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To evaluate the safety and efficacy of prolonged ingestion of Lactobacillus acidophilus L-92 (L-92) on skin symptoms in adult atopic dermatitis (AD) patients, a placebo-controlled double-blinded parallel-group comparison study was performed. This included daily administration of heat-killed and dried L-92 or placebo for 24wk in 50 AD patients who were 16yr old or older. The severity of skin symptoms was evaluated at baseline and at 4, 8, 12, 16, 20, and 24wk during the intervention using the investigator global assessment, eczema area and severity index, and scoring atopic dermatitis. Serum cytokine and blood marker levels were also measured at baseline and at 4, 8, 16, and 24wk during the intervention. No adverse events were reported during the study period. Compared with the placebo group, the L-92 group showed significant decreases in investigator global assessment, eczema area and severity index, and scoring atopic dermatitis. Subjective symptoms in adult AD patients were reduced by intake of L-92. Furthermore, it was suggested that sustained ingestion of L-92 resulted in suppression of scratching behavior and maintenance of remission status of skin symptoms. Sixteen weeks after the study commenced, a significant decrease in lactate dehydrogenase and a significant increase in transforming growth factor-β were observed in the L-92 group compared with the placebo group. In the L-92 group, a significant elevation of IL-12 (p70) level at the end of treatment period compared with before the treatment was observed. This study suggested that L-92 suppresses type-2-helper-T-cell-dominant inflammation by activating regulatory T cells and type 1 helper T cells.

d-Amino acids are now recognized to be widely present in mammals. Renal d-amino-acid oxidase (DAO) is associated with conversion of d-amino acids to the corresponding α-keto acids, but its contribution in vivo is poorly understood because the α-keto acids and/or l-amino acids formed are indistinguishable from endogenous compounds. First, we examined whether DAO is indispensable for conversion of d-amino acids to their α-keto acids by using the stable isotope tracer technique. After a bolus intravenous administration of d-[2H7]leucine to mutant mice lacking DAO activity (ddY/DAO−) and normal mice (ddY/DAO+), elimination of d-[2H7]leucine and formation of α-[2H7]ketoisocaproic acid ([2H7]KIC) and l-[2H7]leucine in plasma were determined. The ddY/DAO−mice, in contrast to ddY/DAO+mice, failed to convert d-[2H7]leucine to [2H7]KIC and l-[2H7]leucine. This result clearly revealed that DAO was indispensable for the process of chiral inversion of d-leucine. We further investigated the effect of renal mass reduction by partial nephrectomy on elimination of d-[2H7]leucine and formation of [2H7]KIC and l-[2H7]leucine. Renal mass reduction slowed down the elimination of d-[2H7]leucine. The fraction of conversion of d-[2H7]leucine to [2H7]KIC in sham-operated rats was 0.77, whereas that in five-sixths-nephrectomized rats was 0.25. The elimination behavior of d-[2H7]leucine observed in rats suggested that kidney was the principal organ responsible for converting d-leucine to KIC.

The stereoselective pharmacokinetics of selenomethionine enantiomers in rats has been studied to evaluate the chiral inversion of d -selenomethionine to the l -enantiomer. After bolus intravenous administration of d - or l -selenomethionine to rats, the plasma concentrations of these two enantiomers were determined by stereoselective gas chromatography–mass spectrometry with selected ion monitoring. This method involved derivatization of selenomethionine enantiomers with HCl in methanol to form methyl ester followed by N -acylation with (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form the diastereomeric amide, and separation of the diastereomer on GC with an achiral column. Plasma concentrations of administered d - and l -selenomethionine declined with terminal half-lives of 96 ± 17 min and 91 ± 6 min, respectively. l -Selenomethionine appeared rapidly in plasma after administration of d -selenomethionine, whereas d -selenomethionine was not detected in plasma after administration of l -selenomethionine. The fraction of conversion of d -selenomethionine to l -selenomethionine was estimated to be 61.3 ± 14.5%. The present method evaluates the stereoselective pharmacokinetics of selenomethionine enantiomers, including the estimation of the metabolic chiral inversion.

