Extracellular aaRSs drive autoimmune and inflammatory responses in rheumatoid arthritis via the release of cytokines and PAD4.

OBJECTIVES: Recent studies demonstrate that extracellular-released aminoacyl-tRNA synthetases (aaRSs) play unique roles in immune responses and diseases. This study aimed to understand the role of extracellular aaRSs in the pathogenesis of rheumatoid arthritis (RA). METHODS: Primary macrophages and fibroblast-like synoviocytes were cultured with aaRSs. aaRS-induced cytokine production including IL-6 and TNF-α was detected by ELISA. Transcriptomic features of aaRS-stimulated macrophages were examined using RNA-sequencing. Serum and synovial fluid (SF) aaRS levels in patients with RA were assessed using ELISA. Peptidyl arginine deiminase (PAD) 4 release from macrophages stimulated with aaRSs was detected by ELISA. Citrullination of aaRSs by themselves was examined by immunoprecipitation and western blotting. Furthermore, aaRS inhibitory peptides were used for inhibition of arthritis in two mouse RA models, collagen-induced arthritis and collagen antibody-induced arthritis. RESULTS: All 20 aaRSs functioned as alarmin; they induced pro-inflammatory cytokines through the CD14-MD2-TLR4 axis. Stimulation of macrophages with aaRSs displayed persistent innate inflammatory responses. Serum and SF levels of many aaRSs increased in patients with RA compared with control subjects. Furthermore, aaRSs released PAD4 from living macrophages, leading to their citrullination. We demonstrate that aaRS inhibitory peptides suppress cytokine production and PAD4 release by aaRSs and alleviate arthritic symptoms in a mouse RA model. CONCLUSIONS: Our findings uncovered the significant role of aaRSs as a novel alarmin in RA pathogenesis, indicating that their blocking agents are potent antirheumatic drugs.

Protocol for the RETHINK study: a randomised, double-blind, parallel-group, non-inferiority clinical trial comparing acetaminophen and NSAIDs for treatment of chronic pain in elderly patients with osteoarthritis of the hip and knee.

INTRODUCTION: In patients with chronic pain, oral analgesics are essential treatment options to manage pain appropriately, improve activities of daily living abilities and achieve a higher quality of life (QOL). It is desirable to select analgesics for elderly patients based on comparative data on analgesic effect and risk of adverse events; however, there are few comparative studies so far. The purpose of this study is to determine whether the efficacy and safety of acetaminophen are non-inferior to non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of chronic pain associated with osteoarthritis of the hip and knee in elderly patients. METHODS AND ANALYSIS: This study is a multicentre, randomised controlled, double-blind, parallel-group study to compare the analgesic effect and adverse events between acetaminophen or NSAIDs (loxoprofen or celecoxib). A total of 400 elderly patients with osteoarthritis of the hip and knee will be recruited from five institutions in Japan. Patients of 65 years or older with osteoarthritis-related pain will be registered and randomly assigned to acetaminophen, loxoprofen or celecoxib with 2:1:1 allocation. The primary endpoint is change in the Brief Pain Inventory (BPI) item 3 (worst pain) score from baseline to week 8. The secondary endpoints are BPI item 3 score change from baseline to week 4, health-related QOL measured by Short Form-8 Health Survey, and occurrence of adverse events including gastrointestinal disorders and abnormal liver function. Data will be analysed in accordance with a predefined statistical analysis plan. ETHICS AND DISSEMINATION: This study protocol was approved by the Kyushu University Hospital Certified Institutional Review Board for Clinical Trials on 28 January 2021 (KD2020004) and the chief executive of each participating hospital. The results of the study will be submitted to international peer-reviewed journals, and the main findings will be presented at international scientific conferences. TRIAL REGISTRATION NUMBER: jRCTs071200112.

Risk factors for insufficient reduction after short-segment posterior fixation for thoracolumbar burst fractures: Does the interval from injury onset to surgery affect reduction of fractured vertebrae?

