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PubMed2005

Selective visualisation of neuroepithelial bodies in vibratome slices of living lung by 4-Di-2-ASP in various animal species.

Pulmonary neuroepithelial bodies (NEBs) are extensively innervated organoid groups of neuroendocrine cells that lie in the epithelium of intrapulmonary airways. Our present understanding of the morphology of NEBs is comprehensive, but direct physiological studies have so far been challenging because the extremely diffuse distribution of NEBs makes them inaccessible in vivo and because a reliable in vitro model is lacking. Our aim has been to optimise an in vitro method based on vibratome slices of living lungs, a model that includes NEBs, the surrounding tissues and at least part of their complex innervation. This in vitro model offers satisfactory access to pulmonary NEBs, provided that they can be differentiated from other tissue elements. The model was first optimised for living rat lung slices. Neutral red staining, reported to stain rabbit NEBs, proved unsuccessful in rat slices. On the other hand, the styryl pyridinium dye, 4-(4-diethylaminostyryl)-N-methylpyridinium iodide (4-Di-2-ASP), showed brightly fluorescent cell groups, reminiscent of NEBs, in the airway epithelium of living lung slices from rat. In addition, nerve fibres innervating the NEBs were labelled. The reliable and specific labelling of pulmonary NEBs by 4-Di-2-ASP was corroborated by immunostaining for protein gene-product 9.5. Live cell imaging and propidium iodide staining further established the acceptable viability of 4-Di-2-ASP-labelled NEB cells in lung slices, even over long periods. Importantly, the in vitro model and 4-Di-2-ASP staining procedure for pulmonary NEBs appeared to be equally reproducible in mouse, hamster and rabbit lungs. Diverse immunocytochemical procedures could be applied to the lung slices providing an opportunity to combine physiological and functional morphological studies. Such an integrated approach offers additional possibilities for elucidating the function(s) of pulmonary NEBs in health and disease.

Animals↗
PubMed1999

Biopharmaceutical approaches for developing and assessing oral peptide delivery strategies and systems: in vitro permeability and in vivo oral absorption of salmon calcitonin (sCT).

PURPOSE: To evaluate a biopharmaceutical approach for selecting formulation additives and establishing the performance specifications of an oral peptide delivery system using sCT as a model peptide. METHODS: The effect of formulation additives on sCT effective permeability and transepithelial electrical resistance (TEER) was evaluated in side-by-side diffusion chambers using rat intestinal segments. Baseline regional oral absorption of sCT was evaluated in an Intestinal and Vascular Access Port (IVAP) dog model by administration directly into the duodenum, ileum, and colon by means of surgically implanted, chronic catheters. The effect of varying the input rate and volume of the administered solution on the extent of sCT absorption was also evaluated. Citric acid (CA) was utilized in all studies to cause a transient reduction in local pH. In vitro samples and plasma samples were analyzed by radioimmunoassay (RIA). Two oral delivery systems were prepared based on the results of the in vitro and IVAP studies, and evaluated in normal dogs. RESULTS: Maximal permeability enhancement of sCT was observed using taurodeoxycholate (TDC) or lauroyl carnitine (LC) in vitro. Ileal absorption of sCT was higher than in other regions of the intestine. Low volume and bolus input of solution formulations was selected as the optimal condition for the IVAP studies since larger volumes or slower input rates resulted in significantly lower sCT bioavailability (BA). Much lower BA of sCT was observed when CA was not used in the formulation. The absolute oral bioavailability (mean+/-SD) in dogs for the control (sCT + CA) and two proprietary sCT delivery systems was 0.30%+/-0.05%, 1.10+/-0.18%, and 1.31+/-0.56%, respectively. CONCLUSIONS: These studies demonstrate the utility of in vitro evaluation and controlled in vivo studies for developing oral peptide delivery strategies. Formulation additives were selected, the optimal intestinal region for delivery identified, and the optimal release kinetics of additives and actives from the delivery system were characterized. These methods were successfully used for devising delivery strategies and fabricating and evaluating oral sCT delivery systems in animals. Based on these studies, sCT delivery systems have been fabricated and tested in humans with favorable results.

Administration, Oral↗
PubMed2005

Quantitative phase-field modeling of two-phase growth.

