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At least 289 records · Page 16Linked to original sources
PubMed1998

Use of model-based compartmental analysis to study effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on vitamin A kinetics in rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic, widespread environmental contaminant that has dramatic adverse effects on the metabolism of vitamin A. We used model-based compartmental analysis to investigate sites and quantitative impacts of TCDD on vitamin A kinetics in rats given on oral loading dose of TCDD in oil (3.5 micrograms/kg) followed by weekly maintenance doses (0.7 microgram/kg) or oil only. [3H]Retinol in its plasma transport complex (experiment 1) of lymph containing chylomicrons labeled mainly with [3H]retinyl esters (experiment 2) were administered i.v., and tracer kinetics in plasma, liver, carcass, urine, and feces were measured for up to 42 days. TCDD treatment caused significant reductions in liver vitamin A levels and significant changes in tracer kinetics and tracer excretion. A four-compartment model was used to fit tracer data for experiment 1; for experiment 2, compartments were added to describe the metabolism of newly absorbed vitamin A. The compartmental models predict that TCDD caused a slight delay in plasma clearance (via an increased recycling to plasma), and in liver processing, of chylomicron-derived vitamin A. Models for both experiments predict that TCDD exposure did not affect the fractional uptake of plasma retinol from the rapidly turning-over extravascular pool, but it doubled the fractional transfer of recycled retinol from slowly turning-over pools of vitamin A to plasma. The residence time for vitamin A was reduced by 70% in TCDD-treated rats, transfer into urine and feces was tripled, and vitamin A utilization rates were significantly increased. Since our results do not indicate that retinol esterification is inhibited, we hypothesize that some of the significant effects of TCDD on vitamin A metabolism result from increased catabolism and mobilization of vitamin A from slowly turning-over pools (especially the liver).

Animals↗
PubMed1998

Development of a compartmental model describing the dynamics of vitamin A metabolism in men.

Model-based compartmental analysis was used with the Simulation, Analysis and Modeling (SAAM) computer programs to analyze data on plasma retinoid kinetics in adult male subjects for 7 d after a single oral dose of 105 mumol of [8,9,19-13C]retinyl palmitate. We present here the data for one subject and discuss in detail the steps taken to develop a physiologically-based compartmental model that describes the dynamic behavior of plasma retinyl esters, [12C]retinol, [8,9,19-13C]retinol, and the sum of [12C] and [13C]retinol. First an absorption model was developed to fit data on the plasma appearance and disappearance of retinyl esters; this was used as input in development of models for labeled and unlabeled retinol. The large oral load of labeled vitamin A perturbed the unlabeled tracee system, and thus parallel models for tracer and tracee were developed; and a time-variant fractional transfer coefficient was incorporated into the tracee model. Following the absorption model, four-compartment models were developed to describe the dynamics of both labeled and unlabeled retinol. These models predict that, in spite of the large vitamin A load, the absorption efficiency was 34%; hepatic (presumably parenchymal cell) processing of the absorbed dose was essentially complete by 24 h; and, by 7 days, approximately 80% of the absorbed dose was in a compartment that presumably represents stored liver retinyl esters. The model also predicts that approximately 50 mumol of retinol passed through the plasma each day, compared to an estimated utilization rate of 4 mumol/day. This project provides unique and important information about whole-body vitamin A dynamic in humans, and presents approaches to specific modeling issues that may be encountered by others.

Adult↗
PubMed1998

Compartmental models of vitamin A and beta-carotene metabolism in women.

We have developed compartmental models of vitamin A and beta-carotene (beta C) metabolism in women living under controlled conditions on diets with known concentrations of vitamins and carotenoids. Fourteen healthy adult women were given either retinyl-d4 acetate, or beta C-d8 before breakfast. Natural and stable-isotopes of retinol and beta C were collected in serum for up to 95 days or 20 days, respectively. Stable isotopes were separated from other components and measured by GC-MS or HPLC-UV. Preformed retinyl-d4 acetate metabolism in all women tested can be accurately described by a simple four-compartment model. However, the model did not fit one women initially, when she had marginal vitamin A status. We tested the hypothesis that dietary changes of beta C intake have important roles on the kinetics of vitamin A metabolism. Dietary changes of beta C intake did not influence the turnover rate of retinol in any compartment. However, it did result in changes in steady-state masses and residence times of retinol in several compartments. A working compartmental model for beta C metabolism was developed. The kinetics of retinol-d4 formed from beta C is more complicated than the pre-formed retinol-d4. Results suggest that beta C-d8 readily converts into retinol-d4 with high inter-individual variability.

