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PubMed1997

Cell culture models of interspecies selectivity to organophosphorous insecticides.

In toxicology, the need to reduce uncertainties in human risk assessment is met by understanding why species and individuals within that species respond differently to chemical exposure. This kind of information is needed when extrapolating data from experimental (i.e., whole animal) systems to the human condition in terms of risk assessment. In 1993 the Neurotoxicology Division of the Environmental Protection Agency funded several investigators to examine this phenomenon (i.e., interspecies selectivity) using cell culture models. Organophosphorous (OP) insecticides were examined since they are characterized by an extremely divergent interspecies response. In 1995, a symposium entitled Novel Insights into Chemical Neurotoxicity, sponsored by the Society for In Vitro Biology featured this research. In it, a historical overview of the phenomenon of interspecies selectivity to OP insecticides was given, current explanations for it were discussed and contemporary in vitro models being used to explain it, were described. Data from these studies have helped to redefine the underlying mechanisms that characterize and influence the cross-species response to insecticides. These experiments have refocused the explanation of this phenomenon to include cellular metabolism, target enzyme baseline activities, and receptor-mediated electrophysiological and second-messenger events. Several investigators on this panel also reported on the use of subcellular markers (e.g., target esterases, second messengers, ionic fluxes) to differentiate neuropathy-causing OP compounds from acetylcholinesterase inhibitors. After these presentations, technical considerations used in the designed of in vitro neurotoxicity studies were discussed.

Animals↗
PubMed1986

Evolutionary principles for general frequency-dependent two-phenotype models in sexual populations.

The evolutionary dynamics in general two-sex two-phenotype frequency-dependent selection models are studied with respect to underlying multi-allele one-locus genetic systems. Two classes of equilibria come into play: genotypic equilibria, with equilibrium allelic frequencies independent of the phenotype, and phenotypic equilibria, which are characterized by equal mean phenotypic fitnesses. The exact conditions for genotypic equilibria to exist and be stable and for phenotypic equilibria to exist and be evolutionarily attractive are examined. Using adequate definitions of mean fitnesses in general contexts of frequency-dependent selection in dioecious populations, we show that two phenotypes, when they can coexist in the population, tend to balance their fitnesses as far as is allowed by the genetic system as more alleles responsible for phenotype determination are introduced into the population.

Alleles↗
PubMed1980

[Selection of a statistical model for evaluation of the reliability of the results of toxicological analyses. I. Discussion on selected statistical models for evaluation of the systems of control of the results of toxicological analyses].

2 statistical models for evaluation of toxicological studies results have been presented. Model I. after R. Hoschek and H. J. Schittke (2) involves: 1. Elimination of the values deviating from most results-by Grubbs' method (2). 2. Analysis of the differences between the results obtained by the participants of the action and tentatively assumed value. 3. Evaluation of significant differences between the reference value and average value for a given series of measurements. 4. Thorough evaluation of laboratories based on evaluation coefficient fx. Model II after Keppler et al. As a criterion for evaluating the results the authors assumed the median. Individual evaluation of laboratories was performed on the basis of: 1. Adjusted test "t" 2. Linear regression test.

Models, Theoretical↗
PubMed2000

Joint effects of natural selection and recombination on gene flow between Drosophila ananassae populations.

We estimated DNA sequence variation in a 5.7-kb fragment of the furrowed (fw) gene region within and between four populations of Drosophila ananassae; fw is located in a chromosomal region of very low recombination. We analyzed gene flow between these four populations along a latitudinal transect on the Indian subcontinent: two populations from southern, subtropical areas (Hyderabad, India, and Sri Lanka) and two from more temperate zones in the north (Nepal and Burma). Furthermore, we compared the pattern of differentiation at fw with published data from Om(1D), a gene located in a region of normal recombination. While differentiation at Om(1D) shows an isolation-by-distance effect, at fw the pattern of differentiation is quite different such that the frequencies of single nucleotide polymorphisms are homogenized over extended geographic regions (i.e., among the two populations of the northern species range from Burma and Nepal as well as among the two southern populations from India and Sri Lanka), but strongly differentiated between the northern and southern populations. To examine these differences in the patterns of variation and differentiation between the Om(1D) and fw gene regions, we determine the critical values of our previously proposed test of the background selection hypothesis (henceforth called F(ST) test). Using these results, we show that the pattern of differentiation at fw may be inconsistent with the background selection model. The data depart from this model in a direction that is compatible with the occurrence of recent selective sweeps in the northern as well as southern populations.

