Faculty Profiles - NAKASHIMA Hiroaki

A Longitudinal Study on the Effect of Exercise Habits on Locomotive Syndrome and Quality of Life during the Coronavirus Disease 2019 Pandemic Reviewed

Ito, S; Nakashima, H; Segi, N; Ouchida, J; Oishi, R; Yamauchi, I; Ishizuka, S; Takegami, Y; Seki, T; Hasegawa, Y; Imagama, S

JOURNAL OF CLINICAL MEDICINE Vol. 13 ( 5 ) 2024.3

Language：English Publisher：Journal of Clinical Medicine

During the COVID-19 pandemic, this study investigated the potential of exercise habits to improve quality of life (QOL) and prevent locomotive syndrome (LS) in residents of Yakumo-cho, Hokkaido, Japan. Participants from the 2018 health checkup were surveyed in February 2022, focusing on 200 respondents. These individuals were divided based on their 2018 exercise habits (at least 1 h per week): the exercise group (E group) and the non-exercise group (N group), further categorized in 2022 into the 2022E and 2022N groups. QOL was measured using the SF-36 (physical functioning, general health, physical role, physical pain, vitality, social functioning, emotional role, and mental health) and EuroQoL 5-dimension 5-level questionnaires (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and LS was assessed with the 25-question geriatric locomotive function scale. These showed no significant change in exercise habits from 2018 to 2022. In the non-LS group, the 2022E group had higher vitality and emotional role functioning scores compared to the 2022N group. For those with LS, the 2022E group reported less physical pain. Notably, the LS incidence was significantly lower in the 2022E group. This study concludes that consistent exercise habits positively impact QOL and reduce the LS risk, underscoring the importance of regular physical activity, especially during challenging times like a pandemic. These findings highlight the broader benefits of maintaining exercise routines for public health, particularly in periods of global health crises. Based on our findings, we recommend that people continue to exercise at least one hour per week to prevent LS.

DOI： 10.3390/jcm13051385

Calcitriol ameliorates motor de fi cits and prolongs survival of<i> Chrne</i>-de fi cient mouse, a model for congenital myasthenic syndrome, by inducing Rspo2 Reviewed

Ohkawara, B; Tomita, H; Inoue, T; Zhang, SC; Kanbara, S; Koshimizu, H; Miyasaka, Y; Takeda, JI; Nishiwaki, H; Nakashima, H; Ito, M; Masuda, A; Ishiguro, N; Ogi, T; Ohno, T; Imagama, S; Ohno, K

NEUROTHERAPEUTICS Vol. 21 ( 2 ) page： e00318 2024.3

Language：English Publisher：Neurotherapeutics

Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including congenital myasthenic syndromes (CMS). Germline mutations in CHRNE encoding the acetylcholine receptor (AChR) ε subunit are the most common cause of CMS. An active form of vitamin D, calcitriol, binds to vitamin D receptor (VDR) and regulates gene expressions. We found that calcitriol enhanced MuSK phosphorylation, AChR clustering, and myotube twitching in co-cultured C2C12 myotubes and NSC34 motor neurons. RNA-seq analysis of co-cultured cells showed that calcitriol increased the expressions of Rspo2, Rapsn, and Dusp6. ChIP-seq of VDR revealed that VDR binds to a region approximately 15 kbp upstream to Rspo2. Biallelic deletion of the VDR-binding site of Rspo2 by CRISPR/Cas9 in C2C12 myoblasts/myotubes nullified the calcitriol-mediated induction of Rspo2 expression and MuSK phosphorylation. We generated Chrne knockout (Chrne KO) mouse by CRISPR/Cas9. Intraperitoneal administration of calcitriol markedly increased the number of AChR clusters, as well as the area, the intensity, and the number of synaptophysin-positive synaptic vesicles, in Chrne KO mice. In addition, calcitriol ameliorated motor deficits and prolonged survival of Chrne KO mice. In the skeletal muscle, calcitriol increased the gene expressions of Rspo2, Rapsn, and Dusp6. We propose that calcitriol is a potential therapeutic agent for CMS and other diseases with defective neuromuscular signal transmission.

