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At least 91 records · Page 5Linked to original sources
PubMed2006

Ecstasy-induced reduction of the availability of the brain serotonin transporter as revealed by [11C](+)McN5652-PET and the multi-linear reference tissue model: loss of transporters or artifact of tracer kinetic modelling?

In a previous positron emission tomography (PET) study with the serotonin transporter (SERT) ligand [(11)C](+)McN5652, we found protracted reduction of the availability of the brain SERT in users of the drug ecstasy. However, the multi-linear reference tissue method for the quantification of SERT availability used in this study is prone to effects of altered levels of statistical noise that could simulate reduction of SERT. The aim of the present study was to take into account this confound by re-evaluation of the data now using a modelling approach that is rather insensitive to alterations in the level of statistical noise. A total of 116 subjects (30 current, 29 former ecstasy users, 29 drug-naive, 28 polydrug controls) in whom [(11)C](+)McN5652-PET had been performed previously were re-evaluated. The equilibrium specific-to-non-specific partition coefficient V"( 3) was obtained voxel-wise by application of the simplified reference tissue method (SRTM), which provides quite unbiased results up to rather large noise levels. Voxel-based comparisons between the groups were performed using statistical parametric mapping. V"(3) was reduced in the striatum and in the thalamus in current ecstasy users. This was confirmed by volume-of-interest-based analysis. This result suggests that the ecstasy-induced reduction of SERT availability in SERT-rich brain regions reported previously indicates reduced SERT binding potential rather than being an artifact of tracer kinetic modelling. SRTM analysis did not confirm previous findings in neocortical brain areas.

Adult↗
PubMed1985

Multicompartment kinetic models for lead. II. Linear kinetics and variable absorption in humans without excessive lead exposures.

Multicompartment models with constant fractional transfer rates have been fitted to experimental data on lead metabolism in four subjects studied by M. B. Rabinowitz, G. W. Wetherill, and J. D. Kopple (Science 182, 725-727, 1973; Environ. Health Perspect. 7, 145-153, 1974; Arch. Environ. Health 31, 220-223, 1976; J. Clin. Invest. 58, 260-270, 1976; J. Lab. Clin. Med. 90, 238-248, 1977). Long-term retention is estimated for blood, soft tissue, cortical and trabecular bone pools, and for facial hair. The absorption of lead from diet is shown to change with time, but no evidence was found for other variable or nonlinear kinetic mechanisms of lead metabolism in humans without excessive lead exposure.

Diffusion↗
PubMed1995

Analysis of time courses of metabolic precursors and products in heterogeneous rat brain tissue: limitations of kinetic modeling for predictions of intracompartmental concentrations from total tissue activity.

The efficacy of various kinetic models to predict time courses of total radioactivity and levels of precursor and metabolic products was evaluated in heterogeneous samples of freeze-blown brain of rats administered [14C]deoxyglucose ([14C]DG). Two kinetic models designed for homogeneous tissues, i.e., a no-product-loss, three-rate-constant (3K) model and a first-order-product-loss, four-rate-constant (4K) model, and a third kinetic model designed for heterogeneous tissues without product loss [Tissue Heterogeneity (TH) Model] were examined. In the 45-min interval following a pulse of [14C]DG, the fit of the TH Model to total tissue radioactivity was not statistically significantly better than that of the 3K Model, yet the TH Model described the time courses of [14C]DG and its metabolites more accurately. The TH- and 4K-Model-predicted time courses of [14C]DG and its metabolites were similar. Whole-brain glucose utilization (CMRglc) calculated with the TH or 3K Model, approximately 75 mumol 100 g-1 min-1, was similar to values previously determined by model-independent techniques, whereas CMRglc calculated with the 4K Model was 44% higher. In a separate group of rats administered a programmed infusion to attain a constant arterial concentration of [14C]DG that minimizes effects of tissue heterogeneity as well as any product loss, CMRglc calculated with all three models was 79 mumol 100 g-1 min-1 at 45 min after initiation of the infusion. Statistical comparisons of goodness of fit of total tissue radioactivity were, therefore, not indicative of which models best describe the tissue precursor and product pools or which models provide the most accurate rates of glucose utilization.

Animals↗
PubMed2001

Kinetic model of in vivo folding and inclusion body formation in recombinant Escherichia coli.

