Tokue Mieda

Mesenchymal Stem Cells as a Potential Therapeutic Tool for Spinocerebellar Ataxia

Spinocerebellar ataxia (SCA) is a devastating progressive neurodegenerative disorder, for which no effective treatments have been developed. However, some studies have shown that an intracerebellar or intrathecal injection of mesenchymal stem cells (MSCs) was partially effective in some genetic mouse models of cerebellar ataxia such as SCA1 and Lurcher mutant. MSCs likely exert their therapeutic efficacy by secreting innate factors to induce neuronal growth and synaptic connection and reduce apoptosis. In this review, we introduce the therapeutic influence of MSCs on each mouse model for cerebellar ataxia and the possible mechanisms underlying the action of MSCs. We also introduce studies on the safety and effectiveness of umbilical cord MSCs for patients with SCA.

Association between neck and shoulder pain, back pain, low back pain and body composition parameters among the Japanese general population.

BackgroundNeck and shoulder pain, back pain and low back pain are common symptoms in Japanese subjects, and it is important to elucidate the pathology and associated factors of these pains due to their frequency and impact on the quality of life (QOL) and activities of daily living (ADL). The purpose of the present study was to investigate whether body composition is associated with these pains.MethodsWe collected the data of 273 Japanese subjects regarding the presence and the visual analogue scale (VAS) of neck and shoulder pain, back pain, low back pain and body composition parameters calculated using bioelectrical impedance analysis (BIA) technology. Furthermore, we investigated the association between these pains and the body composition using statistical methods.ResultsAccording to a multivariate analysis adjusted for age and gender, lower total body water ratio was significantly associated with the presence of neck and shoulder pain at present (P < 0.05); additionally, total body muscle mass (standardized β = −0.26, 95 % CI, −0.17 - -0.008, P < 0.05), total body water (standardized β = −0.27, 95 % CI, −0.23 - -0.04, P < 0.01), appendicular muscle mass (standardized β = −0.29, 95 % CI, −0.36 - -0.04, P < 0.05), and the appendicular muscle mass index (AMI) (standardized β = −0.24, 95 % CI, −1.18 - -0.20, P <0.01) were negatively correlated with the VAS of neck and shoulder pain, whereas no body composition parameters were significantly associated with back pain, low back pain at present and any type of chronic pain.ConclusionsThe present study demonstrated that some body composition parameters regarding body water and body muscle were associated or correlated with the presence or intensity of neck and shoulder pain.

Mesenchymal stem cells attenuate peripheral neuronal degeneration in spinocerebellar ataxia type 1 knockin mice

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disorder in which an abnormally expanded polyglutamine tract is inserted into causative ataxin‐1 proteins. We have previously shown that SCA1 knockin (SCA1‐KI) mice over 6 months of age exhibit a degeneration of motor neuron axons and their encasing myelin sheaths, as reported in SCA1 patients. We examined whether axon degeneration precedes myelin degeneration or vice versa in SCA1‐KI mice and then attempted to mitigate motor neuron degeneration by intrathecally administering mesenchymal stem cells (MSCs). Temporal examination of the diameters of motor neuron axons and their myelin sheaths revealed a decrease in diameter of the axon but not of the myelin sheaths in SCA1‐KI mice as early as 1 month of age, which suggests secondary degeneration of the myelin sheaths. We injected MSCs into the intrathecal space of SCA1‐KI mice at 1 month of age, which resulted in a significant suppression of degeneration of both motor neuron axons and myelin sheaths, even 6 months after the MSC injection. Thus, MSCs effectively suppressed peripheral nervous system degeneration in SCA1‐KI mice. It has not yet been clarified how clinically administered MSCs exhibit significant therapeutic effects in patients with SCA1. The morphological evidence presented in this current mouse study might explain the mechanisms that underlie the therapeutic effects of MSCs that are observed in patients with SCA1.

Impairment of spinal motor neurons in spinocerebellar ataxia type 1-knock-in mice

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of polyglutamine repeats in the Ataxin-1 protein. An accumulating body of cerebellar, histological and behavioral analyses has proven that SCA1-knock-in mice (in which the endogenous Atxn1 gene is replaced with mutant Atxn1 that has abnormally expanded 154 CAG repeats) work as a good tool, which resembles the central nervous system pathology of SCA1 patients. However, the peripheral nervous system pathology of the model mice has not been studied despite the fact that the clinical manifestation is also characterized by peripheral involvement. We show here that spinal motor neurons are degenerated in SCA1-knock-in mice. Histologically, some spinal motor neurons of the SCA1-knock-in mice have polyglutamine aggregates in their nuclei and also thinner and demyelinated axons. Electrophysiological examinations of the mice showed slower nerve conduction velocities in spinal motor neurons and lower amplitudes of muscle action potential, compared to wild-type mice. Consistently, the mice displayed decrease in rearing number and total rearing time. These results suggest that the knock-in mice serve as a definite model that reproduces peripheral involvement and are therefore useful for research on the peripheral nervous system pathology in SCA1 patients.

