Application of mathematical methods in dynamic nuclear medicine studies.

Dynamic nuclear medicine studies can generate large quantities of data, and their analysis consists essentially of a reduction of these data to a small number of relevant parameters which will assist in clinical decision making. This review examines some of the mathematical techniques that have been used in the process of data reduction and attempts to explain the principles behind their application. It particularly identifies the techniques that have stood the test of time and demonstrated their usefulness, many of which are now available as standard tools on nuclear medicine processing computers. These include curve processing tools such as smoothing, fitting and factor analysis, as well as tools based on empirical models, such as the Patlak/Rutland plot and deconvolution. Compartmental models and vascular models are also examined and the review finishes with a summary of some functional images and condensed images. It is concluded that an appreciation of the principles and limitations of these mathematical tools is valuable for their correct usage and interpretation of the results produced.

Transferrin-dependent uptake and dosimetry of Auger-emitting diagnostic radionuclides in human spermatozoa.

UNLABELLED: Localization of Auger-emitting radionuclides within spermatozoa could lead to the induction of transmissible genetic damage. We have quantified in vitro uptake of the widely used diagnostic Auger-emitters, (111)In and 99mTc, by ejaculated human spermatozoa and investigated the role of transferrin in their cellular localization. The resultant dose to sperm heads, including cellular dosimetry for Auger emissions, has been calculated for each radionuclide and compared with that achieved using conventional macrodosimetry. METHODS: Freshly isolated human spermatozoa were incubated in a physiological salt solution containing (111)In-chloride, 99mTc-pertechnetate or the transferrin-binding isotope 59Fe-citrate as a positive control. Cellular uptake mechanisms were investigated with transferrin competition and temperature dependence studies. The percentage uptake of each radionuclide was determined, and the dose to individual sperm heads was calculated using both conventional macrodosimetric methods and by consideration of radionuclide localization and energy deposition at the cellular level, including Auger electron emissions from (111)In and 99mTc. RESULTS: On in vitro incubation, human spermatozoa were found to accumulate (111)In and 59Fe but not 99mTc. Cell uptake of (111)In and 59Fe was transferrin-mediated; however, an alternative transferrin-independent uptake pathway was also present for (111)In. The dose to sperm heads from (111)In, calculated using measured uptake and cellular dosimetry, was found to be larger than that calculated using conventional dosimetry by a factor of more than 100. In contrast, conventional dosimetry was adequate for 99mTc and 59Fe. CONCLUSION: Isolated human spermatozoa appear to accumulate transferrin-binding isotopes, such as the Auger-emitter (111)In. If this uptake mechanism operates in the male reproductive tract, the resultant high dose to the sperm head could indicate that contraception may be advisable after large diagnostic doses of (111)In and, possibly, other transferrin-binding radionuclides. Such precautions could prevent transmission of any genetic damage from irradiated spermatozoa.

Metallothionein, glutathione, and cystine transport in pulmonary artery endothelial cells and NIH/3T3 cells.

Both glutathione (gamma-glutamylcysteinylglycine; GSH) and the metalloprotein metallothionein (MT) are composed of approximately one-third cysteine. Both have antioxidant activity and are induced by oxidant stresses and heavy metals. Intracellular cysteine levels may depend on uptake and reduction of extracellular cystine. GSH synthesis can be limited by the activity of the xc- cystine transport system, which is induced by oxidants and other stresses. MT is induced by treatments that also increase GSH levels and may compete with GSH for intracellular cysteine. We investigated the induction of MT and GSH and cystine transport in NIH/3T3 cells and bovine pulmonary artery endothelial cells exposed to cadmium (Cd) or arsenite. Cd and arsenite increased MT and GSH in both cells. Increases in MT and GSH were accompanied by increases in cystine uptake. Inhibition of cystine transport by glutamate decreased GSH levels and blocked Cd-induced GSH increases in both cell types. MT levels were not significantly affected, suggesting that MT synthesis is less sensitive to intracellular cysteine levels than GSH synthesis.

Quantifying the value of diagnostic tests.

This paper considers the different statistics that can be derived from studies on the value of diagnostic tests. Well-accepted quantities, such as sensitivity and specificity, are reviewed and the value of the likelihood ratio in communicating particular test results is highlighted. A new quantity, the 'diagnostic value index', is proposed and various examples of its application in nuclear medicine studies are presented. This new index is based on a weighted average of the likelihood ratios for all possible outcomes of the test, the average being weighted according to how frequently a particular outcome occurs. This index provides an objective and quantitative means of comparing the diagnostic value of different tests, or of comparing the value of a given test in different patient groups. It is hoped that this will be a useful aid to clinical decision-making concerning referrals for diagnostic tests.

Cellular dosimetry of diagnostic radionuclides for spherical and ellipsoidal geometry.

