Lianshun Jia

PTEN deletion prevents ischemic brain injury by activating the mTOR signaling pathway

It is increasingly clear that the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a negative regulator of neuronal cell survival. However, its molecular mechanisms remain poorly understood. Here we found that PTEN/mTOR is critical for controlling neuronal cell death after ischemic brain injury. Male rats were subjected to MCAO (middle cerebral artery occlusion) followed by pretreating with bpv (pic), a potent inhibitor for PTEN, or by intra-cerebroventricular infusion of PTEN siRNA. bpv (pic) significantly decreased infarct volume and reduced the number of TUNEL-positive cells. We further demonstrated that although bpv (pic) did not affect brain injury-induced mTOR protein expression, bpv (pic) prevented decrease in phosphorylation of mTOR, and the subsequent decrease in S6. Similarly, down-regulation of PTEN expression also reduced the number of TUNEL-positive cells, and increased phospho-mTOR. These data suggest that PTEN deletion prevents neuronal cell death resulting from ischemic brain injury and that its neuroprotective effects are mediated by increasing the injury-induced mTOR phosphorylation.

Increased miR‐195 aggravates neuropathic pain by inhibiting autophagy following peripheral nerve injury

Following peripheral nerve injury (PNI) microglia proliferates and adopts inflammation that contributes to development and maintenance of neuropathic pain. miRNAs and autophagy are two important factors in the regulation of inflammation. However, little is known about whether miRNAs regulate neuroinflammation and neuropathic pain by controlling autophagy. In the study, we demonstrated that miR‐195 levels were markedly increased in rats subjected to L5 spinal nerve ligation (SNL). Upregulated miR‐195 was also found in spinal microglia of rats with SNL. The overexpression of miR‐195 contributed to lipopolysaccharide‐induced expression of proinflammatory cytokines IL‐1β, TNF‐α, and iNOS in cultured microglia. Upregulated miR‐195 also resulted in increased mechanical and cold hypersensitivity after PNI, whereas miR‐195 inhibition reduced mechanical and cold sensitivity. We further demonstrated that PNI significantly inhibited microglial autophagy activation, whereas miR‐195 inhibitor treatment increased autophagy activation and suppressed neuroinflammation in vivo and in vitro. More important, autophagy inhibition impaired miR‐195 inhibitor‐induced downregulation of neuroinflammation and neuropathic pain. Additionally, ATG14 was identified as the functional target of miR‐195. Conclusions: These data demonstrated that miR‐195/autophagy signaling represents a novel pathway regulating neuroinflammation and neuropathic pain, thus offering a new target for therapy of neuropathic pain.

Upregulated miR-29b promotes neuronal cell death by inhibiting Bcl2L2 after ischemic brain injury

It is increasingly clear that microRNAs (miRNAs) play an important role in controlling cell survival. However, the functional significance of miRNAs in ischemic brain injury remains poorly understood. In the present study, we assayed the expression levels of miR-29b after ischemic brain injury, and defined the target genes and biological functions of miR-29b. We found that the miR-29b levels were significantly increased in rat brain after transient middle cerebral artery occlusion and neurons after oxygen–glucose deprivation. Moreover, ectopic expression of miR-29b promoted neuronal cell death, whereas its repression decreased cell death. Furthermore, we verified that miR-29b directly targeted and inhibited Bcl2L2 gene expression, and then increased neuronal cell death. Importantly, Bcl2L2 overexpression rescued neuronal cell death induced by miR-29b. These results suggest an important role of miR-29b in regulating neuronal cell death, thus offering a new target for the development of therapeutic agents against ischemic brain injury.

Direct repair of defect in lumbar spondylolysis and mild isthmic spondylolisthesis by bone grafting, with or without facet joint fusion.

