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Pyramidal neurons in the electrosensory lateral line lobe (ELL) of weakly electric fish activate in an environment of time-varying electric fields, which are generated by the fish itself, while how these pyramidal neurons would behave or what kinds of firing patterns these neurons would produce under different electric fields is still unclear. In this research, the firing behaviors of ELL pyramidal neuron under DC and AC electric field stimulus are investigated in a two-compartment neuron model. By means of numerical simulations we show that firing patterns of the model ELL pyramidal neuron are much diverse under different values of DC electric field, and neuronal spike frequency exhibits a monotone decreasing trend with the linearly increased DC fields, moreover, the transition mode between these firing patterns with the variation of DC electric fields demonstrates an explicit periodic route. While for AC electric fields, neuronal firing frequency periodically transforms with the increase of AC frequency, particularly, a special transition pattern (from multi-period bursting to spiking) repeatedly appears with the change of AC frequency. Our simulation results indicate that ELL pyramidal neurons fire dynamically under the time-varying electric fields, the diversity of firing patterns and their periodic transition modes may imply the potential roles of these dynamical firings in the coding strategy of sensory information processing. [ABSTRACT FROM AUTHOR]

Purpose: To investigate blood to tissue water transfer in human brain, in vivo and spatially resolved using a T2-based arterial spin labeling (ASL) method with 3D readout. Materials and Methods: A T2-ASL method is introduced to measure the water transfer processes between arterial blood and brain tissue based on a 3D-GRASE (gradient and spin echo) pulsed ASL sequence with multiecho readout. An analytical mathematical model is derived based on the General Kinetic Model, including blood and tissue compartment, T1 and T2 relaxation, and a blood-to-tissue transfer term. Data were collected from healthy volunteers on a 3 T system. The mean transfer time parameter Tbl→ex (blood to extravascular compartment transfer time) was derived voxelwise by nonlinear least-squares fitting. Results: Whole-brain maps of Tbl→ex show stable results in cortical regions, yielding different values depending on the brain region. The mean value across subjects and regions of interest (ROIs) in gray matter was 440 ± 30 msec. Conclusion: A novel method to derive whole-brain maps of blood to tissue water transfer dynamics is demonstrated. It is promising for the investigation of underlying physiological mechanisms and development of diagnostic applications in cerebrovascular diseases. J. Magn. Reson. Imaging 2013;37:332-342. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

An MR image-based computational model of a murine KHT sarcoma is presented that allows the calculation of plasma fluid and solute transport within tissue. Such image-based models of solid tumors may be used to optimize patient-specific therapies. This model incorporates heterogeneous vasculature and tissue porosity to account for nonuniform perfusion of an MR-visible tracer, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was conducted following intravenous infusion of Gd-DTPA to provide 1 h of tracer-concentration distribution data within tissue. Early time points (19 min) were used to construct 3D K and porosity maps using a two-compartment model; tracer transport was predicted at later time points using a 3D porous media model. Model development involved selecting an arterial input function (AIF) and conducting a sensitivity analysis of model parameters (tissue, vascular, and initial estimation of solute concentration in plasma) to investigate the effects on transport for a specific tumor. The developed model was then used to predict transport in two additional tumors. The sensitivity analysis suggests that plasma fluid transport is more sensitive to parameter changes than solute transport due to the dominance of transvascular exchange. Gd-DTPA distribution was similar to experimental patterns, but differences in Gd-DTPA magnitude at later time points may result from inaccurate selection of AIF. Thus, accurate AIF estimation is important for later time point prediction of low molecular weight tracer or drug transport in smaller tumors. [ABSTRACT FROM AUTHOR]

