Search

BackgroundAlthough spinal schwannomas generally grow very slowly, it has been reported that these clinical growths and their associated neurological symptoms accelerate during pregnancy. Because these cases are rare, surgical intervention for this tumor during pregnancy poses a significant challenge. The change of pregnancy-related hormones, such as estrogen and progesterone, is considered to have an effect on the clinical symptoms of spinal tumors. Expressions of the receptors for estrogen and progesterone in orbital and vestibular schwannomas have been reported; however, those expressions in spinal schwannomas have not been examined.Case presentationA 36-year-old woman at 8 weeks' gestation suffered from developing neck pain and neurological symptoms in the right upper extremity. Magnetic resonance imaging (MRI) confirmed the presence of a cervical intradural extramedullary tumor. Under general anesthesia, using intraoperative neurophysiological monitoring of motor-evoked potentials (MEPs), spinal tumor resection following a hemi-laminoplasty was performed in a prone position at 12 weeks gestation. The pathological diagnosis following surgery was spinal schwannoma. Her neurological symptoms were significantly improved after surgery and she delivered a healthy baby in her 40th week of pregnancy. At a 12-month follow-up, no abnormalities were observed during medical examinations of both mother and child. An immunohistochemical study identified the expression of estrogen receptors, but not progesterone receptors, in the spinal schwannoma.ConclusionsA cervical spinal schwannoma was successfully removed under general anesthesia at 12 weeks gestation by coordination between orthopaedic, obstetric and anesthesia teams. For the first time, an immunohistochemical analysis showed that the expression of estrogen receptors was identified in spinal schwannoma cells, suggesting the possibility that these hormone receptors in spinal schwannoma might contribute to the worsening of neurological symptoms during pregnancy.

We investigated the relationship between paravertebral muscles and perimuscular connective tissues of the thoracolumbar fascia region and the four types of pain in patients suffering from chronic low back pain. A total of 17 patients with chronic low back pain participated in this study. Ultrasound imaging method was used to measure the thickness and echogenicity of the paravertebral muscles and perimuscular connective tissues. The measurement site considered in this study was located lateral to the midpoint between L2-3 and L4-5 spines. In addition, age, gender, BMI, numerical rating scale and the short-form McGill pain questionnaire 2 (includes questions with respect to continuous pain, intermittent pain, neuropathic pain and affective descriptors) were used for assessment. Statistical analysis was performed using correlation analysis and multiple regression analysis. A significant association was observed between paravertebral muscle echogenicity at L2-3 and the numerical rating scale (r = 0.499), between paravertebral muscle echogenicity at L4-5 with numerical rating scale (r = 0.538) and intermittent pain (r = 0.594), and between perimuscular connective tissue thickness at L2-3 and numerical rating scale (r = 0.762). We observed that the factor influencing perimuscular connective tissue thickness at L2-3 and L4-5 was intermittent pain (β = 0.513, β = 0.597, respectively). It was also observed that some of the imaging findings were associated with age and BMI. In conclusion, we observed that paravertebral muscle echogenicity and perimuscular connective tissue thickness in patients with chronic low back pain were associated with pain, especially intermittent pain.

Study Design This study is a retrospective review. Objective Central sensitization (CS) is a neurological phenomenon that involves hypersensitivity of the central nervous system. The central sensitization inventory (CSI) was developed as a screening tool to assess CS-related symptoms. The purpose of this study was to evaluate the association of preoperative CSI scores with patient-reported outcome measures (PROMs) including neurological symptoms for patients who underwent spine surgeries in a multicenter study. Methods A consecutive 673 patients who underwent spine surgery at 8 different institutions were included in this study. Preoperative CSI scores were assessed for all subjects. The participants completed the following PROMs: the Oswestry Disability Index (ODI), the Japanese Orthopaedic Association (JOA) back pain evaluation questionnaire (JOABPEQ) for lumbar spinal diseases, and the JOA cervical myelopathy evaluation questionnaire (JOACMEQ) for cervical spinal diseases. The association of CSI scores with PROMs was statistically evaluated. Results The average CSI score for the total subjects was 23.6 ± 13.5. The subjects with CS-related symptoms (CSI ≥ 40) were 13.2% (n = 89). The CSI score showed a significant and weak-to-moderate correlation with the PROMs including neurological symptoms that included all the domains of the JOACMEQ for cervical spinal diseases, and JOABPEQ and ODI for lumbar spinal diseases. Among these, psychological factors had the most influence on the correlation with CSI score. Conclusion Central sensitization evaluated by the CSI is related to neurological symptoms and health-related quality of life in patients undergoing elective spine surgery.

While it is known that the degenerated intervertebral disc (IVD) is one of the primary reasons for low-back pain and subsequent need for medical care, there are currently no established effective methods for direct treatment. Nuclear factor-κB (NF-κB) is a transcription factor that regulates various genes’ expression, among which are inflammatory cytokines, in many tissues including the IVD. NF-κB decoy is an oligodeoxynucleotide containing the NF-κB binding site that entraps NF-κB subunits, resulting in suppression of NF-κB activity. In the present preclinical study, NF-κB decoy was injected into degenerated IVDs using the rabbit anular-puncture model. In terms of distribution, NF-κB decoy persisted in the IVDs up to at least 4 weeks after injection. The remaining amount of NF-κB decoy indicated that it fit a double-exponential-decay equation. Investigation of puncture-caused degeneration of IVDs showed that NF-κB decoy injection recovered, dose-dependently, the reduced disc height that was associated with reparative cell cloning and morphological changes, as assessed through histology. Gene expression, by quantitative real-time polymerase chain reaction (qRT-PCR), showed that NF-κB decoy attenuated inflammatory gene expression, such as that of interleukin-1 and tumor necrosis factor-α, in rabbit degenerated IVDs. NF-κB decoy also reduced the pain response as seen using the “pain sensor” nude rat xenograft-radiculopathy model. This is the first report demonstrating that NF-κB decoy suppresses the inflammatory response in degenerated IVDs and restores IVD disc height loss. Therefore, the intradiscal injection of NF-κB decoy may have the potential as an effective therapeutic strategy for discogenic pain associated with degenerated IVDs.

Background The expression of the receptor activator of nuclear factor kappa B (RANK) /RANK ligand (RANKL) /osteoprotegerin (OPG) system and its association with the progression of intervertebral disc (IVD) degeneration has recently been reported in a human IVD. However, the effect of the RANK/RANKL/OPG system on the matrix metabolism of human IVD cells, especially on the expression of catabolic factors relevant to IVD degeneration, remains unknown. The purpose of this study was to examine the expression of the RANK/RANKL/OPG system, and then to evaluate the effect of this system on the expression of catabolic factors by human IVD cells. Methods Annulus fibrosus (AF) and nucleus pulposus (NP) cells isolated by sequential enzyme digestion from human IVD tissues obtained during spine surgeries were monolayer cultured. The expression of the RANK/RANKL/OPG system was determined using immunohistochemical methods and real-time polymerase chain reaction (PCR). To evaluate the influence of interleukin-1 beta (IL-1β) stimulation on the mRNA expression of RANK, RANKL, and OPG, recombinant human IL-1β (rhIL-1β) was administered in the culture media of IVD cells. To examine the influence of RANKL signaling on the expression of matrix metalloprotease-3 (MMP-3), MMP-13, and IL-1β, the cells were cultured with exogenous recombinant human RANKL (rhRANKL), recombinant human OPG (rhOPG) or anti-human RANKL mouse monoclonal antibody (ahRANKL-mAB) with or without rhIL-1β. Results Immunoreactivity to RANK/RANKL/OPG and the mRNA expression of the three genes were obviously identified in both AF and NP cells. rhIL-1β stimulation significantly upregulated the mRNA expression level of RANK/RANKL/OPG. The mRNA expression of catabolic factors was significantly upregulated by stimulation of rhRANKL in the presence of rhIL-1β. On the other hand, the administration of either rhOPG or ahRANKL-mAB significantly suppressed the mRNA expression of catabolic factors that had been upregulated by rhIL-1β stimulation. The suppressive effect of ahRANKL-mAB against rhIL-1β stimulation was also confirmed by the protein expression of MMP-3. Conclusions The present study showed that the RANK/RANKL/OPG system may be involved in the progression of IVD degeneration. This study also suggested the potential use of anti-RANKL monoclonal antibody and OPG as therapeutic agents to suppress the progression of IVD degeneration.

