Biomedical subjects

D M Foster

Publications and source records attributed to D M Foster.

At least 19 recordsLinked to original sources

PubMed2001

Statistical analysis of spatial pattern: a comparison of grid and hierarchical sampling approaches.

Previous studies have combined random-site hierarchical sampling designs with analysis of variance techniques, and grid sampling with spatial autocorrelation analysis. We illustrate that analysis techniques and sampling designs are interchangeable using densities of an infaunal bivalve from a study in Poverty Bay, New Zealand. Hierarchical designs allow the estimation of variances associated with each level, but high-level factors are imprecisely estimated, and they are inefficient for describing spatial pattern. Grid designs are efficient for describing spatial pattern, and are amenable to conventional analysis. Our example deals with a continuous spatial habitat, but our conclusions also apply in disjunct or patchy habitats. The influence of errors in positioning is also assessed. The advantages of systematic sampling are reviewed, and more efficient hierarchical approaches are identified. The distinction between biological and statistical significance in all analyses is emphasised.

Animals↗

PubMed2000

Surface expression and rapid internalization of macrosialin (mouse CD68) on elicited mouse peritoneal macrophages.

Macrosialin, the mouse homolog of human CD68, is a heavily glycosylated transmembrane protein found almost exclusively in macrophages. Its function remains uncertain. It has a high affinity for oxidized low-density lipoprotein (LDL) in ligand blots and antibodies against the human homolog, CD68, inhibit the binding of oxidized LDL to a human monocyte-derived cell line (THP-1). However, there is still controversy as to whether macrosialin, found predominantly in late endosomes, is expressed at all on the plasma membrane. The present studies, done in thioglycollate-elicited peritoneal macrophages, confirm that macrosialin is predominantly intracellular but show clearly that 10-15% of it is expressed on the cell surface. Exchange with intracellular pools occurs at an extremely high rate. The results are compatible with a surface function, including internalization of bound ligands or adhesion to surfaces.

Animals↗

PubMed1999

Pharmacokinetic-pharmacodynamic modeling of the psychomotor stimulant effect of cocaine after intravenous administration: timing performance deficits.

We investigated dose-response cocaine pharmacokinetic and metabolite profiles in a within-subject design after intravenous bolus cocaine administration (1-4 mg/kg) in rats under a food-limited regimen. Cocaine was rapidly distributed (T1/2beta = 1.09 min) and eliminated (T1/2alpha = 14.93 min). Norcocaine was not detected. The free fraction of cocaine was 31.3-33.1% for serum cocaine concentrations of 0.5 to 1 microg/ml. Parallel pharmacodynamics was studied using performance on a contingency-controlled timing behavior, a differential reinforcement of low rate schedule (45 s) in 3-h sessions. Cocaine increased the shorter-response rate and decreased the density of reinforcement in a dose- and time-related fashion. The increased shorter-response rate is the stimulatory effect herein reported. The changes in shorter-response rate and the density of reinforcement were directly interpretable as functions of cocaine concentrations in the respective hypothetical effect compartments by using sigmoidal Emax and inhibitory Emax models, respectively. Because the concentration at half of Emax for the shorter-response rate (EC50 = 0.467 microg/ml) was greater than that for density of reinforcement (IC50 = 0.070 microg/ml), the former began to return toward baseline sooner than the latter. Only as cocaine concentration decreased to values smaller than the EC50 did the density of reinforcement begin to return toward baseline. Thus, the density of reinforcement is an index for evaluating the deficit in timing performance. The concentration-effect plot confirmed that the intensity of the effects of cocaine depends solely on concentration regardless of the dose. These results demonstrated that the pharmacokinetic-pharmacodynamic analysis allows the identification of the stimulant action of cocaine, which in turn delineates its consequence on timing performance.

Animals↗

PubMed1998

A rapid assay of endotoxin in whole blood using autologous neutrophil dependent chemiluminescence.

