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PubMed1987

A model for follicular selection and ovulation: lessons from superovulation.

A model for selection of the preovulatory follicle during the normal ovarian cycle is proposed. During menstruation the concentration of FSH rises to a level high enough to "activate" a single small antral follicle (2-4 mm dia.) so that it can produce large amounts of oestradiol. As the follicle develops, the concentration of FSH is suppressed below this threshold level by the secretion of oestradiol and inhibin. The dominant follicle becomes increasingly sensitive to FSH so that it continues to develop in an environment which inhibits development of other follicles. Multiple ovulation can be achieved by extending the period during which the level of FSH remains above this threshold level (e.g. during treatment with clomiphene or gonadotrophins). Although multiple ovulation occurs when the gate is widened in this way, the follicles are never completely synchronous as they continue to grow at approximately the same rate. Current evidence suggests that ovulation occurs at random between the two ovaries in successive cycles and that the corpus luteum exerts an inhibitory effect on folliculogenesis by suppressing the secretion of FSH and LH. These observations are compatible with the hypothesis that while small antral follicles are recruited continuously, at all stages of reproductive life, selection of the dominant follicle requires the unique gonadotrophic environment which is only present in the early follicular phase. The follicle of the month is, therefore, selected by chance because it is at the right place at the right time.

Animals↗
PubMed2002

17beta-estradiol matrixpatch removal and reapplication in postmenopausal women: theoretical predictions with an oscillating diffusion coefficient model.

The pharmacokinetic performance of a matrix system for transdermal beta-estradiol (E(2)) delivery after multiple consecutive dosing in postmenopausal women undergoing hormone replacement therapy was investigated. The E(2) plasma profiles determined during the third application in 16 postmenopausal women were compared with results obtained in a published clinical study using the same patch in 24 postmenopausal women without E(2) pretreatment; they were compared with a theoretical diffusion/pharmacokinetic model. A conventional theoretical model with constant model parameter (CPM) obtained from in vitro mass balance experiments in a Franz cell type set up described successfully the transdermal E(2) bioavailability parameter AUC(0-96h) (4341.9 +/- 1513.1; calculated 4250.8) and C(average) (45.0 +/- 13.2; calculated 41.2). Also, experimentally, there was no significant drop in E(2) plasma values after patch removal and reapplication; this was corroborated by calculations. Accumulation of E(2) did not occur when several patches were applied consecutively over a period of 3 weeks. Steady state was achieved following application of the first patch. However, the differences between recorded E(2) plasma profiles and theoretical results detected at specific measurement points cannot be explained by the CPM model. Experimentally obtained plasma profiles were always lower in the morning and higher in the evening than predicted on the basis of the model. Measurements of in vivo skin temperature in the postmenopausal women showed oscillating temperature profiles in the form of a cosinor function: The temperature mesor of untreated postmenopausal women was 34.8 degrees C with an acrophase at 17.0 o'clock (95% CI: 14.30-19.30) and an amplitude of +/- 0.4 degrees C (p = 0.1). During the application of the patch the average temperature next to a patch rose 0.3 degrees C, which was statistically significant (p = 0.1). In the skin under the application of the matrix patch a mesor temperature was detected as 35.6 degrees C with an amplitude of +/- 0.5 degrees C with an acrophase at 17.51 o'clock (95% CI: 14.30-21.00) (p = 0.05). The temperature period was 24 h for all measurements and the maximum temperature was observed at about 16.30 h, and a minimum at about 5.00 h. A linear dependency was detected in in vitro experiments between the log of E(2) permeability and the temperature for stripped skin, epidermis/dermis layer, as well as for the matrix. Modeling of E(2) plasma profiles with oscillating diffusion coefficients (ODM1) with a sine wave function results in this equation: D(1) = D(0x) + Da(x).sin(k.t). D(0x) is the diffusion coefficient determined at 35.6 degrees C, k is 1/24 h, D(a) is the diffusion coefficient of the temperature amplitude, h is hour, and x stands for the respective diffusion layer. It was shown that the experimental E(2) plasma profile variations are more pronounced than can simply be explained by skin temperature variations alone (ODM1 model). A simplex fit with an oscillating diffusion coefficient in the form of a sine wave function for the stratum corneum (ODM2 model) resulted in a temperature amplitude of 1.1 degrees C, about twice as high as was determined in the in vivo measurements (ODM2 model). Therefore, other circadian parameterlike blood flow might superimpose the temperature profile. The improvement in data analysis by incorporating oscillating diffusion coefficients (ODM1 and 2) over CPM was judged from a comparison of experimental data with the calculated plasma profiles with the AIC, Akaikes model selection criterion, which allows ranking between models because it is independent of the scaling of the data points. ODM1 and ODM2 improved the data analysis over CPM by allowing better calculation of experimental C(max), t(max), the time to reach to C(max), and the fluctuation, f. No difference between CPM, ODM1, or ODM2 was found for the bioavailability parameter C(average) and AUC(0-96h).

