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PubMed2001

Models of respiratory rhythm generation in the pre-Bötzinger complex. III. Experimental tests of model predictions.

We used the testable predictions of mathematical models proposed by Butera et al. to evaluate cellular, synaptic, and population-level components of the hypothesis that respiratory rhythm in mammals is generated in vitro in the pre-Bötzinger complex (pre-BötC) by a heterogeneous population of pacemaker neurons coupled by fast excitatory synapses. We prepared thin brain stem slices from neonatal rats that capture the pre-BötC and maintain inspiratory-related motor activity in vitro. We recorded pacemaker neurons extracellularly and found: intrinsic bursting behavior that did not depend on Ca(2+) currents and persisted after blocking synaptic transmission; multistate behavior with transitions from quiescence to bursting and tonic spiking states as cellular excitability was increased via extracellular K(+) concentration ([K(+)](o)); a monotonic increase in burst frequency and decrease in burst duration with increasing [K(+)](o); heterogeneity among different cells sampled; and an increase in inspiratory burst duration and decrease in burst frequency by excitatory synaptic coupling in the respiratory network. These data affirm the basis for the network model, which is composed of heterogeneous pacemaker cells having a voltage-dependent burst-generating mechanism dominated by persistent Na(+) current (I(NaP)) and excitatory synaptic coupling that synchronizes cell activity. We investigated population-level activity in the pre-BötC using local "macropatch" recordings and confirmed these model predictions: pre-BötC activity preceded respiratory-related motor output by 100-400 ms, consistent with a heterogeneous pacemaker-cell population generating inspiratory rhythm in the pre-BötC; pre-BötC population burst amplitude decreased monotonically with increasing [K(+)](o) (while frequency increased), which can be attributed to pacemaker cell properties; and burst amplitude fluctuated from cycle to cycle after decreasing bilateral synaptic coupling surgically as predicted from stability analyses of the model. We conclude that the pacemaker cell and network models explain features of inspiratory rhythm generation in vitro.

Animals↗

PubMedDate not supplied

2001 Harry M. Vars Research Award. Enteral nutrients alter enterocyte function within an in vitro model similar to an acute in vivo rat model during hypoxia.

BACKGROUND: Early enteral nutrition in patients following traumatic injury is an important intervention. However, after shock-resuscitation, intestinal hypoperfusion persists despite adequate systemic resuscitation. Our previous in vivo rat studies indicate that hypoperfusion impairs mucosal function in the small intestine. Therefore, the current study sought to improve previous in vitro models by the following means: (1) We used Caco-2 monolayers stably transfected with the brush-border sodium-glucose co-transporter (SGLT-1); and (2) we created an environment that mimicked the physiologic enterocyte environment. We hypothesized that hypoxic alterations of epithelial function in an in vitro model are comparable to those of an in vivo rat model. METHODS: After 21 days, monolayers were randomized to receive 24 hours of incubation in a normoxic or hypoxic environment. Cells were further randomized to receive 1 of 4 nutrient treatments: mannitol (an osmotic control), glucose (uses SGLT-1 and is metabolized), 3-O-methylglucose (3-O-mg; uses SGLT-1 and is not metabolized), or fructose (does not use SGLT-1 but can be metabolized). RESULTS: Transepithelial resistance (p = .007) and short-circuit current (p = .05) were lower in hypoxic groups. When compared with normoxic groups, hypoxic groups had significantly impaired glucose (p < .001) but not glutamine transport, irrespective of nutrient treatment. Additionally, adenosine triphosphate/adenosine diphosphate ratio was reduced (p = .01) and lactate concentration was increased (p < .001) during hypoxia. CONCLUSIONS: In summary, results from this in vitro study using Caco-2BBe cells stably transfected with SGLT-1 correspond to results obtained in the in vivo rat model. Therefore, this is an appropriate in vitro model in which to study cellular alterations caused by the hypoxic small intestine, with the goal of ensuring safe early enteral nutrition following traumatic injury.