Adult↗
PubMed2004

Compartmentalization and transport in beta-lactam antibiotics biosynthesis.

Classical strain improvement of beta-lactam producing organisms by random mutagenesis has been a powerful tool during the last century. Current insights in the biochemistry and genetics of beta-lactam production, in particular in the filamentous fungus Penicillium chrysogenum, however, make a more directed and rational approach of metabolic pathway engineering possible. Besides the need for efficient genetic methods, a thorough understanding is needed of the metabolic fluxes in primary, intermediary and secondary metabolism. Controlling metabolic fluxes can be achieved by adjusting enzyme activities and metabolite levels in such a way that the main flow is directed towards the desired product. In addition, compartmentalization of specific parts of the beta-lactam biosynthesis pathways provides a way to control this pathway by clustering enzymes with their substrates inside specific membrane bound structures sequestered from the cytosol. This compartmentalization also requires specific membrane transport steps of which the details are currently uncovered.

Acremonium↗
PubMed1992

Blood platelet kinetics in normal subjects modelled by compartmental analysis.

The purpose of this study was to describe the function of platelets throughout their life span by expressing their in vivo distribution and kinetic behaviour in mathematical terms by using multicompartmental analysis. The distribution of indium-111 labelled platelets in five normal subjects was imaged and quantified with a scintillation camera image processing system. Serial blood samples were also obtained. The data were modelled using the SAAM (Simulation Analysis and Modelling) compartmental computer program. Five models were entertained to evaluate the role of platelets that were either functional or injured during collection and their interaction with the liver, spleen and vascular endothelium. Models were evaluated by comparing F values calculated from the least squares estimate obtained from each model. The Dornhorst function was used to describe the sequestration of platelets in the compartmental model. Results indicated that the data could not be satisfactorily simulated when compartments were included that simulated only functional and sequestered platelets (model 1). It was necessary to include compartments that simulated the kinetics of collection-injured platelets in the liver (model 2) and spleen (model 3). The model that simulated the interaction with the vascular endothelium (model 5) showed a visual but not significant improvement in the fitting of the observed data compared to model 3. The mean organ uptake and range indicated in parentheses were calculated at equilibrium. There were 20% (15%-27%) of the injected platelets in the spleen, 10% (8%-11%) in the liver and 70% (64%-75%) in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1975

Subcellular compartmentalization of the luteal cell in the ovary of the dog.

The compartmentalization of the parenchyma of the corpus luteum in the dog was studied by both 100 and 1000 KV electron microscopy. The organells within the luteal cell are oriented with a high degree of consistency towards the pericapillary space. Characteristically, the avascular pole and the lateral margins of the cell posses predominantly stacked and whorled cisternae of agranular ER. In the central medial portions of the cell, pleomorphic mitochondria with tubulo-vesicular cristae and anastomosing tubules of agranular ER predominate. However, the distribution of organelles in this compartment is graded. Mitochondria predominate in the central medial areas while tubular ER is more dominant peripherally. Microfilaments are ubiquitous in this compartment and run a longitudinal course between and around the subcellular components towards the pericapillary space. The Golgi apparatus is large and prominent and is positioned over the pole of the nucleus that faces the basal lamina. Coated vesicles are abundant in the Golgi regions and along the lateral surface of the cell. Three distinct regional specializations of the cell surface exist. The basal surface contains long pleomorphic cytoplasmic folds that fill the pericapillary space, are interconnected by small gap junctions and contain abundant multivesicular bodies. The lateral cell surface is covered with microvilli and is organized into tortuous intercellular channels and canaliculi. These are interrupted at intervals by cytoplasmic protrusions that extend from one cell well into the cytoplasm of the next. Large, well-developed gap junctions line the margins of the cells furthest removed from the pericapillary space. Finally, the individual cells exhibit heterogeneity with respect to the amount one subcellular organelle or compartment is expressed relative to another. These observations are discussed in relation to the subcellular compartmentalization of progesterone synthesis and release.

Animals↗
PubMed1984

Compartmentalization of single muscle units in cat lateral gastrocnemius.

