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Yoshimura N.,Tokyo Yamate Medical Center | Watanabe M.,Tokyo Medical and Dental University | Motoya S.,Sapporo Kosei General Hospital | Tominaga K.,Dokkyo Medical University | And 4 more authors.
Gastroenterology | Year: 2015

Background & Aims AJM300 is an orally active small-molecule antagonist of the α4 integrin subunit. We performed a randomized trial to investigate the efficacy and safety of AJM300 in patients with active ulcerative colitis (UC). Methods In a double-blind, placebo-controlled, phase 2a study, 102 patients with moderately active UC (Mayo Clinic scores of 6-10, endoscopic subscores ≤2, and rectal bleeding subscores ≤1) who had inadequate response or intolerance to mesalamine or corticosteroids were randomly assigned to receive AJM300 (960 mg) or placebo 3 times daily for 8 weeks. The primary end point was a clinical response at week 8, defined as a decrease in Mayo Clinic score of at least 3 points and a decrease of at least 30% from baseline, with a decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Results Clinical response rates were 62.7% and 25.5% at week 8 in the AJM300 group and placebo group, respectively (odds ratio [OR] = 5.35; 95% confidence interval [CI]: 2.23-12.82; P =.0002). Rates of clinical remission (Mayo Clinic score ≤2 and no subscore >1) were 23.5% and 3.9% in the AJM300 group and placebo groups, respectively (OR = 7.81; 95% CI: 1.64-37.24; P =.0099), and rates of mucosal healing (endoscopic subscores of 0 or 1) were 58.8% and 29.4% (OR = 4.65; 95% CI: 1.81-11.90; P =.0014). No serious adverse event, including progressive multifocal leukoencephalopathy, was observed, although more investigations are needed to confirm the safety profile of this drug. Conclusions AJM300 was well tolerated and more effective than placebo in inducing clinical response, clinical remission, and mucosal healing in patients with moderately active UC. ClinicalTrials.jp no: JapicCTI-132293. © 2015 AGA Institute. Source


Matsue Y.,Kameda Medical Center | Suzuki M.,Kameda Medical Center | Torii S.,Tokai University | Yamaguchi S.,Tomishiro Central Hospital | And 12 more authors.
Journal of Cardiac Failure | Year: 2016

Background More efficacious and/or safer decongestive therapy is clearly needed in acute heart failure (AHF) patients complicated by renal dysfunction. We tested the hypothesis that adding tolvaptan, an oral vasopressin-2 receptor antagonist, to conventional therapy with loop diuretics would be more effective treatment in this population. Methods and Results A multicenter, open-label, randomized control trial was performed, and 217 AHF patients with renal dysfunction (estimated glomerular filtration rate 15–60 mL • min−1 • 1.73 m−2) were randomized 1:1 to treatment with tolvaptan (n = 108) or conventional treatment (n = 109). The primary end point was 48-hour urine volume. The tolvaptan group showed more diuresis than the conventional treatment group (6464.4 vs 4999.2 mL; P < .001) despite significantly lower amounts of loop diuretic use (80 mg vs 120 mg; P < .001). Dyspnea relief was achieved significantly more frequently in the tolvaptan group at all time points within 48 hours except 6 hours after enrollment. The rate of worsening of renal function (≥0.3 mg/dL increase from baseline) was similar between the tolvaptan and conventional treatment groups (24.1% vs 27.8%, respectively; P = .642). Conclusions Adding tolvaptan to conventional treatment achieved more diuresis and relieved dyspnea symptoms in AHF patients with renal dysfunction. Clinical Trial Registration URL: http://www.umin.ac.jp/ctr/index/htm/ Unique identifier: UMIN000007109 © 2016 Elsevier Inc. Source


Suzuki K.,National Institute of Mental Health | Kobayashi T.,National Institute of Mental Health | Kobayashi T.,Tokyo Yamate Medical Center | Moriyama K.,National Institute of Mental Health | And 8 more authors.
No To Hattatsu | Year: 2015

