Biomedical subjects

Yuji Kuge

Publications and source records attributed to Yuji Kuge.

At least 19 recordsLinked to original sources

PubMed2007

99mTc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits.

PURPOSE: Apoptosis is commonly observed in advanced atherosclerotic lesions. 99mTc-annexin A5 (99mTc-annexin V) has been proposed as a potential tracer for imaging apoptosis in atherosclerotic plaques. Accordingly, we determined the usefulness of 99mTc-annexin A5 as an atherosclerosis imaging tracer in a rabbit model (myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits; WHHLMI rabbits) of spontaneous atherosclerosis. METHODS: The WHHLMI and control rabbits were injected intravenously with 99mTc-annexin A5. After in vivo planar imaging, the radioactivity in the aorta was measured. Autoradiography, TUNEL staining, Azan-Mallory staining and immunohistological studies were performed serially throughout the aorta. RESULTS: 99mTc-Annexin A5 accumulation in the aorta of the WHHLMI rabbits was 5.6-fold higher than in that of control rabbits. Autoradiography showed heterogeneous multifocal accumulation of 99mTc-annexin A5 in WHHLMI rabbits. 99mTc-Annexin A5 accumulation was highest in the atheromatous lesions (6.2+/-2.5, %IDxBW/mm2x10(3)), followed in decreasing order by neointimal (4.9+/-1.3), fibroatheromatous (4.5+/-1.9), and collagen-rich lesions (3.3+/-1.4). The regional 99mTc-annexin A5 accumulation was significantly correlated with the TUNEL-positive cell density, macrophage density and "vulnerability index," an index of the morphological destabilized characteristics. The in vivo imaging clearly visualized the atherosclerotic lesions in WHHLMI rabbits. CONCLUSION: The present study in WHHLMI rabbits showed higher 99mTc-annexin A5 accumulation in grade IV atheroma than in other more stable lesions. 99mTc-Annexin A5 may be useful in identifying atheroma that is at higher risk for rupture and possibly in assessing the response to anti-atherosclerotic therapy.

Animals↗

PubMed2006

Is MIBG a substrate of P-glycoprotein?

PURPOSE: Radionuclide therapy with 131I-labelled meta-iodobenzylguanidine ([131I]MIBG) is effective in cases where it is difficult to carry out surgical resection or debulking of neuroendocrine tumours (NETs). However, it has recently been reported that P-glycoprotein (P-gp) is expressed in these NETs. Therefore, it is important to clarify whether MIBG is a substrate of P-gp or not. In this study, using a human cell line which overexpresses P-gp, LLC-GA5-COL150, we investigated this question. METHODS: The transcellular transport and accumulation of [125I]MIBG were measured using monolayer cultures grown in Transwell chambers. [125I]MIBG was added to either the basolateral or the apical side, aliquots of the incubation medium on the other side were taken at specified times, and the radioactivity was measured. For accumulation experiments, the cells on the filters were solubilised and the radioactivity in aliquots was measured. RESULTS: There were no significant differences in the transport of MIBG between LLC-PK1 and LLC-GA5-COL150 monolayers in either direction until 60 min. With respect to the accumulation of MIBG, there were no significant differences between LLC-PK1 and LLC-GA5-COL150 cells in either direction. CONCLUSION: MIBG is not a substrate of P-gp. Therefore, radionuclide therapy with MIBG would be useful in the treatment of NETs expressing P-gp.

3-Iodobenzylguanidine↗

PubMed2006

Myocardial flow reserve is influenced by both coronary artery stenosis severity and coronary risk factors in patients with suspected coronary artery disease.