Aggregation of misfolded proteins can reduce the yield in recombinant protein production. The underlying complex processes are additionally influenced by cellular physiology. Nevertheless, a lumped-parameter model of kinetic competition between folding and aggregation was sufficient to track properly the specific concentration of a human protein produced in E. coli and its partitioning into soluble and insoluble cell fractions. Accurate estimation of the protein-specific parameters required informative experiments, which were designed using the Fisher information matrix. The model was employed to calculate the influence of the specific glucose uptake rate in high-cell-density cultivation of E. coli on accumulation and aggregation of the recombinant protein. Despite its simplicity, the model was flexible and unbiased concerning unidentified mechanisms. Assuming an exponentially decreasing production rate, the irreversible aggregation step was found to follow first order kinetics, while assuming a constant production rate with simultaneous degradation, the model predicted transient aggregation only. Implications for strain and process development are discussed.

Escherichia coli↗
PubMed2005

Non-Michaelis-Menten kinetics model for conductance of low-conductance potassium ion channels.

A reduced kinetics model is proposed for ion permeation in low-conductance potassium ion channels with zero net electrical charge in the selectivity filter region. The selectivity filter is assumed to be the only conductance-determining part of the channel. Ion entry and exit rate constants depend on the occupancy of the filter due to ion-ion interactions. The corresponding rates are assumed slow relative to the rates of ion motion between binding sites inside the filter, allowing a reduction of the kinetics model of the filter by averaging the entry and exit rate constants over the states with a particular occupancy number. The reduced kinetics model for low-conductance channels is described by only three states and two sets of effective rate constants characterizing transitions between these states. An explicit expression for the channel conductance as a function of symmetrical external ion concentration is derived under the assumption that the average electrical mobility of ions in the selectivity filter region in a limited range of ion concentrations does not depend on these concentrations. The simplified conductance model is shown to provide a good description of the experimentally observed conductance-concentration curve for the low-conductance potassium channel Kir2.1, and also predicts the mean occupancy of the selectivity filter of this channel. We find that at physiological external ion concentrations this occupancy is much lower than the value of two ions observed for one of the high-conductance potassium channels, KcsA.

Animals↗
PubMedDate not supplied

Tracer kinetic modeling in nuclear cardiology.

The introduction of tracer kinetic modeling techniques in conjunction with nuclear imaging has allowed the assessment of physiologic processes in the myocardium in a noninvasive and quantitative manner. Alongside the development of novel radiopharmaceuticals for both positron emission tomography and single photon emission computed tomography is the clarification of their pharmacology, pharmacokinetics, and modeling strategies for assessment of physiologic rates from imaging data. Image analysis and tracer kinetic modeling techniques used in nuclear cardiology must address unique considerations related to the heart. The most commonly used tracers and modeling techniques are presently discussed, with particular attention given to methods that allow absolute quantitation of physiologic processes. The applications of these techniques are obvious in research protocols and may find more use in future clinical studies.

Coronary Circulation↗
PubMed2000

A kinetic model for energy spilling-associated product formation in substrate-sufficient continuous culture.

It has been demonstrated that excess substrate can cause uncoupling between anabolism and catabolism, which leads to energy spilling. However, the Luedeking-Piret equation for product formation does not account for the energy spilling-associated product formation due to substrate excess. Based on the growth yield and energy uncoupling models proposed earlier, a kinetic model describing energy spilling-associated product formation in relation to residual substrate concentration was developed for substrate-sufficient continuous culture and was further verified with literature data. The parameters in the proposed model are well defined and have their own physical meanings. From this model, the specific productivity of unit energy spilling-associated substrate consumption, and the maximum product yield coefficient, can be determined. Results show that the majority of energy spilling-associated substrate consumption was converted to carbon dioxide and less than 6% was fluxed into the metabolites, while it was found that the maximum product yield coefficients varied markedly under different nutrient limitations. The results from this research can be used to develop the optimized bioprocess for maximizing valuable product formation.

Energy Metabolism↗
PubMed2003

Two-dimensional correlation analysis for a kinetic model of consecutive reactions.

We have systematically studied a kinetic scheme of consecutive reactions by using generalized two-dimensional (2D) correlation analysis as reported by Noda. The correlations between reactant-intermediate, intermediate-product, and reactant-product pairs are analyzed with the related rate constants and absorption coefficients. When the reference spectrum is set at zero, the synchronous and asynchronous correlation spectra for the kinetic model are almost free from the influence of poor quality signals. If an appropriate reference spectrum is selected, the intermediate can be feasibly distinguished from other species involved in the reaction. A ratio of asynchronous to synchronous correlation intensity yields a coherence spectrum, which is characterized by different plateau-type peak intensities. When a steady-state condition fits the kinetic model, the peak summation of reactant-intermediate and intermediate-product correlation will approach the intensity of the reactant-product correlation. The coherence spectrum is useful for pattern recognition of the reaction scheme and also provides an effective way to identify the location and the extent of spectral overlap between two peaks.

