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Takamasa Kitajima,1 Satoshi Marumo,1 Hisanori Amimoto,2 Yusuke Shiraishi,3 Haruka Yamaki,3 Masahiro Shirata,3 Daiki Inoue,1 Motonari Fukui1 1Respiratory Disease Center, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan; 2Department of Respiratory Medicine, Kobe City Medical Center West Hospital, Kobe, Japan; 3Department of Respiratory Medicine, Kyoto University, Graduate School of Medicine, Kyoto, JapanCorrespondence: Takamasa Kitajima, Respiratory Disease Center, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan, Tel +81-6-6312-8831, Fax +81-6-6361-8867, Email m-kitajima@kitano-hp.or.jpPurpose: An episodic increase in transcutaneous carbon dioxide pressure (PtcCO2) is often recognized in patients with advanced chronic obstructive pulmonary disease (COPD) by overnight PtcCO2 monitoring. This phenomenon, called episodic nocturnal hypercapnia (eNH), mainly corresponds to rapid eye movement (REM) sleep-related hypoventilation. However, it is unclear whether eNH is associated with the frequency of COPD exacerbation. We aimed to investigate whether a relationship exists between COPD exacerbation and eNH.Patients and Methods: We enrolled consecutive patients with stable, severe, or very severe COPD with a daytime arterial carbon dioxide pressure (PaCO2) < 55.0 mmHg who underwent overnight PtcCO2 monitoring from April 2013 to January 2017. We retrospectively analyzed the prevalence of eNH and sleep-associated hypoventilation (SH) as defined by the American Academy of Sleep Medicine. Moreover, we compared the relationship between the frequency of COPD exacerbations in the previous year and eNH or SH.Results: Twenty-four patients were included in this study. The study patients had a mean daytime PaCO2 and nocturnal PtcCO2 of 43.3 ± 6.8 mmHg and 42.9 ± 9.6 mmHg, respectively. Six (25.0%) and 11 (45.9%) of the 24 patients met the SH and eNH criteria, respectively. The odds ratios of SH and eNH for at least one annual exacerbation were 1.0 [95% confidence interval (CI): 0.16– 6.00] and 11.1 [95% CI: 1.39– 87.7], respectively. The odds ratios of SH and eNH for at least two annual exacerbations were 0.3 [95% CI: 0.04– 2.64] and 6.6 [95% CI: 1.06– 39.4], respectively.Conclusion: In patients with advanced COPD and a daytime PaCO2 < 55.0 mmHg, eNH may be associated with a history of more frequent exacerbations than SH. Further studies are required to validate these findings.Keywords: episodic nocturnal hypercapnia, sleep-associated hypoventilation, exacerbations, arterial carbon dioxide pressure, rapid eye movement

Taro Kishi,1 Ikuo Nomura,1 Kenji Sakuma,1 Tsuyoshi Kitajima,1 Kazuo Mishima,2 Nakao Iwata11Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 2Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, JapanObjective: This study was a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials, investigating the efficacy and tolerability/safety of melatonin receptor agonists, such as ramelteon and melatonin, for patients with bipolar disorder.Methods: We carried out a literature search through PubMed and the Cochrane Library from the date of inception to January 6, 2019. The risk ratio (RR), number needed to treat (NNT), and standardized mean difference (SMD) ±95% CI were calculated. The primary outcome was all-cause discontinuation.Results: We identified three ramelteon (n=746) and two melatonin (n=53) studies. One of these two melatonin studies reported only data on all-cause discontinuation, whereas the other study did not report data relevant for a meta-analysis. We found no significant differences between the treatment and placebo groups regarding all-cause discontinuation, neither individually (p: ramelteon=0.86, melatonin=1.00) nor pooled together (p=0.85). Although we found no significant differences between ramelteon and placebo regarding the relapse due to mania/hypomania or mixed episode; Pittsburgh Sleep Quality Index scores; depression scales scores; Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form scores; and the incidence of individual adverse events, such as headaches, insomnia, somnolence, anxiety, and dizziness, ramelteon was associated with a lower incidence of relapse due to depression than placebo (RR=0.67, 95% CI=0.48–0.94, p=0.02, NNT=14).Conclusion: Ramelteon might prevent relapse due to depression in patients with bipolar disorder. However, because of the small number of studies included in the present systematic review and meta-analysis, further studies comparing ramelteon and placebo with larger samples of patients with bipolar disorder are warranted. We also did not evaluate the efficacy and safety of melatonin for patients with bipolar disorder in detail.Keywords: ramelteon, melatonin, bipolar disorder, relapse, systematic review, meta-analysis

