Effects of thyroid disease on glucose oxidative metabolism in man. A compartmental model analysis.

Glucose oxidation to CO(2) in man at the fasted, steady state has been investigated in normal, hypothyroid, patients by monitoring the specific activity of plasma glucose and expired CO(2) after intravenous injection of glucose-1-(14)C, glucose-6-(14)C, and sodium bicarbonate-(24)C in tracer amounts. Making certain stoichiometric assumptions about the oxidation of the C-1 and C-6 carbons of glucose to CO(2), the data are incorporated into a multicompartmental model describing the kinetics of plasma glucose, plasma bicarbonate, and the conversion of glucose to CO(2) by the hexose monophosphate pathway and all other series and parallel pathways which oxidize glucose carbon to CO(2) (EMP-TCA). This formulation separates the distribution kinetics of glucose and bicarbonate from the kinetics of glucose oxidation to CO(2). It allows the calculation of a minimal fraction (varphi(t)) of glucose irreversibly oxidized to CO(2) which is based entirely on the duration of the experimental data. This calculation is independent of the extrapolative implications of the model beyond the experimental interval and of the particular model chosen to fit the data. All modeling and data fitting were performed on a digital computer with the SAAM program. Based on a 300 min experiment the analysis suggests that in hypothyroidism there is a decrease in the rate of glucose metabolized irreversibly (rhoG). There is also a decrease in the minimal fraction (varphi(300)) which is completely oxidized to CO(2) by way of the EMP-TCA. rhoG and varphi(300) are 0.56 and 0.42 mmole/min respectively as compared to 0.89 and 0.50 mmole/min respectively in normals. However, the fraction of the C-1 of glucose metabolized irreversibly which undergoes oxidation to CO(2) by the hexose monophosphate pathway (Psi) is not different from normal (0.07 and 0.07 respectively). The hyperthyroid studies suggest that rhoG and varphi(300) are within the normal range (1.01 and 0.46 mmoles/min respectively as compared to 0.89 and 0.50 mmole/min respectively in normals). However, Psi is decreased to less than half the normal value (0.03 as compared to 0.07 in normals).

Transport of plasma free fatty acids and triglycerides in man: a theoretical analysis.

Three different multicompartmental models of free fatty acid (FFA) and very low density lipoprotein triglyceride fatty acid (VLDL-TGFA) transport in man are formulated from plasma FFA and VLDL-TGFA tracee and tracer data collected over a 24 hr interval after the injection of palmitate-(14)C. All modeling and data fitting were performed on a digital computer using the SAAM program. Structural differences in the three models relate to the position of the slowly turning over compartment required to generate the late portion of the plasma VLDL-TGFA tracer data. The positions of this slow compartment are along the hepatic pathway from FFA to VLDL-TGFA (model A) or in the distribution system of VLDL-TGFA (model B) or in the distribution system of FFA (model C). Although all three models are equally consistent with our experimental data and are supported by observations of others, each reveals inconsistency with some data obtained from the literature. Consequently, a combination model of FFA-TGFA transport, incorporating properties of models A, B, and C would be more consistent with all available data. Experiments that would help to determine the quantitative significance of each of the slow compartments in the combination model are suggested. Several other models suggesting recycling of plasma VLDL-TGFA through the plasma FFA pool, kinetic heterogencity of the plasma VLDL-TGFA pool, and contamination of plasma VLDL-TGFA radioactivity with low density lipoprotein (LDL) TGFA radioactivity were tested. The first model does not explain the late portion of the plasma VLDL-TGFA tracer data. The second and third models, while consistent with our tracee and tracer data, have steady-state implications with respect to the extent of kinetic heterogeneity and size of the LDL-TGFA contaminant that make them unlikely. Assumptions underlying other investigator's models of FFA and TGFA transport in man are reviewed within the logical framework of our models. Quantitative differences among the various models are shown by evaluating all of the models with respect to a common set of plasma FFA and VLDL-TGFA data.

Effect of low density lipoprotein receptor deficiency on the metabolism of apolipoprotein B-100 in blood plasma. Kinetic studies in normal and Watanabe heritable hyperlipidemic rabbits.

