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PubMed1994

Models to explain dose-response relationships that exhibit a downturn phase.

Over a broad dose (or concentration) range, dose-response relationships frequently display a bell-shaped form. Mechanisms leading to this phenomenon may be manifold, but so far they have not been adequately identified. In this article, Vladimir Pliska discusses two models that are based on multiple-state cell-signaling pathways and enable an estimate of generally applicable descriptors. These can be used for expression of drug potency and for similar purposes.

Algorithms↗
PubMed1999

The Use of a Nonlinear Muscle Model in Explaining the Relationship Between Duration, Amplitude, and Peak Velocity of Human Rapid Movements.

Rapid human movements exhibit a quasilinear relationship between their amplitude and maximum velocity and a log-like relationship between their amplitude and duration. The authors demonstrate that those well-observed relations can be obtained with a simple nonlinear muscle model and a pulse-step control scheme. That result encourages the use of nonlinear musculoskeletal models with simple control schemes for modeling human ballistic movements.

Journal Article↗
PubMed1995

A modified single-strand annealing model best explains the joining of DNA double-strand breaks mammalian cells and cell extracts.

The joining of DNA double-strand breaks in vivo is frequently accompanied by the loss of a few nucleotides at the junction between the interacting partners. In vitro systems mimic this loss and, on detailed analysis, have suggested two models for the mechanism of end-joining. One invokes the use of extensive homologous side-by-side alignment of the partners prior to joining, while the other proposes the use of small regions of homology located at or near the terminus of the interacting molecules. to discriminate between these two models, assays were conducted both in vitro and in vivo with specially designed substrates. In vitro, molecules with limited terminal homology were capable of joining, but analysis of the junctions suggested that the mechanism employed the limited homology available. In vivo, the substrates with no extensive homology end-joined with equal efficiency to those with extensive homology in two different topological arrangements. Taken together, these results suggest that extensive homology is not a prerequisite for efficient end-joining, but that small homologies close to the terminus are used preferentially, as predicted by the modified single-strand annealing model.

Base Sequence↗
PubMed1979

A multivariate analysis of interstate variation in fertility of teenage girls.

A multiple regression model was used to determine the correlates of state-to-state variation in fertility of teenage girls. The independent variables were the abortion-t0-live birth ratio, contraception/conception ratio, racial composition, adult personal income, per cent urban population, and adult educational attainment. The model explained 69 per cent of the interstate variation in 1974 fertility. Both the racial composition and the abortion ratio were significantly (p less than .01) correlated with fertility. With 1970--1974 change in fertility as the dependent variable, the model explained 80 per cent of the variation, with income as the most strongly correlated variable. The contraception/conception ratio was also significant (p less than .01), as was racial composition (p less than .05). Factor analysis of the independent variables showed that the six variables were well accounted for by three factors representing culture/education status, abortion availability, and contraception availability. The analysis showed that utilization of both contraception and abortion was important in determining the fertility of a state's teenagers. Increased availability of publicly subsidized contraception in low income areas and increased availability of abortion in low income and rural areas might be expected to result in decreased fertility of teenage girls.

Abortion, Induced↗
PubMedDate not supplied

A model to explain the difference between changes in refraction and central ocular surface power after laser in situ keratomileusis.

PURPOSE: After refractive surgery, changes in central ocular surface power are usually less than actual changes in refraction. The aim of this paper was to examine the theoretical changes in the radius of the epithelial-stromal interface and corneal stromal refractive index which could take place to account for some of the empirical findings. METHODS: The parameters of an aspheric human eye model featuring gradient index optics was modified using data from a clinical study evaluating effects of laser in situ keratomileusis (LASIK) for correction of moderate to high myopia. Computations were performed to determine: 1) theoretical postoperative radius of the epithelial-stromal interface and hence distribution of epithelial thickness, and 2) refractive index of the stroma when the epithelium was of fixed uniform thickness. RESULTS: Within the central 2-mm diameter refractive zone of the cornea after LASIK for myopia, either of two factors could account for the difference between changes in central ocular surface power and the actual change in ocular refraction: 1) a steepening of the epithelial-stromal interface resulting from a 400% centrifugal increase in epithelial thickness, or 2) a reduction in stromal refractive index from an average of 1.376 to 1.364. CONCLUSION: The difference between the observed changes in refraction and central ocular surface power could be explained by reduction in stromal refractive index and this could be secondary to a 6.5% increase in water content of the stroma during the postoperative period. The epithelial-stromal interface after LASIK is unlikely to steepen by the extent predicted by our model. This surface is not the source of the difference between the change in refraction and change in central ocular surface power.