Low back pain (LBP) is now regarded as the first cause of disability worldwide and should be a priority for future research on prevention and therapy. Intervertebral disc (IVD) degeneration is an important pathogenesis of LBP. Platelet-rich plasma (PRP) is an autologous blood concentrate that contains a natural concentration of autologous growth factors and cytokines and is currently widely used in the clinical setting for tissue regeneration and repair. PRP has great potential to stimulate cell proliferation and metabolic activity of IVD cells in vitro. Several animal studies have shown that the injection of PRP into degenerated IVDs is effective in restoring structural changes (IVD height) and improving the matrix integrity of degenerated IVDs as evaluated by magnetic resonance imaging (MRI) and histology. The results of this basic research have shown the great possibility that PRP has significant biological effects for tissue repair to counteract IVD degeneration. Clinical studies for evaluating the effects of the injection of PRP into degenerated IVDs for patients with discogenic LBP have been reviewed. Although there was only one double-blind randomized controlled trial, all the studies reported that PRP was safe and effective in reducing back pain. While the clinical evidence of tissue repair of IVDs by PRP treatment is currently lacking, there is a great possibility that the application of PRP has the potential to lead to a feasible intradiscal therapy for the treatment of degenerative disc diseases. Further large-scale studies may be required to confirm the clinical evidence of PRP for the treatment of discogenic LBP.

Koji Akeda, Norihiko Takegami, Junichi Yamada, Tatsuhiko Fujiwara, Akinobu Nishimura, Akihiro Sudo Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, JapanCorrespondence: Koji AkedaDepartment of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, JapanTel +81-59-231-5022Fax +81-59-231-5211Email k_akeda@clin.medic.mie-u.ac.jpPurpose: Central sensitization (CS) is defined as the increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. CS has been proposed as an underlying mechanism of chronic pain in musculoskeletal disorders including low back pain (LBP). A Central Sensitization Inventory (CSI) has recently been developed for screening participants with CS. However, the association of CS with chronic LBP (cLBP) in the general population remains unknown. The purpose of this study was to investigate the association of CS with cLBP using the CSI in a population-based cohort of a Japanese mountain village.Participants and Methods: Participants aged more than 50 years were recruited from the inhabitants of a mountain village in Japan. Participants completed the following patient-reported outcome measures. Severity of CS was assessed by the CSI. LBP intensity was measured on a numerical rating scale (NRS). Health-related quality of life (QOL) was measured using the EuroQol 5-dimension (EQ-5D), EuroQol-visual analogue scales (EQ-VAS), and the Oswestry Disability Index (ODI). The association of CS and each parameter was statistically evaluated.Results: A total of 272 participants (average age: 72.1 years-old) were analyzed in this study, and 28.3% had cLBP. Average NRS, ODI and CSI scores were significantly higher in the cLBP group than in the without LBP (LBP−) group. There was a significant correlation between CSI and NRS scores (r=0.34, P< 0.0001), ODI (r=0.60, P< 0.0001), EQ5D (r=− 0.55, P< 0.0001) and EQ-VAS (r=− 0.52, P< 0.0001). A multiple regression analysis identified that ODI, EQ-VAS and age were factors significantly associated with CSI.Conclusion: The results of this study suggest that CS is involved in the pathological condition of cLBP in the local residents of a Japanese mountain village.Keywords: central sensitization, low back pain, Central Sensitization Inventory, general population

Background Previous clinical studies reported that thoracolumbar vertebral fractures (VFs) associated with high energy spine trauma cause adjacent intervertebral disc (IVD) degeneration; however, the effect of non-traumatic VFs on the progression of adjacent disc degeneration remains to be determined. The purpose of this study was to examine the association between non-traumatic VFs and degenerative changes of adjacent IVDs. Methods Ninety-eight consecutive patients undergoing spinal surgery were included in this study. VFs were semi-quantitatively evaluated by lateral lumbar radiography. Five hundred eighty-eight vertebral bodies (from T12 to L5) and 486 discs (from T12/L1 to L4/L5) were analyzed. The degree of IVD degeneration was evaluated by magnetic resonance imaging (MRI) and classified into two groups according to Pfirrmann’s classification. Grades I, II and III were defined as the early stage of IVD degeneration and Grades IV and V as the advanced stage. Intradiscal vacuum phenomena (VPs) were evaluated by computed tomography. Adjacent IVDs were categorized according to the locations of VFs (superior, inferior, and bilateral). Associations between the presence of VFs and the extent of IVD degeneration or the presence of VPs were statistically analyzed. Results IVDs adjacent to VFs were identified in 115 IVDs (31.1% of total; superior: 11.4%, bilateral: 8.6%, inferior: 11.1%). The presence of VFs was significantly associated with MRI grades of adjacent IVD degeneration (P P P Conclusion This study showed that VFs were an independent related factor for adjacent disc degeneration and occurrence of intradiscal VPs. VFs may affect the micro-environment of adjacent IVDs, leading to disc degeneration and disc rupture.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population., Koda et al. present the results of a randomized phase 3 trial comparing granulocyte colony-stimulating factor versus placebo in patients with acute spinal cord injury. While the primary endpoint was not met, a sub-analysis revealed a trend towards superior efficacy of G-CSF versus placebo in an elderly population.

Background With improving prognosis for recipients of liver transplantation, the necessity of medical care for musculoskeletal disorders, including spinal diseases, of these patients is also increasing. Only few reports are available on cases of spine surgery following liver transplantation. Furthermore, a case of lateral access surgery following liver transplantation has not thus far been reported. The purpose of this study is to present first two cases of patients treated with lateral access spine surgery following liver transplantation.Case presentation Case 1. A 49-year-old female had received living donor liver transplantation (LT) for acute-on-chronic liver failure (ACLF) ten years prior to spine surgery. The patient underwent two levels of lateral lumbar interbody fusion (LLIF) followed by posterior lumbar interbody fusion (PLIF) for degenerative lumbar disease. Although neurological symptoms in the lower extremity improved, a liver disorder resulting from acetaminophen-induced hepatotoxicity occurred at an early stage following spine surgery.Case 2. A 66-year-old female had received living donor liver transplantation for hepatocellular carcinoma (HCC) six years prior to spine surgery. She underwent posterior instrumentation surgery followed by T12 corpectomy using a wide-foot print expandable cage for T12 vertebral collapse. Following surgery, her weakened muscle strength in the lower extremities were significantly improved. Conclusions Lateral access spine surgery for lumbar and thoracolumbar lesions can be successfully performed for patients following liver transplantation. However, careful follow-up should be performed for complications related to the function of the liver graft following spine surgery.Conclusions Lateral access spine surgery for lumbar and thoracolumbar lesions can be successfully performed for patients following liver transplantation. However, careful follow-up should be performed for complications related to the function of the liver graft following spine surgery.