Takamasa Kitajima, Satoshi Marumo, Hiroshi Shima, Masahiro Shirata, Satoru Kawashima, Daiki Inoue, Yuko Katayama, Ryo Itotani, Minoru Sakuramoto, Motonari Fukui Respiratory Disease Center, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan Purpose: Episodic nocturnal hypercapnia (eNH) caused by rapid eye movement (REM) sleep-related hypoventilation is often noted in patients with advanced COPD. The purpose of this study was to clarify the clinical significance of eNH and the effectiveness of eNH-targeted noninvasive positive pressure ventilation (NPPV). Patients and methods: We enrolled patients with stable, severe, or very severe COPD with daytime arterial partial oxygen pressure PaO2 ≥55 mmHg and daytime arterial partial carbon dioxide pressure PaCO2

Xi Yang,1,2 Liping Zhu,1 Seiichi Tada,1 Di Zhou,3 Takashi Kitajima,1 Takashi Isoshima,1 Yasuhiro Yoshida,1,4 Mariko Nakamura,1,5 Weiqun Yan,2 Yoshihiro Ito1,3 1Nano Medical Engineering Laboratory, RIKEN, Saitama, Japan; 2School of Pharmaceutical Sciences, Jilin University, Jilin, People’s Republic of China; 3Emergent Bioengineering Materials Research Team, RIKEN Center for Emergent Matter Science, Saitama, 4Department of Biomaterials and Bioengineering, Graduate School of Dental Medicine, Hokkaido University, Hokkaido, 5Dental Hygiene Program, Kibi International College, Okayama, Japan Abstract: Recombinant human gelatin was conjugated with dopamine using carbodiimide as a surface modifier. This dopamine-coupled human gelatin (D-rhG) was characterized by 1H-nuclear magnetic resonance, mass spectroscopy, and circular dichroism. D-rhG-coated surface properties were analyzed by physicochemical methods. Additionally, cell attachment and growth on the modified surfaces was assessed using human umbilical endothelial cells. Binding of gelatin onto titanium was significantly enhanced by dopamine conjugation. The thickness of the D-rhG coating depended on the treatment pH; thicker layers were formed at higher pH values, with a maximum thickness of 30 nm. D-rhG enhanced the binding of collagen-binding vascular endothelial growth factor and cell adhesion as compared with gelatin alone, even at the same surface concentration. The D-rhG surface modifier enhanced substrate binding by creating an adhesive nanointerface that increased specific protein binding and cell attachment. Keywords: recombinant human gelatin, dopamine, natural catechols, cell adhesion, cell culture, titanium

