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Biomedical subjects

M Berman

Publications and source records attributed to M Berman.

At least 163 records · Page 9Linked to original sources
PubMed1980

Benign recurrent intrahepatic cholestasis: studies of bilirubin kinetics, bile acids, and cholangiography.

Three patients with benign recurrent intrahepatic cholestasis are described. They had had between five and 16 attacks of cholestasis. Between attacks the liver function tests, including serum bile acids, were normal. Serial serum bilirubin and bile acid estimations during the cholestasis in one patient revealed a consistent discrepancy between the serum bilirubin and bile acid concentrations during three consecutive attacks. In the other two patients the serum concentrations of bile acids and bilirubin varied in parallel. Analysis of the individual serum bile acids did not reveal high concentrations of any 'toxic' bile acid. In one patient, plasma bromsulphthalein (BSP) curves were obtained during both remission and cholestatic periods. The 45 minute retention was slightly increased (10.8%) during remission. During the cholestasis, the 45 minute retention (25%) and the fractional extraction coefficient (Ke=0.069 min-1) were markedly abnormal. The hepatic clearance of unconjugated radiobilirubin was normal at all times in this patient, although during cholestasis, conjugated bilirubin reflexed from the liver to the plasma and was then cleared slowly with a half life of approximately 12 hours. Treatment with corticosteroids, cholestyramine, and phenobarbitone was unsatisfactory.

Adult↗
PubMed1980

A model for carbon kinetics among plasma alanine, lactate, and glucose.

To account for the exchange of carbon atoms among alanine, lactate, and glucose in vivo, [2,3-3H]- and [U-14C]alanine or [3-3H]- and [U-14C]glucose were injected simultaneously to nonanesthetized normal dogs. The concentrations in plasma of 14C-labeled alanine, lactate, and glucose, and the injected 3H-labeled substrate were followed for 160 min after injection of the tracers. An integrated kinetic model describing the exchange of carbon atoms among substrates was developed from these data. The analysis suggests that there is a very rapid exchange of the carboxyl carbon of alanine with lactate in contrast to carbons 2 and 3. The model was used to calculate the fluxes of carbon atoms among the substrates in a steady state. In normal dogs plasma alanine and lactate contribute 14% of the carbon atoms released into the circulation as glucose.

Alanine↗
PubMed1980

Transfer of carbon atoms among circulating glucose, alanine, and lactate in pancreatectomized dogs.

The rates of transfer of carbon atoms (mg C . kg body wt-1 . min-1) among plasma glucose, alanine, and lactate have been calculated in pancreatectomized dogs from the tracer concentration versus time curves in the plasma after an intravenous injection of either [2,3-3H]- and [U-14C]alanine or [3-3H]- and [U-14C]glucose. The calculations were based on an integrated kinetic model derived earlier from experimental data. In comparison to normal dogs, in insulin-deprived pancreatectomized dogs, the rate of turnover of glucose (mg C . kg-1 . min-1) is increased about twofold, but the turnover rates of lactate and alanine are not changed significantly. About twice as much carbon is transferred from lactate to glucose, whereas the transfer of carbon from alanine is increased by 47%. Carbon transfer to glucose from unidentified sources is also doubled. In conclusion, in the pancreatectomized dog, gluconeogenesis is increased not by an increased production of alanine and lactate but by an increased diversion of their carbon atoms to glucose at the expense of other pathways.

Alanine↗
PubMed1980

Stromal vascularization prevents corneal ulceration.

Experiments were performed with a model of focal, thermal-induced ulceration to test the clinical impression that vascularization prevents ulceration of the corneal stroma. Slow-release polymers containing a vasoproliferase agent (tumor angiogenesis factor) were placed in corneal pockets 2 mm central to the limbus of albino rabbits. These polymers elicited blood vessel ingrowth up to the implant. Control eyes received empty polymers which caused minimal to no vessel growth. Polymers were removed, and each cornea received a focal, thermal burn placed just central to the polymer site. All control corneas ulcerated: most (79%) developed deep stromal or perforating ulcers. Only 25% of prevascularized corneas developed stromal ulcers, and none was deep or perforating. After thermal burns, vessels in both groups grew at the same linear rate toward the burned area. There was a direct relationship between the distance separating the nearest blood vessel and the burned area at the time of burning and the maximum depth of stromal ulceration. Thus prevention of or less severe stromal ulceration is correlated with the earlier presence of vessels in the burned area.

