Publications by authors named "Rie Yamamoto"

58 Publications

Intussusception caused by small intestine metastasis of malignant pleural mesothelioma: a case report.

J Surg Case Rep 2021 Feb 22;2021(2):rjab003. Epub 2021 Feb 22.

Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, Hiroshima 734-8530, Japan.

Malignant pleural mesothelioma (MPM) is an aggressive form of malignant tumor that originates in the pleural mesothelioma and presents as a local disease in the affected hemithorax. Small intestine metastasis is a rare complication. Herein, the case of a patient with jejunal intussusception caused by small intestine metastasis of MPM has been reported. A 72-year-old man with MPM was admitted to our hospital for abdominal pain. Computed tomography revealed small intestine intussusception. An emergency surgery was performed, and the tumor and intussusception were located in the upper jejunum. Histopathological examination of the resected jejunum revealed that the tumor was a small intestinal metastasis of the MPM from the chest wall. This case showed that MPM may metastasize to the small intestine, and metastatic tumors may cause intussusception.
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http://dx.doi.org/10.1093/jscr/rjab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899189PMC
February 2021

Glucocorticoid treatment is associated with ICU-acquired hypernatremia: a nested case-control study.

Clin Exp Nephrol 2021 Feb 22;25(2):131-139. Epub 2020 Sep 22.

Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Hypernatremia is a major electrolyte disorder associated with death among critically ill patients. Glucocorticoid therapy may cause hypernatremia in refractory septic shock patients, but the association between glucocorticoid and intensive care unit (ICU)-acquired hypernatremia (IAH) remains unclear. The aim of this study was to clarify whether glucocorticoid administration was associated with IAH.

Methods: This was a nested case-control study using data from an established cohort including 121 IAH cases identified from 1756 patients who were admitted to ICU in a tertiary care facility in Japan. We included patients who were admitted with a normal range of serum sodium concentrations (130-149 mEq/L) from January 1, 2013 to December 31, 2015 and remained in ICU for ≥ 2 days. Hypernatremia was defined as serum sodium concentration ≥ 150 mEq/L. Each case was matched to one control.

Results: Multivariable conditional logistic regression revealed high-dose glucocorticoid {odds ratio (OR), 4.15 [95% confidence interval (CI) 1.29-13.4]}, acute kidney injury (AKI) [OR, 2.72 (95% CI 1.31-5.62)], and osmotic diuretics [OR, 3.44 (95% CI 1.41-8.39)] to be significantly associated with IAH. The contents and amounts of fluid infusion were not significantly associated with IAH. There were also significant duration-response effects between duration of glucocorticoid use and IAH; however, pulse glucocorticoid administration was not associated with IAH.

Conclusion: In this nested case-control study, we demonstrated a significant association between IAH and high-dose glucocorticoid with significant duration-response effects. Serum sodium concentrations should be monitored carefully in critically ill patients administered prolonged high-dose glucocorticoid.
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http://dx.doi.org/10.1007/s10157-020-01967-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506169PMC
February 2021

Comparison of bioelectrical impedance analysis in healthy pregnant women and patient on hemodialysis.

Ther Apher Dial 2021 Apr 3;25(2):160-165. Epub 2020 Jul 3.

Department of Nephrology, Wakayama Medical University, Tanabe, Wakayama, Japan.

Pregnant woman undergoing dialysis face challenges such as miscarriage and stillbirth when carrying a baby to term. A complication of prenatal care is the difficulty in properly managing body fluids. We compare fluid volumes between healthy pregnant women and two pregnant women undergoing dialysis using bioelectrical impedance analysis (BIA). Data of 52 healthy pregnant women at various stages of their pregnancy were analyzed for the study. We included these many cases so as to collect sufficient data to compare them with our two cases of women undergoing dialysis who successfully completed their term deliveries. Fluid volumes were measured every week before and after dialysis using BIA. We also measured the levels of human atrial natriuretic peptide after dialysis. During dialysis, the dry weight (DW) of pregnant patients is altered based on the state of the amniotic fluid and fetus. However, evaluating body fluid and DW using radiography is difficult in pregnant women. BIA offers a mostly harmless alternative for such measurements. Using BIA, we were able to easily measure body fluid volume and change the setting of DW for dialysis. Thus, our successful example can serve as a reference for future cases of pregnant women undergoing dialysis. Nevertheless, given that the state of the fetus and amniotic fluid affect the results of dialysis, it is important that we use not only BIA but also a comprehensive evaluation to determine dialysis settings in pregnant women.
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http://dx.doi.org/10.1111/1744-9987.13530DOI Listing
April 2021

ASP1126, a Novel Sphingosine-1-Phosphate-Selective Agonist With a Favorable Safety Profile, Prolongs Allograft Survival in Rats and Nonhuman Primates in Combination With Tacrolimus With a Broad Safety Margin for Bradycardia.

Transplant Proc 2019 Jul - Aug;51(6):2081-2098

Drug Discovery Research, Astellas Pharma Inc, Ibaraki, Japan.

