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A mathematical model of potassium ion diffusion in dentinal tubules.

Desensitizing agents containing potassium ions (K+) are believed to inactivate intradental nerves by raising extracellular [K+]. A mathematical model was used to investigate factors affecting [K+] in dentinal tubules. The most important factors affecting the steady-state tubular [K+] were the tubular fluid-flow velocity, salivary [K+] and the permeability to potassium (k) of the barrier between the tubule and the pulp. Tubular [K+] decreased with increasing outward flow velocity and increasing k. whereas the dimensions of the tubule and odontoblast process had little effect. Following a 1 min simulated application of 500 mmol/1 K+ to the dentine surface, [K+] at the inner end of the tubule increased above steady-state levels for 20-30 min. The maximum [K+] attained at the inner end of the tubule was around 30 mmol/l for an impermeable barrier (k = 0) and flow velocity of 1.4 microns/s, but lower maximum tubular [K+] were achieved when either the outward flow velocity or k was increased. The model suggests that applying potassium-containing preparations to dentine may increase [K+] at the inner ends of dentinal tubules to levels sufficient to inactivate intradental nerves. However, the localized increase in [K+] is transient, and the concentration change will be lessened by conditions that increase the tubular fluid-flow velocity or the permeability of the barrier between the tubule and pulp.

Dentin↗

Intraoperative bleeding: a mathematical model for minimizing hemoglobin loss.

BACKGROUND: The rationale for intraoperative blood transfusion is often based on incorrect concepts and criteria. STUDY DESIGN AND METHODS: A mathematical model based on physiologic measures and describing the usual pattern of surgical blood loss is presented, and a theoretical means of minimizing intraoperative hemoglobin loss with hypervolemic hemodilution is proposed. RESULTS: Intraoperative hemoglobin loss is often overestimated especially in connection with high-volume blood loss. The model of intraoperative hypervolemic hemodilution shows significant improvement in hemoglobin concentration in the immediate postoperative period, compared with normovolemic conditions. The difference is most marked at a high volume of blood loss and a high degree of maintained hypervolemia. CONCLUSION: The practice of intraoperative blood transfusion according to volume of blood lost is to be discouraged, and regular monitoring of the hematocrit is necessary to avoid unnecessary transfusion. The theoretical advantages of hypervolemic hemodilution warrant further testing of the model in a clinical setting.

Blood Loss, Surgical↗

An enzyme mechanism language for the mathematical modeling of metabolic pathways.

MOTIVATION: As a first step toward the elucidation of the systems biology of complex biological systems, it was our goal to mathematically model common enzyme catalytic and regulatory mechanisms that repeatedly appear in biological processes such as signal transduction and metabolic pathways. RESULTS: We describe kMech, a Cellerator language extension that describes a suite of enzyme mechanisms. Each enzyme mechanism is parsed by kMech into a set of fundamental association-dissociation reactions that are translated by Cellerator into ordinary differential equations that are numerically solved by Mathematica. In addition, we present methods that use commonly available kinetic measurements to estimate rate constants required to solve these differential equations.

Algorithms↗

Estimation of ferrokinetic parameters by a mathematical model in patients with primary acquired sideroblastic anaemia.

Ferrokinetic parameters were estimated in eight patients with primary acquired sideroblastic anaemia (PASA) by means of a mathematical model of iron kinetics. Both plasma 59Fe clearance and red cell utilization curves were used to identify the model parameters. The close agreement between experimental and theoretical data proved that the model can describe iron kinetics in sideroblastic anaemia. Ineffective erythropoiesis was found to be major factor in the production of the anaemia. Various degrees and patterns of peripheral haemolysis were observed. The storage iron was always markedly increased and a large non-erythroid iron turnover was calculated in the most severely affected patients. The results are compared with present knowledge of erythropoiesis in PASA.

Aged↗

A mathematical model of CO2 effect on cardiovascular regulation.

