Cilostazol Attenuates AngII-Induced Cardiac Fibrosis in apoE Deficient Mice

Cardiac fibrosis is characterized by the net accumulation of extracellular matrix in the myocardium and is an integral component of most pathological cardiac conditions. Cilostazol, a selective inhibitor of phosphodiesterase type III with anti-platelet, anti-mitogenic, and vasodilating properties, is widely used to treat the ischemic symptoms of peripheral vascular disease. Here, we investigated whether cilostazol has a protective effect against Angiotensin II (AngII)-induced cardiac fibrosis. Male apolipoprotein E-deficient mice were fed either a normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, the mice were infused with saline or AngII (1000 ng kg(-1) min(-1)) for 28 days. AngII infusion increased heart/body weight ratio (p < 0.05), perivascular fibrosis (p < 0.05), and interstitial cardiac fibrosis (p < 0.0001), but were significantly attenuated by cilostazol treatment (p < 0.05, respectively). Cilostazol also reduced AngII-induced increases in fibrotic and inflammatory gene expression (p < 0.05, respectively). Furthermore, cilostazol attenuated both protein and mRNA abundance of osteopontin induced by AngII in vivo. In cultured human cardiac myocytes, cilostazol reduced mRNA expression of AngII-induced osteopontin in dose-dependent manner. This reduction was mimicked by forskolin treatment but was cancelled by co-treatment of H-89. Cilostazol attenuates AngII-induced cardiac fibrosis in mice through activation of the cAMP-PKA pathway

生殖細胞特異的ヒストンバリアントにおける新規リン酸化修飾の発見と生理的機能の解明

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 白髭 克彦, 東京大学教授 秋山 徹, 東京大学教授 渡邊 嘉典, 東京大学教授 高橋 直樹, 東京大学准教授 岡田 由紀University of Tokyo(東京大学

Inhibition of interleukin-6 signaling attenuates aortitis, left ventricular hypertrophy and arthritis in interleukin-1 receptor antagonist deficient mice

The aim of the present study was to examine whether inhibition of Interleukin (IL)-6 signaling by MR16-1, an IL-6 receptor antibody, attenuates aortitis, cardiac hypertrophy, and arthritis in IL-1 receptor antagonist deficient (IL-1RA KO) mice. Four weeks old mice were intraperitoneally administered with either MR16-1 or non-immune IgG at dosages that were adjusted over time for 5 weeks. These mice were stratified into four groups: MR16-1 treatment groups, KO/MR low group (first 2.0 mg, following 0.5 mg/week, n=14) and KO/MR high group (first 4.0 mg, following 2.0 mg/week, n=19) in IL-1RA KO mice, and IgG treatment groups, KO/IgG group (first 2.0 mg, following 1.0 mg/week, n=22) in IL-1RA KO mice, and wild/IgG group (first 2.0 mg, following 1.0 mg/week, n=17) in wild mice. Aortitis, cardiac hypertrophy and arthropathy were histologically analyzed. Sixty-eight percent of the KO/IgG group developed aortitis (53% developed severe aortitis). In contrast, only 21% of the KO/MR high group developed mild aortitis, without severe aortitis (P<0.01, vs KO/IgG group). Infiltration of inflammatory cells, such as neutrophils, T cells, and macrophages, was frequently observed around aortic sinus of the KO/IgG group. Left ventricle and cardiomyocyte hypertrophy were observed in IL-1RA KO mice. Administration of high dosage of MR16-1 significantly suppressed cardiomyocyte hypertrophy. MR16-1 attenuated the incidence and severity of arthritis in IL-1RA KO mice in a dose-dependent manner. In conclusion, blockade of IL-6 signaling may exert a beneficial effect to attenuate severe aortitis, left ventricle hypertrophy, and arthritis

Voluntary Elbow Extension-Flexion Using Single Joint Hybrid Assistive Limb (HAL) for Patients of Spastic Cerebral Palsy: Two Cases Report