Morphological and Functional Attenuation of Degeneration of Peripheral Neurons by Mesenchymal Stem Cell-Conditioned Medium in Spinocerebellar Ataxia Type 1-Knock-in Mice.

Spinocerebellar ataxia type 1 (SCA1) is caused by the ataxin‐1 protein (ATXN1) with an abnormally expanded polyglutamine tract and is characterized by progressive neurodegeneration. We previously showed that intrathecal injection of mesenchymal stem cells (MSCs) during the nonsymptomatic stage mitigates the degeneration of the peripheral nervous system (PNS) neurons in SCA1‐knock‐in (SCA1‐KI) mice. We tested in this study whether the therapeutic effects of MSCs in SCA1‐KI mice could be reproduced with MSC‐releasing factor(s).

Bony ankylosis of the facet joint of the cervical spine in rheumatoid arthritis: Its characteristics and relationship to the clinical findings

Abstract Objectives: The purpose of this study was to clarify the characteristics of bony ankylosis of the facet joint of the cervical spine in rheumatoid arthritis (RA) patients who required cervical spine surgery, and its relationship to the clinical findings. Methods: Eighty consecutive RA patients with cervical spine disorder who received initial surgery were reviewed. The occurrence of bony ankylosis of the facet joint of the cervical spine was investigated using computed tomography (CT) before surgery. We also evaluated the severity of neurological symptoms and the plain wrist radiographs taken before surgery; furthermore, we evaluated each patient’s medical history for total knee arthroplasty (TKA) or hip arthroplasty (THA). Results: The preoperative CT imaging demonstrated bony ankylosis of the facet joint of the cervical spine in 45 facet levels of 19 cases (BA + group). In all patients, responsible instability or stenosis was demonstrated just caudal or on the cranial side of those bony ankylosis. Before surgery, the BA + group included significantly more patients showing severe cervical myelopathy (p < 0.05), and significantly more cases showing progressed ankylosis in the wrist joint bilaterally (p < 0.01). There were also significantly more patients who received two or more TKA or THA before the cervical spine surgery in the BA + group (p < 0.01). Conclusions: Bony ankylosis of the facet joint of the cervical spine may be a risk factor of instability or stenosis at the adjacent disc level and severe cervical myelopathy. Furthermore, its ankylosis was demonstrated in RA patients with severe destroyed joints.

Prevalence of Chronic Nonspecific Low Back Pain and Its Associated Factors among Middle-Aged and Elderly People: An Analysis Based on Data from a Musculoskeletal Examination in Japan

Study Design A cross-sectional study. Purpose To clarify the prevalence of chronic nonspecific low back pain (CNSLBP) and its associated factors among middle-aged and elderly Japanese individuals using data from a musculoskeletal examination conducted in general Japanese populations. Overview of Literature Most studies evaluating low back pain-associated factors have been conducted in Western countries, but they have not always evaluated CNSLBP. Methods We obtained data on 213 subjects aged >50 years who responded to a survey regarding age, gender, body mass index, lifestyle-related diseases (diabetes mellitus, hypertension, and hyperlipidemia), glucocorticoid use, smoking and alcohol-drinking habits, labor intensity, and chronic low back pain (CLBP) and underwent screening for lumbar spinal stenosis, evaluation for quality of life (QOL), and evaluation for specific spinal pathology via thoracolumbar spine X-rays. We investigated the prevalence of CNSLBP and association between CNSLBP and measured variables. Results The prevalence of CNSLBP and chronic specific low back pain (CSLBP) was 15.4% and 9.3%, respectively. Among the subjects with CLBP, 62.2% had CNSLBP. In age-adjusted logistic models, smoking habits (p=0.049, odds ratio [OR]=2.594), low back pain (p<0.001, OR=0.974), lumbar function (p=0.001, OR=0.967), and social function (p=0.023, OR=0.976) in the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) were significantly associated with CNSLBP, whereas EQ-5D utility score (p=0.024, OR=0.068), low back pain (p=0.007, OR=0.981), lumbar function (p=0.001, OR=0.963), walking ability (p=0.001, OR=0.968), and social function (p=0.002, OR=0.966) in JOABPEQ were significantly associated with CSLBP. Conclusions CNSLBP among middle-aged and elderly individuals was associated with smoking habits and decreased QOL; however, CSLBP was considered to be more multilaterally associated decreased QOL.

