Hiroaki Hirata

Fas ligand plays an important role for the production of pro‐inflammatory cytokines in intervertebral disc nucleus pulposus cells

It is suggested that pro‐inflammatory cytokines, which are produced by interaction of the intervertebral nucleus pulposus cells and macrophages, may be linked to the cause of pain of the intervertebral disc herniation. This study carries out the in vitro experiments to examine the mechanism, with the use of the co‐culture of an immortalized cell line of nucleus pulposus of the human intervertebral disc and the macrophage cell line. As a result, it is found that the production of pro‐inflammatory cytokines is significantly larger at the co‐culture group than at the independent culture group. Also, at the co‐culture group of macrophages and intervertebral nucleus pulposus cells with over‐expression of fas ligand (FasL), the production of pro‐inflammatory cytokines is found to be far larger. Furthermore, it is found that these pro‐inflammatory cytokines are produced mainly by the intervertebral nucleus pulposus cells with over‐expression of FasL, and that the expression of a disintegrin and metalloproteinase (ADAM) 10, which controls the expression of FasL and activates reverse signaling inside cells, also increases. From these findings, it is suggested that FasL and ADAM10 play an important role in the production of pro‐inflammatory cytokines coming from interaction of the intervertebral nucleus pulposus cells and macrophages.

A rat tail temporary static compression model reproduces different stages of intervertebral disc degeneration with decreased notochordal cell phenotype

The intervertebral disc nucleus pulposus (NP) has two phenotypically distinct cell types—notochordal cells (NCs) and non‐notochordal chondrocyte‐like cells. In human discs, NCs are lost during adolescence, which is also when discs begin to show degenerative signs. However, little evidence exists regarding the link between NC disappearance and the pathogenesis of disc degeneration. To clarify this, a rat tail disc degeneration model induced by static compression at 1.3 MPa for 0, 1, or 7 days was designed and assessed for up to 56 postoperative days. Radiography, MRI, and histomorphology showed degenerative disc findings in response to the compression period. Immunofluorescence displayed that the number of DAPI‐positive NP cells decreased with compression; particularly, the decrease was notable in larger, vacuolated, cytokeratin‐8‐ and galectin‐3‐co‐positive cells, identified as NCs. The proportion of TUNEL‐positive cells, which predominantly comprised non‐NCs, increased with compression. Quantitative PCR demonstrated isolated mRNA up‐regulation of ADAMTS‐5 in the 1‐day loaded group and MMP‐3 in the 7‐day loaded group. Aggrecan‐1 and collagen type 2α‐1 mRNA levels were down‐regulated in both groups. This rat tail temporary static compression model, which exhibits decreased NC phenotype, increased apoptotic cell death, and imbalanced catabolic and anabolic gene expression, reproduces different stages of intervertebral disc degeneration.

Accelerated Development of Cervical Spine Instabilities in Rheumatoid Arthritis: A Prospective Minimum 5-Year Cohort Study

Objective To clarify the incidence and predictive risk factors of cervical spine instabilities which may induce compression myelopathy in patients with rheumatoid arthritis (RA). Methods Three types of cervical spine instability were radiographically categorized into “moderate” and “severe” based on atlantoaxial subluxation (AAS: atlantodental interval >3 mm versus ≥10 mm), vertical subluxation (VS: Ranawat value <13 mm versus ≤10 mm), and subaxial subluxation (SAS: irreducible translation ≥2 mm versus ≥4 mm or at multiple). 228 “definite” or “classical” RA patients (140 without instability and 88 with “moderate” instability) were prospectively followed for >5 years. The endpoint incidence of “severe” instabilities and predictors for “severe” instability were determined. Results Patients with baseline “moderate” instability, including all sub-groups (AAS+ [VS− SAS−], VS+ [SAS− AAS±], and SAS+ [AAS± VS±]), developed “severe” instabilities more frequently (33.3% with AAS+, 75.0% with VS+, and 42.9% with SAS+) than those initially without instability (12.9%; p<0.003, p<0.003, and p = 0.061, respectively). The incidence of cervical canal stenosis and/or basilar invagination was also higher in patients with initial instability (17.5% with AAS+, 37.5% with VS+, and 14.3% with SAS+) than in those without instability (7.1%; p = 0.028, p<0.003, and p = 0.427, respectively). Multivariable logistic regression analysis identified corticosteroid administration, Steinbrocker stage III or IV at baseline, mutilating changes at baseline, and the development of mutilans during the follow-up period correlated with the progression to “severe” instability (p<0.05). Conclusions This prospective cohort study demonstrates accelerated development of cervical spine involvement in RA patients with pre-existing instability—especially VS. Advanced peripheral erosiveness and concomitant corticosteroid treatment are indicators for poor prognosis of the cervical spine in RA.

