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Purpose: The incident at the Fukushima Daiichi nuclear power station in 2011 has again raised concerns with the public regarding radiation exposure, especially so in medical workers and patients undergoing treatment involving the use of radiation. Radioisotopes are currently used during sentinel node navigation surgery (SNNS) in operating rooms without radiation monitoring. To re-evaluate the safety issues, the potential effective dose (Epoten) from 99m Tc-tin (-Sn) colloid in breast cancer surgery was estimated and personal dose equivalents, Hp(10) and Hp(0.07), were measured during SNNS. Materials and methods: Seventeen breast cancer patients were enrolled. One day before SNNS, 99m Tc-Sn colloid was injected around the tumor and radiation exposure rates were measured using survey meters. Personal dose equivalents for the surgical workers were measured. Hp(10) and Hp(0.07) for the body and Hp(0.07) for the hands were recorded using semiconductor detectors and ring-type glass dosimeters. Results: The maximum Epoten was 29 μSv per 74 MBq injection. The maximum Hp(10) for the primary and assisting surgeons, nurse, and anesthetist was 3.7, 1.4, 0.3 and 0.6 μSv per SNNS, respectively. The maximum Hp(0.07) for the hands was 100 μSv. Maximum radiocontamination 20 times higher than background (0.05 μSv/h) was detected in bloody gauze. Conclusion: The workers' radiation dose exposure from SNNS was not high, although radiation management such as a temporary cooling off period may be required.

Quantitative small-animal PET of mice requires successful delivery of radiotracers into the venous system. Intravenous injection of radiotracers via lateral tail veins is the most commonly used method of administration and can be technically challenging. Evaluation of the quality of an intravenous injection is necessary to determine whether small-animal PET is quantitatively accurate. The purpose of this study was to evaluate and compare the quality of 50 consecutive intravenous injections into mouse tail veins using both quantitative and qualitative methods. Methods: During 18 F-FDG intravenous injection, qualitative assessment of the injection was performed and classified according to specific criteria as good, intermediate, or poor. Small-animal PET scans of the body and tail were acquired, and tail injection sites were quantitatively assessed in terms of percentage injected dose per gram and classified as low, medium, or high uptake of 18 F-FDG. Qualitative and quantitative methods were compared. To assess baseline amounts of 18FFDG in the tail without a tail injection, 3 additional mice were injected by the intraperitoneal method, imaged, and quantitatively assessed in the same manner. The in vivo imaging data were validated on 7 additional mice by sacrificing them after scans, removing their tails, rescanning the tails, and then measuring the tail radioactivity ex vivo in a g-counter and correlating it with the in vivo amount. Results: Validation of in vivo imaging to ex vivo data yielded an excellent correlation, with an r 2 value of 0.95. Comparison of qualitative and quantitative methods yielded 45 matching results (42 good and low, 2 intermediate and medium, and 1 poor and high). There were 5 cases of mismatching results (1 false-negative and 4 false-positive) between qualitative and quantitative methods. Low-uptake tail injections were comparable to the intraperitoneal injection values. Using qualitative methods, accuracy was true 90% (45/50) of the time. The overall rate of successful intravenous injections was 92% (46/50) using quantitative methods. Conclusion: Qualitative assessment is all that is necessary if the intravenous injection is classified as good. In intermediate, poor, or uncertain classifications, a scan of the tail should be performed for quantitative assessment.

Brain-specific angiogenesis inhibitor 2 (BAI2) is a member of adhesion-G protein-coupled receptors (GPCRs). BAI2 is dominantly expressed in the brain and its physiological ligands and functions are still unclear. Adhesion-GPCRs, including BAI2, commonly have a long N-terminal extracellular region (ECR) containing the GPCR proteolysis site (GPS) and the cleavage of the ECR at the GPS domain is suspected to be important for their function. In this study, we analyzed the proteolytic processing of BAI2 and its activation mechanism. Several cleaved C-terminal fragments of BAI2 were identified in mouse hippocampus. We confirmed that mutation in the GPS domain caused inhibition of the proteolysis of BAI2, which indicated the possibility that BAI2 was cleaved at the GPS domain. The association of the ECR putatively cleaved at the GPS domain and the C-terminal seven-transmembrane (7TM) fragment was detected by co-immunoprecipitation. We also found that furin prohormone convertase cleaved BAI2 at another site in the ECR. Additionally, the C-terminal fragment cleaved at the GPS domain specifically activated the nuclear factor of activated T-cells (NFAT) pathway. These results suggest that BAI2 is a functional GPCR regulated by proteolytic processing and activates the NFAT pathway.

