Comparison of the Effectiveness of Pharmacological Treatments for Patients with Chronic Low Back Pain: A Nationwide, Multicenter Study in Japan.

INTRODUCTION: Chronic low back pain (CLBP) is a leading cause of disability, yet there is limited high-quality evidence to identify the most suitable pharmacological therapy. The purpose of this Japanese nationwide, multicenter, prospective study was to compare the effectiveness of four representative drug therapies-acetaminophen, celecoxib, loxoprofen, and a tramadol and acetaminophen (T+A) combination drug-to establish evidence for a drug of choice for CLBP. METHODS: Patients with CLBP (N=471) received one of the four treatments and were evaluated, prospectively and comprehensively, once every month for six months using a visual analog scale (VAS) for LBP, the Japanese Orthopedic Association (JOA) score, the JOA Back Pain Evaluation Questionnaire (JOABPEQ), the Roland-Morris Disability Questionnaire (RDQ), the EuroQol five-dimensions three-levels (EQ-5D-3L), and the Short Form-8 item health survey (SF-8). We conducted multivariable linear regression analyses of the four drugs at 1 and 6 months after drug allocation. Differences with P<0.05 were considered statistically significant. RESULTS: Patients who received acetaminophen showed a significant improvement from baseline in the mental health subscale of the JOABPEQ at one month (P=0.02) and the JOA score at six months (P<0.01). None of the other outcome measures among the four drugs differed significantly. Across groups, all outcome measures, except the mental component summary (MCS) score of the SF-8, improved equivalently, although most measurements showed no obvious cumulative effect over six months. The MCS score of the SF-8 decreased gradually over six months in all groups. CONCLUSIONS: Most of the outcome measures among the treated groups were not significantly different, indicating similar treatment effects of the four drugs for CLBP. Our study indicated the limit of each outcome measure for evaluating the patient status, suggesting that a single outcome measure is insufficient to reflect treatment effectiveness.

Impact of background factors on outcomes of pharmacological therapy for chronic low back pain: A nationwide multicenter prospective study.

BACKGROUND: Chronic low back pain (CLBP) is a major cause of chronic pain with nociceptive, neuropathic or both pain components, and a leading cause of disability. The objectives of this study were to determine the impact of background factors including previous use of drugs on outcomes of pharmacological therapy for CLBP in a nationwide multicenter prospective study. METHODS: The subjects were 474 patients (male: 41.9%, median age: 73.0) with CLBP. Background factors that could influence outcomes after pharmacological treatment for 6 months were examined: age, gender, body mass index (BMI), duration of CLBP, osteoporosis, history of spinal surgery, history of malignant tumor, smoking habit, employment status (yes or no), exercise habit (frequency), number of live-in family members, having something to do for pleasure, Center for Epidemiologic Studies depression scale (CES-D) score, and medication at baseline. Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS) for LBP, JOA Back Pain Evaluation Questionnaire (JOABPEQ), Roland-Morris Disability Questionnaire (RDQ), Short-form 8-item health survey (SF-8), and EQ-5D were used for evaluation at baseline and after 6 months. Multivariate linear regression models were used in statistical analysis. RESULTS: Drugs for neuropathic pain at baseline (p < 0.001), Tramacet® at baseline (p < 0.05), weak opioids at baseline (p < 0.05), older age (p < 0.001), long disease duration (p < 0.005), history of spinal surgery (p < 0.001), and smoking habit (p < 0.001) had significant negative effects on outcomes. Employment (p < 0.05), exercise habit (p < 0.05), and CED-D at baseline (p < 0.001) had positive effects on outcomes. CONCLUSIONS: This is the first study to identify significant prognostic factors for outcomes of pharmacological treatment of CLBP. The neuropathic pain component of CLBP at baseline is a major significant negative factor for most outcomes involving improved pain, activities of daily life, and quality of life. Treatment strategies developed with consideration of these factors may be advantageous for recovery from CLBP.

Impact of Consultation Length on Satisfaction in Patients with Chronic Low Back Pain: A Nationwide Multicenter Study in Japan.