The kinetics of apolipoprotein (apo) B-100 in particles containing apo E (B,E particles) or lacking apo E (B particles) were studied in Watanabe heritable hyperlipidemic (WHHL) rabbits deficient in low density lipoprotein (LDL) receptors, and compared with those of normal rabbits after injection of radioiodinated very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and LDL. In both groups results of kinetic modeling were consistent with the hypothesis that all apo B enters the plasma in VLDL, mainly as B,E particles, followed by delipidation and partial conversion to IDL and LDL, with concomitant conversion of some B,E particles to B particles. In WHHL rabbits, production of VLDL apo B was reduced by 40%, but LDL production was increased threefold. Defective removal of B,E and B particles in all three lipoprotein classes, coupled with preserved processes of delipidation, can account for the observed increases in the concentration of apo B (threefold in VLDL, fivefold in IDL, and twenty-twofold in LDL) in WHHL rabbits.

Very low density lipoprotein triglyceride transport in type IV hyperlipoproteinemia and the effects of carbohydrate-rich diets.

Transport of plasma-free fatty acids (FFA) and of fatty acids in triglycerides of plasma very low density lipoproteins (VLDL-TGFA) was studied in two normal subjects, five patients with type IV hyperlipoproteinemia, and two patients with type I hyperlipoproteinemia. After intravenous pulse-labeling with albumin-bound 1-palmitate-(14)C, specific radioactivity of plasma FFA and VLDL-TGFA were determined at intervals up to 24 hr. The results were analyzed using several different multicompartmental models each compatible with the experimental data. Fractional transport of VLDL-TGFA was distinctly lower (no overlap) in the type IV patients than in the control subjects, both on a usual balanced diet (40% of calories from carbohydrate) and on a high-carbohydrate diet (80% of calories). However, net or total transport of VLDL-TGFA in the type IV patients was not clearly distinguishable from that in the control subjects, there being considerable overlap on either diet. The results suggest that in this group of type IV patients the underlying defect leading to the increased pool size of VLDL-TGFA is not overproduction but a relative defect in mechanisms for removal of VLDL-TGFA. Since some of these type IV patients had only a moderate degree of hypertriglyceridemia at the time they were studied, and since it is not established that patients with the type IV phenotype constitute a biochemically homogeneous population, the present results should not be generalized. Four studies were done (in two control subjects and two type IV patients) in which the kinetic parameters in the same individual were determined on the balanced diet and on the high-carbohydrate diet. All subjects showed an increase in VLDL-TGFA pool size. Using two of the models for analysis, all showed an increase in net transport of VLDL-TGFA; using the third model, three of the four studies showed an increase in VLDL-TGFA transport. The results are compatible with the interpretation that the carbohydrate-induced increase in VLDL-TGFA, both in controls and type IV patients, is at least in part due to an increased rate of production of VLDL-TGFA. The magnitude of the increase was approximately the same in controls and patients. Thus, metabolic adjustment to a high-carbohydrate regimen in these type IV patients may not be basically different from that in normal controls; the higher levels of VLDL-TGFA reached may simply be another reflection of a defective removal mechanism. An alternative interpretation, compatible with the data, would involve both a carbohydrate-induced increase in fractional rate of release of VLDL-TGFA from liver to plasma and a decrease in fractional removal of VLDL-TGFA from plasma without increase in net production rate. The simpler hypothesis of a single primary effect on net VLDL-TGFA production from FFA seems more likely.

Metabolism of apolipoprotein B-100 in large very low density lipoproteins of blood plasma. Kinetic studies in normal and Watanabe heritable hyperlipidemic rabbits.

