Regional sympathetic denervation after myocardial infarction in humans detected noninvasively using I-123-metaiodobenzylguanidine.

Transmural myocardial infarction in dogs produces denervation of sympathetic nerves in viable myocardium apical to the infarct that may be arrhythmogenic. It is unknown whether sympathetic denervation occurs in humans. The purpose of this study was to use iodine-123-metaiodobenzylguanidine (MIBG), a radiolabeled guanethidine analog that is actively taken up by sympathetic nerve terminals, to image noninvasively the cardiac sympathetic nerves in patients with and without ventricular arrhythmias after myocardial infarction. Results showed that 10 of 12 patients with spontaneous ventricular tachyarrhythmias after myocardial infarction exhibited regions of thallium-201 uptake indicating viable perfused myocardium, with no MIBG uptake. Such a finding is consistent with sympathetic denervation. One patient had frequent episodes of nonsustained ventricular tachycardia induced at exercise testing that was eliminated by beta-adrenoceptor blockade. Eleven of the 12 patients had ventricular tachycardia induced at electrophysiologic study and metoprolol never prevented induction. Sympathetic denervation was also detected in two of seven postinfarction patients without ventricular arrhythmias. Normal control subjects had no regions lacking MIBG uptake. This study provides evidence that regional sympathetic denervation occurs in humans after myocardial infarction and can be detected noninvasively by comparing MIBG and thallium-201 images. Although the presence of sympathetic denervation may be related to the onset of spontaneous ventricular tachyarrhythmias in some patients, it does not appear to be related to sustained ventricular tachycardia induced at electrophysiologic study.

Leukocyte labeling with technetium-99m tin colloids.

Triple density gradients of metrizamide in plasma (MP) were used to characterize label distribution in human leukocyte preparations incubated with 99mTc tin colloids. Less than 50% of the cell-associated radioactivity was specifically bound to leukocytes when heparinized blood was rotated with stannous fluoride colloid ([Tc]SFC). Labeling efficiency in leukocyte rich plasma (LRP) averaged 44%, of which greater than 90% was specifically bound to leukocytes. MP-gradient analysis also revealed that leukocyte labeling did not occur with stannous chloride colloid, nor when citrate was present during rotation with [Tc]SFC. When citrate was added after labeling to "solubilize" unbound [Tc]SFC, radiocolloid was removed from the leukocytes, indicating that the mechanism of [Tc]SFC labeling is adherence rather than phagocytosis. Technetium-labeled neutrophils exhibited normal in vitro chemotaxis and no lung uptake in vivo. Technetium-labeled mononuclear leukocytes, on the other hand, exhibited prolonged lung transit in vivo. Neither [Tc]SFC cell preparation showed signs of in vivo reoxidation to pertechnetate.

Stoichiometric Tc-99m RBC labeling using stable kit solutions of stannous chloride and EDTA: concise communication.

An in vitro Tc-99m labeling method is described, which utilizes stable stock solutions of stannous chloride and disodium edetate (EDTA). The kit procedure requires as little as 1 ml of patient blood, can be performed in only 15 min, and gives labeling yields in excess of 98%. By using EDTA, the binding capacity of RBCs for technetium is sufficient to produce Tc-99m RBC doses with specific concentration greater than 50 mCi/ml for first-pass cardiac studies. Scintigrams reveal a slight amount of bladder activity and splenic uptake, but at no time has the thyroid, stomach, or normal bowel been visualized. The predominant 20-hr blood-clearance half-time results in excellent image quality for over 24 hr--an essential property for following intermittent GI bleeding or for performing repeat cardiac function studies over a several-hour time interval.

In vivo kinetics of canine leukocytes labeled with technetium-99m HM-PAO and indium-111 tropolonate.

Two weeks after the introduction of osteomyelitis in three dogs, autologous leukocytes were dual-labeled with both [99mTc]HM-PAO and [111In]tropolonate, and reinjected. Blood sampling and imaging were then performed. Two weeks later, the same dogs received simultaneous injections of singly-labeled [99mTc]WBC and [111In]WBC for comparison. For both studies, blood samples were drawn over 6 hr to determine the respective blood clearance half-time (TB) and % recovery (%R0) of cell-bound radioactivity. There were no significant differences in the average TB results of the 99mTc and 111In groups, either within or between the dual- and singly-labeled studies. The %R0 of singly-labeled [99mTc]WBC was about half that of the other groups (p less than 0.01); however, this difference was attributed to the dissimilar radiochemical purity of the [99mTc]HM-PAO reagents. Region of interest analysis of the 6 and 24 hr images revealed no significant differences between either cell label in the relative or absolute in vivo uptake at known sites of osteomyelitis, noninfected surgery, and normal bone marrow.

