Development of radioiodine-labeled mequitazine for evaluation of hepatic CYP2D activity.

Background: As drug-metabolizing enzyme activities are affected by a variety of factors, such as drug-drug interactions, a method to evaluate drug-metabolizing enzyme activities in real time is needed. In this study, we developed a novel SPECT imaging probe for evaluation of hepatic CYP2D activity. Methods: Iodine-123- and 125-labeled 4-iodobenzylmequitazine (123/125I-BMQ) was synthesized with high labeling and purity. CYP isozymes involved in the metabolism of 125I-BMQ in mouse liver microsomes were evaluated, and the utility of 123/125I-was assessed from biological distribution and SPECT imaging evaluation in normal and CYP2D-inhibited mice. Results: In vitro metabolite analysis using mouse liver microsomes showed that 125I-BMQ is specifically metabolized by CYP2D. Biological distribution and SPECT imaging of 123/125I-BMQ in normal mice showed that injection 123/125I-BMQ accumulated early in the liver and was excreted into the gallbladder and intestines. In CYP2D-inhibited mice, accumulation in the liver was increased, but accumulation in the gallbladder and intestines, the excretory organ, was delayed. Since only metabolites of 125I-BMQ are detected in bile, visualization and measuring of the accumulation of metabolites over time in the intestine, where bile is excreted, could predict the amount of metabolites produced in the body and evaluate CYP2D activity, which would be useful in determining the dosage of various drugs metabolized by CYP2D. Conclusion: 123/125I-BMQ is useful as a SPECT imaging probe for comprehensive and direct assessment of hepatic CYP2D activity in a minimally invasive and simple approach.

Image Quality of Cardiac Silicon Photomultiplier PET/CT Using an Infant Phantom of Extremely Low Birth Weight.

The lack of pediatrics-specific equipment for nuclear medicine imaging has resulted in insufficient diagnostic information for newborns, especially low-birth-weight infants. Although PET offers high spatial resolution and low radiation exposure, its use in newborns is limited. This study investigated the feasibility of cardiac PET imaging using the latest silicon photomultiplier (SiPM) PET technology in infants of extremely low birth weight (ELBW) using a phantom model. Methods: The study used a phantom model representing a 500-g ELBW infant with brain, cardiac, liver, and lung tissues. The cardiac tissue included a 3-mm-thick defect mimicking myocardial infarction. Organ tracer concentrations were calculated assuming 18F-FDG myocardial viability scans and 18F-flurpiridaz myocardial perfusion scans and were added to the phantom organs. Imaging was performed using an SiPM PET/CT scanner with a 5-min acquisition. The data acquired in list mode were reconstructed using 3-dimensional ordered-subsets expectation maximization with varying iterations. Image evaluation was based on the depiction of the myocardial defect compared with normal myocardial accumulation. Results: Increasing the number of iterations improved the contrast of the myocardial defect for both tracers, with 18F-flurpiridaz showing higher contrast than 18F-FDG. However, even at 50 iterations, both tracers overestimated the defect accumulation. A bull's-eye image can display the flow metabolism mismatch using images from both tracers. Conclusion: SiPM PET enabled cardiac PET imaging in a 500-g ELBW phantom with a 1-g heart. However, there were limitations in adequately depicting these defects. Considering the image quality and defect contrast,18F-flurpiridaz appears more desirable than 18F-FDG if only one of the two can be used.

Improved Correlation of 18F-Flortaucipir PET SUVRs and Clinical Stages in the Alzheimer Disease Continuum with the MUBADA/PERSI-Based Analysis.

