[Finite element analysis of the effect of plate placement angle on cervical spine stability in anterior cervical fusion surgery].

OBJECTIVE: Using the method of finite element analysis, to compare the biomechanical properties between the plate deviating from the long axis of the cervical spine and the standard placement of the plate in the anterior cervical fusion surgery. METHODS: A healthy female volunteer was selected and CT scan (C1-T1) was performed. Using Mimics 19.0, Geomagic Studio 2015, Solidworks 2018, Ansys Workbench 17.2 to establish a lower cervical spine (C3-C7) model and to verify the reliability of the model. Subsequently, anterior cervical plates of different angles and lengths were placed to establish an anterior cervical discectomy fusion (ACDF) model. Applying 73.6 N axial pressure and 1 NM pure moment on C3 to make the model produce flexion, extension, lateral bending and rotation activities, observed the model stress cloud diagram and recorded the maximum stress value of the instrument and the intervertebral mobility. RESULTS: The lower cervical spine (C3-C7) finite element model was established and verified against the published literature on the range of motion (ROM) of cervical spine. Effect of steel plate offset axis on stress distribution, maximum stress value and intervertebral ROM of internal fixation apparatus was minimal, and the mechanical effect of steel plate offset was less in double section steel plate than in single section steel plate. CONCLUSION: Little effect on the mechanical stability of the cervical spine was anticipated when the anterior cervical plate was not perfectly aligned with the long axis of the cervical spine. If the tilt of the plate in clinical surgery is less than 20°, there is no need to readjust the position of the plate.

Deep brain stimulation in post-traumatic dystonia: A case series study.

AIMS: Deep brain stimulation (DBS) has been proposed as an effective treatment for drug-intolerant isolated dystonia, but whether it is also efficacious for posttraumatic dystonia (PTD) is unknown. Reports are few in number and have reached controversial conclusions regarding the efficacy of DBS for PTD treatment. Here, we report a case series of five PTD patients with improved clinical benefit following DBS treatment. METHODS: Five patients with disabling PTD underwent DBS therapy. The clinical outcomes were assessed with the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) at baseline and the last follow-up visit (at more than 12 months). RESULTS: Patients 1 and 3 received unilateral globus pallidus internus (GPi) DBS for contralateral dystonia. The subthalamic nucleus (STN) was chosen as target for patients 2 and 4, due to a lesion located in the globus pallidus. Patient 5 had an electrode in the ventral intermediate nucleus (VIM) for treating predominant tremor of left upper extremity, with unexpected improvement of focal hand dystonia. The scores of BFMDRS movement exhibited favorable improvement in all five patients at the last follow-up, ranging from 52.4% to 78.6%. CONCLUSIONS: Deep brain stimulation may be an effective and safe treatment for medically refractory PTD, but this needs to be confirmed by further studies.

Bilateral anterior capsulotomy enhances medication compliance in patients with epilepsy and psychiatric comorbidities.

OBJECTIVES: Patients with epilepsy and refractory comorbid psychiatric disorders often experience functional impairments and a lower quality of life as well as showing a lack of compliance with anti-epileptic medication regimens. We reasoned that widespread clinical benefits could be gained if the psychiatric comorbidities among these patients were reduced. In this study, we assessed the utility of anterior capsulotomy in managing medication-refractory comorbid psychotic symptoms and aggression in patients with epilepsy. METHODS: In this retrospective case series, we evaluated the clinical outcomes of 13 epilepsy patients with severe psychiatric comorbidities who had received bilateral anterior capsulotomy. Clinical outcome assessments were performed at 1 week, 6 months, 1 year, and several years after surgery focusing on: (a) severity of psychotic symptoms, as assessed by the 18-item Brief Psychiatric Rating Scale and the Positive and Negative Syndrome Scale; (b) severity of impulsivity and aggression, measured by the Barratt Impulsiveness Scale-11 and the Buss-Perry Aggression Scale; and (c) social function and quality of life, assessed by the Social Disability Screening Scale and the Quality of Life in Epilepsy. RESULTS: After anterior capsulotomy, patients displayed significant improvements of psychotic symptoms, as well as of impulsivity and aggression, along with improvements of social function and quality of life. The clinical benefits to patients were evident within 6 months after surgery and remained stable or continued to improve at a much slower rate thereafter. Furthermore, after anterior capsulotomy all patients complied with epilepsy interventions that they did not comply with prior to surgery. No significant side effects or complications occurred during the study. CONCLUSION: Anterior capsulotomy seems to be a safe and effective treatment for epilepsy patients with otherwise intractable comorbid psychotic symptoms and aggression. Moreover, this neurosurgical treatment may improve the patients' social function, quality of life, and compliance with anti-epilepsy medication regimens.

MAGEA6 promotes human glioma cell survival via targeting AMPKα1.

Melanoma antigen A6 (MAGEA6)/TRIM28 complex is a cancer-specific ubiquitin ligase, which degradates tumor suppressor protein AMP-activated protein kinase (AMPK). We show that MAGEA6 is uniquely expressed in human glioma tissues and cells, which is correlated with AMPKα1 downregulation. It is yet absent in normal brain tissues and human astrocytes/neuronal cells. MAGEA6 knockdown by targeted-shRNA in glioma cells restored AMPKα1 expression, causing mTORC1 in-activation and cell death/apoptosis. Reversely, AMPKα1 knockdown or mutation ameliorated glioma cell death by MAGEA6 shRNA. In vivo, Glioma xenograft tumor growth in mice was largely inhibited following expressing MAGEA6 shRNA. AMPKα1 upregulation and mTORC1 inhibition were observed in MAGEA6 shRNA-bearing xenograft tissues. Collectively, MAGEA6 promotes glioma cell survival possibly via targeting AMPKα1.