PURPOSE: Myocardial flow reserve (MFR) measurement has an important role in assessing the functional severity of coronary artery stenosis. However, a discrepancy between the anatomical severity of coronary artery stenosis and MFR is often observed. Such a discrepancy may be explained by coronary risk factors. In this study, we aimed to investigate the influence of coronary artery stenosis severity and risk factors on MFR. METHODS: Seventy-four patients suspected to have coronary artery disease and seven age-matched healthy volunteers were enrolled. Myocardial blood flow (MBF) and MFR were measured using 15O-labelled water PET. Regional MFR was calculated in regions with significant coronary artery stenosis (stenotic regions) and in regions without significant stenosis (remote regions). The contributions of coronary artery stenosis severity and coronary risk factors were assessed using univariate and multivariate analyses. RESULTS: In stenotic regions, MFR correlated inversely with coronary artery stenosis severity (r=-0.50, p<0.01). Univariate analysis did not show any significant difference in MFR between the patients with and the patients without each risk factor. In remote regions, however, MFR was significantly decreased in the diabetes and smoking groups (each p<0.05). By multivariate analysis, diabetes and smoking were independent predictors of MFR (each p<0.05). In the group with more than one risk factor, MFR was significantly lower (2.78+/-0.79) than in the other group (3.40+/-1.22, p<0.05). CONCLUSION: MFR is influenced not only by coronary stenosis severity but also by coronary risk factors. In particular, the influence of risk factors should be considered in regions without severe coronary stenosis.

Blood Flow Velocity↗

PubMed2006

Loss of neuronal integrity: a cause of hypometabolism in patients with traumatic brain injury without MRI abnormality in the chronic stage.

PURPOSE: Traumatic brain injury (TBI) causes brain dysfunction in many patients. However, some patients have severe brain dysfunction but display no abnormalities on magnetic resonance imaging (MRI). There have been some reports of hypometabolism even in such patients. The purpose of this study was to investigate the relationship between metabolic abnormality and loss of neuronal integrity in TBI patients with some symptoms but without MRI abnormalities. METHODS: The study population comprised ten patients with TBI and ten normal volunteers. All of the patients were examined at least 1 year after the injury. ( 15)O-labelled gas PET and [(11)C]flumazenil (FMZ) positron emission tomography (PET) were carried out. The cerebral metabolic rate of oxygen (CMRO(2)) and binding potential (BP) images of FMZ were calculated. Axial T2WI, T2*WI and FLAIR images were obtained. Coronal images were added in some cases. RESULTS: All of the patients had normal MRI findings, and all showed areas with abnormally low CMRO(2). Low uptake on BP images was observed in six patients (60%). No lesions that showed low uptake on BP images were without low CMRO(2). On the other hand, there were 14 lesions with low CMRO(2) but without BP abnormalities. CONCLUSION: These results indicate that there are metabolic abnormalities in TBI patients with some symptoms after brain injury but without abnormalities on MRI. Some of the hypometabolic lesions showed low BP, indicating a loss of neuronal integrity. Thus, FMZ PET may have potential to distinguish hypometabolism caused by neuronal loss from that caused by other factors.

Adult↗

PubMed2006

Estimation of oxygen metabolism in a rat model of permanent ischemia using positron emission tomography with injectable15O-O2.

The threshold of cerebral blood flow (CBF) into infarction in rats has been indicated to be similar to that in patients. However, CBF does not reflect metabolic function, and so estimations of oxygen metabolism have been required. Here, we estimated changes in oxygen metabolism after occluding the right middle cerebral artery (MCA) in rats using an injectable (15)O-O(2) we developed. A decrease in CBF (left: 0.67+/-0.22 mL/min/g, right: 0.44+/-0.17 mL/min/g, P<0.05) and compensatory increase in the oxygen extraction fraction (OEF) (left: 0.42+/-0.13, right: 0.50+/-0.19, P<0.05) were observed at 1-h after occlusion. In contrast, a marked decrease in CBF and the cerebral metabolic rate for oxygen and a collapse of the compensatory OEF mechanism were found at 24 h after occlusion. Injectable (15)O-O(2) could be used to reliably estimate oxygen metabolism in an infarction rat model with positron emission tomography.

