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PubMed2004

Mass transfers in a fluidized bed bioreactor using alginate beads for a future bioartificial liver.

Fluidized bed bioreactor with alginate beads may be an alternative to hollow fiber cartridge to host hepatocytes for bioartificial liver purposes. After the bioreactor design and the characterization of fluid mechanics, the present study was aimed at analyzing bi-directional mass transfers of calibrated species between external fluid and empty beads. Static (batch) and dynamic (fluidized bed bioreactor) experimental conditions were analyzed. A simple modelling approach permitted the definition of mass transfer coefficients. The motion of beads within the bioreactor clearly enhanced mass transfer kinetics, but did not alter the amount exchanged. The shear enhanced diffusion coefficient for VitB12 was 20 times higher in the fluidized bed bioreactor than under batch conditions, proving the efficiency of such a device.

Alginates↗
PubMed2003

[Development of drug delivery system based on a new administration route for targeting to the specific region in the liver].

Development of drug delivery systems to achieve site-specific delivery or prolonged retention in the circulation has attracted attention, because new types of drugs are expected to be created with advances in life science and biotechnology such as the Human Genome Project. We have tried to develop a new administration route for drug targeting to the liver, since drug administration by the intravenous and oral routes makes it difficult to achieve a local site of action in the liver. Although direct application to the liver surface should result in local drug distribution, drug absorption from the liver surface has not been reported in the literature. Therefore we analyzed the absorption mechanism of several organic anions and dextrans with different molecular weights as model drugs, after application to the rat liver surface in vivo, employing a cylindrical diffusion cell. Every compound appeared gradually in the plasma, followed by excretion into the bile and/or urine, indicating the possibility of drug absorption from the liver surface. A specific transport system might not be involved in the absorption process from the liver surface, because the effect of dose and transport inhibitors on the absorption was not recognized. In addition, molecular weight was found to be a determining factor in absorption from the liver surface. The targeting efficacy was considerably enhanced by application to the liver surface, as compared with intravenous administration. Moreover, we have identified important physicochemical and pharmaceutical factors determining the absorption rate of a drug from the liver surface for clinical use. Consequently, drug application to the liver surface could improve availability in the desired site of a new drug such as bioactive compounds and genomic medicines, by combination with appropriate chemical and pharmaceutical formulation modifications.

Animals↗
PubMed2001

Transferring skills--from south to north.

The primary aim of western-trained speech and language therapists (SLTs) working in the 'South' is not to train further SLTs but to transfer a range of practical skills to carers, health and education workers working directly with under-served populations. Considering current areas of service need in the UK, a model of primary health care has been applied to the western model, resulting in further discussion of potential applications to future SLT practice in the UK.

Developing Countries↗
PubMed2005

Peritoneal transport dynamics of glucose and icodextrin: the in vitro comparative studies.

We performed in vitro experiments with the isolated rabbit parietal peritoneum to evaluate the importance of fluid stirring intensification and of chemical modification of mesothelium and interstitium to the peritoneal transport of glucose and icodextrin. We used a mathematical model of mass transport to calculate the diffusive permeability coefficient, P, in centimeters per second. In control conditions (intact tissue; stirring rate: 11 mL/min), the rate of glucose (2.0 g/dL) transfer remained constant, and no differences were observed for transport from the interstitial to the mesothelial (I-->M) side of the membrane or in the opposite direction (M-->I). The value of P (+/- standard error of the mean) was 2.731 +/- 0.472 x 10(-4) cm/s. In contrast, the icodextrin (7.5 g/dL) I-->M transport rate was higher than that for M-->I (P: 0.319 +/- 0.038 x 10(-4) cm/s and 0.194 +/- 0.035 x 10(-4) cm/s respectively). Dynamics of the icodextrin M-->I transfer were constant, but I-->M increased by 50% over time. The intensification of the stirring rate increased the value of P at varying rates: the increase was greater for icodextrin than for glucose, and greater for the I-->M transport direction than for the M-->I direction for both solutes. Chemical modification (by 2.5 mmol/L sodium deoxycholate) increased glucose and icodextrin I-->M transfer a mean of 41% and 81% respectively, but increased M-->I transfer by 70% and 224% respectively. The dynamics of glucose and icodextrin peritoneal transfer in vitro are different: glucose diffusion is constant, but I-->M icodextrin transfer increases over time and is greater than M-->I transfer Fluid stirring intensification and chemical injury to the peritoneum enhance diffusion of glucose and icodextrin. Glucose and icodextrin M-->I transfer but not I-->M transfer is restricted more by tissue barriers than by stagnant fluid layers.

