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Akihiro Uchida,1,* Taro Yasuma,1,2,* Atsuro Takeshita,1,2,* Masaaki Toda,2 Yuko Okano,1,2 Kota Nishihama,1 Corina N D’Alessandro-Gabazza,2 Valeria Fridman D’Alessandro,2 Chisa Inoue,1 Takehiro Takagi,3 Hiroyuki Mukaiyama,4 Norio Takagi,4 Katsumi Shimizu,4 Yutaka Yano,1 Esteban C Gabazza2 1Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan; 2Department of Immunology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan; 3Iwasaki Hospital, Tsu, Mie, Japan; 4Tanisake Corporation, Gifu, Japan*These authors contributed equally to this workCorrespondence: Esteban C GabazzaDepartment of Immunology, Mie University School of Medicine, Edobashi 2-174, Tsu-City, Mie, 514-8507, JapanTel +81 59 231 5037Fax +81 59 231 5225Email gabazza@doc.medic.mie-u.ac.jpIntroduction: Diabetes mellitus is a serious threat to public health worldwide. It causes a substantial economic burden, mental and physical disabilities, poor quality of life, and high mortality. Limonite is formed when iron-rich materials from the underground emerge and oxidized on the ground surface. It is currently used to purify contaminated water, absorption of irritant gases, and improve livestock breeding. Limonite can change the composition of environmental microbial communities. In the present study, we evaluated whether limonite can ameliorate glucose metabolism abnormalities by remodeling the gut microbiome.Methods: The investigation was performed using mouse models of streptozotocin-induced diabetes mellitus and high-calorie diet-induced metabolic syndrome.Results: Oral limonite supplement was associated with significant body weight recovery, reduced glycemia with improved insulin secretion, increased number of regulatory T cells, and abundant beneficial gut microbial populations in mice with diabetes mellitus compared to control. Similarly, mice with obesity fed with limonite supplements had significantly reduced body weight, insulin resistance, steatohepatitis, and systemic inflammatory response with significant gut microbiome remodeling.Conclusion: This study demonstrates that limonite supplement ameliorates abnormal glucose metabolism in diabetes mellitus and obesity. Gut microbiome remodeling, inhibition of inflammatory cytokines, and the host immune response regulation may explain the limonite’s beneficial activity under pathological conditions in vivo.Keywords: insulin resistance, limonite, diabetes, streptozotocin, metabolic syndrome, gut microbiome

Saki Yamamoto,1 Akira Iwata,1 Yuki Yano,1 Toshimitsu Ohmine,1 Keisuke Honma,1 Kazuma Senzaki,1 Minami Fujiwara,1 Takayuki Murakami,1 Junji Inoue,1 Yuki Sano,2 Shuji Okagawa,3 Yuta Otsuki,4 Hideyuki Wanaka,5 Masataka Kataoka,1 Hiroshi Iwata61Department of Physical Therapy, Faculty of Comprehensive Rehabilitation, Osaka Prefecture University, Habikino, Osaka, Japan; 2Department of Rehabilitation, Osaka General Medical Center, Osaka, Osaka, Japan; 3Department of Rehabilitation, Tatsumi Hospital, Ikeda, Osaka, Japan; 4Department of Rehabilitation, Kisei Hospital, Osaka, Osaka, Japan; 5Department of Rehabilitation, Kobe Rosai Hospital, Kobe, Hyogo, Japan; 6Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, JapanPurpose: Movement velocity of the limbs or trunk plays an important determinant of gait speed in older adults. Movement velocity-focused training of the lower limbs or trunk has recently been shown to be an effective intervention to improve gait ability. Because movement velocities of various body regions are significantly correlated, movement velocity training of the upper limbs may also be effective for improving gait speed. Therefore, the purpose of this study was to investigate whether movement velocity training of the upper limbs in a seated position is effective for improving gait ability.Patients and methods: This study was a nonrandomized controlled trial. The participants were older adults residing in geriatric health service facilities. They were assigned to the movement velocity training of the upper limbs group (n=26) or control group (n=15). The participants in the training group performed exercises (three times per week for 10 weeks) to move the upper limbs as quickly as possible. The outcomes were gait speed, movement velocity, and quadriceps strength. These measurements were performed preintervention and 4, 8, and 10 weeks after intervention.Results: A significant time–group interaction was found for maximum gait speed and movement velocity of the upper limbs. Bonferroni post-hoc test showed significant improvement in gait speed between preintervention and 10 weeks after intervention in the training group. The movement velocity of the upper limbs was significantly improved between preintervention and 4, 8, and 10 weeks after intervention.Conclusion: Movement velocity training of the upper limbs showed significant and clinically relevant improvements in maximum gait speed at 10 weeks after intervention. This training is a potentially useful intervention and can be safely performed.Keywords: older people, movement velocity training, arm, gait speed, seated position

