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PubMed1994

Significance of viable skin layers in percutaneous permeation and its implication in mathematical models: theoretical consideration based on parameters for betamethasone 17-valerate.

The role of viable skin layers (viable epidermis and dermis) is examined by the three-layer model using parameter values for betamethasone 17-valerate. The mathematical three-layer diffusion model indicates that the lag time and half-life after vehicle removal in epidermis and split-thickness skin are longer than those in stratum corneum without viable layers, even if drug flux at steady-state is minimally altered. The theoretical values of the lag time and half-life predicted for epidermis and split-thickness-skin samples are compatible with the values observed in another in vitro study. The results predicted by the three-layer model indicate that the simplified model (single-layer or compartment model), which regards the whole skin as one diffusion layer or one compartment, may be warranted because all three skin layers have the same half-life after vehicle removal. The parameters used in the simplified model are estimated from some of the following values directly obtainable in the experiment: flux from skin and amount in the whole skin at steady-state, lag time, and drug concentration or amount maintained to be unchanged in the donor site. However, the simplified model often cannot resolve some discrepancy between the data and model (e.g., the ratio of the half-life to lag time) even if the data may be explained by the three-layer model.

Betamethasone Valerate↗
PubMed1995

Drug release from hydrophilic matrices. 2. A mathematical model based on the polymer disentanglement concentration and the diffusion layer.

A comprehensive model is developed to describe the swelling/dissolution behaviors and drug release from hydrophilic matrices. The major thrust of this model is to employ an important physical property of the polymer, the polymer disentanglement concentration, rho p,dis, the polymer concentration below which polymer chains detach off the gelled matrix. For (hydroxypropyl)methylcellulose (HPMC) in water, we estimate that rho p,dis scales with HPMC molecular weight, M, as rho p,dis varies M-0.8. Further, matrix dissolution is considered similar to the dissolution of an object immersed in a fluid. As a result, a diffusion layer separating the matrix from the bulk solution is incorporated into the transport regime. An anisotropic expansion model is also introduced to account for the anisotropic expansion of the matrix where surface area in the radial direction dominates over the axial surface area. The model predicts that the overall tablet size and the characteristic swelling time correlate with rho p,dis qualitatively. Two scaling laws are established for fractional polymer (mp(t)/mp(infinity)) and drug (md(t)/md(infinity)) released as mp(t)/mp(infinity) varies M-1.05 and md(t)/md(infinity) varies M-0.24, consistent with the limiting polymer molecular weight effect on drug release. Model predictions for polymer and drug release agree well with observations, within 15% error. Evolution of water concentration profiles and the detailed structure of a swollen matrix are discussed.

Benzodiazepines↗
PubMed1997

Drainage and Coalescence in Standing Foams

A theoretical model is presented for the drainage, collapse, and coalescence in standing foams. The foam is assumed to consist of pentagonal dodecahedra and coalescence is assumed to occur due to a variation in the sizes of the films which constitute the faces of these polyhedra. Even in a monodispersed foam containing bubbles having the same volume, the film areas are not identical, but are distributed randomly about a mean. This leads to a nonuniformity of film-drainage rates and hence of film thicknesses within any volume element in the foam. Smaller films drain faster and rupture earlier, causing the bubbles containing them to coalesce. The evolution of coalescence is monitored via the mean bubble volume which varies in the vertical direction. The model is also able to predict the evolution of the surfactant concentration profile as it changes due to coalescence and collapse. Simulations are performed to examine the effect of various parameters, such as the apparent diffusion coefficient of the surfactant, the distribution of film sizes, and the concentrations of surfactant and salt in the foaming solution on the drainage and collapse behavior of the foam.

Journal Article↗
PubMed2006

Structure, dynamics and topology of membrane polypeptides by oriented 2H solid-state NMR spectroscopy.

