DISTRIBUTION OF IODINE-127 IN MARINE ORGANISMS FROM COASTAL WATERS AROUND AOMORI, JAPAN.

We measured the concentrations and determined the distribution of the stable isotope 127I in the marine organisms. Marine fish were collected from the Pacific Ocean near Aomori, Japan. The mean 127I concentrations in the muscle of marine fish ranged from 0.67 µg g-1-wet weight (ww) in cherry salmon to 0.84 µg g-1-ww in fat greenling. Among the tissues measured, the muscle showed the lowest levels of 127I in all fish species. The highest 127I concentration in the tissues of marine fish was observed in the ovary of fat greenling. The mean 127I concentration in the of Japanese scallop ranged from 0.06 µg g-1-ww in adductor muscle to 5.49 µg g-1-ww in mid-gut gland. The 127I concentrations in seaweeds were 67 µg g-1-dry weight (dw) in sea lettuce and 1783 µg g-1-dw in kombu. Thus, the distribution of 127I concentration in marine organisms varied considerably depending on the tissue.

A phase I/IIa trial of atorvastatin in Japanese patients with acute Kawasaki disease with coronary artery aneurysm: Study protocol of a multicenter, single-arm, open-label trial.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis complicated with coronary artery abnormalities (CAAs). Intravenous immunoglobulin reduces the occurrence of CAAs, but significant number of KD patients with CAAs still exists. Thus, new approaches to prevent and attenuate CAAs are warranted. Atorvastatin has been shown to promote endothelial cell homeostasis and suppress vascular inflammation and has received enthusiasm as a potentially new candidate treatment for KD. In the United States, a phase I/IIa dose-escalation study of atorvastatin in KD patients with CAAs demonstrated the safety and pharmacokinetic data of atorvastatin. However, due to the uncertainty in the application of these results to other populations, we aim to examine the tolerability and generate pharmacokinetics data in Japanese KD patients. METHODS: This is a multicenter, single-arm, open-label, phase I/IIa study of atorvastatin in acute KD patients with CAAs in Japan. A minimum of 9 and a maximum of 18 KD patients (2 years-17 years old) will be recruited for a 3 + 3 dose-escalation study of a 6-week course of atorvastatin (0.125-0.5 mg/kg/day). The primary outcome will be safety of atorvastatin. The secondary outcomes will be pharmacokinetics of atorvastatin, activity of atorvastatin and echocardiographic assessment of CAAs. The activity of atorvastatin will include assessment of C-reactive protein or high sensitivity C-reactive protein and white blood cell levels. DISCUSSION: This study will provide evidence of the safety, tolerability, and pharmacokinetics of atorvastatin in Japanese KD patients and may lead new standard therapy for acute-phase KD associated with CAA complications. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCTs031180057). Registered December 19, 2018, https://jrct.niph.go.jp/en-latest-detail/jRCTs031180057.

Polypharmacy is associated with malnutrition and activities of daily living disability among daycare facility users: A cross-sectional study.

ABSTRACT: Polypharmacy influences malnutrition and activities of daily living (ADL) in older individuals owing to side effects such as anorexia. This study aimed to examine whether polypharmacy (5 or more drugs) is associated with malnutrition and ADL disability among daycare facility users.This cross-sectional study was performed in a daycare facility specializing in rehabilitation. Malnutrition was defined according to the Global Leadership Initiative on Malnutrition criteria and ADL disability according to the "criteria for determination of the daily life independence level (bedridden level) of elderly with disabilities."In total, 103 of the 134 included individuals were analyzed. Thirty-three (32.0%) participants were malnourished, 46 (44.7%) had ADL disability, 58 (56.3%) qualified as cases of polypharmacy, and 9 (8.7%) experienced loss of appetite. Multivariable logistic regression analysis showed that polypharmacy was independently associated with malnutrition and ADL disability. Separate analyses of each type of drug revealed that proton pump inhibitors (that impair protein absorption and assimilation), anticonstipation drugs, and antihypertensive drugs were associated with malnutrition, whereas proton pump inhibitors, anticonstipation drugs, antidyslipidemia drugs, and antidiabetic drugs were associated with ADL disability. The only factor related to anorexia was the loss of pleasure of eating, which in turn was related to psychological stress.The side effects of polypharmacy among individuals with malnutrition and ADL disability may include impaired protein absorption and assimilation caused by proton pump inhibitors, but not anorexia. Further multicenter prospective studies are required to confirm these findings.