Abstract: In this work the existence of a global attractor is proved for the solution semiflow of the coupled two-compartment Gray–Scott equations with the homogeneous Neumann boundary condition on a bounded domain of space dimension . The grouping estimation method combined with a new decomposition approach is introduced to overcome the difficulties in proving the absorbing property and the asymptotic compactness of this four-component reaction–diffusion systems with cubic autocatalytic nonlinearity and linear coupling. The finite dimensionality of the global attractor is also proved. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate in a two-compartment heterogeneous mechanical model of the lung how different loads applied to one compartment, while the other is kept constant, would modify gas distribution between the two pathways under high-frequency percussive ventilation (HFPV). Additionally, these results were compared with those generated in the same model by pressure-controlled ventilation (PCV). Methods: Analysis was based on a Siemens lung simulator, representing a fixed branch of the system with an elastance equal to 45 cmHO/L and a resistance of 20 cmHO/L/s, and a single-compartment lung simulator, representing a variable pathway of the model, presenting three elastic loads varying between 35 and 85 cmHO/L and three resistive loads varying between 5 and 50 cmHO/L/s. Each simulator represented one compartment of the model connected to a central airway that was ventilated with either a volumetric diffusive respirator (VDR-4; Percussionaire Corporation, Sandpoint, ID, USA) or a Siemens Servo 900c ventilator. Flow and pressures were measured in each branch of the model under nine conditions representing the combinations of three elastic and three resistive loads (variable branch) while the loads in the other pathway were kept constant. Results: HFPV was able to avoid hyperinflation and reduce tidal volume in a bicompartmental heterogeneous lung model. Under HFPV, gas distribution between the two compartments was not constrained by their time constants. PCV yielded gas distribution as determined by the time constant of each compartment. Conclusions: HFPV accommodated volume distribution without overinflating compartments with low time constants, thus possibly presenting a potential protective behavior in mechanically heterogeneous lungs. [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]

Abstract: Introduction: No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69mg THC). Methods: Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3mg, 49.1mg, and 69.4mg THC. Blood samples were collected over a period of 0–8h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Results: Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were C max =175ng/mL, T max =14min, and AUC0–8h =8150ng×min/mL for the 69.4mg THC dose. Median model results show an almost linear dose response relation for C max/Dose=2.8×10−6/mL and AUC0–8h/Dose=136×10−6 min/mL. However, for increasing dose level, there was a clear decreasing trend: C max/Dose=3.4, 2.6 and 2.5×10−6/mL and AUC0–8h/Dose=157, 133 and 117×10−6 min/mL for the 29.3, 49.1 and 69.4mg dose, respectively. Within the restriction of 8h of observation, the apparent terminal half life of THC was 150min. Conclusion: The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8h after smoking cannabis with a high THC content (up to 23%). [ABSTRACT FROM AUTHOR]

There are two prominent features for place cells in rat hippocampus. The firing rate remarkably increases when rat enters the cell’s place field and reaches a maximum around the center of place field, and it decreases when the animal approaches the end of the place field. Simultaneously the spikes gradually and monotonically advance to earlier phase relative to hippocampal theta rhythm as the rat traverses along the cell’s place field, known as temporal coding. In this paper, we investigate whether two main characteristics of place cell firing are independent or not by mainly focusing on the generation mechanism of the unimodal tuning of firing rate by using a reduced CA1 two-compartment neuron model. Based on recent evidences, we hypothesize that the coupling of dendritic with the somatic compartment is not constant but dynamically regulated as the animal moves further along the place field, in contrast to previous two-compartment modeling. Simulations show that the regulable coupling is critically responsible for the generation of unimodal firing rate profile in place cells, independent of phase precession. Predictions of our model accord well with recent observations like occurrence of phase precession with very low as well as high firing rate (Huxter et al. Nature 425:828–832, 2003) and persistency of phase precession after transient silence of hippocampus activity (Zugaro et al. Nat Neurosci 8:67–71, 2005. [ABSTRACT FROM AUTHOR]

Based on the semi-static two compartment model, the bioaccumulation and elimination of zinc by tissues of Styela clava were investigated, the kinetic parameters of accumulation rate constant k1, elimination rate constant k2, bioconcentration factor FBC, biological half life B1/2 and the maximum equilibrium concentration QAmax were obtained by non-linear regression. The results show that zinc can be accumulated by S. clava from aquatic environment. FBC decreases with the increasing metal concentration in water, and when the accumulation achieves balance, QAmax shows positive correlation to metal concentrations in water. Concentrations of zinc in different tissues of S. clava are listed as: gonad > digestive gland > other part > crust. B1/2 of zinc is 11.36 - 23.98 d in the phase of elimination. Zn can be accumulated in gonad of S. clava largely and the digestive gland can be used to monitor the pollution of zinc in sea water. [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]