The metabolism of radioiodinated apo B-100 in large VLDL from normal and Watanabe heritable hyperlipidemic (WHHL) rabbits, with diameters exceeding 450 A, was studied in corresponding recipient rabbits. In both cases approximately 87% of the particles contained apolipoprotein (apo) E (B,E particles). In normal rabbits, apo B in these B,E particles was removed from blood plasma much more rapidly than apo B in B,E particles in smaller VLDL and few of the large B,E particles were converted to lipoproteins of higher density. In WHHL rabbits, approximately 60% of the apo B in B,E particles in large VLDL was removed at a comparably rapid rate, but an appreciable fraction of the remainder, which was removed slowly, was converted to particles of higher density, as are the B,E particles in smaller VLDL. From kinetic analysis of these and other data, an hypothesis was formulated from which it is estimated that apo B in large VLDL accounts for 18 and 41% of apo B transport in normal and WHHL rabbits, respectively, despite the fact that these lipoproteins contain less than 5% of the apo B in total VLDL. Failure to account for the contribution of large VLDL to VLDL turnover may lead to serious underestimation of total apo B transport in the blood.

A compartmental model of zinc metabolism in healthy women using oral and intravenous stable isotope tracers.

A mathematical model of zinc metabolism in six healthy women (average age: 30 +/- 11 y) was developed by using stable isotopes of zinc. After equilibration on a constant diet containing 7.0 mg Zn/d, an oral tracer highly enriched in 67Zn and an intravenous tracer highly enriched in 70Zn were administered simultaneously. Multiple plasma and 24-h urine samples were collected for the next 7 d with complete fecal collections for 11 d. Tracer-trace ratios in plasma, urine, and feces were calculated from isotope ratios of 67Zn to 66Zn and 70Zn to 66Zn measured by using inductively coupled plasma-mass spectrometry. An a priori identifiable model composed of seven compartments was developed to describe the kinetics of both tracers as well as that of naturally occurring zinc. The parameters of the model were fitted to the data by using the SAAM-CONSAM modeling software and were estimated with good precision. Several important, not directly measurable zinc variables were estimated (mean +/- SEM) from the model including the fractional absorption from the gastrointestinal tract (0.279 +/- 0.043), the rates of endogenous secretion (2.79 +/- 0.49 mg/d) and excretion (2.01 +/- 0.35 mg/d), the fractional turnover rate of the plasma pool (131 +/- 20/d), and the sizes (7.2 +/- 1.2 and 77.1 +/- 6.4 mg) and fractional turnover rates (22.3 +/- 7.1 and 1.49 +/- 0.18/d) of the fast and slow tissue pools equilibrating with the plasma, respectively.

Effect of acute zinc depletion on zinc homeostasis and plasma zinc kinetics in men.

BACKGROUND: Zinc homeostasis and normal plasma zinc concentrations are maintained over a wide range of intakes. OBJECTIVE: The objective was to identify the homeostatic response to severe zinc depletion by using compartmental analysis. DESIGN: Stable zinc isotope tracers were administered intravenously to 5 men at baseline (12.2 mg dietary Zn/d) and after 5 wk of acute zinc depletion (0.23 mg/d). Compartmental modeling of zinc metabolism was performed by using tracer and mass data in plasma, urine, and feces collected over 6-14 d. RESULTS: The plasma zinc concentration fell 65% on average after 5 wk of zinc depletion. The model predicted that fractional zinc absorption increased from 26% to essentially 100%. The rate constants for zinc excretion in the urine and gastrointestinal tract decreased 96% and 74%, respectively. The rate constants describing the distribution kinetics of plasma zinc did not change significantly. When zinc depletion was simulated by using an average mass model of zinc metabolism at baseline, the only change that accounted for the observed fall in plasma zinc concentration was a 60% reduction in the rate constant for zinc release from the most slowly turning over zinc pool. The large changes in zinc intake, excretion, and absorption-even when considered together-only explained modest reductions in plasma zinc mass. CONCLUSION: The kinetic analysis with a compartmental model suggests that the profound decrease in plasma zinc concentrations after 5 wk of severe zinc depletion was mainly due to a decrease in the rate of zinc release from the most slowly turning over body zinc pool.

A simple technique for measuring relative renal blood flow.