The transition of microglia from the normal resting state to the activated state is associated with an increased expression of peripheral benzodiazepine receptors (PBR). The extent of PBR expression is dependent on the level of microglial activation. A PBR ligand, [11C]PK11195, has been used for imaging of the activation of microglia in vivo. We evaluated whether [11C]PK11195 PET can indicate differences of microglial activation between no treatment and lipopolysaccharide (LPS) treatment in a rat artificial injury model of brain inflammation. On day 1, a small aliquot of absolute ethanol was injected into the rat right striatum (ST) to produce artificial brain injury. On day 3, MRI scans were performed to evaluate and select rats showing a similar degree of brain injury. Then LPS or vehicle was administered intraperitoneally. On day 4, PET scans were performed after a bolus injection of [11C]PK11195. Eleven rats (7 LPS administered rats, 4 LPS non-administered rats) were evaluated. We used uptake ratios of the integral of right and left striatum from 0 to 60 min as an estimate of PBR distribution volume (V 60). The number of activated microglia and mRNA expression of inflammatory cytokines (TNFα, IL-1β) were assessed by isolectin-B4 staining and RT-PCR, respectively. Right/left ST V 60 ratios of LPS group were significantly higher than those of non-LPS group (P

To investigate whether [(11)C]PK-11195, a specific peripheral benzodiazepine receptors (PBRs) ligand for positron emission tomography (PET), can show activated microglia in a rat brain injury model.On day 1, ethanol was injected into the rat's right striatum (ST) using a stereotaxic operative procedure. On day 3, head magnetic resonance imaging (MRI) scans for surgically treated rats were performed to evaluate ethanol injury morphologically. On day 4, dynamic PET scans (17 injured rats and 7 non-injured controls) were performed for 60 min with an animal PET scanner under chloral hydrate anesthesia following a bolus injection of [(11)C]PK-11195 through tail vein. Because PBRs are present throughout the brain, there is no suitable receptor-free reference region. The reference tissue model may not be applicable because of low target to background ratio for low affinity of [(11)C]PK-11195 to PBRs. We evaluated the PBRs binding with regions of interest (ROIs)-based approach to estimate total distribution volume (V). We used an integral from 0 min to 60 min (V (60)) as an estimate of V. On the coronal PET image, ROIs were placed on bilateral ST. Differences in right/left ST V (60) ratios between lesioned and unlesioned control rats were compared using unpaired t tests. Immunohistochemical staining was performed for confirming the presence of activated microglia following decapitation on the PET experiment day.The right/left ST V (60) ratios in lesioned rats (1.07 +/- 0.08) were significantly higher than those in unlesioned control rats (1.00 +/- 0.06, P0.05). On immunohistochemical staining, activated microglia were exclusively observed in the injured right ST but not in the noninjured left ST of the injury rats and the bilateral ST of the non-injured control rats.These results suggest that [(11)C]PK-11195 PET imaging would be a useful tool for evaluating microglial activation in a rat brain injury model.

