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At least 469 records · Page 26Linked to original sources
PubMed2006

A model for quantitative changes in the magnetic resonance parameters of muscle in children after therapeutic irradiation.

PURPOSE/OBJECTIVE: This study aimed to develop objective models of radiation effects on musculature in children with soft tissue sarcoma using treatment dosimetry and clinical and quantitative magnetic resonance imaging (MRI) parameters that may be used to guide treatment planning or predict side effects. METHODS: In the initial 13 patients undergoing external beam radiation therapy (RT) on a Phase II study of conformal or intensity-modulated RT for the treatment of soft tissue sarcoma approved by an Institutional Review Board, we evaluated quantitative MRI changes in the musculature to assess radiation-related treatment effects. Patients with soft tissue sarcoma, including Ewing's sarcoma, had quantitative T1, T2 and dynamic enhanced MRI (DEMRI) performed before, during (Week 4) and after RT (Week 12). Regions of interest were selected in consistent locations within and outside the high-dose regions (on ipsilateral and contralateral sides when available). Mean RT dose, T1, T2 and DEMRI parameters were calculated and modeled using a mixed random coefficient dose model. RESULTS: The mean doses to the high- and low-dose regions were 56.4 Gy (41.8-75.3 Gy) and 13.0 Gy (0.1-37.5 Gy), respectively. Compared with tissues distant from the tumor bed, maximal enhancement was significantly increased in tissues adjacent to the tumor/tumor bed prior to RT (60.6 vs. 44.2, P=.045) and remained elevated after 12 weeks. T1 was significantly elevated in tissues adjacent to the tumor bed prior to RT (942.4 vs. 759.0, P=.0078). The slope of longitudinal change in T1 was greater for tissues that received low-dose irradiation than those that received high-dose irradiation (P=.0488). The effect of dose on the slope of T2 was different (P=.0333) when younger and older patients are compared. CONCLUSIONS: Acute affects of irradiation in muscle are quantifiable via MRI. These models provide evidence that quantifiable MRI parameters may be correlated with patient parameters of radiation dose and clinical factors including patient age. Long-term follow-up will be required to determine if acute changes correlate with clinically significant late effects.

Child↗
PubMed1984

Mechanism of cell-mediated cytotoxicity at the single cell level. VIII. Kinetics of lysis of target cells bound by more than one cytotoxic T lymphocyte.

We measured the effects of having multiple cytotoxic T lymphocytes (CTL) bound to one target cell by using the single-cell cytotoxicity in agarose assay. We found that even though there is variability in the time at which individual target cells are lysed, we can identify a general trend: the mean rate of lysis increases with the number of CTL bound per target cell, reaching a maximum when the CTL-target cell ratio is three. Combining a quantitative model for the rate of lethal hitting in multicellular conjugates with a multi-event model for the rate of target cell disintegration, we developed a new multistage kinetic model for predicting the rate of target cell lysis in multiple lymphocyte-target cell conjugates. The variability in the time at which target cells are hit and the variability in the time until they disintegrate are incorporated into the model. By analyzing our measured data in the context of the multistage kinetic model, we were able to estimate via nonlinear least squares regression the target cell disintegration rate, but not the lethal hitting rate. Lethal hitting appeared to be too fast, when compared with disintegration, to significantly affect the time of target cell lysis. By using previously determined values of the lethal hitting rate for single lymphocyte-target cell conjugates and by postulating that lymphocytes act independently of each other in delivering lethal hits, we were able to estimate the rate at which target cells are hit in multiple-lymphocyte single target cell conjugates. By using this estimate of the lethal hitting rate and the regression estimate of the disintegration rate, the multistage kinetic model gave a quantitative fit to our data. From this analysis, we found that the rate at which a target cell disintegrates after being lethally hit increases with the number of CTL per conjugate. This result is quite surprising, because once the first hit has been received, a target cell can disintegrate in a killer cell-independent manner. Under the conditions of our experiment, it appears as if target cell disintegration is not killer cell-independent. Furthermore, our analysis of the time course of target cell disintegration suggests that the process is not governed by simple first order kinetics, but rather by a more complex multistep mechanism.

Animals↗
PubMed2004

[Joint modeling of quantitative longitudinal data and censored survival time].