Corneal Stroma↗
PubMed1998

A biological model to explain the association between human rhinovirus respiratory infections and bronchial asthma.

Human rhinoviruses (HRVs) are a frequent cause or upper respiratory tract infections in children and adults, and can exacerbate existing pulmonary disease. The major group of HRV attach to the receptor intercellular adhesion molecule (ICAM)-1, which is expressed on many cell types including epithelial cells. To study the influence of biological mediators on ICAM-1 expression, and consequently HRV attachment and infection, we have established an in vitro model system to evaluate the effects or pre-exposure to different cytokines on surface expression of ICAM-1 of uninfected and HRV-14-infected epithelial cells. The results of our studies show that the cytokines interleukin (IL)-1 beta, IL-8 and tumour necrosing factor (TNF)alpha increased ICAM-1 expression on epithelial cells. Epithelial cells infected with live HRV-14 displayed a significant upregulation of ICAM-1 compared to baseline. In contrast, interferon (IFN)gamma, whilst increasing the level of ICAM-1 expression on uninfected cells, induced a marked persistent downregulation of ICAM-1 expression on HRV-infected epithelial cells. In addition, IFN gamma appeared to completely override the ICAM-1 upregulation induced by IL-1 beta, IL-8 and TNF alpha, during HRV infection. We have further demonstrated that type 2 T-helper cell (Th2)-associated cytokines, predominantly IL-13, induce a marked upregulation or epithelial cell surface ICAM-1, thus increasing cellular binding sites for HRV attachment. As the airway mucosa or asthmatic subjects is predominantly infiltrated by activated type 2 T-helper cells with a simultaneous decrease of type 1 T-helper cells, our observations could explain the increased susceptibility to human rhinovirus infection observed in asthma.

Adult↗
PubMed1986

Effects of puromycin, cycloheximide and noradrenaline on cell migration within the crypts and on the villi of the small intestine. A model to explain cell movement in both regions.

The normal process of cell migration, occurring as part of the replacement scheme within the small intestinal epithelium, was investigated extensively. The effects of puromycin, cycloheximide and noradrenaline on the movement of tritiated thymidine [( 3H]TdR) prelabelled crypt or villus cells have been studied. These studies have led to the formulation of a model for the mechanism of cell migration, postulating that the crypts and villi behave as separate units, with regard to cell migration, in addition to their distinct structural and functional properties. It is proposed that crypt cell migration is an active process requiring protein synthesis and protein glycosylation, whilst movement of villus epithelial cells is passive, depending on the continued contraction of smooth muscle cells in the lamina propria.

Animals↗
PubMed1999

A model to explain the rapid pressure decrease after air-inflation of diseased middle ears.

OBJECTIVES: Air-inflation in humans and monkeys with significant negative middle ear pressure or with middle ear inflammation was shown to cause greater than ambient middle ear pressure initially, followed by a rapid rate of pressure decrease to approach the preinflation value. STUDY DESIGN: A mathematical model of middle ear pressure regulation is presented and used to simulate air-inflation of the normal and diseased middle ear. MATERIALS AND METHODS: The model represents the total volume of the middle ear as consisting of three subcompartments representing the airspace, effusion, and mucosa/blood. Gas exchange among those compartments was assumed to be diffusion limited, and the gas exchange between the mucosa/blood compartment and systemic blood was assumed to be perfusion limited. Disease was modeled as an increase in mucosal blood flow or, alternatively, as an increase in the volumes of the effusion and mucosa/blood compartments. RESULTS: The predictions of the model agree better with the experimental data when the increased rate of pressure change after middle ear inflation in diseased ears is driven by an increased volume of the effusion compartment as opposed to an increased perfusion rate. The responsible mechanism is a rapid redistribution among subcompartments of the gas volume introduced into the air compartment. CONCLUSIONS: These results suggest that middle ear inflation with inert gas can be used to diagnose the presence and relative amount of middle ear effusion, and that current protocols for treating otitis media with effusion using inflation need to be modified to optimize their intended effect.

Animals↗
PubMed1991

Development of a semiquantitative food frequency questionnaire to assess food, energy and nutrient intake in Denmark.