Flux and pathway of iodine dissolution from brackish lake sediment in the northeast of Japan.

Sediment is one of the most important entities controlling the environmental dynamics of iodine. We previously evaluated the dissolution flux of iodine from aquatic sediment to its overlying water in a brackish lake through an incubation experiment with a sediment core sample, reporting the regulation factors of this flux, such as the temperature and oxygenic conditions. In this study, factors controlling the seasonal variation in the dissolution flux of iodine were investigated via an incubation experiment using the sediment core samples collected in autumn and summer. The dissolution flux in this study was significantly smaller than that reported in our previous study. The iodine concentration detected in the overlying water of the sediment during incubation in this study was positively correlated with the concentrations of some inorganic ions, such as Na+, Cl-, and SiO42-, while these correlations were not confirmed in our previous study. As the dissolution of sedimentary iodine includes two pathways, which are the diffusion of sedimentary pore water and degradation of organic matter on surface sediment, correlations potentially indicate that the dissolution flux estimated in this study has a larger contribution from sedimentary pore water than that in our previous study. In addition, the higher flux estimated in our previous study was considered to be caused by the larger contribution from iodine derived from the degradation of phytoplanktonic organic matter on surface sediment. Assuming that the dissolution fluxes estimated in the previous and present studies are representative of the fluxes during and excluding the high productivity season in Lake Obuchi, respectively, we estimated the annual flux at 2.7 g y-1 m-2, which is comparable with our previous estimation.

Evaluation of radioiodine (129I) dissolution from sediment of a brackish lake beside a spent nuclear fuel reprocessing plant in Japan.

Dissolution fluxes of stable (127I) and radioactive (129I) isotopes of iodine from a brackish lake sediment beside a spent nuclear fuel reprocessing plant in Japan were evaluated through two kinds of experiments: incubation using a sediment core sample for 24 h, and observation of 127I and 129I concentrations in sedimentary pore water. For 127I, the dissolution flux evaluated in the incubation experiment was comparable with that obtained from the vertical gradient of 127I concentration in pore water in the observation experiment. This suggests that degradation of organic matter in the surface sediment is an important source of dissolved 127I found in the water. For 129I, the dissolution flux estimated in the incubation experiment showed negative values, indicating the transfer of 129I to the sediment from the overlying water (i.e., absorption). Moreover, the flux evaluated from the observation experiment was positive. This result suggests that degradation of organic matter in the surface sediment is scarcely important to the supply of 129I from the sediment to the water in the studied lake. The dissolution flux of 129I estimated in the observation experiment was smaller than the absorption flux of 129I in the incubation experiment. This potentially indicates that the dissolution of sedimentary 129I does not significantly change 129I concentrations in the water and sediment of the lake. This hypothesis was consistent with previous research conducted for the studied lake.

Short-term metabolism of biologically incorporated 125I ingested by olive flounder (Paralichthys olivaceus).

Iodine-129 with a long half-time of 1.6 × 107 y was discharged into the Pacific Ocean during the final safety tests of the first commercial nuclear fuel reprocessing plant in Japan, at Rokkasho, Aomori Prefecture. Olive flounder (Paralichthys olivaceus) is an important fishery along this coast. It is necessary to determine whether 129I accumulates in this species to assess the possible public acceptance. We developed a short-term metabolism model of 125I in the flounder using retention data for 1-6 days after the olive flounder had ingested a freshwater fish species, medaka (Oryzias latipes), that had been labeled with 125I by keeping them in water containing 125I for 7 days. A single compartment model constructed from whole-body retention data for 125I in the olive flounder, excluding the gastrointestinal tract and its contents, revealed a biological half-time of 2.9 days for 125I. When the gill and other tissues were separated to individual compartments, the biological half-time in the gill was three times longer than that in the other tissue, though the half-time in the gill is not statistically significant. The distribution of 125I among various tissues in the flounder 6 days after the ingestion of labeled medaka once a day for 6 days differed from that of stable I, suggesting that the biological half-time is longer in certain tissues. Further study is necessary to elucidate the metabolism of radioiodine in the flounder.

Evaluation of dissolution flux of iodine from brackish lake sediments under different temperature and oxygenic conditions.