Animals↗
PubMed1989

Model life table fitting by maximum likelihood estimation: a procedure to reconstruct paleodemographic characteristics from skeletal age distributions.

A procedure is presented that uses the regression coefficients for the Coale and Demeny west model life tables to model selected demographic characteristics from skeletal age-at-death distributions. Model death distributions were constructed and compared to a given skeletal distribution, using methods of maximum likelihood estimation to determine the best fit. Two chi-square tests are employed to evaluate the degree of fit. The resulting model includes estimates of demographic characteristics including gross reproductive rate, crude birth rate and life expectancy. The procedure is applied to three archaeological skeletal samples as test cases: two from eastern North America and one from Mexico. These display a range of correspondence (between the best fitting model and the data) from good to poor. The proposed procedure is a potentially powerful tool for both reconstructing paleodemographic rates and illuminating differences between typical human patterns and those found in archaeological populations.

Actuarial Analysis↗
PubMed1987

Social selection in human populations: protected polymorphism of deleterious alleles with incomplete penetrance.

Population dynamics of two alleles, A1 and A2, at a locus under social selection have been studied by considering incomplete penetrance of the three genotypes. A social selection model is constructed by assuming that the fitness of an individual is determined by his or her own phenotype as well as parental phenotypes. For both multiplicative and additive fitness models, sufficient conditions for a protected polymorphism depend on the reduced fitness of affected individuals (gamma), the reduced fitness of all individuals resulting from affected parents (beta), and the penetrance probabilities, f1, f2, and f3, for the three genotypes, A1A1, A1A2, and A2A2. These conditions reduce to two biologically important cases: 1) f1 less than f2 greater than f3 and beta less than -gamma/(1 - gamma) and 2) f1 greater than f2 less than f3 and beta greater than - gamma/(1 - gamma), and the most common form of the equilibrium frequency of the allele A2 is given by (f1 - f2)/(f1 - 2f2 + f3).

Adult↗
PubMed1998

Increased apolipoprotein E mRNA in the hippocampus in Alzheimer disease and in rats after entorhinal cortex lesioning.

The distribution of apolipoprotein E (ApoE) mRNA was characterized in the hippocampus of humans with Alzheimer disease (AD) and in rats with experimental lesions (unilateral ablation of the entorhinal cortex) that model selected features of AD. In both AD and the lesion model, we observed a shift in the location of astrocytes containing prevalent ApoE mRNA from the neuropil to regions with densely packed neurons. The increased abundance of ApoE mRNA in astrocytes close to neuron cell bodies could be indicative of lipid uptake in regions where neurons are degenerating or where synaptic remodeling is taking place.

Alzheimer Disease↗
PubMed1990

Sleep problems in the community elderly as predictors of death and nursing home placement.

In 1984-85, 1855 elderly residents of an urban community responded to a comprehensive baseline interview that included questions regarding an extensive set of sleep characteristics and problems. During the subsequent 3 1/2 years of follow-up, 16.7% of the respondents died and 3.5% were placed in nursing homes. The predictive significance of each sleep characteristic for mortality and for nursing home placement was determined separately for males and females, using Cox proportional hazards models. Selected demographic and psychosocial variables were also entered into the models. Age, problems with activities of daily living (ADL), self-assessed health, income, cognitive impairment, depression and whether respondents were living alone were controlled for statistically. Of the many variables analyzed, in males insomnia was the strongest predictor of both mortality and nursing home placement. For mortality, the relative hazard associated with insomnia exceeded the hazards associated with age, ADL problems, fair-poor health and low income. For nursing home placement, the hazard associated with insomnia exceeded that associated with cognitive impairment. The relationships of insomnia to mortality and nursing home placement were U-shaped, with a worse outcome if insomnia complaints over the preceding 2 weeks were either prominent (numerous or frequent) or absent. For females, insomnia was a borderline predictor of mortality and did not predict nursing home placement at all. Symptoms of the restless legs syndrome predicted mortality for females in some Cox regression models. Reported sleep duration, symptoms of sleep apnea and frequent use of hypnotic drugs did not predict mortality or nursing home placement in either sex.

