A biosensor for D-2-hydroxyglutarate in frozen sections and intraoperative assessment of IDH mutation status.

The oncometabolite D-2-hydroxyglutarate (D-2-HG) has emerged as a valuable biomarker in tumors with isocitrate dehydrogenase (IDH) mutations. Efficient detection methods are required and rapid intraoperative determination of D-2-HG remains a huge challenge. Herein, D-2-HG dehydrogenase from Achromobacter xylosoxidans (AX-D2HGDH) was found to have high substrate specificity. AX-D2HGDH dehydrogenizes D-2-HG and reduces flavin adenine dinucleotide (FAD) bound to the enzyme. Interestingly, the dye resazurin can be taken as another substrate to restore FAD. AX-D2HGDH thus catalyzes a bisubstrate and biproduct reaction: the dehydrogenation of D-2-HG to 2-ketoglutarate and simultaneous reduction of non-fluorescent resazurin to highly fluorescent resorufin. According to steady-state analysis, a ping-pong bi-bi mechanism has been concluded. The Km values for resazurin and D-2-HG were determined as 0.56 µM and 10.93 µM, respectively, suggesting high affinity to both substrates. On the basis, taking AX-D2HGDH and resazurin as recognition and fluorescence transducing element, a D-2-HG biosensor (HGAXR) has been constructed. HGAXR exhibits high sensitivity, accuracy and specificity for D-2-HG in different biological samples. With the aid of HGAXR and the matched low-cost palm-size detecting device, D-2-HG levels in frozen sections of resected brain tumor tissues can be measured in a direct, simple and accurate manner with a fast detection (1-3 min). As the technique of frozen section is familiar to surgeons and pathologists, HGAXR and the portable device can be easily integrated into the current workflow, having potential to provide rapid intraoperative pathology for IDH mutation status and guide decision-making during surgery.

Establishment and validation of a novel integrin-based prognostic gene signature that sub-classifies gliomas and effectively predicts immunosuppressive microenvironment.

The integrin family members play a key role in cancer immunomodulation and prognosis. We comprehensively analyzed the expression patterns and clinical significance of integrin family-related genes in gliomas. A total of 2293 gliomas from the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and Gliovis platform were enrolled for analyses. Twenty-six integrin coding genes showed different expression patterns between glioma and normal brain tissues. We screened an integrin family-related gene signature (ITGA5, ITGA9, ITGAE, ITGB7 and ITGB8) that showed independent prognostic value and sub-classified gliomas into different prognostic and molecular clusters, further composed an integrin-based risk score model associated with glioma malignant clinical features, overall survival (OS), and immune microenvironment alterations. Besides, glioma patients with high-risk scores showed chemotherapeutic resistance and more immune cells infiltration as well as high immune checkpoints expression. Concurrently, we also revealed that high-risk score group presented resistance to T cell-mediated cancer killing process and lower rates of response to immune checkpoint blockade (ICB) treatment. In conclusion, our study identified a valuable integrin gene signature that predicted gliomas OS effectively, and sub-classified them into different phenotypes and accompanied with immunological changes, possibly acted as a biomarker for ICB treatment.

Role of the voltage­gated sodium channel Nav1.6 in glioma and candidate drugs screening.

