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At least 973 records · Page 54Linked to original sources
PubMed2003

Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings.

The in vitro release characteristics of eight low-molecular-weight drugs (clindamycin, 17beta-estradiol, 17beta-estradiol-3-acetate, 17beta-estradiol diacetate, metronidazole, norethisterone, norethisterone acetate and oxybutynin) from silicone matrix-type intravaginal rings of various drug loadings have been evaluated under sink conditions. Through modelling of the release data using the Higuchi equation, and determination of the silicone solubility of the drugs, the apparent silicone elastomer diffusion coefficients of the drugs have been calculated. Furthermore, in an attempt to develop a quantitative model for predicting release rates of new drug substances from these vaginal ring devices, it has been observed that linear relationships exist between the log of the silicone solubility of the drug (mg x ml(-1)) and the reciprocal of its melting point (K(-1)) (y=3.558x-9.620, R=0.77), and also between the log of the diffusion coefficient (cm(2) s(-1)) and the molecular weight of the drug molecule (g x mol(-1)) (y=-0.0068x-4.0738, R=0.95). Given that the silicone solubility and silicone diffusion coefficient are the major parameters influencing the permeation of drugs through silicone elastomers, it is now possible to predict through use of the appropriate mathematical equations both matrix-type and reservoir-type intravaginal ring release rates simply from a knowledge of drug melting temperature and molecular weight.

Administration, Intravaginal↗
PubMed1997

Mr. Chips: an ideal-observer model of reading.

The integration of visual, lexical, and oculomotor information is a critical part of reading. Mr. Chips is an ideal-observer model that combines these sources of information optimally to read simple texts in the minimum number of saccades. In the model, the concept of the visual span (the number of letters that can be identified in a single fixation) plays a key, unifying role. The behavior of the model provides a computational framework for reexamining the literature on human reading saccades. Emergent properties of the model, such as regressive saccades and an optimal-viewing position, suggest new interpretations of human behavior. Because Mr. Chip's "retina" can have any (one-dimensional) arrangement of high-resolution regions and scotomas, the model can simulate common visual disorders. Surprising saccade strategies are linked to the pattern of scotomas. For example, Mr. Chips sometimes plans a saccade that places a decisive letter in a scotoma. This article provides the first quantitative model of the effects of scotomas on reading.

Algorithms↗
PubMed2000

Adenosine primes the opening of mitochondrial ATP-sensitive potassium channels: a key step in ischemic preconditioning?

BACKGROUND: Adenosine can initiate ischemic preconditioning, and mitochondrial ATP-sensitive potassium (K(ATP)) channels have emerged as the likely effectors. We sought to determine the mechanistic interactions between these 2 observations. METHODS AND RESULTS: The mitochondrial flavoprotein oxidation induced by diazoxide (100 micromol/L) was used to quantify mitochondrial K(ATP) channel activity in intact rabbit ventricular myocytes. Adenosine (100 micromol/L) increased mitochondrial K(ATP) channel activity and abbreviated the latency to mitochondrial K(ATP) channel opening. These potentiating effects were entirely prevented by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (100 micromol/L) or by the protein kinase C inhibitor polymyxin B (50 micromol/L). The effects of adenosine and diazoxide reflected mitochondrial K(ATP) channel activation, because they could be blocked by the mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (500 micromol/L). In a cellular model of simulated ischemia, adenosine mitigated cell injury; this cardioprotective effect was blocked by 5-hydroxydecanoate but not by the surface-selective K(ATP) channel blocker HMR1098. Moreover, adenosine augmented the cardioprotective effect of diazoxide. A quantitative model of mitochondrial K(ATP) channel gating reproduced the major experimental findings. CONCLUSIONS: Our results support the hypothesis that adenosine receptor activation primes the opening of mitochondrial K(ATP) channels in a protein kinase C-dependent manner. The findings provide tangible links among various key elements in the preconditioning cascade.

Adenosine↗
PubMed2002

Reaction diffusion model of the enzymatic erosion of insoluble fibrillar matrices.