Angiogenesis Inducing Agents↗
PubMed1980

Evidence for a role of the plasminogen activator--plasmin system in corneal ulceration.

Plasminogen is present in the cornea andcan be activated to plasmin by plasminogen activator. Plasmin is able, in turn, to activate latent collagenase. This system could initiate and perpetuate the collagen degradation of corneal ulceration. This report details evidence for such a system in the cornea. Plasmin has been found to activate latent collagenase from organ cultures of ulcerating rabbit corneas and from fibroblast cultures derived from such corneas. As in the case of activation by trypsin, activation by plasmin results in the conversion of the 40,000 MW latent form to an active species of 23,000 MW. Explants of normal or alkali-burned, ulcerating corneas demonstrated plasminogen-dependent lysis of fibrin clots; frozen sections of such corneas demonstrated that lysis begins in the superficial stroma near the periphery of the cornea. Multiply freeze-thawed ulcerating corneas, but not normal corneas, showed initial lysis, not peripherally but at the ulcer region containing polymorphonuclear leukocytes. The fact that the peripheral lytic pattern existed in corneas that were obtained from eyes prefrozen in liquid nitrogen before excision of the corneas would suggest that plasminogen activator is normally contained in cells in vivo and is not made only in response to tissue injury. There was no correlation between the location of blood vessels or the presence of the corneal endothelium and the plasminogen-dependent lysis. Plasminogen activator from the ulcerating cornea and from fibroblasts was characterized by sodium dodecyl sulfate--gel electrophoresis of its cleavage products of plasminogen. The activator cleaves plasminogen into heavy- and light-chain fragments similar to those produced from plasminogen by urokinase. Plasminogen activator activity was quantitated by a new assay that restricts diffusion of the enzyme to one dimension into a narrow bore tube. The addition of plasminogen daily to cultures of ulcerating corneas resulted in earlier rises of plasminogen activator, collagenase, and collagen degradation fragments in the culture media. Although total plasminogen activator levels were not increased by the addition of plasminogen to culture, levels of both collagenase and solubilized collagen were approximately doubled. It is concluded that the plasminogen activator--plasmin system might play an important role in the destruction of stromal matrix in corneal ulceration.

Animals↗
PubMed1980

The metabolism of apolipoprotein B in subjects with hypertriglyceridemia and polydisperse LDL.

This research concerns the metabolism of apolipoprotein B (apoB) in hypertriglyceridemic subjects with polydisperse or heterogeneous LDL. Five subjects maintained under constant dietary control had blood samples fractionated into very low density lipoprotein (VLDL), Sf 20, Sf 10, and Sf 4 LDL, and plasma free leucine, and in three subjects VLDL was further fractionated by size. Apo B was isolated, and the masses of the plasma apo B pools were measured for these lipoproteins. Following injection of [3H]leucine as a metabolic tracer the specific activity of apo B in these lipoproteins and of plasma leucine were measured over 7 or 14 days. The kinetic data were examined using multicompartmental analysis and interpreted in terms of our previous model of apo B metabolism (1975. Federation Proc. 24: 2263.). Newly synthesized apo B, secreted as large VLDL, is metabolized by a delipidation chain yielding intermediate density lipoprotein (IDL), consisting of small VLDL and Sf 20 LDL, and eventually forms small, Sf4 LDL. LDL is metabolized in a steplike process from Sf 20 to Sf 10 and Sf 4 LDL. A second major biosynthetic input in apo B enters directly into IDL and 1/4 to 2/3 of newly synthesized apo B enters plasma by this route. Total apo B synthesis in these subjects is 5- to 10-fold greater than reported for normals. The rate of transport of VLDL apo B and IDL is slower than normal with a residence time which is increased about twofold; however, the VLDL apo B pool is enlarged 5- to 10-fold, and thus the quantity of apo B entering and leaving this pool per hour is much greater than in the normal. Two major pathways for apo B catabolism occur. Between 1/3 and 2/3 of apo B is metabolized through LDL, disappearing from plasma as Sf 4 LDL. The remainder of apo B disappears from plasma IDL directly. The four major findings in this kinetic study of apo B metabolism in hypertriglyceridemic subjects with polydisperse LDL are: 1) The marking increase in apo B synthesis; 2) the biosynthetic input of much of this apo B directly into IDL; 3) the large catabolic pathway of apo B which leaves IDL, and 4) the stepwise metabolism of LDL by which Sf 20, Sf 10 and Sf 4 LDL are generated.

