The paracellular shunt of proximal tubule.
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Absorption↗
Biomedical subjects
A M Weinstein
Publications and source records attributed to A M Weinstein.
A mathematical model of rat cortical collecting duct: determinants of the transtubular potassium gradient.
In assessing disorders of potassium excretion, urine composition is used to calculate the transtubular gradient (TTKG), as an estimate of tubule fluid concentration, at a point when the fluid was last isotonic to plasma, namely, within the cortical collecting duct (CCD). A mathematical model of the CCD has been developed, consisting of principal cells and alpha- and beta-intercalated cells, and which includes Na(+), K(+), Cl(-), HCO, CO(2), H(2)CO(3), phosphate, ammonia, and urea. Parameters have been selected to achieve fluxes and permeabilities compatible with data obtained from perfusion studies of rat CCD under the influence of both antidiuretic hormone and mineralocorticoid. Both epithelial (flat sheet) and tubule models have been configured, and model calculations have focused on the determinants of the TTKG. Using the epithelial model, luminal K(+) concentrations can be computed at which K(+) secretion ceases (0-flux equilibrium), and this luminal concentration derives from the magnitude of principal cell peritubular uptake of K(+) via the Na-K-ATPase, relative to principal cell peritubular membrane K(+) permeability. When the model is configured as a tubule and examined in the context of conditions in vivo, osmotic equilibration of luminal fluid produces a doubling of the initial K(+) concentration, which, depending on delivered load, may be substantially greater than the zero-flux equilibrium value. Under such circumstances, the CCD will be a site for K(+) reabsorption, although the relatively low permeability ensures that this reabsorptive flux is likely to be small. Osmotic equilibration may also raise luminal NH(3) concentrations well above those in cortical blood. In this situation, diffusive reabsorption of NH(3) provides a mechanism for base reclamation without the metabolic cost of active proton secretion.
Acids↗
The bandwagon is outside waiting. Eliminating the obstacles to automated and online prescription systems.
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Clinical Pharmacy Information Systems↗
The processing of automatic thoughts of drug use and craving in opiate-dependent individuals.
This study investigated the processing of sentences describing craving and withdrawal in opiate-dependent individuals. Eighteen patients who attended a methadone maintenance clinic for obtaining methadone, 18 patients who were not treated with methadone, and 18 control family members performed on a computerized contextual priming task. The task was priming sentences (craving, withdrawal, or neutral) to words (addiction, neutral, or nonwords). The methadone group was slower to process all sentences compared with family members. They were also faster to process drug-related words following withdrawal-related sentences compared with neutral words following neutral sentences. Finally, they were slower to recognize neutral words following neutral sentences compared with the nonmethadone group. Results suggest that the processing of information describing withdrawal and craving for drugs plays an important role in opiate dependence.
Adult↗
Quantitative IgE antibody assays in allergic diseases.
During the past several years, immunoassays for specific IgE antibodies have been refined to permit reporting results in mass units. Thus quantitative immunoassays for IgE antibodies may be an adjunct to skin tests. In cases of food allergy among children with atopic dermatitis, cutoff values for IgE antibody concentrations to egg, milk, peanut, and fish have been derived to provide 95% positive and 90% negative predictive values. Food-specific IgE antibody determinations can also be used to predict which food allergies are resolving spontaneously. Elevated egg-specific IgE antibody levels in infancy are associated with significantly increased risk for development of inhalant allergies later in childhood. In cases of inhalant allergy, specific IgE antibody levels correlate closely with results of inhalation challenge studies in cat-sensitive persons. Also, mite-specific IgE antibody levels correlate significantly with the mite allergen contents of reservoir dust in the homes of mite-sensitive persons. Immunoassays for quantitation of specific IgE antibodies may be used to document allergen sensitization over time and to evaluate the risk of reaction on allergen exposure. However, immunoassays and skin tests are not entirely interchangeable, and neither will replace the other in appropriate circumstances.
Antibodies, Anti-Idiotypic↗
A mathematical model of the outer medullary collecting duct of the rat.
