Publications by authors named "Masahiko Watanabe"

1,095 Publications

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Utility of Power tool and Intraoperative Neuromonitoring for Percutaneous Pedicle Screw Placement in Single Position Surgery: A Technical Note.

Authors:
Akihiko Hiyama Satoshi Nomura Daisuke Sakai Masahiko Watanabe

World Neurosurg 2021 Oct 11. Epub 2021 Oct 11.

Department of Orthopaedic Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Objective: This study aimed to demonstrate the utility of power tools and intraoperative neuromonitoring of percutaneous pedicle screw (PPS) insertion (so-called PPS monitoring) by single-position surgery (SPS) after lateral lumbar interbody fusion (LLIF).

Methods: A retrospective analysis of medical records from a single center was performed to identify patients who underwent SPS for LLIF and posterior fixation using PPS during intraoperative CT navigation from 2020 to 2021. We investigated the PPS insertion time and screw positional accuracy of patients who underwent SPS involving power tools and PPS monitoring during this period. In this technical note, we report on this surgical technique.

Results: Twenty-four patients (mean age 72.0 ± 8.5 years, range 53-81 years) were included in this study. There were no intraoperative complications in all cases. Posterior fixation using PPS was added in all cases and a total of 106 PPSs were inserted. It took an average of 6.2 ± 2.4 seconds to insert the PPS from the PPS insertion point to the end using a power tool and PPS monitoring. Moreover, there were no cases of pedicle breaches.

Conclusions: Similar to previous reports related to power tools in the prone position, the lateral decubitus SPS technique can also use power tools to save PPS insertion time. Furthermore, we suggest that the use of PPS monitoring may prevent erroneous PPS insertions by utilizing intraoperative CT navigation in advance.
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http://dx.doi.org/10.1016/j.wneu.2021.09.113DOI Listing
October 2021

Comparison of periarticular multidrug injection versus epidural catheter in 55 patients undergoing total hip arthroplasty: a prospective randomized controlled trial.

Authors:
Taku Ukai Goro Ebihara Masahiko Watanabe

Orthop Traumatol Surg Res 2021 Sep 30:103094. Epub 2021 Sep 30.

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, 259-1193 Isehara, Kanagawa, Japan.

Introduction: Epidural catheter (EC) and periarticular multidrug injection (PMDI) are widely performed for reducing total hip arthroplasty (THA) postoperative pain. However, the more effective analgesic technique between the two is unclear. Thus, we aimed to answer the following questions: (1) does PMDI contribute to less postoperative pain than EC? (2) is there any difference in side-effect occurrence between the methods? (3) does PMDI provide better functional recovery than EC? (4) is there any difference in inflammatory parameters between the methods?

Hypothesis: PMDI would reduce postoperative pain and side effects, provide better functional recovery, and contribute to lower inflammation compared with EC.

Materials And Methods: This single-center, randomized controlled trial was conducted from 2017 to 2019 and enrolled 55 patients randomly allocated into two groups (28 patients: PMDI, 27 patients: EC). The primary outcome was evaluated using the pain visual analogue scale (VAS). The secondary outcomes were narcotic consumption, side effects, hip range of motion (ROM), ratio of patients performing the straight leg raise (SLR) on postoperative day (POD) 1, the day the patient started using a walker and cane, and inflammatory parameters (white blood cell [WBC], and C-reactive protein [CRP]). Paired t-tests and Fisher's exact test were used for comparisons.

Results: There were no significant differences in the pain VAS scores between groups. The EC group experienced significantly more side effects than the PMDI group (p<0.01). ROM of the PMDI group on POD 3 was significantly better than the EC group (p<0.05). Furthermore, more patients in the PMDI group could perform SLR than those in the EC group on POD 1 (p=0.01). On POD 1, the WBC count was significantly higher (p<0.01) in the PMDI group, whereas CRP levels were significantly lower in the PMDI group (p<0.05) and remained lower than the EC group on POD 3 (p<0.01).

Discussion: The patients in the PMDI and EC groups had comparable postoperative pain. Those in the PMDI group had lower side effects. Functional recovery was comparable between the patients in the PMDI and EC groups. Compared to the EC group, the PMDI group had higher WBC count and lower CRP levels.

Level Of Evidence: I ; Prospective randomized controlled trial.
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http://dx.doi.org/10.1016/j.otsr.2021.103094DOI Listing
September 2021

Associations between Clinical Findings and Severity of Diffuse Idiopathic Skeletal Hyperostosis in Patients with Ossification of the Posterior Longitudinal Ligament.

Authors:
Takashi Hirai Soraya Nishimura Toshitaka Yoshii Narihito Nagoshi Jun Hashimoto Kanji Mori Satoshi Maki Keiichi Katsumi Kazuhiro Takeuchi Shuta Ushio Takeo Furuya Kei Watanabe Norihiro Nishida Kota Watanabe Takashi Kaito Satoshi Kato Katsuya Nagashima Masao Koda Hiroaki Nakashima Shiro Imagama Kazuma Murata Yuji Matsuoka Kanichiro Wada Atsushi Kimura Tetsuro Ohba Hiroyuki Katoh Masahiko Watanabe Yukihiro Matsuyama Hiroshi Ozawa Hirotaka Haro

J Clin Med 2021 Sep 14;10(18). Epub 2021 Sep 14.

Department of Orthopedic Surgery, University of Yamanashi, Chuo 409-3898, Japan.

Background: This study investigated how diffuse idiopathic skeletal hyperostosis (DISH) influences clinical characteristics in patients with cervical ossification of the posterior longitudinal ligament (OPLL). Although DISH is considered unlikely to promote neurologic dysfunction, this relationship remains unclear.

Methods: Patient data were prospectively collected from 16 Japanese institutions. In total, 239 patients with cervical OPLL were enrolled who had whole-spine computed tomography images available. The primary outcomes were visual analog scale pain scores and the results of other self-reported clinical questionnaires. Correlations were sought between clinical symptoms and DISH using the following grading system: 1, DISH at T3-T10; 2, DISH at both T3-10 and C6-T2 and/or T11-L2; and 3, DISH beyond the C5 and/or L3 levels.

Results: DISH was absent in 132 cases, grade 1 in 23, grade 2 in 65, and grade 3 in 19. There were no significant correlations between DISH grade and clinical scores. However, there was a significant difference in the prevalence of neck pain (but not in back pain or low back pain) among the three grades. Interestingly, DISH localized in the thoracic spine (grade 1) may create overload at the cervical spine and lead to neck pain in patients with cervical OPLL.

Conclusion: This study is the first prospective multicenter cross-sectional comparison of subjective outcomes in patients with cervical OPLL according to the presence or absence of DISH. The severity of DISH was partially associated with the prevalence of neck pain.
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http://dx.doi.org/10.3390/jcm10184137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468753PMC
September 2021

Mutagenicity of carcinogenic heterocyclic amines in Salmonella typhimurium YG strains and transgenic rodents including gpt delta.

Authors:
Takehiko Nohmi Masahiko Watanabe

Genes Environ 2021 Sep 16;43(1):38. Epub 2021 Sep 16.

School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan.