Abstract. Forty-six patients with lumbar spondylolysis and mild isthmic spondylolisthesis were managed with direct repair of the defect with or without facet joint fusion in the affected segment. There were 24 males and 22 females, ranging in age from 15 to 56 years (average, 38.2 years). These patients had experienced clinical symptoms due to spondylolysis for between 4 months and 20 years (average, 5.3 years). Of 46 patients, 28 had no spondylolisthesis, 11 had Meyerding grade I vertebral slippage and 7 had grade II. Direct repair of 98 defects was performed on these patients. Twenty-six patients, in whom the disc adjacent to the defect was determined as degenerative by magnetic resonance imaging (MRI), simultaneously underwent facet joint fusion; 17 in one segment and 9 in two segments. The average period of follow-up was 50 months (24–92 months). Ninety-four defects achieved bony healing. As a result, 28 patients were graded as having an excellent outcome, 15 good, and 3 fair. Bone grafting in the defects achieves union between the loose lamina and the anterior element of lumbar vertebrae, and reconstructs the anatomic structure and physiologic functions of the lumbar vertebrae. There was no significant difference in outcome between the spondylolytic/spondylolisthetic patients with non-degenerative disc, who were treated with direct repair of defect only, and those with degenerative disc, who additionally underwent a fusion procedure (P>0.05). The present series demonstrates a satisfactory result and a high rate of bony healing of the pars defect by this operative procedure in patients with lumbar spondylolysis and mild isthmic spondylolisthesis. Preoperative assessment of the disc degeneration with MRI is of great assistance in making the protocol choice of whether to opt for fusion.

Surgical treatment of nonunited fractures of the odontoid process, with special reference to occipitocervical fusion for unreducible atlantoaxial subluxation or instability

Abstract Fifty-seven consecutive patients treated surgically for nonunited fractures of the odontoid process were reviewed. All patients presented late, exhibiting neurological deficits subsequent to nonunion. Delay in presentation was between ¶6 and 120 months (mean 32 months) after the original injury, due to missed diagnosis or inappropriate management. Seven patients who were reduced in traction underwent a Gallie atlantoaxial fusion. In the remaining 50 patients who were unreducible, an occipitocervical arthrodesis was performed. They were followed up for a minimum of 2 years, except one who died from postoperative respiratory failure. All patients obtained a solid bony union, including two in whom nonunion occurred following atlantoaxial fusion, and occipitocervical fusion was added as a rescue. Thirty-eight patients achieved excellent neurological recovery, nine still had some disability, five retained their neurological deficits and two reported a deterioration. In two patients, a recurrence in a traumatic episode was experienced long after a resolution. Our findings demonstrate that occipitocervical arthrodesis is preferable for unreducible subluxation or instability of atlantoaxial articulation in nonunion of odontoid fractures.

Surgical technique: Hemilaminectomy and unilateral lateral mass fixation for cervical ossification of the posterior longitudinal ligament.

BackgroundSurgical approaches for cervical ossification of the posterior longitudinal ligament (OPLL) include anterior, posterior, or combined decompression with or without fusion. The goal of surgery is to decompress the spinal cord while maintaining the stability and sagittal alignment of the cervical spine. C5 palsy has been reported as a postoperative complication of cervical laminectomy or laminoplasty characterized as motor weakness of the muscles supplied with C5 nerve roots. Several studies have shown this phenomenon was partially attributable to posterior shift of spinal cord.Description of TechniqueThe rationale for choosing hemilaminectomy is to control postoperative posterior shift of the spinal cord and afford more stability by preserving ligamentous attachments and posterior bony elements as much as possible. After a fixation system of lateral mass screws and rods is installed unilaterally, laminae are removed from the underlying dura using a high-speed burr and Kerrison laminectomy rongeur on the other side. The spinous processes are preserved.Patients and MethodsPatients with multilevel continuous/mixed cervical OPLL are good candidates for this technique. We retrospectively reviewed 146 patients who had multilevel continuous/mixed cervical OPLL and underwent surgery from January 2006 to January 2010. Neurologic condition was evaluated using the improvement ratio (IR) of the Japanese Orthopaedic Association (JOA) score for cervical myelopathy.ResultsThe mean JOA score increased from 10 points before surgery to 14 points at last followup. The mean IR of neurologic function (JOA score) was 59%. C5 palsy was not observed in any patient after decompression, and cervical lordosis changed from 8.7° preoperatively to 9.1° at last followup.ConclusionsFor patients with multilevel continuous/mixed cervical OPLL without fixed kyphosis, multilevel hemilaminectomy with unilateral lateral mass fixation is an effective alternative technique.Level of EvidenceLevel IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Chondrosarcomas of the cervical and cervicothoracic spine: surgical management and long-term clinical outcome.