Foods to be included in a Danish self-administered semiquantitative food frequency questionnaire were identified from food tables developed, together with data collected, for the survey 'Dietary habits in Denmark, 1985'. The questionnaire was to be used in a prospective study on diet, cancer and health, and the aim was to rank individuals with regard to intake of 19 different nutrients considered of prime importance in human carcinogenesis. The questionnaire for the dietary survey included 247 foods and recipes. From stepwise multiple regression analyses with the intake of each of the 19 nutrients as the dependent variable and the intake of the 247 foods and recipes as independent variables, the foods in the models explaining 90% of the between-person variability were considered for the final questionnaire. All relevant analyses were performed for the study group as a whole, for men and women separately, and in each gender for subgroups of energy intake. Taken together, the models explaining 90% of the between-person variability identified a total of 74 foods or recipes, which were important predictors of the intake of one or more of the nutrients considered. A few foods were excluded and a few foods were added to the final questionnaire based on common biological background information, and on information on foods providing important amounts of given nutrients, but which failed to contribute to regression analyses. The 92 foods and recipes, which were included in the final questionnaire provided altogether 81% of the average total supply of the nutrients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2000

Coupling of neural activation to blood flow in the somatosensory cortex of rats is time-intensity separable, but not linear.

Changes in cerebral blood flow (CBF) because of functional activation are used as a surrogate for neural activity in many functional neuroimaging studies. In these studies, it is often assumed that the CBF response is a linear-time invariant (LTI) transform of the underlying neural activity. By using a previously developed animal model system of electrical forepaw stimulation in rats (n = 11), laser Doppler measurements of CBF, and somatosensory evoked potentials, measurements of neural activity were obtained when the stimulus duration and intensity were separately varied. These two sets of time series data were used to assess the LTI assumption. The CBF data were modeled as a transform of neural activity (N1-P2 amplitude of the somatosensory evoked potential) by using first-order (linear) and second-order (nonlinear) components. Although a pure LTI model explained a large amount of the variance in the data for changes in stimulus duration, our results demonstrated that the second-order kernel (i.e., a nonlinear component) contributed an explanatory component that is both statistically significant and appreciable in magnitude. For variations in stimulus intensity, a pure LTI model explained almost all of the variance in the CBF data. In particular, the shape of the CBF response did not depend on intensity of neural activity when duration was held constant (time-intensity separability). These results have important implications for the analysis and interpretation of neuroimaging data.

Animals↗
PubMed1986

Allosteric inhibition as a model to explain flatter displacement curves in binding experiments: application to "heterogeneous" serotonin receptors.

Flattened or biphasic inhibition curves are usually interpreted by postulating the presence of two sites which are labelled with the same affinity by the ligand and can be recognized using the appropriate inhibitor with different selective affinities. We found that a priori this type of curve, can be equally fitted by another model, the allosteric model, on account of the mathematical equivalence of the two model functions when the 3H-ligand concentration is kept constant (i.e. inhibition experiments). A new approach consisting of three-dimensional analysis of the experimental data (3H-ligand binding as a function of ligand and inhibitor concentrations, simultaneously) permitted a statistical discrimination between the two models. The examples, used as tool for the present study, are the flattened or biphasic inhibition curves obtained by displacing 3H-serotonin with the neuroleptic spiperone. The results are discussed in relation to the general interpretation of this type of "anomalous" binding data and to the specific field of serotonergic receptor subtypes.

Allosteric Regulation↗
PubMed1998

A model to explain the various paradoxes associated with mantle noble gas geochemistry.

As a result of an energetic accretion, the Earth is a volatile-poor and strongly differentiated planet. The volatile elements can be accounted for by a late veneer ( approximately 1% of total mass of the Earth). The incompatible elements are strongly concentrated into the exosphere (atmosphere, oceans, sediments, and crust) and upper mantle. Recent geochemical models invoke a large primordial undegassed reservoir with chondritic abundances of uranium and helium, which is clearly at odds with mass and energy balance calculations. The basic assumption behind these models is that excess "primordial" 3He is responsible for 3He/4He ratios higher than the average for midocean ridge basalts. The evidence however favors depletion of 3He and excessive depletion of 4He and, therefore, favors a refractory, residual (low U, Th) source Petrological processes such as melt-crystal and melt-gas separation fractionate helium from U and Th and, with time, generate inhomogeneities in the 3He/4He ratio. A self-consistent model for noble gases involves a gas-poor planet with trapping of CO2 and noble gases in the shallow mantle. Such trapped gases are released by later tectonic and magmatic processes. Most of the mantle was depleted and degassed during the accretion process. High 3He/4He gases are viewed as products of ancient gas exsolution stored in low U environments, rather than products of primordial reservoirs.