Adult↗
PubMed1980

Effect of plasma from cyclophosphamide-treated mice on CFU-S in an in vivo culture system.

Various studies suggest that humoral substances, capable of stimulating CFU-S proliferation, are released into the plasma in response to depletion of the CFU-S population by cytotoxic substances such as cyclophosphamide. To test this hypothesis, we placed 0.25 ml of a murine marrow cell suspension with an equal volume of plasma from either normal mice or from mice previously injected with 5 mg of cyclophosphamide into cellulose dialysis tubing. These tubes were then incubated in the peritoneal cavity of mice for 1-7 days. The CFU-S content of the tubes was then assayed. The CFu-S content of suspensions in normal mouse plasma declined to one-fourth of the initial value after 7 days, whereas those in plasma from mice that received cyclophosphamide 7 days previously were essentially unchanged in number. These data suggest that 7 days after injection of cyclophosphamide, the plasma contains a factor that either prevents death of CFU-S or stimulates them to proliferate. An alternative explanation is that normal plasma contains an inhibitor of CFU-S growth that is lacking in plasma of cyclophosphamide-treated mice.

Animals↗
PubMed1979

Potassium-stimulated ATPase activity and hydrogen transport in gastric microsomal vesicles.

The Mg2+-dependent, K+-stimulated ATPase of microsomes from pig gastric mucosa has been studied in relation to observed active H+ transport into vesicular space. Uptake of fluorescent dyes (acridine orange and 9-aminoacridine) was used to monitor the generated pH gradient. Freeze-fracture electron microscopy showed that the vesicular gastric microsomes have an asymmetric distribution of intramembraneous particles (P-face was particulate; E-face was relatively smooth. Valinomycin stimulated both dye uptake and K+-ATPase (valinomycin-stimulated K+-ATPase); stimulation by valinomycin was due to increased K+ entry to some intravesicular activating site, which in turn depends upon the accompanying anion. Using the valinomycin-stimulated K+-ATPase and H+ accumulation as an index, the sequence for anion permeation was NO-3 greater than Br- greater than Cl- greater than I- greater than acetate approximately isethionate. When permeability to both K+ and H+ was increased (e.g using valinomycin plus a protonophore or nigericin), stimulation of K+-ATPase was much less dependent on the anion and the observed dissipation of the vesicular pH gradient was consistent with an 'uncoupling' of ATP hydrolysis from H+ accumulation. Thiocyanate interacts with valinomycin inhibiting the typical action of the K+ ionophore. But stimulation of ATPase activity was seen by adding 10 mM SCN- to membranes preincubated with valinomycin. From the relative activation of the valinomycin-stimulated K+-ATPase, it appears that SCN- is a very permeant anion which can be placed before NO-3 in the sequence of permeation. Valinomycin-stimulated ATPase and H+ uptake showed similar dependent correlations, including: dependence on [ATP] and [K+], pH optima, temperature activation, and selective inhibition by SH- or NH2-group reagents. These results are consistent with a pump-leak model for the gastric microsomal K+-ATPase which was simulated using Nernst-Planck conditions for passive pathways and simple kinetics for the pump. The pump is a K+/H+ exchange pump requiring K+ at an internal site. Rate of K+ entry would depend on permeability to K+ as well as the counterion, either (1) the anion to accompany K+ or (2) the H+ efflux path as an exchange ion. The former leads to net accumulation of H+ and anion, while the latter results in non-productive stimulation of ATP hydrolysis.

Adenosine Triphosphatases↗
PubMed1979

Mathematical model for adriamycin (doxorubicin) pharmacokinetics.