Bone turnover markers and the factors associated with atypical femur fractures among Japanese patients

Many previous reports have indicated that atypical femur fractures (AFFs) are associated with the administration of bisphosphonates (BPs). A number of risk factors and hypotheses regarding the pathogenesis of AFFs have been reported to date. The purpose of the present study was to identify the factors associated with AFFs in Japanese individuals and to elucidate the association between bone metabolism and AFFs by evaluating bone turnover markers (BTMs). We prospectively reviewed all patients with femur fractures and identified the patients with AFFs and typical femur fractures (TFFs). We collected the demographic and clinical data that were relevant to the present study, namely age, gender, affected side, affected site, concomitant medical history, and comorbid conditions, and measured the levels of BTMs within 24h after trauma. Welchs test and Fishers exact probability test were used for the statistical analyses. A total of 338 patients, including 10 patients with AFFs and 328 patients with TFFs, were analyzed under the inclusion criteria. The use of BPs (p<0.001) and collagen disease and chronic granulomatous disease (CD/CGD) (p=0.025) were more frequently observed in patients with AFFs than in patients with TFFs, while the levels of BTMs, including N-terminal propeptides of type 1 procollagen (P1NP), isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b) and undercarboxylated osteocalcin (ucOC) were significantly lower in patients with AFFs than in patients with TFFs. Furthermore, the level of TRACP-5b was found to be significantly lower in patients with atypical subtrochanteric fractures than in atypical diaphyseal fractures (p=0.025). Moreover, the levels of P1NP (p=0.016) and TRACP-5b (p=0.015) were found to be significantly lower in patients with AFFs than in patients with TFFs in a subgroup analysis of BPs users. The use of BPs was considered to be a factor associated with AFFs. Our comparison of the BTMs in patients with AFFs and TFFs indicated that the severe suppression of bone turnover was associated with the pathogenesis of AFFs. The extent of the influence of suppressed turnover on the pathogenesis of AFFs may differ depending on the fracture site.

Successful hemostatic management of major surgery for cervical spondylotic myelopathy in a patient with severe factor XI deficiency

Factor XI deficiency (FXID) is a rare bleeding disorder caused by mutations in the F11 gene. Spontaneous bleeding in patients with factor XI deficiency is rare, but major bleeding may occur after surgery or trauma. The basic method for hemostatic treatment is replacement of the missing factor using FXI concentrate or fresh frozen plasma (FFP). We report the case of a 72-year-old male with severe FXID who underwent a laminoplasty under sufficient, but minimal, FFP transfusion. Through detailed monitoring of activated partial thromboplastin time (APTT) and FXI activity at the perioperative period, we succeeded in hemostatic management of major surgery without significant blood loss and fluid overload. From the course of this case, we found that measuring FXI activity is superior to measuring APTT. Furthermore, we identified a novel homozygous mutation in F11 [NM_000128.3:c.1041C > A:p.(Tyr347*)] by whole exome sequencing.

Assessment of the Relationship between Pelvic Tilt and the Sacro-Femoral-Pubic Angle in Middle-Aged and Elderly Asian Individuals

Study Design Cross-sectional study. Purpose The purpose of this study was to evaluate the correlation between pelvic tilt (PT) and the sacro-femoral-pubic (SFP) angle, which is easier to identify than PT, in middle-aged and elderly Asian subjects from the general population. Overview of Literature Measuring PT is important in the diagnosis and treatment of adult spinal deformity. However, identifying femoral heads, which are necessary to determine PT, using sagittal radiographs is often difficult. Methods Standing coronal and sagittal pelvic radiographs of individuals aged more than 50 years were taken during a local medical examination. The subjects were divided into female, male, and total groups at the time of evaluation. Linear regression analysis was performed to investigate the relationship between PT and the SFP angle, which were obtained from the X-rays. Results The present study included 291 subjects. There were no statistically significant differences between the left and right SFP angles, and there was gender difference regarding the SFP angle. However, a gender difference was observed regarding PT. The correlation between PT and the SFP angle was substantiated in each group. Pearsons correlation coefficients between PT and the SFP angle in the total, female, and male groups were 0.696, 0.853, and 0.619, respectively. In the linear regression analysis, PT was calculated as follows: PT=60.1−0.77×(SFP angle) in the total group, PT=62.8−0.80×(SFP angle) in the female group, and PT=51.5−0.64×(SFP angle) in the male group. Conclusions A significant correlation between PT and the SFP angle was observed in middle-aged and elderly Asian subjects from the general population.