DOI： 10.1016/j.neurot.2024.e00318

An Update of a Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Role and Timing of Decompressive Surgery Reviewed

Fehlings, MG; Tetreault, LA; Hachem, L; Evaniew, N; Ganau, M; Mckenna, SL; Neal, CJ; Nagoshi, N; Rahimi-Movaghar, V; Aarabi, B; Hofstetter, CP; Wengel, VT; Nakashima, H; Martin, AR; Kirshblum, S; Pinto, RR; Marco, RAW; Wilson, JR; Kahn, DE; Newcombe, VFJ; Zipser, CM; Douglas, S; Kurpad, SN; Lu, Y; Saigal, R; Samadani, U; Arnold, PM; Hawryluk, GWJ; Skelly, AC; Kwon, BK

GLOBAL SPINE JOURNAL Vol. 14 ( 3_SUPPL ) page： 174S - 186S 2024.3

Language：English Publisher：Global Spine Journal

Study Design: Clinical practice guideline development. Objectives: Acute spinal cord injury (SCI) can result in devastating motor, sensory, and autonomic impairment; loss of independence; and reduced quality of life. Preclinical evidence suggests that early decompression of the spinal cord may help to limit secondary injury, reduce damage to the neural tissue, and improve functional outcomes. Emerging evidence indicates that “early” surgical decompression completed within 24 hours of injury also improves neurological recovery in patients with acute SCI. The objective of this clinical practice guideline (CPG) is to update the 2017 recommendations on the timing of surgical decompression and to evaluate the evidence with respect to ultra-early surgery (in particular, but not limited to, <12 hours after acute SCI). Methods: A multidisciplinary, international, guideline development group (GDG) was formed that consisted of spine surgeons, neurologists, critical care specialists, emergency medicine doctors, physical medicine and rehabilitation professionals, as well as individuals living with SCI. A systematic review was conducted based on accepted methodological standards to evaluate the impact of early (within 24 hours of acute SCI) or ultra-early (in particular, but not limited to, within 12 hours of acute SCI) surgery on neurological recovery, functional outcomes, administrative outcomes, safety, and cost-effectiveness. The GRADE approach was used to rate the overall strength of evidence across studies for each primary outcome. Using the “evidence-to-recommendation” framework, recommendations were then developed that considered the balance of benefits and harms, financial impact, patient values, acceptability, and feasibility. The guideline was internally appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. Results: The GDG recommended that early surgery (≤24 hours after injury) be offered as the preferred option for adult patients with acute SCI regardless of level. This recommendation was based on moderate evidence suggesting that patients were 2 times more likely to recover by ≥ 2 ASIA Impairment Score (AIS) grades at 6 months (RR: 2.76, 95% CI 1.60 to 4.98) and 12 months (RR: 1.95, 95% CI 1.26 to 3.18) if they were decompressed within 24 hours compared to after 24 hours. Furthermore, patients undergoing early surgery improved by an additional 4.50 (95% 1.70 to 7.29) points on the ASIA Motor Score compared to patients undergoing surgery after 24 hours post-injury. The GDG also agreed that a recommendation for ultra-early surgery could not be made on the basis of the current evidence because of the small sample sizes, variable definitions of what constituted ultra-early in the literature, and the inconsistency of the evidence. Conclusions: It is recommended that patients with an acute SCI, regardless of level, undergo surgery within 24 hours after injury when medically feasible. Future research is required to determine the differential effectiveness of early surgery in different subpopulations and the impact of ultra-early surgery on neurological recovery. Moreover, further work is required to define what constitutes effective spinal cord decompression and to individualize care. It is also recognized that a concerted international effort will be required to translate these recommendations into policy.

DOI： 10.1177/21925682231181883

An appropriate method for predicting the femoral angle on whole-body X-ray images from full-spine X-ray images Reviewed

Ito, K; Nakashima, H; Kagami, Y; Ouchida, J; Satake, K; Tsushima, M; Tomita, H; Ode, Y; Nagatani, Y; Imagama, S; Kanemura, T