The Alzheimer disease (AD) continuum is a neurodegenerative disorder with cognitive decline and pathologic changes. Tau PET imaging can detect tau pathology, and 18F-flortaucipir PET imaging is expected to visualize progression through the stages of AD, for which quantitative assessment is essential. Two measurement methods, statistically defined multiblock barycentric discriminant analysis (MUBADA)/parametric estimation of reference signal intensity (PERSI) and anatomically defined tau meta-volume of interest (VOI)/cerebellar gray matter (CGM) for SUV ratio (SUVR), were compared in this study to assess their relationship to AD clinical stage using 2 open multicenter PET databases. Methods: Data were selected for 106 cases from 2 databases, AMED Preclinical AD study (AMED-PRE) (n = 15) and Alzheimer Disease Neuroimaging Initiative 3 (n = 91). The data of the participants were categorized into 4 groups based on the clinical criteria. Tau PET imaging was conducted using 18F-flortaucipir, and the 2 SUVR measurement methods, MUBADA/PERSI and tau meta-VOI/CGM, were compared among different clinical categories: amyloid-negative cognitively normal, preclinical AD, amyloid-negative mild cognitive impairment (MCI), and amyloid-positive MCI. Results: Significant differences were found between cognitively normal and preclinical AD, as well as between cognitively normal and amyloid-positive MCI and between amyloid-negative MCI and -positive MCI in SUVR derived by MUBADA/PERSI, whereas SUVR by tau meta-VOI/CGM did not provide significant differences between any pair. The tau meta-VOI/CGM method consistently provided higher SUVRs and larger individual variations than MUBADA/PERSI, with a mean SUVR difference of 0.136 for the studied databases. Conclusion: MUBADA/PERSI provided the SUVR of 18F-flortaucipir uptake with better association with the clinical severity of the AD continuum and with smaller variability. The results support the usefulness of MUBADA/PERSI as a quantitative measure of 18F-flortaucipir uptake in multicenter studies using different PET systems and scanning methods. However, limitations of the study include the small sample size and the unbalanced distribution among clinical categories in the AMED Preclinical AD study database.

[18F]FDG-labelled stem cell PET imaging in different route of administrations and multiple animal species.

Stem cell therapy holds great promise for tissue regeneration and cancer treatment, although its efficacy is still inconclusive and requires further understanding and optimization of the procedures. Non-invasive cell tracking can provide an important opportunity to monitor in vivo cell distribution in living subjects. Here, using a combination of positron emission tomography (PET) and in vitro 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) direct cell labelling, the feasibility of engrafted stem cell monitoring was tested in multiple animal species. Human mesenchymal stem cells (MSCs) were incubated with phosphate-buffered saline containing [18F]FDG for in vitro cell radiolabelling. The pre-labelled MSCs were administrated via peripheral vein in a mouse (n = 1), rats (n = 4), rabbits (n = 4) and non-human primates (n = 3), via carotid artery in rats (n = 4) and non-human primates (n = 3), and via intra-myocardial injection in rats (n = 5). PET imaging was started 10 min after cell administration using a dedicated small animal PET system for a mouse and rats. A clinical PET system was used for the imaging of rabbits and non-human primates. After MSC administration via peripheral vein, PET imaging revealed intense radiotracer signal from the lung in all tested animal species including mouse, rat, rabbit, and non-human primate, suggesting administrated MSCs were trapped in the lung tissue. Furthermore, the distribution of the PET signal significantly differed based on the route of cell administration. Administration via carotid artery showed the highest activity in the head, and intra-myocardial injection increased signal from the heart. In vitro [18F]FDG MSC pre-labelling for PET imaging is feasible and allows non-invasive visualization of initial cell distribution after different routes of cell administration in multiple animal models. Those results highlight the potential use of that imaging approach for the understanding and optimization of stem cell therapy in translational research.

Magnetic resonance imaging of umbilical cord stem cells labeled with superparamagnetic iron oxide nanoparticles: effects of labelling and transplantation parameters.

