics on a test cohort, and the performance was equivalent to that in the experimental cohort. From the perspective of preventive medicine, opportunistic screening of bone mineral density using abdominal CT images and the TCM approach can facilitate early detection of osteoporosis and osteopenia and, with in-time treatment, slow down their progression. [ABSTRACT FROM AUTHOR]

Background/Aim. Methotrexate (MTX) plays a significant role in the treatment of various diseases, but the toxicity remains the main issue of its use, especially when administered in high doses. Considering altered pharmacokinetics of MTX as a factor strongly implicated in the large interpatient variability and unexpected toxicity in certain patients, the accurate description of MTX pharmacokinetic behaviour of both low and high doses is of the utmost importance. Therefore, the objective of this study was to determine the pharmacokinetics of MTX after intravenous (iv) administration in ascending doses of 5, 40, 80 and 160 mg/kg in rats and to select the appropriate mathematical model describing MTX pharmacokinetics. Methods. Plasma concentrations of MTX were measured using the liquid chromatography - mass spectrometry (LC/MS) method. Pharmacokinetic parameters were calculated by non-compartmental and two-compartmental integer-order analyses. Results. MTX showed linear pharmacokinetics following iv administration up to the dose of 80 mg/kg. The administration of a high dose of MTX (160 mg/kg) resulted in the similar pharmacokinetic behaviour as when applied in the twice lower dose (80 mg/kg), which can be explained by dose-dependent changes in the expression of solute carrier (SLC) and ATP binding cassette (ABC) transport proteins and intracellular metabolism. Furthermore, the classical two-compartment model could not explain the pharmacokinetics of MTX in a small percentage of experimental animals, which opens up new strategies for the use of fractional order pharmacokinetic models in MTX therapy optimisation. Conclusion. These results of pharmacokinetic analyses may be helpful in adjusting the dosage regimen of MTX, but the application of novel pharmacokinetic models, such as those based on fractional calculus, is still needed in the process of MTX therapy optimisation.

The objective was to explore variations of temperature distribution and coagulation zone size computed by a two-compartment radiofrequency ablation (RFA) model when including simultaneously reversible changes in the tissue electrical conductivity (σ) due to temperature and irreversible changes due to thermal coagulation. Two-compartment (tumor and healthy tissue) models were built and simulated. Reversible change of σ was modeled by a piecewise function characterized by increments of +1.5%/℃ up to 100 ℃, and a 100 times smaller value from 100 ℃ onwards. Irreversible changes of σ were modeled using an Arrhenius model. We assumed that both tumor and healthy tissue had a different initial σ value (as suggested by the experimental data in the literature) and tended towards a common value as thermal damage progressed (necrotized tissue). We modeled a constant impedance protocol based on 90 V pulses voltage and three tumor diameters (2, 3 and 4 cm). Computer simulations showed that the differences between both models were only 0.1 and 0.2 cm for axial and transverse diameters, respectively, and this small difference was reflected in the similar temperature distributions computed by both models. In view of the available experimental data on changes of electrical conductivity in tumors and healthy tissue during heating, our results suggest that irreversible changes in electrical conductivity do not have a significant impact on coagulation zone size in two-compartment RFA models.