Knowledge of the structure, dynamics and interactions of polypeptides when associated with phospholipid bilayers is key to understanding the functional mechanisms of channels, antibiotics, signal- or translocation peptides. Solid-state NMR spectroscopy on samples uniaxially aligned relative to the magnetic field direction offers means to determine the alignment of polypeptide bonds and domains relative to the bilayer normal. Using this approach the (15)N chemical shift of amide bonds provides a direct indicator of the approximate helical tilt, whereas the (2)H solid-state NMR spectra acquired from peptides labelled with 3,3,3-(2)H(3)-alanines contain valuable complimentary information for a more accurate analysis of tilt and rotation pitch angles. The deuterium NMR line shapes are highly sensitive to small variations in the alignment of the C(alpha)-C(beta) bond relative to the magnetic field direction and, therefore, also the orientational distribution of helices relative to the membrane normal. When the oriented membrane samples are investigated with their normal perpendicular to the magnetic field direction, the rate of rotational diffusion can be determined in a semi-quantitative manner and thereby the aggregation state of the peptides can be analysed. Here the deuterium NMR approach is first introduced showing results from model amphipathic helices. Thereafter investigations of the viral channel peptides Vpu(1-27) and Influenza A M2(22-46) are shown. Whereas the (15)N chemical shift data confirm the transmembrane helix alignments of these hydrophobic sequences, the deuterium spectra indicate considerable mosaic spread in the helix orientations. At least two peptide populations with differing rotational correlation times are apparent in the deuterium spectra of the viral channels suggesting an equilibrium between monomeric peptides and oligomeric channel configurations under conditions where solid-state NMR structural studies of these peptides have previously been performed.

Deuterium↗
PubMed2001

Backbone dynamics in dihydrofolate reductase complexes: role of loop flexibility in the catalytic mechanism.

To elucidate the influence of local motion of the polypeptide chain on the catalytic mechanism of an enzyme, we have measured (15)N relaxation data for Escherichia coli dihydrofolate reductase in three different complexes, representing different stages in the catalytic cycle of the enzyme. NMR relaxation data were analyzed by the model-free approach, corrected for rotational anisotropy, to provide insights into the backbone dynamics. There are significant differences in the backbone dynamics in the different complexes. Complexes in which the cofactor binding site is occluded by the Met20 loop display large amplitude motions on the picosecond/nanosecond time scale for residues in the Met20 loop, the adjacent betaF-betaG loop and for residues 67-69 in the adenosine binding loop. Formation of the closed Met20 loop conformation in the ternary complex with folate and NADP(+), results in attenuation of the motions in the Met20 loop and the betaF-betaG loop but leads to increased flexibility in the adenosine binding loop. New fluctuations on a microsecond/millisecond time scale are observed in the closed E:folate:NADP(+) complex in regions that form hydrogen bonds between the Met20 and the betaF-betaG loops. The data provide insights into the changes in backbone dynamics during the catalytic cycle and point to an important role of the Met20 and betaF-betaG loops in controlling access to the active site. The high flexibility of these loops in the occluded conformation is expected to promote tetrahydrofolate-assisted product release and facilitate binding of the nicotinamide ring to form the Michaelis complex. The backbone fluctuations in the Met20 loop become attenuated once it closes over the active site, thereby stabilizing the nicotinamide ring in a geometry conducive to hydride transfer. Finally, the relaxation data provide evidence for long-range motional coupling between the adenosine binding loop and distant regions of the protein.

Binding Sites↗
PubMed2003

The swapping of terminal arms in ribonucleases: comparison of the solution structure of monomeric bovine seminal and pancreatic ribonucleases.

Bovine seminal ribonuclease (BS-RNase), the only dimeric protein among the pancreatic-like ribonucleases, is endowed with special structural features and with biological functions beyond enzymatic activity. In solution, the protein exists as an equilibrium mixture of two forms, with or without exchange (or swapping) of the N-terminal arms. After selective reduction and alkylation of the two intrachain disulfide bridges, the dimeric protein can be transformed into a monomeric derivative that has a ribonuclease activity higher than that of the parent dimeric protein but is devoid of the special biological functions. A detailed investigation of the structural features of this protein in solution, in comparison with those of other monomeric ribonucleases, may help unveil the structural details which induce swapping of the N-terminal arms of BS-RNase. The solution structure of the recombinant monomeric form of BS-RNase, as determined by 3D heteronuclear NMR, shows close similarity with that of bovine pancreatic ribonuclease (RNase A) in all regions characterized by regular elements of secondary structure. However, significant differences are present in the flexible regions, which could account for the different behavior of the two proteins. To characterize in detail these regions, we have measured H/D exchange rate constants, temperature coefficients and heteronuclear NOEs of backbone amides for both RNase A and monomeric BS-RNase. The results indicate a large difference in the backbone flexibility of the hinge peptide segment 16-22 of the two proteins, which could provide the molecular basis to explain the ability of BS-RNase subunits to swap their N-terminal arms.

Animals↗
PubMed2001

Self-organized dynamics on a curved growth interface.