Animals↗

PubMed2006

Synthesis and evaluation of radioiodinated (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter.

PURPOSE: Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT. METHODS: (S,S)-(123/125)I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of (3)H-nisoxetine and (S,S)-(125)I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-(125)I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-(123)I-IPBM were carried out in the common marmoset. RESULTS: (S,S)-(125)I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-(125)I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-(125)I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-(123)I-IPBM allowed brain NET imaging in the common marmoset with SPECT. CONCLUSION: These results suggest that (S,S)-(123)I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.

Animals↗

PubMed2006

Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression.

UNLABELLED: Although several COX-2 inhibitors have recently been radiolabeled, their potential for imaging COX-2 expression remains unclear. In particular, the sulfonamide moiety of COX-2 inhibitors may cause slow blood clearance of the radiotracer, due to its affinity for carbonic anhydrase (CA) in erythrocytes. Thus, we designed a methyl sulfone-type analogue, 5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole (IMTP). In this study, the potential of radioiodinated IMTP was assessed in comparison with a (125)I-labeled celecoxib analogue with a sulfonamide moiety ((125)I-IATP). METHODS: The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of (125)I-IMTP and (125)I-IATP was determined by the ex vivo tissue counting method in rats. Distribution of the labeled compounds to rat blood cells was measured. RESULTS: The COX-2 inhibitory potency of IMTP (IC(50) = 5.16 microM) and IATP (IC(50) = 8.20 microM) was higher than that of meloxicam (IC(50) = 29.0 microM) and comparable to that of SC-58125 (IC(50) = 1.36 microM). The IC(50) ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of (125)I-IMTP and (125)I-IATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of (125)I-IMTP was much faster than that of (125)I-IATP. Distribution of (125)I-IATP to blood cells (88.0%) was markedly higher than that of (125)I-IMTP (18.1%), which was decreased by CA inhibitors. CONCLUSIONS: Our results showed a high inhibitory potency and selectivity of IMTP for COX-2. The substitution of a sulfonamide moiety to a methyl sulfone moiety effectively improved the blood clearance of the compound, indicating the loss of the cross reactivity with CA in (125)I-IMTP. (123)I-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression.

Animals↗

PubMed2006

Smoking cessation normalizes coronary endothelial vasomotor response assessed with 15O-water and PET in healthy young smokers.

UNLABELLED: Cigarette smoking is one of the risk factors of cardiovascular diseases and is related to abnormal peripheral and coronary vascular vasomotion. Coronary vascular endothelial dysfunction is caused by chronic smoking in smokers without epicardial coronary artery stenosis. The coronary endothelial vasomotion abnormality is restored by interventions such as l-arginine or vitamin C infusion. However, to our knowledge, the effect of smoking cessation on coronary vasomotor response has not been elucidated. Therefore, the aim of this study was to assess the effect of smoking cessation on coronary vasomotor response by quantitative myocardial blood flow (MBF) measurement using (15)O-water and PET. METHODS: Fifteen young smokers (Brinkman index > 100; mean age +/- SD, 26 +/- 4 y) with no evidence of heart disease or cardiovascular risk factors, except for smoking, and age-matched nonsmokers (n = 12) were enrolled in this study. MBF was measured at rest, during the cold pressor test (CPT), before and at 1 and 6 mo after smoking cessation. In addition, MBF measurement during adenosine triphosphate (ATP) infusion was performed before and at 6 mo after smoking cessation. In nonsmokers, MBF was measured at rest, during ATP infusion, and during the CPT. RESULTS: MBF at rest and during ATP infusion did not differ between smokers and nonsmokers (0.73 +/- 0.12 vs. 0.80 +/- 0.15 mL/g/min and 3.15 +/- 1.43 vs. 3.69 +/- 0.76 mL/g/min, respectively; P = not significant). In contrast, MBF during the CPT in smokers was lower than that in nonsmokers (0.90 +/- 0.19 vs. 1.12 +/- 0.28 mL/g/min; P < 0.05). There was no significant difference in MBF either at rest or during ATP infusion between before and after smoking cessation, but MBF during the CPT increased at 1 mo in comparison with before cessation of smoking (0.90 +/- 0.19 vs. 1.02 +/- 0.22 mL/g/min; P < 0.01). An improvement of MBF response to the CPT was preserved at 6 mo after smoking cessation. CONCLUSION: Coronary vasomotor abnormality assessed by MBF response to the CPT was improved at 1 mo after smoking cessation. These findings indicate that coronary endothelial dysfunction may be reversible within 1 mo after smoking cessation in healthy young smokers.

