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Social science research on medical technology: utility and limitations.

Policies could be better devised and better implemented if greater use were made of the social sciences. However, the social sciences have quite often not produced knowledge adequate to permit resolution of pressing social problems. An example of both of these statements is found in the area of policies toward medical technology. Medical technology has become a major public policy issue in most industrialized countries, primarily science research has led to general formulations as to how medical technology is developed and diffused. In addition, specific studies of medical technology have identified factors that impede of facilitate the development and diffusion of medical technology. However, few studies have been done of public policy mechanisms. Effects of formal policies have not been evaluated, and organizations developed to implement policies toward medical technologies have not been studied. Programs cannot be improved without evaluation, nor can successful approaches be diffused more widely. The development and implementation of public policy toward medical technology would profit if social scientists were to become involved in its examination.

Diffusion of Innovation↗

Quantification of supplemental enzymes in animal feedingstuffs by radial enzyme diffusion.

Methods are described which facilitate quantification of supplemental cellulase, protease and alpha-amylase when added to animal feedingstuffs at normal industrial inclusion levels. The methods entail extraction of the enzymes from the feedingstuffs by agitation in buffer followed by quantification of extract activity using radial diffusion techniques. A linear relationship between the diameter of the zone of hydrolyzed substrate and the log of the enzyme activity applied is observed over a broad activity range. Assay of a feedingstuff supplemented with 1 kg t(-1) cellulase, protease and alpha-amylase yielded net supplemental activity recoveries of 104+/-11.7%, 91.3+/-6.74% and 126+/-29.5%, respectively. A similar assay method did not prove sufficiently sensitive to facilitate detection of xylanase at typical in-feed inclusion levels. The levels of endogenous cellulase, protease and alpha-amylase activity detected in the unsupplemented feedingstuffs were equivalent to 6.4+/-0.47%, 6.6+/-0.82% and 29.0+/-14.1%, respectively, of a 1 kg t(-1) supplement. The methods are technically straightforward and will facilitate determination of enzyme stabilities during processes such as high-temperature pelleting of feedingstuffs, as well as allowing more rigorous quality control related to enzyme-supplemented animal feedingstuffs.

Animal Feed↗

Development of a quantitative tool for measuring changes in the coefficient of conductivity of plasmodesmata induced by developmental, biotic, and abiotic signals.

The regulation of intercellular and interorgan communication is pivotal for cell fate decisions in plant development and probably plays a significant role in the systemic regulation of gene expression and in defense reactions against pathogens or other biotic and abiotic environmental factors. In plants, symplasmic cell-to-cell communication is provided by plasmodesmata (Pd), coaxial membranous tunnels that span cell walls interconnecting adjacent cytoplasms. Macromolecules, proteins, and RNA may be transported through Pd by passive diffusion or by a facilitated mechanism. A quantitative tool was developed to measure the coefficient of conductivity, C(Pd), for diffusion-driven transport via Pd and to assess changes in the coefficient induced by developmental, biotic and abiotic signals. (GFP)C(Pd), the coefficient of conductivity for cell-to-cell spread of green-fluorescent protein (GFP), a protein with a Stokes radius of 2.82 nm, was determined in epidermal cells of sink and source leaves of wild-type and transgenic Nicotiana benthamiana plants expressing the movement protein of tobacco mosaic virus (MP(TMV)) incubated both in dark and light and at 16 and 25 degrees C. Under all conditions, Pd in source leaves conducted macromolecules, with (GFP)C(Pd)sink>(GFP)C(Pd)source. Light down-regulated (GFP)C(Pd) (all conditions); down-regulation was stronger for sink cells. The effect of MP(TMV) on (GFP)C(Pd) between epidermal cells was dependent on temperature and leaf development; at 16 degrees C, MP(TMV) down-regulated (GFP)C(Pd) only in source leaves, while at 25 degrees C, MP(TMV) had no significant effect. This quantitative tool should be useful for investigating differences in Pd conductivity that are induced by mutations or silencing.