Modified house-keeping gene expression in a rat tail compression loading-induced disc degeneration model.

House‐keeping genes (HKGs) are generally used as endogenous controls for molecular normalization in quantitative PCR analysis. However, whether all the so‐called HKGs are useful for intervertebral disc research is controversial. Our objective was, using a prevalidated rat tail static compression loading‐induced disc degeneration model, to clarify the feasibility of common HKGs for gene‐quantification in the nucleus pulposus cells. In real‐time RT‐PCR for five HKGs [β‐actin, β‐glucuronidase, β‐2 microglobulin, glyceraldehyde 3‐phosphate dehydrogenase (GAPDH), and lactate dehydrogenase A (LDHA)], static compression at 1.3 MPa for up to 56 days demonstrated messenger RNA (mRNA) expression levels of consistent β‐2 microglobulin and GAPDH, slightly up‐regulated β‐glucuronidase, and fairly down‐regulated β‐actin and LDHA. Especially, β‐actin had a drastic suppression to 0.15‐fold in the loaded relative to unloaded discs at 7 days. In immunofluorescence, β‐actin showed a significant down‐regulation to almost undetectable levels from 28 days, while GAPDH was constantly detected throughout. β‐Actin mRNA and protein‐distribution are thought to be affected by the loading treatment, however, GAPDH mRNA and protein‐distribution can retain relatively stable expressions. Under prolonged static compression, β‐actin and probably LDHA are inappropriate, and GAPDH is a feasible HKG as internal references in the disc cells.

Predictive Risk Factors of Cervical Spine Instabilities in Rheumatoid Arthritis: A Prospective Multicenter Over 10-year Cohort Study

Study Design. A prospective multicenter cohort study for more than 10 years of outpatients with rheumatoid arthritis (RA). Objective. To identify predictive risk factors of cervical spine instabilities, which may induce compression myelopathy in patients with RA. Summary of Background Data. Many reports described the natural course of cervical spine involvement in RA. Only a few studies, however, conducted comprehensive evaluation of its prognostic factors. Methods. Cervical spine instability was radiographically defined as atlantoaxial subluxation with the atlantodental interval greater than 3 mm, vertical subluxation (VS) with the Ranawat value less than 13 mm, and subaxial subluxation with irreducible translation of 2 mm or higher. The “severe” category of instability was defined as atlantoaxial subluxation with the atlantodental interval of 10 mm or lower, vertical subluxation with the Ranawat value of 10 mm or higher, and subaxial subluxation with translation of 4 mm or higher or at multiple levels. Of 503 “definite” or “classical” patients with RA without baseline “severe” instability, 143 were prospectively followed throughout for more than 10 years. The Cox proportional hazards regression analysis was performed to determine predictors for the development of “severe” instabilities. To exclude biases from the low follow-up rate, similar assessments were performed in 223 patients followed for more than 5 years from baseline. Results. The incidence of cervical spine instabilities and “severe” instabilities significantly increased during more than 10 years in both 143 and 223 cohorts (all P < 0.01). Multivariable Cox proportional hazards models found that baseline mutilating changes (hazard ratio [HR]=19.15, 95% confidence interval [95% CI] = 3.96–92.58, P < 0.01), corticosteroid administration (HR = 4.00, 95% CI = 1.76–9.11, P < 0.01), and previous joint surgery (HR = 1.99, 95% CI = 1.01–3.93, P = 0.048) correlated with the progression to “severe” instability in 143 cases and also in 223 cases (HR = 8.12, 95% CI = 2.22–29.64, P < 0.01; HR = 3.31, 95% CI = 1.68–6.53, P < 0.01; and HR = 2.07, 95% CI = 1.16–3.69, P = 0.014, respectively). Conclusion. Established mutilating changes, concomitant corticosteroid treatment, and previous joint surgery are relatively robust indicators for a poor prognosis of the cervical spine in patients with RA, based on the consistency in more than 10-year analysis of two different settings. Level of Evidence: 3

Preliminary Evaluation of the Pathomechanisms of Dysphagia After Occipitospinal Fusion: Kinematic Analysis by Videofluoroscopic Swallowing Study.