Two-dimensional (2D) analyses of intervertebral disc (IVD) height and foramen measurements following lateral lumbar interbody fusion (LLIF) have been reported. However, three-dimensional (3D) morphometric analysis of intervertebral structure using 3D computed tomography (3D CT) provides increased precision for measuring morphological changes. The purpose of this study was to evaluate 3D changes of lumbar IVD height and foramen diameter in degenerative lumbar disease patients following LLIF. Subject-based 3D CT lumbar models were created for 26 patients before and following LLIF. IVD height (whole and five anatomical zones) and foramen diameter (minimum and maximum) were measured based on the model using custom software. The sagittal placement of cages (SPC) and cross-sectional area of the thecal sac (CSA) were measured. Changes in these parameters by LLIF were quantified and statistically analysed. Following LLIF, disc height increased by an average of 2.9 mm (P

Study design Biochemical and immunohistochemical analyses by the human intervertebral disc (IVD) cells and tissues. Objective To examine the expression of glial cell line-derived neurotrophic factor (GDNF) and its receptors, GDNF family receptor (GFR) α1 and rearranged during transfection (RET) in the human IVD cells and the tissues with the early and advanced stages of degeneration. Summary of background data The neurotrophin family, including nerve growth factor, has been reported to be expressed in the IVDs and plays a role in hyperalgesia and neuronal sensitization. Despite having properties similar to the nerve growth factor, the expression of GDNF in the IVD remains unknown. Methods Human IVD cells were cultured in monolayer. Immunohistochemical analyses and western blotting were performed to examine the protein levels of GDNF and its receptors. To examine the effect of proinflammatory cytokines, cells were cultured in the presence of interleukin-1β (IL-1β). The immunohistochemical expression of these proteins was also evaluated using human IVD tissues with different stages of degeneration. Results Immunofluorescent reactivity against anti-GDNF, GFRα1, and RET antibodies was identified in human IVD cells. In protein extracts from IVD cells, those protein expressions were also identified by Western blot. IL-1β significantly stimulated the mRNA expression of GDNF compared with that of the control group. There was no significant effect of IL-1β on the mRNA expression of GFRα1 and RET. The percentage of GDNF-immunopositive cells in advanced degenerated discs was significantly higher than that in early degenerated discs, whereas those of GFRα1 and RET showed no significant differences. Conclusions GDNF and its receptors were constitutively expressed in the human IVD cells. GDNF expression was significantly enhanced by proinflammatory stimuli, and in the microenvironment with advanced tissue degeneration. Level of evidence N/A.

Background The progression of intervertebral disc (IVD) degeneration leads to rupture within IVD tissues. The location and appearance of areas of gaseous radiolucency in the IVD, known as vacuum phenomena (VPs), are considered to indirectly indicate the position and extent of IVD rupture. The clinical significance of VPs in degenerated IVDs is not fully understood. The purpose of this study is to assess and classify the morphology of IVD ruptures by the presence of intradiscal VPs, and to examine the association between morphological VP-positive IVD ruptures and degenerative lumbar diseases. Methods IVD rupture was evaluated by the presence of VPs using computed tomography (CT) imaging. VP shape (spot, linear, island) was classified using sagittal imaging, and VP distribution (A-N: anterior AF-NP; N: NP only; N-P: NP-posterior AF; A-N-P: anterior and posterior AF-NP) was classified using axial imaging. The disc height index (DHI) was calculated from lateral radiographs. Disc degeneration and lumbar spinal stenosis were evaluated by MRI grade. Results In the VP shape analysis, the island type was the most common, followed by linear and spot types. In the VP distribution analysis, A-N was the most common group, followed by N, N-P and A-N-P. Intra- and inter-observer reliabilities were statistically sufficient to classify different rupture shapes and distributions. The DHI tended to be lower in discs that contained VPs, especially in the anterior AF area. The shape and distribution of intradiscal VPs were significantly associated with the degree of disc degeneration and lumbar spinal stenosis graded by MRI. Discs with VPs extending from the NP into the anterior and/or posterior AF had a significantly higher proportion of advanced disc degeneration (Pfirrmann’s classification: grades IV and V). Conclusions This is the first study to analyze the morphology of IVD rupture evaluated by the presence of intradiscal VPs using CT imaging. This classification can comprehensively present the shape and axial distribution of VPs within IVDs. Intradiscal VPs are associated with the progression of disc degeneration and lumbar spinal stenosis.

Locomotive syndrome (LS) encompasses conditions that may lead to the need for nursing services. We aimed to quantify the association between exercise habits during youth or the middle-age years and both physical function and the presence of LS in Japanese elderly people.We examined 460 participants of the eighth, ninth, and tenth iterations of the Miyagawa study. Participants were divided into an LS group and a no-LS group according to their scores on the 25-question Geriatric Locomotive Function Scale. The following physical function tests were performed: grip strength, 6-m walk at normal and maximum speed, single-leg stance time with eyes open, and chair stand time. The frequency of past physical activity was determined by interview.Ninety-seven participants (21.1%) were classified as having LS. The LS group had worse physical function than the no-LS group. Exercise habits between the ages of 25 and 50 years were significantly related to later LS.Participants with LS were less likely to report a regular exercise habit between the ages of 25 and 50 years than participants without LS. Participants who reported regular exercise habits in middle age had better physical function during old age. Regular exercise habits in middle age appear to protect against LS during the older years.

Study DesignPreliminary clinical trial.PurposeTo determine the safety and initial efficacy of intradiscal injection of autologous platelet-rich plasma (PRP) releasate in patients with discogenic low back pain.Overview of LiteraturePRP, which is comprised of autologous growth factors and cytokines, has been widely used in the clinical setting for tissue regeneration and repair. PRP has been shown in vitro and in vivo to potentially stimulate intervertebral disc matrix metabolism.MethodsInclusion criteria for this study included chronic low back pain without leg pain for more than 3 months; one or more lumbar discs (L3/L4 to L5/S1) with evidence of degeneration, as indicated via magnetic resonance imaging (MRI); and at least one symptomatic disc, confirmed using standardized provocative discography. PRP releasate, isolated from clotted PRP, was injected into the center of the nucleus pulposus. Outcome measures included the use of a visual analog scale (VAS) and the Roland-Morris Disability Questionnaire (RDQ), as well as X-ray and MRI (T2-quantification).ResultsData were analyzed from 14 patients (8 men and 6 women; mean age, 33.8 years). The average follow-up period was 10 months. Following treatment, no patient experienced adverse events or significant narrowing of disc height. The mean pain scores before treatment (VAS, 7.5±1.3; RDQ, 12.6±4.1) were significantly decreased at one month, and this was generally sustained throughout the observation period (6 months after treatment: VAS, 3.2±2.4, RDQ; 3.6±4.5 and 12 months: VAS, 2.9±2.8; RDQ, 2.8±3.9; pConclusionsWe demonstrated that intradiscal injection of autologous PRP releasate in patients with low back pain was safe, with no adverse events observed during follow-up. Future randomized controlled clinical studies should be performed to systematically evaluate the effects of this therapy.

Background Impaired lumbar artery flow has been reported in clinical and epidemiological studies to be associated with low back pain and lumbar disc degeneration. However, it has not been experimentally demonstrated that impaired lumbar artery flow directly induces intervertebral disc (IVD) degeneration by affecting IVD matrix metabolism. The purpose of this study was to evaluate whether ligation of the lumbar artery can affect degenerative changes in the rabbit IVD. Methods New Zealand White rabbits (n = 20) were used in this study. Under general anesthesia, the third and fourth lumbar arteries were double-ligated using vascular clips. The blood flow to the L3/L4 disc (cranial disc) was reduced by ligation of the third lumbar artery and that of the L5/L6 disc (caudal disc) by ligation of the fourth lumbar artery. The blood flow to the L4/L5 disc (bilateral disc) was decreased by ligation of both the third and fourth lumbar arteries. The L2/L3 disc was used as the control. Disc height was radiographically monitored biweekly until 12 weeks after surgery. The rabbits were sacrificed at 4, 8, and 12 weeks after surgery and magnetic resonance imaging (MRI) T2-mapping, histology and immunohistochemistry were assessed. Results Lumbar artery ligation did not induce significant changes in disc height between control and ischemic discs (cranial, bilateral and caudal discs) during the 12-week experimental period. T2-values of ischemic discs had no significant trend to be lower than those of the control L2/L3 discs. Histologically, Safranin-O staining changed following ligation of corresponding IVD lumbar arteries. Histological grading scores for disc degeneration, which correlated significantly with MRI T2-values, had significant changes after the surgery. Immunohistochemical analysis showed that the ligation of lumbar arteries significantly affected a change in the percentage of HIF-1α immunoreactive cells of ischemia discs compared to that of control discs four weeks after the surgery (p

The patient was a 13-year-old boy who complained of pain in both buttocks. Plain and reconstructive computed tomography (CT) images showed an ossified lesion within the dura mater at the L5–S2 levels, and arachnoiditis ossificans in the lumbosacral area was suspected. In the operative findings obtained after cutting the dura, a bone fragment 4.5 × 0.5 × 0.5 cm in size was observed in the center of the strongly adhesive nerve bundle of the cauda equina, which was removed en bloc. The postoperative clinical course of the patient was excellent. The case, along with a review of literature is presented.