Animals↗
PubMed2002

Structural defects within the carbamate tunnel of carbamoyl phosphate synthetase.

The X-ray crystal structure of carbamoyl phosphate synthetase (CPS) from Escherichia coli has unveiled the existence of two molecular tunnels within the heterodimeric enzyme. These two interdomain tunnels connect the three distinct active sites within this remarkably complex protein and apparently function as conduits for the transport of unstable reaction intermediates between successive active sites. The operational significance of the ammonia tunnel for the migration of NH3 is supported experimentally by isotope competition and protein modification. The passage of carbamate through the carbamate tunnel has now been assessed by the insertion of site-directed structural blockages within this tunnel. Gln-22, Ala-23, and Gly-575 from the large subunit of CPS were substituted by mutagenesis with bulkier amino acids in an attempt to obstruct and/or hinder the passage of the unstable intermediate through the carbamate tunnel. The structurally modified proteins G575L, A23L/G575S, and A23L/G575L exhibited a substantially reduced rate of carbamoyl phosphate synthesis, but the rate of ATP turnover and glutamine hydrolysis was not significantly altered. These data are consistent with a model for the catalytic mechanism of CPS that requires the diffusion of carbamate through the interior of the enzyme from the site of synthesis within the N-terminal domain of the large subunit to the site of phosphorylation within the C-terminal domain. The partial reactions of CPS have not been significantly impaired by these mutations, and thus, the catalytic machinery at the individual active sites has not been functionally perturbed.

Alanine↗
PubMed2005

Elasticity and critical bending moment of model colloidal aggregates.

The bending mechanics of singly bonded colloidal aggregates are measured using laser tweezers. We find that the colloidal bonds are capable of supporting significant torques, providing a direct measurement of the tangential interactions between particles. A critical bending moment marks the limit of linear bending elasticity, past which small-scale rearrangements occur. These mechanical properties underlie the rheology and dynamics of colloidal gels formed by diffusion-limited cluster aggregation, and give critical insight into the contact interactions between Brownian particles.

Journal Article↗
PubMed1978

Topical effects of 16,16 dimethyl prostaglandin E2 on gastric acid secretion and mucosal permeability to hydrogen ions in dogs.

The effects of luminal instillation of 16,16 dimethyl PGE2 (dmPGE2) on gastric acid secretion and back diffusion of H+ were studied in anaesthetised dogs which were prepared with a segment of the greater curvature of the stomach mounted in a double lumen chamber. This model permitted simultaneous evaluation of two segments of mucosa, one control and the other test, supplied by the same vascular pedicle. Imfusion of histamine (1.0 microgram/kg/min, intravenously) stimulated brisk acid secretion in both chambers. Topical application of 25 microgram dmPGE2 in 20 ml 0.3 M HC1 to the test chamber for 30 minutes prevented acid secretion from the test mucosa during a second histamine infusion. Since the control chamber showed no evidence of inhibition this indicates that dmPGE2 acted directly on the secretory cells, rather than after absorption from the bloodstream. This observation, however, does not exclude a possible local effect on mucosal blood flow. Direct exposure of the gastric mucosa to dmPGE2 increased the rate of back diffusion of H+ because of disruption of the permeability barrier, indicated by increased H+ back diffusion, Na+ efflux, and a reduction in potential difference. However, H+ loss was small compared to the reduction in acid output.

Animals↗
PubMed2001

Individual-based modelling of biofilms.

