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Biomedical subjects

J A Jacquez

Publications and source records attributed to J A Jacquez.

At least 19 recordsLinked to original sources
PubMed1992

Theory of production rate calculations in steady and non-steady states and its application to glucose metabolism.

I present a review and synthesis of the basic theory, steady state, and non-steady state for the calculation of metabolite production rates for systems that have a central well-mixed compartment that is the site of tracer input and sampling. The theory is then applied to the calculation of glucose production. If the only inputs are into the central compartment, an experimental design that involves varying tracer infusion rates to maintain constant specific activity in the central compartment and the same constant specific activity in the peripheral compartments allows calculation of the endogenous production. That holds even if the models are unidentifiable. The correct equation and Steele's pool fraction approximation reduce to the same result for this experimental design. However, that does not justify the use of Steele's equation when there are deviations from the exact experimental design. When the specific activity in the central compartment is not constant, model-dependent correction terms to Steele's equation are needed.

Animals↗
PubMed1991

Assessing risk factors for transmission of infection.

Commonly used measures of effect, such as risk ratios and odds ratios, may be quite biased when used to assess the effect of factors that alter transmission risks given exposure to infected individuals. This is demonstrated in a simulation model involving a higher-risk behavior and a lower-risk behavior affecting the sexual transmission of human immunodeficiency virus. The bias arises because population contact patterns between higher-risk and lower-risk persons change their relative probabilities of exposure to an infected individual as an epidemic progresses. The assessment of contact patterns is thus central to risk assessment for contagious diseases. A new formulation of selective mixing presented here, together with a structured mixing specification of the social settings of contact, provides a theoretic framework for the investigation of contact pattern determinants.

Bias↗
PubMed1991

Reproduction numbers and thresholds in stochastic epidemic models. I. Homogeneous populations.

We compare threshold results for the deterministic and stochastic versions of the homogeneous SI model with recruitment, death due to the disease, a background death rate, and transmission rate beta cXY/N. If an infective is introduced into a population of susceptibles, the basic reproduction number, R0, plays a fundamental role for both, though the threshold results differ somewhat. For the deterministic model, no epidemic can occur if R0 less than or equal to 1 and an epidemic occurs if R0 greater than 1. For the stochastic model we find that on average, no epidemic will occur if R0 less than or equal to 1. If R0 greater than 1, there is a finite probability, but less than 1, that an epidemic will develop and eventuate in an endemic quasi-equilibrium. However, there is also a finite probability of extinction of the infection, and the probability of extinction decreases as R0 increases above 1.

Computer Simulation↗
PubMed1990

The effects of population structure on the spread of the HIV infection.

A model for the spread of human immunodeficiency virus (HIV) in a population of male homosexuals is presented. The population is divided into five groups on the basis of degree of sexual activity. Within each group, the individuals are classified as 1) susceptible; 2) infective; or 3) removed because of a lack of sexual activity associated with advanced acquired immunodeficiency disease (AIDS). The infective individuals are further subdivided into four stages of infection. Analyses of the model address two questions with regard to the spread of HIV: (1) What is the effect of level of sexual activity on an individual's risk for infection, and (2) What is the effect that assumptions about mixing between groups have on both individual risk and transmission throughout a population? Results from analyses using a number of different parameter estimates show that increased levels of sexual activity increase the likelihood that an individual will become infected. In addition, the initial spread of the disease is markedly affected by variation in the amount of contact among individuals from different subpopulations. The steady-state incidence of the disease is not markedly affected by variation in the contact patterns, but the size of the steady-state population and therefore the proportion of infected individuals in the population does vary significantly with changes in the degree of mixing among subpopulations. These results show clearly the sensitivity of model outcomes to variation in the patterns of contact among individuals and the need for better data on such interactions to aid in understanding and predicting the spread of HIV.

HIV Infections↗
PubMed1990

Parameter estimation: local identifiability of parameters.