Administration, Cutaneous↗
PubMed1994

Mutation load and mutation-selection-balance in quantitative genetic traits.

Haldane (1937) showed that the reduction of equilibrium mean fitness in an infinite population due to recurrent deleterious mutations depends only on the mutation rate but not on the harmfulness of mutants. His analysis, as well as more recent ones (cf. Crow 1970), ignored back mutation. The purpose of the present paper is to extend these results to arbitrary mutation patterns among alleles and to quantitative genetic traits. We derive first-order approximations for the equilibrium mean fitness (and the mutation load) and determine the order of the error term. For a metric trait under mutation-stabilizing-selection balance our result differs qualitatively from that of Crow and Kimura (1964), whose analysis is based on a Gaussian assumption. Our general approach also yields a mathematical proof that the variance under the usual mutation-stabilizing-selection model is, to first order, micro/s (the house-of cards approximation) as micro/s tends to zero. This holds for arbitrary mutant distributions and does not require that the population mean coincide with the optimum. We show how the mutant distribution determines the order of the error term, and thus the accuracy of the house-of-cards approximation. Upper and lower bounds to the equilibrium variance are derived that deviate only to second order as micro/s tends to zero. The multilocus case is treated under the assumption of global linkage equilibrium.

Alleles↗
PubMed2004

Optimal-sensitivity analysis of ion channel gating kinetics.

We propose a new approach to analysis of kinetic models for ion channel gating, based on application of fluctuating voltages through a voltage clamp, in addition to conventional techniques. We show that the channel kinetics can be probed in a much more sensitive way, leading to more efficient model selection and more reliable estimates of model parameters. We use wavelet transform as an analytic tool for fluctuating currents and parametric dispersion plots as a measure of model compatibility with experimental data.

Algorithms↗
PubMed2004

Modeling of the pyruvate production with Escherichia coli in a fed-batch bioreactor.

A family of 10 competing, unstructured models has been developed to model cell growth, substrate consumption, and product formation of the pyruvate producing strain Escherichia coli YYC202 ldhA::Kan strain used in fed-batch processes. The strain is completely blocked in its ability to convert pyruvate into acetyl-CoA or acetate (using glucose as the carbon source) resulting in an acetate auxotrophy during growth in glucose minimal medium. Parameter estimation was carried out using data from fed-batch fermentation performed at constant glucose feed rates of q(VG)=10 mL h(-1). Acetate was fed according to the previously developed feeding strategy. While the model identification was realized by least-square fit, the model discrimination was based on the model selection criterion (MSC). The validation of model parameters was performed applying data from two different fed-batch experiments with glucose feed rate q(VG)=20 and 30 mL h(-1), respectively. Consequently, the most suitable model was identified that reflected the pyruvate and biomass curves adequately by considering a pyruvate inhibited growth (Jerusalimsky approach) and pyruvate inhibited product formation (described by modified Luedeking-Piret/Levenspiel term).

Bioreactors↗
PubMed1992

Relatedness and inclusive fitness with inbreeding.

Relatedness arising in kin selection theory is measured by a variable taking as values two pedigree indices in populations with inbreeding when selection is weak. This variable reduces to a single pedigree index when inbreeding is caused by partial selfing or partial sib-mating. General inclusive fitness formulations of kin selection models based on such a variable of relatedness are proposed.

Animals↗
PubMed1984

Social selection in human populations: differential modification of the fitness by the sex of an affected parent.