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of 5 G protein-coupled receptors (S1P to S1P). Among these, S1P is a major regulator of lymphocyte trafficking. Fingolimod, whose active metabolite, fingolimod phosphate, acts as a nonselective S1P-receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating lymphocyte trafficking via downregulation of S1P expression on lymphocytes. Here, we describe the pharmacologic profile of a novel S1P agonist, ASP1126. ASP1126 preferentially activated S1P compared to S1P in rat and human guanosine-5'-(γ-thio)-triphosphate (GTPγS) assays. Oral single administration of ASP1126 decreased the number of peripheral lymphocytes and repeated dosing showed a cumulative effect on lymphopenia in both rats and monkeys. ASP1126 prolonged allograft survival in a rat heterotopic heart transplantation model in combination with a subtherapeutic dose of tacrolimus that was independent of drug-drug interactions. In addition, in nonhuman primate (NHP) renal transplantation, pretreatment with ASP1126 reduced not only the number of naive T cells and central memory T cells but also effector memory T cells in the peripheral blood, all of which could contribute to acute graft rejection and prolonged allograft survival in combination with tacrolimus. Further, we confirmed that ASP1126 has a broad ranging safety margin with respect to its effect on lung weight in rats and bradycardia in NHPs, which were the adverse events found in clinical studies of fingolimod. ASP1126 with improved safety profile has the potential to be an adjunct therapy in combination with tacrolimus in clinical transplantation.
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http://dx.doi.org/10.1016/j.transproceed.2019.05.012DOI Listing
November 2019

Spontaneous remission of giant cell arteritis: possible association with a preceding acute respiratory infection and seropositivity to antibodies.

Nagoya J Med Sci 2019 Feb;81(1):151-158

Department of Nephrology, Toyohashi Municipal Hospital, Toyohashi, Japan.

Recent epidemiological or immunopathological studies demonstrate the possible association between giant cell arteritis and infectious agents including . A 62-year-old Japanese man with type 1 diabetes mellitus developed biopsy-proven giant cell arteritis after acute upper respiratory infection. Serological examination indicated concurrent re-infection with . Clinical manifestations of the vasculitis subsided within a month without any immunosuppressive therapy, and no relapse was observed for the following 12 months. The natural history of this disease is unclear and spontaneous remission is rarely reported. The self-limiting nature of the infection could contribute to this phenomenon.
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http://dx.doi.org/10.18999/nagjms.81.1.151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433628PMC
February 2019

A Case of Chronic Calcium Oxalate Nephropathy due to Short Bowel Syndrome and Cholecystectomy.

Case Rep Nephrol Dial 2018 May-Aug;8(2):147-154. Epub 2018 Aug 10.

Department of Nephrology, Wakayama Medical University, Wakayama, Japan.

Background: Oxalate nephropathy is a rare disease. Especially chronic oxalate nephropathy still has many unknown aspects as compared to acute oxalate nephropathy with relatively well-known causality.

Case Presentation: The patient was a 70-year-old woman who had a history of small bowel resection 25 years before, cholecystectomy 10 years before, and renal stones (calcium oxalate stones) 7 years before. She had been suffering from chronic diarrhea and had been treated by a local physician. The patient was found to have renal dysfunction (creatinine 3.09 mg/dL, eGFR 12.3 mL/min/1.73 m, hemoglobin 7.8 g/dL) and was referred to our department. The patient was admitted to our hospital for further investigation. Renal ultrasound showed hepatorenal echo contrast in an opposite manner and clear contrast between the renal cortex and medullary pyramid. Renal biopsy was performed, and histological examination showed tubulointerstitial disorder due to deposition of calcium oxalate. Daily urinary excretion of calcium oxalate was significantly increased. The patient was encouraged to drink water and administered vitamin B, citric acid, K and Na hydrate. Thereafter, her symptoms improved.

Conclusion: Case reports of chronic oxalate neuropathy are rare in the literature, and its underlying mechanism has not been understood. Our patient had a history of small bowel resection and cholecystectomy. We considered that her short bowel syndrome had influenced the development of calcium oxalate nephropathy.
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http://dx.doi.org/10.1159/000491630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120416PMC
August 2018

Targeting macrophages to treat intracranial aneurysm.

Oncotarget 2017 Dec 28;8(62):104704-104705. Epub 2017 Sep 28.

Department of Molecular Pharmacology, Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan; Alliance Laboratory for Advanced Medical Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Kyoto, Japan.

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http://dx.doi.org/10.18632/oncotarget.21368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739593PMC
December 2017

A sphingosine-1-phosphate receptor type 1 agonist, ASP4058, suppresses intracranial aneurysm through promoting endothelial integrity and blocking macrophage transmigration.

Br J Pharmacol 2017 07 27;174(13):2085-2101. Epub 2017 May 27.

Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background And Purpose: Intracranial aneurysm (IA), common in the general public, causes lethal subarachnoid haemorrhage on rupture. It is, therefore, of utmost importance to prevent the IA from rupturing. However, there is currently no medical treatment. Recent studies suggest that IA is the result of chronic inflammation in the arterial wall caused by endothelial dysfunction and infiltrating macrophages. The sphingosine-1-phosphate receptor type 1 (S1P receptor) is present on the endothelium and promotes its barrier function. Here we have tested the potential of an S1P agonist, ASP4058, to prevent IA in an animal model.

Experimental Approach: The effects of a selective S1P agonist, ASP4058, on endothelial permeability and migration of macrophages across an endothelial cell monolayer were tested in vitro using a Transwell system, and its effects on the size of IAs were evaluated in a rat model of IA.

Key Results: S1P receptor was expressed in endothelial cells of human IA lesions and control arterial walls. ASP4058 significantly reduced FITC-dextran leakage through an endothelial monolayer and suppressed the migration of macrophages across the monolayer in vitro. Oral administration of ASP4058 reduced the vascular permeability, macrophage infiltration and size of the IAs by acting as an S1P agonist in the rat model. This effect was mimicked by another two structurally-unrelated S1P agonists.

Conclusion And Implications: A selective S1P agonist is a strong drug candidate for IA treatment as it promotes the endothelial cell barrier and suppresses the trans-endothelial migration of macrophages in IA lesions.
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http://dx.doi.org/10.1111/bph.13820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466536PMC
July 2017

[Efforts and the Future Agenda for Introducing the Quality Management System ISO 15189 in Akita University Hospital].

