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Capillary permeability of 131I-albumin in skeletal muscle.

Capillary permeability of 131I-albumin in skeletal muscle was determined by applying the "single injection, residue detection" method to the autoperfused cat gastrocnemius muscle preparation. Experiments at zero venous pressure gave an average capillary extraction fraction, E, of 0.028 at a plasma flow of about 3 ml X (100 g)-1 X min-1. The permeability-surface area product, PS, was on average 0.075 ml X (100 g)-1 X min-1. Experiments at a venous pressure of 10 mm Hg gave essentially the same PS product (0.070 ml X (100 g)-1 X min-1. Further experiments demonstrated that stagnant intravascular pools of 131I-albumin were not present. The free diffusion coefficient in water at 37 degrees of the purified 131I-albumin was 0.0631 X 10-5 cm2 X sec-1). The distribution volume for 131I-albumin in the interstitial space was 3.5 ml X (100 g)-1 X sec-1. Assuming a capillary surface area of 70 cm2 X g-1 the permeability coefficient was calculated to be 18 X 10(-8) cm X sec-1 which is about 3 to 10 times higher than values obtained by lymph sampling methods. The results indicate that the predominant transcapillary transport mechanism for 131I-albumin is diffusion. When analyzed according to the theory of restricted diffusion the results are compatible with transcapillary diffusion through pores with an effective equivalent pore radius of 145 A.

Albumins↗

Galactic cosmic radiation model and its applications.

A model for the differential energy spectra of galactic cosmic radiation as a function of solar activity is described. It is based on the standard diffusion-convection theory of solar modulation. Estimates of the modulation potential based on fitting this theory to observed spectral measurements from 1954 to 1989 are correlated to the Climax neutron counting rates and to the sunspot numbers at earlier times taking into account the polarity of the interplanetary magnetic field at the time of observations. These regression lines then provide a method for predicting the modulation at later times. The results of this model are quantitatively compared to a similar Moscow State University (MSU) model. These model cosmic ray spectra are used to predict the linear energy transfer spectra, differential energy spectra of light (charge < or = 2) ions, and single event upset rates in memory devices. These calculations are compared to observations made aboard the Space Shuttle.

Computer Simulation↗

Induced dipole moment of purple membranes. Theoretical analysis.

The induced dipole moment of a purple membrane parallel to the membrane surface was analysed based on the two-dimensional fluctuation theory of counterions. The observed polarizability previously measured by electric dichroism and its dependence on the membrane size were derived from theory for the case where the interaction between counterions was screened. The screening effect of salts on the induced dipole moment was estimated from the theory on diffuse double layers.

Journal Article↗

Estimation of demography and mutation rates from one million haploid genomes.

As genetic sequencing costs have plummeted, datasets with sizes previously unthinkable have begun to appear. Such datasets present opportunities to learn about evolutionary history, particularly via rare alleles that record the very recent past. However, beyond the computational challenges inherent in the analysis of many large-scale datasets, large population-genetic datasets present theoretical problems. In particular, the majority of population-genetic tools require the assumption that each mutant allele in the sample is the result of a single mutation (the "infinite-sites" assumption), which is violated in large samples. Here, we present DR EVIL, a method for estimating mutation rates and recent demographic history from very large samples. DR EVIL avoids the infinite-sites assumption by using a diffusion approximation to a branching-process model with recurrent mutation. This approach results in tractable likelihoods that are accurate for rare alleles. We show that DR EVIL performs well in simulations and apply it to rare-variant data from one million haploid samples. We identify mutation-rate heterogeneity even after accounting for trinucleotide context and methylation status. We also predict that at modern sample sizes, the alleles at most polymorphic sites with high mutation rates represent the descendants of multiple mutation events.

Haploidy↗

Theoretical analysis and verification of concentration distribution model in the ultrafiltration process.

Based on the assumed flat model, Navier-Stokes equation for two-dimensional laminar flow fluid and the theory for diffusion and mass transfer, we obtained theoretical results with regarding to the concentration distribution in separation process by mass transfer model in the ultrafiltration process. Through theoretical analysis and experimental verification of concentration distribution, it was known that this model could not only preferably describe the concentration distribution of ultrafiltration process but also forecast concentration polarization phenomenon.

Models, Theoretical↗

Development of a long-acting therapeutic system: Part I: A method to produce silicon rubbers with well-defined microstructures.