Predicting the time course of in vivo biodegradation is a key issue in the design of an increasing number of biomedical applications such as sutures, tissue analogs and drug-delivery devices. The design of such biodegradable devices is hampered by the absence of quantitative models for the enzymatic erosion of solid protein matrices. In this work, we derive and simulate a reaction diffusion model for the enzymatic erosion of fibrillar gels that successfully reproduces the main qualitative features of this process. A key aspect of the proposed model is the incorporation of steric hindrance into the standard Michaelis-Menten scheme for enzyme kinetics. In the limit of instantaneous diffusion, the model equations are analogous to the standard equations for enzymatic degradation in solution. Invoking this analogy, the total quasi-steady-state approximation is used to derive approximate analytical solutions that are valid for a wide range of in vitro conditions. Using these analytical approximations, an experimental-theoretical method is derived to unambiguously estimate all the kinetic model parameters. Moreover, the analytical approximations correctly describe the characteristic hyperbolic dependence of the erosion rate on enzyme concentration and the zero-order erosion of thin fibers. For definiteness, the analysis of published experimental results of enzymatic degradation of fibrillar collagen is demonstrated, and the role of diffusion in these experiments is elucidated.

Binding Sites↗
PubMed2003

Community modelling: a tool for correlating estimates of exposure with perception of odour from municipal solid waste (MSW) landfills.

Odours from municipal solid waste landfills have the potential to cause significant annoyance and impact to amenity in the environment surrounding sites. In order to assess the impact of odorous emissions on surrounding communities a quantitative model to predict annoyance was developed. The overall objective of this research was to develop the major components of the model namely, assessment of odorous emissions, dispersion and reception by the surrounding community around the landfill site. This study used community modelling as a tool to find a link between dispersion and perception of odour. The research completed a year-round monitoring program engaging people within the local community as regular odour monitors. Estimates of exposure from dispersion analysis were used to compare incidents causing complaint and intensity-concentration plots were fitted for each monitor whose reports were found to be logically consistent with regard to the intensity scaling. Human responses to the vast range of odour intensities, from highly intense source odours through to less intense dispersed odours at monitors' locations, were found to differ greatly. It was observed that the psychophysical models based on the Weber-Fechner law and Power law fitted the data consistently well for the entire range of the intensity scale used, 1-7. However, the other two models, based on Beidler's law and Laffort's equation showed an inconsistency with the intensity scales >3.

Air Movements↗
PubMed1995

Optimized model of oriented-line-target detection using vertical and horizontal filters.

A line-element target differing sufficiently in orientation from a background of line elements can be visually detected easily and quickly; orientation thresholds for such detection are lowest when the background elements are all vertical or all horizontal. A simple quantitative model of this performance was constructed from three processing stages: (1) linear filtering by two classes of anisotropic filters, (2) nonlinear point transformation, and (3) estimation of a signal-to-noise ratio based on responses to images with and without a target. A Monte Carlo optimization procedure (simulated annealing) was used to determine the model parameter values required for providing an accurate description of psychophysical data on orientation increment thresholds.

Humans↗
PubMedDate not supplied

On the physical interpretation of QSAR models.

Multidimensional quantitative structure-activity models (QSAR) developed using molecular structure descriptors and regression analysis techniques have found wide utility and acceptance. However, it is often difficult to extract a physical interpretation of such models because of the types of descriptors involved and the multidimensional nature of the model. The work described here illustrates a method of model interpretation that employs partial least squares (PLS) analysis. Structure-activity relationship information is derived from the positions of specific sets of structures in the PLS score plots and the weights for each variable in the PLS components. Using these data, information regarding major structure-activity trends, trend exceptions, and unique or outlying observations is easily obtained. Examples of this methodology are illustrated using QSAR equations developed for the inhibition of quinolone-resistant bacterial DNA gyrase and human topoisomerase-II inhibition by a series of quinolone antibacterial agents.