Introduction: It is well-known that many patients will have adverse reactions such as headache and nausea after undergoing myelography, but we have often seen cases where symptoms such as lower back pain and leg pain were alleviated following myelography. To the best of our knowledge, such clinical cases of post-myelographic alleviation have not been reported. Materials and Methods: A total of 325 patients with a degenerative lumbar spinal disorder who underwent myelography were prospectively investigated at four hospitals from April 2012 to March 2014 to survey the post-myelographic alleviation of lower back and leg pain prospectively. The severities of lower back pain, leg pain and numbness of the lower extremities were evaluated and intermittent claudication distance was measured before myelography. The magnetic resonance imaging (MRI) findings and myelographic findings were also evaluated for the patients that their symptoms were improved. Results: Thirty-five of 325 cases (10.8%) of these patients had their symptoms alleviated after undergoing myelography; 26 cases of lower back pain, two cases of leg pain, two cases of numbness of the lower extremity, and five cases of intermittent claudication. Conclusion: In the patients of a degenerative lumbar spinal disorder, about 10% cases with lower back pain or intermittent claudication had post-myelographic alleviation. Intradural injection therapy might be a therapeutic method to alleviate these symptoms.

Background Nuclear factor-kappaB (NF-κB) is considered to play an important role in the response to ischemia/reperfusion (I/R) injury in flap surgery. To inhibit NF-κB, synthetic double-stranded oligodeoxynucleotide (ODN) was used as a decoy. The present study aimed to evaluate the suppressive effects of NF-κB against I/R injury of experimental rat flap model. Methods An extended epigastric island flap was raised and ischemia was induced for 3 h. NF-κB decoy ODN (group D) or single-strand ODN (control; group S) was injected via the contralateral artery when the pedicle was clamped. Transfection efficiency was evaluated with fluorescein isothiocyanate (FITC)-labeled ODN. The effects of NF-κB decoy ODN were analyzed in groups D and S, and an untreated group (group N). Results FITC-labeled ODN was distributed over the entire flap. Mean survival rate of the flap was significantly higher in group D than in the other groups (group D: 57.9%; group S: 31.1%; group N 31.7%; p

Purpose: To determine the expression and distribution of bone morphogenetic protein (BMP)-7 and related molecules during peripheral nerve regeneration and to assess whether administration of parathyroid hormone (PTH) drug (1-34) potentiates the intrinsic upregulation of BMP-7/Smad signaling. Methods: The rat sciatic nerves were crushed with an aneurysm clip resulting in axonal degeneration. In the normal nerve, and at 1, 2, 4, and 8 weeks after injury, BMP-7, BMP receptors, p-Smad 1/5/8, and Noggin, the endogenous BMP antagonist, were evaluated. Additionally, the distribution of BMP-7 was assessed by fluorescent double immunostaining. In vitro studies were also performed to examine the effect of BMP-7 and PTH (1-34) administration on rat Schwann cells (SCs). Results: Aneurysm clip made reliable animal model of the nerve injury with recovery at 8 weeks after the injury. BMP-7/Smad protein and mRNA were significantly upregulated on axon-SCs units at 1 week after injury, and this upregulated expression was maintained for 4 weeks. Besides, significant upregulation of Noggin’s expression was observed on axon-SCs units at 2 weeks after injury. Moreover, fluorescent double immunostaining showed co-localization between expression of BMP-7 and p75NTR during axonal regeneration. In the in vitro study, administration of BMP-7 induced significant proliferation of SCs. Application of PTH (1-34) upregulated BMP-7 on SCs. Discussion/conclusion: BMPs were reported to be involved in protection and recovery after injury as well as in neurogenesis. Our current study showed that BMP/Smad signaling molecules were upregulated on dedifferentiated SCs after peripheral nerve injury and that administration of BMP-7 increased SC viability in vitro. These results suggested that axonal regeneration could be induced via upregulation of endogenous BMP-7 on SCs by PTH (1-34) administration.

Introduction Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. Methods and analysis The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m 2 /day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). Ethics and dissemination The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. Trial registration number UMIN000018752.

Background: Obesity is likewise becoming more prevalent in patients with lumbar spinal canal stenosis, but few studies have examined relationships between obesity levels and surgical outcomes for this condition. The purpose of the present study is to determine the influence of body-mass index (BMI) on outcomes of surgery for lumbar spinal canal stenosis. Materials and Methods: The subjects comprised 118 patients who had underwent posterolateral fusion in a single intervertebral disc space with spinal instrumentation using a pedicle screw and rod system. Obesity levels were classified into three groups according to BMI:  35, severely obese group (n=12); 25 to

Bone morphogenic proteins (BMPs) may have neurotrophic functions but there is limited evidence of these functions in the peripheral nervous system. We therefore investigated the expression of BMPs and BMP receptors (BMPRs) in normal and injured peripheral nerves. In 10 of 15 Sprague-Dawley rats, a 3-mm segment of sciatic nerve was resected at the trifurcation in the thigh. One day (n = 5) and 7 days (n = 5) after transection, proximal and distal stumps were removed and immunohistochemically analyzed for BMP-2, -7, BMPR-1A, -1B, and -2. The other five animals served as normal controls. In normal nerves, BMP-2 expression was localized at Ranvier’s node, and BMP-7 and BMPR-1B were expressed in several axon-Schwann cell units, whereas other receptors were not expressed. After nerve transection, BMP-7 expression was upregulated at both proximal and distal stumps along with Schwann cell columns during Wallerian degeneration. BMPRs were also upregulated compared with the normal nerve. The upregulation in BMP expression after nerve transection suggests that BMPs may play a role in the healing response of the peripheral nerve.

Study design A case of lumbar metastasis of a choriocarcinoma is presented. Objective To present and review a rare case of metastatic choriocarcinoma in the lumbar spine. Summary of background data Choriocarcinoma is a highly anaplastic malignancy derived from trophoblastic cells characterized by the secretion of human chorionic gonadotropin (hCG) and early hematogenous metastasis. However, metastatic choriocarcinoma in the spine is extremely rare. Although 2 cases of metastasis in lumbar and/or sacral vertebra have been reported, the efficacy of surgical treatment for the spinal metastasis of choriocarcinoma is not yet known. Methods The clinical course, radiologic features, pathology, and outcome of the treatment of metastatic choriocarcinoma of the lumbar spine is reported. Results A 38-year-old female patient with abnormal uterine bleeding 6 weeks after a normal-term delivery showed high serum levels of hCG. A whole body image analysis revealed a lesion in the L2 vertebra. After computed tomography-guided needle biopsy, a clinical and pathologic diagnosis of lumbar metastasis of choriocarcinoma was made. Surgical resection of the localized L2 vertebra lesion was performed by total en bloc spondylectomy after a poor response to initial chemotherapy with methotrexate. Postsurgically, the serum level of hCG explosively increased and local recurrences around the original L2 vertebra and epidural metastasis abruptly developed. Lung metastases also occurred concurrently and progressed and the patient eventually died to the disease. Conclusion We have reported a rare case of lumbar metastasis of choriocarcinoma after a normal-term pregnancy. This is the first report of lumbar metastasis of choriocarcinoma treated by spinal surgery. Because surgical resection of a lumbar metastasis of choriocarcinoma involves a substantial risk of profuse hemorrhage, local recurrence and the spread of metastasis, multiagent chemotherapy in combination with radiotherapy should be preformed before surgical resection.

