Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

RSPO3 is a novel contraction-inducible factor identified in an "in vitro exercise model" using primary human myotubes.

The physiological significance of skeletal muscle as a secretory organ is now well known but we can only speculate as to the existence of as-yet-unidentified myokines, especially those upregulated in response to muscle contractile activity. We first attempted to establish an "insert-chamber based in vitro exercise model" allowing the miniature but high cell-density culture state enabling highly developed contractile human myotubes to be readily obtained by applying electric pulse stimulation (EPS). By employing this in vitro exercise model, we identified R-spondin 3 (RSPO3) as a novel contraction-inducible myokine produced by cultured human myotubes. Contraction-dependent muscular RSPO3 mRNA upregulation was confirmed in skeletal muscles of mice subjected to sciatic nerve mediated in situ contraction as well as those of mice after 2 h of running. Pharmacological in vitro experiments demonstrated a relatively high concentration of metformin (millimolar range) to suppress the contraction-inducible mRNA upregulation of human myokines including RSPO3, interleukin (IL)-6, IL-8 and CXCL1. Our data also suggest human RSPO3 to be a paracrine factor that may positively participate in the myogenesis processes of myoblasts and satellite cells. Thus, the "insert chamber-based in vitro exercise model" is a potentially valuable research tool for investigating contraction-inducible biological responses of human myotubes usually exhibiting poorer contractility development even in the setting of EPS treatment.

Tissue accumulation of neutrophil extracellular traps mediates muscle hyperalgesia in a mouse model.

Accumulation of uric acid (UA) during muscular trauma is a factor involved in the development of muscle hyperalgesia. Neutrophil extracellular traps (NETs), DNA-based reticular structures to capture UA, play a central role in the pain onset of gout attacks; however, the involvement of NETs via the elevation of local UA level in muscle hyperalgesia due to injuries from muscle overuse remains unknown. The triceps surae muscles (TSMs) in the unilateral hindlimb of mice were electrically stimulated to induce excessive muscle contraction. Mechanical withdrawal thresholds, tissue UA levels, neutrophil recruitment, and protein amount of citrullinated histone 3 (citH3), a major marker of NETs, were investigated. Furthermore, whether neutrophil depletion, extracellular DNA cleavage, and administration of the urate-lowering agent febuxostat improved muscle hyperalgesia caused by NET formation was examined. CitH3 expression upon neutrophil recruitment was significantly increased in the stimulated TSMs with increased tissue UA levels, whereas febuxostat administration improved muscle hyperalgesia with decreased citH3 and tissue UA levels, as observed in neutrophil depletion and extracellular DNA digestion. The underlying mechanism of muscle hyperalgesia associated with locally recruited neutrophils forming NETs due to increased tissue UA levels potentially plays a significant role in creating a vicious circle of muscle pain.

Feeder-supported in vitro exercise model using human satellite cells from patients with sporadic inclusion body myositis.

Contractile activity is a fundamental property of skeletal muscles. We describe the establishment of a "feeder-supported in vitro exercise model" using human-origin primary satellite cells, allowing highly-developed contractile myotubes to readily be generated by applying electrical pulse stimulation (EPS). The use of murine fibroblasts as the feeder cells allows biological responses to EPS in contractile human myotubes to be selectively evaluated with species-specific analyses such as RT-PCR. We successfully applied this feeder-supported co-culture system to myotubes derived from primary satellite cells obtained from sporadic inclusion body myositis (sIBM) patients who are incapable of strenuous exercise testing. Our results demonstrated that sIBM myotubes possess essentially normal muscle functions, including contractility development, de novo sarcomere formation, and contraction-dependent myokine upregulation, upon EPS treatment. However, we found that some of sIBM myotubes, but not healthy control myotubes, often exhibit abnormal cytoplasmic TDP-43 accumulation upon EPS-evoked contraction, suggesting potential pathogenic involvement of the contraction-inducible TDP-43 distribution peculiar to sIBM. Thus, our "feeder-supported in vitro exercise model" enables us to obtain contractile human-origin myotubes, potentially utilizable for evaluating exercise-dependent intrinsic and pathogenic properties of patient muscle cells. Our approach, using feeder layers, further expands the usefulness of the "in vitro exercise model".

The 5-Year Course of Neck Pain Among Natural Disaster Survivors: The Association of Prior Neck Pain with New Episodes of Neck Pain.

OBJECTIVE: Neck pain is a common health problem among both the general population and natural disaster survivors. However, the long-term course of neck pain has rarely been reported. The aim of this study was to elucidate the 5-year course of neck pain among survivors of the Great East Japan Earthquake (GEJE) by assessing the association of neck pain 2 and 4 years after the disaster with that at 7 years. STUDY DESIGN: Longitudinal study. METHODS: A panel study was conducted on GEJE survivors (n = 1,821) through the administration of a self-reported questionnaire at 2 (first time point), 4 (second time point), and 7 years (third time point) after the disaster. Multivariate logistic regression analyses were performed to assess the association between prior neck pain and subsequent neck pain. RESULTS: The rates of neck pain at the first, second, and third time points were 20.7%, 21.1%, and 20.1%, respectively. Neck pain at the first time point was significantly associated with neck pain at the third time point (adjusted odds ratio [95% confidence interval]: 5.96 [4.53-7.83]). Furthermore, neck pain at the first and second time points was significantly associated with neck pain at the third time point (adjusted odds ratio [95% confidence interval]: 5.71 [4.19-7.78] for neck pain at either time point; 15.94 [10.99-23.12] for neck pain at both time points; P for trend <0.001). CONCLUSIONS: Prior neck pain was significantly associated with neck pain 5 years later, and the effect was stronger with an increase of prior neck pain episodes. Clinicians should base their selection of treatment method on an individual's history of neck pain.