With the aging population, osteoporosis has become an important public health issue. The purpose of this study was to establish a two-compartment model (TCM) to quantify the volumetric bone mineral density (vBMD) of the lumbar spine using abdominal computed tomography (CT) images. The TCM approach uses water as the bone marrow equivalent and K2HPO4 solution as the cortical bone equivalent. A phantom study was performed to evaluate the accuracy of vBMD estimation at 100 kVp and 120 kVp. The data of 180 patients who underwent abdominal CT imaging and dual-energy X-ray absorptiometry (DXA) within one month were retrospectively collected. vBMD of L1–L4 vertebrae were calculated, and the receiver-operating characteristic curve analysis was performed to establish the diagnostic thresholds for osteoporosis and osteopenia in terms of vBMD. The average difference between the measured vBMD following TCM and the theoretical vBMD of the self-made phantom was 0.2%, and the maximum difference was 0.5%. vBMD of lumbar vertebrae obtained from TCM and aBMD obtained by DXA had a significant positive correlation (r = 0.655 to 0.723). The average diagnostic threshold for osteoporosis was 0.116 g/cm3. The sensitivity, specificity, and accuracy were 95.7%, 75.6.5%, and 80.0%, respectively. The average diagnostic threshold for osteopenia was 0.126 g/cm3. The sensitivity, specificity, and accuracy were 81.3%, 82.5%, and 82.7%, respectively. The aforementioned threshold values were used to perform the diagnostics on a test cohort, and the performance was equivalent to that in the experimental cohort. From the perspective of preventive medicine, opportunistic screening of bone mineral density using abdominal CT images and the TCM approach can facilitate early detection of osteoporosis and osteopenia and, with in-time treatment, slow down their progression.

The most aggressive tumor cells, which often reside in a hypoxic environment, can release vast amounts of lactate and protons via monocarboxylate transporters (MCTs). This additional proton efflux exacerbates extracellular acidification and supports the formation of a hostile environment. In the present study we propose a novel, data-based model for this proton-coupled lactate transport in cancer cells. The mathematical settings involve systems coupling nonlinear ordinary and stochastic differential equations describing the dynamics of intra- and extracellular proton and lactate concentrations. The data involve time series of intracellular proton concentrations of normoxic and hypoxic MCF-7 breast cancer cells. The good agreement of our final model with the data suggests the existence of proton pools near the cell membrane, which can be controlled by intracellular and extracellular carbonic anhydrases to drive proton-coupled lactate transport across the plasma membrane of hypoxic cancer cells.

Abstract Background The large potential of the soil organic carbon (SOC) pool to sequester CO2 from the atmosphere could greatly ameliorate the effect of future climate change. However, the quantity of carbon stored in terrestrial soils largely depends upon the magnitude of SOC mineralization. SOC mineralization constitutes an important part of the carbon cycle, and is driven by many biophysical variables, such as temperature and moisture. Methods Soil samples of a pine forest, an oak forest, and a pine and oak mixed forest were incubated for 387 days under conditions with six temperature settings (5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C) and three levels of soil moisture content (SMC, 30%, 60%, 90%). The instantaneous rate of mineralized SOC was periodically and automatically measured using a Li-Cor CO2 analyzer. Based on the measured amount of mineralized SOC, carbon fractions were estimated separately via first-order kinetic one- and two-compartment models. Results During the 387 day incubation experiment, accumulative mineralized carbon ranged from 22.89 mg carbon (C) ·g− 1 SOC at 30 °C and 30% SMC for the mixed forest to 109.20 mg C·g− 1 SOC at 15 °C and 90% SMC for the oak forest. Mineralized recalcitrant carbon varied from 18.48 mg C·g− 1 SOC at 30 °C and 30% SMC for the mixed forest to 104.98 mg C·g− 1 SOC at 15 °C and 90% SMC for the oak forest, and contributed at least 80% to total mineralized carbon. Conclusions Based on the results of this experiment, the soil organic matter of the pure broadleaved forest is more vulnerable to soil microbial degradation in northern China; most of the amount of the mineralized SOC derived from the recalcitrant carbon pool. Labile carbon fraction constitutes on average 0.4% of SOC across the three forest types and was rapidly digested by soil microbes in the early incubation stage. SOC mineralization markedly increased with soil moisture content, and correlated parabolically to temperature with the highest value at 15 °C. No significant interaction was detected among these variables in the present study.