Hepatocyte nuclear factor 1 alpha (HNF1alpha) is a liver enriched homeodomain-containing transcription factor that has been shown to transactivate the promoters of several cytochrome P450 (CYP) genes, including CYP2E1, CYP1A2, CYP7A1, and CYP27, in vitro. In humans, mutations in HNF1alpha are linked to the occurrence of maturity onset diabetes of the young type 3, an autosomal dominant form of non-insulin-dependent diabetes mellitus in which afflicted subjects generally develop hyperglycemia before 25 years of age. Mice lacking HNF1alpha also develop similar phenotypes reminiscent of non-insulin-dependent diabetes mellitus. To investigate a potential role for HNF1alpha in the regulation of CYPs in vivo, the expression of major CYP genes from each family was examined in the livers of mice lacking HNF1alpha. Analysis of CYP gene expression revealed marked reductions in expression of Cyp1a2, Cyp2c29 and Cyp2e1, and a moderate reduction of Cyp3a11. In contrast Cyp2a5, Cyp2b10 and Cyp2d9 expression were elevated. There are also significant changes in the expression of genes encoding CYPs involved in fatty acid and bile acid metabolism characterized by a reduction in the expression of Cyp7b1, and Cyp27 as well as elevations in Cyp4a1/3, Cyp7a1, Cyp8b1, and Cyp39a1 expression. These results point to a critical role for HNF1alpha in the regulation of CYPs in vivo and suggest that this transcription factor may have an important influence on drug metabolism as well as lipid and bile acid homeostasis in maturity onset diabetes of the young type 3 diabetics.

Purpose: Because of the recent innovative growth in computer technology, digital imaging, and the Internet, we can take advantage of these facilities for education and clinical work in nuclear medicine. We developed a tele-nuclear medicine conference system with electronic mail (e-mail) on the Internet.Methods: Twenty-one physicians (20 radiologists, 1 neurologist), 6 technologists and 2 medical students in six university hospitals (Japan 5, Canada 1), 5 local hospitals in Japan participated in this project. We used digital still cameras (330k pixels) equipped with a floppy disk drive and 10 x optical zoom to digitize images with JPEG compression (640×480 matrix). The images were attached to e-mail messages (containing a brief description of each case). The mail was sent simultaneously to all members on the mailing list. Scintigram and SPECT images as well as other radiological images were sent by e-mail. Reply mails about each case were sent to all members via the mailing list.Results: During a period of 6 months, 18 cases (tumor/infection: 7, bone: 6, cardiovascular: 1, neurology; 3, endocrine: 1) with 144 e-mails (average 5.6/case) were submitted to the conference. The average period of discussion was 15.6 days. The number of attached images was 1 to 9 (average, 4.2/e-mails). JPEG compression rate was 1/10 to 1/20. The quality of the images was good enough for discussion. Some cases required additional images for further discussion.Conclusion: Our tele-nuclear medicine conference with an electronic mailing list and digital camera was simple and low-cost. The conference system was useful for education and clinical work.

The C57BL/6, 129, and B6,129 mouse strains or stocks have been commonly used to generate targeted mutant mice. The pathology of these mice is not well characterized. In studies of these aging mice, we found high incidences of hyalinosis (eosinophilic cytoplasmic change) in the glandular stomach, respiratory tract, bile duct, and gall bladder of B6,129 CYP1A2-null and wild-type mice as well as in both sexes of the background 129S4/SvJae strain. The gastric lesions of the glandular stomach were found in 95.7% of female CYP1A2-null mice as well as in 45.7% of female 129S4/SvJae animals. The eosinophilic protein isolated from characteristic hyaline gastric lesions was identified as Ym2, a member of the chitinase family. Immunohistochemistry, using rabbit polyclonal antibodies to oligopeptides derived from the Ym1 sequence, detected focal to diffuse reactivity within both normal and abnormal nasal olfactory and respiratory epithelium, pulmonary alveolar macrophages, bone marrow myeloid cells, and the squamous epithelium of the forestomach and epithelium of the glandular stomach. Alveolar macrophages in acidophilic pneumonia, a major cause of death of aging 129 mice, and in mice with the me mutation also were highly immunoreactive. The possible cause of this protein excess in gastric and other lesions and its possible functions are discussed.

Microsomal epoxide hydrolase (mEH) is a conserved enzyme that is known to hydrolyze many drugs and carcinogens, and a few endogenous steroids and bile acids. mEH-null mice were produced and found to be fertile and have no phenotypic abnormalities thus indicating that mEH is not critical for reproduction and physiological homeostasis. mEH has also been implicated in participating in the metabolic activation of polycyclic aromatic hydrocarbon carcinogens. Embryonic fibroblast derived from the mEH-null mice were unable to produce the proximate carcinogenic metabolite of 7,12-dimethylbenz[a]anthracene (DMBA), a widely studied experimental prototype for the polycylic aromatic hydrocarbon class of chemical carcinogens. They were also resistant to DMBA-mediated toxicity. Using the two-stage initiation-promotion skin cancer bioassay, the mEH-null mice were found to be highly resistant to DMBA-induced carcinogenesis. In a complete carcinogenesis bioassay, the mEH mice were totally resistant to tumorigenesis. These data establish in an intact animal model that mEH is a key genetic determinant in DMBA carcinogenesis through its role in production of the ultimate carcinogenic metabolite of DMBA, the 3,4-diol-1,2-epoxide.