Radionuclides which emit Auger electrons are widely used in diagnostic nuclear medicine. Studies have shown possible uptake of these in developing germ cells within the testes. In addition, mature sperm within the reproductive tract may be subject to uptake of radionuclides from the circulating blood pool. Though much work has been carried out concerning cellular dosimetry applied to spherical sources, such an approach may lead to significant errors when considering spermatids and spermatozoa, which are almost ellipsoidal in shape (with the long axis twice the short). A numerical method for determining geometrical reduction factors has been developed and used in conjunction with experimentally determined range-energy relationships for electrons, to determine dose gradients and S factors for homogeneous distributions of four commonly used diagnostic radionuclides (99mTc, 111In, 123I and 201Tl) throughout source regions of both spherical and ellipsoidal geometry at typical cellular dimensions. The results indicate that assumption of spherical geometry is acceptable when determining S factors for late-type germ cells, but introduces error into calculations of dose distribution towards the edge of the cell.

Technegas and Pertechnegas particle size distribution.

Technegas and Pertechnegas are radioactive aerosols produced in a commercial generator and used for lung scintigraphy. The aerosols are produced by first evaporating to dryness standard technetium-99m generator eluate (99mTcO4 in normal saline) in a graphite crucible (the simmer stage) and then heating this to 2500 degrees C (the "burn" stage). The aim of this work was to measure the particle size distributions of these agents and relate this to regional lung deposition. Factors that may vary during production of the aerosol in routine use were investigated to determine whether they influenced the particle size. Activity size distributions were measured using a serial wire-screen diffusion battery. The Technegas size distribution was approximately log-normal with an activity median diameter of 158 nm and a geometric standard deviation of 1.5. The results for Pertechnegas were similar. The median size increased with the number of simmers and with the time from generation. The increase in size with the number of simmers is thought to be due to the increased salt content in the crucible prior to the "burn". The predicted lung deposition is 37% in the alveolar region and 5% in the bronchial region. Significant changes in deposition are not predicted over the range of particle sizes measured.

Texture analysis of technegas lung ventilation images.

Technegas lung ventilation images sometimes have 'hot spots', particularly in patients with respiratory disease. A novel technique is presented for quantifying this 'spottiness' using morphological texture analysis. A set of 32 images from patients with various respiratory diseases is studied. Images are filtered at a range of scales using morphological opening, and the slopes of image metrics versus structuring element size are used as texture parameters. The results are compared with the opinions of three experienced nuclear medicine physicians who have classified the images into two groups, 'spotty' and 'non-spotty', and have ranked the former. For the spotty images, the computer and observer ranks are compared; the highest correlation is rs = 0.66 (p = 0.01) for a single parameter, and rs = 0.71 (p < 0.01) for a combination of two parameters. Using a pair of parameters, 83% and 90% correct classification rates are obtained for the spotty and non-spotty classes, respectively. It is concluded that these texture parameters provide a useful measure of image spottiness, and it is demonstrated that this technique is superior to previously published methods. The practical value of the technique is illustrated using two applications.

Angiotensin II as a risk factor for cyclosporin nephrotoxicity in patients with psoriasis.

Abnormalities of the renin-angiotensin system after low-dose cyclosporin (5 mg/kg/day or less) have not been adequately defined in patients with normal kidneys. 27 patients with psoriasis were assessed before starting cyclosporin, after three months of cyclosporin (5 mg/kg/day or less) and then finally three months after finishing cyclosporin. On each occasion plasma renin activity (PRA), aldosterone, angiotensin II and atrial natriuretic peptide (ANP) were measured together with total renal blood flow (RBF), GFR and filtration fraction (FF) following an i.v. bolus injection of Tc-99m DTPA. Significant renal hemodynamic toxicity was defined as > 25% fall in RBF or > 20% fall in GFR. Using these criteria we identified 12 patients with hemodynamic toxicity (Group A) and 15 patients whose GFR and RBF did not fall significantly (Group B). In Group A a significant fall in GFR (p < 0.001) and reduction in renal blood flow (p < 0.04) were associated with significant rises in both ambulant and recumbent angiotensin II (p < 0.0005). PRA, aldosterone and ANP did not significantly alter. GFR partially recovered after withdrawal of cyclosporin although RBF remained significantly lower compared to initial values. In Group B there was no significant change in GFR or RBF although there was a reversible fall in FF (p < 0.02). There were no significant differences in angiotensin II, PRA, aldosterone or ANP. Circulating angiotensin II rises in patients who develop cyclosporin nephrotoxicity and may be responsible for mediating the hemodynamic effects.

Altered clearance of N-1 methylnicotinamide associated with the use of low doses of cyclosporine.