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In this study, crucian carp (Carassius auratus) was exposed to graded levels of waterborne Cr6+ (0, 0.1, 1 and 10 mg/L) for 28 days and subsequently transferred to clean water for 20 days. Fish tissues were collected every 4 days. The Cr6+ levels in tissues were determined and the potential health risks from consuming fish muscle and fish head were assessed. The results indicated that the Cr6+ contents in the head were always higher than those in muscle and that 10 mg/L Cr6+ treatment conferred risk in fish head consumption throughout the entire experimental period. A further kinetic study on the accumulation and depuration of Cr6+ in tissues indicated that compared to muscle, the higher Cr6+ content in fish head was attributed to the greater uptake rate (k 1) and kinetic bioconcentration factor (BCF k), although the k 1 and BCF k values in the muscle and head were lower than those in the liver, kidney, intestines and gills. The maximum Cr6+ concentrations in tissues at theoretical equilibrium (C max) ranged from 0.55 mg/kg in muscle to 112 mg/kg in intestines with exposure to 10 mg/L Cr6+. Moreover, the results of the distributions and transitions of Cr6+ in fish tissues demonstrated that fish head and muscle were short-term storage organs while the kidney was a long-term storage organ for Cr6+. Overall, compare to muscle, fish head has a higher capacity for Cr6+ accumulation, which poses a higher potential health risk to humans, especially to children, once the fish is contaminated by Cr6+. • The kinetics of Cr6+ in fish tissues were studied using a two-compartment model. • Fish head has a higher uptake rate for Cr6+ than that in fish muscle. • The relative burdens of Cr6+ in fish tissues were firstly reported. • Fish head and muscle could be short-term storage organs of Cr6+. • Kidney could be a long-term storage organ of Cr6+. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this study was to compare histologically determined cellularity and extracellular space to dynamic contrast-enhanced magnetic resonance imaging (DCE MRI)-based maps of a two-compartment model''s parameters describing tumor contrast agent extravasation, specifically tumor extravascular extracellular space (EES) volume fraction (v e), tumor plasma volume fraction (v p) and volume-normalized contrast agent transfer rate between tumor plasma and interstitium (K TRANS/V T). Materials and Methods: Obtained v e, v p and K TRANS/V T maps were estimated from gadolinium diethylenetriamine penta-acetic acid DCE T 1-weighted gradient-echo images at resolutions of 469, 938 and 2500 μm. These parameter maps were compared at each resolution to histologically determined tumor type, and the high-resolution 469-μm maps were compared with automated cell counting using Otsu''s method and a color-thresholding method for estimated intracellular (V intracellular) and extracellular (V extracellular) space fractions. Results: The top five K TRANS/V T values obtained from each tumor at 469 and 938 μm resolutions are significantly different from those obtained at 2500 μm (P<.0001) and from one another (P=.0014). Using these top five K TRANS/V T values and the corresponding tumor EES volume fractions v e, we can statistically differentiate invasive ductal carcinomas from noninvasive papillary carcinomas for the 469- and 938-μm resolutions (P=.0017 and P=.0047, respectively), but not for the 2500-μm resolution (P=.9008). The color-thresholding method demonstrated that v e measured by DCE MRI is statistically similar to histologically determined EES. The V extracellular obtained from the color-thresholding method was statistically similar to the v e measured with DCE MRI for the top 10 K TRANS/V T values (P>.05). DCE MRI-based K TRANS/V T estimates are not statistically correlated with histologically determined cellularity. Conclusion: DCE MRI estimates of tumor physiology are a limited representation of tumor histological features. Extracellular spaces measured by both DCE MRI and microscopic analysis are statistically similar. Tumor typing by DCE MRI is spatial resolution dependent, as lower resolutions average out contributions to voxel-based estimates of K TRANS/V T. Thus, an appropriate resolution window is essential for DCE MRI tumor diagnosis. Within this resolution window, the top K TRANS/V T values with corresponding v e are diagnostic for the tumor types analyzed in this study. [Copyright &y& Elsevier]