INTRODUCTION: Chronic low back pain (CLBP) is a major health burden worldwide and requires patient satisfaction with treatment. Consultation length can be an important factor in patient satisfaction, but few studies have investigated the impact of consultation length on satisfaction in patients with CLBP. This study tried to elucidate the impact of consultation length on clinical outcomes in patients with CLBP. METHODS: This study is part of an analysis using the database of the nationwide, multicenter cohort for CLBP performed by the Project Committee of the Japanese Society for Spine Surgery and Related Research. A total of 427 patients aged 20-85 years (median age, 73.0 years; female, 58.6%) with CLBP were prospectively followed-up monthly for 6 months. Multivariable nonlinear regression analyses were performed to assess the effect of consultation length on outcome measures including subjective satisfaction score, EuroQol 5-dimension, Japanese Orthopaedic Association (JOA) score, Roland-Morris Disability Questionnaire, JOA Back Pain Evaluation Questionnaire, visual analog scale (VAS) and Medical Outcome Survey short-form 8-item health survey that evaluated at the next phase. Furthermore, we assessed whether the effect of consultation length on patient satisfaction was modified by the baseline Brief Scale for Psychiatric Problems in Orthopaedic Patients (BS-POP) score for patient and physician versions. RESULTS: VAS for CLBP was the only score that correlated significantly with consultation length (P = 0.018). Satisfaction score showed a significant positive correlation with consultation length in patients with the highest baseline BS-POP scores (P < 0.2). Moreover, consultation lengths more than 7.6 min and 15.1 min offered increase of satisfaction if patients show the highest BS-POP scores on patient and physician versions, respectively. CONCLUSIONS: These findings suggest that a sufficiently long consultation is an important factor for subjective satisfaction in the patients with CLBP, particularly in patients with psychological problems.

Cost-effectiveness analysis of the pharmacological management of chronic low back pain with four leading drugs.

BACKGROUND: Chronic low back pain is a major health problem that has a substantial effect on people's quality of life and places a significant economic burden on healthcare systems. However, there has been little cost-effectiveness analysis of the treatments for it. Therefore, the purpose of this prospective observational study was to evaluate the cost-effectiveness of the pharmacological management of chronic low back pain. METHODS: A total of 474 patients received pharmacological management for chronic low back pain using four leading drugs for 6 months at 28 institutions in Japan. Outcome measures, including EQ-5D, the Japanese Orthopaedic Association (JOA) score, the JOA back pain evaluation questionnaire (BPEQ), the Roland-Morris Disability Questionnaire, the Medical Outcomes Study SF-8, and the visual analog scale, were investigated at baseline and every one month thereafter. The incremental cost-utility ratio (ICUR) was calculated as drug cost over the quality-adjusted life years. An economic estimation was performed from the perspective of a public healthcare payer in Japan. Stratified analysis based on patient characteristics was also performed to explore the characteristics that affect cost-effectiveness. RESULTS: The ICUR of pharmacological management for chronic low back pain was JPY 453,756. Stratified analysis based on patient characteristics suggested that the pharmacological treatments for patients with a history of spine surgery or cancer, low frequency of exercise, long disease period, low scores in lumbar spine dysfunction and gait disturbance of the JOA BPEQ, and low JOA score at baseline were not cost-effective. CONCLUSIONS: Pharmacological management for chronic low back pain is cost-effective from the reference willingness to pay. Further optimization based on patient characteristics is expected to contribute to the sustainable development of a universal insurance system in Japan.

Combined surgery and chondrocyte cell-sheet transplantation improves clinical and structural outcomes in knee osteoarthritis.

Current cartilage regenerative therapies are not fully effective in treating osteoarthritis of the knee (OAK). We have developed chondrocyte sheets for autologous transplantation and tested these in in vitro and in vivo preclinical studies, and have reported that the transplantation of chondrocyte sheets promoted hyaline cartilage repair in rat, rabbit, and minipig models. However, autologous transplantation of chondrocyte sheets has yet to be reported in humans. Here, we report our combination therapy in which conventional surgical treatment for OAK, is followed by autologous chondrocyte sheet transplantation for cartilage repair. Eight patients with OAK and cartilage defects categorized arthroscopically as Outerbridge grade III or IV receive the therapy. Patients are thoroughly assessed by preoperative and postoperative X-rays, magnetic resonance imaging (MRI), arthroscopy, Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm Knee Score (LKS), and a laser-induced photoacoustic method to assess cartilage viscoelasticity. Arthroscopic biopsies of all patients are performed 12 months after transplantation for histological evaluation. The properties of the chondrocyte sheets are evaluated using gene expression analysis to investigate the ability to predict the clinical and structural outcomes of the therapy. For this small initial longitudinal series, combination therapy is effective, as assessed by MRI, arthroscopy, viscoelasticity, histology, and the clinical outcomes of KOOS and LKS. Gene marker sets identified in autologous chondrocyte sheets may be predictive of the overall KOOS, LKS, and histological scores after therapy. These predictive gene sets may be potential alternative markers for evaluating OAK treatment.