BACKGROUND: In epidemiology, we are often interested in the association between the evolution of a quantitative variable and the onset of an event. The aim of this paper is to present a joint model for the analysis of Gaussian repeated data and survival time. Such models allow, for example, to perform survival analysis when a time-dependent explanatory variable is measured intermittently, or to study the evolution of a quantitative marker conditionally to an event. METHODS: They are constructed by combining a mixed model for repeated Gaussian variables and a survival model which can be parametric or semi-parametric (Cox model). RESULTS: We discuss the hypotheses underlying the different joint models proposed in the literature and the necessary assumptions for maximum likelihood estimation. The interest of these methods is illustrated with a study of the natural history of dementia in a cohort of elderly persons.

Biometry↗
PubMed2006

Comparison of conventional, model-based quantitative planar, and quantitative SPECT image processing methods for organ activity estimation using In-111 agents.

Accurate quantification of organ radionuclide uptake is important for patient-specific dosimetry. The quantitative accuracy from conventional conjugate view methods is limited by overlap of projections from different organs and background activity, and attenuation and scatter. In this work, we propose and validate a quantitative planar (QPlanar) processing method based on maximum likelihood (ML) estimation of organ activities using 3D organ VOIs and a projector that models the image degrading effects. Both a physical phantom experiment and Monte Carlo simulation (MCS) studies were used to evaluate the new method. In these studies, the accuracies and precisions of organ activity estimates for the QPlanar method were compared with those from conventional planar (CPlanar) processing methods with various corrections for scatter, attenuation and organ overlap, and a quantitative SPECT (QSPECT) processing method. Experimental planar and SPECT projections and registered CT data from an RSD Torso phantom were obtained using a GE Millenium VH/Hawkeye system. The MCS data were obtained from the 3D NCAT phantom with organ activity distributions that modelled the uptake of (111)In ibritumomab tiuxetan. The simulations were performed using parameters appropriate for the same system used in the RSD torso phantom experiment. The organ activity estimates obtained from the CPlanar, QPlanar and QSPECT methods from both experiments were compared. From the results of the MCS experiment, even with ideal organ overlap correction and background subtraction, CPlanar methods provided limited quantitative accuracy. The QPlanar method with accurate modelling of the physical factors increased the quantitative accuracy at the cost of requiring estimates of the organ VOIs in 3D. The accuracy of QPlanar approached that of QSPECT, but required much less acquisition and computation time. Similar results were obtained from the physical phantom experiment. We conclude that the QPlanar method, based on 3D organ VOIs and accurate models of the projection process, provided a substantial increase in accuracy of organ activity estimates from planar images compared to CPlanar processing and had accuracy approaching that of QSPECT.

Algorithms↗
PubMed1999

Classification of protein sequences by homology modeling and quantitative analysis of electrostatic similarity.

Protein electrostatics plays a key role in ligand binding and protein-protein interactions. Therefore, similarities or dissimilarities in electrostatic potentials can be used as indicators of similarities or dissimilarities in protein function. We here describe a method to compare the electrostatic properties within protein families objectively and quantitatively. Three-dimensional structures are built from database sequences by comparative modeling. Molecular potentials are then computed for these with a continuum solvation model by finite difference solution of the Poisson-Boltzmann equation or analytically as a multipole expansion that permits rapid comparison of very large datasets. This approach is applied to 104 members of the Pleckstrin homology (PH) domain family. The deviation of the potentials of the homology models from those of the corresponding experimental structures is comparable to the variation of the potential in an ensemble of structures from nuclear magnetic resonance data or between snapshots from a molecular dynamics simulation. For this dataset, the results for analysis of the full electrostatic potential and the analysis using only monopole and dipole terms are very similar. The electrostatic properties of the PH domains are generally conserved despite the extreme sequence divergence in this family. Notable exceptions from this conservation are seen for PH domains linked to a Db1 homology (DH) domain and in proteins with internal PH domain repeats.

Data Interpretation, Statistical↗
PubMed1984

Effects of oligomycin and quercetin on the hydrolytic activities of the (Na+ +K+)-dependent ATPase.

Quercetin inhibited a dog kidney (Na+ + K+)-ATPase preparation without affecting Km for ATP or K0.5 for cation activators, attributable to the slowly-reversible nature of its inhibition. Dimethyl sulfoxide, a selector of E2 enzyme conformations, blocked this inhibition, while the K+-phosphatase activity was at least as sensitive to quercetin as the (Na+ + K+)-ATPase activity, all consistent with quercetin favoring E1 conformations of the enzyme. Oligomycin, a rapidly-reversible inhibitor, decreased the Km for ATP and the K0.5 for cation activators, and its inhibition was also diminished by dimethyl sulfoxide. Although oligomycin did not inhibit the K+-phosphatase activity under standard assay conditions, a reaction presumably catalyzed by E2 conformations, its effects are nevertheless accommodated by a quantitative model for that reaction depicting oligomycin as favoring E1 conformations. The model also accounts quantitatively for effects of both dimethyl sulfoxide and oligomycin on Vmax, Km for substrate, and K0.5 for K+, as well as for stimulation of phosphatase activity by both these reagents at low K+ but high Na+ concentrations.