Takahiro Matsumoto,1,2* Yuki Matsushima,1* Masaaki Toda,1 Ziaurahman Roeen,1 Corina N D'Alessandro-Gabazza,1,5 Josephine A Hinneh,1 Etsuko Harada,1,3 Taro Yasuma,4 Yutaka Yano,4 Masahito Urawa,1,5 Tetsu Kobayashi,5 Osamu Taguchi,5 Esteban C Gabazza1 1Department of Immunology, Mie University Graduate School of Medicine, Tsu, Mie Prefecture, 2BONAC Corporation, BIO Factory 4F, Fukuoka, 3Iwade Research Institute of Mycology, 4Department of Endocrinology, Diabetes and Metabolism, 5Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Mie Prefecture, Japan *These authors contributed equally to this work Background: Previous studies have demonstrated the beneficial activity of activated protein C in allergic diseases including bronchial asthma and rhinitis. However, the exact mechanism of action of activated protein C in allergies is unclear. In this study, we hypothesized that pharmacological doses of activated protein C can modulate allergic inflammation by inhibiting dendritic cells. Materials and methods: Dendritic cells were prepared using murine bone marrow progenitor cells and human peripheral monocytes. Bronchial asthma was induced in mice that received intratracheal instillation of ovalbumin-pulsed dendritic cells. Results: Activated protein C significantly increased the differentiation of tolerogenic plasmacytoid dendritic cells and the secretion of type I interferons, but it significantly reduced lipopolysaccharide-mediated maturation and the secretion of inflammatory cytokines in myeloid dendritic cells. Activated protein C also inhibited maturation and the secretion of inflammatory cytokines in monocyte-derived dendritic cells. Activated protein C-treated dendritic cells were less effective when differentiating naïve CD4 T-cells from Th1 or Th2 cells, and the cellular effect of activated protein C was mediated by its receptors. Mice that received adoptive transfer of activated protein C-treated ovalbumin-pulsed dendritic cells had significantly less airway hyperresponsiveness, significantly decreased lung concentrations of Th1 and Th2 cytokines, and less plasma concentration of immunoglobulin E when compared to control mice. Conclusion: These results suggest that dendritic cells mediate the immunosuppressive effect of activated protein C during allergic inflammation. Keywords: allergy, dendritic cells, coagulation, protein C pathway

Hiroyuki Konya,1 Yuzo Yano,1 Satoshi Matsutani,1 Taku Tsunoda,2 Takashi Ikawa,2 Yoshiki Kusunoki,2 Toshihiro Matsuo,2 Masayuki Miuchi,2 Tomoyuki Katsuno,3 Tomoya Hamaguchi,4 Jun-ichiro Miyagawa,2 Mitsuyoshi Namba21Department of Internal Medicine, Ashiya Municipal Hospital, Ashiya, 2Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, 3Division of Innovative Diabetes Treatment, Hyogo College of Medicine, Nishinomiya, 4Division of Diabetes, Department of Internal Medicine, Itami City Hospital, Itami, Hyogo, JapanAbstract: Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as α-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.Keywords: dipeptidyl peptidase-4, incretin hormones, saxagliptin, type 2 diabetes mellitus, Japan, efficacy, safety, patient acceptability

