Search

Background: Exosome-like nanoparticles (ELNs) mediate interspecies intercellular communications and modulate gene expression., Hypothesis/purpose: In this study, we isolated and purified ELNs from the dried rhizome of Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR-ELNs), a traditional natural medicine, and investigated their potential as neuroinflammatory therapeutic agents., Methods: ALR-ELN samples were isolated and purified using differential centrifugation, and their physical features and microRNA contents were analyzed through transmission electron microscopy and RNA sequencing, respectively. BV-2 microglial murine cells and primary mouse microglial cells were cultured in vitro , and their ability to uptake ALR-ELNs was explored using fluorescence microscopy. The capacity of ALR-ELNs to modulate the anti-inflammatory responses of these cells to lipopolysaccharide (LPS) exposure was assessed through mRNA and protein expression analyses., Results: Overall, BV-2 cells were found to internalize ALR-ELNs, which comprised three microRNAs (ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p) that could have anti-inflammatory activity. Pretreatment of BV-2 cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide, interleukin-1β, interleukin-6, and tumor necrosis factor-α. Notably, the mRNA levels of Il1b, Il6, iNos, ccl2 , and cxcl10 in BV-2 cells, which increased upon LPS exposure, were significantly reduced following ALR-ELN treatment. Moreover, the mRNA levels of heme oxygenase 1, Irf7, ccl12 , and Irg1 also increased significantly following ALR-ELN treatment. In addition, pretreatment of primary mouse microglial cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide., Conclusion: Our findings indicate that ALR-ELNs exhibit anti-inflammatory effects on murine microglial cells. Further validation may prove ALR-ELNs as a promising neuroinflammatory therapeutic agent., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kawada, Ishida, Morisawa, Jobu, Higashi, Aizawa, Yagi, Izawa-Ishizawa, Niimura, Abe, Goda, Miyamura and Ishizawa.)

Objective: Exosome-like nanoparticles (ELNs), which are plant-derived extracellular membrane vesicles, can regulate mammalian gene expression. ELNs can cross the blood-brain barrier, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation-related diseases. Here, we investigated the anti-neuroinflammatory potential of ELNs extracted from Allium tuberosum (A-ELNs)., Methods: A-ELNs were extracted, and their miRNA profile was characterized. A-ELNs were also applied to BV-2 microglial and MG-6 cells derived from C57/BL6 mice stimulated with lipopolysaccharide (LPS), followed by an examination of levels of inflammatory-related factors. To test their drug-carrying potential, A-ELNs were mixed with dexamethasone, an anti-inflammatory drug, to prepare dexamethasone-incorporated A-ELNs (Dex-A-ELNs)., Key Findings: A-ELNs showed a particle size of 145 ± 2 nm and characteristic miRNAs. A-ELNs significantly decreased the LPS-induced nitric oxide (NO) and inflammatory cytokines levels in BV-2 and MG-6 cells. The mRNA expression of heme oxygenase-1 was significantly increased, and that of inducible NO synthase and inflammatory cytokines was significantly decreased by A-ELNs in BV-2 cells. Dex-A-ELNs inhibited NO production in BV-2 cells more potently than either A-ELNs or dexamethasone alone., Conclusion: A-ELNs can alleviate microglial inflammation. Their effects can be potentiated by incorporating anti-inflammatory drugs, such as dexamethasone, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We evaluated long-term changes in conjunctival bulge after medial rectus muscle (MR) tightening using the plication method., Study Design: Retrospective and observational., Methods: Patients who underwent MR plication for exotropia from December 2016-March 2020 at Okayama University Hospital were included. Thirty two eyes of 27 patients were enrolled. The thickness from the conjunctiva to sclera (TCS) at the limbus and insertion sites were measured using anterior segment optical coherence tomography preoperatively and 1 month, 4 months, and 12 months postoperatively. Correlations between the 1- and 12 month postoperative TCS and amount of MR tightening were analyzed., Results: Preoperative and 4 month postoperative TCS at the limbus site were not significantly different (P=0.07). The 12 month postoperative TCS at the insertion site was significantly thinner than at 1 month postoperative (P<0.01), although significantly thicker than the preoperative TCS (P<0.01). No significant correlations were found between the amount of MR tightening (in mm) and 1- or 12 month postoperative TCS at the limbus (P=0.62 and P=0.98, respectively) and insertion (P=0.50 and P=0.24, respectively) sites., Conclusion: The TCS at the insertion site peaked at 1 month postoperatively, continued to decrease for longer than 4 months postoperatively, continuing until 12 months postoperatively. The TCS at the insertion site 12 months postoperatively is thicker than preoperatively. The TCS at both the limbus and insertion sites was not related to the amount of medial rectus muscle tightening., (© 2023. Japanese Ophthalmological Society.)

Aberrant melanin overproduction can significantly impact an individual's appearance and cause mental and psychological distress. Current inhibitors of melanin production exert harmful side effects due to inadequate selectivity; thus a need to develop more selective melanin synthesis inhibitors is necessary. Extracellular vesicles are important agents of intercellular signalling in prokaryotes and eukaryotes. Recently, plant-derived nanoparticles, similar to mammalian exosomes, have attracted attention for their use in health research. In this study, to investigate the potential of plant-derived exosome-like nanoparticles (ELNs) as inhibitors of melanin production, we used hot water to extract ELNs from the rhizome of Atractylodes lancea (A-ELNs). The size of A-ENLs ranged from 34 to 401 nm and carried three microRNA: ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p. These A-ENLs were applied to B16-F10 melanoma cells treated with α-melanocyte-stimulating hormone (α-MSH). After A-ELNs were taken up by B16-F10 cells, their melanin levels were significantly reduced. Furthermore, A-ELNs significantly reduced tyrosinase activity in B16-F10 cells and mRNA expression of microphthalmia-associated transcription factor ( Mitf ), tyrosinase, tyrosinase-related protein 1, and DOPA chrome tautomerase. These results suggest that A-ELN suppresses melanogenic enzymes expression by downregulating Mitf , thereby inhibiting melanin synthesis. Hence, A-ELN can be developed into a novel topical drug after additional studies and optimization., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Nerve inflammation is linked to the development of various neurological disorders. This study aimed to examine whether Glycyrrhizae Radix effectively influences the duration of the pentobarbital-induced loss of righting reflex, which may increase in a mouse model of lipopolysaccharide (LPS)-induced nerve inflammation and diazepam-induced γ-aminobutyric acid receptor hypersensitivity. Furthermore, we examined the anti-inflammatory effects of Glycyrrhizae Radix extract on LPS-stimulated BV2 microglial cells, in vitro. Treatment with Glycyrrhizae Radix significantly decreased the duration of pentobarbital-induced loss of righting reflex in the mouse model. Furthermore, treatment with Glycyrrhizae Radix significantly attenuated the LPS-induced increases in interleukin-1β, interleukin-6, and tumor necrosis factor-alpha at the mRNA level, and it significantly reduced the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus 24 h after LPS treatment. Treatment with Glycyrrhizae Radix also suppressed the release of nitric oxide, interleukin-1β, interleukin-6, and tumor necrosis factor protein in culture supernatants of LPS-stimulated BV2 cells. In addition, glycyrrhizic acid and liquiritin, active ingredients of Glycyrrhizae Radix extract, reduced the duration of pentobarbital-induced loss of righting reflex. These findings suggest that Glycyrrhizae Radix, as well as its active ingredients, glycyrrhizic acid and liquiritin, may be effective therapeutic agents for the treatment of nerve inflammation-induced neurological disorders., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Background and Objectives: Hyponatremia is among the most prevalent electrolyte abnormalities observed in patients with cancer during chemotherapy. Therefore, managing hyponatremia is crucial since it causes a severe electrolyte imbalance that can lead to significant mortality, and this study aimed to investigate the relationship between hyponatremia, anticancer drugs, and cancer types. Materials and Methods: Reported odds ratios were calculated and evaluated based on adverse event reports submitted to the Japanese Adverse Drug Event Report (JADER) database. Results: Overall, 2943 patients had hyponatremia. Notably, cisplatin, pemetrexed, and etoposide had marked hyponatremia signals. In addition, significant hyponatremia signals were detected for oesophageal, lung, and renal cancers. Conclusions: Hyponatremia has been reported in women and patients with lung cancer receiving cisplatin, with a growing trend in the number of elderly patients receiving cisplatin. Furthermore, since the onset of hyponatremia during cisplatin administration is frequently reported within 10 days, patient information should be thoroughly examined before and monitored throughout the administration, which can contribute to the early detection and prevention of hyponatremia.