Biological Transport, Active↗

Dentin permeation: comparison of diffusion with filtration.

A comparison was made between the rate of iodide permeation of dentin by diffusion and by filtration. Before acid etching, filtration only doubled the rate of iodide permeation relative to that obtained by diffusion. After acid etching, filtration produced a 32-fold increase in permeation. Acid etching, by removing occluding debris, facilitates filtration more than diffusion.

Acid Etching, Dental↗

Cross-linked high amylose starch derivatives for drug release III. Diffusion properties.

Acetate (Ac-), aminoethyl (AE-) and carboxymethyl (CM-) derivatives of cross-linked high amylose starch (HASCL-6) were previously shown to control the release of drugs over 20 h from highly loaded (up to 60% drug) monolithic tablets. This report presents a diffusion analysis, aimed to facilitate a better understanding of the mechanisms involved in the control of the drug release from these hydrogels. The diffusion was found to depend on the molecular weight of the diffusant, whereas the partition coefficient depended on the affinities of the diffusant for the polymers and for the dissolution media via attractive or repulsive ionic interactions. The diffusion was also affected by the swelling of CM-HASCL-6, which, unexpectedly, increased with the decrease of the ionic strength. This diffusion analysis completes the swelling studies of HASCL-6 and of its derivatives, allowing the prediction of release kinetics of various active agents.

Acetaminophen↗

Extracellular space diffusion in central nervous system: anisotropic diffusion measured by elliptical surface photobleaching.

Diffusion in the extracellular space (ECS) is crucial for normal central nervous system physiology. The determinants of ECS diffusion include viscous interactions with extracellular matrix/plasma membranes ("viscosity") and ECS geometry ("tortuosity"). To resolve viscosity versus tortuosity effects, we measured direction-dependent (anisotropic) diffusion in ECS in mouse spinal cord by photobleaching using an elliptical spot produced by a cylindrical lens in the excitation path. Anisotropic diffusion slowed fluorescence recovery when the long axis of the ellipse was parallel versus perpendicular to the direction of faster diffusion. A mathematical model was constructed to deduce diffusion coefficients (D(x), D(y)) from fluorescence recovery measured for parallel and perpendicular orientations of the long axis of the ellipse. Elliptical spot photobleaching was validated by photobleaching aqueous-phase fluorophores on a diffraction grating, where diffusion is one-dimensional. Measurement of the diffusion of 70 kDa FITC-dextran in spinal cord in living mice indicated that viscosity slows diffusion by approximately 1.8-fold compared with its diffusion in solution. ECS geometry hinders diffusion across (but not along) axonal fibers in spinal cord further by approximately fivefold. In cerebral cortex, however, approximately 50% of the hindrance to ECS diffusion comes from viscosity and approximately 50% from tortuosity. We suggest that the extracellular matrix might have evolved to facilitate rather than hinder diffusion even for large molecules.

Animals↗

Temporal diffusion spectroscopy: theory and implementation in restricted systems using oscillating gradients.

The theory of temporal diffusion spectra is reviewed. In contrast to q-space spectroscopy, which measures the displacement spectrum of spins in a spatial domain, the spectral density of the velocity correlation function (VCF) in the temporal domain is considered. It is demonstrated that casting diffusion in this domain may facilitate measurements of microscopic geometry and the decomposition of the diffusion signal into components due to disperse flow and restricted diffusion. An oscillating gradient (OG) method of diffusion spectroscopy was developed and implemented. Microscopic pore sizes, surface-to-volume ratios (S/Vs), and diffusion path tortuosities were extracted from model systems using this method. Cases are discussed in which this type of experiment may allow the characterization of pore geometry when spatial domain experiments fail. OGs may be combined with imaging sequences to map complex patterns of diffusion and flow. Moreover, scalar apparent diffusion coefficient (ADC) measurements in complex biological systems may be subtly dependent on specific pulse sequence parameters. Thus, scalar ADC measurements using gradient pulses with different frequency spectra may give different results. Conversely, the frequency dependence of motion-sensitizing gradient pulses may be exploited to deduce the origin of ADC changes.