Pharmacokinetic studies of high-dose treosulfan were carried out in seven paediatric patients (age range: 2–15 years) undergoing treosulfan-based conditioning regimen prior to allogeneic haematopoietic SCT. Treosulfan was administered intravenously in a daily dose of 10, 12 or 14 g/m2 within 2 h. Five out of seven patients received 12 g/m2. The plasma concentrations of treosulfan and its quantity eliminated with urine were determined using a validated HPLC method with refractometric detection. Pharmacokinetic parameters were evaluated following first dose using a two-compartment disposition model. These studies demonstrated a dose-dependent increase of area under the concentration (AUC) and maximum concentrationplasma (Cmax), but there was variability of these parameters. Rapid clearance of tresoulfan was observed, especially in 10 and 12 g/m2 doses. Terminal half-life (t0.5) of treosulfan was in the range of 1.71–2.15 h, but the mean percent of parent drug eliminated with urine was 30%, range 16.3–45.4% of the total dose eliminated during the first 12 h after administration. The results of this study confirmed the linear pharmacokinetics of treosulfan, as used in children. However, variability of pharmacokinetic results observed in children studied demonstrates the need for pharmacokinetic evaluation in each paediatric patient undergoing the treosulfan-based preparative regimen, including those using different doses. This approach could enable further reduction of the risk of early and late organ toxicity related to high-dose treosulfan in paediatric patients.Bone Marrow Transplantation (2008) 42, S67–S70; doi:10.1038/bmt.2008.287 [ABSTRACT FROM AUTHOR]

Two forms of regional chemotherapy for the treatment of advanced melanoma or sarcoma of the extremity are isolated limb perfusion (ILP) and the more recently described isolated limb infusion (ILI). Melphalan is the most commonly employed agent in both ILP and ILI, although it is often used in conjunction with other cytotoxic and/or biologic therapies. While ILP and ILI are far more effective for the treatment of extremity disease than is systemic therapy, there is still significant room for improvement in outcomes, from the standpoint of both response rate and toxicity. An understanding of the pharmacokinetics of regional chemotherapy would allow for the prediction of tumor response and toxicity and therefore patient outcomes. In addition, elucidating the mechanisms of drug resistance would lead to opportunities to develop effective chemo-modulators that enhance the effectiveness of ILP and ILI. This paper reviews progress in these two key areas of active investigation. [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]

Abstract: During competitive hybridization the specific and non-specific fractions of tested biomolecules in solution bind jointly with the specific probes immobilized in a separate cell of a microchip. The application of two-compartment model to the two-component hybridization allows analytically investigating the underlying kinetics. It is shown that the behaviour with the non-monotonous growth of complexes formed by the non-specific fraction on a probe cell is a typical feature of competitive hybridization for both diffusion-limited and reaction-limited kinetics. The physical reason behind such an evolution consists in the fact that the characteristic hybridization time for the perfect complexes turns out longer with respect to that for the mismatch complexes. This behaviour should be taken into account for the choice of optimum hybridization and washing conditions for the analysis of specific fraction. [Copyright &y& Elsevier]

Abstract: The therapeutic activity and toxicity of drugs often depends on the accumulation of drugs in the peripheral anatomical compartment rather than the central compartment. In the routine practice of therapeutic drug monitoring (TDM) and pharmacokinetic studies, drug concentration determined by intermittent blood sampling is used as a surrogate for calculating the drug concentration in the peripheral compartment tissues. Microdialysis, a relatively less invasive procedure, has been used for estimation of free drug levels in dermal, subcutaneous and muscle tissues. Transcutaneous extraction of drugs from the dermal tissue is a good noninvasive alternative to phlebotomy and microdialysis. This requires a technique, which can facilitate the extraction of significant and reproducible amounts of drugs from the dermal extracellular fluid (ECF) within a short sampling duration. In the present work, we assessed the feasibility of electroporation and transcutaneous extraction (ETE) method for determining the time course of drugs in dermal ECF, using salicylic acid (SA) as a test drug. Electroporation protocol was optimized based on the in vitro diffusion studies of salicylic acid across rat skin. The concentration-time profile of total SA was determined in rats after a single i.v. bolus administration. The in vivo permeability coefficient (P in vivo) of rat skin was determined under steady state plasma concentration of drug created by i.v. bolus followed by constant rate infusion of SA. The pharmacokinetic parameters of the drug were determined using a two-compartment pharmacokinetic model. The theoretical predicted time course of free SA in the dermal ECF after a single i.v. bolus administration was calculated using standard formulae. The concentration of free SA determined by ETE is in good agreement with that calculated using two-compartment pharmacokinetic model. This study thus provides a credible evidence for the validity of ETE technique for determining the concentration of SA in the dermal ECF. [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]