Gliomas remain a clinical challenge, common and fatal. Treatment of glioblastoma remains elusive, and researchers have focused on discovering new mechanisms and drugs. It has been well established that the expression of voltage­gated sodium channels (VGSCs) is abnormally increased in numerous malignancies and, in general, is rarely expressed in the corresponding normal tissues. This suggests that ion channel activity appears to be associated with malignant progression of tumors. VGSCs remain largely unknown as to how their activity leads to an increase in cancer cell activity or invasiveness. Certain sodium ion channel subtypes (for instance, Nav1.5 and Nav1.7) are associated with metastasis and invasion in cancers including breast and colorectal cancers. A previous study by the authors explored the expression of certain ion channels in glioma, but there are few studies related to Nav1.6. The current study aimed to elucidate the expression and role of Nav1.6 in glioma and to screen potential drugs for the treatment of glioma by virtual screening and drug sensitivity analysis. Nav1.6 relative expression of mRNA and protein was determined by reverse transcription­quantitative PCR and western blot analysis. Cell proliferation was determined by Cell Counting Kit­8 assay. Cell migration was assessed by cellular wound healing assay. Cell invasion and apoptosis were detected by Transwell cell invasion assay and flow cytometry. Last but not least, FDA­approved drugs were screened using virtual screening, molecular docking and NCI­60 drug sensitivity analyses based on the expression and structure of Nav1.6. In glioma cells, Nav1.6 was significantly upregulated and expressed mostly in the cytoplasm and cell membrane; its expression was positively correlated with pathological grade. A172 and U251 cells exhibited reduced proliferation, migration and invasion when Nav1.6 expression was knocked down, and apoptosis was increased. TNF­α (100 pg/ml) acting on glioma cells was found to upregulate the expression level of Nav1.6, and TNF­α was involved in the process of Nav1.6 promoting malignant progression of glioma. Finally, certain FDA­approved drugs were identified by virtual screening and drug sensitivity analysis. In conclusion, the present study demonstrated the expression and role of Nav1.6 in glioma and identified several FDA­approved drugs that are highly correlated with Nav1.6 and could be candidate drugs for patients with glioma.

Classification and microsurgical treatment of foramen magnum meningioma.

BACKGROUND: To investigate the classification and microsurgical treatment of foramen magnum meningioma (FMM). METHODS: We retrospectively analyzed 76 patients with FMM and classified them into two classifications, classification ABS according to the relationship between the FMM and the brainstem and classification SIM according to the relationship between the FMM and the vertebral artery (VA). All patients underwent either the far lateral approach (54 cases) or the suboccipital midline approach (22 cases). RESULTS: Of the 76 cases, 47 cases were located ahead of the brainstem (A), 16 cases at the back of the brainstem (B), and 13 cases were located laterally to the brainstem (S). There were 15 cases located superior to the VA (S), 49 cases were inferior (I), and 12 cases were mixed type (M). Among 76 cases, 71 cases were resected with Simpson grade 2 (93.42%), 3 with Simpson grade 3 (3.95%), and 2 with Simpson grade 4 (2.63%). We summarized four anatomical triangles: triangles SOT, VOT, JVV, and TVV. The mean postoperative Karnofsky performance score was improved in all patients (p < 0.05). However, several complications occurred, including hoarseness and CSF leak. CONCLUSION: ABS and SIM classifications are objective indices for choosing the surgical approach and predicting the difficulty of FMMs, and it is of great importance to master the content, position relationship with the tumor, and variable anatomical structures in the four "triangles" for the success of the operation.

Correlation of the prognostic value of FNDC4 in glioblastoma with macrophage polarization.

BACKGROUND: Glioblastoma is among the most malignant tumors in the central nervous system and characterized by strong invasion and poor prognosis. Fibronectin type III domain-containing 4 (FNDC4) plays various important roles in the human body, including participating in cellular metabolism and inflammatory responses to cardiovascular diseases, influencing immune cells, and exerting anti-inflammatory effects; however, the role of FNDC4 in glioblastoma has not been reported. METHODS: In this study, bioinformatics databases, including TCGA, CGGA, GTEx, and TIMER, were used to analyze the differential expression of FNDC4 genes and cell survival, in addition to investigating its relationship with immune cell infiltration. Additionally, we overexpressed FNDC4 in glioblastoma cell lines U87 and U251 by lentiviral transfection and detected changes in proliferation, cell cycle progression, and apoptosis. Following collection of monocytes from the peripheral blood of healthy individuals and transformation into M0 macrophages, we performed flow cytometry to detect the polarizing effect of exogenous FNDC4, as well as the effect of FNDC4-overexpressing glioblastoma cells on macrophage polarization in a co-culture system. RESULTS: We identified that significantly higher FNDC4 expression in glioblastoma tissue relative to normal brain tissue was associated with worse prognosis. Moreover, we found that FNDC4 overexpression in U87 and U251 cells resulted in increased proliferation and affected the S phase of tumor cells, whereas cell apoptosis remained unchanged. Furthermore, exogenous FNDC4 inhibited the M1 polarization of M0 macrophages without affecting M2 polarization; this was also observed in glioblastoma cells overexpressing FNDC4. CONCLUSIONS: FNDC4 expression is elevated in glioblastoma, closely associated with poor prognosis, and promoted the proliferation of glioblastoma cells, affected the S phase of tumor cells while inhibiting macrophage polarization.