Adult↗

PubMed2005

Aggravation of hemorrhagic transformation by early intraarterial infusion of low-dose vascular endothelial growth factor after transient focal cerebral ischemia in rats.

Vascular endothelial growth factor (VEGF) is a unique growth factor associated with angiogenesis, vascular permeability, and neuroprotection. The aim of this study was to observe the effects of early intraarterial infusion of low-dose VEGF on ischemia/reperfusion injury after transient focal cerebral ischemia in rats. Male Sprague-Dawley rats were subjected to 2 h of focal ischemia by middle cerebral artery occlusion. After the 2 h ischemia, the rats were infused with 0.3 microg/kg of VEGF (n = 15), or the vehicle as a control (n = 15), via the reperfused internal carotid artery. The brains were collected after a 1 h, 6 h, or 72 h reperfused period. Severity of ischemic cellular injury, serum extravasation, hemorrhagic transformation, and matrix metalloproteinase (MMP)-2 and -9 expressions were compared between the VEGF-treated and control groups. No significant difference in the extent of ischemic cellular injury and serum extravasation was observed between the two groups. However, vessel numbers with hemorrhagic transformation were significantly greater in the VEGF-treated group than in the control group after the 72 h reperfusion (9.4 +/- 1.6 versus 2.6 +/- 1.5; P = 0.028). The severity of hemorrhagic transformation was not correlated with the extent of ischemic cellular injury or serum extravasation. MMP-2 and -9 expressions were not enhanced in the VEGF-treated group compared with the control group. These results suggest that exogenous VEGF administered intravascularly at a very early point in reperfusion aggravates hemorrhagic transformation. The aggravated hemorrhagic transformation does not seem to depend on the enlargement of ischemic cellular injury, serum extravasation, or overexpressions of MMP-2 and -9.

Animals↗

PubMed2005

Bilateral induction of the S-100A9 gene in response to spreading depression is modulated by the cyclooxygenase-2 activity.

Cyclooxygenase-2 (COX-2) was reported to be induced in the infarcted human brain. Spreading depression (SD) is thought to play a role in this induction. In this study, we correlated the expression of SD-associated genes with COX-2 production in brains after SD. Rats were divided into 3 groups: rats that did not undergo SD (group I saline controls, n=7), rats that underwent unilateral SD as a result of KCl application (group II, n=9), and rats that were pretreated with the selective COX-2 inhibitor, JTE-522 3 h before the induction of SD (group III, n=7). The expression of the SD-associated genes, S-100A9, and mitogen-activated proteinkinase phosphatase (cpg21) was analyzed 2 h later using a cDNA array. In group II, COX-2 and cpg21 mRNA expression, as determined by RT-PCR, were significantly upregulated in the hemisphere undergoing SD. While the expression of S-100A9 mRNA was bilaterally upregulated in these animals, this expression was significantly reduced in group III, and was accompanied by reduced bilateral production of PGE(2). Thus, the bilateral induction of expression of the S-100A9 gene in response to SD was associated with COX-2 activation.

Animals↗

PubMed2005

Quantitative analysis of myocardial glucose utilization in patients with left ventricular dysfunction by means of 18F-FDG dynamic positron tomography and three-compartment analysis.

