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Biomedical subjects

R Pfeffer

Publications and source records attributed to R Pfeffer.

At least 19 recordsLinked to original sources
PubMed1995

A case management program for chemically dependent clients with multiple needs.

As part of a 3-year federal demonstration project, San Francisco health clinics provided case management services to chemically dependent individuals who were low-income and often homeless. Many of those participating in the project had also been diagnosed with HIV infection and/or mental illness. The intent of the demonstration project was to use case management as a mechanism for strengthening the linkages between substance abuse treatment and primary care systems. Case management was adopted as the catalyst for increased communication between medical personnel and other service providers to develop a more comprehensive approach to responding to the myriad of client needs. A specially designed management information system (MIS) was developed to help document client information and case management activities, as well as provide a tickler system to improve client continuity. This report integrates both qualitative and quantitative findings to provide a context for understanding case management activities, client problems and successes, and the systemic problems facing clients and case managers in linking primary care, substance abuse treatment, and mental health services.

Adolescent↗
PubMed1993

High affinity dopamine D2 receptor radioligands. 3. [123I] and [125I]epidepride: in vivo studies in rhesus monkey brain and comparison with in vitro pharmacokinetics in rat brain.

Studies of [123I]epidepride uptake in rhesus monkey brain were performed using single photon tomography. Striatal uptake peaked at 0.85% of administered dose/g at 107 min post-injection, then declined slowly to 0.70% of administered dose/g at 6 h. Striatal:posterior brain ratios rose from 2 at 25 min to 6.8 at 105 min, to 15 at 4 h and to 58 at 6.4 h. [123I]Epidepride was displaced by haloperidol (0.1 and 1 mg/kg) with a half-life of washout of 55 min. Little displacement of [123I]epidepride was observed following administration of 1 or 2 mg/kg d-amphetamine, respectively, indicating [123I]epidepride is not easily displaced by endogenous dopamine. In vitro equilibrium binding studies using rat striatum revealed a KD of 46 pM and Bmax of 33 pmol/g tissue at 37 degrees C, while at 25 degrees C the KD was 25 pM and the Bmax 32 pmol/g tissue. In vitro kinetic analysis of association and dissociation curves revealed a half-life for receptor dissociation at 37 degrees C of 15 min and 79-90 min at 25 degrees C. Allowing for the temperature difference, there is good correspondence between in vivo and in vitro dissociation kinetics at 25 degrees C. Increasing in vitro incubation temperature from 25 to 37 degrees C caused a 6-fold increase in the dissociation rate, suggesting that there is a change in binding kinetics at the dopamine D2 receptor at 37 degrees C compared to in vivo binding. The results of this study indicate that [123I]epidepride is an excellent radioligand for SPECT studies of the dopamine D2 receptor in man.

Amphetamine↗
PubMed1991

A mathematical model for the receptor mediated cellular regulation of the low density lipoprotein metabolism.

A prototype mathematical model for Brown and Goldstein's pioneering studies on the LDL receptor mediated pathway for the regulation of the cellular content of cholesterol has been developed in this paper. In order to analyze the essential features of this complex system quantitatively and still reflect the framework of the total system, six important processes are considered in the model. They are: (1A, B) the hydrolysis and synthesis of the LDL receptor; (2) the binding of LDL to its receptors; (3) the hydrolysis of LDL; (4) the storage of cholesteryl esters; (5) the regulation of de novo synthesis of cholesterol; and (6) the efflux of free cholesterol to the external medium. All these processes form a system to let the cells take up enough cholesterol from the external medium for their utilization and yet avoid the excessive accumulation of the lipid within the cells. The validity of the model is tested by showing that it can predict many of experimental curves obtained for human fibroblasts in tissue culture studies. The main purpose of the model is to determine how the free cholesterol level in the cell is related to the external LDL concentration and the regulatory capacity of the cells to adapt to a changing LDL environment. In addition, the model reveals an important behavior of SMC, i.e., for a slowly increasing LDL concentration in the extracellular medium, the rate of intracellular degradation of LDL will first increase and then become saturated. It is proposed based on these results that the saturation of LDL degradation by SMCs and the subsequent increase in subendothelial LDL levels in regions of high macromolecular permeability might play a vital role in the formation of the early foam cell lesion.

Cells, Cultured↗
PubMed1989

Bile acid synthesis in cell culture.

Confluent cultures of Hep G2 cells were found to synthesize chenodeoxycholic and cholic acids continually. Chenodeoxycholic acid was synthesized at the rate of 58 +/- 8.6 micrograms/96 h, a rate more than 7-fold greater than that for cholic acid. Addition of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol but not the -3 alpha, 7 alpha-diol was followed by an increase in cholic acid synthesis, thus indicating a relatively low 12 alpha-hydroxylase activity. Endogenous synthesis of monohydroxy bile acid ester sulfates was found, with maximum rates of 135 and 74 micrograms/96 h for lithocholic and 3 alpha-hydroxy-5-cholenoic acids, respectively. Incubation of Hep G2 cells in medium containing 25% D2O permitted a comparison of the precursor/product relationship of cholesterol with 3 beta-hydroxy-5-cholenoic acid. The pattern of incorporation of deuterium was in accordance with that expected, thus allowing the conclusion that this monohydroxy bile acid is derived from cholesterol and should be considered together with chenodeoxycholic and cholic acids as a primary bile acid.