Aged↗
PubMed2005

Choice of models for the analysis and forecasting of hospital beds.

There is growing concern that current health care services are not sustainable. The compartmental flow model provides the opportunity for improved decision-making about bed occupancy decisions, particularly those of a strategic nature. This modelling can be applied to complement infrastructure and workforce-planning methods. Discussion about appropriateness of the level of model complexity, the degree of fit and the ability to use compartmental flow models for generalization and forecasting has been lacking. The authors investigated model selection and assessment in relation to hospital bed compartment flow models. A compartment model for a range of scenarios was created. The training and test data related to the 1998 and 1999 calendar years, respectively. The majority of scenarios tested were based upon commonly used periods that describe periods of time. The goodness-of-fit achieved by optimisation was measured against the training and test data. Model fit improved with increasing complexity as expected. The analysis of model fit against the test data showed that increasing model complexity did result in over-fitting, and better prediction was achieved with a relatively simple model. In terms of generalisation, the seasonal models performed best. Single day census type models, which have been used by Millard and his colleagues, were also generated. The performance of these models was similar, but inferior to that of the models generated from a full year of training data. The additional data make the models better able to capture the variation across the year in activity.

Bed Occupancy↗
PubMed2005

Intrasexual selection in Verreaux's sifaka (Propithecus verreauxi verreauxi).

Studies of sexual selection show that both female choice and male-male competition can influence the evolution and expression of male phenotypes. In this regard, it is important to determine the functional basis through which male traits influence variation in male reproductive success. In this study, we estimate the strength and type of sexual selection acting on adult males in a population of wild lemur, Verreaux's sifaka (Propithecus verreauxi verreauxi). The data used in this study were collected at Beza Mahafaly Special Reserve, southwest Madagascar. We conducted paternity analyses on 70 males in order to estimate the distribution of reproductive success in this population. Paternity data were combined with morphometric data in order to determine which morphological traits covary with male fitness. Five morphological traits were defined in this analysis: body size, canine size, torso shape, arm shape, and leg shape. We utilized phenotypic selection models in order to determine the strength and type of selection acting directly on each trait. Our results show that directional selection acts on leg shape (a trait that is functionally related to locomotor performance), stabilizing selection acts on body mass and torso shape, and negative correlational selection acts on body mass and leg shape. We draw from biomechanical and kinematic studies of sifaka locomotion to provide a functional context for how these traits influence male mating competition within an arboreal environment. Verreaux's sifaka and many other gregarious lemurs are sexually monomorphic in body mass and canine size, despite a high frequency and intensity of male-male aggressive competition. Our results provide some insight into this paradox: in our population, there is no directional selection acting on body mass or canine size in males. The total pattern of selection implicates that behaviors relating to locomotor performance are more important than behaviors relating to fighting ability during intrasexual contests.

Animals↗
PubMed1998

Diffusion-limited, but not perfusion-limited, compartmental models describe cerebral nitrous oxide kinetics at high and low cerebral blood flows.

This study aimed to evaluate the relative importance of diffusion-limited vs. perfusion-limited mechanisms in compartmental models of blood-tissue inert gas exchange in the brain. Nitrous oxide concentrations in arterial and brain efferent blood were determined using gas chromatographic analysis during and after 15 min of nitrous oxide inhalation, at separate low and high steady states of cerebral blood flow (CBF) in five sheep under halothane anesthesia. Parameters and model selection criteria of various perfusion- or diffusion-limited structural models of the brain were estimated by simultaneous fitting of the models to the mean observed brain effluent nitrous oxide concentration for both blood flow states. Perfusion-limited models returned precise, credible estimates of apparent brain volume but fit the low CBF data poorly. Diffusion-limited models provided better overall fit of the data, which was best described by exchange of nitrous oxide between a perfusion-limited brain compartment and an unperfused compartment. In individual animals, during the low CBF state, nitrous oxide kinetics displayed either fast, perfusion-limited behavior or slow, diffusion-limited behavior. This variability was exemplified in the different parameter estimates of the diffusion limited models fitted to the individual animal data sets. Results suggest that a diffusion limitation contributes to cerebral nitrous oxide kinetics.