Study Design A retrospective review study. Objectives To estimate the clinical outcome of various resection protocols in patients with chondrosarcoma (CHS) at the challenging region of cervical and cervicothoracic spine (CCT). Summary of Background Data It is challenging to surgically manage CHS of the spine. Although total en-bloc resection has proven to be an ideal treatment, this option is not always feasible in the spine because of the constrains of critical neurovascular structures in the vicinity. Lesions at the CCT region pose even more difficulties, and few large clinical series concerning various protocols and long-term outcomes of these lesions exist at present. Methods Fifteen patients with CHS at the CCT region who underwent surgical management in our institute were retrospectively studied. Twelve piecemeal resections and 3 en-bloc resections were performed. Intraoperative local chemotherapy and postoperative cyberknife radiotherapy were given as adjuvant therapy. Neurologic status, local recurrence, distant metastasis, and treatment-related complications were evaluated. Results The mean follow-up time was 58.7 months (median 37 mo; ranging from 18 to 141 mo). Local recurrence was detected in 5 of 5 cases (100%) treated by intracapsular piecemeal resection, and in 1 of 7 cases (14.3%) treated by extracapsular piecemeal resection, whereas no recurrence was found in 3 cases treated by en-bloc resection. Of the 6 recurrent patients, 5 died of disease 24 to 46 months after present surgery, and the remaining patient was alive with disease in the final follow-up. There were no signs of recurrence in the remaining 9 patients. Conclusions For CHS at the CCT region, intralesional piecemeal resection has a poor prognosis and should be avoided. Oncologically, en-bloc resection remains the best form of disease management and should be the primary treatment of choice. For cases in which an uncontaminated en-bloc resection could not be achieved, the extracapsular piecemeal resection with adjuvant therapy including local chemotherapy and cyberknife radiotherapy is an effective and achievable option.

Intervertebral thoracic disc calcification associated with ossification of posterior longitudinal ligament in an eleven-year-old child.

Study Design. Intervertebral disc calcification of T6–T7, T7–T8 discs associated with ossification of posterior longitudinal ligament (OPLL) in a child is reported. Objective. To discuss the natural history and management of calcification of T6–T7, T7–T8 discs with OPLL. Summary of Background Data. Calcified intervertebral discs are rare in children. Cervical disc calcification has already been described. However, thoracic disc calcification associated with OPLL has not been reported. Methods. An 11-year-old boy presented with progressive back pain for 6 months. Neurologic examination showed numbness in both lower extremities. The knee jerk reflex of the patient was hypertonic. The muscle strength of both lower extremities were Grade 4, with reduction. He was treated with a lumbar belt for 2 weeks. Results. Initial thoracic spine radiograph and CT scan showed two adjacent calcified discs of T6–T7, T7–T8 associated with T6–T7 OPLL, resulting in marked spinal canal stenosis. His neurologic symptoms subsided and his back pain disappeared after a 2-week conservative treatment. Three months later CT scan showed that the calcification of T6–T7, T7–T8 discs was aggravated, but the T6–T7 OPLL was relieved. Conclusion. The natural history of intervertebral disc calcification is usually benign. In this case, the improvement of OPLL is associated with the stabilization of the maturely fused calcified disc. Spontaneous resolution of the OPLL and recovery of normal neurologic function can be expected with conservative treatment.

Anterior decompression and interbody fusion with BAK/C for cervical disc degenerative disorders.