Background and Objectives : The aim of this study is to investigate the characteristics of gastrointestinal bleeding events associated with BCR-ABL tyrosine kinase inhibitor (TKI) treatment, using the reporting odds ratio (ROR) of the adverse event reports submitted to the Japanese Adverse Drug Event Report database between 2004 and 2020, and to examine the number of reported TKI-related gastrointestinal bleeding cases according to sex and age, as well as the actual number of TKI prescriptions issued in Japan. Materials and Methods : The RORs and 95% confidence intervals (CIs) of gastrointestinal bleeding events related to TKIs were calculated using the data of the 595,121 included cases. Results : Significant gastrointestinal bleeding events were detected for dasatinib (crude ROR: 4.47, 95% CI: 3.77-5.28) and imatinib (crude ROR: 1.22, 95% CI: 1.01-1.46). In multiple logistic regression analyses, significant gastrointestinal bleeding events were detected for dasatinib (adjusted ROR: 8.02, 95% CI: 5.75-10.2), imatinib (adjusted ROR: 1.81, 95% CI: 1.2-2.72), age (≥60 years, adjusted ROR: 2.22, 95% CI: 2.1-2.36), reporting year (adjusted ROR: 1.04, 95% CI: 1.04-1.05), and male sex (adjusted ROR: 1.47, 95% CI: 1.37-1.57). Interaction analysis revealed that the association of gastrointestinal bleeding with dasatinib was affected by age (≥60 years) and sex (female), with the number and proportion of dasatinib-related gastrointestinal bleeding cases increasing among those aged ≥60 years. Conclusions : Specific TKIs and patient characteristics were associated with gastrointestinal bleeding. Our results aid the prompt identification and treatment of TKI-related gastrointestinal bleeding.

Neuroinflammation is associated with the development of hypoactive delirium, which results in poor clinical outcomes. Drugs effective against hypoactive sur have not yet been established. Yokukansan has an anti-neuroinflammatory effect, making it potentially effective against hypoactive delirium. This study aimed to examine the effect of Yokukansan on the pentobarbital-induced loss of righting reflex duration extended with lipopolysaccharide (LPS)-induced neuroinflammation and diazepam-induced gamma-aminobutyric acid receptor stimulation in a mouse model. The active ingredients in Yokukansan and its anti-neuroinflammatory effect on the hippocampus were also investigated. Furthermore, we examined the in vitro anti-inflammatory effects of Yokukansan on LPS-stimulated BV2 cells, a murine microglial cell line. Findings revealed that treatment with Yokukansan significantly decreased the duration of pentobarbital-induced loss of righting reflex by attenuating the LPS-induced increase in interleukin-6 and tumor necrosis factor-alpha levels in the hippocampus. Moreover, treatment with Yokukansan significantly decreased the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus after 24 h of LPS administration. In addition, glycyrrhizic acid, an active ingredient in Yokukansan, partially decreased the duration of pentobarbital-induced loss of righting reflex. Treatment with Yokukansan also suppressed the expression of inducible nitric oxide, interleukin-6, and tumor necrosis factor mRNA in LPS-stimulated BV2 cells. Thus, these findings suggest that Yokukansan and glycyrrhizic acid may be effective therapeutic agents for treating neuroinflammation-induced hypoactive delirium., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Abstract: Poor adherence to medication in patients with heart failure (HF) is associated with poor clinical outcomes. Although social support has been reported to improve medication adherence in patients with HF, the detailed underlying mechanism of this association is unclear. This study investigated appropriate social support types to ensure medication adherence, as well as patient characteristics that benefit from such social support in patients with HF. This was a retrospective observational study investigating the association of social support with medication adherence in 824 patients with HF who were registered in a prospective multicenter database. First, we analyzed the association between social support types and poor medication adherence leading to hospitalization. An interaction analysis was performed to detect patients' characteristics that benefited most from social support in terms of medical adherence. Fifty patients (6.1%) were hospitalized for poor adherence to medications. Multivariable analysis revealed that not receiving assisted living, which was defined as having supporting individuals at least once a week, was independently associated with poor medication adherence-related hospitalization. An interaction analysis revealed that patients with dementia benefited from assisted living significantly, whereas male patients or current smokers did not. Summarily, assisted living at least once a week was appropriate for improving medication adherence in patients with HF and was particularly effective in patients with dementia. Performed in a super-aging region in Japan, this study may also suggest the relevance of social support in preventing HF exacerbation in other developed countries that will experience an aging society in the near future., Competing Interests: H. Kitaoka reports the receipt of personal fees from Takeda Pharmaceutical Company, Ltd; Daiichi-Sankyo Company; Mitsubishi Tanabe Pharma Corporation, Ltd; and grants from Takeda Pharmaceutical Company, Ltd; Daiichi-Sankyo Company; Bayer Yakuhin, Ltd; Otsuka Pharmaceutical, Ltd; and Actelion Pharmaceuticals Japan, Ltd. The remaining authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Use of 5-aminolevulinic acid for photodynamic malignant tumor diagnosis reportedly causes intraoperative hypotension (systolic blood pressure < 70 mmHg) during urologic surgery. However, its association with intraoperative hypotension in malignant glioma surgery and underlying mechanisms has not yet been elucidated.. This study aimed to investigate whether 5-aminolevulinic acid administration is associated with intraoperative hypotension in malignant glioma surgery and explore the mechanisms of 5-aminolevulinic acid-induced hypotension in vitro., Methods: In this retrospective multicenter cohort study, we investigated intracellular nitric oxide as a candidate mediator of hypotension in response to 5-aminolevulinic acid in vitro in human umbilical vein endothelial cell cultures., Results: Of 142 patients, 94 underwent 5-aminolevulinic acid-guided surgery. Systolic blood pressure was significantly lower throughout surgery with 5-aminolevulinic acid administration. 5-Aminolevulinic acid administration was an independent risk factor for intraoperative hypotension according to multivariable logistic regression analysis (89% vs. 56%; odds ratio = 6.72, 95% confidence interval [2.05-22.1], P = 002). In subgroup analysis of the 5-aminolevulinic acid group, increasing age and use of renin-angiotensin system inhibitors had a synergistic effect with 5-aminolevulinic acid on decreased blood pressure. In the vascular endothelial cell culture study, 5-aminolevulinic acid induced a significant increase in intracellular nitric oxide generation., Conclusions: 5-Aminolevulinic acid administration was associated with intraoperative hypotension in malignant glioma surgery, with increasing age and use of renin-angiotensin system inhibitors boosting the blood pressure-lowering effect of 5-aminolevulinic acid. According to in vitro results, the low blood pressure induced by 5-aminolevulinic acid may be mediated by a nitric oxide increase in vascular endothelial cells., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sarcopenic obesity is associated with increased visceral fat and decreased muscle mass, resulting in decreased insulin sensitivity, increased production of inflammatory cytokines, and oxidative stress. In this study, we first evaluated the effects of herbal medicines on the transcriptional activity of the Sirtuin 1 (sirt1) promoter in vitro as an indicator of their therapeutic effect. Our data suggested that hot water Saikokeishikankyoto (SKK) extracts increased sirt1 transcriptional activity in vitro, identifying it as a candidate therapeutic for evaluation in the KKAy type 2 diabetic obesity mouse model. These in vivo evaluations revealed that SKK treatment increased the wet weight and muscle fiber content in cross sections of the gastrocnemius muscle (GA) and restored motor function in these animals. In addition, SKK treatment reduced tumor necrosis factor-α (TNFα) expression in the sera and suppressed Atrogin1 and MuRF1 transcription in the GA samples. This treatment also increased sirt1 expression in these tissues. These results suggest that SKK inhibits skeletal muscle atrophy and improves motor function in KKAy mice by suppressing inflammation. In actual clinical practice, SKK is expected to inhibit muscle atrophy and improve motor dysfunction in sarcopenic obesity., (© 2021. The Author(s).)

