SEARCH · PubMed Health

Results for “computational modelling”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 649 records · Page 36Linked to original sources

PubMed1994

Computer model challenges breast cancer treatment strategy.

The breast cancer treatment failure rate remains unacceptably high. The current breast cancer treatment paradigm, based primarily on Gompertzian kinetics and animal models, advocates short-course, intensive chemotherapy subsequent to tumor debulking, citing drug resistance and host toxicity as the primary reasons for treatment failure. To better understand treatment failure, we have studied breast cancer from the perspective of computer modeling. Our results demonstrate breast cancers grow in an irregular fashion; this differs from the Gompertzian mode of animal models and thus challenges the validity of the current paradigm. Clinical and laboratory data support the concept of irregular growth rather than the common claim that human tumors grow in a Gompertzian fashion. Treatment failure mechanisms for breast cancer appear to differ from those for animal models, and thus treatments optimize on animal models may not be optimal for breast cancer. A failure mechanism consistent with our results involves temporarily dormant tumor cells in anatomical or pharmacological sanctuary, which eventually result in aggressive metastatic disease.

Animals↗

PubMed2006

A method of quantification of stress shielding in the proximal femur using hierarchical computational modeling.

Stress shielding is a biomechanical phenomenon causing adaptive changes in bone strength and stiffness around metallic implants, which potentially lead to implant loosening. Accordingly, there is a need for standard, objective engineering measures of the "stress shielding" performances of an implant that can be employed in the process of computer-aided implant design. To provide and test such measures, we developed hierarchical computational models of adaptation of the trabecular microarchitecture at different sites in the proximal femur, in response to insertion of orthopaedic screws and in response to hypothetical reductions in hip joint and gluteal muscle forces. By identifying similar bone adaptation outcomes from the two scenarios, we were able to quantify the stress shielding caused by screws in terms of analogous hypothetical reductions in hip joint and gluteal muscle forces. Specifically, we developed planar lattice models of trabecular microstructures at five regions of interest (ROI) in the proximal femur. The homeostatic and abnormal loading conditions for the lattices were determined from a finite element model of the femur at the continuum scale and fed to an iterative algorithm simulating the adaptation of each lattice to these loads. When screws were inserted to the femur model, maximal simulated bone loss (17% decrease in apparent density, 10% decrease in thickness of trabeculae) was at the greater trochanter and this effect was equivalent to the effect of 50% reduction in gluteal force and normal hip joint force. We conclude that stress shielding performances can be quantified for different screw designs using model-predicted hypothetical musculoskeletal load fractions that would cause a similar pattern and extent of bone loss to that caused by the implants.

Arthroplasty, Replacement, Hip↗

PubMed2006

Computational model of vascular endothelial growth factor spatial distribution in muscle and pro-angiogenic cell therapy.

Members of the vascular endothelial growth factor (VEGF) family of proteins are critical regulators of angiogenesis. VEGF concentration gradients are important for activation and chemotactic guidance of capillary sprouting, but measurement of these gradients in vivo is not currently possible. We have constructed a biophysically and molecularly detailed computational model to study microenvironmental transport of two isoforms of VEGF in rat extensor digitorum longus skeletal muscle under in vivo conditions. Using parameters based on experimental measurements, the model includes: VEGF secretion from muscle fibers; binding to the extracellular matrix; binding to and activation of endothelial cell surface VEGF receptors; and internalization. For 2-D cross sections of tissue, we analyzed predicted VEGF distributions, gradients, and receptor binding. Significant VEGF gradients (up to 12% change in VEGF concentration over 10 mum) were predicted in resting skeletal muscle with uniform VEGF secretion, due to non-uniform capillary distribution. These relative VEGF gradients were not sensitive to extracellular matrix composition, or to the overall VEGF expression level, but were dependent on VEGF receptor density and affinity, and internalization rate parameters. VEGF upregulation in a subset of fibers increased VEGF gradients, simulating transplantation of pro-angiogenic myoblasts, a possible therapy for ischemic diseases. The number and relative position of overexpressing fibers determined the VEGF gradients and distribution of VEGF receptor activation. With total VEGF expression level in the tissue unchanged, concentrating overexpression into a small number of adjacent fibers can increase the number of capillaries activated. The VEGF concentration gradients predicted for resting muscle (average 3% VEGF/10 mum) is sufficient for cellular sensing; the tip cell of a vessel sprout is approximately 50 mum long. The VEGF gradients also result in heterogeneity in the activation of blood vessel VEGF receptors. This first model of VEGF tissue transport and heterogeneity provides a platform for the design and evaluation of therapeutic approaches.