Chemical carcinogens to humans have been usually identified by epidemiological studies on the relationships between occupational or environmental exposure to the agents and specific cancer induction. In contrast, carcinogenic heterocyclic amines were identified under the principle that mutagens in bacterial in the Ames test are possible human carcinogens. In the 1970s to 1990s, more than 10 heterocyclic amines were isolated from pyrolysates of amino acids, proteins, meat or fish as mutagens in the Ames test, and they were demonstrated as carcinogens in rodents. In the 1980s and 1990s, we have developed derivatives of the Ames tester strains that overexpressed acetyltransferase of Salmonella typhimurium. These strains such as Salmonella typhimurium YG1024 exhibited a high sensitivity to the mutagenicity of the carcinogenic heterocyclic amines. Because of the high sensitivity, YG1024 and other YG strains were used for various purposes, e.g., identification of novel heterocyclic amines, mechanisms of metabolic activation, comparison of mutagenic potencies of various heterocyclic amines, and the co-mutagenic effects. In the 1990s and 2000s, we developed transgenic mice and rats for the detection of mutagenicity of chemicals in vivo. The transgenics were generated by the introduction of reporter genes for mutations into fertilized eggs of mice and rats. We named the transgenics as gpt delta because the gpt gene of Escherichia coli was used for detection of point mutations such as base substitutions and frameshifts and the red/gam genes of λ phage were employed to detect deletion mutations. The transgenic rodents gpt delta and other transgenics with lacI or lacZ as reporter genes have been utilized for characterization of mutagenicity of heterocyclic amines in vivo. In this review, we summarized the in vitro mutagenicity of heterocyclic amines in Salmonella typhimurium YG strains and the in vivo mutagenicity in transgenic rodents. We discussed the relationships between in vitro and in vivo mutagenicity of the heterocyclic amines and their relations to the carcinogenicity.
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http://dx.doi.org/10.1186/s41021-021-00207-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444484PMC
September 2021

Characterisation of lamina I anterolateral system neurons that express Cre in a Phox2a-Cre mouse line.

Authors:
Wafa A A Alsulaiman Raphaelle Quillet Andrew M Bell Allen C Dickie Erika Polgár Kieran A Boyle Masahiko Watanabe R Brian Roome Artur Kania Andrew J Todd Maria Gutierrez-Mecinas

Sci Rep 2021 09 9;11(1):17912. Epub 2021 Sep 9.

Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.

A recently developed Phox2a::Cre mouse line has been shown to capture anterolateral system (ALS) projection neurons. Here, we used this line to test whether Phox2a-positive cells represent a distinct subpopulation among lamina I ALS neurons. We show that virtually all lamina I Phox2a cells can be retrogradely labelled from injections targeted on the lateral parabrachial area (LPb), and that most of those in the cervical cord also belong to the spinothalamic tract. Phox2a cells accounted for ~ 50-60% of the lamina I cells retrogradely labelled from LPb or thalamus. Phox2a was preferentially associated with smaller ALS neurons, and with those showing relatively weak neurokinin 1 receptor expression. The Phox2a cells were also less likely to project to the ipsilateral LPb. Although most Phox2a cells phosphorylated extracellular signal-regulated kinases following noxious heat stimulation, ~ 20% did not, and these were significantly smaller than the activated cells. This suggests that those ALS neurons that respond selectively to skin cooling, which have small cell bodies, may be included among the Phox2a population. Previous studies have defined neurochemical populations among the ALS cells, based on expression of Tac1 or Gpr83. However, we found that the proportions of Phox2a cells that expressed these genes were similar to the proportions reported for all lamina I ALS neurons, suggesting that Phox2a is not differentially expressed among cells belonging to these populations. Finally, we used a mouse line that resulted in membrane labelling of the Phox2a cells and showed that they all possess dendritic spines, although at a relatively low density. However, the distribution of the postsynaptic protein Homer revealed that dendritic spines accounted for a minority of the excitatory synapses on these cells. Our results confirm that Phox2a-positive cells in lamina I are ALS neurons, but show that the Phox2a::Cre line preferentially captures specific types of ALS cells.
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http://dx.doi.org/10.1038/s41598-021-97105-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429737PMC
September 2021

Comparison of properties determined using electromechanical assessment (Arthro-BST™) with macroscopic and histological properties in symptomatic human articular cartilage of the hip.

Authors:
Taku Ukai Masato Sato Shiho Wasai Takumi Takahashi Haruka Omura Masahiko Watanabe

Arthritis Res Ther 2021 08 31;23(1):227. Epub 2021 Aug 31.

Department of Orthopedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Bohseidai, Isehara, Kanagawa, 259-1193, Japan.

Background: Cartilage degeneration is assessed using various methods. Although macroscopic evaluation can directly measure cartilage degeneration, it cannot accurately assess cartilage properties. Histological examination is one of the most accurate methods for evaluating cartilage degeneration. However, it is invasive and requires collection of cartilage tissue. In contrast, the Arthro-BST™ probe can assess cartilage properties noninvasively. This study aimed to evaluate the effectiveness of the Arthro-BST in assessing cartilage degeneration by comparing macroscopic (International Cartilage Repair Society [ICRS] classification) and histological evaluations (modified Mankin score and Osteoarthritis Research Society International [OARSI] histological grade).

Methods: Fourteen femoral heads were excised from 13 patients during surgery to treat hip osteoarthritis or femoral fracture. The ICRS score was used for macroscopic evaluation of cartilage degeneration. The Arthro-BST was applied at sites matching the areas of cartilage damage. The sites assessed using the ICRS classification and Arthro-BST were evaluated histologically (modified Mankin score and OARSI histological grade), and these were compared with the Arthro-BST results.

Results: The ICRS classification identified significant differences between grades 1 and 3 (p < 0.01), between grades 1 and 4 (p < 0.01), between grades 2 and 3 (p < 0.01), and between grades 2 and 4 (p < 0.01). Significant correlations were observed between the Arthro-BST results and the ICRS score, modified Mankin score (structure, cellularity, matrix staining, total score), and OARSI histological grade.

Conclusions: In the assessment of hip osteoarthritis, the Arthro-BST results correlated with those of macroscopic and histological evaluations. The Arthro-BST is useful for assessing hip osteoarthritis and may be helpful for noninvasive assessment of cartilage degeneration.
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http://dx.doi.org/10.1186/s13075-021-02611-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406846PMC
August 2021

Long-term outcomes of open modified inferior capsular shift for traumatic anterior shoulder instability: over 20 years of follow-up.

Authors:
Naoki Takatori Yoshiyasu Uchiyama Takeshi Imai Masahiko Watanabe

J Shoulder Elbow Surg 2021 Aug 24. Epub 2021 Aug 24.

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Tokyo, Japan.

Background: This study aimed to assess the long-term outcomes of the open modified inferior capsular shift procedure across more than 20 years in patients with traumatic anterior shoulder instability.

Methods: Participants in this study comprised 84 patients (86 shoulders; 67 men, 17 women). Mean follow-up was 28.0 years. We compared recurrent instability rate after surgery, apprehension, revision rate, satisfaction, return to preinjury sporting activity, and patient background characteristics between recurrent and non-recurrent groups. Twenty-seven patients who were examined directly were evaluated for differences in range of motion and muscle strength between affected and non-affected sides. Clinical outcome scores used for this study were the Western Ontario Shoulder Instability Index, and Rowe score.