Individual differences in gut microbiota can affect the pharmacokinetics of drugs. Yokukansan is a traditional Japanese kampo medicine used to treat peripheral symptoms of dementia and delirium. A study examining the pharmacokinetics of the components of yokukansan reported large individual differences in the pharmacokinetics of glycyrrhizic acid (GL). It is known that GL is metabolized by intestinal bacteria to glycyrrhetinic acid (GA), which is absorbed in the gastrointestinal tract. Thus, the gut microbiota may affect GL pharmacokinetics. We aimed to clarify the relationship between the gut microbiota composition and pharmacokinetics of GL in yokukansan. Mice were orally administered yokukansan, following the administration of various antibiotics, and the plasma concentration of GA and composition of gut microbiota were measured. The GA plasma concentration was low in mice treated with amoxicillin and vancomycin. The composition of gut microbiota revealed a different pattern from that of the control group. Mice with low plasma levels of GA had lower levels of the phylum Bacteroides and Firmicutes. Additionally, bacteria, such as those belonging to the genera Parabaceroides, Bacteroides, Ruminococcus and an unknown genus in families Lachnospiraceae and Ruminococcaceae, exerted positive correlations between the gene copies and plasma GA levels. These bacteria may contribute to the absorption of GA in the gastrointestinal tract, and multiple bacteria may be involved in GL pharmacokinetics. The pharmacokinetics of GL may be predicted by evaluating the composition of gut bacteria, rather than by evaluating the amount of a single bacterium.

In obese patients with type 2 diabetes, reduced insulin sensitivity, increased production of inflammatory cytokines, and increased oxidative stress were observed, which lead to decreased protein synthesis and increased proteolysis in the skeletal muscles. Juzentaihoto (JTT) is herbal medicine and we have previously reported that the administration of JTT hot water extract alleviates skeletal muscle atrophy in a mouse model with streptozotocin-induced type 1 diabetes. In this study, we evaluated the inhibitory effects of JTT on muscle atrophy in a mouse model with obesity and type 2 diabetes. JTT was administered to KKAy mice with type 2 diabetic obesity and its effects on the skeletal muscles were evaluated. After JTT administration in KKAy mice, the wet weight and muscle fibre cross-sectional area of gastrocnemius increased and the time duration of exercise in the rotarod test improved. In addition, the serum levels of tumour necrosis factor-α and interleukin-6 decreased, adiponectin levels increased, and homeostasis model assessment for insulin resistance improved. Furthermore, JTT administration decreased the mRNA levels of ubiquitin ligase (atrogin-1, muscle RING-finger protein-1), increased the mRNA levels of Sirtuin1 in gastrocnemius. Our results suggest that JTT improves insulin resistance, suppresses inflammation, and reduces oxidative stress in KKAy mice, thereby suppressing skeletal muscle atrophy. JTT administration in clinical practice is expected to improve muscle atrophy in patients with obesity and type 2 diabetes.

Bevacizumab is an inhibitor of vascular endothelial growth factor (VEGF) that prevents tumor growth. While bevacizumab is therapeutically effective, it induces several adverse events. Among these, central nervous system (CNS) ischemia can lead to death or permanent disability. In this study, we reviewed the Japanese Adverse Drug Event Report database to analyze the occurrence of CNS ischemia after bevacizumab administration. Significant associations between the occurrence of CNS ischemia and bevacizumab use were detected (adjusted reporting odds ratios (ROR): 2.68, 95% confidence interval (CI): 2.00-3.59, p < 0.001). Furthermore, an association between diagnosis of glioma and bevacizumab use was also detected (p < 0.001). These events occurred early after the start of treatment and then gradually decreased; however, more than half of CNS ischemia events were reported beyond 30 d after the first administration. In addition, a logistic regression suggested that CNS ischemia caused by bevacizumab was associated with glioma, underlying hypertension and aging. A poor prognosis was reported for several cases occurring in elderly patients (over 60 years of age). Although bevacizumab is a useful pharmacological treatment for cancer, caution should be taken to avoid severe adverse events. Accordingly, the patient's general and medical condition should be carefully examined before initiating treatment, and blood pressure should be continuously assessed throughout treatment with bevacizumab to prevent CNS ischemia.

Aggression is the most common adverse effect of antiepileptic drugs (AEDs). This study aimed to investigate the association of aggression with AED use. The reporting odds ratio (ROR) from adverse event reports, submitted to the Japanese Adverse Drug Event Report database between 2004 and 2020, was used to calculate and investigate the association between AEDs and aggression. We also analyzed the association of aggression with the combined use of AEDs and the relationship between AED-associated aggression and patient characteristics. A total of 433 patients developed aggression. Significant aggression signals were detected for perampanel (crude ROR: 325.04, 95% confidence interval (CI): 118.48-752.58, p < 0.01), levetiracetam (crude ROR: 17.14, 95% CI: 10.33-26.90, p < 0.01), lacosamide (crude ROR: 16.90, 95% CI: 2.02-62.51, p < 0.01), lamotrigine (crude ROR: 15.98, 95% CI: 9.99-24.39, p < 0.01), valproate (crude ROR: 6.68, 95% CI: 4.27-10.02, p < 0.01), and carbamazepine (crude ROR: 2.47, 95% CI: 1.17-4.59, p < 0.01). The combined therapy with perampanel and levetiracetam had a significant aggression signal (adjusted ROR: 25.90, 95% CI: 1.14-59.10, p < 0.01). In addition, we found that aggression frequently occurred in patients <60 year (adjusted ROR: 2.88, 95% CI: 1.49-5.56, p < 0.01) treated with levetiracetam. These results may be useful for minimizing the risk of aggression during the treatment of AEDs.