The development of arterial spin labeling (ASL) techniques has provided a useful strategy for quantitative measurement of cerebral blood flow (CBF). However, quantification of transit time has historically been difficult to achieve without prolonged scan times, since ASL has suffered from low signal-to-noise ratio (SNR). Continuous ASL (CASL) has recently been implemented on the 3T magnetic resonance (MR) system, which can provide a more favorable perfusion signal SNR because of the higher Lamor frequency and prolonged T1 times. Therefore, the goal of the present study was to determine whether CASL perfusion imaging on the 3T MR system could evaluate transit time within a reasonable scan time. This study describes a theoretical framework for measuring arterial transit time using a two-compartment model, followed by application of the model to CASL perfusion data obtained from six normal subjects. CBF and arterial arrival time maps were successfully created using a two-parameter fitting procedure, and the transit time obtained with this model was consistent with those obtained from previous reports. However, the CBF values calculated with the present model were lower than those reported when using 1.5T. Possible reasons for this discrepancy, including transit time, CBV, label efficiency and MT effect, are discussed. [Copyright &y& Elsevier]

We describe experimental apparatus, methodology and mathematical algorithms to measure diffusion and partition for typical small ionic solutes and inulin (a medium size solute) in statically loaded cartilage. The partition coefficient based on tissue water (KH2O) of Na+ increased from 1.8 to 4.5 and for SO4−2 decreased from 0.5 to 0.1, when the applied presure was raised from zero to 22 atm KH2O of inulin decreased from 0.3 to 0.05, for an increase in pressure from zero to 11 atm. Our theoretical interpretation of the results is that the partition coefficient can be expressed as a function of fixed charge density (FCD) for both loaded and unloaded cartilage. The partition coefficient shows good agreement with the ideal Gibbs–Donnan equilibrium, particularly when FCD is based on extrafibrillar water (EFW). The diffusion coefficients, D¯ also decreased with an increase in applied pressure; raising the pressure from 0 to 22 atm resulted in the following changes in the values of D¯: for Na+ from 2.86×10−6 to 1.51×10−6 cm2/s, for SO4−2 from 1.58×10−6 to 7.5×10−7 cm2/s, for leucine from 1.69×10−6 to 8.30×10−7 cm2/s and for inulin from 1.80×10−7 to 3.30×10−8 cm2/s. For the three small solutes (two charged and one neutral) the diffusion coefficient D¯ is highly correlated with the fraction of fluid volume in the tissue. These experimental results show good agreement with the simple model of Mackie and Meares: hence solute charge does not affect the diffusion of small solutes under load. For inulin D¯ & K show some agreement with a modified Ogston model based on two major components, viz., glycosaminoglycans (GAG) and core protein. We conclude that the changes in the partition and diffusion coefficients of small and medium size solutes in statically loaded cartilage can be interpreted as being due to the reduction in hydration and increase in FCD. The change in the latter affects the partition of small ionic solutes and the partition and diffusion of larger molecules. Our results throw light on the ionic environment of chondrocytes in loaded cartilage as well as on the transport of solutes through the matrix. [Copyright &y& Elsevier]

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]

Magnani et al. (Planta 199, 296–306, 1996) have described a model of the root in which apoplastic transport of water occurs in the older (basal) regions, and intercellular transport occurs in the younger (apical) regions. They tested this model by performing pressure-clamp experiments on excised root systems, and found that their model gave a good fit to the data. In the present study, their model is extended to include solute transport across an apical root ‘membrane’, with reflection coefficient, σ. When σ = 1 (i.e. no apoplastic transport across the root membrane) the model yields solutions for the volume flow rate that are identical in form to those of Magnani et al. (1996). Hence, given that their solutions provide a good description of the data, it seems possible to explain these data without invoking apoplastic water transport in the apical zone. For σ < 1, the predicted behaviour is more complex. It is concluded that the analysis of Magnani et al. (1996) overestimates the apoplastic hydraulic conductance of the basal zone (which could, in principle, be zero), and underestimates the intercellular hydraulic conductance of the apical zone. The magnitude of these errors depends on the solute permeability of the apical root membrane. The analysis suggests that solute transport parameters should be included in models of water transport across plant roots, even when σ ≈ 1. For the exosmotic pressure clamp, this is emphasized by considering the case where σ = 1, and the basal region is replaced with a chamber filled with water. Under this regime, the volume-relaxation time constant does not depend on the membrane hydraulic conductance, but is determined by the solute permeability. [ABSTRACT FROM AUTHOR]

