Kenichi Otoshi

The reactions of glial cells and endoneurial macrophages in the dorsal root ganglion and their contribution to pain-related behavior after application of nucleus pulposus onto the nerve root in rats.

Study Design. Controlled, interventional, animal study. Objective. To observe the reaction of glial cells and endoneurial macrophages in the dorsal root ganglion (DRG) after application of nucleus pulposus (NP) and investigate whether activated DRG glial cells play a role in the pathogenesis of neuropathic pain. Summary of Background Data. Peripheral nerve injury activated DRG and spinal cord glial cells and several cytokines and neurotrophins released from these activated glial cells might induce pain hypersensitivity. Methods. Adult male Sprague-Dawley rats were used. NP harvested from the tail was applied to the left L5 DRG. Behavioral testing was performed to investigate the mechanical withdrawal threshold. The numbers of activated satellite glial cells and endoneurial macrophages were counted, and the expressions of tumor necrosis factor-alpha (TNF-&agr;) and glial cell-line derived neurotrophic factor (GDNF) were examined by double-labeled immunohistochemistry and immunoblotting. Results. The mechanical withdrawal threshold was significantly decreased for 28 days and then gradually recovered (P < 0.05). Long-term activation of endoneurial macrophages and satellite glial cells in the DRG was observed, and the reactions of these cells correlated well with pain-related behavior. TNF-&agr; was expressed in both endoneurial macrophages and activated satellite glial cells, and TNF-&agr; expression was significantly increased in the early stage (P < 0.05). Activated satellite glial cells also expressed GDNF, and its expression was significantly increased and persisted for 28 days (P < 0.05). Conclusion. Activation of DRG glial cells and endoneurial macrophages plays an important role in the pathogenesis of the neuropathic pain state. TNF-&agr; actively released from activated glial cells and endoneurial macrophages in the DRG might initiate and maintain the neuropathic pain together with TNF-&agr; derived from the applied NP. In the recovery phase, persistent expression of GDNF from activated satellite glial cells might play an important role to restore the function of damaged neurons and recover from neuropathic pain.

Anti-HMGB1 neutralization antibody improves pain-related behavior induced by application of autologous nucleus pulposus onto nerve roots in rats.

Study Design. Controlled, interventional, animal study. Objective. To examine the involvement of high-mobility group box 1 (HMGB1) in the neuropathic pain state induced by the application of nucleus pulposus onto the dorsal root ganglion (DRG) and to investigate the effect of HMGB1 neutralization antibody in the pathogenesis. Summary of Background Data. HMGB1 is a potent proinflammatory mediator when present extracellularly, and anti-HMGB1 neutralization antibody inhibits inflammation, cytokine expression, and macrophage activation. Methods. Thirty-nine adult female Sprague-Dawley rats (200–300 g) were used. The left L5/6 facet joint was removed, and the L5 DRG was exposed. Nucleus pulposus harvested from the tail was applied to the left L5 DRG. Then, 400 &mgr;g of anti-HMGB1 neutralization antibody was administered intraperitoneally after surgery. Behavioral testing using von Frey hairs was performed to investigate the mechanical withdrawal threshold. Neuronal damage was investigated by counting the number of activating transcription factor 3 (ATF3) neurons. The expressions of tumor necrosis factor-&agr; (TNF-&agr;) and HMGB1 were measured by double-labeled immunohistochemistry and immunoblotting. Results. Immunoblotting of harvested nucleus pulposus revealed HMGB1 in the nucleus pulposus. Double-labeled immunohistochemistry revealed that macrophages in the applied nucleus pulposus expressed HMGB1 and TNF-&agr;. Administration of anti-HMGB1 neutralization antibody significantly reduced the TNF-&agr; expression in the DRG and improved the pain-related behavior from day 2 to day 14. Conclusion. HMGB1 appears to play an important role in the development of pain-related behavior induced by the application of nucleus pulposus onto the DRG. HMGB1 from applied nucleus pulposus and actively secreted from macrophages would act as a proinflammatory mediator together with proinflammatory cytokines. HMGB1 blocking therapy might become a new treatment method for neuropathic pain.

