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Bioadhesive tablets for controlled transdermal delivery of drugs.

Transdermal bioadhesive tablets were formulated by the direct compression method and evaluated. Carboxyfluorescein (CF) was used as a model permeant. The compression parameters were kept consistent and the composition of the formulation was varied to alter the release rate of the drug from the formulations. The dosage form was evaluated for physicochemical, adherence, and in vitro diffusion parameters. The transdermal flux of the drug decreased with the increasing ratio of Ethyl cellulose (EC)/hydroxypropyl cellulose (HPC). The test formulations were subjected to pharmacokinetic studies in mice. The formulations were able to maintain a steady state plasma concentration up to 12 hours. They were found to be safe for transdermal use as interpreted from skin irritation studies carried out on rabbits.

Administration, Cutaneous↗
PubMed2005

Revised estimates for continuous shoreline fumigation: a PDF approach.

A probability density function (PDF) fumigation model is presented here to study the dispersion of air pollutants emitted from a tall stack on the shoreline. This work considers dispersion of the pollutants in the stable layer and within the thermal internal boundary layer (TIBL) proceeds independently. The growth of TIBL is considered parabolic with distance inland. Turbulence is taken as homogeneous and stationary. Dispersion of particles (contaminant) in lateral and vertical directions is assumed independent of each other. This assumption allows us to consider the position of particles in both directions as independent random variables. The lateral dispersion distribution within the TIBL is considered as Gaussian and independent of height. A skewed bi-Gaussian vertical velocity PDF is used to account for the physics of dispersion due to different characteristics of updrafts and downdrafts within the TIBL. We have used Weil (J.C. Weil, A diagnosis of the asymmetry in top-down and bottom-up diffusion using a Lagrangian stochastic model, J. Atmos. Sci., 47 (1990) 501-515) solutions to find out the parameters of this PDF. Incorporating finite Lagrangian integral time scale for the vertical velocity component, it is observed that it reduces the vertical dispersion in the beginning and moves the point of maximum concentration further downwind. Due to little dispersion in the beginning, there is more plume to be dispersed causing higher concentrations at large distances. The model has considered Weil and Brower's (J.C. Weil, P.R. Brower, Estimating convective boundary layer parameters for diffusion applications, Maryland Power Plant Siting Program Rep. PPSP-MP-48, Department of Natural Resources, Annapolis, MD, 1985, 37 pp.) convective limit to analyze dispersion characteristics within TIBL. The revised model discussed here is evaluated with the data available from the Nanticoke field experiment on fumigation conducted in summer of 1978 in Ontario, Canada. The results of revised model are in good agreement with the observed data.

Air Pollutants↗
PubMed2003

Serial magnetic resonance imaging in experimental primate stroke: validation of MRI for pre-clinical cerebroprotective trials.

Precise assessment of stroke outcome is critical for pre-clinical testing of cerebroprotective strategies. Differences in stroke volume measured by various magnetic resonance imaging (MRI) techniques are documented in humans, but not well described in experimental primate stroke. This study characterizes changes in stroke volume using serial MRI scans in a baboon model of reperfused cerebral ischemia. The location/area of hyperintensity on MRI corresponded with the TTC-stained infarct region. T2-weighted fast spin echo (T2W FSE), fluid attenuated inversion recovery (FLAIR), and diffusion weighted imaging (DWI) showed a decrease in infarct volume between 72 h and nine days post-ischemia (p = ns, p = 0.029, and p = 0.006). T2W FSE and FLAIR demonstrated an increase in infarct volume from 24 h to nine days post-ischemia, while DWI displayed a decrease over the same period. While early T2W FSE, FLAIR, and DWI all correlated with late infarct volume (p < 0.001), 72 h T2W FSE was the best direct measure (2.39% +/- 1.40% unity deviation). Serial MRI in a nonhuman primate model of focal cerebral ischemia recapitulates findings in clinical stroke. MRI at 72 h accurately predicts late infarct volume.