PURPOSE: Myocardial glucose utilization (MGU) is altered in various heart diseases. The aim of this study was to quantitatively assess regional myocardial glucose utilization in patients with left ventricular (LV) dysfunction by dynamic( 18)F-fluorodeoxyglucose positron emission tomography (FDG PET). METHODS: A total of 18 subjects were studied, including ten with LV dysfunction (seven with idiopathic dilated cardiomyopathy and three with aortic regurgitation; NYHA II in 8 and III in 2) and eight healthy normal volunteers. Patients with diabetes mellitus were excluded. A dynamic PET study was performed for 40 min following the injection of 370 MBq of FDG after 50-g glucose loading. On the basis of a three-compartment model, MGU, K1, k2, and k3 were computed on a pixel by pixel basis to generate LV myocardial parametric maps. FDG standardized uptake value (SUV) was also calculated using static images obtained 40 min after FDG injection. These metabolic values were compared with myocardial flow distribution (%Flow), LVEF, LV volumes, and LV wall thickening (WT) determined by gated myocardial single-photon emission computed tomography using QGS software in eight myocardial segments. RESULTS: MGU correlated positively with LV volumes and negatively with LVEF. K(1) was significantly higher in the segments of the patients than in those of the normal volunteers (0.082+/-0.055 vs 0.041+/-0.017 ml min(-1) g(-1), p<0.05), although there was no difference in MGU between the groups. On the other hand, SUV, k2, and k3 did not differ significantly between the groups. Among the patients, the K1 values were significantly higher in the areas with impaired WT (%WT<17%) (0.109+/-0.063 vs 0.069+/-0.062 ml min(-1) g(-1), p<0.05) and in the areas with flow reduction (%Flow<71%) (0.112+/-0.076 vs 0.071+/-0.046 ml min(-1) g(-1), p<0.05). CONCLUSION: These results indicate that glucose utilization was preserved in the patients with LV dysfunction, mainly due to an increase in glucose transport, particularly in the regions with severely impaired LV function. Thus, the quantitative assessment of myocardial glucose utilization by FDG dynamic PET may provide useful information for assessing the regional myocardial metabolic status in patients with LV dysfunction.

Aged↗

PubMed2005

Evaluating performance of a pixel array semiconductor SPECT system for small animal imaging.

OBJECTIVES: Small animal imaging has recently been focused on basic nuclear medicine. We have designed and built a small animal SPECT imaging system using a semiconductor camera and a newly designed collimator. We assess the performance of this system for small object imaging. METHODS: We employed an MGC 1500 (Acrorad Co.) camera including a CdTe semiconductor. The pixel size was 1.4 mm/pixel. We designed and produced a parallel-hole collimator with 20-mm hole length. Our SPECT system consisted of a semiconductor camera with the subject holder set on an electric rotating stage controlled by a computer. We compared this system with a conventional small animal SPECT system comprising a SPECT-2000H scanner with four Anger type cameras and pinhole collimators. The count rate linearity for estimation of the scatter was evaluated for a pie-chart phantom containing different concentrations of 99mTc. We measured the FWHM of the 99mTc SPECT line source along with scatter. The system volume sensitivity was examined using a flood source phantom which was 35 mm long with a 32-mm inside diameter. Additionally, an in vivo myocardial perfusion SPECT study was performed with a rat. RESULTS: With regards to energy resolution, the semiconductor camera (5.6%) was superior to the conventional Anger type camera (9.8%). In the count rate linearity evaluation, the regression lines of the SPECT values were y = 0.019x + 0.031 (r2 = 0.999) for our system and y = 0.018x + 0.060 (r2 = 0.997) for the conventional system. Thus, the scatter count using the semiconductor camera was less than that using the conventional camera. FWHMs of our system and the conventional system were 2.9 +/- 0.1 and 2.0 +/- 0.1 mm, respectively. Moreover, the system volume sensitivity of our system [0.51 kcps/(MBq/ ml)/cm] was superior to that of the conventional system [0.44 kcps/(MBq/ml)/cm]. Our system provided clear images of the rat myocardium, sufficient for practical use in small animal imaging. CONCLUSIONS: Our SPECT system, utilizing a semiconductor camera, permits high quantitative analysis by virtue of its low scatter radiation and high sensitivity. Therefore, this system may contribute to molecular imaging of small animals and basic medical research.