Bacterial Proteins↗
PubMed2002

Mathematical modeling for breast cancer risk assessment. State of the art and role in medicine.

Women at increased risk of breast cancer have important opportunities for early detection and prevention. There are, however, serious drawbacks to the available interventions. The magnitude of breast cancer risk is a crucial factor in the optimization of medical benefit when considering the efficacy of risk-reduction methods, the adverse effects of intervention, and economic and quality-of-life outcomes. Breast cancer risk assessment has become increasingly quantitative and is amenable to computerization. The assembly of risk factor information into practical, quantitative models for clinical and scientific use is relatively advanced for breast cancer, and represents a paradigm for broader risk management in medicine. Using a case-based approach, we will summarize the major breast cancer risk assessment models, compare and contrast their utility, and illustrate the role of genetic testing in risk management. Important considerations relevant to clinical oncology practice include the role of risk assessment in cancer prevention, the logistics of implementing risk assessment, the ramifications of conveying risk information with limited genetic counseling, and the mechanisms for genetics referral. Medical professionals can embrace new preventive medicine techniques more effectively by utilizing quantitative methods to assess their patients' risks.

Breast Neoplasms↗
PubMed2004

Iron chelation can modulate UVA-induced lipid peroxidation and ferritin expression in human reconstructed epidermis.

BACKGROUND/PURPOSE: As ferritin has been identified as an important factor in antioxidant defense in cultured human skin cells, we evaluated UVA-induced lipid hydroperoxides (LPO) production and ferritin expression in reconstructed human epidermis in vitro. RESULTS: Ferritin is regularly present in the basal layer of unirradiated epidermis both in the human skin in vivo and in the reconstructed human epidermis in vitro. Following acute UVA exposure, ferritin expression increased in basal epidermal cells in both models. Quantitative analysis showed that, in reconstructed human epidermis, LPO and ferritin levels increased linearly with the UVA dose. An iron chelator, OR10141, inhibited these inductions. CONCLUSION: These findings demonstrate that reconstructed human epidermis is a useful in vitro model to study UVA-induced oxidative stress and protection afforded by iron chelators, antioxidants or UVA absorbers.

Adult↗
PubMed2006

A mathematical model of glioblastoma tumor spheroid invasion in a three-dimensional in vitro experiment.

Glioblastoma, the most malignant form of brain cancer, is responsible for 23% of primary brain tumors and has extremely poor outcome. Confounding the clinical management of glioblastomas is the extreme local invasiveness of these cancer cells. The mechanisms that govern invasion are poorly understood. To gain insight into glioblastoma invasion, we conducted experiments on the patterns of growth and dispersion of U87 glioblastoma tumor spheroids in a three-dimensional collagen gel. We studied two different cell lines, one with a mutation to the EGFR (U87DeltaEGFR) that is associated with increased malignancy, and one with an endogenous (wild-type) receptor (U87WT). We developed a continuum mathematical model of the dispersion behaviors with the aim of identifying and characterizing discrete cellular mechanisms underlying invasive cell motility. The mathematical model quantitatively reproduces the experimental data, and indicates that the U87WT invasive cells have a stronger directional motility bias away from the spheroid center as well as a faster rate of cell shedding compared to the U87DeltaEGFR cells. The model suggests that differences in tumor cell dispersion may be due to differences in the chemical factors produced by cells, differences in how the two cell lines remodel the gel, or different cell-cell adhesion characteristics.

Brain Neoplasms↗
PubMed2004

Atypia in the assessment of breast cancer risk: implications for management.

Proliferative disease accounts for as much as one-third of all biopsies for benign disease and 5-10% of proliferative lesions show atypia ductal or lobular hyperplasia. Nearly 40% of women with a family history of breast cancer and atypical hyperplasia subsequently develop breast cancer. A quantitative model developed by Gail and colleagues estimates the probability of developing breast cancer over time. Risk factors in the model include current age, ages at menarche and first live birth, number of previous biopsies, the presence of cellular atypia, and the number of first-degree relatives with breast cancer. Atypical hyperplasia approximately doubles the risk of developing invasive breast cancer within any quantitative risk profile. Ductal lavage provides a minimally invasive method of collecting breast epithelial cells. The procedure opens the possibility of repeatable tracking of breast cytology over time, but its role as a risk assessment tool remains to be fully defined.