1. It has previously been shown that perfusion with high O2-affinity-erythrocytes decreases venous PO2 (PVO2) and decreases O2 uptake (V.O2) in contracting muscle at the same O2 delivery (arterial O2 concentration × flow). A linear V.O2–PVO2 relationship has been obtained with a V.O2-axis intercept, suggesting that, during this type of hypoxia, V.O2 is composed of a PVO2-dependent and -independent V.O2. However, the V.O2– PVO2 relation during hypoxic hypoxia has not been examined. 2. To clarify this relation, PVO2 and V.O2 have been measured in contracting gastrocnemius (1 Hz trains of 0.2 s isometric tetani) under both normoxic and hypoxic conditions during 5 min of stimulation. 3. Venous O2 changes proportionally with O2 delivery. Each V.O2–PVO2 relation was linear, with the mean described by the equation V.O2 = 5.06 + 0.41 × PVO2 (n = 6, r = 0.81, P < 0.05). The V.O2-axis intercept was significantly different from zero (P < 0.05). 4. These results were similar to those obtained during hypoxia induced by high O2-affinity-erythrocytes. We conclude that there is a linear relationship between PVO2 and V.O2 above the V.O2-axis intercept, regardless of the type of hypoxia. [ABSTRACT FROM AUTHOR]

The area function method for assessing zero-order ( k) drug absorption rates was compared to four other methods under conditions where variation occurs in the plasma concentration data and in the elimination rate constant ( k or k) for one- or two-compartment models. For deviant k values of a one-compartment model, the most accurate recovery of k occurred with the area function method and nonlinear least-squares regression, followed by the Wagner-Nelson and moment analysis methods. With deviant k values for a two-compartment model, the order of superiority of the methods was: area function ≈ nonlinear regression > Loo-Riegelman > moment analysis. Moment analysis should generally be reserved for use as an estimation rather than calculation technique. The area function procedure offers particular advantages in ease of data analysis and accuracy of recovered parameters. [ABSTRACT FROM AUTHOR]

Blood has been considered as a simplified tissue model, both physiologically and physically consisting in two compartments, extra-cellular and intra-cellular. In the physiologic condition (300 mOsm), the relaxation rates of red cell suspensions in saline increased linearly with the hematocrit in the range 0–0.80 according to Fullerton's model of fast proton exchanges between the two compartments (Fullerton GD, Potter JL, Dornbluth NC. NMR relaxation of protons in tissues and other macromolecular water solutions. Magn Reson Imaging 1982;1:209–228). In experiments of osmotic variations, between 200 and 900 mOsm at three constant red cell numbers in the samples, non-linear variations of relaxation rates with red cell volume were observed. In the hyperosmotic domain, the particularly high increase in blood transverse relaxation rate with the decreasing cell volume has been attributed to the progressive water-protein organization in the cellular compartment. A generalised form of the fast exchange model has been applied to extended experimental conditions of red cells, by introducing the red cell volume ratio of modified to iso-osmotic values, and the volume fraction of iso-osmotic red cells. [ABSTRACT FROM AUTHOR]

In nonstationary flow the estimation of the mean flow with an indicator dilution technique can be described by applying a two-compartment model for the system between the injection site and detection site. The aim of this study was to investigate whether the two-compartment approach could be used in experimental situations as encountered in nonsteady blood flow during artificial ventilation. For this reason a two-compartment function was fitted to probability density functions associated with distributed models. The choice of the distributed functions was based on their superiority over other approaches with regard to the representation of the dispersion process of the indicator. Moreover, reference functions enable the practicability of fitting the two-compartment model as a function of the skewness of the curve to be studied. The first passage times (f.p.t.) distribution and the local density random walk (l.d.r.w.) distribution were used as reference functions. Good similarity between the two-compartment curves and the distributed curves was established for the skewness range found in the indicator dilution curves (i.d.c.s.) obtained at the right and left sides of the heart. The closer similarity to the l.d.r.w distribution could be explained theoretically. Moreover, it is concluded that in this skewness range the ratio of the slopes of the ascending and descending limbs at the inflection points of a curve gives an estimate of the time-constant ratio of the compartments of the compartment model. [ABSTRACT FROM AUTHOR]

In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HCl (mean 60 mg, range 10-225 mg) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65-630 ng·ml and from 5 to 55 ng·ml, whereas the peak concentrations were 124-1255 ng·ml and 10 - 301 ng·ml for methadone and EDDP, respectively. The calculated ratios between the area under the curve (AUC) for methadone and the AUC for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of methadone are best described using a two-compartment model. The mean body clearance was 1.64 ml·min·kg, whereas the mean elimination rate constant (β) and plasma half-life ( tβ) were 0.026·h (range 0.013-0.053·h) and 31.2 h (range 13-53 h), respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance. [ABSTRACT FROM AUTHOR]