BACKGROUND: Many surgeons have encountered patients who could not immediately undergo surgery to treat spinal fractures because they had associated injuries and/or because a complete diagnosis was delayed. For such patients, practitioners might assume that delays could mean that the eventual reduction would be insufficient. However, no report covered risk factors for insufficient reduction of fractured vertebra including duration from injury onset to surgery. The purpose of this study is to investigate the risk factors for insufficient reduction after short-segment fixation of thoracolumbar burst fractures. METHODS: Our multicenter study included 253 patients who sustained a single thoracolumbar burst fracture and underwent short-segment fixation. We measured the local vertebral body angle (VBA) on roentgenograms, before and after surgery, and then calculated the reduction angle and reduction rate of the fractured vertebra by using the following formula: [Formula: see text] A multiple logistical regression analysis was performed to identify risk factors for insufficient reduction. The factors that we evaluated were age, gender, affected spine level, time elapsed from injury to surgery, inclusion of vertebroplasty with surgery, load-sharing score (LSS), AO classification (type A or B), preoperative VBA, and the ratio of canal compromise before surgery. RESULTS: There were 140 male and 113 female patients, with an average age of 43 years, and the mean time elapsed between injury and surgery was 3.8 days. The mean reduction angle was 12°, and the mean reduction rate was 76%. The mean LSS was 6.4 points. Multiple linear regression analysis revealed that a higher LSS, a larger preoperative VBA, a younger age, and being female disposed patients to having a larger reduction angle and reduction rate. The time elapsed from injury to surgery had no relation to the quality of fracture reduction in the acute period. CONCLUSIONS: Our findings indicate that if there is no neurologic deficit, we might not need to hurry surgical reduction of fractured vertebrae in the acute phase.

Determination of gastric atrophy with artificial intelligence compared to the assessments of the modified Kyoto and OLGA classifications.

Background and Aim: Gastric atrophy is a precancerous lesion. We aimed to clarify whether gastric atrophy determined by artificial intelligence (AI) correlates with the diagnosis made by expert endoscopists using several endoscopic classifications, the Operative Link on Gastritis Assessment (OLGA) classification based on histological findings, and genotypes associated with gastric atrophy and cancer. Methods: Two hundred seventy Helicobacter pylori-positive outpatients were enrolled. All patients' endoscopy data were retrospectively evaluated based on the Kimura-Takemoto, modified Kyoto, and OLGA classifications. The AI-trained neural network generated a continuous number between 0 and 1 for gastric atrophy. Nucleotide variance of some candidate genes was confirmed or selectively assessed for a variety of genotypes, including the COX-21195, IL-1ß 511, and mPGES-1 genotypes. Results: There were significant correlations between determinations of gastric atrophy by AI and by expert endoscopists using not only the Kimura-Takemoto classification (P < 0.001), but also the modified Kyoto classification (P = 0.046 and P < 0.001 for the two criteria). Moreover, there was a significant correlation with the OLGA classification (P = 0.009). Nucleotide variance of the COX-2, IL-1ß, and mPGES-1genes was not significantly associated with gastric atrophy determined by AI. The area under the curve values of the combinations of AI and the modified Kyoto classification (0.746) and AI and the OLGA classification (0.675) were higher than in AI alone (0.665). Conclusion: Combinations of AI and the modified Kyoto classification or of AI and the OLGA classification could be useful tools for evaluating gastric atrophy in patients with H. pylori infection as the risk of gastric cancer.

Adjacent-segment disease after L3-4 posterior lumbar interbody fusion: does L3-4 fusion have cranial adjacent-segment degeneration similar to that after L4-5 fusion?

OBJECTIVE: Posterior lumbar interbody fusion (PLIF) is a widely accepted procedure for degenerative lumbar diseases, and there have been many reports concerning adjacent-segment disease (ASD) after PLIF. In the reports of ASD in which the fusion level was limited to 1 segment, all reports describe ASD of the L3-4 segment after L4-5 PLIF. On the basis of these reports, it is thought that ASD mainly occurs at the cranial segment. However, no report has covered ASD after L3-4 PLIF. Therefore, the authors investigated ASD after L3-4 PLIF. METHODS: In conducting a retrospective case series analysis, the authors reviewed a surgical database providing details of all spine operations performed between 2006 and 2017 at a single institution. During that period, PLIF was performed to treat 632 consecutive patients with degenerative lumbar diseases. Of these patients, 71 were treated with L3-4 PLIF alone, and 67 who were monitored for at least 2 years (mean 5.8 years; follow-up rate 94%) after surgery were enrolled in this study. Radiological ASD (R-ASD), symptomatic ASD (S-ASD), and operative ASD (O-ASD) were evaluated. These types of ASD were defined as follows: R-ASD refers to radiological degeneration adjacent to the fusion segment as shown on plain radiographs; S-ASD is a symptomatic condition due to neurological deterioration at the adjacent-segment degeneration; and O-ASD refers to S-ASD requiring revision surgery. RESULTS: All patients had initial improvement of neurological symptoms after primary PLIF. R-ASD was observed in 32 (48%) of 67 patients. It occurred at the cranial segment in 12 patients and at the caudal segment in 24; R-ASD at both adjacent segments was observed in 4 patients. Thus, the occurrence of R-ASD was more significant in the caudal segment than in the cranial segment. S-ASD was observed in 10 patients (15%), occurring at the cranial segment in 3 patients and at the caudal segment in 7. O-ASD was observed in 6 patients (9%): at the cranial segment in 1 patient and at the caudal segment in 5. Thus, the rate of involvement of the caudal segment was 67% in R-ASD, 70% in S-ASD, and 83% in O-ASD. CONCLUSIONS: The incidences of R-ASD, S-ASD, and O-ASD were 48%, 15%, and 9%, respectively, after L3-4 PLIF for degenerative lumbar diseases. In contrast to ASD after L4-5 PLIF, ASD after L3-4 PLIF was more frequently observed at the caudal segment than at the cranial segment. In follow-up for patients with L3-4 PLIF, surgeons should pay attention to ASD in the caudal segment.