The distribution of muscle fibers in single muscle units in cat lateral gastrocnemius (LG) muscle was analyzed using the method of glycogen depletion. Single, type FF motor units in LG were identified by stimulation of dissected ventral rootlets and then activated to produce depletion of glycogen in their innervated muscle fibers. Serial histological sections were made of the entire triceps surae muscles and then reacted for the demonstration of glycogen. Projected tracings of the sections were used to compare the distribution of glycogen depleted muscle fibers to the heads of the LG muscle. Results of analysis of single muscle units indicate that the muscle fibers innervated by single cat LG type FF motor units are distributed to the same regions of muscle which are innervated by primary branches of the nerve to the LG muscle. The single units are thus compartmentalized. These results support the hypothesis that each of the neuromuscular compartments of LG contains a unique population of motor units. It is suggested that compartmentalization of muscles about primary branches of their muscle nerves may from a major organizational principle in the design of skeletal muscles.

Animals↗
PubMed1985

Intranuclear compartmentalization of DNA-dependent RNA polymerases: association of RNA polymerase I with nucleolar organizing chromosomes.

The compartmentalization of chromatin-bound RNA polymerases was examined with HeLa chromosomes fractionated according to their size in sucrose/glycerol gradients. There was a good correlation between the enrichment of nucleolus-organizing chromosomes, i.e., D and G group chromosomes, and the level of chromosome-associated RNA polymerase form I activity. A profile of DEAE-Sephadex chromatography of enzymes solubilized from chromosome fractions also supported the view that form I was associated with D and G group chromosomes. The amount of form I associated with unfractionated chromosomes was nearly identical to that of nuclei, indicating that this enzyme is probably quantitatively conserved even when chromatin undergoes extensive condensation. Since the chromatin-bound form I enzyme can be reactivated with heparin, it seems that this enzyme is in the initiated state, probably being bound to rDNA throughout the mitotic cycle. Thus, the absence of rRNA synthesis in mitosis is due to neither unavailability of enzyme to rDNA nor to the release of some factors necessary for transcriptional processes. Form II enzyme was associated uniformly with all chromosome fractions. Taken together, the present findings suggest that the intranuclear compartmentalization of RNA polymerases persists not only in interphase stages, but also in mitosis, during which most other nuclear proteins are released into the cytoplasm.

Cell Fractionation↗
PubMed1990

Kinetics of heat-damaged homologous erythrocytes. A five-compartmental analysis.

A new theoretical five-compartmental model (5CM) was developed for analysis of the clearance of heat-damaged erythroctes (HDE) labelled with chromium 51. Besides the HDE-spleen interaction, this new model also takes into account the interaction between extrasplenic reticuloendothelial (RES) sites and HDE, i.e. the hepatic clearance of fragmented erythrocytes (FE). Accordingly, HDE clearance curves are analysed into three exponential components, the fastest of which describes the RES-FE interaction, whereas the others describe the splenic clearance of spherocytes. Therefore, an estimation of the effective liver blood flow for HDE (ELBF) was achieved, along with a series of parameters describing splenic function. The 5CM proved to be more efficient than a previously proposed three-compartmental model (3CM) in the mathematical description of HDE clearance. Comparison was made by applying both models to 37 experimental curves obtained from 20 patients with congenital hemolytic anemias. The values for the splenic function parameters calculated by 5CM analysis and the strong correlations observed among them offer evidence that this model provides an adequate approximation to the real conditions under which HDE clearance takes place. Furthermore, a detailed quantitative analysis of the pooling of spherocytes within the spleen was attempted in this work, and this phenomenon was found to compete with splenic irreversible spherocyte trapping. The ELBF proved to be closely correlated with the hemodynamic splenic parameters, following first-order kinetics, as do low-dose colloids.

Chromium Radioisotopes↗
PubMed1980

Compartmentalization of self-reproducing machineries: multiplication of microsystems with self-instructing polymerization of amino acids.

A theoretical model is presented for the self-instructing polymerization of free amino acids which proceeds inside microsystems which are phase-separated from the solution of thermal polyamino acids. It is shown theoretically that a compartmentalized microsystem fixes inside itself only the process with a faster macromolecular multiplication as time passes, even if the catalytic polymerization alone could spontaneously decrease the corresponding reaction rate. The compartmentalized machinery of macromolecular multiplication cannot reach its stationary state. The machinery is inevitably multiplied and alternates with those with either faster rates of macromolecular multiplication or slower rates of macromolecular degradation during their time development. These results are based upon the dynamic process that any material system acts by itself so as to remove any flow disequilibrium, that is, to maintain the continuity of material flow.

Amino Acids↗
PubMed1994

Effects of chronic exposure to ammonia on glutamate and glutamine interconversion and compartmentation in homogeneous primary cultures of mouse astrocytes.