3-O-Methylglucose↗

PubMed2001

Examining theoretical models through research synthesis. The benefits of model-driven meta-analysis.

Quantitative research synthesis methods can be used to examine theoretical models for substantive research questions. Model-driven syntheses can address more complex questions than have typically been addressed in quantitative reviews in a more systematic and organized manner than in a traditional narrative review. A rationale and set of objectives for syntheses involving models are reviewed. The author describes how to incorporate models into each stage of a review, outlining problems and limitations that may arise at each stage. Examples from several model-driven syntheses illustrate the points made in the article.

Data Collection↗

PubMed2004

Applications of hierarchical linear models for evaluations of health interventions: demystifying the methods and interpretations of multilevel models.

Despite the wide availability of statistical programs designed to deal with longitudinal data from a multilevel perspective, many applied researchers remain unfamiliar with the benefits of this methodology, particularly for the evaluation of interventions. The authors present an example of multilevel modeling as part of the analysis of evaluation data from an HIV intervention study. Strategies for understanding multilevel models using longitudinal (panel) data are demonstrated and discussed. The authors illustrate how multiple linear regression models provide a convenient conceptual background to understanding how hierarchical linear models can be developed and interpreted. Multilevel analysis results are compared and contrasted with typical approaches through general linear models for repeated-measures data. Analyses are presented using the SPSS and HLM 5 software.

Analysis of Variance↗

PubMed2006

Stochastic modeling of oligodendrocyte generation in cell culture: model validation with time-lapse data.

BACKGROUND: The purpose of this paper is two-fold. The first objective is to validate the assumptions behind a stochastic model developed earlier by these authors to describe oligodendrocyte generation in cell culture. The second is to generate time-lapse data that may help biomathematicians to build stochastic models of cell proliferation and differentiation under other experimental scenarios. RESULTS: Using time-lapse video recording it is possible to follow the individual evolutions of different cells within each clone. This experimental technique is very laborious and cannot replace model-based quantitative inference from clonal data. However, it is unrivalled in validating the structure of a stochastic model intended to describe cell proliferation and differentiation at the clonal level. In this paper, such data are reported and analyzed for oligodendrocyte precursor cells cultured in vitro. CONCLUSION: The results strongly support the validity of the most basic assumptions underpinning the previously proposed model of oligodendrocyte development in cell culture. However, there are some discrepancies; the most important is that the contribution of progenitor cell death to cell kinetics in this experimental system has been underestimated.

Algorithms↗

PubMed2006

An object simulation model for modeling hypothetical disease epidemics - EpiFlex.

BACKGROUND: EpiFlex is a flexible, easy to use computer model for a single computer, intended to be operated by one user who need not be an expert. Its purpose is to study in-silico the epidemic behavior of a wide variety of diseases, both known and theoretical, by simulating their spread at the level of individuals contracting and infecting others. To understand the system fully, this paper must be read together in conjunction with study of the software and its results. EpiFlex is evaluated using results from modeling influenza A epidemics and comparing them with a variety of field data sources and other types of modeling. EpiFlex is an object-oriented Monte Carlo system, allocating entities to correspond to individuals, disease vectors, diseases, and the locations that hosts may inhabit. EpiFlex defines eight different contact types available for a disease. Contacts occur inside locations within the model. Populations are composed of demographic groups, each of which has a cycle of movement between locations. Within locations, superspreading is defined by skewing of contact distributions. RESULTS: EpiFlex indicates three phenomena of interest for public health: (1) R0 is variable, and the smaller the population, the larger the infected fraction within that population will be; (2) significant compression/synchronization between cities by a factor of roughly 2 occurs between the early incubation phase of a multi-city epidemic and the major manifestation phase; (3) if better true morbidity data were available, more asymptomatic hosts would be seen to spread disease than we currently believe is the case for influenza. These results suggest that field research to study such phenomena, while expensive, should be worthwhile. CONCLUSION: Since EpiFlex shows all stages of disease progression, detailed insight into the progress of epidemics is possible. EpiFlex shows the characteristic multimodality and apparently random variation characteristic of real world data, but does so as an emergent property of a carefully constructed model of disease dynamics and is not simply a stochastic system. EpiFlex can provide a better understanding of infectious diseases and strategies for response.