Identification of a five-gene signature deriving from the vacuolar ATPase (V-ATPase) sub-classifies gliomas and decides prognoses and immune microenvironment alterations.

Aberrant expression of coding genes of the V-ATPase subunits has been reported in glioma patients that can activate oncogenic pathways and result in worse prognosis. However, the predictive effect of a single gene is not specific or sensitive enough. In this study, by using a series of bioinformatics analyses, we identified five coding genes (ATP6V1C2, ATP6V1G2, TCIRG1, ATP6AP1 and ATP6AP2) of the V-ATPase that were related to glioma patient prognosis. Based on the expression of these genes, glioma patients were sub-classified into different prognosis clusters, of which C1 cluster performed better prognosis; however, C2 cluster showed more malignant phenotypes with oncogenic and immune-related pathway activation. The single-cell RNA-seq data revealed that ATP6AP1, ATP6AP2, ATP6V1G2 and TCIRG1 might be cell-type potential markers. Copy number variation and DNA promoter methylation potentially regulate these five gene expressions. A risk score model consisted of these five genes effectively predicted glioma prognosis and was fully validated by six independent datasets. The risk scores also showed a positive correlation with immune checkpoint expression. Importantly, glioma patients with high-risk scores presented resistance to traditional treatment. We also revealed that more inhibitory immune cells infiltration and higher rates of "non-response" to immune checkpoint blockade (ICB) treatment in the high-risk score group. In conclusion, our study identified a five-gene signature from the V-ATPase that could sub-classify gliomas into different phenotypes and their abnormal expression was regulated by distinct mechanisms and accompanied with immune microenvironment alterations potentially act as a biomarker for ICB treatment.

T cell immune regulator 1 is a prognostic marker associated with immune infiltration in glioblastoma multiforme.

Glioma is the most common primary brain tumor and glioblastoma multiforme (GBM) is the most malignant brain glioma with the worst prognosis. T cell immune regulator 1 (TCIRG1) constitutes the V0a3 subunit of vacuolar ATPase (V-ATPase), and the function of V-ATPase in malignant tumors, such as breast cancer, melanoma and hepatocellular carcinoma, has been reported. However, the effect of the TCIRG1 subunit on GBM remains to be fully elucidated. mRNA levels of TCIRG1 in different cancer types and the corresponding normal tissues were extracted from the Oncomine and Tumor Immune Estimation Resource (TIMER) databases. The Gene Expression Omnibus (access number: GSE16011), the Chinese Glioma Genome Atlas and The Cancer Genome Atlas were used to investigate the mRNA level of TCIRG1 in glioma. Protein level validation in glioma was performed using western blotting. The Database for Annotation, Visualization and Integrated Discovery was used to analyze Gene Ontology (GO) categories for genes correlated with TCIRG1 in GBM. Protein-protein interaction (PPI) networks and module analyses were performed using Cytoscape software and the MCODE plugin. The correlation between tumor immune cell infiltration and TCIRG1 expression was explored using the TIMER database. Additionally, the correlation between TCIRG1 and the gene signature of immune infiltration was explored through TIMER and Gene Expression Profiling Interactive Analysis. External validation of TCIRG1 expression according to immune signatures in GBM was performed using the GSE16011 dataset with the GlioVis online tool. It was found that TCIRG1 expression was increased in GBM and numerous malignant tumors and may serve as a biomarker of the mesenchymal subtype of GBM. GO category analysis of positively correlated genes revealed that TCIRG1 was correlated with the immune response in GBM. PPI network and module analyses also supported the potential function of TCIRG1 in the local immune response. The expression of TCIRG1 was associated with various immune markers. It was therefore speculated that TCIRG1 is associated with glioma malignancy and may be a marker of unfavorable prognosis in patients with GBM, and it could be regarded as a prognostic biomarker and an indicator of immune infiltration in GBM.

Thrombospondin-1 is a prognostic biomarker and is correlated with tumor immune microenvironment in glioblastoma.