Accumulation of radioactivity was studied in primary cultures of mouse astrocytes as a function of time of exposure (4-60 min) to 50 microM glutamate and 200 microM glutamine (initial concentrations), of which either glutamate or glutamine was 14C-labeled. Both the glutamate pool and the glutamine pool were compartmentalized. Initially, by far the major intracellular glutamate pool (> or = 90%) was derived from extracellular glutamate and could be converted to glutamine. This allowed a rather accurate determination of metabolic flux from glutamate to glutamine, which under control conditions amounted to 2.0-2.2 nmol/min per mg protein. After chronic exposure to 3 mM ammonia for 3 days this flux was significantly increased to 3.1-3.6 nmol/min per mg protein. Acute exposure to ammonia caused a smaller, apparent increase, which was not statistically significant. The glutamine content was compartmentalized at all stages of the incubation. It consisted of at least two different pools. One of these was accessible to extracellular glutamine and could be converted to intracellular glutamate (constituting a sizeable fraction of the total glutamate pool after longer incubation), whereas the other constituted endogenously derived glutamine, formed from accumulated glutamate. The specific activity of the precursor pool for glutamate synthesis could not be accurately determined and relatively exact fluxes therefore not be calculated. There was, however, no evidence that chronic exposure to ammonia decreases the rate of glutamine hydrolysis.

Ammonia↗
PubMed1984

Mathematical basis for the measurement of absolute and fractional cardiac output with diffusible tracers by compartmental analysis methods.

Using compartmental analysis methods, a mathematical basis is given for the measurement of absolute and fractional cardiac output with diffusible tracers. Cardiac output is shown to be the product of the blood volume and the sum of the rate constants of tracer egress from blood, modified by a factor reflecting transcapillary diffusibility, the transfer fraction. The return of tracer to the blood and distant (intracellular) events are shown to play no role in the solution. Fractional cardiac output is the ratio of the rate constant of tracer egress from blood to an organ, divided by the sum of the egress constants from blood. Predominantly extracellular ions such as sodium or bromide are best suited for this technique, although theoretically any diffusible tracer whose compartmental model can be solved may be used. It is shown that fractional cardiac output is independent of the transfer fraction, and therefore can be measured accurately by tracers which are not freely diffusible.

Animals↗
PubMed1983

Glial membrane specializations and the compartmentalization of the lamina ganglionaris of the housefly compound eye.

Membrane specializations in the lamina ganglionaris of the housefly are investigated using conventional thin-section EM, freeze-fracture replication and the diffusion of colloidal lanthanum. All glial cells in the lamina are coupled by gap junctions. Desmosomes also link all glia except the epithelial glia. Extensive glia-glial and glia-neuronal septate junctions are present in the pseudocartridge zone and nuclear layer. Septate junctions in the nuclear layer intermingle with bands of interglial and glia-neuronal tight junctions. Tight junctions are also found between satellite and epithelial glia at the border of the nuclear and plexiform layers, between adjacent epithelial glial cells in the plexiform layer, between epithelial and marginal glia at the proximal boundary of the optic neuropil, between marginal glial cells, and between marginal glia and axons. Colloidal lanthanum, introduced through an incision in the cornea, penetrates the retina but is occluded from the neuropil by septate junctions in the pseudocartridge zone. The disposition of tight and septate junctions is described in relation to the compartmentalization of the lamina. Two major compartments are delineated. The first represents the nuclear layer and contains the cell bodies of second-order visual neurons (monopolar neurons). The second compartment constitutes the plexiform layer of the lamina. Within the plexiform layer, each optic cartridge is partitioned into a separate subcompartment. Also, tracheoles and axons of long visual fibres are isolated from the optic cartridges by glial tight junctions. Morphological evidence for compartmentalization is correlated with previously established electrical properties of the insect lamina ganglionaris.

Animals↗
PubMedDate not supplied

Compartmentation of creatine kinases during perinatal development of mammalian heart.

Maturation of the cardiac cell is characterized by increasing diversity of isozymic expression of creatine kinases. Expression of the M-CK isozyme always precedes that of mitochondrial isozyme (mi-CK), however the expression of an isoform does not inform about its localization or cellular function. The functional role of isozymes binding to sites of energy utilization and production characteristic of the adult myocardium can be evidenced by the functional coupling of M-CK to myofibrillar ATPase and mito-CK to translocase in Triton X-100 and saponin skinned fibers. Functional activity of M-CK and mito-CK were investigated during perinatal development. Both functional activities appear during late fetal life in species mature at birth like guinea pig, and in the first postnatal weeks in immature species like rat or rabbit. Thus, the functional activity of bound CK isozymes is not associated with birth per se but with the general process of cell maturation. Localization of CK in the cytosol appears optimal for the transfer of glycolytic production of ATP to sites of utilization in an immature heart. During cell maturation, the increasing contribution of oxidative phosphorylation to ATP production, the apparition and binding of mi-CK to mitochondria, the binding of M-CK to myofibrils, turn the cell in a compartmentalized system of energy production. This provides the cellular basis for energy transfer by the PCr-Cr-CK system between sites of ATP production and utilization. Compartmentation of both Ca handling and energy turnover leads to a highly structured cell organization and could be essential for the efficiency of heart function.