The Process of Tendon Regeneration in an Achilles Tendon Resection Rat Model as a Model for Hamstring Regeneration After Harvesting for Anterior Cruciate Ligament Reconstruction

PURPOSE The purpose of this study was to clarify the mechanism of tendon regeneration by investigating macroscopically, histologically, and biomechanically. METHODS Fifty, adult, female Sprague-Dawley rats were used. The Achilles tendon in the left hind limb was removed totally by use of the tendon-stripping device. Rats were killed at 2, 7, 30, 90, and 180 days after surgery, and the regenerate tendons were dissected. Contralateral Achilles tendons were used as normal controls. Gross anatomic changes, microscopic remodeling, and recovery of biomechanical properties of regenerate tendons were investigated. The expressions of type I collagen, type III collagen, and transforming growth factor β1 were also investigated by immunohistochemistry. RESULTS The regenerate tendons formed in all specimens. In the early phase, hematoma and soft granulation tissue were observed at the harvest defect. These gradually matured with time, and the microscopic structure became quite similar to normal at 180 days after surgery. These findings occurred uniformly along the entire length of the regenerate tendon. However, the biomechanical properties were significantly inferior to the normal tendons (P < .05). Transforming growth factor β1 was well co-localized with inflammatory cells and fibroblasts in the regenerate tendons. The type I-type III collagen ratio in the regenerate tendon was significantly decreased in the early phase (P < .05) but gradually increased with time. CONCLUSIONS Tendon regeneration and maturation occurred uniformly along the length of regenerate tendons. The hematoma that initially occupies the harvest defect acted as a scaffold for fibroblast precursor cells from the surrounding peritendinous tissue and tendon sheath. The mechanical properties of regenerate tendon were significantly inferior to contralateral control even at 180 days after surgery, and the alteration of the collagen composition would have an influence on mechanical properties of regenerate tendon. CLINICAL RELEVANCE Clinicians should be cautious about using reharvested hamstring tendons for ligament reconstruction surgery.

Overactive bladder symptom severity is associated with falls in community-dwelling adults: LOHAS study

Objectives To examine the association between overactive bladder (OAB) symptom severity and falls and the contribution of OAB symptoms to falls in a community-dwelling population. Design Cross-sectional study. Setting 2 Japanese municipalities. Participants A total of 2505 residents aged over 40 years, who participated in health check-ups conducted in 2010. OAB symptom assessed via overactive bladder symptom score (OABSS) was divided into six categories based on distribution and Japanese clinical guidelines. Mobility problems and depressive symptoms were assessed via the Timed Up and Go test and the short form of the Center for Epidemiologic Studies Depression Scale, respectively. Primary outcome measures Self-reported any fall and frequent fall (≥2) over the 1-month period. Independent contributions to any fall and frequent falls were assessed via logistic regression to generate population-attributable fractions (PAFs), assuming separate causal relationships between OAB symptoms, mobility problems and depressive symptoms and any or frequent falls. Results Among the total 1350 participants (mean age: 68.3 years) analysed, any fall and frequent falls were reported by 12.7% and 4.4%, respectively. Compared with no OABSS score, moderate-to-severe OAB and mild OAB were associated with any fall (adjusted ORs 2.37 (95% CI 1.12 to 4.98) and 2.51 (95% CI 1.14 to 5.52), respectively). Moderate-to-severe OAB was also strongly associated with frequent falls (adjusted OR 6.90 (95% CI 1.50 to 31.6)). Adjusted PAFs of OAB symptoms were 40.7% (95% CI 0.7% to 64.6%) for any fall and 67.7% (95% CI −23.1% to 91.5%) for frequent falls. Further, these point estimates were similar to or larger than those of mobility problems and depressive symptoms. Conclusions An association does indeed exist between OAB symptom severity and falls, and OAB symptoms might be important contributors to falls among community-dwelling adults. Further longitudinal studies are warranted to examine whether or not OAB symptoms predict risk of future falls and fall-related injuries.

Analgesic effects of prostaglandin E2 receptor subtype EP1 receptor antagonist: experimental study of application of nucleus pulposus.

Study Design. The effect of an EP1 receptor antagonist on pain-related behavior induced by nucleus pulposus (NP) applied to the dorsal root ganglion (DRG) in rats was investigated. Objective. We investigated pain-related behavior, the amount of prostaglandin E2 (PGE2), and neural damage to the DRG after application of NP to the DRG after administration of an EP1 receptor antagonist. Summary of Background Data. PGE2 induces mechanical allodynia and hyperalgesia, which are mediated by PGE2 receptors. EP1 is one of the PGE2 receptor subtypes. An EP1 antagonist reduces hyperalgesia, allodynia, and c-fos expression in the rat chronic nerve constriction model. Methods. Sprague-Dawley rats (n = 103) were used. Animals receiving NP were divided into three experimental groups (n = 12 in each group): saline, high-dose (5 mg/kg) EP1 receptor antagonist (RA), and low-dose (2.5 mg/kg) EP1-RA (orally once daily for 5 days). Animals in the sham group did not receive NP. Von Frey tests were used for pain-behavior testing. The amount of PGE2 in DRG and the number of activating transcription factor-3 (ATF3) immunoreactive positive cells were compared among groups. Results. The mechanical thresholds in the three groups decreased 7 days after surgery (just before treatment). The threshold in both the high- and low-dose EP1-RA groups increased at 11 days (5 days after treatment) and continued for 14 days. The thresholds in both the low- and high-dose EP1-RA groups increased significantly compared with the saline group (P < 0.05). The amount of PGE2 was significantly increased in the NP group compared with the sham and naïve animals after application of NP. ATF3 expression was increased by NP but was not increased after administration of the EP1-RA. Conclusion. An EP1 receptor antagonist improves pain-related behavior in the rat model and might be a potential agent to improve pain-related behavior in patients with lumbar disc herniation.