Breast Neoplasms↗
PubMed2002

A comprehensive model for the allosteric regulation of mammalian ribonucleotide reductase. Functional consequences of ATP- and dATP-induced oligomerization of the large subunit.

Reduction of NDPs by murine ribonucleotide reductase (mRR) requires catalytic (mR1) and free radical-containing (mR2) subunits and is regulated by nucleoside triphosphate allosteric effectors. Here we present a new, comprehensive, and quantitative model for allosteric control of mRR enzymatic activity based on molecular mass, ligand binding, and enzyme activity studies. In this model, nucleotide binding to the specificity site (s-site) drives formation of an active R1(2)R2(2) dimer, ATP or dATP binding to the adenine-specific site (a-site) results in formation of an inactive tetramer, and ATP binding to the newly described hexamerization site (h-site) drives formation of active R1(6)R2(6) hexamer. In contrast, an earlier phenomenological model [Thelander, L., and Reichard, P. (1979) Annu. Rev. Biochem. 67, 71-98] (the "RT" model) ignores aggregation state changes and mistakenly rationalizes ATP activation versus dATP inhibition as reflecting different functional consequences of ATP versus dATP binding to the a-site. Our results suggest that the R1(6)R2(6) heterohexamer is the major active form of the enzyme in mammalian cells, and that the ATP concentration is the primary modulator of enzyme activity, coupling the rate of DNA biosynthesis with the energetic state of the cell. Using the crystal structure of the Escherichia coliR1 hexamer as a model for the mR1 hexamer, a scheme is presented that rationalizes the slow isomerization of the tetramer form and suggests an explanation for the low enzymatic activity of tetramers complexed with R2. The similar specific activities of R1(2)R2(2) and R1(6)R2(6) are inconsistent with a proposed model for R2(2) docking with R1(2) [Uhlin, U., and Eklund, H. (1994) Nature 370, 533-539], and an alternative is suggested.

Adenine↗
PubMed2001

MR microscopy of multicomponent diffusion in single neurons.

This study examines multicomponent diffusion in isolated single neurons and discusses the implications of the results for macroscopic water diffusion in tissues. L7 Aplysia neurons were isolated and analyzed using a 600 MHz Bruker wide-bore instrument with a magnetic susceptibility-matched radiofrequency microcoil. Using a biexponential fit, the apparent diffusion coefficients (ADCs) from the cytoplasm (with relative fraction) were 0.48 +/- 0.14 x 10(-3) mm2 x s(-1) (61 +/- 11%) for the fast component, and 0.034 +/- 0.017 x 10(-3) mm2 x s(-1) (32 +/- 11%) for the slow component (N = 10). Diffusion in the nucleus appears to be primarily monoexponential, but with biexponential analysis it yields 1.31 +/- 0.32 x 10(-3) mm2 x s(-1) (89 +/- 6%) for the fast component and 0.057 +/- 0.073 x 10(-3) mm2 x s(-1) (11 +/- 6%) for the slow (N = 5). The slow component in the nucleus may be explained by cytoplasmic volume averaging. These data demonstrate that water diffusion in the cytoplasm of isolated single Aplysia neurons supports a multiexponential model. The ADCs are consistent with previous measurements in the cytoplasm of single neurons and with the slow ADC measurement in perfused brain slices. These distributions may explain the multiple compartments observed in tissues, greatly aiding the development of quantitative models of MRI in whole tissues.

Animals↗
PubMed2003

Predictive role of serum procollagen III peptide and Knodell's index in survival prognosis of patients with hepatitis B virus liver cirrhosis.