Animals↗
PubMed1996

Imaging of thoracoabdominal masses: the difficulty of compartmentalization.

Over the past 3 years we have encountered eight cases of masses in the thoracoabdominal junction or paradiaphragmatic region. To determine exact compartmentalization of the tumors prior to treatment, a detailed imaging evaluation, including conventional radiography, ultrasound, computerized tomography, and magnetic resonance imaging, was conducted. Despite these extensive examinations, we erred in three cases with regard to the compartmental limitation of the tumors. The imaging picture of para- or transdiaphragmatic penetration of masses can be very misleading and is at times resolved only at surgery.

Abdominal Neoplasms↗
PubMed1977

Compartmental analysis of potassium efflux from growth-oriented heart cells.

Radioisotopic flux studies were initiated with a new preparation of growth-oriented heart cells to determine the contribution of heterogeneous cell types and the limitations of extracellular diffusion in quantitating the passive movement of potassium ions. The efflux of potassium-42 from contractile preparations, which contain two populations of cells, cardiac muscle and fibroblastlike, could be resolved into two components similar to that described for naturally occurring preparations of cardiac muscle. Compartmental analysis of the efflux data, using analog and digital computational methods, resolved the tracer kinetics into a slow compartment (k=0.015 min-1) associated with fibroblastlike cells and a fast compartment (k=0.067 min-1) associated with the cardiac muscle cells. The rate constants derived from compartmental analysis were independent of tracer equilibration and preparation dry weight. Analytical measurements of the preparations provided a quantitative basis for determing the transmembrane potassium fluxes from the tracer kinetics. Cardiac muscle cells stimulated at a rate of 150 min-1 in the presence of 5.4 mM external potassium were found to have a potassium efflux of 15.7 pmoles cm-2sec-1 whereas the value obtained for the fibroblastlike cells was 1.88 pmoles cm-2sec-1. Diffusional limitations of 42K efflux were analyzed for several important variables which can affect isotopic reflux, namely, transmembrane flux, cell volume-to-surface area and cell packing fraction.

Animals↗
PubMed1989

Pharmacokinetics of a single dose of ofloxacin in healthy elderly subjects using noncompartmental and compartmental models.

The pharmacokinetics of ofloxacin following a single 200 mg oral dose were studied in twelve healthy elderly volunteers. Relevant pharmacokinetic parameters were analysed by both noncompartmental and compartmental models. In compartmental analysis, the data on plasma concentrations was best described by an open two-compartment model. A zero-order absorption behaviour was found in some volunteers. The terminal half-lives were slightly prolonged and ranged from 6.2-11.6 h. A linear relationship was found between the renal clearance of the drug and the estimated creatinine clearance. Computer predictions of a multiple 200 mg dose regimen showed no important accumulation of ofloxacin. The recommendation of some authors that, in general, ofloxacin dosage may be halved in the elderly could not be confirmed. This has to be determined through further clinical experience in elderly ill subjects.

Aged↗
PubMed2001

Compartmental model identification based on an empirical Bayesian approach: the case of thiamine kinetics in rats.

Compartmental models are a very popular tool for the analysis of experiments in living systems. There are three main aspects that have to be taken into account: the degree of detail of the model, its a priori identifiability and the a posteriori (numerical) identifiability. In some cases, where standard approaches are adopted, the models can be either a priori or a posteriori unidentifiable. The paper proposes model identification within a Bayesian framework, to solve a posteriori unidentifiability problems. In particular, a stochastic simulation algorithm is proposed to perform a Bayesian identification of compartmental models, and an empirical Bayesian technique is proposed to propagate information among multiple experiments. The power of this methodology was demonstrated by evaluating the kinetics of thiamine under several experimental conditions. The complexity of the existing model (nine parameters) and limited experimental data (8/12 for each model) caused a posteriori identifiability problems when standard approaches were adopted. The application of the methodology identifies all 28 models (four tissues under seven different conditions).

Animals↗