Dissolution flux of iodine from aquatic sediments in a brackish lake (Lake Obuchi), facing the Pacific Ocean and adjacent to a nuclear fuel reprocessing plant in northeast Japan, was evaluated using incubation experiments on sediment core samples. The experiments were performed under three different temperatures (29, 17, and 6 °C) and oxygenic (air flow, N2 gas flow, and untreated) conditions for 48 h. The total dissolved iodine (TDI) concentration (i.e., the sum of iodide, iodate, and dissolved organic iodine, DOI) increased under all temperatures and oxygenic conditions in the first 6 h of incubation. From 6 to 27 h, noticeable increases in TDI concentration only occurred at high temperatures. Dissolution fluxes of iodine estimated by linear regression analysis of the measured TDI concentration in the first 6 h were always higher than those estimated in the first 27 h. This result indicates that dissolution flux of iodine should be evaluated through short-term (within several hours) incubation experiments because absorption reactions which transport iodine from the overlying water back to the sediment become active in the long-term. No substantial difference in dissolution flux, estimated by TDI concentration, was observed under different oxygenic conditions in the first 6 h. However, dissolution flux increased significantly with an increase in temperature. Increases in flux and temperature were significantly and positively correlated (R2 = 0.90), suggesting that temperature was the dominant factor that regulated iodine flux during the incubation. Changes in TDI concentration at all temperatures and oxygenic conditions corresponded to those in iodide concentration, indicating that iodide was the main form of iodine dissolved from the sediments. In later stages of the experiments, from 27 to 48 h, the TDI concentration in overlying water increased only at high temperature, while concentrations at medium and low temperatures remained constant or decreased. In particular, oxic experiments showed substantial decreases in iodide concentration at medium and low temperatures. This suggests that oxic conditions promote the absorption of iodine from the overlying water to the sediments. Finally, the dissolution flux of radioiodine (iodine-129) from the sediments of Lake Obuchi to the overlying water was estimated by combining these results with data from earlier studies. The results suggest that only 0.006% of the iodine-129 accumulated in the sediments is released through dissolution to the overlying water per year, suggesting that this radioactive isotope is essentially stable in the sediments.

The effects of glycine, L-threonine, and L-cystine supplementation to a 9% casein diet on the conversions of L-tryptophan to nicotinamide and to serotonin in rats.

Nicotinamide and serotonin are synthesized from L-tryptophan in mammals. It is important to know the nutritional factors affecting the synthesis of nicotinamide and serotonin. We investigated the effects of amino acid composition. Young adult rats were fed ad libitum for 21 d a low-protein (9% casein) diet([1] control), or one of the low protein diets supplemented with following amino acids: [2] glycine, L-threonine, and L-cystine, [3] L-threonine and L-cystine, [4] glycine and L-cystine, and [5] glycine and L-threonine. The amounts of glycine, L-threonine and L-cystine supplementations were 2%, 0.078%, and 0.2%, respectively, and the amino acid contents of all diet were adjusted with supplementation of L-glutamic acid. The body weight gain, food efficiency ratio, and the amino acid nutrition biomarker, which is the urinary excretion ratio of (N(1)-methyl-2-pyridone-5-carboxamide+N(1)-methyl-4-pyridone-3-carboxamide)/N(1)-methylnicotinamide, improved by adding the amino acids glycine, L-threonine and L-cystine to a 9% casein diet. The conversion percentage of L-tryptophan to nicotinamide decreased with the addition of the amino acids glycine, L-threonine and L-cystine to a 9% casein diet, while the concentrations of serotonin in the brain, stomach and small intestine were not affected at all. The effects of each amino acid on body weight gain and the conversion ratios were also investigated. Glycine did not affect these variables. L-Cystine improved the body weight gain, the food efficiency ratio and the urine ratio, and decreased the conversion percentage. L-Threonine did not affect body weight gain or food efficiency ratio; however, it improved the urine ratio and decreased the conversion percentage.

Java medaka: a proposed new marine test fish for ecotoxicology.

Java medaka (Oryzias javanicus), which is distributed in estuarine waters of East to Southeast Asia, is proposed here for consideration as a new marine test fish. Semi-static acute toxicity tests were conducted at 26 degrees C for 1 week, 2 weeks, and 1 month old Java-medaka exposed to 4-chlorophenol and zinc, and 2 weeks olds exposed to potassium dichromate (hexavalent chromium) and sodium hypochlorite (residue chlorine). Ninety-six hours LC50s of 4-chlorophenol, zinc, hexavalent chromium, and residue chlorine were from 3.0 to 4.1, from 12.4 to 14.7, 7.4, and 0.05 mg/L, respectively. There were no large differences in sensitivity for 4-chlorophenol and zinc among the three growth stages. Compared with other fish species, these LC50s were relatively low suggesting that Java medaka has relatively high sensitivity to chemicals. This fish is quite easy to keep in the laboratory, with low mortalities at early stages and it takes about 3 months to mature from hatching, suggesting that this fish can be used not only for short-term toxicity tests but also for early life stage toxicity tests. From these results, Java-medaka is highly recommended as a marine test fish for ecotoxicity tests.

