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PubMed1994

Simulations of the alpha motoneuron pool electromyogram reflex at different preactivation levels in man.

The alpha motoneuron pool and the surface electromyogram (EMG) of the human soleus muscle are modelled, respectively, by an alpha motoneuron pool model generating the firing patterns in the motor units of the muscle and by a muscle model using these discharge patterns to simulate the surface EMG. In the alpha motoneuron pool model, we use a population of motoneurons in which cellular properties like cell size and membrane conductance are distributed according to experimentally observed data. By calculating the contribution from each motor unit, the muscle model predicts the EMG. Wave forms of the motor unit action potentials in the surface EMG are obtained from experimental data. Using the model, we are able to give a quantitative prediction of the motoneuron pool activity and the reflex EMG output at different preactivation levels. The simulated data are consistent with experimentally obtained results in healthy humans. During static isometric muscle preactivations, the simulations show that the reflex strength is highly dependent on the intrinsic threshold properties of the alpha motoneuron pool.

Computer Simulation↗
PubMed2002

Estimates of lateral and longitudinal bond energies within the microtubule lattice.

We developed a stochastic model of microtubule (MT) assembly dynamics that estimates tubulin-tubulin bond energies, mechanical energy stored in the lattice dimers, and the size of the tubulin-GTP cap at MT tips. First, a simple assembly/disassembly state model was used to screen possible combinations of lateral bond energy (DeltaG(Lat)) and longitudinal bond energy (DeltaG(Long)) plus the free energy of immobilizing a dimer in the MT lattice (DeltaG(S)) for rates of MT growth and shortening measured experimentally. This analysis predicts DeltaG(Lat) in the range of -3.2 to -5.7 k(B)T and DeltaG(Long) plus DeltaG(S) in the range of -6.8 to -9.4 k(B)T. Based on these estimates, the energy of conformational stress for a single tubulin-GDP dimer in the lattice is 2.1-2.5 k(B)T. Second, we studied how tubulin-GTP cap size fluctuates with different hydrolysis rules and show that a mechanism of directly coupling subunit addition to hydrolysis fails to support MT growth, whereas a finite hydrolysis rate allows growth. By adding rules to mimic the mechanical constraints present at the MT tip, the model generates tubulin-GTP caps similar in size to experimental estimates. Finally, by combining assembly/disassembly and cap dynamics, we generate MT dynamic instability with rates and transition frequencies similar to those measured experimentally. Our model serves as a platform to examine GTP-cap dynamics and allows predictions of how MT-associated proteins and other effectors alter the energetics of MT assembly.

Dimerization↗
PubMed2002

The benefits of 3D modelling and animation in medical teaching.

Three-dimensional models created using materials such as wax, bronze and ivory, have been used in the teaching of medicine for many centuries. Today, computer technology allows medical illustrators to create virtual three-dimensional medical models. This paper considers the benefits of using still and animated output from computer-generated models in the teaching of medicine, and examines how three-dimensional models are made.

Computer Simulation↗
PubMed2001

Similarity in perception: a window to brain organization.

This paper presents a neural model of similarity perception in identification tasks. It is based on self-organizing maps and population coding and is examined through five different identification experiments. Simulating an identification task, the neural model generates a confusion matrix that can be compared directly with that of human subjects. The model achieves a fairly accurate match with the pertaining experimental data both during training and thereafter. To achieve this fit, we find that the entire activity in the network should decline while learning the identification task, and that the population encoding of the specific stimuli should become sparse as the network organizes. Our results, thus, suggest that a self-organizing neural model employing population coding can account for identification processing while suggesting computational constraints on the underlying cortical networks.

Brain↗
PubMed2001

Estimating probability of non-response to treatment using mixture distributions.

Repeat measurements of patient characteristics are often used to assess response to treatment. In this paper we discuss a normal mixture model for the observed change in the characteristic of interest in treated patients. The methods described can be used to estimate the overall proportion of non-response to treatment and also the probability that a patient has not responded to treatment given his or her observed change. The model parameters are estimated using maximum likelihood, and the delta method is used to construct a pointwise confidence band for the conditional probability that a patient is a non-responder to treatment. The work was initially motivated by analysis issues in the Fracture Intervention Trial (FIT), a randomized trial of the osteoporosis drug alendronate, and the method is illustrated with data from that study. We also evaluate key aspects of the estimation procedure with two simulation studies. In the first, the data generation model is the assumed normal mixture model, and in the second, the data are generated according to a shifted and scaled central t-distribution model suggested by the FIT data.

Aged↗
PubMed1989

The generation of socioeconomic surfaces for public policymaking.

