Confocal 3D DNA cytometry: assessment of required coefficient of variation by computer simulation.
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Computer Simulation↗
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Comparison of computer simulations of total lung deposition to human subject data in healthy test subjects.
A mathematical model was used to predict the deposition fractions (DF) of PM within human lungs. Simulations using this computer model were previously validated with human subject data and were used as a control case. Human intersubject variation was accounted for by scaling the base lung morphology dimensions based on measured functional residual capacity (FRC) values. Simulations were performed for both controlled breathing (tidal volumes [VT] of 500 and 1000 mL, respiratory times [T] from 2 to 8 sec) and spontaneous breathing conditions. Particle sizes ranged from 1 to 5 microns. The deposition predicted from the computer model compared favorably with the experimental data. For example, when VT = 1000 mL and T = 2 sec, the error was 1.5%. The errors were slightly higher for smaller tidal volumes. Because the computer model is deterministic (i.e., derived from first principles of physics), the model can be used to predict deposition fractions for a range of situations (i.e., for different ventilatory parameters and particle sizes) for which data are not available. Now that the model has been validated, it may be applied to risk assessment efforts to estimate the inhalation hazards of airborne pollutants.
Adult↗
Blood glucose control by intermittent loop closure in the basal mode: computer simulation studies with a diabetic model.
A semiclosed loop, bedside insulin infusion system using a simple basal infusion algorithm consisting of a linear transition between two insulin delivery rates as blood glucose (BG) increases has been developed. A theoretical study using computer simulation has now been undertaken to examine the effect of BG sampling frequency and algorithm parameters on BG control. A model for BG control by exogenous insulin in the individual with diabetes was developed from a model for healthy subjects and from clinical data in the literature. Results of computer simulation using this model showed a decrease in BG stability as the sampling interval increased from 1 to 4 h. Simulations also showed a decrease in BG stability as the sensitivity of the control algorithm increased. Choice of an appropriate basal control algorithm involved a compromise between stability, sampling interval, and metabolic control. We conclude that satisfactory metabolic control can be obtained using intermittent BG sampling in the basal state; sampling at intervals of 3 h combined with a basal control algorithm whereby insulin delivery rate increases linearly from 0.5 to 2.5 U/h over the BG range 2-12 mmol/L appears suitable for most diabetic persons. Three-hour sampling offers a good compromise between degree of metabolic control and clinical effort involved.
Blood Glucose↗
[A computer simulation of outcome in early screening studies of cancers of the mouth cavity].
The purpose of the simulation was to design a specific cancer screening programme for squamous cell carcinomas of the head and neck to make detailed estimates of the outcomes of different screening programme options. Therefore, a mathematical model of screening (Eddy) was transformed and simulated with a computer programme. The model is designed as a Markov chain with 7 states and filled with clinical and epidemiological data. The results of the simulation are interpreted as representative for cancer of the oral cavity. Basing on the different system model outputs, mortality with and without screening, effect on life expectancy of the individual and the entire screened population, are discussed. For a screening interval of 6 months the increase in life expectancy for a person with cancer of the oral cavity is 5.3 years, for the entire population (men older than 40 years), however, life expectancy increases only by 9.8 days. The proportion of patients saved from tumour-associated death rose to 65%. The simulation showed a rapidly decreasing effect of the screening programme with longer screening intervals. Therefore, a public cancer screening programme is only useful with a screening interval of 6 months, and the effect on life expectancy is limited. For oropharynx and hypopharynx the possibilities of early stage detection of carcinomas are limited and nearly 60% of the cases with carcinoma of the larynx are already being treated at an early stage. The importance of public health education is emphasised.
Adult↗
Computer simulation of biological systems. Current trends.
The current status of mathematical models of biological systems is reviewed. Advances in supercomputer hardware allows more complex models to be constructed. The new generation of microcomputers are quite adequate for many computer simulations of biological systems. A theory of modeling is being developed to improve the relationship between the real biological system and the model. Deterministic models, stochastic models and applications of control theory and optimization methods are discussed. Examples given include models of molecular structure, of experimental techniques, and of biochemical reactions. It is recommended that experimental biologists consider the use of microcomputers to model the system under study as a part of their research program.