Rinsho Byori 2017 02;65(2):225-226

Quality management systems are the tools that document the processes and responsibilities to achieve quality policies and objectives. Recently, increasing numbers of clinical laboratories have been certified for ISO 15189, an international certification for hospital laboratories. However, our laboratory remains in the preparation process. Major obstacles in our hospital are the tight budget and the timing of introducing the ISO 15189 system because of the old equipment in our laboratory. To overcome these problems, we have made efforts including study workshops with invited lecturers with expertise, joining the prefectural work- shop for clinical technicians. We have also started to prepare standard operational procedures for each la- boratory test. As the preparation advances, it has become clear that gaining the understanding of the signifi- cance of ISO 15189 of hospital executives is indispensable, especially in respect to funding. It is our respon- sibility to achieve standardized and improved laboratory examinations, in order to contribute to high-quality medical care, research, and education. Achieving the certification for ISO 15189 offers a great opportunity to improve our skills in laboratory medicine.
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February 2017

ASP0028 in combination with suboptimal-dose of tacrolimus in Cynomolgus monkey renal transplantation model.

Transpl Immunol 2017 02 7;40:57-65. Epub 2017 Jan 7.

Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Canada. Electronic address:

FTY720, a S1P-receptor modulator, has shown to be effective in several transplant and autoimmune disease models, via modulating lymphocyte homing into secondary lymphoid organs (SLOs), and thereby reducing these cells in peripheral blood. ASP0028, a newly developed S1P/S1P-selective agonist, presented comparable efficacy to FTY720 and wider safety margins than FTY720. In this study, we assessed the efficacy and safety of ASP0028 co-administered with suboptimal-dose of tacrolimus in the Cynomolgus monkey renal transplantation model. Seven animals in group-1 or group-2 received mono-tacrolimus 1.0mg/kg once a day (QD), or ASP0028 0.6mg/kg plus tacrolimus 1.0mg/kg QD, respectively. Eight animals in group-3 received ASP0028 1.2mg/kg plus tacrolimus 1.0mg/kg QD. The allograft median survival time (MST) in group-2 and group-3 were significantly extended to 41 and 61.5days, versus that of 28days in group-1 (p=0.036 and 0.001, respectively). ASP0028 administration remarkably reduced absolute numbers of peripheral lymphocytes, particularly subsets of CD4/ or CD8/naive and central memory cells, CD4/Treg cells, and to a lesser extent on B cells, but not CD4/ or CD8/effector memory cells and NK cells. These data show ASP0028 combined with suboptimal-dose of tacrolimus effectively prolongs renal allograft survival in nonhuman primates (NHPs) with well tolerated safety, supporting its further investigation to optimize CNI-sparing regimens.
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http://dx.doi.org/10.1016/j.trim.2017.01.002DOI Listing
February 2017

Angiotensin II receptor blockade promotes repair of skeletal muscle through down-regulation of aging-promoting C1q expression.

Sci Rep 2015 Sep 25;5:14453. Epub 2015 Sep 25.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.

Disruption of angiotensin II type 1 (AT1) receptor prolonged life span in mice. Since aging-related decline in skeletal muscle function was retarded in Atgr1a(-/-) mice, we examined the role of AT1 receptor in muscle regeneration after injury. Administration of AT1 receptor blocker irbesartan increased the size of regenerating myofibers, decreased fibrosis, and enhanced functional muscle recovery after cryoinjury. We recently reported that complement C1q, secreted by macrophages, activated Wnt/β-catenin signaling and promoted aging-related decline in regenerative capacity of skeletal muscle. Notably, irbesartan induced M2 polarization of macrophages, but reduced C1q expression in cryoinjured muscles and in cultured macrophage cells. Irbesartan inhibited up-regulation of Axin2, a downstream gene of Wnt/β-catenin pathway, in cryoinjured muscles. In addition, topical administration of C1q reversed beneficial effects of irbesartan on skeletal muscle regeneration after injury. These results suggest that AT1 receptor blockade improves muscle repair and regeneration through down-regulation of the aging-promoting C1q-Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.1038/srep14453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585890PMC
September 2015

Effects of medetomidine and xylazine on intraocular pressure and pupil size in healthy Beagle dogs.

Vet Anaesth Analg 2015 Nov 20;42(6):623-8. Epub 2015 Feb 20.

Veterinary Teaching Hospital, Kurashiki University of Science and the Arts, Kurashiki, Japan.

Objective: To determine the effects of intramuscular (IM) administration of medetomidine and xylazine on intraocular pressure (IOP) and pupil size in normal dogs.

Study Design: Prospective, randomized, experimental, crossover trial.

Animals: Five healthy, purpose-bred Beagle dogs.

Methods: Each dog was administered 11 IM injections of, respectively: physiological saline; medetomidine at doses of 5, 10, 20, 40 and 80 μg kg(-1), and xylazine at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg kg(-1). Injections were administered at least 1 week apart. IOP and pupil size were measured at baseline (before treatment) and at 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours post-injection.

Results: A significant decrease in IOP was observed at 6 hours after 80 μg kg(-1) medetomidine compared with values at 0.25 and 0.50 hours, although there were no significant changes in IOP from baseline. In dogs treated with 8.0 mg kg(-1) xylazine, significant reductions in IOP were observed at 4 and 5 hours compared with that at 0.25 hours after administration. In dogs treated with 5, 10, 20 and 40 μg kg(-1) medetomidine and 0.5, 1.0 and 2.0 mg kg(-1) xylazine, there were no significant changes in IOP. Pupil size did not change significantly after any of the medetomidine or xylazine treatments compared with the baseline value.