D-Leucine is considered to be converted into the L-enantiomer by two steps: oxidative deamination to form alpha-ketoisocaproic acid (KIC) and subsequent stereospecific reamination of KIC. We investigated the pharmacokinetics of leucine enantiomers and KIC in rats to evaluate how deamination of D-leucine, reamination of KIC, and decarboxylation of KIC were affected to the overall extent that converted D-leucine into the L-enantiomer. After intravenous administrations of D-[(2)H(7)]leucine, L-[(2)H(7)]leucine, or [(2)H(7)]KIC, their plasma concentrations together with endogenous L-leucine and KIC were determined by gas chromatography-mass spectrometry. The rapid appearances of [(2)H(7)]KIC and L-[(2)H(7)]leucine were observed after administration of D-[(2)H(7)]leucine, whereas no detectable amount of D-[(2)H(7)]leucine was found after administrations of [(2)H(7)]KIC or L-[(2)H(7)]leucine. The fraction of conversion from D-[(2)H(7)]leucine into [(2)H(7)]KIC (F(D-->KIC)) was estimated by using the area under the curve (AUC) of [(2)H(7)]KIC on the D-[(2)H(7)]leucine administration [AUC(KIC(D))] and that of [(2)H(7)]KIC on the [(2)H(7)]KIC administration (AUC(KIC)) to yield 70.1%. The fraction of conversion from [(2)H(7)]KIC to L-[(2)H(7)]leucine (F(KIC-->L)) was 40.2%. The fraction of conversion from D-leucine to the L-enantiomer (F(D-->L)) was considered to be the product of F(D-->KIC) and F(KIC-->L), indicating that 28.2% of D-[(2)H(7)]leucine was metabolized to L-[(2)H(7)]leucine via [(2)H(7)]KIC. These results suggested that the relatively low conversion of D-leucine into the L-enantiomer might depend on irreversible decarboxylation of KIC. Regardless of [(2)H(7)]KIC, F(D-->L) was also calculated directly using AUC(L(D)) and AUC(L) to yield 27.5%. There were no differences between the two F(D-->L) values, suggesting that almost all of the formation of L-[(2)H(7)]leucine from D-[(2)H(7)]leucine occurred via [(2)H(7)]KIC as an intermediate.

Objective:Boron neutron-capture therapy (BNCT) has been used to inhibit the growth of various types of cancers. In this study, we developed a 10BSH-entrapped water-in-oil-in-water (WOW) emulsion, evaluated it as a selective boron carrier for the possible application of BNCT in hepatocellular carcinoma treatment.Methods:We prepared the 10BSH-entrapped WOW emulsion using double emulsification technique and then evaluated the delivery efficacy by performing biodistribution experiment on VX-2 rabbit hepatic tumour model with comparison to iodized poppy-seed oil mix conventional emulsion. Neutron irradiation was carried out at Kyoto University Research Reactor with an average thermal neutron fluence of 5 × 1012 n cm−2. Morphological and pathological analyses were performed on Day 14 after neutron irradiation.Results:Biodistribution results have revealed that 10B atoms delivery with WOW emulsion was superior compared with those using iodized poppy-seed oil conventional emulsion. There was no dissemination in ab...

To clarify the relationship of prenatal arsenic exposure to hemoglobin concentrations and anemia during pregnancy, a longitudinal study was conducted of 364 participants during early pregnancy from October 2006 to March 2011 in Tehran, Iran. Maternal whole blood (taken between 8-12 and 20-24 weeks of gestation, and at delivery) and umbilical cord blood samples were collected for arsenic measurement. The mean concentration of maternal blood arsenic in the first trimester of pregnancy was significantly lower in anemic women compared with non-anemic participants (mean ± SD: 12.4 ± 3.4 versus 14.8 ± 4.0 μg/L, respectively, p < 0.001). Maternal whole blood arsenic levels in the first and third trimesters were significantly (p < 0.05) correlated with hemoglobin concentrations measured throughout gestation (r = 0.312, 0.424, and 0.183). Multiple logistic regression analysis demonstrated that increased maternal blood arsenic levels in the first trimester were significantly negatively associated to anemia during pregnancy (OR = 0.85, CI: 0.77-0.94, p < 0.01). The present study showed that prenatal blood arsenic exposure was not a risk factor for the occurrence of anemia.