Study design In vitro studies of the effects of proinflammatory cytokines on the production of nerve growth factor (NGF) by human intervertebral disc (IVD) cells. Objective To determine the constitutive expression and production of NGF and the effect of cytokines on the expression of NGF by human IVD cells. Summary of the background data NGF may play a role in the collateral sprouting of sensory axons, neural survival, and regulation of nociceptive sensory neurons. NGF is known to be up-regulated by proinflammatory cytokines. Methods The presence of NGF protein was analyzed by immunohistochemistry using human IVD cells obtained from cadaveric human spines with no known disc disease (MRI Thompson grades 2-4). The effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) on NGF production and mRNA expression of NGF by IVD cells were examined. The expression of NGF receptors, trkA and p75, was also assessed immunohistochemically. Results Cadaveric anulus fibrosus (AF) and nucleus pulposus (NP) cells cultured in vitro in monolayer and in alginate beads positively stained with an anti-NGF antibody. The constitutive production of NGF protein in IVD cells was low (NP) or not detectable (AF). The expression of NGF mRNA was detectable in both cell types. IL-1beta and TNF-alpha up-regulated the NGF mRNA expression and the secretion of NGF protein into the media. TrkA was immunolocalized in AF and NP cells. Conclusion Our results demonstrate, for the first time, that human AF and NP cells constitutively express NGF protein and mRNA, and that the proinflammatory cytokines IL-1beta and TNF-alpha stimulate the production of NGF. The precise role of NGF produced by IVD cells in the generation of discogenic pain or on the metabolism of IVD cells, especially under certain physiologic conditions in which cytokines are up-regulated, needs to be clarified in future experimentation.

Study design A case of recurrent giant cell reparative granuloma (GCRG) of the lumbar spine successfully treated with denosumab is reported; a fully human monoclonal antibody against the receptor activator of nuclear factor kappa B (RANK) ligand (RANKL). Objective To report the first case of recurrent GCRG of the lumbar spine treated with denosumab. Summary of background data GCRG is a non-neoplastic osteofibrous lesion usually found in the maxilla and mandible but rarely in the spine. It is clinically distinct from giant cell tumor of bone (GCTB), although common histological characteristics such as the proliferation of spindle-shaped stromal cells and multinucleated giant cells are shared. Denosumab has recently been reported to be effective for unresectable GCTB; however, there is only one report of its effect on GCRG. Moreover, the effect of denosumab on GCRG of the spine is unknown. Methods The clinical course, radiological features, pathology, and treatment outcome of a patient with recurrent GCRG of the lumbar spine treated with denosumab are documented. Results Denosumab treatment was used for this patient with unresectable recurrent GCRG of the lumbar spine. Follow-up lumbar radiography showed significant bone formations in the tumor lesion after 3 months of treatment. On follow-up computerized tomography scans of the L2 and L3 vertebral lesions, the replacement of osoteolytic lesions by the formation of cortical-like bone tissue was clearly identified. Conclusion We report the first case of recurrent GCRG of the spine successfully treated with denosumab. Treatment with denosumab induced significant bone formation in the unresectable lumbar lesion with stable clinical improvement during the 12-month follow-up period without apparent complications. Denosumab shows promise as a new alternative treatment option for osteoclastic giant cell-rich tumors, such as GCRG, especially for unresectable lesions of the spine. Level of evidence 4.

STUDY DESIGN In vivo histologic study of nerve ingrowth in the rabbit anular-puncture disc degeneration model. OBJECTIVE To examine innervation of intervertebral discs and surrounding tissues in the rabbit anular-puncture model with various magnitudes of injury. SUMMARY OF BACKGROUND DATA A rabbit anular-puncture model of disc degeneration was recently established. However, to our knowledge, the neuropathologic changes in the degenerated disc and surrounding tissues in this model have not been examined. METHODS Anular punctures with an 18-gauge needle at depths of 1 and 5 mm were randomly performed at the L2-L3 or L4-L5 discs in New Zealand white rabbits (n = 16; 3.0-3.5 kg). The degree of disc degeneration was followed radiographically, and was further evaluated by magnetic resonance imaging and histology at sacrifice 4 or 12 weeks after the puncture. To identify nerve ingrowth into the discs, the L2-L3 to L4-L5 discs were immunostained with an antibody against protein gene product 9.5, a general marker for nerve fibers. RESULTS Significant decreases in disc height and signal intensity in magnetic resonance imaging were observed only in the 5 mm punctured discs (P < 0.05). In all the discs, including nonpunctured control discs, protein gene product 9.5-immunoreactive fibers were only occasionally observed in the outermost part of the anulus fibrosus. In the 5 mm punctured discs, nucleus pulposus tissues were extruded, and scar tissues formed outside the discs. No nerve ingrowth into the needle track lesion at the anular puncture site was observed. However, protein gene product 9.5-immunoreactive fibers were observed in scar tissues on the surface of the puncture site. This finding was more evident in the 5 mm than in the 1 mm punctured discs (P < 0.05). CONCLUSIONS This study indicates that in the rabbit anular-puncture disc degeneration model, disc degeneration associated with a higher nerve growth into the scar tissue was more evident when induced by a 5 mm than a 1 mm puncture. Although nerve ingrowth was observed in the extruded disc tissue, nerve ingrowth into the outer anulus, which has been reported in patients with discogenic pain, was not observed during the short observation period in this disc degeneration model. The limitation in assessing pain by behavior analysis or histologic evaluation of nerve ingrowth should be considered. Further studies to identify a surrogate marker of pain should be encouraged.

Background Considerable controversy exists concerning the mechanism of axonal regeneration in end-to-side neurorrhaphy. The authors studied the mode of axonal regeneration in end-to-side neurorrhaphy without a perineurial window using a rat sciatic nerve model. Methods Twenty-seven rats were used. A 10-mm segment of peroneal nerve was harvested and coapted to the ipsilateral tibial nerve in end-to-side fashion using a T-shaped silicone chamber to minimize the tibial nerve damaged by surgery. To explain the role of nerve damage on axonal regeneration in end-to-side neurorrhaphy, we also used an isogenic nerve transplantation model in which the peroneal nerve remained intact. The mode of axonal regeneration was studied with electron microscopy, morphometric analysis, immunofluorescence, and immunohistochemistry. Results Both morphometric analysis and immunolabeling of neurofilaments demonstrated that regenerating axons emerge at sites far proximal to the coaptation site, travel within the tibial nerve, traverse the perineurium circumferentially around the coaptation site, and then invade into the peroneal nerve. Electron microscopy and a double-labeled immunofluorescence study with antibodies against neurofilament and tenascin-C confirmed large-scale axonal penetration into the perineurium around the coaptation site. Immunofluorescence with antibody against NG2, a marker of axonal regeneration, prevented the possibility of collateral sprouting at the coaptation site. In addition, an end-to-side neurorrhaphy model with an isogenic peroneal nerve clearly demonstrated that nerve damage is a prerequisite for axonal regeneration through end-to-side neurorrhaphy. Conclusions The authors could not locate the site of axonal sprouting in end-to-side neurorrhaphy without a perineurial window; however, this study cast doubts on current hypothesis on the mode of axonal regeneration in end-to-side neurorrhaphy.