Cell- and Tissue-Based Therapy↗

PubMed2001

Computational modeling of non-Fourier motion: further evidence for a single luminance-based mechanism.

It is generally assumed that the perception of non-Fourier motion requires the operation of some nonlinearity before motion analysis. We apply a computational model of biological motion processing to a class of non-Fourier motion stimuli designed to investigate nonlinearity in human visual processing. The model correctly detects direction of motion in these non-Fourier stimuli without recourse to any preprocessing nonlinearity. This demonstrates that the non-Fourier motion in some non-Fourier stimuli is directly available to luminance-based motion mechanisms operating on measurements of local spatial and temporal gradients.

Fourier Analysis↗

PubMed2006

Performance estimation of a Venturi scrubber using a computational model for capturing dust particles with liquid spray.

A Venturi scrubber has dispersed three-phase flow of gas, dust, and liquid. Atomization of a liquid jet and interaction between the phases has a large effect on the performance of Venturi scrubbers. In this study, a computational model for the interactive three-phase flow in a Venturi scrubber has been developed to estimate pressure drop and collection efficiency. The Eulerian-Lagrangian method is used to solve the model numerically. Gas flow is solved using the Eulerian approach by using the Navier-Stokes equations, and the motion of dust and liquid droplets, described by the Basset-Boussinesq-Oseen (B-B-O) equation, is solved using the Lagrangian approach. This model includes interaction between gas and droplets, atomization of a liquid jet, droplet deformation, breakup and collision of droplets, and capture of dust by droplets. A circular Pease-Anthony Venturi scrubber was simulated numerically with this new model. The numerical results were compared with earlier experimental data for pressure drop and collection efficiency, and gave good agreements.

Air Pollutants↗

PubMed2004

A computer model of fractal myocardial perfusion heterogeneity to elucidate mechanisms of changes in critical coronary stenosis and hypotension.

Critical coronary stenosis (critical CS) alone does not lead to an alteration of fractal dimension (D) under resting conditions in a pig model, indicating undisturbed local myocardial perfusion. If critical CS is combined with hypovolemic anemia the resulting hypotension leads to a significant decline of D. The mechanisms involved in this phenomenon have not yet been elucidated. A computer program was developed enabling calculation of D for normal vascular trees, for single vessel coronary stenosis (CS), and for CS in combination with reduced coronary perfusion pressure (CPP). The values of D obtained by the computer program were compared to those available from an existing animal study to confirm that changes of D can largely be explained by changes of arterial branching pattern simulated by the computer program. Using our computer model, D was 1.15+/-0.06 in normal vascular trees. Third branch critical CS did not alter (1.14+/-0.06; n.s.), whereas critical CS combined with a reduction of CPP to 40 mmHg reduced D (1.07+/-0.03; P < 0.05). These data are comparable to those obtained in the animal study, and therefore show that alterations of vessel diameter and regional blood flow can largely explain changes of fractal dimension during critical CS and hypotension while changes of functional myocardial parameters might play a minor role.

Animals↗

PubMed1989

Low-frequency oscillations in arterial pressure and heart rate: a simple computer model.