Journal Article↗
PubMed1996

The use of dental sealants by Ohio dentists.

OBJECTIVES: To assess the extent to which Ohio dentists report using pit and fissure sealants and factors associated with sealant use. METHODS: A mail survey of a random sample of Ohio dentists was conducted in 1989 and repeated in 1992 with a newly drawn sample. Only responses from general dentists were analyzed using univariate analyses and multiple regression. RESULTS: Dentists who reported using sealants increased from 79.4 percent in 1989 to 91.8 percent in 1992. In 1992, 42.9 percent were low-level users (< 15% of school-aged patients), 41.7 percent were moderate-level users (15-39%), and 15.3 percent were high-level users (> 39%). Over three-fourths of sealant-using dentists expressed some degree of willingness to seal incipient caries. The level of sealant use was associated with dentists' knowledge about sealants, conservative management of dental caries, number of children seen in the practice, and influence of insurance coverage for sealants. The regression model explained 22.0 percent of the variance. Clinical factors associated with the level of use were: dentists' willingness to seal premolars; caries-free teeth; teeth with deep, narrow pits and fissures; teeth with small, frank occlusal caries; and patients 18 years of age or older. This regression model explained only 15.1 percent of the variance. CONCLUSIONS: The grate majority of Ohio dentists report using sealants. The percent of reported sealant users increased between 1989 and 1992. Ohio dentists are not consistent with regard to the percent of their child patients for whom they apply sealants or their willingness to seal incipient caries. Dentists continue to identify lack of insurance coverage for sealant application as a major barrier to patients receiving the service.

Adolescent↗
PubMed1981

A simple electrostatic model can explain the effect of pH upon the force-pCa relation of skinned frog skeletal muscle fibers.

The relative force-pCa relation of skinned frog skeletal muscle fibers is shifted along the pCa axis by changes in pH. This shift has been interpreted as arising from competition between H+ and Ca2+ for a binding site on troponin. Unfortunately, binding studies have been unable to confirm such competition. Alternatively, however, the data fit a model where H+ influences the degree of dissociation of ionizable groups on the surface of the thin filaments, thus altering the electrostatic potential surrounding the filaments. Alterations in the potential will, in turn, change the concentration of Ca2+ near the troponin binding sites in accordance with the Boltzmann relation. A simple model, based upon the Gouy-Chapman relation between surface potential and charge density, provides a quantitative explanation for the shift of the relative force-pCa curve with pH, given a reasonable estimate of the surface charge density on the thin filament. A best fit is obtained when the ionizable groups giving rise to the potential have a log proton ionization constant (pKa) of 6.1, similar to that for the imidazole group on histidine, and when the density of these groups is near that estimated from amino acid analysis of thin filament proteins and from filament geometry. In preliminary experiments, reaction of skinned frog fibers with diethylpyrocarbonate (DEP) at pH 6 shifted the force-pCa curve toward lower Ca2+. This would be expected in the model since DEP at pH 6 is reported to specifically react with histidine imidazole groups and to irreversibly decrease their pKa, which would increase the net negative charge of the filaments.

Animals↗
PubMed2000

The influence of trust and perceptions of risks and benefits on the acceptance of gene technology.

A causal model explaining acceptance of gene technology was tested. It was hypothesized that trust in institutions using gene technology or using modified products has a positive impact on perceived benefit and a negative influence on perceived risk of this technology. Furthermore, perceived benefit and perceived risk determine acceptance of biotechnology. In other words, trust has an indirect influence on the acceptance of the technology. The postulated model was tested using structural equation modeling procedures and data from a random quota sample of 1001 Swiss citizens between 18 and 74 years old. Results indicated that the proposed model fits the data very well. The same causal model explains females' and males' acceptance of gene technology. Gender differences were found for the latent variables trust, perceived benefit, and acceptance of gene technology. Females indicated more trust, perceived less benefit, and demonstrated less acceptance than did males. No significant difference was observed for perceived risk. The implications of the results are discussed.

Adolescent↗