Adriamycin (doxorubicin), an active antineoplastic drug, is rapidly distributed across cell membranes and is concentrated within cells. Binding to protein and to tissue readily occurs. The drug is metabolized to both fluorescent and nonfluorescent compounds, the liver being the main organ of biotransformation and elimination. A multicompartment, open model that accounts for these processes has been derived. The model assumes an initial volume of distribution of 60% of body weight and includes two peripheral adriamycin compartments and a subsystem for adriamycinol, a major metabolite. Plasma and urine concentrations of adriamycin and adriamycinol were determined for four patients treated with adriamycin (60 mg/m2), and these concentrations were used to calculate rate constants for the model. Concentrations were measured by fluorescence assay after thin-layer chromatographic separation of parent compound and metabolites. Differential equations were solved by the SAAM computer program. Evaluation of adriamcinol pharmacokinetics suggests that the previously reported high concentrations of adriamycinol immediately after IV infusion of adriamycin are an artifact of the fluorescence method and that observed plasma concentrations of adriamycinol are the sum of adriamycinol concentrations and approximately 10% of the adriamycin concentrations. Corrected peak plasma concentrations of adriamycinol occur 2--12 h after infusion of adriamycin.

Doxorubicin↗
PubMed1979

A mathematical model for membrane transport of amino acid and Na+ in vesicles.

A model with a carrier having sites for both amino acid and Na+ can account for AIB (alpha-aminoisobutyric acid) transport kinetics observed in membrane vesicles from SV3T3 (simian virus 40-tranformed Balb/c33 cells) and 3T3 (the parent cell line). The main feature of this cotransport model is that Na+ binding to carrier decreases the effective Km for AIB transport. Na+ transport kinetics observed in both vesicle systems can be described by passive (possibly facilitated) diffusion. The lag of Na+ transport across the membrane compared to that for AIB, coupled to the Na+-dependent decrease in the Km for AIB, accounts for the overshoot in intravesicular AIB observed for SV3T3 in the presence of an initial Na+ gradient. Extra-vesicular Na+ maintains a decrease in the Km for AIB influx before intra-vesicular Na+ has accumulated to balance it with a comparable decrease in the Km for AIB efflux. 3T3 vesicles display little overshoot, and this finding can be explained mostly by a lower carrier affinity for Na+.

Aminoisobutyric Acids↗
PubMed1979

The composition and metabolism of high density lipoprotein subfractions.

The composition and metabolism of high density lipoprotein (HDL) subfractions were investigated in seven normal individuals. Mean HDL2 (d, 1.063-1.125 g/ml) composition (by weight) was 43% protein, 28% phospholipid, 23% cholesterol, and 6% triglyceride, and mean HDL3 (d, 1.125-1.21 g/ml) composition was 58% protein, 22% phospholipid, 14% cholesterol, and 5% triglyceride. The mean apoA-I; apoA-II weight ratio was 4.75 for HDL2 and 3.65 for HDL3. HDL2 protein was proportionally slightly richer in C apolipoproteins and higher molecular weight constituents (including apoE) than HDL3. Kinetic studies utilized radiolabeled HDLA (d, 1.09-1.21 g/ml), HDL2, and HDL3 demonstrated rapid exchange of apoA-I and apoA-II radioactivity among HDL subfractions, similar fractional rates of catabolism of apoA-I and apo A-II within HDL, and similar radioactivity decay within HDL subfractions. Mean plasma residence time was 5.74 days for radiolabeled HDL2 and 5.70 days for radiolabedled HDL3. Differences in HDL protein mass among individuals were largely due to alterations in catabolism, and in general both HDL2 and HDL3 were catabolized via a plasma and a nonplasma pathway. Data from simultaneous radiolabeled very low density lipoprotein and HDL studies in 2 individuals are consistent with the concept that apoC-II and apoC-III are catabolized at a different rate than are apo A-I and apo A-II within the HDL density range.

Adult↗
PubMed1979

Analysis of 47Ca kinetics in normal subjects by means of a compartmental model with a non-exchangeable plasma calcium fraction.

1. 47Ca kinetic studies were performed in eight normal young adult males. Plasma, urinary and faecal stable and radioactive calcium and whole-body radioactivity were measured for up to 40 days after intravenous administration of the tracer. 2. The plasma radioactivity data could be fitted to the sum of four exponentials corresponding to a four-compartment model, but this model did not account for the consistently greater 47Ca specific radioactivities in plasma relative to those in urine at the same time in five of the subjects. 3. A non-exchangeable fraction of plasma calcium estimated as 5% of the mass in the plasma compartment was postulated to account for this finding. 4. An estimate of the insensible losses of calcium was obtained from the whole-body radioactivity counting data.

Adult↗
PubMed1979

Zinc metabolism in humans: a kinetic model.

