Non-operative management of shoulder osteoarthritis: Current concepts.

Glenohumeral osteoarthritis (OA) is one of the most common causes of shoulder pain. Conservative treatment options include physical therapy, pharmacological therapy, and biological therapy. Patients with glenohumeral OA present shoulder pain and decreased shoulder range of motion (ROM). Abnormal scapular motion is also seen in patients as adaptation to the restricted glenohumeral motion. Physical therapy is performed to (1) decrease pain, (2) increase shoulder ROM, and (3) protect the glenohumeral joint. To decrease pain, it should be assessed whether the pain appears at rest or during shoulder motion. Physical therapy may be effective for motion pain rather than rest pain. To increase shoulder ROM, the soft tissues responsible for the ROM loss need to be identified and targeted for intervention. To protect the glenohumeral joint, rotator cuff strengthening exercises are recommended. Administration of pharmacological agents is the major part next to physical therapy in the conservative treatment. The main aim of pharmacological treatment is the reduction of pain and diminution of inflammation in the joint. To achieve this aim, non-steroidal anti-inflammatory drugs are recommended as first-line therapy. Additionally, the supplementation of oral vitamin C and vitamin D can help to slow down cartilage degeneration. Depending on the individual comorbidities and contraindications, sufficient medication with good pain reduction is thus possible for each patient. This interrupts the chronic inflammatory state in the joint and, in turn, enables pain-free physical therapy. Biologics such as platelet-rich plasma, bone marrow aspirate concentrate, and mesenchymal stem cells have gathered increased attention. Good clinical outcomes have been reported, but we need to be aware that these options are helpful in decreasing shoulder pain but neither stopping the progression nor improving OA. Further evidence of biologics needs to be obtained to determine their effectiveness. In athletes, a combined approach of activity modification and physical therapy can be effective. Oral medications can provide patients with transient pain relief. Intra-articular corticosteroid injection, which provides longer-term effects, must be used cautiously in athletes. There is mixed evidence for the efficacy of hyaluronic acid injections. There is still limited evidence regarding the use of biologics.

Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5.

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

Low Back Pain in School-Aged Martial Arts Athletes in Japan: A Comparison among Judo, Kendo, and Karate.

Martial arts, such as judo, kendo, and karate, are popular worldwide, not only among adults but also among children and adolescents. Although low back pain (LBP) is considered to be a common problem in these sports, it has been scarcely studied, especially in young athletes. The purpose of this study was to elucidate the point prevalence of and factors related to LBP among school-aged athletes in judo, kendo, and karate. A cross-sectional study was conducted in school-aged athletes (age, 6-15 years; n = 896) using a self-reported questionnaire. Multiple logistic regression models were used to assess the factors related to LBP along with the odds ratio (OR) and 95% confidence interval (95% CI). Variables included in the analysis were sex, age, body mass index, team level, number of days and hours of training, frequency of participation in games, practice intensity, and lower extremity pain. The prevalence of LBP was 6.9% in judo, 4.7% in kendo, and 2.9% in karate. Older age was significantly associated with LBP in judo (adjusted OR, 2.12 [95% CI, 1.24-3.61]), kendo (1.77 [1.27-2.47]), and karate (2.22 [1.14-4.33]). Lower extremity pain was significantly associated with LBP in judo (6.56 [1.57-27.34]) and kendo (21.66 [6.96-67.41]). Coaches should understand the characteristics of LBP in each martial art to develop strategies to prevent LBP among school-aged martial arts athletes.

The effect of anti-IL-6 receptor antibody for the treatment of McH-lpr/lpr-RA1 mice that spontaneously developed destructive arthritis and enthesitis.

BACKGROUND: McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop destructive arthritis and enthesitis in the ankle. There is no published data that drug treatment has been trialed on these mice. This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of arthritis and enthesitis in McH-lpr/lpr-RA1 mice. METHODS: Male McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16-1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines. RESULTS: Tissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at 14 and 17 weeks of age. The kappa coefficient was 0.77. However, progression of entheseal ossification persisted in the MR16-1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16-1 treated groups. CONCLUSIONS: Administration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for destructive arthritis and enthesitis. IL-6 signal blockade could contribute to the treatment of destructive arthritis, and further studies should be carried out to confirm its potential in the prevention of enthesopathy developed to ossification.

Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury.