Accurate prediction of blood toxin concentration during and after dialysis will greatly contribute to the determination of dialysis treatment conditions. Conventional models, namely single-compartment model and two-compartment model, have advantages and disadvantages in terms of accuracy and practical application. In this study, we attempted to derive the mathematical model that predicts blood toxin concentrations during and after dialysis, which has both accuracy and practicality. To propose the accurate model, a new two-compartment model was mathematically derived by adapting volume-averaging theory to the mass transfer around peripheral tissues. Subsequently, to propose a practical model for predicting the blood toxin concentration during dialysis, an analytical solution expressed as algebraic expression was derived by adopting variable transformation. Furthermore, the other analytical solution that predicts rebound phenomena after dialysis was also derived through similar steps. The comparisons with the clinical data revealed that the proposed analytical solutions can reproduce the behavior of the measured blood urea concentration during and after dialysis. The analytical solutions proposed as algebraic expressions will allow a doctor to estimate the blood toxin concentration of a patient during and after dialysis. The proposed analytical solutions may be useful to consider the treatment conditions for dialysis, including the rebound phenomenon.

Objectives: The purpose of this study was to develop a quantitative method for myocardial blood flow (MBF) measurement using contrast-enhanced multidetector computed tomography (MDCT) images with bolus tracking and helical scanning. Materials and Methods: Nine canine models of left anterior descending artery stenosis were prepared and underwent MDCT perfusion imaging during adenosine infusion to study a wide range of flow parameters. Neutron-activated microspheres were injected to document MBF during adenosine infusion. Six animals underwent dynamic MDCT perfusion imaging, and K1 and k2 (which represent the first-order transfer constants from left ventricular blood to myocardium and from myocardium to the vascular system, respectively) were measured using a two-compartment model. The results were compared against microsphere MBF measurements, and the extraction fraction (E) of contrast agent and the mean value of k1/k2 were calculated. Six animals then underwent helical CT perfusion imaging, and neutron-activated microspheres were injected to document MBF during adenosine infusion. For each animal, based on E, K1/k2, time-registered helical CT myocardial data, and arterial input function data, tables of myocardial CT values versus MBF were simulated for various MBF values to create look-up tables from the myocardial CT value to MBF. The CT-derived MBF values were compared against the microsphere MBF measurements. Results: A strong linear correlation was observed between the MDCT-derived MBF and the microsphere MBF (y = 1.065x – 0.616, R2 = 0.838). Conclusions: Regional MBF can be measured accurately using a combination of bolus tracking and time-registered helical CT data from contrast-enhanced MDCT scanning during adenosine stress.

Neural computation is performed by transforming input signals into sequences of action potentials (APs), which is metabolically expensive and limited by the energy available to the brain. The metabolic efficiency of single AP has important consequences for the computational power of the cell, which is determined by its biophysical properties and morphologies. Here we adopt biophysically-based two-compartment models to investigate how dendrites affect energy efficiency of APs in cortical pyramidal neurons. We measure the Na+ entry during the spike and examine how it is efficiently used for generating AP depolarization. We show that increasing the proportion of dendritic area or coupling conductance between two chambers decreases Na+ entry efficiency of somatic AP. Activating inward Ca2+ current in dendrites results in dendritic spike, which increases AP efficiency. Activating Ca2+-activated outward K+ current in dendrites, however, decreases Na+ entry efficiency. We demonstrate that the active and passive dendrites take effects by altering the overlap between Na+ influx and internal current flowing from soma to dendrite. We explain a fundamental link between dendritic properties and AP efficiency, which is essential to interpret how neural computation consumes metabolic energy and how biophysics and morphologies contribute to such consumption.