ULTRASONOGRAPHIC ASSESSMENT OF THE FLEXOR PRONATOR MUSCLES AS A DYNAMIC STABILIZER OF THE ELBOW AGAINST VALGUS FORCE

Flexor pronator muscles (FPMs) play a key role in stabilizing the elbow joint against valgus forces. However, no studies have investigated the in vivo kinematics of FPMs against these forces on the elbow. This study aimed to clarify the in vivo contribution of each FPM as a dynamic stabilizer in a clinical situation.Twelve healthy volunteers participated in this study. Verbal informed consent was obtained from all subjects. The elbow was flexed to 90 degrees, and the forearm was placed in the neutral position. Manual valgus stress was applied to the elbow joint until maximal shoulder external rotation was achieved. The width of the ulnohumeral joint space and the ulnar shift of the sublime tubercle were measured before and after isometric contraction of FPMs using ultrasonography.The horizontal distances were decreased 1.1±0.6 mm after forearm pronation, 0.6±0.5 mm after wrist palmar flexion, 0.1±0.4 mm after wrist ulnar flexion, and 0.2±0.5 mm after finger flexion. Significant changes were observed during forearm pronation, wrist palmar flexion, and finger flexion but not during wrist ulnar flexion (p<0.05). The sublime tubercle was significantly shifted 0.5±0.1 mm medially after forearm pronation, 0.2±0.1 mm medially after wrist palmar flexion, and 0.1±0.1 mm laterally after wrist ulnar flexion and finger flexion (p<0.05). The FPMs, especially the pronator teres and the flexor carpi radialis, function as dynamic stabilizers against elbow valgus stress. The results of this study may be useful in developing injury prevention and rehabilitation strategies for throwing injuries of the elbow.

Age-Specific Prevalence and Clinical Characteristics of Humeral Medial Epicondyle Apophysitis and Osteochondritis Dissecans: Ultrasonographic Assessment of 4249 Players:

Background: Traction apophysitis of medial epicondyle (MEC) lesions and osteochondritis dissecans (OCD) of the capitellum are common elbow injuries in adolescent baseball players. However, the age-specific prevalence of these pathologies and their influence on elbow pain remain unknown. Purpose: To investigate the age-specific prevalence of each MEC lesion and capitellar OCD and to identify the incidence of elbow pain in each condition. Study Design: Descriptive epidemiology study. Methods: Study participants consisted of 4249 baseball players aged 6 to 17 years. A questionnaire was used to assess history of elbow pain, and morphological changes of the elbow joint were assessed using ultrasonography. Results: Regarding MEC lesions, fragmented (FG) and irregular (IR) lesions both reached their greatest respective prevalence at 11 to 12 years of age. After 14 years of age, IR decreased sharply, whereas FG was maintained at approximately 10%. Hypertrophic (HT) lesions increased sharply, reaching over 50% at 16 years of age, while there was a decrease in IR and FG lesions in the same age group. The prevalence of capitellar OCD remained the same (approximately 2%) throughout all ages except for in players aged 7 to 8 years (>7%). Players with MEC lesions had significantly greater prevalence of a history of elbow pain compared with those without (68.0% vs 39.1%) and were at a significantly greater risk for FG lesions (odds ratio [OR], 4.04; 95% CI, 3.16-5.22) compared with IR (OR, 3.22; 95% CI, 2.44-4.27) and HT lesions (OR, 2.03; 95% CI, 1.75-2.36). Players with capitellar OCD also had a significantly greater risk of a history of elbow pain (OR, 2.34; 95% CI, 1.40-4.11). Conclusion: Controlling the amount of practice and its intensity according to the condition of each player in the preadolescent and adolescent periods may be important in accelerating bony healing and decreasing preventable elbow pain in adulthood.