A phase-field model that allows for quantitative simulations of low-speed eutectic and peritectic solidification under typical experimental conditions is developed. Its cornerstone is a smooth free-energy functional, specifically designed so that the stable solutions that connect any two phases are completely free of the third phase. For the simplest choice for this functional, the equations of motion for each of the two solid-liquid interfaces can be mapped to the standard phase-field model of single-phase solidification with its quartic double-well potential. By applying the thin-interface asymptotics and by extending the antitrapping current previously developed for this model, all spurious corrections to the dynamics of the solid-liquid interfaces linear in the interface thickness W can be eliminated. This means that, for small enough values of W, simulation results become independent of it. As a consequence, accurate results can be obtained using values of W much larger than the physical interface thickness, which yields a tremendous gain in computational power and makes simulations for realistic experimental parameters feasible. Convergence of the simulation outcome with decreasing W is explicitly demonstrated. Furthermore, the results are compared to a boundary-integral formulation of the corresponding free-boundary problem. Excellent agreement is found, except in the immediate vicinity of bifurcation points, a very sensitive situation where noticeable differences arise. These differences reveal that, in contrast to the standard assumptions of the free-boundary problem, out of equilibrium the diffuse trijunction region of the phase-field model can (i) slightly deviate from Young's law for the contact angles, and (ii) advance in a direction that forms a finite angle with the solid-solid interface at each instant. While the deviation (i) extrapolates to zero in the limit of vanishing interface thickness, the small angle in (ii) remains roughly constant, which indicates that it might be a genuine physical effect, present even for an atomic-scale interface thickness.

Journal Article↗
PubMed1994

Differential control of band 3 lateral and rotational mobility in intact red cells.

Measurements of integral membrane protein lateral mobility and rotational mobility have been separately used to investigate dynamic protein--protein and protein-lipid interactions that underlie plasma membrane structure and function. In model bilayer membranes, the mobilities of reconstituted proteins depend on the size of the diffusing molecule and the viscosity of the lipid bilayer. There are no direct tests, however, of the relationship between mechanisms that control protein lateral mobility and rotational mobility in intact biological membranes. We have measured the lateral and rotational mobility of band 3 in spectrin-deficient red blood cells from patients with hereditary spherocytosis and hereditary pyropoikilocytosis. Our data suggest that band 3 lateral mobility is regulated by the spectrin content of the red cell membrane. In contrast, band 3 rotational mobility is unaffected by changes in spectrin content. Band 3 lateral mobility and rotational mobility must therefore be controlled by different molecular mechanisms.

Anion Exchange Protein 1, Erythrocyte↗
PubMed2004

Awakening consumer stewardship of health benefits: prevalence and differentiation of new health plan models.

CONTEXT: Despite widespread publicity of consumer-directed health plans, little is known about their prevalence and the extent to which their designs adequately reflect and support consumerism. OBJECTIVE: We examined three types of consumer-directed health plans: health reimbursement accounts (HRAs), premium-tiered, and point-of-care tiered benefit plans. We sought to measure the extent to which these plans had diffused, as well as to provide a critical look at the ways in which these plans support consumerism. Consumerism in this context refers to efforts to enable informed consumer choice and consumers' involvement in managing their health. We also wished to determine whether mainstream health plans-health maintenance organization (HMO), point of service (POS), and preferred provider organization (PPO) models-were being influenced by consumerism. DATA SOURCES/STUDY SETTING: Our study uses national survey data collected by Mercer Human Resource Consulting from 680 national and regional commercial health benefit plans on HMO, PPO, POS, and consumer-directed products. STUDY DESIGN: We defined consumer-directed products as health benefit plans that provided (1) consumer incentives to select more economical health care options, including self-care and no care, and (2) information and support to inform such selections. We asked health plans that offered consumer-directed products about 2003 enrollment, basic design features, and the availability of decision support. We also asked mainstream health plans about their activities that supported consumerism (e.g., proactive outreach to inform or influence enrollee behavior, such as self-management or preventive care, reminders sent to patients with identified medical conditions.) DATA COLLECTION/EXTRACTION METHODS: We analyzed survey responses for all four product lines in order to identify those plans that offer health reimbursement accounts (HRAs), premium-tiered, or point-of-care tiered models as well as efforts of mainstream health plans to engage informed consumer decision making. PRINCIPAL FINDINGS: The majority of enrollees in consumer-directed health plans are in tiered models (primarily point-of-care tiered networks) rather than HRAs. Tiers are predominantly determined based on both cost and quality criteria. Enrollment in HRAs has grown substantially, in part because of the entry of mainstream managed care plans into the consumer-directed market. Health reimbursement accounts, tiered networks, and traditional managed care plans vary in their capacity to support consumers in managing their health risks and selection of provider and treatment options, with HRAs providing the most and mainstream plans the least. CONCLUSIONS: While enrollment in consumer-directed health plans continues to grow steadily, it remains a tiny fraction of all employer-sponsored coverage. Decision support in these plans, a critical link to help consumers make more informed choices, is also still limited. This lack may be of concern in light of the fact that only a minority of such plans report that they monitor claims to protect against underuse. Tiered benefit models appear to be more readily accepted by the market than HRAs. If they are to succeed in optimizing consumers' utility from health benefit spending, careful attention needs to be paid to how well these models inform consumers about the consequences of their selections.