Glioblastoma (GBM) is the most common malignant brain tumor and the most aggressive type of glioma, characterized by strong invasive potential and rapid recurrence despite severe treatment methods, such as maximal tumor resection followed by chemotherapy and radiotherapy. Thrombospondin-1 (THBS1) was first discovered in platelets and subsequent studies have indicated its functions in the development of several cancers, including breast cancer, melanoma, gastric cancer, cervical cancer and GBM. However, to the best of our knowledge, the expression profiles of THBS1 in GBM subtypes remain unknown, and the underlying mechanism by which THBS1 expression is regulated, and its effect on the local immune response in GBM, remains unclear. The present study used public datasets from The Cancer Genome Atlas, the Chinese Glioma Genome Atlas, the Gene Expression Omnibus, the Ivy Glioblastoma Atlas Project, Tumor Immune Estimation Resource, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data and the Human Protein Atlas to investigate the prognostic value of THBS1 and its expression profiles, as well as its correlation with the local immune response in GBM. The results demonstrated that THBS1 was a biomarker of the pathological malignancy of glioma, and predicted the mesenchymal subtype of GBM. Furthermore, DNA methylation of THBS1 may be an important mechanism by which THBS1 expression is regulated in GBM. The hypomethylation or overexpression of THBS1 predicted an unfavorable prognosis in patients with GBM. Additionally, THBS1 was correlated with immune and inflammatory responses in GBM. Thus, the findings of the present study provide insight into the potential value of THBS1 in the treatment of GBM.

Transient Receptor Potential Ankyrin 1 Mediates Hypoxic Responses in Mice.

Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel that is broadly expressed in sensory pathways, such as the trigeminal and vagus nerves. It is capable of detecting various irritants in inspired gasses and is activated during hypoxia. In this study, the role of TRPA1 in hypoxia-induced behavioral, respiratory, and cardiovascular responses was examined through four lines of experiments using TRPA1 knockout (KO) mice and wild type (WT) littermates. First, KO mice showed significantly attenuated avoidance behavior in response to a low (15%) oxygen environment. Second, the wake-up response to a hypoxic ramp (from 21 to 10% O2 in 40 s) was measured using EEG electrodes. WT mice woke up within 30 s when oxygen was at 13-14%, but KO mice did not wake up until oxygen levels reached 10%. Histological analysis confirmed that mild (13% O2) hypoxia resulted in an attenuation of trigeminal neuronal activation in KO mice. Third, the ventilatory response to hypoxia was measured with whole body plethysmography. KO mice showed attenuated responses to mild hypoxia (15% O2) but not severe hypoxia (10% O2). Similar responses were observed in WT mice treated with the TRPA1 blocker, AP-18. These data clearly show that TRPA1 is necessary for multiple mild hypoxia (13-15% O2)-induced physiological responses. We propose that TRPA1 channels in the sensory pathways innervating the airway can detect hypoxic environments and prevent systemic and/or cellular hypoxia from occurring.

Serine Incorporator 2 (SERINC2) Expression Predicts an Unfavorable Prognosis of Low-Grade Glioma (LGG): Evidence from Bioinformatics Analysis.

Serine Incorporator 2 (SERINC2) is a transmembrane protein that incorporates serine into membrane lipids. The function of SERINC2 in tumors has been reported, but the role of SERINC2 in gliomas is not fully understood. RNA-sequencing data from The Cancer Genome Atlas (TCGA) (530 cases of low-grade glioma (LGG) and 173 cases of glioblastoma multiforme (GBM)) and microarray data from Gene Expression Omnibus (GEO) (Accession No. GSE16011, 284 cases gliomas were included) were acquired. Bioinformatics analysis was performed as the primary method to examine the function of SERINC2 and its correlated genes in glioma. SERINC2 was highly expressed in GBM compared with LGG and normal brain tissues. Elevated SERINC2 expression predicted shorter 5-, 10-, and 15-year overall survival (OS) of LGG patients and isocitrate dehydrogenase-1 (IDH-1) mutation-type LGG patients but had no effect on the OS of GBM patients. Cox regression analysis showed that SERINC2 was an independent factor in LGG OS. Methylation analysis found that 13 CpG methylation sites (methylation450k) correlated with SERINC2 expression in LGG. The mRNA expression level of SERINC2 was significant lower in the DNA deletion group than in the intact and amplification groups. A total of 390 copositive and 244 conegative correlation genes with SERINC2 were obtained from LGG in TCGA-LGG and GSE16011. Gene ontology (GO) category and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the copositive correlation genes were primarily enriched in the mitotic process and cell cycle. Combining the results from the protein-protein interaction (PPI) network of SERINC2 correlation genes and CytoHubba led to the selection of 10 hub genes (CDC20, FN1, AURKB, AURKA, KIF2C, BIRC5, CCNB2, UBE2C, CCNA2, and CENPE). OncoLnc analysis confirmed that high expression levels of these hub genes were associated with poor OS in LGG. Our results suggested that aberrant SERINC2 expression existed in glioma and that its expression might be a potential prognostic marker in LGG patients. CDC20, FN1, AURKB, AURKA, KIF2C, BIRC5, CCNB2, UBE2C, CCNA2, and CENPE may be potential biomarkers and therapeutic targets for LGG.