Cell tracking with magnetic resonance imaging (MRI) is important for evaluating the biodistribution of transplanted cells. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have emerged as a promising therapeutic tool in regenerative medicine. We examined the UC-MSCs labeled with superparamagnetic (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO) in terms of cell functioning and imaging efficiency in vitro and in vivo. The UC-MSCs were co-incubated with SPIO or USPIO at a concentration of 50 or 100 µg/mL of label. Viability and proliferation were assessed by Trypan blue dye exclusion and MTT assay, respectively. Differentiation (chondrogenesis, osteogenesis, and adipogenesis) was induced to examine the impact of labelling on stemness. For in vitro experiments, we used 7-T MRI to assess the T2 values of phantoms containing various concentrations of cell suspensions. For in vivo experiments, nine neonatal rats were divided into the control, SPIO, and USPIO groups. The UC-MSCs were injected directly into the rat brains. MRI images were obtained immediately and at 7 and 14 days post injection. The UC-MSCs were successfully labeled with SPIO and USPIO after 24 h of incubation. Cell viability was not changed by labelling. Nevertheless, labelling with 100 µg/mL USPIO led to a significant decrease in proliferation. The capacity for differentiation into cartilage was influenced by 100 µg/mL of SPIO. MRI showed that labeled cells exhibited clear hypointense signals, unlike unlabeled control cells. In the USPIO-labeled cells, a significant (P < 0.05) decrease in T2 values (= improved contrast) was observed when compared with the controls and between phantoms containing the fewest and the most cells (0.5 × 106 versus 2.0 × 106 cells/mL). In vivo, the labeled cells were discernible on T2-weighted images at days 0, 7, and 14. The presence of SPIO and USPIO particles at day 14 was confirmed by Prussian blue staining. Microscopy also suggested that the regions occupied by the particles were not as large as the corresponding hypointense areas observed on MRI. Both labels were readily taken up by the UC-MSCs and identified well on MRI. While SPIO and USPIO provide improved results in MRI studies, care must be taken while labelling cells with high concentrations of these agents.

Comparison of Chemical Exchange Saturation Transfer Imaging with Diffusion-weighted Imaging and Magnetic Resonance Spectroscopy in a Rat Model of Hypoxic-ischemic Encephalopathy.

PURPOSE: This study aimed to evaluate the effect of chemical exchange saturation transfer (CEST) on the ischemic regions in hypoxic-ischemic encephalopathy (HIE) in comparison with diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS) using a 7T-MRI. METHODS: We used neonatal rats (n = 8), aged 8 days, to clarify the progression of HIE. The rat model of HIE was developed by ligating and severing the left common carotid artery, followed by 45 minutes of recovery, and 60 minutes of hypoxia (8% O2/92% N2; 34°C). At 0-2 and 24 hours after the onset of HIE, CEST imaging, DWI, and MRS were performed with a 7T-MRI. The magnetization transfer ratio (MTR) asymmetry curves and four MTR asymmetry maps at 0.5, 1.0, 2.0, and 3.5 ppm were calculated using the CEST images. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps were calculated by DWI, and brain metabolites were assessed by MRS. RESULTS: In the ischemic regions of neonatal rats, FA was significantly increased at 0-2 hours and decreased at 24 hours after the onset of HIE. ADC in the ipsilateral side was significantly lower than that of contralateral side. All rats with HIE showed hypointense areas on MTR asymmetry maps (2.0 and 3.5 ppm), that did not correspond with the hyperintense areas on DWI. In addition, a significant increase in lactate levels was observed at 0-2 and 24 hours after the onset of HIE. CONCLUSION: CEST MTR maps did not correspond with the hyperintense areas on DWI at 0-2 and 24 hours after the onset of HIE. The change of multi offset CEST signal may be primarily related to the brain metabolites and pH alterations, such as that caused by lactate, after the onset of HIE.

Neurite orientation dispersion and density imaging for evaluating the severity of neonatal hypoxic-ischemic encephalopathy in rats.