Consumer Behavior↗
PubMedDate not supplied

Contribution of astrocytes to synaptic transmission in the rat supraoptic nucleus.

Astrocytes, besides supporting metabolic and scaffolding functions, play a prominent role in the modulation of neuronal communication. In particular, they are responsible for clearing synaptically-released glutamate via highly specific transporters located on their plasma membrane. Since glutamate is the main excitatory neurotransmitter in the central nervous system (CNS), astrocytes are likely to play a central role in the regulation of synaptic processing and overall cellular excitability. We recently investigated the influence of astrocytes on glutamatergic and GABAergic transmission in the rat supraoptic nucleus (SON) of the hypothalamus. This nucleus is part of the hypothalamus-neurohypophysial system (HNS), which constitutes a conspicuous example of activity-dependent neuroglial plasticity, in which certains physiological conditions, such as parturition, lactation, and dehydration are accompanied by a structural remodeling of the neurones, their synaptic inputs and their surrounding glia. The use of pharmacological inhibitors of glutamate transporters on this model, in which a physiological change in the astrocyte environment occurs, has brought new insights on the contribution of astrocytes to both excitatory and inhibitory neurotransmissions. The astrocytic environment of neurons appears to control glutamate uptake and diffusion in the extracellular space. This has direct repercussions on the tonic level of activation of presynaptic glutamate receptors and, as a consequence, on the release of neurotransmitter. This short review summarizes data obtained so far, which clearly support the view that astrocytes are indeed a third partner in synaptic transmission, and which show that the supraoptic nucleus represents a remarkable model to study dynamic physiological interactions between astrocytes and neurons.

Animals↗
PubMed2003

Glycerol conductance and physical asymmetry of the Escherichia coli glycerol facilitator GlpF.

The aquaglyceroporin GlpF is a transmembrane channel of Escherichia coli that facilitates the uptake of glycerol by the cell. Its high glycerol uptake rate is crucial for the cell to survive in very low glycerol concentrations. Although GlpF allows both influx and outflux of glycerol, its structure, similar to the structure of maltoporin, exhibits a significant degree of asymmetry. The potential of mean force characterizing glycerol in the channel shows a corresponding asymmetry with an attractive vestibule only at the periplasmic side. In this study, we analyze the potential of mean force, showing that a simplified six-step model captures the kinetics and yields a glycerol conduction rate that agrees well with observation. The vestibule improves the conduction rate by 40% and 75% at 10- micro M and 10-mM periplasmic glycerol concentrations, respectively. In addition, neither the conduction rate nor the conduction probability for a single glycerol (efficiency) depends on the orientation of GlpF. GlpF appears to conduct equally well in both directions under physiological conditions.

Aquaporins↗
PubMed2002

Y genetic data support the Neolithic demic diffusion model.

