Dual and opposing role of retinoic acid receptor signaling in mesenchymal stem cells for tendon ossification in mice.

Heterotopic ossification is abnormal bone formation in soft tissues that occurs primarily after injury and major surgery. This condition often causes local pain and limits joint motion in the affected limb. Currently, there is no effective treatment or prophylaxis for this condition other than surgical removal of the lesion. Recent studies suggest that retinoic acid receptor (RAR) agonists are effective in suppressing heterotopic ossification in patients with Fibrodysplasia Ossificans Progressiva, a congenital disorder characterized by progressive ossification of soft tissue, by suppressing the aberrant differentiation of mesenchymal stem cells in muscle. In this study, we aimed to elucidate the potential use of RAR agonists in suppressing injury-induced ectopic tendon ossification using a mouse Achilles tenotomy model. Contrary to our initial hypothesis, administration of RAR agonists throughout the experimental period (5 weeks) accelerated ectopic tendon ossification in our model. Of note, in vitro differentiation experiments using tendon-derived mesenchymal stem cells revealed that RAR agonists play opposing roles in osteogenic and chondrogenic differentiation, promoting the former and suppressing the latter. Indeed, we found that RAR agonists suppressed tendon ossification when administered before cartilage nodule formation, but promoted it when administered after. These results suggest that RAR agonists have a dual and opposing effect on tendon ectopic ossification, depending on the duration and timing of their administration. Our data may provide a basis for further investigation of the potential use of RAR agonists in the treatment of injury-induced heterotopic ossification.

Suppression of TNF-α activity by immobilization rescues Mkx expression and attenuates tendon ossification in a mouse Achilles tenotomy model.

Traumatic heterotopic ossification is a condition in which extraskeletal bone formation occurs in soft tissues after injury. It most commonly occurs in patients who had major orthopedic surgery and in those with severe extremity injuries. The lesion causes local pain and can impair motor function of the affected limb, but there is currently no established prophylaxis or treatment for this condition. In this study, we show that immobilization at an early stage of the inflammatory response after injury can attenuate ossification formation in a murine Achilles tenotomy model. Gene expression analysis revealed a decrease in the expression of Tnf and an increase in the expression of Mkx, which encodes one of the master regulators of tendon differentiation, Mohawk. Notably, we found that TNF-α suppressed the expression of Mkx transcripts and accelerated the osteogenic differentiation of tendon-derived mesenchymal stem cells (MSCs), suggesting that TNF-α acts as a negative regulator of Mkx transcription. Consistent with these findings, pharmaceutical inhibition of TNF-α increased the expression of Mkx transcripts and suppressed bone formation in this mouse model. These findings reveal the previously unrecognized involvement of TNF-α in regulating tendon MSC fate through suppression of Mkx expression and suggest that TNF-α is a potential target for preventing traumatic heterotopic ossification.

Outpatient Rehabilitation of a Patient with Functional Neurological Disorder Receiving Workers' Compensation Benefits: A Case Report.

Background: Functional neurological disorder (FND) is a clinical syndrome characterized by abnormal involuntary movements and specific clinical features that are incongruent with known neurologic diseases. Clinical information is lacking on outpatient rehabilitation for patients with FND. Case: A 28-year-old woman visited our hospital for gait disturbance. She had experienced an occupational accident 20 months earlier. Her injuries were relatively minor, but subsequently, she was unable to move her ankle voluntarily and began receiving workers' compensation benefits. The patient had persistent gait disturbance and preferred to walk with an ankle-foot orthosis. However, at her first visit, her ankle could move while walking without her ankle brace. Nerve conduction studies showed no abnormalities. Shortly after receiving an explanation regarding the diagnosis of FND, the patient was able to move her ankle voluntarily; however, her gait disturbance was partially persistent. After outpatient rehabilitation, she was able to walk in different types of footwear without an ankle brace. Satisfied with the result, she agreed to end rehabilitation and her access to workers' compensation. Discussion: After diagnosis and rehabilitation for FND following an occupational injury, our patient was eventually able to walk without an ankle brace. In this case, providing the patient with information regarding a diagnosis of FND and obtaining her informed consent for subsequent rehabilitation may have helped to improve the symptoms of FND.

Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of lateral epicondylitis of the humerus - Secondary publication.

