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At least 289 records · Page 16Linked to original sources
PubMed1983

Quantitative model for multiple levels of drug resistance in clinical tumors.

A mathematical model to examine the effect of cellular differentiation on phenotypic drug resistance in neoplasms is proposed. Attention is restricted to the maintenance of stem cell proliferative capacity. For fixed mutation rates, tumors in which loss of stem cell capacity occurs with high frequency will have a higher proportion of resistant stem cells than those in which such loss is infrequent. The acquisition of multiple levels of drug resistance will proceed at a disproportionately accelerated pace, which leads to greater degrees of incurability for tumors with a stem cell compartment of a given size. This model directly predicts that the phenotypic heterogeneity of slow-growing advanced clinical tumors will be very great. However, as this heterogeneity depends on both the size and the age of the tumor, there will be a period early in the development of the tumor when it should be susceptible to drug-induced cure. This potential for curability at an early stage may not be reflected in the pattern of drug responsiveness of the advanced tumor.

Antineoplastic Agents↗
PubMedDate not supplied

[Quantitative model of human erythrocyte glycolysis. II. Effect of arsenate on glycolysis. Experimental study of the relationship between the rate of glycolysis and the ATP concentration].

The effect of arsenate on human erythrocyte glycolysis was studied. The stationary rate of glucose consumption rises and then drops with a gradual increase of arsenate concentration while ATP and glucose-6-phosphate concentrations drop monotonically. A plot of glucose consumption rate against ATP concentration gives a bell-like curve. This curve is the same for different donors if it is plotted in relative units with values at zero arsenate concentration taking for 100%, while the absolute values obtained for separate donors are very different. The normal (physiological) point is situated on the steeply descending part of the curve.

Adenosine Triphosphate↗
PubMed1980

Comparison of nineteen quantitative models for assessment of localized left ventricular wall motion abnormalities.

The usefulness of 19 models (8 of half-axis models, 3 radial models, and 8 segmental area models) for detection of local left ventricular wall motion abnormalities was analyzed in biplane cineventriculograms of 14 normals, 12 patients with anteroseptal, 10 with inferior, and 8 with posterolateral infarction. Extent of shortening of 22 half-axes and decrease of 24 areas were calculated in each projection. Mean values and one-sigma deviation were calculated for all axes in the group of normals and for those axes which pertained to segments of myocardial infarction in the group of coronary artery disease patients. Area model 3.5 yielded the largest number of significantly different areas between normal and infarcted ventricles. Sensitivity for recognition of myocardial infarction was calculated at 90% specificity by means of receiver operating characteristic curves. The greatest sensitivities were obtained with radial model 2.3, which yielded 83.3% true positive results for anteroseptal infarction, 90% for inferior infarction, and 87.5% for posterolateral infarctions. The best area model 3.5 yielded sensitivity between 67.5 and 80% only. Thus, in contrast to the literature, receiver operating characteristic analysis revealed radial model 2.3 to be most accurate in the assessment of local wall motion abnormalities.

Coronary Disease↗
PubMed1997

Effect of polyamine-induced compaction and aggregation of DNA on the formation of radiation-induced strand breaks: quantitative models for cellular radiation damage.

The yield of DNA single-strand breaks, G(SSB), upon gamma irradiation of SV40 DNA and SV40 minichromosomes in aqueous solution under aerobic conditions was determined at physiological ionic strength in the presence of various potential radioprotective agents. Putrescine (PUT), spermidine (SPD), glutathione, trans-4,5-dihydroxy-1,2-dithiane, 2-mercaptoethyl disulfide and cystamine, all at 0.1-10 mM, spermine (SPM, 0.1-1 mM) and WR-33278 (WRSSWR, 0.1-2 mM) lowered G(SSB) of SV40 DNA. These results were expected from the ability of these agents to scavenge OH radical in the bulk solution. However, SPD, above 10 mM, and SPM and WRSSWR, each above 2 mM, produced dramatic radioprotection attributed to polyamine-induced compaction and aggregation of the DNA (PICA effect). The DNA of SV40 minichromosomes was inherently less radiosensitive and was subject to a PICA effect at lower polyamine concentrations, i.e. approximately 5 mM SPD, approximately 0.6 mM SPM and approximately 0.5 mM WRSSWR. The PICA effect decreased G(SSB) for SV40 DNA and minichromosomes by one to two orders of magnitude, depending upon the scavenging capacity of the medium. The final yields were similar for SV40 DNA and minichromosomes and were comparable to the corresponding yield determined for cells. Results for the yield of double-strand breaks indicated that the yield of double-strand breaks, G(DSB), for DNA and minichromosomes is subject to a PICA effect by SPM and SPD comparable to that measured for G(SSB). Values of G(SSB) for SV40 DNA and minichromosomes subjected to the PICA effect were well approximated by calculations based upon a 30-nm cylinder assumed to model their condensed states. The results indicate that a major fraction of the formation of SSBs in condensed DNA and minichromosomes results from nonscavengeable radical intermediates. Minichromosomes subjected to the PICA effect of 2 mM SPM were protected against formation of radiation-induced SSBs 1.5-fold by 20 mM DTT but 5-fold by 10 mM DTT plus 10 mM WR-1065 relative to 2 mM SPM alone. Thus WR-1065 is capable of providing marked protection of compacted and aggregated minichromosomes, a protection ascribed to the chemical repair of DNA radicals by WR-1065.