We experimentally address long-time dynamics of an artificially curved growth interface in directional solidification. Repetitive cell nucleations are found to appear in a disordered way, but to eventually organize themselves in a coherent way, for long times. This behavior is recovered by simulation of a nonlinear advection-diffusion model for phase dynamics. The existence of a periodic attractor is supported by the derivation of a Lyapunov functional for this model.

Journal Article↗
PubMed1981

Diffusion of oxygen through the mouse ear.

Oxygen tension differences across the mouse ear have been measured polarographically under conditions of no blood flow. For some experiments the ear was split into two by cleavage along the central cartilage plate, and the diffusion of oxygen measured in both directions across these asymmetrical preparations. Measurements were also made on ears from which the stratum corneum had been removed by stripping with Sellotape. It was possible to relate these results to a simple multi-layer diffusion model. The main barrier to diffusion of oxygen resides in the stratum corneum, whose permeability is estimated to be 1 . 2 X 10(-8) ml O2 atm-1 cm-1 S-1. The permeability of the rest of the ear is 4 . 7 X 10(-7) ml O2 atm-1 cm-1 S-1. The inhibition of tissue respiration by the local injection of solutions of sodium amytal, potassium cyanide and other substances reduced the oxygen gradients by factors of between 3 and 7. Cooling the ear from room temperature to 0 degree C reduced the gradients by a factor of about 4.

Animals↗
PubMed1992

Migraine with aura: a vicious cycle perpetuated by potassium-induced vasoconstriction.

Two hypotheses have dominated attempts to understand the etiology of migraine with aura or classic migraine; the vascular spasm model proposed by Wolff and colleagues, and the spreading cortical depression hypothesis. Neither can provide a fully satisfactory explanation for the syndrome, however. We propose that classic migraine is both spreading cortical depression and localized ischemia linked in a vicious cycle by potassium induced vasoconstriction. The cycle can be initiated by any event which raises the local cortical ECF potassium concentration to approximately 20 mM. Such an event could be a localized burst of activity of a group of cells, localized metabolic impairment, or a transient reduction in blood flow to a region of the cortex. Once this level of potassium concentration is reached, it may result in localized depolarization of neurons, releasing more potassium into the ECF. Glial siphoning can distribute the potassium preferentially toward the blood vessels in the area, leading to an elevation in potassium concentration in the ECF surrounding the vascular smooth muscle of the arterioles. Above approximately 15 mM, vascular smooth muscle increases its tension in response to elevations in potassium. Therefore, as cortical ECF potassium concentration rises above 15 to 20 mM, localized vasoconstriction occurs, thereby reducing both the supply of oxygen for aerobic metabolism and the removal of potassium in the blood. Under these conditions, the effectiveness of the mechanisms which control potassium concentration is impaired and unable to prevent additional elevations in potassium. As the concentration continues to rise, vasoconstriction becomes more intense, perpetuating the cycle that results in localized depression of cortical neuronal activity and ischemia. The condition is propagated to adjacent regions of the cortex by diffusion and glial-mediated spread of potassium. In many respects, the hypothesis unites the vascular spasm and spreading depression models. If verified, it may provide insight into the causes of classic migraine as well as give direction toward development of effective therapies.

Humans↗
PubMed2005

A model of Barchan dunes including lateral shear stress.

Barchan dunes are found where sand availability is low and wind direction quite constant. The two dimensional shear stress of the wind field and the sand movement by saltation and avalanches over a barchan dune are simulated. The model with one dimensional shear stress is extended including surface diffusion and lateral shear stress. The resulting final shape is compared to the results of the model with a one dimensional shear stress and confirmed by comparison to measurements. We found agreement and improvements with respect to the model with one dimensional shear stress. Additionally, a characteristic edge at the center of the windward side is discovered which is also observed for big barchans. Diffusion effects reduce this effect for small dunes.

Computer Simulation↗
PubMed2004

Analysis of direct solar ultraviolet irradiance measurements in the French Alps. Retrieval of turbidity and ozone column amount.

Direct ultraviolet spectral solar irradiance is regularly obtained by the difference between global and diffuse irradiances at the French Alpine station of Briançon; the data of years 2001 and 2002 are analyzed in this paper. Comparison with modeled values is used for cloud screening, and an average UV-A aerosol optical depth is used as an index of turbidity; it is found to be around 0.05 for the clear winter days and around 0.2 in summer. Langley plots are used to verify the instrument calibration; they confirm the expected uncertainty smaller than 5%. The ozone total column amount is estimated with an uncertainty between -3 and Dobson units; comparisons with TOMS (Total Ozone Mapping Spectrometer) overpass values shows agreement within the expected uncertainties of both instruments.

