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R C Boston

Publications and source records attributed to R C Boston.

At least 19 recordsLinked to original sources
PubMed1994

A modelling procedure for the analysis of dynamic drug--DNA interactions probed during active transcription of the DNA.

A multicompartment simulation analysis (CONSAM) has been used to describe the in vitro inhibition of transcription of DNA by echinomycin. The model assumes that at all drug blockage sites the fractional amount of blocked RNA polymerase is defined by the relative drug occupancy at that site (and is released at a rate defined by the drug dissociation rate), with all remaining enzyme being rapidly transferred past that site. The solution to the 48 parameters (three per drug site, 16 sites), which fully described the echinomycin-DNA transcription data set, can readily be accomplished without manual intervention within an hour on a MS-DOS, 486D-based microcomputer, compared to several months for a similar solution by Monte-Carlo simulation (requiring repeated intervention). The adequacy of the parameters to describe the model was confirmed by four independent criteria. The approach is applicable to the analysis of any enzyme system where an inhibitor of any type (interacting in either a reversible or irreversible manner) prevents the processive movement of enzyme along the template.

Base Sequence↗
PubMed1992

Application of models to determination of nutrient requirements: experimental techniques employing tracers.

This paper concerns some issues involved in the design of tracer experiments for the development of whole-body compartmental models of nutrient metabolism. It focuses on tracer administration protocol, use of multiple tracers, sampling strategy, measurement types and experiment duration in a pragmatic approach to obtaining data suitable for analysis and interpretation with use of models.

Animals↗
PubMed1991

A modified minimal model analysis of insulin sensitivity and glucose-mediated glucose disposal in insulin-dependent diabetes.

Although glucose utilization is impaired in insulin-dependent diabetes mellitus (IDDM), it is unclear whether this is due to reductions in insulin sensitivity (Si) and/or glucose-mediated glucose disposal (SG). The minimal model of Bergman et al can be applied to a frequently sampled intravenous glucose tolerance test (FSIGT) to simultaneously estimate Sl and SG, but cannot accommodate data from diabetics. Exogenous insulin approximating the normal pattern of insulin secretion was infused during FSIGTs in eight young non-obese C-peptide-negative IDDM subjects, but with the total dose modified to achieve sufficient glucose disappearance rates (KG) to allow analysis of data. The minimal model was modified to model the effects of the exogenous insulin on glucose kinetics to estimate SI and SG. Despite deliberately achieving supranormal plasma-free insulin levels during the FSIGT ("first-phase insulin" = 62 +/- 9 SE mU/L; "second phase insulin" = 34 +/- 9 mU/L), the diabetics showed low-normal KG values (1.3 +/- 0.29 min-1 X 10(2). Using the model, good parameter resolution (fractional SD [FSD] less than .5) was achieved (IDDM v controls: SI = 2.5 +/- 0.6 v 8.3 +/- 1.5 min-1.mU-1.L-1 X 10(4); SG = 1.6 +/- 0.5 v 2.6 +/- 0.2 min-1 X 10(2); P less than .05). This reduction in SG was confirmed in the same IDDM subjects by FSIGT during basal insulin infusion only (SG = 1.0 +/- 0.3 min-1 X 10(2)).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

A new approach to the quantitative estimation of nitrogen metabolic pathways in the rumen.