Based on the free-volume theory of diffusion in rubbers it is shown that the diffusion coefficient D of a permeating drug can be written as the product of two probabilities D approximately w(1)w(2). The polymer chains in a rubber are subject to thermal vibrations. Hence collisions between vibrating polymer segments and permeating drug molecules can occur. w(1) describes the probability that by such a collision a drug molecule experiences an energy exchange which is large enough to overcome its interactions with its neighborhood. w(2) describes the probability that a permeating drug molecule will find in its immediate neighborhood a free volume being equal or larger than its own volume. Diffusion takes place if the drug molecule experiences a sufficiently large exchange of momentum and finds at the same time a sufficiently large free volume. As both events are independent their overall probability is given by the product of the two probabilities. For a given rubber and a given species of drug molecules in a first approximation w(1) can be considered as constant. This means the diffusion coefficient is mainly determined by w(2). This probability, however, is strongly determined by the microstructure of the rubber. In this study a procedure is developed allowing for a straightforward synthesis of silicone rubbers with defined network density.

Delayed-Action Preparations↗

Midwives and the fetal nuchal cord: a survey of practices and perceptions.

A systematic search of studies of intrapartum management of the nuchal umbilical cord at term found no published controlled studies in this area. A postal survey containing both structured and open questions and a request for local protocols and guidelines was sent to all 637 midwives in 7 maternity units in England. There were 401 (63%) responses. There appeared to be no unit guidelines for this area of practice. Midwife approaches to nuchal cord during birth varied, and included clamping and cutting of loose nuchal cords and a hands-off approach to tight nuchal cords. Reasons for specific actions included doing what had been taught during midwifery training and learning from previous personal experiences. Theories of diffusion of innovation and of planned behaviour may provide a conceptual basis for understanding the adoption of specific practices. Future qualitative and controlled studies are needed to explore the nature and consequences of varying approaches to intrapartum nuchal cord management.

Clinical Competence↗

Local measurements of viscoelastic parameters of adherent cell surfaces by magnetic bead microrheometry.

A magnetic bead microrheometer has been designed which allows the generation of forces up to 10(4) pN on 4.5 micron paramagnetic beads. It is applied to measure local viscoelastic properties of the surface of adhering fibroblasts. Creep response and relaxation curves evoked by tangential force pulses of 500-2500 pN (and approximately 1 s duration) on the magnetic beads fixed to the integrin receptors of the cell membrane are recorded by particle tracking. Linear three-phasic creep responses consisting of an elastic deflection, a stress relaxation, and a viscous flow are established. The viscoelastic response curves are analyzed in terms of a series arrangement of a dashpot and a Voigt body, which allows characterization of the viscoelastic behavior of the adhering cell surface in terms of three parameters: an effective elastic constant, a viscosity, and a relaxation time. The displacement field generated by the local tangential forces on the cell surface is visualized by observing the induced motion of assemblies of nonmagnetic colloidal probes fixed to the membrane. It is found that the displacement field decays rapidly with the distance from the magnetic bead. A cutoff radius of Rc approximately 7 micron of the screened elastic field is established. Partial penetration of the shear field into the cytoplasm is established by observing the induced deflection of intracellular compartments. The cell membrane was modeled as a thin elastic plate of shear modulus mu * coupled to a viscoelastic layer, which is fixed to a solid support on the opposite side; the former accounts for the membrane/actin cortex, and the latter for the contribution of the cytoskeleton to the deformation of the cell envelope. It is characterized by the coupling constant chi characterizing the elasticity of the cytoskeleton. The coupling constant chi and the surface shear modulus mu * are obtained from the measured displacements of the magnetic and nonmagnetic beads. By analyzing the experimental data in terms of this model a surface shear modulus of mu * approximately 2 . 10(-3) Pa m to 4 . 10(-3) Pa m is found. By assuming an approximate plate thickness of 0.1 micron one estimates an average bulk shear modulus of mu approximately (2 / 4) . 10(-4) Pa, which is in reasonable agreement with data obtained by atomic force microscopy. The viscosity of the dashpot is related to the apparent viscosity of the cytoplasm, which is obtained by assuming that the top membrane is coupled to the bottom (fixed) membrane by a viscous medium. By application of the theory of diffusion of membrane proteins in supported membranes we find a coefficient of friction of bc approximately 2 . 10(9) Pa s/m corresponding to a cytoplasmic viscosity of 2 . 10(3) Pa s.

3T3 Cells↗

Atmospheric cosmic rays and solar energetic particles at aircraft altitudes.