Nilotinib is used as standard treatment in managing chronic myeloid leukaemia (CML). A 23-year-old man with CML and on nilotinib was admitted to the intensive care unit due to respiratory failure. Three years prior, he developed pleural effusion from dasatinib therapy thus, his CML regimen was changed to nilotinib. Although the pleural effusion had once improved, the chest imaging revealed left-dominant bilateral pleural effusion. Endotracheal intubation and left thoracic drainage were performed. Nilotinib treatment was discontinued, and approximately 60 hours later, nilotinib concentrations of 927 and 2092 ng/mL were determined in his blood and pleural effusion, respectively. Severe pleural effusion may be induced in patients administering nilotinib, and nilotinib concentrations in blood and pleural effusion can be elevated in patients with nilotinib-related pleural effusion. Cross-occurrence of pleural effusions needs to be monitored precisely, especially in patients who are switched to other tyrosine kinase inhibitors after dasatinib treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To describe our surgical outcomes using a novel muscle transposition procedure, or double-under muscle transposition (DUT), in the treatment of paralytic strabismus., Methods: In this surgery, the split halves of the superior and inferior rectus muscles opposite the paralyzed muscle are disinserted, crossed under both the remaining half and the paralyzed muscle, and anchored at opposite corners of the insertion of the paralyzed muscle. The medical records of consecutive patients who underwent DUT were retrospectively reviewed. Outcome measures were angle of deviation and duction deficit., Results: Seven patients were included. Diagnoses included WEBINO (n = 1), rupture of the medial rectus muscle (n = 1), and abducens nerve palsy (n = 5). DUT alone was performed in 3 patients; DUT combined with antagonist muscle recession, in 4 patients. One patient underwent the surgery bilaterally. Mean follow-up was 17 ± 18+ months (range, 7-57). Preoperative angles of distance deviation ranged from 25 Δ to 142 Δ in magnitude. All except a single patient had duction limitation of grade -5. The mean change in distance deviation for DUT alone for each operated eye was 60 Δ ± 6 Δ (53 Δ -65 Δ ); for combined surgery, 69 Δ  ± 23 Δ (range, 52 Δ -103 Δ ). Final mean angle of deviation at distance was +2 Δ ± 3 Δ (-4 Δ to 0 Δ ), although an additional surgery was required for large overcorrections in 2 patients. Duction limitation improved in all patients. One patient experienced a postoperative vertical deviation., Conclusions: DUT may be an alternative for patients with severely paralytic strabismus not likely to resolve with previously reported muscle transposition surgeries. Overcorrection may occur in some cases., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Delirium in patients with acute decompensated heart failure (ADHF) is associated with poor clinical outcomes. Although some medications have been reported as risk factors for delirium, their impact on patients with ADHF is still unclear. This study aimed to determine the association of specific medication use with delirium and their additive predictive value in models based on conventional risk factors., Methods and Results: In this single-center, retrospective study, 650 patients treated for ADHF were included. Fifty-nine patients (9.1%) had delirium. In multivariate analysis, anxiolytic benzodiazepines [odds ratio (OR): 6.4, 95% confidence interval (CI): 2.8-15], mechanical ventilation or noninvasive positive pressure ventilation (OR: 6.0, 95% CI: 2.9-12), depression (OR: 3.2, 95% CI: 1.5-6.5), intensive care or high care unit admission (OR: 2.9, 95% CI: 1.5-5.6), male sex (OR: 2.0, 95% CI: 1-3.7), and age (OR: 1.1, 95% CI: 1-1.1) were independently associated with severe delirium. The predictive model that included anxiolytic benzodiazepines had a significantly better discriminatory ability for the incidence of severe delirium than the conventional model., Conclusions: The use of anxiolytic benzodiazepines was independently correlated with severe delirium, and their use in models based on conventional risk factors had an additive value for predicting delirium in patients with ADHF., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To determine the frequency, symptoms and risk factors for adverse reactions to two-times instillation of 1% cyclopentolate in children., Study Design: Prospective, observational study., Methods: The subjects were 646 patients who underwent cycloplegic refraction with cyclopentolate (mean age; 7.0 ± 3.5 years, age range; 0-15 years). Five minutes after instillation of 0.4% oxybuprocaine hydrochloride, a 1% cyclopentolate eye drop was instilled twice, with an interval of 10 min. Fifty minutes later, two certified orthoptists evaluated adverse reactions using a questionnaire and interviewed the patients' guardians. The relationship between the adverse reaction rates and age, gender, additional instillation, complications of the central nervous system (CNS), time of day and season were analysed using binominal and polytomous logistic regression models., Results: The overall frequency of adverse reactions was 18.3% (118/646 patients). The main symptoms included conjunctival injection (10.5%, 68/646), drowsiness (6.8%, 44/646) and facial flush (2.2%, 14/646). The odds ratio (OR) of conjunctival injection increased with patient's age (p < 0.05), in boys (p < 0.01) and in winter (p < 0.001). In contrast, the OR of drowsiness decreased with age (p < 0.001). Facial flush was observed mostly in children younger than 4 years. CNS complications were not a significant risk factor for any of the symptoms., Conclusions: Adverse reactions to 1% cyclopentolate eye drops were more frequent than previously expected, but all were mild and transient. The probability of each symptom was associated with a clear age-specific trend., (© 2020 The Authors Ophthalmic and Physiological Optics © 2020 The College of Optometrists.)

Sarcopenia is a disease whose symptoms include decreased muscle mass and weakened muscle strength with age. In sarcopenia, decreased production of insulin-like growth factor-1 (IGF-1) increases ubiquitin ligases, such as Atrogin1 and Muscle RING-Finger Protein-1 (MuRF1), by activating forkhead box O (FOXO), and inflammatory cytokines and oxidative stress increase the expression of ubiquitin ligases by activating the transcription factor nuclear factor-kappa B (NF-κB). In addition, increased levels of ubiquitin ligases cause skeletal muscle atrophy. Conversely, sirtuin 1 (Sirt1) is known to regulate the expression of ubiquitin ligases by suppressing the activities of NF-κB and FOXO. In this study, we evaluated the effect that juzentaihoto hot water extract (JTT) has on skeletal muscle atrophy and motor function by administering it to senescence-accelerated mouse prone-8 (SAMP8). The group treated with JTT displayed larger gastrocnemius muscle (GA) and extensor digitorum longus (EDL) weights, larger GA muscle fiber cross-sectional areas, and motor function decline during rota-rod tests. JTT also increased IGF-1 serum levels, as well as mRNA Sirt1 levels in GA. Serum levels of tumor necrosis factor-α, interleukin-6, and mRNA levels of Atrogin1 and MuRF1 in GA were reduced by JTT. The muscle fiber cross-sectional area of GA was correlated with the mRNA levels of Sirt1 in GA. The results of this study suggested that JTT administration suppresses skeletal muscle atrophy and motor function decline in SAMP8 mice. This effect may be associated with the increased expression levels of Sirt1 and IGF-1 by JTT.

High-performance/low-cost platinum (Pt)-based electrocatalysts have been established by top-coating both sides of a titanium plate with Pt nanoparticles. The average diameter of the Pt nanoparticles used in this study is approximately 100 nm. Three types of Pt top-coated Pt/Ti electrocatalysts, each having different top-coated Pt layer thicknesses, are prepared. Type I is a monolayered Pt top-coated type, in which the thickness of the top-coated Pt layer is approximately 100 nm; Type II is a few-layered type with a top-coated Pt layer thickness of approximately 200 nm, and Type III is a multilayered type with a top-coated Pt layer thickness of approximately 750 nm. The mass loading of Pt is 0.0215 mg cm -2 for Type I, 0.043 mg cm -2 for Type II, and 0.161 mg cm -2 for Type III. The electrocatalytic activities of each type of Pt/Ti electrocatalyst are evaluated through the electrolysis of acidic water and tap water. Type I gives the highest electrocatalytic efficiencies, which are comparable or even better than the electrocatalytic efficiencies of the state-of-the-art commercially available Pt/C electrode and other metal-/carbon-based HER catalysts. For example, in the case of the electrolysis of acidic water at an overpotential of 0.15 V, Type I shows a Tafel slope of 29 mV dec -1 and a current density of 27.5 mA cm -2 . Even in the case of the electrolysis of tap water, Type I gives an HER Faradaic efficiency of 92%. A model of water (H 2 O), hydronium ions (H 3 O + ), and hydroxyl ions (OH - ) properly adsorbing on the Pt (111) facet is proposed to explain the electrocatalytic mechanism. New insights into the distinguishing properties of the resultant electrolyzed hydrogen water (EHW), namely, the healthy beneficial effects of EHW, are also described, and a new concept of storing and carrying reductive hydrogen (H*) by free Pt nanoparticles is proposed.

Background: To detect significant factors associated with excessive postoperative exo-drift in young patients with intermittent exotropia who had undergone unilateral lateral rectus muscle recession and medial rectus muscle resection., Methods: We retrospectively examined the records of 64 consecutive patients < 18 years old who underwent surgery between April 2004 and December 2011. We sought risk factors for excessive postoperative exo-drift among patients' demographic and clinical characteristics using univariate and multivariable linear regression analysis., Results: Younger patients (P = 0.007), and those with larger preoperative exo-deviation at distance (P = 0.033), a lower incidence of peripheral fusion at distance (P = 0.021) or a greater postoperative initial eso-deviation (P = 0.001), were significantly more likely to have an excessive postoperative exo-drift (> 20 prism diopters). Univariate analysis revealed significant associations between excessive postoperative exo-drift and age at surgery (P = 0.004), preoperative exo-deviation at distance (P = 0.017) and postoperative initial eso-deviation at distance (P < 0.001). Multivariable linear regression analysis showed that postoperative initial eso-deviation at distance (P = 0.008) was significantly associated with postoperative exo-drift., Conclusions: Postoperative exodrift in unilateral RR is predicted by the initial postoperative eso-deviation, which may offset the overcorrection. However, the exo-drift is greater in cases with a large preoperative exo-deviation and/or at a younger age, and should be followed carefully.