Rumen nitrogen metabolism values were estimated by the use of a single injection of 15(NH4)2SO4 into the rumen of sheep and consecutive 15N enrichment measurements in the rumen ammonia pool, rumen non-NH3-N (NAN) pool, rumen purine pool and blood urea-N (BUN) pool for a period of 24 h. Synthesis and degradation of N compounds in the rumen and passage of N to and from the rumen were evaluated on a chemical rather than a microbial basis; microbial fractions were not separated. This model was examined in two experiments. In Expt 1 a ram (55 kg) was given a semi-synthetic diet (1067 g dry matter (DM), 22.8 g N) in which soya-bean meal provided over 90% of the N. In Expt 2, two rams (45 kg) were given in three consecutive periods a semi-synthetic basal diet containing: (1) roasted soya-bean meal (SBM, 725 g DM, 14.8 g N/d); or (2) fishmeal (FM, 728 g DM, 15.5 g N/d); or (3) raw soya-bean meal (RSBM, 724 g DM, 13.8 g N/d). In all these rations, the main protein source provided over 90% of the N. In Expt 1, 68.3% of N intake was degraded directly to NH3 in the rumen, 21.2% escaped rumen degradation and 10.5% was incorporated into stable N compounds in the rumen. Net NH3 transfer to the blood was 30.4%, NH3 flow from the rumen was 6.6% and rumen NAN output was 63% of N intake. In Expt 2, rumen NAN output was larger (7.67, 14.36 and 8.89 g N/d for diets containing SBM, FM and RSBM respectively; P less than 0.05) and net NH3 loss to the blood was smaller (6.1, 0.39 and 4.17 g N/d for diets SBM, FM and RSBM respectively; P less than 0.05) for diet FM as compared with the soya-bean diets. The percentage of rumen NAN that was synthesized from NH3 was larger for diet RSBM (36.4, 40.3 and 49.1 for diets SBM, FM and RSBM respectively; P less than 0.05) than for the other two rations. NH3 pool sizes (g N) were 0.463, 0.385 and 0.301 for diets SBM, FM and RSBM respectively (P less than 0.05), while their hourly turnover rates were 15.8, 26.1 and 5.12 for diets SBM, FM and RSBM respectively (P less than 0.01), indicating no correlation between pool size and its turnover rate.(ABSTRACT TRUNCATED AT 400 WORDS)

Ammonia↗
PubMed1990

Fluorinated anthracyclines: interactions with DNA.

Four fluorine containing derivatives of anthracyclines (daunomycin and adriamycin) were synthesised, and comprised C-13, 1,1,1-trifluoroethyl-hydrazones of each anthracycline, and C-14 4-F and 4-CF3-benzoate esters of adriamycin. All four derivatives intercalated into DNA in a manner similar to their parent anthracycline. The ester derivatives exhibited 3-4-fold higher binding affinity to DNA, and slower DNA dissociation kinetics than adriamycin. This stabilisation derives from additional contacts of the C-14 side chain to the DNA minor groove. The hydrazone derivatives showed lower binding affinity to DNA, and dissociated from DNA 3-4 times faster than the parent compound. The 19F resonance of the bound drug was broadened to 120 Hz and shifted 60 Hz downfield (0.32 ppm) relative to the sharp (7.5 Hz) peak of the free drug. These values imply a rapid exchange between the free and DNA bound forms (DNA lifetime greater than 5 ms), with the fluorine group residing in a hydrophobic region in close contact with the DNA minor groove. The 4-8 fold lesser specific potency of the ester derivatives supports the concept that DNA binding is an important factor, but not sole determinant of biological activity of these analogues.

Animals↗
PubMed1990

Application of the SAAM modeling program to minimal model analysis of intravenous glucose tolerance test data.

The minimal model approach to analysis of intravenous glucose tolerance tests (IVGTT) yields estimates of parameters representing insulin sensitivity, glucose-mediated glucose disposal and pancreatic responsiveness. The precision of these estimates can deteriorate if the glucose and insulin data lack well-defined structure or freedom from data noise (random error). The precision of parameter estimates can be enhanced if data sets from two or more IVGTTs, obtained under different experimental conditions in the same subject, are analysed together in one data file. Following initial fitting using CONSAM, the conversational version of the modeling program SAAM, those parameters whose estimates remain at the same value under the different experimental conditions are constrained. This effectively reduces the number of adjustable parameters, and their estimates can then be fine-tuned with enhanced precision using the batch version of SAAM.

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↗
PubMed1989

Alternative method for minimal model analysis of intravenous glucose tolerance data.

The minimal models of glucose-insulin kinetics were used to analyze sets of data obtained from human subjects and dogs during frequently sampled intravenous glucose tolerance tests (FSIGTs). Analysis of some data sets from both species resulted in poor identification of parameters. To improve the parameter resolution, the information base on which the parameters are estimated was enlarged. This was accomplished by incorporating into the analysis 1) glucose data obtained between 0 and 8 min of the FSIGT and some of the insulin data obtained prior to the insulin peak and 2) a second set of FSIGT data for each individual obtained during a physiological perturbation. As a result, data analysis was considerably enhanced, with parameter fractional standard deviation being routinely reduced to less than 0.5. Analysis of stimulated data with noise levels for glucose and insulin set between 0.05 and 0.15 confirmed the improvement in parameter estimates. This modified approach to analysis of FSIGTs therefore consistently leads to well-defined kinetic descriptions of experimental data in various situations and supports the usefulness of the minimal model in examining the complex interplay between the parameters that influence overall glucose tolerance.

