The combination of db-cAMP and ChABC with poly(propylene carbonate) microfibers promote axonal regenerative sprouting and functional recovery after spinal cord hemisection injury.

This study describes the use of poly(propylene carbonate) (PPC) electrospun microfibres impregnated with a combination of dibutyryl cyclic adenosine monophosphate (db-cAMP) and chondroitinase ABC (ChABC) in the treatment of right-side hemisected spinal cord injury (SCI). Release of db-cAMP and/or ChABC from the microfibres was assessed in vitro using high-performance liquid chromatography (HPLC). Drug-impregnated microfibres were implanted into the hemisected thoracic spinal cord of rats, and treatment was evaluated using functional recovery examinations and immunohistochemistry. Our results demonstrated that the microfibres containing db-cAMP and/or ChABC displayed a stable and prolonged release of each agent. Sustained delivery of db-cAMP and/or ChABC was found to promote axonal regenerative sprouting, functional recovery, and reduced glial scar formation when compared to untreated control animals. The combination of both db-cAMP and ChABC was determined to be more effective than using either drug alone in the treatment of SCI. These findings demonstrate the feasibility of using PPC electrospun microfibres for multi-drug combination therapy in SCI.

Secreted Protein Acidic and Rich in Cysteine Modulates Molecular Arterial Homeostasis of Human Arterial Smooth Muscle Cells In Vitro.

Secreted protein acidic and rich in cysteine (SPARC) is widely expressed in the vascular smooth muscle cells (VSMCs) of human intracranial aneurysms (IAs), but the effect and underlying mechanism of SPARC on VSMCs during the formation and progression of IAs needs to be probed. Human umbilical arterial smooth muscle cells (HUASMCs) were treated with a gradient concentrations of SPARC in vitro for different time. Cell counting kit-8 (CCK-8) assay, cell cycle, and cell apoptosis were used to investigate the effect of SPARC on HUASMCs. After exposure to 2 and 4 µg/ml SPARC, cell viability were 89.3 ± 2.00 %, and 87.57 ± 2.17 % (P < 0.05 vs. control), respectively. Induced by 2 µg/ml SPARC, the proportion of cells in G0/G1 phase was 74.77 ± 1.33 % (P < 0.05 vs. control), and the early and late apoptosis ratio were 7.38 ± 1.25 % and 4.86 ± 0.81 % (P < 0.01 vs. control), respectively. After exposure to 2 µg/ml SPARC for 2, 6, 12, 24, and 48 h, Western blot analysis showed that the protein level of p21 was upregulated significantly at 2-12 h (P < 0.05 vs. control), while the expression of p53 remained stable within 48 h. The expression of Bax protein increased markedly and peaked at 24 (P < 0.01 vs. control), while Bcl2 protein decreased significantly at 48 h (P < 0.01 vs. control). Cleaved caspase3 was also upregulated dramatically and peaked at 24 h (P < 0.05 vs. control). The protein level of MMP2 increased significantly and peaked at 24 h (P < 0.01 vs. control), while TIMP2 remained stable and even reduced at 48 h (P < 0.05 vs. control). Taken together, SPARC could arrest HUASMCs in G0/G1 phase by overexpression of p21 and induce mitochondria-mediated apoptosis in vitro, which could result in the decreased cell viability. Besides, SPARC might also lead to the activation of MMP2 instead of MMP9. These results indicated SPARC could reduce the self-repair capability and increase injury of media layer and internal elastic lamina of intracranial artery, which would disrupt the normal homeostatic mechanism controlling vascular repair, thus promoting the formation and progression of IAs.

Potential Diagnostic and Prognostic Value of Plasma Circulating MicroRNA-182 in Human Glioma.