Computer Simulation↗
Carbohydrates and drug discovery--the role of computer simulation.
Recent advances in the molecular modelling of carbohydrates have brought this technique to a level comparable with that of protein and nucleic acid simulations. After a brief introduction to the techniques used in the computer simulation of carbohydrates and carbohydrate interactions, an overview of applications in the field of carbohydrate-related drug discovery is presented.
Antithrombin III↗
Computer simulation for postmortem cooling processes in the outer ear.
INTRODUCTION: A simulation using a computer model was undertaken to investigate postmortem cooling patterns in the outer ear. METHODS: Cooling patterns were analyzed using a 3-dimensional head model built from brain CT images of a volunteer. The simulation was verified with a case subject under constant environmental conditions to obtain an appropriate heat transmission coefficient. RESULTS: The cooling pattern of the head model agreed with that of the case subject when the heat transmission coefficient was 6W/m(2) degrees C, and it could be approximated to a single exponential curve. DISCUSSION: This is the first simulative study to show the postmortem cooling pattern of the head of an adult human. Our head model will prove useful to predict the cooling patterns of not only the outer ear but also of the entirety of the head.
Body Temperature↗
Cellular sodium transport in arterial wall--summary of studies by digital computer simulation.
The distribution of electrolytes between extracellular and intracellular compartments is of greater functional significance in biological tissues than the total amount. A method commonly employed for the study of a substance distribution among different spaces is the continuous outflow and radioisotope counting of a fragment of tissue previously incubated with a radioactive tracer (here 22Na+). The experimental data can be analyzed within the frame of a compartmental analysis system which is defined by transport rate constants (kij) and solved when all kij are numerically determined. In practical applications the direct solution requires measurements in different compartments or knowledge of the initial condition for each compartment, but this is not possible in most biological tissues where the experimentally observable data represent the summation of tracer in all compartments at each point in time. The availability of the SAAM (Simulation, Analysis And Modelling) computer program allows for a powerful simulation procedure to arrive at values for kij. Experimental data and specifications for a chosen model are entered in the SAAM format. A simulated 'inflow' experiment is made by the computer by assigning to kij some estimate values. All initial conditions are now zero, since at the beginning there is no radioactive tracer in any compartment. After a time equivalent in the experimental realm to achieving constant specific activity, a 'time change' programmed into the computer takes place so that the outflow part of the experiment is developed with the same kij as for the inflow part, the final conditions for the inflow before the time change being the initial conditions for the outflow. An iterative procedure modifies the initial estimates of kij to seek the best fit. By coupling a powerful simulation procedure to an advanced radionuclide tracer biological methodology, we have been able to find effects of the hormone aldosterone and of experimental hypertension on Na+ distribution in arterial wall years before such effects were demonstrated by purely conventional experimental techniques. This computer simulation procedure may be suited to other experimental situations in which outflow data are the only available.
Aldosterone↗
Designing computer simulations.
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Computer Simulation↗
Monte Carlo computer simulation of water-amino acid interactions.
The sensitivity of computer simulated solvent structures to changes in both non-bonded (Lennard-Jones) coefficients and partial atomic charges has been investigated with use of amino acid hydrate crystals in which the water structure is well defined experimentally. The polarizable electropole (p.e.) model of water has been extended to describe water-protein interactions; thus, the cooperative nature of the hydrogen bond (i.e. non-pair additive effects) is allowed for through a polarizable dipole. By means of Monte Carlo calculations, the predicted water positions were found to be very sensitive to the input parameters used to define both the non-bonded and electrostatic interactions. Root mean square deviations between simulated and X-ray structures were not always adequate to describe these differences and so more detailed comparisons were made. Non-pair additive effects were shown to lead to large changes in water dipoles, the values of which depended specifically on the system under consideration.
Amino Acids↗
Pharmacokinetic computer simulations of the relationship between in vivo and in vitro neuroreceptor subtype selectivity of radioligands.