Bile Acids and Salts↗
PubMed1988

On the time dependent diffusion of macromolecules through transient open junctions and their subendothelial spread. 2. Long time model for interaction between leakage sites.

In Part 1 of this study (Weinbaum et al., 1988) a short time model has been proposed to describe the initial time dependent leakage of macromolecules at short distances (5 microns or less) from the exit of a transient open junction which the authors have hypothesized as a characteristic feature of endothelial cells in the process of turnover (Weinbaum et al., 1985). This open junction pathway has also been proposed (Weinbaum et al., 1988) to be the primary ultrastructural correlate of the 20 nm diameter large pore suggested by Renkin et al. (1977) using the predictions of cylindrical pore theory. The short time model in (Weinbaum et al., 1988), however, has major limitations in that it neglects the interaction between leakage sites, macromolecular entry through other pathways, the finite thickness of the vessel wall and the curvature of the cell perimeter. The longer time model developed herein will attempt to describe each of these features and also present an improved model and analytic solution for the steady state flux and uptake. In the previous steady state model developed by Weinbaum et al. (1985) the effect of the resistance of the transient open junctions and the non-isotropic diffusion in the underlying tissue due to the internal elastic lamina (IEL) were both neglected. New solutions are first presented which describe the effect of these important model refinements on the steady state macromolecular permeability of the major arteries. Time dependent solutions are then presented to predict the transient longer time labeling following the introduction of tracer macromolecules of varying size. These solutions and the corresponding short time solutions in Weinbaum et al. (1988) are the first solutions to our knowledge to describe the difficult time-dependent boundary value problem to determine how the channel exit concentration and flux at a leaky junction vary with time. This is accomplished by casting the boundary value problem in the form of an integral equation for the unknown flux at the cleft exit and then solving this problem using a specially designed numerical technique. The theoretical predictions are used to interpret the behavior of the localized leaks to HRP and albumin that have been reported in Stemerman et al. (1986) and our own recent experiments (Lin et al., 1988).

Animals↗
PubMed1988

On the time-dependent diffusion of macromolecules through transient open junctions and their subendothelial spread. I. Short-time model for cleft exit region.

In this two-part study we shall quantitatively study, using time-dependent models, the hypothesis that transient open junctions associated with widely scattered endothelial cells undergoing mitosis are the structural equivalent for the large pore pathway via which macromolecules the size of albumin or larger cross the vascular endothelium. In an earlier steady-state model [Am. J. Physiol. 248, H945-960 (1985)], the authors demonstrated that such an open-junction pathway could quantitatively account for the regional differences in macromolecular permeability observed in various mammalian arteries in regions of enhanced cell turnover as indicated by 3H-thymidine although these cells were less than 1% of the population and the open junctions occupied less than 10(-5) of the endothelial surface. The time-dependent models described herein have been used to identify a time window and size of probe molecule wherein this hypothesis could be tested experimentally in the larger blood vessels. The first stages of these experiments have now been completed and provide convincing evidence that the junctions of virtually all endothelial cells in the M phase of the cell cycle are leaky to macromolecules (Lin et al., 1988). The statistical frequency of such leakage sites has also been determined. The time-dependent models developed herein contain two important refinements that were not contained in the earlier steady state model. First the finite resistance of the open cleft as a function of molecular size is accounted for by introducing a diffusion coefficient ratio Dj/Dz describing the relative resistance of the open cleft compared to the subendothelial tissue in the direction normal to the endothelial surface. Second the non-isotropy of the vessel wall due to the elastic lamina is considered by introducing a second diffusion coefficient ratio Dx/Dz describing the relative resistance in the lateral as compared to the normal direction. This second ratio can be as large as 100 for the arterial intima, but is of order unity for capillaries. In Part I a short time model is presented to describe the initial labeling of the open cleft and the subendothelial space in the vicinity of the cleft exit following the introduction of a tracer macromolecule. This model is valid for both larger vessels and capillaries since wall thickness and curvature and the interaction between leakage sites does not enter into the model description. In Part II (Wen et al., 1988) a long-time model is developed for larger vessels only which is valid for greater times including steady-state labeling.

Albumins↗
PubMed1986

A theoretical model to study the effect of convection and leaky junctions on macromolecule transport in artery walls.

A mathematical model is presented herein to determine the effect of convection on macromolecular transport across an artery wall due to transmural or osmotic pressure differences. The model is based on an extension of the leaky junction-cell turnover model of Weinbaum et al. (1985) to take into account a combined transport mechanism of convection and diffusion and also to provide the leaky junctions in the model with a finite resistance, thus allowing the results to be extended to intercellular clefts with a retarding extracellular matrix or to macromolecules whose dimensions are nearly the same as the junctional width. The results from this improved model show that the effect of pressure on transarterial macromolecular transport is important especially for cell turnover rates greater than 1% and that significant changes in the equilibrium balance of the cholesterol carrying LDL molecules in the arterial wall can occur due to a very small fraction of leaky junctions. At very high turnover rates (large fraction of leaky junctions) the effect of convection on macromolecular transport becomes dramatic and explains the very large increases in uptake observed experimentally after artificially inducing extensive endothelial damage.

