Physiological significance of the rate constants in compartmental analysis.

Transfer (rate) constants in compartmental analysis are generally considered solely in operational terms, and little attention has been paid to their physiological interpretation. In this study we have examined the significance of their roles in physiological terms and the implications of this interpretation. When freely diffusible tracers are introduced into the blood stream by bolus injection, the sum of the exit rate constants from the blood compartment gives the number of blood volumes turned over per unit time; when multiplied by the blood volume, this value is the cardiac output. When corrected for body weight, the product yields the cardiac index, a biological constant for large mammals. The ratio of the rate constant supplying an organ to the exit-constant sum gives fractional cardiac output, and when multiplied by the cardiac output the ratio gives organ blood flow, independent of diffusibility. For freely diffusible tracers, organ blood flow can be calculated directly from the product of the organ rate constant and blood volume. At equilibrium and at equal concentration, the ratio of rate constants between adjacent compartments gives their relative volumes; this interpretation is fundamental when partitioning compartments for detailed analysis. These considerations have been validated by testing in both animals and man. Multiple solution sets may occur in mammillary models. Knowledge of the physiological interpretation of intercompartmental rate constants is of importance not only in model interpretation but in model validation, where this information serves as an independent check on model structure and its realization.

Quantitation of regional ventilation during the washout phase of lung scintigraphy: measurement in patients with severe COPD before and after bilateral lung volume reduction surgery.

STUDY OBJECTIVES: We sought to investigate the effect of lung volume reduction surgery (LVRS) on regional lung ventilation. DESIGN: Retrospective analysis of routinely acquired data before and after LVRS. SETTING: Large, urban, university medical center. PATIENTS: Twenty-nine patients with severe emphysema. INTERVENTION: Bilateral LVRS. MEASUREMENTS AND RESULTS: (133)Xe washout curves during lung scintigraphy exhibit a biphasic pattern (the first component of the washout curve [m(r)] corresponds to an initial rapid phase in washout that reflects larger airways emptying, and the second component [m(s)] reflects a slower phase of washout that is attributed to gas elimination via smaller airways). We analyzed six standardized regions of the lung (upper, mid, and lower zones of the right and left lung), and calculated m(r) and m(s) for each lung region. The mean (+/- SE) baseline FEV(1) was 0.69+/-0.04 L, total lung capacity (TLC) was 139 +/-4% predicted, and the residual volume (RV)/TLC ratio was 65+/-2%. The mean improvement in FEV(1) 3 months post-LVRS was 38%. Post-LVRS, m(r) and m(s) increased in 79 and 74 lung regions, respectively, and there was no relationship with respect to lung regions that had or had not been operated on. The increase in m(s), however, significantly correlated with the increase in FEV(1) (r = 0.66; p<0.0001) and the decrease in RV/TLC (r = -0.67; p<0.0001). An increase in m(s) also correlated with a decrease in PaCO(2) (r = -0.39; p = 0.03), but m(r) showed no relationship with any parameter. CONCLUSIONS: Small airways ventilation in lung regions that had and had not been operated on is associated with a greater improvement in lung mechanics following LVRS.

An analytical solution set for a four-compartment mixed mammillary/catenary model.

The purpose of this study was to extract the intercompartmental rate constants analytically from the coefficients and exponents of the exponential sum fitted to tracer data points for a unique four-compartment mixed mammillary/catenary (extended mammillary, radial) model, with losses solely from the central (blood) compartment. This model is useful in estimating myocardial and skeletal blood flow. Using Laplace transforms, the transfer functions of the exponential sum and the differential equations describing the model were obtained and the corresponding coefficients equated sequentially, which yielded the intercompartmental rate constants. Three solution sets of rate constants were found for the model, each of which satisfies both transfer functions. A program written in BASIC is provided, which requires only the coefficients and exponents of the exponential terms as input; the output is the three sets of rate constants. An example is given as an aid in debugging. Only one solution set of the three was physiologically realizable in the example, but the bounds defining these limits are not known. The advantages and limitations of the method are discussed. The method is suitable for initializing a non-linear least-squares fitting program for the rate constants. The appropriate physiological solution set for this model yields fractional and total myocardial or skeletal blood flow in a subject in the steady state.

The MIRD perspective 1999. Medical Internal Radiation Dose Committee.

The MIRD schema is a general approach for medical internal radiation dosimetry. Although the schema has traditionally been used for organ dosimetry, it is also applicable to dosimetry at the suborgan, voxel, multicellular and cellular levels. The MIRD pamphlets that follow in this issue and in coming issues, as well as the recent monograph on cellular dosimetry, demonstrate the flexibility of this approach. Furthermore, these pamphlets provide new tools for radionuclide dosimetry applications, including the dynamic bladder model, S values for small structures within the brain (i.e., suborgan dosimetry), voxel S values for constructing three-dimensional dose distributions and dose-volume histograms and techniques for acquiring quantitative distribution and pharmacokinetic data.

MIRD pamphlet No. 17: the dosimetry of nonuniform activity distributions--radionuclide S values at the voxel level. Medical Internal Radiation Dose Committee.