Animals↗

PubMed2005

Biologic correlates of intratumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-II in experimental tumor.

UNLABELLED: The biologic mechanisms involved in the intratumoral heterogeneous distribution of 18F-FDG have not been fully investigated. To clarify factors inducing heterogeneous 18F-FDG distribution, we determined the intratumoral distribution of 18F-FDG by autoradiography (ARG) and compared it with the regional expression levels of glucose transporters Glut-1 and Glut-3 and hexokinase-II (HK-II) in a rat model of malignant tumor. METHODS: Rats were inoculated with allogenic hepatoma cells (KDH-8) into the left calf muscle (n = 7). Tumor tissues were excised 1 h after the intravenous injection of 18F-FDG and sectioned to obtain 2 adjacent slices for ARG and histochemical studies. The regions of interest (ROIs) were placed on ARG images to cover mainly the central (CT) and peripheral (PT) regions of viable tumor tissues and necrotic/apoptotic (NA) regions. The radioactivity in each ROI was analyzed quantitatively using a computerized imaging analysis system. The expression levels of Glut-1, Glut-3, and HK-II were determined by immunostaining and semiquantitative evaluation. The hypoxia-inducible factor 1 (HIF-1) was also immunostained. RESULTS: ARG images showed that intratumoral 18F-FDG distribution was heterogeneous. The accumulation of 18F-FDG in the CT region was the highest, which was 1.6 and 2.3 times higher than those in the PT and NA regions, respectively (P < 0.001). The expression levels of Glut-1, Glut-3, and HK-II were markedly higher in the CT region (P < 0.001) compared with those in the PT region. The intratumoral distribution of 18F-FDG significantly correlated with the expression levels of Glut-1, Glut-3, and HK-II (r = 0.923, P < 0.001 for Glut-1; r = 0.829, P < 0.001 for Glut-3; and r = 0.764, P < 0.01 for HK-II). The positive staining of HIF-1 was observed in the CT region. CONCLUSION: These results demonstrate that intratumoral 18F-FDG distribution corresponds well to the expression levels of Glut-1, Glut-3, and HK-II. The elevated expression levels of Glut-1, Glut-3, and HK-II, induced by hypoxia (HIF-1), may be contributing factors to the higher 18F-FDG accumulation in the CT region.

Animals↗

PubMed2005

Enhanced apoptotic reaction correlates with suppressed tumor glucose utilization after cytotoxic chemotherapy: use of 99mTc-Annexin V, 18F-FDG, and histologic evaluation.