Given that the traditional methods of estimating pharmacokinetic parameters are constrained by the sensitivity of their initial value and incapability of evolutionary algorithm to determine search range, this paper proposes a hybrid invasive weed optimization (HIWO) algorithm by combining the Hooke-Jeeves (HJ) and invasive weed optimization (IWO) algorithm. Using the HIWO algorithm for the parameter optimization by the experiment of extravascular administration two-compartment model, we can see that the proposed method is not only better than traditional feathering method (FM) in terms of numerical stability, but also better than HJ and IWO in terms of error minimization. The experimental results show that HIWO algorithm is a feasible method to optimize the pharmacokinetic parameters, which has higher precision and stronger robustness than the other techniques. [ABSTRACT FROM AUTHOR]

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Disentangling the tissue microstructural information from the diffusion magnetic resonance imaging (dMRI) measurements is quite important for extracting brain tissue specific measures. The autocorrelation function of diffusing spins is key for understanding the relation between dMRI signals and the acquisition gradient sequences. In this paper, we demonstrate that the autocorrelation of diffusion in restricted or bounded spaces can be well approximated by exponential functions. To this end, we propose to use the multivariate Ornstein-Uhlenbeck (OU) process to model the matrix-valued exponential autocorrelation function of three-dimensional diffusion processes with bounded trajectories. We present detailed analysis on the relation between the model parameters and the time-dependent apparent axon radius and provide a general model for dMRI signals from the frequency domain perspective. For our experimental setup, we model the diffusion signal as a mixture of two compartments that correspond to diffusing spins with bounded and unbounded trajectories, and analyze the corpus-callosum in an ex-vivo data set of a monkey brain.

The in vivo performances of most drugs after extravascular administration are fitted well with the two-compartment pharmacokinetic (PK) model, but the estimation of absorption rate constant (k a ) for these drugs becomes difficult during unavailability of intravenous PK data. Herein, we developed a novel method, called the direct method, for estimating the k a values of drugs without using intravenous PK data, by proposing a new PK parameter, namely, maximum apparent rate constant of disposition (k max ). The accuracy of the direct method in k a estimation was determined using the setting parameters (k 12 , k 21 , and k 10 values at high, medium, and low levels, respectively) and clinical data. The results showed that the absolute relative error of k a estimated using the direct method was significantly lower than that obtained using both the Loo-Riegelman method and the statistical moment method for the setting parameters. Human PK studies of telmisartan, candesartan cilexetil, and tenofovir disoproxil fumarate indicated that the k a values of these drugs were accurately estimated using the direct method based on good correlations between the k a values and other PK parameters that reflected the absorption properties of drugs in vivo (T max , C max , and C max /AUC 0-t ). This novel method can be applied in situations where intravenous PK data cannot be obtained and is expected to provide valuable support for PK evaluation and in vitro-in vivo correlation establishment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Yi, Wang, Cheng and Zhang.)

This work is the first report on the dissipation and final residue of cloransulam-methyl on soybean plant at field conditions. A fast, simple, and reliable residue analytical method for determination of cloransulam-methyl in soybean matrices and soil was developed based on quick, easy, cheap, effective, rugged, and safe (QuEChERS) sample preparation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection. The average recoveries of cloransulam-methyl in soybean matrices and soil ranged from 80 to 105 %, with RSDs between 3-11%. The limit of detection (LOD) was 0.001 mg kg-1 for soybean grain, plant, and soil and was 0.005 mg kg-1 for soybean straw. This method was then used to characterize dissipation of cloransulam-methyl in soybeans and soil from three locations in China for the first time. Cloransulam-methyl dissipated quickly in soybean plant with half-lives (T1/2) of 0.21-0.56 days. The dissipation dynamic in soil was characterized using both first-order kinetics model and two-compartment model, and the half-lives were similar, ranging from 0.44 to 5.53 days at three experimental sites in 2012 and 2013. The final residue data showed a very low level of cloransulam-methyl in soil (≤0.026 mg kg-1), soybean grain (≤0.001 mg kg-1), and straw (≤0.005 mg kg-1) samples at harvest time. With the faster and simple analytical method on soybean and soil, rapid dissipation of cloransulam-methyl was observed at three geospatial locations in China, and the terminal residue levels were negligible, so mammalian ingestion exposure is minimal. [ABSTRACT FROM AUTHOR]

