Microglial depletion impairs glial scar formation and aggravates inflammation partly by inhibiting STAT3 phosphorylation in astrocytes after spinal cord injury.

Astrocytes and microglia play an orchestrated role following spinal cord injury; however, the molecular mechanisms through which microglia regulate astrocytes after spinal cord injury are not yet fully understood. Herein, microglia were pharmacologically depleted and the effects on the astrocytic response were examined. We further explored the potential mechanisms involving the signal transducers and activators of transcription 3 (STAT3) pathway. For in vivo experiments, we constructed a contusion spinal cord injury model in C57BL/6 mice. To deplete microglia, all mice were treated with colony-stimulating factor 1 receptor inhibitor PLX3397, starting 2 weeks prior to surgery until they were sacrificed. Cell proliferation was examined by 5-ethynyl-2-deoxyuridine (EdU) and three pivotal inflammatory cytokines were detected by a specific Bio-Plex ProTM Reagent Kit. Locomotor function, neuroinflammation, astrocyte activation and phosphorylated STAT3 (pSTAT3, a maker of activation of STAT3 signaling) levels were determined. For in vitro experiments, a microglia and astrocyte coculture system was established, and the small molecule STA21, which blocks STAT3 activation, was applied to investigate whether STAT3 signaling is involved in mediating astrocyte proliferation induced by microglia. PLX3397 administration disrupted glial scar formation, increased inflammatory spillover, induced diffuse tissue damage and impaired functional recovery after spinal cord injury. Microglial depletion markedly reduced EdU+ proliferating cells, especially proliferating astrocytes at 7 days after spinal cord injury. RNA sequencing analysis showed that the JAK/STAT3 pathway was downregulated in mice treated with PLX3397. Double immunofluorescence staining confirmed that PLX3397 significantly decreased STAT3 expression in astrocytes. Importantly, in vitro coculture of astrocytes and microglia showed that microglia-induced astrocyte proliferation was abolished by STA21 administration. These findings suggest that microglial depletion impaired astrocyte proliferation and astrocytic scar formation, and induced inflammatory diffusion partly by inhibiting STAT3 phosphorylation in astrocytes following spinal cord injury.

Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway.

BACKGROUND: The therapeutic effects of adipose-derived mesenchymal stem cell (ADSC) transplantation have been demonstrated in several models of central nervous system (CNS) injury and are thought to involve the modulation of the inflammatory response. However, the exact underlying molecular mechanism is poorly understood. Activation of the Jagged1/Notch signaling pathway is thought to involve inflammatory and gliotic events in the CNS. Here, we elucidated the effect of ADSC transplantation on the inflammatory reaction after spinal cord injury (SCI) and the potential mechanism mediated by Jagged1/Notch signaling pathway suppression. METHODS: To evaluate the therapeutic effects of ADSC treatment and the potential inhibitory effects of ADSCs on Notch signaling, mice were subjected to contusion SCI, and GFP-labeled ADSCs were injected into the lesion site immediately after the injury. Locomotor function, spinal cord tissue morphology, and the levels of Notch-related proteins and proinflammatory transcripts were compared between groups. To validate the hypothesis that the therapeutic effects of ADSCs are partly due to Notch1 signaling inhibition, a Jagged1 small interfering RNA (siRNA) was injected into the spinal cord to knock down Jagged1/Notch signaling. Neuronal staining and analyses of microglia/macrophage activation and signaling pathways were performed. RESULTS: We demonstrated that ADSCs survived in the injured spinal cord for at least 28 days without differentiating into glial or neuronal elements. ADSC treatment resulted in significant downregulation of proinflammatory mediator expression and reduced ionized calcium-binding adapter molecule 1 (IBA1) and ED-1 staining in the injured spinal cord, eventually improving functional recovery. The augmentation of the Jagged1/Notch signaling pathway after SCI was suppressed by ADSC transplantation. The inhibition of the Jagged1/Notch signaling pathway by Jagged1 siRNA resulted in decreases in SCI-induced proinflammatory cytokines and the activation of microglia and an increase in the survival of neurons. Furthermore, Jagged1 knockdown suppressed the phosphorylation of JAK/STAT3 in astrocytes following SCI. CONCLUSION: The results of this study demonstrated that the therapeutic effects of ADSCs in SCI mice were partly due to Jagged1/Notch signaling pathway inhibition and a subsequent reduction in JAK/STAT3 phosphorylation in astrocytes.