Cystamine↗
PubMed1998

Pheromone deactivation catalyzed by receptor molecules: a quantitative kinetic model.

A quantitative model of pheromone-receptor interaction and pheromone deactivation, the supposed rate-limiting processes underlying the receptor potential kinetics, is worked out for the moth Antheraea polyphemus. In this model, the pheromone interacts with the receptor molecule while bound to the reduced form of the pheromone binding protein. The receptor molecules--besides their receptor function--catalyze the observed shift of the pheromone-binding protein from the reduced to the oxidized form (Ziegelberger, G., Eur. J. Biochem., 232, 706-711, 1995), which deactivates the pheromone bound to pheromone binding protein. With the following parameters, the model fits morphological, radiometric, electrophysiological and biochemical data: a maximum estimate of 1.7 x 10(7) receptor molecules/cell (with 40,000 units/micron 2 of receptor cell membrane), rate constants k1 = 0.2/(s.microM) for the association, k2 = 10/s for the dissociation of the ternary complex of binding protein, pheromone and receptor, and k3 = 10/s for the deactivation via the redox shift. With these parameters, the duration of elementary receptor potentials elicited by single pheromone molecules (approximately 50 ms) reflects the lifetime of the ternary complex, tau = 1/(k2 + k3). The receptor occupancy produced by the model for threshold stimuli fits the sensitivity of the receptor cell to single pheromone molecules.

Animals↗
PubMed1984

Analysis of variability in albumin content of sister hepatoma cells and a model for geometric phenotypic variability (quantitative shift model).

A model (quantitative shift model) is presented that can account for the phenomenon termed geometric phenotypic variability in which quantitative variation occurs along a square root 2-fold geometric series. The model is based on data for variability in albumin content in hepatoma cells and has three basic assumptions: (i) The albumin genes on each chromosome are active and under independent quantitative regulation. (ii) The rate of albumin gene transcription per cell is the sum of the rates of transcription of the genes of each chromosome. (iii) The mechanism that controls the rate of transcription is highly variable so that at each cell cycle there is a high probability (P = 0.1-0.3) that on the newly synthesized chromatid the rate of transcription of the albumin gene will be different from that of the old chromatid. However, if the rate is different, it will usually be either half or twice the levels of the old chromatid. A computer program was developed based on the model that can generate quantitative diversity in single cells that mimics the pattern of variability in albumin content between sister hepatoma cells, among cells in clonal colonies, and in cell populations where the periodicities in single-cell distributions are compared by Fourier transform analysis. It was determined that the rate of phenotypic variability is indirectly proportional to the magnitude of the quantitative shift in albumin content and that it can be as high as 0.3 per cell per generation. Also, the square root 2 factor in geometric phenotypic variability appears to be an average of a family of values and not the actual value of the smallest quantal shift.

Animals↗
PubMed1999

Commentary: model building, quantitative testing, and model comparison.

The final goal is to create mathematical models that are based on our current knowledge of the underlying physiology and that explain all of the experimental data available. To do this, we suggest a consideration of several potential mathematical structures in the formulation of models and the formal comparison of these various structures with other models in the literature. However, when making these comparisons, one must pay careful attention to the systems being modeled and the data sets chosen to represent those systems.

Data Interpretation, Statistical↗
PubMed2006

Mechanism of rectified lateral motion of particles near electrodes in alternating electric fields below 1 kHz.