Intra-articular administration of EP2 enhances the articular cartilage repair in a rabbit model.

We have reported the usefulness of chondrocyte sheets on articular cartilage repair in animal experiments. Here, we investigated the regenerative effects of EP2 signalling with or without chondrocyte sheets. Forty-five rabbits were used, with six rabbits in each of the six groups and nine rabbits for chondrocytes and synovial cells harvesting to fabricate triple-layered chondrocyte sheets: osteochondral defect only (control, Group A), EP2 agonist (Group B), EP2 antagonist (Group C), chondrocyte sheets (Group D), EP2 agonist and chondrocyte sheets (Group E), and EP2 antagonist and chondrocyte sheets (Group F). After surgery, the weight distribution ratio was measured as an indicator of pain alleviation. Injections of the EP2 agonist or EP2 antagonist were given from 4 weeks after surgery. The rabbits were sacrificed at 12 weeks, and the repaired tissues were evaluated for histology. The weight distribution ratio and International Cartilage Repair Society grading were as follows: Group A: 40.5% ± 0.2%, 14.8 ± 0.5; Group B: 43.4% ± 0.7%, 25.4 ± 0.8; Group C: 38.7% ± 0.7%, 13.7 ± 0.3; Group D: 48.6% ± 0.6%, 40.2 ± 0.5; Group E: 49.1% ± 0.3%, 40.5 ± 0.4; and Group F; 46.8% ± 0.4%, 38.7 ± 0.5. Significant differences in histology and pain alleviation were observed between groups except between Groups A and C, between Groups D and E, and between Groups D and F. These findings show that the intra-articular administration of an EP2 agonist achieved pain alleviation and tissue repair. However, no synergistic effect with chondrocyte sheets was observed.

Platelet-activated serum might have a therapeutic effect on damaged articular cartilage.

Platelet-activated serum (PAS) was collected from rabbits. This contains high concentrations of growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-BB, and transforming growth factor-beta (TGF-ß). PAS was injected into the knee joints of Japanese White rabbits subjected to anterior cruciate ligament transection (ACL-T) to investigate its therapeutic effects on articular cartilage. The effect of Avastin (an anti-VEGF monoclonal antibody) on VEGF expression was also investigated. The levels of VEGF, PDGF-BB, and TGF-ß in PAS, platelet-rich plasma (PRP) and autologous serum from untreated rabbits were analysed by enzyme-linked immunosorbent assays. The samples (n = 24 rabbits) were divided into control (C), PAS (S), Avastin (A) and PAS + Avastin (S + A) treatment groups. Intra-articular injections were administered weekly for 7 weeks after ACL-T, during which the weight distribution ratios of the damaged limbs were evaluated. Histological evaluation was performed 12 weeks after ACL-T using Mankin score. The VEGF, PDGF-BB and TGF-ß expression levels were significantly higher (P < 0.05) in the PAS than in the PRP or autologous serum samples. The weight distribution ratios of damaged limbs improved significantly after ACL-T in all treatment groups (P < 0.05). The proximal medial, distal medial and lateral aspects of joints in the treatment groups showed significant differences in Mankin scores compared with controls (P < 0.05). The damaged limb weight distribution ratios, Mankin scores and articular cartilage structure did not differ significantly among the three treatment groups, which all showed significant improvements in structure compared with controls. Copyright © 2017 John Wiley & Sons, Ltd.

The effects of using vitrified chondrocyte sheets on pain alleviation and articular cartilage repair.