Computer Simulation↗

PubMed2004

Simulation-based parameter estimation for complex models: a breast cancer natural history modelling illustration.

Simulation-based parameter estimation offers a powerful means of estimating parameters in complex stochastic models. We illustrate the application of these ideas in the setting of a natural history model for breast cancer. Our model assumes that the tumor growth process follows a geometric Brownian motion; parameters are estimated from the SEER registry. Our discussion focuses on the use of simulation for computing the maximum likelihood estimator for this class of models. The analysis shows that simulation provides a straightforward means of computing such estimators for models of substantial complexity.

Algorithms↗

PubMed1996

A mechanism-mediated model for carcinogenicity: model content and prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 25 organic chemicals.

A hierarchical model consisting of quantitative structure-activity relationships based mainly on chemical reactivity was developed to predict the carcinogenicity of organic chemicals to rodents. The model is comprised of quantitative structure-activity relationships, QSARs based on hypothesized mechanisms of action, metabolism, and partitioning. Predictors included octanol/water partition coefficient, molecular size, atomic partial charge, bond angle strain, atomic acceptor delocalizibility, atomic radical superdelocalizibility, the lowest unoccupied molecular orbital (LUMO) energy of hypothesized intermediate nitrenium ion of primary aromatic amines, difference in charge of ionized and unionized carbon-chlorine bonds, substituent size and pattern on polynuclear aromatic hydrocarbons, the distance between lone electron pairs over a rigid structure, and the presence of functionalities such as nitroso and hydrazine. The model correctly classified 96% of the carcinogens in the training set of 306 chemicals, and 90% of the carcinogens in the test set of 301 chemicals. The test set by chance contained 84% of the positive thio-containing chemicals. A QSAR for these chemicals was developed. This posttest set modified model correctly predicted 94% of the carcinogens in the test set. This model was used to predict the carcinogenicity of the 25 organic chemicals the U.S. National Toxicology Program was testing at the writing of this article.

Animals↗

PubMed2002

Fitting structural equation models using estimating equations: a model segregation approach.

Problems such as improper solution, non-convergence, subsets of variables having different distribution, and latent variables with single indicators are common in the practice of structural equation modelling. In such cases, it may be feasible to fix some model parameters at prespecified values while concentrating on estimating some other parameters. This paper formulates such a model fitting process through a model segregation approach. The statistical properties of this procedure are studied using the theory of estimating equations and optimal estimating functions. The dependency of the new parameter estimates on those of the prespecified parameter estimates is characterized for several commonly used estimating equations. A rescaled model fit statistic is proposed. Examples illustrate various applications of this procedure.

Behavioral Sciences↗

PubMed2005

Stability of attachment-related anxiety and avoidance and their relationships with the five-factor model and the psychobiological model of personality.

OBJECTIVES: The stability of attachment-related anxiety and avoidance and their relationship with influential personality models are issues worth further investigation. Studying discriminant validity with respect to aspects of personality deemed as prevalently heritable, such as temperament, is particularly important. Our aims were to examine the stability of attachment dimensions and to study their relationship with psychological distress, the Big Five factors, and temperament and character dimensions. METHODS: The Experiences in Close Relationships (ECR) questionnaire, the State-Trait Anxiety Inventory (STAI), the Zung depression scale (ZDS), the Temperament and Character Inventory (TCI-125), and the Big Five Questionnaire (BFQ) were administered to 222 undergraduate and graduate students. After 1 month, 115 participants completed again the ECR, the STAI, and the ZDS. RESULTS: Attachment-related anxiety was modestly correlated with depression and anxiety, while attachment-related avoidance was modestly correlated with depression. The test-retest reliability of ECR scores was high. Changes in attachment-related anxiety were not related to changes in depression or anxiety, and changes in attachment-related avoidance were modestly correlated with changes in depression. In separate multiple regression models also including gender and age, attachment-related anxiety was correlated with harm avoidance, reward dependence, low novelty seeking, low self-directedness and low cooperativeness; low energy/extraversion and low emotional stability; attachment-related avoidance was correlated with low reward dependence and tended to be correlated with low self-directedness. CONCLUSIONS: These findings corroborate the reliability and the convergent and discriminant validity of the ECR, and support the notion that the attachment dimensions are only modestly related to psychological distress and are not redundant with constructs developed within influential personality models such as the five-factor model and the psychobiological model.