Special attention to nurses' protection during the COVID-19 epidemic.

As of March 8, 2020, the novel coronavirus disease 2019 (COVID-19) had caused 80,815 human infections and 3073 deaths in China, including more than 3000 infections among medical staff. Guangdong Second Provincial General Hospital (Guangzhou, Guangdong Province, China), a provincial emergency hospital, has treated more than 35 confirmed cases of COVID-19 and more than 260 suspected cases. Most of nurses' work involves direct contact with patients. As nurses have high vulnerability to COVID-19, it is necessary to establish hospital-specific protocols to reduce the risk of nurses' infection in interactions with COVID-19 patients. Our hospital has maintained a "zero nurse infection" rate while battling SARS in 2003 and during the present COVID-19 epidemic. The following are the key measures implemented in our hospital.

Anatomic study and clinical significance of the dorsal meningovertebral ligaments of the thoracic dura mater.

STUDY DESIGN: A dissection-based study of 18 embalmed thoracic specimens. OBJECTIVE: To investigate the properties and clinical significance of the dorsal meningovertebral ligaments of the thoracic dura mater. SUMMARY OF BACKGROUND DATA: Previously, we performed a comprehensive anatomic study on the dorsal meningovertebral ligaments in the lumbosacral and cervical regions, whereby we concluded that the ligaments were an anatomic factor leading to dural laceration and hemorrhage during flavectomy and laminectomy. Unfortunately, thus far, no systematic anatomic study has been undertaken to examine the dorsal meningovertebral ligaments of the thoracic dura mater. METHODS: Eighteen adult embalmed cadavers were studied, and the morphology, orientation, attachment site, and distribution traits of the dorsal meningovertebal ligaments were observed. In addition, the length, width, or diameter and thickness of the ligaments were measured using a Vernier caliper. Two meningovertebal ligaments were removed for histological examination. RESULTS: In the thoracic region, the dorsal meningovertebral ligaments anchored the dura mater to the lamina or ligamentum flavum. The meningovertebral ligaments displayed a relatively even distribution along the upper thoracic region (T1-T7) and a gradual increase in frequency in the lower thoracic region from T7 to T12. The meningovertebral ligaments protrude into the dura and correspondingly become an integral part of the dura. Some ligaments are accompanied by or are attached to blood vessels. Histological examination of the meningovertebral ligaments revealed fibrous connective tissue. CONCLUSION: The dorsal meningovertebral ligaments exist between the dural sac and ligamentum flavum or lamina in the thoracic spine. Based on their anatomic features, meningovertebral ligaments may be one potential cause for dural laceration and epidural hemorrhage. We propose that, during thoracic flavectomy and laminectomy, the meningovertebral ligaments should first be identified and properly handled, thereby minimizing the occurrence of relevant complications. LEVEL OF EVIDENCE: N/A.

Anterior decompression and fusion versus posterior laminoplasty for multilevel cervical compressive myelopathy.

The optimal surgical strategy for anterior or posterior approaches remains controversial for multilevel cervical compressive myelopathy caused by multisegment cervical spondylotic myelopathy (MCSM) or ossification of the posterior longitudinal ligament (OPLL). A systematic review and meta-analysis was conducted evaluating the clinical results of anterior decompression and fusion (ADF) compared with posterior laminoplasty for patients with multilevel cervical compressive myelopathy. PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials and nonrandomized cohort studies conducted from 1990 to May 2013 comparing ADF with posterior laminoplasty for the treatment of multilevel cervical compressive myelopathy due to MCSM or OPLL. The following outcome measures were extracted: Japanese Orthopedic Association (JOA) score, recovery rate, complication rate, reoperation rate, blood loss, and operative time. Subgroup analysis was conducted according to the mean number of surgical segments. Eleven studies were included in the review, all of which were prospective or retrospective cohort studies with relatively low quality indicated by GRADE Working Group assessment. A definitive conclusion could not be reached regarding which surgical approach is more effective for the treatment of multilevel cervical compressive myelopathy. Although ADF was associated with better postoperative neural function than posterior laminoplasty in the treatment of multilevel cervical compressive myelopathy due to MCSM or OPLL, there was no apparent difference in the neural function recovery rate between the 2 approaches. Higher rates of surgery-related complication and reoperation should be taken into consideration when ADF is used for patients with multilevel cervical compressive myelopathy. The surgical trauma associated with corpectomy was significantly higher than that associated with posterior laminoplasty.