A rapid (30 min) whole blood assay for the detection of lipopolysaccharide (LPS) is described. This chemiluminescent (CL) assay utilizes the CR1 and CR3 receptor-induced oxidant production of polymorphonuclear leucocytes as a detection platform. The differential priming of neutrophils in whole blood by LPS-antibody complexes allows the specificity of the assay to be achieved. Oxidant released in response to complement opsonized zymosan results in luminol oxidation and subsequent light emission. This is dependent on heat labile putative complement proteins in the plasma. The assay consists of a control which measures baseline whole blood neutrophil oxidant production. The test assay contains murine monoclonal IgM antibody against the Lipid A epitope of LPS and measures the enhanced chemiluminescent response of the neutrophils in the presence of LPS-antibody complexes. Maximal sensitivity of the CL assay is dependent upon optimal antigen-antibody equivalence and duration of pre-incubation with the whole blood sample. The quantification of LPS is possible by inclusion of a positive control containing a maximally reactive LPS dose (800 pg/ml Escherichia coli 055:B5 LPS at an antibody concentration of 0.8 microg/assay). The CL assay is insensitive to variations in patient neutrophil concentration over a minimum range of 0.5 to 20 x 10(9) cells/l. The CL assay is widely reactive with the LPS of many strains of gram negative bacteria but not with the cell wall products of gram positive bacteria or Candida and Aspergillus. In comparison to acid extraction chromogenic LAL, the CL assay demonstrates superior recovery precision and accuracy in in vitro studies. This was reproducible over a wide range of LPS concentrations (0.017-1.6 EU/ml or 20-2000 pg/ml). This assay may be a clinically useful tool for the diagnosis of infection or endotoxin in patients.

Antibodies, Bacterial↗

PubMed1998

Developing and testing integrated multicompartment models to describe a single-input multiple-output study using the SAAM II software system.

As measurement devices become more sophisticated, it is possible to design more complex input-output studies, i.e., studies where data are obtained from several sites in the system under study. To interpret the resulting data requires models which can integrate known information about the system under study while simultaneously describing the data. In this chapter, we will illustrate how to develop and test a model structure for a single-input multiple-output study using the SAAM II software system. This system has been designed to make the use of sound modeling principles easy. It will be assumed that a known amount of a radiolabeled substance was injected as a bolus into plasma, that this substance can bind to and be taken up by red cells, that its only route of elimination is through the urine, and that external measurements are possible over a target organ. The steps in developing a model structure will make use of SAAM II's forcing function capability to show how the system can be decoupled; this will permit us to postulate model structures for the various subsystems accessible to measurement. We will then show how to use this information to postulate a model describing all the data, and how to test this model structure. This will permit us to comment on those parts of the system not accessible for experimental measurement. We will end with a general discussion of how to test for goodness-of-fit and model order.

Computer Simulation↗

PubMed1998

Compartmental models: theory and practice using the SAAM II software system.

Understanding in vivo the functioning of metabolic systems at the whole-body or regional level requires one to make some assumptions on how the system works and to describe them mathematically, that is, to postulate a model of the system. Models of systems can have different characteristics depending on the properties of the system and the database available for their study; they can be deterministic or stochastic, dynamic or static, with lumped or distributed parameters. Metabolic systems are dynamic systems and we focus here on the most widely used class of dynamic (differential equation) models: compartmental models. This is a class of models for which the governing law is conservation of mass. It is a very attractive class to users because it formalizes physical intuition in a simple and reasonable way. Compartmental models are lumped parameter models, in that the events in the system are described by a finite number of changing variables, and are thus described by ordinary differential equations. While stochastic compartment models can also be defined, we discuss here the deterministic versions--those that can work with exact relationships between model variables. These are the models most widely used in discussions of endocrinology and metabolism. In this chapter, we will discuss the theory of compartmental models, and then discuss how the SAAM II software system, a system designed specifically to aid in the development and testing of multicompartmental models, can be used.

Blood Glucose↗

PubMed1998

Approaches to population kinetic analysis with application to metabolic studies.

Population kinetic analysis is the methodology traditionally used to quantify inter-subject variability in pharmacokinetic studies. In the statistics literature, it is also called analysis of repeated measurement data or analysis of longitudinal data. In this work, we will state the population kinetics problem and give some historical background to its significance. Then we will describe and apply to case studies in intermediary metabolism various two-stage and other parametric methods for nonlinear mixed effects models. We will then briefly review the software available for population kinetic analysis.

Computer Simulation↗

PubMed1998

SAAM II: Simulation, Analysis, and Modeling Software for tracer and pharmacokinetic studies.

Kinetic analysis and integrated systems modeling have contributed substantially to our understanding of the physiology and pathophysiology of metabolic systems and the distribution and clearance of drugs in humans and animals. In recent years, many researchers have become aware of the usefulness of these techniques in the experimental design. With this has come the recognition that the discipline of kinetic analysis requires its own expertise. The expertise can impact experimental design in many ways, from the collaborative and service activities in which individuals interact in formal ways to the development of software tools to aid in kinetic analysis. The purpose of this report is to describe one such software tool, Simulation, Analysis, and Modeling Software II (SAAM II). In the first part, we describe in general how the user can take advantage of the capabilities of the software system, and in the second part, we give three specific examples using multicompartmental models found in lipoprotein (apolipoprotein B [apoB] kinetics) and diabetes (glucose minimal model) research.