Results: Nine shoulders (10.5%) showed recurrent instability, as dislocation in 3 shoulders and subluxation in 6 shoulders, but no revisions were required. All patients with recurrent instability were males with new trauma. Three shoulders developed recurrent instability ≤5 years after surgery, and the remaining 6 shoulders showed recurrent instability >5 years after surgery. No significant differences in any patient characteristic were identified between recurrent and non-recurrent groups. Significant differences between affected and non-affected sides were seen in mean active range of motion or muscle strength for external rotation in the anatomical position or in 90° of abduction. Western Ontario Shoulder Instability Index and Rowe score were significantly worse in the recurrent group than in the non-recurrent group. Patients reported that 84 shoulders (97.7%) were "much better". Most athletes (88.4%) had returned to sports activity at a level >70%.

Conclusion: We investigated long-term outcomes of the open modified inferior capsular shift procedure for traumatic anterior shoulder instability. Our data suggest that recurrent instability might result from new trauma even if a long time has passed since the open modified inferior capsular shift procedure, so follow-up should be continued as long as possible after surgery. As in other reports, satisfaction was high and clinical scores were good. We thus believe this surgical method offers good results even after more than 20 years.
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http://dx.doi.org/10.1016/j.jse.2021.07.021DOI Listing
August 2021

Somnolence and Dizziness During Mirogabalin Treatment in Patients With Neuropathic Pain Related to Lumbar Disease Who Switched From Pregabalin: A Retrospective Study.

Authors:
Tsutomu Akazawa Gen Inoue Masahiro Tanaka Tasuku Umehara Toshihiro Nagai Yusuke Oshita Takayuki Imura Masayuki Miyagi Wataru Saito Kosuke Sako Satoshi Nomura Akihiko Hiyama Hiroyuki Katoh Daisuke Sakai Masato Sato Atsuhiro Yoshida Masahiro Iinuma Hisateru Niki Masashi Takaso Masahiko Watanabe

Global Spine J 2021 Jul 30:21925682211031185. Epub 2021 Jul 30.

Kanagawa Spine Research Society, Isehara, Kanagawa, Japan.

Study Design: Multicenter retrospective study.

Objectives: To investigate adverse events (AEs) in patients with neuropathic pain related to lumbar disease who switched to mirogabalin from pregabalin.

Methods: This study surveyed the records of 82 patients with peripheral neuropathic leg pain related to lumbar disease who switched to mirogabalin from pregabalin. We evaluated AEs associated with pregabalin and mirogabalin, the continuation rate of mirogabalin, and the pain-relieving effect at 4 weeks after switching from pregabalin to mirogabalin. We compared patients who switched due to lack of efficacy (LoE group) and patients who switched due to AEs (AE group).

Results: The incidence rates of somnolence and dizziness with pregabalin were 12.2% and 14.6%, respectively, while the incidence rates with mirogabalin were reduced to 7.3% for somnolence and 4.9% for dizziness. The incidence of AEs with pregabalin was significantly higher in the AE group (LoE group: 11.1%, AE group 100%), especially for somnolence (LoE group: 3.2%, AE group: 47.1%) and dizziness (LoE group: 4.8%, AE: 52.9%). After switching, the incidences of AEs with mirogabalin were not significantly different between the 2 groups (LoE group: 15.9%, AE group: 23.5%), including for somnolence (LoE group: 7.9%, AE group: 5.9%) and dizziness (LoE group: 4.8%, AE group: 5.9%). There were no significant differences in continuation rate of mirogabalin or the pain-relieving effect between groups.

Conclusions: The patients who experience somnolence and dizziness with pregabalin might be able to continue safely receiving treatment for their pain by switching to mirogabalin.
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http://dx.doi.org/10.1177/21925682211031185DOI Listing
July 2021

Mesenchymal Stem Cell Sheet Promotes Functional Recovery and Palliates Neuropathic Pain in a Subacute Spinal Cord Injury Model.

Authors:
Kazuyoshi Yamazaki Masahito Kawabori Toshitaka Seki Soichiro Takamiya Kotaro Konno Masahiko Watanabe Kiyohiro Houkin Miki Fujimura

Stem Cells Int 2021 9;2021:9964877. Epub 2021 Jul 9.

Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Japan.

Stem cell therapy has been shown to reverse the sequelae of spinal cord injury (SCI). Although the ideal treatment route remains unknown, providing a large number of stem cells to the injured site using less invasive techniques is critical to achieving maximal recovery. This study was conducted to determine whether administration of bone marrow stem cell (BMSC) sheet made on its own without a scaffold is superior to intramedullary cell transplantation in a rat subacute SCI model. Adult female Sprague-Dawley rats were subjected to SCI by 30 g clip compression at the level of Th6 and Th7 and were administered BMSC cell sheet (7 × 10 cells, subdural), cell suspension (7 × 10 cells, intramedullary), or control seven days after the injury. Motor and sensory assessments, as well as histological evaluation, were performed to determine the efficacy of the different cell transplantation procedures. While both the cell sheet and cell intramedullary injection groups showed significant motor recovery compared to the control group, the cell sheet group showed better results. Furthermore, the cell sheet group displayed a significant sensory recovery compared to the other groups. A histological evaluation revealed that the cell sheet group showed smaller injury lesion volume, less inflammation, and gliosis compared to other groups. Sensory-related fibers of -opioid receptors (MOR, interneuron) and hydroxytryptamine transporters (HTT, descending pain inhibitory pathway), located around the dorsal horn of the spinal cord at the caudal side of the SCI, were preserved only in the cell sheet group. Stem cells could also be found inside the peri-injured spinal cord in the cell sheet group. BMSC cell sheets were able to promote functional recovery and palliate neuropathic pain more effectively than intramedullary injections, thus serving as a good treatment option for SCI.
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http://dx.doi.org/10.1155/2021/9964877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285204PMC
July 2021

Radiographs assessment of changes in the psoas muscle at L4-L5 level after single-level lateral lumbar interbody fusion in patients with postoperative motor weakness.

Authors:
Akihiko Hiyama Hiroyuki Katoh Satoshi Nomura Daisuke Sakai Masato Sato Masahiko Watanabe

J Clin Neurosci 2021 Aug 9;90:165-170. Epub 2021 Jun 9.

Department of Orthopaedic Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. Electronic address:

The purposes of this study were (1) to investigate postoperative changes in cross-sectional area (CSA) and signal intensity (SI) of the psoas muscle (PS) using magnetic resonance imaging (MRI) and (2) to compare the CSA and SI of the PS between patients with and without motor weakness after single-level lateral lumbar interbody fusion (LLIF) at level L4-L5. Sixty patients were divided into two groups-those with postoperative motor weakness and those without-and the two groups were compared. Baseline demographics and clinical characteristics, such as operation time and blood loss, length of hospital stay, and postoperative complications, were recorded. The CSA and SI of the PS were obtained from the MRI regions of interest defined by manual tracing. Patients who developed motor weakness after surgery were significantly older (p = 0.040). The operation time (p = 0.868), LLIF operative time (p = 0.476), and estimated bleeding loss (p = 0.168) did not differ significantly between groups. In both groups, the CSA and SI of the left and right PS increased after surgery. The change in the CSA of the left PS was significantly higher in patients with weakness (247.6 ± 155.2 mm) than without weakness (152.2 ± 133.1 mm) (p = 0.036). The change in SI of the left PS did not differ between the two groups (p = 0.530). To prevent postoperative motor weakness regardless of the operation time, surgeons should be aware of the potential for surgical invasive of the PS during LLIF in older people.
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http://dx.doi.org/10.1016/j.jocn.2021.05.057DOI Listing
August 2021

Compression of the Median Nerve and Ulnar Nerve's Deep Palmar Branch by a Ganglion Cyst in the Carpal Tunnel: A Case Report.