To determine whether externally monitored early renal uptake of 131I-hippurate is proportional to renal blood flow, the renal uptake of 131I-hippurate at 1--2 min after injection was compared with the renal accumulation of radioactive carbonized microspheres in dogs. A renal artery catheter equipped with a balloon was used to decrease renal blood flow unilaterally. One minute after the intravenous injection of 100 muCi of 131I-hippurate, about 1 muCi of either 85Sr- or 98Nb-labeled carbon microspheres was injected into the left ventricle. Radioactivity was measured over both kidneys. The total radioactivity within each kidney region of interest was corrected for background and integrated over the 1--2 min after injection. Thirteen measurements of relative renal blood flow were made for seven dogs. The dogs were then killed and both kidneys were excised and counted for the radioactivity of the microspheres. The 1--2-min relative renal uptake of 131I-hippurate correlated well with relative microsphere uptake, suggesting that relative renal blood flow can be simply determined from the external measurement of renal uptake of 131I-hippurate.

The specificity of pyrophosphate myocardial scintigrams in patients with prior myocardial infarction: concise communication.

Fifty-five patients with old (9 days to 10 yr) transmural infarcts but with no evidence of recent infarction, were imaged with Tc-99m pyrophosphate. Discrete uptake was rare in the setting of an old infarct. Diffuse uptake was neither sensitive to, nor specific for, acute infarction. Prior infarction will rarely cause diagnostic error if the discrete pattern is required for a positive diagnosis.

Comparison of Ga-67 citrate images obtained with rectilinear scanner and large-field Anger camera.

Two methods for Ga-67 citrate imaging were compared on 20 patients. Scans were performed using approximately equal procedure time with two instruments: (A) a dual 5-in. rectilinear scanner with medium-energy collimator, with a single window spanning both the 93-keV and the 185-keV spectral peaks; and (B) a large-field (15-in. diam) Anger camera equipped with moving table, medium-energy collimator, and three windows covering the 93-keV, 185-keV, and 300-keV peaks separately. Sixteen abnormal sites and 24 normal sites were selected for comparison. Each site was evaluated by four physicians experienced in interpreting Ga-67 citrate images. The observers performed significantly better using the images obtained with the large-field camera (three windows) than with the dual 5-in. scanner (single window).

Thallium-20 1 myocardial perfusion scintigraphy for the clinical clarification of normal, abnormal and equivocal electrocardiographic stress tests.

Sixty-five patients were studied with stress electrocardiography and thallium-20 1 relative myocardial perfusion scintigraphy. Results were correlated with selective coronary angiography. Scintigraphy was more sensitive (85 versus 67 percent), more specific (89 versus 63 percent) and significantly more accurate (87 versus 65 percent) than stress electrocardiography for the diagnosis of significant coronary arterial lesions in patients with isoelectric S-T segments at rest. Stress scintigraphy helped clarify the equivocal stress test due to left bundle branch block, left ventricular hypertrophy, drugs, hyperventilation and other conditions and was more accurate than the stress electrocardiogram (89 versus 53 percent) even in the presence of a depressed S-t segment at rest. Thallium-20 1 scintigraphy is a safe and simple noninvasive method for identifying abnormal myocardial perfusion, stress-induced ischemia and, indirectly, significant coronary arterial lesions.

Thallium-201 myocardial perfusion scintigraphy to evaluate patients after coronary bypass surgery.

To determine the utility of thallium-201 stress scintigraphy in assessing the results of coronary bypass surgery, chest pain, stress electrocardiograms and scintigrams were evaluated in 27 patients postoperatively. These findings were compared with coronary angiographic data in which a significant postoperative lesion was defined as 75 percent or more stenosis in a graft, its distal vessel or in an ungrafted native vessel. As an indicator of postoperative coronary lesions, chest pain lacked sensitivity (60 percent) and was nonspecific (20 percent). The stress electrocardiogram had poor sensitivity (60 percent) and good specificity (86 percent) but was not helpful in six patients who had equivocal or suboptimal tests. The scintigram had good sensitivity (77 percent) and was highly specific for the diagnosis of coronary stenosis. It was significantly more specific than chest pain (P less than 0.01), gave excellent localizing information and added to the accuracy of both conclusive and inconclusive stress tests. In nine patients with preoperative stress scintigrams, comparison of pre- and postoperative studies reflected the éffects of bypass surgery on coronary perfusion. Scintigraphy is a useful technique for the noninvasive evaluation of the patient after coronary bypass surgery, and postoperative scintigraphy alone is of great value in documenting surgical results.