STUDY DESIGN In vitro study on the effects of pulsed low intensity ultrasound on the cellular metabolism of bovine intervertebral disc cells. OBJECTIVE To determine whether pulsed low intensity ultrasound has effects on cell proliferation and extracellular matrix metabolism by bovine intervertebral disc cells. SUMMARY OF BACKGROUND DATA The application of pulsed low intensity ultrasound is known to be effective in stimulating fracture and cartilage repair. However, the effects of pulsed low intensity ultrasound on intervertebral disc cells are not known. METHODS Cells of the nucleus pulposus and inner and outer anulus fibrosus were enzymatically isolated from bovine coccygeal tissue and precultured in alginate beads for 14 days. In the ultrasound group, pulsed low intensity ultrasound was administered to the culture for 20 minutes daily for an additional 20 days. The control group was cultured in the same way but without administration of ultrasound. Cell viability, DNA content, proteoglycan and collagen synthesis, and proteoglycan content at days 10 and 20 after the initiation of treatment were evaluated. Characterization of newly synthesized collagen and proteoglycan was performed. RESULTS No significant differences in cell viability and DNA content were observed between the two groups. On day 20, proteoglycan synthesis was increased by the application of pulsed low intensity ultrasound in nucleus pulposus and inner and outer anulus fibrosus cells (24%-26% increase, P < 0.001). The application of pulsed low intensity ultrasound increased proteoglycan content in alginate beads containing inner and outer anulus fibrosus cells (P < 0.05). Collagen synthesis by cells isolated from all three zones of the intervertebral disc was increased by the application of pulsed low intensity ultrasound (16%-19% increase, P < 0.05-0.0001). CONCLUSIONS The application of pulsed low intensity ultrasound stimulated extracellular matrix metabolism in intervertebral disc cells. Pulsed low intensity ultrasound may prove useful for the physical stimulation of cell metabolism for tissue engineering of intervertebral disc tissue.

We investigated the feasibility of using Schwann cell transplantation to enhance reinnervation after direct nerve-to-muscle neurotization (NMN). The denervated anterior tibial muscle was neurotized by tibial nerve implantation, and Schwann cell suspension (transplantation group) or an equivalent volume of culture medium (control group) was injected at the implantation site. In the control group, few axons invaded the muscle, demonstrating that skeletal muscle was poorly permissive to the advancement of axons. In the transplantation group, a large number of regenerating axons grew for a longer distance throughout the muscle, and reinnervated motor endplates were significantly more abundant. Enhanced reinnervation and functional recovery of the muscle in the transplantation group was confirmed by a significant increase in the compound muscle action potential and in muscle weight. These results suggest that intramuscular Schwann cell transplantation has potential as a cell therapy to improve functional recovery after NMN.

Study design A prospective study of 209 patients undergoing spinal surgery. Objective To determine the incidence of venous thromboembolic diseases, including deep venous thrombosis (DVT) and pulmonary embolism (PE), and to evaluate the effectiveness of an institutional protocol for venous thromboembolic diseases during the spinal surgery perioperative period. Summary of background data Although patients undergoing spinal surgery are at risk of venous thromboembolism (VTE), there are no universally accepted guidelines for VTE prophylaxis. Methods Between December 2006 and January 2011, 209 patients undergoing spinal surgery (121 males, 88 females; average age: 64 yr), who also had ultrasonographic assessments of both legs before and after surgery, were prospectively assessed. A pneumatic sequential compression device and standard compression stockings were used for primary VTE prophylaxis. In Mie University Hospital protocol, pharmacological agents were not used for VTE prophylaxis after surgery. However, when a distal type DVT was found preoperatively, an anticoagulant medication was administered until 6 hours prior to surgery. After detection of DVTs, weekly ultrasonography assessed the DVT. Results Twenty-three patients (11.0%) showed VTE in the spinal surgery perioperative period. Nine patients (4.3%) had VTE (PE with proximal DVT, 1 [0.5%]; distal DVT, 8 [3.8%]) before surgery. In the one case of asymptomatic PE with proximal DVT, an inferior vena cava filter was placed before surgery. Fourteen patients (6.7%) developed new-onset VTE (PE with proximal DVT, 2 [1.0%]; distal DVT, 12 [5.9%]) after spinal surgery. New-onset PE with proximal DVT occurred in 2 patients after surgery. Follow-up ultrasonographic assessment showed that the DVT disappeared completely in 85% (17/20) of patients with a distal type DVT during the perioperative period. Conclusion DVT assessment using ultrasonography is important for proper management of VTE during the perioperative period of spinal surgery, especially for high-risk patients, such as those with advanced age or neurological deficit. The institutional protocol for VTE using pneumatic sequential compression device and compression stockings is effective, although the administration of chemoprophylaxis should be considered for high-risk patients, such as those with spinal tumors and spinal trauma.

We presented a very rare case of adult Fielding type I atlantoaxial rotatory fixation (AARF). We performed awake manual reduction of the dislocation without need for anesthesia, achieving excellent outcomes, and no previous reports have described awake reduction without the need for anesthesia. AARF in this case was attributed to excessive extension and rotation forces applied to the cervical spine. For the management of adult Fielding type I AARF, early diagnosis and early reduction may lead to excellent outcomes.

The present study aims to determine the relationship between osteoporosis (OP), vertebral fracture (VF) and mortality.We followed up 1024 residents of Miyagawa village every 2 years for a mean of 8.4 years between 1997 and 2009. The residents were assessed every 2 years. We defined OP as T scores for bone mineral density that were2.5 standard deviations below peak bone mass. VF was assessed by lateral radiography of the thoracic and lumbar spine. The participants were allocated as follows depending on the presence or absence of OP and VF: with OP and without VF (OP group), with VF and without OP (VF group), with OP and VF (OP + VF group) and without OP and VF (Control group). We determined survival/mortality rates until 2011 by reviewing medical histories and death certificates.By 2011, 304 participants had died. The respective 5-year survival rates for the OP + VF, OP, VF and Control groups were 80.6%, 93.7%, 87.8% and 94.2%. Mortality rates were significantly worse for the OP + VF group than the Control group (OP + VF Hazard Ratio: 1.89; 95% CI, 1.27-2.77).Prevention of osteoporotic VF in elderly persons is very important from the viewpoint of increasing life expectancy.

There has been only one report on the physical characteristics of patients with developmental cervical spinal canal stenosis. The objective of this consecutive clinical study was to identify the physical characteristics of patients with developmental cervical spinal canal stenosis. The subjects were 243 patients with cervical spine disease who received treatment in our department between April 2001 and March 2002. These patients were divided into two groups (the groups of patients with and without spinal canal stenosis) on the basis of their lateral cervical spine radiographs. The six items examined were height, weight, sitting height, inter inner canthal distance, upper arm length, and head circumference in each patient, and then their values were compared between the two groups. The mean inter inner canthal distance was 2.7 cm in the group of patients with spinal canal stenosis and 3.5 cm in the group of patients without spinal canal stenosis; a significant difference (P

Background Studies have shown that ischemia-reperfusion (I/R) produces free radicals leading to lipid peroxidation and damage to skeletal muscle. The purposes of this study were 1) to assess the histological findings of gastrocnemius muscle (GC) and tibialis anterior muscle (TA) in I/R injury model mice, 2) to histologically analyze whether a single pretreatment of edaravone inhibits I/R injury to skeletal muscle in murine models and 3) to evaluate the effect of oxidative stress on these muscles. Methods C57BL6 mice were divided in two groups, with one group receiving 3 mg/kg intraperitoneal injections of edaravone (I/R + Ed group) and the other group receiving an identical amount of saline (I/R group) 30 minutes before ischemia. Edaravone (3-methy-1-pheny1-2-pyrazolin-5-one) is a potent and novel synthetic scavenger of free radicals. This drug inhibits both nonenzymatic lipid peroxidation and the lipoxygenase pathway, in addition to having potent antioxidant effects against ischemia reperfusion. The duration of the ischemia was 1.5 hours, with reperfusion at either 24 or 72 hours (3 days). Specimens of gastrocnemius (GC) and anterior tibialis (TA) were removed for histological evaluation and biochemical analysis. Results This model of I/R injury was highly reproducible in histologic muscle damage. In the histologic damage score, the mean muscle fibers and inflammatory cell infiltration in the I/R + Ed group were significantly less than the corresponding values of observed in the I/R group. Thus, pretreatment with edaravone was observed to have a protective effect on muscle damage after a period of I/R in mice. In addition, the mean muscle injury score in the I/R + Ed group was also significantly less than the I/R group. In the I/R + Ed group, the mean malondialdehyde (MDA) level was lower than in the I/R group and western-blotting revealed that edaravone pretreatment decreased the level of inducible nitric oxide synthase (iNOS) expression. Conclusions Edaravone was found to have a protective effect against I/R injury by directly inhibiting lipid peroxidation of the myocyte by free radicals in skeletal muscles and may also reduce the secondary edema and inflammatory infiltration incidence of oxidative stress on tissue.