Anesthetics, Inhalation↗
PubMed2001

Diffusion-limited tissue equilibration and arteriovenous diffusion shunt describe skeletal muscle nitrous oxide kinetics at high and low blood flows in sheep.

This study evaluated the relative importance of perfusion and diffusion mechanisms in compartmental models of blood : tissue inert gas exchange in skeletal muscle. Nitrous oxide kinetics in a hind limb skeletal muscle bed were determined during and after 20 min of nitrous oxide inhalation, at separate low and high steady states of hind limb blood flow in five sheep under halothane anaesthesia. Nitrous oxide concentrations in arterial and femoral vein blood were determined using gas chromatographic analysis and femoral vein blood flow was monitored continuously. Parameters and model selection criteria of various perfusion- or diffusion-limited structural models of skeletal muscle were estimated by simultaneous fitting of the models to the mean observed femoral vein nitrous oxide concentration for both blood flow states. Purely perfusion-limited models fit the data poorly. Models that allowed a diffusion-limited exchange of nitrous oxide between a perfusion-limited tissue compartment and an unperfused deep compartment provided better overall fit of the data and credible parameter estimates. The data was best described by allowing, in addition to diffusion-limited tissue equilibration, counter current diffusion of nitrous oxide between arterial and venous blood. The level of tissue blood flow modifies the magnitudes of both these diffusion effects. These results suggest a dual role of diffusion in blood : tissue inert gas equilibration in skeletal muscle.

Algorithms↗
PubMed2006

Predicting germination response to temperature. I. Cardinal-temperature models and subpopulation-specific regression.

BACKGROUND AND AIMS: The purpose of this study was to compare the relative accuracy of different thermal-germination models in predicting germination-time under constant-temperature conditions. Of specific interest was the assessment of shape assumptions associated with the cardinal-temperature germination model and probit distribution often used to distribute thermal coefficients among seed subpopulations. METHODS: The seeds of four rangeland grass species were germinated over the constant-temperature range of 3-38 degrees C and monitored for subpopulation variability in germination-rate response. Subpopulation-specific germination rate was estimated as a function of temperature and residual model error for three variations of the cardinal-temperature model, non-linear regression and piece-wise linear regression. The data were used to test relative model fit under alternative assumptions regarding model shape. KEY RESULTS: In general, optimal model fit was obtained by limiting model-shape assumptions. All models were relatively accurate in the sub-optimal temperature range except in the 3 degrees C treatment where predicted germination times were in error by as much as 70 d for the cardinal-temperature models. CONCLUSIONS: Germination model selection should be driven by research objectives. Cardinal-temperature models yield coefficients that can be directly compared for purposes of screening germplasm. Other model formulations, however, may be more accurate in predicting germination-time, especially at low temperatures where small errors in predicted rate can result in relatively large errors in germination time.

Germination↗
PubMed1999

The effects of deleterious mutations on linked, neutral variation in small populations.

The effects of recessive, deleterious mutations on genetic variation at linked neutral loci can be heterozygosity-decreasing because of reduced effective population sizes or heterozygosity-increasing because of associative overdominance. Here we examine the balance between these effects by simulating individual diploid genotypes in small panmictic populations. The haploid genome consists of one linkage group with 1000 loci that can have deleterious mutations and a neutral marker. Combinations of the following parameters are studied: gametic mutation rate to harmful alleles (U), population size (N), recombination rate (r), selection coefficient (s), and dominance (h). Tight linkage (r </= 10(-4)) gives significant associative effects, leading either to strong reduction of heterozygosity when the product Nhs is large or to a clear increase when the product Nhs is small, the boundary between these effects being 1 < Nhs < 4 in our simulations. Associative overdominance can lead to heterozygosities that are larger than predicted by the background selection models and even larger than the neutral expectation.

Alleles↗
PubMed1998

Modeling INR data to predict maintenance fluindione dosage.