Conclusions And Clinical Relevance: Low or moderate doses of medetomidine or xylazine did not induce significant changes in IOP or pupil size. In contrast, high doses of medetomidine or xylazine induced significant changes up to 8 hours after treatment, but values remained within the normal canine physiological range. The results of this study suggest a lack of significant change in IOP and pupil size in healthy dogs administered low or moderate doses of xylazine or medetomidine.
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http://dx.doi.org/10.1111/vaa.12249DOI Listing
November 2015

Comparison of antibody molecules produced from two cell lines with contrasting productivities and aggregate contents.

Biol Pharm Bull 2015 12;38(2):306-16. Epub 2014 Dec 12.

Bio-process Research and Development Laboratories, Kyowa Hakko Kirin Co., Ltd., 100-1 Hagiwara-machi, Takasaki; Graduate School of Engineering, Gunma University, 1-5-1 Tenjin-cho, Kiryu 376-8515, Japan.

Cell culture processes that produce therapeutic antibodies with high productivity (titer) and low aggregate content reduce the risk of adverse effects and expense to patients. To elucidate the mechanism of aggregate formation, we compared trastuzumab samples produced from two contrasting cell lines: cell line A, which exhibits high titer and low aggregate content, and cell line B, which exhibits low titer and high aggregate content. Cell line B produced significantly fewer (approximately 1/3) antibodies compared with cell line A and contained higher (approximately 3-fold) percentages of aggregates. The aggregates of antibodies found in the protein A-purified samples of cell line B were associated mostly with noncovalent interactions. Cell line B exhibited a low content of monomers/dimers of light chains in the medium and within cells. Because light chains are essential for the correct folding of heavy chains and secretion of mature antibodies, the characteristics of cell line B may be attributed to low levels of light chain production. In addition, protein A-purified antibodies from cell line B (but not those from cell line A) contained fragments that are expected to expose the hydrophobic CH3 domain, which may serve as nuclei for aggregation.
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http://dx.doi.org/10.1248/bpb.b14-00729DOI Listing
December 2015

Titer of trastuzumab produced by a Chinese hamster ovary cell line is associated with tricarboxylic acid cycle activity rather than lactate metabolism.

J Biosci Bioeng 2015 Apr 7;119(4):478-85. Epub 2014 Nov 7.

Graduate School of Engineering, Gunma University, 1-5-1 Tenjin-cho, Kiryu-shi, Gunma 376-8515, Japan.

Achieving high productivity and quality is the final goal of therapeutic antibody development, but the productivity and quality of antibodies are known to be substantially dependent on the nature of the cell lines expressing the antibodies. We characterized two contrasting cell lines that produce trastuzumab, namely cell line A with a high titer and a low aggregate content and cell line B with a low titer and a high aggregate content to identify the causes of the differences. We observed the following differences: cell growth (A > B), proportion of defucosylated oligosaccharides on antibodies (A < B), and proportion of covalent antibody aggregates (A > B). Our results suggest that the high monoclonal antibody (mAb) titers in cell line A is associated with the high proliferation and is not caused by the lactate metabolism shift (switching from lactate production to net lactate consumption). Rather, these differences can be accounted for by the following: levels of tricarboxylic acid cycle intermediates (A > B), ammonium ion levels (A ≤ B), and oxidative stress (A > B).
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http://dx.doi.org/10.1016/j.jbiosc.2014.09.017DOI Listing
April 2015

ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile.

PLoS One 2014 27;9(10):e110819. Epub 2014 Oct 27.

Tsukuba Research Center, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of five G protein-coupled receptors (S1P1-S1P5). S1P1 is a major regulator of lymphocyte trafficking, and fingolimod, whose active metabolite fingolimod phosphate acts as a nonselective S1P receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating the lymphocyte trafficking by inducing down regulation of lymphocyte S1P1. Here, we detail the pharmacological profile of 5-{5-[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (ASP4058), a novel next-generation S1P receptor agonist selective for S1P1 and S1P5. ASP4058 preferentially activates S1P1 and S1P5 compared with S1P2, 3, 4 in GTPγS binding assays in vitro. Oral administration of ASP4058 reduced the number of peripheral lymphocytes and inhibited the development of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Further, ASP4058 prevented relapse of disease in a mouse model of relapsing-remitting EAE. Although these immunomodulatory effects were comparable to those of fingolimod, ASP4058 showed a wider safety margin than fingolimod for bradycardia and bronchoconstriction in rodents. These observations suggest that ASP4058 represents a new therapeutic option for treating multiple sclerosis that is safer than nonselective S1P receptor agonists such as fingolimod.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110819PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210206PMC
June 2015

Identification and quantification of amyloid beta-related peptides in human plasma using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Proc Jpn Acad Ser B Phys Biol Sci 2014 ;90(3):104-17

Koichi Tanaka Laboratory of Advanced Science and Technology, Shimadzu Corporation.

Proteolytic processing of the amyloid precursor protein (APP) by β-secretase and γ-secretase leads to the generation and deposition of amyloid β (Aβ) in Alzheimer's disease (AD). N-terminally or C-terminally truncated Aβ variants have been found in human cerebrospinal fluid and cultured cell media using immunoprecipitation and mass spectrometry. Unfortunately, the profile of plasma Aβ variants has not been revealed due to the difficulty of isolating Aβ from plasma. We present here for the first time studies of Aβ and related peptides in human plasma. Twenty-two Aβ-related peptides including novel peptides truncated before the β-secretase site were detected in human plasma and 20 of the peptides were identified by tandem mass spectrometry. Using an internal standard, we developed a quantitative assay for the Aβ-related peptides and demonstrated plasma dilution linearity and the precision required for their quantitation. The present method should enhance the understanding of APP processing and clearance in AD progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997810PMC
http://dx.doi.org/10.2183/pjab.90.104DOI Listing
October 2014

Effects of various phytochemicals on indoleamine 2,3-dioxygenase 1 activity: galanal is a novel, competitive inhibitor of the enzyme.