Animals↗
PubMed1995

A time encoding method for single-shot imaging.

A new 2D single-shot imaging technique is introduced that uses only one dimension of Fourier encoding. The second dimension is encoded in time, rather than using phase encoding. The data is acquired in the form of a closely spaced echo train with each echo produced from a different physical line in the object. A 1D Fourier transform is applied to each echo for image reconstruction. Because only the desired lines are excited, there can be no aliasing in the time encoding direction even when the object is much larger than the field of view. This technique is also very insensitive to motion, as motion-related artifacts do not propagate in the time encoding direction.

Acrylic Resins↗
PubMed1999

Getting across the nuclear pore complex.

The nuclear pore complex (NPC) connects the cytoplasm and nucleus through the nuclear envelope and serves as the pipeline for moving material between the two compartments. Macromolecules that move through the NPC range in size from the very small (for example, ions and ATP) to the very large (for example, ribonucleoprotein particle complexes). Unlike translocation across other organelle membranes, proteins do not have to be unfolded to be transported through the NPC, and the NPC also routinely transports large, multicomponent substrates in both directions. This review focuses on current understanding of the different mechanisms by which macromolecules move across the NPC.

Animals↗
PubMed2002

Numerical simulations of microtubule self-organisation by reaction and diffusion.

This article addresses the physical chemical processes underlying biological self-organisation by which a homogenous solution of reacting chemicals spontaneously self-organises. Theoreticians have predicted that self-organisation can arise from a coupling of reactive processes with molecular diffusion. In addition, the presence of an external field, such as gravity, at a critical moment early in the process may determine the morphology that subsequently develops. The formation, in-vitro, of microtubules, a constituent of the cellular skeleton, shows this type of behaviour. The preparations spontaneously self-organise by reaction-diffusion and the morphology that develops depends upon the presence of gravity at a critical bifurcation time early in the process. Here, we present numerical simulations of a population of microtubules that reproduce this behaviour. Microtubules can grow from one end whilst shrinking from the other. The shrinking end leaves behind a chemical trail of high tubulin concentration. Neighbouring microtubules preferentially grow into these regions, whilst avoiding regions of low tubulin concentration. The chemical trails produced by individual microtubules thus activate and inhibit the formation of neighbouring microtubules and this progressively leads to self-organisation. Gravity acts by way of its directional interaction with the macroscopic density fluctuations present in the solution arising from microtubule disassembly.

Animals↗
PubMed2005

Controlling the motion of interacting particles: homogeneous systems and binary mixtures.

We elaborate on recent results on the transport of interacting particles for both single-species and binary mixtures subject to an external driving on a ratchetlike asymmetric substrate. Moreover, we also briefly review motion control without any spatial asymmetric potential (i.e., no ratchet). Our results are obtained using an analytical approach based on a nonlinear Fokker-Planck equation as well as via numerical simulations. By increasing the particle density, the net dc ratchet current in our alternating (ac)-driven systems can either increase or decrease depending on the temperature, the drive amplitude, and the nature of the inter-particle interactions. This provides an effective control of particle motion by just changing the particle density. At low temperatures, attracting particles can condense at some potential minima, thus breaking the discrete translational symmetry of the substrate. Depending on the drive amplitude, an agglomeration or condensation results either in a drop to zero or in a saturation of the net particle velocity at densities above the condensation density-the latter case producing a very efficient rectification mechanism. For binary mixtures we find three ways of controlling the particle motion of one (passive) B species by means of another (active) A species: (i) Dragging the target particles B by driving the auxiliary particles A, (ii) rectifying the motion of the B particles on the asymmetric potential created by the A-B interactions, and (iii) dynamically modifying (pulsating) this potential by controlling the motion of the A particles. This allows to easily control the magnitude and direction of the velocity of the target particles by changing either the frequency, phase and/or amplitude of the applied ac drive(s).

Biophysics↗
PubMed1999

A framework for effective management of change in clinical practice: dissemination and implementation of clinical practice guidelines.