IL-6-PAD4 axis in the earliest phase of arthritis in knock-in gp130F759 mice, a model for rheumatoid arthritis.

Objective: Animal models for human diseases are especially valuable for clarifying molecular mechanisms before or around the onset. As a model for rheumatoid arthritis (RA), we utilise knock-in mice gp130F759. They have a Y759F mutation in gp130, a common receptor subunit for interleukin 6 (IL-6) family cytokines. Definitive arthritis develops around 8 months old and the incidence reaches 100% around 1 year old. Careful examination in the clinical course revealed very subtle resistance in flexibility of joints at 5 months old. Therefore, pathophysiological changes in gp130F759 were examined to dissect molecular mechanisms for preclinical phase of RA. Methods: Severity of arthritis in gp130F759 was evaluated with a clinical score system and histological quantification. Serum cytokines, autoantibodies and C reactive protein (CRP) were measured. Changes in the synovium were analysed by real-time PCR, flow cytometry and immunohistochemistry. Results: Around 5 months old, various types of cytokines, rheumatoid factor (RF), anti-circular citrullinated peptide IgM and CRP increased in the sera of gp130F759. Enhancement of neovascularisation, synovial hyperplasia and fibrosis was observed. Also, increases in haematopoietic cells dominated by innate immune cells and gene expression of Il6 and Padi4 were detected in the joints. Il6 was expressed by non-haematopoietic synovial cells, whereas PAD4 protein was detected in the synovial neutrophils. Padi4 is induced in neutrophils in vitro by IL-6. Increases of phospho-STAT3 and PAD4 protein were detected in the synovium. Deletion of IL-6 in gp130F759 normalised the amount of PAD4 protein in the joints. Conclusion: The IL-6-PAD4 axis operates in the earliest phase of arthritis in gp130F759, implicating it in early RA.

Risk factors for a kyphosis recurrence after short-segment temporary posterior fixation for thoracolumbar burst fractures.

Short-segment temporary posterior spinal instrumentation has been widely used to treat thoracolumbar burst fractures. However, kyphosis recurrence without hardware failure has become a concern. Therefore, we investigated risk factors for kyphosis recurrence after short-segment temporary fixation for thoracolumbar burst fractures. Our prospective multicenter study involved 76 consecutive patients with thoracolumbar burst fractures who underwent short-segment temporary posterior fixation using ligamentotaxis with Schanz screws and without fusion. Patients were divided into two groups -kyphosis recurrence and no kyphosis recurrence- according to correction loss of the kyphotic angle. Clinical and radiographic data were examined to reveal the risk factors for postoperative kyphosis recurrence. After surgery, all patients experienced fracture union. Kyphotic deformity was reduced significantly, and maintenance of the reduced vertebra was successful. However, mean 9.1° loss of correction in kyphotic angle was observed. Statistical analysis revealed that a high ratio of canal compromise before surgery, as seen on computed tomography scanning, and a large preoperative kyphotic angle influenced kyphosis recurrence. In conclusion,short-segment temporary posterior fixation yields satisfactory results regarding reduction and maintenance of fractured vertebrae. However, correction loss after implant removal is associated with a high compromised canal ratio before surgery and a large preoperative kyphotic angle.

Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice.