Combined bone scintigraphy and indium-111 leukocyte scans in neuropathic foot disease.

It is difficult to diagnose osteomyelitis in the presence of neurotrophic osteoarthropathy. We performed combined [99mTc]MDP bone scans and indium-111 (111In) leukocyte studies on 35 patients who had radiographic evidence of neuropathic foot disease and clinically suspected osteomyelitis. The [111In]leukocyte study determined if there was an infection and the bone scan provided the anatomic landmarks so that the infection could be localized to the bone or the adjacent soft tissue. Seventeen patients had osteomyelitis and all showed increased [111In]leukocyte activity localized to the bone, giving a sensitivity of 100%. Among the 18 patients without osteomyelitis, eight had no accumulation of [111In]leukocytes, seven had the [111In]leukocyte activity correctly localized to the soft tissue, two had [111In]leukocyte activity mistakenly attributed to the bone, and one had [111In]leukocyte accumulation in a proven neuroma which was mistakenly attributed to bone. These three false-positive results for osteomyelitis reduced the specificity to 83%. Considering only the 27 patients with a positive [111In]leukocyte study, the combined bone scan and [111In]leukocyte study correctly localized the infection to the soft tissues or bone in 89%. Uninfected neurotrophic osteoarthropathy does not accumulate [111In]leukocytes. We found the combined bone scan and [111In] leukocyte study useful for the detection and localization of infection to soft tissue or bone in patients with neuropathic foot disease.

Comparison of purified indium-111 granulocytes and indium-111 mixed leukocytes for imaging of infections.

Several methods have been proposed for the separation and labeling of white blood cells for the diagnosis of suspected infection. We retrospectively compared 105 patients imaged with 111In purified granulocytes (GRAN) to 106 patients imaged with 111In mixed leukocytes (MIX). We found that in acute infection the sensitivity of GRAN and MIX were both high and not statistically different. In chronic infections the sensitivities were lower than for acute infections. Again, there was no significant difference between GRAN and MIX with the borderline significant exception of MIX being superior to GRAN in chronic soft tissue infections (p = 0.06). We then had independent observers blindly grade the degree of lesion visualization. We found that delayed images visualized the lesions better than early images (p = 0.0001) and acute infection was better visualized than chronic infection (p = 0.03). We concluded that, in routine clinical practice, MIX is probably the agent of choice for three reasons: (a) easier preparation, (b) comparable sensitivity in acute infection and, (c) borderline superior sensitivity in chronic infection.

Clinical comparison of indium-111 acetylacetone and indium-111 tropolone granulocytes.

This clinical study compares the efficacy of two 111In white blood cells preparations. Seventy-six patients were imaged after an injection of granulocytes (GRAN) isolated on a Ficoll-Hypaque gradient and labeled with [111In]acetylacetone (ACAC) in saline; 105 patients were imaged after an injection of GRAN isolated on a metrizamide-plasma gradient and labeled with [111In]tropolone (TROP) in plasma. Early (2-4 hr), intermediate (4-6 hr), and delayed (24 hr) images were obtained. The specificity was quite high (94-100%) in both preparations and no statistical differences could be found. The sensitivity for ACAC-GRAN for the early, intermediate, and delayed images were 39%, 63%, and 64%, respectively; for TROP-GRAN it was 80%, 89%, and 92%, respectively. In all cases the TROP-GRAN images were significantly more sensitive than the ACAC-GRAN images obtained at the same time after injection (p less than 0.001 for early and delayed images, 0.01 less than p less than 0.025 for intermediate images). For ACAC-GRAN the intermediate and delayed images were significantly more sensitive than the early images, while no significant difference could be found for TROP-GRAN. In a blinded experiment, the ability of TROP-GRAN to demonstrate a lesion was compared to that of ACAC-GRAN. TROP-GRAN demonstrated the lesions better than ACAC-GRAN, both in the early and late images (p less than 0.001). TROP-GRAN visualization scores at 4-6 hr equaled those obtained 24 hr after injection. In conclusion, GRAN separated and labeled in plasma with TROP are superior to those separated and labeled in saline with ACAC in three ways: higher visualization scores, earlier visualization of the lesion, and greater sensitivity.

PET imaging of oxidative metabolism abnormalities in sympathetically denervated canine myocardium.