PLoS One 2014 12;9(2):e88789. Epub 2014 Feb 12.

Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto-City, Kyoto, Japan.

Indoleamine 2,3-dioxygenase (IDO) 1, that catalyzes the first and rate-limiting step in the degradation of L-tryptophan, has an important immunomodulatory function. The activity of IDO1 increases in various inflammatory diseases, including tumors, autoimmune diseases, and different kinds of inflammation. We evaluated the suppressive effect of plant extracts or phytochemicals on IDO1 induction and activity; sixteen kinds of plants extracts and fourteen kinds of phytochemicals were examined. As a result, the methanol extracts of Myoga flower buds, which are traditional Japanese foods, and labdane-type diterpene galanal derived from Myoga flowers significantly suppressed IDO1 activity. The Lineweaver-Burk plot analysis indicated that galanal is a competitive inhibitor. Galanal attenuated L-kynurenine formation with an IC₅₀ value of 7.7 µM in the assay system using recombinant human IDO1, and an IC₅₀ value of 45 nM in the cell-based assay. Further, mechanistic analysis revealed that galanal interfered with the transcriptional function of the nuclear factor-κB and the interferon-γ signaling pathway. These effects of galanal are important for immune response. Because the inhibitory effect of galanal on IDO1 activity was stronger than that of 1-methyl tryptophan, a tryptophan analog, galanal may have great potential as the novel drug for various immune-related diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088789PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923053PMC
January 2015

Iontophoretic transdermal delivery of glycyrrhizin: effects of pH, drug concentration, co-ions, current intensity, and chemical enhancers.

Chem Pharm Bull (Tokyo) 2013 ;61(12):1275-81

Department of Device Development, TTI ellebeau, Inc.

The aim of the present study was to evaluate the feasibility of transdermal delivery of glycyrrhizin, an agent used in the treatment of chronic hepatitis C, by cathodal iontophoresis using Ag/AgCl electrodes in vitro. The effects of donor pH (pH 4-7), concentration of drug (0.025-0.2% (w/v)), concentration of external chloride ions (Cl(-)) (0-133 mM), current strength (0-0.5 mA/cm(2)), and permeation enhancers (urea and Tween 80) on the skin permeability of glycyrrhizin were examined in in vitro skin permeation studies using porcine ear skin as the membrane. The cumulative amount of permeated glycyrrhizin and the steady-state skin permeation flux of glycyrrhizin across porcine skin increased in a pH-dependent manner. The skin permeability of glycyrrhizin was independent of the concentration of drug and competed only with a high external Cl(-) concentration. The skin permeation flux of glycyrrhizin increased with the current (R(2)=0.8955). The combination of iontophoresis and enhancers provided an additive or synergistic effect, and a skin permeation flux of about 60 µg/h/cm(2) was achieved. The plasma concentration of glycyrrhizin in humans, extrapolated from the in vitro steady-state permeation flux across porcine skin, was within the therapeutic level. These results suggest that cathodal iontophoresis can be used as a transdermal drug delivery system for glycyrrhizin using reasonable patch sizes and acceptable levels of current intensity.
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http://dx.doi.org/10.1248/cpb.c13-00548DOI Listing
July 2014

Adiponectin attenuates human eosinophil adhesion and chemotaxis: implications in allergic inflammation.

J Asthma 2013 Oct 17;50(8):828-35. Epub 2013 Jul 17.

Department of Infection, Allergy, Clinical Immunology and Laboratory Medicine, Akita University Graduate School of Medicine , Akita , Japan.

Objective: Growing evidence has shown an association between obesity and asthma. Adiponectin, an adipocyte-derived cytokine, is known to have anti-inflammatory effects with reduced concentrations in obese subjects. Recent findings raised the intriguing possibility that adiponectin might play a role in allergic inflammation, although the mechanistic basis for their relationship remains unclear. The purpose of this study was to examine whether adiponectin might affect functions of eosinophils, which play an important role in the pathogenesis of asthma.

Methods: Human peripheral blood eosinophils were purified to study expression of adiponectin receptors AdipoR1 and AdipoR2 using RT-PCR and flow cytometry. The effect of adiponectin on eosinophil survival was investigated using annexin V and propidium iodide staining. Eotaxin-induced cell adhesion was investigated using ICAM-1-coated plates. A Boyden chamber and real-time horizontal migration system were used for eotaxin-directed chemotaxis assay. Expression of eotaxin receptor CCR3 and intracellular calcium influx were assessed by flow cytometry.

Results: AdipoR1 and AdipoR2 were expressed in human eosinophils. Adiponectin did not affect eosinophil survival or CCR3 expression; however, eotaxin-enhanced adhesion was inhibited by pretreatment with adiponectin. Adiponectin also diminished eotaxin-directed chemotactic responses by disturbing both velocity and directionality. Calcium influx in response to eotaxin was attenuated by adiponectin.

Conclusions: These results indicate that adiponectin attenuates the eosinophil functions induced by eotaxin without affecting cell viability. The inhibitory effect was associated with diminished calcium signaling rather than altering of surface receptor expression. Increasing circulating adiponectin might be a novel therapeutic modality for treatment of asthma, especially in obese asthmatics.
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http://dx.doi.org/10.3109/02770903.2013.816725DOI Listing
October 2013

Self-organizing map analysis using multivariate data from theophylline tablets predicted by a thin-plate spline interpolation.