Algorithms↗
PubMed1999

Interactions of influenza virus with cultured cells: detailed kinetic modeling of binding and endocytosis.

We performed a detailed kinetic analysis of the uptake of influenza virus (A/PR8/34) by Madin Darby canine kidney (MDCK) cells in culture. Experimental procedures were based on the relief of fluorescence self-quenching of the fluorescent probe octadecylrhodamine B chloride (R18) incorporated in the viral envelope. Equilibrium for binding of influenza virus to MDCK cells (2.5 x 10(6)/mL) was reached quicker with temperature increases due to a faster dynamic mobility of the particles. We deduced that there are two kinds of binding sites for influenza virus in MDCK cells and determined the kinetic parameters of the binding process (adhesion and detachment rate constants), using a mass action kinetic model. As the temperature increases, the number of binding sites for influenza virus decreases, especially the high-affinity binding sites, whereas the value of the affinity constant for virus binding to the binding site, k, increases. Nevertheless, the binding association constant at equilibrium Ki, which is given by Ki = Niki, where Ni is the number of binding sites per cell, declines as the temperature increases. When endocytosis occurs, the total uptake of virions by the cells is larger than that observed in the process of binding at the same temperature, and the uptake proceeds for longer times. Using our mass kinetic model, we determined that at 20 degrees C, the rate constant of endocytosis, epsilon, for influenza virus with this cell line is 2.6 x 10(-)4 s-1, i.e., in the same range as in studies on endocytosis of liposomes.

Animals↗
PubMed2004

Non-linear reduction for kinetic models of metabolic reaction networks.

Kinetic models of metabolic networks are essential for predicting and optimizing the transient behavior of cells in culture. However, such models are inherently high dimensional and stiff due to the large number of species and reactions involved and to kinetic rate constants of widely different orders of magnitude. In this paper we address the problem of deriving non-stiff, reduced-order non-linear models of the dominant dynamics of metabolic networks with fast and slow reactions. We present a method, based on singular perturbation analysis, which allows the systematic identification of quasi-steady-state conditions for the fast reactions, and the derivation of explicit non-linear models of the slow dynamics independent of the fast reaction rate expressions. The method is successfully applied to detailed models of metabolism in human erythrocytes and Saccharomyces cerevisiae.

Carbon↗
PubMed1996

Determining the adequacy of sodium balance in hemodialysis using a kinetic model.

The importance of sodium balance avoiding intradialytic cardiovascular instability and interdialytic hypertension and pulmonary edema is well known. An early analytical single-pool kinetic model created to evaluate sodium balance in hemodialysis, using flame photometry to determine plasma and dialysate sodium concentrations, has been shown to have a level of imprecision of +/- 2.8 mEq/l in predicting end-dialysis sodium plasma water concentrations (NaPWt). The ionometric determination of sodium concentrations seems to be more accurate and refers to the activity of the sodium capable of crossing dialysis membranes. On the basis of the theoretical premises of the model mentioned above, we developed a computerized single-pool kinetic model which makes it possible to calculate the ionized dialysate sodium activity (NaDI) required to reach a pre-established target of end-dialysis blood sodium activity (NaBI). Thirty-seven non-diabetic and anuric patients undergoing regular thrice-weekly hemodialysis were given their usual dialysis treatment, with NaDI at the usual value for each patient (range 137-147 mEq/l) and kept constant throughout dialysis. At the beginning and end of the session, NaDI and NaBI were measured in quadruplicate by means of a Nova-1 device (Direct Potentiometry, Pabisch Instruments). The validity of this kinetic model was tested by considering the difference between predicted and observed (P-O) NaBI at the end of dialysis [(t)]. P-O NaBI(t) was -0.37 +/- 0.42 mEq/l, which was statistically different from 0 (p < 0.001). When P-O NaBI(t) was plotted against ONaBI(t), it was more negative at the higher values of ONaBI(t). P-O intradialytic sodium removal (Nag) was -12.5 +/- 17.8 mEq/session, which was also statistically different from 0 (p < 0.001). The imprecision of this kinetic model was less than 0.84 mEq/l, as estimated by doubling the SD of P-O NaBI(t) (0.42 = 0.84 mEq/l). Although the reasons for its inaccuracy especially at higher ONaBI(t) values remain to be clarified, these data are the expression of a satisfactory clinical model.

Aged↗
PubMed2004

"Population" approach improves parameter estimation of kinetic models from dynamic PET data.

