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J J Distefano

Publications and source records attributed to J J Distefano.

11 recordsLinked to original sources
PubMed1996

Steady-state regulation of whole-body thyroid hormone pool sizes and interconversion rates in hypothyroid and moderately T3-stimulated rats.

Steady-state regulation of whole-body T3 and T4 distribution and metabolism were directly evaluated and compared in hypothyroid, euthyroid, and in euthyroid rats moderately T3-stimulated by continuous infusion of 0.15 microg/day L-T3 per 100 g BW, thereby supplementing euthyroid T3 sources by two thirds. Our goal was to develop deeper insights into the hierarchy, quantitative adequacy, and sensitivity of this regulatory system, in response to these hormone production challenges in constant steady state. We used a novel whole-body steady-state experiment design model and data analysis approach, which entails nonexclusive whole-body homogenate extracts and blood collected after 7-day infusions of tracer T3 (T3*) or T4*, quantitatively analyzed chromatographically for T3*, T4* and metabolite* concentrations. Hormone regulation implications across the 3 groups were assessed by comparing (per 100g BW) total body T4 to T3 and T3 from T4 conversion rates (CR(4-3) and CR(3-4)), total body pool sizes (Qtot) and distribution volumes (V(D)), total body production (PR), or plasma appearance rates (PAR), plasma clearance rates (PCR), and elimination rates (k). In the hypothyroid rats, absolute production of T3 from T4 was only a fourth of that in euthyroids: CR(3-4) = 1.55 vs. 6.77 ng/h, but the percent (efficiency) of whole-body T4 converted to T3 was more than double that in euthyroids: %CR(4-3) = 45.4% vs. 21.0%, reflecting an effective doubling of type I and/or type II 5'-deiodinase activity on a whole-body basis in response to severe curtailment of thyroidal production. Whole-body T3 pools and T3 production and clearance rates were all about 2 to 3 times lower in hypo- than in euthyroids: minimum Qtot = 36.8 vs. 100 ng, V(D3) = 148 vs. 236 ml, PAR3 = 3.44 vs. 9.09 ng/h, PCR3 = 13.8 vs. 21.3 ml/h; and nearly all T4 pool size, production, clearance and elimination rates also were very substantially reduced: PCR4 = 0.540 vs. 0.941 ml/h, PR4 = 4.11 vs. 38.3 ng/h, Qtot4 = 128 vs. 702 ng, k4 = 0.0322 vs. 0.0530 h(-1). In moderately T3-stimulated rats, presumed central feedback effects of the added T3 on T4 production and total body pool size also were quite pronounced: PR4 = 21.4 ng/h and Qtot4 = 346 ng were reduced to about half that in euthyroids, but T4 elimination indices were virtually unchanged, and T3 production and elimination were minimally affected. Thus, overall, stabilizing negative feedback regulation of TH functioning at different hierarchical levels is quite bidirectionally sensitive. We found very tight (inhibitory) control over thyroidal T4 secretion, possibly also T3 secretion, and probably also absolute T3 production from T4, in response to moderate (+68%) supplements in T3 production; and the efficiency of total body T3 production from available T4 was amplified substantially in the severe primary hypothyroid state, although not nearly enough to compensate for the malady. Finally, the blood to total body pool fractions (Qb/Qtot) of both T3 and T4, but not the plasma or blood hormone levels, remained remarkably constant in response to these oppositely directed hormone production challenges, suggesting this ratio as an actively regulated, homeostatically-maintained entity.

Animals↗
PubMed1995

An algorithm for identifiable parameters and parameter bounds for a class of cascaded mammillary models.

A complex structural identifiability problem for a class of unidirectionally interconnected n-compartment linear mammillary models with multiple inputs is discussed. This class is particularly useful in the study of drug/metabolite kinetics and other interconversion kinetic processes. An explicit algorithm is developed for this model class that provides identifiable parameter combinations, parameter bounds, steady-state pool sizes, and production rates, with input forcing and output measurements in central compartments. A six-compartment model of the combined dynamics of the prohormone thyroxine (T4) and hormone triiodothyronine (T3) illustrates how physiological parameter values or their smallest ranges, such as tissue T4 to T3 conversion rates and separate T4 and T3 production rates, can be determined from stimulus-response measurements in plasma alone.

Algorithms↗
PubMed1994

Direct measurement of whole body thyroid hormone pool sizes and interconversion rates in fasted rats: hormone regulation implications.

Food deprivation markedly reduces thyroid hormone levels in mammalian plasma, but existing data are incomplete and equivocal regards extrathyroidal hormone production and other indices of overall hormone economy. We have used a novel experiment design and analysis to directly measure the whole-body rate of conversion of T4 into T3 and several other steady-state whole organism parameters, in 4-day fasted and fed control rats. Trace amounts of 125I-labeled T3 (T3) or T4 (T*4) were infused for 7 days from osmotic minipumps implanted sc. On day 7, rats were anesthetized, bled, and killed and carcasses were frozen in liquid N2, pulverized, homogenized, and extracted. Extracts and plasma samples were chromatographed on both Sephadex and HPLC. Tracer infusion rates, whole rat tissue weights, and steady state tissue, blood, and plasma T*3, T*4, and total radioactivity concentrations provided all kinetic parameters of interest from simple steady state computations. T4 secretion (SR4) and whole body pool sizes were reduced 49-55% in fasted rats. But the most notable results were that the percent of available extrathyroidal T4 converted to T3 in fasted [41.6 +/- 7.9% (SD)] was 87% greater than that in the fed (22.3 +/- 7.69%) rats and this, in turn, generated an absolute rate of production of T3 from T4 not significantly different in fasted vs. fed controls (7.17 +/- 2.40 vs. 7.54 +/- 3.10 ng/h.100 g BW). The surprisingly high 42% conversion ratio in fasting is explained in part by larger T3 blood pools (which are not sites of T3 production from T4) relative to tissue T3 pools in fasted rats, not accounted for in earlier whole-body studies. In contrast with this finding of an increased T4 to T3 conversion ratio in fasted rats, based on whole body measurements, T3 plasma concentrations (Cp3), clearance rates (PCR3), appearance rates (PAR3 = PCR3Cp3), and more conventional indirect estimates of the T4 to T3 conversion ratio (100 PAR3/SR4) were all substantially reduced, consistent with reports in fasting humans limited to measurements of T3 and T3 turnover in plasma and interpreted as indicative of reduced whole body T4 or T3 conversion. Directly measured total T3 extrathyroidal distribution volumes, reduced 55% in the fasted group from 241 +/- 19.5 to 109 +/- 8.14 ml/100 g BW, are also of interest because fed rat values are 27-61% greater than virtually all previous estimates of this index of total body T3.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Decomposition-based qualitative experiment design algorithms for a class of compartmental models.