Journal Article↗
PubMedDate not supplied

Cleaning solutions as a cause of diffuse lamellar keratitis.

PURPOSE: To assess the capability of two microkeratome cleaning solutions in causing diffuse lamellar keratitis (DLK) in a rabbit model of laser in situ keratomileusis (LASIK). METHODS: Two cleaning solutions (Palmolive 2:100 and Cidezyme 2:250) were tested. These solutions were diluted with balanced salt solution according to directions from the Hansatome microkeratome manual. Two additional solutions were prepared using an additional ten-fold dilution, creating a total of four study solutions. A LASIK flap was created in one eye each of 25 rabbits using the ALK Chiron microkeratome. The rabbits were divided into five study groups. The flaps were reflected and a drop of one of the study solutions (or BSS, control group) was placed on the interface. After 1 minute, the solution was washed out from the interface and the flap was repositioned. The eyes were examined at the slit lamp on postoperative days 1, 2, 3, 5, and 7. RESULTS: In 12 eyes, a flap displacement was identified. Four eyes showed flap retraction and five others, epithelial ingrowth in flap margins. The incidence of these events did not differ among groups. Thirteen eyes were then evaluated for DLK. No DLK-like interface inflammation was seen in the studied eyes. CONCLUSION: The cleaning solutions, when diluted as recommended by the microkeratome manufacturer, when in contact with the corneal stroma, and provided that the interface was washed with BSS did not cause DLK interface inflammation in rabbit LASIK models.

Animals↗
PubMed1997

Autoantibodies: diagnostic fingerprints and etiologic perplexities.

Autoantibodies are a hallmark of systemic rheumatic diseases, organ-specific autoimmune diseases and paraneoplastic syndromes. Cell biologists have used autoantibodies as probes to define the structure and function of novel macromolecules and to determine the chromosomal location of their respective genes. The observation that many autoantibodies appear before the clinical expression of disease suggests that they are not epiphenomena. Some autoantibodies are disease-specific markers and are in aid to establishing a diagnosis. Although it has been difficult to link autoantibodies to pathogenesis, they can be used to predict disease progression and outcome. For example, autoantibodies directed against topoisomerase are associated with progression of scleroderma to diffuse skin involvement and severe systemic disease, whereas antibodies to centromere proteins predict a more slowly progressive disease and development of a limited variant of scleroderma. Certain models of autoantibody production hold promise of a clearer understanding of the mechanisms that underlie autoimmunity. Drugs such as procainamide and hydralazine induce the production of chromatin autoantibodies. Exposure to heavy metals (e.g., mercury) is also linked to the development of autoantibodies. The data provide evidence that the autoimmune response is driven by autoantigens, which are multimolecular complexes involved in essential cellular functions.

Animals↗
PubMed1996

Transport and elimination of recombinant human NGF during long-term delivery to the brain.

The gene for human nerve growth factor (NGF) has been cloned into a mammalian cell line and large quantities of recombinant human NGF (rhNGF) can now be produced for clinical use, but little is known about the fate of rhNGF following delivery to the brain. In this study, we implanted polymer matrices containing 125I-labeled rhNGF into the brains of adult rats and measured spatial distributions of the released protein for 8 weeks after implantation. NGF content in the tissue was determined by counting gamma radiation in thick (1 mm) sections and by autoradiography of thin (20 microns) sections. For the first several days, the rate of NGF release from the polymer matrix was high (approximately 100 ng/day); maximal NGF concentrations, measured at the polymer-tissue interface, were correspondingly high (> 20 micrograms/ml) though day 4. At later times, the release rate decreased (2-10 ng/day) and lower maximal concentrations were observed (1-10 micrograms/ml). NGF levels were always highest in the tissue sections closest to the polymer; during the 8 weeks of the experiment, NGF levels measured in thick sections decreased 100-fold, from 30 ng/section at day 2 to 0.3 ng/section at day 54. The first 10-fold decrease occurred during the first 10 days of the study; a further 6 weeks was required to achieve the second 10-fold decrease. Throughout the experiment, the majority of NGF remained within a restricted zone around the polymer at all times; the mass of NGF decreased to 10% of the maximal level within 2-3 mm of the polymer matrix. At early times (< 1 week), radiolabel corresponding to > 20 pg of NGF was also detected in regions of the brain further removed from the polymer. Comparison of local rhNGF concentration profiles with a simple mathematical model indicated that rhNGF diffuses through the brain interstitial space and is eliminated with a half-life of approximately 45 min, although elimination appears to be substantially slower in white matter regions. This limited ability of NGF to penetrate and be retained within the brain tissue indicates that NGF will need to be delivered almost directly to the target tissue for efficacy.