The purpose of this study was to derive new formulas to provide an optimal surgical procedure and optimal amount of recession-resection (RR) surgery in intermittent exotropia (IXT) with a disparity in angle of deviation depending on the fixation distance. The records of 117 consecutive patients with IXT who underwent RR surgery between March 2008 and December 2011 at Okayama University Hospital were retrospectively examined. Multivariable linear regression analysis was performed using the observed corrective angle of deviation at distance or near fixation as the dependent variable, and amounts of lateral rectus muscle (LR) recession (mm) and medial rectus muscle (MR) resection, and age at surgery (years) as independent variables. Two simultaneous formulas were derived: corrective angle of deviation at distance fixation (°)=1.8×recession (mm)+1.6× resection (mm)+0.15×age (years)-6.6, and corrective angle at near fixation (°)=1.5×recession (mm)+1.7× resection (mm)+0.18×age (years)-3.8. Comparisons of coefficient values of the formulas between distance and near fixation revealed that LR recession was more affected by the corrective angle in distance than near fixation. MR resection was more affected at near than distance fixation. We found that our new formulas estimated the appropriate amount of unilateral RR surgery., Competing Interests: No potential conflict of interest relevant to this article was reported.

Juzentaihoto is a herbal medicine with reported anti-inflammatory effects, and it is predicted to improve inflammation and insulin sensitivity within obesity. In the present study, juzentaihoto hot water extract (JTT) was administered to obese type 2 diabetic model mice (KKAy) for 56 days. In addition, the effects of JTT on the adipose tissue, glucose metabolism, and blood lipids were evaluated for examining its impact on insulin sensitivity and obesity. As a result of JTT administration, KKAy mice exhibited suppressed adipocyte hypertrophy, decreased the mRNA levels of tumor necrosis factor α, and increased the mRNA levels of adiponectin in epididymal fat tissue. In addition, fasting blood glucose levels, blood triglyceride, and total cholesterol decreased. In summary, these data indicated that JTT administration suppressed the production of inflammatory cytokines and increased adiponectin levels in the adipose tissue. Therefore, with improved insulin sensitivity, blood glucose, and lipid decreased.

Yokukansan is a Kampo formula that is commonly used by the elderly because it is expected to improve peripheral symptoms of dementia and delirium. However, side effects from its use are frequently reported in the elderly. In particular, pseudoaldosteronism caused by the licorice contained in yokukansan leads to hypertension, hypokalemia, and muscle weakness, which may result in death. This study aimed to identify the risk factors of pseudoaldosteronism with yokukansan use. Using cases reported in the Japanese Adverse Drug Report (JADER) database, the reporting odds ratio (ROR) was calculated and compared to assess the risk of pseudoaldosteronism for each licorice-containing Kampo formula. We also analyzed the risk factors for pseudoaldosteronism in patients taking yokukansan. Yokukansan (ROR 2.4, 95% confidence interval (CI) 1.9-2.8; p < 0.001) had a higher risk of pseudoaldosteronism than that of other licorice-containing Kampo formulas. Furthermore, the results of a logistic regression analysis in patients taking yokukansan showed that the licorice dose (OR 1.5, 95% CI 1.2-2.0; p < 0.01), older age (<70 years, OR 5.9, 95% CI 1.8-20; p < 0.01), dementia (OR 2.8, 95% CI 1.6-4.9; p < 0.001), low body weight (<50 kg, OR 2.2, 95% CI 1.1-3.5; p = 0.034) were risk factors for pseudoaldosteronism, Although not significant, treatment with loop diuretics (OR 1.8, 95% CI 0.98-3.5; p = 0.059) tended to increase the risk of pseudoaldosteronism. In summary, patients must understand the risk factors when considering taking yokukansan and reduce the licorice dose they consume.

In optogenetics, red-shifted channelrhodopsins (ChRs) are eagerly sought. We prepared six kinds of new chromophores with one double bond inserted into the polyene side chain of retinal (A1) or 3,4-didehydroretinal (A2), and examined their binding efficiency with opsins (ReaChR and ChrimsonR). All analogs bound with opsins to afford new ChRs. Among them, A2-10ex (an extra double bond is inserted at the C10-C11 position of A2) showed the greatest red-shift in the absorption spectrum of ChrimsonR, with a maximum absorbance at 654 nm (67 nm red-shifted from that of A1-ChrimsonR). Moreover, a long-wavelength spectral boundary of A2-10ex-ChrimsonR was extended to 756 nm, which reached into the far-red region (710-850 nm).

In diabetic patients, skeletal muscle atrophy occurs due to increased oxidative stress and inflammation. Skeletal muscle atrophy reduces the QOL of patients and worsens life prognosis. Therefore, development of preventive therapy for muscle atrophy in hyperglycemic state is eagerly awaited. Juzentaihoto is a medicinal herb that has a function to supplement physical strength, and it is expected to prevent muscle atrophy. To determine the preventive effect of juzentaihoto on muscle atrophy in hyperglycemic state, streptozotocin (STZ) was administered to induce diabetes in mice and the preventive effect of juzentaihoto was evaluated. Mice that received juzentaihoto extract (JTT) showed that the decrease in muscle fiber cross-sectional area in the gastrocnemius muscle was reversed. Additionally, the expression level of tumor necrosis factor α (TNF-α), an inflammatory cytokine, in serum decreased, and that of ubiquitin ligase (atrogin-1, muscle RING-finger protein-1) mRNA in skeletal muscle decreased. An anti-inflammatory cytokine interleukin-10 showed increased levels in the serum and increased levels in spleen cell culture supernatant collected from mice that received JTT. JTT had no effect on the blood glucose level. These results suggest that prophylactic administration of JTT to STZ-induced diabetic mice affects immune cells such as in spleen, causing an anti-inflammatory effect and inhibiting excessive activation of the ubiquitin-proteasome system, to reverse muscle atrophy.

A decrease in skeletal muscle mass and motor function occurs in diabetic patients. In type 1 diabetic patients, in particular, fast-type fiber-dominated muscle atrophy occurs due to increased oxidative stress and inflammation. Juzentaihoto is a herbal medicine that has been found to be effective in reducing oxidative stress. In this study, juzentaihoto hot water extract (JTT) was administered prophylactically to mice with diabetic oxidative stress, which was induced by an injection of streptozotocin, and the effects on skeletal muscle mass, motor function, and antioxidant activity were evaluated. In mice that were administered JTT, skeletal muscle atrophy and loss of motor function were suppressed. Additionally, the administration of JTT increased the mRNA expression level of Sirt1 and the activity of superoxide dismutase in the gastrocnemius. In addition to skeletal muscle atrophy, atrophy of the liver, spleen and thymus gland, and kidney hypertrophy were also suppressed. Furthermore, in order to evaluate the antioxidant activity of 10 constituent crude drugs that comprise juzentaihoto, Sirt1 transcriptional activity in C2C12 cells was evaluated. The Sirt1 transcriptional activity was increased by Cinnamomi Cortex, Astragali Radix, and Glycyrrhizae Radix extracts. These three constituent crude drugs play an important function in the antioxidant action of juzentaihoto, suggesting that juzentaihoto can prevent muscle atrophy by decreasing oxidative stress.