The development is explained of a technique to generate 'modeled' surfaces of census-type socioeconomic survey data that offer the potential to overcome many of the problems inherent in the analysis and presentation of such data in conventional area-based form. Potential benefits of the modeled surfaces include a level of resolution that arguably can provide a more finely focused spatial basis for the generation of a wide range of spatial indicators that can aid public policy making. This type of application requires that the method is set within a flexibly managed information framework and includes suitable tests for the reliability of the generated surfaces.

Demography↗
PubMed2002

Prediction of aqueous solubility of organic compounds using a quantitative structure-property relationship.

A quantitative structure-property relationship (QSPR) was developed for predicting the aqueous solubility of drug-like compounds from their chemical structures. A set of 321 structurally diverse drugs or related compounds, with their intrinsic aqueous solubility collected from literature, was used in this analysis. The data were divided into a training set (n = 267) for building the model and a randomly chosen testing set (n = 54) for assessing the predictive ability of the model. A series of molecular descriptors was calculated directly from chemical structures and a set of eight descriptors, including dipole moment, surface area, volume, molecular weight, number of rotatable bonds/total bonds, number of hydrogen-bond acceptors, number of hydrogen-bond donors and density, was chosen for the final model. The eight-descriptor model generated by multiple linear regression was further optimized by a genetic algorithm guided selection method. The model has a correlation coefficient (r) of 0.95 and a root-mean-square (rms) error of 0.56 log unit. It predicts the solubility of testing set compounds with a reasonable degree of accuracy (r = 0.84 and rms = 0.86 log unit). The present model can serve as a tool for medicinal chemists to guide their early synthetic efforts in arriving at appropriate analogs.

Algorithms↗
PubMed1996

Extended glycoprotein structure of the seven domains in human carcinoembryonic antigen by X-ray and neutron solution scattering and an automated curve fitting procedure: implications for cellular adhesion.

Carcinoembryonic antigen (CEA) is one of the most widely used cell-surface tumour markers for tumour monitoring and for targeting by antibodies. It is heavily glycosylated (50% carbohydrate) and a monomer is constructed from one V-type and six C2-type fold domains of the immunoglobulin superfamily. The solution arrangement at low resolution of the seven domains in CEA cleaved from its membrane anchor was determined by X-ray and neutron scattering. Guinier analyses showed that the X-ray radius of gyration RG of CEA was 8.0 nm. The length of CEA was 27 to 33 nm, and is consistent with an extended arrangement of seven domains. The X-ray cross-sectional radius of gyration RXS was 2.1 nm, and is consistent with extended carbohydrate structures in CEA. The neutron data gave CEA a relative molecular mass of 150,000, in agreement with a value of 152,500 from composition data, and validated the X-ray analyses. The CEA scattering curves were analysed using an automated computer modelling procedure based on the crystal structure of CD2. The V-type and C2-type domains in CD2 were separated, and the C2-type domain was duplicated five times to create a linear seven-domain starting model for CEA. A total of 28 complex-type oligosaccharide chains in extended conformations were added to this model. By fixing the six interdomain orientations to be the same, three-parameter searches of the rotational orientations between the seven domains gave 4056 possible CEA models. The best curve fits from these corresponded to a family of zig-zag models. The long axis of each domain was set at 160(+/-25) degrees relative to its neighbour, and the two perpendicular axes were orientated at 10(+/-30) degrees and -5(+/-35) degrees. Interestingly, the curve fit from this model is within error of that calculated from a CEA model generated directly from the CD2 crystal structure by the superposition of adjacent domains. Zig-zag models of this type imply that the protein face of the GFCC' beta-sheet in neighbouring CEA domains lie on alternate sides of the CEA structure. Such a model has implications for the adhesion interactions between CEA molecules on adjacent cells or for the antibody targeting of CEA.

Amino Acid Sequence↗
PubMed1990

The impact of taxation on the distribution of wealth in an economy with changing population.

The authors examine the determinants of the personal distribution of income and wealth using an overlapping generations model in which all individuals are assumed to be identical except for their inherited wealth. "It is shown that, in general, higher tax rates reduce distributive inequality as long as the rate of interest is exogenously given. In steady state, however, where the rate of interest is determined endogenously, increasing taxation and higher social security payments both diminish the capital labor ratio so that the rate of interest rises. If this interest effect is strong enough then it may outbalance the tendency toward more equality because higher interest rates enhance initial differences in the distribution of both income and wealth and, eventually, the inequality in the distribution of income and wealth in the society." The geographical focus is on developed countries.

Developed Countries↗
PubMed1998

Identification of a model cardiac glycoside receptor: comparisons with Na+,K+-ATPase.