Diffusion Magnetic Resonance Imaging↗

Diffusion tensor MRI of the human kidney.

This study characterizes the diffusion anisotropy of the human kidney using a diffusion-weighted, single-shot echo planar imaging (EPI) sequence in order to access the full apparent diffusion tensor (ADT) within one breathhold. The fractional anisotropy (FA) of the cortex and the medulla were found to be 0.22 +/- 0.12 and 0.39 +/- 0.11, respectively (N = 10), which emphasizes the need for rotationally invariant diffusion measurements for clinical applications. Additional limitations for clinical diffusion imaging on the kidney are the strong susceptibility variations within the abdomen that restrict the use of imaging techniques employing long echo trains, and the severe motion sensitivity that limits the available imaging time to one breath-hold. To overcome these problems an isotropic, diffusion-weighted, segmented EPI protocol that facilitates the acquisition of high-resolution diffusion-weighted images within a single breath-hold was implemented. Using this method, the apparent diffusion coefficient (ADC) of the cortex and medulla were found to be 2.89 +/- 0.28. 10(-9) m2/s and 2.18 +/- 0.36. 10(-9) m2/s (N = 10).

Anisotropy↗

Time- and depth-dependent changes in crosslinking and oxidation of shelf-aged polyethylene acetabular liners.

Since crosslinking and oxidation of ultrahigh-molecular-weight polyethylene (UHMWPE) have important roles in determining the wear resistance of UHMWPE total joint components, the time and depth dependence of crosslinking and oxidation of new shelf-aged (2-11 years), ready-to-implant acetabular liners were studied by using solvent extraction and Fourier transform infrared spectroscopy. The ultrastructure of these materials also was examined by using low-voltage scanning electron microscopy in an oil-free vacuum. Oxidation levels increased with time and with depth (p < 0.0001) from the surface of the older liners to a maximum value at about 1-2 mm below the surface, then decreased. They were minimal at the midsection of the liners. The crosslinking of these liners decreased with time and depth (p < 0.0001) and was inversely proportional to the level of oxidation. High and depth-dependent oxidation levels were observed in all older liners made from GUR 415 and 412 resins but were distinctly absent from a comparably aged (i.e., 9 years) liner made from 1900 CM-resin. Some liners showed varying degrees of inhomogeneous and discontinuous morphologic ultrastructure in addition to varying amounts of porosity while others had a more homogeneous ultrastructure. Oxidation and crosslinking of polyethylene are time- and depth-dependent processes that are mutually competitive. We suggest that resin choice and perhaps consolidation-related variables lead to differences in polyethylene's ultrastructure. These ultrastructural differences in polyethylene's inhomogeneities, that is, the type (interconnected or closed-cell) or extent may affect the oxidation resistance of polyethylene. While oxygen diffusion to free radicals in polyethylene already is known to explain some of these time- and depth-dependent effects, perhaps such ultrastructural variations also may facilitate or retard oxygen diffusion in this material. Resin-based ultrastructural variability partially may explain the variability in the clinical performance of polyethylene total joint implant components. Thus resin choice or processing modifications related to polyethylene's ultrastructure may increase its oxidation resistance and ultimately improve the clinical wear performance of polyethylene total joint orthopedic implants.

Acetabulum↗

Evaluating colloidal phosphorus delivery to surface waters from diffuse agricultural sources.