The effect of using vitrified-thawed chondrocyte sheets on articular cartilage repair was examined because the methods for storing chondrocyte sheets are essential for allogeneic chondrocyte sheet transplantation. Six Japanese white rabbits were used as sources of articular chondrocytes and synovial cells. Chondrocytes were harvested from the femur, and synovial cells were harvested from inside the knee joints. After coculture of the chondrocytes with synovial cells, triple-layered chondrocyte sheets were fabricated. Eighteen rabbits were used, with six rabbits in each of three groups: osteochondral defect only (control, group A); chondrocyte sheets (group B); and vitrified-thawed chondrocyte sheets (group C). An osteochondral defect was created on the femur. After transplantation, the weight distribution ratio of the undamaged and damaged limbs was measured as a pain-alleviating effect. The rabbits were euthanized at 12 weeks, and the transplanted tissues were evaluated for histology (Safranin O staining and immunostaining) using the International Cartilage Repair Society grading system. For both evaluations, significant differences were observed between groups A and B, and between groups A and C (p < 0.05). No significant differences were observed between groups B and C. Thus, pain-alleviating effects and tissue repair were achieved using vitrified-thawed chondrocyte sheets. Copyright © 2017 John Wiley & Sons, Ltd.

Characterization of layered chondrocyte sheets created in a co-culture system with synoviocytes in a hypoxic environment.

Endeavouring to repair and regenerate articular cartilage using cell sheets, we have previously established a co-culture system of chondrocytes and synoviocytes, and have reported the successful and rapid production of chondrocyte sheets. In the present study, to examine the effects of oxygen concentration on the chondrocyte sheets, we co-cultured human articular chondrocytes and human synoviocytes in 2%, 5% and 21% oxygen, and measured chondrocyte metabolic activity and proliferation activities under each condition for 14 days in culture. Layered chondrocyte sheets were also created under each condition and the proteoglycan (PG) level was compared with the gene expression of type I collagen (COL1), COL2, COL27, tissue metallopeptidase inhibitor 1 (TIMP1), fibronectin-1 (FN1), SRY-related HMG Box 9 (SOX9), aggrecan-1 (ACAN), integrin-α10 (ITGα10), matrix metalloproteinase 3 (MMP3), MMP13 and a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS5). Compared with 5% and 21% oxygen, the 2% condition caused significantly greater cell metabolic activity and proliferation (p < 0.05). The 2% condition produced a 10% greater PG level compared with 21% oxygen (p < 0.05). All conditions increased the expression of chondrocyte-specific genes, such as COL2, and were associated with low expression levels of catabolic factors, such as MMP3 and MMP13. These observations indicated that the specificity of the chondrocyte sheets was maintained under all conditions. The culture times did not differ between the 5% and 21% conditions. Compared with 21% oxygen, layered chondrocyte sheets rich in extracellular matrix were created 2.85 days earlier in 2% oxygen, which is similar to the level found in deep cartilage. Copyright © 2016 John Wiley & Sons, Ltd.

Modified Elmslie-Trillat Procedure for Recurrent Dislocation of the Patella.

Many groups have reported good to excellent clinical outcomes of the Elmslie-Trillat (ET) procedure for recurrent dislocation of the patella. However, the mean follow-up period of these studies was no more than 5 years. We hypothesized that the long-term postoperative outcomes of the modified ET procedure for recurrent dislocation of the patella would be acceptable compared with those of other procedures. The long-term postoperative outcomes of patients treated with the modified ET procedure were examined. A total of 31 knees in 27 patients with recurrent dislocation of the patella who underwent a modified ET procedure (without medial capsular plication) were evaluated. The mean follow-up period was 13.0 years. Pre- and postoperative radiographs were examined to determine the Q-angle, tilting angle, lateral shift ratio, sulcus angle, congruence angle, and Insall-Salvati index. Clinical outcomes were evaluated based on the Fulkerson patellofemoral joint evaluation score, Kujala score, and the presence of the apprehension sign. Radiological evaluation revealed significant postoperative improvements in the Q-angle, tilting angle, lateral shift ratio, congruence angle, Kujala score, and Fulkerson score (p < 0.001). Sixty-eight percent of all patients had a "good" or "excellent" Fulkerson score. The apprehension sign continued to be shown for six knees. Progression of osteoarthritic changes was observed in three knees, and one knee was symptomatic. The modified ET procedure provided satisfactory outcomes based on radiological and clinical evaluations. These results show the long-term effectiveness and safety of the modified ET procedure for recurrent patellar dislocation.