Understanding the emergence of the complex organization of biofilms from the interactions of its parts, individual cells and their environment, is the aim of the individual-based modelling (IbM) approach. This IbM is version 2 of BacSim, a model of Escherichia coli colony growth, which was developed into a two-dimensional multi-substrate, multi-species model of nitrifying biofilms. It was compared with the established biomass-based model (BbM) of Picioreanu and others. Both models assume that biofilm growth is due to the processes of diffusion, reaction and growth (including biomass growth, division and spreading). In the IbM, each bacterium was a spherical cell in continuous space and had variable growth parameters. Spreading of biomass occurred by shoving of cells to minimize overlap between cells. In the BbM, biomass was distributed in a discrete grid and each species had uniform growth parameters. Spreading of biomass occurred by cellular automata rules. In the IbM, the effect of random variation of growth parameters of individual bacteria was negligible in contrast to the E. coli colony model, because the heterogeneity of substrate concentrations in the biofilm was more important. The growth of a single cell into a clone, and therefore also the growth of the less abundant species, depended on the randomly chosen site of attachment, owing to the heterogeneity of substrate concentrations in the biofilm. The IbM agreed with the BbM regarding the overall growth of the biofilm, due to the same diffusion-reaction processes. However, the biofilm shape was different due to the different biomass spreading mechanisms. The IbM biofilm was more confluent and rounded due to the steady, deterministic and directionally unconstrained spreading of the bacteria. Since the biofilm shape is influenced by the spreading mechanism, it is partially independent of growth, which is driven by diffusion-reaction. Chance in initial attachment events modifies the biofilm shape and the growth of single cells because of the high heterogeneity of substrate concentrations in the biofilm, which again results from the interaction of diffusion-reaction with spreading. This stresses the primary importance of spreading and chance in addition to diffusion-reaction in the emergence of the complexity of the biofilm community.

Algorithms↗
PubMed1993

How to ventilate lungs as small as 12.5% of normal: the new technique of intratracheal pulmonary ventilation.

We wished to determine in a laboratory animal model how much residual lung was needed to sustain total gas exchange. In a series of young, healthy lambs weighing approximately 10 kg that were sedated and paralyzed, we progressively excluded from gas exchange all the left lung (a total of 43%), plus the right lower and cardiac lobes (81%), plus the right middle lobe (87.5%). In some studies, the respective lobes were surgically removed; in others, the bronchi and the pulmonary arteries to the respective lobes were ligated. We provided pulmonary ventilation using the pressure control mode (Servo 900 C) at a tidal volume of 20 mL/kg multiplied by the fraction of the remaining lungs, a respiratory rate up to 120/min, a peak inspiratory pressure of 12-15 cm H2O, and a positive end-expiratory pressure of 3 cm H2O. Those lambs with at least both the right upper lobe (RUL) and right middle lobe remaining (19% of total lungs) were weaned to room air on mechanical ventilation within 48 h. Ventilating RUL (12.5% of remaining lung) with the same ventilator required a substantially higher tidal volume and peak inspiratory pressure to result in adequate alveolar ventilation but led to respiratory failure and death within 8 h. We then applied a newly developed system of intratracheal pulmonary ventilation to ventilate the RUL (12.5% of remaining lung) alone. A continuous flow of humidified mixture of air and oxygen was directly passed into the trachea at the level of the carina through a diffuser at a tidal volume of 2.5 mL/kg. A single valve controlled expiration and respiratory rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Reverse iontophoretic monitoring in premature neonates: feasibility and potential.

Premature neonates represent a fragile patient population, often subjected to intensive clinical care and multiple drug therapy, which must be monitored carefully and continuously. The difficult and painful nature of repetitive blood sampling, particularly in this population, has provided considerable impetus for the development of noninvasive methods for monitoring blood analytes. Reverse iontophoresis, a relatively new technology already used for the transdermal monitoring of blood glucose levels in adults, may be particularly well-suited to exploit the unique properties of preterm neonatal skin. The underdevelopment of the premature infant's epidermis, and more specifically the stratum corneum (SC), results in an increased permeability to molecular transport. In this study, we have investigated the feasibility of reverse iontophoretic monitoring of two model drugs, caffeine and theophylline, which are often administered to premature neonates. To this purpose, tape-stripped porcine skin in vitro, which has been previously demonstrated to be an excellent model for premature neonatal skin, was employed. Reverse iontophoresis across intact membranes enabled a quantifiable extraction of both drugs predominantly at the cathode compartment. The mechanism of extraction of these essentially neutral drugs (caffeine and theophylline being uncharged at pH 7.4) was electroosmosis. However, when the SC was removed by progressive tape-stripping, the amounts of drugs extracted by reverse iontophoresis were equivalent to those obtained by passive diffusion. In these circumstances, therefore, the benefit and usefulness of the applied electric field had been lost. In summary, the absence of an at least partially functional skin barrier obviates, in the case of neutral molecules, the control (and directional transport) offered by iontophoresis; in contrast, for ionized species, where the principal iontophoretic transport mechanism is electromigration, the approach should be valid.