Cerebral palsy (CP) patients with spastic diplegia struggle to perform activities of daily life (ADL) using their upper arms. The single-joint-type Hybrid Assistive limb (HAL) for upper limbs is a new portable robot that can provide elbow motion support in accordance with bioelectric activation of patient's biceps and triceps brachii muscles. The purpose of this study is to assess the feasibility and efficacy of the use of HAL for CP patients. Two patients were enrolled in this study. (Case 1: a 19-years-old male, at the Gross Motor Function Classification System (GMFCS) level IV, Case 2: a 17-years-old male at GMFCS level III). Both these patients experienced difficulty in voluntary elbow extension in ADLs. The HAL intervention (eight sessions; voluntary extension-flexion training of the elbow with HAL and clinical evaluation) was conducted for both sides in Case 1 and for the right side in Case 2. Clinical assessments were conducted as follows: Surface electromyography was used to evaluate the muscle activities of the biceps, triceps brachii, trapezius, and pectoralis major during elbow extension-flexion. The voluntary extension-flexion angles of the elbow, the coactivation index of the biceps and triceps brachii muscles, synergy analysis, and the Action Research Arm Test (ARAT) scores were assessed before and after the HAL sessions; the FIM score was evaluated before and after the entire intervention. In Case 1, the voluntary extension angle tended to increase after the HAL sessions. In both cases, the ARAT scores improved after the sessions. The FIM scores improved after HAL intervention. The voluntary extension-flexion of the elbow using the HAL may be a feasible option for rehabilitation of CP patients

Robot-assisted voluntary initiation reduces control-related difficulties of initiating joint movement: A phenomenal questionnaire study on shaping and compensation of forward gait

金沢大学国際基幹教育部Humans employ various control strategies to initiate and maintain bodily movement. In case that the normal gait function is impaired, exoskeleton robots provide motor assistance during therapy. While the robotic control system builds on kinematic gait functions, the patient’s voluntary efforts to initiate motion also contribute to the effectiveness of the therapy process. However, it is currently not well understood how voluntary initiation as a subjective capacity affects the physiological level of motor control. In order to understand the functional nexus between voluntary initiation and motor control, we interviewed patients undergoing robotic gait rehabilitation with the HAL exoskeleton robot about their experience and command of voluntarily initiating forward gait while using the HAL system. Their reports provide phenomenal evidence for voluntary initiation as a distinct cognitive act that comes as phenomenal performance. Furthermore, phenomenal evidence about the functional relation of intention and initiation correlates with FIM-M gait scores. Based on the assumption that HAL reduces control-related difficulties of voluntarily initiating joint movement, we identified two cognitive control strategies, shaping and compensation of gait, that imply a heterarchic organization of the human system of action control. © 2018 Grüneberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Robotic rehabilitation training with a newly developed upper limb single-joint Hybrid Assistive Limb (HAL-SJ) for elbow flexor reconstruction after brachial plexus injury: A report of two cases

This study aimed to evaluate the effectiveness and safety of using the upper limb single-joint Hybrid Assistive Limb (upper limb HAL-SJ) during elbow flexion training following elbow flexor reconstruction for brachial plexus injury (BPI). We present the cases of two patients in whom the upper limb HAL-SJ was implemented 5 and 7 months postoperatively following elbow flexor reconstruction for BPI. They underwent elbow flexor reconstruction with intercostal nerve crossing-to-musculocutaneous nerve (ICN-MCN crossing) after BPI. Postoperative training using the upper limb HAL-SJ was started from the Medical Research Council (MRC) grade 1 elbow flexion power to MRC grade 3 once every week or every 2 weeks. Both patients could implement elbow training using the upper limb HAL-SJ even in MRC grade 1 of their elbow flexion power. Training with the upper limb HAL-SJ was performed safely and effectively in two patients with elbow flexor reconstruction with ICN crossing after BPI

Robot-assisted voluntary initiation reduces control-related difficulties of initiating joint movement: A phenomenal questionnaire study on shaping and compensation of forward gait

Humans employ various control strategies to initiate and maintain bodily movement. In case that the normal gait function is impaired, exoskeleton robots provide motor assistance during therapy. While the robotic control system builds on kinematic gait functions, the patient’s voluntary efforts to initiate motion also contribute to the effectiveness of the therapy process. However, it is currently not well understood how voluntary initiation as a subjective capacity affects the physiological level of motor control. In order to understand the functional nexus between voluntary initiation and motor control, we interviewed patients undergoing robotic gait rehabilitation with the HAL exoskeleton robot about their experience and command of voluntarily initiating forward gait while using the HAL system. Their reports provide phenomenal evidence for voluntary initiation as a distinct cognitive act that comes as phenomenal performance. Furthermore, phenomenal evidence about the functional relation of intention and initiation correlates with FIM-M gait scores. Based on the assumption that HAL reduces control-related difficulties of voluntarily initiating joint movement, we identified two cognitive control strategies, shaping and compensation of gait, that imply a heterarchic organization of the human system of action control

Voluntary Ambulation by Upper Limb-Triggered HAL® in Patients with Complete Quadri/Paraplegia Due to Chronic Spinal Cord Injury