Algorithms↗

PubMed1996

Prostatic acid phosphatase levels (enzymatic method) from completely sectioned, clinically benign, whole prostates.

Clinically benign, whole untrimmed prostates were obtained from 104 patients at autopsy, completely sectioned, and examined microscopically. The histological and gross findings of the prostate were correlated with premortem prostatic acid phosphatase levels (PAP, enzymatic method, ACA, Dupont Co.) to determine how often carcinoma of the prostate (CAP) affected PAP levels and to identify other findings within the prostate associated with elevated PAP levels. Sixty (58%) prostates did not have CAP, 34 (33%) had CAP smaller than 1 ml in volume, and 10 (10%) had CAP larger than 1 ml in volume. PAP levels were elevated (greater than 1 U/L) in 8 of 60 (13%) prostates without CAP, in 2 of the 34 (6%) prostates with CAP smaller than 1 ml, and in 1 of the 10 (10%) prostates with CAP larger than 1 ml. These differences were not statistically significant. Likewise, a statistically significant correlation between PAP levels and patient age, patient race, severe inflammation, of high grade prostatic intraepithelial neoplasia (PIN) was not found. However, there was a statistically significant correlation between PAP levels and prostate weight (p < 0.0001). This study suggest that PAP cannot distinguish between patients with clinically undetected CAP and patients without CAP. Furthermore, elevated PAP levels are often not due to metastatic CAP and additional evidence should be present, even in patients with known CAP, before an elevated PAP level is considered to be conclusive evidence of metastatic CAP.

Acid Phosphatase↗

PubMed1996

Design and analysis of lipid tracer kinetic studies.

A fundamental problem in lipid metabolism is designing experiments to quantitate the kinetics of the plasma lipids and lipoproteins in the body. Tracers have been used extensively. In this review, we will combine our knowledge of the theory and application of tracer kinetic studies to discuss current state of the art methodologies for lipid metabolism. We will review the use of stable and radioactive isotopes pointing out the importance of the measurement variables, and the theory and application of noncompartmental and compartmental models to interpret the data.

Humans↗

PubMed1996

Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs.

We have previously shown that transport of plasma insulin into the central nervous system (CNS) is mediated by a saturable mechanism consistent with insulin binding to blood-brain barrier insulin receptors and subsequent transcytosis through microvessel endothelial cells. Since glucocorticoids antagonize insulin receptor-mediated actions both peripherally and in the CNS, we hypothesized that glucocorticoids also impair CNS insulin transport. Nine dogs were studied both in the control condition and after 7 days of high-dose oral dexamethasone (DEX) administration (12 mg/day) by obtaining plasma and cerebrospinal fluid (CSF) samples over 8 h for determination of immunoreactive insulin levels during a 90-min euglycemic intravenous insulin infusion (plasma insulin approximately 700 pmol/l). From these data, the kinetics of CNS insulin uptake and removal were determined using a mathematical model with three components (plasma-->intermediate compartment, hypothesized to be brain interstitial fluid-->CSF). DEX increased basal insulin levels 75% from 24 +/- 6 to 42 +/- 30 pmol/l (P < 0.005) and slightly increased basal glucose levels from 5.0 +/- 0.7 to 5.3 +/- 1.0 mmol/l (P < 0.05). DEX also lowered the model rate constant characterizing CNS insulin transport by 49% from 5.3 x 10(-6) +/- 4.0 x 10(-6) to 2.7 x 10(-6) +/- 1.2 x 10(-6) min-2 (P < or = 0.001). As glucocorticoids are known to reduce CSF turnover, we also hypothesized that the model rate constant associated with CSF insulin removal would be decreased by DEX. As expected, the model rate constant for CSF insulin removal decreased 47% from 0.038 +/- 0.013 to 0.020 +/- 0.088 min-1 (P < or = 0.0005) during DEX treatment. We conclude that DEX impairs CNS insulin transport. This finding supports our hypothesis that insulin receptors participate in the CNS insulin transport process and that this process may be subject to regulation. Moreover, since increasing brain insulin transport reduces food intake and body adiposity, this observation provides a potential mechanism by which glucocorticoid excess leads to increased body adiposity.

Animals↗

PubMed1995

Evaluation of age-specific normal ranges for prostate-specific antigen.