Animals↗
PubMed2001

Quantitative analysis of three-dimensional-resolved fiber architecture in heterogeneous skeletal muscle tissue using nmr and optical imaging methods.

The determination of principal fiber directions in structurally heterogeneous biological tissue substantially contributes to an understanding of its mechanical function in vivo. In this study we have depicted structural heterogeneity through the model of the mammalian tongue, a tissue comprised of a network of highly interwoven fibers responsible for producing numerous variations of shape and position. In order to characterize the three-dimensional-resolved microscopic myoarchitecture of the intrinsic musculature of the tongue, we viewed its fiber orientation at microscopic and macroscopic length scales using NMR (diffusion tensor MRI) and optical (two-photon microscopy) imaging methods. Diffusion tensor imaging (DTI) of the excised core region of the porcine tongue resulted in an array of 3D diffusion tensors, in which the leading eigenvector corresponded to the principal fiber orientation at each location in the tissue. Excised axially oriented lingual core tissues (fresh or paraffin-embedded) were also imaged with a mode-locked Ti-Sapphire laser, (76 MHz repetition rate, 150 femtosecond pulse width), allowing for the visualization of individual myofibers at in situ orientation. Fiber orientation was assessed by computing the 3D autocorrelation of discrete image volumes, and deriving the minimal eigenvector of the center voxel Hessian matrix. DTI of the fibers, comprising the intrinsic core of the tongue, demonstrated directional heterogeneity, with two distinct populations of fibers oriented orthogonal to each other and in-plane to the axial perspective. Microscopic analysis defined this structural heterogeneity as discrete regions of in-plane parallel fibers, with an angular separation of ~80 degrees, thereby recapitulating the macroscopic angular relationship. This analysis, conceived at two different length scales, demonstrates that the lingual core is a spatially complex tissue, composed of repeating orthogonally oriented and in-plane fiber patches, which are capable of jointly producing hydrostatic elongation and displacement.

Algorithms↗
PubMedDate not supplied

Reforms in nursing education across Western Europe: from agenda to practice.

The overall goal of this research was to analyze implementation processes translating the nursing education reform agenda into practice across 20 Western European countries. The analysis centered on the substantial changes in structure and ethos created in nursing programs and the adjustments required from nursing faculty members as part of their integration into higher education institutions. Based on the model of implementing organizational change by Pettigrew, Ferlie, and McKee, three major implementation domains were analyzed: (1) the adjustment of nursing faculty members into higher education settings and toward their new roles; (2) the applicability of the graduate profile; and (3) the adequacy of the nursing curriculum for higher education institution and the reformed health care systems. A critical analysis of the scientific literature and policy documents revealed a striking similarity with regard to the difficulties and concerns appearing in the various Western European countries implementing nursing education reforms. Three sorts of difficulties emerge repeatedly in the reforming nursing education programs. These difficulties are related to (1) the adjustment of nursing faculty members into higher education settings and toward their new roles, (2) the competencies held by graduates of preregistration programs, and (3) the content and structure of the nursing curriculum. Future questions, lessons, and potential directions are discussed in this article.

Adaptation, Psychological↗
PubMed1991

Diarrhea in ciguatera fish poisoning: preliminary evaluation of pathophysiological mechanisms.