The morphology and clinical significance of the dorsal meningovertebra ligaments in the cervical epidural space.

BACKGROUND CONTEXT: The dural sac is anchored within the vertebral canal by connective tissue called meningovertebral ligaments in the epidural space. During flavectomy and laminectomy, inadvertent disruption of the dorsal meningovertebral ligaments may lead to dura laceration and cerebrospinal fluid (CSF) leaks. All the described dorsal meningovertebral ligaments were located in the lumbar region. A rare study is available about dorsal meningovertebral ligaments of the cervical spinal dura to the adjacent vertebrae. PURPOSE: To identify and describe the dorsal meningovertebral ligaments at each cervical level and discuss their clinical significance. STUDY DESIGN: A dissection-based study of 22 embalmed cadavers. METHODS: The anatomy was studied in 22 whole cervical cadavers (11 females, 11 males), prepared with formaldehyde, whose ages at the time of death ranged from 55 to 78 years. The vertebral canal was divided to expose the dural sac and the spinal nerve roots. At all levels of the cervical vertebra, the morphology, quantity, origin, insertion, and spatial orientation of the dorsal meningovertebral ligaments were determined and the length, width or diameter, and thickness of the ligaments were measured with vernier calipers. RESULTS: The dorsal meningovertebral ligaments in the cervical region anchored the posterior dural sac to the ligamentum flavum or laminae. The number of attachment points on the ligamentum flavum was relatively larger than that on the lamina, and the occurrence rate of dorsal meningovertebral ligaments was 100% at C1-C2 and C4--C5. The thickest ligaments were observed at the C1 and C2 vertebrae. The length of the ligaments varied from 1.50 to 35.22 mm, and the orientation of the ligaments mostly was craniocaudal. The morphology of the dorsal meningovertebral ligaments was divided into four types: strip type, cord type, grid type, and thin slice type. CONCLUSIONS: In the cervical spine, the dorsal meningovertebral ligaments exist between the posterior dural sac and the ligamentum flavum or lamina. The dorsal meningovertebral ligaments may be of clinical importance to surgeons. Dissecting the dorsal meningovertebral ligaments before the cervical flavectomy and laminectomy may be an important step in reducing postoperative dura laceration and CSF leaks, which may result in significant benefits for patients and health-care organizations.

Anterior corpectomy versus posterior laminoplasty for multilevel cervical myelopathy: a systematic review and meta-analysis.

BACKGROUND: Surgical strategy for multilevel cervical myelopathy resulting from cervical spondylotic myelopathy (CSM) or ossification of posterior longitudinal ligament (OPLL) still remains controversial. There are still questions about the relative benefit and safety of direct decompression by anterior corpectomy (CORP) versus indirect decompression by posterior laminoplasty (LAMP). OBJECTIVE: To perform a systematic review and meta-analysis evaluating the results of anterior CORP compared with posterior LAMP for patients with multilevel cervical myelopathy. METHODS: Systematic review and meta-analysis of cohort studies comparing anterior CORP with posterior LAMP for the treatment of multilevel cervical myelopathy due to CSM or OPLL from 1990 to December 2012. An extensive search of literature was performed in Pubmed, Embase, and the Cochrane library. The quality of the studies was assessed according to GRADE. The following outcome measures were extracted: pre- and postoperative Japanese orthopedic association (JOA) score, neurological recovery rate (RR), surgical complications, reoperation rate, operation time and blood loss. Two reviewers independently assessed each study for quality and extracted data. Subgroup analysis was conducted according to the mean number of surgical segments. RESULTS: A total of 12 studies were included in this review, all of which were prospective or retrospective cohort studies with relatively low quality. The results indicated that the mean JOA score system for cervical myelopathy and the neurological RR in the CORP group were superior to those in the LAMP group when the mean surgical segments were <3, but were similar between the two groups in the case of the mean surgical segments equal to 3 or more. There was no statistical difference in the surgical complication rate between the two groups when the mean surgical segments <3, but were significantly higher incidences of surgical complications and complication-related reoperation in the CORP group compared with the LAMP group in the case of the mean surgical segments equal to 3 or more. Besides, the operation time in the CORP group was longer than that in the LAMP group, and the average blood loss was significantly more in the CORP group compared with the LAMP group. CONCLUSION: Based on the results above, anterior CORP and fusion is recommended for the treatment of multilevel cervical myelopathy when the involved surgical segments were <3. Given the higher rates of surgical complications and complication-related reoperation and the higher surgical trauma associated with multilevel CORP, however, it is suggested that posterior LAMP may be the preferred method of treatment for multilevel cervical myelopathy when the involved surgical segments were equal to 3 or more. In addition, taking the limitations of this study into consideration, it was still not appropriate to draw a strong conclusion claiming superiority for CORP or LAMP. A well-designed, prospective, randomized controlled trial is necessary to provide objective data on the clinical results of both procedures.