The effect of changes in arterial CO2 tension on the cardiovascular system is analyzed by means of a mathematical model. The model is an extension of a previous one that already incorporated the main reflex and local mechanisms triggered by O2 changes. The new aspects covered by the model are the O2-CO2 interaction at the peripheral chemoreceptors, the effect of local CO2 changes on peripheral resistances, the direct central neural system (CNS) response to CO2, and the control of central chemoreceptors on ventilation and tidal volume. A statistical comparison between model simulation results and various experimental data has been performed. This comparison suggests that the model is able to simulate the acute cardiovascular response to changes in blood gas content in a variety of conditions (normoxic hypercapnia, hypercapnia during artificial ventilation, hypocapnic hypoxia, and hypercapnic hypoxia). The model ascribes the observed responses to the complex superimposition of many mechanisms simultaneously working (baroreflex, peripheral chemoreflex, CNS response, lung-stretch receptors, local gas tension effect), which may be differently activated depending on the specific stimulus under study. However, although some experiments can be reproduced using a single basal set of parameters, reproduction of other experiments requires a different combination of the mechanism strengths (particularly, a different strength of the local CO2 mechanism on peripheral resistances and of the CNS response to CO2). Starting from these results, some assumptions to explain the striking differences reported in the literature are presented. The model may represent a valid support for the interpretation of physiological data on acute cardiovascular regulation and may favor the synthesis of contradictory results into a single theoretical setting.

Animals↗

[The mathematical model of the blood circulation and external respiration functional state during high-pressure oxygenation or hyperoxia].

Based on the minimal energy uptake, the proposed mathematical model of blood circulation and external respiration functioning during high-pressure oxygenation or hyperoxia allows solution of the optimization task with restrictions dictated by adequate functioning of the two systems. Optimal levels of oxygen and carbon dioxide pressure in arterial and venous blood, minute blood volume and alveolar ventilation as a function of O2 partial pressure in inspired gas mixture were determined. Calculations are compared with experimentally derived values.

Blood Circulation↗

Clinical data sets of human immunodeficiency virus type 1 reverse transcriptase-resistant mutants explained by a mathematical model.

Treatment of human immunodeficiency virus type 1 (HIV-1) infection during the clinical latency phase with drugs inhibiting reverse transcriptase (RT) reduces the HIV-1 RNA load and increases the CD4+ T-cell count. Typically, however, the virus evolves mutations in the RT gene that circumvent the drugs. We develop a mathematical model for this situation. The model distinguishes quiescent from activated CD4+ T cells, incorporates the fact that only activated cells can become productively infected by HIV-1, embodies empirical estimates for the drug resistance and the mutation frequency for each of the HIV-1 drug-resistant mutants, and assumes the antiviral immune response to remain constant over the course of the experiments. We analyze clinical data on the evolution of drug-resistant mutants for the RT inhibitors lamivudine and zidovudine. The results show that the evolutionary sequence of the drug-resistant mutants in both data sets is accounted for by our model, given that lamivudine is more effective than zidovudine. Thus, current empirical estimates of the mutation frequencies and the drug resistances of the mutants suffice for explaining the data. We derive a critical treatment level below which the wild-type HIV-1 RNA load can rebound before the first drug-resistant mutant appears. Our zidovudine data confirm this to be the case. Thus, we demonstrate in the model and the data that the rebound of the HIV-1 RNA load in the case of zidovudine is due to the outgrowth of wild-type virus and the first drug-resistant mutant, whereas that in the case of lamivudine can only be due to the drug-resistant mutants. The evolution of drug resistance proceeds slower in the case of zidovudine because (i) zidovudine is not as effective as lamivudine and (ii) the first zidovudine drug-resistant mutant is competing with the rebounding wild-type virus.

Drug Resistance, Microbial↗

Mathematical modeling and optimization of cellulase protein production using Trichoderma reesei RL-P37.

The enzyme cellulase, a multienzyme complex made up of several proteins, catalyzes the conversion of cellulose to glucose in an enzymatic hydrolysis-based biomass-to-ethanol process. Production of cellulase enzyme proteins in large quantities using the fungus Trichoderma reesei requires understanding the dynamics of growth and enzyme production. The method of neural network parameter function modeling, which combines the approximation capabilities of neural networks with fundamental process knowledge, is utilized to develop a mathematical model of this dynamic system. In addition, kinetic models are also developed. Laboratory data from bench-scale fermentations involving growth and protein production by T. reesei on lactose and xylose are used to estimate the parameters in these models. The relative performances of the various models and the results of optimizing these models on two different performance measures are presented. An approximately 33% lower root-mean-squared error (RMSE) in protein predictions and about 40% lower total RMSE is obtained with the neural network-based model as opposed to kinetic models. Using the neural network-based model, the RMSE in predicting optimal conditions for two performance indices, is about 67% and 40% lower, respectively, when compared with the kinetic models. Thus, both model predictions and optimization results from the neural network-based model are found to be closer to the experimental data than the kinetic models developed in this work. It is shown that the neural network parameter function modeling method can be useful as a "macromodeling" technique to rapidly develop dynamic models of a process.