Authors:
Sho Yanagisawa Takehiko Takagi Mitsuhiko Kodama Yuka Kobayashi Masahiko Watanabe

JBJS Case Connect 2021 Jul 15;11(3). Epub 2021 Jul 15.

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara-shi, Kanagawa, Japan.

Case: A 39-year-old woman presented with a ganglion cyst in the carpal tunnel simultaneously compressing the right median nerve and the deep palmar branch of the ulnar nerve. During surgery, the soft tissue was exposed under the median nerve and on the deep palmar branch of the ulnar nerve running transversely in the deep area of the carpal tunnel.

Conclusion: Simultaneous compression of the median nerve and deep palmar branch of the ulnar nerve is extremely rare; however, such a pathoanatomical relationship must be considered while examining a patient because these nerves are located close to each other.
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http://dx.doi.org/10.2106/JBJS.CC.20.00692DOI Listing
July 2021

Expression of type one cannabinoid receptor in different subpopulation of kisspeptin neurons and kisspeptin afferents to GnRH neurons in female mice.

Authors:
Tamás Wilheim Krisztina Nagy Mahendravarman Mohanraj Kamil Ziarniak Masahiko Watanabe Joanna Sliwowska Imre Kalló

Brain Struct Funct 2021 Sep 14;226(7):2387-2399. Epub 2021 Jul 14.

Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, P.O. Box 67, Budapest, 1450, Hungary.

The endocannabinoids have been shown to target the afferents of hypothalamic neurons via cannabinoid 1 receptor (CB1) and thereby to influence their excitability at various physiological and/or pathological processes. Kisspeptin (KP) neurons form afferents of multiple neuroendocrine cells and influence their activity via signaling through a variation of co-expressed classical neurotransmitters and neuropeptides. The differential potency of endocannabinoids to influence the release of classical transmitters or neuropeptides, and the ovarian cycle-dependent functioning of the endocannabinoid signaling in the gonadotropin-releasing hormone (GnRH) neurons initiated us to study whether (a) the different subpopulations of KP neurons express CB1 mRNAs, (b) the expression is influenced by estrogen, and (c) CB1-immunoreactivity is present in the KP afferents to GnRH neurons. The aim of the study was to investigate the site- and cell-specific expression of CB1 in female mice using multiple labeling in situ hybridization and immunofluorescent histochemical techniques. The results support that CB1 mRNAs are expressed by both the GABAergic and glutamatergic subpopulations of KP neurons, the receptor protein is detectable in two-thirds of the KP afferents to GnRH neurons, and the expression of CB1 mRNA shows an estrogen-dependency. The applied estrogen-treatment, known to induce proestrus, reduced the level of CB1 transcripts in the rostral periventricular area of the third ventricle and arcuate nucleus, and differently influenced its co-localization with vesicular GABA transporter or vesicular glutamate transporter-2 in KP neurons. This indicates a gonadal cycle-dependent role of endocannabinoid signaling in the neuronal circuits involving KP neurons.
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http://dx.doi.org/10.1007/s00429-021-02339-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354884PMC
September 2021

An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum.

Authors:
Esther Suk King Lai Hisako Nakayama Taisuke Miyazaki Takanobu Nakazawa Katsuhiko Tabuchi Kouichi Hashimoto Masahiko Watanabe Masanobu Kano

Front Neural Circuits 2021 28;15:676891. Epub 2021 Jun 28.

Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10-15 (P10-15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD.
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http://dx.doi.org/10.3389/fncir.2021.676891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273702PMC
June 2021

Prognostic Impact of Lateral Pelvic Node Dissection on the Survival of Patients in Low Rectal Cancer Subgroups Based on Lymph Node Size.

Authors:
Koya Hida Daisuke Nishizaki Atsuhiko Sumii Ryosuke Okamura Yoshiharu Sakai Tsuyoshi Konishi Tomonori Akagi Tomohiro Yamaguchi Takashi Akiyoshi Meiki Fukuda Seiichiro Yamamoto Shigeki Arizono Mamoru Uemura Hirotoshi Hasegawa Kenji Kawada Satoshi Morita Masahiko Watanabe

Ann Surg Oncol 2021 Oct 13;28(11):6179-6188. Epub 2021 Jul 13.

Department of Surgery, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Background: Lateral pelvic node (LPN) dissection (LPND) is considered a promising technique for treating low rectal cancer; however, there is insufficient evidence of its prognostic value. Using centrally reviewed preoperative pelvic magnetic resonance (MR) images, this study aimed to find the patient population who has benefited from LPND.

Patients And Methods: MR images of patients from 69 institutes with stage II-III low rectal cancer were reviewed by experienced radiologists. Recurrence-free survival (RFS), overall survival (OS), and short-term outcomes were measured.

Results: In total, 731 preoperative MR images were reviewed (excluding patients with short-axis LPN ≥ 10 mm). Of these, 322 underwent total mesorectum excision (TME) without LPND (non-LPND group), and 409 underwent TME with LPND (LPND group). Preoperative treatment was performed for 40% and 25% of patients in the non-LPND and LPND groups, respectively. The incidence of postoperative complications was higher in the LPND group (44.5%) than in the non-LPND group (33.2%; P = 0.002). Among patients with LPNs < 5 mm, OS and RFS curves were not significantly different between the groups. Among patients with LPNs ≥ 5 mm, the LPND group had significantly higher 5-year OS and RFS than the non-LPND group (OS: 81.9% versus 67.3%; RFS: 69.4% versus 51.6%). On multivariate analysis of LPN ≥ 5 mm cases, LPND was independently associated with RFS.

Conclusions: Despite the high incidence of postoperative complications, this study showed the prognostic impact of LPND on low rectal cancer patients with LPNs (≥ 5 mm, < 10 mm short axis) measured by experienced radiologists. Trial registration UMIN-ID: UMIN000013919.
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http://dx.doi.org/10.1245/s10434-021-10312-7DOI Listing
October 2021

The impact of ossification spread on cervical spine function in patients with ossification of the posterior longitudinal ligament.

Authors:
Keiichi Katsumi Takashi Hirai Toshitaka Yoshii Satoshi Maki Kanji Mori Narihito Nagoshi Soraya Nishimura Kazuhiro Takeuchi Shuta Ushio Takeo Furuya Kei Watanabe Norihiro Nishida Kota Watanabe Takashi Kaito Satoshi Kato Katsuya Nagashima Masao Koda Kenyu Ito Shiro Imagama Yuji Matsuoka Kanichiro Wada Atsushi Kimura Tetsuro Ohba Hiroyuki Katoh Yukihiro Matsuyama Hiroshi Ozawa Hirotaka Haro Katsushi Takeshita Masahiko Watanabe Morio Matsumoto

Sci Rep 2021 07 12;11(1):14337. Epub 2021 Jul 12.

Department of Orthopaedic Surgery, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo , Japan.