Hiroyuki Konya,1 Tomoyuki Katsuno,2 Taku Tsunoda,1 Yuzo Yano,1 Mai Kamitani,1 Masayuki Miuchi,2 Tomoya Hamaguchi,3 Jun-Ichiro Miyagawa,2 Mitsuyoshi Namba2 1Department of Internal Medicine, Ashiya Municipal Hospital, Ashiya, Hyogo, Japan; 2Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan; 3Division of Innovative Diabetes Treatment, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan Abstract: Patients with diabetes mellitus are at increased risk from cardiovascular-related morbidity and mortality as compared with healthy individuals. An association between the postprandial metabolic state and atherogenesis has been observed in patients with diabetes mellitus. In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), treatment with an α-glucosidase inhibitor (α-GI) in patients with impaired glucose tolerance not only reduced the rate of conversion from impaired glucose tolerance to type 2 diabetes mellitus (T2DM), but was also associated with a reduction in the risk of cardiovascular events. These results suggested the importance of treating postprandial hyperglycemia in the early stages of T2DM. Glinides are rapid and short-acting insulin secretagogues that bind to the sulfonylurea receptors on pancreatic β-cells to facilitate rapid insulin secretion, restore postprandial early insulin secretion, and reduce the postprandial glucose spike. Moreover, α-GIs reduce postprandial hyperglycemia and insulin secretion by delaying the digestion of carbohydrates and polysaccharides in the small intestine. Then, both glinides and α-GI have beneficial effects for treating patients with T2DM and impaired glucose tolerance. Considering the ameliorating effects of these drugs on postprandial metabolic disorders, combinations of glinides and α-GI might constitute a promising therapeutic strategy for managing patients with T2DM, and also appear to be suitable for Japanese people, who consume more carbohydrates, such as polished rice, than Caucasians. It has recently been reported that combined use of mitiglinide and voglibose reduces postprandial insulin secretion and blunts diurnal glycemic changes in T2DM patients. This therapy can thus be regarded as being suitable for achieving strict postprandial glycemic control. In this report, we outline the effects of this combination therapy on postprandial plasma glucose and assess its safety. Keywords: mitiglinide, voglibose, combination therapy, type 2 diabetes mellitus, postprandial hyperglycemia

Spectroscopic techniques, including photoelectron spectroscopy, diffuse reflectance, and x-ray absorption, are used to investigate the electronic structure and the local structure of LaOBiS 2 − x Se x thermoelectric material. It is found that Se substitution effectively suppresses local distortion that can be responsible for the increased carrier mobility together with a change in the electronic structure. The results suggest a possible way to control thermoelectric properties by tuning of the local crystal structure of these materials. [ABSTRACT FROM AUTHOR]

The basic design of the superconducting triplet quadrupoles (STQs) magnet is described along with its cryostat, thus emphasizing newly developed gas-cooled, multiple-electrode current leads. The cryostat characterized by gas-cooled current leads with multiple electrodes is discussed.

Magnets for the beam transport line from the Superconducting Ring Cyclotron (SRC) to the superconducting fragment separator (BigRIPS) are described. These magnets are resistive type and the beam line consists of two kinds of dipoles and three kinds of quadrupoles.

The SRC is cooled down and excited without quenches, where the mechanical support structure and the cryogenic cooling system have worked properly. Acceleration cavity, vacuum system and beam diagnostic system are installed and tested under the stray fields arising from the sector magnets.

The ion optics calculations of the BigRIPS can be used by performing the measurements of the magnetic field distributions of the superconducting triplet quadrupoles (STQs) and the room-temperature dipoles for the BigRIPS separator. The results of magnetic field-map measurement of the superferric-types STQ and dipole magnet including the field mapping device are described.

The status and overview of the superconducting in-flight radioactive-isotope (RI)-beam separator BigRIPS at RIKEN are discussed. Large acceptances in its ion optics and adoption of two-stage separator scheme are the two main features of the BigRIPS separator.

The cool-down and excitation results of the superconducting ring cyclotron (SRC) sector magnets are presented. Results suggest that all coils were fully excited on 11/7 without quench and all the main coils transited to superconducting phase on 10/13.

Three superferric quadrupoles with a pole-tip radius of 170mm and a design fieldgradient of 14.1 T/m are constructed for use as spectrometer elements. The results of quench protection tests, measured heat loads and field-maps are described.

K2500-superconducting ring cyclotron with 6-sectors is being constructed at RIKEN as one of the energy booster of the existing K540 ring cyclotron. The magnet reached the designed field with one quench and training effect are clearly observed, which show that it would works well to inject the beam into the superco9nductivity cyclotron.