We have previously reported that low-frequency oscillations in arterial blood pressure (ABP) and heart rate (HR) occur when conscious dogs experience severe blood loss. These low-frequency oscillations are generated by enhancement of the sympathetic nervous system and inhibition of the parasympathetic nervous system. We have developed a simple computer model to elucidate those properties critical to the generation of these oscillations. Our model incorporates several important features: 1) arterial baroreceptor feedback loops, which relate ABP to targeted HR and total peripheral resistance (TPR) values; 2) two effector outputs, HR and TPR, which are controlled by the outputs of vagal, beta-adrenergic, and alpha-adrenergic effector mechanisms; 3) a fixed beat-to-beat stroke volume; and 4) a wind-kessel model, which represents the peripheral circulation. Each effector mechanism is modeled as a low-pass filter in series with a delay. The vagal effector mechanism slows the HR after a 100-ms delay and reaches maximal HR at that time. The beta-adrenergic effector mechanism speeds HR after a 2.5-s delay and then increases to maximal HR 7.5 s later. The alpha-adrenergic effector mechanism begins vasoconstriction after a 5-s delay and then reaches maximal contraction 15 s later. Computer simulations of inhibition of the vagal effector mechanism and activation of the adrenergic effector mechanisms elicit low-frequency oscillations in ABP and HR. These oscillations are similar to those observed experimentally in the dog during hemorrhage. We conclude that the slow temporal response of the alpha-adrenergic effector mechanism controlling TPR is the critical element in predicting the observed low-frequency oscillations in ABP and HR.

Animals↗

PubMed2005

Airway identification within planar gamma camera images using computer models of lung morphology.

PURPOSE: Quantification of inhaled aerosols by planar gamma scintigraphy could be improved if a more comprehensive assessment of aerosol distribution patterns among lung airways were obtained. The analysis of planar scans can be quite subjective because of overlaying of small, peripheral airways with large, conducting airways. Herein, a computer modeling technique of the three-dimensional (3-D) branching structure of human lung airways was applied to assist in the interpretation of planar gamma camera images. METHODS: Airway dimensions were derived from morphometric data, and lung boundaries were formulated from scintigraphy protocols. Central, intermediate, and peripheral regions were superimposed on a planar view of the 3-D simulations, and airways were then tabulated by type, number, surface area, and volume in each respective region. RESULTS: These findings indicate that the central region, for example, consists mostly of alveolated airways. Specifically, it was found that alveolated airways comprise over 99% of the total number of airways, over 95% of the total airway surface area, and approximately 80% of the total airway volume in the central region. CONCLUSIONS: The computer simulations are designed to serve as templates that can assist in the interpretation of aerosol deposition data from scintigraphy images.

Computer Simulation↗

PubMed1995

Use of computer models to assess exposure to agricultural chemicals via drinking water.

Surveys of drinking water quality throughout the agricultural regions of the world have revealed the tendency of certain crop protection chemicals to enter water supplies. Fortunately, the trace concentrations that have been detected are generally well below the levels thought to have any negative impact on human health or the environment. However, the public expects drinking water to be pristine and seems willing to bear the costs involved in further regulating agricultural chemical use in such a way so as to eliminate the potential for such materials to occur at any detectable level. Of all the tools available to assess exposure to agricultural chemicals via drinking water, computer models are one of the most cost-effective. Although not sufficiently predictive to be used in the absence of any field data, such computer programs can be used with some degree of certainty to perform quantitative extrapolations and thereby quantify regional exposure from field-scale monitoring information. Specific models and modeling techniques will be discussed for performing such exposure analyses. Improvements in computer technology have recently made it practical to use Monte Carlo and other probabilistic techniques as a routine tool for estimating human exposure. Such methods make it possible, at least in principle, to prepare exposure estimates with known confidence intervals and sufficient statistical validity to be used in the regulatory management of agricultural chemicals.

Agrochemicals↗

PubMed1988

Haloperidol binding to monoclonal antibodies. Predictions of three-dimensional combining site structure via computer modeling.