Adolescent↗

PubMed2005

The community action model: a community-driven model designed to address disparities in health.

The community action model is a 5-step, community-driven model designed to build communities' capacity to address health disparities through mobilization. Fundamental to the model is a critical analysis identifying the underlying social, economic, and environmental forces that create health and social inequities in a community. The goal is to provide communities with the framework necessary to acquire the skills and resources to plan, implement, and evaluate health-related actions and policies. The model was developed in the context of tobacco-related health disparities. Concrete policy outcomes demonstrate the model's potential application to a wide variety of grassroots policy development efforts.

California↗

PubMed2002

A review of molecular modeling approaches to pharmacophore models and structure-activity relationships of ion channel modulators in CNS.

Through pharmacophore models and providing quantitative analysis of structure-activity relationships (QSAR), molecular modeling techniques can be useful tools to study the interactions of ion channels and their modulators. The present review focuses on molecular modeling approaches that defined pharmacophore models of ion channel modulators in the CNS. The commonality and subtlety of the pharmacophore models of various ion channel modulators are discussed which can be used as a framework for the design of ion channel modulators.

Central Nervous System↗

PubMed2004

Lesions and dysfunctions of the nucleus basalis as Alzheimer's disease models: general and critical overview and analysis of the long-term changes in several excitotoxic models.

The cholinergic hypothesis of Alzheimer's Disease (AD) has led to a number of animal models to study in vivo the pathogeny of cortical cholinergic involution. The lesion of the cholinergic neurons of the basal forebrain, especially of the nucleus basalis magnocellularis (nbm) of rodents, has been the most utilized method for obtaining these models. Toxic substances such as quinolic, kainic, NMDA, ibotenic and quisqualic acids, the specific cholinergic toxin AF64, amyloid, and antibodies to neurotrophic factors; etc, have been used to produce such lesions. These investigations have helped our understanding of the role of cerebral cholinergic innervation in cognitive disorders and their treatments. However, this research has provided conflicting results, and much controversy has developed surrounding the role of the cholinergic systems and the suitability of these models. It is very important to take into account the exact type of nbm/cortical lesion produced, and its evolution, if meaningful results are to be obtained. This review covers the theoretical and practical use of nbm lesion models, and examines the main positive and negative results obtained by different authors in the light of our own observations on the long-term (3 years) morphological and biochemical changes that occur in several kinds of nbm-lesion model rats. The changes seen were very different, but many of them were increased up to the end of life with no clear relationship with the development of the original lesion.

Alzheimer Disease↗

PubMed1991

Computer simulation model of swine production systems: I. Modeling the growth of young pigs.

Theoretical concepts and relationships were used to develop a deterministic pig growth model. The model predicts, in a continuous form, growth and body composition of boars, barrows, and gilts according to genotype, diet, and management conditions. The model is aggregated at the whole-animal level with three main elements of body composition; total body DNA, total body protein mass (PT), and total body mass of lipids, with PT determining the secondary elements of ash and moisture. The primary factors regulating growth were associated with cellular hyperplasia and hypertrophy in agreement with the basic concepts described by Baldwin and Black (1979). Differential equations representing DNA accretion and protein synthesis and degradation were adapted from Oltjen et al. (1985). Normal pig protein growth was characterized from published data. Body PT was used to reflect several metabolic activities related to animal size and age, as in some prior models. Dietary energy and protein were used in sequence until requirements are satisfied, first for maintenance, then for protein growth, and finally for fat deposition. A comparison between experimental and simulated results illustrates that the model may simulate growth and body composition of young pigs adequately.