Kinetic modeling is used to indirectly measure physiological parameters from dynamic positron emission tomography (PET) data. Usually, the unknown parameters of the model are estimated, in any given region of interest (ROI), by least squares (LS). However, when the signal-to-noise ratio (SNR) of PET data is too low, LS does not allow reliable parameter estimation. To overcome this problem, we study in this paper the applicability of approaches originally developed in the pharmacokinetic/pharmacodynamic literature and referred to as "population approaches." In particular, we consider the iterative two stage (ITS) method, which, given a set of M ROIs drawn on PET images of a given individual, estimates the unknown model parameters of each ROI by exploiting the information contained in all the M ROIs. After having revised the theory behind ITS, we assess its performance versus LS by using Monte Carlo simulations which allow us to evaluate the bias of the two methods in a variety of situations. Then, we compare the performance of LS and ITS in two case studies on [18F]FDG kinetics in human skeletal muscle. Both simulated and real case studies results show that a population approach is of potential in modeling PET images since it allows to reliably estimate model parameters also in those ROIs where either a bad SNR or a poor sampling (e.g., infrequent scanning and/or short experiment duration) make the use of LS unsuccessful.

Algorithms↗
PubMed2006

Estimating constants for metabolism of atrazine in freshly isolated rat hepatocytes by kinetic modeling.

This study estimated the kinetic constants for oxidative metabolism of atrazine (ATRA) and its chlorotriazine (Cl-TRI) metabolites, 2-chloro-4-ethylamino-6-amino-1,3,5-triazine (ETHYL), 2-chloro-4-amino-6-isopropylamino-1,3,5-triazine (ISO), and diaminochlorotriazine (DACT), using freshly isolated rat hepatocytes. Hepatocytes were incubated with 1.74, 44, 98, and 266 microM ATRA. Disappearance of ATRA and formation of the Cl-TRI metabolites were quantified over 90 min. At all incubation concentrations, ATRA was preferentially metabolized to ETHYL, producing ETHYL concentrations approximately 6 times higher than those of ISO. DACT concentrations peaked at 44 microM ATRA and decreased with increasing incubation concentrations, indicating non-linear metabolic behavior of ATRA with respect to DACT formation. A series of kinetic models were developed from these data to describe the dose and time-dependent oxidative metabolism of ATRA and the Cl-TRI metabolites. An integrated model for all the chloro-triazines included multi-substrate competitive inhibition of metabolism to describe the non-linear behavior of DACT production in relation to ATRA while simultaneously simulating the time-course behavior of the Cl-TRIs at all four ATRA concentrations. The maximal metabolic rate (V(max)) of ATRA metabolism and the Michaelis-Menten constant (K(M)) for the reaction were 1.6 microM/min and 30 microM, respectively. V(max) and K(M) values for ETHYL and ISO metabolism to DACT were also estimated using this modeling approach.

Animals↗
PubMed1984

Kinetic model for the study of gene expression in the developing sea urchin.

We have derived a kinetic model to assist in the study of gene expression for systems in which rapid changes in cell number occur. This kinetic model is based upon development of the sea urchin embryo, and considers changes in the number of cells, the fraction of each cell-cycle spent in mitosis, and the overall rate of transcription. We have applied this kinetic model to the accumulation of actin messenger RNA which occurs early in sea urchin embryogenesis. This analysis demonstrates that the rapid increase in cell number profoundly influences the kinetics of mRNA accumulation, and that failure to take into account the work performed by each cell can lead to significant misinterpretations of data on the expression of specific genes.

Actins↗
PubMed2003

A theoretical graph method for search and analysis of critical phenomena in biochemical systems. II. Kinetic models of biochemical oscillators including two and three substances.

Four kinetic models of hypothetical complex reactions containing minimal two-substance or three-substance oscillators were constructed on the basis of the graphical rules suggested in the preceding work. The kinetic models are thought to be a part of one of four general biochemical systems: 1) system of mutual protein phosphorylation/dephosphorylation; 2) autophosphorylation of multisubunit protein; 3) association/dissociation of proteins or protein-containing structures during protein-protein or protein-ligand interaction; and 4) two-substrate enzymatic reaction with substrate inhibition by one substrate. Graphical rules of oscillator association with surrounding medium were considered. The graphical criteria of the oscillation generator elimination and criteria of oscillation damping were obtained. Both damped and undamped oscillations of reaction components were obtained by numerical integration of the mathematical models of these reactions. The areas of changes of model parameters and variables, within which the oscillations exist, were found.

Biological Clocks↗
PubMed1997

Can nitrogen-13 ammonia kinetic modeling define myocardial viability independent of fluorine-18 fluorodeoxyglucose?