Social selection model of two alleles at a locus has been constructed where the fitness of offspring is modified differentially by the sex of an affected parent. It has been shown that the equilibrium frequency of deleterious alleles depends on the loss of fitness of an individual due to the trait (gamma), due to an affected mother (beta 1) and affected father (beta 2), and the probability that the heterozygote develops the trait (h). The equilibrium gene frequency is given approximately by alpha/hs for 0 less than h less than or equal to 1 and square root alpha/s for h = 0, where s = gamma + (beta 1 + beta 2) (1 - gamma)/2 for multiplicative models. The same result holds for the additive model if the value of gamma is small.

Alleles↗
PubMed2006

Virtual screening for aryl hydrocarbon receptor binding prediction.

The overall goal of this study has been to validate computational models for predicting aryl hydrocarbon receptor (AhR) binding. Due to the unavailability of the AhR X-ray crystal structure we have decided to use QSARs models for the binding prediction virtual screening. We have built up CoMFA, Volsurf, and HQSAR models using as a training set 84 AhR ligands. Additionally, we have built a hybrid model combining two of the final selected models in order to give a single operational system. The results show that CoMFA, VolSurf, HQSAR, and the hybrid models gives good results (R(2) equal to 0.91, 0.79, 0.85, and 0.82 and q(2) 0.62, 0.58, 0.62, and 0.70, respectively). Since the techniques analyzed show a good correlation and good prediction also for an external test set, particularly the HQSAR and the hybrid model, we can conclude that these models can be used for predicting AhR binding in virtual screening.

Dioxins↗
PubMed2004

Maintenance of clonal diversity in Dipsa bifurcata (Fallén, 1810) (Diptera: Lonchopteridae). II. Diapause stabilizes clonal coexistence.

We analyze a selection model analogous to a one-locus, two-allele haploid system that can explain recurrent seasonal changes in diversity for communities with diapausing species or populations with diapausing clones. The model demonstrates the potential influence of differential diapause on the stability of species and clonal coexistence and, by extension, on the maintenance of genetic polymorphism in general. Using estimates of clonal fitness values from populations of the parthenogenetic spear-winged fly Dipsa bifurcata (Fallén, 1810) (Diptera: Lonchopteridae), the model explains the long-term stable oscillation of clonal frequencies exhibited by these populations. In general, clones or species that share the same spatial habitat can persist in stable coexistence if there are differences not only in their temporarily fluctuating fitness values but also in their dormancy patterns.

Animals↗
PubMed2000

A tiered approach to deterministic models for indoor air exposures.

There are a number of deterministic mathematical approaches available for modeling indoor air pollution concentrations. These models range in complexity from simple saturation vapor pressure models to models using computational fluid dynamics, with many in between these extremes. This range reflects the variety of ways pollutant generation, transport, and mixing are treated in the different models. In selecting which model to use, a tiered approach is useful. The tiered approach considers the goal of the modeling, the availability of model inputs, and the degree of uncertainty that is acceptable. The simpler models are easy to use and the inputs are often readily available. However, they usually have an inherently high degree of uncertainty which requires conservative assumptions that may result in overestimates of concentrations. The more complex models are more difficult to use and require more precise inputs. However, they have the potential to allow the modeler to reduce or quantify uncertainty. This ability to address uncertainty may be limited by the understanding of and the availability of the model inputs. An application example of the tiered approach using a completely mixed space model, a two-zone model, and a turbulent diffusion model illustrates the selection criteria for model use and the model performances. Ultimately, an understanding of the principles behind the models and their inherent strengths and weaknesses is required for their appropriate application to exposure assessment.

Air Movements↗
PubMed2000

Reproductive effort in viscous populations.

Here I study a kin selection model of reproductive effort, the allocation of resources to fecundity versus survival, in a patch-structured population. Breeding females remain in the same patch for life. Offspring have costly, partial long-distance dispersal and compete for breeding sites, which become vacant upon the death of previous occupants. The main result is that the evolutionarily stable reproductive effort decreases as offspring dispersal rate increases. The result can be understood as follows: In a well-mixed population with global competition, neither adults nor juveniles compete with relatives, but in a patch-structured population with dispersal restricted to the juvenile phase, juveniles experience relatively less competition with relatives than adults, thus making juveniles relatively more valuable. Because this asymmetry between adults and juveniles decreases with the dispersal rate, so does the evolutionarily stable level of allocation to fecundity.

Animals↗
PubMed2004

Health-related quality of life parameters as prognostic factors in a nonmetastatic breast cancer population: an international multicenter study.