For biological systems one often cannot set up experiments to measure all of the state variables. If only a subset of the state variables can be measured, it is possible that some of the system parameters cannot influence the measured state variables or that they do so in combinations that do not define the parameters' effects separately. Such parameters are unidentifiable and are in theory unestimable. Given a model of the system, linear or nonlinear, and initial estimates of the values of all parameters, we exhibit a simple theory and describe a program for checking the local identifiability of the parameters at the initial estimates for given experiments on the model. The program, IDENT, is available from the authors.

Animals↗
PubMed1989

A resource facility for kinetic analysis: modeling using the SAAM computer programs.

Kinetic analysis and integrated system modeling have contributed significantly to understanding the physiology and pathophysiology of metabolic systems in humans and animals. Many experimental biologists are aware of the usefulness of these techniques and recognize that kinetic modeling requires special expertise. The Resource Facility for Kinetic Analysis (RFKA) provides this expertise through: (1) development and application of modeling technology for biomedical problems, and (2) development of computer-based kinetic modeling methodologies concentrating on the computer program Simulation, Analysis, and Modeling (SAAM) and its conversational version, CONversational SAAM (CONSAM). The RFKA offers consultation to the biomedical community in the use of modeling to analyze kinetic data and trains individuals in using this technology for biomedical research. Early versions of SAAM were widely applied in solving dosimetry problems; many users, however, are not familiar with recent improvements to the software. The purpose of this paper is to acquaint biomedical researchers in the dosimetry field with RFKA, which, together with the joint National Cancer Institute-National Heart, Lung and Blood Institute project, is overseeing SAAM development and applications. In addition, RFKA provides many service activities to the SAAM user community that are relevant to solving dosimetry problems.

Animals↗
PubMed1988

Effect of sodium-restricted diet and posture on norepinephrine kinetics in humans.

We used compartmental analysis to analyze the kinetics of distribution and metabolism of norepinephrine (NE) and to determine whether the increase in plasma norepinephrine concentration (PNE) during sodium restriction in humans is due to sympathetic nervous system (SNS) activation. [3H]-NE infusion and postinfusion decay were measured in young subjects in the supine position and during 60 min of standing during normal sodium (NS) diet and after 7 days of 10 meq/day sodium-restricted (SR) diet. The mean supine PNE was greater during SR diet compared with NS diet (154 +/- 9 vs. 185 +/- 12 pg/ml, P = 0.02, n = 10). During both NS and SR diets, upright PNE increased (163 +/- 4 vs. 359 +/- 38 pg/ml and 182 +/- 8 vs. 401 +/- 26 pg/ml, respectively, multivariate one-way analysis of variance, P less than 0.001, alpha = 0.05). The increases of PNE with both SR diet and upright posture were accompanied by a fall in NE metabolic clearance rate (MCR1). During SR diet this was due to a fall in the volume of distribution of NE (6.1 +/- 0.4 vs. 5.0 +/- 0.4 liters, P = 0.003, n = 10). In contrast to the effect of upright posture to increase NE release into the extra-vascular compartment (NE2), during SR diet there was no change in NE2 (1.63 +/- 0.09 vs. 1.62 +/- 0.1 micrograms.min-1.m-2, P = 0.97, n = 10). Thus the increase in PNE during SR diet in humans can be explained by a fall in the volume of distribution of NE, resulting in a decrease in MCR1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Inhibition of adenylate cyclase is mediated by the high affinity conformation of the alpha 2-adrenergic receptor.