In the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-α (TNF-α) transgenic (hTNF-Tg) mice. Single-drug treatments with etanercept and tacrolimus attenuated the clinical signs but not the radiographic changes associated with the development of arthritis in mice. On the contrary, combined treatment significantly suppressed the radiographic progression and also improved the clinical signs. The combined treatment exhibited synergistic effects of the two drugs in reducing the serum matrix metalloproteinase-3 level and the number of peripheral CD11bhigh osteoclast precursor cells. Moreover, tacrolimus inhibited the cytokine-induced osteoclast differentiation in synergy with etanercept in an in vitro assay. Interestingly, tacrolimus did not inhibit the production of antidrug antibodies (ADAs) against etanercept in the hTNF-Tg mice. This result implies that the synergistic effects of etanercept and tacrolimus are not due to secondary effects derived from the suppression of ADA production by tacrolimus but are due to their primary effects. These findings suggest that concomitant treatment with etanercept and tacrolimus may be one of preferable treatment options to control disease activities for patients with rheumatoid arthritis, especially for those with bone resorption.

SPACIA1/SAAL1 Deletion Results in a Moderate Delay in Collagen-Induced Arthritis Activity, along with mRNA Decay of Cyclin-dependent Kinase 6 Gene.

This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). SPACIA1/SAAL1-deficient mice were generated and used to create mouse models of CIA in mild or severe disease conditions. Cell cycle-related genes, whose expression levels were affected by SPACIA1/SAAL1 small interfering RNA (siRNA), were screened. Transcriptional and post-transcriptional effects of SPACIA1/SAAL1 siRNA on cyclin-dependent kinase (cdk) 6 gene expression were investigated in human RASFs. SPACIA1/SAAL1-deficient mice showed later onset and slower progression of CIA than wild-type mice in severe disease conditions, but not in mild conditions. Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1/SAAL1 siRNA at the post-transcriptional level. The exacerbation of CIA depends on SPACIA1/SAAL1 expression, although CIA also progresses slowly in the absence of SPACIA1/SAAL1. The CDK6, expression of which is up-regulated by the SPACIA1/SAAL1 expression, might be a critical factor in the exacerbation of CIA.

Controllable Risk Factors for Neurologic Complications in Posterior Lumbar Interbody Fusion as Revision Surgery.

BACKGROUND: The main concern with revision lumbar surgery is the possibility of neurologic complications. This retrospective study was conducted to clarify the risk factors, especially the effects of nerve stretching, for postoperative neurologic complications in posterior lumbar interbody fusion (PLIF) without excessive nerve retraction by bilateral total facetectomy as revision surgery. METHODS: Between 2005 and 2015, 50 consecutive patients underwent revision PLIF for recurrent stenosis or recurrent disc herniation. The patients were divided into two groups: patients with neurological complications (NC group) and patients without neurological complications (non-NC group). Radiological examinations to evaluate the magnitude of nerve stretching included the following pre- and postoperative plain radiograph measurements: anterolisthesis at flexion, intervertebral lordosis in the neutral position, and posterior disc height in the neutral position. RESULTS: Sixteen patients (32%) had neurological complications. The decrease in intervertebral lordosis was significantly greater in the NC group than that in the non-NC group (0.8° vs. -1.5°, P<0.05). Distraction of the posterior disc height was significantly greater in the NC group than that in the non-NC group (5.0 mm vs. 2.6 mm, P < 0.01). Neurological complications were seen in all patients with a decrease in intervertebral lordosis >3° and distraction of the posterior disc height >3 mm. CONCLUSIONS: Decreased intervertebral lordosis, and distraction of the posterior disc height, which can be controlled by surgeons, appear to be risk factors for neurological complications following revision PLIF. In revision PLIF, surgeons should create segmental lordosis without excessive disc height distraction.

Fusion Rate and Clinical Outcomes in Two-Level Posterior Lumbar Interbody Fusion.

BACKGROUND: Posterior lumbar interbody fusion (PLIF) has become a general surgical method for degenerative lumbar diseases. Although many reports have focused on single-level PLIF, few have focused on 2-level PLIF, and no report has covered the fusion status of 2-level PLIF. The purpose of this study is to investigate clinical outcomes and fusion for 2-level PLIF by using a combination of dynamic radiographs and multiplanar-reconstruction computed tomography scans. METHODS: This study consisted of 48 consecutive patients who underwent 2-level PLIF for degenerative lumbar diseases. We assessed surgery duration, estimated blood loss, complications, clinical outcomes as measured by the Japanese Orthopaedic Association score, lumbar sagittal alignment as measured on standing lateral radiographs, and fusion status as measured by dynamic radiographs and multiplanar-reconstruction computed tomography. Patients were examined at a follow-up point of 4.8 ± 2.2 years after surgery. Thirty-eight patients who did not undergo lumbosacral fusion comprised the lumbolumbar group, and 10 patients who underwent lumbosacral fusion comprised the lumbosacral group. RESULTS: The mean Japanese Orthopaedic Association score improved from 12.1 to 22.4 points by the final follow-up examination. Sagittal alignment also was improved. All patients had fusion in the cranial level. Seven patients had nonunion in the caudal level, and the lumbosacral group (40%) had a significantly poorer fusion rate than the lumbolumbar group (97%) did. CONCLUSIONS: Surgical outcomes of 2-level PLIF were satisfactory. The fusion rate at both levels was 85%. All nonunion was observed at the caudal level and concentrated at L5-S level in L4-5-S PLIF.