Adult↗
PubMed1988

Hormonal effects of norepinephrine on acute glucose disposal in humans: a minimal model analysis.

It is not known whether circulating norepinephrine (NE) has a direct hormonal influence on glucose disposal. This study examines whether moderate elevation of NE alters the disposal of an acute intravenous (IV) glucose load, as analysed by the minimal model of Bergman. Eight healthy normal subjects were infused with either 25 ng/kg/min NE (plasma NE 1,284 +/- 259 pg/mL) or normal saline (plasma NE 314 +/- 86 pg/mL), 30 minutes prior to and during an IV glucose tolerance test (GTT). There was a small but significant rise (P less than .05) in basal blood glucose levels during the initial 30-minute NE infusion which was accompanied by a 40% increase (0.39 +/- .02 to 0.59 +/- .07 nmol/L, P less than .01) in nonesterified fatty acid levels (NEFA). Insulin, C-peptide, and glucagon levels did not change. NE impaired the rate of acute glucose disposal (Kg 1.74 +/- 0.24 v 2.10 +/- 0.23 (min-1, P less than .05). Minimal model analysis revealed a corresponding 35% decrease in insulin sensitivity (SI 4.85 +/- 1.51 v 7.28 +/- 1.16 min-1 microU-1 mL-1 x 10(4), P less than .05) but no significant differences between glucose-mediated glucose disposal or pancreatic B-cell responsiveness. The glucose disposition index (si* phi2), a direct measure of an individual's overall insulin- mediated glucose disposal, was reduced by 70% in the NE-infussed subjects (si* phi2 69 +/-22 v 223 +/- 76 mg-1 ml-1 min-3 x 10(2), p< .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Effects of epinephrine infusion on determinants of intravenous glucose tolerance in dogs.

Effects of four- to fivefold elevations of epinephrine (EPI) on glucose (Glc) metabolism were assessed in eight dogs before and after an intravenous Glc tolerance test, performed 30 min (short EPI) and 72 h (long EPI) after start of EPI infusion. Short EPI increased plasma nonesterified fatty acids (NEFA; 0.46 +/- 0.08 to 0.78 +/- 0.12 mmol/l, P less than 0.05), but Glc and insulin were unchanged. After long EPI, NEFA returned to control but Glc increased from 5.1 +/- 0.1 to 5.7 +/- 0.2 mmol/l (P less than 0.05). EPI reduced overall Glc tolerance (KG) from 3.5 +/- 0.7 to 2.5 +/- 0.2 (short EPI, P less than 0.05) and 2.3 +/- 0.3%/min (long EPI, P less than 0.02). Minimal model analysis showed that short EPI decreased insulin sensitivity (SI) from 7.9 +/- 1.1 to 4.2 +/- 1.2 min-1 per mU/l X 10(-4) (P less than 0.005) and increased pancreatic responsiveness (phi 1 from 3.7 +/- 0.3 to 7.4 +/- 2.9 mU/l.min-1 per mg/dl, P less than 0.025; phi 2 from 2.6 +/- 0.7 to 4.9 +/- 1.2 mU/l.min-2 per mg/dl). After long EPI SI, phi 1, and phi 2 returned to control. In contrast, Glc-mediated Glc disposal (SG) was decreased from 3.5 +/- 0.5 X 10(-2) to 2.8 +/- 0.6 X 10(-2) (short EPI) and 1.3 +/- 0.6 X 10(-2) min-1 (long EPI, P less than 0.02). We conclude that prolonged infusion of EPI leads to adaptation to its acute effects on NEFA, SI, phi 1, and phi 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Daunomycin-DNA dissociation kinetics.