There still is no general agreement on the origins of the European gene pool, even though Europe has been more thoroughly investigated than any other continent. In particular, there is continuing controversy about the relative contributions of European Palaeolithic hunter-gatherers and of migrant Near Eastern Neolithic farmers, who brought agriculture to Europe. Here, we apply a statistical framework that we have developed to obtain direct estimates of the contribution of these two groups at the time they met. We analyze a large dataset of 22 binary markers from the non-recombining region of the Y chromosome (NRY), by using a genealogical likelihood-based approach. The results reveal a significantly larger genetic contribution from Neolithic farmers than did previous indirect approaches based on the distribution of haplotypes selected by using post hoc criteria. We detect a significant decrease in admixture across the entire range between the Near East and Western Europe. We also argue that local hunter-gatherers contributed less than 30% in the original settlements. This finding leads us to reject a predominantly cultural transmission of agriculture. Instead, we argue that the demic diffusion model introduced by Ammerman and Cavalli-Sforza [Ammerman, A. J. & Cavalli-Sforza, L. L. (1984) The Neolithic Transition and the Genetics of Populations in Europe (Princeton Univ. Press, Princeton)] captures the major features of this dramatic episode in European prehistory.

Animals↗
PubMed1994

An MRI study of drying in granular beds of nonporous particles.

MRI is used to study the role of capillary and gravitational forces in controlling mass transport of water during isothermal drying of granular beds of nonporous particles. A new model is presented that shows how capillary and gravitational forces relate to Fickian diffusion driven by a chemical potential gradient. In granular beds, where capillary and gravitational forces dominate, the image profiles give direct information on the dependence of the degree of saturation on capillary suction pressure. The effects of changing particle size and surface tension on the profiles is investigated quantitatively, and it is shown that high capillary pressures create anomalies in the drying profiles.

Algorithms↗
PubMed2006

From ultraslow to fast lithium diffusion in the 2D ion conductor Li0.7TiS2 probed directly by stimulated-echo NMR and nuclear magnetic relaxation.

7Li stimulated-echo NMR and classical relaxation NMR techniques are jointly used for the first time for a comprehensive investigation of Li diffusion in layer-structured Li0.7TiS2. One single 2D Li diffusion process was probed over a dynamic range of almost 10 orders of magnitude. So far, this is the largest dynamic range being measured by 7Li NMR spectroscopy directly, i.e., without the help of a specific theoretical model. The jump rates obey a strict Arrhenius law, determined by an activation energy of 0.41(1) eV and a preexponential factor of 6.3(1)x10(12) s-1, and range between 1x10(-1) s-1 and 7.8x10(8) s-1 (148-510 K). Ultraslow Li jumps in the kHz to sub-Hz range were measured directly by recording 7Li spin-alignment correlation functions. The temperature and, in particular, the frequency dependence of the relaxation rates fully agree with results expected for 2D diffusion.

Journal Article↗
PubMed2002

Photon migration in turbid media using a cumulant approximation to radiative transfer.

A photon transport model for light migration in turbid media based on a cumulant approximation to radiative transfer is presented for image reconstruction inside an infinite medium or a bounded medium with a planar geometry. This model treats weak inhomogeneities through a Born approximation of the Boltzmann radiative transfer equation and uses the second-order cumulant solution of photon density to the Boltzmann equation as the Green's function for the uniform background. It provides the correct behavior of photon migration at early times and reduces at long times to the center-moved diffusion approximation. At early times, it agrees much better with the result from the Monte Carlo simulation than the diffusion approximation. Both approximations agree well with the Monte Carlo simulation at later times. The weight function for image reconstruction under this proposed model is shown to have a strong dependence at both early and later times on absorption and/or scattering inhomogeneities located in the propagation direction of and close to the source, or in the field of view of and close to the detector. This effect originates from the initial ballistic motion of incident photons, which is substantially underestimated by the diffusion approximation.

Journal Article↗
PubMed1982

Effects of gravity and branching on longitudinal gas mixing in glass tube models.

We investigated the effects of gravity and branching on gas mixing in glass tube models. The mixed gas (5% He and 5% SF6) was made to flow through a straight tube and tubes with bifurcated branches, and the effective axial diffusion coefficient (Deff) was measured. The direction of the branches was varied from upward to downward by 90% turns, and the flow distribution to each branch was separately controlled. In the case of a straight horiontal tube, the flow velocity dependency of the Deff of He and SF6 was observed as we expected from Aris' equation. In the case of glass tubes with branches, the Deff of SF6 was greater in the downward-directed branches than it was in the upward-directed branches when gas mixing occurred at the front of the gas mixture; however, when gas mixing occurred at the tail, the opposite effects were observed. These characteristics were more marked at slower flow rates and when the flow to each branch was different. Our findings suggest that gravity has an effect on gas mixing in glass tube airway models, especially at a low flow rate and uneven flow distribution.