The availability of high-affinity anti-digoxin monoclonal antibodies (mAbs) offers the potential for their use as models for the characterization of the relationship between receptor structure and cardiac glycoside binding. We have characterized the binding of anthroylouabain (AO), a fluorescent derivative of the cardiac glycoside ouabain, to mAbs 26-10, 45-20, and 40-50 [Mudgett-Hunter, M., et al. (1995) Mol. Immunol. 22, 477] and lamb kidney Na+, K+-ATPase by monitoring the resultant AO fluorescence emission spectra, anisotropy, lifetime values, and Förster resonance energy transfer (FRET) from protein tryptophan(s) (Trp) to AO. These data suggest that the structural environment in the vicinity of the AO-binding site of Na+,K+-ATPase is similar to that of mAb 26-10 but not mAbs 45-20 and 40-50. A model of AO complexed to the antigen binding fragment (Fab) of mAb 26-10 which was generated using known X-ray crystal structural data [Jeffrey, P. D., et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10310] shows a heavy chain Trp residue (Trp-H100) that is close ( approximately 3 A) to the anthroyl moiety. This is consistent with the energy transfer seen upon AO binding to mAb 26-10 and suggests that Trp-H100, which is part of the antibody's cardiac glycoside binding site, is a major determinant of the fluorescence properties of bound AO. In contrast, the generated model of AO complexed to Fab 40-50 [Jeffrey, P. D., et al. (1995) J. Mol. Biol. 248, 344] shows a heavy chain Tyr residue (Tyr-H100) which is part of the cardiac glycoside binding site, located approximately 10 A from the anthroyl moiety. The closest Trp residues (H52 and L35) are located approximately 17 A from the anthroyl moiety, and no FRET is observed despite the fact that these Trp residues are close enough for significant FRET to occur. The energy transfer seen upon AO binding to Na+,K+-ATPase suggests the presence of one completely quenched or two highly quenched enzyme Trp residues approximately 10 and approximately 17 A, respectively, from the anthroyl moiety. These data suggest that the Na+,K+-ATPase Trp residue(s) involved in fluorescence energy transfer to AO is likely to be part of the cardiac glycoside binding site.

Animals↗
PubMed1997

A dynamic model of ventricular interaction and pericardial influence.

A mathematical model describing the dynamic interaction between the left and the right ventricle over the complete cardiac cycle is presented. The pericardium-bound left and right ventricles are represented as two coupled chambers consisting of the left and right free walls and the interventricular septum. Time-varying pressure-volume relationships characterize the component compliances, and the interaction of these components produces the globally observed ventricular pump properties (total chamber pressure and volume). The model 1) permits the simulation of passive (diastolic) and active (systolic) ventricular interaction, 2) provides temporal profiles of hemodynamic variables (e.g., ventricular pressures, volumes, and flow) that agree well with reported observations, and 3) can be used to examine the effect of the pericardium on ventricular interaction and ventricular mechanics. It can be reduced to equivalency with models previously reported by invoking simplifying assumptions. Furthermore, model-generated "dynamic interaction gains" are employed to quantify the mode and degree of ventricular interaction. The model also yields qualitative predictions of septal and free wall displacements similar to those detected experimentally via M-mode echocardiography. Such analogies may be extended easily to the study of pathophysiological states via appropriate modifications to 1) the pressure-volume characteristics of the component walls (and/or pericardium) and/or 2) the specific time course of activation of the ventricular free wall or the septum. A limited number of examples are included to demonstrate the utility of the model, which may be used as an adjunct to new experimental investigations into ventricular interaction.

Blood Volume↗
PubMed2003

Pharmacology of human experimental anxiety.

This review covers the effect of drugs affecting anxiety using four psychological procedures for inducing experimental anxiety applied to healthy volunteers and patients with anxiety disorders. The first is aversive conditioning of the skin conductance responses to tones. The second is simulated public speaking, which consists of speaking in front of a video camera, with anxiety being measured with psychometric scales. The third is the Stroop Color-Word test, in which words naming colors are painted in the same or in a different shade, the incongruence generating a cognitive conflict. The last test is a human version of a thoroughly studied animal model of anxiety, fear-potentiated startle, in which the eye-blink reflex to a loud noise is recorded. The evidence reviewed led to the conclusion that the aversive conditioning and potentiated startle tests are based on classical conditioning of anticipatory anxiety. Their sensitivity to benzodiazepine anxiolytics suggests that these models generate an emotional state related to generalized anxiety disorder. On the other hand, the increase in anxiety determined by simulated public speaking is resistant to benzodiazepines and sensitive to drugs affecting serotonergic neurotransmission. This pharmacological profile, together with epidemiological evidence indicating its widespread prevalence, suggests that the emotional state generated by public speaking represents a species-specific response that may be related to social phobia and panic disorder. Because of scant pharmacological data, the status of the Stroop Color-Word test remains uncertain. In spite of ethical and economic constraints, human experimental anxiety constitutes a valuable tool for the study of the pathophysiology of anxiety disorders.