Recent studies show that naïve T cells bearing identical T cell receptors experience heterogeneous differentiation and clonal expansion processes. The factors controlling this outcome are not well characterized, and their contributions to immune cell dynamics are similarly poorly understood. In this study, we develop a computational model to elaborate mechanisms occurring within and between two important physiological compartments, lymph nodes and blood, to determine how immune cell dynamics are controlled. Our multi-organ (multi-compartment) model integrates cellular and tissue level events and allows us to examine the heterogeneous differentiation of individual precursor cognate naïve T cells to generate both effector and memory T lymphocytes. Using this model, we simulate a hypothetical immune response and reproduce both primary and recall responses to infection. Increased numbers of antigen-bearing dendritic cells (DCs) are predicted to raise production of both effector and memory T cells, and distinct "sweet spots" of peptide-MHC levels on those DCs exist that favor CD4+ or CD8+ T cell differentiation toward either effector or memory cell phenotypes. This has important implications for vaccine development and immunotherapy. [ABSTRACT FROM AUTHOR]

Aim: The study was designed to establish relationship between the plasma concentration and QTc interval prolonging effect of fexofenadine and demonstrate the phenomenon of anticlockwise hysteresis. Materials and Methods: Six subjects were given fexofenadine 60 mg tablet orally under stable conditions, and their drug concentrations were measured at regular intervals. At predetermined time, their ECGs were recorded. Data were analyzed and plotted graphically. Design and Setting: Randomized parallel design, single group study conducted at clinical research organization of Ahmadabad. Results: In all subjects time taken for maximum plasma concentration of fexofenadine (Tmax) was around 3 h and the value of average maximum plasma concentration was 460.63 ng/mL, the effect of fexofenadine on the heart (measured as QTc interval prolongation) was maximum (Emax) after 6 h and average QTc interval was 469.75 ms. Thus, the time to maximum concentration of fexofenadine did not match with the maximum effect on the heart as measured by QTc interval. Conclusion: The relationship between the drug concentration and drug effect on the heart are at two different time scales. It can be understood by two-compartment model of pharmacokinetics, and this retardation or lagging of an effect behind the concentration is known as hysteresis. The increase of QTc was not beyond 500 ms and not sustained, demonstrating overall cardiac safety of fexofenadine. [ABSTRACT FROM AUTHOR]

Pulse dye densitometry (PDD) enables the evaluation of hemodynamic state as well as liver function. A repeated examination, even after a short pause (or under stress condition), enables to follow safely the dynamics of liver pathology. From presented parameters we have evaluated as reliable the C5-clearance, an expression of equilibrium state in the two compartment liver system. Furthermore, T-index expresses ratio of C5 value to cardiac output, it is a sensitive indicator of the blood pole, i.e. sinusoidal uptake, which is in very good correlation with staging of hepatopathies. The isolated h constant in correlation to T-index is valuable For functional grading. The Japanese automatic analyzer of indocyanine green (ICG) dilution and elimination curves, after incorporation of a two compartment mathematical model, becomes more useful for complex hepatological diagnostics. Non-invasive PDD is becoming of uppermost importance to clinical interest, yielding comparable results as other complicated and invasive examinations and may be, therefore, repeated in short time intervals for different indications with minimal stress of examined patient. [ABSTRACT FROM AUTHOR]

The alpine regions of Austria were among the most contaminated territories outside of the former USSR after the Chernobyl accident. In the investigated province of Salzburg the median 137Cs surface deposition was 31.4kBqm−2 with maximum values exceeding 90kBqm−2 (May 1986). To quantify the transfer of 137Cs and 90Sr from vegetation to milk in these seminatural conditions nine seasonally grazed alps were identified and vegetation and milk sampled during summer 2002 and summer 2003. Mean±SD milk transfer coefficients (fm) for 137Cs and 90Sr were 0.0071±0.0009dl−1, and 0.0011±0.0004dl−1, respectively; which for 137Cs is markedly higher than those fm values found in intensive agricultural systems. Transfer kinetics for 137Cs into cow milk were approximated using a 2-compartment model with a short and a long-term component. Fitting the model to empirical data results in reliable estimates of the time constant of the short-term component, biological half-life 1.06±0.28d, whereas the estimates of the long-term component are subject to high uncertainties. [Copyright &y& Elsevier]