Galactic cosmic rays, which are thought to be produced and accelerated by a variety of mechanisms in the Milky Way galaxy, interact with the solar wind, the earth's magnetic field, and its atmosphere to produce hadron, lepton, and photon fields at aircraft altitudes that are quite unlike anything produced in the laboratory. The energy spectra of these secondary particles extend from the lowest possible energy to energies over an EeV. In addition to cosmic rays, energetic particles, generated on the sun by solar flares or coronal mass ejections, bombard the earth from time to time. These particles, while less energetic than cosmic rays, also produce radiation fields at aircraft altitudes which have qualitatively the same properties as cosmic rays. The authors have calculated atmospheric cosmic-ray angular fluxes, spectra, scalar fluxes, and ionization, and compared them with experimental data. Agreement with these data is seen to be good. These data have been used to calculate equivalent doses in a simplified human phantom at aircraft altitudes and the estimated health risks to aircraft crews. The authors have also calculated the radiation doses from several large solar energetic particle events (known as GLEs, or Ground Level Events), which took place in 1989, including the very large event known as GLE 42, which took place on September 29th and 30th of that year. The spectra incident on the atmosphere were determined assuming diffusive shock theory. Unfortunately, there are essentially no experimental data with which to compare these calculations.

Aerospace Medicine↗

Partitioning of a-factor analogues into membranes: analysis of binding and importance for biological activity.

Analogues of the a-factor mating pheromone of the yeast Saccharomyces cerevisiae were used to measure interactions of the pheromones with lipid vesicles and with isolated yeast membranes. The binding of the analogues of a-factor to vesicles and to membranes was best described as a partitioning of the pheromones into the lipid phase. The partitioning was enhanced by the negative surface potential of the membranes and was well described by the Gouy-Chapman theory of diffuse double layers. From the analysis of the binding of the pheromones to synthetic vesicles of known surface potential, effective charges and intrinsic partition coefficients were obtained for the pheromones. The information was used in subsequent experiments with yeast membranes to determine the intrinsic partition coefficients of the a-factor analogues and the charge density of the yeast membranes. Derivatives of a-factor with different alkyl chains in place of the normal C-terminal farnesyl displayed biological activity that paralleled the degree of partitioning of the pheromones into vesicles. Demethylation of the C-terminus decreased the partition coefficient by 6-fold and decreased the biological activity of the pheromone by greater than 2500-fold. The results show that a-factor can effectively partition into membrane bilayers and that the partitioning is probably involved in the subsequent recognition of the pheromone by the a-factor receptor.

4-Butyrolactone↗

Plaque as a biofilm: pharmacological principles of drug delivery and action in the sub- and supragingival environment.

Dental plaque is the diverse microbial community, embedded in a matrix of host and bacterial polymers, growing on teeth as a biofilm. Dental plaque develops naturally, and contributes to the host defences by preventing colonization by exogenous species. The composition of dental plaque varies at distinct surfaces as a result of the inherent biological and physical properties at these sites; the balance of the predominant bacterial populations shifts in disease. Plaque has an open architecture, with channels traversing from the biofilm surface through to the enamel. This structure affects the movement of molecules within plaque, and gradients in key determinants develop. Bacteria growing on a surface display a novel phenotype; one consequence of which is an increased resistance to antimicrobial agents. Resistance can result from restricted inhibitor penetration (diffusion-reaction theory), slower bacterial growth rates, transfer of resistance genes, suboptimal environmental conditions for inhibitor activity, and the expression of a resistant phenotype. Such biofilm-associated traits, coupled with the pharmacokinetic profile of orally delivered antimicrobial agents (high concentrations for short periods/lower concentrations for longer periods), affect the mode of action and efficacy of antimicrobials. Agents with a broad spectrum of activity in laboratory studies may display a far narrower inhibitory profile under the conditions prevailing in the mouth. This may result in a selective inhibition of species implicated in disease, or reduced production of virulence factors, while preserving the benefits associated with a resident oral microflora.

Administration, Topical↗

Non-invasive method for quantitative evaluation of exogenous compound deposition on skin.

Topical application of active compounds on skin is common to both pharmaceutical and cosmetic industries. Quantification of the concentration of a compound deposited on the skin is important in determining the optimum formulation to deliver the pharmaceutical or cosmetic benefit. The most commonly used techniques to date are either invasive or not easily reproducible. In this study, we have developed a noninvasive alternative to these techniques based on spectrofluorimetry. A mathematical model based on diffusion approximation theory is utilized to correct fluorescence measurements for the attenuation caused by endogenous skin chromophore absorption. The limitation is that the compound of interest has to be either fluorescent itself or fluorescently labeled. We used the method to detect topically applied salicylic acid. Based on the mathematical model a calibration curve was constructed that is independent of endogenous chromophore concentration. We utilized the method to localize salicylic acid in epidermis and to follow its dynamics over a period of 3 d.

Administration, Topical↗

An autoradiographic study of regional blood flow distribution in the rat kidney during ureteric obstruction--the role of vasoactive compounds.