A mathematical model of the outer medullary collecting duct (OMCD) has been developed, consisting of alpha-intercalated cells and a paracellular pathway, and which includes Na(+), K(+), Cl(-), HCO(3)(-), CO(2), H(2)CO(3), phosphate, ammonia, and urea. Proton secretion across the luminal cell membrane is mediated by both H(+)-ATPase and H-K-ATPase, with fluxes through the H-K-ATPase given by a previously developed kinetic model (Weinstein AM. Am J Physiol Renal Physiol 274: F856-F867, 1998). The flux across each ATPase is substantial, and variation in abundance of either pump can be used to control OMCD proton secretion. In comparison with the H(+)-ATPase, flux through the H-K-ATPase is relatively insensitive to changes in lumen pH, so as luminal acidification proceeds, proton secretion shifts toward this pathway. Peritubular HCO(3)(-) exit is via a conductive pathway and via the Cl(-)/HCO(3)(-) exchanger, AE1. To represent AE1, a kinetic model has been developed based on transport studies obtained at 38 degrees C in red blood cells. (Gasbjerg PK, Knauf PA, and Brahm J. J Gen Physiol 108: 565-575, 1996; Knauf PA, Gasbjerg PK, and Brahm J. J Gen Physiol 108: 577-589, 1996). Model calculations indicate that if all of the chloride entry via AE1 recycles across a peritubular chloride channel and if this channel is anything other than highly selective for chloride, then it should conduct a substantial fraction of the bicarbonate exit. Since both luminal membrane proton pumps are sensitive to small changes in cytosolic pH, variation in density of either AE1 or peritubular anion conductance can modulate OMCD proton secretory rate. With respect to the OMCD in situ, available buffer is predicted to be abundant, including delivered HCO(3)(-) and HPO(4)(2-), as well as peritubular NH(3). Thus, buffer availability is unlikely to exert a regulatory role in total proton secretion by this tubule segment.
Acid-Base Equilibrium↗
A hydrodynamic mechanosensory hypothesis for brush border microvilli.
In the proximal tubule of the kidney, Na(+) and HCO(3)(-) reabsorption vary proportionally with changes in axial flow rate. This feature is a critical component of glomerulotubular balance, but the basic mechanism by which the tubule epithelial cells sense axial flow remains unexplained. We propose that the microvilli, which constitute the brush border, are physically suitable to act as a mechanosensor of fluid flow. To examine this hypothesis quantitatively, we have developed an elastohydrodynamic model to predict the forces and torques along each microvillus and its resulting elastic bending deformation. This model indicates that: 1) the spacing of the microvilli is so dense that there is virtually no axial velocity within the brush border and that drag forces on the microvilli are at least 200 times greater than the shear force on the cell's apical membrane at the base of the microvilli; 2) of the total drag on a 2.5-microm microvillus, 74% appears within 0.2 microm from the tip; and 3) assuming that the structural strength of the microvillus derives from its axial actin filaments, then a luminal fluid flow of 30 nl/min produces a deflection of the microvillus tip which varies from about 1 to 5% of its 90-nm diameter, depending on the microvilli length. The microvilli thus appear as a set of stiff bristles, in a configuration in which changes in drag will produce maximal torque.
Animals↗
Water does not flow across the tight junctions of MDCK cell epithelium.
Although it has been known for decades that the tight junctions of fluid-transporting epithelia are leaky to ions, it has not been possible to determine directly whether significant transjunctional water movement also occurs. An optical microscopic technique was developed for the direct visualization of the flow velocity profiles within the lateral intercellular spaces of a fluid-absorptive, cultured renal epithelium (MDCK) and used to determine the velocity of the fluid flow across the tight junction. The flow velocity within the lateral intercellular spaces fell to near zero adjacent to the tight junction, showing that significant transjunctional flow did not occur, even when transepithelial fluid movement was augmented by imposition of osmotic gradients.
Animals↗
A mathematical model of the inner medullary collecting duct of the rat: pathways for Na and K transport.
