Temporal changes of the ambient dose rate in the forest environments of Fukushima Prefecture following the Fukushima reactor accident.

Approximately 70% of the total land area affected by the fallout from the Fukushima accident is forested, and therefore monitoring of the ambient dose rate in forest environments is essential to ensure that the population and natural habitats of these areas are protected from radiological hazards. However, there are little available data on the ambient dose rate for forest environments. This study investigated temporal changes in the ambient dose rate in different forest environments of Fukushima Prefecture. We conducted repeated measurements of the ambient dose rate in 2014 and 2016 at the same measurement points as those used by the Ministry of Agriculture, Fishery and Forestry of Japan (MAFF) in 2011. The measurements revealed that the decreasing trend in the ambient dose rate varied among the different forest types and time periods. The ambient dose rate in EGC decreased slower than that induced by the physical decay of radiocesium for the period of 2011-2014. However, such slow declining trend of ambient dose rate was likely followed by quick reduction during the following years (2014-2016 and 2011-2016). On the other hand, in MBL and DBF forests, the ambient dose rate decreased 10-20% faster than that induced solely by physical decay of radiocesium for the observation period 2011-2016.

Temporal changes of the ambient dose rate in the forest environments of Fukushima Prefecture following the Fukushima reactor accident.

Approximately 70% of the total land area affected by the fallout from the Fukushima accident is forested, and therefore monitoring of the ambient dose rate in forest environments is essential to ensure that the population and natural habitats of these areas are protected from radiological hazards. However, there are little available data on the ambient dose rate for forest environments. This study investigated temporal changes in the ambient dose rate in different forest environments of Fukushima Prefecture. We conducted repeated measurements of the ambient dose rate in 2014 and 2016 at the same measurement points as those used by the Ministry of Agriculture, Fishery and Forestry of Japan (MAFF) in 2011. The measurements revealed that the decreasing trend in the ambient dose rate varied among the different forest types and time periods. The ambient dose rate in EGC decreased slower than that induced by the physical decay of radiocesium for the period of 2011-2014. However, such slow declining trend of ambient dose rate was likely followed by quick reduction during the following years (2014-2016 and 2011-2016). On the other hand, in MBL and DBF forests, the ambient dose rate decreased 10-20% faster than that induced solely by physical decay of radiocesium for the observation period 2011-2016.

Evaluation of motion correction processing in equine bone scintigraphy by Scheffé's method of paired comparisons.

Equine bone scintigraphy is usually performed with horses in standing position under sedation. However, swaying motion often leads to poor-quality images. To examine the usefulness of motion correction (MC) processing, equine bone scintigrams were evaluated using Scheffé's method of paired comparisons. A significant difference in evaluation scores was detected by analysis of variance (F test, P<0.01). According to all observers, Yardstick analysis scores were higher for images use of MC processing than for those no use of MC processing, for all parts. Overall scores of 5 observers were as follows: without MC 100% acquisition time (AT, lowest), use of MC with 25% AT, MC 50% AT, MC 75% AT and MC 100% AT (highest). Thus, MC processing shortens AT in equine bone scintigraphy, and it contributes to a reduction in the external radiation exposure of nurses/technicians.

An autoradiogram of skeletal muscle from a pig raised on a farm within 20 km of the Fukushima Daiichi nuclear power plant.

We utilized autoradiography to visualize radioactive contamination in the skeletal muscles of a pig raised within 20 km of the Fukushima Daiichi nuclear power plant following the nuclear accident. The autoradiogram of control muscle showed relatively homogenous exposure. In contrast, the autoradiogram of affected muscle showed a heterogeneous and sporadically dense imaging pattern. Photo luminescence densities of the affected and control muscles were 3.89 ± 0.67 and 2.13 ± 0.43 PSL/mm(2), respectively. This difference indicated that radioactive cesium was distributed in the skeletal muscle of the affected pig.

Early-stage bioassay for monitoring radioactive contamination in living livestock.