Ulinastatin vaginal suppositories, used to prevent threatened premature delivery, are frequently used in hospitals. However, there is no established method for quantifying ulinastatin contained in suppositories. Therefore, we investigated a simple and efficient method for quantifying ulinastatin contained in suppositories. Our analytical method involved removal of the base; optimising the enzyme inhibition reaction time and enzyme reaction time; and measuring the absorbance. The modified method was reproducible, operation time was significantly shortened, and cost was reduced to approximately 1/17 of that of the previously reported method. This simple and rapid quantitative method could contribute to the improvement of quality control of ulinastatin vaginal suppositories as an extemporaneous hospital preparation.

We investigated variances in the stability and amount of postoperative exodrift among age groups of intermittent exotropia (XPT) patients who underwent unilateral lateral rectus muscle recession and medial rectus muscle resection. We analyzed the cases of 110 consecutive patients who underwent the surgery in 2004-2011, dividing the patients into groups by their age at surgery: <10, 10-19, and ≥20 years. We performed a regression analysis (dependent variable: postoperative exodrift (°); independent variable: number of days post-surgery) using the formula of curve lines. When the tangent line slope was = 0.01 (°/days) for each group, we defined the numbers of days until alignment became stable as the 'stable days.' We evaluated the between-group differences in the amount of exodrift calculated for the stable days. The coefficients and coefficients of determination for the fitting curves were: <10 year group: f(x)=12.2 (1-e-0.0183x) (r2=0.588, p<0.05); 10-19 year group: f(x)=10.0 (1-e-0.0178x) (r2=0.453, p<0.05); ≥20 year group: f(x)=3.40 (1-e-0.0382x) (r2=0.217, p<0.05). There were 389 , 388, and 153 stable days, and the estimated postoperative exodrift with long-term follow-up was 11.5±3.7°, 9.3±4.4°, and 4.1±3.6° for the < 10 year, 10-19 year, and ≥ 20 year groups, respectively (≥20 year vs. other 2 groups, p<0.05). Longer periods and more postoperative exodrift were associated with younger age at surgery. The postoperative evaluation was approx. ≥ 1 year post-surgery in patients aged < 20. These findings may contribute to evaluating XPT's success rate and prognoses., Competing Interests: No potential conflict of interest relevant to this article was reported.

Dipeptidyl peptidase IV (DPP IV, DPP4, or DAP IV) preferentially cleaves substrate peptides with Pro or Ala at the P1 position. The substrate recognition mechanism has been fully elucidated for mammalian DPP IV by crystal structure analyses but not for bacterial orthologues. Here, we report the crystal structures of a bacterial DPP IV (PmDAP IV) in its free form and in complexes with two kinds of dipeptides as well as with a non-peptidyl inhibitor at 1.90 to 2.47 Å resolution. Acyl-enzyme intermediates were observed for the dipeptide complexes of PmDAP IV, whereas tetrahedral intermediates were reported for the oligopeptide complexes of mammalian DPP IVs. This variation reflects the different structural environments of the active site Arg residues, which are involved in the recognition of a substrate carbonyl group, of mammalian and bacterial enzymes. A phylogenetic analysis revealed that PmDAP IV is a closer relative of dipeptidyl peptidases 8 and 9 (DPP8 and DPP9, DPP IV-family enzymes) than DPP IV. These results provide new insights into the substrate recognition mechanism of bacterial DAP IVs and may assist in the development of selective inhibitors for DAP IVs from pathogenic asaccharolytic bacteria, which utilise proteins or peptides as an energy source.

Dipeptidyl aminopeptidase IV (DAP IV or DPP IV) from Pseudoxanthomonas mexicana WO24 (PmDAP IV) preferentially cleaves substrate peptides with Pro or Ala at the P1 position [NH 2 -P2-P1(Pro/Ala)-P1'-P2'…]. For crystallographic studies, the periplasmic form of PmDAP IV was overproduced in Escherichia coli, purified and crystallized in complex with the tripeptide Lys-Pro-Tyr using the hanging-drop vapour-diffusion method. Kinetic parameters of the purified enzyme against a synthetic substrate were also determined. X-ray diffraction data to 1.90 Å resolution were collected from a triclinic crystal form belonging to space group P1, with unit-cell parameters a = 88.66, b = 104.49, c = 112.84 Å, α = 67.42, β = 68.83, γ = 65.46°. Initial phases were determined by the molecular-replacement method using Stenotrophomonas maltophilia DPP IV (PDB entry 2ecf) as a template and refinement of the structure is in progress.

Extracellular-superoxide dismutase (EC-SOD) is a secreted antioxidative enzyme, and its presence in vascular walls may play an important role in protecting the vascular system against oxidative stress. EC-SOD expression in cultured cell lines is regulated by various cytokines including tumor necrosis factor-α (TNF-α). TNF-α is a major mediator of pathophysiological conditions and may induce or suppress the generation of various types of mediators. Epigenetics have been defined as mitotically heritable changes in gene expression that do not affect the DNA sequence, and include DNA methylation and histone modifications. The results of the present study demonstrated that TNF-α significantly decreased EC-SOD level in fibroblasts with an accompanying increase in methylated DNA. In DNA methylation and demethylation, cytosine is methylated to 5-methylcytosine (5mC) by DNA methyltransferase (DNMT), and 5mC is then converted to 5-hydroxymethylcytosine (5hmC) and cytosine in a stepwise manner by ten-eleven translocation methylcytosine dioxygenases (TETs). However, DNMT did not participate in TNF-α-induced DNA methylation within the EC-SOD promoter region. On the other hand, TNF-α significantly suppressed TET1 expression and EC-SOD mRNA levels were decreased by the silencing of TET1 in fibroblasts. These results demonstrate that the down-regulation of EC-SOD by TNF-α is regulated by DNA methylation through reductions in TET1., Competing Interests: No potential conflicts of interest were disclosed.

The quantity of heavy metals in soil is measured after 2-mm sieving in Japan for risk assessment of direct soil ingestion. A study was conducted on the relationship between the size of soil particles and quantity of heavy metals in soil, and the particle-size distribution of soil adhered to children's hands, and the risks of direct intake of soil considering the particle sizes ingested were evaluated. The results showed that smaller particles had a tendency to contain more heavy metals than bigger ones, that the particle size of approximately 90% of the soil particles from playgrounds adhered to children's hands was less than 100 μm, and that 2-mm sieving in preparation for measuring heavy metal content caused underestimation of the risk of direct soil intake. The amount of heavy metals on children's hands after playing outside was investigated. Various metals and soil were adhered to their hands, and the amount of soil adhered could be estimated from the concentration of metals. To develop accurate risk assessment, the particle-size distribution of ingested soil and more detailed scenarios of soil intake are necessary., (© 2014 Society for Risk Analysis.)

In this study, a method for removing water from biosolids that uses dimethyl ether (DME) as an extractant was considered. This study evaluates the applicability of the DME dewatering method to biosolid cakes by using a DME flow-type experimental apparatus. It was found that a high dewatering ratio is clearly achieved by increasing the liquefied DME/biosolid ratio and lowering the liquefied DME linear velocity. As the liquefied DME/biosolid ratio was increased, the carbon content in dewatered biosolid showed a slight decrease and the TOC concentration in separated liquid increased significantly. Finally, the input energy Es to remove 1 kg of water from the biosolid cake, using both the DME dewatering method and the conventional drying method was estimated. The calculation shows that Es for the DME dewatering process is approximately a third of Es for the conventional thermal drying process.