This study was designed to construct a pharmacokinetic/pharmacodynamic model describing the evolution of International Normalized Ratio (INR) under oral anticoagulation treatment by fluindione in patients and to develop a method for individualization of fluindione dosage. Three indirect response models describing the concentration-INR relationship were tested using a nonparametric estimation method. INR was modelled as a quantity being produced and eliminated. According to a log-likelihood ratio test, the evolution of INR was best modelled as an inhibition of its elimination by fluindione. The selected model was evaluated in 24 additional patients with INR measurements (after 2, 3, 4, 6, and 10 doses). Using a Bayesian method with data until day 4, INR was correctly predicted for days 6 and 10. The population characteristics of fluindione were estimated, pooling the two groups of patients. A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state. Prescription rules for fluindione were derived using this method retrospectively on the 73 patients in this study.

Anticoagulants↗
PubMed2006

Surface-source modeling and estimation using biomagnetic measurements.

We propose a number of electric source models that are spatially distributed on an unknown surface for biomagnetism. These can be useful to model, e.g., patches of electrical activity on the cortex. We use a realistic head (or another organ) model and discuss the special case of a spherical head model with radial sensors resulting in more efficient computations of the estimates for magnetoencephalography. We derive forward solutions, maximum likelihood (ML) estimates, and Cramér-Rao bound (CRB) expressions for the unknown source parameters. A model selection method is applied to decide on the most appropriate model. We also present numerical examples to compare the performances and computational costs of the different models and illustrate when it is possible to distinguish between surface and focal sources or line sources. Finally, we apply our methods to real biomagnetic data of phantom human torso and demonstrate the applicability of them.

Action Potentials↗
PubMed2004

Robust model-based vasculature detection in noisy biomedical images.

This paper presents a set of algorithms for robust detection of vasculature in noisy retinal video images. Three methods are studied for effective handling of outliers. The first method is based on Huber's censored likelihood ratio test. The second is based on the use of a alpha-trimmed test statistic. The third is based on robust model selection algorithms. All of these algorithms rely on a mathematical model for the vasculature that accounts for the expected variations in intensity/texture profile, width, orientation, scale, and imaging noise. These unknown parameters are estimated implicitly within a robust detection and estimation framework. The proposed algorithms are also useful as nonlinear vessel enhancement filters. The proposed algorithms were evaluated over carefully constructed phantom images, where the ground truth is known a priori, as well as clinically recorded images for which the ground truth was manually compiled. A comparative evaluation of the proposed approaches is presented. Collectively, these methods outperformed prior approaches based on Chaudhuri et al. (1989) matched filtering, as well as the verification methods used by prior exploratory tracing algorithms, such as the work of Can et aL (1999). The Huber censored likelihood test yielded the best overall improvement, with a 145.7% improvement over the exploratory tracing algorithm, and a 43.7% improvement in detection rates over the matched filter.

Algorithms↗
PubMed2003

Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age.