Ossification of the posterior longitudinal ligament (OPLL) is a progressive disease. The bridging of ossified lesions to the vertebral body gradually increases, thereby decreasing the mobility of the cervical spine; thus, cervical spine function may decrease over time. However, cervical spine function in patients with cervical OPLL has not been evaluated in large prospective studies. Therefore, we conducted a prospective multicenter study to clarify whether ossification spread can influence cervical spine function and quality of life (QOL) in patients with cervical OPLL. In total, 238 patients (162 men, 76 women; mean age, 63.9 years) were enrolled from 16 institutions. Each patient underwent whole spine computed tomography and was evaluated for cervical spine function and QOL using the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ). In the multivariate regression analysis, a higher neck VAS score and a larger number of bridge formations of OPLL in the whole spine were significant predictors of adverse outcomes related to cervical spine function. This is the first prospective multicenter study to reveal the impact of ossification spread on cervical spine function. These findings are important to understand the natural course of OPLL and can serve as controls when evaluating postoperative cervical spine function.
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http://dx.doi.org/10.1038/s41598-021-93602-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275804PMC
July 2021

Cell differentiation is disrupted by MYO5B loss through Wnt/Notch imbalance.

Authors:
Izumi Kaji Joseph T Roland Sudiksha Rathan-Kumar Amy C Engevik Andreanna Burman Anna E Goldstein Masahiko Watanabe James R Goldenring

JCI Insight 2021 Aug 23;6(16). Epub 2021 Aug 23.

Section of Surgical Sciences and.

Functional loss of myosin Vb (MYO5B) induces a variety of deficits in intestinal epithelial cell function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). The impact of MYO5B loss on differentiated cell lineage choice has not been investigated. We quantified the populations of differentiated epithelial cells in tamoxifen-induced, epithelial cell-specific MYO5B-knockout (VilCreERT2 Myo5bfl/fl) mice utilizing digital image analysis. Consistent with our RNA-sequencing data, MYO5B loss induced a reduction in tuft cells in vivo and in organoid cultures. Paneth cells were significantly increased by MYO5B deficiency along with expansion of the progenitor cell zone. We further investigated the effect of lysophosphatidic acid (LPA) signaling on epithelial cell differentiation. Intraperitoneal LPA significantly increased tuft cell populations in both control and MYO5B-knockout mice. Transcripts for Wnt ligands were significantly downregulated by MYO5B loss in intestinal epithelial cells, whereas Notch signaling molecules were unchanged. Additionally, treatment with the Notch inhibitor dibenzazepine (DBZ) restored the populations of secretory cells, suggesting that the Notch pathway is maintained in MYO5B-deficient intestine. MYO5B loss likely impairs progenitor cell differentiation in the small intestine in vivo and in vitro, partially mediated by Wnt/Notch imbalance. Notch inhibition and/or LPA treatment may represent an effective therapeutic approach for treatment of MVID.
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http://dx.doi.org/10.1172/jci.insight.150416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409988PMC
August 2021

Correlational analysis of chemokine and inflammatory cytokine expression in the intervertebral disc and blood in patients with lumbar disc disease.

Authors:
Akihiko Hiyama Kaori Suyama Daisuke Sakai Masahiro Tanaka Masahiko Watanabe

J Orthop Res 2021 Jun 30. Epub 2021 Jun 30.

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

The involvement of intervertebral disc (IVD) tissues, whole blood (WB) cytokines, and chemokines in pain in patients with lumbar degenerative disc disease (LDD) is unknown. We investigated the relationships between inflammatory cytokines and chemokines in human IVD tissues and WB samples and their association with pain. Expression levels of chemokines and cytokine gene expression were measured in samples from 20 patients with LDD and compared between IVD tissues and WB samples. The associations between WB chemokine and cytokine gene expression levels and pain intensity (numeric rating scale) were also analyzed. The mRNA of C-C chemokine ligand 20 (CCL20), C-C chemokine receptor 6 (CCR6), interleukin-6 (IL-6), IL-1β, IL-17, and tumor necrosis factor-α (TNF-α) was expressed in degenerated IVD tissues. Pearson's product-moment correlation analysis produced positive correlations between CCR6 and IL-6 expression levels in IVD tissues (r = 0.845, p < 0.001) and WB samples (r = 0.963, p < 0.001). WB IL-6 and CCR6 mRNA expression levels correlated significantly with present pain, maximum pain, and average pain. By contrast, low back pain (LBP) did not correlate with serum chemokine/cytokine expression. This is the first study to report correlations between chemokine and inflammatory cytokine gene expression levels in IVD tissues and WB samples in patients with LDD in relation to pain intensity. WB CCR6 and IL-6 gene expression levels correlated significantly with present pain, maximum pain, and average pain, but not with LBP. These data provide a new understanding of the role of chemokines and inflammatory cytokines in patients with LDD and may lead to new treatment strategies for pain.
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http://dx.doi.org/10.1002/jor.25136DOI Listing
June 2021

The impact of diabetes mellitus on spinal fracture with diffuse idiopathic skeletal hyperostosis: A multicenter retrospective study.

Authors:
Tatsuya Yamamoto Eijiro Okada Takehiro Michikawa Toshitaka Yoshii Tsuyoshi Yamada Kei Watanabe Keiichi Katsumi Akihiko Hiyama Masahiko Watanabe Yukihiro Nakagawa Motohiro Okada Teruaki Endo Yasuyuki Shiraishi Kazuhiro Takeuchi Shunji Matsunaga Keishi Maruo Kenichiro Sakai Sho Kobayashi Tetsuro Ohba Kanichiro Wada Junichi Ohya Kanji Mori Mikito Tsushima Hirosuke Nishimura Takashi Tsuji Masao Koda Atsushi Okawa Masashi Yamazaki Morio Matsumoto Kota Watanabe

J Orthop Sci 2021 Jun 20. Epub 2021 Jun 20.

Dept. of Orthopaedic Surgery, Keio University, Tokyo, Japan; Japanese Organization of the Study for Ossification of Spinal Ligament (JOSL), Tokyo, Japan. Electronic address:

Background: Patients with diffuse idiopathic skeletal hyperostosis (DISH) are susceptible to spinal column injuries with neurological deterioration. Previous studies indicated that the prevalence of diabetes mellitus (DM) in patients with DISH was higher than that in patients without DISH. This study investigates the impact of DM on surgical outcomes for spinal fractures in patients with DISH.

Methods: We retrospectively evaluated 177 spinal fractures in patients with DISH (132 men and 45 women; mean age, 75 ± 10 years) who underwent surgery from a multicenter database. The subjects were classified into two groups according to the presence of DM. Perioperative complications, neurological status by Frankel grade, mortality rate, and status of surgical site infection (SSI) were compared between the two groups.

Results: DM was present in 28.2% (50/177) of the patients. The proportion of men was significantly higher in the DM group (DM group: 86.0% vs. non-DM group: 70.1%) (p = 0.03). The overall complication rate was 22.0% in the DM group and 19.7% in the non-DM group (p = 0.60). Poisson regression model revealed that SSI was significantly associated with DM (DM group: 10.0% vs. non-DM group: 2.4%, Relative risk: 4.5) (p = 0.048). Change in neurological status, mortality rate, instrumentation failure, and nonunion were similar between both groups. HbA1c and fasting blood glucose level (SSI group: 7.2% ± 1.2%, 201 ± 67 mg/dL vs. non-SSI group: 6.6% ± 1.1%, 167 ± 47 mg/dL) tended to be higher in patients with SSI; however, there was no significant difference.

Conclusions: In spinal fracture in patients with DISH, although DM was an associated factor for SSI with a relative risk of 4.5, DM did not negatively impact neurological recovery. Perioperative glycemic control may be useful for preventing SSI because fasting blood glucose level was high in patients with SSI.
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http://dx.doi.org/10.1016/j.jos.2021.03.021DOI Listing
June 2021

Impact of postoperative complications after primary tumor resection on survival in patients with incurable stage IV colorectal cancer: A multicenter retrospective cohort study.