Molecular hydrogen has been shown to have neuroprotective effects in mouse models of acute neurodegeneration. The effect was suggested to be mediated by its free-radical scavenger properties. However, it has been shown recently that molecular hydrogen alters gene expression and protein phosphorylation. The aim of this study was to test whether chronic ad libitum consumption of molecular hydrogen-enriched electrochemically reduced water (H-ERW) improves the outcome of lipopolysaccharide (LPS)-induced neuroinflammation. Seven days after the initiation of H-ERW treatment, C57Bl/6 mice received a single injection of LPS (0.33 mg/kg i.p.) or an equivalent volume of vehicle. The LPS-induced sickness behaviour was assessed 2 h after the injection, and recovery was assessed by monitoring the spontaneous locomotor activity in the homecage for 72 h after the administration of LPS. The mice were killed in the acute or recovery phase, and the expression of pro- and antiinflammatory cytokines in the hippocampus was assessed by real-time PCR. We found that molecular hydrogen reduces the LPS-induced sickness behaviour and promotes recovery. These effects are associated with a shift towards anti-inflammatory gene expression profile at baseline (downregulation of TNF- α and upregulation of IL-10). In addition, molecular hydrogen increases the amplitude, but shortens the duration and promotes the extinction of neuroinflammation. Consistently, molecular hydrogen modulates the activation and gene expression in a similar fashion in immortalized murine microglia (BV-2 cell line), suggesting that the effects observed in vivo may involve the modulation of microglial activation. Taken together, our data point to the regulation of cytokine expression being an additional critical mechanism underlying the beneficial effects of molecular hydrogen.

In Japan, environmental standards for contaminants in groundwater and in leachate from soil are set with the assumption that they are used for drinking water over a human lifetime. Where there is neither a well nor groundwater used for drinking, the standard is thus too severe. Therefore, remediation based on these standards incurs excessive effort and cost. In contrast, the environmental-assessment procedure used in the United States and the Netherlands considers the site conditions (land use, existing wells, etc.); however, a risk assessment is required for each site. Therefore, this study proposes a new framework for judging contamination in Japan by considering the merits of the environmental standards used and a method for risk assessment. The framework involves setting risk-based concentrations that are attainable remediation goals for contaminants in soil and groundwater. The framework was then applied to a model contaminated site for risk management, and the results are discussed regarding the effectiveness and applicability of the new methodology., (© 2011 Society for Risk Analysis.)

Calcination is the second step in a washing-calcination-conversion system in which treated municipal solid waste incinerator fly ash and bottom ash can be reused as raw material in the cement industry and can decompose or stabilize hazardous compounds, reduce residue amounts, and alter residue characteristics. In this research, only fly ash is discussed. Chloride reduction is important if treated fly ash is to be reused in cement; however, the relationship between washed fly ash properties and chloride reduction by calcination is not well understood. This study used washed residues of three types of fly ash-raw fly ash (RFA) from the boiler or economizer of an incineration system, fly ash collected in a bag filter injected with calcium hydroxide (Ca(OH)2) for acid removal (CaFA), and fly ash collected in a bag filter injected with sodium bicarbonate (NaHCO3) for acid removal (NaFA)-in calcination experiments with varying temperature (400-1100 degrees C) and atmosphere (100% nitrogen [N2] at 25 mL/min or 10% oxygen [O2] [90% N2] at fluxes of 25, 50, and 75 mL/min). From the perspective of chloride reduction, heating to 1000 degrees C with 1-hr heating time, 1-hr holding time, and an atmosphere of 10% O2/90% N2 was most suitable for calcination. Under these conditions, chloride levels were reduced by 91, 52, and 96% in washed residues of RFA, CaFA, and NaFA, respectively. Among the washed residues, the weight of the washed residue of NaFA decreased the most.

We proposed a method for the deodorising and dewatering of biosolids. In the proposed method, liquefied dimethyl ether (DME) was used as an extractant for odorous components and water. We developed a bench-scale experiment to almost completely deodorize and dewater biosolids by using liquefied DME at room temperature. The deodorized and dewatered biosolids have sufficient caloric density and can be used as a carbon neutral fuel.

Background: T-cell damage by increased oxidative stress in end-stage renal disease (ESRD) patients undergoing chronic haemodialysis (HD) led to the increased T-cell apoptosis and the alteration of surface markers and Th1/Th2 ratio in CD4(+) T lymphocytes. Antioxidant electrolysed-reduced water (ERW) was used as the dialysate in ESRD patients undergoing chronic HD to test for improved oxidative stress-related T-cell apoptosis, alterations of surface markers and intracellular cytokine profile., Methods: We evaluated apoptosis formation by annexin V, CD25-related surface markers, and cytokine ratio of Th1/Th2 in CD4(+) T lymphocytes and Tc1/Tc2 in CD8(+) T lymphocytes of 42 ESRD patients haemodialysed with ERW for 1 year., Results: In comparison to 12 healthy individuals, the ESRD patients had more T-cell apoptosis and less CD3(+), CD4(+) and CD8(+) T cells and CD25/CD69/CD94/CD3(+) phenotypes at baseline. Lower intracellular IL-2 and IFN-gamma levels in the Th1/CD4(+) and Tc1/CD8(+) cells and higher intracellular IL-4, IL-6 and IL-10 levels in the Th2/CD4(+) and Tc2/CD8(+) cells were also noted in the ESRD patients. After a 1-year ERW treatment, the patients had a decrease in T-cell apoptosis and increases in CD3(+), CD4(+) and CD8(+) cell numbers and CD25/CD69/CD94/CD3(+) phenotypes in the T cells. The intracellular IL-2 and IFN-gamma levels in the Th1/Tc1 cells significantly (P < 0.05) increased and the intracellular IL-4, IL-6 and IL-10 levels in the Th2/Tc2 cells decreased. Furthermore, the Th1/Th2 and Tc1/Tc2 cytokine ratios were improved toward a normal status., Conclusion: One-year ERW treatment effectively ameliorated T-cell apoptosis, altered CD25-related surface markers and intracellular cytokine profile in the HD patients.

Chloride in fly ash from municipal solid waste incinerators (MSWIs) is one of the obstructive substances in recycling fly ash as building materials. As a result, we have to understand the behavior of chlorides in recycling process, such as washing. In this study, we used X-ray absorption near edge structure (XANES) and X-ray diffraction (XRD) to study the chloride behavior in washed residue of raw fly ash (RFA). We found that a combination of XRD and XANES, which is to use XRD to identify the situation of some compounds first and then process XANES data, was an effective way to explain the chlorides behavior in washing process. Approximately 15% of the chlorine in RFA was in the form of NaCl, 10% was in the form of KCl, 51% was CaCl(2), and the remainder was in the form of Friedel's salt. In washing experiments not only the mole percentage but also the amount of soluble chlorides including NaCl, KCl and CaCl(2) decreases quickly with the increase of liquid to solid (L/S) ratio or washing frequency. However, those of insoluble chlorides decrease slower. Moreover, Friedel's salt and its related compound (11CaO.7Al(2)O(3).CaCl(2)) were reliable standards for the insoluble chlorides in RFA, which are strongly related to CaCl(2). Washing of RFA promoted the release of insoluble chlorides, most of which were in the form of CaCl(2)., (Copyright 2010 Elsevier B.V. All rights reserved.)

The relationship between the formation of chlorinated aromatic (aromatic-Cl) compounds and ferric chloride in the solid phase during a thermal process motivated us to study the chemical characteristics of iron in a model solid sample, a mixture of FeCl(3) x 6H(2)O, activated carbon, and boron nitride, with increasing temperature. Fe K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy revealed drastic changes in the chemical form of amorphous iron, consistent with other analytical methods, such as X-ray diffraction using synchrotron radiation (SR-XRD) and Fourier-transform infrared (FT-IR) spectroscopy. Atomic-scale evidence of the chlorination of aromatic carbon was detected by Cl-K X-ray absorption near edge structure (XANES) spectroscopy. These results showed the thermal formation mechanism of aromatic-Cl compounds in the solid phase with ferric chloride. We attribute the formation of aromatic-Cl compounds to the chlorination of carbon, based on the oxychlorination reaction of FeCl(3) at temperatures in excess of ca. 300 degrees C, when the carbon matrix is activated by carbon gasification, catalyzed by Fe(2)O(3), and surface oxygen complexes (SOC) generated by a catalytic cycle of FeCl(2) and FeOCl. Chemical changes of trace iron in a thermal process may offer the potential to generate aromatic-Cl compounds in the solid phase.