Yasuyuki Shiozaki,1,2 Takashi Kitajima,4 Tetsuro Mazaki,1,2 Aki Yoshida,1 Masato Tanaka,1 Akihiro Umezawa,5 Mariko Nakamura,6 Yasuhiro Yoshida,3 Yoshihiro Ito,4 Toshifumi Ozaki,1 Akihiro Matsukawa2 1Department of Orthopedic Surgery, Okayama University, Okayama, Okayama, Japan; 2Department of Pathology and Experimental Medicine, Okayama University, Okayama, Okayama, Japan; 3Department of Biomaterials, Graduate School of Medical, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Okayama, Japan; 4Nano Medical Engineering Laboratory, RIKEN, Wako, Saitama, Japan; 5National Research Institute for Child Health and Development, Okura, Tokyo, Japan; 6Department of Health and Welfare Program, Kibi International University Junior College, Takahashi, Okayama, Japan Purpose: Bone defects and nonunions are major clinical skeletal problems. Growth factors are commonly used to promote bone regeneration; however, the clinical impact is limited because the factors do not last long at a given site. The introduction of tissue engineering aimed to deter the diffusion of these factors is a promising therapeutic strategy. The purpose of the present study was to evaluate the in vivo osteogenic capability of an engineered bone morphogenetic protein-4 (BMP4) fusion protein. Methods: BMP4 was fused with a nanosized carrier, collagen-binding domain (CBD), derived from fibronectin. The stability of the CBD-BMP4 fusion protein was examined in vitro and in vivo. Osteogenic effects of CBD-BMP4 were evaluated by computer tomography after intramedullary injection without a collagen–sponge scaffold. Recombinant BMP-4, CBD, or vehicle were used as controls. Expressions of bone-related genes and growth factors were compared among the groups. Osteogenesis induced by CBD-BMP4, BMP4, and CBD was also assessed in a bone-defect model. Results: In vitro, CBD-BMP4 was retained in a collagen gel for at least 7 days while BMP4 alone was released within 3 hours. In vivo, CBD-BMP4 remained at the given site for at least 2 weeks, both with or without a collagen–sponge scaffold, while BMP4 disappeared from the site within 3 days after injection. CBD-BMP4 induced better bone formation than BMP4 did alone, CBD alone, and vehicle after the intramedullary injection into the mouse femur. Bone-related genes and growth factors were expressed at higher levels in CBD-BMP4-treated mice than in all other groups, including BMP4-treated mice. Finally, CBD-BMP4 potentiated more bone formation than did controls, including BMP4 alone, when applied to cranial bone defects without a collagen scaffold. Conclusion: Altogether, nanocarrier-CBD enhanced the retention of BMP4 in the bone, thereby promoting augmented osteogenic responses in the absence of a scaffold. These results suggest that CBD-BMP4 may be clinically useful in facilitating bone formation. Keywords: BMP4, bone repair, bone tissue engineering, osteogenesis

The use of in situ scanning tunneling microscopy and ex situ atomic force microscopy is made to study the surface morphology of GaN(0001) grown on sapphire substrates by plasma assisted molecular beam epitaxy. The results reveal that most surface defects are related to surface termination of threading dislocations with screw components.

The time-averaged two-dimensional (2D) and time-dependent 2D-t profiles of the net excitation rate of the excited atom and ion in a parallel-plate capacitively coupled plasma reactor in Ar as a function of the driving frequency from one to 100 MHz is presented. At a pressure of 1.0 Torr, the efficiency of a very high frequency plasma source for plasma production in capacitively coupled parallel-plate electrodes is demonstrated by the increase in the spatially integrated net excitation rate of Ar(3 p5), with an increase in the driving frequency above four MHz.

The developments of an 11-year superconducting generator research and development effort in Japan are reported. Progress involves the fabrication of three types of 70MW class superconducting generators. Development processes were based on scalable rotor and stator models. The first model machine was scheduled for installation in late 1996 and reliability and performance tests are scheduled for early 1997.

This paper describes recent results of the R&D on the 70MW class superconducting generators called model machines in an 11-year period project conducted by Super-GM. Three types of model machines are under manufacturing now. Static excitation tests of two slow response excitation type model machines are performed. The test facility is also under construction.

The Engineering Research Assn. for Superconductive Generation Equipment and Materials has developed slow-response and quick-response excitation-type rotors and a model stator as part of its 11-year program to develop 70-MW superconducting generators. At present, model machines based on its rotor and stator designs are being built. When finished, they will be tested under actual load conditions using the motor-generator technique.

This paper describes recent results of the R&D on the 70 MW class superconducting generator (hereinafter called model machine) in Super-GM, according to an 11-year period program since 1988.

Superconducting generators offer many advantages. A prominent one is to improve stability of electric power systems. This inherent advantage is further enhanced by performing quick-response excitation control. Characteristic design of a superconducting generator with quick-response excitation includes the adoption of high voltage and low AC loss field winding, high strength and high electric resistance winding support shaft, and a single damper system. We developed elemental technologies for these technical tasks, and founded the base for establishing quick-response superconducting generators.

The development of superconducting generators is an 8-year program at Japan's Engineering Research Assn for Superconductive Generation and Materials. Current work is focused on the design, construction and testing of three types of 70-MW prototype machines, two slow-response and a fast-response models. So far, the research effort has yielded a field winding model, a partial rotor model and a stator core cooling model.