When a pharmacokinetic (PK) two-compartment body model with first-order absorption is fitted to blood levels of a drug, the estimates of the PK parameters may have considerable errors and can cause wrong predictions in other features of the system. The objectives of this report were to illustrate this problem, to provide an easy way to prevent wrong estimation, and to investigate the origin of the mistake. A simple way to prevent wrong interpretation of the calculated PK parameters is to inspect the PK profiles visually. Without observing a clear biphasic profile, one should not apply the two-compartment model if the resulting parameters are to be interpreted and used for further simulations. We investigated the origin of this ambiguity in terms of the relative order of magnitude of microconstants (ka , k12 , k21 , and k10 ) and of hybrid constants (A and B ). The observed parameter errors will not be of any relevance if the calculated parameters are used only to predict future blood levels over the same time-span. However, if these parameters are used to predict any other characteristic of the system, erroneous predictions may result. [ABSTRACT FROM AUTHOR]

The distribution and elimination of intravenous digoxin were investigated in seven neonates and infants with heart failure. Serum digoxin concentrations during a 24 h period were determined by radioimmunoassay, usingI as tracer. The serum values declined biexponentially after the injection and could be fitted to a two-compartment open model by non-linear least-squares regression. The calculated mean half-lives of the distribution (alpha) phase in neonates and infants were 37 and 28 min, respectively. The mean half-life of the elimination (beta) phase in neonates was 44 h, as compared to 19 h in infants. The mean volume of the central compartment and the mean volume of distribution at steady-state were calculated to be 1.3 and 9.9 l/kg, respectively; no significant differences between neonates and infants were found. The relation between these volumes indicates that digoxin is extensively distributed in tissues. The steady-state distribution volumes of digoxin in neonates and infants exceed those reported in adults. The larger volume of distribution might explain in part why infants with cardiac insufficiency require larger doses of digoxin than adults (on a mg/kg body weight basis) to obtain the same serum concentrations. Elimination of digoxin from the body was slower in neonates than in infants. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of tranexamic acid has been investigated in two healthy volunteers. The behaviour of the drug can be described in terms of a two compartment open model; the disposition (biological) half-life was 2.7 h and 1.9 h, respectively. In five normal volunteers the mean total recovery in urine 48 h after dosing was 94.8%. The renal clearance in the two subjects, adjusted to 1.73 m body surface area, was 135 and 132 ml/min/1.73 m, respectively, indicating that tranexamic acid is eliminated by glomerular filtration and that neither tubular excretion nor absorption takes place. [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 method of Tsoukias and George (T and G) is a commonly used linear approximation of pulmonary nitric oxide (NO) dynamics that can be used to calculate bronchial NO output (J aw NO) and alveolar NO concentration (C A NO). We aimed to investigate how flow rate range in exhaled NO measurements and levels of pulmonary NO parameters affect the accuracy of the T and G method. This study has three parts. (a) A theoretical part demonstrating how different exhalation flow rates and NO parameter levels affect the accuracy of the T and G method, (b) testing how exhalation flow rate range affects the method in a sample of asthmatic and healthy subjects, and (c) a meta-analysis of published literature to test whether minimum flow rate has an association with the NO parameter values. We found that both the chosen exhalation flow rates and magnitude of the pulmonary NO parameters affect the accuracy of the T and G method. Underestimation of J aw NO increased with lower flow rates and higher bronchial diffusion factor of NO (D aw NO), while overestimation of C A NO increased with higher D aw NO and bronchial wall NO concentration (C aw NO) and lower C A NO. Of the NO parameters, C A NO was the most prone to bias and high D aw NO was the most significant factor causing the bias. Furthermore, we found that using 40 ml s -1 as the lowest flow rate in our sample and 50 ml s -1 in the meta-analysis compared to 100 ml s -1 resulted in higher C A NO, but J aw NO was not statistically significantly affected. We have provided objective evidence that not only the flow rates used but also the magnitude of NO output in the test subjects affect the accuracy of the T and G method. We suggest that flow rates below 100 ml s -1 should not be used with the T and G method to maintain accuracy., (© 2021 IOP Publishing Ltd.)

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.