BACKGROUND: The guidelines presented herein provide recommendations for the management of patients with lateral epicondylitis of the humerus. These recommendations are endorsed by the Japanese Orthopaedic Association (JOA) and Japan Elbow Society. METHODS: The JOA lateral epicondylitis guideline committee revised the previous guidelines on the basis of the "Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014", which emphasized the importance of the balance between benefit and harm, and proposed a desirable method for preparing clinical guidelines in Japan. These guidelines consist of 11 clinical questions (CQs), 9 background questions (BQs), and 3 future research questions (FRQs). For each CQ, outcomes from the literature were collected and evaluated systematically according to the adopted study design. RESULTS: The committee proposed recommendations for each CQ by determining the level of evidence and assessing the consensus rate. Physical therapy was the best recommendation with the best evidence. The BQs and FRQs were answered by collecting evidence based on the literature. CONCLUSIONS: The guidelines presented herein were reviewed systematically, and recommendations were proposed for each CQ. These guidelines are expected to be widely used not only by surgeons or physicians but also by other healthcare providers, such as nurses, therapists, and athletic trainers.

Preoperative and postoperative shoulder position sense in patients who underwent arthroscopic Bankart repair for traumatic shoulder joint instability.

BACKGROUND: Proprioceptive feedback is a reflex dislocation prevention mechanism that contributes to shoulder joint stability. In patients with Bankart lesions, the anteroinferior glenohumeral ligament complex is damaged and reduces the likelihood of tensile stress. As a result, proprioceptive feedback does not work, which leads to instability. Surgical reconstruction is indicated to restore proprioception, but the details of recovery after arthroscopic surgery are unknown. The purpose of this study is to investigate whether arthroscopic Bankart repair can improve the position sense of the shoulder. METHODS: We used the isokinetic dynamometer Biodex System 3 (Biodex, Shirley, NY, USA) to investigate preoperative and postoperative joint position sense in 140 shoulders (137 men, 3 women) undergoing arthroscopic Bankart repair for traumatic shoulder joint instability. The control subjects comprised 40 shoulders of healthy volunteers (all men). Active position sense was measured by setting the shoulder external rotation to 75° based on 90° abduction and neutral internal/external rotation position. Reproductive angle inaccuracy (RAI) was measured thrice, and the mean value was calculated. The RAI was measured preoperatively, 6 months and 1 year postoperatively, and at the final observation (range, 16-96 months; mean, 31.5 months). RESULTS: Mean RAI was significantly higher (6.4°) preoperatively in the traumatic shoulder instability group than in the control group (5.0°). Mean postoperative RAI changed to 5.0, 4.9, and 4.7° at 6 months, 1 year, and final observation, respectively (mean, 31.5 months). RAI recovered to the same level as the control group at 6 months after the surgery and was maintained the same level until final observation. CONCLUSION: Position sense was significantly worse in patients with traumatic shoulder joint instability than in healthy volunteers, and a significant improvement in position sense was observed after reconstruction of the anteroinferior glenohumeral ligament complex by arthroscopic Bankart repair. Therefore, arthroscopic Bankart repair is a favorable procedure that can improve the position sense of the shoulder in patients with traumatic shoulder instability.

Comparison of reliability, validity and responsiveness of the Japanese Orthopaedic Association Shoulder 36 Ver. 1.3 among different diagnoses of shoulder lesions.

BACKGROUND: Shoulder 36 (Sh-36) is an original quality of life measure for shoulder lesions with high reliability and validity; however, in some cases, especially in those with a Bankart lesion, we observed no improvement in Sh-36 during the postoperative follow-up. Sh-36 may be less effective for a certain shoulder lesion. This study aimed to compare the reliability, validity, and responsiveness of Sh-36 among different representative diagnoses of shoulder lesions. METHODS: Sh-36 and the Disability of the Arm, Shoulder and Hand (DASH) were measured in 192 patients with a Bankart lesion (Bankart group), rotator cuff tear (Cuff group), and SLAP lesion (SLAP group) who underwent arthroscopic surgery. Both measures were evaluated before surgery, and at 3, 6, 9, 12, 18, and 24 months postoperatively, and reliability, validity, and responsiveness of Sh-36 and the DASH were compared among the three groups. RESULTS: Significant postoperative improvement was observed in the three groups (p < 0.0001) within 9 months. No marked improvement was observed after 9 months in the Bankart and SLAP groups due to the ceiling effect; however, most domains of Sh-36 increased continuously in the Cuff group during the whole follow-up period. Reliability and construct validity were sufficient in all the groups. The longitudinal validity was sufficient in most domains for the three groups; however, the standardized response mean in the Bankart group was lower than that in other two groups, indicating low responsiveness in this group because of the ceiling effect. CONCLUSIONS: Sh-36 was a valid and reliable instrument in patients who have undergone arthroscopic shoulder surgery, especially for patient with a rotator cuff tear with high responsiveness. However, Sh-36 had lower standard response mean representing lower responsiveness in the Bankart group due to the ceiling effect and may not be ideal for longitudinal follow-up in patients with a Bankart lesion.