Theories from social and behavioural science can make an important contribution to the process of developing a conceptual framework for improving use of clinical practice guidelines and clinician performance. A conceptual framework for guideline dissemination and implementation is presented which draws on relevant concepts from diffusion of innovation theory, the transtheoretical model of behaviour change, health education theory, social influence theory, and social ecology, as well as evidence from systematic literature reviews on the effectiveness of various behaviour change strategies. The framework emphasises the need for preimplementation assessment of (a) readiness of clinicians to adopt guidelines into practice, (b) barriers to change as experienced by clinicians, and (c) the level at which interventions should be targeted. It also incorporates the need for multifaceted interventions, identifies the type of barriers which will be addressed by each strategy, and develops the concept of progression through stages of guideline adoption by clinicians, with the use of appropriately targeted support strategies. The potential value of the model is that it may enable those involved in the process of guideline dissemination and implementation to direct strategies to target groups more effectively. Clearly, the effectiveness and utility of the model in facilitating guideline dissemination and implementation requires validation by further empirical research. Until such research is available, it provides a theoretical framework that may assist in the selection of appropriate guideline dissemination and implementation strategies.

Diffusion of Innovation↗
PubMed2004

Fluid flow and convective transport of solutes within the intervertebral disc.

Previous experimental and analytical studies of solute transport in the intervertebral disc have demonstrated that for small molecules diffusive transport alone fulfils the nutritional needs of disc cells. It has been often suggested that fluid flow into and within the disc may enhance the transport of larger molecules. The goal of the study was to predict the influence of load-induced interstitial fluid flow on mass transport in the intervertebral disc. An iterative procedure was used to predict the convective transport of physiologically relevant molecules within the disc. An axisymmetric, poroelastic finite-element structural model of the disc was developed. The diurnal loading was divided into discrete time steps. At each time step, the fluid flow within the disc due to compression or swelling was calculated. A sequentially coupled diffusion/convection model was then employed to calculate solute transport, with a constant concentration of solute being provided at the vascularised endplates and outer annulus. Loading was simulated for a complete diurnal cycle, and the relative convective and diffusive transport was compared for solutes with molecular weights ranging from 400 Da to 40 kDa. Consistent with previous studies, fluid flow did not enhance the transport of low-weight solutes. During swelling, interstitial fluid flow increased the unidirectional penetration of large solutes by approximately 100%. Due to the bi-directional temporal nature of disc loading, however, the net effect of convective transport over a full diurnal cycle was more limited (30% increase). Further study is required to determine the significance of large solutes and the timing of their delivery for disc physiology.

Animals↗
PubMed2006

Three-dimensional fiber architecture of the nonpregnant human uterus determined ex vivo using magnetic resonance diffusion tensor imaging.

The global muscle and collagen fiber orientation in the human uterus has been analyzed hitherto by various standard microscopic techniques. However, no widely accepted model of the fiber architecture of the myometrium could be acquired. The purpose of the present study was to investigate the uterus by magnetic resonance (MR) diffusion tensor imaging (DTI) in a 3D macroscopic approach. Ex vivo MR DTI measurements were performed on five uteri from nonpregnant patients. The main diffusion directions reflecting the orientation of directional structures in the examined tissues were determined from diffusion-weighted spin-echo measurements. A fiber tracking algorithm was used to extrapolate the fiber architecture. The method was validated against histological slides and indirectly through the analysis of leiomyomas, which exhibit less anisotropy than normal myometrium. Significant anisotropy was found in most regions of all examined nonpregnant human uteri. But only two systems of fibers were found running circularly along the intramural part of the uterine tubes. They merged caudally and built a close fitting envelope of circular layers around the uterine cavity. On the cervix, circular fibers were observed in the outer part as well as mostly longitudinal fibers in the inner part. These results confirm the existence of directional structures in the complex fiber architecture of the human uterus. They also indicate that MR DTI is a beneficial and complementary tool to standard microscopic techniques to determine the intrinsic fiber architecture in human organs.