Cellulase↗

A mathematical model of the P-glycoprotein pump as a mediator of multidrug resistance.

Cells displaying the classic multidrug resistant (MDR) phenotype possess a transmembrane protein (p170 or P-glycoprotein) which can actively extrude cytotoxic agents from the cytoplasm. A mathematical model of this drug efflux pump has been developed. Outward transport is modeled as a facilitated diffusion process. Since energy-dependent efflux of cytotoxic agents requires that ATP also bind to p170, the model includes a dynamic calculation for efflux rate which considers Michaelis-Menten kinetics for both the substrate agent and ATP. The final system consists of one partial differential equation (PDE) for the facilitated diffusion of substrate agents out of the cell, a 2 x 2 ordinary differential equation (ODE) system for the dynamic calculation of the ATP-ADP pool, and a dynamic algebraic calculation of the efflux rate given substrate levels at the interior cell membrane interface and ATP levels in the cell. A stability analysis of the ATP-ADP pool distribution and a simplistic closed form solution of the linearized PDE are included. Numerical simulations are also provided.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

[The synthesis of mathematical models of the branched axons and dendrites].

A mathematical apparatus of computer modelling was elaborated reflecting more completely the real morphological and electrophysiological features of axons and dendrites without restrictions and simplifications which were typical of the existing models of these structures. Equivalent electrical circuits of branching axons and dendrites were constructed with in-series and node connections of standard four-terminal networks corresponding to elementary segments with active or passive membrane. Basing on these circuits the equations were obtained describing electrical phenomena in branching neuronal processes. They were generalized for the case of multiple binary branching with arbitrary symmetry and geometry of the branches. A difference scheme common for the whole class of models under consideration was also constructed and an algorithm was elaborated for numerical solution of the obtained system of difference equations. The suggested model allows synthetizing a variety of models of branching axons and dendrites, that promotes the possibilities of model investigation of electrotonus, propagated excitation and their interactions.

Animals↗

High-dose methotrexate: a clinical and pharmacokinetic evaluation. Treatment of advanced squamous cell carcinoma of the head and neck using a prospective mathematical model and pharmacokinetic surveillance.

Some of 66 patients with head and neck tumors were treated with high-dose methotrexate monochemotherapy. The use of a prospective mathematical model with pharmacokinetic surveillance proved to be reliable, practical, and useful. By this means chemotherapy could be individualized, with a resultant marked reduction in the frequency and severity of toxicity. The onset of clinical toxic manifestations was significantly correlated with a poor therapeutic response and poor prognosis. The patients were classified in to three groups according to poor, intermediate, and good pharmacokinetic parameters calculated after an intravenous identification dose of methotrexate. These group allocations had a very high prognostic value with regard to toxicity, and especially to the quality of therapeutic response to high-dose methotrexate. They are suggested as useful guidelines in the prescription of high-dose methotrexate chemotherapy.

Adult↗

Mlab--a mathematical modeling tool.

An interactive interpreter called Mlab is described. One uses Mlab by typing commands. In this sense, Mlab is a programming language. It has various mathematical and graphical facilities which make it a useful tool for mathematical modeling. The curve fitting capabilities of Mlab are augmented with differential-equation-handling and matrix-manipulation capabilities which provide a powerful and civilized facility for curve fitting. Many people are engaged in this activity, and, in general, they use programs which are neither sufficiently general nor easy to use. (Some conventional programming is usually required, for example.) Mlab purports to be easier than alternate approaches. The nature of Mlab is discussed with accompanying examples. The main example is the use of curve fitting to determine molecular weight from ultracentrifuge data. This example was chosen because it exhibits a special feature of Mlab, namely the root operator, which appears in the definition of the model function.

Computers↗

Mathematical modelling of stimulus-secretion coupling in the pancreatic B-cell. II. Calcium-stimulated calcium release.

