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PubMed1982

Kinetics of acetylthiocholine binding to electric eel acetylcholinesterase in glycerol/water solvents of increased viscosity. Evidence for a diffusion-controlled reaction.

Steady-state kinetic studies were made on the very efficient enzyme hydrolysis of acetylthiocholine by electric eel acetylcholinesterase (acetylcholine acetylhydrolase, EC 3.1.1.7) in glycerol/water solvents of increased viscosity. Determinations of the very fast minimum substrate association rate constants kmin, (2 . 10(8) M-1 . s-1 at I approximately 0.1 M and 25 degrees C) from the Michaelis parameters, V/(Km[E0]), were made at low substrate concentrations in order to obtain kmin directly. kmin was shown to be strongly dependent upon viscosity, which is characteristic of a diffusion-controlled reaction. kmin is as large or larger than plausible models for a simple diffusion-controlled reaction between a charged enzyme and substrate would suggest. Enhancement of the diffusion-controlled reaction through nonspecific binding of substrate to the highly negatively charged acetylcholinesterase followed by two-dimensional surface diffusion in a random walk to the active site may be a factor in this enzyme mechanism. Evidence for this comes from the viscosity dependence of kmin. Using the surface diffusion model it is estimated that the binding-site target area on acetylcholinesterase is effectively increased a minimum of 8-fold.

Acetylcholinesterase↗
PubMed2005

Signaling interactions between squamous and columnar epithelia of the Drosophila wing disc.

Understanding the interactions between distinct epithelial cells would help us to understand the development of tissues. Drosophila imaginal discs, which are made up of two types of epithelial cells, provide good model systems for such studies. The disc proper or the columnar epithelial cells are apposed to a layer of squamous epithelial cells (the peripodial membrane). We have examined organization of peripodial and disc proper cells vis-à-vis their polarity since cell polarity plays an important role in the polarized transport of signaling molecules. With the help of polarity-specific cell markers, we have observed that apical surfaces of peripodial and disc proper cells face each other. This provides the cellular basis for the recently demonstrated signaling interactions between peripodial and disc proper cells during disc patterning. We also report significant similarities as well as differences between peripodial and disc proper cells in Engrailed-dependent wingdisc-patterning events, which make them an appropriate model system for studying the mechanism of diffusion of signal molecules, such as Hedgehog. Results with wild-type and two mutant forms of Hedgehog suggest that direct cell-cell contact is a requirement for the movement of wild-type Hedgehog signal and reconfirm that cholesterol-modification of Hedgehog makes it a short-range signaling molecule by restricting its movement.

Animals↗
PubMed1996

Characterization of edema by diffusion-weighted imaging in experimental traumatic brain injury.

The objective of this study was to use diffusion-weighted magnetic resonance imaging (DWI) to help detect the type of edema that develops after experimental trauma and trauma coupled with hypotension and hypoxia (THH). Reduction in the apparent diffusion coefficients (ADCs) is thought to represent cytotoxic edema. In a preliminary series of experiments, the infusion edema model and middle cerebral artery occlusion models were used to confirm the direction of ADC change in response to purely extracellular and cytotoxic edema, respectively. The ADCs increased (p<0.05) in the case of extracellular edema and decreased (p<0.001) in cytotoxic edema. Following these initial experiments, a new impact acceleration model was used to induce traumatic brain injury. Thirty-six adult Sprague-Dawley rats were separated into four groups; sham, trauma alone, hypoxia and hypotension (HH), and THH. Following trauma, a 30-minute insult of hypoxia (PaO2 of 40 mm Hg) and hypotension (mean arterial blood pressure (MABP) of 30 mm Hg) were imposed and the animals were resuscitated. The DWI was carried out at four 1-hour intervals postinjury, and MABP, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral blood flow (CBF) were monitored. The ADCs in the control and HH groups remained unchanged. The ADCs in the THH group rapidly decreased from a control level of 0.68 +/- 0.05 x 10(-3) mm2/second to 0.37 +/- 0.09 x 10(-3) mm2/second by 3 hours posttrauma (p < 0.001). In this group, the decreased CBF and CPP during secondary insult remained low despite resuscitation, with the ICP increasing to 56 +/- 7 mm Hg by 3 hours. In the trauma alone group, the rise in ICP reached a maximum value (28 +/- 3 mm Hg) at 30 minutes with a significant and sustained increase in CBF despite a gradual decrease in CPP. The ADCs in this group were not significantly reduced. The data lead the authors to suggest that the rise in ICP following severe trauma coupled with secondary insult in this model is predominately caused by cytotoxic edema and that ischemia plays a major role in the development of brain edema after head injury.