Effects of estrone on full life cycle of Java medaka (Oryzias javanicus), a new marine test fish.

Estrone is a natural estrogen detected in sewage treatment works effluents and in estuarine waters. However, there is little information on the effects of estrone on marine fish. This study investigated the effects of estrone on reproduction of the estuarine fish, Java medaka (Oryzias javanicus). Java medaka were exposed to concentrations of 39, 198, 484, 1,188, and 3,701 ng/L of estrone from embryonic stages up to adult stages for 239 d after hatching. The fertility and egg numbers of Java medaka exposed to 1,188 and 3,701 ng/L were significantly lower than that of control. The hepatic vitellogenin concentrations in male Java medaka exposed to estrone greater than 484 ng/L were significantly higher than that of control. Oocytes in testis (testis-ova) were not detected in the males in any of the exposure groups. The lowest-observed-effect concentration and no-observed-effect concentration for Java medaka were 484 and 198 ng/L of estrone. These results suggest that in relatively low estrone concentrations, 39 and 198 ng/L, Java medaka will not be affected by exposure to estrone.

Effects of 17beta-estradiol on the reproduction of Java-medaka (Oryzias javanicus), a new test fish species.

17beta-estradiol (E2) is a female hormone which is known to be one of the strongest estrogenic chemicals in the environment. The present study investigated the effects of E2 on the reproduction of the estuarine fish, Java-medaka (Oryzias javanicus). Starting from the embryonic stages, Java-medaka was exposed for 6 months to 9.5, 16, 68, 159 and 243 ng/l of E2. The fecundity of Java-medaka exposed to E2 levels >16 ng/l was significantly lower than that of the control. The appearance of secondary sexual characteristics seemed to be inhibited by exposure to 159 and 243 ng/l E2. Vitellogenin concentrations in the liver of male fish exposed to 68, 159 and 243 ng/l were significantly higher than that of the control. Thirty-three and sixty percent of male fishes exposed to 159 and 243 ng/l, respectively, had testis-ova. These results suggest that reproduction in the Java-medaka, especially the male fish, could be affected by exposure to E2 concentrations greater than 16 ng/l.

Impaired liver regeneration in mice by lipopolysaccharide via TNF-alpha/kallikrein-mediated activation of latent TGF-beta.

BACKGROUND & AIMS: Because impaired regeneration after surgical treatment of the liver is influenced by circulating endotoxin, the underlying molecular mechanism was investigated. METHODS: Lipopolysaccharide (LPS) was injected intraperitoneally into mice, followed 24 hours later by 67% partial hepatectomy. We measured serum tumor necrosis factor (TNF) alpha levels as well as proliferating cell nuclear antigen labeling index, transforming growth factor (TGF) beta expression, and plasma kallikrein (PLK) activities in regenerating livers. We also examined the effect of LPS, TNF-alpha, and PLK on latent TGF-beta activation in homotypic and heterotypic cultures of rat or mouse hepatic stellate cells and Kupffer cells. RESULTS: Serum TNF-alpha levels increased after LPS (500 ng/g body wt) injection and after partial hepatectomy, accompanying TGF-beta-mediated suppression of hepatic proliferating cell nuclear antigen labeling index. This suppression was mimicked by a combination of preadministration of 50 ng/g body wt LPS and postoperative administration of 5 ng/g body wt TNF-alpha. In vitro, LPS stimulated Kupffer cells to secrete TNF-alpha, which enhanced PLK activity on the hepatic stellate cell surface through increasing PLK binding, thereby inducing proteolytic activation of latent TGF-beta and its autoinduction. Blockade of TGF-beta, TNF-alpha, or PLK activity prevented LPS-induced impaired regeneration in vivo. CONCLUSIONS: LPS provokes TNF-alpha/PLK-mediated proteolytic activation of latent TGF-beta in hepatic stellate cells, leading to impaired liver regeneration after partial hepatectomy.