Objective Thyroid hormones cross the placenta and promote fetal development and growth. The present study investigated whether an increase in maternal thyroid-stimulating hormone (TSH) concentration between the first and third trimesters is a determinant of birth weight during normal pregnancy. Methods Maternal thyroid hormones and TSH were longitudinally measured at 12, 25, and 36 weeks of pregnancy in 163 healthy pregnant women. Low birth weight (LBW) was defined as less than 2500 g. ∆TSH 12–36 W was calculated as the difference in TSH concentrations between 12 and 36 weeks of pregnancy. Results Of the 163 neonates, 10 (6.1%) were LBW neonates. Free triiodothyronine and free thyroxine levels were similar at all gestational ages in the normal birth weight (Normal) and LBW groups. However, the median ∆TSH 12–36 W value was higher in the LBW than the Normal group (1.67 vs. 0.54 mIU/L, P = 0.008). Multivariate linear regression analysis showed that ∆TSH 12–36 was inversely correlated with birth weight (β = − 0.179, P = 0.008). Conclusion An increase in maternal TSH concentration between the first and third trimesters is an independent determinant of birth weight in normal pregnancy.

A method for determination of alpha-ketoisocaproic acid (KIC) and [4,5,5,5,6,6,6-2H7]alpha-ketoisocaproic acid ([2H7]KIC) in rat plasma was developed using gas chromatography-mass spectrometry-selected ion monitoring (GC-MS-SIM). [5,5,5-2H3]alpha-Ketoisocaproic acid ([2H3]KIC) was used as an analytical internal standard to account for losses associated with the extraction, derivatization and chromatography. The keto acids were extracted by cation-exchange chromatography using BondElut SCX cartridge and derivatized with N-phenyl-1,2-phenylenediamine to form N-phenylquinoxalinone derivatives. Quantitation was performed by SIM of the respective molecular ions at m/z 278, 281 and 285 for the derivatives of KIC, [2H3]KIC and [2H7]KIC on the electron impact method. The limit of detection was found to be 70 fmol per injection (S/N=3) and the limit of quantitation for [2H7]KIC was around 50 nM in rat plasma. Endogenous KIC concentrations in 50 microl of rat plasma were measured with relative intra- and inter-day precision of 4.0% and 3.3%, respectively. The intra- and inter-day precision for [2H7]KIC spiked to rat plasma in the range of 0.1 to 10 microM gave good reproducibility with relative standard deviation (RSD) of 6.5% and 5.4%, respectively. The intra- and inter-day relative errors (RE) for [2H7]KIC were less than 6.4% and 3.8%, respectively. The method was applied to determine the plasma concentration of [2H7]KIC after an intravenous administration of [2H7]KIC in rat.

Distribution of Sm and Ce in mice was investigated after inhalation exposure to their oxide particles of 5 μm diameter and 15 mg/m 3 . Sm and Ce were mainly distributed in lung, their concentrations decreased with passing time, and their concentrations in lung were correlated with exposure periods. Concentrations of Ce were lower than that of Sm in each point. Sm was also distributed in the other organs and bone but Ce was scarcely detected. These results suggest that the behaviors of Sm and Ce inhaled were different, although their chemical properties are similar.

A method for the stereoselective assay of d - and l -enantiomers of both leucine and [2H7]leucine in rat plasma was developed using gas chromatography–mass spectrometry–selected-ion monitoring. dl -[2H3]leucine was used as an internal standard. The method involved purification by cation-exchange chromatography using BondElut SCX cartridge and derivatization with hydrochloric acid in methanol to form methyl ester followed by subsequent chiral derivatization with (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form diastereomeric amide. The derivatization made the separation of the leucine enantiomers possible with good gas chromatographic behavior. Quantitation was performed by selected-ion monitoring of the quasi-molecular ions of the diastereomers on the chemical ionization method. The sensitivity, specificity, accuracy and reproducibility of the method were demonstrated to be satisfactory for application to pharmacokinetic studies of leucine enantiomers.