A quantitative model is developed that describes the kinetics of the early phases of zinc metabolism in humans. The model is based on averaged data obtained over 5 days from 17 atients with smell and/or taste dysfunction who were given 69mZn in trace amounts orally and intravenously. A function describing the rate of entry of 69mZn into systemic plasma following ingestion of the isotope is derived showing that about 37% of the ingested zinc enters plasma. Gastrointestinal absorption is essentially completed by 4 h. Sixty-seven percent of the absorbed zinc in the portal circulation is extracted by the liver before being released into the systemic circulation and agrees with the calculated extraction efficiency from the systemic circulation. There are both rapid and slow exchnage phases between plasma and liver and between plasma and red cells. The calculated steady-state zinc values for plasma, red cells, and liver agree with previously reported measured values implying there are no additional zinc pools in these tissues. The tracer data, however, account for only 10% of total body zinc, the remaining 90% in tissues whose kinetics are too slow to be resolved from a 5-day study.

Adult↗
PubMed1979

Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects.

A model for the synthesis and degradation of very low density lipoprotein triglyceride (VLDL-TG) in man is proposed to explain plasma VLDL-TG radioactivity data from studies conducted over a 48-h interval after injection of glycerol labeled with 14C, 3H, or both. The curve describing the radioactivity of plasma VLDL triglycerides reaches a maximum at about 2 h, after which the decay is biphasic in all cases; the late curvature becoming evident only after 8--12 h. To fit the complex curve, it was necessary to postulate two pathways for the incorporation of plasma glycerol into VLDL-TG, one much slower than the other. A process of stepwise delipidation of VLDL in the plasma compartment, previously proposed for VLDL apoprotein models, was also necessary. Predicted VLDL-TG synthesis rates calculated with this model can differ significantly from those based on experiments of shorter duration in which the slow VLDL-TG component is not apparent. The results of these studies strongly support the interpretation that the late, slow component of the VLDL-TG activity curve is predominantly due to the slowly turning-over precursor compartment in the conversion pathway and is not due either to a slow compartment in the labeled precursor, plasma free glycerol, or to an exchange of plasma VLDL-TG with an extravascular compartment. It also cannot, in these studies, be attributed to a slowly turning-over VLDL-TG moiety in the plasma. The model was tested with data from 59 studies including normal subjects and patients with obesity and(or) various forms of hyperlipoproteinemia. Good fits were obtained in all cases, and the estimated parameter values and their uncertainties for 13 normolipemic nonobese subjects are presented. Sensitivty testing was carried out to determine how critical various parameter estimations are to the assumptions introduced in the modeling.

Glycerol↗
PubMed1979

Transport of very low density lipoprotein triglycerides in varying degrees of obesity and hypertriglyceridemia.

Measurements of transport of triglycerides (TG) in very low density lipoproteins (VLDL) were carried out in 59 patients by injection of radioactive glycerol, determinations of specific activities of VLDL-TG for 48 h thereafter, and treatment of the data by multicompartmental analysis. The patients were divided into three groups: normal weight (89-120% ideal weight), mildly obese (120-135% ideal weight), and markedly obese (135% ideal weight). They had varying levels of VLDL-TG ranging from normal to markedly elevated. In many subjects, there was a positive correlation between concentrations and transport of VLDL indicating that overproduction of VLDL-TG contributed to hypertriglyceridemia. In others, and particularly in several markedly obese subjects, transport rates were greatly increased without significant hypertriglyceridemia, suggesting that they had enhanced capacity to clear TG. In all groups, however, there were patients whose degree of hypertriglyceridemia seemed out of proportion to their transport rates. This finding and the fact that many patients have increased secretion of VLDL-TG without elevated plasma TG suggests that both overproduction of VLDL-TG and insufficient enhancement of clearance contributed to the development of hypertriglyceridemia.The data showed a poor correlation between transport rates determined by our multicompartment analysis and single-exponential analysis used previously by other investigators (r = 0.46); this comparison was not improved by segregating patients according to their degree of obesity. Although two conversion pathways (fast and slow synthetic paths) were required to fit the data, there was no correlation between transport rates and the ratio of the two pathways. Also, despite the known pathway of conversion of VLDL to low density lipoprotein, no correlation was found between VLDL-TG transport rates and estimated low density lipoprotein-cholesterol concentrations.

Biological Transport↗