To improve the monitoring of patients on low doses of cyclosporine there is a need for new tests of tubular function. N-1 methylnicotinamide (NMM) is an endogenous organic cation that is secreted by the proximal tubule and its clearance can be measured. In 27 patients with psoriasis, serial measurements of NMN clearance, plasma aldosterone, plasma chloride, bicarbonate, and magnesium were compared with changes in the radionuclide measurement of glomerular filtration rate and renal blood flow before, during, and after a 3-month course of low-dose cyclosporine (< 5 mg/kg/d). N-1 methylnicotinamide clearance decreased significantly with cyclosporine only (2.5 mg/kg/d, n = 10, P < 0.01). Recovery of NMN clearance lagged behind that of glomerular filtration rate and renal blood flow. Serum magnesium decreased significantly on cyclosporine (2.5 mg/kg, n = 10, P < 0.01; 5 mg/kg, n = 9, P < 0.0001). In the whole group, plasma potassium increased significantly (n = 27, P < 0.02) and plasma aldosterone was inappropriately low. Low doses of cyclosporine in psoriasis cause a reduced clearance of NMN, hypomagnesemia, and a variable hyperchloremic acidosis. Nifedipine may alter these biochemical variables without necessarily improving renal hemodynamics. The delayed recovery of NMN clearance in comparison with renal haemodynamic measurements following cyclosporine therapy suggests that this noninvasive test of tubular function may be a marker of persisting cyclosporine nephrotoxicity and that it should be evaluated further.

Modulation of abnormalities in renal haemodynamics and vasoactive mediators by nifedipine in patients with psoriasis on low-dose cyclosporin.

Ten patients with psoriasis received a 3-month course of cyclosporin (2.5 mg/kg/day) followed by a 3-month washout period, before commencing a 3-month course of cyclosporin and nifedipine SR 20 mg b.d. Serial haemodynamic and biochemical measurements were performed before, during, and after treatment. Total renal blood flow (RBF) was measured following an intravenous injection of [99mTc]-DTPA based on a renographic analysis of the first-pass effect in the kidneys, and GFR was estimated from the subsequent clearance of this radiotracer. A significant individual change in RBF or GFR was taken as 25% and 20% respectively. Simultaneous assays of the circulating vasoactive mediators renin, aldosterone, angiotensin II, and atrial natriuretic peptide were performed. Two patients withdrew from the study because they could not tolerate nifedipine, leaving eight for complete analysis. The significant reductions in RBF and GFR which occurred on cyclosporin alone (P < 0.05; ANOVA) did not occur with added nifedipine. Four months after this second course, RBF and GFR had recovered. The response to nifedipine was, however, variable and unpredictable. Of the four patients to show a significant decline in GFR on cyclosporin alone, only two showed a significant improvement on the combined therapy. Of the six patients who showed a significant decline in RBF on cyclosporin alone, only four showed benefit from the added nifedipine. Nifedipine suppresses the increase in blood pressure which occurred on cyclosporin alone. The circulating concentration of angiotensin II was significantly less on cyclosporin and nifedipine than on cyclosporin alone (P < 0.05; Student's t test).(ABSTRACT TRUNCATED AT 250 WORDS)

The F-15 diuresis renogram in suspected obstruction of the upper urinary tract.

The results are presented of the first long-term follow-up study of patients with suspected obstruction of the upper urinary tract investigated by a modified form of diuresis renography (F - 15 renography). The incidence of equivocal results from diuresis renography is significantly reduced by the use of the F - 15 renogram. F - 15 renography provides a reliable assessment of the upper urinary tract in patients with suspected obstruction and is recommended in the investigation of equivocal upper urinary tract dilatation.

The importance of using anterior and posterior views in the calculation of differential renal function using 99Tcm-DMSA.

Radionuclide techniques for determining relative renal function are well established. One simple method uses the count rate from static images obtained using 99Tcm-dimercaptosuccinic acid (DMSA). We have reviewed 277 DMSA scans and shown that it is important to obtain the geometric mean of counts from the anterior and posterior views in order to correct for the different amounts of attenuation for each kidney. If counts were obtained from the posterior view only, erroneous results would be obtained in 8% of children under 13 years, in 28% of patients aged between 13 and 20 years and in 32% of patients over 20 years of age.

A comparison of technetium-99m-thiodiglycolic acid and iodine-123-hippuran in the evaluation of equivocal upper urinary tract obstruction.

In a comparative trial, 21 patients (mean age 43 (range 19-66) years) with dilated upper urinary tracts underwent diuresis renography with both 123I-hippuran and the experimental agent. 99Tcm-thiodiglycolic acid (TDG). Deconvolution analysis of the derived renograms was also performed and the transit times were calculated. Excellent agreement was found between results with the two radiopharmaceuticals. There was complete agreement in interpretation of the response to diuresis with both agents and 84% agreement in the transit time estimations. Good images were produced with both agents and 99Tcm-TDG is considered to be a useful alternative to 123I-hippuran.