Ciguatera fish poisoning is a clinical syndrome consisting of a combination of gastrointestinal and neurological symptoms occurring after eating toxin-containing tropical reef fish; it is a major cause of morbidity in Hawaii, the South Pacific, Australia, and the Caribbean. In an effort to define pathophysiological mechanisms responsible for the diarrheal component of the illness, we examined the effect of crude and fractionated toxin preparations on isolated rabbit ileal tissue in a Ussing chamber model. Both the crude toxin preparation (prepared from toxic Ctenochaetus strigosus) and 10% and 50% methanol-chloroform toxin fraction (prepared from a pool of toxic fish samples) gave a striking increase in transepithelial electrical potential difference and short-circuit current. Enterotoxic activity seemed to be mediated by calcium. When examined by light microscopy, the intestinal mucosa was not damaged by the toxin preparations used. Our data demonstrate that toxins involved in ciguatera fish poisoning directly stimulate intestinal fluid secretion without accompanying tissue damage and suggest that calcium is the "second messenger" mediating the process.

Animals↗
PubMed2001

Glycosaminoglycan network geometry may contribute to anisotropic hydraulic permeability in cartilage under compression.

Resistance to fluid flow within cartilage extracellular matrix is provided primarily by a dense network of rod-like glycosaminoglycans (GAGs). If the geometrical organization of this network is random, the hydraulic permeability tensor of cartilage is expected to be isotropic. However, experimental data have suggested that hydraulic permeability may become anisotropic when the matrix is mechanically compressed, contributing to cartilage biomechanical functions such as lubrication. We hypothesized that this may be due to preferred GAG rod orientations and directionally-dependent reduction of inter-GAG spacings which reflect molecular responses to tissue deformations. To examine this hypothesis, we developed a model for effects of compression which allows the GAG rod network to deform consistently with tissue-scale deformations but while still respecting limitations imposed by molecular structure. This network deformation model was combined with a perturbation analysis of a classical analytical model for hydraulic permeability based on molecular structure. Finite element analyses were undertaken to ensure that this approach exhibited results similar to those emerging from more exact calculations. Model predictions for effects of uniaxial confined compression on the hydraulic permeability tensor were consistent with previous experimental results. Permeability decreased more rapidly in the direction perpendicular to compression than in the parallel direction, for matrix solid volume fractions associated with fluid transport in articular cartilage. GAG network deformations may therefore introduce anisotropy to the permeability (and other GAG-associated matrix properties) as physiological compression is applied, and play an important role in cartilage lubrication and other biomechanical functions.

Animals↗
PubMed1992

Diffusion control in blood coagulation. Activation of factor X by factors IXa/VIIIa assembled on human monocyte membranes.

This study examines mechanisms that regulate the activation of blood coagulation proteases on intact cell membranes. The activation of factor X by factors IXa and VIIIa assembled on viable monocytes is presented as a biologically relevant model for membrane-dependent proteolysis of coagulation zymogens. The hypothesis that this reaction is limited by diffusion was tested by comparing predicted with observed concentration dependence, temperature dependence, and effective rate coefficient. Rates of factor X catalysis were measured using a chromogenic substrate specific for the product, factor Xa. The value of KR and of K1/2, i.e. concentrations giving half-maximal rates in reciprocal functional titrations with substrate and enzyme, respectively, were directly correlated with the concentration of the titrated component. Arrhenius plots constructed over temperatures encompassing 10-35 degrees C were biphasic with downward concavity. Apparent activation energies were 6.01 +/- 0.93 and 35.84 +/- 8.9 kcal/mol for the interval above and below the inflection point, respectively. The effective rate coefficient calculated from apparent kinetic parameters was 3.58 +/- 0.1 x 10(12) M-1 s-1. This rate is similar to the maximal rate of collision between factor X molecules and the monocyte, i.e. 2.9 x 10(12) M-1 s-1 estimated from the steady-state von Smoluchowski equation for uniformly reacting spherical particles. The observed agreement between predicted and experimental results indicates that under biologically relevant conditions, the rate of factor X activation by the intrinsic protease is controlled by diffusion of factor X toward the catalytic site.

Blood Coagulation↗
PubMed2000

The Application of Diffusing-Wave Spectroscopy to Monitor the Phase Behavior of Emulsion-Polysaccharide Systems.