Pharmacokinetic computer simulations reveal a discrepancy between the in vivo and in vitro neuroreceptor subtype selectivity of radioligands. For radioligands with an in vitro neuroreceptor subtype selectivity between 0.1 and 10.0, the in vivo neuroreceptor subtype selectivity appears to be constrained to be between 0.1 and 10.0, but, in general, is not equal to the in vitro selectivity. For example, if the in vitro selectivity is 1.0 (that is, the radioligand is nonselective in vitro) the in vivo selectivity may be thought of as a random variable having a significant nonzero probability for values as low as 0.1 or as high as 10.0, with a moderate peak at a value of 1.0. For a radioligand whose in vitro subtype selectivity is greater than 10.0, the in vivo selectivity is bounded above by the in vitro subtype selectivity, but may be several orders of magnitude lower than the in vitro subtype selectivity. Thus, in spite of the discrepancy between the in vivo and in vitro neuroreceptor subtype selectivity of radioligands, there are two useful inferences about the in vivo selectivity that might be drawn from knowledge of the in vitro selectivity: (1) If the in vitro selectivity is between 0.1 and 10.0, then, at best, the in vivo selectivity might be as high as 10.0. (2) If the in vitro selectivity is greater than 10.0, then, at best, the in vivo selectivity might be as high as the in vitro selectivity.
Animals↗
Predicting the usefulness of therapeutic drug monitoring of mycophenolic acid: a computer simulation.
The usefulness of therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) was investigated with a computer simulation model. For a fixed-dose (FD) and a concentration-controlled (CC) MMF dosing regimen exposure to mycophenolic acid (MPA) was compared. A nonlinear mixed-effects model (NONMEM) for MPA based on extensive pharmacokinetic data from 140 renal transplant recipients who all used cyclosporine and corticosteroids as maintenance immunosuppressive therapy provided Bayesian estimates for MPA oral clearance on 9 occasions during the first 24 weeks after transplantation. In 45 of these patients, the estimates for MPA oral clearance were used to calculate values for the area under the curve (AUC) of MPA. In the CC group, MMF doses were adjusted based on the calculated AUC, targeting at an AUC level of 45 mg.h/L. In the FD group, MMF doses were fixed at 1000 mg. On day 7 after transplantation, significantly more AUC values were on target (AUC range 30-60 mg.h/L) in the CC group than in the FD group: 76% versus 13%, respectively, P < 0.001. To accomplish this, a doubling of MMF dose was necessary in more than half of the patients after the AUC assessment on day 3 after transplantation. Between-patient variability (BPV) in AUC (average CV% for all occasions) was reduced in the CC regimen: 23% versus 44% in the FD group. By using TDM, adequate MPA exposure appears to be obtained more rapidly, and BPV in exposure is reduced. To reach target AUC levels as soon as possible in this cyclosporine-treated population, it appears that larger MMF doses as currently recommended are necessary in the first month after transplantation.
Administration, Oral↗
Interface design and cognitive style in learning an instructional computer simulation.
An experimental design was used to investigate how cognitive style interacts with interface design to affect users' abilities to learn to use a computer simulation. Eighteen nursing students were assigned to two groups, based on their cognitive style, and asked to solve 3 physiologic problems using 3 interface designs: a strip-chart display, an integrated balloon display, and an etiologic display. Students were given up to 2 minutes to solve each problem by administering 6 different hypothetical drugs targeted at different aspects of the simulated hemodynamic system. A mixed-design analysis of variance was used to determine the effects of interface design and cognitive style on number of problems solved, time to initiate treatment, percentage of time system maintained within normal parameters, and number of drugs used. We found that the effects of cognitive style on performance were mediated by interface design and tended to decrease with practice.
Analysis of Variance↗
Computer simulation improves on laboratory benchmarking.
Benchmarking of hospital laboratory services is about to take a new twist, as computer simulations allow managers to see proposed efficiency improvements in action before investing in new equipment or staff changes.
Benchmarking↗
Action potential refractory period in axonal demyelination: a computer simulation.