UNLABELLED: Cancer chemotherapy enhances the apoptosis, whereas apoptosis is a suicidal mechanism requiring energy. We determined the relationship between apoptosis and glucose utilization during cancer chemotherapy using (99m)Tc-annexin V ((99m)Tc-annexin A5) and (18)F-FDG and compared their uptake with histologic findings in a rat tumor model. METHODS: Allogenic hepatoma cells (KDH-8) were inoculated into the left calf muscle of male Wistar rats (WKA). Eleven days after the inoculation, the rats were randomly divided into 3 groups: The first group (n = 7) received a single dose of gemcitabine (90 mg/kg, intravenously), the second group (n = 8) received cyclophosphamide (150 mg/kg, intraperitoneally), and the third group (n = 7) was untreated and served as the control group. We injected (99m)Tc-annexin V 48 h after the chemotherapy and then injected (18)F-FDG to all rats 1 h before sacrifice. Six hours after (99m)Tc-annexin V injection, the rats were sacrificed and the organs, including the tumor, were removed and radioactivity was counted. The radioactivities of (18)F and (99m)Tc in the organs were determined using normalization by tissue weight. Histologic evaluation by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method and the immunostaining of glucose transporter-1 (GLUT-1) were also performed to obtain the indices of apoptosis and glucose utilization, respectively. The rate of positively stained cells was calculated and analyzed statistically. RESULTS: After chemotherapy using gemcitabine and cyclophosphamide, the (99m)Tc-annexin V uptake (percentage injected dose per gram x kg [(%ID/g) x kg]; mean +/- SD) in tumor increased significantly (0.062 +/- 0.012 (%ID/g) x kg in the gemcitabine-treated group and 0.050 +/- 0.012 (%ID/g) x kg in the cyclophosphamide group vs. 0.031 +/- 0.005 (%ID/g) x kg in the control group; P < 0.01). In contrast, the (18)F-FDG in tumor decreased significantly (0.483 +/- 0.118 (%ID/g) x kg in the gemcitabine group and 0.583 +/- 0.142 (%ID/g) x kg in the cyclophosphamide group) compared with that in the control group (0.743 +/- 0.084 (%ID/g) x kg; P < 0.01). In addition, (18)F-FDG uptake in tumor negatively correlated with (99m)Tc-annexin V uptake (r = -0.75; P < 0.01). In the gemcitabine and cyclophosphamide groups, the rate of TUNEL positively stained cells was significantly higher than that in the control group (10.2% +/- 1.7% and 8.0% +/- 1.5% vs. 5.2% +/- 1.5%; P < 0.01), whereas the GLUT-1 expression level showed no definite changes in histologic analyses. CONCLUSION: These data indicate that an enhanced apoptotic reaction correlated with suppressed tumor glucose utilization after cytotoxic chemotherapy as determined using radiotracers and histologic evaluation. The increase in (99m)Tc-annexin V and the decrease in (18)F-FDG in tumor can be useful markers for predicting therapeutic outcomes and for prognosis at the early stage of chemotherapy.

Animals↗

PubMed2004

Temporal and topographic profiles of cyclooxygenase-2 expression during 24 h of focal brain ishemia in rats.

Substantial increases in cyclooxygenase-2 (COX-2) mRNA and protein levels were demonstrated in the peri-infarct and focal ischemic areas after 3-24 and 12-24 h, respectively, in rats. In the ischemic core, significant increases in COX-2 mRNA followed 6 h of ischemia, though the peak level was about one-third of that in the peri-infarct area. Increases in COX-2 protein in the ischemic core were not observed during ischemic periods. Diffuse, neuronal COX-2 staining was found in peri-infarct areas as well as in discrete, immunoreactive neurons in the ischemic core. Robust increases in prostaglandin E2 levels in the peri-infarct area were demonstrated following 24 h of ischemia. Prostaglandin production as well as COX-2 expression in ischemic tissues depended on the degree and duration of the reduction in cerebral blood flow.

Analysis of Variance↗

PubMed2004

Use of a standardized uptake value for parametric in vivo imaging of benzodiazepine receptor distribution on [11C]flumazenil brain PET.

To simplify the acquisition protocol of carbon-11 labeled flumazenil (FMZ) positron emission tomography (PET) for distribution volume (DV) images, we attempted to obtain standardized uptake value (SUV) images compatible with DV images, and assessed the applicability of this method in patients with unilateral cerebrovascular diseases (CVD). [(11)C]FMZ PET was performed in ten normal subjects. A DV image and ten sequential 5-min SUV images were generated for each subject. We investigated the correlation coefficient (r) and standard estimation of error (SEE) between the latter ten static images and the DV image using the pixel-by-pixel method, thereby determining the optimum acquisition phase. The same FMZ PET procedure was performed in 15 patients with unilateral CVD. Twenty regions of interest (ROIs) were positioned both in lesioned areas and in symmetrical regions. DV and SUV in the optimum phase for each ROI were calculated to compare the lesion-to-normal (L/N) ratio of DV and that of SUV. The highest r and a low SEE (r=0.957, SEE=633) were observed from 30 to 35 min after tracer administration in the study of normal subjects. A high r (0.945) and a low SEE (0.0438) between the DV L/N ratio and the SUV L/N ratio were obtained in the study of patients. Our study suggests that SUV images acquired from 30 to 35 min after FMZ administration are a suitable alternative to DV images not only in normal subjects but also in patients with unilateral CVD. This simple method seems to be valuable for the identification of altered neuronal activity in patients with CVD.