PURPOSE: To evaluate the utility of neurite orientation dispersion and density imaging (NODDI) for longitudinally assessing neonatal hypoxic-ischemic (HI) encephalopathy severity with 7.0 T magnetic resonance imaging. METHODS: Thirteen 8-day-old Wistar rats underwent unilateral ligation of the left common carotid artery followed by mild (1 h; n = 6) or severe (2 h; n = 7) hypoxic exposure (8% O2, 34 °C). Diffusion-weighted, T2-weighted (T2W), and flow-sensitive alternating inversion recovery images were obtained with a horizontal 7.0 T scanner at 1, 24, 72, and 168 h after HI insult. The fractional anisotropy (FA), apparent diffusion coefficient (ADC), intracellular volume fraction (ICVF), isotropic volume fraction (ISO), orientation dispersion index (ODI), and cerebral blood flow (CBF) values were calculated for each group (mild and severe) at each time point (1, 24, 72, and 168 h). ICVF, ISO, and ODI were the NODDI parameters. RESULTS: Left hemisphere brain damage was identified as slight hyperintensity on T2W images after 1 h in both groups. In the severe group only, the signal hyperintensity increased time-dependently over 168 h. The ADC and CBF were not significantly different between the groups within any region. The ICVF and ODI were significantly higher in the severe vs. mild group at various points between 1 and 168 h (cortex, striatum, or white matter), whereas the FA was significantly higher in the mild vs. severe group at 168 h (cortex and white matter). The ISO was higher in the severe vs. mild group at 72 h (striatum) and 168 h (all regions), while the ISO was significantly higher in the mild vs. severe group at 24 h (all regions). CONCLUSION: Here, ODI, a NODDI metric, identified early differences between mild and severe HI injuries. Our findings support the potential utility of NODDI for determining neonatal HI encephalopathy severity in rats.

Evaluation of Glucose Uptake and Uncoupling Protein 1 Activity in Adipose Tissue of Diabetic Mice upon ß-Adrenergic Stimulation.

PURPOSE: Regulation of metabolic activity in adipose tissue is of great concern for treating obesity. This study aimed to evaluate the adrenergic regulation of glucose uptake and the thermogenic program in adipose tissues in mouse models of both type 1 and 2 diabetes mellitus (DM). PROCEDURES: Male mice were treated with streptozotocin to induce type 1 (T1) DM, and obese ob/ob mice were used for the type 2 (T2) DM model. After selective ß3-adrenoreceptor stimulation by CL 316,243 (CL) treatment, 2-deoxy-D-[14C]glucose ([14C]DG) was administered to DM and corresponding control mice. Radioactivity and uncoupling protein 1 (UCP1) expression were measured and analyzed in adipose tissues. RESULTS: In T1DM, [14C]DG uptake in brown adipose tissue (BAT) decreased both at rest and upon CL stimulation, and UCP1 expression was preserved. However, CL treatment enhanced [14C]DG uptake without impairing UCP1 expression in inguinal white adipose tissue (iWAT). In this model, CL could not alter blood glucose levels. In T2DM mice, the blood glucose level was significantly lowered by CL treatment. There was no decrease in CL-induced [14C]DG uptake in BAT, and UCP1 expression was maintained. However, [14C]DG uptake was not increased in iWAT and no UCP1 expression was observed in iWAT (browning). CONCLUSIONS: The metabolic response against adrenergic stimulation varied depending on the type of adipose tissue and DM. This could be important for the therapeutic activation of adipose tissue metabolism in obese diabetic patients.

Different Efflux Transporter Affinity and Metabolism of 99mTc-2-Methoxyisobutylisonitrile and 99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer.

BACKGROUND: Little is known about the affinity and stability of 99mTc-labeled 2-methoxyisobutylisonitrile (99mTc-MIBI) and tetrofosmin (99mTc-TF) for imaging of multiple drug resistance transporters in cancer. We examined the affinity of 99mTc-labeled compounds for these transporters and their stability. METHODS: 99mTc-MIBI and 99mTc-TF were incubated in vesicles expressing P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP)1-4, or breast cancer resistance protein with and without verapamil (MDR1 inhibitor) or MK-571 (MRP inhibitor). Time activity curves of 99mTc-labeled compounds were established using SK-N-SH neuroblastoma, SK-MEL-28 melanoma, and PC-3 prostate adenocarcinoma cell lines, and transporter expression of multiple drug resistance was measured in these cells. The stability was evaluated. RESULTS: In vesicles, 99mTc-labeled compounds had affinity for MDR1 and MRP1. 99mTc-TF had additional affinity for MRP2 and MRP3. In SK-N-SH cells expressing MDR1 and MRP1, MK-571 produced the highest uptake of both 99mTc-labeled compounds. 99mTc-MIBI uptake with inhibitors was higher than 99mTc-TF uptake with inhibitors. 99mTc-TF was taken up more in SK-MEL-28 cells expressing MRP1 and MRP2 than PC-3 cells expressing MRP1 and MRP3. 99mTc-MIBI was metabolized, whereas 99mTc-TF had high stability. CONCLUSION: 99mTc-MIBI is exported via MDR1 and MRP1 (MRP1 > MDR1) at greater levels and more quickly compared to 99mTc-TF, which is exported via MDR1 and MRP1-3 (MRP1 > MDR1; MRP1, 2 > MRP3). Because 99mTc-MIBI is metabolized, clinical imaging for monitoring MDR and shorter examination times may be possible with an earlier scanning time on late phase imaging. 99mTc-TF has high stability and accurately reflects the function of MDR1 and MRP1-3.