Authors:
Yusuke Fujita Koya Hida Nobuaki Hoshino Yoshiharu Sakai Tsuyoshi Konishi Akiyoshi Kanazawa Michitoshi Goto Shuji Saito Tadashi Suda Masahiko Watanabe

Ann Gastroenterol Surg 2021 May 25;5(3):354-362. Epub 2021 Jan 25.

Department of Surgery Kitasato University School of Medicine Kanagawa Japan.

Aims: Primary tumor resection for patients with incurable stage IV colorectal cancer can prevent tumor-related complications but may cause postoperative complications. Postoperative complications delay the administration of chemotherapy and can lead to the spread of malignancy. However, the impact of postoperative complications after primary tumor resection on survival in patients with incurable stage IV colorectal cancer remains unclear. Therefore, this study aimed to investigate how postoperative complications after primary tumor resection affect survival in this patient group.

Methods: We reviewed data on 966 patients with stage IV colorectal cancer who underwent palliative primary tumor resection between January 2006 and December 2007. We examined the association between major complications (National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grade 3 or more) and overall survival using Cox proportional hazard model and explored risk factors associated with major complications using multivariable logistic regression analysis.

Results: Ninety-three patients (9.6%) had major complications. The 2-year overall survival rate was 32.7% in the group with major complications and 50.3% in the group with no major complications. Patients with major complications had a significantly poorer prognosis than those without major complications (hazard ratio: 1.62; 95% confidence interval: 1.21-2.18;  < .01). Male, rectal tumor, and open surgery were identified to be risk factors for major complications.

Conclusions: Postoperative complications after primary tumor resection was associated with decreased long-term survival in patients with incurable stage IV colorectal cancer.
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http://dx.doi.org/10.1002/ags3.12433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164466PMC
May 2021

The characteristics of the young patients with cervical ossification of the posterior longitudinal ligament of the spine: A multicenter cross-sectional study.

Authors:
Kanji Mori Toshitaka Yoshii Takashi Hirai Satoshi Maki Keiichi Katsumi Narihito Nagoshi Soraya Nishimura Kazuhiro Takeuchi Shuta Ushio Takeo Furuya Kei Watanabe Norihiro Nishida Kota Watanabe Takashi Kaito Satoshi Kato Katsuya Nagashima Masao Koda Kenyu Ito Shiro Imagama Yuji Matsuoka Kanichiro Wada Atsushi Kimura Tetsuro Ohba Hiroyuki Katoh Yukihiro Matsuyama Hiroshi Ozawa Hirotaka Haro Katsushi Takeshita Masahiko Watanabe Morio Matsumoto

J Orthop Sci 2021 Jun 3. Epub 2021 Jun 3.

Department of Orthopedic Surgery, Keio University, School of Medicine, Tokyo, Japan; Japanese Organization of the Study for Ossification of Spinal Ligament (JOSL), Tokyo, Japan.

Background: Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by heterotopic bone formation in the posterior longitudinal ligament of the spine. Although the patients with OPLL are more common in the 60s and 70s, we know that there are markedly young patients (e.g., early 40s). However, to the best of our knowledge, there is few reports characterize young patients with cervical OPLL in terms of the imaging features, subjective symptoms, and ADL problems.

Methods: This is the multicenter cross-sectional study. Two hundred and thirty-seven Japanese symptomatic patients with cervical OPLL confirmed by standard X-rays collected from 16 institutions belonging to the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament formed by the Japanese Ministry of Health, Labor and Welfare were recruited. Whole spine CT data as well as demographic data such as age, gender, patients-based evaluations, and the 36-item Short Form Health Survey (SF-36) were evaluated.

Results: Young group (≦ 45 years old) consisted of 23 patients (8 females and 15 males), accounting for 9.7% of the total. Their characteristics were high body mass index (BMI), significant involvement of trauma in the onset and deterioration of symptoms, and the predominance of thoracic OPLL. The patient-based evaluations did not show a significant difference between the young and non-young groups, or between the genders in the young group except for bodily pain (BP) of SF-36. Female patients in young group had significantly lower BP score of SF-36 than that of male in young group.

Conclusions: Characteristics of young patients with cervical OPLL were high BMI, significant involvement of trauma in the onset and deterioration of symptoms, lower BP score of SF-36 in female, and the predominance of thoracic OPLL.
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http://dx.doi.org/10.1016/j.jos.2021.04.010DOI Listing
June 2021

mGluR1 signaling in cerebellar Purkinje cells: Subcellular organization and involvement in cerebellar function and disease.

Authors:
Miwako Yamasaki Atsu Aiba Masanobu Kano Masahiko Watanabe

Neuropharmacology 2021 08 4;194:108629. Epub 2021 Jun 4.

Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, 060-8638, Japan.

The cerebellum is essential for the control, coordination, and learning of movements, and for certain aspects of cognitive function. Purkinje cells are the sole output neurons in the cerebellar cortex and therefore play crucial roles in the diverse functions of the cerebellum. The type 1 metabotropic glutamate receptor (mGluR1) is prominently enriched in Purkinje cells and triggers downstream signaling pathways that are required for functional and structural plasticity, and for synaptic responses. To understand how mGluR1 contributes to cerebellar functions, it is important to consider not only the operational properties of this receptor, but also its spatial organization and the molecular interactions that enable its proper functioning. In this review, we highlight how mGluR1 and its related signaling molecules are organized into tightly coupled microdomains to fulfill physiological functions. We also describe emerging evidence that altered mGluR1 signaling in Purkinje cells underlies cerebellar dysfunction in ataxias of human patients and mouse models.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108629DOI Listing
August 2021

Effect of Whole Tissue Culture and Basic Fibroblast Growth Factor on Maintenance of Tie2 Molecule Expression in Human Nucleus Pulposus Cells.

Authors:
Kosuke Sako Daisuke Sakai Yoshihiko Nakamura Jordy Schol Erika Matsushita Takayuki Warita Natsumi Horikita Masato Sato Masahiko Watanabe

Int J Mol Sci 2021 Apr 29;22(9). Epub 2021 Apr 29.

Department of Orthopedic Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Previous work showed a link between Tie2 nucleus pulposus progenitor cells (NPPC) and disc degeneration. However, NPPC remain difficult to maintain in culture. Here, we report whole tissue culture (WTC) combined with fibroblast growth factor 2 (FGF2) and chimeric FGF (cFGF) supplementation to support and enhance NPPC and Tie2 expression. We also examined the role of PI3K/Akt and MEK/ERK pathways in FGF2 and cFGF-induced Tie2 expression. Young herniating nucleus pulposus tissue was used. We compared WTC and standard primary cell culture, with or without 10 ng/mL FGF2. PI3K/Akt and MEK/ERK signaling pathways were examined through western blotting. Using WTC and primary cell culture, Tie2 positivity rates were 7.0 ± 2.6% and 1.9 ± 0.3% ( = 0.004), respectively. Addition of FGF2 in WTC increased Tie2 positivity rates to 14.2 ± 5.4% ( = 0.01). FGF2-stimulated expression of Tie2 was reduced 3-fold with the addition of the MEK inhibitor PD98059 ( = 0.01). However, the addition of 1 μM Akt inhibitor, 124015-1MGCN, only reduced small Tie2 expression ( = 0.42). cFGF similarly increased the Tie2 expression, but did not result in significant phosphorylation in both the MEK/ERK and PI3K/Akt pathways. WTC with FGF2 addition significantly increased Tie2 maintenance of human NPPC. Moreover, FGF2 supports Tie2 expression via MEK/ERK and PI3K/Akt signals. These findings offer promising tools and insights for the development of NPPC-based therapeutics.
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http://dx.doi.org/10.3390/ijms22094723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124367PMC
April 2021

Accuracy of Percutaneous Pedicle Screw Placement after Single-Position versus Dual-Position Insertion for Lateral Interbody Fusion and Pedicle Screw Fixation Using Fluoroscopy.