A mathematical model of the inner medullary collecting duct (IMCD) of the rat has been developed representing Na+, K+, Cl-, HCO3-, CO2, H2CO3, phosphate, ammonia, and urea. Novel model features include: finite rates of hydration of CO2, a kinetic representation of the H-K-ATPase within the luminal cell membrane, cellular osmolytes that are regulated in defense of cell volume, and the repeated coalescing of IMCD tubule segments to yield the ducts of Bellini. Model transport is such that when entering Na+ is 4% of filtered Na+, approximately 75% of this load is reabsorbed. This requirement renders the area-specific transport rate for Na+ comparable to that for proximal tubule. With respect to the luminal membrane, there is experimental evidence for both NaCl cotransport and an Na+ channel in parallel. The experimental constraints that transepithelial potential difference is small and that the fractional apical resistance is greater than 85% mandate that more than 75% of luminal Na+ entry be electrically silent. When Na+ delivery is limited, an NaCl cotransporter can be effective at reducing luminal Na+ concentration to the observed low urinary values. Given the rate of transcellular Na+ reabsorption, there is necessarily a high rate of peritubular K+ recycling; also, given the lower bound on luminal membrane Cl- reabsorption, substantial peritubular Cl- flux must be present. Thus, if realistic limits on cell membrane electrical resistance are observed, then this model predicts a requirement for peritubular electroneutral KCl exit.
Animals↗
A mathematical model of the inner medullary collecting duct of the rat: acid/base transport.
A mathematical model of the inner medullary collecting duct (IMCD) of the rat has been developed that is suitable for simulating luminal buffer titration and ammonia secretion by this nephron segment. Luminal proton secretion has been assigned to an H-K-ATPase, which has been represented by adapting the kinetic model of the gastric enzyme by Brzezinski et al. (P. Brzezinski, B. G. Malmstrom, P. Lorentzon, and B. Wallmark. Biochim. Biophys. Acta 942: 215-219, 1988). In shifting to a 2 H+:1 ATP stoichiometry, the model enzyme can acidify the tubule lumen approximately 3 pH units below that of the cytosol, when luminal K+ is in abundance. Peritubular base exit is a combination of ammonia recycling and HCO3- flux (either via Cl-/HCO3- exchange or via a Cl- channel). Ammonia recycling involves NH4(+) uptake on the Na-K-ATPase followed by diffusive NH3 exit [S. M. Wall. Am. J. Physiol. 270 (Renal Physiol. 39): F432-F439, 1996]; model calculations suggest that this is the principal mode of base exit. By virtue of this mechanism, the model also suggests that realistic elevations in peritubular K+ concentration will compromise IMCD acid secretion. Although ammonia recycling is insensitive to carbonic anhydrase (CA) inhibition, the base exit linked to HCO3- flux provides a CA-sensitive component to acid secretion. In model simulations, it is observed that increased luminal NaCl entry increases ammonia cycling but decreases peritubular Cl-/HCO3- exchange (due to increased cell Cl-). This parallel system of peritubular base exit stabilizes acid secretion in the face of variable Na+ reabsorption.
Animals↗
Dynamics of cellular homeostasis: recovery time for a perturbation from equilibrium.
In the collecting duct in vivo, the principal cell encounters a wide range in luminal flow rate and luminal concentration of NaCl. As a consequence, there are substantial variations in the transcellular fluxes of Na+ and Cl-, conditions which would be expected to perturb cell volume and cytosolic concentrations. Several control mechanisms have been identified which can potentially blunt these perturbations, and these entail cellular regulation of the luminal membrane Na+ channel and peritubular membrane K+ and Cl- channels. To illustrate the impact of these regulated channels, a mathematical model of the principal cell of the rat cortical collecting duct has been developed, in which ion channel permeabilities are either constant or regulated. In comparison to the model with fixed permeabilities, the model with regulated channels demonstrates enhanced cellular homeostasis following steady-state variation in luminal NaCl. However, in the transient response to a cytosolic perturbation, the difference in recovery time between the models is small. An approximate analysis is presented which casts these models as dynamical systems with constant coefficients. Despite the presence of regulated ion channels, concordance of each model with its linear approximation is verified for experimentally meaningful perturbations from the reference condition. Solution of a Lyapunov equation for each linear system yields a matrix whose application to a perturbation permits explicit estimation of the time to recovery. Comparison of these solution matrices for regulated and non-regulated cells confirms the similarity of the dynamic response of the two models. These calculations suggest that enhanced homeostasis by regulated channels may be protective, without necessarily hastening recovery from cellular perturbations.
Animals↗
Cognitive processing in post-traumatic stress disorder.