Effects of a cell-free method using collagen vitrigel incorporating TGF-ß1 on articular cartilage repair in a rabbit osteochondral defect model.

We studied the ability of collagen vitrigel material to repair cartilage in vivo when used alone or with transforming growth factor-ß (TGF-ß). We measured the time course and quantity of TGF-ß1 released from the collagen vitrigel in vitro to quantify the controlled release of TGF-ß1. Over 14 days, 0.91 ng of TGF-ß was released from the collagen vitrigel. Osteochondral defects were made in the femoral trochlear groove in 36 Japanese white rabbits, which were divided into three groups: untreated group (group A), collagen vitrigel-implanted group (group B), and TGF-ß1-incorporated collagen vitrigel-implanted group (group C). The weight distribution ratio between the affected and unaffected limbs served as an indicator of pain. Animals were sacrificed at 4 and 12 weeks after surgery, and their tissues were assessed histologically. The weight distribution ratio increased in all groups and did not differ significantly between groups at 12 weeks. Group A needed 6 weeks to attain maximum improvement, and groups B and C showed near-maximum improvement at 4 and 2 weeks, respectively. The International Cartilage Repair Society II score improved significantly in group C relative to the other groups. These findings suggest that sustained, slow release of TGF-ß caused early pain mitigation and cartilage repair. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2592-2602, 2017.

A Japanese nationwide multicenter survey on perioperative complications of corrective fusion for elderly patients with adult spinal deformity.

BACKGROUND: Recently, corrective fusion surgery for patients with adult spinal deformity (ASD) has become common in Japan. This study aimed to clarify the status of surgeries for ASD in Japan, focusing on perioperative complications. A nationwide multicenter survey gathering information on surgically treated ASD patients was conducted by the committee for Adult Spinal Deformity of the Japanese Scoliosis Society. METHODS: This study was a review of retrospectively collected data from 18 spine scoliosis centers belonging to the Japanese Scoliosis Society. Patients who underwent corrective fusion surgery for ASD between 2011 and 2013 were included. Demographics, comorbidities, surgical data, and complications were investigated. RESULTS: A total of 1192 patients (mean age, 57.7 years) were included in this study. Of these, 611 patients were aged less than 65 years and 581 patients were aged 65 years or greater. The age distribution had two peaks, in the third and eighth decades. Deformities caused by degeneration represented 67% of the pathology in patients aged over 65 years; however, non-degenerative disease such as adult idiopathic scoliosis and syndromic or congenital deformity represented over 60% of pathology in patients aged less than 65 years. The iatrogenic deformity and reoperation rates were both less than 3%. The mean operation time and estimated blood loss were 370 min and 1642 ml, respectively. Major perioperative complications occurred in 160 patients (14.5%). The incidence of complications was significantly higher in patients aged over 65 years, including neurological deficits, hemorrhagic shock, hematoma, heart failure, and surgical site infection (p < 0.05). CONCLUSIONS: Older (aged over 65 years) ASD patients showed greater rates of deformity due to the occurrence of degeneration and vertebral fractures, as well as a higher incidence of peri-and postoperative complications. Efforts to reduce perioperative complications are therefore imperative, especially for elderly ASD patients in our aging society.

Reconstitution of the complete rupture in musculotendinous junction using skeletal muscle-derived multipotent stem cell sheet-pellets as a "bio-bond".