We analyze data on the impact of testosterone on the dynamics of Mn2+ accumulation measured by magnetic resonance imaging in three songbird brain areas: the nucleus robustus arcopallii (RA), area X, and the high vocal center (HVC). Birds with and without testosterone were included in the experiment, and repeated measurements were available in both a preand post-drug administration period. We formulate a nonlinear modeling strategy, allowing for the incorporation of (1) within-bird correlation, (2) the nonlinearity of the profiles, and (3) the effect of treatment. For two of the outcomes (RA and area X), biological theory suggests a parametric form, but for HVC this is not the case. Because the HVC outcome bears some resemblance with the two-compartment model known from pharmacokinetics, this model was considered a sensible choice. We use a different model, based on fractional polynomials, as a sensitivity analysis for the latter. All methods used provide good fits to the data, confirm results from previous, simple analyses undertaken in the literature, but were able to detect additional effects of treatment that had so far gone undetected. The fractional polynomial and two-compartment models provide similar substantive conclusions; the two together can be seen as a form of sensitivity analysis. [ABSTRACT FROM AUTHOR]

We propose a population pharmacokinetic (PK) model with time-dependent covariates measured with errors. This model is used to model S-oxybutynin's kinetics following an oral administration of Ditropan, and allows the distribution rate to depend on time-dependent covariates blood pressure and heart rate, which are measured with errors. We propose two two-step estimation methods: the second-order two-step method with numerical solutions of differential equations (2orderND), and the second-order two-step method with closed form approximate solutions of differential equations (2orderAD). The proposed methods are computationally easy and require fitting a linear mixed model at the first step and a nonlinear mixed model at the second step. We apply the proposed methods to the analysis of the Ditropan data, and evaluate their performance using a simulation study. Our results show that the 2orderND method performs well, while the 2orderAD method can yield PK parameter estimators that are subject to considerable biases. [ABSTRACT FROM AUTHOR]

Accurate prediction of blood toxin concentration during and after dialysis will greatly contribute to the determination of dialysis treatment conditions. Conventional models, namely single-compartment model and two-compartment model, have advantages and disadvantages in terms of accuracy and practical application. In this study, we attempted to derive the mathematical model that predicts blood toxin concentrations during and after dialysis, which has both accuracy and practicality. To propose the accurate model, a new two-compartment model was mathematically derived by adapting volume-averaging theory to the mass transfer around peripheral tissues. Subsequently, to propose a practical model for predicting the blood toxin concentration during dialysis, an analytical solution expressed as algebraic expression was derived by adopting variable transformation. Furthermore, the other analytical solution that predicts rebound phenomena after dialysis was also derived through similar steps. The comparisons with the clinical data revealed that the proposed analytical solutions can reproduce the behavior of the measured blood urea concentration during and after dialysis. The analytical solutions proposed as algebraic expressions will allow a doctor to estimate the blood toxin concentration of a patient during and after dialysis. The proposed analytical solutions may be useful to consider the treatment conditions for dialysis, including the rebound phenomenon. [ABSTRACT FROM AUTHOR]