Chem Pharm Bull (Tokyo) 2013 ;61(3):304-9

Department of Pharmaceutics, Hoshi University, Shinagawa-ku, Tokyo, Japan.

The "quality by design" concept in pharmaceutical formulation development requires the establishment of a science-based rationale and a design space. We integrated thin-plate spline (TPS) interpolation and Kohonen's self-organizing map (SOM) to visualize the latent structure underlying causal factors and pharmaceutical responses. As a model pharmaceutical product, theophylline tablets were prepared based on a standard formulation. The tensile strength, disintegration time, and stability of these variables were measured as response variables. These responses were predicted quantitatively based on nonlinear TPS. A large amount of data on these tablets was generated and classified into several clusters using an SOM. The experimental values of the responses were predicted with high accuracy, and the data generated for the tablets were classified into several distinct clusters. The SOM feature map allowed us to analyze the global and local correlations between causal factors and tablet characteristics. The results of this study suggest that increasing the proportion of microcrystalline cellulose (MCC) improved the tensile strength and the stability of tensile strength of these theophylline tablets. In addition, the proportion of MCC has an optimum value for disintegration time and stability of disintegration. Increasing the proportion of magnesium stearate extended disintegration time. Increasing the compression force improved tensile strength, but degraded the stability of disintegration. This technique provides a better understanding of the relationships between causal factors and pharmaceutical responses in theophylline tablet formulations.
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http://dx.doi.org/10.1248/cpb.c12-00895DOI Listing
December 2013

Multi epitope-targeting immunoprecipitation using F(ab') fragments with high affinity and specificity for the enhanced detection of a peptide with matrix-assisted laser desorption ionization-time-of-flight mass spectrometry.

Anal Chem 2013 Mar 26;85(6):3152-9. Epub 2013 Feb 26.

Koichi Tanaka Laboratory of Advanced Science and Technology, Shimadzu Corporation, Nakagyo-ku, Kyoto, Japan.

Human plasma has been frequently studied using mass spectrometry for new biomarker discovery, although detection of low-abundance biological molecules can be challenging due to sample complexity and dynamic protein concentration ranges of plasma proteins. While immunoprecipitation coupled with mass spectrometric analysis is an essential method for overcoming this difficulty, its sensitivity can be insufficient to detect clinically relevant circulating biomarkers because of limited antibody affinity or specificity. To increase antibody affinity, we developed a strategy using a F(ab') fragment coupled to polyethylene glycol. We produced hetero-F(ab')-(PEG)24 beads composed of two monoclonal antiamyloid β antibodies (6E10 and 4G8) that are specific for different epitopes of amyloid β and assessed the detection limit of amyloid β(1-28)-spiked human plasma. In human plasma, the detection limit of amyloid β(1-28) was 6.14 pM, which was 25- to 50-fold more sensitive than single IgG-protein G beads. In addition, an introduction of polyethylene glycol as a linker reduced nonspecific binding, leading to highly specific MS detection. Finally, the present IP method enabled the detection of endogenous amyloid β(1-40) in 250 μL of human plasma with matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). This technique provides a powerful approach for enhancing the sensitivity and specificity of immunoprecipitation (IP)-MS for detection of low-abundance peptides in plasma and has the potential to accelerate MS-based clinical applications.
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http://dx.doi.org/10.1021/ac303344hDOI Listing
March 2013

Improvement of mass spectrometry analysis of glycoproteins by MALDI-MS using 3-aminoquinoline/α-cyano-4-hydroxycinnamic acid.

Anal Bioanal Chem 2013 May 5;405(12):4289-93. Epub 2013 Feb 5.

Koichi Tanaka Laboratory of Advanced Science and Technology, Shimadzu Corporation, Nakagyo-ku, Kyoto, Japan.

Protein glycosylation analysis is important for elucidating protein function and molecular mechanisms in various biological processes. We previously developed a glycan analysis method using a 3-aminoquinoline/α-cyano-4-hydroxycinnamic acid liquid matrix (3-AQ/CHCA LM) and applied it to the quantitative glycan profiling of glycoproteins. However, information concerning glycosylation sites is lost; glycopeptide analysis is therefore required to identify the glycosylation sites in glycoproteins. Human epidermal growth factor receptor 2 (HER2) is a glycoprotein that plays a role in the regulation of cell proliferation, differentiation, and migration. Several reports have described the structure of HER2, but the structures of N-glycans attached to this protein remain to be fully elucidated. In this study, 3-AQ/CHCA LM was applied to tryptic digests of HER2 to reveal its N-glycosylation state and to evaluate the utility of this LM in characterizing glycopeptides. Peptide sequence coverage was considerably improved compared to analysis of HER2 using α-cyano-4-hydroxycinnamic acid or 2,5-dihydroxybenzoic acid. Most of the peaks observed using only this LM were localized at the inner or outer regions of sample spots. Furthermore, five of the peptide peaks that were enriched within the inner region were confirmed to be glycosylated by MS/MS analysis. Three glycosylation sites were identified and their glycan structures were elucidated. The reduction in sample complexity by on-target separation allowed for higher sequence coverage, resulting in effective detection and characterization of glycopeptides. In conclusion, these results demonstrate that MS-based glycoprotein analysis using 3-AQ/CHCA is an effective method to identify glycosylation sites in proteins and to elucidate the glycan structures of glycoproteins in complex samples.
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http://dx.doi.org/10.1007/s00216-013-6771-yDOI Listing
May 2013

Sudden asphyxia caused by retropharyngeal hematoma after blunt thyrocervical artery injury.

J Emerg Med 2012 Sep 25;43(3):451-6. Epub 2012 Feb 25.

Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Kanagawa, Japan.