Animals↗
PubMed1985

A steady-state filtration model for transluminal water movement in small and large blood vessels.

It is now generally accepted that the intercellular cleft between adjacent endothelial cells is the primary pathway for the transluminal movement of water and small ions in the vasculature. A steady-state theoretical model has been developed to show quantitatively how the geometry of the intercellular cleft between adjacent endothelial cells is related to both the water movement and pressure distribution in the subendothelial space and to examine how the existence of a subendothelial interaction layer affects the hydraulic resistance of the media of vessels of varying wall thickness. The velocity and pressure fields in the media are described using porous matrix theory based on Darcy's law and a lubrication-type analysis is used to describe the flow in a variable geometry intercellular cleft. These two equations are solved simultaneously to determine the unknown pressure distribution beneath the endothelium and the flow in the arterial media. Application of this model shows that, when the tight junction in the cleft is 26 A or less, more than half of the total hydraulic resistance of the wall occurs across the endothelial cell monolayer, for a vessel whose wall thickness is less than 0.02 cm. This finding is in good agreement with the experimental findings of Vargas, et al. (1978) for rabbit aorta. Contrary to previous belief, the model shows that the filtration resistance of an arterial wall with intact endothelium does not scale linearly with wall thickness due to the highly nonlinear resistance of the endothelial interaction layer.

Animals↗
PubMed1985

Effect of cell turnover and leaky junctions on arterial macromolecular transport.

A new quantitative model is presented to explore the changes in vascular permeability that would result if the intercellular clefts around widely scattered endothelial cells were to become leaky to macromolecules in the range of roughly 4-10 nm during normal cell turnover. Although these open junctions occupy less than 10(-5) of the en face area of the endothelial surface, it is shown that the endothelial permeability can increase by 50-100% due to the experimentally observed regional variations in turnover in the larger arteries, whereas in the thinner walled veins and smaller arteries the subendothelial concentration is not significantly elevated. These results provide a very plausible explanation for the observed focal differences in the uptake of 125I-albumin and 131I-fibrinogen in blue and white areas and the nonselectivity of the local enhancement in uptake for these two molecules as a function of molecular size. The model has important implications for the localization of atherogenesis and the importance of endothelial cell turnover on the transport of proteins in vessels of all sizes.

Arteries↗
PubMed1985

Cadmium reduces extraocular muscle contractility in vitro and in vivo.

Cadmium, a blocker of calcium channels in various excitable cells, reduces the contractility of extraocular muscles. When applied to rat extraocular muscles in vitro, it reduces the sustained or tonic tension generated by the tonic multiply innervated fibers of the global layer of the muscles. When injected in vivo into rabbit extraocular muscles, it produces a temporary paralysis of the muscles and a deviation of the eye position. These effects are presumed to involve a blockade of the calcium channels of the muscle fibers and of the neuromuscular junctions. It is proposed that, on the basis of these effects, a non-surgical treatment of strabismus could be developed.

Animals↗
PubMed1981

Diffusion of macromolecules across the arterial wall in the presence of multiple endothelial injuries.

In this paper, the two-phase arterial wall model developed by Weinbaum and Caro [2] has been extended to obtain analytic solutions for the steady-state flux, uptake and concentration of macromolecules in the arterial wall due to the presence of periodically dispersed local sites of enhanced permeability. In the endothelial cell layer these sites are believed to be associated with the dying and regeneration of individual cells in the endothelial monolayer. Nir and Pfeffer [9] obtained similar solutions for a single dying cell in an otherwise undamaged endothelial cell layer. However this model requires that multiple cell turnover sites be spaced sufficiently far apart such that no interaction between neighboring sites takes place and hence cannot be applied to closely spaced endothelial injuries which have been observed experimentally in physiological studies. The theoretical predictions of the present model compare very favorably with experimental results for the enhanced uptake found in blue versus white areas reported in morphological studies of the endothelial surface (Bell, et al. [10, 11]).

Animals↗
PubMed1980

A case-control study of menopausal estrogen therapy and breast cancer.

The association between estrogen replacement therapy and female breast cancer was studied in two Los Angeles area retirement communities. The 138 study cases of breast cancer occurring in residents younger than 75 years were compared with age- and race-matched community control subjects. The risk ratio for a total cumulative dose in excess of 1,500 mg was estimated to be 2.5 in women with intact ovaries. This increase was present using various independent sources of drug usage information but was inconsistent at low dose and undetectable in oophorectomized women. No important sources of confounding could be identified, and no risk modifiers could be identified except for a history of surgically confirmed benign breast disease. In such women with intact ovaries, the risk ratio for a high cumulative dose rose to 5.7 relative to nonusers with normal breasts.

Age Factors↗