The Status of Stress Myocardial Perfusion Imaging Using 99mTc Pharmaceuticals in Japan: Results from a Nationwide Survey.

OBJECTIVES: To appropriately use one-day myocardial perfusion imaging (MPI) with 99mTc radiopharmaceuticals (i.e. to avoid shine-through artifacts), injection doses need to be optimized and dose ratios between the 1st and 2nd scans should be maintained at ≥ 3. However, the current state of practice in Japan is unclear. Thus, the aim of this study was to clarify the details of MPI protocols using 99mTc radiopharmaceuticals in Japan. METHODS: A nationwide survey was conducted in June and July 2016. Questionnaires about stress MPI protocols using 99mTc radiopharmaceuticals were sent to 641 nuclear medicine facilities. RESULTS: Responses were received from 246 facilities. One-day protocols were used in 97.1% of the facilities. The most common injection dose ratio was 2.5. Only 18.2% of facilities achieved the recommended injection dose ratio. Stress-only protocols were performed in only 1.7% of facilities; the primary reasons for not performing stress-only protocols were as follows: 1) "The reading-physician cannot interpret the image just after the first scan," and 2) "Preparation of radiopharmaceuticals and scan arrangements turn out to be complicated." CONCLUSION: Approximately 80% of nuclear medicine facilities do not follow the recommended injection dose ratio. Stress-only protocols are ideal, but are performed at very few facilities. Both optimization and standardization of stress MPI protocols using 99mTc radiopharmaceuticals are needed in Japan.

123I-iomazenil whole-body imaging to detect hepatic carboxylesterase drug-metabolizing enzyme activity.

OBJECTIVES: Drugs are mainly metabolized by hepatic enzymes, the activity of which can differ between individuals. Although it is ideal to measure the hepatic clearance of liver-targeted drugs in individualized medicine, blood enzyme tests typically measure metabolic drug clearance in the entire body, and not just in the liver. We investigated whether I-iomazenil imaging can directly assess and quantify the activity of hepatic drug-metabolizing enzymes. MATERIALS AND METHODS: Hepatic enzymes that metabolize I-iomazenil were identified by thin-layer chromatography in mouse liver homogenates with bis(4-nitrophenyl) phosphate (BNPP) inhibitor for carboxylesterase enzymes and nicotinamide adenine dinucleotide phosphate (NADPH) generator for cytochrome P450 enzymes. Whole-body images of mice were acquired using I-iomazenil with and without BNPP, and the distribution was also obtained. The metabolism of I-iomazenil in the blood, liver, gall bladder, and bladder was investigated by thin-layer chromatography. RESULTS: From the in-vitro metabolism of I-iomazenil using BNPP, the enzyme converting I-iomazenil to I-R-COOH was identified as carboxylesterase, and that converting I-iomazenil to M2 was identified as cytochrome P450 in experiments with and without an NADPH generator. The biological distribution and whole-body imaging showed increased accumulation in the liver of mice administered BNPP compared with normal mice, but decreased levels in the gall bladder and small intestine. The main fraction in bile and urine was I-R-COOH, with two unknown metabolites (M1 and M2), I, and I-iomazenil also being present. CONCLUSION: I-iomazenil whole-body imaging has good possibility of direct measurement of hepatic carboxylesterase activity as accumulation of I-R-COOH in the gall bladder through bile and in the bladder through urine.