OBJECTIVES: To compare the traditional normal range (TNR) of 0.0 to 4.0 ng/mL for serum prostate-specific antigen (PSA) to age-specific normal ranges (ASNRs). METHODS: An autopsy series of completely sectioned, clinically benign prostates from 171 consecutive Caucasian men over the age of 40 years was selected. These patients were divided into those having no prostate cancer at autopsy, prostate cancer less than 1 cc in volume, and prostate cancer at least 1 cc in volume. The PSA values of each group were compared using both the TNR and the ASNR. RESULTS: Twenty-three of 105 (21.9%) patients with no cancer had elevated PSA values by the TNR, whereas only 18 (17.1%) were elevated using the ASNR. Nine of 54 (16.7%) with cancer less than 1 cc were elevated using the TNR, and 7 of 54 (13.0%) using the ASNR. Of 12 patients with cancer at least 1 cc, all had elevated PSA levels using the TNR and 11 (91.7%) were elevated using the ASNR. All discrepancies between the TNR and ASNR occurred in the 60- to 79-year age range. CONCLUSIONS: Use of ASNRs appears helpful in increasing the specificity of PSA by eliminating some elevated values in patients in their 60s and 70s.

Adult↗

PubMed1994

Characteristics of prostatic infarcts and their effect on serum prostate-specific antigen and prostatic acid phosphatase.

OBJECTIVES: To determine how prostatic infarcts affect serum prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) levels. METHODS: Two hundred eighteen clinically benign, whole prostates were obtained at autopsy, completely sectioned, and examined histologically. PSA and PAP levels were determined from premortem serum. RESULTS: Six of the 218 (2.8%) prostates had infarcts. The infarcts were usually multiple and usually located in the central and/or middle concentric zones of the middle third of the prostate without a preference for a particular lobe. Serum PSA by immunoradiometric assay were elevated in all 6 cases. Serum PAP by both enzymatic assay (ACA), and immunoradiometric assay were available for 5 cases and were elevated by both methods in 2 cases, approached elevated levels by both methods in 1 case, and were normal by both methods in 2 cases. The PSA and PAP levels appeared to be affected more by the age than by the size of the infarct. CONCLUSIONS: Prostatic infarcts elevate PSA levels more frequently than PAP levels, and prostatic infarcts may be responsible for some unexplained elevations of serum PSA and PAP levels.

Acid Phosphatase↗

PubMed1993

Estimation of protein fractional synthetic rate from tracer data.

The fractional synthetic rate (FSR) is a key parameter characterizing protein turnover that is estimated from tracer kinetic data. Formulas to estimate this parameter usually assume a precursor-product model. Assuming this model is correct, we discuss these formulas to estimate the FSR in the steady and non-steady state both for the radioactive and stable isotope tracer. Then we deal with the non-steady-state case where the FSR becomes time varying and derive formulas for its estimation. A non-steady-state case study on the flooding-dose technique for measuring protein turnover is presented.

Homeostasis↗

PubMed1993

Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain.

By acting in the central nervous system, circulating insulin may regulate food intake and body weight. We have previously shown that the kinetics of insulin uptake from plasma into cerebrospinal fluid (CSF) can best be explained by passage through an intermediate compartment. To determine if transport kinetics into this compartment were consistent with an insulin receptor-mediated transport process, we subjected overnight fasted, anesthetized dogs to euglycemic intravenous insulin infusions for 90 min over a wide range of plasma insulin levels (69-5,064 microU/ml) (n = 10). Plasma and CSF samples were collected over 8 h for determination of immunoreactive insulin levels, and the kinetics of insulin uptake from plasma into CSF were analyzed using a compartmental model with three components (plasma-->intermediate compartment-->CSF). By sampling frequently during rapid changes of plasma and CSF insulin levels, we were able to precisely estimate three parameters (average standard deviation 14%) characterizing the uptake of insulin from plasma, through the intermediate compartment and into CSF (k1k2); insulin entry into CSF and insulin clearance from the intermediate compartment (k2 + k3); and insulin clearance from CSF (k4). At physiologic plasma insulin levels (80 +/- 7.4 microU/ml), k1k2 was determined to be 10.7 x 10(-6) +/- 1.3 x 10(-6) min-2. With increasing plasma levels, however, k1k2 decreased progressively, being reduced sevenfold at supraphysiologic levels (5,064 microU/ml). The apparent KM of this saturation curve was 742 microU/ml (approximately 5 nM). In contrast, the rate constants for insulin removal from the intermediate compartment and from CSF did not vary with plasma insulin (k2 + k3 = 0.011 +/- 0.0019 min-1 and k4 = 0.046 +/- 0.021 min-1). We conclude that delivery of plasma insulin into the central nervous system is saturable, and is likely facilitated by an insulin-receptor mediated transport process.

Animals↗

PubMed1993

Articular pharmacokinetics of protein-bound antirheumatic agents.