Efficacy of nonviral gene transfer of human hepatocyte growth factor (HGF) against ischemic-reperfusion nerve injury in rats.

Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.

Epidemiological patterns of traumatic musculoskeletal injuries and non-traumatic disorders in Japan Self-Defense Forces.

BACKGROUND: The epidemiological patterns of musculoskeletal injuries or disorders in military personnel have not been well documented and a better understanding is required for proper preventative measures and treatment. Here, we investigated musculoskeletal injuries or disorders among members of the Japan Self-Defense Forces. METHODS: All orthopedic patients (n = 22,340) who consulted to Japan Self-Defense Forces Hospitals were investigated for their type of injury or disorder, the injured body part, the mechanism, and the cause of injuries. RESULTS: Thirty-nine percent of the cases were classified as traumatic injuries, and 61% were classified as non-traumatic disorders. Of the traumatic injury patients, the injured body part was the upper extremity in 32%, the trunk in 23%, and the lower extremities in 45% of the cases. The most common injured body location was the knee followed by the hand/finger and ankle. Exercise was the most common cause of injury, followed by traffic accident and military training. Contusions were the most common traumatic injuries, followed by sprains and fractures. Of non-traumatic disorders, the lower extremities were reported as the injured part in 43% of the disorders. Lumbar spine disorders were the most common non-traumatic disorders, followed by tendon and joint disorders. CONCLUSIONS: Over one-third of orthopedic cases among members of the Japan Self-Defense Forces are traumatic injuries, with the knee being the body part most commonly injured and exercise being the leading cause of injury.

Recovery of Shoulder Rotational Muscle Strength After Arthroscopic Bankart Repair.

BACKGROUND: Shoulder rotational muscles act as dynamic stabilizers of the glenohumeral joint, and the recovery of muscle strength plays an important role in stabilizing the joint during postoperative rehabilitation. However, temporal changes in muscle strength after arthroscopic Bankart repair have not been clarified. PURPOSE: To better understand the temporal recovery of shoulder rotational muscle strength after arthroscopic Bankart repair. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Isokinetic concentric shoulder rotational muscle strength was evaluated in 50 patients who were diagnosed with recurrent dislocations of the glenohumeral joint and treated with arthroscopic Bankart repair. RESULTS: The mean peak torque/weight and total work were reduced significantly at 1.5 months after surgery (P < .0001) and returned to preoperative levels by 6 months for external rotation and 4.5 months for internal rotation. The contralateral peak torque ratios reached preoperative levels by 6 months after surgery. The ipsilateral peak torque ratios were reduced between 1.5 and 3 months after surgery and returned to preoperative levels at 6 months for external rotation and 4.5 months for internal rotation. CONCLUSION: Isokinetic shoulder rotational muscle strength after arthroscopic Bankart repair recovered to preoperative levels by 6 months for external rotation and 4.5 months for internal rotation.

Incidence and Characteristics of Traumatic Shoulder Instability in Japanese Military Cadets.

Little is known regarding the incidence of the shoulder instability in Japan. The aim of this study was to evaluate the incidence of traumatic shoulder instability among Japanese military cadets. A prospective cohort study was performed to capture all traumatic shoulder instability events between 2009 and 2012 among cadets in a military educational academy of the Japan Self Defense Forces. The total number of cadets in the cohort was 5,402 (average age 20.6 years). The incidence of instability events, including dislocation or subluxation, was calculated. Chronicity, demographics of participants, mechanism of injury, and athletic events were also evaluated. The incidence of traumatic dislocation was 4.1/1,000 person-years and that of subluxation was 6.1/1,000 person-years. The incidence of primary dislocation or subluxation was 5.4/1,000 person-years and that of recurrent dislocation or subluxation was 4.7/1,000 person-years. Of first dislocations or subluxations, 92% occurred during sports activities, including after-school sports activities, military training, and gym classes. In conclusion, the overall incidence of shoulder instability events among Japanese military cadets was 10.3/1,000 person-years, and was extremely high. Most shoulder instability events occurred during sports activities, and a program to prevent such injuries during sports activities is necessary for young participants.