The amino acid sequences of five monoclonal antibodies (designated mAbs A-E) which bind to the dopaminergic D-2 antagonist, haloperidol, with a variety of affinities (Kd = 4-810 nM), have been used to build theoretical, three-dimensional, computer models of the variable region combining sites. Physiocochemical interactions which have been previously determined from in vitro binding data have been used to orient the drug molecule within the combining site model. The results indicate that hydrophobic, aromatic, and ionic amino acids are involved in specific interactions with the antagonist molecule. For example, fluorescence quenching data suggests that a tryptophan residue is intimately involved in the binding of haloperidol by mAb A. Examination of the modeled structure reveals five tryptophans within the variable fragment, only one of which (H-50) is within the classical beta-barrel binding pocket and is readily accessible to the antigen. Haloperidol's relatively electron poor fluorophenyl ring system stacks with the electron-rich tryptophan ring system at a distance of 3.3 A and in so doing, places haloperidol's positively charged piperidinyl nitrogen atom within hydrogen bond distance of the negatively charged Glu-95 and Asp-100A residues of the H3 loop (Glu-H-95 and Asp-H-100A). This type of analysis for each antibody provides an interesting profile of changes in amino acid composition and hypervariable loop length which markedly effect binding affinity and specificity for a series of proteins which have similar combining site.

Amino Acid Sequence↗

PubMed2002

Study of atrial arrhythmias in a computer model based on magnetic resonance images of human atria.

The maintenance of multiple wavelets appears to be a consistent feature of atrial fibrillation (AF). In this paper, we investigate possible mechanisms of initiation and perpetuation of multiple wavelets in a computer model of AF. We developed a simplified model of human atria that uses an ionic-based membrane model and whose geometry is derived from a segmented magnetic resonance imaging data set. The three-dimensional surface has a realistic size and includes obstacles corresponding to the location of major vessels and valves, but it does not take into account anisotropy. The main advantage of this approach is its ability to simulate long duration arrhythmias (up to 40 s). Clinically relevant initiation protocols, such as single-site burst pacing, were used. The dynamics of simulated AF were investigated in models with different action potential durations and restitution properties, controlled by the conductance of the slow inward current in a modified Luo-Rudy model. The simulation studies show that (1) single-site burst pacing protocol can be used to induce wave breaks even in tissue with uniform membrane properties, (2) the restitution-based wave breaks in an atrial model with realistic size and conduction velocities are transient, and (3) a significant reduction in action potential duration (even with apparently flat restitution) increases the duration of AF. (c) 2002 American Institute of Physics.

Journal Article↗

PubMed2001

Ventilation-perfusion inhomogeneity increases gas uptake in anesthesia: computer modeling of gas exchange.

Ventilation-perfusion (VA/Q) inhomogeneity was modeled to measure its effect on overall gas exchange during maintenance-phase N(2)O anesthesia with an inspired O(2) concentration of 30%. A multialveolar compartment computer model was used based on physiological log normal distributions of VA/Q inhomogeneity. Increasing the log standard deviation of the distribution of perfusion from 0 to 1.75 paradoxically increased O(2) uptake (VO(2)) where a low mixed venous partial pressure of N(2)O [high N(2)O uptake (VN(2)O)] was specified. With rising mixed venous partial pressure of N(2)O, a threshold was observed where VO(2) began to fall, whereas VN(2)O began to rise with increasing VA/Q inhomogeneity. This phenomenon is a magnification of the concentrating effects that VO(2) and VN(2)O have on each other in low VA/Q compartments. During "steady-state" N(2)O anesthesia, VN(2)O is predicted to paradoxically increase in the presence of worsening VA/Q inhomogeneity.

Anesthesia↗

PubMed2003

Hypochlorous acid-mediated oxidation of lipid components and antioxidants present in low-density lipoproteins: absolute rate constants, product analysis, and computational modeling.