Postoperative Spinal Subdural Lesions Following Lumbar Spine Surgery: Prevalence and Risk Factors.

STUDY DESIGN: Retrospective case-control study. PURPOSE: To clarify the prevalence and risk factors for spinal subdural lesions (SSDLs) following lumbar spine surgery. OVERVIEW OF LITERATURE: Because SSDLs, including arachnoid cyst and subdural hematoma, that develop following spinal surgery are seldom symptomatic and require reoperation, there are few reports on these pathologies. No study has addressed the prevalence and risk factors for SSDLs following lumbar spine surgery. METHODS: We conducted a retrospective analysis of the magnetic resonance (MR) images and medical records of 410 patients who underwent lumbar decompression surgery with or without instrumented fusion for degenerative disorders. SSDLs were classified into three grades: grade 0, no obvious lesion; grade 1, cystic lesion; and grade 2, lesions other than a cyst. Grading was based on the examination of preoperative and postoperative MR images. The prevalence of SSDLs per grade was calculated and risk factors were evaluated using multivariate logistic regression analysis. RESULTS: Postoperative SSDLs were identified in 123 patients (30.0%), with 50 (12.2%) and 73 (17.8%) patients being classified with grade 1 and 2 SSDLs, respectively. Among these, one patient was symptomatic, requiring hematoma evacuation because of the development of incomplete paraplegia. Bilateral partial laminectomy was a significantly independent risk factor for SSDLs (odds ratio, 1.52; 95% confidence interval, 1.20-1.92; p<0.001). In contrast, a unilateral partial laminectomy was a protective factor (odds ratio, 0.11; 95% confidence interval, 0.03-0.46; p=0.002). CONCLUSIONS: The prevalence rate of grade 1 SSDLs was 30%, with no associated clinical symptoms observed in all but one patient. Bilateral partial laminectomy increases the risk for SSDLs, whereas unilateral partial laminectomy is a protective factor.

Temporary short-segment pedicle screw fixation for thoracolumbar burst fractures: comparative study with or without vertebroplasty.

BACKGROUND CONTEXT: Short-segment posterior spinal instrumentation for thoracolumbar burst fracture provides superior correction of kyphosis by an indirect reduction technique, but it has a high failure rate. PURPOSE: The purpose of the study we report here was to compare outcomes for temporary short-segment pedicle screw fixation with vertebroplasty and for such fixation without vertebroplasty. STUDY DESIGN: This is a prospective multicenter comparative study. PATIENT SAMPLE: We studied 62 consecutive patients with thoracolumbar burst fracture who underwent short-segment posterior instrumentation using ligamentotaxis with Schanz screws with or without vertebroplasty. OUTCOME MEASURES: Radiological parameters (Cobb angle on standing lateral radiographs) were used. METHODS: Implants were removed approximately 1 year after surgery. Neurologic function, kyphotic deformity, canal compromise, and fracture severity were evaluated prospectively. RESULTS: After surgery, all patients with neurologic deficit had improvement equivalent to at least one grade on the American Spinal Injury Association impairment scale and had fracture union. Kyphotic deformity was reduced significantly, and reduction of the vertebrae was maintained with and without vertebroplasty, regardless of load-sharing classification. Although no patient required additional anterior reconstruction, kyphotic change was observed at disc level mainly after implant removal with or without vertebroplasty. CONCLUSIONS: Temporary short-segment fixation yielded satisfactory results in the reduction and maintenance of fractured vertebrae with or without vertebroplasty. Kyphosis recurrence may be inevitable because adjacent discs can be injured during the original trauma.

Prediction of Postoperative Clinical Recovery of Drop Foot Attributable to Lumbar Degenerative Diseases, via a Bayesian Network.