JOURNAL OF ORTHOPAEDIC SCIENCE Vol. 29 ( 2 ) page： 489 - 493 2024.3

Language：English Publisher：Journal of Orthopaedic Science

Introduction: The importance of lower-limb compensation in patients with spinal malalignment due to spinal pathologies has been emphasized. The latest whole-body X-ray images (WBX) have enabled evaluations of whole-body alignment from head to toe. However, WBX is still not commonly available. Thus, the present study aimed to examine an alternative measurement method of the femoral angle on usual full-spine X-ray images (FSX) that approximates the femoral angle on WBX. Methods: A total of 50 patients (age, 52.8 ± 25.3 years; female, n = 26; male, n = 24) underwent WBX and FSX. The following parameters were measured on lateral view X-rays: WBX and FSX femoral angle (angle between the femoral axis and a perpendicular line); FSX femoral distance (distance from the center of femoral head to the distal femur on FSX); WBX intersection length (length between the center of the femoral head and the intersection point [the point at which the line connecting the center of the femoral head and the midpoint of the femoral condyle intersects the center line of the femur] on WBX). Results: The WBX femoral angle, and FSX femoral angle were 0.16 ± 4.2°, and −0.53 ± 4.1°, respectively. The FSX femoral distance was 102.7 ± 41.1 mm. An ROC curve analysis revealed that the cut-off value of the FSX femoral distance associated with minimal difference in the WBX and FSX femoral angles (<3°) was 73 mm (sensitivity 83.3%, specificity 87.5%, AUC 0.80). The WBX intersection length was 105.3 ± 27.3 mm. Conclusion: To calculate the femoral angle on FSX that approximates the WBX femoral angle, the femoral distance on FSX ≥73 mm is preferable. We suggest using the FSX femoral distance within the range of 80 mm–130 mm as a simple numerical value that meets all criteria.

DOI： 10.1016/j.jos.2023.02.007

Influence of the timing of surgery forcervical spinal cord injury without bone injury in the elderly: A retrospective multicenter study Reviewed

Nori, S; Watanabe, K; Takeda, K; Yamane, J; Kono, H; Yokogawa, N; Sasagawa, T; Ando, K; Nakashima, H; Segi, N; Funayama, T; Eto, F; Yamaji, A; Furuya, T; Yunde, A; Nakajima, H; Yamada, T; Hasegawa, T; Terashima, Y; Hirota, R; Suzuki, H; Imajo, Y; Ikegami, S; Uehara, M; Tonomura, H; Sakata, M; Hashimoto, K; Onoda, Y; Kawaguchi, K; Haruta, Y; Uei, H; Sawada, H; Nakanishi, K; Misaki, K; Terai, H; Tamai, K; Shirasawa, E; Inoue, G; Kiyasu, K; Iizuka, Y; Takasawa, E; Funao, H; Kaito, T; Yoshii, T; Ishihara, M; Okada, S; Imagama, S; Kato, S

JOURNAL OF ORTHOPAEDIC SCIENCE Vol. 29 ( 2 ) page： 480 - 485 2024.3

Language：English Publisher：Journal of Orthopaedic Science

Background: Although previous studies have demonstrated the advantages of early surgery for traumatic spinal cord injury (SCI), the appropriate surgical timing for cervical SCIs (CSCIs) without bone injury remains controversial. Here, we investigated the influence of relatively early surgery within 48 h of injury on the neurological recovery of elderly patients with CSCI and no bone injury. Methods: In this retrospective multicenter study, we reviewed data from 159 consecutive patients aged ≥65 years with CSCI without bone injury who underwent surgery in participating centers between 2010 and 2020. Patients were followed up for at least 6 months following CSCI. We divided patients into relatively early (≤48 h after CSCI, n = 24) and late surgery (>48 h after CSCI, n = 135) groups, and baseline characteristics and neurological outcomes were compared between them. Multivariate analysis was performed to identify factors associated with neurological recovery. Results: The relatively early surgery group demonstrated a lower prevalence of cardiac disease, poorer baseline American Spinal Injury Association (ASIA) impairment scale grade, and lower baseline ASIA motor score (AMS) than those of the late surgery group (P < 0.030, P < 0.001, and P < 0.001, respectively). Although the AMS was lower in the relatively early surgery group at 6 months following injury (P = 0.001), greater improvement in this score from baseline to 6-months post injury was observed (P = 0.010). Multiple linear regression analysis revealed that relatively early surgery did not affect postoperative improvement in AMS, rather, lower baseline AMS was associated with better AMS improvement (P < 0.001). Delirium (P = 0.006), pneumonia (P = 0.030), and diabetes mellitus (P = 0.039) negatively influenced postoperative improvement. Conclusions: Although further validation by future studies is required, relatively early surgery did not show a positive influence on neurological recovery after CSCI without bone injury in the elderly.