Background. Significant and/or complete rupture in the musculotendinous junction (MTJ) is a challenging lesion to treat because of the lack of reliable suture methods. Skeletal muscle-derived multipotent stem cell (Sk-MSC) sheet-pellets, which are able to reconstitute peripheral nerve and muscular/vascular tissues with robust connective tissue networks, have been applied as a "bio-bond". Methods. Sk-MSC sheet-pellets, derived from GFP transgenic-mice after 7 days of expansion culture, were detached with EDTA to maintain cell-cell connections. A completely ruptured MTJ model was prepared in the right tibialis anterior (TA) of the recipient mice, and was covered with sheet-pellets. The left side was preserved as a contralateral control. The control group received the same amount of the cell-free medium. The sheet-pellet transplantation (SP) group was further divided into two groups; as the short term (4-8 weeks) and long term (14-18 weeks) recovery group. At each time point after transplantation, tetanic tension output was measured through the electrical stimulation of the sciatic nerve. The behavior of engrafted GFP(+) tissues and cells was analyzed by fluorescence immunohistochemistry. Results. The SP short term recovery group showed average 64% recovery of muscle mass, and 36% recovery of tetanic tension output relative to the contralateral side. Then, the SP long term recovery group showed increased recovery of average muscle mass (77%) and tetanic tension output (49%). However, the control group showed no recovery of continuity between muscle and tendon, and demonstrated increased muscle atrophy, with coalescence to the tibia during 4-8 weeks after operation. Histological evidence also supported the above functional recovery of SP group. Engrafted Sk-MSCs primarily formed the connective tissues and muscle fibers, including nerve-vascular networks, and bridged the ruptured tendon-muscle fiber units, with differentiation into skeletal muscle cells, Schwann cells, vascular smooth muscle, and endothelial cells. Discussion. This bridging capacity between tendon and muscle fibers of the Sk-MSC sheet-pellet, as a "bio-bond," represents a possible treatment for various MTJ ruptures following surgery.

Isolated Muscle Transfer to Restore Elbow Flexion in Children with Arthrogryposis.

BACKGROUND: Arthrogryposis is the general term given to conditions characterized by multiple joint contractures resulting in substantial disability most frequently involving a child. Early muscle transfer reconstructive surgery reliably restores elbow flexion. In the present study, we aimed to determine which preoperative condition is best able to restore elbow flexion in patients with arthrogryposis. METHODS: We retrospectively reviewed five children (seven cases) who underwent elbow flexor reconstruction (Steindler flexorplasty, four cases; latissimus dorsi transfer, two cases; pectoralis major transfer, one case). Upper-extremity function was assessed on the basis of range of elbow extension and flexion and elbow flexor muscle power pre- and postoperatively. RESULTS: The mean postoperative active flexion and extension range of motion was 82.1° (60° to 100°) and -15.0° (-40° to 0°) respectively. Mean postoperative elbow flexor muscle power was graded as a 3.4 (2 to 4) as measured with the Medical Research Council (MRC) scale. The preoperative passive elbow flexion angle was found to correlate with postoperative muscle power (MRC) (r = 0.830, p = 0.042) and postoperative active elbow flexion angle (r = 0.902, p = 0.027). Age at operation was not found to correlate with postoperative muscle power (MRC) (r = -0.063, p = 0.878) or active elbow flexion angle (r = -0.134, p = 0.743). CONCLUSIONS: We found a positive correlation between preoperative passive elbow flexion/range of elbow motion and postoperative results including active range of motion and transferred muscle power. Diminished preoperative elbow flexion appeared to correlate with having a poor outcome. The present results suggest that choosing another muscle, such as the gracilis, may be beneficial for muscle transfer in more severe cases of arthrogryposis.

Congenital Anomalies of the Extremities Occurring in Siblings.

BACKGROUND: When examining children with congenital anomalies of the extremities, it is not uncommon for parents to ask about the possibility of similar anomalies occurring in their next child. However, the inheritance of the disease in many congenital anomalies of the extremities has never been elucidated. METHODS: In the present study we reviewed cases of their occurrence in siblings that we encountered in our department, and we investigated their characteristics. RESULTS: The results did not reveal any disease specificity, but a tendency for bilateral cases and male cases (cases in brothers) to be more common was observed. CONCLUSIONS: In recent years there have been reports of the discovery of causative genes in some congenital anomalies, but because cases of occurrence in siblings with no familial occurrence in the past are seen, there may be a variety of causative genes in many congenital anomalies. In the present study there were many male cases (cases in brothers) and many bilateral cases, and there appears to have been a strong possibility of familial occurrence in such cases, but there were also quite a few exceptions. It is necessary to bear the possibility of heredity in mind in every case and provide the parents with an explanation.

Sagittal alignment of the cervical spine in adolescent idiopathic scoliosis: a comparative study of 42 adolescents with idiopathic scoliosis and 24 normal adolescents.