Rapamycin is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, plays an important role in multiple cellular functions. Our previous study showed rapamycin treatment in acute phase reduced the neural tissue damage and locomotor impairment after spinal cord injury (SCI). However, there has been no study to investigate the therapeutic effect of rapamycin on neuropathic pain after SCI. In this study, we examined whether rapamycin reduces neuropathic pain following SCI in mice. We used a mouse model of thoracic spinal cord contusion injury, and divided the mice into the rapamycin-treated and the vehicle-treated groups. The rapamycin-treated mice were intraperitoneally injected with rapamycin (1 mg/kg) 4 h after SCI. The rapamycin treatment suppressed phosphorylated-p70S6K in the injured spinal cord that indicated inhibition of mTOR. The rapamycin treatment significantly improved not only locomotor function, but also mechanical and thermal hypersensitivity in the hindpaws after SCI. In an immunohistochemical analysis, Iba-1-stained microglia in the lumbar spinal cord was significantly decreased in the rapamycin-treated mice. In addition, the activity of p38 MAPK in the lumbar spinal cord was significantly attenuated by rapamycin treatment. Furthermore, phosphorylated-p38 MAPK-positive microglia was relatively decreased in the rapamycin-treated mice. These results indicated rapamycin administration in acute phase to reduce secondary neural tissue damage can contribute to the suppression of the microglial activation in the lumbar spinal cord and attenuate the development of neuropathic pain after SCI. The present study first demonstrated that rapamycin has significant therapeutic potential to reduce the development of neuropathic pain following SCI. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:93-103, 2017.

The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes--implications for osteoarthritis.

OBJECTIVE: Idiopathic osteoarthritis is the most common form of osteoarthritis (OA) world-wide and remains the leading cause of disability and the associated socio-economic burden in an increasing aging population. Traditionally, OA has been viewed as a degenerative joint disease characterized by progressive destruction of the articular cartilage and changes in the subchondral bone culminating in joint failure. However, the etiology of OA is multifactorial involving genetic, mechanical and environmental factors. Treatment modalities include analgesia, joint injection with steroids or hyaluronic acid, oral supplements including glucosamine and chondroitin sulfate, as well as physiotherapy. Thus, there is significant interest in the discovery of disease modifying agents. One such agent, glucosamine (GlcN) is commonly prescribed even though the therapeutic efficacy and mechanism of action remain controversial. Inflammatory cytokines, including IL-1ß, and proteinases such as MMP-13 have been implicated in the pathogenesis and progression of OA together with an associated CpG demethylation in their promoters. We have investigated the potential of GlcN to modulate NF-kB activity and cytokine-induced abnormal gene expression in articular chondrocytes and, critically, whether this is associated with an epigenetic process. METHOD: Human chondrocytes were isolated from the articular cartilage of femoral heads, obtained with ethical permission, following fractured neck of femur surgery. Chondrocytes were cultured for 5 weeks in six separate groups; (i) control culture, (ii) cultured with a mixture of 2.5 ng/ml IL-1ß and 2.5 ng/ml oncostatin M (OSM), (iii) cultured with 2mM N-acetyl GlcN (Sigma-Aldrich), (iv) cultured with a mixture of 2.5 ng/ml IL-1ß, 2.5 ng/ml OSM and 2mM GlcN, (v) cultured with 1.0 µM BAY 11-7082 (BAY; NF-kB inhibitor: Calbiochem, Darmstadt, Germany) and, (vi) cultured with a mixture of 2.5 ng/ml IL-1ß, 2.5 ng/ml OSM and 1.0 µM BAY. The levels of IL1B and MMP13 mRNA were examined using qRT-PCR. The percentage DNA methylation in the CpG sites of the IL1ß and MMP13 proximal promoter were quantified by pyrosequencing. RESULT: IL1ß expression was enhanced over 580-fold in articular chondrocytes treated with IL-1ß and OSM. GlcN dramatically ameliorated the cytokine-induced expression by 4-fold. BAY alone increased IL1ß expression by 3-fold. In the presence of BAY, IL-1ß induced IL1B mRNA levels were decreased by 6-fold. The observed average percentage methylation of the -256 CpG site in the IL1ß promoter was 65% in control cultures and decreased to 36% in the presence of IL-1ß/OSM. GlcN and BAY alone had a negligible effect on the methylation status of the IL1B promoter. The cytokine-induced loss of methylation status in the IL1B promoter was ameliorated by both GlcN and BAY to 44% and 53%, respectively. IL-1ß/OSM treatment increased MMP13 mRNA levels independently of either GlcN or BAY and no change in the methylation status of the MMP13 promoter was observed. CONCLUSION: We demonstrate for the first time that GlcN and BAY can prevent cytokine-induced demethylation of a specific CpG site in the IL1ß promoter and this was associated with decreased expression of IL1ß. These studies provide a potential mechanism of action for OA disease modifying agents via NF-kB and, critically, demonstrate the need for further studies to elucidate the role that NF-kB may play in DNA demethylation in human chondrocytes.

Total dorsal ramus block for the treatment of chronic low back pain: a preliminary study.