DOI： 10.1016/j.jos.2023.01.004

The anatomical relationship between the celiac artery and the median arch ligament in degenerative spinal surgery Reviewed

Kagami, Y; Nakashima, H; Ito, K; Satake, K; Tsushima, M; Ouchida, J; Morita, Y; Ode, Y; Segi, N; Imagama, S; Kanemura, T

JOURNAL OF ORTHOPAEDIC SCIENCE Vol. 29 ( 2 ) page： 502 - 507 2024.3

Language：English Publisher：Journal of Orthopaedic Science

Background: This study aimed to characterize the anatomical relationship between the spine, the celiac artery (CA), and the median arcuate ligament using preoperative contrast-enhanced computed tomography (CT) images of patients with spinal deformity who underwent surgical correction. Methods: This retrospective study included 81 consecutive patients (34 males, 47 females; average age: 70.2 years). The spinal level at which the CA originated, the diameter, extent of stenosis, and calcification were determined using CT sagittal images. Patients were divided into two groups: CA stenosis group and non-stenosis group. Factors associated with stenosis were examined. Results: CA stenosis was observed in 17 (21%) patients. CA stenosis group had significantly higher body mass index (24.9 ± 3.9 vs. 22.7 ± 3.7, p = 0.03). In the CA stenosis group, J-type CA (upward angling of the course by more than 90° immediately after descending) was more frequently observed (64.7% vs. 18.8%, p < 0.001). The CA stenosis group had lower pelvic tilt (18.6 ± 6.7 vs. 25.1 ± 9.9, p = 0.02) than non-stenosis group. Conclusions: High BMI, J-type, and shorter distance between CA and MAL were risk factors for CA stenosis in this study. Patients with high BMI undergoing fixation of multiple intervertebral corrective fusions at the thoracolumbar junction should undergo preoperative CT evaluation of the anatomy of CA to assess the poteitial risk of celiac artery compression syndrome.

DOI： 10.1016/j.jos.2023.02.015

Cellular senescence is associated with osteonecrosis of the femoral head while mesenchymal stem cell conditioned medium inhibits bone collapse Reviewed

特集整形外科領域における医療安全最前線各論脊椎脊髄手術を安全に施行するための術中脊髄モニタリング

世木直喜, 中島宏彰, 今釜史郎

関節外科　基礎と臨床 Vol. 43 ( 2 ) page： 168 - 176 2024.2

Okamoto, M; Nakashima, H; Sakai, K; Takegami, Y; Osawa, Y; Watanabe, J; Ito, S; Hibi, H; Imagama, S

SCIENTIFIC REPORTS Vol. 14 ( 1 ) page： 3329 2024.2

Language：English Publisher：Scientific Reports

Osteonecrosis of the femoral head (ONFH) is a type of ischemic osteonecrosis that causes pain, loss of function, and femoral head collapse. Here, we analyzed samples of femoral heads excised from patients with ONFH to clarify the relationship between ischemic osteonecrosis and cellular senescence. X-gal staining was strong and p16INK4a-positive cells were abundant in the transitional region of ONFH. The β-galactosidase-positive cells in the transitional region were also positive for nestin, periostin, or DMP-1. In contrast, no β-galactosidase-positive cells were detected in the healthy region. The senescence-associated p16INK4a, p21, and p53 were upregulated in ONFH tissue. We also examined and analyzed a mouse ischemic femoral osteonecrosis model in vivo to verify the association between ONFH and cellular senescence. Human mesenchymal stem cell-conditioned medium (MSC-CM) was administered to determine its therapeutic efficacy against cellular senescence and bone collapse. MSC-CM reduced the number of senescent cells and downregulated the aforementioned senescence-related genes. It also decreased the number of empty lacunae 4 weeks after ischemia induction and promoted bone formation. At 6 weeks post-surgery, MSC-CM increased the trabecular bone volume, thereby suppressing bone collapse. We conclude that cellular senescence is associated with ONFH and that MSC-CM suppresses bone collapse in this disorder.