Oxidation of low-density lipoproteins (LDL) is believed to contribute to the increased uptake of LDL by macrophages, which is an early event in atherosclerosis. Hypochlorous acid (HOCl) has been implicated as one of the major oxidants involved in these processes. In a previous study, the rates of reaction of HOCl with the reactive sites in proteins were investigated (Pattison, D. I., and Davies, M. J. (2001) Chem. Res. Toxicol. 14, 1453-1464). The work presented here expands on those studies to determine absolute second-order rate constants for the reactions of HOCl with various lipid components and antioxidants in aqueous solution (pH 7.4). The reactions of HOCl with phosphoryl-serine and phosphoryl-ethanolamine are rapid (k approximately 10(5) M(-)(1) s(-)(1)) and of comparable reactivity to many of the protein sites. The major products formed in these reactions are chloramines, which decay to give both nitrogen- and carbon-centered radicals. Subsequent reactions of these species may induce oxidation of the LDL lipid component. In contrast, phosphoryl-choline reacted much more slowly (k < 10(-)(2) M(-)(1) s(-)(1)). Reaction of HOCl with 3-pentenoic acid was used as a model of lipid double bonds and yielded k = 9 M(-)(1) s(-)(1). The reactions of the lipid-soluble antioxidants, alpha-tocopherol and ubiquinol-10, with HOCl were investigated with model compounds. For the reactions of HOCl with both Trolox and ubiquinol-0, k = 1.3 x 10(3) M(-)(1) s(-)(1); thus, these lipid soluble antioxidants are relatively ineffective as direct scavengers for HOCl as compared to water soluble antioxidants (e.g., ascorbate, k ca. 10(6) M(-)(1) s(-)(1)). The reaction of HOCl with hydroquinone (a simple model for ubiquinol-10) was also investigated both in aqueous solution (k = 45 M(-)(1) s(-)(1)) and in a less polar environment (k approximately 0.5 M(-)(1) s(-)(1) in THF). A computational model was developed using these kinetic parameters to predict which LDL targets are oxidized with varying molar excesses of HOCl, in both the absence and the presence of added ascorbate. The results from these models compare well with experimental data and can be used to predict the effects of HOCl-mediated oxidation on LDL composition.

Antioxidants↗

PubMed2005

Computational modelling of H+-coupled peptide transport via human PEPT1.

H+-coupled peptide transporter 1 (PEPT1) mediates the transport of small peptides and peptide-like drugs in a pH- and voltage-dependent manner. Here, we investigated the transport mechanisms of PEPT1 for neutral and charged substrates by experimental studies and computational simulation. Uptake studies revealed that the Michaelis-Menten constant (Km) of glycylsarcosine (Gly-Sar), a neutral substrate, decreased with a fall in pH from 7.4 to 5.5, but at pH 5.0, the Km increased again. In contrast, the Km value of an anionic substrate, ceftibuten, declined steadily with decreasing pH. Based on these findings and information from the literature, we hypothesized the transport mechanisms in which (1) H+ binds to not only the H+-binding site, but also the substrate-binding site; and (2) H+ at the substrate-binding site inhibits the interaction of neutral and cationic substrates, but is necessary for that of anionic substrates. To validate these hypotheses, a computational model was constructed and various properties of substrate transport by PEPT1 were simulated. Our model reproduced the voltage dependence, hyperbolic saturation and bell-shaped pH-profile of Gly-Sar transport. Moreover, the various transport properties of negatively and positively charged substrates were also reconstructed. These findings indicated that the inferred mechanisms are able to sufficiently interpret the transport of both neutral and charged substrates by PEPT1.

Anions↗

PubMed2003

Influence of consonantal context on the pronunciation of vowels: a comparison of human readers and computational models.

In two experiments, we found that college students' pronunciations of vowels in nonwords are influenced both by preceding and following consonants. The predominance of rimes in previous studies of reading does not appear to arise because readers are unable to pick up associations that cross the onset-rime boundary, but rather because English has relatively few such associations. Comparisons between people's vowel pronunciations and those produced by various computational models of reading showed that no model provided a good account of human performance on nonwords for which the vowel shows contextual conditioning. Possible directions for improved models are suggested.

Adolescent↗

PubMed1989

How are dreams made? Towards a computational model.