Soil samples from the ground surface and feces and blood from a mixed-breed male pig were collected on April 10, 2011 at a farm within 20 km of the Fukushima Daiichi nuclear power plant. The radioactivity of each sample was measured using a Ge semiconductor detector. Despite the fact that the pig had been fed non-contaminated imported feed, (131)I, (134)Cs and (137)Cs were detected in the feces, and (134)Cs and (137)Cs were detected in the blood clots. Because it is considerably difficult to measure radioactive contamination in the edible muscle of living livestock, bioassays are an option for the screening of radioactive contamination in living livestock to ensure food safety.

[Guideline draft of appropriate use of 131I-MIBG for internal radiotherapy of neuroendocrine tumors].

I3I-MIBG has been used for therapy of unresectable neuroendocrine tumors including malignant pheochromocytomas and neuroblastomas in foreign countries since the '80s when its clinical therapeutic trials were initiated. In Japan, 131I-MIBG for therapy has not been approved by Health and Labor Ministry, however, personally imported 131I-MIBG is now available in limited institutions for therapeutic purpose. This guideline draft was made to provide the information about 131I-MIBG radiotherapy including related side effects for doctors, nurses, patients and their families, to prevent the adverse effects of this therapy and to protect radiation injuries from this tracer. The appendices were also attached concerning practical guidance for attending physicians, patient management and referring physicians for their conveniences.

Possible mechanism for species difference on the toxicity of pivalic acid between dogs and rats.

In a high dose toxicity study of pivalic acid (PA), PA caused skeletal muscle disorder in dog, and a significant increase of pivaloyl carnitine (PC) was observed in canine muscle, but not in rat muscle. In order to understand species difference of the toxicity of PA, we compared the in vitro metabolism of PA among dog, rat and rabbit, especially focussing on the carnitine conjugate. Canine muscle showed low, but significant carnitine conjugating activity, while that of rat was negligible. Canine kidney mitochondria had significant activity in the pivaloyl CoA synthesis (7 nmol/mg protein/h), but muscle mitochondria showed only trace activity. Both kidney and muscle mitochondria displayed similar carnitine acyltransferase activity (2-3 nmol/mg protein/h) towards pivaloyl CoA. On the other hand, with respect to the activity of carnitine acyltransferase in the reverse direction using PC as substrate, canine muscle mitochondria showed higher activity than that of kidney mitochondria. This means that PC is not the final stable metabolite, but is converted easily to pivaloyl CoA in canine muscle. These results suggest one of the possible mechanisms for canine selective muscle disorder to be as follows. Only canine muscle can metabolize PA to its carnitine conjugate slowly, but significantly. In canine muscle, PC is not the final stable metabolite; it is easily converted to pivaloyl CoA. As carnitine conjugation is thought to be the only detoxification metabolic route in canine muscle, under certain circumstances such as carnitine deficiency, the risk of exposure with toxic pivaloyl CoA might increase and the CoASH pool in canine muscle might be exhausted, resulting in toxicity in canine muscle.

Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats.

The Ministry of Health and Welfare, Japan banned coadministration of carbapenems, such as panipenem/betamipron (PAPM), meropenem (MEPM), and valproic acid (VPA) because clinical reports have indicated that the coadministration caused seizures in epileptic patients due to lowered plasma levels of VPA. In this study, we have clarified the mechanism of the drug-drug interaction using PAPM, MEPM, and doripenem [S-4661; (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-caboxylic acid monohydrate], a newly synthesized carbapenem. In vitro experiments using monkey liver slices suggested that the apparent synthetic rate of VPA glucuronide (VPA-G) increased in the presence of carbapenems. However, no such increase was observed in the experiment using monkey liver microsomes. Although no increase of uridine 5'-diphosphate D-glucuronic acid was found in monkey liver slices in the presence of carbapenems, potent inhibitory activity of carbapenems for the hydrolysis of VPA-G was found in monkey and rat liver homogenate. In vivo hydrolysis of VPA-G was clearly shown by the existence of VPA in plasma after dosing of VPA-G to rats, and its inhibition by carbapenems was also clearly shown by the negligible levels of VPA in rat plasma after coadministration of carbapenems and VPA-G. These results clearly indicate one of the important causes of drug interaction as follows: carbapenems would inhibit the hydrolytic enzyme, which is involved in the hydrolysis of VPA-G to VPA, resulting in a decrease of plasma concentration of VPA.