The functional significance of high affinity agonist binding to receptors that interact with guanine nucleotide regulatory proteins has remained controversial. Preincubation of human platelet membranes with the full alpha 2-agonist UK 14,304 in the absence of GTP increases the potency of the agonist to inhibit adenylate cyclase in a pre-steady state (15-sec) assay. The EC50 after preincubation (6 +/- 1 nM) is within a factor of 2 of the high affinity Kd for [3H]UK 14,304 binding determined under identical conditions (2.7 +/- 0.1 nM). In contrast, in the usual steady state measurements (15 min) or in pre-steady state measurements without agonist preincubation, the EC50 values (74 +/- 1 and 207 +/- 8 nM, respectively) are near the low affinity Kd for [3H]UK 14,304 binding. Reduction of the GTP concentration in steady state adenylate cyclase assays also decreases the EC50 for UK 14,304 from 40 +/- 5 nM at 10 microM GTP to 14 +/- 5 nM with no added GTP. Both sets of experimental observations are accommodated by a complete kinetic model of inhibition in which the high affinity ternary complex of drug, receptor, and G protein leads to the response. Explicit rate parameters are included for agonist binding, receptor-G protein interactions, GTP binding, and hydrolysis. Despite the functional role of the high affinity state of the alpha 2-receptor in this model, the steady state EC50 for agonist-mediated inhibition correlates best with the Kd of low affinity agonist binding in the presence of high levels of GTP. Under conditions in which formation of the high affinity ternary complex is favored, the EC50 for responses approaches the high affinity Kd.

Adenylyl Cyclase Inhibitors↗
PubMed1987

Does myoglobin contribute significantly to diffusion of oxygen in red skeletal muscle?

We have examined the role of myoglobin to facilitate O2 diffusion to active mitochondria in skeletal muscle by constructing computer-simulation experiments. Steady-state mitochondrial O2 consumption under different conditions of supply partial pressure of O2 (PO2) in a system with and without myoglobin were examined for a one-dimensional slab of tissue. O2 consumption by mitochondria was saturable with the mitochondria located in bands at uniform intervals throughout the tissue. Under these conditions, myoglobin provides a measurable increase in O2 transport for supply PO2 below 10 Torr and diffusion lengths expected for skeletal muscle fibers. We conclude that under circumstances where hypoxia lowers PO2 below 10 Torr that myoglobin begins to provide a measurable increase in O2 delivery to mitochondria.

Homeostasis↗
PubMed1987

Norepinephrine metabolism in humans. Kinetic analysis and model.

The present study was undertaken to quantify more precisely and to begin to address the problem of heterogeneity of the kinetics of distribution and metabolism of norepinephrine (NE) in humans, by using compartmental analysis. Steady-state NE specific activity in arterialized plasma during [3H]NE infusion and postinfusion plasma disappearance of [3H]NE were measured in eight healthy subjects in the supine and upright positions. Two exponentials were clearly identified in the plasma [3H]NE disappearance curves of each subject studied in the supine (r = 0.94-1.00, all P less than 0.01) and upright (r = 0.90-0.98, all P less than 0.01) positions. A two-compartment model was the minimal model necessary to simultaneously describe the kinetics of NE in the supine and upright positions. The NE input rate into the extravascular compartment 2, estimated with the minimal model, increased with upright posture (1.87 +/- 0.08 vs. 3.25 +/- 0.2 micrograms/min per m2, P less than 0.001). Upright posture was associated with a fall in the volume of distribution of NE in compartment 1 (7.5 +/- 0.6 vs. 4.7 +/- 0.3 liters, P less than 0.001), and as a result of that, there was a fall in the metabolic clearance rate of NE from compartment 1 (1.80 +/- 0.11 vs. 1.21 +/- 0.08 liters/min per m2, P less than 0.001). We conclude that a two-compartment model is the minimal model that can accurately describe the kinetics of distribution and metabolism of NE in humans.

Adult↗
PubMed1987

Identifiability: the first step in parameter estimation.

The observations in an experiment define a set of observational parameters that are functions of the basic kinetic parameters of the model of the system. The problem of identifiability is concerned with whether the observational parameters uniquely specify the basic kinetic parameters. As such, it depends only on the functional relation between the two levels of parameters and not on errors of observation and the estimation procedure. It should be checked before doing the experiment. Given initial estimates of the basic kinetic parameters, identifiability can be checked, in a local sense, from data generated by simulating the experiment on the model.

Computer Simulation↗
PubMed1986

Different production and decay rates of six renin forms isolated from rat plasma.