OBJECTIVE: Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are long-chain polyunsaturated fatty acids found in breast milk and recently added to infant formulas. Their importance in infant nutrition was recognized by the rapid accretion of these fatty acids in the brain during the first postnatal year, reports of enhanced intellectual development in breastfed children, and recognition of the physiologic importance of DHA in visual and neural systems from studies in animal models. These considerations led to clinical trials to evaluate whether infant formulas that are supplemented with DHA or both DHA and ARA would enhance visual and cognitive development or whether conversion of linoleic acid and alpha-linolenic acid, the essential fatty acid precursors of ARA and DHA, respectively, at the levels found in infant formulas is sufficient to support adequately visual and cognitive development. Visual and cognitive development were not different with supplementation in some studies, whereas other studies reported benefits of adding DHA or both DHA and ARA to formula. One of the first trials with term infants that were fed formula supplemented with DHA or both DHA and ARA evaluated growth, visual acuity (Visual Evoked Potential; Acuity Card Procedure), mental and motor development (Bayley Scales of Infant Development), and early language development (MacArthur Communicative Developmental Inventories). Growth, visual acuity, and mental and motor development were not different among the 3 formula groups or between the breastfed and formula-fed infants in the first year of life. At 14 months of age, infants who were fed the formula with DHA but no ARA had lower vocabulary production and comprehension scores than infants who were fed the unsupplemented control formula or who were breastfed, respectively. The present follow-up study evaluated IQ, receptive and expressive vocabulary, visual-motor function, and visual acuity of children from the original trial when they reached 39 months of age. METHODS: Infants were randomized within 1 week after birth and fed a control formula (n = 65), one containing DHA (n = 65), or one containing both ARA and DHA (n = 66) to 1 year of age. A comparison group (n = 80) was exclusively breastfed for at least 3 months after which the infants continued to be exclusively breastfed or were supplemented with and/or weaned to infant formula. At 39 months, standard tests of IQ (Stanford Binet IQ), receptive vocabulary (Peabody Picture Vocabulary Test-Revised), expressive vocabulary (mean length of utterance), visual-motor function (Beery Visual-Motor Index), and visual acuity (Acuity Card Procedure) were administered. Growth, red blood cell fatty acid levels, and morbidity also were evaluated. RESULTS: Results were analyzed using analysis of variance or linear regression models. The regression model for IQ, receptive and expressive language, and the visual-motor index controlled for site, birth weight, sex, maternal education, maternal age, and the child's age at testing. The regression model for visual acuity controlled for site only. A variable selection model also identified which of 22 potentially prognostic variables among different categories (feeding groups, the child and family demographics, indicators of illness since birth, and environment) were most influential for IQ and expressive vocabulary. A total of 157 (80%) of the 197 infants studied at 12 months participated in this follow-up study. Characteristics of the families were representative of US families with children up to 5 years of age, and there were no differences in the demographic or family characteristics among the randomized formula groups. As expected, the formula and breastfed groups differed in ethnicity, marital status, parental education, and the prevalence of smoking. Sex, ethnicity, gestational age at birth, and birth weight for those who participated at 39 months did not differ from those who did not. The 12-month Bayley mental and motor scores and 14-month vocabulary scores of the children who participated also were were not different from those who did not. At 39 months, IQ, receptive and expressive language, visual-motor function, and visual acuity were not different among the 3 randomized formula groups or between the breastfed and formula groups. The adjusted means for the control, ARA+DHA, DHA, and breastfed groups were as follows: IQ scores, 104, 101, 100, 106; Peabody Picture Vocabulary Test, 99.2, 97.2, 95.1, 97.4; mean length of utterance, 3.64, 3.75, 3.93, 4.08; the visual-motor index, 2.26, 2.24, 2.05, 2.40; and visual acuity (cycles/degree), 30.4, 27.9, 27.5, 28.6, respectively. IQ was positively associated with female sex and maternal education and negatively associated with the number of siblings and exposure to cigarette smoking in utero and/or postnatally. Expressive language also was positively associated with maternal education and negatively associated with the average hours in child care per week and hospitalizations since birth but only when the breastfed group was included in the analysis. The associations between maternal education and child IQ scores are consistent with previous reports as are the associations between prenatal exposure to cigarette smoke and IQ and early language development. Approximately one third of the variance for IQ was explained by sex, maternal education, the number of siblings, and exposure to cigarette smoke. Growth achievement, red blood cell fatty acid levels, and morbidity did not differ among groups. CONCLUSIONS: We reported previously that infants who were fed an unsupplemented formula or one with DHA or with both DHA and ARA through 12 months or were breastfed showed no differences in mental and motor development, but those who were fed DHA without ARA had lower vocabulary scores on a standardized, parent-report instrument at 14 months of age when compared with infants who were fed the unsupplemented formula or who were breastfed. When the infants were reassessed at 39 months using age-appropriate tests of receptive and expressive language as well as IQ, visual-motor function and visual acuity, no differences among the formula groups or between the formula and breastfed groups were found. The 14-month observation thus may have been a transient effect of DHA (without ARA) supplementation on early vocabulary development or may have occurred by chance. The absence of differences in growth achievement adds to the evidence that DHA with or without ARA supports normal growth in full-term infants. In conclusion, adding both DHA and ARA when supplementing infant formulas with long-chain polyunsaturated fatty acids supports visual and cognitive development through 39 months.

Arachidonic Acid↗