UNLABELLED: This study was designed to test the hypothesis that regional sympathetic denervation produces perfusion and metabolic alterations in myocardial tissue under resting conditions. METHODS: PET studies of myocardial sympathetic innervation, myocardial perfusion and oxygen utilization using [11C]hydroxyephedrine (HED), [13N]ammonia and 1-[11C]acetate, respectively, were performed before and approximately 2 and 8 wk after surgical left thoracotomy and regional chemical sympathetic denervation (n = 5). A second group of animals underwent the same surgical procedure but, so that they could serve as a sham control group, were not sympathetically denervated (n = 5). The second group of animals was imaged before and 2 wk after surgery. Images of the retention of [11C]HED taken from 50 to 60 min postinjection were used to differentiate sympathetically innervated and denervated regions of the left ventricle. Regions of interest were defined on polar plots of the [11C]HED retention, including the sympathetically denervated territory and normally innervated regions. Regions defined on the HED polar plots were then transferred to the [13N]ammonia and 1-[11C]acetate image data, and tracer kinetic models were fit to the regional time-activity curves to generate estimates of myocardial perfusion and oxidative metabolism. RESULTS: The average percentage of the left ventricle denervated in the group I animals was 13.1% +/- 7.3%. Significant reductions in oxidative metabolism were observed in the sympathectomized tissue both at 2 and 8 wk after surgery (22% and 15% reductions, respectively). Significant alterations in regional perfusion were not observed. No significant changes in oxidative metabolism or perfusion were observed in the sham control group. CONCLUSION: Regional sympathetic denervation alters oxidative metabolism but not perfusion in the denervated region of the heart.

Evaluation of complicating osteomyelitis with Tc-99m MDP, In-111 granulocytes, and Ga-67 citrate.

Studies with gallium-67 and three-phase bone imaging (TPBS), though very sensitive, are not very specific in evaluating suspected osteomyelitis (OM) that is superimposed upon other diseases causing increased bone turnover. A total of 57 patients with suspected OM were studied; this included 48 with increased bone turnover. All of the patients were studied with granulocytes labeled with In-111 acetylacetone (In-111 GRAN), TPBS and 29 of these patients had Ga-67 studies as well. In-111 GRAN had a sensitivity of 100% in acute OM and 60% in chronic OM, with a specificity of 96%. Gallium-67 was excellent in ruling out OM when the study was normal, or in ruling in OM when the relative uptake of Ga-67 exceeded the uptake of Tc-99m MDP, or when the Ga-67 in bone had a different distribution from the TPBS. Unfortunately, these criteria were met in only 28% of our subjects. We conclude that when added to TPBS, the In-111 GRAN study plays an important role in detecting complicating OM.

A color spot test for the detection of Kryptofix 2.2.2 in [18F]FDG preparations.

A color spot test is described that can confirm the absence of Kryptofix 2.2.2 in 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) in less than 5 min. Pretreated strips of plastic-backed silica gel 60 thin-layer chromatographic medium, saturated with iodoplatinate reagent, are over-spotted with separate droplets of final product [18F]FDG and Kryptofix standard solutions. A blue-black circular spot is clearly visible at Kryptofix concentrations as low as 2 micrograms/mL.

Solid-phase reversible trap for [11C]carbon dioxide using carbon molecular sieves.

A simple, maintenance-free trapping technique which concentrates and purifies no-carrier-added 11CO2 from gas targets is described. The trap requires no liquid nitrogen cooling and has no moving parts besides solenoid valves. It employs carbon molecular sieves to adsorb 11CO2 selectively from gas targets at room temperature. Nitrogen, O2, CO, NO and moisture in the target gas which could interfere with subsequent radiochemical steps are not retained. Trapping efficiency of 1 g of sieve for 11CO2 from a 240 cm3 target gas dump and helium flush cycle is > 99%, and the adsorbed 11CO2 is recovered quantitatively as a small concentrated bolus from the carbon sieve trap by thermal desorption. This durable trap has performed reliably for more than 1 y with a single charge of carbon sieve. It has simplified the production, and improved the yields of several 11C-radiochemicals at this laboratory.

Back-to-back "one-pot" [18F]FDG syntheses in a single Siemens-CTI chemistry process control unit.

Simple changes in the chemistry, plumbing, and programming of the Siemens-CTI chemistry process control unit (CPCU) effectively double its output by enabling two back-to-back "1-pot" syntheses of 2-[18F]fluoro-2-deoxy-D-glucose in a single unit. Replacement of Kryptofix 2.2.2 with tetramethylammonium carbonate and elimination of diethyl ether from the procedure shorten synthesis time to 48 min, improve process and end-product safety, and increase end-of-synthesis yields from 37% to 52% by minimizing steps and transfer losses.