BACKGROUND: Previous studies showed the aberrant expression of microRNA-182 (miR-182) in glioma tissue. However, the exact role of circulating miR-182 in glioma remains unclear. Here, we confirmed the expression of plasma circulating miR-182 in glioma patients, and further explored its potential diagnostic and prognostic value. MATERIAL/METHODS: Real-time quantitative PCR (RT-PCR) was used to measure circulating cell-free miR-182 from 112 glioma patients and 54 healthy controls. RESULTS: Our findings showed that the level of circulating miR-182 in glioma patients was higher than that in healthy controls (P<0.001), which was significantly associated with KPS score (P=0.025) and WHO grade (P<0.001). The area under the receiver operating characteristic (ROC) curve (AUC) was 0.778. The optimal cut-off value was 1.56, and the sensitivity and specificity were 58.5% and 85.2%, respectively. Interestingly, a high predictive value of circulating miR-182 was observed in high-grade glioma (AUC=0.815). However, the AUC was lower in low-grade glioma (AUC=0.621). Kaplan-Meier analysis demonstrated that the cumulative 5-year overall survival rate in the high miR-182 group was significantly lower than that in the low miR-182 group in both overall survival (OS) (P=0.003) and disease-free survival (DFS) (P=0.006). Moreover, multivariate Cox analysis revealed that circulating miR-182 was an independent prognostic indicator for OS (P=0.034) and DFS (P=0.013). CONCLUSIONS: These results suggest that circulating miR-182 may be a potential noninvasive biomarker for the diagnosis and prognosis of human glioma.

Interplay of VEGFa and MMP2 regulates invasion of glioblastoma.

Neovascularization plays a substantial role in the regulation of invasion of glioblastoma. However, the underlying molecular basis remains largely unknown. Both vascular endothelial growth factor a (VEGFa) and matrix metalloproteinases 2 (MMP2) are essential for cancer neovascularization and cancer invasion in that they promote endothelial mitogenesis and permeability, and promote extracellular matrix degradation, respectively. In the current study, we found strong positive correlation of VEGFa and phosphorylated MMP2 levels in the glioblastoma from the patients. Thus, we used a human glioblastoma line, A-172, to examine the interaction of VEGFa and MMP2. We found that overexpression of VEGFa in A-172 cells increased MMP2 levels, while inhibition of VEGFa in A-172 cells decreased MMP2 levels. On the other hand, forced changes in MMP2 levels in A-172 cells did not affect VEGFa levels. These data suggest that VEGFa may regulate MMP2 in glioblastoma, while MMP2 did not appear to affect VEGFa levels. We then examined the signaling pathways involved in the regulation of MMP2 levels by VEGFa. Application of a specific extracellular-related kinase 1/2 (ERK1/2) inhibitor, but not application of either an protein kinase B (Akt) inhibitor, or a Jun N-terminal kinase (JNK) inhibitor to VEGFa-overexpressing A-172 cells substantially abolished the effect of VEGFa on MMP2 activation, suggesting that VEGFa may increase MMP2 levels via ERK/mitogen-activated protein kinase (MAPK), but not phosphatidylinositol 3-kinase (PI3K) or JNK signaling pathways in glioblastoma. Moreover, adapted VEGFa levels were found to directly and positively affect the glioblastoma development in an intracranial glioblastoma implantation model. Taken together, our data suggest that anti-VEGFa treatment in glioblastoma may inhibit neovascularization not only by VEGFa itself but also by its regulatory effect on MMP2.

Benefits of a frame-based stereotactic surgical planning system for the treatment of spontaneous intracerebral haematomas.

OBJECTIVE: Frame-based stereotactic surgical planning systems (SSPSs) have been used for deep brain stimulation and radioneurosurgery. Here, we evaluated the feasibility, safety and efficacy of using a SSPS to aid spontaneous intracerebral haematoma (ICH) treatment. METHODS: Patients with moderate spontaneous putamen haematomas were randomized into two groups: treatment (group A) and control (group B). In group B, the catheter for evacuating haematomas was inserted into a target point, located at the centre of the haematoma, using conventional frame-based stereotactics; urokinase thrombolysis was subsequently delivered through the catheter. In group A, this procedure was assisted by a SSPS, which designed both the target point and trajectory in the haematoma through virtual reality. Duration of evacuating haematomas and number of urokinase injections was compared between groups. RESULTS: In total, 65 patients were recruited: in group A (n = 30), the duration of evacuating haematomas (35.27 ± 9.17 h) was shorter than in group B (n = 35; 67.77 ± 13.82 h). There were fewer urokinase injections in group A (3.63 ± 1.16) than in group B (6.40 ± 1.29). CONCLUSIONS: The feasibility, efficacy and safety of spontaneous ICH treatment were optimized by the use of a frame-based SSPS.