Imaging of the thyroid and parathyroid using a cardiac cadmium zinc telluride camera: Phantom studies.

Purpose: Cadmium zinc telluride (CZT) detectors have recently been introduced to the field of clinical nuclear cardiology. However, the feasibility of using them for organs other than the heart remains unclear. The aim of this study was to evaluate the potential of a cardiac CZT camera to acquire thyroid and parathyroid images. We used custom-made phantoms and the currently available standard protocols for CZT, instead of a sodium-iodine scintillation (NaI) camera. Materials and Methods: Thyroid phantoms with or without parathyroid adenomas were made from agar using radiopharmaceuticals (99mTc or 123I) and imaged using CZT and NaI cameras. Using the CZT camera data, we prepared maximum intensity projection (MIP) images and planar equivalent (PE) images. Image counts were compared to those from the NaI camera, and the radioactivity of the phantoms was measured. For parathyroid imaging, three different protocols with the NaI camera were tested using MIP images. Results: For thyroid imaging, MIP could provide images as clear as those obtained from the NaI camera. The radioactivity and image counts correlated better for the PE images than the MIP images, especially for 123I images. We succeeded in obtaining clear parathyroid adenoma images from MIP images using all three protocols. Conclusion: A cardiac CZT camera can effectively perform qualitative and quantitative assessments of the thyroid and parathyroid organs.

Optimal injected dose ratio of a very rapid 1-day protocol of myocardial perfusion imaging with cadmium-zinc-telluride single-photon emission tomography: simulation and phantom study.

OBJECTIVE: Cadmium-zinc-telluride detectors enable shorter acquisition durations in myocardial perfusion imaging (MPI), but the time interval of sequential scanning is still unchanged in clinical practice. We designed a very rapid 1-day protocol of MPI using cadmium-zinc-telluride single-photon emission tomography and evaluated the optimal dose ratio between two scanning acquisitions by means of simulations and phantom experiments. METHODS: We intended to perform a 1-day MPI within 140 min and simulate radioactivities in the second scan under various injected dose ratios. To apply this, a cardiac phantom was scanned with various radioactivities and scans were compared with a reference scan with the ideal tracer concentrations. RESULTS: In the stress-first protocol, the dose ratio 1 : 5 was enough to show the same regional percentage uptake compared with the reference. However, in the rest-first protocol, the regional percentage uptakes were higher than those of the reference image even with a 1 : 6 dose ratio. CONCLUSION: The injected dose ratio 1 : 5 is optimal in a stress-first rapid 1-day protocol. The rest-first protocol is not appropriate because a dose ratio greater than 1 : 6 is required to withdraw shine-through artifacts.

Current status of stress myocardial perfusion imaging pharmaceuticals and radiation exposure in Japan: Results from a nationwide survey.

BACKGROUND: Ionizing radiation generated during medical imaging procedures is a matter of concern. However, the current status of radiopharmaceutical use in stress myocardial perfusion imaging (MPI) and the radiation exposure from these radiopharmaceuticals is unknown in Japan. METHODS AND RESULTS: A nationwide survey was conducted from June through July 2016. The questionnaires on the radiopharmaceuticals used and their administered doses during stress MPI were sent to 641 nuclear medicine facilities. The responses were collected from 431 facilities and the effective dose (ED) for an adult with standard body weight was calculated. Forty-three percent of the facilities used only 201TlCl, 35% used only 99mTc radiopharmaceuticals, and the remaining 22% used both. The two main reasons for using 201TlCl instead of 99mTc radiopharmaceuticals were "more familiarity with the usage of 201TlCl than 99mTc radiopharmaceuticals" and "apprehension about increasing the burden of physicians performing tracer injection twice." The mean ED was 14.0 ± 5.5 mSv (range, 3.9 to 25.2 mSv), which was higher than that reported in other countries. CONCLUSIONS: The ED of stress MPI radiopharmaceuticals in Japan is probably higher than the world standard because more than 50% of the facilities still use 201TlCl. We recommend revising the routine stress MPI protocol to reduce the effects of ionizing radiation.