STUDY DESIGN Immunohistochemical and biochemical analyses of the rat intervertebral disc (IVD) tissue renin-angiotensin system (tRAS). OBJECTIVE To examine the expression and function of tRAS in the rat IVD. SUMMARY OF BACKGROUND DATA Angiotensin II (Ang II), the major effector of tRAS, is a hormone that contributes to inflammation and fibrosis in many organs. The expression of tRAS in the rat IVD has not been determined. METHODS tRAS expression in rat and bovine IVDs was examined using real-time polymerase chain reaction (rat) and immunohistochemistry (rat and bovine). Rat annulus fibrosus cells in monolayer culture were used to examine the biological role of tRAS in vitro. The effect of Ang II peptide on extracellular matrix metabolism was assessed by real-time polymerase chain reaction. RESULTS mRNA of tRAS components, including angiotensin converting enzyme, Ang II, Ang II receptor type 1, Ang II receptor type 2, and Cathepsin D (a renin-like enzyme), was clearly confirmed by real-time polymerase chain reaction analysis. In rat and bovine annulus fibrosus and nucleus pulposus cells in monolayer culture, immunohistochemical analysis showed that each tRAS component was clearly expressed. In rat IVD tissues, immunoreactivity to each antibody for tRAS components was also observed. Proliferation of rat annulus fibrosus cells was mildly stimulated by Ang II peptide. Ang II peptide also had minor stimulatory effect on the expression of the extracellular matrix components, growth factors, and catabolic proteins. CONCLUSION Our results demonstrate for the first time that the tRAS components necessary to activate tRAS have been found in the normal rat IVD at both mRNA and protein levels. To elucidate the association between tRAS and the process of IVD degeneration, the expression and function of tRAS in the human degenerated IVD should be examined in a future study.

Introduction Platelet-rich plasma (PRP) is a fraction of plasma in which several growth factors are concentrated at high levels. The active soluble releasate isolated following platelet activation of PRP (PRP-releasate) has been demonstrated to stimulate the metabolism of IVD cells in vitro. The in vivo effect of PRP-releasate on degenerated IVD remains unknown. The purpose of this study was to determine the reparative effects of autologous PRP-releasate on degenerated intervertebral discs (IVDs). Methods To induce disc degeneration, New Zealand white rabbits (n = 12) received anular puncture in two noncontiguous discs. Autologous PRP and PPP (platelet-poor plasma) were isolated from fresh blood using two centrifugation techniques. Four weeks after the initial puncture, releasate isolated from clotted PPP or PRP (PPP- or PRP-releasate), or phosphate-buffered saline (PBS; control) was injected into the punctured discs. Disc height, magnetic resonance imaging (MRI) T2-mapping and histology were assessed. Results Anular puncture produced a consistent disc narrowing within four weeks. PRP-releasate induced a statistically significant restoration of disc height (PRP vs. PPP and PBS, P

We describe four cases of delayed union in female patients with severe osteoporotic vertebral fractures, which were treated in a similar but less costly method to kyphoplasty. Due to domestic regulations, inflatable tamps for kyphoplasty are not available to every clinical orthopedists in Japan. In our clinical experience of four cases of delayed lumbar spine union between 2009 and 2010, we performed vertebroplasty using a reduction and spreading prod (Oyamada prod) for fracture reduction and a pediatric uromatic balloon (Medicon Co. Ltd.) to enlarge the pre-existing cavity. Our clinical results were comparable to those of kyphoplasty procedures performed in the USA. Our procedure could be used to overcome the shortage of medical supplies in developing countries or in countries such as Japan, which often prioritize financial concerns over providing optimal health care. Our method could serve as a useful com promise for moribund patients considering its cost efficiency.

Symptomatic Tarlov (perineural cysts) are uncommon. In the following hemodialysis case, cauda equina syndrome was not detected after combined spinal-epidural anesthesia untilthe patient reported a lack of sensation in the perianal area 14 days postoperatively. She had normal motor function of her extremities. A laminectomy and cyst irrigation was performed. After the operation, her sphincter disturbance subsided gradually and her symptoms had disappeared.

Osteosarcoma (OS) is the most common primary malignant tumor of the bone and often forms pulmonary metastases, which are the most important prognostic factor. For further elucidation of the mechanism underlying the progression and metastasis of human OS, a culture system mimicking the microenvironment of the tumor in vivo is needed. We report a novel three-dimensional (3D) alginate spheroid culture system of murine osteosarcoma. Two different metastatic clones, the parental Dunn and its derivative line LM8, which has a higher metastatic potential to the lungs, were encapsulated in alginate beads to develop the 3D culture system. The beads containing murine OS cells were also transplanted into mice to determine their metastatic potential in vivo. In this culture system, murine OS cells encapsulated in alginate beads were able to grow in a 3D structure with cells detaching from the alginate environment. The number of detaching cells was higher in the LM8 cell line than the Dunn cell line. In the in vivo alginate bead transplantation model, the rate of pulmonary metastasis was higher with LM8 cells compared with that of Dunn cells. The cell characteristics and kinetics in this culture system closely reflect the original malignant potential of the cells in vivo.

Lumbar fusion combined with unilateral pedicle screw fixation has received favourable clinical reports. However, there are very few reports about the biomechanical properties of this system. The purpose of this study was to compare the biomechanics of a unilateral pedicle screw system with a bilateral system. Two fresh lumbar vertebral columns from human cadavers were used. Seven models were prepared by the sequential damage and spinal instrumentation of each specimen. Bending and rotation tests were performed to clarify the range of motion for each model using a 6-axis material tester that we have developed. We showed that the unilateral pedicle screw system offers only uneven fixation. This results in dispersion of rigidity depending on the direction of bending and rotation. The bilateral pedicle screw system, however, allows excellent fixation in all directions.

Background X-ray images of lumbar degenerative diseases often show not only claw osteophytes, but also pairs of osteophytes that form in a direction away from the adjacent disc. We have investigated the direction of the formation of anterior lumbar vertebral osteophytes across the lumbar vertebrae using a sufficient number of lumbar radiographs, because osteophytes images can provide essential information that will contribute to the understanding of the pathology and progress of lumbar spine degeneration. Methods The direction of the formation of 14,250 pairs of anterior lumbar vertebral osteophytes across the adjacent intervertebral discs in 2,850 patients who were all over 60 years old was investigated. Anterior lumbar vertebral osteophytes were distributed into six groups based on the direction of extension of each pair of osteophytes across the intervertebral disc space. Results In L1–L2 and L2–L3, the number of patients classified into groups B (the pair of osteophytes extended in the direction of the adjacent disc) and C (almost complete bone bridge formation by a pair of osteophytes across the intervertebral disc space) was larger than that classified into group D (the pair of osteophytes extended in a direction away from the adjacent disc). In L3–L4, L4–L5 and L5-S1, the number of patients in group D was greater than that of patients belonging to groups B and C. Conclusion Our study showed that pairs of osteophytes frequently formed in the direction of the adjacent disc in the upper lumbar vertebrae (L1–L2 and L2–L3) and in the direction away from the adjacent disc in middle or lower lumbar vertebrae (L3–L4, L4–L5, and L5-S1).