Long-term follow-up of bilateral subthalamic deep brain stimulation for refractory tardive dystonia.

BACKGROUND: No effective treatment for tardive dystonia (TD) has been well established. Deep brain stimulation (DBS) can ameliorate motor manifestations in primary dystonia, and may also be an effective approach for TD. OBJECTIVES: This study aimed to illuminate the long-term efficacy and safety of subthalamic nucleus (STN)-DBS in treating TD. METHODS: Ten patients with refractory TD underwent STN-DBS therapy and were assessed by the Burke-Fahn-Marsden dystonia rating scale (BFMDRS), Abnormal Involuntary Movement Scale (AIMS), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and the Short Form (36) Health Survey (SF-36) at four time points: pre-operation, 1 week post-operation, 6 months post-operation, and at a final long-term postsurgical follow-up time point. RESULTS: The mean follow-up time was 65.6 ± 30.4 months (range, 12-105 months). At the first follow-up, BFMDRS motor and disability scores had improved by 55.9± 28.3% and 62.6± 32.0%, respectively, while AIMS scores improved by 53.3± 26.7%. At the second follow-up, BFMDRS motor and disability scores improved further, by 87.3± 17.0% and 84.3% ± 22.9%, respectively, while AIMS scores improved by 88.4 ± 16.1%. At the last follow-up, this benefit was sustained and had plateaued. Quality of life was improved significantly at the long-term follow-up, and the HAMA and HAMD scores displayed a significant reduction that persisted after the first follow-up. CONCLUSION: STN-DBS may be an effective and acceptable procedure for TD, leading to persistent and significant improvement in both movement and psychiatric symptoms.

GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings.

Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621's cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)'s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent.

Ubiquitin-protein ligase E3C promotes glioma progression by mediating the ubiquitination and degrading of Annexin A7.

The ubiquitin-protein ligase E3C (UBE3C) belongs to the E3 ligase enzyme family and implicates in the ubiquitin-proteasome pathway, thus regulates physiological and cancer-related processes. Here, we investigated the expression and roles of UBE3C in glioma. We demonstrated that UBE3C was overexpressed in glioma tissues and cell lines. Inhibition of UBE3C expression in glioma cells significantly decreased cell migration and invasion in vitro. Mechanistically, we disclosed that UBE3C physically interacted with and ubiquitinated tumor suppressor gene annexin A7 (ANXA7), resulting in ubiquitination and degradation of ANXA7. Our results also revealed that increased UBE3C expression was accompanied by a reduction in ANXA7 protein expression in glioma tissues, but not ANXA7 mRNA. Importantly, the inhibition of ANXA7 expression in gliomas cells with UBE3C interference could rescue the cell invasion. Clinically, UBE3C overexpression significantly correlated with high-grade tumors (p < 0.05), poor overall survival, and early tumor recurrence. Thus, our data reveal that high UBE3C expression contributes to glioma progression by ubiquitination and degradation of ANXA7, and thus presents a novel and promising target for glioma therapy.

Tetraspanin 8-rictor-integrin α3 complex is required for glioma cell migration.

The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis. Glioma cell invasion and migration are the main causes of death. In the current study, we studied the expression and the potential functions of tetraspanin 8 (Tspan8) in malignant gliomas. We found that Tspan8 expression level is high in both malignant glioma tissues and in several human glioma cell lines, where it formed a complex integrin α3 and rictor, the latter is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Disruption of this complex, through siRNA-mediated knockdown of anyone of these three proteins, inhibited U251MG glioma cell migration in vitro. We further showed that Tspan8-rictor association appeared required for mTORC2 activation. Knockdown of Tspan8 by the targeted siRNAs prevented mTOR-rictor (mTORC2) assembly as well as phosphorylation of AKT (Ser-473) and protein kinase C α (PKCα) in U251MG cells. Together, these results demonstrate that over-expressed Tspan8 in malignant glioma forms a complex with rictor and integrin α3 to mediate mTORC2 activation and glioma cell migration. Therefore, targeting Tspan8-rictor-integrin α3 complex may provide a potential therapeutic intervention for malignant glioma.

Over-expression of tetraspanin 8 in malignant glioma regulates tumor cell progression.

Tumor cell invasion and proliferation remain the overwhelming causes of death for malignant glioma patients. To establish effective therapeutic methods, new targets implied in these processes have to be identified. Tetraspanin 8 (Tspn8) forms complexes with a large variety of trans-membrane and/or cytosolic proteins to regulate several important cellular functions. In the current study, we found that Tspn8 was over-expressed in multiple clinical malignant glioma tissues, and its expression level correlated with the grade of tumors. Tspn8 expression in malignant glioma cells (U251MG and U87MG lines) is important for cell proliferation and migration. siRNA-mediated knockdown of Tspn8 markedly reduced in vitro proliferation and migration of U251MG and U87MG cells. Meanwhile, Tspn8 silencing also increased the sensitivity of temozolomide (TMZ), and significantly increased U251MG or U87MG cell death and apoptosis by TMZ were achieved with Tspn8 knockdown. We observed that Tspn8 formed a complex with activated focal adhesion kinase (FAK) in both human malignant glioma tissues and in above glioma cells. This complexation appeared required for FAK activation, since Tspn8 knockdown inhibited FAK activation in U251MG and U87MG cells. These results provide evidence that Tspn8 contributes to the pathogenesis of glioblastoma probably by promoting proliferation, migration and TMZ-resistance of glioma cells. Therefore, targeting Tspn8 may provide a potential therapeutic intervention for malignant glioma.