OBJECTIVE: To determine the changes in regional renal blood flow during ureteric obstruction and to examine the role of vasoactive mediators in effecting these changes. MATERIALS AND METHODS: Renal blood flow in Sprague-Dawley rats was assessed after periods of ureteric obstruction using a quantitative autoradiographic technique based on Kety's theory of diffusion of an inert tracer (14C-iodoantipyrine). Prostaglandins, thromboxanes and renin-angiotensin were inhibited pharmacologically using diclofenac sodium and enalapril. RESULTS: Baseline blood flow to the outer cortex, inner cortex and medulla was 807, 258 and 105 mL/100 g/min, respectively. There was an increase in outer cortical blood flow after 10 min of ureteric obstruction which became significant at 30 min (P < 0.05). There was a significant decrease in inner cortical and medullary blood flow at 30 min, to 210 and 68 mL/100 g/min, respectively (P < 0.05). Diclofenac sodium abolished the increase in outer cortical blood flow. After 24 h of unilateral ureteric obstruction, outer cortical blood flow decreased to 492 mL/100 g/min; inner cortical blood flow also decreased but to a lesser extent, to 190 mL/100 g/min. Inhibition of prostaglandins, thromboxanes and the renin-angiotensin system reduced the degree of renal vasoconstriction but there was still a significant decrease in outer cortical perfusion despite the presence of these blocking agents. CONCLUSIONS: The control of the renal vasculature involves a complex interplay between a variety of vasoactive mediators. Quantitative autoradiography offers the opportunity to evaluate changes in regional renal perfusion with high resolution and will allow a greater understanding of the pathophysiology of renal diseases.

Animals↗

The bias against new innovations in health care: value uncertainty and willingness to pay.

This paper offers a model for the bias found in willingness-to-pay valuations against new treatments. For example, this bias provides an explanation for patient preferences that make it difficult for formularies to take treatments off their lists, even when newer treatments would appear to be clearly preferable. The appeal of the model, which is based on imperfect information, is that it is consistent with rational preferences and rational behavior by patients, which are necessary for standard models and methods related to decision theory, cost-effectiveness, and efficiency.

Attitude↗

Spin-label oximetry: kinetic study of cell respiration using a rapid-passage T1-sensitive electron spin resonance display.

An unusual ESR display has been developed that exhibits sensitivity to bimolecular collisions of dissolved oxygen in water with nitroxide radical spin probes at oxygen concentrations as low as 0.1 microM, requiring only 1 microliter of sample. The method involves observation of the ESR rapid-passage signal when tuned to the dispersion using a loop-gap resonator. The bimolecular collision rate determines the phase of the signal. The method has been used in a closed-chamber geometry to study respiration of asynchronous populations of Chinese hamster ovary (CHO) cells. An integral of the Michaelis-Menten equation permits direct comparison with experiment and is shown to be incompatible with the data. The theory of diffusion limitation also is developed and shown to be inconsistent with experiment. The average oxygen concentration is found to decrease as Vmaxt, where t is the time after sealing the chamber, to a critical oxygen concentration of 5.2 microM. Below 5.2 microM, the concentration can be fitted to an exponential form, exp(-t/tau), where tau = 15 sec for 4000 cells per microliter. It is believed that this experimental behavior is determined by complex enzyme kinetics.

Animals↗

Intermediates can accelerate protein folding.

The effect of intermediates on the rate of protein folding is explored by applying Kramers' theory of diffusive barrier crossing in the high friction limit. Intermediates are represented as local minima in the transition barrier. We observe that very large or very small additional barriers created by the intermediates slow down the folding process. The rate of folding markedly increases, however, when the additional barriers become >1 kBT but leave the overall barrier height unchanged. This rate-enhancing effect is caused by a favorable entropic contribution to the free energy of activation, and it increases with the number of intermediates up to a limiting value. From these calculations, we conclude that optimized transition barriers should contain partially folded high energy intermediates.

Animals↗

Strengthening environmental and educational nutrition programmes in worksite cafeterias and supermarkets in The Netherlands.

The purpose of this study was to assess conditions for the adoption and continued implementation of different healthy nutrition programmes in worksite cafeterias and supermarkets, i.e. an educational programme and two environmental programmes (a food labelling programme and a food supply programme). Twenty semi-structured interviews were conducted with representatives of worksite cafeterias and supermarkets. Concepts of theories of diffusion were used as a framework for the study. Questions were formulated about the attributes of the innovation, and organizational and personal characteristics that might influence programme adoption and implementation. Results indicated that educational and environmental programmes in both worksite cafeterias and supermarkets should meet specific requirements regarding programme design, methods and materials in order to be adopted and implemented. Besides, some important implementation strategies of the educational and environmental programmes were identified. It is concluded that it seems feasible to conduct educational and environmental intervention programmes in worksite cafeterias and supermarkets, but that certain conditions for adoption and continued implementation have to be met. Based on the implications of this study, the development of an educational programme, a labelling programme and a food supply programme was completed.

Decision Making, Organizational↗