Patients with aneurysmal subarachnoid hemorrhage (SAH) frequently have deficits in learning and memory that may or may not be associated with detectable brain lesions. We examined mediators of long-term potentiation after SAH in rats to determine what processes might be involved. There was a reduction in synapses in the dendritic layer of the CA1 region on transmission electron microscopy as well as reduced colocalization of microtubule-associated protein 2 (MAP2) and synaptophysin. Immunohistochemistry showed reduced staining for GluR1 and calmodulin kinase 2 and increased staining for GluR2. Myelin basic protein staining was decreased as well. There was no detectable neuronal injury by Fluoro-Jade B, TUNEL, or activated caspase-3 staining. Vasospasm of the large arteries of the circle of Willis was mild to moderate in severity. Nitric oxide was increased and superoxide anion radical was decreased in hippocampal tissue. Cerebral blood flow, measured by magnetic resonance imaging, and cerebral glucose metabolism, measured by positron emission tomography, were no different in SAH compared with control groups. The results suggest that the etiology of loss of LTP after SAH is not cerebral ischemia but may be mediated by effects of subarachnoid blood such as oxidative stress and inflammation.

Effects of folic acid (FA) and folinic acid (FNA) on the embryotoxicity of pyrimethamine (PYR), an antifolate drug, were examined in mice. PYR and FA were administered orally, and FNA was injected intraperitonially for 7 days from day 9 to 15 of pregnancy. The incidence of embryotoxicity including intrauterine deaths and malformations, was 33.5 % in the PYR 50 mg/kg/day group. However, all the fetuses were resorbed in the PYR 50 + FA 50 mg/kg/day group, and FA potentiated the embryotoxicity of PYR. On the contrary, FNA reduced the embryotoxicity of PYR (PYR 50 + FNA 10mg/kg/day; 8.5%). Plasma concentrations of PYR and 5-methyltetrahydrofolic acid (5MF), a principal form of folate in plasma, were determined after single oral administration of PYR 50 mg/kg with or without FA 50 mg/kg to non-pregnant mice. Plasma 5MF concentration decreased drastically in the group receiving PYR with FA, compared with the PYR alone group. The pharmacokinetics of PYR were not affected by co-administration of FA. Therefore, we consider that the potentiated embryotoxicity of PYR by oral FA results from a decrease of plasma 5MF concentration in dams.

Brain-specific angiogenesis inhibitor 2 (BAI2) is a transmembrane protein that is predominantly expressed in the brain. Although BAI2 is supposed to correlate with antiangiogenesis in the brain, its psychiatric function is still unclear. In this study, we examined the influence of BAI2 gene disruption on mood-related behavior using BAI2-deficient mice. BAI2-deficient mice showed significant antidepressant-like behavior in the social defeat test and in the tail suspension test compared with wild-type mice. On the other hand, BAI2-deficient mice had normal basal locomotor activity in the home cage and in the open field test, and normal learning ability and memory retention in the Morris water maze test. Additionally, we found that hippocampal cell proliferation in BAI2-deficient mice was higher than that in wild-type mice. These results indicate that BAI2 has an important role related to depression and influences the hippocampal neurogenesis. BAI2 may be a novel therapeutic target for mood-related disorders.