Authors:
Akihiko Hiyama Hiroyuki Katoh Daisuke Sakai Masato Sato Masahiro Tanaka Masahiko Watanabe

Asian Spine J 2021 May 4. Epub 2021 May 4.

Department of Orthopaedic Surgery, Tokai University School of Medicine, Isehara, Japan.

Study Design: Retrospective study.

Purpose: The purpose of this study was to compare the accuracy of percutaneous pedicle screw (PPS) placement between prone and lateral decubitus positions during lateral lumbar interbody fusion (LLIF) and to evaluate the tendency of PPS positioning based on simple computed tomography measurements with patients in the lateral decubitus position.

Overview Of Literature: There is insufficient information in the literature regarding the accuracy of inserting a PPS using fluoroscopy in patients in the lateral decubitus position.

Methods: We included 62 patients who underwent combined LLIF surgery and PPS fixation for degenerative lumbar spondylolisthesis with spinal canal stenosis. We compared the patient demographics and the accuracy of fluoroscopy-guided PPS placement between two groups: patients who remained in the lateral decubitus position for the pedicle screw fixation (single-position surgery [SPS] group) and those who were turned to the prone position (dual-position surgery [DPS] group).

Results: There were 40 patients in the DPS group and 22 in the SPS group. Of the 292 PPSs, only 12 were misplaced. In other words, 280/292 screws (95.9%) were placed correctly in the pedicle's cortical shell (grade 0). PPS insertion did not cause neurological, vascular, or visceral injuries in either group. The breach rates for the DPS and SPS groups were 4.1% (grade 1, 5 screws; grade 2, 3 screws; grade 3, 0 screw) and 4.1% (grade 1, 2 screws; grade 2, 2 screws; grade 3, 0 screw), respectively. Although there were no statistically significant differences, the downside PPS had more screw malpositioning than the upside PPS.

Conclusions: We found that PPS insertion with the patient in the decubitus position under fluoroscopic guidance might be as safe and reliable a technique as PPS insertion in the prone position, with a misplacement rate similar to that previously published.
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http://dx.doi.org/10.31616/asj.2020.0526DOI Listing
May 2021

Candidates for Intra-Articular Administration Therapeutics and Therapies of Osteoarthritis.

Authors:
Eriko Toyoda Miki Maehara Masahiko Watanabe Masato Sato

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan.

Osteoarthritis (OA) of the knee is a disease that significantly decreases the quality of life due to joint deformation and pain caused by degeneration of articular cartilage. Since the degeneration of cartilage is irreversible, intervention from an early stage and control throughout life is important for OA treatment. For the treatment of early OA, the development of a disease-modifying osteoarthritis drug (DMOAD) for intra-articular (IA) injection, which is attracting attention as a point-of-care therapy, is desired. In recent years, the molecular mechanisms involved in OA progression have been clarified while new types of drug development methods based on gene sequences have been established. In addition to conventional chemical compounds and protein therapeutics, the development of DMOAD from the new modalities such as gene therapy and oligonucleotide therapeutics is accelerating. In this review, we have summarized the current status and challenges of DMOAD for IA injection, especially for protein therapeutics, gene therapy, and oligonucleotide therapeutics.
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http://dx.doi.org/10.3390/ijms22073594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036705PMC
March 2021

Development of Injectable Polydactyly-Derived Chondrocyte Sheets.

Authors:
Shiho Wasai Eriko Toyoda Takumi Takahashi Miki Maehara Eri Okada Ryoka Uchiyama Tadashi Akamatsu Masahiko Watanabe Masato Sato

Int J Mol Sci 2021 Mar 21;22(6). Epub 2021 Mar 21.

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

We are conducting a clinical study of the use of allogeneic polydactyly-derived chondrocyte sheets (PD sheets) for the repair of articular cartilage damage caused by osteoarthritis. However, the transplantation of PD sheets requires highly invasive surgery. To establish a less invasive treatment, we are currently developing injectable fragments of PD sheets (PD sheets-mini). Polydactyly-derived chondrocytes were seeded in RepCell™ or conventional temperature-responsive inserts and cultured. Cell counts and viability, histology, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR), and flow cytometry were used to characterize PD sheets-mini and PD sheets collected from each culture. To examine the effects of injection on cell viability, PD sheets-mini were tested in four experimental conditions: non-injection control, 18 gauge (G) needle, 23G needle, and syringe only. PD sheets-mini produced similar amounts of humoral factors as PD sheets. No histological differences were observed between PD sheets and PD sheets-mini. Except for , expression of cartilage-related genes did not differ between the two types of PD sheet. No significant differences were observed between injection conditions. PD sheets-mini have characteristics that resemble PD sheets. The cell viability of PD sheets-mini was not significantly affected by needle gauge size. Intra-articular injection may be a feasible, less invasive method to transplant PD sheets-mini.
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http://dx.doi.org/10.3390/ijms22063198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004148PMC
March 2021

Potential of Exosomes for Diagnosis and Treatment of Joint Disease: Towards a Point-of-Care Therapy for Osteoarthritis of the Knee.

Authors:
Miki Maehara Eriko Toyoda Takumi Takahashi Masahiko Watanabe Masato Sato

Int J Mol Sci 2021 Mar 6;22(5). Epub 2021 Mar 6.

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan.

In the knee joint, articular cartilage injury can often lead to osteoarthritis of the knee (OAK). Currently, no point-of-care treatment can completely address OAK symptoms and regenerate articular cartilage to restore original functions. While various cell-based therapies are being developed to address OAK, exosomes containing various components derived from their cells of origin have attracted attention as a cell-free alternative. The potential for exosomes as a novel point-of-care treatment for OAK has been studied extensively, especially in the context of intra-articular treatments. Specific exosomal microRNAs have been identified as possibly effective in treating cartilage defects. Additionally, exosomes have been studied as biomarkers through their differences in body fluid composition between joint disease patients and healthy subjects. Exosomes themselves can be utilized as a drug delivery system through their manipulation and encapsulation of specific contents to be delivered to specific cells. Through the combination of exosomes with tissue engineering, novel sustained release drug delivery systems are being developed. On the other hand, many of the functions and activities of exosomes are unknown and challenges remain for clinical applications. In this review, the possibilities of intra-articular treatments utilizing exosomes and the challenges in using exosomes in therapy are discussed.
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http://dx.doi.org/10.3390/ijms22052666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961842PMC
March 2021

Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Authors:
Masao Koda Hideki Hanaoka Yasuhisa Fujii Michiko Hanawa Yohei Kawasaki Yoshihito Ozawa Tadami Fujiwara Takeo Furuya Yasushi Ijima Junya Saito Mitsuhiro Kitamura Takuya Miyamoto Seiji Ohtori Yukei Matsumoto Tetsuya Abe Hiroshi Takahashi Kei Watanabe Toru Hirano Masayuki Ohashi Hirokazu Shoji Tatsuki Mizouchi Norio Kawahara Masahito Kawaguchi Yugo Orita Takeshi Sasamoto Masahito Yoshioka Masafumi Fujii Katsutaka Yonezawa Daisuke Soma Hiroshi Taneichi

Brain 2021 04;144(3):789-799

G-SPIRIT Study Group, Chiba, Japan.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.
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http://dx.doi.org/10.1093/brain/awaa466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041047PMC
April 2021

Cobalt-chromium versus titanium alloy rods for correction of adolescent idiopathic scoliosis based on 1-year follow-up: a multicenter randomized controlled clinical trial.