Adult↗

PubMed2004

Feasibility of 99mTc-annexin V for repetitive detection of apoptotic tumor response to chemotherapy: an experimental study using a rat tumor model.

UNLABELLED: Annexin V (annexin A5), a human protein with a high affinity for phosphatidylserine, labeled with (99m)Tc can detect apoptosis in vivo. In the repetitive detection of apoptosis with (99m)Tc-annexin V, however, the specific binding of annexin V to phosphatidylserine might affect the subsequent detection of apoptosis with this compound. To determine whether there is interference with repetitive doses of annexin V, we evaluated the effects of previous administration of cold annexin V on accumulation of (99m)Tc-annexin V in tumors in an experimental tumor model. METHODS: Rats bearing hepatoma received cyclophosphamide (150 mg/kg, intraperitoneally) 11 d after the tumor inoculation. Cold annexin V (20 microg/kg, intravenously) was administered 24 h before or after the cyclophosphamide treatment (n = 7/group). (99m)Tc-Annexin V was injected intravenously (radioactive dose, 5-23 MBq/kg; mass dose, 20 microg/kg), and radioactivity in tissues was determined 6 h later. RESULTS: Accumulation of (99m)Tc-annexin V in tumors was not significantly affected by previous treatment with cold annexin V before or after chemotherapy. CONCLUSION: These results demonstrate the feasibility of (99m)Tc-annexin V imaging for repetitive detection of apoptosis, which is highly required in the clinical setting.

Animals↗

PubMed2004

Reduced oxidative metabolic response in dysfunctional myocardium with preserved glucose metabolism but with impaired contractile reserve.

UNLABELLED: The recovery of function in myocardium defined as viable by (18)F-FDG PET may differ from that defined by dobutamine stress echocardiography (DSE). The aim of this study was to investigate the difference in the oxidative metabolic response between myocardial segments with preserved contractile reserve (CR) and those without CR, in segments with and without preserved glucose metabolism (GM), using (11)C-acetate PET. METHODS: Twenty patients with previous myocardial infarction (left ventricular ejection fraction, 37.1% +/- 16.5%) underwent dynamic (11)C-acetate PET at rest and during dobutamine (7.5 microg/kg/min) infusion. GM was evaluated using (18)F-FDG PET and CR was evaluated using DSE. Dysfunctional segments were divided into 3 groups: group A (n = 26) with preserved CR and GM, group B (n = 15) without CR but with preserved GM, and group C (n = 41) without CR and without preserved GM. RESULTS: Resting oxidative metabolism (k mono = monoexponential clearance rate) was preserved in group A and group B (0.052 +/- 0.011/min vs. 0.051 +/- 0.012/min, P = not significant) but was reduced in group C (0.040 +/- 0.015/min) (P < 0.03 vs. group A and group B). The change in k mono, as a measure of the metabolic response to low-dose dobutamine, was significantly higher in group A (0.018 +/- 0.012) than that in group B (0.0075 +/- 0.0096, P < 0.03) and group C (0.0080 +/- 0.012, P < 0.005). CONCLUSION: Viable segments based on (18)F-FDG PET have preserved resting oxidative metabolism. However, segments without CR but with preserved GM show a reduction in the oxidative metabolic response to low-dose dobutamine infusion. The decrease in CR may be related to the reduction in the metabolic response to inotropic stimulation despite preservation of tissue viability on (18)F-FDG PET.

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