Occupational true aneurysm of the ulnar artery: a case report of hypothenar hammer syndrome.

A 32-year-old male patient was admitted to the hospital with a pulsing mass of the right palm. He was an electrical construction engineer who frequently used a screwdriver. Computed tomography (CT) examination revealed a 22- × 30-mm saccular aneurysm of the right ulnar artery. The ulnar artery aneurysm was resected, and we could perform direct anastomosis of the ulnar artery. The dilated true aneurysm was compatible with a traumatic origin. A postoperative enhanced CT examination showed smooth reconstruction of the palmar arch. An occupational true aneurysm of the ulnar artery could be treated by resection and direct anastomosis.

Therapeutic effect of exendin-4, a long-acting analogue of glucagon-like peptide-1 receptor agonist, on nerve regeneration after the crush nerve injury.

Glucagon-like peptide-1 (GLP-1) is glucose-dependent insulinotropic hormone secreted from enteroendocrine L cells. Its long-acting analogue, exendin-4, is equipotent to GLP-1 and is used to treat type 2 diabetes mellitus. In addition, exendin-4 has effects on the central and peripheral nervous system. In this study, we administered repeated intraperitoneal (i.p.) injections of exendin-4 to examine whether exendin-4 is able to facilitate the recovery after the crush nerve injury. Exendin-4 injection was started immediately after crush injury and was repeated every day for subsequent 14 days. Rats subjected to sciatic nerve crush exhibited marked functional loss, electrophysiological dysfunction, and atrophy of the tibialis anterior muscle (TA). All these changes, except for the atrophy of TA, were improved significantly by the administration of exendin-4. Functional, electrophysiological, and morphological parameters indicated significant enhancement of nerve regeneration 4 weeks after nerve crush. These results suggest that exendin-4 is feasible for clinical application to treat peripheral nerve injury.

Ultraviolet light-irradiated photocrosslinkable chitosan hydrogel to prevent bone formation in both rat skull and fibula bone defects.

In the field of orthopaedic surgery, an orthopaedic surgeon sometimes requires to suppress excessive bone formation, such as ectopic bone formation, ossifying myositis and radio-ulnar synostosis, etc. Ultraviolet (UV) light irradiation of a photocrosslinkable chitosan (Az-CH-LA) generates an insoluble hydrogel within 30 s. The purpose of this study was to evaluate the ability of the photocrosslinked chitosan hydrogel (PCH) to inhibit bone formation in an experimental model of bone defect. Rat calvarium and fibula were surgically injured and PCH was implanted into the resultant bone defects. The PCH implants significantly prevented bone formation in the bone defects during the 4 and 8 week observation periods. In the PCH-treated defects, fibrous tissues infiltrated by inflammatory cells were formed by day 7, completely filling the bone defects. In addition to these findings, expression of osteocalcin and runt-related gene 2 (RUNX2) mRNA, both markers of bone formation, was lower in the PCH-treated defects than in the controls. In contrast, collagen type 1α2 and α-smooth muscle actin (α-SMA) mRNA levels were significantly higher in the PCH-treated defects after 1 week. PCH stimulated the formation of fibrous tissue in bone defects while inhibiting bone formation. Thus, PCH might be a promising new therapeutic biomaterial for the prevention of bone formation in orthopaedic surgery.

An fMRI study of musicians with focal dystonia during tapping tasks.

Musician's dystonia is a type of task specific dystonia for which the pathophysiology is not clear. In this study, we performed functional magnetic resonance imaging to investigate the motor-related brain activity associated with musician's dystonia. We compared brain activities measured from subjects with focal hand dystonia and normal (control) musicians during right-hand, left-hand, and both-hands tapping tasks. We found activations in the thalamus and the basal ganglia during the tapping tasks in the control group but not in the dystonia group. For both groups, we detected significant activations in the contralateral sensorimotor areas, including the premotor area and cerebellum, during each tapping task. Moreover, direct comparison between the dystonia and control groups showed that the dystonia group had greater activity in the ipsilateral premotor area during the right-hand tapping task and less activity in the left cerebellum during the both-hands tapping task. Thus, the dystonic musicians showed irregular activation patterns in the motor-association system. We suggest that irregular neural activity patterns in dystonic subjects reflect dystonic neural malfunction and consequent compensatory activity to maintain appropriate voluntary movements.

Photocrosslinkable chitosan hydrogel can prevent bone formation in both rat skull and fibula bone defects.