Colloid-facilitated phosphorus (P) delivery from agricultural soils in different hydrological pathways was investigated using a series of laboratory and field experiments. A soil colloidal P test was developed that yields information on the propensity of different soils to release P attached to soil colloids. The relationship between turbidity of soil extracts and total phosphorus (TP) was significant (r2 = 0.996, p < 0.001) across a range of agricultural soils, and a strong positive relationship (r2 = 0.86, p < 0.001) was found between "colloidal P" (H2O-CaCl2 extracts) and turbidity. Linear regression of the proportion of fine clay (<2 microm) for each soil type evaluated against the (H2O-CaCl2) colloidal P fraction gave a weak but positive relationship (r2 = 0.38, p = 0.082). The relative contribution of different particle-size fractions in transporting P in agricultural runoff from grassland soils was evaluated using a randomized plot experiment. A significant difference (p = 0.05) in both TP and reactive phosphorus (RP) in subsurface flow was recorded for different particle-size fractions, with most TP transferred either in association with the 2-microm fraction or with the 0.001-microm or smaller fractions. Total P concentrations in runoff were higher from plots receiving P amendments compared with the zero-P plots; however, these differences were only significant for the >0.45-microm particle-size fractions (p = 0.05), and may be evidence of surface applications of organic and inorganic fertilizers being transferred through the soil either as intact organic colloids or attached to mineral particles. Our results highlight the potential for drainage water to mobilize colloids and associated P during rainfall events.

Agriculture↗

Intestinal absorption of bile acids in the rabbit: different transport rates in jejunum and ileum.

BACKGROUND & AIMS: A direct comparison of jejunal and ileal absorption rates of bile acids has not been reported. The aim of this study was to compare the relative transport rates of different bile acids in the jejunum and ileum. METHODS: Jejunal and ileal rabbit intestinal segments were separately perfused with bile acid solutions, and dose-response curves were obtained for taurocholate, ursodeoxycholate, chenodeoxycholate, deoxycholate, and their glycoconjugates. Membrane fluidity and bile acid transport were assessed in brush border membrane vesicles. RESULTS: Taurocholate showed active transport in the ileum and no transport in the jejunum. Unconjugated bile acids showed passive diffusion in the two tracts, whereas glycoconjugated bile acids showed both components of transport in the ileum and passive diffusion in the jejunum (lower in the latter). A higher membrane fluidity and lower cholesterol-to-phospholipid ratio were found in the jejunum. Ursodeoxycholate reduced bile acid uptake into membrane vesicles from both ileum and jejunum. CONCLUSIONS: Active transport is limited to the ileum. Passive diffusion is higher through a less fluid membrane with a higher cholesterol-to-phospholipid ratio in the ileum than in the jejunum. Ursodeoxycholate inhibition may be at the level of a facilitated, sodium-independent diffusion in the jejunum.

Animals↗

Cytoplasmic transport of fatty acids in rat enterocytes: role of binding to fatty acid-binding protein.

The intracellular movement of fatty acids is thought to be facilitated through codiffusion with fatty acid-binding protein (FABP). This facilitation may occur by decreasing binding to immobile membranes, leading to faster cytoplasmic diffusion. The aims of this study were to measure the intracellular transport of 12-N-methyl-(7-nitrobenzo-2-oxa-1,3-diazol)aminostearate (NBD-stearate) in villus rat enterocytes and to determine 1) the mechanism of its cytoplasmic transport and 2) if its transport rate correlated with the known variation of FABP binding capacity along the length of the small intestine. Two-dimensional laser photobleaching was used to measure the movement of a fluorescent fatty acid NBD-stearate in enterocytes isolated from different segments of rat intestine. The fraction of NBD-stearate found in the cytostol of enterocytes was determined by differential centrifugation. Cytoplasmic transport of NBD-stearate occurred solely by diffusion and not by convection. Diffusion was homogeneous (nondirectional), consistent with isotropic diffusion. The diffusion rate varied with location along the intestine, correlating with the local FABP concentration and measured cytosolic binding. We conclude that cytoplasmic proteins like FABP promote the intracellular transport of fatty acids by enhancing their diffusive flux. We suggest that facilitation is not specific for a particular cell type but occurs in a variety of cells that transport fatty acids and may contain different types of FABP.