PURPOSE: Kyphosis of the cervical spine has been reported in patients with adolescent idiopathic scoliosis (AIS). However, few reports have compared sagittal spine alignment of AIS patients with that of the normal population. The purposes of this study were (1) to analyze the characteristics of sagittal alignment, including the cervical spine, in AIS patients with a single thoracic curve (Lenke type 1) compared with the age-matched normal population and (2) to quantify the changes in sagittal alignment of the cervical spine and thoracic kyphosis following posterior spinal fusion. METHODS: In study 1, pre- and postoperative X-ray were measured for the following sagittal plane parameters: lumbar lordosis angle (L1-S1; LL), thoracic kyphosis angle (Th5-12; TK), sacral slope (SS), C7 plumb line (C7PL), cervical lordosis angle (C2-C7 angle; CL), and T1 slope. These measurements were then evaluated with CL and other parameters using spearman rank correlation coefficient between two groups. Comparison was made with the sagittal plane parameters from preoperative 42 AIS (AIS group) with main thoracic curve and 24 normal populations (Control group). In study 2, 38 operative AIS patients had at least 1-year follow-up. These patients (38 AIS patients after the correction surgery) were enrolled. We collected for each patient on pre- and postoperative sagittal plane parameters of X-ray. RESULTS: In study 1, LL and C7PL did not differ significantly between the groups. Although CL was observed in 10 of the 24 patients (41.7 %) in the Control group, the CL was smaller in the AIS group, with 6 of 42 patients (14.3 %). The CL correlated significantly with T1 slope (r = 0.634), C7PL (r = 0.684), and TK (r = 0.311) in the AIS group, and with T1 slope (r = 0.681) and C7PL (r = 0.451) in the Control group. No correlations were observed with respect to the TK. In study 2, the mean CL improved significantly from 7.2° kyphosis preoperatively to 0.1° kyphosis postoperatively. Interestingly, Spearman correlation analysis showed that the postoperative CL correlated significantly with postoperative TK (r = 0.607), postoperative T1 slope (r = 0.701), and postoperative C7PL (r = 0.373). CONCLUSIONS: There were no effects of scoliosis on sagittal spine parameters such as LL and C7PL in AIS patients with a main thoracic curve. Cervical spine alignment was affected by the thoracic deformity in the sagittal plane, as shown by the reduction in the CL after the operation. These findings suggest that TK may be a cause of cervical kyphosis in AIS patients.

CD146 defines commitment of cultured annulus fibrosus cells to express a contractile phenotype.

Characterization of cells is important for facilitating cell-based therapies for degenerative diseases of intervertebral discs. For this purpose, we analyzed mouse annulus fibrosus cells by flowcytometory to detect phenotypic change in their primary cultures. After examination of sixteen cell surface proteins, we focused on CD146 that solely increased during culture expansion. CD146 is known to be a marker for mesenchymal stem cells and for their vascular smooth muscle commitment with expression of contractile phenotype enhanced by SM22α. We sorted CD146+ cells to elucidate their characteristics and the key factors that play a role in this change. Whole cell cultures showed the ability for tripotent differentiation toward mesenchymal lineages, whereas sorted CD146+ cells did not. Expression of CD146 was elevated by addition of transforming growth factor ß1, and sorted CD146+ cells expressed higher levels of mRNA for SM22α and Elastin than did CD146- cells. Morphologically, CD146+ cells more broadly deposited extracellular type I collagen than CD146- cells and showed filamentous actin bundles traversing their cytoplasm and cell-cell junctions. Moreover, CD146+ cells demonstrated significantly higher gel contraction properties than CD146- cells when they were embedded in collagen gels. Human annulus fibrosus CD146+ cells also showed higher contractility. Immunohistochemistry determined CD146+ cells localized to the outermost annulus layers of mouse intervertebral disc tissue with co-expression of SM22α. These results suggest that increment of CD146 expression indicates gradual change of cultured annulus fibrosus cells to express a contractile phenotype and that transforming growth factor ß1 enhances this cellular commitment. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1361-1372, 2016.

Modified step-cut osteotomy for correction of post-traumatic cubitus varus deformity: a report of 19 cases.