An attempt was made to simulate in a mathematical model one of the two major effects of glucose upon 45Ca fractional outflow rate from prelabelled pancreatic islets, namely the increase in effluent radioactivity which is currently ascribed to the displacement of 45Ca from intracellular sites, as resulting from a facilitated influx of unlabelled 40Ca into the islet cells. The occurrence of such a rise in effluent radioactivity and its suppression in the absence of extracellular Ca2+ could only be simulated if the release of Ca by the vacuolar system was assumed to be stimulated by a rise in the cytosolic Ca concentration. It is proposed therefore that, in islets like in muscle, a process of Ca-stimulated Ca release may participate in the regulation of intracellular Ca distribution.

Animals↗

A mathematical model of a high sulphate wastewater anaerobic treatment system.

As an aid to the design and operation of anaerobic digesters treating high sulphate waste waters, a mathematical model describing this treatment process has been developed. Apart from sulphate reduction, the model includes those reactions which occur either prior to sulphate reduction or in competition with it. These include, hydrolysis of solid substrates, acidogenesis. beta oxidation of long chain fatty acids, acetogenesis and methanogenesis. By incorporating terms for these reactions the model is able to simulate sulphate reduction using a wide range of carbon sources. Acid/base equilibrium chemistry is included in order to predict the pH and unionized component concentrations, needed for calculating inhibition. An activity based model is used, with the activity coefficients calculated using Debye-Hückle theory. The mass transfer rates of hydrogen, methane, carbon dioxide and hydrogen sulphide from the liquid to the vapour phase are also included. A number of different reactor types may be simulated, including a dynamic batch. steady state CSTR and dynamic CSTR. By separating the hydraulic and solids residence times, high rate reactors such as UASB and packed bed reactors may also be simulated. The model has been used to successfully predict the dynamic and steady state behaviour of a number of different reactor types, utilizing both simple and complex carbon sources.

Bacteria, Anaerobic↗

A mathematical model of forces in the knee under isometric quadriceps contractions.

OBJECTIVE: To predict the knee's response to isometric quadriceps contractions against a fixed tibial restraint.Design. Mathematical modelling of the human knee joint. BACKGROUND: Isometric quadriceps contraction is commonly used for leg muscle strengthening following ligament injury or reconstruction. It is desirable to know the ligament forces induced but direct measurement is difficult. METHODS: The model, previously applied to the Lachmann or 'drawer' tests, combines an extensible fibre-array representation of the cruciate ligaments with a compressible 'thin-layer' representation of the cartilage. The model allows the knee configuration and force system to be calculated, given flexion angle, restraint position and loading. RESULTS: Inclusion of cartilage deformation increases relative tibio-femoral translation and decreases the ligament forces generated. For each restraint position, a range of flexion angles is found in which no ligament force is required, as opposed to a single flexion angle in the case of incompressible cartilage layers. CONCLUSIONS: Knee geometry and ligament elasticity are found to be the most important factors governing the joint's response to isometric quadriceps contractions, but cartilage deformation is found to be more important than in the Lachmann test. RELEVANCE: Estimation of knee ligament forces is important when devising exercise regimes following ligament injury or reconstruction. The finding of a 'neutral zone' of zero ligament force may have implications for rehabilitation of the ligament-injured knee.

Cartilage↗

A mathematical model of internal time processing in temporal lobe epilepsy.

Based on known relationships between epileptic and nonepileptic cortical cerebral blood flow, electrocorticographic factors and epileptogenicity, a mathematical model for internal time processing is derived. The model suggests that the human brain has mechanisms for internal processing of real, reverse and imaginary time.

Brain↗

Mechanisms mediating anti-CD3 antibody efficacy: insights from a mathematical model of type 1 diabetes.

Anti-CD3 antibody therapy, a promising clinical approach for the treatment of type 1 diabetes (T1D), was investigated using a mathematical model of T1D in the female nonobese diabetic (NOD) mouse. Analyses of model simulation results indicate that, in addition to the known direct effects of anti-CD3 antibody on T lymphocytes, two additional mechanisms are required for sustained disease remission: (a) rapid regrowth of healthy beta cells following clearance of islet inflammation and (b) enhanced regulatory T cell activity and/or phenotypic changes in antigen presenting cells (APCs) that promote a stable regulatory environment in the pancreas.

Animals↗