Authors:
Daisuke Sakai Masato Tanaka Jun Takahashi Yuki Taniguchi Jordy Schol Akihiko Hiyama Haruo Misawa Shugo Kuraishi Hiroki Oba Yoshitaka Matsubayashi So Kato Ryo Sugawara Masato Sato Masahiko Watanabe Katsushi Takeshita

J Neurosurg Spine 2021 Mar 19:1-10. Epub 2021 Mar 19.

6Department of Orthopaedics, Jichi Medical University, Tochigi, Japan.

Objective: For instrumented correction surgery for adolescent idiopathic scoliosis (AIS), surgeons are increasingly switching from titanium (Ti) alloy rods to stiffer cobalt-chromium (CoCr) rods. The authors conducted the first multicenter randomized controlled clinical trial to investigate whether these materials affect the outcomes in terms of spine correction and quality of life (QOL). This trial was registered at UMIN Clinical Trials Registry on September 3, 2012, under the identifier UMIN000008838 (level of evidence 1).

Methods: Female AIS patients (Lenke types 1-3, patient age 10-19 years) were recruited at 5 Japanese institutions and randomized into two cohorts: 6.0-mm-diameter Ti rods were placed in one group, and 6.0-mm-diameter CoCr rods were placed in the other. Patients were followed up at 2 weeks and 3, 6, and 12 months with radiographic examination to quantify the sagittal and coronal correction (Cobb angle, thoracic kyphosis, rib hump, and apical vertebral rotation). Patients completed questionnaires (Scoliosis Research Society-22r, 12-Item Short-Form Health Survey, and Scoliosis Japanese Questionnaire-27) at 6 and 12 months to assess QOL.

Results: A total of 69 AIS patients were randomized to the demographically similar Ti (n = 37) or CoCr (n = 32) cohort. Four adverse events were recorded, two in each cohort, but these were not related to the rod material. At the final follow-up, both Ti and CoCr cohorts showed significant improvement in spinal correction, including the Cobb angle, thoracic kyphosis, and rib hump size. The correction rates were 68.4% and 67.1% for the Ti and CoCr cohorts, respectively. No parameters differed significantly between the cohorts at any time. Survey data showed improved but similar outcomes in both cohorts.

Conclusions: Both treatments (Ti and CoCr) produced similar results and were efficient in engendering clinically significant spine corrections. Clinical trial registration no.: UMIN000008838 (UMIN Clinical Trials Registry).
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http://dx.doi.org/10.3171/2020.9.SPINE201486DOI Listing
March 2021

Association of NAT2 genetic polymorphism with the efficacy of Neurotropin® for the enhancement of aggrecan gene expression in nucleus pulposus cells: a pilot study.

Authors:
Tomoko Nakai Daisuke Sakai Yoshihiko Nakamura Natsumi Horikita Erika Matsushita Mitsuru Naiki Masahiko Watanabe

BMC Med Genomics 2021 03 11;14(1):79. Epub 2021 Mar 11.

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.

Background: Intervertebral disc degeneration, one of the major causes of low-back pain, results from altered biosynthesis/turnover of extracellular matrix in the disc. Previously, we reported that the analgesic drug Neurotropin® (NTP) had an anabolic effect on glycosaminoglycan synthesis in cultured nucleus pulposus (NP) cells via the stimulation of chondroitin sulfate N-acetylgalactosaminyltransferase 1. However, its effect on the aggrecan core protein was not significantly detected, because of the data variance. A microarray analysis suggested that the effect of NTP on aggrecan was correlated with N-acetyltransferase 2 (NAT2), a drug-metabolizing enzyme. Specific NAT2 alleles are known to correlate with rapid, intermediate, and slow acetylation activities and side effects of various drugs. We investigated the association between the efficacy of NTP on aggrecan expression and the NAT2 genotype in cell donors.

Methods: NP cells were isolated from intervertebral disc tissues donated by 31 Japanese patients (28-68 years) who underwent discectomy. NTP was added to the primary cell cultures and its effect on the aggrecan mRNA was analyzed using real-time quantitative PCR. To assess acetylator status, genotyping was performed based on the inferred NAT2 haplotypes of five common single-nucleotide polymorphisms using allele-specific PCR.

Results: The phenotype frequencies of NAT2 in the patients were 0%, 42.0%, and 58.0% for slow, intermediate, and rapid acetylators, respectively. The proportions of responders to NTP treatment (aggrecan upregulation, ≥ 1.1-fold) in the intermediate and rapid acetylators were 76.9% and 38.9%, respectively. The odds ratio of the comparison of the intermediate acetylator status between responders and nonresponders was 5.2 (95% CI 1.06-26.0, P = 0.036), and regarding the 19 male patients, this was 14.0 (95% CI 1.54-127.2, P = 0.012). In the 12 females, the effect was not correlated with NAT2 phenotype but seemed to become weaker along with aging.

Conclusions: An intermediate acetylator status significantly favored the efficacy of NTP treatment to enhance aggrecan production in NP cells. In males, this tendency was detected with higher significance. This study provides suggestive data of the association between NAT2 variants and the efficacy of NTP treatment. Given the small sample size, results should be further confirmed.
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http://dx.doi.org/10.1186/s12920-021-00926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948325PMC
March 2021

Effect of Platelet-Rich Plasma on M1/M2 Macrophage Polarization.

Authors:
Ryoka Uchiyama Eriko Toyoda Miki Maehara Shiho Wasai Haruka Omura Masahiko Watanabe Masato Sato

Int J Mol Sci 2021 Feb 26;22(5). Epub 2021 Feb 26.

Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Osteoarthritis of the knee (OAK) is a chronic degenerative disease and progresses with an imbalance of cytokines and macrophages in the joint. Studies regarding the use of platelet-rich plasma (PRP) as a point-of-care treatment for OAK have reported on its effect on tissue repair and suppression of inflammation but few have reported on its effect on macrophages and macrophage polarization. Based on our clinical experience with two types of PRP kits Cellaid Serum Collection Set P type kit (leukocyte-poor-PRP) and an Autologous Protein Solution kit (APS leukocyte-rich-PRP), we investigated the concentrations of humoral factors in PRPs prepared from the two kits and the effect of humoral factors on macrophage phenotypes. We found that the concentrations of cell components and humoral factors differed between PRPs purified using the two kits; APS had a higher concentration of M1 and M2 macrophage related factors. The addition of PRP supernatants to the culture media of monocyte-derived macrophages and M1 polarized macrophages revealed that PRPs suppressed M1 macrophage polarization and promoted M2 macrophage polarization. This research is the first to report the effect of PRPs purified using commercial kits on macrophage polarization.
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http://dx.doi.org/10.3390/ijms22052336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956636PMC
February 2021
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