The availability of quantitative three-dimensional in vivo data on radionuclide distributions within the body makes it possible to calculate the corresponding nonuniform distribution of radiation absorbed dose in body organs and tissues. This pamphlet emphasizes the utility of the MIRD schema for such calculations through the use of radionuclide S values defined at the voxel level. The use of both dose point-kernels and Monte Carlo simulation methods is also discussed. PET and SPECT imaging can provide quantitative activity data in voxels of several millimeters on edge. For smaller voxel sizes, accurate data cannot be obtained using present imaging technology. For submillimeter dimensions, autoradiographic methods may be used when tissues are obtained through biopsy or autopsy. Sample S value tabulations for five radionuclides within cubical voxels of 3 mm and 6 mm on edge are given in the appendices to this pamphlet. These S values may be used to construct three-dimensional dose profiles for nonuniform distributions of radioactivity encountered in therapeutic and diagnostic nuclear medicine. Data are also tabulated for 131I in 0.1-mm voxels for use in autoradiography. Two examples illustrating the use of voxel S values are given, followed by a discussion of the use of three-dimensional dose distributions in understanding and predicting biologic response.

Soft-tissue uptake of technetium-99m-MDP after prostate cryoablation.

Prominent soft-tissue uptake of 99mTc-methylene diphosphonate (MDP) within the prostate bed was found after cryoablation for prostate carcinoma. CT, MRI and sonographic studies demonstrated liquifactive necrosis of the prostate bed. The probable etiology for 99mTc-MDP uptake in this case is necrosis with subsequent neovascular hyperemia and microscopic calcium deposits. Three-phase scintigraphy with 99mTc-MDP appears to be useful for localizing the extent of soft tissue inflammation and necrosis.

The many causes of subclinical hyperthyroidism.

Subclinical hyperthyroidism, defined as serum thyroid hormone levels in the reference range with low serum TSH concentration, is a well recognized clinical entity, but little information is available concerning the prevalence of the disorders that produce it. We conducted a 24-month retrospective survey of subclinical hyperthyroidism patients referred to a university hospital nuclear medicine service for diagnostic studies. Twenty-four consecutive patients were evaluated (22 outpatients and 2 inpatients). All patients had highly sensitive TSH determination, thyroid hormone levels, radioiodine uptake and scan (except for 2 postpartum women), and, selectively, TSH-receptor antibody (TRAb), serum thyroglobulin, antithyroid antibodies, T3-suppression test, and erythrocyte sedimentation rate. A TSH value of about 0.1 microIU/mL was used as the cutoff. Only one patient in the group had a nonthyroidal disorder. In 14 patients (61%) subclinical hyperthyroidism was self-limited, due to silent thyroiditis (5 patients), iodine-induced hyperthyroidism (3 patients), postpartum thyroiditis (2 patients), subacute thyroiditis (2 patients), and probable hemorrhage into a functioning nodule (2 patients). Of the non-self-limited disorders (39%), Graves' disease accounted for 6 patients and solitary or multinodular goiter for 3. Graves' disease proved difficult to diagnose because the thyroid gland was normal in size in two of the six patients, TRAb was positive in only two of six, and the radioiodine uptake and gradient were normal in all six; the T3-suppression test was positive in two of two patients. We conclude that the causes of subclinical hyperthyroidism are the disorders that commonly produce overt thyrotoxicosis in medical practice, Graves' disease being the most frequent. However, the tests used to diagnose overt Graves' disease often fail in the setting of subclinical hyperthyroidism, except possibly the T3-suppression test.

Recent advances in gastric emptying scintigraphy.

Gastric emptying scintigraphy was introduced more than 25 years ago by Griffith and still remains the gold standard to assess gastric emptying. Test meals, radiopharmaceutical and acquisition procedures have been refined and optimized over the years and the test procedure is now well standardized. However, in its most common use, gastric emptying scintigraphy provides little information on gastric physiology and pathophysiology. Over the last decade, modeling of the liquid- and solid-emptying curves has provided some insight into the complex gastric physiology. Compartmental analysis of the stomach has also provided information on the pathophysiological mechanisms of delayed gastric emptying. Over the past 5 years, the most dramatic development in gastric emptying scintigraphy has been the introduction of digital antral scintigraphy. Digital antral scintigraphy consists primarily of dynamic imaging of the stomach and a refined Fourier transform processing method. This new procedure allows for the visualization of antral contractions and, like manometry, permits quantitative characterization of the frequency and amplitude of these contractions. Overall, this new procedure provides a unique, noninvasive tool to characterize gastric motility, to define the pathophysiological mechanisms of gastric motor disorders, and to evaluate the effect of new gastrokinetic compounds.

Dynamic antral scintigraphy to characterize gastric antral motility in functional dyspepsia.