Animals↗
PubMed2005

Economic analysis of the implementation of autologous transfusion technologies throughout England.

OBJECTIVES: This study aims to provide the first estimates of the costs and effects of the large scale introduction of autologous transfusion technologies into the United Kingdom National Health Service. METHODS: A model was constructed to allow disparate data sources to be combined to produce estimates of the scale, costs, and effects of introducing four interventions. The interventions considered were preparing patients for surgery (PPS) clinics, preoperative autologous donation (PAD), intraoperative cell salvage (ICS), and postoperative cell salvage (PoCS). RESULTS: The key determinants of cost per operation are the anticipated level of reductions in blood use, the mean level of blood use, mean length of stay, and the cost of the technology. The results show the potential for considerable reductions in blood use. The greatest reductions are anticipated to be through the use of PPS and ICS. Vascular surgery, transplant surgery, and cardiothoracic surgery appear to be the specialties that will benefit most from the technologies. CONCLUSIONS: Several simplifications were used in the production of these estimates; consequently, caution should be used in their interpretation and use. Despite the drawbacks in the methods used in the study, the model shows the scale of the issue, the importance of gathering better data, and the form that data must take. Such preliminary modeling exercises are essential for rational policy development and to direct future research and discussion among stakeholders.

Blood Loss, Surgical↗
PubMed1976

Studies on the human pharmacokinetics of isophosphamide (NSC-109724).

The pharmacokinetics of isophosphamide (IP) in man has been studied using 14C-labeled drug and differential extraction of unchanged drug from metabolites by CHCl3 extraction of plasma and urine. The plasma decay of IP is biphasic with a terminal half-life of 15.2 hours which is twice that reported for cyclophosphamide (CP). The fraction of drug metabolized is 49% for IP compared to 88% reported for CP. This is consistent with the six-times larger pseudometabolic pharmacokinetic rate constant reported for CP (0.26 hr-1) than found by us for IP (0.04 hr-1). The renal clearance for IP (21.3 ml/min) is two times that of CP (10.7 ml/min). In addition to an analysis of the kinetics of disposition and elimination of unchanged IP, an analysis of the pharmacokinetics of total metabolite of IP in plasma and urine was made. A nonlinear pharmacokinetic model which includes a term for biotransformation according to Michaelis and Menten revealed that the total metabolites do not diffuse from a small plasma space of 2.1 liters but are excreted directly via the urine. In contrast to the biexponential plasma decay of single, high-dose IP (5 g/m2), multiple-dose IP (2.4 g/m2/day X 3) shows a monoexponential decay with a half-life of 6.9 hours, a pseudometabolic rate constant of 0.08 hour-1, and a renal clearance of 18.7 ml/minute. The fraction of drug metabolized (79.7%) calculated from the pharmacokinetic parameters agrees with the fraction of drug recovered in urine as total metabolites (72.8%). This is distinctly different from high-dose IP (48.6%) but similar to the fraction of drug metabolized as reported for CP (88.0%). This suggests that the pharmacokinetic transfer constant for IP metabolism is dose dependent, an observation that may be useful in developing new IP regimens.

Cyclophosphamide↗
PubMed1983

A simple model for simulation of oxygen transport in the microcirculation.

A mathematical model of deoxygenation of blood in the microcirculation is used to estimate the mass transfer resistance in the blood and to examine certain assumptions used in prior work on simulation of the microcirculation: the treatment of blood as a continuum and the use of a single-step reaction kinetics model. The erythrocytes are treated as cylindrical slugs which alternate with plasma gaps such that oxygen transport is by radial diffusion in the cell. The system of equations including reaction kinetics and oxyhemoglobin diffusion is solved numerically. The results are of direct applicability in estimation of oxygen concentration profiles in tissue. The results also indicate that the resistance to oxygen transport in the capillary (relative to that in the surrounding tissue) is much higher than predicted by the continuum approach used by most prior workers. The resistance in the capillary is a significant fraction of the overall resistance. Other results give quantitative estimates of the error incurred from use of a single-step kinetic model.