Differences in accumulation and the transport mechanism of l- and d-methionine in high- and low-grade human glioma cells.

INTRODUCTION: Although [S-methyl-11C]-labeled L-methionine and D-methionine (11C-L-MET and 11C-D-MET) are useful radiotracers for positron emission tomography imaging of brain tumors, it is not known whether the accumulation and transport mechanisms underlying uptake of 11C-D-MET and 11C-L-MET are the same. 11C-L-MET is mainly taken up by the amino acid transport system L. We evaluated accumulation and the transport mechanism of D-MET in high- and low-grade human glioma cells in vitro. METHODS: The expression of transport system genes in high- (A172 and T98G) and low-grade (SW1088 and Hs683) glioma cells was quantitatively analyzed. Accumulation of [S-methyl-3H]-L-MET (3H-L-MET) and [S-methyl-3H]-D-MET (3H-D-MET) in these cells was compared during 60min of incubation. The transport mechanism of 3H-L-MET and 3H-D-MET was investigated by incubating the cells with these compounds and examining the effect of the inhibitors 2-amino-2-norbornane-carboxylic acid or α-(methylamino) isobutyric acid. RESULTS: Absolute expression levels of system L and system alanine-serine-cysteine (ASC) in high-grade glioma cells were higher than in low-grade cells. In high-grade glioma cells, expression of system ASC genes was higher than that of system L genes. 3H-D-MET, which is transported by systems L and ASC, accumulated at higher levels than 3H-L-MET at all incubation times because 3H-D-MET is more sensitive to system ASC than 3H-L-MET. Conversely, in low-grade glioma cells with lower expression of system L and ASC, 3H-D-MET accumulated at higher levels than 3H-L-MET in early incubation times because 3H-D-MET may be more sensitive to system ASC than system L. CONCLUSION: 3H-D-MET was mainly transported by systems L and ASC and sensitive to system ASC, whereas 3H-L-MET was transported by system L in human glioma cells. In vitro, the accumulation of 3H-D-MET was significantly higher than that of 3H-L-MET during the entire incubation time in high-grade glioma cells, and in early incubation times in low-grade glioma cells.

Reconstruction of semiautomated cardiac regions of interest using iodine-123 metaiodobenzylguanidine myocardial scintigraphy.

INTRODUCTION: Analysis using cardiac iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy with regions of interest (ROIs) is useful for assessing myocardial sympathetic activity. However, manual placement of the cardiac ROI is sometimes difficult because myocardial MIBG uptake is reduced in patients with heart failure. A new method was developed to reconstruct the semiautomated cardiac ROI in a sympathetic denervated heart. MATERIALS AND METHODS: Using dynamic planar data, a summed image was generated and the matrix size was changed. Then, the radial count profiles originating from the center of the left ventricle were generated to extract the myocardial count profiles. An asymmetric Gaussian distribution was fitted to each profile and the epicardial border was defined by the threshold method. This program was tested in 50 patients, and its reproducibility was validated when compared with the manual tracing method. RESULTS: The semiautomated method yielded a better quality image compared with the standard image with higher counts. Cardiac ROIs were generated successfully in each patient within normal limits. The intraobserver and interobserver agreements were excellent (P<0.0001 each). This approach showed a significantly higher consistency in measuring the heart-to-mediastinum ratio as compared with the manual tracing method (P<0.05). CONCLUSION: The semiautomated method is useful in generating cardiac ROIs with high reproducibility in myocardial MIBG imaging.

Unusually increased metaiodobenzylguanidine uptake in a gastrointestinal stromal tumor of the stomach.

A 70-year-old woman with a submucosal gastric tumor was referred to our hospital for surgical treatment. Upon examination, it was found that she had hypertension, and abdominal computed tomography revealed swelling on both adrenal glands. The patient was examined with gamma camera imaging and iodine-123 metaiodobenzylguanidine (MIBG), because her hypertension was thought to be due to a suspected adrenomedullary tumor. The planar image showed an unexpected abnormal uptake of MIBG in the upper abdomen. On single-photon emission computed tomographic images, the area of abnormal tracer uptake was thought to correspond to the known gastric tumor. The surgical procedure and histological assessments revealed that the gastric tumor was a gastrointestinal stromal tumor (GIST). MIBG can accumulate in GISTs as well as in neuroendocrine tumors of the medulla of the adrenal glands. Although the cause of radiolabeled MIBG uptake in GISTs is uncertain, further studies are necessary to establish the significance of MIBG scintigraphy in GIST imaging.