A 40-year-old male tried to clean a urinal at his home storing 900 mL of a toilet cleaner containing 9.8% nitric acid to remove calcium deposit, and clean the toilet floor for twenty minutes. Immediately after using the cleaner, he experienced eye irritation. He washed out the toilet cleaner. However, he thereafter experienced dyspnea, a compressive sensation in his chest, and chest and back pain about 40 minutes after the cleaning the toilet. He monitored his symptoms overnight and found them to gradually improve. However, the symptoms still remained the next morning and therefore he came to our department on foot. He had no particular past or family history. On arrival, his physiological findings and chest computed tomography scan were negative for any abnormalities. His arterial blood gas analysis revealed a mild abnormality of oxygenation. Observation without any drugs revealed that a complete remission of his symptoms occurred after approximately 4 weeks. Based on the results of the experiments, contact with the mucosal membrane and nitric acid gas produced by any accidentally coexisting metals or contact with moisture, including nitric acid produced by a reaction between CaCO3 and cleaner, may have been the mechanism of occurrence for the symptoms observed in this case. This is the first reported case of nitric acid poisoning due to the use of a toilet cleanser intended for household use.

To assess the association between birth weight and maternal blood lead (BPb) levels, 386 pregnant women and their newborn offspring were surveyed. Mean±SD (range) maternal BPb concentrations were 0.98±0.55 (0.10-3.99), 0.92±0.63 [

The organic Se compounds (particularly selenomethionine [SeMet]) in plants and yeasts are very effective chemoprotectants for mammalian cancer. To characterize the dynamics of selenomethionine utilization pathways, we intravenously injected (82)Se-enriched SeMet into mice under different nutritional states (Se-adequate and Se-deficient mice) and then measured their endogenous and exogenous (82)Se levels. Furthermore, we quantified Se compounds and selenoproteins in liver, kidneys, plasma, and urine. The average recoveries of exogenous (82)Se from solid tissues, urine, and feces were 81% for Se-adequate mice and 84% for Se-deficient mice. Exogenous (82)Se was distributed in the hepatic and renal cytosols as cellular glutathione peroxidase (cGPx), selenosugar, and SeMet within 1 h after injection. Synthesis of cGPx was maintained until 72 h after injection, regardless of the Se nutritional status. Whereas plasma levels of exogenous (82)Se as selenoprotein P (Sel-P) peaked at 6 h after injection, those of Se-containing albumin (SeAlb), extracellular GPx, and SeMet peaked at 1 h after injection. These results suggest three Se transport pathways in mice injected with SeMet: SeAlb (within 1 h after injection); SeMet (from 1 to 72 h after injection); and Sel-P (from 6 to 72 h after injection). The amount of Sel-P in Se-deficient mice was 1.5 times that of Se-adequate mice, and this increase was much larger than Se-containing compounds other than Sel-P. Our results indicate that Sel-P has an important role in Se transport when the nutritional supply of Se is insufficient.

Mohsen Vigeh1, Kazuhito Yokoyama2, Takehisa Matsukawa2, Atsuko Shinohara3, Mohammad Reza Afshinrokh4 and Katsumi Ohtani1 Hazard assessment and Epidemiology Research Group, National Institute of Occupational Safety and Health, Japan Department of Epidemiology and Environmental Health, Juntendo University Faculty of Medicine, Japan Research Institute for Cultural Studies, Seisen University, Japan Deputy for Health, Tehran University of Medical Sciences, Iran

A method for the stereoselective determination of d - and l -enantiomers of selenomethionine in mouse plasma was developed using gas chromatography–mass spectrometry with selected-ion monitoring (GC–MS-SIM). dl -[ 2 H 3, 82 Se]selenomethionine was used as analytical internal standard to account for losses associated with the extraction, derivatization and chromatography. Selenomethionine enantiomers in mouse plasma were purified by cation-exchange chromatography using BondElut SCX cartridge and derivatized with HCl in methanol to form methyl ester followed by subsequent N -acylation with optically active (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form diastereomeric amide. Quantification was performed by SIM of the molecular-related ions of the diastereomers on the chemical ionization mode. The intra- and inter-day precision for d - and l -selenomethionine spiked to mouse plasma gave good reproducibility with relative standard deviation of 3% and 3% for d -selenomethionine and 6% and 3% for l -selenomethionine, respectively. The estimated amounts were in good agreement with the actual amounts spiked, the intra- and inter-day relative error being 5% and 2% for d -selenomethionine and 2% and 1% for l -selenomethionine, respectively. The present method is sensitive enough to determine pharmacokinetics of selenomethionine enantiomers.