The dissociation of daunomycin from DNA was examined using a sodium dodecyl sulfate-sequestered stopped flow procedure. Two dissociation processes were observed with calf thymus and bacterial DNA, with approximately 45% of the amplitude associated with the faster process. Both processes were largely independent of DNA sequence for bacterial DNA, comprising 30-70% (G + C) content. The rate of both processes increased by a similar amount with increasing ionic strength. The faster process decreased with decreasing drug loading, whereas the slower process was independent of drug loading. Only one dissociation event was observed for the dissociation of daunomycin from four different synthetic polydeoxynucleotides. All observations are consistent with a parallel model of sodium dodecyl sulfate-induced dissociation of daunomycin from DNA, where the two processes observed reflect two resolvable processes that may be comprised of a series of rate constants for the dissociation of drug from differing environments. The slower process observed with bacterial DNA (0.5-0.7 sec-1) is related to dissociation from preferential 5'-CA DNA-binding sites, whereas the faster process reflects dissociation of drug from lower affinity sites on heterogenous DNA (3.2-4.1 sec-1). Dissociation of daunomycin from four different synthetic polydeoxynucleotides (which did not contain the 5'-CA preferential daunomycin-binding site) exhibited dissociation rates characteristic of low affinity sites (3.3-4.8 sec-1).

Base Composition↗
PubMed1987

Quantitation of phosphorus excretion in sheep by compartmental analysis.

The control of phosphorus excretion in sheep has been examined by constructing a kinetic model that contains a mechanistic set of connections between blood and gastrointestinal tract. The model was developed using experimental data from chaff-fed sheep and gives an accurate description of the absorption and excretion of phosphorus in feces and urine of the ruminating sheep. Simulation of the response to an intravenous phosphorus infusion by adding an inflow of 2 g/day of phosphorus into the compartment describing blood, predicted values for fecal output of phosphorus lower than found experimentally. However, by alteration of the parameters describing absorption or salivation, the predictions approached experimental values. Similarly simulation of the conditions existing when a liquid diet was infused directly into the abomasum, i.e., a decrease in salivation rate [L(4.1)] and dietary phosphorus entering compartment 5 (abomasum) instead of compartment 4 (rumen), gave incorrect predictions for plasma and urinary phosphorus, but when the parameter for urinary phosphorus was increased the predicted values approached experimental values. These results indicated the main control site for phosphorus excretion in the ruminating sheep was the gastrointestinal tract, whereas for the nonruminating sheep fed the liquid diet, control was exerted by the kidney. A critical factor in the induction of adaptation of phosphorus reabsorption by the kidney was the reduction in salivation, and since this response occurred independently of marked changes in the delivery of phosphorus to the kidney, a humoral factor may be involved in this communication between salivary gland and kidney.

Animals↗
PubMed1986

The methodology of compartmental modeling as applied to the investigation of lipoprotein metabolism.

The statements to this point only give a cursory review of the beginning (20 years) of the kinetic approach to the classification of lipoproteins and subsystems which are involved in their synthesis and metabolism. At the present time the following partial list of theoretical findings expressed through model building can be made for the lipid and lipoprotein field: A cascade process of delipidation for VLDL exists and the rate of this process is decreased in subjects with hyperlipoproteinemia. ApoC recycles between VLDL and HDL in response to the dynamics of the delipidation cascade. New synthesis of apoB first appears with newly synthesized VLDL. VLDL apoB synthesis decreased in hyperlipidemic states examined. Multiple synthesis pathways exist for the triglyceride moiety of VLDL as determined by the transit time of a precursor through the conversion pathway. Thus the isotopic precursor methods now yield the same results as the more invasive techniques. Kinetic heterogeneity of VLDL, IDL, LDL, and HDL has been established. Kinetic heterogeneity for apoA-I, apoA-II, apoB, apoC-2 and apoC-3 have been established. The presence of direct pathways for IDL and LDL synthesis have been established. Irreversible loss of apoC from HDL has been predicted using models. Synthesis of apoC has been found to be invariant in hyperlipoproteinemic states studied. Hepatic cholesterol compartments associated with the formation of bile acids and biliary cholesterol derive a majority of their cholesterol from newly synthesized and lipoprotein-free cholesterol. More than 85% of the free cholesterol in the beta-lipoproteins cycles directly through the HDL. Free cholesterol recycles between HDL and tissue pools and between HDL and beta-lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

The maintenance, distribution and development of biomedical computer software: an exercise in software engineering.