Comparison of Awake and Asleep Deep Brain Stimulation for Parkinson's Disease: A Detailed Analysis Through Literature Review.

OBJECTIVES: Deep brain stimulation (DBS) for Parkinson's disease (PD) has been applied to clinic for approximately 30 years. The goal of this review is to explore the similarities and differences between "awake" and "asleep" DBS techniques. METHODS: A comprehensive literature review was carried out to identify relevant studies and review articles describing applications of "awake" or "asleep" DBS for Parkinson's disease. The surgical procedures, clinical outcomes, costs and complications of each technique were compared in detail through literature review. RESULTS: The surgical procedures of awake and asleep DBS surgeries rely upon different methods for verification of intended target acquisition. The existing research results demonstrated that the stereotactic targeting accuracy of lead placement obtained by either method is reliable. There were no significant differences in clinical outcomes, costs, or complications between the two techniques. CONCLUSION: The surgical and clinical outcomes of asleep DBS for PD are comparable to those of awake DBS.

Systematic identification of lncRNA-based prognostic biomarkers for glioblastoma.

Glioblastoma (GBM), a primary malignant tumor of the central nervous system, has a very poor prognosis. Analysis of global GBM samples has revealed a variety of long non-coding RNAs (lncRNAs) associated with prognosis; nevertheless, there remains a lack of accurate prognostic markers. Using RNA-Seq, methylation, copy number variation (CNV), mutation and clinical follow-up data for GBM patients from The Cancer Genome Atlas, we performed univariate analysis, multi-cluster analysis, differential analysis of different subtypes of lncRNA and coding genes, weighted gene co-expression network analyses, gene set enrichment analysis, Kyoto Encyclopedia of Genes and Genomes analysis, Gene Ontology analysis, and lncRNA CNV analyses. Our analyses yielded five lncRNAs closely related to survival and prognosis for GBM. To verify the predictive role of these five lncRNAs on the prognosis of GBM patients, the corresponding RNA-seq data from Chinese Glioma Genome Atlas were downloaded and analyzed, and comparable results were obtained. The role of one lncRNA LINC00152 has been observed previously; the others are novel findings. Expression of these lncRNAs could become effective predictors of survival and potential prognostic biomarkers for patients with GBM.

The effect of marital status on glioma patient survival: analysis of 617 cases: A SEER-based study.

To study the effect of marital status on survival outcome in people diagnosed with glioma, not otherwise specified using the Surveillance, Epidemiology, and End Results (SEER) database.We chose patients diagnosed with glioma between 2000 and 2014 from the SEER database and recorded their disease-related data. We then analyzed overall 5-year cause-specific survival with respect to different marital statuses. There were 617 patients (262 women and 355 men). Of these, 54.0% (n = 333), 24.6% (n = 152), 8.6% (n = 53), and 12.8% (n = 79) were married, single, divorced (or separated), and widowed, respectively. The 5-year cause-specific survival was 39.30%, 64.50%, 60.40%, and 10.10% in the married, single, divorce (or separated), and widowed groups, respectively. The widowed group had substantially higher risk of glioma-related death than did the married group (hazard ratio 1.77, 95% confidence interval 1.337-2.344, P < .001). Being widowed provided higher risk of glioma mortality compared than did marital statuses. Widowed people should be given more support and psychological intervention by society.

Downregulation of adult and neonatal Nav1.5 in the dorsal root ganglia and axon of peripheral sensory neurons of rats with spared nerve injury.