Axonal demyelination leads to an increase in the refractory period for propagation of the action potential. Computer simulations were used to investigate the mechanism by which changes in the passive properties of the internodal membrane increase the refractory period. The properties of the voltage dependent ion channels can be altered to restore conduction in demyelinated nerve fibers. The ability of these alterations to decrease the refractory period of demyelinated model nerve fibers was compared. The model nerve fiber contained six nodes. The action potential was stimulated at node one and propagated to node six. The internode between nodes three and four was demyelinated in a graded manner. The absolute refractory period for propagation of the action potential through the demyelinated internode increased as the number of myelin wraps was reduced to less than 25% of the normal value. The increase in refractory period was found to be due to a reduction in the rate or repolarization of the action potential at node three. The delay in repolarization reduced the rate of recovery of inactivated Na channels and slowed the closing of K channels. The rate of repolarization of node three was reduced by the conduction delay for the depolarization of node four caused by demyelination of the preceding internode. In these simulations the increase in refractory period due to demyelination was eliminated by slowing the onset of Na channel inactivation. A small reduction of the K conductance also decreased the refractory period. However, larger reductions eliminated this effect.
Action Potentials↗
Computer simulation of cerebellar information processing.
Although many functions have been ascribed to the cerebellum, the uniformity of its synaptic organization suggests that a single, characteristic computation may be common to all. Computer simulations are useful in examining this cerebellar computation, as they inherently address function at the level of information processing. Progress is facilitated by factors that make the cerebellum particularly amenable to such analysis. We review progress from two contrasting approaches. Top-down simulations begin with hypotheses about computational mechanisms and then ask how such mechanisms might operate within the cerebellum. Bottom-up simulations attempt to build a representation of the cerebellum that reflects known cellular and synaptic components as accurately as possible. We describe recent advances from these two approaches that are leading to an understanding of what information the cerebellum processes and how its neurons and synapses accomplish this task.
Action Potentials↗
Computer simulations of mitosis and interdependencies between mitosis orientation, cell shape and epithelia reshaping.
Finite element-based computer simulations are used to investigate mitosis and how mitosis, cell shape, and epithelium reshaping depend on each other. Frame- and cell-oriented patterns of mitosis with growing and non-growing daughter cells are considered. Previous simulations have shown that applied stresses or strains can reshape cells so that their long axes are aligned in the principal stretch direction. The simulations reported here show that this can produce global alignment of the mitosis cleavage planes. Other simulations reported here show that mitoses with suitably aligned cleavage planes can drive epithelium reshaping. Formulas that quantify these and other dependencies are derived. These formulas provide quantitative relationships against which current hypotheses regarding epithelia reshaping in real biological systems can be evaluated.
Animals↗
Computational simulation of intracoronary flow based on real coronary geometry.
OBJECTIVE: To assess the feasibility of computationally simulating intracoronary blood flow based on real coronary artery geometry and to graphically depict various mechanical characteristics of this flow. METHODS: Explanted fresh pig hearts were fixed using a continuous perfusion of 4% formaldehyde at physiological pressures. Omnipaque dye added to lead rubber solution was titrated to an optimum proportion of 1:25, to cast the coronary arterial tree. The heart was stabilized in a phantom model so as to suspend the base and the apex without causing external deformation. High resolution computerized tomography scans of this model were utilized to reconstruct the three-dimensional coronary artery geometry, which in turn was used to generate several volumetric tetrahedral meshes of sufficient density needed for numerical accuracy. The transient equations of momentum and mass conservation were numerically solved by employing methods of computational fluid dynamics under realistic pulsatile inflow boundary conditions. RESULTS: The simulations have yielded graphic distributions of intracoronary flow stream lines, static pressure drop, wall shear stress, bifurcation mass flow ratios and velocity profiles. The variability of these quantities within the cardiac cycle has been investigated at a temporal resolution of 1/100th of a second and a spatial resolution of about 10 microm. The areas of amplified variations in wall shear stress, mostly evident in the neighborhoods of arterial branching, seem to correlate well with clinically observed increased atherogenesis. The intracoronary flow lines showed stasis and extreme vorticity during the phase of minimum coronary flow in contrast to streamlined undisturbed flow during the phase of maximum flow. CONCLUSIONS: Computational tools of this kind along with a state-of-the-art multislice computerized tomography or magnetic resonance-based non-invasive coronary imaging, could enable realistic, repetitive, non-invasive and multidimensional quantifications of the effects of stenosis on distal hemodynamics, and thus help in precise surgical/interventional planning. It could also add insights into coronary and bypass graft atherogenesis.
Animals↗