Low Back Pain in Young Sports Players: A Cross-sectional Study in Japan.

STUDY DESIGN: A cross-sectional study. OBJECTIVE: The purpose of this large cohort study was to assess the prevalence of low back pain (LBP) among young players participating in several types of sports. SUMMARY OF BACKGROUND DATA: LBP is a significant problem among young sports players. Sport discipline among young players is thought to be associated with LBP. However, similar previous studies did not specifically analyze LBP by age and sex. METHODS: A cross-sectional study was conducted with young sports players (ages 6-15 years, n = 7277) using a self-reported questionnaire. The prevalence of LBP was assessed using the variables of age, sex, and sport discipline. RESULTS: The point prevalence of LBP among young sports players was 5.0%. The participants between 6 and 8 years' old had the lowest prevalence of LBP (0.4%-1.3%), which increased with aging and reached the highest proportion of 13.5% to 14.8% at 13 to 14 years. Furthermore, female players had significantly higher proportions of LBP than male players (8.1% vs. 3.7%). Regarding sport discipline, the prevalence of LBP was higher in basketball, handball, and volleyball. CONCLUSION: The prevalence of LBP among young sports players was different for age, sex, and sport discipline. Further studies are needed to clarify the association of sport-specific movements to LBP in each sport discipline. This may assist in developing programs or strategies for preventing LBP among young sports players.Level of Evidence: 3.

Association of musculoskeletal pain in other body parts with new-onset shoulder pain: a longitudinal study among survivors of the Great East Japan Earthquake.

OBJECTIVE: Shoulder pain is a common health problem coexisting with other musculoskeletal pain. However, the effects of pre-existing musculoskeletal pain on the development of shoulder pain are not clear. The present study aimed to elucidate the association between coexisting musculoskeletal pain at other body sites and new-onset shoulder pain among survivors of the Great East Japan Earthquake (GEJE). DESIGN: This is a longitudinal study. SETTING: The study was conducted at the severely damaged coastal areas in Ishinomaki and Sendai cities. PARTICIPANTS: The survivors who did not have shoulder pain at 3 years after the GEJE were followed up 1 year later (n=2131). INTERVENTIONS: Musculoskeletal pain (low back, hand and/or foot, knee, shoulder and neck pain) was assessed using self-reported questionnaires. MAIN OUTCOME MEASURES: The outcome of interest was new-onset shoulder pain, which was defined as shoulder pain absent at 3 years but present at 4 years after the disaster. The main predictive factor for new-onset shoulder pain was musculoskeletal pain in other body parts at 3 years after the GEJE; this was categorised according to the number of pain sites (0, 1, ≥2). Multiple regression analyses were conducted to calculate the odds ratio (OR) and 95% confidence interval (CI) for new-onset shoulder pain due to musculoskeletal pain in other body parts. RESULTS: The incidence of new-onset shoulder pain was 6.7% (143/2131). Musculoskeletal pain in other body parts was significantly associated with new-onset shoulder pain. Using the survivors without other musculoskeletal pain as reference, the adjusted OR and 95% CI for new-onset shoulder pain were 1.86 (1.18 to 2.94) for those with one body part and 3.22 (2.08 to 4.98) for those with ≥2 body parts presenting with musculoskeletal pain (p<0.001). CONCLUSIONS: Pre-existing musculoskeletal pain in other body parts was significantly associated with new-onset shoulder pain among survivors; this provides useful information for clinical and public health policies.

A 5-year Longitudinal Study of Low Back Pain in Survivors of the Great East Japan Earthquake.

STUDY DESIGN: A longitudinal panel study. OBJECTIVE: The aim of this study was to examine the occurrence of low back pain (LBP), especially the association of previous LBP with further episodes of LBP, in survivors of the Great East Japan Earthquake (GEJE) during the course of 5 years. SUMMARY OF BACKGROUND DATA: LBP is common among survivors of natural disasters, but its long-term course is not clear. METHODS: A 5-year longitudinal study was conducted among survivors of the GEJE (n = 1821). The presence of LBP was assessed using a self-reported questionnaire at 2, 4, and 7 years after the disaster (termed the first, second, and third time points, respectively). Multiple logistic regression analysis was performed to assess a potential association between LBP at the first and second time points with LBP at the third time point, and the odds ratios (ORs) and 95% confidence intervals (CI) were calculated. RESULTS: The prevalence of LBP was 25.3%, 27.3%, and 27.2% at the first, second, and third time points, respectively. The occurrence of LBP at the first time point was significantly associated with LBP at the third time point, and the adjusted odds ratio (OR) (95% confidence interval [CI]) was 5.47 (4.28-6.98). Furthermore, LBP at the first and second time points was significantly associated with LBP at the third time point. Compared to no LBP at the first and second time points, the adjusted OR (95% CIs) for LBP at the third time point was 4.12 (3.14-5.41) in the case of LBP at either of the first or second time points and 10.73 (7.80-14.76) for LBP at both time points (P for trend < 0.001). CONCLUSION: Previous LBP was associated with LBP 5 years later among survivors of the GEJE. Furthermore, the effect on subsequent LBP was stronger with a higher frequency of previous LBP episodes.Level of Evidence: 3.