Recent research has suggested an abnormal attentional bias to threat in anxiety disorders. We have assessed the processing of thoughts of trauma, panic attacks, general fear and positive affect in a cohort of 15 war veterans with post-traumatic stress disorder (PTSD) and an age- and sex-matched normal control group. Subjects with PTSD showed delayed processing of self-referential sentences when the themes of the sentences were traumatic experiences or positive affect, compared with controls. However, they were more efficient than control subjects in the processing of sentences describing situations of panic attacks and general fear. It would therefore appear that in patients with PTSD, cognitive processing is hindered by personally relevant themes of past traumatic experiences, whereas it may be facilitated by information related to general threat or internal body sensations of panic.
Adult↗
Acid/base transport in a model of the proximal tubule brush border: impact of carbonic anhydrase.
A mathematical model of the brush border of the proximal tubule (T. A. Krahn, P. S. Aronson, and A. M. Weinstein. Bull. Math. Biol, 56: 459-490, 1994) has been extended by the inclusion of CO2 and H2CO3 as diffusible species and by the inclusion of finite rate constants for the hydration of CO2. This permits the simulation of carbonic anhydrase (CA) activity and its inhibition. We confirm the result of our previous study, which is that, in the presence of CA, the unstirred layer has only a modest effect on the observed formic acid permeability. CA inhibition results in disequilibrium pH gradients, and the effect of these gradients on formic acid permeability depends on the presence of other membrane transport proteins. We also examined the impact of CA activity on the flux of total CO2 through the brush border. Under physiological conditions, CA inhibition depressed NaHCO3 reabsorption through the brush border by interfering with the HCO3(-)-facilitated diffusion of CO2. However, the determination of brush-border CO2 permeability, using an imposed CO2 gradient, was relatively uninfluenced by CA activity. Finally, we inserted a kinetic representation of the Na+/H+ exchanger into the brush-border model. Even when luminal and cytosolic diffusion coefficients were increased 1,000-fold, there was no effect on brush-border Na+ flux. This suggests that variations in the unstirred layer cannot be responsible for the flow dependence of Na+ reabsorption.
Absorption↗
Coupling of entry to exit by peritubular K+ permeability in a mathematical model of rat proximal tubule.
In the proximal tubule in vivo, glomerulotubular balance requires that tubule epithelial cells accommodate a twofold variation in Na+ reabsorption through the Na+/H+ exchanger of the luminal membrane. In a mathematical model of proximal tubule, in which permeability coefficients are fixed, doubling flux through the Na+/H+ antiporter produces a substantial increase in cell volume and cytosolic HCO3-. In this model, it is possible to vary peritubular K+ permeability with changes in luminal Na+ entry, so that cell volume is constrained to be constant. In these calculations, the model predicts that peritubular hyperpolarization and nearly constant cytosolic HCO3- will accompany increases in luminal Na+ entry. Realistic models of variable peritubular K+ permeability might include a functional dependence on flux through the Na(+)-K(+)-adenosinetriphosphatase, cytosolic pH, or cell volume. When K+ permeability is represented as a function of any of these variables, homeostatic control of cell volume and pH can be obtained over a physiological variation of Na+/H+ flux. However, when luminal Na+ entry is via Na(+)-glucose cotransport, volume homeostasis is best when peritubular K+ permeability depends on the rate of active Na+ transport. For any modulator of K+ permeability, realistic constraints on the value of this parameter suggest that peritubular K+ permeability is, by itself, not sufficient to maintain cell volume within narrow limits. Parallel activation of another exit pathway, such as peritubular Na(+)-3 HCO3- cotransport, may be required to achieve the necessary homeostasis.
Animals↗
Visual ERPs evidence for enhanced processing of threatening information in anxious university students.
There is accumulating evidence that highly anxious individuals selectively attend to threatening information; however, contrary to expectations, there is no evidence of enhanced processing of threat stimuli in those individuals. We investigated this question by using a sample of 20 University students who were split into two groups consisting of 10 high-anxious and 10 low-anxious subjects according to Spielberger Trait Anxiety Inventory score (median STAI = 40). Without emphasizing speed, subjects were required to decide whether visually presented words (positive, neutral, or threat) matched semantically with previous priming sentences (threat or positive) displayed on a computer screen (altogether, two types of priming sentences and three types of probe words). There was a fixed interval of 1.1 seconds between priming sentences (SI) and probe words (S2) as well as between each priming sentence word. Response time and visual event-related potentials (ERPs) were recorded in both conditions. The results showed that, compared to the Low-Anxious group, the amplitude of N100 and P400 were enhanced for the High-Anxious group in the threat priming conditions. Low-anxious individuals showed almost identical processing of threat-related situations and positive situations. Furthermore, the P400 peak latency was shorter for emotional incongruous probes in high-anxious individuals. ERPs results of the experiment suggest that highly anxious individuals deploy more processing resources to threatening information. This bias in information processing occurs in the absence of any behavioral changes (indicated by reaction times). Attentional bias in anxiety therefore implies that threatening information is given a priority over other information and is more persistently activated in anxiety states.