BACKGROUND: Drop foot resulting from degenerative lumbar diseases can impair activities of daily living. Therefore, predictors of recovery of this symptom have been investigated using univariate or/and multivariate analyses. However, the conclusions have been somewhat controversial. Bayesian network models, which are graphic and intuitive to the clinician, may facilitate understanding of the prognosis of drop foot resulting from degenerative lumbar diseases. QUESTIONS/PURPOSES: (1) To show a layered correlation among predictors of recovery from drop foot resulting from degenerative lumbar diseases; and (2) to develop support tools for clinical decisions to treat drop foot resulting from lumbar degenerative diseases. METHODS: Between 1993 and 2013, we treated 141 patients with decompressive lumbar spine surgery who presented with drop foot attributable to degenerative diseases. Of those, 102 (72%) were included in this retrospective study because they had drop foot of recent development and had no diseases develop that affect evaluation of drop foot after surgery. Specifically, 28 (20%) patients could not be analyzed because their records were not available at a minimum of 2 years followup after surgery and 11 (8%) were lost owing to postoperative conditions that affect the muscle strength evaluation. Eight candidate variables were sex, age, herniated soft disc, duration of the neurologic injury (duration), preoperative tibialis anterior muscle strength (pretibialis anterior), leg pain, cauda equina syndrome, and number of involved levels. Manual muscle testing was used to assess the tibialis anterior muscle strength. Drop foot was defined as a tibialis anterior muscle strength score of less than 3 of 5 (5 = movement against gravity and full resistance, 4 = movement against gravity and moderate resistance, 3 = movement against gravity through full ROM, 3- = movement against gravity through partial ROM, 2 = movement with gravity eliminated through full ROM, 1 = slight contraction but no movement, and 0 = no contraction). The two outcomes of interest were postoperative tibialis anterior muscle strength (posttibialis anterior) of 3 or greater and posttibialis anterior strength of 4 or greater at 2 years after surgery. We developed two separate Bayesian network models with outcomes of interest for posttibialis anterior strength of 3 or greater and posttibialis anterior strength of 4 or greater. The two outcomes correspond to "good" and "excellent" results based on previous reports, respectively. Direct predictors are defined as variables that have the tail of the arrow connecting the outcome of interest, whereas indirect predictors are defined as variables that have the tail of the arrow connecting either direct predictors or other indirect predictors that have the tail of the arrow connecting direct predictors. Sevenfold cross validation and receiver-operating characteristic (ROC) curve analyses were performed to evaluate the accuracy and robustness of the Bayesian network models. RESULTS: Both of our Bayesian network models showed that weaker muscle power before surgery (pretibialis anterior ≤ 1) and longer duration of neurologic injury before treatment (> 30 days) were associated with a decreased likelihood of return of function by 2 years. The models for posttibialis anterior muscle strength of 3 or greater and posttibialis anterior muscle strength of 4 or greater were the same in terms of the graphs, showing that the two direct predictors were pretibialis anterior muscle strength (score ≤ 1 or ≥ 2) and duration (≤ 30 days or > 30 days). Age, herniated soft disc, and leg pain were identified as indirect predictors. We developed a decision-support tool in which the clinician can enter pretibialis anterior muscle strength and duration, and from this obtain the probability estimates of posttibialis anterior muscle strength. The probability estimates of posttibialis anterior muscle strength of 3 or greater and posttibialis anterior muscle strength of 4 or greater were 94% and 85%, respectively, in the most-favorable conditions (pretibialis anterior ≥ 2; duration ≤ 30 days) and 18% and 14%, respectively, in the least-favorable conditions (pretibialis anterior ≤ 1; duration > 30 days). On the sevenfold cross validation, the area under the ROC curve yielded means of 0.78 (95% CI, 0.68-0.87) and 0.74 (95% CI, 0.64-0.84) for posttibialis anterior muscle strength of 3 or greater and posttibialis anterior muscle strength of 4 or greater, respectively. CONCLUSIONS: The results of this study suggest that the clinician can understand intuitively the layered correlation among predictors by Bayesian network models. Based on the models, the decision-support tool successfully provided the probability estimates of posttibialis anterior muscle strength to treat drop foot attributable to lumbar degenerative diseases. These models were shown to be robust on the internal validation but should be externally validated in other populations. LEVEL OF EVIDENCE: Level III, therapeutic study.

Differences in the time of onset of postoperative upper limb palsy among surgical procedures: a meta-analysis.

