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PubMed2004

A comparative study of an accelerated life-test model and a toxicokinetics-based model for the analysis of Porcellio scaber survival data.

Statistical models have long been used for reliability analysis and risk assessment. In the present study, an accelerated life-test model was used to analyze a set of dose-time-response data obtained with the terrestrial isopod Porcellio scaber. Survival data were experimentally obtained by exposing P. scaber to diazinon (a nonpersistent insecticide) at six concentrations between 2 and 11.31 microg/g (toxicant/soil). Survival data are presented on a weekly basis. The accelerated life-test model assumed a log-normal distribution and constant variance across all diazinon concentrations. Model parameters were obtained by maximum likelihood estimation. The accelerated life-test model was compared to a toxicokinetics-based model reported in the literature. Survival predictions made by both models were compared with the observed data. Both the accelerated life-test model and the toxicokinetics-based model underestimated toxicity at a diazinon concentration of 8 microg/g. Overall, however, the accelerated life-test model outperformed the toxicokinetics-based model, with survival predictions closer to the observed data in most cases and a stronger correlation between predicted and observed survivals. However, as a statistical model, the accelerated life-test model did not reveal mechanistic information, and only statistical and distributional interpretations of its model parameters could be made.

Animals↗
PubMed2003

Hologram quantitative structure-activity relationships investigations of non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as TIBO, HEPT and dipyridodiazepinone are effective against HIV-1 RT. These NNRTIs are chemically and structurally diverse, but they all bind to a common allosteric site of HIV-1 RT. These inhibitors exhibit high potency, low cytotoxicity and produce few side effects. However, the emergency of drug-resistance viral strain has limited the therapeutic efficiency of the NNRTIs. Several different QSAR studies were reported to identify important structural features responsible for the inhibitory activity of these NNRTIs. In this study, hologram quantitative structure-activity relationships (HQSAR) was applied to three different data sets, 70 TIBO, 101 HEPT and 125 dipyridodiazepinone derivatives. Starting geometries of compounds were taken from available X-ray crystallographic data. Modification and full geometry optimization of all derivatives were performed, based on quantum chemical calculations at the HF/3-21G level of theory. All derived HQSAR models produce satisfying predictive ability and yield r(2)(cv) values ranging from 0.62-0.84. Moreover, it was also found that the quality of models enhances as the size of fragments increases. The obtained HQSAR results indicate the similarity of the interactions of these three different NNRTIs with the inhibition pocket of the enzyme. Comparisons of different QSAR methods on these NNRTIs data sets were also considered and it could be shown that HQSAR results yield superior predictive models than other 2D-QSAR approaches. In particular, the predictive ability of the models derived from dipyridodiazepinone analogues was significantly improved and apparently revealed differentiating structural requirements between WT and Y181C HIV RT inhibition. Additionally, the quality of QSAR models constructed by CoMFA and HQSAR methods are comparable and the interpretations of the models reinforce each other. It suggests an advantage of HQSAR as a useful tool in designing new potent inhibitors with enhanced HIV-1 RT inhibition activity, especially against mutant enzyme.

Anti-HIV Agents↗
PubMed1997

Deformable models and the analysis of medical images.

Deformable models are a popular and vigorously researched model-based approach to computer-assisted medical image analysis. The widely recognized efficacy of deformable models stem from their ability to segment, match and track images of anatomic structures by exploiting (bottom-up) constraints derived from the image data together with (top-down) a priori knowledge about the location, size and shape of structures of interest. Deformable models are capable of accommodating the often significant variability of biological structures over time and across different individuals. Furthermore, they support highly intuitive interaction mechanisms that allow medical scientists and practitioners to bring their expertise to bear on the model-based image interpretation task as necessary. In this paper we will review deformable models and present some recent developments in the methodology, including topologically adaptable deformable models, an approach that permits segmentation and reconstruction of topologically complex anatomical structures.

Computer Simulation↗
PubMed1985

Computerized models for strategic planning and marketing.

In the rapidly changing health care industry, planning and marketing based primarily on historical information is no longer sufficient. The use of computerized models to evaluate alternatives is proposed as a key part of strategic planning and marketing. The general concept, approach, components, and uses of such models are described in general, followed by an example model including the inputs, formats, and outputs, Finally, the use and interpretation of such models are discussed.