OBJECTIVE: To evaluate the use of total dorsal ramus block, which blocks all three major branches (medial, intermediate, and lateral branches) of lumbar dorsal ramus, for chronic low back pain. METHODS: Spread of local anesthetics with radiocontrast dye (total volume of 5 ml per administration) after total dorsal ramus block to the L4-L5 level was evaluated using computed tomography (CT) in patients with chronic low back pain (n=14; mean age, 71 years). In another group of patients, the effects of the total dorsal ramus block (n=21; mean age, 71 years) were compared with those of trigger point injection (n=22; mean age 73 years). RESULTS: In all cases, the CT findings after total dorsal ramus block revealed the injectant spread over medial, intermediate, and lateral branches of both L3 and L4, those innervate the L4-L5 facet joint and surrounding back muscles. Significant alleviation of rest and motion pains evaluated with visual analogue scale was observed after total dorsal ramus block compared to the trigger point injection up to 7 days after the treatment (p<0.01). CONCLUSIONS: The results of this preliminary study show that the total dorsal ramus block procedure may sufficiently block all three branches of the lumbar dorsal ramus at the targeted level with significant pain reduction.

Effects of therapeutic magnetic stimulation on acute muscle atrophy in rats after hindlimb suspension.

In most subjects with spinal cord injury, the spinal neurons below the level of injury are spared. Therefore, it is conceivable that the skeletal muscles innervated by these spinal nerves can be activated by applying therapeutic magnetic stimulation along the dorsal spine. The purpose of this study was to evaluate the ability of magnetic stimulation to prevent acute muscle atrophy in rats after hindlimb suspension. Forty adult male Wistar rats were randomly assigned to stimulated and non-stimulated (control) groups. Their hindlimbs were unweighted using a suspension method, causing muscle atrophy. In the stimulation group, magnetic stimulation (20 Hz, 60 min per day) was applied to the sciatic nerve for 10 days. After the stimulation period, the tibialis anterior (TA) and extensor digitorum longus (EDL) were surgically removed and histologically measured. The lesser diameters of type 1, 2A, and 2B muscle fibers were significantly greater in the stimulated group than in the non-stimulated group for both the TA and EDL (p < 0.05). The mean difference in lesser fiber diameter was 20% (range, 14%-27%). These results suggest that therapeutic magnetic stimulation is an effective method of preventing muscle atrophy.

Clinical application of acceleration sensor to detect the swing phase of stroke gait in functional electrical stimulation.

Functional electrical stimulation (FES) can improve the gait of stroke patients by stimulating the peroneal nerve in the swing phase of the affected leg, causing dorsiflexion of the foot that allows the toes to clear the ground. A sensor can trigger the electrical stimulation automatically during the stroke gait. We previously used a heel sensor system, which detects the contact pressure of the heel, in FES to correct foot drop gait. However, the heel sensor has disadvantages in cosmetics and durability. Therefore, we have replaced the heel sensor with an acceleration sensor that can detect the swing phase based on the acceleration speed of the affected leg, using a machine learning technique (Neural Network). We have used a signal for heel contact in a gait using the heel sensor before training with the Neural Network. The accuracy of the Neural Network detector was compared with a swing phase detector based on the heel sensor. The Neural Network detector was able to detect similarly the swing phase in the heel sensor. The largest difference in timing of the swing phase was less than 60 milliseconds in normal subjects and 80 milliseconds in stroke patients. We were able to correct foot drop gait using FES with an acceleration sensor and Neural Network detector. The present results indicate that an acceleration sensor positioned on the thigh, which is cosmetically preferable to systems in which the sensor is farther from the entry point of the electrodes, is useful for correction of stroke gait using FES.

The effect of magnetic stimulation on unloaded soleus muscle of rat: changes in myosin heavy chain mRNA isoforms.

This study assessed the potential application and the effectiveness of functional magnetic stimulation (FMS) for preventing skeletal muscle atrophy in adult rats. FMS using magnetic stimulator was performed to rat soleus muscle by placing a round magnetic coil on the back of 3rd-5th lumbar vertebral level at 20 Hz frequency for 60 min/day up to 10 days. A reverse transcriptase-polymerase chain reaction was applied to evaluate relative amounts of mRNAs specific to four myosin heavy chain (MHC) isoforms [MHCIbeta, MHCIIa, MHCIIb, and MHCIId(x)] in rat soleus muscle during contractile activity by magnetic stimulation. Ten-day unloading by hindlimb suspension induced a drastic decrease of MHCIbeta and MHCIIa mRNA expressions, while MHCIIb and MHCIId(x) mRNA was not decreased. The magnetic stimulation resuscitated the down-regulation of the mRNA levels of MHCIbeta and MHCIIa. These results suggest that magnetic stimulation on acute atrophied muscles is useful for preventing the muscle atrophy.

Grasping power by means of functional electrical stimulation in a case of C6 complete tetraplegia.

Grasping power (GP) by means of functional electrical stimulation (FES) was measured in a case of C6 complete tetraplegia. This was compared with GP by means of the dynamic tenodesis effect, the flexor hinge splint and the GP of normal female. Palmar grasp strength by means of FES was approximately 16% of the control group and 2.4 times greater than the flexor hinge splint. Lateral grasp strength by FES was approximately 13% of the control group. Our results suggest that FES is more effective than the flexor hinge splint in increasing the GP of tetraplegic patients, and that a stronger and stable GP, which is not affected by wrist position, makes FES practical for improving activities of daily living (ADL).