Anti-Anxiety Agents↗
PubMed2000

A mechanistic, predictive model of dose-response curves for cell cycle phase-specific and -nonspecific drugs.

In vitro dose-response curves for anticancer agents are useful for predicting the clinical response to chemotherapy, and models to capture the time-dependency of dose-response curves are necessary for potential clinical extrapolation. Usually, the modified Hill model is used (see Levasseur et al., Cancer Res., 58: 5749-5761, 1998), although this model is neither mechanistic nor predictive for understanding how drug and tumor cell characteristics affect the shape of the dose-response curve. A new exponential kill (EK) model is proposed to predict the shape of dose-response curves based on the cell cycle phase specificity of a drug, the cell cycle time, the duration and concentration of drug exposure at the site of action, and a scaling factor for the level of drug resistance. Explicit analytical equations are presented for predicting the ICx (the concentration required to reduce cell growth by x%), the maximum cell kill achievable at high doses after a given duration of drug exposure, and the slope of the survival fraction versus log (concentration) plot at the ICx. Numerical solutions illustrate that there may be an optimal, finite duration of drug exposure that maximizes cell kill for a given area under the concentration versus time curve, and an analytical equation is given to calculate when such an optimal, finite duration exists. The EK model generates sigmoidal dose-response curves, like those seen empirically and previously described by the Hill model, which eventually plateau with increasing drug concentration at levels that depend on the cell cycle specificity of the drug, the cell cycle time, and the duration of exposure to the drug. This study includes no original data. Instead, empirical results in the literature are used to test the model. Because data by Levasseur et al. (1998) was fit to the Hill model assuming the plateau in the effect versus concentration curve to be independent of exposure duration, a full test of the model is not possible using their published data. Some tests of the EK model were possible, however, showing that EK model predictions yield good fits to in vitro data published in that and in another study. In addition, combining the EK model with a pharmacokinetic model resulted in predictions that were consistent with results of clinical studies comparing etoposide given in different schedules. Further tests of the model are necessary.

Antineoplastic Agents↗
PubMed1996

The new organization of the health care delivery system.

The U.S. health care system is restructuring at a dizzying pace. In many parts of the country, managed care has moved into third-generation models emphasizing capitated payment for enrolled lives and, in the process, turning most providers and institutions into cost centers to be managed rather than generators of revenue. While the full impact of the new managed care models remains to be seen, most evidence to date suggests that it tends to reduce inpatient use, may be associated with greater use of physician services and preventive care, and appears to result in no net differences either positive or negative with regard to quality or outcomes of care in comparison with fee-for-service plans. Some patients, however, tend to be somewhat less satisfied with scheduling of appointments and the amount of time spent with providers. There is no persuasive evidence that managed care lowers the rate of growth in overall health care costs within a given market. Further, managed care performance varies considerably across the country, and the factors influencing managed care performance are not well understood. Organized delivery systems are a somewhat more recent phenomenon representing various forms of ownership and strategic alliances among hospitals, physicians, and insurers designed to provide more cost-effective care to defined populations by achieving desired levels of functional, physician-system, and clinical integration. Early evidence suggests that organized delivery systems that are more integrated have the potential to provide more accessible coordinated care across the continuum, and appear to be associated with higher levels of inpatient productivity, greater total system revenue, greater total system cash flow, and greater total system operating margin than less integrated delivery forms. Some key success factors for developing organized delivery systems have been identified. Important roles are played by organizational culture, information systems, internal incentives, total quality management, physician leadership, and the growth of group practices. This chapter describes the growth and evolution of managed care and organized delivery systems, the research evidence regarding managed care and organized delivery systems, and the likely future organization of the health system in light of recent trends and evidence. It also highlights some of the more important public policy implications of the new health care infrastructure.

Cost Control↗
PubMed1978

Experience with a Fourier method for determining the extracellular potential fields of excitable cells with cylindrical geometry.