BACKGROUND CONTEXT: The time of onset of postoperative upper limb palsy (ULP), also referred to as C5 palsy, varies among patients. Although some studies addressed the relationship between the time of onset of ULP and the potential etiologies, no meta-analysis has been conducted regarding the association between the time of onset of ULP and other factors such as surgical procedure type and treated diseases. PURPOSE: This study aimed to elucidate differences in the time of onset of ULP among spinal surgical procedures and treated diseases to understand its etiology. STUDY DESIGN: This is a meta-analysis. OUTCOME MEASURES: The time of onset of ULP after cervical decompression surgery. METHODS: We conducted a meta-analysis via searches of the PubMed, EMBASE, and Cochrane Library databases. Upper limb palsy within 2 days postoperatively or at 3 days or more postoperatively was defined as early- and late-onset, respectively. We calculated the pooled prevalence of early- and late-onset ULP with regard to surgical procedures and diseases using a random effects model. The proportion of early-onset ULP relative to all ULP was also determined. Surgical procedures were categorized into four procedures: (1) anterior cervical discectomy and fusion (ACDF); (2) anterior cervical corpectomy and fusion (ACCF); (3) laminoplasty or laminectomy (LPN); and (4) posterior spinal fusion with decompression (PSF). Treated diseases were classified as ossification of the posterior longitudinal ligament (OPLL) and non-OPLL. RESULTS: The pooled prevalence of early-onset ULP was significantly stratified across three groups of surgical procedures (PSF [9.0%]>ACCF [3.7%] and LPN [2.5%]>ACDF [0.6%]). In the pooled analysis of late-onset ULP prevalence, three procedures (PSF [4.3%], ACCF [2.8%], and LPN [2.9%]) were similar, but ACDF (1.0%) was associated with a significantly lower prevalence than LPN. The prevalence of both early- and late-onset ULP was significantly higher with OPLL than without OPLL. However, the proportion of early-onset ULP relative to all ULP was similar between non-OPLL and OPLL (50.8% vs. 49.5%). CONCLUSIONS: The high prevalence of early-onset ULP in PSF is attributable to a lag correction effect, which is triggered by posterior correction and fusion through comparison with LPN. The combination of our meta-analysis results and previous knowledge facilitates our understanding of the etiology of ULP.

Surgical outcomes of temporary short-segment instrumentation without augmentation for thoracolumbar burst fractures.

BACKGROUND: Short-segment posterior spinal instrumentation for thoracolumbar burst fracture provides superior correction of kyphosis by an indirect reduction technique, but it has a high failure rate. We investigated the clinical and radiological results of temporary short-segment pedicle screw fixation without augmentation performed for thoracolumbar burst fractures with the goal of avoiding treatment failure by waiting to see if anterior reconstruction was necessary. METHODS: We studied 27 consecutive patients with thoracolumbar burst fracture who underwent short-segment posterior instrumentation using ligamentotaxis with Schanz screws and without augmentation. Implants were removed approximately 1 year after surgery. Neurological function, kyphotic deformity, canal compromise, fracture severity, and back pain were evaluated prospectively. RESULTS: After surgery, all patients with neurological deficit had improvement equivalent to at least 1 grade on the American Spinal Injury Association impairment scale and had fracture union. Kyphotic deformity was reduced significantly, and maintenance of the reduced vertebra was successful even without vertebroplasty, regardless of load-sharing classification. Therefore, no patients required additional anterior reconstruction. Postoperative correction loss occurred because of disc degeneration, especially after implant removal. Ten patients had increasing back pain, and there are some correlations between the progression of kyphosis and back pain aggravation. CONCLUSION: Temporary short-segment fixation without augmentation yielded satisfactory results in reduction and maintenance of fractured vertebrae, and maintenance was independent of load-sharing classification. Kyphotic change was caused by loss of disc height mostly after implant removal. Such change might have been inevitable because adjacent endplates can be injured during the original spinal trauma. Kyphotic change after implant removal may thus be a limitation of this surgical procedure.

Surgical outcomes for painless drop foot due to degenerative lumbar disorders.

STUDY DESIGN: Twenty patients presenting with painless drop foot who had undergone lumbar spine surgery for degenerative lumbar diseases were included in this retrospective study. OBJECTIVE: This study aims to investigate which causative factors and patient symptoms significantly affected surgical outcome. SUMMARY OF BACKGROUND DATA: Drop foot is a neuromuscular condition that results in dorsiflexion palsy of the ankle. Patients with drop foot often complain of leg pain. Rarely, patients experience painless drop foot due to lumbar degenerative disease. For these patients, the only purpose of surgery is to improve the palsy; this makes it difficult to determine whether surgical intervention is indicated. No studies have focused on the results of surgical treatment for painless drop foot caused by degenerative lumbar diseases. METHODS: Preoperative strength of the tibialis anterior and duration of palsy were recorded and considered with surgical outcome. RESULTS: Sixty-five percent of patients recovered from drop foot after surgery. Drop foot was caused mainly by impairment of the L5 nerve root. Patients with a longer duration of palsy had poorer results. CONCLUSIONS: Duration of palsy had the greatest effect on recovery. As the only goal of this surgery is improvement in the strength of the tibialis anterior, caution must be exercised when considering surgery for patients with longstanding palsy.