Preceding Poor Physical Function Is Associated with New-Onset Musculoskeletal Pain among Older Natural Disaster Survivors: A Longitudinal Study after the Great East Japan Earthquake.

Musculoskeletal pain is a major problem among survivors of natural disasters. Functional disabilities in older adults increase after disasters and can lead to musculoskeletal pain. However, the effects of poor physical function on musculoskeletal pain after natural disasters remain unclear. This study aimed to elucidate the association of poor physical function with new-onset musculoskeletal pain among older survivors after the Great East Japan Earthquake (GEJE). Survivors aged ≥ 65 years, 3 years after the GEJE, were assessed longitudinally for 1 year (n = 646). Musculoskeletal pain was assessed using a self-reported questionnaire, and new-onset musculoskeletal pain was defined as absence and presence of pain at 3 years and 4 years, respectively, after the disaster. Physical function at 3 years after the disaster was assessed using the Kihon Checklist physical function score, which consists of 5 yes/no questions, and poor physical function was defined as a score of ≥ 3/5. Multivariate logistic regression analyses were used to assess the association of poor physical function with new-onset musculoskeletal pain. The incidence of new-onset musculoskeletal pain was 22.4%. Participants with poor physical function had a significantly higher rate of new-onset musculoskeletal pain. Compared with high physical function, the adjusted odds ratio (95% confidence interval) for new-onset musculoskeletal pain was 2.25 (1.37-3.69) in poor physical function (P = 0.001). Preceding poor physical function was associated with new-onset musculoskeletal pain among older survivors after the GEJE. There is need to focus on the maintenance of physical function to prevent musculoskeletal pain after natural disasters.

Musculoskeletal pain in other body sites is associated with new-onset low back pain: a longitudinal study among survivors of the great East Japan earthquake.

BACKGROUND: Low back pain (LBP) is a common health problem experienced after natural disasters. LBP is often concurrent with other musculoskeletal pain; however, the effects of preexisting musculoskeletal pain on the development of LBP are not clear. The purpose of this study was to elucidate the association of musculoskeletal pain in other body sites with new-onset LBP among survivors of the Great East Japan Earthquake (GEJE). METHODS: A longitudinal study was conducted with survivors of the GEJE. The survivors who did not have LBP at the 3 year time period after the GEJE were followed up 1 year later (n = 1782). Musculoskeletal pain, such as low back, hand and/or foot, knee, shoulder, and neck pain, were assessed with self-reported questionnaires. The outcome of interest was new-onset LBP, which was defined as LBP absent at 3 years but present at 4 years after the disaster. The main predictor was musculoskeletal pain in other body sites 3 years after the GEJE, which was categorized according to the number of pain sites (0, 1, ≥ 2). Multiple regression analyses were performed to calculate the odds ratio (OR) and 95% confidence interval (CI) for new-onset LBP due to musculoskeletal pain in other body sites. RESULTS: The incidence of new-onset LBP was 14.1% (251/1782). Musculoskeletal pain in other body sites was significantly associated with new-onset LBP. Including people without other musculoskeletal pain as a reference, the adjusted OR and 95% CI for new-onset LBP were 1.73 (1.16-2.57) for people with one musculoskeletal pain site and 3.20 (2.01-5.09) for people with ≥ 2 sites (p <  0.001). CONCLUSIONS: Preexisting musculoskeletal pain in other body sites was associated with new-onset LBP among survivors in the recovery period after the GEJE.

Recurrence of ossification of ligamentum flavum at the same intervertebral level in the thoracic spine: a report of two cases and review of the literature.

PURPOSE: Ossification of the ligamentum flavum (OLF) is a possible cause of thoracic myelopathy. We report two rare cases with recurrent thoracic myelopathy caused by OLF markedly re-extended at the same intervertebral level after the primary surgery. METHODS: Both patients had thoracic myelopathy caused by OLF and underwent decompressive laminectomy and resection of the OLF in the primary surgery. However, the neurological conditions gradually deteriorated following recovery after the primary surgery due to the recurrent OLF at the same intervertebral level. RESULTS: These patients were successfully treated by revision surgery via resection of the recurrent OLF and posterior spinal fusion with instrumentation. Two years after the second surgery, the neurological disturbance was resolved satisfactorily, and re-growth of the resected ossified lesion was not observed. CONCLUSIONS: The recurrence of OLF following resection of the ossified lesions is exceedingly rare but should be noted in patients treated surgically for thoracic myelopathy due to OLF.