The expression of SPARC in human intracranial aneurysms and its relationship with MMP-2/-9.

OBJECTIVE: SPARC is a key determinant of invasion and metastasis in some tumors, such as gliomas, melanomas and prostate tumors. SPARC can change the composition and structure of the matrix and promote angiogenesis; these effects are closely related to clinical stage and the prognosis of tumors such as meningiomas. However, little is known about the expression of SPARC in intracranial aneurysms. The goal of this study was to establish the role of SPARC in human intracranial aneurysms. METHODS: Thirty-one intracranial aneurysms were immunohistochemically stained for SPARC, MMP-2 and MMP-9. As controls, normal Circle of Willis arteries were similarly immunostained. All specimens were retrieved during autopsies and were embedded in paraffin. To evaluate the expression levels of SPARC, MMP-2 and MMP-9, western blotting was also performed in three available intracranial aneurysm specimens. The limited availability of fresh intracranial aneurysm tissue was the result of the majority of patients choosing endovascular embolization. RESULTS: The results showed that SPARC, MMP-2 and MMP-9 were strongly expressed in intracranial aneurysm tissues; however, these proteins were expressed minimally or not at all in normal Circle of Willis arteries. The western blot results showed that the expression levels of SPARC, MMP-2 and MMP-9 were significantly up-regulated in intracranial aneurysms relative to the expression levels in the normal Circle of Willis arteries. Data analysis showed that SPARC was significantly correlated with MMP-2 and MMP-9, also with age and risk factors but not with the Hunt-Hess grade or with sex. CONCLUSION: The results indicate that SPARC is widely expressed in human intracranial aneurysms, and its expression correlates with MMP-2 and MMP-9 expression, age and risk factors but not with the Hunt-Hess grade. The results of this study suggest that SPARC has a pathogenic role in the alteration of the extracellular matrix of intracranial arteries during aneurysm formation.

Four patients with painful tic convulsive and a brief review of surgical treatment.

We present four patients with unusual painful tic convulsive: three were due to neurovascular compression; one was secondary to a cerebellopontine angle epidermoid cyst. We discuss these patients and those in the literature to determine the appropriate therapy for this rare disease.

Surgical treatment of primary trigeminal neuralgia: comparison of the effectiveness between MVD and MVD+PSR in a series of 210 patients.

AIM: To evaluate the effectiveness of microvascular-decompression (MVD) or MVD+partial-sensory-rhizotomy (PSR) on the treatment of primary trigeminal neuralgia (TN). MATERIAL AND METHODS: 210 TN patients were retrospectively studied, among which there're 142 cases underwent MVD and 68 cases underwent MVD+PSR. RESULTS: In MVD group, pain vanished in 128, obviously relieved in 9, and 137 cases were profited from MVD. In 82 cases with a follow-up over 2 years, pain vanished in 74, pain sometime occurred in 5 which could be relieved by oral medicine, 3 cases could not be controlled effectively by medicine. In MVD+PSR group, pain completely vanished in 67 cases, not changed in 1 case. In 47 cases with a follow-up over 2 years, pain sometime occurred in 2 which could be relieved by carbamazepine, the others were completely pain-free. The short-term pain-free rate of MVD+PSR group was obviously higher than MVD group(P < 0.05), after a follow-up over 2 years, the former was still higher than the later, 95.7% and 90.2% respectively, without significant difference in statistics. CONCLUSION: MVD+PSR was obviously superior to MVD in completely eliminating pain in short-term period after operation, however, longer pain-free rate need even longer time to follow up. Identifying the responsible vascular exactly and handling it reasonably were key to both groups.

[Aberrant methylation of NF2, TIMP-3 and THBS1 genes and their diagnostic values in meningiomas].