Study Design A retrospective clinical study of 64 patients who underwent anterior cervical discectomy and fusion (ACDF) with BAK/C for disc degenerative disorders. Objective To evaluate the long-term outcome of BAK/C in the treatment of cervical disc degenerative disorders. Summary of Background Data ACDF has been demonstrated to be effective in the treatment of cervical disc degenerative disorders. BAK/C, a kind of thread cage widely used for interbody fusion in the lumbar spine, was used in the cervical spine to avoid the donor site complications of traditional autologous bone graft. Methods Sixty-four patients with cervical disc degenerative disorders underwent ACDF with BAK/C technique in our institution between September 1997 and December 2000. All the patients were followed up for at least 6 years. The changes of segmental stability, bone fusion, cervical lordosis, and intervertebral height on radiographs were evaluated in detail immediately after operation, at 6 and 12 months postoperatively, and yearly thereafter. The clinical outcome of neurologic improvement and pain relief was also investigated. Results Solid fusion was achieved at 1 year postoperatively in all patients, and the segmental stability was maintained during the whole follow-up. The cervical lordosis and intervertebral height were well restored immediately after operation, and gradually lost during the follow-up. Especially, the anterior height of intervertebral space decreased significantly after 1 year, when compared with the anterior height immediately after operation. BAK/C subsidence was observed in 9 patients, including 5 with 1-level fusion, 1 with 2–separated-level fusion, and 3 with 2–adjacent-level fusion, according to the standard of loss of intervertebral height more than 3 mm. BAK/C fusion was generally effective in the treatment of cervical disc degenerative disorders, according to the evaluation of neurologic improvement and pain relief. However, neck pain tended to reoccur in the patients with cage subsidence, and 2 of them even needed revision surgery because of the recurrence of myelopathy and progressive neck pain. Conclusions Although BAK/C technique was generally effective and safe in the treatment of cervical disc degenerative disorders, the pitfalls of cage design resulted in the disability of maintenance of cervical lordosis and intervertebral height in the long-term follow-up. Cage subsidence, which tended to develop in the patients with 2-level fusion, was possibly responsible for the recurrence of neck pain.

Removal of posterior longitudinal ligament in anterior decompression for cervical spondylotic myelopathy.

Study Design The clinical and radiologic results of the patients with removed posterior longitudinal ligament (PLL) were compared with those of the patients with preserved PLL in the treatment of cervical spondylotic myelopathy (CSM). Objective To investigate effect of resection of the PLL in anterior decompression for CSM. Summary of Background Data Anterior decompression has been proved to be effective in the treatment of CSM, and the pathogenic matters including herniated disc, proliferative osteophyte, and ossification of posterior longitudinal ligament should be definitely removed. However, it still remains controversial to remove degenerative or hypertrophic PLL, considering the potential risks of dura tears and neurologic injury. Methods Between March 1997 and December 2002, 58 patients who underwent anterior decompression for CSM were included in this study. Among them, the PLL was removed in 31 patients (PLL removed group) and that was preserved in the other 27 patients (PLL preserved group). The clinical [Japanese Orthopedic Association (JOA) score] and radiologic (diameter of the spinal cord on magnetic resonance image) results were compared between 2 groups. The risk of complications and reoperation was also evaluated. Results With a 12-month follow-up, the mean JOA score increased from 10.4±1.8 to 15.2±1.2 in PLL removed group and that increased from 10.7±1.6 to 14.6±1.1 in PLL preserved group. The improvement rate between 2 groups was significantly different (74%±23% vs. 63%±21%, P<0.01). Radiologic study showed that the increase of diameter of the spinal cord in PLL removed group was significantly greater than that in PLL preserved group (3.78±1.25 mm vs. 2.02±1.03 mm P<0.01). Only 1 patient with PLL removed developed cerebrospinal fluid leakage after operation, and 8 patients (5 with PLL preserved and 3 with PLL removed) need posterior revision surgery. Conclusions Removal of PLL was generally safe and helpful to get more decompression in anterior approach for CSM, although more technically demanding.