UV light irradiation to a photocrosslinkable chitosan (Az-CH-LA) resulted in an insoluble and flexible hydrogel within 30 s. The purpose of this study was to evaluate the ability of the photocrosslinkable chitosan to inhibit bone formation in the bone defects. A 5-mm-diameter defect was made in the rat calvarium, and then photocrosslinkable chitosan was implanted and irradiated with UV for 30 s. Furthermore, a 2-mm defect was made in the fibula of a rat hind leg, and then photocrosslinkable chitosan was implanted and irradiated with UV. Bone formations in the rat skull and fibula defects with photocrosslinkable chitosan hydrogel were significantly prevented for 8 weeks. Thus, the chitosan hydrogel has an inhibitory effect on bone formation.

Nonviral retrograde gene transfer of human hepatocyte growth factor improves neuropathic pain-related phenomena in rats.

Peripheral nerve injury occasionally causes chronic neuropathic pain with hyperalgesia and allodynia. However, its treatment is difficult. Here, we used a chronic constriction injury (CCI) model in rats to investigate the effects on experimental neuropathic pain of the human hepatocyte growth factor (HGF) gene delivered into the nervous system by retrograde axonal transport following its repeated intramuscular transfer, using liposomes containing the hemagglutinating virus of Japan (HVJ). CCI (control) rats exhibited marked mechanical allodynia and thermal hyperalgesia, and decreased blood flow in sciatic nerve and hind paw. All these changes were significantly reversed by HGF gene transfer. In the sciatic nerve in HGF-treated rats, the size-frequency distributions for myelinated and unmyelinated axons each showed a rightward shift, the number of myelinated axons >5 microm in diameter was significantly increased, and the mean diameter of unmyelinated axons was significantly increased (versus CCI rats). Levels of P2X3, P2X4, and P2Y1 receptor mRNAs, and of interleukin-6 (IL-6) and activating transcription factor 3 (ATF3) mRNAs, were elevated in the ipsilateral dorsal root ganglia and/or sciatic nerve by CCI, and these levels were decreased by HGF gene transfer. These results may point toward a potential new treatment strategy for chronic neuropathic pain in this model.

Recovery of shoulder rotational muscle strength after a combined Bankart and modified Bristow procedure.

The objective of this study was to determine the influence of rotational muscle strength on shoulder function after a combined open Bankart and modified Bristow procedure and to determine the time of recovery for shoulder rotational strength. Fourteen patients were investigated by use of the relationship between the Rowe score and isokinetic concentric muscle strength. Forty patients were measured regarding the time course of muscle strength preoperatively and at 1.5, 3, 4.5, 6, 9, and 12 months postoperatively. There was a positive correlation coefficient between the Rowe score and muscle strength. The mean peak torque was significantly lower than the preoperative level at 1.5 and 3 months after surgery (P < .01) and recovered by 4.5 months after surgery. The contralateral peak torque ratio continued to increase until 12 months after surgery. These results indicate that high-level sports activities should be delayed until 9 to 12 months after a Bankart and modified Bristow procedure.

The growth rate of the humerus: long-term follow-up of treatment of solitary bone cyst of the proximal humerus using cannulated screws: a case report.

Although the growth of the proximal epiphysis of the humerus is thought to contribute 80% of the total increase in humeral length, few articles have provided evidence for this. A 9-year-old boy with a pathological fracture at the humeral neck, owing to a solitary bone cyst, was treated by the decompression method using cannulated screws for 7.5 years. During this period, we measured the longitudinal humeral bone growth. The value obtained for the longitudinal growth contribution of the proximal humerus was 88% in this particular case.

Functional analysis of upper limb deformities in osteogenesis imperfecta.

The charts and radiographs of 159 children with osteogenesis imperfecta (OI) were retrospectively reviewed to measure the severity of upper limb deformities and to evaluate the functional outcome using the Pediatric Evaluation of Disability Inventory (PEDI). The patients were classified according to the Sillence classification modified by Glorieux: 51 type 1, 33 type 3, 54 type 4, and 21 5ype 5. Fifty-nine patients (37.1%) had deformities of their upper limbs. Children with type 3 OI had the highest incidence and the most severe deformities. The humerus was the most commonly involved bone, followed by the ulna and radius. Upper limb deformities were classified into four groups according to the severity of the maximum deformity angle. The mean self-care scores of PEDI were significantly low only in the group with severe deformities, but mobility scores were dramatically decreased in both the moderate and severe deformity groups. Therefore, upper limb deformities in children with OI do not represent only a cosmetic problem, but may also significantly impair functional activities of daily living.