Background: Retropharyngeal hematomas are often associated with blunt cervical spine injury. Generally, they improve with conservative treatment; however, rarely, airway obstruction occurs due to delayed swelling of retropharyngeal hematoma.

Objectives: To report a case of sudden asphyxia due to retropharyngeal hematoma caused by blunt thyrocervical artery injury.

Case Report: A 30-year-old woman was admitted to the Emergency Department of Tokai University Hospital 4h after injury in a motor vehicle collision. On arrival, she had severe dyspnea and neck swelling; thereafter, a 26-mm-thick retropharyngeal swelling was visualized on lateral cervical plain X-ray study, extending from C1 anterior vertebrae to mediastinum. Emergency intubation was performed for the asphyxia. Because extravasation of contrast agent was observed in the hematoma on emergency contrast-enhanced computed tomography (CT) scan, emergency angiography was performed, from which we diagnosed a hemorrhage from the right thyrocervical artery.

Conclusion: If a patient with a non-displaced cervical spine injury suffers airway obstruction due to retropharyngeal hematoma, vigorous hemorrhage from a thyrocervical artery injury should be considered as the cause, and emergency contrast-enhanced CT scan of the neck should be performed after emergent tracheal intubation.
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http://dx.doi.org/10.1016/j.jemermed.2011.05.094DOI Listing
September 2012

Agonist-independent constitutive activity of angiotensin II receptor promotes cardiac remodeling in mice.

Hypertension 2012 Mar 30;59(3):627-33. Epub 2012 Jan 30.

Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.

The angiotensin II (Ang II) type 1 (AT(1)) receptor mainly mediates the physiological and pathological actions of Ang II, but recent studies have suggested that AT(1) receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in culture cells. To elucidate the role of Ang II-independent AT(1) receptor activation in the pathogenesis of cardiac remodeling, we generated transgenic mice overexpressing AT(1) receptor under the control of α-myosin heavy chain promoter in angiotensinogen-knockout background (AT(1)Tg-AgtKO mice). In AT(1)Tg-AgtKO hearts, redistributions of the Gα(q11) subunit into cytosol and phosphorylation of extracellular signal-regulated kinases were significantly increased, compared with angiotensinogen-knockout mice hearts, suggesting that the AT(1) receptor is constitutively activated independent of Ang II. As a consequence, AT(1)Tg-AgtKO mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in AT(1)Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for the AT(1) receptor, but not by its derivative candesartan-7H, deficient of inverse agonism attributed to a lack of the carboxyl group at the benzimidazole ring. Our results demonstrate that constitutive activity of the AT(1) receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT(1) receptor is upregulated in the heart.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.175208DOI Listing
March 2012

Acute renal failure and metabolic acidosis due to oxalic acid intoxication: a case report.

Tokai J Exp Clin Med 2011 Dec 20;36(4):116-9. Epub 2011 Dec 20.

Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Most of the reports of oxalic acid intoxication are in cases of ethylene glycol intoxication. These symptoms are known to be central nerve system manifestations, cardiopulmonary manifestations and acute renal failure. There have been only a few reports of direct oxalic acid intoxication. However, there have been a few recent reports of oxalic acid intoxication due to the ingestion of star fruit and ascorbic acid. We herein report the case of a patient with acute renal failure and metabolic acidosis caused directly by consumption of oxalic acid. During the initial examination by the physician at our hospital, the patient presented with tachypnea, a precordinal burning sensation, nausea and metabolic acidosis. After admission, the patient developed renal failure and anion gap high metabolic acidosis, but did not develop any CNS or cardio-pulmonary manifestations in the clinical course. The patient benefitted symptomatically from hemodialysis.
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December 2011

In vitro and in vivo transdermal iontophoretic delivery of naloxone, an opioid antagonist.

Int J Pharm 2012 Jan 15;422(1-2):132-8. Epub 2011 Nov 15.

Department of Device Development, TTI ellebeau, Inc., 4-8-8, Higashi-Shinagawa, Shinagawa-ku, Tokyo 140-0002, Japan.

Aim: The feasibility of transdermal delivery of naloxone, an opioid antagonist, by anodal iontophoresis patches using Ag/AgCl electrodes was investigated.

Methods: To examine the effect of current strength, species variation and drug concentration on skin permeability of naloxone, in vitro skin permeation studies were performed using rat dorsal skin and porcine ear skin as the membrane. To determine in vivo transdermal absorption rate of naloxone, the iontophoretic patch system was applied to the dorsal skin of conscious rat with a constant current supply for 24h.

Results: The in vitro steady-state skin permeation flux of naloxone current-proportionally (0-360 μA/cm(2)) increased without significant differences between these two different skin types. The in vitro delivery rate through the porcine skin was found to be independent of the concentration of naloxone hydrochloride dehydrate in the donor patch over the range from 1 to 10% (w/v). In the in vivo pharmacokinetic study, plasma concentrations of naloxone steadily increased and sustained steady-state levels from 4h to 24h after the initiation of current application. In vivo steady-state transdermal absorption rates at 90 and 180 μA/cm(2) were 136 and 305 μg/h/cm(2), respectively.

Conclusion: These results suggest that the transdermal delivery rates of naloxone by anodal iontophoresis are sufficient for the management of intoxication in opioid-overdosed patients.
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http://dx.doi.org/10.1016/j.ijpharm.2011.10.042DOI Listing
January 2012

In-vitro and in-vivo transdermal iontophoretic delivery of tramadol, a centrally acting analgesic.

J Pharm Pharmacol 2011 Nov 27;63(11):1437-45. Epub 2011 Sep 27.

Department of Device Development, TTI ellebeau, Inc., Higashi-Shinagawa, Shinagawa-ku, Tokyo, Japan.