We investigated whether polychlorinated biphenyls (PCBs) and water could be simultaneously removed from river sediment by solvent extraction using liquefied dimethyl ether (DME) as the extractant. DME exists in a gaseous state at normal temperature and pressure and can dissolve organic substances and some amount of water; therefore, liquefied DME under moderate pressure (0.6-0.8 MPa) at room temperature can be effectively used to extract PCBs and water from contaminated sediment, and it can be recovered from the extract and reused easily. First, we evaluated the PCB and water extraction characteristics of DME from contaminated sediment. We found that 99% of PCBs and 97% of water were simultaneously extracted from the sediment using liquefied DME at an extraction time of 4320 s and a liquefied DME/sediment ratio of 60 mL g(-1). The extraction rate of PCBs and water was expressed in terms of a pseudo-first-order reaction rate. Second, we estimated the amount of DME that was recovered after extraction. We found that 91-92% of DME could be recovered. In other words, approximately 5-10% of DME was lost during extraction and recovery. It is necessary to optimize this process in order to recover DME efficiently. The extraction efficiency of the recovered DME is similar to that of the pure DME. From the results, we conclude that solvent extraction using liquefied DME is suitable for extracting PCBs and water from contaminated sediment., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Many environmental organic chemicals have chloride in their structure. Thus, researching the chlorination mechanism of carbon is of interest. Dioxins are typically concentrated in fly ash collected from the post-combustion zone during the operation of municipal solid waste incinerators. In this study, we report the application of Cl-K near-edge X-ray-absorption fine structure (NEXAFS) in determining the chlorination mechanism of carbon in fly ash. The separation of a chloride-carbon (C-Cl) bond was readily recognizable as a peak in the Cl-K NEXAFS spectrum. Chlorination effects could be estimated using Cl K-edge NEXAFS with no dependence on metal species. Analysis of Cl K-edge NEXAFS spectra showed the reduction of copper(II) chloride at 300°C and oxidation of iron(III) chloride at 400°C in connection with the chlorination of carbon.

We investigated the behaviour of siloxanes, which adversely affect biogas engines, as well as their concentration levels in sewage sludge biogas in Japan. We also performed experiments on the absorptive removal of siloxanes using various adsorbents and determined the main adsorbent characteristics required for the removal of siloxanes. The results of our study on the concentration and composition of siloxanes in biogas were similar to previous reports. Moreover, we found that the concentration of siloxanes changes in relation to the outside air temperature based on real-time measurements of siloxanes using a continuous analyser. We further speculated that the continuous analyser would accurately indicate the siloxane concentration in model biogas but overestimate the siloxane concentration in actual biogas because of positive interference by VOCs and other biogas components. In the siloxane adsorption experiment, the equilibrium uptake of both cyclic siloxanes, D4 and D5, was positively related to the BET-specific surface area of the adsorbents and the fraction of the external surface area taken up by relatively large diameter pores. We attributed the adsorption results to the fact that the siloxane molecules are generally larger than micropores; therefore, they are less susceptible to adsorption to micropores. Based on these results, we concluded that adsorbents with large BET-specific surface areas, especially those with a high external specific surface area and pores of relatively large diameters, are desired for the removal of siloxanes.

We estimated benzene risk using a novel framework of risk assessment that employed the measurement of radiation dose equivalents to benzene metabolites and a PBPK model. The highest risks for 1 microg/m(3) and 3.2 mg/m(3) life time exposure of benzene estimated with a linear regression were 5.4 x 10(-7) and 1.3 x 10(-3), respectively. Even though these estimates were based on in vitro chromosome aberration test data, they were about one-sixth to one-fourteenth that from other studies and represent a fairly good estimate by using radiation equivalent coefficient as an "internal standard."

To efficiently reduce and reuse fly ash from incinerators, we suggest trying a new alkaline reagent to neutralize the acid compounds in discharged gas from incinerators and reuse fly ash as the raw material in the cement industry. Normally the washing process includes a pretreatment method to remove chlorides to comply with the strict standards for cement. We examined chloride behavior in washing experiments by X-ray absorption near edge structure (XANES) and X-ray diffraction (XRD) for two kinds of fly ash: (1) fly ash collected in a bag filter with the injection of calcium hydroxide (Ca(OH) 2 ) for acid gas removal (CaFA), and (2) fly ash collected in a bag filter with the injection of sodium bicarbonate (NaHCO 3 ) for acid gas removal (NaFA). We found that the insoluble chlorides in both CaFA and NaFA combined calcium chloride (CaCl 2 ), with some sodium chloride (NaCl) also possibly combined. Under some conditions, the combined CaCl 2 and NaCl were released. In particular, when the liquid/solid ratio was greater than 3 or the washing frequency was doubled, less chlorine, insoluble chlorine, and CaCl 2 were left in the residues of NaFA than in the residues of CaFA. As a result, it is desirable to use NaHCO 3 as the alkaline reagent instead of Ca(OH) 2 in the air pollution control system of incinerators for recycling fly ash as a raw material in the cement industry.

There are few reports on the physiological effects of metal nanoparticles (nps), especially with respect to their functions as scavengers for superoxide anion radical (O2(.-)) and hydroxyl radical (.OH). We tried to detect the scavenging activity of Pt nps using a hypoxanthine-xanthine oxidase system for O2(.-) and using a Fenton and a UV/H2O2 system for .OH. Electron spin resonance analysis revealed that 2 nm particle size Pt nps have the ability to scavenge O2(.-) and .OH. The calculated rate constant for the O2(.-)-scavenging reaction was 5.03 +/- 0.03 x 10(7) M (-1) s (-1). However, the analysis of the Fenton and UV/H 2O 2 system in the presence of Pt nps suggested that the .OH-scavenging reaction cannot be determined in both systems. Among particle sizes tested from 1 to 5 nm, 1 nm Pt nps showed the highest O2(.-)-scavenging ability. Almost no cytotoxicity was observed even after adherent cells (TIG-1, HeLa, HepG2, WI-38, and MRC-5) were exposed to Pt nps at concentrations as high as 50 mg/L. Pt nps scavenged intrinsically generated reactive oxygen species (ROS) in HeLa cells. Additionally, Pt nps significantly reduced the levels of intracellular O2(.-) generated by UVA irradiation and subsequently protected HeLa cells from ROS damage-induced cell death. These findings suggest that Pt nps may be a new type of antioxidant capable of circumventing the paradoxical effects of conventional antioxidants.

Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis. Tumor cells are exposed to higher oxidative stress compared to normal cells. Numerous reports have demonstrated that the intracellular redox (oxidation/reduction) state is closely associated with the pattern of VEGF expression. Electrolyzed reduced water (ERW) produced near the cathode during the electrolysis of water scavenged intracellular H(2)O(2) and decreased the release of H(2)O(2) from a human lung adenocarcinoma cell line, A549, and down-regulated both VEGF transcription and protein secretion in a time-dependent manner. To investigate the signal transduction pathway involved in regulating VEGF expression, mitogen-activated kinase (MAPK) specific inhibitors, SB203580 (p38 MAPK inhibitor), PD98059 (ERK1/2 inhibitor) and JNKi (c-Jun N-terminal protein kinase inhibitor) were applied. The results showed that only PD98059 blocks VEGF expression, suggesting an important role for ERK1/2 in regulating VEGF expression in A549 cells. As well, ERW inhibited the activation of extracellular signal-regulated kinase (ERK) in a time-dependent manner. Co-culture experiments to analyze in vitro tubule formation assay revealed that A549 cell-derived conditioned medium significantly stimulated the formation of vascular tubules in all analyzed parameters; tubule total area, tubule junction, number of tubules, and total tubule length. ERW counteracted the effect of A549 cell-conditioned medium and decreased total tube length (p<0.01). The present study demonstrated that ERW down-regulated VEGF gene transcription and protein secretion through inactivation of ERK.

Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses.