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PubMedDate not supplied

Application of physiology-based pharmacokinetic and pharmacodynamic modeling to individualized target-controlled propofol infusions.

This study compared the ability of the physiology-based pharmacokinetic (PBPK) model with that of compartmental models used in propofol infusion devices to predict the pharmacokinetics and pharmacodynamics of propofol in various patient groups (children, pregnant women, young men, normal weight adults, and obese adults). With a PBPK model, loss of consciousness (LOC) and recovery of consciousness (ROC) corresponded to a narrow range of brain tissue concentrations (2.2-4.0 mg/L). With the compartmental models, predicted effect concentrations were also within a narrow range at LOC, but were outside the range at ROC. In individuals of normal weight, coefficients of variation (CV) of the predicted brain or effect concentrations at LOC were in a similar range-between 18% and 32%. In obese individuals, however, interindividual CV values for brain or effect concentrations were 41% (PBPK) and 93% (compartmental). This comparison suggests the increased flexibility of PBPK models over compartmental models, the latter of which rely heavily on the patient group from which the model was derived. The incorporation of PBPK models may provide target-controlled infusions with enhanced ability to predict response in a wide variety of patients.

Adult↗
PubMed1998

Bone mineral density in the lumbar spine as determined by dual-energy X-ray absorptiometry. Comparison of whole-body scans and dedicated regional scans.

PURPOSE: To compare bone mineral in the lumbar spine as measured by either consecutive regional or whole-body dual-energy X-ray absorptiometry (DXA), and to develop models that predict regional results from whole-body results. MATERIAL AND METHODS: In 180 children and young adults, bone mineral in the lumbar spine was measured by a Hologic QDR-1000/W DXA scanner, using either whole-body software (which can give data for the lumbar spine subregion) or dedicated lumbar spine software. Data on 139 persons were used to compare the two methods and to develop models that predict the result of a regional scan from the result of a whole-body scan. Data on the remaining 41 persons were used to control these models. RESULTS: Bone mineral content, bone area, and bone mineral areal density (BMDA) of the lumbar spine were measured significantly lower by whole-body scans than by regional scans (p < 0.0001). The difference was larger for the lower values of bone area and BMDA. We developed models that predicted lumbar spine BMDA from whole-body results. When these models were controlled in another group, the mean error between the methods was non-significant and the error was unrelated to the BMDA value. However, the variance of the error was only minimally reduced. CONCLUSIONS: Lumbar spine bone mineral was measured significantly lower by whole-body DXA than by regional DXA. Based on local data, models were developed that removed the significant difference between the methods.

Absorptiometry, Photon↗
PubMedDate not supplied

Multivariate analysis results of radiotherapy for laryngeal cancer.

We assess the impact of radiotherapy in the treatment of laryngeal cancer and evaluate the value of the standard dose (linear quadratic plus time model) and other variables to predict tumor control and survival. Between 1972 and 1989, 80 patients with laryngeal cancer received comprehensive radiotherapy. Patients with stage I laryngeal glottic cancer (T1-N0-M0) were excluded from this study. Mean follow-up was 15 months (range 4 to 181). The mean age was 64.8 years (range 40 to 92). Standard dose varied from 32.65 to 81.81 Gy (mean 66.78). The 5-year overall survival and tumor-specific survival rates were 44.9 +/- 5.8% and 51.4 +/- 5.9%, respectively. Five-year local control and locoregional control rates were 66.4 +/- 5.7% and 61.9 +/- 5.8%, respectively. Multivariate analysis showed that local control was significantly predicted by T stage (p = .032), but not by standard dose (p = .906). Independently significant factors predicting tumor-specific survival included stage (p = .006), site (p = .019), and age (p = .001). Local control and survival were significantly predicted by the TNM-staging classification. The standard dose did not predict local recurrence or survival.

Adult↗
PubMed2003

Modeling the impact of random screening and contact tracing in reducing the spread of HIV.

Mathematical models can help predict the effectiveness of control measures on the spread of HIV and other sexually transmitted diseases (STDs) by reducing the uncertainty in assessing the impact of intervention strategies such as random screening and contact tracing. Even though contact tracing is one of the most effective methods used for controlling treatable STDs, it is still a controversial strategy for controlling HIV because of cost and confidentiality issues. To help estimate the effectiveness of these control measures, we formulate two models with random screening and contact tracing based on the differential infectivity (DI) model and the staged-progression (SP) model. We derive formulas for the reproductive numbers and the endemic equilibria and compare the impact that random screening and contact tracing have in slowing the epidemic in the two models. In the DI model the infected population is divided into groups according to their infectiousness, and HIV is largely spread by a small, highly infectious, group of superspreaders. In this model contact tracing is an effective approach to identifying the superspreaders and has a large effect in slowing the epidemic. In the SP model every infected individual goes through a series of infection stages and the virus is primarily spread by individuals in an initial highly infectious stage or in the late stages of the disease. In this model random screening is more effective than for the DI model, and contact tracing is less effective. Thus the effectiveness of the intervention strategy strongly depends on the underlying etiology of the disease transmission.

Contact Tracing↗
PubMed2002

Superior therapeutic profile of poly-L-glutamic acid-paclitaxel copolymer compared with taxol in xenogeneic compartmental models of human ovarian carcinoma.

Previous preclinical studies with ectopic tumor models have demonstrated remarkable improvements in the therapeutic profile of paclitaxel, formulated as a copolymer with poly-L-glutamic acid, compared with paclitaxel in the clinical formulation, Taxol. In this study, we evaluated these formulations in two human ovarian carcinoma xenograft models, NMP-1 and HEY, in nude mice. i.p. implantation in female nude mice of either cell line gave rise to progressive disease within the peritoneum, in the parenchyma of visceral organs, and eventually at extraperitoneal sites; the resultant, increasing morbidity then required host sacrifice. i.p. administration of multiple-dose Taxol at its maximum tolerated dose 1 week after tumor implantation afforded minimal or no increased survival compared with controls in either model. Consistent with the predictions of drug copolymer behavior, paclitaxel, as the poly-L-glutamic acid-paclitaxel copolymer, displayed much less toxicity than Taxol in these hosts. When evaluated for antitumor efficacy in both the Taxol-resistant NMP-1 and HEY models, significant improvement in survival, and even some cures, were observed after a single i.p. treatment with this copolymer. The observed antitumor response correlated with histopathological analysis of peritoneal and extraperitoneal tumor burden in comparing control HEY mice sacrificed near the onset of morbidity with mice receiving paclitaxel copolymer. We conclude that both the i.p. NMP-1 and HEY models have significant value in establishing the efficacy of candidate agents, which might address Taxol-resistant human ovarian carcinoma. Furthermore, the poly-L-glutamic acid-paclitaxel copolymer has a superior therapeutic profile in these Taxol-resistant compartmental models.

Animals↗
PubMed1977

Application of the mathematics of coupled oscillator systems to the analysis of the neural control of locomotion.

In many animals, the activities of limb motor neurons are rhythmic during locomotion. In some animals it is known that each limb is innervated by a local control center that resides in a discrete portion of the central nervous system. Each local control center is a biological oscillator. Since each limb moves with the same frequency as each other limb and with regulated phase delay with respect to each other limb, then it follows that the local control centers are coupled to one another. The locomotory pattern generator within the central nervous system is therefore a coupled oscillator system. The mathematics of coupled oscillator systems can assist in the construction of a model of the neural pattern generator. This model can be utilized to formulate testable predictions concerning the neural control of locomotion. Experimental data gathered from organisms in several phylums are consistent with the predictions of the model.

Action Potentials↗
PubMedDate not supplied

Parametric mean survival time analysis in gastric cancer patients.

BACKGROUND: The mean survival time (MS) has acquired increasing importance as an outcome indicator for patient care and technology assessment. The authors use lifelong follow-up data from gastric cancer patients to study whether the MS is predictable from 5-year follow-up information based on 2 parametric models. METHODS: The authors used 3597 gastric cancer patients operated on between 1950 and 1969 to create 50 groups. For each group, the disease-related survival curve (DRSC) was estimated from the 5-year follow-up data using the Boag model. The MS for the group was then estimated by combining the DRSC with the survival curve for the age and sex-matched contemporaries (control group) based on the competing risk model. Alternatively, it was estimated by using the DRSC and the MS for the control group (the survival limit model). These predicted MS values were compared with the full follow-up observations. RESULTS: Although individual prediction errors varied depending on the group size (63 to 3597 patients) and the length of MS (0.3 to 20.2 years), the mean prediction errors were reasonably small; the survival limit model overestimated MS by 4.7% (95% confidence interval [CI], 1.6 to 7.8) and the competing risk model by 3.2% (95% CI, 0.1 to 6.5). CONCLUSIONS: MS for gastric cancer patients is parametrically predictable from 5-year follow-up data. This analysis should be applicable to other diseases showing log-normal failure time distributions.

Aged↗
PubMed2004

Robust control of initiation of prokaryotic chromosome replication: essential considerations for a minimal cell.

A genomically and chemically detailed mathematical model of a "minimal cell" would be useful to understand better the "design logic" of cellular regulation. A "minimal cell" will be a prokaryote with the minimum number of genes necessary for growth and replication in an ideal environment (i.e., preformed precursors, constant temperature, etc.). The Cornell single-cell model of Escherichia coli serves as the basic framework upon which a minimal cell model can be constructed. A critical issue for any cell model is to describe a mechanism for control of initiation of chromosome replication. There is strong evidence that the essence of chromosome replication control is highly conserved in eubacteria and even extends to the archae. A generalized mechanism is possible based on binding of the protein DnaA-ATP to the origin of replication (oriC) as a primary control. Other features, such as regulatory inactivation of DnaA (RIDA) by conversion of DnaA-ATP to DnaA-ADP and titration of DnaA by binding to other DnaA boxes on the chromosome, have emerged as critical elements in obtaining a functional system to control initiation of chromosome synthesis. We describe a biologically realistic model of chromosome replication initiation control embedded in a complete whole-cell model that explicitly links the external environment to the mechanism of replication control. The base model is deterministic and then modified to include stochastic variation in the components for replication control. The stochastic model allows evaluation of the model's robustness, employing a low standard deviation of interinitiation time as a measure of robustness. Four factors were examined: DnaA synthesis rate; DnaA-ATP binding sites at oriC; the binding rate of DnaA-ATP to the nonfunctional DnaA boxes; and the effect of changing the number of nonfunctional binding sites. The observed DnaA synthesis rate (2000 molecules/cell) and the number of DnaA binding sites per origin (30) are close to the values predicted by the model to provide good control (low variance of interinitiation time), with a reasonable expenditure of cell resources. At relatively high binding rates for DnaA-ATP to the DnaA boxes (10(16) M(-1) s(-1)), increasing the number of DnaA binding sites to about 300, improved control (but little further improvement was seen by extension to 1000 boxes); however, at a low binding rate (10(10) M(-1) s(-1)), an increase in DnaA boxes had an adverse effect on control. The combination of all four factors is probably necessary to obtain a robust control system. Although this mechanism of replication initiation control is highly conserved, it is not clear if simpler control in a minimal cell might exist based on experimental observations with Mycoplasma. This issue is discussed in this investigation.

Bacterial Proteins↗
PubMed2006

Capability and limitations of first-order and diffusion approaches to describe long-term sorption of chlortoluron in soil.

This paper compares the capability of a first-order and a spherical diffusion model to describe and predict long-term sorption and desorption processes of chlortoluron in two soils. Chlortoluron sorption was investigated at different time scales utilizing one rate experiment (120 days) and two sorption/desorption experiments. Experimental periods for sorption and desorption were set to 1 day (five desorption steps) and 30 days (three desorption steps), respectively. Upon fitting, the two models satisfactorily described the whole set of data. The spherical diffusion model performed better than the first-order model. We then tested the predictive capability of the models by predicting 30-day sorption/desorption data using kinetic parameters fitted on 1-day sorption/desorption data only. While the spherical diffusion model was able to predict the 30-day data set, the first-order model failed completely. Fitting both models to subsets of the data corresponding to different experimental time scales revealed that the rate parameter as well as the Freundlich coefficient of the first-order model are strongly time-dependent--a property that is not shared by parameters of the spherical diffusion model. The apparent stability of the spherical diffusion model with regard to time dependency of its parameters indicates that sorptive uptake may be diffusion-controlled. This also explains the models greater predictive power across different time scales compared to the first-order model. Finally, we investigate the suitability of solute class specific log-linear relationships between the first-order rate parameter and the Freundlich coefficient presented by earlier researchers in the light of the time dependency observed for the parameters of the first-order model.

Absorption↗
PubMed1995

A basic mathematical model of the immune response.

Interaction of the immune system with a target population of, e.g., bacteria, viruses, antigens, or tumor cells must be considered as a dynamic process. We describe this process by a system of two ordinary differential equations. Although the model is strongly idealized it demonstrates how the combination of a few proposed nonlinear interaction rules between the immune system and its targets are able to generate a considerable variety of different kinds of immune responses, many of which are observed both experimentally and clinically. In particular, solutions of the model equations correspond to states described by immunologists as "virgin state," "immune state" and "state of tolerance." The model successfully replicates the so-called primary and secondary response. Moreover, it predicts the existence of a threshold level for the amount of pathogen germs or of transplanted tumor cells below which the host is able to eliminate the infectious organism or to reject the tumor graft. We also find a long time coexistence of targets and immune competent cells including damped and undamped oscillations of both. Plausibly the model explains that if the number of transformed cells or pathogens exeeds definable values (poor antigenicity, high reproduction rate) the immune system fails to keep the disease under control. On the other hand, the model predicts apparently paradoxical situations including an increased chance of target survival despite enhanced immune activity or therapeutically achieved target reduction. A further obviously paradoxical behavior consists of a positive effect for the patient up to a complete cure by adding an additional target challenge where the benefit of the additional targets depends strongly on the time point and on their amount. Under periodically pulsed stimulation the model may show a chaotic time behavior of both target growth and immune response. (c) 1995 American Institute of Physics.

Journal Article↗
PubMed1989

Psychosocial factors affecting genital herpes recurrences: linear vs mediating models.

Psychosocial factors (emotional distress, stress, health locus of control, and social support) and genital herpes activity (episode frequency, severity, and duration) were assessed for 46 individuals with recurrent genital herpes infections (HSV) in order to predict psychosocial status associated with herpes episodes. Multiple regression analyses revealed that stress and emotional distress accounted for 52% of HSV episode frequency variance, whereas 49% of the episode severity variance was determined by emotional distress and health locus of control. The buffering effects of time and health locus of control were functional only for herpes frequency. Linear predictive models appear to offer a better opportunity for understanding how psychosocial factors affect genital herpes outbreaks than do interactive or buffering models. Results were discussed in terms of the biopsychosocial model of health.

Adolescent↗
PubMed1990

A model of the muscarinic receptor-induced changes in K(+)-current and action potentials in the bullfrog atrial cell.

A model is formulated for characterizing the behavior of the acetylcholine (ACh)-sensitive K+ membrane channel (muscarinic channel) in bullfrog atrial myocytes. Parameters of the muscarinic current model are chosen in fit available data from the literature on bullfrog atrial myocytes (3, 4, 45). This model is subsequently incorporated into a large mathematical model of the bullfrog myocyte that is based on quantitative whole-cell voltage clamp data (40). Simulations are conducted on the active atrial cell model in bathing media containing ACh at different concentrations to explore the effect of this muscarinic channel on the electrical behavior of the myocyte. The model predicts a progressive shortening of the action potential with increasing [ACh], as well as an indirect influence of the muscarinic K+ current on the other membrane currents of the atrial cell. Interpretation of the simulation results provides suggestions for the probable mechanisms underlying the shortening of the action potential due to activity of the muscarinic channel. Specifically, the model predicts that with an increase in ACh concentration: (a) the outward muscarinic current, IK,ACh(t), increases in magnitude but shortens in duration; (b) the calcium current, ICa(t), may increase in magnitude, but when it does so it decreases in duration compared with the control conditions; (c) the intracellular Ca2+ concentration [Ca2+]i waveform during the action potential decreases in both magnitude and duration. Because the contractile activity of the cell is controlled by the [Ca2+]i waveform, the model predicts a decrease in contractile strength with an increase in ACh concentration in the bathing medium; i.e., a negative inotropic effect.

Action Potentials↗
PubMedDate not supplied

The theory of planned behavior: a review of its applications to health-related behaviors.

PURPOSE: To review applications of Ajzen's theory of planned behavior in the domain of health and to verify the efficiency of the theory to explain and predict health-related behaviors. METHODS: Most material has been drawn from Current Contents (Social and Behavioral Sciences and Clinical Medicine) from 1985 to date, together with all peer-reviewed articles cited in the publications thus identified. FINDINGS: The results indicated that the theory performs very well for the explanation of intention; an averaged R2 of .41 was observed. Attitude toward the action and perceived behavioral control were most often the significant variables responsible for this explained variation in intention. The prediction of behavior yielded an averaged R2 of .34. Intention remained the most important predictor, but in half of the studies reviewed perceived behavioral control significantly added to the prediction. CONCLUSIONS: The efficiency of the model seems to be quite good for explaining intention, perceived behavioral control being as important as attitude across health-related behavior categories. The efficiency of the theory, however, varies between health-related behavior categories.