OBJECTIVE: To explore the functions of NF2, TIMP-3 and THBS1 genes in the tumorigenesis or progression of meningiomas and analyze the values of these genes in early diagnosis, therapy and prognostic evaluation in meningiomas. METHODS: A total of 66 cases with histological sections of meningiomas, including solitary (SMs, n = 30) and multiple meningiomas (MMs, n = 36), were retrieved from our departmental archives. All cases were regrouped as benign, atypical and anaplastic (malignant) by hematoxylin & eosin staining according to the recently published WHO classification of nervous system tumors. Genomic DNA was extracted from tumor sections and methylation-specific polymerase chain reaction (MSP) performed to detect the CpG methylation status. Normal brain tissue was used as the control group. And then the differences of methylation rate between SMs and MMs tissues and among different subgroups were analyzed by statistical analyses. RESULTS: The results of methylation in different types of meningiomas demonstrated that the rates of NF2, TIMP-3 and THBS1 methylation were 26.7% (8/30), 16.7% (5/30) and 36.7% (11/30) in 30 SMs tissues and 30.6% (11/36), 22.2% (8/36) and 22.2% (8/36) in 36 MMs tissues respectively. But no aberrant methylation of NF2, TIMP-3 and THBS1 genes was found in normal brain tissue. No significant differences in three types of gene methylation rates existed between SMs and MMs in the I-III grade meningiomas. Nevertheless, there was great difference between grades I, II and III in SMs and MMs while no significant difference was found between grades II and III. CONCLUSION: The methylation of NF2, TIMP-3 and THBS1 is correlated with the tumorigenesis of meningiomas (grade II and III). As an important pathogenetic cause of meningiomas, it may be used as a clinical tool for an early diagnosis of meningiomas.

[Expression and significance of MMP-9, PR, Ki-67 and Survivin in multiple meningiomas].

OBJECTIVE: To detect the expressions of matrix metalloproteinase-9(MMP-9), progesterone receptor(PR), Ki-67 and Survivin in the multiple meningiomas (MMs) and explore its genesis, diagnosis and bionomics features. METHODS: A total of 66 cases with histological sections of meningiomas retrieved from the archives of Department of Pathology of our hospital, including 30 cases of solitary meningiomas (SMs) and 36 cases MMs, were regrouped as benign, atypical and malignant by hematoxylin and eosin staining according to the World Health Organization classification of nervous system tumors. Immunohistochemistry was performed to detect the expressions of MMP-9, PR, Ki-67 and Survivin in 36 cases of MMs and 30 cases of SMs. And normal brain tissue was selected as a control group. The staining intensity was analyzed quantitatively for the differential expressions of MMP-9, PR, Ki-67 and Survivin between SMs and MMs. RESULTS: No expression of MMP-9, PR, Ki-67 and Survivin was detected in 5 normal brain tissues, but the expression rates were 100%, 53%, 23% and 88% respectively for significant difference comparing with normal tissue. The result of statistical analysis showed that there was significant difference in the expression intensity of MMP-9 and PR between two groups. The expression intensity MMP-9 in multiple group was significantly higher in MMs than that in SMs (P < 0.01) while PR was lower in MMs than that in SMs (P < 0.05). But no significant difference was found for the expression of Ki-67 or Survivin between two groups. CONCLUSION: The detections of MMP-9, PR, Ki-67 and Survivin are helpful in the clinical diagnosis and early detection of meningioma.

A standardized method to create peripheral nerve injury in dogs using an automatic non-serrated forceps.

This study describes a method that not only generates an automatic and standardized crush injury in the skull base, but also provides investigators with the option to choose from a range of varying pressure levels. We designed an automatic, non-serrated forceps that exerts a varying force of 0 to 100 g and lasts for a defined period of 0 to 60 seconds. This device was then used to generate a crush injury to the right oculomotor nerve of dogs with a force of 10 g for 15 seconds, resulting in a deficit in the pupil-light reflex and ptosis. Further testing of our model with Toluidine-blue staining demonstrated that, at 2 weeks post-surgery disordered oculomotor nerve fibers, axonal loss, and a thinner than normal myelin sheath were visible. Electrophysiological examination showed occasional spontaneous potentials. Together, these data verified that the model for oculomotor nerve injury was successful, and that the forceps we designed can be used to establish standard mechanical injury models of peripheral nerves.