Adenosine Triphosphatases↗
PubMed2001

A proliferation control network model: the simulation of two-dimensional epithelial homeostasis.

Despite the recent progress in the description of the molecular mechanisms of proliferation and differentiation controls in vitro, the regulation of the homeostasis of normal stratified epithelia remains unclear in vivo. Computer simulation represents a powerful tool to investigate the complex field of cell proliferation regulation networks. It provides huge computation capabilities to test, in a dynamic in silico context, hypotheses about the many pathways and feedback loops involved in cell growth and proliferation controls. Our approach combines a model of cell proliferation and a spatial representation of cells in 2D using the Voronoi graph. The cell proliferation model includes intracellular (cyclins, Cyclin Dependent Kinases - CDKs. Retinoblastoma protein - Rb, CDK inhibitors) and extracellular controls (growth and differentiation factors, integrins). The Voronoi graph associates a polygon with every cell and the set of these polygons defines the tissue architecture. Thus, the model provides a quantitative model of extracellular signals and cell motility as a function of the neighborhood during time dependent simulations. The 2D simulations illustrate the influence of the microenvironment on cell proliferation in basal layers of stratified epithelia and of differential adherence in keratinocytes differentiation and related upward migration. Our results particularly show the role of CDK inhibitors (mainly the protein p27) in the Rb dependent control pathway of the transition from the G1 to S phase of the cell cycle.

Cell Cycle↗
PubMed2004

Kinetics of a cellular nitric oxide/cGMP/phosphodiesterase-5 pathway.

Rat platelets served as a model to evaluate quantitatively how guanylate cyclase (GC)-coupled nitric oxide (NO) receptors and phosphodiesterases (here phosphodiesterase-5) interact to transduce NO signals in cells. The platelets expressed mRNA only for the alpha(1) and beta(1) GC-coupled receptor subunits. In intact platelets, the potency of NO for elevating cGMP (EC(50) = 10 nm) was lower than in lysed platelets (EC(50) = 1.7 nm). The limiting activities of GC and phosphodiesterase in intact platelets were both very high, being equivalent to about 100 microm/s. With low phosphodiesterase activity (imposed by 100 microm sildenafil), the cGMP response over time was hyperbolic in shape for a range of NO concentrations or GC activities due to GC desensitization. Without a phosphodiesterase inhibitor, NO generated only brief cGMP transients, peaking after 2-5 s but amounting maximally to about 150 microm cGMP. The transients were caused partly by GC desensitization, which varied in rate (half-time up to 3 s) and extent (up to 80%) depending on the NO concentration, and partly by an enhancement of the phosphodiesterase catalytic activity with time, which was deduced to be up to 30-fold and to occur with a half-time of up to 5 s. The results were simulated by a quantitative model, which also explains the varied shapes of cGMP responses to NO found in other cells. Downstream phosphorylation in platelets was detectable within 2 s, and, with continuous exposure (1 min), this pathway could be engaged by subnanomolar NO concentrations (EC(50) = 0.5 nm).

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Perceptual similarity in autism.

People with autism have consistently been found to outperform controls on visuo-spatial tasks such as block design, embedded figures, and visual search tasks. Plaisted, O'Riordan, and others (Bonnel et al., 2003; O'Riordan & Plaisted, 2001; O'Riordan, Plaisted, Driver, & Baron-Cohen, 2001; Plaisted, O'Riordan, & Baron-Cohen, 1998a, 1998b) have suggested that these findings might be explained in terms of reduced perceptual similarity in autism, and that reduced perceptual similarity could also account for the difficulties that people with autism have in making generalizations to novel situations. In this study, high-functioning adults with autism and ability-matched controls performed a low-level categorization task designed to examine perceptual similarity. Results were analysed using standard statistical techniques and modelled using a quantitative model of categorization. This analysis revealed that participants with autism required reliably longer to learn the category structure than did the control group but, contrary to the predictions of the reduced perceptual similarity hypothesis, no evidence was found of more accurate performance by the participants with autism during the generalization stage. Our results suggest that when all participants are attending to the same attributes of an object in the visual domain, people with autism will not display signs of enhanced perceptual similarity.

Adult↗
PubMed2004

Diversity and distribution of Frankia strains symbiotic with Ceanothus in California.