In order to account for how dreams are made, both information structures and energy systems must be made more explicit. This paper attempts to spell out in more detail two of the three components that Foulkes postulated as essential to dream construction, namely, memory and planning. It draws on the mechanisms in Mueller's computational model of human daydreaming, in particular, a planner--which consists of personal goals, daydreaming goals, and planning and inference rules for a particular domain--and a set of emotions that determine the choice of daydreaming goals. We analyzed the laboratory REM dream of an adult male subject in terms of the three kinds of goals in Mueller's model: namely, the personal goals that derive form the day residue elicited from the subject prior to the dream; the dream goals of reversal, rehearsal, rationalization, and revenge; and the planning goals or script identified in a metaphoric problem space. The sequence of scenes from the script determines the skeletal structure of the dream, and the emotion of humiliation, decomposed into embarrassment and anger, largely determines the choice of dream goals. Much of the dream content itself is the instantiation of an inference rule for restoring social esteem. Finally, it is argued that the kind and quantity of mechanisms that are postulated by Mueller for human daydreaming are also necessary to account for basic processes of night dream construction.

Computer Simulation↗

PubMed1992

Computer models of a new deoxy-sickle cell hemoglobin fiber based on x-ray diffraction data.

A new x-ray fiber diffraction pattern from deoxygenated sickle cell erythrocytes has been observed. It displays 14 layer lines with a 109 A periodicity compared with the 64 A periodicity of the "classic" sickle cell hemoglobin (HbS) fiber. These data and association energy calculations serve as a basis for computer model building. Systematic searches over four-dimensional parameter space yielded twelve protofilament models that satisfy the following constraints: (a) two HbS molecules be related by twofold screw symmetry with a translational repeat of 109 A; (b) at least one of the substituted residues in HbS, val beta 6, should participate in intermolecular contacts; and (c) the energy of intermolecular interaction be less than -24 kcal/mol. Each of the protofilament models is a zigzag mono-strand that stands in contrast to the double-stranded protofilament of the "classic" fiber. Fiber models were constructed with each of the 12 protofilament models, pseudo-hexagonally packed. Searches of variable packing parameters showed four fiber models with minimal protofilament association energies and minimal differences between calculated transforms and observed data. The R-factor was less than 0.24 for each of these four models. In three of the fiber models the protofilament association energy is between -(93 and 130) kcal, and in a fourth, the energy is -64 kcal. One protofilament model constituted three distinct fiber models of the lower energy class, and a second protofilament model packed with a higher association energy into a fourth fiber model. The selection of a unique fiber model from among these four cannot be made because of the limited available data. Fibers models constructed with any of the ten other protofilament models do not satisfy the conditions of minimal association energy and R-factor.

Anemia, Sickle Cell↗

PubMed1993

Computer model to optimise contrast in chest radiography.

X-ray imaging of the chest is challenging because of the large differences in x-ray attenuation between the mediastinal and lung regions of the chest. This large dynamic range of chest exit exposure, along with associated large changes in the scatter component of the beam, makes film based chest imaging difficult to optimise in terms of image contrast and image receiver latitude. Chest radiographic contrast has been studied in terms of intensifying screen luminance differences, as a function of kVp and scatter rejection. An anatomical model has been derived from CT studies and includes simulation of typical lung, retrocardiac and mediastinal regions with the contrast medium of a 5 mm water equivalent mass. Information has also been obtained on the range of luminance generated in the receptor between the three regions. Comparative patient doses have also been calculated. The computer model consists of analytical algorithms, beginning with the primary spectra generated after the method of Birch and Marshall. The generation of secondary radiation is achieved by an algorithm that parameterises published Monte Carlo data. Grid transmission is calculated for both primary and secondary radiation. The energy absorbed in the screen is calculated to include the absorption of K-characteristic radiation. Simulation of energies from 60-120 kVp with a variety of grids (including no grid) showed that contrast, in all areas of the chest radiograph, was a weak function of kVp and a strong function of scatter rejection. This was most evident in thicker regions such as the mediastinum.(ABSTRACT TRUNCATED AT 250 WORDS)

Computer Simulation↗