Study Design. Kinematic analysis of swallowing function using videofluoroscopic swallowing study (VFSS). Objectives. The aims of this study were to analyze swallowing process in the patients who underwent occipitospinal fusion (OSF) and elucidate the pathomechanism of dysphagia after OSF. Summary of Background Data. Although several hypotheses about the pathomechanisms of dysphagia after OSF were suggested, there has been little tangible evidence to support these hypotheses since these hypotheses were based on the analysis of static radiogram or CT. Considering that swallowing is a compositive motion of oropharyngeal structures, the etiology of postoperative dysphagia should be investigated through kinematic approaches. Methods. Each four patients with or without postoperative dysphagia (group D and N, respectively) participated in this study. For VFSS, all patients were monitored to swallow 5-mL diluted barium solution by fluoroscopy, and then dynamic passing pattern of the barium solution was analyzed. Additionally, O-C2 angle (O-C2A) was measured for the assessment of craniocervical alignment. Results. O-C2A in group D was −7.5 degrees, which was relatively smaller than 10.3 degrees in group N (P = 0.07). In group D, all cases presented smooth medium passing without any obstruction at the upper cervical level regardless of O-C2A, whereas the obstruction to the passage of medium was detected at the apex of mid-lower cervical ocurvature, where the anterior protrusion of mid-lower cervical spine compressed directly the pharyngeal space. In group N, all cases showed smooth passing of medium through the whole process of swallowing. Conclusion. This study presented that postoperative dysphagia did not occur at the upper cervical level even though there was smaller angle of O-C2A and demonstrated the narrowing of the oropharyngeal space towing to direct compression by the anterior protrusion of mid-lower cervical spine was the etiology of dysphagia after OSF. Therefore, surgeon should pay attention to the alignment of mid-cervical spine as well as craniocervical junction during OSF. Level of Evidence: 4

The Prediction and Prevention of Dysphagia after Occipitospinal Fusion by Use of the S-line (swallowing line).

Study Design. Clinical case series and risk factor analysis of dysphagia after occipitospinal fusion (OSF). Objective. The aim of this study was to develop new criteria to avoid postoperative dysphagia by analyzing the relationship among the craniocervical alignment, the oropharyngeal space, and the incidence of dysphagia after OSF. Summary of Background Data. Craniocervical malalignment after OSF is considered to be one of the primary triggers of postoperative dysphagia. However, ideal craniocervical alignment has not been confirmed. Methods. Thirty-eight patients were included. We measured the O-C2 angle (O-C2A) and the pharyngeal inlet angle (PIA) on the lateral cervical radiogram at follow-up. PIA is defined as the angle between McGregors line and the line that links the center of the C1 anterior arch and the apex of cervical sagittal curvature. The impact of these two parameters on the diameter of pharyngeal airway space (PAS) and the incidence of the dysphagia were analyzed. Results. Six of 38 cases (15.8%) exhibited the dysphagia. A multiple regression analysis showed that PIA was significantly correlated with PAS (&bgr; = 0.714, P = 0.005). Receiver-operating characteristic curves showed that PIA had a high accuracy as a predictor of the dysphagia with an AUC (area under the curve) of 0.90. Cases with a PIA less than 90 degrees showed significantly higher incidence of dysphagia (31.6%) than those with a 90 or more degrees of PIA (0.0%) (P = 0.008). Conclusion. Our results indicated that PIA had the high possibility to predict postoperative dysphagia by OSF with the condition of PIA <90°. Based on these results, we defined “Swallowing-line (S-line)” for the reference of 90° of PIA. S-line (−) is defined as PIA <90°, where the apex of cervical lordosis protruded anterior to the “S-line,” which should indicate the patient is at a risk of postoperative dysphagia. Level of Evidence: 4

Intraosseous Epidermoid Cyst in the Femur After an Open Fracture: A Case Report

An intraosseous epidermoid cyst is a rare lesion usually arising from a phalanx in the hand or foot or from the skull1-5. To the best of our knowledge, only one case of an intraosseous epidermoid cyst involving the femur previously has been reported in the literature6. In this case report, we present the clinicopathological features of an intraosseous epidermoid cyst after an open fracture of the femur; we also review previous reports to discuss the etiology and treatment options for intraosseous epidermoid cysts. The patient was informed that data concerning the case would be submitted for publication, and he provided consent. A sixty-four-year-old man had sustained an open fracture of the right femur (Gustilo-Anderson grade IIIA) eleven years previously. After emergency debridement, he had been managed with intramedullary nailing and bone-grafting. After union of the fracture had been achieved, the clinical course was uneventful. Eleven years after the initial surgery for the fracture, the patient was seen at the local hospital with increasing pain in the right thigh. A radiograph showed an osteolytic lesion around the intramedullary nail in the epiphysis of the distal part of the right femur (Fig. 1). The intramedullary nail was extracted, and an open biopsy was performed. The biopsy specimen confirmed the diagnosis of an epidermoid cyst in the femur. An intralesional excision of the cyst was performed, and beta-tricalcium phosphate (β-TCP) (OSferion; Olympus, Tokyo, Japan) was implanted (Fig. 2). Fig. 1 Radiograph showing intramedullary nails and osteolysis in the epiphysis of the distal part of the femur. Fig. 2 Radiograph after the intralesional excision of the cyst and the implantation of β-TCP. Seven months after the second surgery, pain in the right thigh returned. On physical examination, diffuse swelling and heat (calor) were found in the distal aspect of the right …