Qualitative experiment design, to determine experimental input/output configurations that provide identifiability for specific parameters of interest, can be extremely difficult if the number of unknown parameters and the number of compartments are relatively large. However, the problem can be considerably simplified if the parameters can be divided into several groups for separate identification and the model can be decomposed into smaller submodels for separate experiment design. Model decomposition-based experiment design algorithms are proposed for a practical class of large-scale compartmental models representative of biosystems characterized by multiple input sources and unidirectional interconnectivity among subsystems. The model parameters are divided into three types, each of which is identified consecutively, in three stages, using simpler submodel experiment designs. Several practical examples are presented. Necessary and sufficient conditions for identifiability using the algorithm are also discussed.

Algorithms↗
PubMed1992

DIMSUM: an expert system for multiexponential model discrimination.

DIMSUM is a highly automated, rule-based expert system designed to fit multiexponential models of increasing dimension to time series data, followed by selection of the best candidate model based on a user-modifiable and weighted decision tree of statistical criteria for model discrimination. The major features of DIMSUM are 1) an interactive and friendly user interface; 2) options for incorporating prior information about the parameters, the data, and/or the system from which the data were collected, in the form of equality and inequality constraints; 3) a built-in algorithm for automatically obtaining starting values for parameter estimation; 4) a robust weighted least-squares parameter estimation algorithm operating in an adaptive, user-adjustable search space; 5) comprehensive statistical results comparing different order candidate models fitted to the data; and 6) a novel, user-modifiable (learning) rule-based advisory subsystem providing an "expert's" interpretation of these statistical results and an explanation of all advice.

Algorithms↗
PubMed1991

Cut set analysis of compartmental models with applications to experiment design.

Conventional compartmental analysis typically involves equations derived from mass-rate balance considerations for each compartment (pool), with each equation associated with a single pool. However, alternative mathematical descriptions, which effectively group pools into various other configurations, facilitate model analysis in certain applications, e.g., for kinetic experiment design or analysis. Such equivalent models are usually obtained using (often) complex matrix operations. An alternative approach, cut set analysis, can be applied directly to the graph of the compartmental model to readily generate alternative mathematical descriptions in which the needed equivalence transformations are easily performed graphically. This graphical transformation is developed here for linear, time-invariant multicompartmental models in which particular parameter values are the experimental objective. The method potentially provides greater flexibility in analyzing complex compartmental models in theory and practice, and it is exemplified here by application to the design of steady-state kinetic endocrine system studies in experimental animals.

Animals↗
PubMed1989

Hidden oscillations in generalized linear mammaillary compartmental models.

Oscillations due to complex eigenvalues, known to exist but difficult to detect, are sometimes totally hidden in the output of compartmental models, i.e., none of their modes appear in the output. An example is constructed of a class of linear compartmental models with complex eigenvalues, which have oscillating modes appearing in the output for some single-pool-input/single-pool-output (SpISpO) configurations, while for other such configurations all oscillations are totally hidden in the output. To generate the example, generalized mammillary compartmental models are defined in which a central pool exchanges with peripheral submodels called clusters, through individual connector pools, and their transfer functions are calculated corresponding to all SpISpO configurations. When such a model is repetitive, i.e., when it has identical peripheral clusters, and the input or the output is in the central pool, then it is zero-state equivalent, up to a multiplicative constant, with a reduced model having one peripheral cluster only. We analyze the visibility of an eigenvalue, i.e., whether or not the modes associated with it appear in the output, for repetitive generalized mammillary models. Sufficient conditions are given for such models to have oscillating modes appearing in the impulse response for some input/output configurations, while for other such configurations all oscillations are totally hidden, i.e., none appear in the output. A particularly interesting example is presented of a class of linear models with complex eigenvalues satisfying these conditions. This class has the structure of nonlinear models used to describe the process of protein synthesis and turnover.

Animals↗
PubMed1989

Parameter space boundaries for unidentifiable compartmental models.

Methods for dealing with unidentifiable compartmental models are first reviewed, emphasizing the parameter interval analysis and exhaustive modeling approaches. More general methods are presented for generating the set of all nonnegative parameter solutions that localize the parameters within bounded regions of parameter space and extend previously published parameter bounding strategies. Each point of these regions is an equivalent solution of the parameter identification problem. If a point on the boundary is selected, at least one of the parameters vanishes and an equivalent submodel is obtained. This property shows the close relationship between the exhaustive modeling and parameter interval analysis approaches.

Mathematics↗