Droplet aggregation is an important cause of instability in emulsions because it may, on one hand, lead to an increased creaming rate, resulting in fast separation of a concentrated emulsion phase (creamed layer). On the other hand, it may also lead to the formation of a stabilizing, droplet-based network. Early detection of instability is often difficult due to the high turbidity and viscosity of more concentrated food emulsions. The applicability of diffusing-wave spectroscopy (DWS) for monitoring droplet aggregation and creaming was studied using a model system consisting of a protein-stabilized emulsion, to which a soluble polymer ("thickener") was added. This addition leads to an increased solvent viscosity and may induce droplet aggregation. In addition, the redistribution process of emulsion droplets in aggregating concentrated emulsions was directly observed by confocal scanning laser microscopy (CSLM). By DWS the decrease of the droplet mobility caused by the viscosity increase of the continuous phase could be separated from the effect of droplet aggregation. Moreover, a distinction could be made between aggregation, leading to increased creaming rates and that leading to the formation of a stabilizing droplet network. The potential of DWS for in situ measurement of the stability of concentrated emulsions is discussed. Copyright 2000 Academic Press.

Journal Article↗
PubMed2001

Removal of confounding effects of global signal in functional MRI analyses.

Local signals obtained from BOLD fMRI are generally confounded by global effects. In this paper, we make an essential distinction between global effects and the global signal. Global effects have a similar influence on local signals from a large proportion of cerebral voxels. They may reflect diffuse physiological processes or variations in scanner sensitivity and are difficult to measure directly. Global effects are often estimated from the global signal, which is the spatial average of local signals from all cerebral voxels. If the global signal is strongly correlated with experimental manipulations, meaningfully different results may be obtained whether or not global effects are modeled (G. K. Aguirre et al., 1998, NeuroImage, 8, 302-306). In particular, if local BOLD signals make a significant contribution to the global signal, analyses using ANCOVAor proportional scaling models may yield artifactual deactivations. In this paper, we present a modification to the proportional scaling model that accounts for the contribution of local BOLD signals to the global signal. An event-related oddball stimulus paradigm and a block design working memory task were used to illustrate the efficacy of our model.

Acoustic Stimulation↗
PubMed1995

Comparative efficacy of DMP 840 against mouse and human solid tumor models.

BACKGROUND: DMP 840 is a compound from a class of bis-naphthalimide antitumor agents that recently completed Phase I clinical trials at three North American centers and is currently undergoing Phase II testing. Preclinically, it was shown to have curative activity against a variety of human tumor xenograft models. PURPOSE: To test DMP 840 both in vitro and in vivo for antiproliferative activity against predominantly mouse tumor models. METHODS: A disk diffusion soft agar colony formation assay was used to determine the in vitro growth inhibitory activity against a selection of mouse and human tumor cell lines, and the comparable selective mouse solid tumors were used for in vivo testing. RESULT: In vitro DMP 840 exhibited equal cytotoxicity for human tumors (including MX-1 directly cultured from nude mice), mouse tumors and normal cells. In vivo DMP 840 was only modestly active or inactive against the following mouse tumors: Mam 16/C, T/C = 30% (T/C = Percent Tumor Growth Inhibition); Mam 16/C/ADR, T/C = 33%; Colon 38, T/C = 9%; Panc 03, T/C = 53%; Colon 51/A, T/C = 28%; Panc 02, T/C = 52%; P388/0, 36% ILS (Percent Increased Life Span) and P388/ADR, 14% ILS. Furthermore, the antitumor activity was only observed at the highest non-toxic dose and was associated with a large body weight loss. In contrast, the agent was highly active against the human breast tumor MX-1 implanted subcutaneously in either athymic nude or SCID mice (Nudes: T/C = 0%; 1/5 cures; SCIDS: T/C = 0%; 5/5 cures). CONCLUSIONS: Although there was no selective cytotoxicity in our clonogenic assay for human versus mouse tumor cell lines, selective activity in vivo for human xenograft tumors was noted. Overall, this compound is rather unique in its differential degree of in vivo activity for human versus mouse tumors. IMPLICATIONS: Phase II trials, which are ongoing, will help determine if the preclinical in vivo selective activity of DMP 840 translates to clinical activity in man.

Adenocarcinoma↗