Myocardial stress perfusion scintigraphy with rubidium-81 versus stress electrocardiography.

Fifty-six patients who subsequently underwent selective coronary angiography were studied noninvasively with relative myocardial perfusion scintigraphy with rubidium-81 and graded stress electrocardiography in an attempt to evaluate the ability of these tests to identify the presence of significant ischemia and, indirectly, coronary stenosis. Both the sensitivity (0.91) and specificity (0.91) of perfusion scintigraphy were impressive and better than the sensitivity (0.79) and specificity (0.64) of stress electrocardiography, the specificity of scintigraphy significantly so (P less than 0.05). Additionally, perfusion scintigraphy yielded excellent localizing information and was reliable even in the presence of drug effect, conduction abnormalities and nonspecific electrocardiographic abnormalities. Rare cases of triple vessel disease, prior myocardial infarction or single vessel disease with widespread collateral vessels were causes of scintigraphic misdiagnosis. Although ribidium-81 perfusion scintigraphy with the scintillation camera requires special collimation and significant quality control, it provides well resolved images and may prove particularly useful in facilitating quick successive multiple scintigraphic cardiac studies.

Radiographically determined lung volumes at full inspiration and during dynamic forced expiration in normal subjects.

Posteroanterior and lateral radiographs of the lungs of 30 normal adults were obtained at total lung capacity (TLC) and 1 sec after initiation of forced expiration from ttlc. simultaneous spirographic recording of the volume expired (FEV-1) and independent plethysmographic recording of TLC were obtained. Two types of measurements were made from the radiographs: 1) surface areas of the lung fields, measured planimetrically; and 2) combinations of linear distances between selected points. These radiographic measurements and the measured lung volumes were subjected to computer analysis to develop reliable formulas for determining lung volumes solely from radiographs. Formulas derived using planimetry produced multiple correlation coefficients of 0.95 for TLC and 0.89 for volume during forced expiration. Use of linear measurements produced multiple correlation coefficients of 0.92 for TLC and 0.84 for dynamic volume. Thus, in normal subjects, static lung volumes and lung volumes during dynamic forced expiration can be determined from radiographs.

The effect of decreased renal artery perfusion pressure on intrarenal hemodynamics in the dog.

The role of decreased renal artery perfusion pressure in redistribution of renal cortical blood flow during acute hemorrhagic hypotension is unclear. Renal artery hypotension was produced in intact dogs by an intra-aortic balloon catheter placed cephalad to the origins of the renal arteries. Renal cortical perfusion was assessed using selective renal magnification arteriography, isotopically labeled microspheres, and xenon-133 washout. After 60 minutes of decreased renal artery perfusion pressure (40 to 50 mm Hg), no changes were noted in renal cortical perfusion arteriographically. Microsphaere distribution to each cortical zone was unchanged, despite a marked decrease in total renal blood flow and in flow to each zone. 133Xe washout curves permitted two interpretations: Either redistribution of blood flow away from the cortex occurred, or parallel decrease in flow to each zone occurred without redistribution. Results indicate decreased renal artery perfusion pressure does not cause redistribution of renal cortical blood flow in our model.

Contrast-enhanced magnetic resonance imaging estimation of altered capillary permeability in experimental mammary carcinomas after X-irradiation.