We reviewed the outcomes of post-traumatic varus deformity treated with modified step-cut osteotomy in 19 patients (average age, 7.4 years; range, 4.3-16.8 years at time of surgery). The average follow-up period was 29.6 months. The mean range of motion was 15.0°/124.7° (extension/flexion) before surgery and 6.8°/132.6° at final follow-up. The humerus-elbow-wrist angle was -21.1° before surgery and 4.2° at final follow-up, with a loss of 4.4° from the value of the humerus-elbow-wrist angle after the surgery. Osteotomy was fixed with Kirschner wires, and, in five cases, chips of excised bone could be inserted to avoid elbow extension. However, in eight cases, usually concerning younger patients, the elbow was fixed in hyperextension higher than 5°. No patient developed postoperative infections or later complications. Only one patient had transient nerve palsy. The modified step-cut osteotomy can precisely and stably correct the varus deformity in the coronal plane, especially in patients under 10 years of age. To avoid radial nerve palsy, we recommend that the retractors be removed sometimes during the operation.

Circadian factors BMAL1 and RORα control HIF-1α transcriptional activity in nucleus pulposus cells: implications in maintenance of intervertebral disc health.

BMAL1 and RORα are major regulators of the circadian molecular oscillator. Since previous work in other cell types has shown cross talk between circadian rhythm genes and hypoxic signaling, we investigated the role of BMAL1 and RORα in controlling HIF-1-dependent transcriptional responses in NP cells that exist in the physiologically hypoxic intervertebral disc. HIF-1-dependent HRE reporter activity was further promoted by co-transfection with either BMAL1 or RORα. In addition, stable silencing of BMAL1 or inhibition of RORα activity resulted in decreased HRE activation. Inhibition of RORα also modulated HIF1α-TAD activity. Interestingly, immunoprecipitation studies showed no evidence of BMAL1, CLOCK or RORα binding to HIF-1α in NP cells. Noteworthy, stable silencing of BMAL1 as well as inhibition of RORα decreased expression of select HIF-1 target genes including VEGF, PFKFB3 and Eno1. To delineate if BMAL1 plays a role in maintenance of disc health, we studied the spinal phenotype of BMAL1-null mice. The lumbar discs of null mice evidenced decreased height, and several parameters associated with vertebral trabecular bone quality were also affected in nulls. In addition, null animals showed a higher ratio of cells to matrix in NP tissue and hyperplasia of the annulus fibrosus. Taken together, our results indicate that BMAL1 and RORα form a regulatory loop in the NP and control HIF-1 activity without direct interaction. Importantly, activities of these circadian rhythm molecules may play a role in the adaptation of NP cells to their unique niche.

Effect of depression and neuropathic pain using questionnaires on quality of life in patients with low back pain; cross-sectional retrospective study.

PURPOSE: The present study investigated the percentage of low back pain (LBP) patients who have depressive symptoms and neuropathic pain and analyzed the effects of these on the quality of life (QOL) in these patients. METHODS: Of the 650 new patients with LBP that visited the hospital between June 2012 and December 2013, 309 patients who completed questionnaires to assess LBP and QOL were included in the study. The questionnaire included demographic items, the self-rated depression scale (SDS)-Zung, the Japanese version of the PainDETECT questionnaire (PDQ-J), numerical pain rating scale (NRS), and QOL assessments. The patients were divided into two groups according to their SDS-Zung scores: a nondepressed group with SDS scores <40 and a depressed group with SDS-Zung scores ≥50. RESULTS: One hundred twenty-five patients (40.5 %) were classified as nondepressed and 63 (20.4 %) as depressed. The mean PDQ-J score was higher in depressed patients than in nondepressed patients. The frequency of neuropathic pain was greater in depressed patients, with neuropathic pain observed in 17 of the 63 (27 %) depressed LBP patients and 11 of the 125 (9 %) nondepressed LBP patients. The SDS-Zung and PDQ-J scores of LBP patients were correlated significantly (r = 0.261, p < 0.001). Depressed patients had higher pain NRS scores and lower QOL scores compared with nondepressed patients. CONCLUSIONS: Both the depressed patients and those with neuropathic LBP had a higher level of pain, greater pain-related disability, and poorer QOL compared with nondepressed patients. This is the first study to use the SDS-Zung and PDQ-J screening questionnaires to estimate the presence of neuropathic pain associated with depressive symptoms in LBP patients and to evaluate the impact of these on QOL.