By what mechanism do nonsteroidal anti-inflammatory drugs (NSAIDs) move from plasma into synovial fluid and back, and how does binding to plasma albumin in vitro relate to articular transport in vivo? To evaluate these issues, concurrent plasma and synovial fluid data of 8 different NSAIDs from 10 single-dose trials were analysed by a simple compartmental model incorporating intra-articular volume, synovial plasma flow rates and protein transport. All pharmacological and physiological data were taken from published studies of chronic knee effusions in patients with rheumatoid arthritis. The analysis shows that these protein-bound NSAIDs readily leave the vasculature and enter synovial fluid during each transit of synovial microvessels. The mean rate of transport, 0.23 min-1, is consistent with passive diffusion at rates far in excess of those attributable to movement of albumin-bound drug or of the small, free-drug fraction found by equilibrium dialysis. These findings are explained by association and dissociation of NSAIDs and albumin that occur far more rapidly than vascular transit. Ongoing dissociation makes bound drug available for transvascular exchange and thereby diminishes the pharmacokinetic significance of binding data obtained in vitro.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1993

Estimating the fractional synthetic rate of plasma apolipoproteins and lipids from stable isotope data.

The use of isotopic tracer studies to quantitate parameters characterizing apolipoprotein metabolism is enjoying a resurgence. This is due in large part to the availability of a number of stable isotopes and methods to measure them accurately in small quantities. Most experimental protocols in which stable isotopes are used call for endogenous labeling of the apolipoprotein of interest by an infusion of a labeled amino acid. Unlike the radioactively labeled amino acid counterpart in which turnover studies have traditionally been carried out for 72 hours to 14 days, the duration of the stable isotope experiment is normally less than 24 hours. This has contributed to some problems related to estimating the kinetic parameters because simplistic formulas whose underlying assumptions are not applicable to the lipoprotein system under study are often invoked. This is particularly true for the fractional synthetic rate (FSR). The purpose of this review is to address some of these problems. We derive the formula commonly used to estimate the FSR. In so doing, the underlying assumptions are carefully delineated. We then discuss several ways in which the formula is applied. Finally, we discuss the implications of these assumptions when the formula is applied to specific lipoprotein systems.

Apolipoproteins↗

PubMed1992

Protein transfer between A-I-containing lipoprotein subpopulations: evidence of non-transferable A-I in particles with A-II.

Transfer of apolipoproteins (apo) between the two subpopulations of apo A-I-containing lipoproteins in human plasma: those with A-II [Lp(AI w AII)] and those without [Lp(AI w/o AII)], were studied by observing the transfer of 125I-apo from a radiolabeled subpopulation to an unlabeled subpopulation in vitro. When Lp(AI w AII) was directly radioiodinated, 50.3 +/- 7.4 and 19.5 +/- 7.7% (n = 6) of the total radioactivity was associated with A-I and A-II, respectively. In radioiodinated Lp(AI w/o AII), 71.5 +/- 6.8% (n = 6) of the total radioactivity was A-I-associated. Time-course studies showed that, while some radiolabeled proteins transferred from one population of HDL particles to another within minutes, at least several hours were necessary for transfer to approach equilibrium. Incubation of the subpopulations at equal A-I mass resulted in the transfer of 51.8 +/- 5.0% (n = 4) of total radioactivity from [125I]Lp(AI w/o AII) to Lp(AI w AII) at 37 degrees C in 24 h. The specific activity (S.A.) of A-I in the two subpopulations after incubation was nearly identical. Under similar incubation conditions, only 13.4 +/- 4.6% (n = 4) of total radioactivity was transferred from [125I]Lp(AI w AII) to Lp(AI w/o AII). The S.A. of A-I after incubation was 2-fold higher in particles with A-II than in particles without A-II. These phenomena were also observed with iodinated high-density lipoproteins (HDL) isolated by ultracentrifugation and subsequently subfractionated by immunoaffinity chromatography. However, when Lp(AI w AII) radiolabeled by in vitro exchange with free [125I]A-I was incubated with unlabeled Lp(AI w/o AII), the S.A. of A-I in particles with and without A-II differed by only 18% after incubation. These data are consistent with the following: (1) in both populations of HDL particles, some radiolabeled proteins transferred rapidly (minutes or less), while others transferred slowly (hours); (2) when Lp(AI w AII) and Lp(AI w/o AII) were directly iodinated, all labeled A-I in particles without A-II were transferable, but some labeled AI in particles with A-II were not; (3) when Lp(AI w AII) were labeled by in vitro exchange with [125I]A-I, considerably more labeled A-I were transferable. These observations suggest the presence of non-transferable A-I in Lp(AI w AII).

Adult↗