OBJECTIVE: The objective of the study was to improve the accuracy of survival prognosis in patients with liver cirrhosis using procollagen III peptide (PIIIP), as a marker of inflammation and fibrogenesis, and Knodell's histologic activity index (KI) in addition to previously used prognostic factors. PATIENTS AND METHODS: Five-year survival was followed in a group of 75 patients with hepatitis B virus (HBV) liver cirrhosis (patients testing anti-HBe positive and HBV-DNA negative). There were 31 patients with compensated cirrhosis and 44 with decompensated cirrhosis. The diagnostic procedure included clinical, laboratory, ultrasound and pathohistologic examination. We combined PIIIP and KI with other significant variables to achieve the highest possible sensitivity, specificity and accuracy for survival prognosis in HBV liver cirrhosis. The models were compared using ROC analysis. RESULTS: At the end of the five-year period of survival follow-up, there were 39 survivors and 36 patients had died (only three died from an extrahepatic cause). In the quantitative model, the discriminant canonical function (DCF) identified PIIIP, bilirubin, prothrombin time, ascites and KI as statistically significant parameters in the prognosis of five-year survival. Calculation of the score based on DCF yielded an accuracy of 89.3%. In the semiquantitative model, the analysis of variance identified PIIIP, bilirubin, albumin, pro-thrombin time, alkaline phosphatase, ascites and KI as significant variables. When PIIIP was added to the clinicohistologic diagnosis, Child-Pugh score and KI, the level of accuracy improved by 12% (from 78% to 90%), 11% (from 79% to 90%) and 10.6% (from 80% to 90.6%), respectively. When calculated with the three biochemical parameters (alkaline phosphatase, PIIIP and bilirubin) and KI identified by DCF, the accuracy was 90.6%. CONCLUSION: Combining PIIIP and KI with other prognostic parameters is useful in achieving a better precision of survival prognosis in patients with HBV liver cirrhosis.

Adult↗
PubMed1990

Quasielastic light scattering studies of aqueous biliary lipid systems and native bile.

During the past 15 yr, the technique of quasielastic light scattering has been used by a number of laboratories to systematically investigate the aggregative behavior of model bile systems and more recently to characterize particles present in native bile. Quasielastic light scattering investigations of aqueous bile salt solutions have indicated important similarities and differences between the various bile salt species and have led to a quantitative model for the formation of globular and rodlike micelles, based on Small and Ekwall's primary-secondary micelle hypothesis. Studies of aqueous bile salt-lecithin systems have indicated three important aggregation regimens dependent on the lecithin/bile salt molar ratio and total solute concentration. Region I of the phase diagram, which includes the lecithin/bile salt and total solute concentration values found in most mammalian biles, corresponds to a population of "simple" bile salt micelles coexisting in equilibrium with a population of mixed bile salt-lecithin micelles. Region II contains only mixed micelles, whose apparent size and shape vary with lecithin/bile salt and total solute concentration in a manner consistent with a "mixed disc" model. In this model, bile salts not only coat the perimeter of the disc (as proposed in Small's original model) but are also incorporated within the lecithin bilayer, possibly as hydrogen-bonded dimers. Finally, in region III, where total solute concentration values are typically less than the critical micelle concentration of the pure bile salt, the systems contain mixed vesicles (spherical bilayer shells) whose size (approximately 130 to 500A) depends on lecithin/bile salt and total solute concentration in accordance with a simple partition equilibrium that determines the composition of the mixed vesicle bilayer.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Epidermal cell proliferation. II. A comprehensive mathematical model of cell proliferation and migration in the basal layer predicts some unusual properties of epidermal stem cells.