PURPOSE: The purpose of this research was to evaluate whether baseline health-related quality of life (HRQOL) parameters are prognostic factors for survival in locally advanced breast cancer patients. Although the literature highlights the important role of HRQOL parameters in predicting survival in advanced metastatic disease, little evidence exists for earlier stages. PATIENTS AND METHODS: The overall sample consisted of 448 patients randomly assigned to receive cyclophosphamide, epirubicin, and fluorouracil versus epirubicin, cyclophosphamide, and granulocyte colony-stimulating factor. Patients were enrolled in 12 countries. HRQOL baseline scores were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap resampling technique was used to assess the stability of the outcomes. Bootstrap results were then applied for model averaging purposes as a means to account for the observed model selection uncertainty. RESULTS: The final multivariate model retained inflammatory breast cancer (T4d) as the only factor predicting overall survival (OS) with a hazard ratio of 1.375 (95% CI, 1.027 to 1.840; P =.03). The presence of inflammatory breast cancer lowers the median survival time from 6.6 to 4.2 years (36% reduction). None of the preselected HRQOL variables were prognostic for OS or disease-free survival, in either the univariate or multivariate analysis. CONCLUSION: Our findings suggest that baseline HRQOL parameters have no prognostic value in a nonmetastatic breast cancer population.

Adult↗
PubMed2003

[Cyclooxygenase(COX)-2-inhibition in the prevention and treatment of colorectal carcinoma].

Epidemiological studies have found that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk of colorectal cancer (CRC). Cyclooxygenase (COX)-2 expression is present in colorectal cancer and overexpression is associated with metastases and poorer prognosis in multivariate analysis. NSAID treatment results in a reduction of the incidence of colorectal adenoma in patients with familial adenomatous polyposis, in patients with a history of colorectal adenomas and in patients with a history of CRC. Pre-clinical research shows that COX-2 expression is associated with cell proliferation, angiogenesis, apoptosis inhibition and local immune-down modulation. An anticarcinogenic effect has been shown specifically in selective COX-2 inhibitors in animal models. Selective COX-2 inhibitors have fewer adverse effects than the non-selective NSAIDs and are promising chemopreventative and chemotherapeutical agents. The effects of selective COX-2 inhibition in the prevention of and treatment for colorectal carcinoma will be investigated in clinical randomized multicentre trials.

Adenoma↗
PubMed2005

Fossil calibrations and molecular divergence time estimates in centrarchid fishes (Teleostei: Centrarchidae).

Molecular clock methods allow biologists to estimate divergence times, which in turn play an important role in comparative studies of many evolutionary processes. It is well known that molecular age estimates can be biased by heterogeneity in rates of molecular evolution, but less attention has been paid to the issue of potentially erroneous fossil calibrations. In this study we estimate the timing of diversification in Centrarchidae, an endemic major lineage of the diverse North American freshwater fish fauna, through a new approach to fossil calibration and molecular evolutionary model selection. Given a completely resolved multi-gene molecular phylogeny and a set of multiple fossil-inferred age estimates, we tested for potentially erroneous fossil calibrations using a recently developed fossil cross-validation. We also used fossil information to guide the selection of the optimal molecular evolutionary model with a new fossil jackknife method in a fossil-based model cross-validation. The centrarchid phylogeny resulted from a mixed-model Bayesian strategy that included 14 separate data partitions sampled from three mtDNA and four nuclear genes. Ten of the 31 interspecific nodes in the centrarchid phylogeny were assigned a minimal age estimate from the centrarchid fossil record. Our analyses identified four fossil dates that were inconsistent with the other fossils, and we removed them from the molecular dating analysis. Using fossil-based model cross-validation to determine the optimal smoothing value in penalized likelihood analysis, and six mutually consistent fossil calibrations, the age of the most recent common ancestor of Centrarchidae was 33.59 million years ago (mya). Penalized likelihood analyses of individual data partitions all converged on a very similar age estimate for this node, indicating that rate heterogeneity among data partitions is not confounding our analyses. These results place the origin of the centrarchid radiation at a time of major faunal turnover as the fossil record indicates that the most diverse lineages of the North American freshwater fish fauna originated at the Eocene-Oligocene boundary, approximately 34 mya. This time coincided with major global climate change from warm to cool temperatures and a signature of elevated lineage extinction and origination in the fossil record across the tree of life. Our analyses demonstrate the utility of fossil cross-validation to critically assess individual fossil calibration points, providing the ability to discriminate between consistent and inconsistent fossil age estimates that are used for calibrating molecular phylogenies.