The growing reliance of biomedical investigations on computer software in almost all facets of their work places considerable emphasis on the need for the integrated management of the software. In order to efficiently develop, distribute, and maintain the software, tools are required which not only automate these tasks but also, wherever possible, 'semi-intelligently', alert their user to irregular situation. We describe an assortment of such tools routinely used in the management of the SAAM/CONSAM biokinetic software and illustrate their application. Furthermore, using these techniques we have presented some comparative performances of numerical integrators and of computer processors.

Computers↗
PubMed1986

Metabolic consequences of prolonged hyperinsulinemia in humans. Evidence for induction of insulin insensitivity.

Hyperinsulinemia is frequently associated with a variety of insulin-resistant states and has been implicated causally in the development of insulin resistance. This study examines the metabolic consequences of prolonged hyperinsulinemia in humans. Basally and 1 h after cessation of a 20-h infusion of insulin (0.5 mU X kg-1 X min-1, aimed at elevating plasma insulin levels to approximately 30 mU/L) or normal saline, subjects were assessed for glucose turnover with 3-[3H]glucose; insulin sensitivity, as measured by either the euglycemic glucose-clamp technique or the intravenous glucose tolerance test (IVGTT) minimal model method of Bergman; and monocyte insulin-receptor binding. Hepatic glucose production (Ra) was suppressed by greater than 95% during each euglycemic clamp and during the 20-h insulin infusion. After the insulin infusion, Ra and glucose utilization rate returned to the initial basal level within 1 h, as did insulin levels. At that time, insulin sensitivity was significantly decreased, as measured by the "insulin action" parameter during the 40- to 80-min phase of the clamp (0.049 +/- 0.003 vs. 0.035 +/- 0.007 min-1, P less than .05) and during the 80- to 120-min phase (0.047 +/- 0.005 vs. 0.039 +/- 0.007 min-1, .05 less than P less than .1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Movement of water within the body of sheep fed at maintenance under thermoneutral conditions.

Two mature Border Leicester x Merino wethers were maintained with continuous feeding under thermoneutral conditions. Their water balance was recorded for 2 weeks; at the beginning of each week they were given a dose of tritiated water (TOH) into the pulmonary artery or the rumen and samples were taken from both the pulmonary artery and the rumen. A four-compartment model was developed which simultaneously fitted the balance and tracer data. The half-time of TOH in body water was 6.7 days for one sheep and 7.6 days for the other; TOH space was about 55% of liveweight in both sheep. The bidirectional flux of water between the plasma-accessible compartment and 'bound' intracellular water averaged 45 litres per hour and that between plasma-accessible water and rumen water averaged 3.2 litres per hour. The mean residence times of a water molecule in the rumen were, for the two sheep, 60 and 63 min and the time constants for flow from the rumen were 12.3 and 13.4 h. Consideration of the rumen water balance suggested that there was net movement of water from the rumen to the plasma at about 200 ml/h; diffusion accounted for 86% of the influx to and 92% of the efflux from the rumen.

Animals↗
PubMed1983

Fetal and maternal endocrine responses to exercise in the pregnant ewe.

Maternal and fetal concentrations of plasma insulin, pancreatic glucagon, growth hormone (GH), corticosteroids and enteroglucagon, and of blood glucose and lactate, were measured in well-fed, late pregnant ewes before, during and after walking on a treadmill at 0.7 m.s-1, 10 degrees slope for 60 min. Exercise caused rapid and substantial increases in maternal concentrations of glucose, lactate, pancreatic glucagon and corticosteroids, smaller but significant decreases in levels of GH and enteroglucagon, and no change in insulin. With the exception of GH, concentrations of these maternal hormones had returned to pre-exercise levels within 20 min of stopping exercise. The exercise-induced maternal hyperglycaemia was associated with a proportionately similar, rapid increase in fetal blood glucose; fetal blood lactate and plasma corticosteroids also increased, but at slower rates and other fetal hormone concentrations were unchanged. During recovery there was a rapid increase in fetal insulin levels. The results are discussed in terms of the regulation of exercise-induced changes in maternal energy metabolism, and fetal metabolic and hormonal sensitivity to these changes.

Adrenal Cortex Hormones↗