The clustering of 3HTdR labelled cells in the epidermal basal layer and their changes with time have been modelled mathematically and cannot be adequately fitted by an earlier model of the cell kinetic organisation of the skin. A more refined model analysis was performed based on Monte Carlo computer simulations of cell layers which take cell division, cell aging and lateral as well as vertical cell migration into account. A large variety of hypothetical scenarios was tested to see if each could provide a fit to the clustering data. The analysis provides further support for the concept of a cell kinetic heterogeneity with a stem-transit-postmitotic differentiation scheme. In the best overall model scheme three transit divisions are predicted but unlike in the earlier model it is now postulated that postmitotic cells can be produced at all stages in the lineage rather than only at the end of the amplification scheme. Most important, the model predicts that stem cells and most of the transit cells differ in the way they process 3HTdR label. Grain dilution is an important mechanism to explain the fate of some labelled cells in the tissue, but on its own it can only consistently explain the data if the stem cells have a very low labelling index (LI less than or equal to 1%) which implies a very short biologically unreasonable S-phase. If a higher LI (longer S-phase) is assumed for the stem-cells other mechanisms must be predicted to explain the lack of large clusters and the increase in time of the singles. The selective segregation of chromosomes at mitosis is one such mechanism. However, on its own a large number of cells would have to behave in this way (i.e. both stem and T1 cells). If combined with other assumptions such as some grain dilution this selective segregation may be restricted only to stem cells. In addition the model allows cell production and migration rates to be estimated and the analysis can be related to the EPU-concept. Indeed the model itself would tend to automatically generate an EPU like structure. The model quantitatively reproduces LI, PLM, CL and clustering data.

Autoradiography↗
PubMedDate not supplied

Percutaneous absorption, biotransformation, and systemic disposition of parathion in vivo in swine. I. Comprehensive pharmacokinetic model.

Topical exposure to pesticides is a common route of entry for systemic effects. To quantify disposition of parathion (PA) and its major metabolites in a widely accepted animal model for human dermal risk assessment, a comprehensive pharmacokinetic model was formulated following [ring-UL-14C]PA topical (occluded and non-occluded dose of 300 micrograms, 40 micrograms/cm2 on the abdomen and back) and intravenous (300 micrograms) administration in vivo in female weanling pigs. The model was then confirmed with an intravenous p-nitrophenol (PNP) study. Total 14C as well as HPLC-separated PA, paraoxon (PO), PNP, and p-nitrophenyl-beta-D-glucuronide (PNP-G) profiles in plasma and urine, and 14C in blood, stratum corneum, dosed tissues, dosing device, and evaporative loss were determined. The model quantitates the evaporative loss, dosing device binding, percutaneous absorption, first-pass metabolism and its impact on the systemic metabolic profile of PA, as well as the distribution and excretion kinetics of both the parent compound and its metabolites. Model parameters and the simulated amount-time profiles were reported. Occlusion not only enhanced the partition of both PA and PNP into the stratum corneum from the dosed skin surface, but also slowed down the distribution of PA and PNP in the local dosed tissues. A significant finding was that occlusion also altered the first pass biotransformation of PA in the epidermis. PA, PO, and PNP were more easily absorbed into blood from the back than from the abdomen skin. The rate-limiting process in PA percutaneous absorption is the partitioning from skin surface into the stratum corneum.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1997

Mathematical modeling of the dilution curves for ultrasonographic contrast agents.

Most techniques using sonographic contrast agents are based on introducing the agent intravenously. The sonographic changes occur over time and follow a characteristic "skewed gaussian curve," often referred to as the indicator dilution curve. This study uses principles of linear acoustics and tracer kinetics to develop a quantitative model for the indicator dilution curve. A rapid increase in image brightness occurs after bolus injection; brightness peaks after a time related to the blood flow and stability of the contrast agent, which is followed by an asymptotic decrease in image brightness. The net image enhancement, represented by the area under the dilution curve, increases nonlinearly with the injected dose. In stable contrast agents the peak-time and mean transit time are related directly to the flow rate. This relationship changes when the microbubbles of a contrast agent collapse. In an unstable contrast agent the indicator dilution curve is attenuated and peaks earlier than expected on the basis of flow rate. The extent of shift in the mean transit time varies with the half-life of the contrast agent and follows a sigmoid relationship. In conclusion, the properties of the time-videointensity (indicator dilution) curves are significantly affected by the attenuation and stability of the contrast agents. These factors must be taken into consideration in deriving flow related information.

Absorption↗