Comparison of mesenchymal stromal cells from human bone marrow and adipose tissue for the treatment of spinal cord injury.

BACKGROUND AIMS: Bone marrow and subcutaneous adipose tissue are both considered prospective sources of mesenchymal stromal cells (MSCs), which can be used in cell therapy for spinal cord injury (SCI). The present study investigated whether human adipose tissue-derived mesenchymal stromal cells (hADSCs) transplanted into a rat model of SCI would lead to similar or improved neurologic effects compared with human bone marrow-derived mesenchymal stromal cells (hBMSCs). METHODS: hADSCs and hBMSCs were isolated from five adult donors. These MSCs were characterized using flow cytometry, immunocytochemistry, real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Immediately after SCI, 2 × 10(5) hBMSCs or hADSCs were injected into the injured spinal cord. Locomotor function, cell survival and differentiation, spinal cord tissue morphology and brain-derived neurotrophic factor (BDNF) expression were compared between groups. RESULTS: hADSCs and hBMSCs showed similar surface protein expression, and hADSCs showed higher proliferative activity with higher expression of vascular endothelial cell growth factor, hepatocyte growth factor and BDNF than hBMSCs. After transplant, both hADSCs and hBMSCs migrated within the injured spinal cord without differentiating into glial or neuronal elements. Administration of hADSCs was associated with marked changes in the SCI environment, with significant increases in BDNF levels. This was simultaneously associated with increased angiogenesis, preserved axons, decreased numbers of ED1-positive macrophages and reduced lesion cavity formation. These changes were accompanied by improved functional recovery. CONCLUSIONS: The present results suggest that hADSCs would be more appropriate for transplant to treat SCI than hBMSCs.

[Posterior fixation and fusion for treatment of Os odontoideum complicated by atlantoaxial dislocation].

OBJECTIVE: To summarize the techniques and evaluate the therapeutic effect of posterior fixation and fusion in the treatment of Os odontoideum complicated by atlantoaxial dislocation. METHODS: From March, 2007 to October, 2010, 10 patients with Os odontoideum (including 6 male and 4 female patients aged from 20 to 65 years, mean 39.8 years) were treated in our hospital. Before and after the operation, the patients underwent X ray, CT and MRI examinations to measure and evaluate the degree of dislocation and neural compression. After preoperative traction for 1-2 weeks, all the 10 patients showed deductible atlantoaxial dislocation. Through a posterior approach, Atlantoaxial pedicle screws fixation were performed in 9 cases, and C2/3 pedicle-Occiput screw fixation was performed in 1 case. All the patients wore cervical collars as external support for 3 months after the operation. RESULTS: The mean operative time was 3 h in these patients with a mean intraoperative blood loss of 420 ml. The symptoms were relieved after the surgery in all the patients, who showed no neck pain or neurological defects. The patients were followed up for 6 to 52 months (mean 22 months), and bony fusion was observed in all the 10 cases within 6 to 8 months without such complications as internal fixation failure or redislocation of the atlas. CONCLUSION: Patients with Os odontoideum complicated by atlantoaxial dislocation should undergo surgical stabilization to avoid severe neurological injury. Pedicle screw instrument in the atlas allows restoration of the spinal stability, short-segment fusion, and maximal preservation of the mobility of the neck.