In this chapter, well-known solutions that utilize a Fourier transform method for determining the extracellular, volume-conductor potential distribution surrounding elongated excitable cells of cylindrical geometry are reformulated as a discrete Fourier transform (DFT) problem, which subsequently permits the volume-conductor problem to be viewed as an equivalent linear-filtering problem. This DFT formulation is fast and computationally efficient. In addition, it lends itself to the application of some rather well-known techniques in linear systems theory (e.g., the DFT for convolution and least mean-square (Wiener) filtering for optimal prediction of a signal in random noise). Two specific examples are employed to demonstrate the utility of this discrete Fourier method: (1) the single, isolated, active nerve fiber in an essentially infinite volume conductor and (2) the isolated, active nerve trunk in a similar type of extracellular medium. In each of these, our DFT method is employed to obtain both the classical "forward" and "inverse" potential solutions for each volume conductor problem. In the case where the single, active nerve fiber is the bioelectric source in the volume conductor, simulated action-potential data from an invertebrate giant axon is utilized, and potentials at various points in the extracellular medium are calculated. The calculated potential distributions in axial distance z, at various radial distances r, are consistent with well-known experimental fact. When the active nerve trunk acts as the bioelectric source, the DFT method provides calculated potential distributions that are fairly consistent with experimental data under a variety of experimental conditions. For example, in these experiments, a special, isolated frog spinal cord preparation is used that permits separate or combined stimulation of the motor and sensory nerve fiber components of the attached sciatic nerve trunk. By manipulating the stimulus intensity applied to the motor (ventral) or appropriate sensory (dorsal) roots of the spinal cord, a variety of multiphasic extracellular volume-conductor potentials can be recorded from the sciatic nerve. The excellent agreement of model-generated and experimental data, regardless of the complexity of surface potential waveform, tends to validate the modeling assumptions and offer encouragement that this computationally efficient DFT method may be usefully employed in volume-conductor problems where both the bioelectric source, and the surrounding volume conductor, are of a much more complicated nature.

Action Potentials↗
PubMed1980

Population and agricultural development models: the promise of the third generation.

The author briefly describes the work of Malthus and the development of first- and second-generation economic-demographic models. He then discusses a proposed third-generation model which "examines conjointly both consequences and determinants of population growth, and analyzes them at the level of the agricultural household." A project being conducted by the Food and Agricultural Organization to construct a third-generation model using data from the Philippines and two other countries is described

Agriculture↗
PubMed1990

Novel method for the rapid evaluation of packing in protein structures.

There has been considerable effort to predict the structure of proteins from their amino acid sequences. A major problem in all prediction efforts has been that, short of a direct comparison with crystallographic co-ordinates, it is often difficult to evaluate the merit of a model, or "proposed" protein structure. Here, we present a method for evaluating proposed protein structures that does not require a structural model of complete atomic detail. Our method evaluates residue-residue packing density using a simplified model of the polypeptide chain where amino acids are represented as one, two (histidine, tyrosine and phenylalanine), or three (tryptophan) spheres. This method also gives a measure of the appropriateness of residue-residue contacts, thus giving a measure of the amino acid distribution throughout the protein. Amino acid packing and amino acid distribution, as evaluated by this technique, are consistent with the accuracy of model-built structures. We have been able to select the best structures from a set of combinatorially generated models using this method, and we anticipate that it will be useful as a general tool for model-building.

Amino Acid Sequence↗
PubMed2000

The Mt. Hood challenge: cross-testing two diabetes simulation models.

Starting from identical patients with type 2 diabetes, we compared the 20-year predictions of two computer simulation models, a 1998 version of the IMIB model and version 2.17 of the Global Diabetes Model (GDM). Primary measures of outcome were 20-year cumulative rates of: survival, first (incident) acute myocardial infarction (AMI), first stroke, proliferative diabetic retinopathy (PDR), macro-albuminuria (gross proteinuria, or GPR), and amputation. Standardized test patients were newly diagnosed males aged 45 or 75, with high and low levels of glycated hemoglobin (HbA(1c)), systolic blood pressure (SBP), and serum lipids. Both models generated realistic results and appropriate responses to changes in risk factors. Compared with the GDM, the IMIB model predicted much higher rates of mortality and AMI, and fewer strokes. These differences can be explained by differences in model architecture (Markov vs. microsimulation), different evidence bases for cardiovascular prediction (Framingham Heart Study cohort vs. Kaiser Permanente patients), and isolated versus interdependent prediction of cardiovascular events. Compared with IMIB, GDM predicted much higher lifetime costs, because of lower mortality and the use of a different costing method. It is feasible to cross-validate and explicate dissimilar diabetes simulation models using standardized patients. The wide differences in the model results that we observed demonstrate the need for cross-validation. We propose to hold a second 'Mt Hood Challenge' in 2001 and invite all diabetes modelers to attend.

Albuminuria↗