Psychosocial Stress After a Disaster and Low Back Pain-related Interference With Daily Living Among College Students: A Cohort Study in Fukushima

Study Design. A cohort study. Objective. To investigate the association between psychosocial stress and low back pain (LBP)-related interference with daily living among college students. Summary of Background Data. Few longitudinal studies have examined the likelihood of developing LBP in the presence of a designated psychosocial stressor. All participants in the present study were suddenly affected by the Great East Japan disaster after enrolment in our cohort study. Methods. The present study was initiated among 95 students at Fukushima Medical University in January 2011. We assessed psychosocial stress in students using the Japanese version of the Perceived Stress Scale (JPSS). Follow-up surveys were conducted in July 2011 and May 2013, analyzing 94 students. Students were then divided into three groups (improved, −19 to −4; Maintained, −3 to +4; Aggravated, +5 to +22) based on the tertile points of JPSS change from baseline to 4 months after the disaster. LBP-related interference with daily living was assessed using the Brief Pain Inventory (BPI) questionnaire. Linear regression modeling was performed with BPI at 4 months after the disaster as the outcome, and JPSS change, sex, history of LBP, baseline physical activity, and baseline BPI as explanatory variables. Results. We found a significant increase in BPI score for the aggravated stress group (&bgr; coefficient, +0.79; 95% confidence interval, +0.06–+1.53), compared with the improved stress group. History of LBP and higher physical activity were also significantly associated with BPI. Conclusion. The present study suggests that perceived psychosocial stress induced by the disaster may be associated with LBP-related interference with daily living among college students in Fukushima. Level of Evidence: 3

Bony Maturity of the Tibial Tuberosity With Regard to Age and Sex and Its Relationship to Pathogenesis of Osgood-Schlatter Disease: An Ultrasonographic Study:

Background: Although tensile force on an immature tibial tuberosity is considered the main cause of Osgood-Schlatter disease (OSD), the relationship between bony maturity and the pathogenesis of OSD remains obscure. Purpose: To survey the bone maturation process of the tibial tuberosity by age and sex and clarify its relationship to OSD. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 731 Japanese basketball players aged 6 to 14 years were enrolled in this study. Ultrasonographic examination was performed in all participants (1462 knees) to evaluate the bony maturity of the tibial tuberosity by use of the Ehrenborg classification. The age- and sex-specific prevalence of each stage was investigated, and the prevalence of symptomatic OSD and its relationship with bony maturity were also assessed. Results: The process of bone maturation occurred 1 to 2 years earlier in female participants compared with male participants. Among female participants, 59.2% were already at the epiphyseal stage (stage E) by 10 years of age, and 47.4% were skeletally mature by 14 years. Among male participants, conversely, only 8.0% were at stage E by 10 years of age, and only 13.8% were skeletally mature by 14 years. The overall prevalence of symptomatic OSD was 6.8% (males, 6.4%; females, 7.2%), and the onset was 1 year earlier in the female participants. The prevalence of symptomatic OSD tended to increase with age and bony maturity, significantly increasing from the cartilaginous stage (stage C) to the apophyseal stage (stage A) (odds ratio, 9.48) and from stage A to stage E (odds ratio, 2.22). Conclusion: The tibial tuberosity matures earlier in female participants. The risk of OSD is greater in stage A than stage C and in stage E than stage A. The risk of OSD increases with age in males but not in females.

The prevalence of scapular malalignment in elementally school aged baseball player and its association to shoulder disorder

BACKGROUND Various shoulder disorders have been reported to be associated with scapulothoracic joint dysfunction in adult overhead athletes. However, little is known about the prevalence of scapular malalignment and its relationship to shoulder injuries in skeletally immature baseball players. The purpose of the current study was to investigate the prevalence of scapular malalignment in elementary school-aged baseball players, as well as its association with shoulder disorder. METHODS One hundred sixty-nine baseball players in higher elementary school grades (aged 11-12 years) were enrolled in this study. Shoulder pain experience pain over the previous one year, as well as other individual and environmental factors were surveyed by a self-completed questionnaire. Scapula malalignment was assessed using still images of both arms both at the side and in an elevated position. The relative position of the dominant scapula to the non-dominant side was assessed by two independent examiners. RESULTS Scapular malalignment was observed in 126 subjects (74.6%), and the dominant scapula tended to deviate inferiorly and medially, as well as tilt anteriorly, compared with the non-dominant side. Forty-four of the 169 subjects (23.8%) experienced shoulder pain over the one year period. The prevalence of shoulder pain was significantly increased with the increasing scapular anterior tilt and the superior shift of the dominant scapula, whereas no significant correlation between shoulder pain and scapular horizontal shift or upward-downward rotation was observed. CONCLUSION About three-quarters of the elementary school-aged baseball players in the current study presented with scapular malalignment, and those with anterior tilt and superior shift of the dominant scapula were at higher risk of shoulder pain.