We describe the development of a new device that permits handy intraoperative measurement of lumbar segmental instability. The subjects comprised 80 patients with lumbar degenerative disease. Relationships between preoperative radiological assessments and extended distance as measured using our new device were investigated. Mean extended distance measured using the device was 3.7 ± 1.9 mm. Correlation coefficients between angular motion and extended distance, and translational motion and extended distance were 0.76 and 0.66, respectively, revealing significant positive relationships between these values (p

A case of thoracic myelopathy with alkaptonuria (ochronotic spondyloarthropathy) is presented.To present and review the first reported case of an alkaptonuric patient with concomitant thoracic myelopathy.Alkaptonuria, a rare hereditary metabolic disease, is characterized by accumulation of homogentistic acid, ochronosis, and destruction of connective tissue resulting in degenerative spondylosis and arthritis. Despite the high incidence of intervertebral disc diseases among patients with alkaptonuria, neurologic symptoms caused by spinal disease are rare. Thoracic myelopathy in a patient with alkaptonuria has not been previously reported.The clinical course, radiologic features, pathology, and treatment outcome of an alkaptonuria patient with thoracic myelopathy was documented.Myelopathy of the patient was caused by rupture of a thoracic intervertebral disc. The neurologic symptoms of the patient were markedly improved after surgery.We have reported for the first time, that an alkaptonuria patient showed thoracic myelopathy caused by rupture of a thoracic intervertebral disc. Decompression followed by the instrumented fusion of the thoracic spine was effective for improving the neurologic symptoms.

STUDY DESIGN A comparative study of aggrecanases and aggrecan fragmentation profile in the human intervertebral disc at early and advanced stages of disc degeneration. OBJECTIVE To determine differences in the content of the aggrecanases and the profile of aggrecan fragmentation in early and advanced stages of disc degeneration using cadaveric human intervertebral discs. SUMMARY OF BACKGROUND DATA Aggrecanases and aggrecanase-generated aggrecan fragments have been found in human degenerated discs. However, the association between the grade of disc degeneration and the content of the aggrecanases and the profile of aggrecan fragments has not been well studied. METHODS A total of 108 cadaveric donor spines were assessed by MRI T2 imaging and graded based on the Thompson scale. Twelve donor spines (average age, 63 years), each specifically exhibiting 2 different stages (Grade 2 and Grade 4) of disc degeneration at different disc levels, were included in this study. After harvesting the preselected discs, tissue samples were obtained from the center of the nucleus pulposus (NP) and the middle zone of the anulus fibrosus (AF). The amount of the aggrecanases, specifically ADAMTS-4 and ADAMTS-5, and the pattern of aggrecan fragmentation in the isolated tissues were assessed by western blot using specific antibodies. RESULTS In both NP and the AF tissues, the amount of ADAMTS-4 detected was higher in disc tissues with a higher level of degeneration (Grade 4) than in Grade 2 disc tissues with a lower level of degeneration. However, the amount of ADAMTS-5 detected did not differ between the 2 disc tissue grades. The aggrecan fragmentation analysis of these samples demonstrated the presence of aggrecanase-mediated fragmentation in both groups; however, there was no apparent difference in the aggrecan fragmentation profile between discs at early and advanced stages of disc degeneration. CONCLUSION Aggrecanases are involved in aggrecanolysis at both the early and advanced stages of disc degeneration. The aggrecan fragmentation profile analysis demonstrates the involvement of aggrecanases, as well as that of matrix metalloproteinases and/or cathepsins, during disc degeneration.

Study design In vivo study of the effect of injection of osteogenic protein-1 (OP-1) on a rabbit anular needle puncture model of intervertebral disc (IVD) degeneration. Objective To study radiographic, magnetic resonance imaging (MRI), biochemical, and histologic changes in the rabbit IVD after injection of OP-1 into the nucleus pulposus in a needle puncture disc degeneration model. Summary of the background data Growth factors, such as OP-1, have the ability to stimulate synthesis of proteoglycans and collagen in vitro. The in vivo injection of OP-1 into the normal rabbit IVD has increased disc height and proteoglycan content in the anulus fibrosus and nucleus pulposus. However, to our knowledge, no attempts have yet been made to determine the effects of these growth factors in an in vivo model of disc degeneration. Methods New Zealand adolescent white rabbits (n = 90, 8 for baseline evaluation, 82 at 8 times) received an anular puncture in 2 noncontiguous discs with an 18-gauge needle to induce disc degeneration. Four weeks later, either 5% lactose (10 microL) or OP-1 (100 microg in 10 microL 5% lactose) was injected into the center of the nucleus pulposus. The disc height was followed radiographically for up to 24 weeks after the injections. At the 2, 4, 8, 12, and 24-week times after the injection, rabbits were euthanized, and MRI of the harvested spinal columns was obtained to grade the degeneration. The discs injected with OP-1 or lactose and noninjected discs were subjected to biochemical and histologic analysis. The specimens at the 24-week time were limited to histologic evaluation. Results The anular puncture with a needle induced a consistent disc narrowing within 4 weeks. The injection of OP-1 induced a restoration of disc height at 6 weeks, which was sustained for the entire experimental period, up to 24 weeks after the injection. The injection of lactose alone did not change the course of disc narrowing over the same time. MRI grading score showed significant differences between the OP-1 and lactose groups at the 8, 12, and 24-week times, suggesting an increase in water content in the nucleus pulposus of the OP-1 group. The proteoglycan content of the nucleus pulposus and anulus fibrosus was significantly higher in the OP-1 group than in the control group. The degeneration grades of the punctured discs in the OP-1 group were significantly lower than those in the lactose group. Conclusion The results of this study show the feasibility of restoring degenerative rabbit discs by a single injection of OP-1 into the nucleus pulposus. Importantly, the effects of the OP-1 injection on disc height were sustained for up to 24 weeks. The metabolic changes in the cells, following a single injection, might be sustained and, thus, induce long-term changes in disc structure. An efficacy study in large animals is required to show further that the intradiscal injection of OP-1, or bone morphogenetic proteins or growth factors with similar properties would be useful for the structural restoration of the IVD in humans.

Using biochemical, histological, and radiological parameters in a rabbit model of intervertebral disc (IVD) degeneration, the intradiscal injection of a growth factor, such as osteogenic protein-1 (OP-1), has been shown to regenerate the IVD. However, very little is known about how such a biological therapeutic approach affects the biomechanical properties of the degenerated IVD.To investigate the effects of an intradiscal injection of OP-1 on the biomechanical properties of IVDs in the rabbit annular-puncture disc degeneration model and to determine their relationship to biochemical properties.In vivo study on the effects of intradiscally administered OP-1 on the biomechanical and biochemical properties of IVDs in the rabbit annular-puncture disc degeneration model.New Zealand White rabbits (n=16) underwent annulus fibrosus (AF) puncture, using an 18-gauge needle, at L2-L3 and L4-L5 (L3-L4: nonpunctured control). Four weeks later, the punctured discs received an injection of either 5% lactose (10 microL) or OP-1 (100 microg/10 microL of 5% lactose) into the nucleus pulposus (NP). The disc height was radiographically monitored biweekly. After sacrifice and removal of bone-disc-bone complexes 8 weeks postinjection, the dynamic viscoelastic properties of the IVDs were tested by applying a cycle of sinusoidal strain in uniaxial compression at six loading frequencies (0.05 to 2 Hz). The biochemical properties of the dissected IVDs were then analyzed and correlated with the biomechanical properties.A single injection of OP-1 significantly restored disc height when compared with the lactose-injected discs (OP-1 vs. lactose, p.001). The elastic modulus of the IVDs in the OP-1-injected discs was significantly higher than that in the lactose-injected discs at all frequencies (mean: +43%, p.001). The viscous modulus in the OP-1-injected discs was significantly higher at 0.05, 0.2, 0.5, and 1 Hz (mean: +55%, p.001) and showed higher tendencies at other frequencies (p=.08-.09). For both moduli, no significant differences were observed between the OP-1-injected and the nonpunctured control discs. The OP-1 injection significantly increased the proteoglycan (PG) content in the NP and AF, and the collagen content in the NP (p.001-.05). Both elastic and viscous moduli showed significant positive correlations with PG content in the NP and collagen content in the NP and AF (Rho=.357-.466, p=.010-.047).We have shown for the first time that an injection of the growth factor, OP-1, restored the biomechanical properties of IVDs in a rabbit model of IVD degeneration. Comparing biomechanical with biochemical data suggests that the OP-1-induced biomechanical restoration was a consequence of increased activities of anabolic pathways that resulted in biochemical changes in the IVD.