Frankia strains symbiotic with Ceanothus present an interesting opportunity to study the patterns and causes of Frankia diversity and distribution within a particular host infectivity group. We intensively sampled Frankia from nodules on Ceanothus plants along an elevational gradient in the southern Sierra Nevada of California, and we also collected nodules from a wider host taxonomic and geographic range throughout California. The two sampling scales comprised 36 samples from eight species of Ceanothus representing six of the seven major biogeographic regions in and around California. The primary objective of this study was to use a quantitative model to test the relative importance of geographic separation, host specificity, and environment in influencing the identity of Ceanothus Frankia symbionts as determined by ribosomal DNA sequence data. At both sampling scales, Frankia strains symbiotic with Ceanothus exhibited a high degree of genetic similarity. Frankia strains symbiotic with Chamaebatia (Rosaceae) were within the same clade as several Ceanothus symbionts. Results from a classification and regression tree model used to quantitatively explain Frankia phylogenetic groupings demonstrated that the only significant variable in distinguishing between phylogenetic groups at the more local sampling scale was host species. At the regional scale, Frankia phylogenetic groupings were explained by host species and the biogeographic province of sample collection. We did not find any significant correspondence between Frankia and Ceanothus phylogenies indicative of coevolution, but we concluded that the identity of Frankia strains inhabiting Ceanothus nodules may involve interactions between host species specificity and geographic isolation.

California↗
PubMedDate not supplied

Characterization of a developing lumbar arthrodesis in a sheep model with quantitative instability.

BACKGROUND CONTEXT: Mechanical forces have been considered responsible for stress shielding an arthrodesis, but the biology of a developing lumbar fusion has not been well characterized. PURPOSE: A large animal model was used to test the hypothesis that mechanical forces modify the biological processes involved in a developing bony fusion. STUDY DESIGN: Lumbar fusion was performed in an ovine model using custom instrumentation that permitted a controlled degree of anterior-posterior translation after surgery. Fusion sites were evaluated by radiography, microradiography, histology and histomorphometry at time points that corresponded with predicted early and later stages of bone healing. METHODS: Fourteen skeletally mature ewes underwent lumbar spinal fusion under general anesthesia. In the control (stable) group, the spine was rigidly fixed with a cage anteriorly and pedicle screws posteriorly. In the experimental (unstable) group, the spine was destabilized by an annulectomy (with no anterior implant) and custom pedicle screws that allowed 2 mm of anterior-posterior translation. Animals were euthanized 6 and 12 weeks after surgery. RESULTS: Radiographs confirmed that the fusion mass had not fully consolidated at either time point. Microradiographs revealed a trend toward increased bone formation at 6 weeks in the stable case as compared with the unstable, but by 12 weeks, this trend had reversed (p=.03). Intramembranous bone formation was the primary mechanism of healing near the transverse process in animals with both stable and unstable fixation. In the area between the two transverse processes, new bone formation occurred primarily through endochondral ossification. At 12 weeks, the stable case had significantly more cartilage formed (p=.023) but less newly formed bone (p=.07) as compared with the quantitatively unstable. CONCLUSIONS: This clinically realistic animal model allowed characterization of the biology of the developing arthrodesis before fusion. Under stable or unstable conditions, endochondral ossification was the predominant mechanism of new bone formation within the intertransverse process region. This finding, which contrasts with previous reports from small animal models of spine fusion, may reflect a difference in biology that results from the increased size of the intertransverse space in sheep as compared with small animals. Interestingly, mechanical instability increased the formation of new bone within this region, but not at the transverse process. Endochondral ossification therefore appears to respond to mechanical factors in the fusion site. The ovine model shows promise as an alternative to the rabbit model and may provide a more stringent test for potential new surgical and nonsurgical strategies for spine fusion.

Animals↗
PubMed2002

The living legacy of the Harvard Pigeon Lab: quantitative analysis in the wide world.

From the Harvard Pigeon Lab of the 1960s arose a behavior-analytic approach that was quantitative and rigorous, rooted in Herrnstein's matching law. Researchers modified the matching law to describe choice behavior in a variety of different settings and examined its relations with other quantitative models. Beginning in the early 1970s, researchers began using the Harvard Pigeon Lab's quantitative framework to study in the laboratory specific aspects of the world outside the laboratory. Much of this work concerned investigations of self-control-choice of a larger, more delayed reinforcer over a smaller, less delayed reinforcer. Experiments using a quantitative framework derived from the matching law have also been conducted outside the laboratory; however, these have been far less frequent. Current and future researchers will benefit the field by devising new, creative ways to investigate the matching law and related quantitative models outside the laboratory. Such research can help to demonstrate the validity of these models as basic principles of behavior, can enhance public opinion of and rewards for such research, and can stimulate further development of the Harvard Pigeon Lab's quantitative approach by using that approach with new variables.