Biological Transport↗
PubMed2006

Lateral diffusion and percolation in membranes.

An algorithm based on Voronoi tessellation and percolation theory is presented to study the diffusion of model membrane components (solutes) in the plasma membrane. The membrane is modeled as a two-dimensional space with integral membrane proteins as static obstacles. The Voronoi diagram consists of vertices, which are equidistant from three matrix obstacles, joined by edges. An edge between two vertices is said to be connected if solute particles can pass directly between the two regions. The percolation threshold, pc, determined using this passage criterion is pc approximately equal to 0.53. This is smaller than if the connectivity of edges were assigned randomly, in which case the percolation threshold pr=2/3, where p is the fraction of connected edges. Molecular dynamics simulations show that diffusion is determined by percolation of clusters of edges.

Algorithms↗
PubMed2004

Immunomodulatory functions of the diffuse neuroendocrine system: implications for bronchopulmonary dysplasia.

Pulmonary neuroendocrine (NE) cells are believed to be the precursor of NE lung carcinomas, including well-differentiated (carcinoids) and moderately/poorly differentiated (atypical carcinoids and small-cell carcinomas, SCLCs) subtypes. In early studies, we determined mechanisms by which NE cell-derived peptides such as bombesin-like peptide (BLP) promote normal fetal lung development. Postnatally, BLP may normally regulate perinatal adaptation of the pulmonary circulation. However, elevated BLP levels in premature infants shortly after birth predict which infants are at high risk for developing bronchopulmonary dysplasia (BPD, chronic lung disease of newborns). An anti-BLP blocking antibody abrogates clinical and pathological evidence of lung injury in two baboon models of BPD. These observations indicate that BLP mediates lung injury in BPD, supporting a role for BLP as pro-inflammatory cytokines. We have directly tested the effects of BLP on eliciting inflammatory cell infiltrates in vivo. Surprisingly, mast cells are the major responding cell population. These data suggest that the diffuse NE system may be a newly recognized component of innate immunity in multiple organ systems. We speculate that overproduction of NE cell-derived peptides such as BLP may be responsible for a variety of chronic inflammatory disorders.

Amino Acid Sequence↗
PubMedDate not supplied

Parameter estimation in six numeric models of transperitoneal transport of glucose.

Six competing kinetic models of transperitoneal glucose transport were formulated and validated. The models were designed to elucidate the presence or absence of diffusive, nonlymphatic convective and lymphatic convective solute transport. The validation procedure included an assessment of theoretical and practical identifiability, goodness of fit, residual error analysis, and plausibility of parameter estimates. Experimental results were obtained from 21 patients without diabetes. The validation procedure demonstrated that the model that only included diffusion was superior to the other models. Theoretically, both nonlymphatic convective and lymphatic convective transports might exist. However, neither the ultrafiltration sieving coefficient nor the lymphatic flow rate were practically identifiable, probably because any amount of glucose transported by nonlymphatic convective and lymphatic convective transport mechanisms was negligible compared with the amount transported by diffusion. Based on these results, there appear to be problems measuring convective solute transport parameters when the solute transport is in the dialysate-to-blood direction while the fluid transport is in the blood-to-dialysate direction.

Adult↗
PubMed2003

Diffuse reflection of ceramics coated with dielectric thin films.

We have studied the diffuse reflection properties of ceramics in the presence of dielectric thin films on the surface. A simple optical model was proposed in which interference effects in a thin film were considered for light scattered out of a ceramic in various directions. Measurements were performed on angle-resolved reflection spectra of a thin-film-coated alumina ceramic in the case of normal incidence. They showed that the presence of the thin film on the ceramic's surface modified the angular distributions of scattered radiation from that of a bare ceramic, which suggested a way to tailor the scattering properties of a diffuse reflector as needed.

Journal Article↗
PubMed1999

Anomalous surface diffusion of water compared to aprotic liquids in nanopores.