Management of ruptured and unruptured intracranial vertebral artery dissecting aneurysms.

Vertebral artery dissecting aneurysms (VADA) are challenging disorders for neurosurgeons. Between December 2005 and May 2010, we treated 12 patients for DA of the intracranial VA. Three were treated by open surgery, seven underwent endovascular manipulation, and two were conservatively managed. Nine patients presented with subarachnoid hemorrhage from the ruptured aneurysm, and of these, two experienced abrupt re-hemorrhage and three presented with symptoms of brainstem ischemia. One of the two patients with a re-hemorrhage underwent conservative management and died in hospital of re-bleeding at 30 days after initial presentation. No postoperative neurological deficits occurred in patients treated by open surgery or via an endovascular approach. No re-hemorrhage or ischemic symptoms were observed in the 11 remaining patients during the mean 29-month (range: 14-54-month) follow-up. The chosen management strategy should be developed according to the patient's clinical condition and imaging results. Endovascular treatment, which includes several techniques, is the first choice for most patients.

Surgical management and evaluation of prognostic factors influencing postoperative visual outcome of suprasellar meningiomas.

OBJECTIVE: To study the microsurgical technique and the prognostic factors influencing postoperative visual outcome in patients with suprasellar meningiomas (SMs). METHOD: The clinical materials of 45 patients with SMs treated microsurgically between January 2002 and October 2008 were analyzed retrospectively. Patients received ophthalmologic and radiologic assessment before and after operation. Follow-up ranged from 12 to 93 months (median, 39 months). As far as monocular vision was concerned, univariate and multivariate statistical analysis was performed among factors that might influence postoperative visual outcome. RESULTS: In this group, the mean age of the patients was 51 years. Median tumor size was 3.5 cm. The duration of symptoms ranged from 10 days to 35 years (median, 18 months). Total tumor resection was achieved in 40 cases (88.9%) and subtotal in 5 cases (11.1%). With respect to visual outcome of the 90 eyes, 54 eyes (60%) improved, 24 (26.7%) remained unchanged, and 12 (13.3%) had worsened. It has been illustrated that the postoperative visual improvement was determined by various factors, including age, recurrence, duration and severity of visual disturbance, preoperative condition of optic disc, tumor size, location, peritumoral edema, involvement with optic canal, arachnoid membrane interface, and extent of tumor removal. However, the multivariate analysis showed that recurrence, preoperative condition of optic disc, duration of impaired vision, and peritumoral edema are the most influential factors. CONCLUSIONS: Skillful microsurgical techniques are key to resect SMs while getting the desired visual outcome. The recurrence, preoperative condition of optic disc, duration of impaired vision, and peritumoral edema might be the most important factors influencing postoperative visual outcome.

The differentiation of the newborn nerve cells in oculomotor nuclear after oculomotor nerve injury.

Oculomotor nerve injury is a common complication of cranial trauma and craniotomy. For a long time, it has been generally considered that the oculomotor nerve is unable to regenerate and recover functionally after injury. With the development of neuroradiology, microsurgery and neurohistology, it has been reported that the injured oculomotor nerve could be repaired by operation. However, the mechanisms of neural regeneration of the injured oculomotor nerve remain obscure. Therefore, by investigating the differentiation of the newborn nerve cells in oculomotor nuclear after oculomotor nerve injury, the mechanisms of the neural regeneration of the injured oculomotor nerve was studied in the present paper. After animal model establishment, we found that the function of the injured oculomotor nerve could recover at some degree without treatment, at fourth week after the nerve injury. This result confirms that the injured oculomotor nerve per se has the potential to regenerate and repair. At the present study, by BredU stain, BrdU labeling cells were observed in oculomotor nuclear at the fourth week post-operatively. It indicated that the oculomotor nuclear per se has the ability of generating the cells, which will regenerate and differentiate after the nerve injury, without stimulation by exogenous agents. Immunofluorescence double staining was used in this study to show the differentiation of the newborn cells in oculomotor nuclear after oculomotor nerve injury. It is found that they could differentiate into neural progenitor cells, neuronal cells and neuroglial cells. It is suggested that the different differentiation of cells may play a role in the nerve regeneration procedure.