4-Chloro-7-nitrobenzofurazan↗

Performance assessment model development and analysis of radionuclide transport in the unsaturated zone, Yucca Mountain, Nevada.

This paper describes the development and use of a particle-tracking model to perform radionuclide-transport simulations in the unsaturated zone at Yucca Mountain, Nevada. The goal of the effort was to produce a computational model that can be coupled to the project's calibrated 3D site-scale flow model so that the results of that effort could be incorporated directly into the Total System Performance Assessment (TSPA) analyses. The transport model simulates multiple species (typically 20 or more) with complex time-varying and spatially varying releases from the potential repository. Water-table rise, climate-change scenarios, and decay chains are additional features of the model. A cell-based particle-tracking method was employed that includes a dual-permeability formulation, advection, longitudinal dispersion, matrix diffusion, and colloid-facilitated transport. This paper examines the transport behavior of several key radionuclides through the unsaturated zone using the calibrated 3D unsaturated flow fields. Computational results illustrate the relative importance of fracture flow, matrix diffusion, and lateral diversion on the distribution of travel times from the simulated repository to the water table for various climatic conditions. Results also indicate rapid transport through fractures for a portion of the released mass. Further refinement of the model will address several issues, including conservatism in the transport model, the assignment of parameters in the flow and transport models, and the underlying assumptions used to support the conceptual models of flow and transport in the unsaturated zone at Yucca Mountain.

Calibration↗

Presynaptic calcium diffusion and the time courses of transmitter release and synaptic facilitation at the squid giant synapse.

At the squid giant synapse, a presynaptic action potential is accompanied by an influx of calcium ions that continue to be detectable with arsenazo III microspectrophotometry for several seconds. Nevertheless, transmitter release occurs phasically, lasting only about 2 msec. If a second action potential follows within about 100 msec after the first, it releases more transmitter. In this paper, we present a mathematical model of intracellular calcium diffusion with binding to fixed cytoplasmic sites, active extrusion at the surface, and influx during an action potential, to predict the distribution of intracellular calcium following an action potential. With a square law relation between submembrane calcium and transmitter release, the model predicts the phasic release of transmitter and the magnitude and time course of synaptic facilitation following an action potential, as well as the relatively long persistence of free intracellular calcium.

Action Potentials↗

Parameter dependence of myoglobin-facilitated transport of oxygen in the presence of membranes.

Some physicochemical entities involved in the facilitated transport of oxygen along a transport path z1 less than or equal to z less than or equal to zn with membranes impermeable to myoglobin at zi, i = 1,...,n, were identified in an earlier paper [Math. Biosci. 95:209 (1989)]. These entities are the partition between the oxygen and oxymyoglobin flows, the flow transfers taking place near a membrane, and the membrane resistance. Expressions for these entities were obtained that explicitly involve the parameters of the system. In this paper, for the case of prescribed boundary oxygen concentrations x1 and xn, these expressions are incorporated into (i) an explicit representation for the facilitated transport value in terms of the difference, E(x1)-E(xn), between the boundary oxymyoglobin equilibrium values and the sum, gamma, of the membrane resistances, and (ii) a representation for the distribution of the membrane oxygen concentrations xi at zi, i = 2,...,n-1. This makes it possible to analyze the manner in which the facilitated transport depends on the parameters. For a physiological range of parameter values, the facilitated transport was found to increase as either the oxygen-myoglobin association rate constant k', the dissociation rate constant k, the oxygen diffusion coefficient, or the oxymyoglobin diffusion coefficient increases. Thus, the facilitated transport does not depend directly on ratios of chemical and diffusion coefficients. Although the increase in the oxygen diffusion coefficient does not per se affect the chemical conductance, it diminishes the membrane resistance through an interface feature, with a resulting increase in the facilitated transport. For a larger range of values of k' and k, the dependences of the facilitated transport on k' and on k are both biphasic and are similar in shape. However, the mechanisms involved are different: The associated changes in E(x1)-E(xn) and in gamma that result from the increase in k' are opposite to those that result from an increase in k. The use of (i) and (ii) permits, also, discrimination between the different roles of the physicochemical entities involved in a given facilitated transport change. In some cases (e.g., the decreasing phase of the facilitated transport as k' increases), this change depends in an essential manner on a secondary modification of the profile xi, i = 1,...,n, along the transport path.