Health Behavior↗
PubMedDate not supplied

Prediction of elementary school children's externalizing problem behaviors from attentional and behavioral regulation and negative emotionality.

The purpose of this study was to examine the moderating role of individual differences in negative emotionality in the relations of behavioral and attentional (emotional) regulation to externalizing problem behaviors. Teachers' and one parent's reports of children's regulation (attentional and behavioral), emotionality, and problem behavior were obtained when children were in kindergarten to grade 3 and two years later (N = 169; 146 in major analyses); children's behavioral regulation also was assessed with a measure of persistence. According to the best fitting structural equation model, at two ages behavioral dysregulation predicted externalizing behavior problems for children both high and low in negative emotionality, whereas prediction of problem behavior from attentional control was significant only for children prone to negative emotionality. There were unique, additive effects of behavioral and attentional regulation for predicting problem behavior as well as moderating effects of negative emotionality for attentional regulation.

Age Factors↗
PubMed2002

Accumulation of deleterious mutations: additional Drosophila melanogaster estimates and a simulation of the effects of selection.

We report an assay of egg-to-adult viability in full-sibling mutation accumulation (MA) lines derived from a completely homozygous population of Drosophila melanogaster and maintained for 210 generations. A simultaneous evaluation was also made of a large population derived from the same origin and maintained as a control for the same period. We also present computer simulations to explore the possible decline in viability of the control population due to mutation accumulation and the possible effect of selection within and between MA lines. For this purpose, we used two mutational models independent from the data analyzed and based on radically different assumptions. The first model implies a large number of mutations of small effect, whereas the second implies a much smaller number of mutations with much larger effects. The observed rate of decline in mean viability was very small but significant (0.077%). The rate of increase in among line variance (0.189 x 10(-3)) was similar to those obtained previously in the same lines. The simulation results indicated that a model of many mutations of small effect is incompatible with the evolution of the mean viability of the control and MA lines over generations, the distribution of line means after 210 generations of mutation accumulation, and the pattern of line extinction over generations. Basically, this model predicted a large drop in viability, both in the control and particularly the MA lines, that is not observed empirically. It also predicted a rate of line extinction too low in the early generations and too high in the later ones. In contrast, the model based on few mutations of large effect was generally consistent with all the observations.

Animals↗
PubMed2003

Effects of partial lidocaine inactivation of the paramedian pontine reticular formation on saccades of macaques.

To investigate the brain stem control of saccadic eye movements, the paramedian pontine reticular formation (PPRF) in rhesus monkeys was temporarily and partially inactivated with the local anesthetic lidocaine. The influence on ipsilesional, contralesional, and upward saccades was examined. While the effects of the inactivation on contralesional and upward saccades were inconsistent and small, consistent and marked modifications were observed for ipsilesional movements. For ipsilesional, horizontal saccades, all lidocaine injections caused a decrease in peak velocity and a proportional increase in duration, which substantially altered the shape of the velocity profile. The rise in duration usually fell short of preventing hypometric saccades at the peak of the effect. However, as the lidocaine effect dissipated, the amplitude often returned to control, even though the velocity and duration remained compromised. For ipsilesional, oblique saccades, the effect of lidocaine on the horizontal component was similar to that for horizontal saccades. The vertical component of oblique saccades was also influenced, albeit to a much lesser extent: the duration of the vertical component typically increased, while the vertical peak velocity either decreased or exhibited no significant change. These results were compared with simulations of three prominent models for cross-coupling oblique saccades. In general, these results of the temporary inactivation of PPRF are consistent with the predictions of local feedback models for saccadic control.

Anesthetics, Local↗
PubMedDate not supplied

A time series aggregation model for predicting the incidence of syphilis.

The incidence of infectious syphilis is much different from the number of reported cases in any given year; therefore, an estimate of the incidence is needed to formulate effective control programs for the future. A time series aggregation model that predicts the incidence of syphilis was developed. The model accounts for the number of treated but unreported cases, and it provides estimates of incidence for different age and racial groups. As an illustration the model was applied for estimation of the incidence of syphilis in the city of Chicago, Illinois. A sensitivity analysis revealed that a 10% variation in input parameters would cause an error of smaller than or equal to 4.1% in the estimates of incidence.

Age Factors↗