RATIONALE AND OBJECTIVES: Dynamic magnetic resonance imaging (MRI) enhanced with a macromolecular contrast medium, albumin-(Gd-DTPA)35, was used to detect changes in microvascular characteristics in R3230 mammary adenocarcinomas induced by x-irradiation. METHODS: Tumors were implanted in either flank in nine rats. One of the tumors was exposed to single-dose x-irradiation (30 Gy) 3 days before MRI. The contralateral control tumor was shielded from irradiation. RESULTS: Capillary permeability to macromolecular contrast medium in irradiated tumors was elevated significantly (P < .05) compared to the control nonirradiated tumors. The mean estimated permeability surface area product for the irradiated tumors increased more than three-fold; 0.511 +/- .046 mL hr-1 cm-3 compared with 0.121 +/- .011 mL hr-1 cm-3 for the nonirradiated tumors. This radiation-induced increase in permeability was corroborated using a macromolecular Evans blue-protein complex measured in the same tumors using an invasive spectrophotometric technique. CONCLUSIONS: Dynamic MRI-enhanced with macromolecular contrast medium permits noninvasive quantitative estimates of capillary permeability in tumors, with and without x-irradiation. Because the transendothelial permeability for macromolecular solutes likely influences tumoral accumulation of macromolecular chemotherapeutic agents, this noninvasive technique may prove to be clinically useful in tailoring tumor treatment programs which combine radiation and chemotherapy.

Comparison of Gadomer-17 and gadopentetate dimeglumine for differentiation of benign from malignant breast tumors with MR imaging.

RATIONALE AND OBJECTIVES: This study compared gadopentetate dimeglumine (molecular weight, 0.5 kD), a standard contrast medium, and Gadomer-17 (apparent molecular weight, approximately 35 kD), a new, clinically applicable, large-molecular contrast medium, with respect to their microvascular characterizations of experimentally induced breast tumors at magnetic resonance (MR) imaging. MATERIALS AND METHODS: A spectrum of breast tumors, benign through highly malignant, was induced in Sprague-Dawley rats (n = 30) by intraperitoneal administration of N-ethyl-N-nitrosourea (ENU), a potent carcinogen. All animals underwent three-dimensional spoiled gradient-recalled MR imaging, with precontrast imaging and dynamic postcontrast imaging after injection of gadopentetate dimeglumine (0.1 mmol/kg) and Gadomer-17 (0.03 mmol/kg), administered in a random order at a 24-hour interval. Several microvascular parameters were compared: the endothelial transfer coefficient (K(PS)), a measure of microvascular permeability; the fractional plasma volume (fPV), and the plasma equivalent volume. Each MR imaging parameter was correlated with histopathologic findings. RESULTS: With Gadomer-17, the mean values for K(PS) and fPV were significantly greater in carcinomas than in fibroadenomas (P < .004 and .04, respectively). With gadopentetate dimeglumine, the mean values for fPV and PEV were significantly greater in carcinomas (P <. 004 and .02, respectively). Because of the high variability within both fibroadenoma and carcinoma groups, however, there were no significant correlations between K(PS), fPV, or PEV and histopathologic tumor grade as indicated by the Scarff-Bloom-Richardson score, for either agent. CONCLUSION: Although the K(PS) and fPV estimates obtained from dynamic MR imaging data with Gadomer-17 enhancement offer some potential for characterizing breast tumors, none of the quantitative microvascular parameters derived with either agent were significantly correlated with histopathologic tumor grade.

Evaluation of left ventricular performance by gated radionuclide angiography.

Gated radionuclide angiography (RVG) in orthogonal projections was used to evaluate left ventricular volume, ejection fraction, and segmental wall motion. Images of the left ventricle at end-diastole and end-systole were outlined in two projections using a simple manual method. The perimeter drawings were digitized on a desktop computer, interfaced to an XY recorder and left ventricular volumes and ejection fraction calculated. The results were compared to contrast left ventriculography (CVG) in the same projections. RVG and CVG gave similar results for end-diastolic volume (r = .87, P less than 0.001), end-systolic volume (r = .95, P less than 0.001), and ejection fraction (r = .89, P less than 0.001) over a wide range of values. In 92% of all left ventricular segments analyzed, RVG and CVG showed only minor differences in the analysis of wall motion. Reproducibility of the method by a trained observer was excellent. Interobserver trials demonstrated that less well-trained observers consistently over- or underestimated volumes, emphasizing the need for prior experience in RVG analysis. Use of this manual method for analysis of gated equilibrium RVG in orthogonal projections appears to be a reasonably accurate, reproducible method for evaluating left ventricular function.