Study on the practical use of quantitative whole-body auto-radioluminography.

The practical use of quantitative radioluminography (RLG) using reading system BAS 2000 (Fuji Photo Film Ltd., Tokyo, Japan) and STORM 820 (Molecular Dynamics, USA) was examined using a chemical matrix as an internal standard, which offers the benefits of being preservative, inexpensive, and easy to handle. The results were as follows: 1. As the water content is within the range of 65-80% for most organs and tissues, we selected a chemical matrix, Tissue-TEK containing 85% water, as a base for the preparation of a standard curve. 2. The calibration curve prepared using Tissue-Tek as the internal standard was compared with the calibration curve using liver paste preparations as the internal standard. The results showed good linearity in both cases, with almost no difference in the slopes of the two calibration curves. 3. The PSL-BG or MD counts/pixel-BG values of the lowest radioactivity concentration measured for small areas of the region of interest (ROI) showed large fluctuations with both BAS 2000 and STORM 820, but the fluctuation became less than 15% at above 25 mm(2) of ROI. 4. The value of dpm/g calculated using the calibration curve prepared from Tissue-Tex internal standards showed a very good correlation with the values of dpm/g obtained by scraping off the tissue from the remaining block and conducting measurements with a liquid scintillation counter.

Enzymology of a carbonyl reduction clearance pathway for the HIV integrase inhibitor, S-1360: role of human liver cytosolic aldo-keto reductases.

S-1360, a 1,3-diketone derivative, was the first HIV integrase inhibitor to enter human trials. Clinical data suggested involvement of non-cytochrome P450 clearance pathways, including reduction and glucuronidation. Reduction of S-1360 generates a key metabolite in humans, designated HP1, and constitutes a major clearance pathway. For characterization of subcellular location and cofactor dependence of HP1 formation, [(14)C]-S-1360 was incubated with commercially available pooled human liver fractions, including microsomes, cytosol, and mitochondria, followed by HPLC analysis with radiochemical detection. Incubations were performed in the presence and absence of the cofactors NADH or NADPH. Results showed that the enzyme system responsible for generation of HP1 in vitro is cytosolic and NADPH-dependent, implicating aldo-keto reductases (AKRs) and/or short-chain dehydrogenases/reductases (SDRs). A validated LC/MS/MS method was developed for investigating the reduction of S-1360 in detail. The reduction reaction exhibited sigmoidal kinetics with a K(m,app) of 2 microM and a Hill coefficient of 2. The ratio of V(max)/K(m) was approximately 1 ml/(min mg cytosolic protein). The S-1360 kinetic data were consistent with positive cooperativity and a single enzyme system. The relative contributions of AKRs and SDRs were examined through the use of chemical inhibitors. For these experiments, non-radiolabeled S-1360 was incubated with pooled human liver cytosol and NADPH in the presence of inhibitors, followed by quantitation of HP1 by LC/MS/MS. Quercetin and menadione produced approximately 30% inhibition at a concentration of 100 microM. Enzymes sensitive to these inhibitors include the carbonyl reductases (CRs), a subset of the SDR enzyme family predominantly located in the cytosol. Flufenamic acid and phenolphthalein were the most potent inhibitors, with > 67% inhibition at a concentration of 20 microM, implicating the AKR enzyme family. The cofactor dependence, subcellular location, and chemical inhibitor results implicated the aldo-keto reductase family of enzymes as the most likely pathway for generation of the major metabolite HP1 from S-1360.