DOI： 10.1038/s41598-024-53400-w

Do Postural and Walking Stabilities Change over a Decade by Aging? A Longitudinal Study Reviewed

Segi, N; Nakashima, H; Ito, S; Ouchida, J; Oishi, R; Yamauchi, I; Miyairi, Y; Morita, Y; Takegami, Y; Ishizuka, S; Seki, T; Hasegawa, Y; Imagama, S

JOURNAL OF CLINICAL MEDICINE Vol. 13 ( 4 ) 2024.2

Language：English Publisher：Journal of Clinical Medicine

Background: Previous studies have demonstrated that the center of gravity (COG) is more unstable in the elderly than in young people. However, it is unclear whether aging itself destabilizes the COG. This study aimed to investigate changes in COG sway and gait kinematics over time by a longitudinal study of middle-aged and elderly adults. Methods: This study included 198 healthy middle-aged and elderly people who underwent stabilometry at ten-year intervals. The participants’ mean age at baseline was 62.9 ± 6.5 years, and 77 (39%) of them were male. The results of stabilometry (mean velocity, sway area, postural sway center in the medial–lateral direction [X center], and postural sway center in the anterior–posterior direction [Y center]), and results of exercise tests (the height-adjusted maximum stride length [HMSL] and the 10 m walk test [10MWT]) were analyzed. The destabilized group with 11 participants, whose mean velocity exceeded 3 cm/s after 10 years, was compared with the stable group with 187 participants, whose mean velocity did not exceed 3 cm/s. Results: Mean velocity increased significantly over ten years (open-eye, from 1.53 ± 0.42 cm to 1.86 ± 0.67 cm, p < 0.001); however, the sway area did not change significantly. X center showed no significant change, whereas Y center showed a significant negative shift (open-eye, from −1.03 ± 1.28 cm to −1.60 ± 1.56 cm, p < 0.001). Although the results of 10MWT and initial HMSL did not differ significantly, the HMSL in the destabilized group at ten years was 0.64, which was significantly smaller than the 0.72 of others (p = 0.019). Conclusions: The ten-year changes in COG sway in middle-aged and elderly adults were characterized by a significant increase in mean velocity but no significant difference in sway area. Because the destabilized group had significantly smaller HMSL at ten years, instability at the onset of movement is likely to be affected by COG instability.

DOI： 10.3390/jcm13041081

Early versus delayed weight bearing after internal fixation for femoral neck fracture in younger adults: A multicenter retrospective study Reviewed

Hasegawa, K; Takegami, Y; Tokutake, K; Nakashima, H; Mishima, K; Kobayashi, K; Imagama, S

INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED Vol. 55 ( 2 ) page： 111292 2024.2

Language：English Publisher：Injury

Introduction: Femoral neck fracture (FNF) is among the most common and devastating injuries that orthopedic surgeons encounter. However, the incidence of FNF is lower in younger adults than in elderly individuals. In elderly FNF patients, early weight bearing (EWB) is preferred to prevent loss of function and decreased activity. In younger adults, some surgeons decide on delayed-weight bearing (DWB) after surgery because EWB may cause femoral neck shortening. We aimed to compare the postoperative results (clinical outcome, radiological evaluation, and complications) of EWB and DWB after FNF surgery in younger adults. Methods: The study included 151 younger adults (age: ≤65 years at injury; nondisplaced, n = 100; displaced, n = 51) who underwent internal fixation at 11 university-affiliated hospitals in 2016–2020, and who were followed for ≥1 year. Patients were divided into the EWB (EWB in early postoperative period) and DWB (beginning weight bearing at 4 weeks after surgery) groups. The two groups were matched for age, and nondisplaced (EWB and DWB, both n = 24) and displaced (EWB and DWB, both n = 11) FNF were analyzed. The study items were age, sex, body mass index (BMI), Charlson Comorbidity Index (CCI), presence of diabetes, days waiting for surgery, fracture type, Parker mobility score (PMS) at last follow-up examination, pain (Numerical Rating Scale: NRS), radiological evaluation (femoral neck shortening, Canulated Cancellous screws (CCS) backout, and complications (nonunion, femoral head osteonecrosis). Results: The patient backgrounds of the nondisplaced and displaced types did not differ. The PMS was significantly higher in the DWB group at the last follow-up examination (nondisplaced: 8.00±2.20 vs. 6.67±2.22, p = 0.005, displaced: 8.67±0.89 vs. 6.91±2.77, p<0.001). NRS and the amount of femoral neck shortening were significantly lower in the DWB group (nondisplaced: 1.65±0.70 mm vs. 3.94±3.03 mm, p<0.001, displaced: 4.26± 2.64 mm vs. 8.91±5.69 mm, p<0.001). CCS backout did not differ between the groups. One case of each of nonunion and femoral head osteonecrosis were observed in the displaced EWB and DWB groups; these differences were not significant. Conclusions: DWB after internal fixation for FNF in younger adults was associated with better outcomes than EWB.

DOI： 10.1016/j.injury.2023.111292