Gravitation↗
PubMed1985

Quantitative vitreous fluorophotometry applying a mathematical model of the eye.

A slit-lamp fluorophotometric method is presented that permits calculation of a blood-retinal barrier permeability to fluorescein (P) and a diffusion coefficient for fluorescein in the vitreous body (D). The calculations are performed by relating the time course of the free--not protein bound--fluorescein concentration in the bloodstream with the fluorescein concentration profile in the vitreous body. The combination is performed automatically on a computer by applying a simplified mathematical model of the eye. P refers to the area of the barrier of the model eye. In a group of six normal persons, the mean P was (1.1 +/- 0.4) X 10(-7) cm/sec (mean +/- SD), while in six diabetic patients with background retinopathy and macular edema the mean P was (7.1 +/- 3.8 ) X 10(-7) cm/sec. The mean D was (7.4 +/- 3.4) X 10(-6) cm2/sec in the normal group and (9.6 +/- 2.0) X 10(-6) cm2/sec in diabetic patients, corresponding as a first approximation to free diffusion in water. Model calculations show that knowing the fluorescein concentration in the bloodstream is considerably significant for the calculation of the permeability, contributing factors up to 50%. For the low-permeation situation, subtraction of the preinjection scan contributes a factor of 50% for both permeability and diffusion coefficient. The exact placement in the vitreous body of the concentration profile, by applying a formalism that transforms slit-lamp movement to intraocular distance, contributes a factor of 20% on the diffusion coefficient. The permeability obtained with the model can be calculated as the ratio between area of vitreous and plasma fluorescein concentration curves within 20%. Active transport of fluorescein across the blood-retinal barrier in the direction of vitreous to blood does not seem to be significant within the first 2 hr after fluorescein injection.

Blood Physiological Phenomena↗
PubMed2000

Phase space structure and anomalous diffusion in a rotational fluid experiment.

The transport of passive scalars is considered in a model of rotating annulus experiments. The system has a chain of vortices and a jet, separated by a stochastic layer. For special values of the control parameters, the boundary of the stochastic layer can contain self-similar structures of islands with regular trajectories. Two such values are identified, with the structure being on the jet boundary and on the vortex boundary, respectively. The transport properties for both cases were studied by high-precision direct numerical integration of the equations of motion. The presence of such structures is found to significantly affect the statistical properties of the trajectories and the transport exponent. The results of the computations are compared with various theoretical models of anomalous diffusion. The particle behavior was found to depend significantly on the time scale, with different theories being applicable on different time intervals. Some regimes do not match any of the existing theories. (c) 2000 American Institute of Physics.

Journal Article↗
PubMed1993

Brownian dynamics simulations of molecular recognition in an antibody-antigen system.

The crystal structure for an antibody-antigen system, that of the anti-hen egg lysozyme monoclonal antibody HyHEL-5 complexed to lysozyme, is used as the starting point for computer simulations of diffusional encounters between the two proteins. The investigation consists of two parts: first, the linearized Poisson-Boltzmann equation is solved to determine the long-range electrostatic forces between antibody and antigen, and then, the relative motion as influenced by these forces is modeled within Brownian motion theory. The effects of various point mutations on the calculated reaction rate are considered. It is found that charged residues close to the binding site exert the greatest influence in steering the proteins into a configuration favorable for their binding, while more distant mutations are qualitatively described by the Smoluchowski model for the mutual diffusion of two uniformly charged spheres. The antibody residues involved in forming salt links with the lysozyme, Glu-H35 and Glu-H50, appear to be particularly important in electrostatic steering, as neutralization of both of them yields reaction rates that are two to three orders of magnitude below those of wild-type rates. The relative rates obtained from the simulations can be tested through kinetic measurements on mutant protein complexes. Kinetically efficient partners can also be designed and constructed through directed mutagenesis.