Objectives: The feasibility of transdermal delivery of tramadol, a centrally acting analgesic, by anodal iontophoresis using Ag/AgCl electrodes was investigated in vitro and in vivo.

Methods: To examine the effect of species variation and current strength on skin permeability of tramadol, in-vitro skin permeation studies were performed using porcine ear skin, guinea-pig abdominal skin and hairless mouse abdominal skin as the membrane. In an in-vivo pharmacokinetic study, an iontophoretic patch system was applied to the abdominal skin of conscious guinea pigs with a constant current supply (250 µA/cm(2)) for 6 h. An intravenous injection group to determine the pharmacokinetic parameters for estimation of the transdermal absorption rate in guinea pigs was also included.

Key Findings: The in-vitro steady-state skin permeation flux of tramadol current-dependently increased without significant differences among the three different skin types. In the in-vivo pharmacokinetic study, plasma concentrations of tramadol steadily increased and reached steady state (336 ng/ml) 3 h after initiation of current supply, and the in-vivo steady-state transdermal absorption rate was 499 µg/cm(2) per h as calculated by a constrained numeric deconvolution method.

Conclusions: The present study reveals that anodal iontophoresis provides current-controlled transdermal delivery of tramadol without significant interspecies differences, and enables the delivery of therapeutic amounts of tramadol.
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http://dx.doi.org/10.1111/j.2042-7158.2011.01355.xDOI Listing
November 2011

Angiotensin II type 1 receptor signaling regulates feeding behavior through anorexigenic corticotropin-releasing hormone in hypothalamus.

J Biol Chem 2011 Jun 27;286(24):21458-65. Epub 2011 Apr 27.

Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Chiba 260-8670, Japan.

The activation of renin-angiotensin system contributes to the development of metabolic syndrome and diabetes as well as hypertension. However, it remains undetermined how renin-angiotensin system is implicated in feeding behavior. Here, we show that angiotensin II type 1 (AT(1)) receptor signaling regulates the hypothalamic neurocircuit that is involved in the control of food intake. Compared with wild-type Agtr1a(+/+) mice, AT(1) receptor knock-out (Agtr1a(-/-)) mice were hyperphagic and obese with increased adiposity on an ad libitum diet, whereas Agtr1a(-/-) mice were lean with decreased adiposity on a pair-fed diet. In the hypothalamus, mRNA levels of anorexigenic neuropeptide corticotropin-releasing hormone (Crh) were lower in Agtr1a(-/-) mice than in Agtr1a(+/+) mice both on an ad libitum and pair-fed diet. Furthermore, intracerebroventricular administration of CRH suppressed food intake both in Agtr1a(+/+) and Agtr1a(-/-) mice. In addition, the Crh gene promoter was significantly transactivated via the cAMP-responsive element by angiotensin II stimulation. These results thus demonstrate that central AT(1) receptor signaling plays a homeostatic role in the regulation of food intake by maintaining gene expression of Crh in hypothalamus and suggest a therapeutic potential of central AT(1) receptor blockade in feeding disorders.
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http://dx.doi.org/10.1074/jbc.M110.192260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122205PMC
June 2011

Efficacy of portable and percutaneous cardiopulmonary bypass rewarming versus that of conventional internal rewarming for patients with accidental deep hypothermia.

Crit Care Med 2011 May;39(5):1064-8

Department of Emergency and Critical Care Medicine, Tokai University School of Medicine, Shimokasuya Isehara-City, Kanagawa, Japan.

Objective: Since 2001, at our institution, a portable and percutaneous cardiopulmonary bypass system has been used for rewarming of patients with accidental deep hypothermia. Before 2001, a conventional internal rewarming technique was used. The aim of this research is to examine the efficacy of portable and percutaneous cardiopulmonary bypass for rewarming of patients with accidental severe hypothermia and compare it with that of conventional rewarming methods.

Design: Historical study.

Setting: The exclusive emergency medical center and trauma center level 1 in Western Kanagawa, Japan.

Patients: From April 1992 to March 2009, 70 patients with accidental deep hypothermia (core temperature <28°C) were transferred to our hospital. Two patients presented with intracranial hemorrhage on initial head computed tomography scans. These two patients were excluded because each required an emergency operation. Therefore, 68 patients were included in this study. We compared patients' clinical characteristics and outcomes. The parameters included the following: sex, age, vital signs on arrival to our hospital (Glasgow coma Scale scores, systolic blood pressure, heart rate, respiratory rate, core temperature), electrocardiogram on arrival to our hospital, rewarming speed, time of rewarming until 34°C was reached, ventricular fibrillation occurrence rate during rewarming, cause of cold environmental exposure, Glasgow Outcome Scale scores, and mortality. In addition, we divided the conventional and portable and percutaneous cardiopulmonary bypass rewarming groups into two categories depending on whether cardiopulmonary arrest occurred on arrival to our hospital. We also compared the survival rate and average Glasgow Outcome Scale scores for each group.

Interventions: None.

Measurements And Main Results: Patients' clinical backgrounds did not differ significantly between the conventional and portable and percutaneous cardiopulmonary bypass rewarming groups. Glasgow Outcome Scale scores and survival rates of the portable and percutaneous cardiopulmonary bypass rewarming group patients, irrespective of whether cardiopulmonary arrest was experienced on arrival to our hospital, were significantly higher than those of the conventional rewarming group.

Conclusions: Portable and percutaneous cardiopulmonary bypass rewarming can improve the mortality rates and Glasgow Outcome Scale scores of accidental deep hypothermia patients.
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http://dx.doi.org/10.1097/CCM.0b013e31820edd04DOI Listing
May 2011