A rectified electroosmotic flow mechanism and its expression in a quantitative model account for the net lateral motion of colloidal particles above a uniform planar electrode in an alternating electric field that drives a faradaic reaction on the electrode surface. Specific comparison to published particle doublet trajectories at 100 Hz in sodium hydroxide and sodium bicarbonate electrolytes demonstrates that the model quantitatively agrees with the experimental doublet trajectories when only independently measurable parameters are employed. This model reproduces the experimental signatures of the published particle pair motion at 100 Hertz: dependence of the direction of motion on the electrolyte, order of magnitude of the interparticle velocity, invariance of the lateral motion to changes in the particle zeta potential, and observed steady separation between particles that otherwise tend to aggregate. The model is expected to apply up to approximately 1 kHz, at which essentially all of the alternating current flows through the double-layer capacitance and not the faradaic reaction.

Journal Article↗
PubMed2004

Modeling the hemodynamic response to brain activation.

Neural activity in the brain is accompanied by changes in cerebral blood flow (CBF) and blood oxygenation that are detectable with functional magnetic resonance imaging (fMRI) techniques. In this paper, recent mathematical models of this hemodynamic response are reviewed and integrated. Models are described for: (1) the blood oxygenation level dependent (BOLD) signal as a function of changes in cerebral oxygen extraction fraction (E) and cerebral blood volume (CBV); (2) the balloon model, proposed to describe the transient dynamics of CBV and deoxy-hemoglobin (Hb) and how they affect the BOLD signal; (3) neurovascular coupling, relating the responses in CBF and cerebral metabolic rate of oxygen (CMRO(2)) to the neural activity response; and (4) a simple model for the temporal nonlinearity of the neural response itself. These models are integrated into a mathematical framework describing the steps linking a stimulus to the measured BOLD and CBF responses. Experimental results examining transient features of the BOLD response (post-stimulus undershoot and initial dip), nonlinearities of the hemodynamic response, and the role of the physiologic baseline state in altering the BOLD signal are discussed in the context of the proposed models. Quantitative modeling of the hemodynamic response, when combined with experimental data measuring both the BOLD and CBF responses, makes possible a more specific and quantitative assessment of brain physiology than is possible with standard BOLD imaging alone. This approach has the potential to enhance numerous studies of brain function in development, health, and disease.

Algorithms↗
PubMed2005

Three distinct categories of time course of pain produced by oral capsaicin.

UNLABELLED: Humans vary in oral pain tolerance. Our earlier studies noted that the responses of subjects show 1 of 3 qualitative response patterns to a single oral capsaicin concentration, which we termed a tonic pattern (level detection response), a phasic pattern (change detection response), and an integrator pattern (cumulative irritation) response. These patterns were modeled quantitatively as the sum of 3 underlying processes. Two time-varying capsaicin stimulus profiles were designed from the quantitative model. In the ascending step paradigm, 30 ppm capsaicin was presented to 42 subjects for 15 minutes, followed immediately and without explanation by 300 ppm capsaicin for 25 minutes. In the descending step paradigm, 300 ppm capsaicin was presented to 36 other subjects for 24 minutes, followed by 10 ppm for 22 minutes. Subjective burn was rated at 1 minute and then at 3-minute intervals throughout the presentation. Fuzzy cluster analysis identified 3 distinct response phenotypes in each paradigm, corresponding to level detection, change detection, and cumulative irritation response patterns identified previously. Discriminant functions permitted classification of these phenotypes from the response patterns. Thus, these paradigms provide the first quantitative phenotypic description of distinct oral pain responses to a common irritant, capsaicin. PERSPECTIVE: This study examined the time-dependent behavior of pain produced by oral application of capsaicin. Three distinct temporal response phenotypes were identified objectively: level detection, change detection, and cumulative irritation detection. These time-dependent analyses provide a new dimension to understanding individual differences in pain sensation in clinical settings.

Administration, Oral↗
PubMedDate not supplied

Causal reasoning in computer programs for medical diagnosis.

Over the last decade substantial advances have been made in the use of causal pathophysiological knowledge in artificial intelligence-based programs for medical diagnosis. Various forms of causal representations have been used. They include probabilistic models, quantitative models, qualitative models, and models that describe causal relations at multiple levels of detail. This paper briefly analyses these methods using three representative systems. Outstanding problems and possible direction in further exploitation of causal reasoning for medical decision-support systems are also discussed.

Artificial Intelligence↗