Nanoparticles (NPs) can significantly influence toxicity imposed by toxic metals. However, this impact has not been quantified. In this research, we investigated the effect of nano-TiO 2 on lead (Pb) accumulation and the resultant toxicity using water flea Ceriodaphnia dubia (C. dubia) as the testing organism. We used a two-compartment modeling approach, which included a two-compartment accumulation model and a toxicodynamic model, on the basis of Pb body tissue accumulation, to quantify the impact of nano-TiO 2 on Pb toxicity. The effect of algae on the combined toxicity of Pb and nano-TiO 2 was also quantified. The two-compartment accumulation model could well quantify Pb accumulation kinetics in two-compartments of C. dubia , the gut and the rest of the body tissue in the presence of nano-TiO 2. Modeling results suggested that the gut quickly accumulates Pb through active uptake from the mouth, but the rest of the body tissue slowly accumulates Pb from the gut. The predicted Pb distribution within C. dubia was verified by depuration modeling results from an independent depuration test. The survivorship of C. dubia as a function of Pb accumulated in the body tissue and exposure time can be well described using a toxicodynamic model. The effects of algae on Pb accumulation in different compartments of C. dubia and the toxicity in the presence of nano-TiO 2 were also well described using the two-compartment modeling approach. Therefore, the novel two-compartment modeling approach provides a useful tool for assessing the effect of NPs on aquatic ecosystems where toxic metals are present. Image 1 • Nano-TiO 2 enhanced Pb body tissue accumulation in C. dubia through mouth ingestion. • A two-compartment model was developed to quantify Pb body tissue accumulation. • The Pb body tissue accumulation results in the toxicity of Pb. • A toxicodynamic model could link Pb toxicity with the body tissue accumulation. • Algae reduced Pb toxicity by reducing body tissue accumulation and the killing rate. [ABSTRACT FROM AUTHOR]

The objective was to explore variations of temperature distribution and coagulation zone size computed by a two-compartment radiofrequency ablation (RFA) model when including simultaneously reversible changes in the tissue electrical conductivity (σ) due to temperature and irreversible changes due to thermal coagulation. Two-compartment (tumor and healthy tissue) models were built and simulated. Reversible change of σ was modeled by a piecewise function characterized by increments of +1.5%/℃ up to 100 ℃, and a 100 times smaller value from 100 ℃ onwards. Irreversible changes of σ were modeled using an Arrhenius model. We assumed that both tumor and healthy tissue had a different initial σ value (as suggested by the experimental data in the literature) and tended towards a common value as thermal damage progressed (necrotized tissue). We modeled a constant impedance protocol based on 90 V pulses voltage and three tumor diameters (2, 3 and 4 cm). Computer simulations showed that the differences between both models were only 0.1 and 0.2 cm for axial and transverse diameters, respectively, and this small difference was reflected in the similar temperature distributions computed by both models. In view of the available experimental data on changes of electrical conductivity in tumors and healthy tissue during heating, our results suggest that irreversible changes in electrical conductivity do not have a significant impact on coagulation zone size in two-compartment RFA models.

Our study of drug-drug interaction (DDI) started with the clarification of unusually large DDI observed between ramelteon (RAM) and fluvoxamine (FLV). The main cause of this DDI was shown to be the extremely small hepatic availability of RAM (vF h ). Traditional DDI prediction assuming the well-stirred hepatic extraction kinetic ignores the relative increase of vF h by DDI, while we could solve this problem by use of the tube model. Ultimately, we completed a simple and useful method for prediction of DDI. Currently, DDI prediction becomes more complex and difficult when examining issues such as dynamic changes in perpetrator level, inhibitory metabolites, etc. The regulatory agents recommend DDI prediction by use of some sophisticated methods. However, they seem problematic in requiring plural in vitro data that reduce the flexibility and accuracy of the simulation. In contrast, our method is based on the static and two-compartment models. The two-compartment model has advantages in that it uses common pharmacokinetics (PK) parameters determined from the actual clinical data, guaranteeing the simulation of the reference standard in DDI. Our studies confirmed that dynamic changes in perpetrator level do not make a difference between static and dynamic methods. DDIs perpetrated by FLV and itraconazole were successfully predicted by use of the present method where two DDI predictors [perpetrator-specific inhibitory activities toward CYP isoforms (pA i, CYP s) and victim-specific fractional CYP-isoform contributions to the clearance (vf m, CYP s)] are determined successively as shown in the graphical abstract. Accordingly, this approach will accelerate DDI prediction over the traditional methods.