1H nuclear magnetic relaxation dispersion experiments show remarkable differences between water and acetone in contact with microporous glass surfaces containing trace paramagnetic impurities. Analyzed with surface relaxation theory on a model porous system, the data obtained for water show that proton surface diffusion limited by chemical exchange with the bulk phase permits long-range effectively one-dimensional exploration along the pores. This magnetic-field dependence coupled with the anomalous temperature dependence of the relaxation rates permits a direct interpretation in terms of the proton translational diffusion coefficient at the surface of the pores. A universal rescaling applied to these data collected for different pore sizes and on a large variety of frequencies and temperatures, supports this interpretation. The analysis demonstrates that acetone diffuses more slowly, which increases the apparent confinement and results in a two-dimensional model for the molecular dynamics close to surface relaxation sinks. Surface-enhanced water proton diffusion, however, permits the proton to explore a greater spatial extent of the pore, which results in an apparent one-dimensional model for the diffusive motions of the water that dominate nuclear spin relaxation.

Diffusion↗
PubMed1982

Air monitoring network program in Saudi Arabia.

The Kingdom of Saudi Arabia has initiated a program to install air quality network stations throughout the country in order to measure concentration of the ambient air pollutants. The site selection of these stations is an important objective to be accomplished and must be done based on scientific and rational work. To accomplish this objective, a modified version of atmospheric transport and dispersion model, known as air resources laboratories - atmospheric transport and dispersion (ARL- ATAD) model, is used to evaluate long range transport and diffusion of air pollutants from major pollution causing sources such as refineries, open-air burning of associated gases of oil fields and major industries. Hourly meteorological data for a period of three years (from 1977 to 1979) on wind speed, wind direction, pressure, and temperature from 20 synoptic stations in Saudi Arabia is processed and used as model input. In addition to these, meteorological data from three upper air stations is also processed in order to determine base and top of critical inversion heights. Various pollution causing sources are identified within the study area. Air trajectories are drawn with sources as the origins of the trajectories and the dispersion characteristics is studied with distance and time. Based on long term meteorological records, the adversely affected zones are statistically identified for potential station sites.

Air Pollution↗
PubMed1989

The asymptotic transectional/circumferential homogeneity of the solutions of reaction-diffusion systems in/on cylinder-like domains.

It is often reported that an animal with spotty coat markings on its body has a tail with stripe-shaped pattern. In other various biological and chemical phenomena in/on cylinder-like domains, longitudinally periodic band patterns are observed much more often than the other non-uniform patterns. This paper mathematically explains these observations by proving that, in/on a long and narrow cylinder-like domain, any solution of reaction-diffusion system asymptotically loses its spatial dependence in the transectional/circumferential direction.

Animals↗
PubMed1987

On the direction of the diffusional electric field in a mucous layer.

A simple model of the mucous layer is used to illustrate the complex relationship of the diffusional electric field direction in the layer and parameters of the latter. It is shown that the field direction may depend not only on the ratios of mobile microion diffusivities but also on the characteristics of the layer (carboxylic group concentration and dissociation constant). The electric field direction is also shown to vary across the layer under appropriate conditions. The results are used to interpret the electrophoretic mechanism of the transport of macromolecules across the mucous layer on the surface of the digestive tract wall.

Diffusion↗
PubMed2000

Transperitoneal transport of glucose in vitro.

The effect of fluid mixing intensification, damage of mesothelial cells, gentamicin, and icodextrin on the diffusive glucose transport across the peritoneal membrane were evaluated in in vitro studies. A mathematical model of mass transport was used to calculate the diffusive permeability, expressed as a diffusive permeability coefficient (P). In the control conditions, the rate of glucose transfer from the interstitial to the mesothelial side of membrane (I-->M) and in the opposite direction (M-->I) remained constant, and the P value at mean was 2,731 +/- 1,493 x 10-4 (cm x s-1). The change of the stirring rate from 5.5 to 11 ml/min increased P values by about 74% for transport direction I-->M and 58% for M-->I, and the change from 11 to 22 ml/min enhanced P at mean by about 42% for both directions. The damage of the mesothelial layer, using sodium deoxycholate (2.5 mmol/L; 103.6 mg%), increased the glucose transfer from the interstitial to the mesothelial side of the peritoneum by 41% and to the opposite direction by 70%. Addition of icodextrin to the glucose solution increased glucose bidirectional transport at mean by about 14% for I-->M and 24% for M-->I. Furthermore, gentamicin did not change the I-->M transfer, but diminished M-->I transport by about 12%. In conclusion, the reduction of unstirred fluid layers at the mesothelium and the interstitium-fluid interfaces, removal of mesothelium, and addition of icodextrin increased the diffusive glucose transport in vitro; unstirred fluid layers restricted glucose transfer (I-->M) more than the mesothelium; and peritoneal glucose transport, directed from the mesothelial to the interstitial side of the peritoneum, decreased slightly after the addition of gentamicin.