Adult↗
PubMed2006

Spatial and temporal patterns of serotonin release in the rat's lumbar spinal cord following electrical stimulation of the nucleus raphe magnus.

The monoamine neurotransmitter serotonin is released from spinal terminals of nucleus raphe magnus (NRM) neurons and important in sensory and motor control, but its pattern of release has remained unclear. Serotonin was measured by the high-resolution method of fast cyclic voltammetry (2 Hz) with carbon-fiber microelectrodes in lumbar segments (L3-L6) of halothane-anesthetized rats during electrical stimulation of the NRM. Because sites of serotonin release are often histologically remote from membrane transporters and receptors, rapid emergence into aggregate extracellular space was expected. Increased monoamine oxidation currents were found in 94% of trials of 50-Hz, 20-s NRM stimulation across all laminae. The estimated peak serotonin concentration averaged 37.8 nM (maximum 287 nM), and was greater in dorsal and ventral laminae (I-III and VIII-IX) than in intermediate laminae (IV-VI). When measured near NRM-evoked changes, basal monoamine levels (relative to dorsal white matter) were highest in intermediate laminae, while changes in norepinephrine level produced by locus ceruleus (LC) stimulation were lowest in laminae II/III and VII. The NRM-evoked monoamine peak was linearly proportional to stimulus frequency (10-100 Hz). The peak often occurred before the stimulus ended (mean 15.6 s at 50 Hz, range 4-35 s) regardless of frequency, suggesting that release per impulse was constant during the rise but fell later. The latency from stimulus onset to electrochemical signal detection (mean 4.2 s, range 1-23 s) was inversely correlated with peak amplitude and directly correlated with time-to-peak. Quantitative modeling suggested that shorter latencies mostly reflected the time below detection threshold (5-10 nM), so that extrasynaptic serotonin was significantly elevated well within 1 s. Longer latencies (>5 s), which were confined to intermediate laminae, appeared mainly to be due to diffusion from distant sources. In conclusion, except possibly in intermediate laminae, serotonergic volume transmission is a significant mode of spinal control by the NRM.

Afferent Pathways↗
PubMed1997

Molecular mass determination by sedimentation velocity experiments and direct fitting of the concentration profiles.

A new method for the direct molecular mass determination from sedimentation velocity experiments is presented. It is based on a nonlinear least squares fitting procedure of the concentration profiles and simultaneous estimation of the sedimentation and diffusion coefficients using approximate solutions of the Lamm equation. A computer program, LAMM, was written by using five different model functions derived by Fujita (1962, 1975) to describe the sedimentation of macromolecules during centrifugation. To compare the usefulness of these equations for the analysis of hydrodynamic results, the approach was tested on data sets of Claverie simulations as well as experimental curves of some proteins. A modification for one of the model functions is suggested, leading to more reliable sedimentation and diffusion coefficients estimated by the fitting procedure. The method seems useful for the rapid molecular mass determination of proteins larger than 10 kDa. One of the equations of the Archibald type is also suitable for compounds of low molecular mass, probably less than 10 kDa, because this model function requires neither the plateau region nor a meniscus free of solute.

Animals↗
PubMed2005

Kinetics of film formation by interfacial polycondensation.

An approximate analytical model of film formation by interfacial polycondensation is presented. The analysis requires knowledge of a minimal set of certain kinetic parameters (monomer diffusivities and reaction rate constants) and reaction conditions (monomer concentrations and thickness of the unstirred layer). The process proceeds as a succession of two or three markedly different kinetic regimes. Each regime (insipient film formation, slowdown, and diffusion-limited growth) sets a different pattern of local polymer accumulation, with important implications for the structure of the emerging film. At the incipient stage, a loose polymer film begins to emerge in a fixed narrow region inside the boundary layer, followed by gradual densification of the middle part of the film. A condition for film formation is thus formulated on the basis of our analysis. The model predicts that two different scenarios are possible, which depend on the permeability of the polymer: films with a low permeability to both monomers pass through an abrupt slowdown of film growth, whereas permeable films undergo a smooth transition between the incipient film formation and diffusion-limited regimes. The model incorporates the highly important effects of the accumulation of reactive end groups and the decrease of monomer diffusion with the polymer concentration on the kinetics of the process and film characteristics. In addition, the validity of the utilized mean-field approach is analyzed, and the analysis suggests a direct correlation between the roughness and the thickness of the film. The results are in good agreement with an earlier numerical study and the direct structural studies of polyamide membrane films.