Computers↗
PubMed1984

Covariate analysis of competing-risks data with log-linear models.

A general system of log-linear modeling is proposed for analysis of competing-risks data with discrete covariates. The instantaneous cause-specific failure rates, approximated by step-functions, are analyzed by techniques for multidimensional contingency tables. Censored observations are accommodated. Counts of failures of each type, and the amount of follow-up, are summarized in two arrays in which each cell denotes a distinct combination of failure type, time interval and covariate value. Maximum likelihood estimators for the parameters of the model are derived by iterative proportional fitting; the resulting estimates of the number of failures in each cell are used for goodness-of-fit tests. The principal advantages of this approach are its simple display of data, its computational ease for the fitting and comparison of models and its provision of explicit goodness-of-fit tests. Interpretation of the models is facilitated by reference to several alternative models for survivorship and competing risks. The basic model is extended to incorporate stochastic covariates whose values change during follow-up, and to accommodate quantitative covariates.

Analysis of Variance↗
PubMed1985

[Diagnostic use of the mathematical model of nonlinear regression in the interpretation of the crystalline bilirubin loading test in Gilbert's syndrome].

The results of a study conducted both on subjects affected by constitutional hyperbilirubinaemia (Gilbert's syndrome) and healthy subjects using the charge test with crystalline bilirubin are presented. The parameters which are involved in bilirubin kinetics were established by means of non linear regression methods (the Marquardt method). 19 Gilbert syndrome patients and 12 normal control subjects were studied. Important parameters readily applicable to clinical and diagnostic evaluation of subjects suffering from familial cholemia were identified.

Bilirubin↗
PubMed1986

Interpretation of traumatic lumbar puncture. A prospective experimental model.

Contamination of cerebrospinal fluid (CSF) with blood at the time of collection interferes with the interpretation of laboratory studies. Twenty-four children with normal CSF were studied prospectively using an experimental model. Blood was added to clear CSF, producing red cell counts from 1,000 to 600,000 cells per cubic millimeter. The expected values for white blood cell count, protein, percent neutrophils, and glucose were calculated, using the results from uncontaminated CSF, peripheral blood cell counts, blood protein, and the red blood cell count of the contaminated specimen. The ratio of observed values to expected values ranged from 0.13 to 3.00 for CSF white blood cell count (mean 0.96, standard deviation 0.56), from 0.55 to 1.63 for CSF protein (mean 0.97, standard deviation 0.23), and from 0.10 to 2.25 for percent neutrophils in the CSF (mean 1.17, standard deviation 0.41). CSF glucose was unchanged by the addition of blood. Guidelines for interpretation of laboratory studies following traumatic lumbar puncture are suggested.

Blood↗
PubMed1997

Families of stationary patterns producing illusory movement: insights into the visual system.

A computational explanation of the illusory movement experienced upon extended viewing of Enigma, a static figure painted by Leviant, is presented. The explanation relies on a model for the interpretation of three-dimensional motion information contained in retinal motion measurements. This model shows that the Enigma figure is a special case of a larger class of figures exhibiting the same illusory movement and these figures are introduced here. Our explanation suggests that eye movements and/or accommodation changes cause weak retinal motion signals, which are interpreted by higher-level processes in a way that gives rise to these illusions, and proposes a number of new experiments to unravel the functional structure of the motion pathway.

Accommodation, Ocular↗
PubMed1993

Respiratory input impedance up to 256 Hz in healthy humans breathing foreign gases.

