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Biomedical subjects

J Keizer

Publications and source records attributed to J Keizer.

At least 55 records · Page 3Linked to original sources
PubMed1991

Bursting electrical activity in pancreatic beta cells caused by Ca(2+)- and voltage-inactivated Ca2+ channels.

We investigate the hypothesis that two classes of Ca2+ currents, one quickly inactivated by Ca2+ and one slowly inactivated by voltage, contribute to bursting electrical activity in pancreatic islets. A mathematical model of these currents is fit to the experimental whole-cell current-voltage and inactivation profiles, thereby fixing the Ca2+ conductance and all activation and inactivation parameters. Incorporating these currents into a model that includes delayed rectifier K+ channels and ATP-sensitive K+ channels, we show that only abnormal bursting is obtained. Modification of activation parameters to increase Ca2+ channel open times, as suggested by experiment, yields a more robust bursting similar to that observed in intact islets. This reinforces the suggestion that in addition to ATP-sensitive K+ channels, Ca2+ channels may serve as glucose sensors in the beta cell.

Calcium↗
PubMed1991

Long-term follow-up of non-seminomatous testicular cancer patients with mature teratoma or carcinoma at postchemotherapy surgery. EORTC Genitourinary Tract Cancer Cooperative Group (EORTC GU Group)

From 1979 to 1983 the EORTC GU Group treated 239 patients with disseminated non-seminomatous testicular cancer with combination chemotherapy comprising cisplatin, vinblastine and bleomycin in a prospectively controlled trial. The protocol required complete resection of residual masses after induction chemotherapy, provided that serum tumour markers were normal. 102 patients were operated on. 27 patients had mature teratoma (teratoma differentiated) in the resected specimens and 23 had viable cancer. Follow-up data were available for 26 and 22 of these patients, respectively. 23 of 26 patients (88%) with mature teratoma are alive and disease free after a follow-up of 53-110 months (median 92 months). 3 patients developed progressive disease; 1 died. A peculiar case of growing mature teratoma on the forearm is described. 13 of 22 patients (59%) with residual carcinoma are alive and disease free after a follow-up of 74-112 months (median 95 months). The prognosis of patients with carcinoma is shown to be correlated with the completeness of surgery, which in turn is correlated with the initial tumour mass before chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Chloroform bioactivation by microsomes from colonic and ileal mucosa of rat and man.

The cytochrome P-450 system present in colonic and small-intestinal mucosal microsomes from control and beta-naphthoflavone pretreated rats is not able to catalyze the biotransformation of chloroform either oxidatively or reductively. Anoxic incubations of 14CHCl3 with mucosal microsomes obtained from human colon and ileum biopsies resulted in significant levels of covalent binding to lipids but not to protein; no covalent binding was measured after room-air-equilibrated incubations. The bioactivation of CHCl3 by human colonic mucosal microsomes can therefore occur in conditions which may be representative of the physiologically low oxygenation of the outer layers of this tissue. These results support the possibility of an association between colonic cancer and exposure to CHCl3, claimed in some epidemiological studies, but not evident from studies of laboratory animals.

Animals↗
PubMed1990

Kinetics and thermodynamics of metabolite transfer between enzymes.

Based on experimental evidence put forward by Bernhard and others, we explore the kinetics and thermodynamics of the proposed direct and diffusional transfer mechanisms of enzymatic catalysis. Data for transient transfer of NADH between two cognate dehydrogenases (E1 and E2) are combined with steady-state catalytic data to quantify the kinetics of the two transfer mechanisms. In order to rationalize these data we find: (1) that the rate constants for direct transfer of NADH from E1-NADH to E2 must be much larger when a reactive metabolite, M, is bound to E2, (2) that a significant amount of noncatalytic complex E1-E2-M must be formed, and (3) that dissociation constants of the order of 1 microM are required for the ternary complexes involved in direct transfer (E1-NADH-E2). Using values of rate parameters similar to those assumed in these calculations, we proceed to explore the kinetics and thermodynamics of a hypothetical two-enzyme segment of a metabolic pathway that involves direct and diffusional metabolite transfer operating in parallel. Under steady-state conditions, we conclude from our calculations: (1) that the flux through the direct transfer branch would be comparable to or greater than that through the diffusional transfer branch under physiological conditions, (2) that activity effects resulting from physiological concentrations of inert protein enhance the predominance of the direct transfer flux, (3) that significant concentrations of ternary transfer complexes are formed, (4) that changes in the catalytic mechanism involving the ternary complex have little effect, (5) that direct transfer significantly moderates the reduction in metabolic flux caused by protein complexation, and (6) that direct transfer greatly alters the thermodynamics and kinetics of our hypothetical pathways. We conclude, therefore, that direct transfer--when it exists--would have important kinetic, thermodynamic, and physiological consequences in vivo.