Adult↗
A kinetically defined Na+/H+ antiporter within a mathematical model of the rat proximal tubule.
The luminal membrane antiporter of the proximal tubule has been represented using the kinetic formulation of E. Heinz (1978. Mechanics and Engergetics of Biological Transport. Springer-Verlag, Berlin) with the assumption of equilibrium binding and 1:1 stoichiometry. Competitive binding and transport of NH+4 is included within this model. Ion affinities and permeation velocities were selected in a least-squares fit to the kinetic parameters determined experimentally in renal membrane vesicles (Aronson, P.S., M.A. Suhm, and J. Nee. 1983. Journal of Biological Chemistry. 258:6767-6771). The modifier role of internal H+ to enhance transport beyond the expected kinetics (Aronson, P.S., J. Nee, and M. A. Suhm. 1982. Nature. 299:161-163) is represented as a velocity effect of H+ binding to a single site. This kinetic formulation of the Na+/H+ antiporter was incorporated within a model of the rat proximal tubule (Weinstein, A. M. 1994. American Journal of Physiology. 267:F237-F248) as a replacement for the representation by linear nonequilibrium thermodynamics (NET). The membrane density of the antiporter was selected to yield agreement with the rate of tubular Na+ reabsorption. Simulation of 0.5 cm of tubule predicts that the activity of the Na+/H+ antiporter is the most important force for active secretion of ammonia. Model calculations of metabolic acid-base disturbances are performed and comparison is made among antiporter representations (kinetic model, kinetic model without internal modifier, and NET formulation). It is found that the ability to sharply turn off Na+/H+ exchange in cellular alkalosis substantially eliminates the cell volume increase associated with high HCO3- conditions. In the tubule model, diminished Na+/H+ exchange in alkalosis blunts the axial decrease in luminal HCO3- and thus diminishes paracellular reabsorption of Cl-. In this way, the kinetics of the Na+/H+ antiporter could act to enhance distal delivery of Na+, Cl-, and HCO3- in acute metabolic alkalosis.
Alkalosis↗
Weak acid permeability of a villous membrane: formic acid transport across rat proximal tubule.
Chloride/formate exchange, in parallel with Na+/H+ exchange and nonionic diffusion of H2CO2, has been proposed as a mechanism of electroneutral transcellular Cl- reabsorption by the proximal tubule. However, the measured brush border H2CO2 permeability of the rat proximal tubule is at least an order of magnitude too low to support sufficient H2CO2 recycling. To investigate the possibility that an unstirred layer within the brush border might depress the measured H2CO2 permeability, we constructed a mathematical model of a villous membrane. Axial fluxes along villous and intervillous spaces were specified by Nernst-Planck diffusion equations. Model parameters were set to achieve agreement with ion and water fluxes measured in the rat proximal tubule. The equations were solved numerically to generate steady-state concentration profiles in the villous and intervillous spaces. An apparent brush border H2CO2 permeability was determined by perturbing luminal [H2CO2] and calculating the change in H2CO2 flux. Overall, the ratio of apparent brush border H2CO2 permeability to cell membrane H2CO2 permeability was greater than 90%. Contributing to the small decrease in apparent permeability are finite diffusion coefficients, folding of the membrane, and acidification of the luminal solution. An approximate analysis of this system shows the critical parameters of brush border formate transport to be the actual membrane H2CO2 permeability, and the diffusion coefficients of HCO2- and HCO3-. Nevertheless, decreasing the diffusion coefficients by one order of magnitude failed to depress apparent brush border H2CO2 permeability by more than an additional 25%. We conclude that although permeability is systematically underestimated across a villous membrane, unstirred layer effects in the brush border are still too small to resolve the discrepancy between the measured value of H2CO2 permeability and the value needed to allow recycling.
Animals↗
Mathematical models of tubular transport.
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Animals↗