Rat kidney contains six forms of renin, which are in different proportion from those found in plasma. We tested the hypothesis that differential removal and production of the forms might explain the differences between stored and circulating renins. In one group of rats, the six forms of renin were measured in plasma, 10 min after hemorrhage, or after aortic constriction. Plasma was run on an isoelectric focusing gel, and the six peaks of renin activity were expressed either as angiotensin I per hour per milliliter or as a percentage of the total plasma renin concentration. After hemorrhage or aortic constriction, the concentration of each form was significantly increased; the profile of circulating renin was significantly modified, showing an increase in proportion of form 2 and a decrease of forms 4, 5, and 6. In a second group, the disappearance of each form was measured 0 to 100 min after nephrectomy and fitted a two-exponential decay curve. Interpreted as a two-pool system with degradation from pool 1, the degradation rate decreased progressively, going from form 1 to 6. In a third group, arterial and renal venous blood were collected. The profile of secreted renin was calculated from the arterial venous difference. This profile fitted the prediction of the two-compartment model. Our data support the hypothesis that the proportion of each circulating renin form is the result of a balance between the rate of production of renin of constant composition and the degradation of the six forms at different rates.

Animals↗
PubMed1979

Studies on the turnover of proteins of the rat erythrocyte membrane.

The membrane proteins of erythrocytes were labeled by injecting L-[14C]-leucine and later L-[3H]leucine into rats, the two injections being 31 days apart. Control animals received the two isotopic forms of L-leucine simultaneously. Deviations in labeling ratio from control patterns were found on sodium dodecyl sulfate-polyacrylamide gel electrophorograms in restricted regions suggestive of turnover or loss of a few small proteins from the membrane between the 31 days. Most of the ghost proteins show no turnover.

Animals↗
PubMed1978

Comparison using central core model of renal medulla of the rabbit and rat.

The studies presented here use a central core model of the renal medulla, the details of which have been given elsewhere (Foster et al., Mathematical Biosci. 32: 307-335, 337-360, 1976). The central core model of the rabbit medulla predicts concentration gradients and volume flow rates in line with what is known for the rabbit. The handling of urea, however, is not consistent with the scheme proposed by Kokko and Rector (Kidney Intern. 2: 214-233, 1972). Moreover, the low concentration of urea predicted for the urine suggests an absence in the model of some form of mediated transport for urea in the inner medulla. The central core model of the rat medulla failed to predict results consistent with what is known about the rat. Substitution of the rabbit thermodynamic parameters into the model for the rat resulted in predictions that more closely resembled what one might expect, but were not entirely satisfactory. The implication is that there may be an interspecies difference in the concentration machinery between the rabbit and rat.

Animals↗
PubMed1978

Differential labeling of components in human erythrocyte membranes associated with the transport of glucose.

The irreversible inhibition of glucose transport by 1-fluoro-2,4-dinitrobenzene (FDNB) has been used to identify membrane proteins possibly associated with glucose transport in human erythrocytes. D-Glucose was shown to enhance significantly the rate of FDNB inhibition of transport when present during the reaction, whereas cytochalasin B (CB) and D-maltose retarded this FDNB inhibition of transport. This modulation of the inhibition reaction formed basis for a double isotopic differential labeling technique using [14C]- and [3H] FDNB followed by SDS-polyacrylamide gel electrophoresis to distinguish transport-associated polypeptides from bulk membrane dinitrophenylated proteins. Reactions in the presence of CB or maltose revealed the presence of a differentially labeled polypeptide(s), with a molecular weight of approximately 60,000-65,000 daltons. This effect could in part be reversed in the presence of D-glucose but not L-glucose. Reactions in the presence of D-glucose resulted in two regions of differential labeling. One region was around 200,000 daltons and the other corresponded to a 90,000-dalton band. Extraction of membrane proteins with p-chloromercuribenzene sulfonate resulted in no loss of the 60,000-dalton peak, indicating that this labeled polypeptide(s) was firmly anchored in the hydrophobic core of the membrane. These results indicate that as many as three membrane polypeptides are differentially labeled by FDNB under conditions strongly associated with the inhibition of the glucose transport system and may be involved in the regulation of glucose transport.

Biological Transport, Active↗