Currently available data concerning respiratory input impedance (Zrs) at frequencies up to 300 Hz indicate that Zrs is determined mainly by the airways and, in particular, the gas compressibility in the airways and the airway wall compliance. Hence, measurements of Zrs when breathing gases with different physical properties would be useful in investigating airway mechanics and the role of acoustic propagation. Zrs measured with a standard generator (Zst) and corrected for the upper airway shunt (Zrs*) were measured in nine healthy subjects breathing air or a gas mixture consisting of 20% O2 and 80% He or SF6. The frequency band was extended up to 256 Hz for air and He-O2 and up to 128 Hz for SF6-O2. Zrs exhibited a similar pattern for the three gases, with a shift toward low frequencies as the gas density increased. Moreover, the resonance peaks tended to be narrower and higher as the gas density increased. The second frequency of resonance for He-O2, air, and SF6-O2 were 220, 180, and 50 Hz, respectively, for Zrs* and were systematically higher for Zst. Zrs* and Zst data were interpreted in terms of a tricompartmental model that partitioned the airways into two segments: a central one featuring the acoustic propagation in the airways and a peripheral one that included bronchial wall elasticity (Farré et al. J. Appl. Physiol. 67: 1973-1981, 1989). The model was able to interpret the gas dependence of Zrs* but not that of Zst. The influence of the gas physical properties on both Zrs* and Zst confirms that total Zrs at high frequencies is basically that of the airways and that the second resonance is related mainly to the gas compressibility in the airways.

Adult↗
PubMed2002

Comparison of minimum current estimate and dipole modeling in the analysis of simulated activity in the human visual cortices.

Magnetoencephalographic(MEG) data are typically interpreted using source models because of the nonunique inverse problem. Although single current dipoles, adequately representing local active areas, can be identified accurately, multiple and overlapping sources form a challenge for MEG modeling. We tested the performances of multidipole modeling and minimum current estimate (MCE) in the analysis of complicated source configurations. Simulated current sources were placed to physiologically meaningful areas of the human visual cortices. Ten volunteers from the laboratory staff analyzed four different simulations with both dipole modeling and MCE without prior information of the sources. In general, the same sources were found using both modeling methods. The subjects tended to report more false sources with MCE than with dipole model, in part due to their inexperience with the method. Dipole model was more accurate than MCE both in time and space for nonsimultaneous sources but both methods performed similarly when sources overlapped in time. For all source configurations, considerably smaller source amplitudes were reported with MCE than with dipole model.

Computer Simulation↗
PubMed1993

Probabilistic constraint satisfaction with structural models: application to organ modeling by radial contours.

One of the key challenges within medical information sciences is the development of useful models for biological structure and its variability. Many biomedical problems involve the elucidation of structure (for example, from experimental data or from imaging studies), and structural models can often drive the process of inferring precise structure from data. Ideally, model-driven data interpretation combines knowledge about the generic features of a class of biological structures (as contained within a model) with data that provide specific information (often noisy) about a particular instance of the class. In this paper we briefly discuss model-driven determination of biological structure as an example of a structural constraint satisfaction problem. We describe a probabilistic implementation of structural constraint satisfaction, and show that our formulation of a particular organ modeling technology (Radial Contour Models) exhibits promising performance. Our results demonstrate the utility of probabilistic models for the solution of structural constraint satisfaction problems.

Computer Simulation↗
PubMed2006

Additivity rules using similarity models for chemical reactivity: calculation and interpretation of electrofugality and nucleofugality.

A recently proposed, multi-parameter correlation: log k (25 degrees C)=s(f) (Ef + Nf), where Ef is electrofugality and Nf is nucleofugality, for the substituent and solvent effects on the rate constants for solvolyses of benzhydryl and substituted benzhydryl substrates, is re-evaluated. A new formula (Ef=log k (RCl/EtOH/25 degrees C) -1.87), where RCl/EtOH refers to ethanolysis of chlorides, reproduces published values of Ef satisfactorily, avoids multi-parameter optimisations and provides additional values of Ef. From the formula for Ef, it is shown that the term (sfxEf) is compatible with the Hammett-Brown (rho+sigma+) equation for substituent effects. However, the previously published values of N(f) do not accurately account for solvent and leaving group effects (e.g. nucleofuge Cl or X), even for benzhydryl solvolyses; alternatively, if the more exact, two-parameter term, (sfxNf) is used, calculated effects are less accurate. A new formula (Nf=6.14 + log k(BX/any solvent/25 degrees C)), where BX refers to solvolysis of the parent benzhydryl as electrofuge, defines improved Nf values for benzhydryl substrates. The new formulae for Ef and Nf are consistent with an assumption that sf=1.00(,) and so improved correlations for benzhydryl substrates can be obtained from the additive formula: log k(RX/any solvent/25 degrees C)=(Ef + Nf). Possible extensions of this approach are also discussed.

Journal Article↗
PubMed1995

Mechanistic studies of the 1-alkyl-2-pyrrolidones as skin permeation enhancers.