UNLABELLED: We evaluated intragastric food distribution and antral motor activity in patients with functional dyspepsia. METHODS: A standard gastric emptying test and dynamic imaging of the antrum were used to characterize gastric antral motility disturbances and to correlate them with total and compartmental gastric emptying in 25 dyspeptic patients. RESULTS: We found a 40% prevalence of gastroparesis in functional dyspepsia. Solid gastric emptying delay is indicated by a prolonged lag phase and an increase in frequency and amplitude of gastric contractions, resulting in nonexpulsive antral contractions and/or antropyloric dyscoordination. Food retention in the distal stomach and antral distention appears to account for patients' dyspeptic symptoms. CONCLUSION: This study demonstrates that scintigraphy not only detects abnormalities of food distribution in the stomach but also provides information on antral motor activity noninvasively. Dynamic antral scintigraphy and compartmental gastric emptying are useful tools to define the pathophysiology of dyspeptic patients with or without gastroparesis.

Scintigraphic imaging of oncogenes with antisense probes: does it make sense?

Based on the specificity of the Watson-Crick base pairing formation, antisense deoxyoligonucleotides have been used to inhibit the expression of oncogenes in various cancer cells. Activation of an oncogene by means of amplification leads to an increased, detectable amount of the mRNA transcript in the cytoplasm. The aim of this study was to demonstrate that cells which are expressing a particular mRNA transcript do preferentially and specifically retain the antisense probe targeting that mRNA. Using a mouse plasmacytoma cell line (MOPC315) which produces high levels of IgA heavy chain mRNA, a control mouse pre B cell line (7OZ/3B), a human mammary cell line (MCF7) which expresses the erbB2 or neu oncogene, MOPC315 cells as neu-negative controls, and antisense DNA oligonucleotides complementary to the 5' region of the mRNAs and the sense sequence, we have shown that there is a preferential, specific retention of the IgA and neu antisense sequence in MOPC315 and MCF7 cells, respectively. We have further demonstrated that this retention is time and concentration dependent with a maximum at 24 h. We conclude that cancer cells which express a particular oncogene are suitable targets for radiolabeled antisense deoxyoligonucleotides directed toward the oncogene transcript. This work and recent developments in the antisense field lead to the expectation of a new class of radiopharmaceuticals with unique specificity.

Characterization of gastric antral motility disturbances in diabetes using a scintigraphic technique.

In this study, food distribution in the stomach and gastric antral motor activity in patients with longstanding diabetes have been evaluated. With use of a standard gastric emptying test with an acquisition protocol and a refined Fourier algorithm to analyze the data, antral contractions have been characterized and gastric motility parameters were correlated to gastric retention in 20 diabetic patients with or without gastroparesis and in 10 healthy subjects. The results of this study show that, in longstanding diabetes, gastric emptying retardation is accounted for by a retention of food in the proximal stomach, which is reflected by a prolonged lag phase as well as by a reduction in antral motor activity that is determined by a decrease in the amplitude of the antral contractions. This study demonstrates that scintigraphy can noninvasively characterize abnormalities of food distribution in the stomach and provides information similar to that obtained from manometry.

Comparison of left anterior oblique and geometric mean gastric emptying.

A left anterior oblique image (LAO) and the geometric mean of anterior and posterior counts have both been proposed as methods for acquiring gastric emptying data. Both approaches are used to correct for the changes in attenuation that occur as the depth of radiolabeled solids changes during gastric emptying. These two methods were compared by using a power exponential curve fit to calculate a lag phase, an equilibrium emptying rate, and a half-time for gastric emptying in 20 patients. There were no significant differences (mean +/- 1 s.e.m.) in the measured half-emptying time (115 +/- 10 versus 104 +/- 7 min) (p = 0.08) or rate of gastric emptying (0.015 +/- 0.002 versus 0.015 +/- 0.002 min-1) (p = 0.56) for LAO imaging versus the geometric mean. However, the LAO measurements of the lag phase were significantly higher (69 +/- 7 min) than the geometric mean (53 +/- 6 min) measurements (p = 0.004). This resulted in 4/20 (20%) of patients with normal geometric mean lag phase measurements who would have been reclassified as abnormal using the LAO method.

Thallium-201 SPECT increases detectability of thyroid cancer metastases.

Thallium-201- (201Tl) chloride is known to accumulate in metastatic foci of differentiated thyroid carcinoma, but small and deep-seated lesions are generally not detectable by planar imaging. We have evaluated the use of 201Tl-chloride single-photon emission computed tomography (SPECT) in 41 post-thyroidectomy patients with differentiated thyroid carcinoma and one with medullary carcinoma; planar imaging alone was done in eight additional patients (total 50). Of 20 patients with known metastatic disease, planar 201Tl images were positive in 12 (60%) but SPECT revealed an additional 5 (25%) who had metastases (total 85%). SPECT revealed foci as small as 1.0 cm in the neck and 1.5 cm in the lungs, and was particularly useful in detection of disseminated micronodular pulmonary metastases, especially in patients whose scans were negative with diagnostic doses of 131I. Some pitfalls in interpretation of the tomographic reconstructions were found. Thallium-201 SPECT is a marked improvement over planar imaging in the detection of metastases of differentiated thyroid cancer.