[Granular cell tumor in the mediastinum; report of a case].

Granular cell tumor is found in various organs but is rare in the mediastinum. We report a case of 21-year-old woman with a granular cell tumor in the left upper mediastinum. Chest computed tomography (CT) showed a 30 x 20 mm well circumscribed tumor in the left upper mediastinum. Tumor resection was performed. It was found that the tumor involved the sympathetic nerve. Histopathologically, the tumor consisted of cells with eosinophilic granules and diagnosed as a granular cell tumor.

The cutoff value of aldosterone-to-renin ratio for the diagnosis of primary aldosteronism in patients taking antihypertensive medicine.

BACKGROUND: Primary aldosteronism (PA) may account for as much as 6-20% of cases of refractory hypertension referred to hypertension clinics. Because antihypertensive agents affect the physiologic renin-angiotensin-aldosterone system, screening diagnostic tests for PA are generally performed after antihypertensive agents are discontinued. However, such tests can be dangerous for patients with severe hypertension or other cardiovascular complications. However, a reliable cutoff value for the aldosterone-to-renin ratio (ARR) has not been established, especially for Asians, including the Japanese. METHOD: Fifty-five consecutive patients with clinically suspected PA were evaluated from July 10, 2001, to March 1, 2005, at the National Cardiovascular Center in Japan. Every referred patient was screened prospectively for PA with the ARR at the outpatient clinic. The patients tested continued to be treated with a variety of antihypertensive agents. We reviewed the sensitivity, specificity, and accuracy of the ARR without modifying the antihypertensive agents. The diagnosis of PA was established with the results of both abdominal computed tomography and adrenal scintigraphy. RESULTS: Of the 55 patients, 27 were found to have PA, including adrenal adenoma (n = 18) and bilateral adrenal hyperplasia (n = 9). The mean ARR of patients with PA was significantly higher than that of patients without PA. By assuming a cutoff value of the ARR >or= 69 calculated from the receiver operating characteristics curve, the highest sensitivity (81%), specificity (82%), positive-predictive value (81%), and negative-predictive value (81%) were obtained. CONCLUSION: The data suggest that an ARR >or= 69 strongly indicates PA in Japanese patients with hypertension being treated with antihypertensive agents.

Myocardial scintigraphy after pacemaker implantation for congenital complete atrioventricular block.

Patients with isolated congenital complete atrioventricular block (CCAVB) occasionally develop dilated cardiomyopathy (DCM), despite early pacemaker implantation. However, the etiology of the DCM and its relationship to permanent ventricular pacing are not fully understood. Twenty-five patients with CCAVB underwent (99m) technetium (Tc) myocardial perfusion scintigraphy. Five patients were studied before and after pacing, providing a total of 30 image sets, which were divided into three groups; group 1: CCAVB before pacemaker implantation (PMI) (n = 11); group 2: CCAVB after PMI who did not subsequently develop DCM (n = 13); group 3: CCAVB after PMI who subsequently developed DCM (n = 6). Perfusion defects on single-photon-emission computed tomography (SPECT) were identified in group 1, 0 of 11 patients; group 2, 85% of patients; and group 3, 100% of patients. In groups 2 and 3, in patients with right ventricular pacing, the perfusion defects were mainly in the septum or between the apex and septum. On 20 segments' polar maps, the distribution of %uptake showed a similar pattern in groups 2 and 3, the degree of decreased %uptake and the number of segments with decreased %uptake being more severe in group 3. "Artificial" left bundle branch block (LBBB) pattern myocardial contraction induced by right ventricular pacing decreased myocardial perfusion around the apex and septum. Some patients with CCAVB will develop left ventricular dysfunction caused by artificial LBBB-induced interventricular asynchrony.