Journal Article↗
PubMed2000

Self-consistent chaotic transport in fluids and plasmas.

Self-consistent chaotic transport is the transport of a field F by a velocity field v according to an advection-diffusion equation in which there is a dynamical constrain between the two fields, i.e., O(F,v)=0 where O is an integral or differential operator, and the Lagrangian trajectories of fluid particles exhibit sensitive dependence on initial conditions. In this paper we study self-consistent chaotic transport in two-dimensional incompressible shear flows. In this problem F is the vorticity zeta, the corresponding advection-diffusion equation is the vorticity equation, and the self-consistent constrain is the vorticity-velocity coupling z nabla xv=zeta. To study this problem we consider three self-consistent models of intermediate complexity between the simple but limited kinematic chaotic advection models and the approach based on the direct numerical simulation of the Navier-Stokes equation. The first two models, the vorticity defect model and the single wave model, are constructed by successive simplifications of the vorticity-velocity coupling. The third model is an area preserving self-consistent map obtained from a space-time discretization of the single wave model. From the dynamical systems perspective these models are useful because they provide relatively simple self-consistent Hamiltonians (streamfunctions) for the Lagrangian advection problem. Numerical simulations show that the models capture the basic phenomenology of shear flow instability, vortex formation and relaxation typically observed in direct numerical simulations of the Navier-Stokes equation. Self-consistent chaotic transport in electron plasmas in the context of kinetic theory is also discussed. In this case F is the electron distribution function in phase space, the corresponding advection equation is the Vlasov equation and the self-consistent constrain is the Poisson equation. This problem is closely related to the vorticity problem. In particular, the vorticity defect model is analogous to the Vlasov-Poisson model and the single wave model and the self-consistent map apply equally to both plasmas and fluids. Also, the single wave model is analogous to models used in the study of globally coupled oscillator systems. (c) 2000 American Institute of Physics.

Journal Article↗
PubMed1997

Porins of Haemophilus influenzae type b mutated in loop 3 and in loop 4.

Porin (341 amino acids; mass of 37,782 Da) in the outer membrane of Haemophilus influenzae type b (Hib) permits diffusion into the periplasm of small solutes up to a molecular mass of 1400 Da. Molecular modeling of Hib porin identified its structural similarities to OmpF of Escherichia coli and disclosed for Hib porin a shorter length of loop 3 and a longer length of loop 4. By site-directed mutagenesis of the porin gene ompP2, mutant porins were constructed to contain 6 or 12 amino acid deletions either in loop 3 or in surface-exposed loop 4. Wild type Hib porin and mutant porins were expressed in a nontypeable H. influenzae strain deleted for the ompP2 gene. The mutant porins were purified and reconstituted into planar bilayers, tested for channel formation and compared with wild type Hib porin. Mutant Haemophilus porin possessing a 6-amino acid deletion in loop 3 displayed a broad distribution of single channel conductance values, while deletion of 12 amino acids from the same loop destabilized the porin channel. By comparison, deletion of 6 or of 12 amino acids from loop 4 of Hib porin resulted in an increased single channel conductance (1.15 and 1.05 nanosiemens, respectively) compared with wild type Hib porin (0. 85 nanosiemens). The C3 epitope of the poliovirus VP1 capsid protein was inserted either into loop 3 or into loop 4 of Hib porin. By flow cytometry, the C3 epitope was detected as surface-exposed in strains expressing C3 insertion in loop 4; in strains expressing C3 insertion in loop 3, the epitope was inaccessible. We propose that loop 4 of Hib porin, although surface-accessible, is oriented toward the central axis of the pore and that deletions in this loop increase the single channel conductance by widening the pore entrance.