The influences of 1-ethyl-, 1-butyl-, 1-hexyl-, and 1-octyl-2-pyrrolidone in their saline solutions on the transport of beta-estradiol, corticosterone, and hydrocortisone across hairless mouse skin under in vitro conditions have been investigated by the physical model approach. The experimental data were interpreted with a physical model that treats the stratum corneum as a diffusional barrier with a lipoidal pathway and a pore pathway. Enhancement factors (E values) for the lipoidal pathway were calculated from the permeability coefficients and solubility data as a function of the 1-alkyl-2-pyrrolidone concentration for all three permeants. A pattern of increasing E values with increasing 1-alkyl-2-pyrrolidone chain length was found, and the results were essentially the same for all three steroidal permeants. A nearly semilogarithmic linear relationship was also obtained between the enhancement potency and the carbon number of the alkyl chain; there was about an approximately 3.5-fold increase in the enhancement potency per 1-alkyl-2-pyrrolidone methylene group. An important outcome of this research is that the enhancement potencies of the 1-alkyl-2-pyrrolidones were essentially the same as those for the previously studied n-alkanols when compared at the same carbon numbers of the alkyl groups. This result is somewhat surprising as it suggests that the enhancer action resides (in its entirety) in the alkyl group, and the nature of the polar head group may not be intrinsically important in transdermal enhancement of the lipoidal pathway within a class of permeation enhancers.

Administration, Cutaneous↗
PubMed2000

Use of a new label, (13)==(18)O, in the determination of a structural model of phospholamban in a lipid bilayer. Spatial restraints resolve the ambiguity arising from interpretations of mutagenesis data.

A structural model of pentameric phospholamban (Plb) in a lipid bilayer has been derived using a combination of experimental data, obtained from ATR-FTIR site-directed dichroism, and the implementation of the resulting restraints during a molecular dynamics simulation. Plb (residues 24-52) has been synthesised incorporating a new label, 1-(13)C==(18)O, at residues 42 and 43. We have not only determined the tilt of the helices, 10(+/-6) degrees, but also the relative orientation of the transmembrane segments, with an omega angle of -32(+/-10) degrees for L42. This angle is taken as zero in the direction of the helix tilt. Plb is a simple test case where site-directed dichroism has been applied to resolve the indeterminacy arising from the mutagenesis data available. The results presented point specifically to a single structural model for Plb.

Amides↗
PubMed1985

[Transmission behavior of the neuromuscular synapse: interpretation of experimental data by a model].

A model of neuromuscular transmission has been proposed which considers morphological structure and interrelated chemical and electrical mechanisms. The adequate kinetic scheme has been described by means of a system of nonlinear first order differential equations and the network of corresponding electrical processes has been treated as a linear first order differential equation with one variable coefficient. By the analytical investigation of derived differential equations detailed informations about the qualitative behaviour of the solutions were obtained. Present results of modelling characterize the neuromuscular synapse as a "perfect" transfer element, since all the possible dynamic solutions tend to exactly one singular point - the "resting state", independent of initial values and all other parameters. The special time-dependent solutions simulated by computer with biologically relevant parameters are in good agreement with experimentally determined transient response of the neuromuscular synapse. The paper concludes with an outlook of the possible pharmacologic application of the developed model.

Animals↗
PubMed2000

Animal model for cerebral arteriovenous malformation.

BACKGROUND: The present study was conducted to establish an animal model for the investigation of the pathophysiology and haemodynamics of cerebral arteriovenous malformation (AVM) but also to assess therapeutic aspects. METHOD: For anatomic and haemodynamic reasons, dogs were chosen as the animal model. An arteriovenous fistula was created by interposing a segment of the superficial temporal artery between one of the main branches of the middle cerebral artery and the dorsal sagittal sinus. A temporal muscle graft supplied by this artery was implanted intracerebrally in the ischaemic area. FINDINGS: The angiographic and histopathologic findings obtained in the animal model are comparable with the situation found in intracerebral AVM in humans. INTERPRETATION: The animal model of intracerebral AVM established in this study allows for further investigation of the pathophysiology and dynamics of this disorder. It may help to develop better therapeutic options and thus improve the prognosis of affected patients.

Animals↗