Patients with complete paraplegia after spinal cord injury (SCI) are unable to stand or walk on their own. Standing exercise decreases the risk of decubitus ulcers, osteoporosis, and joint deformities in patients with SCI. Conventional gait training for complete paraplegia requires excessive upper limb usage for weight bearing and is difficult in cases of complete quadriplegia. The purpose of this study was to describe voluntary ambulation triggered by upper limb activity using the Hybrid Assistive Limb® (HAL) in patients with complete quadri/paraplegia after chronic SCI. Four patients (3 men, 1 woman) were enrolled in this study. The mean patient age ± standard deviation was 37.2 ± 17.8 (range, 20–67) years. Clinical evaluation before intervention revealed the following findings: case 1, neurological level C6, American Spinal Cord Injury Association impairment scale (AIS) grade B; case 2, T6, AIS A; case 3, T10 AIS A; and case 4, T11, AIS A. The HAL intervention consisted of 10 sessions. Each HAL session lasted 60–90 min. The HAL electrodes for hip and knee flexion-extension were placed on the anterior and posterior sides of the upper limbs contralaterally corresponding to each of the lower limbs. Surface electromyography (EMG) was used to evaluate muscle activity of the tensor fascia lata and quadriceps femoris (Quad) in synchronization with a Vicon motion capture system. The modified Ashworth scale (mAs) score was also evaluated before and after each session. All participants completed all 10 sessions. Cases 1, 2, and 3 demonstrated significant decreases in mAs score after the sessions compared to pre-session measurements. In all cases, EMG before the intervention showed no apparent activation in either Quad. However, gait phase dependent activity of the lower limb muscles was seen during voluntarily triggered ambulation driven by upper limb muscle activities. In cases 3 and 4, active contraction in both Quads was observed after intervention. These findings suggest that upper-limb-triggered HAL ambulation is a safe and feasible option for rehabilitation in patients with complete quadri/paraplegia caused by chronic SCI

Testis-Specific Histone Variant H3t Gene Is Essential for Entry into Spermatogenesis

Jun Ueda, Akihito Harada, Takashi Urahama, Shinichi Machida, Kazumitsu Maehara, Masashi Hada, Yoshinori Makino, Jumpei Nogami, Naoki Horikoshi, Akihisa Osakabe, Hiroyuki Taguchi, Hiroki Tanaka, Hiroaki Tachiwana, Tatsuma Yao, Minami Yamada, Takashi Iwamoto, Ayako Isotani, Masahito Ikawa, Taro Tachibana, Yuki Okada, Hiroshi Kimura, Yasuyuki Ohkawa, Hitoshi Kurumizaka, Kazuo Yamagata, Testis-Specific Histone Variant H3t Gene Is Essential for Entry into Spermatogenesis, Cell Reports, Volume 18, Issue 3, 2017, Pages 593-600, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2016.12.065

Voluntary Elbow Extension-Flexion Using Single Joint Hybrid Assistive Limb (HAL) for Patients of Spastic Cerebral Palsy: Two Cases Report

Cerebral palsy (CP) patients with spastic diplegia struggle to perform activities of daily life (ADL) using their upper arms. The single-joint-type Hybrid Assistive limb (HAL) for upper limbs is a new portable robot that can provide elbow motion support in accordance with bioelectric activation of patient\u27s biceps and triceps brachii muscles. The purpose of this study is to assess the feasibility and efficacy of the use of HAL for CP patients. Two patients were enrolled in this study. (Case 1: a 19-years-old male, at the Gross Motor Function Classification System (GMFCS) level IV, Case 2: a 17-years-old male at GMFCS level III). Both these patients experienced difficulty in voluntary elbow extension in ADLs. The HAL intervention (eight sessions; voluntary extension-flexion training of the elbow with HAL and clinical evaluation) was conducted for both sides in Case 1 and for the right side in Case 2. Clinical assessments were conducted as follows: Surface electromyography was used to evaluate the muscle activities of the biceps, triceps brachii, trapezius, and pectoralis major during elbow extension-flexion. The voluntary extension-flexion angles of the elbow, the coactivation index of the biceps and triceps brachii muscles, synergy analysis, and the Action Research Arm Test (ARAT) scores were assessed before and after the HAL sessions; the FIM score was evaluated before and after the entire intervention. In Case 1, the voluntary extension angle tended to increase after the HAL sessions. In both cases, the ARAT scores improved after the sessions. The FIM scores improved after HAL intervention. The voluntary extension-flexion of the elbow using the HAL may be a feasible option for rehabilitation of CP patients