Enzymes↗
PubMed1990

Domain model for Ca2(+)-inactivation of Ca2+ channels at low channel density.

The "shell" model for Ca2(+)-inactivation of Ca2+ channels is based on the accumulation of Ca2+ in a macroscopic shell beneath the plasma membrane. The shell is filled by Ca2+ entering through open channels, with the elevated Ca2+ concentration inactivating both open and closed channels at a rate determined by how fast the shell is filled. In cells with low channel density, the high concentration Ca2+ "shell" degenerates into a collection of nonoverlapping "domains" localized near open channels. These domains form rapidly when channels open and disappear rapidly when channels close. We use this idea to develop a "domain" model for Ca2(+)-inactivation of Ca2+ channels. In this model the kinetics of formation of an inactivated state resulting from Ca2+ binding to open channels determines the inactivation rate, a mechanism identical with that which explains single-channel recordings on rabbit-mesenteric artery Ca2+ channels (Huang Y., J. M. Quayle, J. F. Worley, N. B. Standen, and M. T. Nelson. 1989. Biophys. J. 56:1023-1028). We show that the model correctly predicts five important features of the whole-cell Ca2(+)-inactivation for mouse pancreatic beta-cells (Plants, T. D. 1988. J. Physiol. 404:731-747) and that Ca2(+)-inactivation has only minor effects on the bursting electrical activity of these cells.

Animals↗
PubMed1989

ATP-sensitive potassium channel and bursting in the pancreatic beta cell. A theoretical study.

Based on the existence of ATP-sensitive potassium channels in the plasma membrane of pancreatic beta cells, we develop a quantitative explanation of the electrical activity observed in pancreatic islets. The proposed mechanism involves the voltage-dependent inward calcium and outward potassium currents described by Rorsman and Trube (1986), which are voltage-activated when an increase in the cytoplasmic ATP/ADP ratio decreases the conductance of the ATP-sensitive potassium channels. It is proposed that modulation of the ATP/ADP ratio occurs through calcium inhibition of oxidative phosphorylation. In this picture the mitochondria serve as a transducer of metabolic activity whose sensitivity is modulated by cytosolic calcium. Solution of the differential equations that describe this mechanism gives rise to both bursting and continuous spiking electrical activity similar to that observed experimentally. While the mechanism for bursting in this model involves the ATP/ADP ratio, the feedback is still provided by calcium, as originally proposed by Chay and Keizer (1983) using a Ca2+-activated potassium conductance. A mixed-model, which includes both ATP-sensitive and Ca2+-activated potassium conductances, also reproduces the experimentally observed electrical activity and may correspond more closely to the actual situation in vivo.

Adenosine Diphosphate↗
PubMed1988

Emergence of organized bursting in clusters of pancreatic beta-cells by channel sharing.

Pancreatic beta-cells in an intact Islet of Langerhans exhibit bursting electrical behavior. The Chay-Keizer model describes this using a calcium-activated potassium (K-Ca) channel, but cannot account for the irregular spiking of isolated beta-cells. Atwater I., L. Rosario, and E. Rojas, Cell Calcium. 4:451-461, proposed that the K-Ca channels, which are rarely open, are shared by several cells. This suggests that the chaotic behavior of isolated cells is stochastic. We have revised the Chay-Keizer model to incorporate voltage clamp data of Rorsman and Trube and extended it to include stochastic K-Ca channels. This model can describe the behavior of single cells, as well as that of clusters of cells tightly coupled by gap junctions. As the size of the clusters is increased, the electrical activity shows a transition from chaotic spiking to regular bursting. Although the model of coupling is over-simplified, the simulations lend support to the hypothesis that bursting is the result of channel sharing.

Action Potentials↗
PubMed1987

Nonequilibrium chemical potentials and free energies for enzyme-catalyzed reactions.

Using the statistical theory of nonequilibrium thermodynamics we explore the nature of nonequilibrium corrections to chemical potentials in simple enzyme-catalyzed reactions. The statistical definition of the chemical potential, which pertains to systems that are at stable steady states, is applied to the Michaelis-Menten reaction scheme in a cellular-sized compartment that communicates with outside reservoirs. Calculations based on the kinetic parameters for hexokinase and triose phosphate isomerase show that substantial corrections to the chemical potential of product (the order of 25 mV) are possible if the reaction is sufficiently far from equilibrium. The dependence of the corrections to the chemical potentials on the size of the cellular compartment are explored, and the relevance of the corrections for understanding the thermodynamics of metabolites is discussed.

Catalysis↗
PubMed1987

Evaluation of mouse lip mucosa reactions after combinations of cis-diammine-1,1-cyclobutanedicarboxylate platinum (II) (CBDCA) and irradiation: single and fractionated treatments.