Amino Acid Sequence↗
PubMed2003

Scattering and separators in dissipative systems.

Scattering of particlelike patterns in dissipative systems is studied, especially we focus on the issue how the input-output relation is controlled at a head-on collision in the one-dimensional(1D) space where traveling pulses interact strongly. It remains an open problem due to the large deformation of patterns at a colliding point. We found that a special type of steady or time-periodic solutions called separators and their stable and unstable manifolds direct the traffic flow of orbits. Such separators are, in general, highly unstable even in the 1D case which causes a variety of input-output relations through the scattering process. We illustrate the ubiquity of separators by using the Gray-Scott model and a three-component reaction diffusion model arising in gas-discharge phenomena.

Journal Article↗
PubMed2005

Geometry of dynamically available empty space is the key to near-arrest dynamics.

We study several examples of kinetically constrained lattice models using dynamically accessible volume as an order parameter. Thereby we identify two distinct regimes exhibiting dynamical slowing, with a sharp threshold between them. These regimes are identified both by a new response function in dynamically available volume, as well as directly in the dynamics. Results for the self-diffusion constant in terms of the connected hole density are presented, and some evidence is given for scaling in the limit of dynamical arrest.

Journal Article↗
PubMed1986

Concentration dependence of halide fluxes and selectivity of the anion pathway in toad skin.

The isolated toad (Bufo bufo) skin was mounted under voltage-clamp conditions in a chamber shown to cause no significant edge damage. The serosal side of the skin was bathed with NaCl-Ringer's, and the passive voltage-sensitive anion conductance studied in its fully voltage activated state, V = -80 mV (apical bath negative). The active sodium currents were eliminated by replacing external Na+ with K+. With [Cl-]o varying between 1.45 mM and 110 mM (gluconate substitution) and [I-]o = 3 mM, the total clamping current (y) and the sum of halide currents (x), estimated from flux measurements, were related by y = 1.0x-3.7 microA cm-2 (r2 = 0.98, n = 50 preparations). The increase in [Cl-]o produced a sigmoidal increase in Cl- influx and clamping current, with the rate coefficient for the influx increasing with [Cl-]o for 1.45 less than [Cl-]o less than 60 mM, but decreasing slightly again as [Cl-]o was further raised to 110 mM. A similar relationship was obtained between the rate coefficient for the Br- influx and [Br-]o, and the I- influx and [Cl-]o, indicating that these three ions are transported by a pathway that is activated by Cl-o and Br-o. The rate coefficients for the influxes ranked as follows, I-:Cl-:Br- = 0.7:1:1.3. The I-/Cl- selectivity was shown to be independent of the degree of Cl-o activation of the anion pathway, and identical with the I-/Cl- selectivity of a furosemide-sensitive, conductive pathway. With [Cl-]o, [Br-]o, or [I-]o = 110 mM, the currents ranked as follows, Cl-:Br-:I- = 1:0.68:0.06, indicating that Cl-, to a lesser extent Br-, and I-, poorly activate the conductive anion pathway. External I- was a potent inhibitor of the Cl-o activation of the Cl- conductance. The unidirectional I- fluxes ([I-]o = [I-]i = 3 mM, [Cl-]o = [Cl-]i = 110 mM) revealed passive transport for V less than -50 mV, active transport for V = o mV, and exchange diffusion for V = 50 mV, confirming our previous finding that depending on the transepithelial potential, the toad skin exhibits three modes of anion transport. A model that shares some properties with that of the anion transport system of the red cell membrane accounts for our findings, and for an inwardly directed active Cl- flux in terms of Cl-/HCO3- exchange.

Animals↗