The relationship between pyrimethamine (PYR) teratogenesis and the plasma level of 5-methyltetrahydrofolic acid (5MF), known as an active form of folate in plasma, was studied in rats using an HPLC-ECD method for 5MF determination. The rat received, for 5 days, in-feed PYR with or without folic acid (FA), which was previously reported as a potentiator of PYR teratogenesis. PYR alone caused a dose-dependent decrease in the plasma 5MF level after the 5 day dosings. A potentiated decrease in the 5MF level was observed after the concomitant dosing of PYR with FA. The concomitant dosing of PYR 1.6 mg/kgBW/day (subteratogenic dose of PYR alone) with FA 50 mg/kg/day, which was 100% teratogenic dose in our previous report, decreased the 5MF level more than that after the dosing of PYR 3.6 mg/kg/day alone (100% teratogenic dose of PYR alone). The sequential changes of the plasma 5MF level after the single oral dosing of PYR 3.6 mg/kg with or without oral FA 50 mg/kg also revealed a strong potentiative effect of oral FA on the 5MF-level-lowering effect of PYR. These results indicate that a decrease in the plasma 5MF level may be related to PYR teratogenesis.

The decrease of plasma 5-methyltetrahydrofolic acid (5-MF) levels, postulated as an indicator of folate status, was studied following the administration of both methotrexate (MTX) alone and MTX with folic acid (FA) using rats as our experimental model. Blood and urine samples were serially collected over a 9 hr period after the administration of MTX, MTX with FA and from a control group to examine the plasma kinetics and the renal clearance of 5-MF. The pharmacokinetics of MTX and the plasma protein binding of 5-MF were also examined. The concentrations of these analytes were assayed using high performance liquid chromatography (HPLC). MTX administration produced decreased plasma 5-MF levels. This observed decrease was potentiated by oral FA administration, suggesting that the folate status was more severely altered by the coadministration of FA. The renal clearance of 5-MF also increased dose-dependently with FA (0.05-5 mg/kg) coadministration. The plasma protein binding of 5-MF was not affected by the FA administration, which indicates that the fraction of 5-MF that was filtered through the glomerular apparatus appeared to be unchanged. In addition, the pharmacokinetic profiles of MTX also appeared not to be affected by the addition of FA. We conclude that the inhibition of reabsorption of 5-MF in the renal tube by concurrent administration of MTX and FA must be one of the causal factors for the demonstrated decrease in the plasma 5-MF levels in rats.

A 78-year-old woman with vulvar Paget's disease was examined with lymphoscintigraphy. Neither regional nor distant metastases nor inguinal or femoral lymph node metastases were evident clinically. Sentinel lymph nodes were identified before and during operation in both groin areas. The patient underwent selective sentinel lymph node sampling with a hand-held gamma probe and local vulvectomy. Histopathologic examination of the specimen revealed intraepithelial Paget's disease, and there was no evidence of cancer (stage T2N0M0). Postoperative lymphedema did not occur. The sentinel lymph node procedure for vulvar Paget's disease may be a promising technique for minimally invasive surgery.

Pyrimethamine (PYR), an inhibitor of dihydrofolate reductase, has been known to induce megaloblastic anemia in human. The dosing of folic acid (PteGlu) or folinic acid (5-formyltetrahydrofolic acid) is recommended for the treatment of PYR-induced anemia, PYR has been also known to be a potent teratogen1,2,3,4. Therefore, we studied the effects of PteGlu and folinic acid on the embryotoxicity of PYR using rats and mice. The plasma level of 5-methyltetrahydrofolic acid (5-CH3-H4PteGlu) was also studied. 5-CH3-H4PteGlu is the principal active folate in plasma and its plasma level reflects folate status in the body.

The effects of folic acid (FA) and folinic acid (FNA) on the tera-togenicity of the antifolate drug pyrimethamine (PYR) were examined in rats. PYR and FA were orally administered with mashed feed. FNA was intraperitoneal-ly injected. The drugs were administered for 5 days of day 11–15 of gestation. Six groups were made; G-I PYR 1.6 (mg/kg/day), G-II PYR 3.6, G-HI PYR 1.6 + FA 50, G-IV PYR 3.6 + FNA 12, G-V FA 50, G-VI control. No malformations were found in G-I, IV, V and VI. All fetuses in G-II and HI had malformations. Main malformations in G-II and III were cleft palate and brachygnathia. Accordingly it might be demonstrated that the teratogenicity of PYR was potentiated by concurrent FA in rats.