Objective: Resilience is defined as the dynamic process of positive adaptation despite the experience of adversity. The aims of this study were to apply the concept of resilience to the mothers of children with autism spectrum disorder (ASD), which we call "parenting resilience" for rearing a child with ASD, and to explain the construct of parenting resilience. Methods: Interviews were conducted with 23 mothers of adults with ASD to collect data on rearing these children from infancy to adulthood. Data were analyzed using a modified grounded-theory approach. Results: The analytic theme was the thought process from the problems associated with raising developmentally challenged children to the implementation of the appropriate coping method. We proposed a model comprising twelve concepts and five categories, i. e., "a sense of motherhood", "self-efficacy", "knowledge of the child's characteristics", "perceived social support", and "foresight". The model assumes that a sense of motherhood and self-efficacy motivate these mothers to cope with the problems associated with developmentally challenged children, and they derive the way of dealing with it from knowledge of the child's characteristics, perceived social support, and foresight. Discussion: We suggest that the construct of parenting resilience for rearing a child with ASD is composed of the proposed categories and concepts. Source


Zhang Y.,RIKEN | Fukui N.,Tokyo University of Science | Yahata M.,RIKEN | Katsuragawa Y.,Center Hospital of the National Center for Global Health and Medicine Center Hospital | And 4 more authors.
Osteoarthritis and Cartilage | Year: 2016

Objective: The aim of this work was to characterize the genome-wide DNA methylation profile of cartilage from three regions of tibial plateau isolated from patients with primary knee osteoarthritis (OA), providing the first DNA methylation study that reflects OA progression. Methods: The unique model system was used to section three regions of tibial plateau: the outer lateral tibial plateau (oLT), the inner lateral tibial plateau (iLT) and the inner medial tibial plateau (iMT) regions which represented the early, intermediate and late stages of OA, respectively. Genome-wide DNA methylation profile was examined using Illumina Infinium HumanMethylation450 BeadChip array. Comparisons of the iLT/oLT and iMT/oLT groups were carried out to identify differentially methylated (DM) probes (DMPs) associated with OA progression. DM genes were analyzed to identify the gene ontologies (GO), pathways, upstream regulators and networks. Results: No significant DMPs were identified in iLT/oLT group, while 519 DMPs were identified in iMT/oLT group. Over half of them (68.2%) were hypo-methylated and enriched in enhancers and OpenSea. Upstream regulator analysis identified many microRNAs. DM genes were enriched in transcription factors, especially homeobox genes and in Wnt/β-catenin signaling pathway. These genes also showed changes in expression when analyzed with expression profiles generated from previous studies. Conclusion: Our data suggested the changes in DNA methylation occurred at the late stage of OA. Pathways and networks enriched in identified DM genes highlighted potential etiologic mechanism and implicated the potential cartilage regeneration in the late stage of knee OA. © 2016 Osteoarthritis Research Society International. Source


Kawaguchi T.,center | Mori M.,Ajinomoto Co. | Saito K.,Tokyo Yamate Medical Center | Suga Y.,Ajinomoto Co. | And 12 more authors.
Journal of Gastroenterology | Year: 2015

Background: In Crohn’s disease (CD), the involvement of food antigens in immune responses remains unclear. The objective of this study was to detect immune responses against food antigens in CD patients and examine the mechanism in a mouse model of colitis. Methods: We enrolled 98 CD patients, 50 ulcerative colitis patients, and 52 healthy controls (HCs) to compare the levels of serum immunoglobulin (Ig)Gs against 88 foods. The presence of serum IgGs against foods was also examined in interleukin (IL)-10 knockout (KO) mice in which CD4+ T cell activation by antigenic food protein was assessed. Mice transferred with IL-10 KO cells received diets with or without food antigens, and the development of colitis was evaluated. Results: The prevalence of IgGs against various foods, especially vegetables, grains, and nuts, was significantly higher in CD patients than in HCs. Similarly, the prevalence of IgGs against food proteins was higher in IL-10 KO mice than in BALB/c mice. Beta-conglycinin, identified as an antigenic food proteins in IL-10 KO mice, induced CD4+ T cell production of interferon-γ and IL-17 through dendritic cell antigen presentation. Elimination of the food antigens ameliorated the development of colitis in mice without altering the composition of their intestinal microbiota. Conclusions: In CD colitis mice, intestinal inflammation via CD4+ T cell hyperactivation was induced by food antigens associated with high serum IgG levels and was ameliorated by the elimination of food antigens. This disrupted immunological tolerance to food antigen, which might act as an exacerbating factor, remains to be elucidated in CD patients. © 2014, The Author(s). Source

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