Animals↗
PubMed1995

An easy-to-use model for O2 supply to red muscle. Validity of assumptions, sensitivity to errors in data.

An easy-to-use capillary cylinder model of O2 supply to muscle is presented that considers all those factors that are known to be most important for realistic results: (1) red blood cell (RBC) O2 unloading along the capillary, (2) effects of the particulate nature of blood, (3) free and hemoglobin-facilitated O2 diffusion and reaction kinetics inside RBCs, (4) free and myoglobin-facilitated O2 diffusion inside the muscle cell, and (5) carrier-free region separating RBC and tissue. In a first approach, a highly simplified yet reasonably accurate treatment of the complex three-dimensional oxygen diffusion field in and next to capillaries is employed. As an alternative, a more realistic description using RBC/capillary diffusing capacity has been included. Model development proceeds step by step and is designed to be easily comprehensible for a broad readership. In spite of the number of features accounted for, the model is simple to apply, even for scientists not specialized in the field of modeling. PO2 distributions calculated by the model are in good qualitative agreement with experimental data and with former modelling results. By means of suitable extensions to the model that are also developed it is shown for a wide range of muscle performances that quite generally the following complication may be neglected safely: (1) complexity of O2 diffusion field near capillaries, (2) deviations of capillary domain cross sections from the circular shape, (3) O2 diffusion parallel to the capillary direction, and (4) PO2 dependence of O2 consumption rate. Finally, a sensitivity analysis is performed in which propagation of errors in the input data into the results is investigated. The interpretation of the calculated sensitivities gives insights in the specific dependencies of muscular O2 supply on the various input parameters. Moreover, basic interrelations governing carrier-facilitated diffusional O2 transport to muscle become apparent and are discussed.

Animals↗
PubMed2006

Framework models of ion permeation through membrane channels and the generalized King-Altman method.

A modern approach to studying the detailed dynamics of biomolecules is to simulate them on computers. Framework models have been developed to incorporate information from these simulations in order to calculate properties of the biomolecules on much longer time scales than can be achieved by the simulations. They also provide a simple way to think about the simulated dynamics. This article develops a method for the solution of framework models, which generalizes the King-Altman method of enzyme kinetics. The generalized method is used to construct solutions of two framework models which have been introduced previously, the single-particle and Grotthuss (proton conduction) models. The solution of the Grotthuss model is greatly simplified in comparison with direct integration. In addition, a new framework model is introduced, generalizing the shaking stack model of ion conduction through the potassium channel.

Algorithms↗
PubMed2007

Three-phase interlines electrochemically driven into insulator compounds: a penetration model and its verification by electroreduction of solid AgCl.

A dynamic three-phase interline model has been developed for the reduction of a solid insulating metal compound to the metal in a suitable electrolyte, focusing on the electrochemically driven penetration of the process (or the three-phase interlines) into the insulator. Consideration is given to the effects of electrochemical, concentration and ohmic polarizations in the reduction-generated porous metal layer on top of the solid compound. Under potentiostatic conditions, reduction in the depth direction (penetration) becomes progressively slower as a result of the rising ohmic and concentration polarizations, whilst the electrochemical polarization exerts a declining effect. The quantitative equations established here also provide simple methods for the determination of some kinetic parameters of the reduction process, including rho (total resistivity) and D(R) (diffusion coefficient). The model has been experimentally verified by electrochemical reduction of solid AgCl with two novel metal|AgCl cylinder electrodes in aqueous solutions.

Journal Article↗
PubMedDate not supplied

[Transport of low molecular weight substances in protein crystals and films].

Diffusion of synthetic dyes in lysozyme crystals and bovine serum albumin (BSA) amorphous films is shown to depend on the size of diffusate molecule far more strongly than in solutions. The diffusion coefficient increases from 10(-8) to 10(-13) cm2 sec-1 on about 1.5 divided by 2--fold increase in diffusate dimensions, the diffusion being completely arrested on reaching the limiting dimensions of about 14 A and 12 A for BSA films and lysozyme crystals, respectively. The diffusion in lysozyme crystals is anisotropic, with a diffusion maximum directed along their screw axes. The diffusion coefficient dependence on the charge of diffusate and its binding to proteins is discussed.

Crystallization↗