The influence of CBDCA (JM8) on the radiation-induced mouse lip mucosal reactions has been tested. Both single and fractionated drug doses were used intraperitoneally at 60 mg/kg and 5 X 25 mg/kg respectively. A single injection of CBDCA did not alter the response to a single radiation dose, whether the drug was given at different time intervals from 24 hr prior, to 96 hr after irradiation. A concomitant treatment of daily CBDCA injections and irradiations for 5 consecutive days demonstrated no change of the capacity to repair sublethal radiation damage. When two equal sized radiation doses were separated by 10 days and CBDCA was administered daily from day 3 to 7, the ability to repopulate the lip mucosa epithelium during the radiation-free period was not influenced.

Animals↗
PubMed1985

Theory of the effect of extracellular potassium on oscillations in the pancreatic beta-cell.

Based on the observation that potassium ions are compartmentalized near the surface of pancreatic beta-cells in mouse islets (Perez-Armendariz, E.M., I. Atwater, and E. Rojas 1985, Biophys. J. 48:741-749), we present a theoretical treatment of the effect of external potassium on oscillations in the pancreatic beta-cell. Our model includes the effects of ionic diffusion, the Ca2+-activated K+ channel, voltage-gated K+ and Ca2+ channels, and some of the effects of glucose. It is described by four ordinary differential equations. Numerical integration of these equations allows us to examine the effect of glucose, external K+, quinine, and tetraethylammonium ion (TEA) on the oscillations in membrane potential, intracellular Ca2+, and compartmentalized K+. The results are in good agreement with experiment.

Animals↗
PubMed1985

The effect of diffusion on the binding of membrane-bound receptors to coated pits.

We have formulated a kinetic model for the primary steps that occur at the cell membrane during receptor-mediated endocytosis. This model includes the diffusion of receptor molecules, the binding of receptors to coated pits, the loss of coated pits by invagination, and random reinsertion of receptors and coated pits. Using the mechanistic statistical theory of nonequilibrium thermodynamics, we employ this mechanism to calculate the two-dimensional radial distribution of receptors around coated pits at steady state. From this we obtain an equation that describes the effect of receptor diffusion on the rate of binding to coated pits. Our equation does not assume that ligand binding is instantaneous and can be used to assess the effect of diffusion on the binding rate. Using experimental data for low density lipoprotein receptors on fibroblast cells, we conclude that the effect of diffusion on the binding of these receptors to coated pits is no more than 84% diffusion controlled. This corresponds to a dissociation rate constant for receptors on coated pits (k-) that is much less than the rate constant for invagination of the pits (lambda = 3.3 X 10(-3)/s) and a correlation length for the radial distribution function of six times the radius of a coated pit. Although the existing experimental data are compatible with any value of k-, we obtain a lower bound for the value of the binding constant (k+) of 2.3 X 10(-2)(micron)2/s. Comparison of the predicted radial distributions with experiment should provide a clear indication of the effect of diffusion on k+.

Coated Pits, Cell-Membrane↗
PubMed1983

Minimal model for membrane oscillations in the pancreatic beta-cell.

Following the experimental findings of Atwater et al. (In Biochemistry Biophysics of the Pancreatic-beta-Cell, George Thieme Verlag, New York, 100-107), we have formulated a mathematical model for ionic and electrical events that take place in pancreatic-beta-cells. Our formulation incorporates a Hodgkin-Huxley type gating mechanism for Ca2+ and K+ channels, in addition to Ca2+ gated K+-channels. Consistent with the experimental observations, our model generates spikes and bursts in beta-cell membrane potentials and gives the correct responses to additions of glucose, quinine, and tetraethylammonium ions. The response of the oscillations to ouabain and changing concentrations of external K+ can be incorporated into the present model, although a more complete treatment would require inclusion of the Na+/K+ pump.

Animals↗
PubMed1978

Maxwell-type constructions for multiple nonequilibrium steady states.

A stochastic analysis is used to obtain Maxwell-type constructions for multiple nonequilibrium steady states in homogeneous systems. The stochastic theory shows that homogeneous molecular fluctuations can nucleate the Maxwell construction only on a time scale that is the order of a Poincaré recurrence time and indicates that hysteresis should be observed. The nonrelevance of homogeneous fluctuations for systems that undergo phase separation or in which spatial structures occur is discussed.

Journal Article↗
PubMed1977

Variational principles in nonequilibrium thermodynamics.

The variational principles introduced by Onsager into nonequilibrium thermodynamics are discussed. Several new variational formulations of the linear laws are introduced including both a Hamiltonian and Lagrangian form. Also an Onsager-Machlup type variational description of fluctuations is shown to apply at steady states even far from equilibrium.

Kinetics↗