Radiofrequency thermocoagulation rhizotomy for recurrent trigeminal neuralgia after microvascular decompression.

BACKGROUND: Microvascular decompression (MVD) is a well accepted surgical treatment strategy for trigeminal neuralgia (TN) with satisfying long-term outcome. However, considerable recurrent patients need more effective management. The purpose of this study was to evaluate the effectiveness of radiofrequency thermocoagulation rhizotomy (RTR) on patients with recurrent TN after MVD. METHODS: Totally 62 cases of recurrent TN after MVD undergoing RTR from January 2000 to January 2010 were retrospectively evaluated. Based on surgical procedures undertaken, these 62 cases were classified into two subgroups: group A consisted of 23 cases that underwent traditional RTR by free-hand; group B consisted of 39 cases that underwent RTR under the guidance of virtual reality imaging technique or neuronavigation system. The patients in group A were followed up for 14 to 70 months (mean, 40 ± 4), and those in group B were followed up for 13 to 65 months (mean, 46 ± 7). Kaplan-Meier analyses of the pain-free survival curves were used for the censored survival data, and the log-rank test was used to compare survival curves of the two groups. RESULTS: All patients in both groups A and B attained immediate pain relief after RTR. Both groups attained good pain relief rate within the first two years of follow-up: 92.3%, 84.6% and 82.6%, 69.6% respectively (P > 0.05). After 2 years, the virtual reality or neuronavigation assisted RTR group (group B) demonstrated higher pain relief rates of 82.5%, 76.2% and 68.8% at 3, 4 and 5 years after operation respectively, while those in group A was 57.2%, 49.6%, and 36.4% (P < 0.05). Low levels of minor complications were recorded, while neither mortalities nor significant morbidity was documented. CONCLUSIONS: RTR was effective in alleviating the pain of TN cases suffering from unsuccessful MVD management. With the help of virtual reality imaging technique or neuronavigation system, the patients could attain better long-term pain relief.

Clinical characteristics and treatment of ectopic meningiomas.

We have examined the clinical characteristics and treatment of ectopic meningiomas (EMs). Samples from 17 patients with EMs were analyzed, and their clinical characteristics, mechanism, and treatment were studied in combination with the literature. The main clinical manifestations of EMs included increased intracranial pressure, epilepsy, local mass, and local occupying effects, but diagnosis of EMs depended on the pathology. Surgical removal can achieve the double objectives of confirmed diagnosis and treatment of tumors. The clinical characteristics of EMs vary with the sites of tumors. Operation is the treatment of first choice. Prognosis is better than that of typical meningiomas.

A rare paraganglioma with skull and brain metastasis.

Cerebral metastasis rarely occurs in paraganglioma. We report the first patient, to our knowledge, with both skull and brain metastases, who underwent abdominal and skull, as well as brain lesion resection over 5 years, with a satisfactory outcome at the 10-year follow-up. We describe the characteristics and explore the possible underlying mechanisms to assist in future diagnosis and treatment of paraganglioma.

Enhanced three-dimensional fast spoiled gradient recalled MRI combined with magnetic resonance angiography for preoperative assessment of patients with trigeminal neuralgia.

Microvascular decompression (MVD) is now a standard treatment for trigeminal neuralgia (tic douloureux). The goal of MVD is to decompress the trigeminal root from offending vessels, aiming at a permanent cure with no or little sensory deficit. Preoperative identification of neurovascular compression, therefore, has potentially important implications for patient selection, surgical planning, and outcomes. In this study, enhanced three-dimensional fast spoiled gradient recalled MRI and three-dimensional magnetic resonance angiography with a 3.0-Tesla MRI system were used to detect the anatomic relationship of neural and vascular structures at the trigeminal root entry zone (TREZ) preoperatively. In 27 of 29 patients (93%), surgical findings were consistent with the imaging results. All patients treated with MVD achieved complete pain relief. The usefulness of high-resolution MRI in revealing the neurovascular contact at the TREZ was demonstrated, and it could be used to facilitate the selection of treatment modality. Thus, MVD can be chosen for patients who are most likely to benefit from this intracranial procedure.