Previous studies demonstrated that Nav1.5 splice variants, including Nav1.5a and Nav1.5c, were expressed in dorsal root ganglia (DRG) neurons. However, since nine Nav1.5 isoforms have been identified, whether other Nav1.5 splice variants, especially the neonatal Nav1.5 splice variant, express in the DRG neurons is still unknown. In this study, we systematically investigated the expression of adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rats with spared nerve injury (SNI) by RT-PCR, DNA sequencing, restriction enzyme digestion, immunohistochemistry and immunofluorescence methods. The results demonstrated that both adult and neonatal Nav1.5 isoforms were expressed in the DRG neurons, but their expression ratio was ~2.5:1. In SNI rat models, the expression of both adult and neonatal Nav1.5 decreased by approximately a half in both mRNA and protein levels. In contrast, the expression of protein kinase C (PKC)-γ, one of the negative modulators for sodium currents, increased by ~1-fold. Taken together, this study first confirmed the expression of both adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rat, but their expression level decreased in pain models. The upregulation of PKC-γ may directly or indirectly downregulate the expression of Nav1.5 isoforms in SNI rat models, which may further involve in the pathological process of neuropathic pain.

Molecular expression of multiple Nav1.5 splice variants in the frontal lobe of the human brain.

Voltage-gated sodium channels serve an essential role in the initiation and propagation of action potentials for central neurons. Previous studies have demonstrated that two novel variants of Nav1.5, designated Nav1.5e and Nav1.5f, were expressed in the human brain cortex. To date, nine distinct sodium channel isoforms of Nav1.5 have been identified. In the present study, the expression of Nav1.5 splice variants in the frontal lobe of the human brain cortex was systematically investigated. The results demonstrated that wild Nav1.5 and its splice variants, Nav1.5c and Nav1.5e, were expressed in the frontal lobe of the human brain cortex. Nav1.5a, Nav1.5b and Nav1.5d splice variants were not detected. However, the expression level of different Nav1.5 variants was revealed to vary. The expression ratio of wild Nav1.5 vs. Nav1.5c and Nav1.5e was approximately 5:1 and 1:5, respectively. Immunochemistry results revealed that Nav1.5 immunoreactivity was predominantly in neuronal cell bodies and processes, including axons and dendrites, whereas little immunoreactivity was detected in the glial components. These results revealed that a minimum of four Nav1.5 splice variants are expressed in the frontal lobe of the human brain cortex. This indicates that the previously reported tetrodotoxin­resistant sodium current was a compound product of different Nav1.5 variants. The present study revealed that Nav1.5 channels have a more abundant expression in the human brain than previously considered. It also provided further insight into the complexity and functional significance of Nav1.5 channels in human brain neurons.

Distribution and function of voltage-gated sodium channels in the nervous system.

Voltage-gated sodium channels (VGSCs) are the basic ion channels for neuronal excitability, which are crucial for the resting potential and the generation and propagation of action potentials in neurons. To date, at least nine distinct sodium channel isoforms have been detected in the nervous system. Recent studies have identified that voltage-gated sodium channels not only play an essential role in the normal electrophysiological activities of neurons but also have a close relationship with neurological diseases. In this study, the latest research findings regarding the structure, type, distribution, and function of VGSCs in the nervous system and their relationship to neurological diseases, such as epilepsy, neuropathic pain, brain tumors, neural trauma, and multiple sclerosis, are reviewed in detail.

Multiple Nav1.5 isoforms are functionally expressed in the brain and present distinct expression patterns compared with cardiac Nav1.5.