Animals↗

PubMed1991

Computer simulation model of swine production systems: III. A dynamic herd simulation model including reproduction.

A dynamic herd simulation model for a swine production unit has been developed. The model is discrete and stochastic and the appropriate random distributions have been defined from the literature or empirically estimated. Theoretical concepts and relationships presented previously are used to simulate growth and the overall life cycle of individual animals. Simulated animals are young pigs (from birth to slaughter age), gilts, and sows. Animal events are farrowing, weaning, mating, end-nursery (transfer from nursery to the growing-finishing facility), and slaughter and are processed individually using a next-event scheduling orientation package. Animals within the herd are culled for different health and reproductive reasons. Genetic parameters, diet composition, and herd management are input variables chosen by the user. The effects of nutrition, genetics, season, and other factors on several reproductive parameters are considered. Model evaluation is performed by studying the output of the model under specified herd situations. The herd model adequately simulates animal flow and dynamics of the herd.

Animal Nutritional Physiological Phenomena↗

PubMed1997

Disability models in geriatrics: comprehensive rather than competing models should be promoted.

The usefulness of different models of disability is discussed. There is no clear-cut demarcation between ability and disability, and a person's functional abilities are highly dependent on societal as well as individual factors. One should not, however, promote models of disability that cover only the social aspects, but rather try to build comprehensive models including medical, psychological and social aspects of disability. The World Health Organization's International Classification of Impairments, Disabilities and Handicaps (ICIDH) provides a useful basis for such model building. The main weakness of the ICIDH is that it fails to take the subjective perceptions of the individual fully into account. Accordingly, it should be supplemented by some model of subjective well-being. Possible relationships between subjective well-being and the ICIDH concepts are discussed.

Aged↗

PubMed2006

Short communication: Further validation of the fat sub-model in the Cornell-Penn-Miner Dairy model.

Recently, a fat sub-model was introduced into the Cornell-Penn-Miner Dairy model (CPM-Dairy; Moate et al., 2004). The principal aim of the work reported here was to validate this fat sub-model in terms of its accuracy in predicting the apparent absorption (intake - feces) of total long-chain fatty acids (LCFA) in lactating dairy cows. The fat sub-model in CPM-Dairy was used to predict the amounts (g/d) of total LCFA apparently absorbed from 63 diets described in 14 published experiments. These predicted amounts (PLCFA) were regressed against the amounts reported to be apparently absorbed (RLCFA). The regression equation was: PLCFA = - 24.8 +/- 25.2 + 1.011 x 0.029 x RLCFA; R2 = 0.95, RMSE = 55.2 g/d. The results show that for a diverse range of diets, the fat model in CPM-Dairy can accurately predict apparent absorption of dietary total LCFA.

Abomasum↗

PubMedDate not supplied

Some flow visualization and laser-Doppler-velocity measurements in a true-to-scale elastic model of a human aortic arch--a new model technique.

Flow studies were done in an elastic true-to-scale silicone rubber model of an aortic arch to study further hemodynamic influences on atherosclerosis. The model was prepared from a cast of a young woman. A revised model technique was used. The model had a compliance similar to that of the human aortic arch. Velocity measurements were done in the model with a two component laser-Doppler-anemometer in steady and pulsatile flow using a calcium chloride solution with a viscosity of eta = 3.18 mPas and density of rho = 1.28 kg/m3 at 20 degrees C. The time average Reynolds numbers over a whole cycle in the ascending aorta was Re = 1350. The Womersley parameter for pulsatile flow was a = 20. The pulse wave velocity in the ascending aorta was about c = 5.4 m/sec. The secondary flow behavior was discussed for steady and pulsatile flow. Reverse flows were found, especially along the inner radius of the aortic arch in the descending aorta in steady and pulsatile flow and also in small areas of the ascending aorta and at the branches of the aortic arch. The formation of atherosclerotic plaques at preferred local flow regions is discussed.

Aorta, Thoracic↗