Ingested manganese chloride as a contrast agent for magnetic resonance imaging.

Solutions of manganese chloride were force-fed to Sprague-Dawley rats. Magnetic resonance (MR) imaging was performed on (a) syringes containing different concentrations of manganese chloride, (b) rats after force feeding and (c) livers excised after sacrifice of the force-fed rats. Imaging was done with a 0.15-T resistive magnet. Multiple pulse sequences were used and T1 values were calculated. The signal intensity and T1 value obtained from a solution depended on the manganese concentration and the pulse sequence employed. At higher concentrations, no signal was produced due to extreme T2 shortening. Absorbed manganese affected the signal intensities and T1 values of the rats' livers. By appropriate selection of manganese concentration and pulse sequence, ingested manganese can serve as a combined gastrointestinal and hepatic MR contrast agent.

Influence of specific activity on myocardial uptake of 123I-mIBG in rats.

Heart and lung uptake of 123I-mIBG was studied in rats 1 h after injection as a function of specific activity (mCi mg-1) and the total loading dose (microgram kg-1) of labelled compound. Absolute lung uptake of the tracer was dependent upon specific activity, declining as the loading dose increased from 0.15 to 4300 micrograms kg-1. Uptake in the total heart was constant at 2.1% up to about 12 micrograms kg-1, at which point the heart uptake also began to decline as the loading dose increased. Myocardial uptake of 123I-mIBG, therefore, appears saturable in the rat and subject to competitive binding and/or displacement with increasing amounts of non-labelled compound.

In-111 granulocyte response to intervening surgery. Evidence of sustained in vivo viability.

A patient with chronic osteomyelitis had surgery performed between the early and delayed images of an In-111 granulocyte scan. The early images showed no uptake, while the delayed images demonstrated marked soft tissue uptake, which was felt to be secondary to the inflammation of the intervening surgery. It was concluded that granulocytes, when labeled with In-111, remain viable and can respond to inflammation that occurs after their injection.

Comparison of technetium-99m sulfur colloid and in vitro labeled technetium-99m RBCs in the detection of gastrointestinal bleeding.

Twenty-seven paired Tc-99m sulfur colloid (SC) and Tc-99m RBC studies were evaluated for the detection of GI bleeding. The only two positive Tc-99m SC studies had positive early Tc-99m RBC studies as well. There were 15 other positive Tc-99m RBC studies (three during the first hour) and these were associated with normal Tc-99m SC scans. Approximately 70% of the positive Tc-99m RBC studies occurred after 1 hour. Tc-99m RBCs should be the initial test in patients with GI bleeding.

Granulocyte-macrophage colony-stimulating factor enhances exudation of neutrophils to sites of inflammatory challenge in vivo.

Priming of neutrophil oxidative responses by granulocyte-macrophage colony-stimulating factor (GM-CSF) has been well documented, but its inhibitory effect on chemotaxis has led to concerns that its therapeutic administration may compromise neutrophil emigration to sites of infection and inflammation. We developed a murine model to determine the biodistribution kinetics of [111In] labeled neutrophils and used this model to study the influence of recombinant GM-CSF on neutrophil influx into inflammatory sites. Murine neutrophils were harvested from the peritoneal exudate 3 h after the intraperitoneal injection of fluid thioglycollate medium, radiolabeled with [111In]tropolonate, and resuspended in 10% acid/citrate/dextrose: 90% Hanks' balanced salt solution (without Ca2+ and Mg2+) at pH 6.5 for re-injection. To assess the in vivo effect of GM-CSF, 22 mice were injected intravenously with labeled neutrophils 1 h prior to intraperitoneal challenge with thioglycollate or saline. Half of the mice also received 2.0 micrograms of recombinant murine GM-CSF intravenously at the time of injection of labeled cells. GM-CSF had no influence on the influx of labeled cells to the peritoneum of animals that received i.p. saline, but increased by nearly 50% the cellular migration elicited by i.p. injection of thioglycollate. We conclude that GM-CSF does not impair, but rather enhances, the ability of circulating neutrophils to respond to thioglycollate-induced inflammation in vivo. The model we describe provides a useful and controllable method to investigate the effects of GM-CSF and other cytokines on the biodistribution kinetics and emigration of neutrophils in vivo.