Primary amyloidoma in epidural and paravertebral space of the lumbar spine.

BACKGROUND CONTEXT: Localized amyloid deposits result in a mass, that is, so-called amyloidoma; it has been reported in every anatomic site, although systemic amyloid deposition is much more common. However, primary lumbar epidural amyloidoma without bony involvement is extremely rare. To the best of our knowledge, only one case has been reported previously. PURPOSE: To report and review the clinical presentations, imaging studies, and treatment of epidural and paravertebral amyloidoma. STUDY DESIGN: A case report and review of the literature. METHODS: Lumbar epidural and paravertebral amyloidoma in a 75-year-old man with neurologic compromise is presented. Laminectomy with mass resection was performed. RESULTS: After surgery, almost complete neurologic improvement was observed. Histologically, definite diagnosis was obtained only after the specific staining of tissue. No sign of local recurrence was evident 1 year after surgery. CONCLUSIONS: Primary amyloidoma, although rare, should be included in the differential diagnosis of epidural mass of the spine. Diagnosis before surgery is difficult as there were no characteristic findings in clinical and imaging studies. Special histologic technique and stains are useful to make a definite diagnosis.

Three-dimensional and multienergy gamma-ray simultaneous imaging by using a Si/CdTe Compton camera.

PURPOSE: To develop a silicon (Si) and cadmium telluride (CdTe) imaging Compton camera for biomedical application on the basis of technologies used for astrophysical observation and to test its capacity to perform three-dimensional (3D) imaging. MATERIALS AND METHODS: All animal experiments were performed according to the Animal Care and Experimentation Committee (Gunma University, Maebashi, Japan). Flourine 18 fluorodeoxyglucose (FDG), iodine 131 ((131)I) methylnorcholestenol, and gallium 67 ((67)Ga) citrate, separately compacted into micro tubes, were inserted subcutaneously into a Wistar rat, and the distribution of the radioisotope compounds was determined with 3D imaging by using the Compton camera after the rat was sacrificed (ex vivo model). In a separate experiment, indium 111((111)In) chloride and (131)I-methylnorcholestenol were injected into a rat intravenously, and copper 64 ((64)Cu) chloride was administered into the stomach orally just before imaging. The isotope distributions were determined with 3D imaging after sacrifice by means of the list-mode-expectation-maximizing-maximum-likelihood method. RESULTS: The Si/CdTe Compton camera demonstrated its 3D multinuclear imaging capability by separating out the distributions of FDG, (131)I-methylnorcholestenol, and (67)Ga-citrate clearly in a test-tube-implanted ex vivo model. In the more physiologic model with tail vein injection prior to sacrifice, the distributions of (131)I-methylnorcholestenol and (64)Cu-chloride were demonstrated with 3D imaging, and the difference in distribution of the two isotopes was successfully imaged although the accumulation on the image of (111)In-chloride was difficult to visualize because of blurring at the low-energy region. CONCLUSION: The Si/CdTe Compton camera clearly resolved the distribution of multiple isotopes in 3D imaging and simultaneously in the ex vivo model.

Bucillamine inhibits CD40-mediated Akt activation and antibody production in mouse B-cell lymphoma.

The improvement of rheumatoid factor titers in patients with rheumatoid arthritis is one of the significant clinical effects of bucillamine (Buc). In this study, we investigated the effects of SA981, an active metabolite of Buc, and methotrexate (MTX) on CD40-mediated antibody production using mouse B-cell lymphoma, BCL1. SA981 significantly attenuated CD40-mediated antibody production in a concentration-dependent manner, but weakly affected cell proliferation. In contrast, MTX did not attenuate CD40-mediated antibody production until it had strongly inhibited cell proliferation at a concentration of 100 nM. CD40 signaling induced protein phosphorylation, including Akt phosphorylation, p38 mitogen-activated protein kinase (p38MAPK), and IκBα. SA981 at a concentration of 30 µM attenuated CD40-mediated Akt phosphorylation, but not p38MAPK or IκBα phosphorylation. MTX at a concentration of 100 nM did not affect CD40-mediated Akt, p38MAPK, or IκBα phosphorylation. Commercially available Akt inhibitor VIII significantly attenuated CD40-mediated IgM production at a concentration of 100 nM without significant inhibition of cell proliferation. These results suggest that SA981 inhibits CD40-mediated antibody production in mouse B-cell lymphoma, at least in part, by attenuation of Akt phosphorylation.