It has previously been demonstrated that there are various voltage gated sodium channel (Nav) 1.5 splice variants expressed in brain tissue. A total of nine Nav1.5 isoforms have been identified, however, the potential presence of further Nav1.5 variants expressed in brain neurons remains to be elucidated. The present study systematically investigated the expression of various Nav1.5 splice variants and their associated electrophysiological properties in the rat brain tissue, via biochemical analyses and whole­cell patch clamp recording. The results demonstrated that adult Nav1.5 was expressed in the rat, in addition to the neonatal Nav1.5, Nav1.5a and Nav1.5f isoforms. Further studies indicated that the expression level ratio of neonatal Nav1.5 compared with adult Nav1.5 decreased from 1:1 to 1:3 with age development from postnatal (P) day 0 to 90. This differed from the ratios observed in the developing rat hearts, in which the expression level ratio decreased from 1:4 to 1:19 from P0 to 90. The immunohistochemistry results revealed that Nav1.5 immunoreactivity was predominantly observed in neuronal cell bodies and processes, whereas decreased immunoreactivity was detected in the glial components. Electrophysiological analysis of Nav1.5 in the rat brain slices revealed that an Na current was detected in the presence of 300 nM tetrodotoxin (TTX), however this was inhibited by ~1 µM TTX. The TTX­resistant Na current was activated at ­40 mV and reached the maximum amplitude at 0 mV. The results of the present study demonstrated that neonatal and adult Nav1.5 were expressed in the rat brain and electrophysiological analysis further confirmed the functional expression of Nav1.5 in brain neurons.

Segmentation of the Cingulum Bundle in the Human Brain: A New Perspective Based on DSI Tractography and Fiber Dissection Study.

The cingulum bundle (CB) is a critical white matter fiber tract in the brain, which forms connections between the frontal lobe, parietal lobe and temporal lobe. In non-human primates, the CB is actually divided into distinct subcomponents on the basis of corticocortical connections. However, at present, no study has verified similar distinct subdivisions in the human brain. In this study, we reconstructed these distinct subdivisions in the human brain, and determined their exact cortical connections using high definition fiber tracking (HDFT) technique on 10 healthy adults and a 488-subject template from the Human Connectome Project (HCP-488). Fiber dissections were performed to verify tractography results. Five CB segments were identified. CB-I ran from the subrostral areas to the precuneus and splenium, encircling the corpus callosum (CC). CB-II arched around the splenium and extended anteriorly above the CC to the medial aspect of the superior frontal gyrus (SFG). CB-III connected the superior parietal lobule (SPL) and precuneus with the medial aspect of the SFG. CB-IV was a relatively minor subcomponent from the SPL and precuneus to the frontal region. CB-V, the para-hippocampal cingulum, stemmed from the medial temporal lobe and fanned out to the occipital lobes. Our findings not only provide a more accurate and detailed description on the associated architecture of the subcomponents within the CB, but also offer new insights into the functional role of the CB in the human brain.

Microsurgical management of pediatric ependymomas of the fourth ventricle via the trans-cerebellomedullary fissure approach: A review of 26 cases.

In the present study, the microsurgical management of 26 ependymomas of the fourth ventricle in children via the trans-cerebellomedullary fissure (CMF) approach was reviewed and evaluated. Clinical data were obtained from 26 ependymomas of the fourth ventricle treated with microsurgery using the trans-CMF approach from March 2006 to September 2010 at the Department of Neurosurgery of The First Affiliated Hospital of China Medical University (Shenyang, China). These data were collected and analyzed. Suboccipital median posterior fossa craniotomy and trans-CMF approach were performed in all cases for the microsurgical removal of the tumors. An additional incision was performed in the inferior medullary velum of 5 patients, in order to obtain adequate exposure of the tumors. As a result, all tumors were well exposed during surgery. Gross total resection (GTR) was achieved in 22 cases, near total resection (NTR) in 3 cases and subtotal resection (STR) in 1 case. All excised tumors were pathologically confirmed. No mortality occurred intraoperatively, and no patient presented with mutism or any other surgery-related complications. One patient suffered from postoperative hydrocephalus and received ventriculoperitoneal shunting, which relieved the symptoms. Over the 3.0-7.5-year follow-up period (mean, 4.8 years), tumor relapse occurred in 1 case with GTR, 2 cases with NTR and 1 case with STR. In total, 3 patients succumbed to tumor relapse and 4 were lost to follow-up. According to the literature and the clinical experience of the present authors, the trans-CMF approach provides safe and sufficient access to the fourth ventricle without the requirement of an incision in the inferior vermis. This approach prevents damage to the normal cerebellum and improves the surgical outcome. Tumor removal, restoration of cerebrospinal fluid circulation and preservation of brainstem function are factors that should be taken into consideration during surgery. For patients with residual tumors, adjuvant radiotherapy and/or chemotherapy may be beneficial.