Algorithms↗
PubMed2002

Matrices of water-soluble drug using natural polymer and direct compression method.

The objective of this research was to find an optimum Carrageenan matrix formulation with the desired drug release and physical properties prepared by direct compression. In order to achieve this, matrices containing 10% theophylline, different Carrageenan level, and different excipient were prepared and evaluated. A selected matrix containing 40% Carrageenan and lactose fast flo was tested for dissolution in three different dissolution media (distilled water, 0.1 N HCl, and phosphate buffer pH 7.4). The same formulation was also tested for dissolution at 50 rpm, 100 rpm, and 150 rpm, and using different dissolution apparatus (Apparatus 1 and 2). All matrices showed a decrease in drug release as the polymer level was increased. Only Avicel PH-101 did not show any significant difference between matrices prepared with 30% and 40% polymer. At 10% polymer level, it appears that the type of diluent used controls the drug release. However, at high polymer level, 30% and 40%, it appears that the polymer level controls the drug release. Phosphate buffer pH 7.4 and 0.1 N HCl increase drug release and appear to increase Carrageenan solubility and decrease gel formation. Also, as the rotational speed of the apparatus was increased, the integrity of the gel layer was decreased, and the release of drug was increased. The drug release from Carrageenan matrices appears to follow the diffusion model for inert matrix up to 90 min. After 90 min, the drug release follows a zero-order model. This study demonstrated that matrices using Carrageenan can be successfully prepared by direct compression.

Carrageenan↗
PubMed2006

Diffusional anisotropy in collagenous tissues: fluorescence imaging of continuous point photobleaching.

Molecular transport in avascular collagenous tissues such as articular cartilage occurs primarily via diffusion. The presence of ordered structures in the extracellular matrix may influence the local transport of macromolecules, leading to anisotropic diffusion depending on the relative size of the molecule and that of extracellular matrix structures. Here we present what we believe is a novel photobleaching technique for measuring the anisotropic diffusivity of macromolecules in collagenous tissues. We hypothesized that macromolecular diffusion is anisotropic in collagenous tissues, depending on molecular size and the local organization of the collagen structure. A theoretical model and experimental protocol for fluorescence imaging of continuous point photobleaching was developed to measure diffusional anisotropy. Significant anisotropy was observed in highly ordered collagenous tissues such as ligament, with diffusivity ratios>2 along the fiber direction compared to the perpendicular direction. In less-ordered tissues such as articular cartilage, diffusional anisotropy was dependent on site in the tissue and size of the diffusing molecule. Anisotropic diffusion was also dependent on the size of the diffusing molecule, with greatest anisotropy observed for larger molecules. These findings suggest that diffusional transport of macromolecules is anisotropic in collagenous tissues, with higher rates of diffusion along primary orientation of collagen fibers.

Animals↗
PubMed1993

Mechanisms of ischemic brain damage with intracerebral hemorrhage.

The results of surgical evacuation of spontaneous intracerebral hematomas are disappointing. This is largely because experimental studies have now confirmed that the brain surrounding an intracerebral hematoma develops profound and extensive ischemia. The volume of this ischemic brain may exceed the volume of the hemorrhage several times. This has been demonstrated experimentally using 14C-iodoantipyrene autoradiography in various modifications of the intracerebral hemorrhage model. These models have demonstrated that the pathophysiology of the ischemia is partly due to direct mechanical compression. There is also a component of the ischemic process induced by vasoconstrictor substances in blood. The diffuse uncontained type of hemorrhage (subarachnoid or intraventricular) causes a global reduction in cerebral perfusion pressure. The focal ischemic event is initiated at the time of hemorrhage and is largely irreversible. The experimental evidence to date indicates that neuroprotective agents (calcium channel blockers and N-methyl-D-aspartate receptor antagonists) reduce ischemic brain damage. Similarly, in immunosuppressed animals the amount of brain edema that follows the initial ischemic insult was reduced. These studies indicate that pharmacological neuroprotective strategies can minimize the brain damage that follows intracerebral hemorrhage. Early removal of the mass lesion may play a role, but it is unlikely to reverse the ischemic process if it is the only treatment offered.

Animals↗