The synthesis of D- and L-selenomethionine labeled with ⁸²Se and three deuteriums at Se-methyl group (D- and L-[²H₃, ⁸²Se]selenomethionine) was described. D- And L-[²H₃, ⁸²Se]selenomethionine were prepared by condensation of (R)- and (S)-2-amino-4-bromobutylic acid with lithium [²H₃, ⁸²Se]methaneselenolate, which was prepared from metal (82)Se and [²H₃]methyl iodide. The optical purities of D- and L-[²H₃, ⁸²Se]selenomethionine were determined by HPLC with a chiral stationary phase column and were found more than 99% ee. The chemical ionization mass spectra showed that the molecular related ion for N-isobutyloxycarbonyl ethyl ester derivatives of [²H₃, ⁸²Se]selenomethionine did not overlap with the m/z values known from that of non-labeled selenomethionine.

Aims Magnesium (Mg) deficiency has been reported to be associated with the development of the metabolic syndrome, cardiovascular diseases, and sudden death. We examined the influence of chronic Mg deficiency on cardiac tolerance to hypoxia/reoxygenation injury. Main methods Mice were fed an Mg-deficient diet for 4 weeks, and then their hearts were excised for Langendorff perfusion experiments. The levels of total Mg in the blood and heart were quantified by atomic absorption spectrometry. Key findings In Mg-deficient mice, the Mg concentration in whole blood was markedly decreased; however, that in the heart remained unchanged. When the hearts of control mice were exposed to hypoxia/reoxygenation, removal of extracellular Mg from a normal Krebs solution containing 1.2 mM Mg resulted in a significant decrease in the recovery of the tension-rate product (TRP) upon reoxygenation. In Mg-deficient mice, the recovery of TRP in the heart was reduced significantly in the absence of extracellular Mg compared to that in controls. The addition of Mg to the perfusate did not improve TRP recovery. During hypoxia/reoxygenation, cardiac damage evaluated by myocardial aspartate amino trasferase (AST) release was greater in hearts of Mg-deficient mice than in that of control mice. Significance These results indicate that chronic Mg deficiency causes severe hypomagnesemia and a decrease in cardiac tolerance to hypoxia, without changing the intracellular Mg content. The decreased tolerance to hypoxia was not affected by the presence or absence of extracellular Mg, suggesting that some intracellular metabolic abnormalities develop in the cardiac myocytes of Mg-deficient mice.

Gold nanoparticles intracellular uptake was investigated using both normal and cancer human cells. Cell uptake was analyzed using Atomic Absorption Spectrometry (AAS). It was found that combining 20nm gold nanoparticles with longer incubation time and lower concentration can optimize the uptake of gold nanoparticles by cancer cell. The findings of this study will help in the design and optimization of the nanoparticles uptake for therapeutic and diagnostic applications of X-ray Drug Delivery System.

Osteopontin (OPN) is a multi-functional cytokine involved in cell survival, migration and adhesion which is associated with tumorigenesis, progression and metastasis. However, the role of OPN in chemo-sensitivity of human lung cancer has not yet been elucidated. The purpose of this study is to investigate the role of OPN in chemo-sensitivity of lung cancer cells. We developed a stable OPN transfectant (SBC-3/OPN) and a control transfectant (SBC-3/NEO) from human small cell lung cancer cell line, SBC-3. SBC-3/OPN cells were more resistant to cisplatin than SBC-3/NEO cells. Multi-drug resistance-associated protein (MRP) does not appear to be involved in the development of acquired chemo-resistance, since MRP inhibitor did not alter chemo-sensitivity. After exposure to cisplatin, the apoptotic SBC-3/OPN cells were reduced in number compared to SBC-3/NEO cells. Treatment with cisplatin revealed that the expression of anti-apoptotic protein, bcl-2, was down-regulated in SBC-3/NEO cells, while that of SBC-3/OPN cells was not altered. In contrast, pro-apoptotic protein, bax, was not altered in both SBC-3/OPN and SBC-3/NEO cells, thus bcl-2/bax ratio was decreased in SBC-3/NEO but not altered in SBC-3/OPN cells. Activation of caspase-3 and caspase-9 was increased in SBC-3/NEO cells, but not in SBC-3/OPN cells. Our results suggest that OPN enhances chemo-resistance of cisplatin in SBC-3 cells by suppressing bcl-2 protein down-regulation, thereby blocking the caspase-9- and caspase-3-dependent cell apoptosis.