Animals↗
PubMed1986

Pharmacokinetics of fentanyl in neonates.

The pharmacokinetics of fentanyl were studied in fourteen neonates undergoing major surgical procedures. Five patients were less than 1 day of age, seven were 1-4 days old, and two were 7-14 days old. Fentanyl was given intravenously, 10 micrograms/kg (n = 1), 25 micrograms/kg (n = 4), or 50 micrograms/kg (n = 9), and plasma concentrations measured at intervals of up to 18 hr. Average weight was 2.9 kg. The injection of 25 or 50 micrograms/kg of fentanyl over 1-3 min was hemodynamically well-tolerated by all patients. Four newborns without respiratory impairment secondary to surgery or disease needed ventilatory support for an average of 24 hr (range 11-40 hr). Plasma concentrations of fentanyl were most appropriately described by a two-compartment model. The mean +/- SEM values of selected model parameters were volume of the central compartment, 1.45 +/- 0.34 L/kg; volume of distribution at steady state, 5.1 +/- 1 L/kg; clearance, 17.94 +/- 4.38 ml X kg-1 X min-1; and terminal elimination half-life (t 1/2 beta), 317 +/- 70 min. In seven patients transient rebound in plasma fentanyl concentrations of 0.5 ng/ml or greater occurred. In three patients with markedly increased intraabdominal pressure, the t 1/2 beta was 1.5-3 times the population mean. Thus fentanyl disposition in neonates is highly variable, but the t 1/2 beta is predictably prolonged in the presence of increased abdominal pressure.

Age Factors↗
PubMed1994

Estimation of chronic phase duration in Ph-positive chronic myelocytic leukemia treated with busulfan: statistical analysis on Japanese patients.

Chronic phase duration was analyzed in 148 Japanese patients with Ph-positive chronic myelocytic leukemia (CML) treated only with busulfan, and multivariate proportional hazard models were constructed to infer the prognosis of a given patient, and to evaluate the prognostic importance of the clinical findings. To make an accurate estimation of an individual patient's prognosis, we introduced a piecewise linear model for describing a hazard function in each prognostic variable. Of the 11 prognostic variables initially analyzed, the absolute count of peripheral basophils was revealed as the most important prognostic factor. A high basophil count was clearly a factor in cases with poor prognosis. The statistical model selection based on the criteria of model approximation finally suggested a model with three covariates; absolute count of peripheral basophils, platelet count, and presence or absence of additional chromosome abnormalities superimposed on the translocation of 9;22. By analyses based on the above model, we estimated that the median of the chronic phase duration for the patients with poor and good prognosis was 12 and 75 months, respectively. The piecewise linear model was well suited for an accurate estimation of an individual patient's prognosis. Thus, the model constructed here would become a reliable control to evaluate investigational approaches, such as hydroxyurea, interferons, and/or bone marrow transplantation.

Adolescent↗
PubMed2006

The evolution of norms.

We develop a two-level selection model in the framework of evolutionary game theory, in which fitness selection at different levels is related to different games. We consider an archipelago of communities, such that selection operates at an individual level inside each community and at a group level whenever evolution of communities is at stake. We apply this model to the evolution of social norms, an open problem of ubiquitous importance in social science. Extensive statistical analysis of our results lead to the emergence of one common social norm, of which the evolutionary outcomes in different communities are simple by-products. This social norm induces reputation-based cooperative behavior, and reflects the evolutionary propensity to promote simple, unambiguous norms, in which forgiveness and repent are welcome, while punishment is implacable.

Biological Evolution↗
PubMedDate not supplied

Population dynamics of mutant alleles under maternal effect in plant populations.

Fitness interactions via maternal effects were analyzed by constructing a mathematical model. Here, the fitness of an individual is determined by its own phenotype and the maternal phenotype. It is assumed that two alternative phenotypic states are determined by two alleles at a single locus. Under this assumption, the model developed here reduces to a social selection model of human populations that considers that the fitness of an individual is determined by the individual as well as the parental phenotypes. The effect on genetic variability of random fluctuations in the magnitude of maternal effects was studied by considering the fixation probability and the equilibrium frequency of mutant genes. It is shown that genetic variability decreases as the magnitude of variation in maternal effect intensity increases.

Alleles↗