Amino Acid Sequence↗
PubMed2001

Lab-on-a-chip sample preparation using laminar fluid diffusion interfaces--computational fluid dynamics model results and fluidic verification experiments.

Microfluidic structures for the generation of laminar fluid diffusion interfaces (LFDIs) for sample preparation and analysis are discussed. Experimental data and the results of fluid modeling are shown. LFDIs are generated when two or more streams flow in parallel in a single microfluidic structure without any mixing of the fluids other than by diffusion of particles across the diffusion interface. It has been shown that such structures can be used for diffusion-based separation and detection applications. The method has been applied to DNA desalting, the extraction of small proteins from whole blood samples, and the detection of various constituents in whole blood, among other examples. In this paper the design and manufacture of self-contained microfluidic cartridges for the extraction of small molecules from a mixture of small and large molecules by diffusion is demonstrated. The cards are operated without any external instrumentation, and use hydrostatic pressure as the driving force. The performance of the cartridges is illustrated by separating fluorescein from a mixture of fluorescein and dextran of molecular weight 2 x 10(6). In a single pass, 98.6% of dextran was retained in the product whereas 43.1% of fluorescein was removed. The method is adjustable for different separation requirements, and computational fluid dynamics (CFD) models are shown that demonstrate the tuning of various microfluidic parameters to optimize separation performance. Other applications of LFDIs for establishment of stable concentration gradients, and the exposure of chemical constituents or biological particles to these concentration gradients are shown qualitatively. Microfluidic chips have been designed for high-throughput screening applications that enable the uniform and controlled exposure of cells to lysing agents, thus enabling the differentiation of cells by their sensitivity to specific agents in an on-chip cytometer coupled directly to the lysing structure.

Chemistry Techniques, Analytical↗
PubMed2006

Time course of acute phase in mouse spinal cord injury monitored by ex vivo quantitative MRI.

During the acute phase of spinal cord injury (SCI), major alterations of white and grey matter are a key issue, which determine the neurological outcome. The present study with ex vivo quantitative high-field magnetic resonance microimaging (MRI) was intended in order to identify sensitive parameters of tissue disruption in a well-controlled mouse model of ischemic SCI. MR imaging evidenced changes as early as the second hour after the lesion in the dorsal horns, which appear swollen. After 4 h, alterations of the white matter of dorsal and lateral funiculi were reflected by a progressive loss of white/grey matter contrast with further ventral extension by the 24th hour. Diffusion tensor imaging and multi-exponential T2 measurements permitted to quantify these physicochemical, time-related, alterations during the 24-h period. This characterization of spatial and temporal evolution of SCI will contribute to better define both the most appropriate targets for future therapies and more accurate therapeutic windows. Upcoming directions include the use of these parameters on in vivo animal models and their application to clinics. Indeed, magnetic resonance techniques appear now as a major non-invasive translation tool in CNS pathologies based on the development of more appropriate pre-clinical models.

Animals↗
PubMed1996

Laser-excited atomic fluorescence spectrometry in a pressure-controlled electrothermal atomizer.

A theoretical model was developed to describe the loss of analyte atoms in graphite furnaces during atomization. The model was based on two functions, one that described the supply of analyte by vaporization, and another that described the removal of the analyte by diffusion. Variation in working pressure was shown to affect the competition between these two processes. Optimal atomization efficiency was predicted to occur at a pressure where the supply of the analyte was maximized, and gas phase interactions between the analyte and matrix were minimized. Experiments to test the model included the direct determination of phosphorus and tellurium in nickel alloys and of cobalt in glass. In all cases, reduction in working pressure from atmospheric pressure to 7 Pa decreased sensitivity by 2 orders of magnitude, but improved temporal peak shape. For the atomization of tellurium directly from a solid nickel alloy, and the atomization of cobalt from an aqueous solution, no change in sensitivity was observed as the working pressure was reduced from atmospheric pressure to approximately 70 kPa. If a reduction in working pressure affected only the diffusion of the analyte, poorer sensitivity should have been obtained. Only a commensurate increase in analyte vaporization could account for maintained sensitivity at lower working pressures. Overall, analyte vaporization was not dramatically improved at reduced working pressures, and maximum atomization efficiency was found to occur near atmospheric pressure.

Fluorescence↗