OBJECTIVES: The hypothesis of this study was that evaluation of myocardial flow and metabolism using nitrogen-13 (N-13) ammonia kinetic modeling with dynamic positron emission tomographic (PET) imaging could identify regions of myocardial scar and viable myocardium as defined by fluorine-18 fluorodeoxyglucose (F-18 FDG) PET. BACKGROUND: Uptake of most perfusion tracers depends on both perfusion and metabolic retention in tissue. This characteristic has limited their ability to differentiate myocardial scar from viable tissue. The kinetic modeling of N-13 ammonia permits quantification of blood flow and separation of the metabolic component of its uptake, which may permit differentiation of scar from viable tissue. METHODS: Sixteen patients, > 3 months after myocardial infarction, underwent dynamic N-13 ammonia and F-18 FDG PET imaging. Regions of reduced and normal perfusion were defined on static N-13 ammonia images. Patients were classified into two groups (group I [ischemic viable], n = 6; group II [scar], n = 10) on the basis of percent of maximal F-18 FDG uptake in hypoperfused segments. Nitrogen-13 ammonia kinetic modeling was applied to dynamic PET data, and rate constants were determined. Flow was defined by K1; volume of distribution (VD = K1/k2) of N-13 ammonia was used as an indirect indication of metabolic retention. RESULTS: Fluorine-18 FDG uptake was reduced in patients with scar compared with normal patients with ischemic viable zones (ischemic viable 93 +/- 27% [mean +/- SD]; scar 37 +/- 16%, p < or = 0.01). Using N-13 ammonia kinetic modeling, flow and VD were reduced in the hypoperfused regions of patients with scar (ischemic viable flow: 0.65 +/- 0.20 ml/min per g, scar: 0.36 +/- 0.16 ml/min per g, p < or = 0.01; VD: 3.9 +/- 1.3 and 2.0 +/- 1.07 ml/g, respectively, p < or = 0.01). For detection of viable myocardium in these patients, the sensitivity and specificity were 100% and 80% for N-13 ammonia PET flow > 0.45 ml/min per g; 100% and 70% for VD > 2.0 ml/g; and 100% and 90% for both flow > 0.45 ml/min per g and VD > 2.0 ml/g, respectively. The positive and negative predictive values for the latter approach were 86% and 100%, respectively. CONCLUSIONS: In this cohort, patients having regions with flow < or = 0.45 ml/min per g or VD < or = 2.0 ml/g had scar. Viable myocardium had both flow > 0.45 ml/min per g and VD > 2.0 ml/g. Nitrogen-13 ammonia kinetic modeling permits determination of blood flow and metabolic integrity in patients with previous myocardial infarction and can help differentiate between scar and ischemic but viable myocardium.

Aged↗
PubMed1986

Characterization of the pituitary response in the TRH test by kinetic modeling.

Applying the principles of chemical kinetics to the time course of TSH concentrations after TRH infusion, individual values for total TSH release from the pituitary, TSH elimination and release rates, and latency for TSH release were found for 40 patients. Justification for using the observed peak TSH elevation as a consistent reflection of the total TSH release was provided by the high correlation between these two (r = 0.97, P less than 0.001). Kinetic modeling indicated that the most consistent reflection of total pituitary TSH response is the TSH elevation over baseline 35 min after TRH (with the peak expected 30 min post-TRH), rather than the area under the curve.

Humans↗
PubMed1983

Kinetic modeling: applications in renal and related diseases.

Kinetic modeling, as the name implies, involves a study of the dynamics or rate of change of process or system to either gain enhanced understanding or predict an outcome. In applying kinetics to extracorporeal treatment both goals are encompassed. For example, in dialysis treatment the question of mortality has been replaced by questions of morbidity and rehabilitation. To improve the latter, it is essential to study the kinetics of interaction between the patient and the treatment process; mathematical models can provide both useful insights and better patient management. The application of kinetics to hemodialysis treatment is best exemplified by urea and heparin modeling in these cases, the amount of dialysis is geared to the patient's dietary protein intake, if the level is within acceptable limits and heparin requirements are assessed by a particular patient's sensitivity to the drug and his/her rate of elimination of the drug. Other useful examples of the applications of kinetic modeling in extracorporeal treatment include hemoperfusion and therapeutic plasmapheresis. Kinetics is not, however, a treatment panacea, or a substitute for thinking; the real benefit of the procedure is that it forces one to focus on a problem from a different perspective. This, in turn, begets new disease and treatment insights as well as improved health care delivery. The future will see a more widespread use of kinetic analysis in a variety of other medical/surgical procedures.

Hemoperfusion↗