Biological Transport, Active↗

Comparative study of drug release from pellets coated with HPMC or Surelease.

The release of metoclopramide hydrochloride (very water soluble cationic drug) and diclofenac sodium (sparingly soluble anionic drug) from pellets coated with hydroxypropylmethylcellulose (HPMC; water-soluble polymer) or ethylcellulose aqueous dispersion (Surelease; water-insoluble polymer) at different coating loads was investigated. The release rates of either drug decreased as the coating load of HPMC increased, but overall, the release was fast, and the majority of both drugs released in about 1 hr, even at the highest coating load. The drug release mechanism for either drug was not affected by the coating load of HPMC or by the type of drug used, and it was found to be mainly diffusion controlled. Diclofenac sodium released slightly more slowly than metoclopramide hydrochloride from HPMC-coated pellets. This was attributed to the lower water solubility of the former drug. The release rate of either drug decreased greatly as the coating load of Surelease increased. The release of both drugs was sustained over 12 hr as the coating load of Surelease increased, and only about 70% of either drug was released after this period at the highest coating load (20%). The mechanism of release of metoclopramide hydrochloride was independent of coating load, and it was predominantly diffusion controlled. However, the mechanism of diclofenac sodium release was dependent on the coating load of Surelease. At low coating loads, diffusion of drug was facilitated due to the presence of more pores at the surface of the coated pellets; therefore, the rate of dissolution of the drug particles was the rate-limiting step. However, at high coating loads, drug release was mainly diffusion controlled. Despite its lower water solubility, diclofenac sodium released slightly faster than metoclopramide hydrochloride from Surelease-coated pellets at equivalent coating loads.

Anti-Inflammatory Agents, Non-Steroidal↗

The application of the convective diffusion model and the film equilibrium model to surfactant-facilitated dissolution of gliclazide.

Gliclazide is practically insoluble in water, and has low dissolution rate. Therefore, it was of interest to improve its dissolution rate using anionic and cationic surfactants. The intrinsic dissolution rates of gliclazide in solutions of sodium dodecyl sulfate (SDS) and in solutions of tetradecyltrimethyl ammonium bromide (TDTMAB) were measured using the rotating disk method to study the convective diffusion transport of drug-loaded micelles. Two different approaches were applied to the experimental data; the convective diffusion model and the film equilibrium model. The two approaches are based on the same fundamental assumptions differing only in their interpretation of the diffusional boundary layer. The results obtained from the film equilibrium model were less satisfactory, and in case of TDTMAB the model was inapplicable (negative diffusion coefficient). While excellent results were obtained from the convective diffusion model. The free solute diffusion coefficient (D(s)) obtained experimentally was 2.47 x 10(-5) cm(2)/s, and the diffusion coefficient of the drug-loaded SDS micelle (D(sm)) estimated was 1.74 x 10(-6) cm(2)/s. The drug-loaded SDS micelle radius was 14 A. The thickness of the diffusional boundary layer was 54 and 22 microm for the free solute and the drug-loaded SDS micelle, respectively. TDTMAB showed lower effect in improving the dissolution rate of gliclazide than SDS. The drug-loaded TDTMAB micelle diffusion coefficient was 1.03 x 10(-6) cm(2)/s. The radius of the drug-loaded TDTMAB micelle and the boundary layer thickness were 24 A and 19 microm, respectively.

Diffusion↗