Animals↗
PubMed2003

Mixture toxicity and its modeling by quantitative structure-activity relationships.

Environmental contaminants are frequently encountered as mixtures, and the behavior of chemicals in a mixture may not correspond to that predicted from data on the pure compounds. This paper reviews current quantitative structure-activity relationship (QSAR) methodology for the analysis of mixture toxicity. Interactions of components in a mixture can cause complex and substantial changes in the apparent properties of its constituents, resulting in synergistic or antagonistic effects as opposed to the ideal reference case of additive behavior: concentration addition (CA) and independent action (IA) are two prominent reference models for the evaluation of joint activity, and both have mechanistic support from pharmacology. After discussing graphical tools for analyzing binary mixtures and joint effect indices suitable also for multicomponent mixtures, water solubility and hydrophobicity of mixtures are analyzed with respect to the property contributions of the individual components. With the former, small but significant deviations from ideal behavior are observed even for simple organics, whereas in the case of low concentrations, mixture hydrophobicity was found to agree approximately with the fractional contributions of the components. A variety of studies suggest that mixtures of compounds exerting only one (narcotic or specific) mode of action can be modeled satisfactorily by assuming CA, whereas the interaction of differently acting compounds tends to yield a less than CA joint activity. The QSARs have been used to predict concentrations of components in mixtures from joint effects and defined mixture ratios and have been developed to predict narcotic-type mixture toxicity from molecular descriptors that are calculated as composite properties according to the fractional concentrations of the mixture components. In the case of ionogenic compounds, initial results suggest that CA may serve as a first-order approximation for the joint effect of un-ionized and ionized compound portions.

Animals↗
PubMed2004

Evaluation of HIV-1 kinetic models using quantitative discrimination analysis.

MOTIVATION: Since the identification of human immunodeficiency virus (HIV) over twenty years ago, many mathematical models of HIV dynamics have been proposed. The purpose of this study was to evaluate intracellular and intercellular scale HIV models that best described the dynamics of viral and cell titers of a person, where parameters were determined using typically available patient data. In this case, 'best' was defined as the model most capable of describing experimental patient data and was determined by Bayesian-based model discrimination analysis and the ability to provide realistic results. RESULTS: Twenty models of HIV-1 viral dynamics were initially evaluated to determine whether parameters could be obtained from readily available clinical data from established HIV-1 patients with stable disease. Based on this analysis, three models were chosen for further examination and comparison. Parameters were estimated using experimental data from a cohort of 338 people monitored for up to 2484 days. The models were evaluated using a Bayesian technique to determine which model was most probable. The model ultimately selected as most probable was overwhelmingly favored relative to the remaining two models, and it accounted for uninfected cells, infected cells and cytotoxic T lymphocyte dynamics. The authors developed a fourth model for comparison purposes by combining the features of the original three models. Parameters were estimated for the new model and the statistical analysis was repeated for all four models. The model that was initially favored was selected again upon model discrimination analysis. CONTACT: srivasta@engr.uconn.edu.

Cohort Studies↗
PubMed2002

Power and sample sizes for linkage with extreme sampling under an oligogenic model for quantitative traits.

Extreme sampling of sibling pairs has been shown to be efficient in terms of statistical power and sample sizes (in number of sibling pairs needed to genotype) to detect a quantitative trait locus (QTL) when the residual distribution is normal. In the present study, the efficiency of extreme sampling strategies to detect each locus under an oligogenic model is analytically explored with a test statistic based on identical-by-descent (IBD) statuses of independent sibling pairs. In the oligogenic model, the joint effect of oligogenes is the sum of the effects of each locus. Under this model, detecting each single locus will depend, in part, on the allele frequencies and magnitudes of effect of the other loci. Effects of two QTLs with different magnitudes of displacement and acting nonepistatically are considered. Three types of extreme sampling-that is, extreme concordant high (ECH), extreme concordant low (ECL), and extreme discordant (ED)-are primarily considered herein. Among these, ED sampling under the oligogenic model is shown to be most efficient in most situations considered here in terms of allele frequency and mode of inheritance. Differences in results between ECH and ECL sampling are purely arbitrary, brought up mostly by the directions of displacement effects. However, power to detect a locus with the lesser (in magnitude) displacement effect does not necessarily increase with extremity of sampling. Combinations of extreme discordant and extreme concordant sibling pairs are briefly discussed.

Alleles↗